WO2021023209A1 - 含氮多环稠环类化合物,其药物组合物、制备方法和用途 - Google Patents
含氮多环稠环类化合物,其药物组合物、制备方法和用途 Download PDFInfo
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- RLXCSEPIBOWMOJ-MRVPVSSYSA-N tert-butyl (2s)-2-(bromomethyl)morpholine-4-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCO[C@H](CBr)C1 RLXCSEPIBOWMOJ-MRVPVSSYSA-N 0.000 description 1
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed 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
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the invention relates to the field of medicinal chemistry, in particular to a nitrogen-containing polycyclic fused ring compound, its pharmaceutical composition, preparation method and application.
- the RET (Rearranged During Transfection) proto-oncogene was first confirmed in 1985 through the transfection of NIH3T3 (mouse embryo fibroblast cell line) cells with human lymphoma DNA (Cell, 1985, 42(2): 581-588 ).
- the RET proto-oncogene is located on chromosome 10q11.2.
- RET protein is a tyrosine kinase receptor containing An extracellular domain composed of cysteine, a transmembrane domain, and an intracellular domain that can catalyze tyrosine kinases (Mol Cell Endocrinol, 2010, 322(1-2): 2-7). RET is involved in cell proliferation, nerve conduction, cell migration and cell differentiation.
- KIF5B-RET is the most common RET fusion gene in non-small cell lung cancer (Cancer, 2013,119(8):1486-1494).
- KIF5B-RET is a fusion gene formed by the chromosome inversion (p11; q11) of the KIF5B (kinesin family member 5B) gene and the RET gene.
- KIF5B-RET fusion protein contains the motor domain and the coiled-coil domain of KIF5B.
- the RET tyrosine kinase activity of the fusion protein can be abnormally activated, thereby promoting lung tumorigenesis (Cancer, 2011,117(12):2709-2718).
- KIF5B-RET fusion kinase was confirmed to have significant oncogenic activity in vitro and in vivo, and the signal transduction pathway of STAT3 may be the main downstream mediator of tumorigenesis .
- KIF5B-RET can regulate the continuous activation of STAT3.
- KIF5B-RET fusion kinase can bind to STAT3 to directly phosphorylate and activate STAT3-Tyr705; it can also activate STAT3-Tyr705 through a JAK/STAT3-dependent pathway, and trigger the phosphorylation of Ser727 through the RAS/RAF/MEK/ERK1 pathway ⁇ .
- RET fusion is the driving force in some cancers.
- This event has promoted the application of multi-kinase inhibitors that have RET inhibitory activity for the treatment of tumor patients loaded with RET fusion protein.
- drugs that can be used to target this oncogene in a targeted manner.
- the current treatments for RET-specific cancers are limited to multi-kinase inhibitors and chemotherapy.
- ORR object sustained release rate
- one of the biggest challenges in cancer treatment is that tumor cells become resistant to a certain period of treatment. Once they are resistant, the treatment options for patients are usually extremely limited. In most cases, cancer has been progressing without being suppressed.
- RET kinase signal transduction plays an important role.
- the mutation of RET 804V the gatekeeper residue of RET, is an important cause of tumor resistance to currently approved non-selective RET inhibitors (such as cabozantinib and vandetanib).
- G810 mutations such as G810R, G810S, and G801C mutations, which lead to the decrease of LOXO-292's ATP binding site, resulting in drug resistance and cancer progression. Therefore, it is necessary to develop compounds with good RET mutation inhibitory activity.
- the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof:
- X 1 , X 2 , X 3 , X 4 , X 5 , X 6 and X 7 are the same or different, and are independently selected from CR 1 or N;
- X 8 is selected from CR 1 R 1 'or NR 1; wherein:
- Each R 1 and R 1' are the same or different, and are independently selected from H, halogen, CN, NH 2 or OH, or
- R 1 and R 1 ' are the same or different, each independently selected from unsubstituted or optionally substituted with one, two, or three R a substituents in the following groups: C 1-6 alkyl, C 3- 6 cycloalkyl, C 1-6 alkoxy or C 3-6 cycloalkyloxy;
- Each R is a same or different, each independently selected from halo, CN, OH, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkoxy;
- A is selected from H, halogen, CN, OH or NH 2 , or
- A is selected from the following groups unsubstituted or optionally substituted with 1, 2, or 3 R b : C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, C 1 -6 alkoxy or C 3-6 cycloalkyloxy;
- Each R b is the same or different, and is independently selected from halogen, CN, OH, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkoxy;
- D and E are the same or different, and are independently selected from H, halogen, CN, OH or NH 2 , or
- D and E are the same or different, and are independently selected from the following groups unsubstituted or optionally substituted with 1, 2, or 3 R c : -C 1-6 alkyl, -C 1-6 alkoxy Group, -O(CH 2 ) n O(CH 2 ) n C 3-6 carbocyclic ring, -O(CH 2 ) n -3-8 membered heterocyclic ring or -O(CH 2 ) n C 6-10 aromatic ring;
- n is the same or different, and is independently selected from 0, 1, 2 or 3;
- heteroatoms in each of the heterocyclic rings, heterocyclic groups and heteroaryl groups in D, E and R c are the same or different, and independently of each other contain 1, 2 or 3 heteroatoms, and the heteroatoms Selected from N, O or S;
- G is selected from the following groups: (1) saturated 4-8 membered heterocyclic ring containing 2 heteroatoms; (2) saturated 7-10 membered heterocyclic ring containing 2 heteroatoms; (3) saturated A 7-11 membered heterospiro ring containing 2 heteroatoms; or (4) a saturated 7-10 membered bicyclic fused heterocyclic ring containing two heteroatoms; the above heteroatoms are selected from N or O, each Each ring independently of each other is optionally unsubstituted or substituted with 1, 2, 3 or 4 R G , each R G is the same or different, and each R G is independently selected from H, halogen, OH, NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy or halogen-substituted C 1-6 alkoxy;
- K is selected from the following groups unsubstituted or optionally substituted with 1, 2, 3 or 4 R K : C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl , -C 1-6 alkylene C 6-10 aromatic ring, -COC 1-6 alkylene C 6-10 aromatic ring, -C 1-6 alkylene 5-10 membered aromatic heterocycle, -COC 1 -6 alkylene 5-10 membered aromatic heterocycle, -CONR K1 R K2 , 3-10 membered heterocyclic group, C 1-6 alkoxy, C 3-6 cycloalkyloxy, C 6-10 aryl Oxy, 5-10 membered heteroaryloxy or 3-10 membered heterocyclyloxy;
- Each R K is the same or different and is independently selected from the following groups: -CN, OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, halogen Substituted C 1-6 alkyl or halogen substituted C 1-6 alkoxy;
- R K1 and R K2 are the same or different, and are independently selected from the following groups: -CN, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, halogen substituted C 1- 6 alkyl or halogen substituted C 1-6 alkoxy;
- Each aromatic heterocyclic ring, heterocyclic ring, and heterocyclic group in the K is the same or different, and independently contains 1 or 2 N atoms.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, X 1 , X 3 and X 4 are all independently selected from CR 1 .
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, X 5 is selected from CR 1 .
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, X 8 is selected from NR 1 .
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, each of R 1 and R 1'is the same or different, and is independently selected from H, F, Cl, Br, CN, NH 2 or OH, or
- R 1 and R 1 ' are the same or different, each independently selected from the group consisting of unsubstituted or optionally substituted with one, two or three of R a: C 1-3 alkyl, C 4- 6 cycloalkyl, C 1-3 alkoxy or C 4-6 cycloalkyloxy.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, each R 1 and R 1'are the same or different, and are independently selected from H, F, Cl, CN or NH 2 , or
- R 1 and R 1 ' are the same or different, each independently selected from unsubstituted or optionally substituted with one, two, or three R a substituents in the following groups: methyl, ethyl, propyl, 5 Member cycloalkyl, 6-membered cycloalkyl, methoxy, ethoxy, propoxy, 5-membered cycloalkyloxy or 6-membered cycloalkyloxy.
- the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, same or different, each R a, independently selected from F, Cl, Br, CN, OH, C 1 -3 alkyl, C 4-6 cycloalkyl or C 1-3 alkoxy;
- the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, same or different, each R a, independently selected from F, Cl, CN, OH, methyl, ethyl Group, propyl, 5-membered cycloalkyl, 6-membered cycloalkyl, methoxy, ethoxy, propoxy, 5-membered cycloalkyloxy or 6-membered cycloalkyloxy.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, X 1 is selected from CH.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, X 3 is selected from CH.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, X 5 is selected from -CH.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, X 5 is selected from CH.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, X 8 is selected from NH.
- the present invention also provides a compound or a pharmaceutically acceptable salt represented by Formula I, X 1 , X 3 , X 4 and X 5 are all selected from CH, and X 8 is selected from NH.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, X 2 is selected from N.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, X 6 is selected from N.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, X 7 is selected from N.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, X 1 , X 3 , X 4 and X 5 are all selected from CH, and X 2 , X 6 and X 7 are all selected from CH. It is selected from N, and X 8 is selected from NH.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, A is selected from H, F, Cl, Br, CN, OH or NH 2 , or
- A is selected from the following groups unsubstituted or optionally substituted with 1, 2, or 3 R b : C 1-3 alkyl, C 4-6 cycloalkyl, C 1-3 alkoxy or C 4-6 cycloalkyloxy; each R b is the same or different and is independently selected from F, Cl, Br, CN, OH, C 1-3 alkyl or C 1-3 alkoxy.
- the present invention also provides a compound or a pharmaceutically acceptable salt represented by formula I, where A is selected from H, F, Cl, CN, OH or NH 2 , or
- A is selected from the following groups unsubstituted or optionally substituted with 1, 2 or 3 R b : methyl, ethyl, propyl, 5-membered cycloalkyl, 6-membered cycloalkyl, methoxy , Ethoxy, propoxy, 5-membered cycloalkyloxy or 6-membered cycloalkyloxy; each Rb is the same or different, and is independently selected from F, Cl, methyl, ethyl, methoxy Or ethoxy.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, A is selected from H, -F, -Cl, -CN, -OH, -NH 2 or -CH 3 , .
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt.
- D and E are the same or different, and are independently selected from H, F, Cl, Br, CN, OH or NH. 2 , or
- D and E are the same or different and are independently selected from the following groups unsubstituted or optionally substituted with 1, 2 or 3 R c : -C 1-3 alkyl, -C 1-3 alkoxy, -O(CH 2 ) n O(CH 2 ) n C 3-6 carbocyclic ring, -O(CH 2 ) n -4-6 membered heterocyclic ring, -O(CH 2 ) n C 6 aromatic ring or -O (CH 2 ) n C 10 aromatic ring.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, D and E are the same or different, and are independently selected from H, F, Cl, Br, CN, OH or NH 2 , or
- D and E are the same or different, and are independently selected from the following groups unsubstituted or optionally substituted with 1, 2 or 3 R c : methyl, ethyl, propyl, methoxy, ethoxy, Propoxy, -O(CH 2 ) n O(CH 2 ) n -3-membered carbocyclic ring, -O(CH 2 ) n O(CH 2 ) n -4-membered carbocyclic ring, -O(CH 2 ) n O (CH 2 ) n -5 membered carbocyclic ring, -O(CH 2 ) n -5 membered heterocyclic ring, -O(CH 2 ) n -6 membered heterocyclic ring, or -O(CH 2 ) n -benzene ring.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, D and E are the same or different, and are independently selected from H, F, Cl, Br, CN, OH or NH. 2 , or
- D and E are the same or different, and are independently selected from the following groups unsubstituted or optionally substituted with 1, 2 or 3 R c : methyl, methoxy, -O(CH 2 ) n O(CH 2 ) n -3-membered carbocyclic ring, -O(CH 2 ) n -6-membered heterocyclic ring or -O(CH 2 ) n -benzene ring.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, each n is the same or different, and is independently selected from 0, 1, or 2.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, each n is the same or different, and is independently selected from 1 or 2.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, each R c is the same or different, and is independently selected from F, Cl, Br, CN, OH, C 1 -3 alkyl, C 3-5 cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, phenyl, C 1-3 alkoxy, 3-5 membered cycloalkyloxy or 4-6 membered saturated heterocyclyloxy group.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, each R c is the same or different, and is independently selected from F, Cl, Br, CN, OH, methyl , Ethyl, propyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 4-membered saturated heterocyclic group, 5-membered saturated heterocyclic group, 6-membered saturated heterocyclic group, 5-membered heteroaryl, 6-membered hetero Aryl, phenyl, methoxy, ethoxy, propoxy, 3-membered cycloalkyloxy, 4-membered cycloalkyloxy, 5-membered saturated heterocyclyloxy or 6-membered saturated heterocyclic ring ⁇ oxy ⁇
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, each R c is the same or different, and is independently selected from F, Cl, Br, CN, OH, methyl , Ethyl, propyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 4-membered saturated heterocyclic group, 5-membered saturated heterocyclic group, 6-membered saturated heterocyclic group, 5-membered heteroaryl, 6-membered hetero Aryl, phenyl, methoxy, ethoxy, propoxy, 3-membered cycloalkyloxy, 4-membered cycloalkyloxy, 5-membered saturated heterocyclyloxy or 6-membered saturated heterocyclic ring ⁇ oxy ⁇
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, each of the heterocyclic ring, heterocyclic group and heteroaryl group in D, E and R c
- the number and types of atoms are the same or different, and independently contain 1 or 2 heteroatoms, and the heteroatoms are selected from N or O.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, each of the heterocyclic ring, heterocyclic group and heteroaryl group in D, E and R c
- the number and types of atoms are the same or different, and independently contain 1 N atom and/or 1 O atom.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, each R c is the same or different, and is independently selected from F, Cl, Br, OH, CN,
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, D is selected from -H, -Br, -Cl, -CH 3 , -NH 2 ,
- the present invention also provides a compound or a pharmaceutically acceptable salt of formula I, E is selected from -H, -Br, -CN, NH 2 , -CH 3 , CF 3 ,
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, E is selected from H, D is selected from -H, -Br, -Cl, -CH 3 , -NH 2 ,
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, G is selected from the following groups: saturated 5-, 6, 7- or 8-membered heterocycles containing 2 N atoms ring.
- the present invention also provides a compound or pharmaceutically acceptable salt represented by formula I, G is selected from the following groups: saturated 5-membered heterocyclic ring containing 2 N atoms, saturated 6-membered A heterocyclic ring containing 2 N atoms, a saturated 7-membered heterocyclic ring containing 2 N atoms and a saturated 8-membered heterocyclic ring containing 2 N atoms.
- the present invention also provides a compound or a pharmaceutically acceptable salt represented by formula I, and G is selected from the following groups:
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, G is selected from the following groups: saturated 7, 8 or 9-membered bridge containing 2 N or O atoms Heterocycle.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, G is selected from the following groups: saturated 8-membered bridged heterocyclic ring containing 2 N or O atoms or saturated The 9-membered bridged heterocyclic ring containing 2 N atoms.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, G is selected from the following groups: a saturated 8-membered bridged heterocyclic ring containing 2 N atoms or a saturated 9 A bridged heterocyclic ring containing 2 N atoms.
- the present invention also provides a compound or a pharmaceutically acceptable salt represented by formula I, and G is selected from the following groups:
- the present invention also provides a compound or a pharmaceutically acceptable salt represented by formula I, and G is selected from the following groups:
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, each RG is the same or different, and each RG is independently selected from H, F, Cl, Br, OH, NH 2 , C 1-3 alkyl, F or Cl substituted C 1-3 alkyl or C 1-3 alkoxy.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, each R G is the same or different, and each R G is independently selected from H, NH 2 , methyl, Ethyl, propyl, F-substituted methyl, F-substituted ethyl, F-substituted propyl, methoxy, ethoxy, or propoxy.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, each R G is the same or different, and each R G is independently selected from H, NH 2 , methyl, F-substituted methyl or methoxy.
- the present invention also provides a compound or pharmaceutically acceptable salt represented by formula I, K is selected from the following groups unsubstituted or optionally substituted with one, two or more R K : K is selected from the following groups unsubstituted or optionally substituted with 1, 2 or 3 R K : C 1-3 alkyl, C 5-6 cycloalkyl, phenyl, -C 1-3 alkylene Benzene ring, -COC 1-3 alkylene benzene ring, -COC 1-3 alkylene biphenyl ring, -C 1-3 alkylene 5-8 member aromatic heterocycle, -COC 1-3 alkylene ring 5-8 membered aromatic heterocyclic ring, -CONR K1 R K2 , 5-6 membered heterocyclic group, C 1-3 alkoxy group, C 3-6 cycloalkyloxy group, C 6-10 aryloxy group, 5 -8 membered heteroaryloxy or 5-8 membered heterocycly
- the present invention also provides a compound or pharmaceutically acceptable salt represented by formula I, K is selected from the following groups unsubstituted or optionally substituted with one, two or more R K : K is selected from the following groups unsubstituted or optionally substituted with 1 or 2 R K : C 1-3 alkyl, C 5-6 cycloalkyl, phenyl, -C 1-3 alkylene benzene ring , -COCH 2 benzene ring, -COCH 2 CH 2 benzene ring, -COCH 2 biphenyl ring, -CH 2 -6 member aromatic heterocyclic ring, -CH 2 CH 2 -6 member aromatic heterocyclic ring, -CO CH 2 -6 Member aromatic heterocyclic ring, -CONR K1 R K2 , 5-membered heterocyclic group, 6-membered heterocyclic group, methoxy, C 5 cycl
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, each of the aromatic heterocyclic ring, heterocyclic ring, heterocyclic group, aromatic ring, aryl group, ring
- the alkyl groups are the same or different, and each aromatic heterocyclic ring, heterocyclic ring or heterocyclic group contains 1 N atom.
- each R K is independently selected from the following groups: -CN, OH, -NH 2 , C 1- 3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, F substituted C 1-3 alkyl, Cl substituted C 1-3 alkyl, F substituted C 1-3 alkoxy Or Cl-substituted C 1-3 alkoxy.
- each R K is independently selected from the following groups: -CN, OH, -NH 2 , methyl, Ethyl, methoxy or ethoxy.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt,
- R K1 and R K2 are the same or different and are independently selected from the following groups: -CN, C 1-3 alkyl, C 1-3 alkoxy, C 4-5 cycloalkyl, F substituted C 1- 3 Alkyl groups, Cl-substituted C 1-3 alkyl groups, F-substituted C 1-3 alkoxy groups or Cl-substituted C 1-3 alkoxy groups.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt,
- R K1 and R K2 are the same or different and are independently selected from the following groups: -CN, OH, -NH 2 , methyl, ethyl, methoxy or ethoxy.
- the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt, K is selected from the following groups:
- the present invention also provides a compound or a pharmaceutically acceptable salt represented by formula I, wherein the heterocyclic group, heterocyclic ring, aromatic heterocyclic ring, heteroaryl group or aryl heterocyclic group contains 1, 2, or 3 heteroatoms selected from N or O.
- the present invention also provides a compound or a pharmaceutically acceptable salt represented by formula I, wherein the heterocyclic group, heterocyclic ring, aromatic heterocyclic ring, heteroaryl group or aryl heterocyclic group contains 1 or 2 Heteroatoms, which are selected from N or O.
- the present invention also provides a compound or a pharmaceutically acceptable salt represented by formula I.
- the heterocyclic group, heterocyclic ring, aromatic heterocyclic ring, heteroaryl group or aryl heterocyclic group contains 1 hetero A 4, 5, 6, 7 or 8 membered ring of atoms, the heteroatom is selected from N or O.
- the present invention also provides a compound or pharmaceutically acceptable salt of formula I, wherein the heterocyclic group, heterocyclic ring, aromatic heterocyclic ring, heteroaryl group or aryl heterocyclic group contains two heterocyclic groups.
- the present invention also provides a compound or pharmaceutically acceptable salt of formula I, wherein the heterocyclic group, heterocyclic ring, aromatic heterocyclic ring, heteroaryl group or aryl heterocyclic group contains two heterocyclic groups.
- the present invention also provides a compound or pharmaceutically acceptable salt of formula I, wherein the heterocyclic group, heterocyclic ring, aromatic heterocyclic ring, heteroaryl group or aryl heterocyclic group contains two heterocyclic groups.
- the present invention also provides a compound or pharmaceutically acceptable salt of formula I, wherein the heterocyclic group, heterocyclic ring, aromatic heterocyclic ring, heteroaryl group or aryl heterocyclic group contains two heterocyclic groups.
- the present invention also provides a compound represented by formula II or a pharmaceutically acceptable salt,
- R 21 is selected from H, NH 2 or -C 1-3 alkyl
- R 23 is selected from H, NH 2 , -C 1-3 alkyl or -C 1-3 alkoxy.
- the present invention also provides a compound represented by formula II or a pharmaceutically acceptable salt,
- R 22 is selected from H, F, Cl, Br, CN, -C 1-3 alkyl, -C 1-3 alkoxy, -O(CH 2 ) m -C 1-3 alkyl or -O( CH 2 ) m -C 1-3 alkoxy, each C 1-3 alkyl group and each C 1-3 alkoxy group may be unsubstituted or be F, Cl, Br, C 1-3 alkyl or C 1-3 alkoxy substitution;
- R 21 is selected from H, NH 2 or methyl
- R 23 is selected from H, NH 2 , methyl or methoxy.
- the present invention also provides a compound represented by formula II or a pharmaceutically acceptable salt,
- R 22 is selected from H, F, Cl, Br, CN, -C 1-3 alkyl, -C 1-3 alkoxy, -O(CH 2 ) m -C 1-3 alkyl or -O( CH 2 ) m -C 1-3 alkoxy, each C 1-3 alkyl group and each C 1-3 alkoxy group may be unsubstituted or be F, Cl, Br, C 1-3 alkyl or C 1-3 alkoxy substitution;
- R 21 is selected from H
- R 23 is selected from methoxy.
- the present invention also provides a compound represented by formula II or a pharmaceutically acceptable salt,
- R 22 is selected from H, F, Cl, CN, methyl, ethyl, methoxy, ethoxy, -O(CH 2 ) m methyl, -O(CH 2 ) m ethyl, -O(CH 2) m methoxy or -O (CH 2) m ethoxy, each methyl, ethyl, methoxy and ethoxy may be unsubstituted or substituted with F, Cl, Br, methyl, ethyl, Methoxy or ethoxy substitution;
- the present invention also provides the following compounds or pharmaceutically acceptable salts thereof:
- the present invention also provides the following compounds or pharmaceutically acceptable salts thereof:
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
- the present invention also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof and the above-mentioned pharmaceutical composition for preparing a medicine.
- the present invention also provides a preferred solution for the use.
- the drug is used to treat, prevent or prevent the mutation, expression, and activity of RET gene, RET kinase protein or any one or more thereof. Or disease or discomfort caused by level imbalance.
- the present invention also provides a preferred solution for the use, wherein one or more point mutations in the RET gene result in a RET protein with one or more amino acid substitutions at one or more of the following amino acid positions Translations of: 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 20, 32, 34, 40, 56, 64, 67, 114, 136, 145, 180, 200, 292, 294 ,321,330,338,360,373,393,423,432,446,505,506,510,511,513,515,525,531,532,533,550,591,593,595,600,602 , 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 633, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675 , 686, 689, 691, 694, 700, 706, 713, 732, 736, 7
- the present invention also provides a preferred solution for the use, wherein one or more point mutations in the RET gene result in a RET protein with one or more amino acid substitutions at one or more of the following amino acid positions Translation: 32, 34, 40, 56, 64, 67, 114, 145, 292, 321, 330, 338, 360, 393, 423, 446, 510, 511, 513, 515, 525, 531, 532, 533 ,550,591,593,595,600,602,603,606,609,611,616,618,619,620,623,624,630,631,632,634,635,636,640,641,648 ,649,664,665,666,675,686,689,691,694,700,706,713,732,736,748,750,765,766,768,769,770,771,777,778,781 ,788,790,791,804,805,806,810,818,819,823,
- the present invention also provides a preferred solution for the use, wherein one or more point mutations in the RET gene result in the translation of RET proteins containing one or more of the following amino acid substitutions: S32L, D34S, L40P , L56M, P64L, R67H, R114H, V145G, V292M, G321R, R330Q, T338I, R360W, F393L, G423R, G446R, A510V, E511K, G513D, C515S, C515W, R525W, C531R, G533C, G533S, G550E, V591I, G550E, V591 , E595D, E595A, R600Q, I602V, K603Q, K603E, Y606C, C609C, C609Y, C609S, C609G, C609R, C609F, C609W
- the present invention also provides a preferred solution for the use, wherein one or more point mutations in the RET gene occur in one or more exons 10, 11, 13, and 13 of the human RET gene. 14, 15, and 16.
- the present invention also provides a preferred solution for the use, wherein the RET gene fusion is selected from: BCR-RET, CLIP 1-RET, KIF5B-RET, CCDC6-RET, NCOA4-RET, TRIM33-RET, ERC1-RET, FGFR1OP-RET, RET-MBD1, RET-RAB61P2, RET-PRKAR1A, RET-TRIM24, RET-GOLGA5, HOOGA5.
- the RET gene fusion is selected from: BCR-RET, CLIP 1-RET, KIF5B-RET, CCDC6-RET, NCOA4-RET, TRIM33-RET, ERC1-RET, FGFR1OP-RET, RET-MBD1, RET-RAB61P2, RET-PRKAR1A, RET-TRIM24, RET-GOLGA5, HOOGA5.
- the present invention also provides a preferred solution for the use.
- the RET gene, RET kinase protein, or any one or more of its mutation, expression, activity or level disorder is RET gene fusion.
- the present invention also provides a preferred solution for the use.
- the disease or discomfort caused by RET gene, RET kinase protein or any one or the expression, activity or level of the disorder is cancer or Cancer metastasis.
- the present invention also provides a preferred solution for the use.
- the disease or discomfort caused by the expression, activity or level of RET gene, RET kinase protein or any one of them is selected from the following one One or more of the following conditions: lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, indifferent thyroid cancer, type 2A or 2B multiple endocrine tumors (MEN2A or MEN2B, respectively), Pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal gangliocytoma (MEN2A or MEN2B type respectively), pheochromocytoma, parathyroid hyperplasia, Breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal gangliocytoma, and combinations thereof.
- the present invention also provides a method for treating, preventing or preventing diseases or disorders mediated by RET activity, which includes: (1) determining whether the disease or discomfort is related to RET gene, RET kinase or any one or more of them Expression, activity or level imbalance is related; and (2) If it is determined that the disease or discomfort is related to the imbalance in the expression, activity or level of RET gene, RET kinase or any one or more of them, then an effective dose of the original The compound provided by the invention or a pharmaceutically acceptable salt thereof or the pharmaceutical composition provided by the invention.
- the present invention also provides a preferred solution for the treatment method, wherein: the disease or condition mediated by RET activity is cancer and/or cancer metastasis.
- the present invention also provides a preferred solution for the treatment method, wherein one or more point mutations in the RET gene result in RET with one or more amino acid substitutions at one or more of the following amino acid positions: Protein translation: 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 20, 32, 34, 40, 56, 64, 67, 114, 136, 145, 180, 200, 292, 294,321,330,338,360,373,393,423,432,446,505,506,510,511,513,515,525,531,532,533,550,591,593,595,600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 633, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765
- the present invention also provides a preferred solution for the treatment method, wherein one or more point mutations in the RET gene result in RET with one or more amino acid substitutions at one or more of the following amino acid positions: Protein translation: 32, 34, 40, 56, 64, 67, 114, 145, 292, 321, 330, 338, 360, 393, 423, 446, 510, 511, 513, 515, 525, 531, 532, 533,550,591,593,595,600,602,603,606,609,611,616,618,619,620,623,624,630,631,632,634,635,636,640,641, 648,649,664,665,666,675,686,689,691,694,700,706,713,732,736,748,750,765,766,768,769,770,771,777,778, 781, 788, 790, 791, 804, 805, 806, 810, 818, 819, 823
- the present invention also provides a preferred solution for the treatment method, wherein one or more point mutations in the RET gene result in the translation of the RET protein containing one or more of the following amino acid substitutions: S32L, D34S, L40P, L56M, P64L, R67H, R114H, V145G, V292M, G321R, R330Q, T338I, R360W, F393L, G423R, G446R, A510V, E511K, G513D, C515S, C515W, R525W, C531R, G533C, G533S, G550E, V591I, G550E G593E, E595D, E595A, R600Q, I602V, K603Q, K603E, Y606C, C609C, C609Y, C609S, C609G, C609R, C609F, C609W
- the present invention also provides a preferred solution for the treatment method, wherein one or more point mutations in the RET gene occur in one or more exons 10, 11, and 13 of the human RET gene. , 14, 15, and 16.
- the present invention also provides a preferred solution for the treatment method, wherein the RET gene fusion is selected from: BCR-RET, CLIP 1-RET, KIF5B-RET, CCDC6-RET, NCOA4-RET , TRIM33-RET, ERC1-RET, FGFR1OP-RET, RET-MBD1, RET-RAB61P2, RET-PRKAR1A, RET-TRIM24, RET-GOLGA5, HOOGA5.
- the RET gene fusion is selected from: BCR-RET, CLIP 1-RET, KIF5B-RET, CCDC6-RET, NCOA4-RET , TRIM33-RET, ERC1-RET, FGFR1OP-RET, RET-MBD1, RET-RAB61P2, RET-PRKAR1A, RET-TRIM24, RET-GOLGA5, HOOGA5.
- the present invention also provides a preferred solution for the treatment method.
- the RET gene, RET kinase protein, or any one or more of its mutation, expression, activity or level disorder is RET gene fusion.
- the present invention also provides a preferred solution for the treatment method, wherein: the disease mediated by RET activity is selected from one or more of the following diseases: lung cancer, papillary thyroid cancer, medullary Thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory thyroid cancer, multiple endocrine tumors of type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer , Papillary renal cell carcinoma, gastrointestinal gangliocytomatosis (MEN2A or MEN2B respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal tract Gangliocytoma and its combination.
- the disease mediated by RET activity is selected from one or more of the following diseases: lung cancer, papillary thyroid cancer, medullary Thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory
- the present invention also provides a compound represented by the following formula I, its stereoisomer, racemate, tautomer, isotope label, nitrogen oxide or pharmaceutically acceptable salt:
- X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 are the same or different, and are independently selected from CR 1 or N;
- X 8 is selected from CR 1 R 1 'or NR 1;
- each of R 1 and R 1 ' are the same or different and independently selected from H, halo, CN, OH, unsubstituted or optionally substituted with one, two or more of the following R a substituents group: C 1 -40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloalkenyl, C 3-40 cycloalkynyl, C 1-40 alkyloxy Group, C 2-40 alkenyloxy, C 2-40 alkynyloxy, C 3-40 cycloalkyloxy, C 3-40 cycloalkenyloxy, C 3-40 cycloalkynyloxy, NR 2 R 3 , -C(O)R 4 , -OCR 5 , -S(O) 2 R 6 , OS(O) 2 R 7 ;
- A is selected from H, halogen, CN, OH, NH 2 , unsubstituted or optionally substituted by one, two or more of the following groups of R b : C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloalkenyl, C 3-40 cycloalkynyl, C 1-40 alkyloxy, C 2-40 alkenyloxy, C 2-40 alkynyloxy, C 3-40 cycloalkyloxy, C 3-40 cycloalkenyloxy, C 3-40 cycloalkynyloxy, NR 2 R 3 , -C(O)R 4 , -OCR 5 , -S(O) 2 R 6 , OS(O) 2 R 7 ;
- D and E are the same or different, and are independently selected from H, halogen, CN, OH, -OR 21 , unsubstituted or optionally substituted by one, two or more of the following groups of R c : C 1-40 Alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloalkenyl, C 3-40 cycloalkynyl, C 6-20 aryl, 5- 20-membered heteroaryl group, 3-20-membered heterocyclic group, NH 2 , provided that at least one of D and E is selected from -OR 21 ;
- R 21 is selected from H, unsubstituted or optionally substituted with one, two or more R d from the following groups: C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloalkenyl, C 3-40 cycloalkynyl, C 6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic group;
- G is selected from the following groups unsubstituted or optionally substituted with one, two or more R e : C 3-40 cycloalkyl, C 3-40 cycloalkenyl, C 3-40 cycloalkynyl, C 6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic group, C 3-40 cycloalkyloxy, C 3-40 cycloalkenyloxy, C 3-40 cycloalkynyloxy Group, C 6-20 aryloxy, 5-20 membered heteroaryloxy or 3-20 membered heterocyclyloxy;
- K is selected from the following groups unsubstituted or optionally substituted with one, two or more R f : H, halogen, CN, OH, unsubstituted or optionally substituted with one, two or more R g
- Each R 2 is the same or different, independently selected from H, C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloalkene Group, C 3-40 cycloalkynyl group, C 6-20 aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclic group, -C(O)R 4 , -S(O) 2 R 6 ;
- Each R 3 is the same or different, independently selected from H, C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloalkene Group, C 3-40 cycloalkynyl group, C 6-20 aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclic group, -C(O)R 4 , -S(O) 2 R 6 ;
- R 2 and R 3 together with the attached N atom form a 5-20 membered heteroaryl group or a 3-20 membered heterocyclic group;
- Each R 4 is the same or different, independently selected from H, C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloalkene Group, C 3-40 cycloalkynyl group, C 6-20 aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclic group, C 1-40 alkyloxy group, C 2-40 alkenyloxy group , C 2-40 alkynyloxy, C 3-40 cycloalkyloxy, C 3-40 cycloalkenyloxy, C 3-40 cycloalkynyloxy, C 6-20 aryloxy, 5 -20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NR 2 R 3 ;
- Each R 5 is the same or different, independently selected from H, C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloalkene Group, C 3-40 cycloalkynyl, C 6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic group, C 1-40 alkylcarbonyl, C 2-40 alkenylcarbonyl, C 2-40 alkynylcarbonyl, C 3-40 cycloalkylcarbonyl, C 3-40 cycloalkenylcarbonyl, C 3-40 cycloalkynylcarbonyl, C 6-20 arylcarbonyl, 5-20 membered heteroarylcarbonyl , 3-20 membered heterocyclic carbonyl;
- Each R 6 is the same or different, independently selected from H, C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloalkene Group, C 3-40 cycloalkynyl group, C 6-20 aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclic group, C 1-40 alkyloxy group, C 2-40 alkenyloxy group , C 2-40 alkynyloxy, C 3-40 cycloalkyloxy, C 3-40 cycloalkenyloxy, C 3-40 cycloalkynyloxy, C 6-20 aryloxy, 5 -20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NR 2 R 3 ;
- Each R 7 is the same or different and is independently selected from H, C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloalkene Group, C 3-40 cycloalkynyl group, C 6-20 aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclic group;
- cyclic group including but not limited to C 3-40 cycloalkyl, C 3-40 cycloalkenyl, C 3-40 cycloalkynyl, 3-20 membered heterocyclic group, etc.
- two of the substituents may also form a bridge ring with the cyclic group, wherein the bridge atoms in the bridge ring other than the bridge head atoms may include 1, 2 , 3, 4 or 5 divalent groups selected from CH 2 , O, NH;
- two of the substituents may also form a cyclic group (including but not limited to C 3- 40 cycloalkyl, C 3-40 cycloalkenyl, C 3-40 cycloalkynyl, 3-20 membered heterocyclic group, etc.).
- X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 are the same or different, and are independently selected from CR 1 or N; for example, X 1 , X 2 , X 3 , at least one of X 4 , X 5 , X 6 , and X 7 is N, for example, 1, 2, 3 , 4 , 5 , 6 or 7 are N;
- X 8 is selected from CR 1 R 1 'or NR 1;
- each R 1 and R 1' are the same or different, and are independently selected from H, halogen, CN, OH, C 1-6 alkyl, C 3-10 cycloalkyl, C 1- 6 alkyloxy;
- A is selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkyloxy;
- D and E are the same or different and are independently selected from H, halogen, CN, NH 2 or -OR 21 , provided that at least one of D and E is selected from -OR 21 ;
- R 2 is selected from unsubstituted or optionally substituted with one, two or more C 1-6 alkyl groups substituted by Rd ;
- each of R a, R b, R c , R d, R e, R f identical or different, each independently selected from halo, CN, OH, unsubstituted or optionally substituted with one, two One or more of the following groups substituted by R g : C 1-6 alkyl, C 1-6 alkyloxy, C 3-10 cycloalkyl, C 3-10 cycloalkyloxy;
- each R g is the same or different and is independently selected from halogen or C 3-10 cycloalkyl
- G is selected from C 3-10 cycloalkyl, C 6-14 aryl, 5-14 membered heteroaryl, 3-10 membered heterocyclic group, for example, 6-7 membered monocyclic ring,
- the heterocyclic group of bicyclic or bridged ring structure may contain 1, 2, 3 heteroatoms independently selected from N, O and S;
- K is selected from -C 1-6 alkyl-C 3-10 cycloalkyl, -C 1-6 alkyl-C 6-14 aryl, -C 1-6 alkyl-5 -14 membered heteroaryl, -C 1-6 alkyl-3-10 membered heterocyclyl, -C(O)NH 2 , -C(O)-C 3-10 cycloalkyl, -C(O) -C 6-14 aryl, -C(O)-5-14 membered heteroaryl, -C(O)-3-10 membered heterocyclic group, -C(O)-C 1-6 alkyl-C 3-10 cycloalkyl, -C(O)-C 1-6 alkyl-C 6-14 aryl, -C(O)-C 1-6 alkyl-5-14 membered heteroaryl, -C (O)-C 1-6 alkyl-3-10 membered heterocyclic group, wherein the C 3-10 cycl
- X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 are the same or different, and are independently selected from CH or N; for example, X 1 , X 2 , At least one of X 3 , X 4 , X 5 , X 6 , and X 7 is N, for example, 1, 2, 3 , 4 , 5 , 6 or 7 are N;
- X 8 is selected from NR 1 ;
- R 1 is H
- A is selected from H, NH 2 , methyl, ethyl, propyl, isopropyl;
- E is H
- D is selected from the following groups: halogen, BnO-, H, CN, NH 2 , OCH 3 ,
- G is selected from
- K is selected from
- the compound has a structure represented by the following formula:
- X 1 , X 2 , X 3 , X 4 , X 5 , A, D, E, G, and K have the above-mentioned definitions.
- the compound of formula I is selected from the following compounds,
- the present invention also provides a preparation method of the compound represented by formula I, which comprises the following steps:
- A, D, E, G, K, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , R 21 have the above definitions; L is selected from leaving Group.
- the leaving group is selected from halogen or OTf.
- the reaction is carried out in the presence of a base, for example in the presence of potassium carbonate.
- the reaction temperature is 50-100°C
- the reaction time is 1-24 hours.
- the reaction may be carried out in the presence of an organic solvent (such as DMF).
- organic solvent such as DMF
- the present invention also provides a method for preparing the compound of formula I-1, which comprises reacting the compound of formula I-2 to prepare the compound of formula I-1:
- A, D, E, G, K, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 have the above definitions.
- the reaction is carried out in the presence of hydrazine hydrate, and X 7 is N and X 8 is NH.
- the reaction is carried out in the presence of an organic solvent (such as DMF).
- organic solvent such as DMF
- the reaction is carried out under heating conditions.
- the present invention also provides a compound represented by formula I-1 or formula I-2:
- the present invention also provides the use of the compound represented by formula I-1 or formula I-2 for preparing the compound represented by formula I.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula I, its stereoisomers, racemates, tautomers, isotope markers, nitrogen oxides or pharmaceutically acceptable compounds. At least one of the accepted salts.
- the pharmaceutical composition further includes one, two or more pharmaceutically acceptable carriers or excipients.
- the pharmaceutical composition further contains one or more additional therapeutic agents.
- the present invention also provides a method for inhibiting cell proliferation in vitro or in vivo, said method comprising making cells and an effective amount of the compound represented by formula I of the present invention, its stereoisomers, racemates, tautomers, Contact with isotope labels, nitrogen oxides, or pharmaceutically acceptable salts, or pharmaceutical compositions thereof.
- the present invention also provides a method for treating diseases mediated by RET kinase, comprising administering to a patient a therapeutically effective amount of a compound represented by formula I, its stereoisomers, racemates, tautomers, and isotope markers , At least one of nitrogen oxides or pharmaceutically acceptable salts.
- the present invention also provides a method for treating RET-related diseases or disorders in a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of the compound represented by formula I of the present invention, its stereoisomers, and Rotation form, tautomer, isotope label, nitrogen oxide or pharmaceutically acceptable salt or pharmaceutical composition thereof.
- the present invention also provides a method for treating cancer and/or inhibiting metastasis associated with a specific cancer in a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of a compound represented by formula I of the present invention, and Stereoisomers, racemates, tautomers, isotopic labels, nitrogen oxides or pharmaceutically acceptable salts or pharmaceutical compositions thereof.
- the present invention also provides a method for treating irritable bowel syndrome (IBS) and/or pain associated with IBS in a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of the formula I of the present invention
- IBS irritable bowel syndrome
- the present invention also provides a method of providing supportive care for cancer patients, including preventing or minimizing gastrointestinal diseases (such as diarrhea) associated with treatment (including chemotherapy treatment), the method comprising administering to the patient a therapeutically effective amount of Formula I of the present invention
- gastrointestinal diseases such as diarrhea
- chemotherapy treatment including chemotherapy treatment
- the present invention also provides that at least one of the compound represented by formula I, its stereoisomer, racemate, tautomer, isotope label, nitrogen oxide, or pharmaceutically acceptable salt is used in preparation It is used in drugs for treating diseases mediated by RET kinase.
- the present invention also provides that at least one of the compound represented by formula I, its stereoisomer, racemate, tautomer, isotope label, nitrogen oxide, or pharmaceutically acceptable salt is used in preparation Use in medicines for treating cancer and/or inhibiting metastasis associated with specific cancers.
- the present invention also provides that at least one of the compound represented by formula I, its stereoisomer, racemate, tautomer, isotope label, nitrogen oxide, or pharmaceutically acceptable salt is used in preparation Use in drugs for the treatment of irritable bowel syndrome (IBS) or pain associated with IBS.
- IBS irritable bowel syndrome
- the present invention also provides that at least one of the compound represented by formula I, its stereoisomer, racemate, tautomer, isotope label, nitrogen oxide, or pharmaceutically acceptable salt is used in preparation Use in medicines to provide supportive care to cancer patients including preventing or minimizing gastrointestinal disorders associated with treatment (including chemotherapy treatment), such as diarrhea.
- treatment including chemotherapy treatment
- the present invention also provides that at least one of the compound represented by formula I, its stereoisomer, racemate, tautomer, isotope label, nitrogen oxide, or pharmaceutically acceptable salt is used in preparation Used in drugs that inhibit RET kinase activity.
- the present invention also provides that at least one of the compound represented by formula I, its stereoisomer, racemate, tautomer, isotope label, nitrogen oxide, or pharmaceutically acceptable salt is used in preparation Used in drugs for the treatment of RET-related diseases or disorders.
- the present invention also provides a method for treating cancer in a patient in need, the method comprising (a) determining whether the cancer is related to the following disorders: the expression of RET gene, RET kinase, or any one of them or Activity or level (for example, RET-related cancer); (b) if it is determined that the cancer is related to the following disorders: the expression or activity or level of RET gene, RET kinase, or any of them (for example, RET-related Cancer), administering a therapeutically effective amount of a compound represented by formula I, its stereoisomers, racemates, tautomers, isotope markers, nitrogen oxides, or pharmaceutically acceptable salts At least one, or a pharmaceutical composition thereof.
- the present invention also provides a method for reversing or preventing acquired resistance to anticancer drugs, the method comprising adding a therapeutically effective amount of a compound represented by formula I, its stereoisomers, racemates, and tautomers At least one of isomers, isotope markers, nitrogen oxides, or pharmaceutically acceptable salts is administered to patients who are at risk of developing or having acquired resistance to anticancer drugs.
- the present invention also provides a method for delaying and/or preventing the development of anticancer drug resistance in an individual, the method comprising administering an effective amount of a compound represented by formula I, its stereoisomers, racemates, and tautomers in the individual At least one of isomers, isotope markers, nitrogen oxides, or pharmaceutically acceptable salts, before, during or after the administration of an effective amount of anticancer drugs.
- the present invention also provides a method for treating an individual suffering from cancer and having an increased possibility of developing resistance to anticancer drugs, which comprises concomitantly administering to the individual (a) an effective amount of a compound represented by formula I, and its stereoisomers , Racemates, tautomers, isotope labels, nitrogen oxides, or at least one of pharmaceutically acceptable salts; and (b) an effective amount of anticancer drugs.
- the present invention also provides methods for treating individuals suffering from RET-related cancers, the cancers having one or more RET inhibitor resistance mutations, the RET inhibitor resistance mutations increase the cancer pair not represented by Formula I
- the resistance of at least one of the compound, its stereoisomer, racemate, tautomer, isotope label, nitrogen oxide, or pharmaceutically acceptable salt for example, in Substitutions at amino acid positions 804, 810, 904, such as V804M, V804L, V804E, G810R, G810S, G810C, G810V, S904F), which include the administration of a compound of formula I before, during or after administration of another other anticancer drug , At least one of its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, or pharmaceutically acceptable salts.
- the present invention also provides a method for treating an individual suffering from RET-related cancer, the method comprising administering a compound represented by formula I, its stereoisomers, or the like before, during or after the administration of another other anticancer drug At least one of racemate, tautomer, isotope label, nitrogen oxide, or pharmaceutically acceptable salt.
- the present invention provides a method for treating cancer (such as RET-related cancer) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof At least one or a pharmaceutical composition thereof.
- cancer such as RET-related cancer
- the numerical ranges described in this specification and claims are equivalent to at least recording each specific integer value therein.
- the numerical range “1-40” is equivalent to recording each integer value in the numerical range “1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and the numerical range
- Each integer value in “11-40” is 11, 12, 13, 14, 15, ..., 35, 36, 37, 38, 39, 40. It should be understood that among one, two or more of the substituents used herein, "more” shall refer to an integer ⁇ 3, such as 3, 4, 5, 6, 7, 8, 9 or 10. .
- halogen means fluorine, chlorine, bromine and iodine.
- C 1-40 alkyl should be understood to preferably mean a linear or branched saturated monovalent hydrocarbon group having 1 to 40 carbon atoms.
- C 1-6 alkyl means straight and branched chain alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms.
- the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Group, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 1,2-dimethylbutyl, etc. or their isomers.
- C 2-40 alkenyl should be understood to preferably mean a straight-chain or branched monovalent hydrocarbon group, which contains one or more double bonds and has 2-40 carbon atoms, preferably “C 2-6 alkenyl” .
- C 2-6 alkenyl should be understood to preferably mean a straight or branched monovalent hydrocarbon group which contains one or more double bonds and has 2, 3, 4, 5 or 6 carbon atoms, especially 2 or 3 carbon atoms (“C 2-3 alkenyl”), it should be understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated.
- the alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)- But-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z) -Pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-ene Group, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3- Alkenyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-eny
- C 2 - 40 alkynyl group is understood to mean a straight or branched divalent hydrocarbon group, which contains one or more triple bonds and having 2 to 40 carbon atoms, preferably "C 2 -C 6 - alkynyl ".
- C 2 -C 6 -alkynyl should be understood to preferably mean a straight-chain or branched monovalent hydrocarbon group, which contains one or more triple bonds and has 2, 3, 4, 5 or 6 carbon atoms, in particular Is 2 or 3 carbon atoms ("C 2 -C 3 -alkynyl").
- the C 2 -C 6 -alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, Pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hexyl -4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methyl But-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl , 1-methylpent-4-ynyl,
- C 3-40 cycloalkyl should be understood to mean a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane, which has 3 to 40 carbon atoms, preferably “C 3-10 cycloalkyl”.
- C 3-10 cycloalkyl should be understood as meaning a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
- the C 3-10 cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic Hydrocarbyl such as decalin ring.
- 3-20 membered heterocyclic group means a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane, which contains the total number of ring atoms of 1-5 heteroatoms independently selected from N, O and S It is a non-aromatic cyclic group of 3-20 (such as 3, 4, 5, 6, 7, 8, 9, 10, etc.), preferably a "3-10 membered heterocyclic group".
- 3-10 membered heterocyclic group means a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane, which contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S , For example, 1, 2, 3 heteroatoms independently selected from N, O and S.
- the heterocyclic group may be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present).
- the heterocyclic group may include but is not limited to: 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl Or trithiaalkyl; or 7-membered ring, such as diazeppanyl.
- the heterocyclic group may be benzo-fused.
- the heterocyclic group may be bicyclic, such as but not limited to a 5, 5-membered ring, such as hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5, 6-membered bicyclic ring, such as hexahydropyrrole And [1,2-a]pyrazine-2(1H)-yl ring.
- the ring containing nitrogen atoms may be partially unsaturated, that is, it may contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadi Azinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl.
- the heterocyclic group is non-aromatic.
- the carbon atom of the 3-20 membered heterocyclic group may be connected to the other group, or it may be a 3-20 membered heterocyclic group.
- the heterocyclic atom on the ring is connected to other groups.
- the nitrogen atom on the piperazinyl group may be connected to other groups.
- the 3-20 membered heterocyclic group is selected from piperidinyl, it can be that the nitrogen atom on the piperidinyl ring and the carbon atom at the para position are connected to other groups.
- C 6-20 aryl should be understood to preferably mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably “C 6-14 aryl” .
- C 6-14 aryl should be understood to preferably mean a monocyclic, bicyclic, or partially aromatic monocyclic or partially aromatic monocyclic ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms.
- Tricyclic hydrocarbon ring (“C 6-14 aryl”), especially a ring with 6 carbon atoms (“C 6 aryl”), such as phenyl; or biphenyl, or one with 9 carbon atoms
- a ring (“C 9 aryl”), such as indanyl or indenyl, or a ring with 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, Either a ring having 13 carbon atoms (“C 13 aryl”), such as fluorenyl, or a ring having 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
- the C 6-20 aryl group When the C 6-20 aryl group is substituted, it may be mono-substituted or multi-substituted.
- there is no restriction on the substitution site for example, ortho, para, or meta substitution can be adopted.
- 5-20 membered heteroaryl should be understood to include such a monovalent monocyclic, bicyclic or tricyclic aromatic ring system which has 5-20 ring atoms and contains 1-5 independently selected from N, O And S heteroatoms, for example "5-14 membered heteroaryl”.
- the term “5-14 membered heteroaryl” should be understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 5 or 6 or 9 or 10 carbon atoms, and it contains 1-5, preferably 1-3 heteroatoms each independently selected from N, O and S and, in addition, in each case The bottom can be benzo-fused.
- the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thio Diazolyl, thio-4H-pyrazolyl, etc.
- the carbon atom on the 5-20 membered heteroaryl ring may be connected to the other group, or it may be a 5-20 membered heterocyclic group.
- the heteroatoms on the aryl ring are connected to other groups.
- the 5-20 membered heteroaryl group When the 5-20 membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Moreover, there is no restriction on the substitution position, for example, the hydrogen connected to the carbon atom on the heteroaryl ring is substituted, or the hydrogen connected to the heteroatom on the heteroaryl ring is substituted.
- heterocyclic group, heteroaryl group or heteroarylene group includes all possible isomeric forms thereof, such as positional isomers thereof. Therefore, for some illustrative non-limiting examples, it can be included in its 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12 -Position etc.
- pyridin-2-yl pyridin-2-yl, pyridin-3-yl, Pyridin-3-yl, pyridin-4-yl and pyridin-4-yl
- thienyl or thiophene include thiophen-2-yl, thiophen-2-yl, thiophen-3-yl and thiophene-3 -Base
- pyrazol-1-yl pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.
- C 1-6 alkyl is also applicable to C 1-6 alkyloxy, -N(C 1-6 alkyl ) 2 , -NHC 1-6 alkyl or -S(O) 2 -C 1-6 alkyl, etc.
- the compound represented by formula I may exist in the form of various pharmaceutically acceptable salts. If these compounds have basic centers, they can form acid addition salts; if these compounds have acid centers, they can form base addition salts; if these compounds contain both acidic centers (such as carboxyl groups) and basic centers ( For example, amino), it can also form internal salts.
- the compound of the present invention may exist in the form of a solvate (such as a hydrate), wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, especially, for example, water, methanol or ethanol.
- a polar solvent as a structural element of the crystal lattice of the compound, especially, for example, water, methanol or ethanol.
- the amount of polar solvent, especially water can be present in a stoichiometric or non-stoichiometric ratio.
- the compound of the present invention may be chiral, and therefore may exist in various enantiomeric forms. Therefore, these compounds may exist in racemate form or optically active form.
- the compounds of the present invention or intermediates thereof can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in synthesis in this form. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with optically active resolving reagents.
- Suitable resolution reagents are optically active acids such as R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, appropriate N-protected amino acids (e.g. N- Benzoyl proline or N-benzenesulfonyl proline) or various optically active camphor sulfonic acids.
- optically active resolving reagents such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers
- Suitable eluents for this purpose are aqueous or alcohol-containing solvent mixtures, for example, hexane/isopropanol/acetonitrile.
- tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule.
- the compounds of the present invention may exhibit tautomerism.
- Tautomeric compounds can exist in two or more mutually convertible species.
- Proton shift tautomers result from the migration of covalently bonded hydrogen atoms between two atoms.
- Tautomers generally exist in an equilibrium form, and an attempt to separate a single tautomer usually produces a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties of the molecule.
- the ketone type is dominant; in phenol, the enol type is dominant.
- the present invention encompasses all tautomeric forms of the compound.
- the corresponding stable isomers can be separated according to known methods, such as extraction, filtration or column chromatography.
- patient refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.
- terapéuticaally effective amount refers to the amount of the active compound or drug that causes a biological or medical response that researchers, veterinarians, physicians or other clinicians are looking for in tissues, systems, animals, individuals or humans. Including one or more of the following: (1) Disease prevention: for example, prevention of disease, disorder or disease in individuals who are susceptible to disease, disorder, or disease but who have not experienced or experienced disease pathology or symptoms. (2) Inhibiting disease: for example, inhibiting the disease, disorder or condition (ie, preventing the further development of the pathology and/or symptoms) in an individual who is experiencing or experiencing the pathology or symptoms of the disease, disorder or condition. (3) Alleviation of disease: for example, alleviation of the disease, disorder or condition (ie reversing the pathology and/or symptoms) in an individual who is experiencing or experiencing the pathology or symptoms of the disease, disorder, or condition.
- Figure 1 is the inhibitory effect of the compound on the tumor of TT cell human medullary thyroid carcinoma xenograft model
- Figure 2 The inhibitory effect of compounds on Ba/F3 cell KIF5B-RET-V804M fusion xenograft model tumors.
- the compound of the present invention can be used as a highly selective and/or very effective RET inhibitor. Such compounds are effective against RET gate residue mutant RET V804M, RET solvent front residue mutant G810R and other clinically relevant RET mutants. And wt-RET has a strong inhibitory effect.
- the compound can also significantly inhibit the growth of TT cell lines derived from thyroid cancer and Ba/F3 cells transformed with various RET mutants, and the inhibitory effect is good.
- the compound largely blocks cellular RET autophosphorylation and its downstream pathways, and can significantly induce TT cell death.
- the representative example compounds of the present invention also have particularly excellent pharmacokinetic properties, and when used as active ingredients, they can be administered to patients in a small dose, thereby reducing the cost of treatment for patients.
- Step A 2-Fluoro-6-hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methylene)-3,,6-diazepine[3.1.1] Heptan-3-yl)pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbaldehyde oxime
- Step B 2-Fluoro-6-hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methylene)-3,6-diazabicyclo[3.3.1] Heptan-3-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-3-acetonitrile
- Step C 2-Fluoro-6-(2-methoxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methylene)-3,6- Diazabicyclo[3.3.1]heptan-3-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-3 -Acetonitrile
- Step C 6-(2-Methoxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methylene)-3,6-diazabicyclo [3.3.1]Heptan-3-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-3-amino
- Step A 4-(Benzyloxy)-6-bromo-2-fluoropyrazole[1,5-a]pyridine-3-carbaldehyde
- Step B 6-Bromo-2-fluoro-4-hydroxypyrazole[1,5-a]pyridine-3-carbaldehyde
- Step C 6-Bromo-2-fluoro-3-carbaldehyde pyrazole [1,5-a]pyridin-4-yl trifluoroethylsulfonate
- Step D 6-Bromo-2-fluoro-4-(6-(6-((6-methoxypyridin-3-yl)methylene)-3,6-diazabicyclo[3.3.1] Heptan-3-yl)pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbaldehyde
- Step E 6-Bromo-4-(6-(6-((6-methoxypyridin-3-yl)methylene)-3,6-diazabicyclo[3.3.1]heptane-3 -Yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine
- Step A 6-((Diphenylmethylene)amino)-2-fluoro-4-(6-((6-methoxypyridin-3-yl)methylene)-3,6-diazepine Bicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbaldehyde
- Step B 6-Amino-2-fluoro-4-(6-((6-methoxypyridin-3-yl)methylene)-3,6-diazabicyclo[3.1.1]heptane-3 -Yl)pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbaldehyde
- Step C 4-(6-(6-((6-Methoxypyridin-3-yl)methylene)-3,6-diazabicyclo[3.3.1]heptan-3-yl)pyridine -3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-amino
- Step A tert-butyl((methylsulfonyl)oxy)carbamate
- Step B 2-[(Aminooxy)sulfonyl]-1,3,5-trimethylbenzene
- tert-butyl ((methylsulfonyl)oxy) carbamate (10.0 g, 31.7 mmol) was added to trifluoroacetic acid (80 mL) in batches. After completion, the reaction system continued to stir at zero for 3 hours; TLC dot plate confirmed the completion of the reaction, the reaction system was poured into a large amount of ice water, and stirred for 15 minutes, a large amount of white solid precipitated, filtered under reduced pressure, a large amount of water to wash the cake until The pH value of the solid is neutral, and it can be filtered under reduced pressure to a solid water content of about 20%, without further purification, and directly used in the next reaction.
- Step D 6-(Benzyloxy)-4-bromo-2-fluoropyrazole [1,5-a]pyridine and 4-(benzyloxy)-6-bromo-2-fluoropyrazole [1,5 -a] pyridine
- Step E 6-(Benzyloxy)-4-bromo-2-fluoropyrazole[1,5-a]pyridine-3-carbaldehyde
- Step F 6-(Benzyloxy)-2-fluoro-4-(6-((6-methoxypyridin-3-yl)methylene)-3,6-diazabicyclo[3.1.1] Heptan-3-yl)pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbaldehyde
- Step G 2-Fluoro-6-hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methylene)-3,6-diaza[3.1.1]hepta Alkyl-3-yl)pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbaldehyde
- Step H 4-(6-(6-((6-methoxypyridine-3-)methylene)3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3 -Yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-ol
- Step I 6-(2-Methoxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methylene)-3,6-diazabicyclo [3.3.1]Heptan-3-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine
- Step A 3-(5-Chloropyrazine-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-tert-butyl carbonate
- Step B 3-(5-Chloropyrazine-2-yl)-3,6-diazabicyclo[3.1.1]heptane dihydrochloride
- Step C 3-(5-Chloropyrazine-2-yl)-6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan alkyl
- Step D 6-((6-Methoxypyridin-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxolane Boran-2-yl)pyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptane
- Step E 6-(Benzyloxy)-2-fluoro-4-(5-(6-((6-methoxypyridin-3-yl)methylene)-3,6-diazabicyclo[3.1 .1]Heptan-3-yl)pyrazin-2-yl)pyrazole[1,5-a]pyridine-3-carbaldehyde
- Step F 2-Fluoro-6-hydroxy-4-(5-(6-((6-methoxypyridin-3-yl)methylene)-3,6-diaza[3.1.1]hepta Alk-3-yl)pyrazin-2-yl)pyrazole[1,5-a]pyridine-3-carbaldehyde
- Step G 4-(5-(6-((6-methoxypyridine-3-)methylene)3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazine- 2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-ol
- Step H 6-(2-Fluoroethoxy)-4-(5-(6-((6-methoxypyridin-3-yl)methylene)-3,6-diazabicyclo[3.3 .1]Heptan-3-yl)pyrazin-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine
- Step A 4-(5-(6-(Benzyloxy)-2-fluoro-3-carbaldehydepyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1- Tert-butyl carbonate
- Step B 4-(5-(2-Fluoro-3-carbaldehyde-6-hydroxypyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-tert-butyl carbonate
- Step C 4-(5-(6-Hydroxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piper Oxazine-1-tert-butyl carbonate
- Step D 4-(5-(6-(2-Fluoroethoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl) (Pyridin-2-yl)piperazine-1-tert-butyl carbonate
- Step E 6-(2-Fluoroethoxy)-4-(6-(piperazin-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyridine Azole[1,5-a]pyridine
- Step F N,N-Diethyl-4-(5-(6-(2-fluoroethoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5- a)pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxamide
- Step A 3-(5-Bromopyridin-2-yl)-3,6-diazabicyclo[3.3.1]heptane-6-tert-butyl carbonate
- Step B 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-3,6-diazepine Heterobicyclo[3.3.1]heptane-6-tert-butyl carbonate
- Step C 3-(5-(6-(Benzyloxy)-2-fluoro-3-carbaldehydepyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6- Diazabicyclo[3.3.1]heptane-6-tert-butyl carbonate
- Step D 3-(5-(2-Fluoro-3-carbaldehyde-6-hydroxypyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo [3.3.1]Heptane-6-tert-butyl carbonate
- Step E 3-(5-(6-Hydroxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)- 3,6-diazabicyclo[3.1.1]heptane-6-tert-butyl carbonate
- Step F 3-(5-(6-(2-Fluoroethoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl) (Pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-tert-butyl carbonate
- Step H 4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(2-fluoroethoxy)-1H-pyridine Azole[3',4':3,4]pyrazole[1,5-a]pyridine
- Step I (3-(5-(6-(2-Fluoroethoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl )Pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)(6-methoxypyridin-3-yl)methyl ketone
- Step A 2,4,6-Trimethylbenzenesulfonic acid 1-amino-3-bromo-5-methoxypyridine-1-ium
- Step B 4-Bromo-2-fluoro-6-methoxypyrazole[1,5-a]pyridine
- Step C 4-Bromo-2-fluoro-6-methoxypyrazole[1,5-a]pyridine-3-carbaldehyde
- Step D 4-Bromo-6-methoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine
- Step E 6-Methoxy-4-(5-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane- 3-yl)pyrazin-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine
- Step A 1-(6-(Benzyloxy)-4-bromo-2-fluoropyrazole[1,5-a]pyridin-3-yl)ethane-1-one
- Step B 1-(4-Bromo-2-fluoro-6-hydroxypyrazole[1,5-a]pyridin-3-yl)ethane-1-one
- Step C 1-(4-Bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridin-3-yl)ethane-1-one
- Step D 4-Bromo-6-ethoxy-3-methyl-1hydro-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine
- Step E 6-Ethoxy-4-(6-(6-((6-methoxypyridin-3-yl)methylene)-3,6-diazabicyclo[3.3.1]heptane -3-yl)pyridin-3-yl)-3-methyl-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine
- Transfected recombinant gene is a confirmed proto-oncogene.
- the single transmembrane receptor tyrosine kinase it encodes is necessary for the development, maturation and maintenance of many tissues and cell types.
- mutations that activate RET include C634W, M918T, gatekeeper mutations V804L, V804M, and solvent front mutation G810R.
- the test combines peptide substrates and a single proprietary monoclonal antibody with HTRF technology, which is a highly sensitive and stable technology for detecting molecular interactions of proteins.
- the enzyme phosphorylates the substrate, then the Eu-labeled antibody binds to the phosphorylated substrate, and streptavidin-XL665 binds to all substrates.
- the TR-FRET signal is generated by the HTRF principle. Once the inhibitor (test compound) is added, a weaker TR-FRET signal is obtained. Based on this, the suppression effect is evaluated.
- Cabozantinib was diluted 3-fold with DMSO from 2mM and 0.2mM, respectively, to a total of 10 concentrations.
- the inhibition rate% is calculated as follows:
- Inhibition rate% [1-(test compound ratio-average ratio of positive control)/(average ratio of negative control-average ratio of positive control)]*100%
- the average ratio of positive control is the average ratio of positive control (20 ⁇ M Cabozantinib) in the sample plate;
- the average ratio of negative controls is the average ratio of negative controls (0.1% DMSO) in the sample plate.
- Min is the positive control drug 20 ⁇ M Cabozantinib Ratio (665/620nM*10000), and Max is the negative control drug DMSORation (665/620nM*10000).
- SD is the standard error
- AVE is the average of Rational (665/620nM*10000).
- step b) Use Echo to transfer 200 nL (prepared in step a) to a 384 cell culture plate.
- the gradient concentration of Cabozantinib and the test compound was 10000, 3333.3, 1111.1, 370.4, 123.4, 41.1, 13.7, 4.5, 1.5, 0.5 nM, and the final concentration of DMSO was 0.5%.
- the TT cell line nutrient medium contains 10% FBS and 1% Penicillin-streptomycin.
- each well contains 800 cells with a volume of 40 ⁇ L, and incubate for 72 hours in a cell incubator.
- ⁇ High control (HC, reading control without inhibition) is: 0.5% DMSO
- ⁇ Low control (LC, control with compound inhibition) is: 1 ⁇ MCEP-32496
- IC 50 was calculated using GraphPad Prism 6software.
- Top and Bottom Plateaus in same units as Y;
- logIC 50 same log units as X
- the TT tumor cells were cultured with F12K medium containing inactivated 10% fetal bovine serum, 100U/mL penicillin, 100 ⁇ g/mL streptomycin and 2mM glutamine in an incubator at 37°C and 5% CO 2 .
- the initial concentration of cell culture is 1 ⁇ 10 6 cells/ml, and the cells are divided into bottles for passage every 3 to 4 days. Tumor cells in the logarithmic growth phase are used for tumor inoculation in vivo.
- mice were orally administered the test compound twice a day for 28 consecutive days.
- Tumor volume Use a vernier caliper to measure the long and short diameters of the tumor.
- Reaction of animals after administration Weigh the experimental animals while measuring the tumor. The relationship between the change of animal weight and the time of administration was recorded. At the same time, observe the survival and health of the mice, such as animal activity and eating during the administration period.
- Relative tumor growth rate T/C(%) TRTV/CRTV ⁇ 100%.
- TRTV treatment group RTV
- CRTV negative control group RTV
- RTV relative tumor volume
- V0 is the tumor volume measured at the time of group administration (that is, the first day of administration)
- Vt is the tumor volume at each measurement.
- Tumor growth inhibition rate TGI(%) (1-T/C) ⁇ 100%.
- Ba/F3 KIF5B-RET-V804M tumor cells use RPMI-1640 medium containing inactivated 10% fetal bovine serum, 100U/ml penicillin, 100 ⁇ g/ml streptomycin and 2mM glutamine at 37°C, The tumor cells are cultured in a 5% CO 2 incubator, and the cells are divided into bottles for passage every 3 to 4 days after the cells are full, and the tumor cells in the logarithmic growth phase are used for tumor inoculation in vivo.
- Ba/F3KIF5B-RET-V804M tumor cells resuspended in the same volume of PBS and Matrigel at a concentration of 5 ⁇ 10 7 /ml were inoculated into the right flank of BALB/c nude mice subcutaneously, 100 ⁇ l/mouse, in the tumor growth When it reaches about 194 mm 3 , the drugs are administered in groups, with 6 animals in each group.
- mice were orally administered the test compound twice a day for 14 consecutive days.
- Tumor volume Use a vernier caliper to measure the long and short diameters of the tumor.
- Reaction of animals after administration Weigh the experimental animals while measuring the tumor. The relationship between the change of animal weight and the time of administration was recorded. At the same time, observe the survival and health of the mice, such as animal activity and eating during the administration period.
- Relative tumor growth rate T/C(%) TRTV/CRTV ⁇ 100%.
- TRTV treatment group RTV
- CRTV negative control group RTV
- RTV relative tumor volume
- V0 is the tumor volume measured at the time of group administration (that is, the first day of administration)
- Vt is the tumor volume at each measurement.
- Tumor growth inhibition rate TGI(%) (1-T/C) ⁇ 100%.
- the present invention relates to the field of medicinal chemistry, in particular to a nitrogen-containing polycyclic fused ring compound represented by formula I, its pharmaceutical composition, preparation method and application.
- the compound of the present invention can be used as a highly selective and very effective RET inhibitor. Such compounds are effective against RET gate residue mutant RET V804M mutation, RET solvent front residue mutant RET G810R and other clinically relevant RET mutants. And RET wt has a strong inhibitory effect.
- the compound can also significantly inhibit the growth of TT cell lines derived from thyroid cancer and Ba/F3 cells transformed with various RET mutants, and can significantly induce the death of TT cells.
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Abstract
本发明涉及药物化学领域,具体涉及式I所示含氮多环稠环类化合物,其药物组合物、制备方法和用途。本发明的化合物可以作为一种高度选择性和非常有效的RET抑制剂,此类化合物对RET看门残基突变体RET V804M突变、RET溶剂前沿残基突变体RET G810R和其他临床相关RET突变体以及RET wt均有较强的抑制作用,该化合物还能显著抑制甲状腺癌来源的TT细胞系和各种RET突变体转化的Ba/F3细胞的生长,并能显著诱导TT细胞死亡。
Description
本申请要求2019年8月5日向中国国家知识产权局提交的,专利申请号为201910719005.2,发明名称为“含氮多环稠环类化合物,其药物组合物、制备方法和用途”的在先申请的优先权。该申请的全文通过引用的方式结合于本申请中。
本发明涉及药物化学领域,具体涉及含氮多环稠环类化合物,其药物组合物、制备方法和用途。
RET(Rearranged During Transfection)原癌基因最初是在1985年,通过NIH3T3(小鼠胚胎成纤维细胞系)细胞与人类淋巴瘤DNA的转染被证实(Cell,1985,42(2):581-588)。RET原癌基因定位于染色体10q11.2,其DNA全长为60kb,含有外显子21个,编码由1100个氨基酸组成的RET蛋白:这种RET蛋白是一种酪氨酸激酶受体,含有一个由半胱氨酸组成的细胞外区、一个跨膜区和一个具有催化酪氨酸激酶作用的细胞内区(Mol Cell Endocrinol,2010,322(1-2):2-7)。RET参与细胞增殖、神经传导、细胞迁移和细胞分化,通过配体/复合受体/RET多蛋白复合物的信号,激活各种下游途径,如RAS/RAF/MEK/ERK,PI3K/AKT和STAT通路,诱导细胞增生(J Clin Oncol,2012,30(2):200-202)。
随着研究的逐步进展,现已发现多种疾病的发生与RET基因突变有密切联系,包括甲状腺乳头状癌(papillary thyroid carcinoma,PTC)(Cell,1990,60(4):557-563)、甲状腺髓样癌(medullary thyroid carcinoma,MTC)(hyroid,2009,19(6):565-612)、多发性内分泌腺瘤病2型(multiple endocrineneoplasia typeⅡ,MEN2)(Endocr Rev,2006,27(5):535-560)、先天性巨结肠(Proc Natl Acad Sci USA,2000,97(1):268-273)、肺腺癌(Nat Med,2012,18(3):375-377)等。目前只有KIF5B-RET、CCDC6-RET、TRIM33-RET、NCOA4-RET这四种RET融合基因在非小细胞肺癌中被报道,而KIF5B-RET是非小细胞肺癌中最常见的RET融合基因(Cancer,2013,119(8):1486-1494)。KIF5B-RET是KIF5B(kinesin family member 5B)基因和RET基因的染色体倒置(p11;q11)形成的一种融合基因,通过全基因组和转录组测序,第一次在非吸烟韩国人的腺癌中被证实;KIF5B-RET在肺癌中的比例很低,在非吸烟者和腺癌患者中更常见,并与其它突变,如EGFR、KRAS、BRAF、ErbB2、EML4-ALK相排斥(Genome Res,2012,22(3):436-445)。KIF5B-RET融合蛋白包含马达结构域和KIF5B的卷曲螺旋结构域,通过卷曲螺旋结构域的二聚化作用,该融合蛋白的RET酪氨酸激酶活性可异常活化,从而促进肺肿瘤发生(Cancer,2011,117(12):2709-2718)。在Qian等的研究中(Mol Cancer,2014,13:176),KIF5B-RET融合激酶被证实在体外和体内都具有显着的致癌活性,STAT3的信号转导途径可能是肿瘤发生的主要下游介质。有证据显示KIF5B-RET可调节STAT3的持续活化。KIF5B-RET融合激酶可以结合STAT3,直接磷酸化和激活STAT3-Tyr705;它也可以通过JAK/STAT3依赖性途径,介导激活STAT3-Tyr705,并通过RAS/RAF/MEK/ERK1途径触发Ser727的磷酸化。
证明RET融合物在一些癌症中是驱动者,这件事促进了已具有RET抑制活性的多激酶 抑制剂(multi-kinase inhibitor)的应用,用于治疗负载RET融合物蛋白质的肿瘤病人。目前尚未有批准药剂可以用来针对性地靶向这一致癌基因,目前RET特异性癌症的治疗方式仅限于多激酶抑制剂和化疗,但这些非特异性治疗临床表现ORR(客观缓释率)不好并且有很大的脱靶毒性。再者,癌症治疗的最大挑战之一是肿瘤细胞对于治疗一定阶段后出现耐药,一旦耐药,病人的治疗方式通常极为有限,且大多数例子中,癌症一直进展、不受抑制。
在甲状腺癌等多种人类癌症中,RET激酶信号转导起着重要作用。其中RET的看门残基体RET 804V突变是导致肿瘤对目前批准的非选择性RET抑制剂(如cabozantinib和vandetanib)耐药的重要原因。分离型家族性甲状腺髓样癌的RET胞外或胞内结构域中的重要突变之一,即激酶ATP结合位点中的看门残基V804M突变,导致现有药物对ATP结合位点亲和力下降。有文献报道(RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies,Journal of Thoracic Oncology,2020,Vol.15,No 4,541-549)选择性RET抑制剂LOXO-292(Selpercatinib)虽然可以避免前面提到的RET 804V突变,但在使用该选择性RET抑制剂后,仍会出现其他突变而导致耐药,比如在非小细胞肺癌中会导致激酶ATP结合位点中溶剂前沿的残基G810突变:如G810R,G810S,G801C突变,导致LOXO-292对ATP结合位点下降,从而出现耐药,癌症发生进展,因此,需要开发具有良好RET突变抑制活性的化合物。
发明内容
为改善上述问题,本发明提供了式I所示的化合物或其药学上可接受的盐:
X
1、X
2、X
3、X
4、X
5、X
6、X
7相同或不同,彼此独立地选自CR
1或N;
X
8选自CR
1R
1’或NR
1;其中:
每个R
1和R
1’相同或不同,彼此独立地选自H、卤素、CN、NH
2或OH,或者
每个R
1和R
1’相同或不同,彼此独立地选自无取代或任选地被1个、2个或3个R
a取代的下列基团:C
1-6烷基、C
3-6环烷基、C
1-6烷氧基或C
3-6环烷基氧基;
每个R
a相同或不同,彼此独立地选自卤素、CN、OH、C
1-6烷基、C
3-6环烷基或C
1-6烷氧基;
A选自H、卤素、CN、OH或NH
2,或者
A选自无取代或任选地被1个、2个或3个R
b取代的下列基团:C
1-6烷基、C
2-6烯基、C
3-6环烷基、C
1-6烷氧基或C
3-6环烷基氧基;
每个R
b相同或不同,彼此独立地选自卤素、CN、OH、C
1-6烷基、C
3-6环烷基或C
1-6烷氧基;
D、E相同或不同,彼此独立地选自H、卤素、CN、OH或NH
2,或者
D、E相同或不同,彼此独立地选自无取代或任选地被1个、2个或3个R
c取代的下列基团:-C
1-6烷基、-C
1-6烷氧基、-O(CH
2)
nO(CH
2)
nC
3-6碳环、-O(CH
2)
n-3-8元的杂环或-O(CH
2)
nC
6-10芳香环;
每个R
c相同或不同,彼此独立地选自卤素、CN、OH、氧代(=O)、C
1-6烷基、C
1-6烷氧基、C
3-6环烷基、3-10元杂环基、5-7元杂芳基、6-10元芳基、C
1-6烷氧基、3-6元环烷基氧基或3-8元杂环基氧基;
每个n相同或不同,彼此独立选自0、1、2或3;
上述D、E和R
c中的每个杂环、杂环基、杂芳基中的杂原子个数和种类相同或不同,彼此独立地含有1、2或3个杂原子,所述杂原子选自N、O或S;
G选自下列基团:(1)饱和的4-8元的含有2个杂原子的杂环;(2)饱和的7-10元的含有2个杂原子的桥杂环;(3)饱和的7-11元的含有2个杂原子的杂螺环;或(4)饱和的7-10元的含有两个杂原子的双环稠合的杂环;上述杂原子选自N或O,每个环彼此独立地任选地不被取代或被1、2、3或4个R
G取代,每个R
G相同或不同,且每个R
G独立地选自H、卤素、OH、NH
2、C
1-6烷基、卤素取代的C
1-6烷基、C
1-6烷氧基或卤素取代的C
1-6烷氧基;
K选自无取代或任选地被1个、2个、3个或4个R
K取代的下列基团:C
1-6烷基、C
3-6环烷基、C
6-10芳基、-C
1-6亚烷基C
6-10芳环、-COC
1-6亚烷基C
6-10芳环、-C
1-6亚烷基5-10元芳杂环、-COC
1-6亚烷基5-10元芳杂环、-CONR
K1R
K2、3-10元杂环基、C
1-6烷氧基、C
3-6环烷基氧基、C
6-10芳基氧基、5-10元杂芳基氧基或3-10元杂环基氧基;
每个R
K相同或不同,彼此独立地选自下列基团:-CN、OH、-NH
2、C
1-6烷基、C
1-6烷氧基、C
3-6环烷基、卤素取代的C
1-6烷基或卤素取代的C
1-6烷氧基;
R
K1和R
K2相同或不同,彼此独立地选自下列基团:-CN、C
1-6烷基、C
1-6烷氧基、C
3-6环烷基、卤素取代的C
1-6烷基或卤素取代的C
1-6烷氧基;
所述K中的每个芳杂环、杂环、杂环基相同或不同,彼此独立地含1或2个N原子。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,X
1、X
3和X
4均独立地选自CR
1。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,X
5选自CR
1。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,X
8选自NR
1。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,每个R
1和R
1’相同或不同,彼此独立地选自H、F、Cl、Br、CN、NH
2或OH,或者
每个R
1和R
1’相同或不同,彼此独立地选自无取代或任选地被1个、2个或3个R
a取代的下列基团:C
1-3烷基、C
4-6环烷基、C
1-3烷氧基或C
4-6环烷基氧基。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,每个R
1和R
1’相同或不同,彼此独立地选自H、F、Cl、CN或NH
2,或者
每个R
1和R
1’相同或不同,彼此独立地选自无取代或任选地被1个、2个或3个R
a取代的下列基团:甲基、乙基、丙基、5元环烷基、6元环烷基、甲氧基、乙氧基、丙氧基、5元环烷基氧基或6元环烷基氧基。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,每个R
a相同或不同,彼此独立地选自F、Cl、Br、CN、OH、C
1-3烷基、C
4-6环烷基或C
1-3烷氧基;
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,每个R
a相同或不同,彼此独立地选自F、Cl、CN、OH、甲基、乙基、丙基、5元环烷基、6元环烷基、甲氧基、乙氧基、丙氧基、5元环烷基氧基或6元环烷基氧基。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,X
1选自CH。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,X
3选自CH。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,X
5选自-CH。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,X
5选自CH。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,X
8选自NH。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,X
1、X
3、X
4和X
5均选自CH,X
8选自NH。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,X
2选自N。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,X
6选自N。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,X
7选自N。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,X
1、X
3、X
4和X
5均选自CH,X
2、X
6和X
7均选自N,X
8选自NH。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,A选自H、F、Cl、Br、CN、OH或NH
2,或者
A选自无取代或任选地被1个、2个或3个R
b取代的下列基团:C
1-3烷基、C
4-6环烷基、C
1-3烷氧基或C
4-6环烷基氧基;每个R
b相同或不同,彼此独立地选自F、Cl、Br、CN、OH、C
1-3烷基或C
1-3烷氧基。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,A选自H、F、Cl、CN、OH或NH
2,或者
A选自无取代或任选地被1个、2个或3个R
b取代的下列基团:甲基、乙基、丙基、5元环烷基、6元环烷基、甲氧基、乙氧基、丙氧基、5元环烷基氧基或6元环烷基氧基;每个Rb相同或不同,彼此独立地选自F、Cl、甲基、乙基、甲氧基或乙氧基。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,A选自H、-F、-Cl、-CN、-OH、-NH
2或-CH
3、。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,D、E 相同或不同,彼此独立地选自H、F、Cl、Br、CN、OH或NH
2,或者
D、E相同或不同,彼此独立地选自无取代或任选地被1、2或3个R
c取代的下列基团:-C
1-3烷基、-C
1-3烷氧基、-O(CH
2)
nO(CH
2)
nC
3-6碳环、-O(CH
2)
n-4-6元的杂环、-O(CH
2)
nC
6芳香环或-O(CH
2)
nC
10芳香环。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,D、E相同或不同,彼此独立地选自H、F、Cl、Br、、CN、OH或NH
2,或者
D、E相同或不同,彼此独立地选自无取代或任选地被1、2或3个R
c取代的下列基团:甲基、乙基、丙基、甲氧基、乙氧基、丙氧基、-O(CH
2)
nO(CH
2)
n-3元碳环、-O(CH
2)
nO(CH
2)
n-4元碳环、-O(CH
2)
nO(CH
2)
n-5元碳环、-O(CH
2)
n-5元的杂环、-O(CH
2)
n-6元的杂环或-O(CH
2)
n-苯环。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,D、E相同或不同,彼此独立地选自H、F、Cl、Br、CN、OH或NH
2,或者
D、E相同或不同,彼此独立地选自无取代或任选地被1、2或3个R
c取代的下列基团:甲基、甲氧基、-O(CH
2)
nO(CH
2)
n-3元碳环、-O(CH
2)
n-6元的杂环或-O(CH
2)
n-苯环。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,每个n相同或不同,彼此独立选自0、1或2。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,每个n相同或不同,彼此独立选自1或2。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,每个R
c相同或不同,彼此独立地选自F、Cl、Br、CN、OH、C
1-3烷基、C
3-5环烷基、4-6元杂环基、5-6元杂芳基、苯基、C
1-3烷氧基、3-5元环烷基氧基或4-6元饱和杂环基氧基。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,每个R
c相同或不同,彼此独立地选自F、Cl、Br、CN、OH、甲基、乙基、丙基、3元环烷基、4元环烷基、4元饱和杂环基、5元饱和杂环基、6元饱和的杂环基、5元杂芳基、6元杂芳基、苯基、甲氧基、乙氧基、丙氧基、3元环烷基氧基、4元环烷基氧基、5元饱和的杂环基氧基或6元饱和的杂环基氧基。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,每个R
c相同或不同,彼此独立地选自F、Cl、Br、CN、OH、甲基、乙基、丙基、3元环烷基、4元环烷基、4元饱和杂环基、5元饱和杂环基、6元饱和的杂环基、5元杂芳基、6元杂芳基、苯基、甲氧基、乙氧基、丙氧基、3元环烷基氧基、4元环烷基氧基、5元饱和的杂环基氧基或6元饱和的杂环基氧基。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,所述D、E和R
c中的每个杂环、杂环基、杂芳基中的杂原子个数和种类相同或不同,彼此独立地含有1或2个杂原子,所述杂原子选自N或O。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,所述D、E和R
c中的每个杂环、杂环基、杂芳基中的杂原子个数和种类相同或不同,彼此独立地含有1个N原子和/或1个O原子。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,G选自下列基团:饱和的5、6、7或8元的含有2个N原子的杂环。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,G选自下列基团:饱和的5元的含有2个N原子的杂环、饱和的6元的含有2个N原子的杂环、饱和的7元的含有2个N原子的杂环和饱和的8元的含有2个N原子的杂环。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,G选自下列基团:饱和的7、8或9元的含有2个N或O原子的桥杂环。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,G选自下列基团:饱和的8元的含有2个N或O原子的桥杂环或饱和的9元的含有2个N原子的桥杂环。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,G选自下列基团:饱和的8元的含有2个N原子的桥杂环或饱和的9元的含有2个N原子的桥杂环。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,每个R
G相同或不同,且每个R
G独立地选自H、F、Cl、Br、OH、NH
2、C
1-3烷基、F或Cl取代的C
1-3烷基或C
1-3烷氧基。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,每个R
G相同或不同,且每个R
G独立地选自H、NH
2、甲基、乙基、丙基、F取代的甲基、F取代的乙基、F取代的丙基、甲氧基、乙氧基或丙氧基。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,每个R
G相同或不同,且每个R
G独立地选自H、NH
2、甲基、F取代的甲基或甲氧基。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,K选自无取代或任选地被一个、两个或多个R
K取代的下列基团:K选自无取代或任选地被1、2或3个R
K取代的下列基团:C
1-3烷基、C
5-6环烷基、苯基、-C
1-3亚烷基苯环、-COC
1-3亚烷基苯环、-COC
1-3亚烷基联苯环、-C
1-3亚烷基5-8元芳杂环、-COC
1-3亚烷基5-8元芳杂环、-CONR
K1R
K2、5-6元杂环基、C
1-3烷氧基、C
3-6环烷基氧基、C
6-10芳基氧基、5-8元杂芳基氧基或5-8元杂环基氧基;
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,K选自无取代或任选地被一个、两个或多个R
K取代的下列基团:K选自无取代或任选地被1或2个R
K取代的下列基团:C
1-3烷基、C
5-6环烷基、苯基、-C
1-3亚烷基苯环、-COCH
2苯环、-COCH
2CH
2苯环、-COCH
2联苯环、-CH
2-6元芳杂环、-CH
2CH
2-6元芳杂环、-CO CH
2-6元芳杂环、-COCH
2CH
2-6元芳杂环、-CONR
K1R
K2、5元杂环基、6元杂环基、甲氧基、C
5环烷基氧基、苯基氧基、6元杂芳基氧基或6元杂环基氧基;
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,所述K中的每个芳杂环、杂环、杂环基、芳环、芳基、环烷基相同或不同,其中每个芳杂环、杂环或杂环基中含有1个N原子。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,每个R
K彼此独立地选自下列基团:-CN、OH、-NH
2、C
1-3烷基、C
1-3烷氧基、C
3-6环烷基、F取代的C
1-3烷基、Cl取代的C
1-3烷基、F取代的C
1-3烷氧基或Cl取代的C
1-3烷氧基。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,每个R
K彼此独立地选自下列基团:-CN、OH、-NH
2、甲基、乙基、甲氧基或乙氧基。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,
R
K1和R
K2相同或不同,彼此独立地选自下列基团:-CN、C
1-3烷基、C
1-3烷氧基、C
4-5环烷基、F取代的C
1-3烷基、Cl取代的C
1-3烷基、F取代的C
1-3烷氧基或Cl取代的C
1-3烷氧基。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,
R
K1和R
K2相同或不同,彼此独立地选自下列基团:-CN、OH、-NH
2、甲基、乙基、甲氧基或乙氧基。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,所述杂环基、杂环、芳杂环、杂芳基或芳杂基含有1、2或3个杂原子,所述杂原子选自N或O。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,所述杂环基、杂环、芳杂环、杂芳基或芳杂基含有1或2个杂原子,所述杂原子选自N或O。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,所述杂环基、杂环、芳杂环、杂芳基或芳杂基是含有1个杂原子的4、5、6、7或8元的环,所述杂原子选自N或O。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,所述杂环基、杂环、芳杂环、杂芳基或芳杂基是含有2个杂原子4、5、6、7或8元的杂环,所述杂原子选自N或O。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,所述杂环基、杂环、芳杂环、杂芳基或芳杂基是含有2个杂原子4、5、6、7或8元的环,所述杂原子选自N。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,所述杂环基、杂环、芳杂环、杂芳基或芳杂基是含有2个杂原子5或6元的环,所述杂原子选自N。
作为优选的实施方式,本发明也提供了式I所示的化合物或药学上可接受的盐,所述杂环基、杂环、芳杂环、杂芳基或芳杂基是含有2个杂原子6元的环,所述杂原子选自N。
作为优选的实施方式,本发明也提供了式II所示的化合物或药学上可接受的盐,
其中,
R
22选自H、卤素、CN、-C
1-6烷基、-C
1-6烷氧基、-O(CH
2)
m-C
1-6烷基或-O(CH
2)
m-C
1-6烷氧基,每个C
1-6烷基和每个C
1-6烷氧基均可不取代或者被卤素、C
1-6烷基或C
1-6烷氧基取代,m=0、 1或2;
R
21选自H、NH
2或-C
1-3烷基;
R
23选自H、NH
2、-C
1-3烷基或-C
1-3烷氧基。
作为优选的实施方式,本发明也提供了式II所示的化合物或药学上可接受的盐,
R
22选自H、F、Cl、Br、、CN、-C
1-3烷基、-C
1-3烷氧基、-O(CH
2)
m-C
1-3烷基或-O(CH
2)
m-C
1-3烷氧基,每个C
1-3烷基和每个C
1-3烷氧基均可不取代或者被F、Cl、Br、C
1-3烷基或C
1-3烷氧基取代;
R
21选自H、NH
2或甲基;
R
23选自H、NH
2、甲基或甲氧基。
作为优选的实施方式,本发明也提供了式II所示的化合物或药学上可接受的盐,
R
22选自H、F、Cl、Br、、CN、-C
1-3烷基、-C
1-3烷氧基、-O(CH
2)
m-C
1-3烷基或-O(CH
2)
m-C
1-3烷氧基,每个C
1-3烷基和每个C
1-3烷氧基均可不取代或者被F、Cl、Br、C
1-3烷基或C
1-3烷氧基取代;
R
21选自H;
R
23选自甲氧基。
作为优选的实施方式,本发明也提供了式II所示的化合物或药学上可接受的盐,
R
22选自H、F、Cl、CN、甲基、乙基、甲氧基、乙氧基、-O(CH
2)
m甲基、-O(CH
2)
m乙基、-O(CH
2)
m甲氧基或-O(CH
2)
m乙氧基,每个甲基、乙基、甲氧基和乙氧基均可不取代或者被F、Cl、Br、甲基、乙基、甲氧基或乙氧基取代;
作为优选的实施方式,本发明也提供了式II所示的化合物或药学上可接受的盐,m=1或2。
本发明还提供了下述化合物或其药学上可接受的盐:
本发明还提供了下述化合物或其药学上可接受的盐:
本发明还提供了一种药物组合物,包含有治疗有效量的上述的化合物或其药学上可接受的盐,和至少一种药学上可接受的辅料。
作为优选的实施方式,本发明也提供了上述的化合物或其药学上可接受的盐及上述的药物组合物用于制备药物的用途.
作为优选的实施方式,本发明也提供了所述的用途的优选方案,所述药物用于治疗、阻止或预防由RET基因、RET激酶蛋白或其任何一种或几种的突变、表达、活性或水平的失调导致的疾病或不适。
作为优选的实施方式,本发明也提供了所述的用途的优选方案,其中,RET基因中的一个或多个点突变导致在以下一个或多个氨基酸位置具有一个或多个氨基酸替换的RET蛋白的翻译:2、3、4、5、6、7、8、11、12、13、20、32、34、40、56、64、67、114、136、145、180、200、292、294、321、330、338、360、373、393、423、432、446、505、506、510、511、513、515、525、531、532、533、550、591、593、595、600、602、603、606、609、611、616、618、619、620、623、624、630、631、632、633、634、635、636、640、641、 648、649、664、665、666、675、686、689、691、694、700、706、713、732、736、748、750、765、766、768、769、770、771、777、778、781、788、790、791、802、804、805、806、810、818、819、823、836、841、843、844、848、852、865、870、873、876、881、882、883、884、886、891、897、898、900、901、904、905、907、908、911、912、918、919、921、922、930、961、972、981、982、1009、1015、1017、1041、1062、1064和1096。
作为优选的实施方式,本发明也提供了所述的用途的优选方案,其中,RET基因中的一个或多个点突变导致在以下一个或多个氨基酸位置具有一个或多个氨基酸替换的RET蛋白的翻译:32、34、40、56、64、67、114、145、292、321、330、338、360、393、423、446、510、511、513、515、525、531、532、533、550、591、593、595、600、602、603、606、609、611、616、618、619、620、623、624、630、631、632、634、635、636、640、641、648、649、664、665、666、675、686、689、691、694、700、706、713、732、736、748、750、765、766、768、769、770、771、777、778、781、788、790、791、804、805、806、810、818、819、823、826、833、836、841、843、844、848、852、865、870、873、876、881、883、884、886、891、897、898、900、901、904、905、907、908、911、912、918、919、921、922、930、961、972、981、982、1009、1015、1017、1041、1064和1096。
作为优选的实施方式,本发明也提供了所述的用途的优选方案,其中RET基因中的一个或多个点突变导致含有以下一个或多个氨基酸取代的RET蛋白的转译:S32L、D34S、L40P、L56M、P64L、R67H、R114H、V145G、V292M、G321R、R330Q、T338I、R360W、F393L、G423R、G446R、A510V、E511K、G513D、C515S、C515W、R525W、C531R、G533C、G533S、G550E、V591I、G593E、E595D、E595A、R600Q、I602V、K603Q、K603E、Y606C、C609C、C609Y、C609S、C609G、C609R、C609F、C609W、C611R、C611S、C611G、C611Y、C611F、C611W、E616Q、C618S、C618Y、C618R、C618G、C618F、C618W、F619F、C620S、C620W、C620R、C620G、C620L、C620Y、C620F、E623K、D624N、C630A、C630R、C630S、C630Y、C630F、C630W、D631N、D631Y、D631A、D631G、D631V、D631E、E632K、E632G、C634W、C634Y、C634S、C634R、C634F、C634G、C634L、C634A、C634T、R635G、T636P、T636M、A640G、A641S、A641T、V648I、S649L、A664D、H665Q、K666E、K666M、K666N、K666R、T675T S686N、S689T、G691S、R694Q、M700L、V706M、V706A、E713K、E732K、G736R、G748C、A750P、S765P、P766S、P766M、E768Q、E768D、L769L、R770Q、D771N、N777S、V778I、Q781R、I788I、L790F、Y791F、Y791N、V804L、V804M、V804E、E805K、Y806E、Y806F、Y806S、Y806G、Y806C、Y806H、Y806N、Y806Y、G810R、G810S、G810A、E818K、S819I、G823E、Y826M、Y826S、R833C、S836S、P841L、P841P、E843D、R844W、R844Q、R844L、M848T、I852M、L865V、L870F、R873W、A876V、L881V、A883F、A883S、A883T、E884K、R886W、S891A、S891S、R897Q、D898V、Y900F、E901K、S904F、S904S、S904C、Y905F、K907E、K907M、R908K、G911D、R912P、R912Q、M918T、M918V、M918L、A919V、E921K、S922P、S922Y、T930M、F961L、R972G、Y981F、R982C、Ml009V、Y1015F、D1017N、V1041G、M1064T和Y1096F。
作为优选的实施方式,本发明也提供了所述的用途的优选方案,其中,RET基因中的一个或多个点突变发生在人类RET基因的一个或多个外显子10、11、13、14、15和16中。
作为优选的实施方式,本发明也提供了所述的用途的优选方案,其中,所述RET基因融合选自:BCR-RET、CLIP 1-RET、KIF5B-RET、CCDC6-RET、NCOA4-RET、TRIM33-RET、ERC1-RET、FGFR1OP-RET、RET-MBD1、RET-RAB61P2、RET-PRKAR1A、RET-TRIM24、 RET-GOLGA5、HOOGA5。KIAA1217-RET、MPRIP-RET、HRH4-RET、RIA-RET、RET-PTC4、FRMD4A-RET、SQSTM1-RET、AFAP1L2-RET、PPFIBP2-RET、EML4-RET、PARD3-RET、MYH10-RET、HTIF1/RET、AFAP1-RET、RASGEF1A-RET、TEL-RET。
作为优选的实施方式,本发明也提供了所述的用途的优选方案,,RET基因、RET激酶蛋白或其任何一种或几种的突变、表达、活性或水平的失调是RET基因融合。
作为优选的实施方式,本发明也提供了所述的用途的优选方案,所述由RET基因、RET激酶蛋白或其任何一种或的表达、活性或水平的失调导致的疾病或不适是癌症或癌转移。
作为优选的实施方式,本发明也提供了所述的用途的优选方案,所述由RET基因、RET激酶蛋白或其任何一种的表达、活性或水平的失调导致的疾病或不适选自以下一种或多种下列病症:肺癌、乳头状甲状腺癌、髓样甲状腺癌、分化型甲状腺癌、复发性甲状腺癌、难分化甲状腺癌、2A或2B型多发性内分泌肿瘤(分别为MEN2A或MEN2B)、嗜铬细胞瘤、甲状旁腺增生、乳腺癌、结直肠癌、乳头状肾细胞癌、胃肠道神经节细胞瘤病(分别为MEN2A或MEN2B型)、嗜铬细胞瘤、甲状旁腺增生、乳腺癌、结直肠癌、乳头状肾细胞癌、胃肠道神经节细胞瘤病及其组合。
本发明还提供了一种治疗、阻止或预防由RET活性介导的疾病或病症的方法,其包括:(1)确定疾病或不适是否与RET基因、RET激酶或其任何一种或多种的表达、活性或水平失调有关;以及(2)如果确定确定疾病或不适与RET基因、RET激酶或其任何一种或多种的表达、活性或水平的失调有关,则向患者给予有效剂量的本发明提供的化合物或其药学上可接受的盐或本发明提供的药物组合物。
作为优选的实施方式,本发明也提供了所述的治疗方法的优选方案,其中:所述由RET活性介导的疾病或病症是癌症和/或癌转移。
作为优选的实施方式,本发明也提供了所述的治疗方法的优选方案,其中,RET基因中的一个或多个点突变导致在以下一个或多个氨基酸位置具有一个或多个氨基酸替换的RET蛋白的翻译:2、3、4、5、6、7、8、11、12、13、20、32、34、40、56、64、67、114、136、145、180、200、292、294、321、330、338、360、373、393、423、432、446、505、506、510、511、513、515、525、531、532、533、550、591、593、595、600、602、603、606、609、611、616、618、619、620、623、624、630、631、632、633、634、635、636、640、641、648、649、664、665、666、675、686、689、691、694、700、706、713、732、736、748、750、765、766、768、769、770、771、777、778、781、788、790、791、802、804、805、806、810、818、819、823、836、841、843、844、848、852、865、870、873、876、881、882、883、884、886、891、897、898、900、901、904、905、907、908、911、912、918、919、921、922、930、961、972、981、982、1009、1015、1017、1041、1062、1064和1096。
作为优选的实施方式,本发明也提供了所述的治疗方法的优选方案,其中,RET基因中的一个或多个点突变导致在以下一个或多个氨基酸位置具有一个或多个氨基酸替换的RET蛋白的翻译:32、34、40、56、64、67、114、145、292、321、330、338、360、393、423、446、510、511、513、515、525、531、532、533、550、591、593、595、600、602、603、606、609、611、616、618、619、620、623、624、630、631、632、634、635、636、640、641、648、649、664、665、666、675、686、689、691、694、700、706、713、732、736、748、750、765、766、768、769、770、771、777、778、781、788、790、791、804、805、806、810、818、819、823、826、833、836、841、843、844、848、852、865、870、873、876、 881、883、884、886、891、897、898、900、901、904、905、907、908、911、912、918、919、921、922、930、961、972、981、982、1009、1015、1017、1041、1064和1096。
作为优选的实施方式,本发明也提供了所述的治疗方法的优选方案,其中RET基因中的一个或多个点突变导致含有以下一个或多个氨基酸取代的RET蛋白的转译:S32L、D34S、L40P、L56M、P64L、R67H、R114H、V145G、V292M、G321R、R330Q、T338I、R360W、F393L、G423R、G446R、A510V、E511K、G513D、C515S、C515W、R525W、C531R、G533C、G533S、G550E、V591I、G593E、E595D、E595A、R600Q、I602V、K603Q、K603E、Y606C、C609C、C609Y、C609S、C609G、C609R、C609F、C609W、C611R、C611S、C611G、C611Y、C611F、C611W、E616Q、C618S、C618Y、C618R、C618G、C618F、C618W、F619F、C620S、C620W、C620R、C620G、C620L、C620Y、C620F、E623K、D624N、C630A、C630R、C630S、C630Y、C630F、C630W、D631N、D631Y、D631A、D631G、D631V、D631E、E632K、E632G、C634W、C634Y、C634S、C634R、C634F、C634G、C634L、C634A、C634T、R635G、T636P、T636M、A640G、A641S、A641T、V648I、S649L、A664D、H665Q、K666E、K666M、K666N、K666R、T675T S686N、S689T、G691S、R694Q、M700L、V706M、V706A、E713K、E732K、G736R、G748C、A750P、S765P、P766S、P766M、E768Q、E768D、L769L、R770Q、D771N、N777S、V778I、Q781R、I788I、L790F、Y791F、Y791N、V804L、V804M、V804E、E805K、Y806E、Y806F、Y806S、Y806G、Y806C、Y806H、Y806N、Y806Y、G810R、G810S、G810A、E818K、S819I、G823E、Y826M、Y826S、R833C、S836S、P841L、P841P、E843D、R844W、R844Q、R844L、M848T、I852M、L865V、L870F、R873W、A876V、L881V、A883F、A883S、A883T、E884K、R886W、S891A、S891S、R897Q、D898V、Y900F、E901K、S904F、S904S、S904C、Y905F、K907E、K907M、R908K、G911D、R912P、R912Q、M918T、M918V、M918L、A919V、E921K、S922P、S922Y、T930M、F961L、R972G、Y981F、R982C、Ml009V、Y1015F、D1017N、V1041G、M1064T和Y1096F。
作为优选的实施方式,本发明也提供了所述的治疗方法的优选方案,其中,RET基因中的一个或多个点突变发生在人类RET基因的一个或多个外显子10、11、13、14、15和16中。
作为优选的实施方式,本发明也提供了所述的治疗方法的优选方案,其中,所述RET基因融合选自:BCR-RET、CLIP 1-RET、KIF5B-RET、CCDC6-RET、NCOA4-RET、TRIM33-RET、ERC1-RET、FGFR1OP-RET、RET-MBD1、RET-RAB61P2、RET-PRKAR1A、RET-TRIM24、RET-GOLGA5、HOOGA5。KIAA1217-RET、MPRIP-RET、HRH4-RET、RIA-RET、RET-PTC4、FRMD4A-RET、SQSTM1-RET、AFAP1L2-RET、PPFIBP2-RET、EML4-RET、PARD3-RET、MYH10-RET、HTIF1/RET、AFAP1-RET、RASGEF1A-RET、TEL-RET。
作为优选的实施方式,本发明也提供了所述的治疗方法的优选方案,RET基因、RET激酶蛋白或其任何一种或几种的突变、表达、活性或水平的失调是RET基因融合。
作为优选的实施方式,本发明也提供了所述的治疗方法的优选方案,其中:所述由RET活性介导的疾病选自一种或多种下列疾病:肺癌、乳头状甲状腺癌、髓样甲状腺癌、分化型甲状腺癌、复发性甲状腺癌、难分化甲状腺癌、2A或2B型多发性内分泌肿瘤(分别为MEN2A或MEN2B)、嗜铬细胞瘤、甲状旁腺增生、乳腺癌、结直肠癌、乳头状肾细胞癌、胃肠道神经节细胞瘤病(分别为MEN2A或MEN2B型)、嗜铬细胞瘤、甲状旁腺增生、乳腺癌、结直肠癌、乳头状肾细胞癌、胃肠道神经节细胞瘤病及其组合。
本发明还提供一种如下式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物或药学上可接受的盐:
其中,X
1、X
2、X
3、X
4、X
5、X
6、X
7相同或不同,彼此独立地选自CR
1或N;
X
8选自CR
1R
1’或NR
1;
其中每一个R
1和R
1’相同或不同,彼此独立地选自H、卤素、CN、OH,无取代或任选被一个、两个或更多个R
a取代的下列基团:C
1-40烷基、C
2-40烯基、C
2-40炔基、C
3-40环烷基、C
3-40环烯基、C
3-40环炔基、C
1-40烷基氧基、C
2-40烯基氧基、C
2-40炔基氧基、C
3-40环烷基氧基、C
3-40环烯基氧基、C
3-40环炔基氧基、NR
2R
3、-C(O)R
4、-OCR
5、-S(O)
2R
6、OS(O)
2R
7;
A选自H、卤素、CN、OH,NH
2,无取代或任选被一个、两个或更多个R
b取代的下列基团:C
1-40烷基、C
2-40烯基、C
2-40炔基、C
3-40环烷基、C
3-40环烯基、C
3-40环炔基、C
1-40烷基氧基、C
2-40烯基氧基、C
2-40炔基氧基、C
3-40环烷基氧基、C
3-40环烯基氧基、C
3-40环炔基氧基、NR
2R
3、-C(O)R
4、-OCR
5、-S(O)
2R
6、OS(O)
2R
7;
D、E相同或不同,彼此独立地选自H、卤素、CN、OH、-O-R
21,无取代或任选被一个、两个或更多个R
c取代的下列基团:C
1-40烷基、C
2-40烯基、C
2-40炔基、C
3-40环烷基、C
3-40环烯基、C
3-40环炔基、C
6-20芳基、5-20元杂芳基、3-20元杂环基、NH
2,条件是D和E中的至少一个选自-O-R
21;
R
21选自H,无取代或任选被一个、两个或更多个R
d取代的下列基团:C
1-40烷基、C
2-40烯基、C
2-40炔基、C
3-40环烷基、C
3-40环烯基、C
3-40环炔基、C
6-20芳基、5-20元杂芳基、3-20元杂环基;
G选自无取代或任选被一个、两个或更多个R
e取代的下列基团:C
3-40环烷基、C
3-40环烯基、C
3-40环炔基、C
6-20芳基、5-20元杂芳基、3-20元杂环基、C
3-40环烷基氧基、C
3-40环烯基氧基、C
3-40环炔基氧基、C
6-20芳基氧基、5-20元杂芳基氧基或3-20元杂环基氧基;
K选自无取代或任选被一个、两个或更多个R
f取代的下列基团:H、卤素、CN、OH,无取代或任选被一个、两个或更多个R
g取代的下列基团:C
1-40烷基、C
2-40烯基、C
2-40炔基、C
3-40环烷基、C
3-40环烯基、C
3-40环炔基、C
6-20芳基、5-20元杂芳基、3-20元杂环基、C
1-40烷基氧基、C
2-40烯基氧基、C
2-40炔基氧基、C
3-40环烷基氧基、C
3-40环烯基氧基、C
3-40环炔基氧基、C
6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR
2R
3、-C(O)R
4、-OCR
5、-S(O)
2R
6、OS(O)
2R
7;
每一个R
2相同或不同,彼此独立地选自H、C
1-40烷基、C
2-40烯基、C
2-40炔基、C
3-40环烷基、C
3-40环烯基、C
3-40环炔基、C
6-20芳基、5-20元杂芳基、3-20元杂环基、-C(O)R
4、-S(O)
2R
6;
每一个R
3相同或不同,彼此独立地选自H、C
1-40烷基、C
2-40烯基、C
2-40炔基、C
3-40环烷基、C
3-40环烯基、C
3-40环炔基、C
6-20芳基、5-20元杂芳基、3-20元杂环基、-C(O)R
4、-S(O)
2R
6;
或者,R
2和R
3与所连的N原子一起形成5-20元杂芳基或3-20元杂环基;
每一个R
4相同或不同,彼此独立地选自H、C
1-40烷基、C
2-40烯基、C
2-40炔基、C
3-40环烷基、C
3-40环烯基、C
3-40环炔基、C
6-20芳基、5-20元杂芳基、3-20元杂环基、C
1-40烷基氧基、C
2-40烯基氧基、C
2-40炔基氧基、C
3-40环烷基氧基、C
3-40环烯基氧基、C
3-40环炔基氧基、C
6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR
2R
3;
每一个R
5相同或不同,彼此独立地选自H、C
1-40烷基、C
2-40烯基、C
2-40炔基、C
3-40环烷基、C
3-40环烯基、C
3-40环炔基、C
6-20芳基、5-20元杂芳基、3-20元杂环基、C
1-40烷基羰基、C
2-40烯基羰基、C
2-40炔基羰基、C
3-40环烷基羰基、C
3-40环烯基羰基、C
3-40环炔基羰基、C
6-20芳基羰基、5-20元杂芳基羰基、3-20元杂环基羰基;
每一个R
6相同或不同,彼此独立地选自H、C
1-40烷基、C
2-40烯基、C
2-40炔基、C
3-40环烷基、C
3-40环烯基、C
3-40环炔基、C
6-20芳基、5-20元杂芳基、3-20元杂环基、C
1-40烷基氧基、C
2-40烯基氧基、C
2-40炔基氧基、C
3-40环烷基氧基、C
3-40环烯基氧基、C
3-40环炔基氧基、C
6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR
2R
3;
每一个R
7相同或不同,彼此独立地选自H、C
1-40烷基、C
2-40烯基、C
2-40炔基、C
3-40环烷基、C
3-40环烯基、C
3-40环炔基、C
6-20芳基、5-20元杂芳基、3-20元杂环基;
每一个R
a、R
b、R
c、R
d、R
e、R
f相同或不同,彼此独立地选自卤素、CN、OH、SH、氧代(=O)、NO
2,无取代或任选被一个、两个或更多个R
g取代的下列基团:C
1-40烷基、C
2-40烯基、C
2-40炔基、C
3-40环烷基、C
3-40环烯基、C
3-40环炔基、C
6-20芳基、5-20元杂芳基、3-20元杂环基、C
1-40烷基氧基、C
2-40烯基氧基、C
2-40炔基氧基、C
3-40环烷基氧基、C
3-40环烯基氧基、C
3-40环炔基氧基、C
6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR
2R
3、-C(O)R
4、-OCR
5、-S(O)
2R
6、OS(O)
2R
7;
每一个R
g相同或不同,彼此独立地选自卤素、CN、OH、SH、氧代(=O)、NO
2,无取代或任选被一个、两个或更多个R
h取代的下列基团:C
1-40烷基、C
2-40烯基、C
2-40炔基、C
3-40环烷基、C
3-40环烯基、C
3-40环炔基、C
6-20芳基、5-20元杂芳基、3-20元杂环基、C
1-40烷基氧基、C
2-40烯基氧基、C
2-40炔基氧基、C
3-40环烷基氧基、C
3-40环烯基氧基、C
3-40环炔基氧基、C
6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR
2R
3、-C(O)R
4、-OCR
5、-S(O)
2R
6、OS(O)
2R
7;或者,当环状基团(包括但不限于C
3-40环烷基、C
3-40环烯基、C
3-40环炔基、3-20元杂环基等)的不同位置被两个或更多个取代基取代时,所述取代基中的两个也可以与所述环状基团形成桥环,其中所述桥环中除桥头原子之外的桥原子可以包含1、2、3、4或5个选自CH
2、O、NH的二价基团;
每一个R
h相同或不同,彼此独立地选自卤素、CN、OH、SH、氧代(=O)、NO
2、无取代或任选被一个、两个或更多个R
g取代的下列基团:C
1-40烷基、C
2-40烯基、C
2-40炔基、C
3-40环烷基、C
3-40环烯基、C
3-40环炔基、C
6-20芳基、5-20元杂芳基、3-20元杂环基、C
1-40烷基氧基、C
2-40烯基氧基、C
2-40炔基氧基、C
3-40环烷基氧基、C
3-40环烯基氧基、C
3-40环炔基氧基、C
6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR
2R
3、-C(O)R
4、-OCR
5、-S(O)
2R
6、OS(O)
2R
7;
或者,当环状基团(包括但不限于C
3-40环烷基、C
3-40环烯基、C
3-40环炔基、3-20元杂环基等)的不同位置被两个或更多个取代基取代时,所述取代基中的两个也可以与所述环状基团形成桥环,其中所述桥环中除桥头原子之外的桥原子可以包含1、2、3、4或5个选自CH
2、O、NH的二价基团;
或者,当一个原子(如碳原子)被两个或更多个取代基取代时,所述取代基中的两个也 可以与其共同连接的原子形成环状基团(包括但不限于C
3-40环烷基、C
3-40环烯基、C
3-40环炔基、3-20元杂环基等)。
根据本发明的实施方案,X
1、X
2、X
3、X
4、X
5、X
6、X
7相同或不同,彼此独立地选自CR
1或N;例如,X
1,X
2,X
3,X
4、X
5、X
6、X
7中的至少一个为N,例如1、2、3、4、5、6或7个为N;
根据本发明的实施方案,X
8选自CR
1R
1’或NR
1;
根据本发明的实施方案,每一个R
1和R
1’相同或不同,彼此独立地选自H、卤素、CN、OH、C
1-6烷基、C
3-10环烷基、C
1-6烷基氧基;
根据本发明的实施方案,A选自H、卤素、CN、OH、C
1-6烷基、C
1-6烷基氧基;
根据本发明的实施方案,D、E相同或不同,彼此独立地选自H、卤素、CN、NH
2或-O-R
21,条件是D和E中的至少一个选自-O-R
21;
根据本发明的实施方案,R
2选自无取代或任选被一个、两个或更多个被R
d取代的C
1-6烷基;
根据本发明的实施方案,每一个R
a、R
b、R
c、R
d、R
e、R
f相同或不同,彼此独立地选自卤素、CN、OH,无取代或任选被一个、两个或更多个R
g取代的下列基团:C
1-6烷基、C
1-6烷基氧基、C
3-10环烷基、C
3-10环烷基氧基;
根据本发明的实施方案,每一个R
g相同或不同,彼此独立地选自卤素或C
3-10环烷基;
根据本发明的实施方案,G选自C
3-10环烷基、C
6-14芳基、5-14元杂芳基、3-10元杂环基,例如6-7元具有单环、双环、桥环结构的杂环基,其可包含1、2、3个独立选自N、O和S的杂原子;
根据本发明的实施方案,K选自-C
1-6烷基-C
3-10环烷基、-C
1-6烷基-C
6-14芳基、-C
1-6烷基-5-14元杂芳基、-C
1-6烷基-3-10元杂环基、-C(O)NH
2、-C(O)-C
3-10环烷基、-C(O)-C
6-14芳基、-C(O)-5-14元杂芳基、-C(O)-3-10元杂环基、-C(O)-C
1-6烷基-C
3-10环烷基、-C(O)-C
1-6烷基-C
6-14芳基、-C(O)-C
1-6烷基-5-14元杂芳基、-C(O)-C
1-6烷基-3-10元杂环基,其中所述C
3-10环烷基、C
6-14芳基、5-14元杂芳基、3-10元杂环基、-C(O)-C
3-10环烷基、-C(O)-C
6-14芳基、-C(O)-5-14元杂芳基、-C(O)-3-10元杂环基、-C(O)-C
1-6烷基-C
3-10环烷基、-C(O)-C
1-6烷基-C
6-14芳基、-C(O)-C
1-6烷基-5-14元杂芳基、-C(O)-C
1-6烷基-3-10元杂环基的环上或非环基团,或-C(O)NH
2还任选被一个、两个或更多个选自OH、卤素、CN、C
1-6烷基、C
1-6烷基氧基的基团取代;其中,所述杂环基可以为吡啶基(例如吡啶-2-基、吡啶-3-基、吡啶-4-基、吡啶-5-基、吡啶-6-基),芳基可以为苯基。
根据本发明示例性的实施方案,其中X
1、X
2、X
3、X
4、X
5、X
6、X
7相同或不同,彼此独立地选自CH或N;例如,X
1,X
2,X
3,X
4、X
5、X
6、X
7中的至少一个为N,例如1、2、3、4、5、6或7个为N;
根据本发明示例性的实施方案,X
8选自NR
1;
根据本发明示例性的实施方案,R
1为H;
根据本发明示例性的实施方案,A选自H、NH
2、甲基、乙基、丙基、异丙基;
根据本发明示例性的实施方案,E为H;
根据本发明示例性的实施方案,D选自如下基团:卤素、BnO-、H、CN、NH
2、OCH
3、
根据本发明的实施方案,所述化合物具有下式所示的结构:
其中,X
1、X
2、X
3、X
4、X
5、A、D、E、G、K具有上文所述的定义。
作为实例,式I化合物选自如下化合物,
本发明还提供式I所示化合物的制备方法,包括如下步骤:
式I-1化合物与化合物R
21-L反应得到式I化合物,
其中,A、D、E、G、K、X
1、X
2、X
3、X
4、X
5、X
6、X
7、X
8、R
21具有如上所述的定义;L选自离去基团。
根据本发明的实施方案,所述离去基团选自卤素或OTf。
根据本发明的实施方案,所述反应在碱的存在下进行,例如在碳酸钾的存在下进行。
根据本发明的实施方案,所述反应的温度为50~100℃,反应时间为1~24小时。
根据本发明的实施方案,所述反应可以在有机溶剂(如DMF)的存在下进行。
本发明还提供式I-1化合物的制备方法,包括由式I-2化合物反应制备式I-1化合物:
其中,A、D、E、G、K、X
1、X
2、X
3、X
4、X
5、X
6、X
7、X
8具有如上所述的定义。
根据本发明的实施方案,所述反应在水合肼的存在下进行,且X
7为N,X
8为NH。
根据本发明的实施方案,所述反应在有机溶剂(如DMF)的存在下进行。
根据本发明的实施方案,所述反应在加热条件下进行。
本发明还提供式I-1或式I-2所示的化合物:
本发明还提供式I-1或式I-2所示的化合物用于制备式I所示化合物的用途。
本发明还提供一种药物组合物,其包含治疗有效量的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物或药学上可接受的盐中的至少一种。
根据本发明的实施方案,所述药物组合物还包括一种、两种或多种药学上可接受的载体或赋形剂。
根据本发明的实施方案,所述药物组合物还进一步含有一种或多种额外的治疗剂。
本发明还提供体外或体内抑制细胞增殖的方法,所述方法包括使细胞与有效量的本发明所述式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、或药学上可接受的盐,或其药物组合物接触。
本发明还提供一种治疗RET激酶介导的疾病的方法,包括给予患者治疗有效量的如式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物或药学上可接受的盐中的至少一种。
本发明还提供了在有治疗需要的患者中治疗RET相关疾病或病症的方法,所述方法包括向所述患者施用治疗有效量的本发明式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物或药学上可接受的盐或其药物组合物。
本发明还提供了在有治疗需要的患者中治疗癌症和/或抑制与特定癌症相关的转移的方法,所述方法包括向所述患者施用治疗有效量的本发明式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物或药学上可接受的盐或其药物组合物。
本发明还提供了在有治疗需要的患者中治疗肠易激综合征(IBS)和/或与IBS相关的疼痛的方法,所述方法包括向所述患者施用治疗有效量的本发明式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物或药学上可接受的盐或其药物组合物。
本发明还提供了为癌症患者提供支持护理的方法,包括预防或最小化与治疗(包括化疗治疗)相关的胃肠疾病(例如腹泻),所述方法包括给予患者治疗有效量的本发明式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物或药学上可接受的盐或其药物组合物。
本发明还提供式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、或药学上可接受的盐中的至少一种在制备用于治疗RET激酶介导的疾病的药物中的用途。
本发明还提供式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、或药学上可接受的盐中的至少一种在制备用于治疗癌症和/或抑制与特定癌症相关 的转移的药物中的用途。
本发明还提供式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、或药学上可接受的盐中的至少一种在制备用于治疗肠易激综合征(IBS)或与IBS相关的疼痛的药物中的用途。
本发明还提供式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、或药学上可接受的盐中的至少一种在制备用于向癌症患者提供支持护理的药物中的用途,所述支持护理包括预防或最小化与治疗(包括化疗治疗)相关的胃肠病症,例如腹泻。
本发明还提供式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、或药学上可接受的盐中的至少一种在制备用于抑制RET激酶活性的药物中的用途。
本发明还提供式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、或药学上可接受的盐中的至少一种在制备用于治疗RET相关疾病或病症的药物中的用途。
本发明还提供用于在有需要的患者中治疗癌症的方法,所述方法包括(a)确定所述癌症是否与下述的失调有关:RET基因、RET激酶、或其中任何一者的表达或活性或水平(例如,RET相关的癌症);(b)如果确定所述癌症与下述的失调有关:RET基因、RET激酶、或其中任何一者的表达或活性或水平(例如,RET相关的癌症),向患者施用治疗有效量的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、或药学上可接受的盐中的至少一种,或其药物组合物。
本发明还提供了用于逆转或预防对抗癌药物的获得性抗性的方法,所述方法包括将治疗有效量的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、或药学上可接受的盐中的至少一种给予处于对抗癌药物发展或具有获得性抗性的风险的患者。
本发明还提供延迟和/或预防个体中抗癌药抗药性发展的方法,所述方法包括在个体中施用有效量的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、或药学上可接受的盐中的至少一种,在此之前、期间或之后施用有效量的抗癌药物。
本发明还提供了治疗患有癌症且对抗癌药物发展抗性的可能性增加的个体的方法,其包括对个体伴随施用(a)有效量的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、或药学上可接受的盐中的至少一种;和(b)有效量的抗癌药物。
本发明还提供了治疗患有RET相关癌症的个体的方法,所述癌症具有一种或多种RET抑制剂抗性突变,所述RET抑制剂抗性突变增加所述癌症对不是式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、或药学上可接受的盐中的至少一种的RET抑制剂的抗性(例如,在氨基酸位置804,810,904处的取代,例如V804M、V804L、V804E、G810R、G810S、G810C、G810V、S904F),其包括在给予另一种其他的抗癌药物之前、期间或之后,给予式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、或药学上可接受的盐中的至少一种。
本发明还提供了治疗患有RET相关癌症的个体的方法,所述方法包括在给予另一种其他的抗癌药物之前、期间或之后,给予式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、或药学上可接受的盐中的至少一种。
本发明提供了在有需要的患者中治疗癌症(例如RET相关癌症)的方法,所述方法包括向所述患者施用治疗有效量的通式I的化合物或其或药学上可接受的盐中的至少一种或其药物组合物。
术语定义与说明
除非另有说明,本申请说明书和权利要求书中记载的基团和术语定义,包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等,可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构,应当属于本申请说明书记载的范围内。
除非另有说明,本说明书和权利要求书记载的数值范围相当于至少记载了其中每一个具体的整数数值。例如,数值范围“1-40”相当于记载了数值范围“1-10”中的每一个整数数值即1、2、3、4、5、6、7、8、9、10,以及数值范围“11-40”中的每一个整数数值即11、12、13、14、15、......、35、36、37、38、39、40。应当理解,本文在描述取代基时使用的一个、两个或更多个中,“更多个”应当是指≥3的整数,例如3、4、5、6、7、8、9或10。
术语“卤素”表示氟、氯、溴和碘。
术语“C
1-40烷基”应理解为优选表示具有1~40个碳原子的直链或支链饱和一价烃基。例如,“C
1-6烷基”表示具有1、2、3、4、5或6个碳原子的直链和支链烷基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。
术语“C
2-40烯基”应理解为优选表示直连或支链的一价烃基,其包含一个或多个双键并且具有2~40个碳原子,优选“C
2-6烯基”。“C
2-6烯基”应理解为优选表示直连或支链的一价烃基,其包含一个或多个双键并且具有2、3、4、5或6个碳原子,特别是2或3个碳原子(“C
2-3烯基”),应理解,在所述烯基包含多于一个双键的情况下,所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。
术语“C
2-
40炔基”应理解为表示直连或支链的一价烃基,其包含一个或多个三键并且具有2~40个碳原子,优选“C
2-C
6-炔基”。术语“C
2-C
6-炔基”应理解为优选表示直连或支链的一价烃基,其包含一个或多个三键并且具有2、3、4、5或6个碳原子,特别是2或3个碳原子(“C
2-C
3-炔基”)。所述C
2-C
6-炔基是例如乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基、戊-1-炔基、戊-2-炔基、戊-3-炔基、戊-4-炔基、己-1-炔基、己-2-炔基、己-3-炔基、己-4-炔基、己-5-炔基、1-甲基丙-2-炔基、2-甲基丁-3-炔基、1-甲基丁-3-炔基、1-甲基丁-2-炔基、3-甲基丁-1-炔基、1-乙基丙-2-炔基、3-甲基戊-4-炔基、2-甲基戊-4-炔基、1-甲基戊-4-炔基、2-甲基戊-3-炔基、1-甲基戊-3-炔基、4-甲基戊-2-炔基、1-甲基戊-2-炔基、4-甲基戊-1-炔基、3-甲基戊-1-炔基、2-乙基丁-3-炔基、1-乙基丁-3-炔基、1-乙基丁-2-炔基、1-丙基丙-2-炔基、1-异丙基丙-2-炔基、2,2-二甲基丁-3-炔基、1,1-二甲基丁-3-炔基、1,1-二甲基丁-2-炔基或3,3- 二甲基丁-1-炔基。特别地,所述炔基是乙炔基、丙-1-炔基或丙-2-炔基。
术语“C
3-40环烷基”应理解为表示饱和的一价单环、双环烃环或桥环烷烃,其具有3~40个碳原子,优选“C
3-10环烷基”。术语“C
3-10环烷基”应理解为表示饱和的一价单环、双环烃环或桥环烷烃,其具有3、4、5、6、7、8、9或10个碳原子。所述C
3-10环烷基可以是单环烃基,如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基,或者是双环烃基如十氢化萘环。
术语“3-20元杂环基”意指饱和的一价单环、双环烃环或桥环烷烃,其包含1-5个独立选自N、O和S的杂原子的总成环原子数为3-20(如原子数为3、4、5、6、7、8、9、10等)的非芳族环状基团,优选“3-10元杂环基”。术语“3-10元杂环基”意指饱和的一价单环、双环烃环或桥环烷烃,其包含1-5个,优选1-3个独立选自N、O和S的杂原子,例如1、2、3个独立选自N、O和S的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地,所述杂环基可以包括但不限于:4元环,如氮杂环丁烷基、氧杂环丁烷基;5元环,如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基;或6元环,如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基;或7元环,如二氮杂环庚烷基。任选地,所述杂环基可以是苯并稠合的。所述杂环基可以是双环的,例如但不限于5,5元环,如六氢环戊并[c]吡咯-2(1H)-基环,或者5,6元双环,如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的,即它可以包含一个或多个双键,例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢恶唑基或4H-[1,4]噻嗪基,或者,它可以是苯并稠合的,例如但不限于二氢异喹啉基。根据本发明,所述杂环基是无芳香性的。所述3-20元杂环基与其它基团相连构成本发明的化合物时,可以为3-20元杂环基上的碳原子与其它基团相连,也可以为3-20元杂环基环上杂环原子与其它基团相连。例如当3-20元杂环基选自哌嗪基时,可以为哌嗪基上的氮原子与其它基团相连。或当3-20元杂环基选自哌啶基时,可以为哌啶基环上的氮原子和其对位上的碳原子与其它基团相连。
术语“C
6-20芳基”应理解为优选表示具有6~20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环,优选“C
6-14芳基”。术语“C
6-14芳基”应理解为优选表示具有6、7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C
6-14芳基”),特别是具有6个碳原子的环(“C
6芳基”),例如苯基;或联苯基,或者是具有9个碳原子的环(“C
9芳基”),例如茚满基或茚基,或者是具有10个碳原子的环(“C
10芳基”),例如四氢化萘基、二氢萘基或萘基,或者是具有13个碳原子的环(“C
13芳基”),例如芴基,或者是具有14个碳原子的环(“C
14芳基”),例如蒽基。当所述C
6-20芳基被取代时,其可以为单取代或者多取代。并且,对其取代位点没有限制,例如可以为邻位、对位或间位取代。
术语“5-20元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系:其具有5~20个环原子且包含1-5个独立选自N、O和S的杂原子,例如“5-14元杂芳基”。术语“5-14元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系:其具有5、6、7、8、9、10、11、12、13或14个环原子,特别是5或6或9或10个碳原子,且其包含1-5个,优选1-3各独立选自N、O和S的杂原子并且,另外在每一种情况下可为苯并稠合的。特别地,杂芳基选自噻吩基、呋喃基、吡咯基、恶唑基、噻唑基、咪唑基、吡唑基、异恶唑基、异噻唑基、恶二唑基、三唑基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物,例如苯并呋喃基、苯并噻吩基、苯并恶唑基、苯并异恶唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等;或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等,以及它们的苯并衍生物,例如喹 啉基、喹唑啉基、异喹啉基等;或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物;或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩恶嗪基等。当所述5-20元杂芳基与其它基团相连构成本发明的化合物时,可以为5-20元杂芳基环上的碳原子与其它基团相连,也可以为5-20元杂芳基环上的杂原子与其它基团相连。当所述5-20元杂芳基被取代时,其可以为单取代或者多取代。并且,对其取代位点没有限制,例如可以为杂芳基环上与碳原子相连的氢被取代,或者杂芳基环上与杂原子相连的氢被取代。
除非另有说明,杂环基、杂芳基或亚杂芳基包括其所有可能的异构形式,例如其位置异构体。因此,对于一些说明性的非限制性实例,可以包括在其1-、2-、3-、4-、5-、6-、7-、8-、9-、10-、11-、12-位等(如果存在)中的一个、两个或更多个位置上取代或与其他基团键合的形式,包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基;噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基;吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基。
术语“氧代”是指取代基中的碳原子、氮原子或硫原子被氧化后形成的氧基取代(=O)。
除非另有说明,本文中术语的定义同样适用于包含该术语的基团,例如C
1-6烷基的定义也适用于C
1-6烷基氧基、-N(C
1-6烷基)
2、-NHC
1-6烷基或-S(O)
2-C
1-6烷基等。
本领域技术人员可以理解,式I所示化合物可以以各种药学上可接受的盐的形式存在。如果这些化合物具有碱性中心,则其可以形成酸加成盐;如果这些化合物具有酸性中心,则其可以形成碱加成盐;如果这些化合物既包含酸性中心(例如羧基)又包含碱性中心(例如氨基),则其还可以形成内盐。
本发明的化合物可以溶剂合物(如水合物)的形式存在,其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂,特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
根据其分子结构,本发明的化合物可以是手性的,因此可能存在各种对映异构体形式。因而这些化合物可以以消旋体形式或光学活性形式存在。本发明的化合物或其中间体可以通过本领域技术人员公知的化学或物理方法分离为对映异构体化合物,或者以此形式用于合成。在外消旋的胺的情况中,通过与光学活性的拆分试剂反应,从混合物制得非对映异构体。适当的拆分试剂的示例是光学活性的酸,例如R和S形式的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳酸、适当的N-保护的氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰基脯氨酸)或各种光学活性的樟脑磺酸。借助光学活性的拆分试剂(例如固定在硅胶上的二硝基苯甲酰基苯基甘氨酸、三乙酸纤维素或其它碳水化合物的衍生物或手性衍生化的异丁烯酸酯聚合物),也可有利地进行色谱对映体拆分。用于此目的的适当的洗脱剂是含水或含醇的溶剂混合物,例如,己烷/异丙醇/乙腈。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在,尝试分离单一互变异构体时通常产生一种混合物,其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如,在很多脂族醛和酮如乙醛中,酮型占优势;而在酚中,烯醇型占优势。本发明包含化合物的所有互变异构形式。
可以根据已知的方法,例如通过萃取、过滤或柱层析来分离相应的稳定异构体。
术语“患者”是指包括哺乳动物在内的任何动物,优选小鼠、大鼠、其它啮齿类动物、兔、 狗、猫、猪、牛、羊、马或灵长类动物,最优选人。
本文中使用的短语“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、系统、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量,它包括以下一项或多项:(1)预防疾病:例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病:例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病:例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。
图1是化合物对TT细胞人源甲状腺髓样癌异种移植模型肿瘤的抑制作用;
图2化合物对Ba/F3细胞KIF5B-RET-V804M融合异种移植模型肿瘤的抑制作用。
本发明的化合物可以作为一种高度选择性和/或非常有效的RET抑制剂,此类化合物对RET看门残基突变体RET V804M,RET溶剂前沿残基突变体G810R和其他临床相关RET突变体以及wt-RET均有较强的抑制作用。该化合物还能显著抑制甲状腺癌来源的TT细胞系和各种RET突变体转化的Ba/F3细胞的生长,且抑制作用良好。此外,该化合物很大程度上阻断细胞RET自磷酸化及其下游通路,并能显著诱导TT细胞死亡。此外,本发明的代表性实施例化合物还具有特别优异的药代动力学性质,作为活性成分时可以较小的剂量给患者施用,从而降低患者的治疗成本。
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
实施例1
6-(2-甲氧基乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-3-氨基(化合物1)
步骤A:2-氟-6-羟基-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,,6-二氮杂[3.1.1]庚烷-3-基)吡啶-3-基)吡唑[1,5-a]吡啶-3-甲醛肟
向2-氟-6-羟基-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,,6-二氮杂[3.1.1]庚烷-3-基)吡啶-3-基)吡唑[1,5-a]吡啶-3-甲醛(100mg,0.21mmol)的乙醇(5.0mL)溶液中加入盐酸羟胺(15mg, 0.21mmol),加热回流12h,直接浓缩用于下步反应。
步骤B:2-氟-6-羟基-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-3-乙腈
将醋酸酐(5.0mL)加入步骤A得到的2-氟-6-羟基-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,,6-二氮杂[3.1.1]庚烷-3-基)吡啶-3-基)吡唑[1,5-a]吡啶-3-甲醛肟中,加热80℃反应2h。反应液倒入冰水中,搅拌30分钟,过滤得固体经柱层析分离得到产品(31mg)。m/z=472[M+1]
+。
步骤C:2-氟-6-(2-甲氧基乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-3-乙腈
向2-氟-6-羟基-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-3-乙腈(30mg,0.06mmol)的DMF(2.0mL)溶液中加入2-溴乙基甲基醚(9mg,0.06mmol),碳酸钾(8.3mg,0.06mmol),加热至80℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(28mg)。
1HNMR(400MHz,DMSO-d
6)δ8.65(d,1H),8.42(d,1H),8.07(d,1H),7.87(d,1H),7.70(d,1H),7.45(d,1H),6.76-6.81(m,2H),4.23-4.25(m,2H),3.82(s,3H),3.67-3.71(m,7H),3.49-3.51(m,5H),2.51(d,1H),1.61(d,1H),1.23(s,1H).m/z=530[M+1]
+。
步骤C:6-(2-甲氧基乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-3-氨基
向2-氟-6-(2-甲氧基乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-3-乙腈(20mg,0.04mmol)的DMF(2.0mL)溶液中加入水合肼(0.2mL),加热至100℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,反相柱层析分离得到产品三氟乙酸盐(3.3mg)。
1HNMR(400MHz,DMSO-d
6)δ10.51(brs,2H),9.56(s,1H),9.37(s,1H),8.38-8.49(m,3H),7.86-7.89(m,2H),7.32(d,1H),6.92-6.94(m,1H),6.80(d,1H),4.64(m,3H), 4.46(d,2H),4.22-4.25(m,4H),3.87-3.90(m,5H),3.70(s,2H),3.32(s,3H),2.09-2.10(m,1H).m/z=542[M+1]
+。
实施例2
6-溴-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物2)
步骤A:4-(苄氧基)-6-溴-2-氟吡唑[1,5-a]吡啶-3-甲醛
零度下,向装有4-(苄氧基)-6-溴-2-氟吡唑[1,5-a]吡啶(380mg,1.2mmol)的DMF(10mL)溶液中滴加入三氯氧磷(1.0g,6.5mmol),滴完后自然升至室温反应过夜。将反应液倒入100mL冰水中,用2N NaOH溶液调节pH=7,用乙酸乙酯萃取,合并有机相,减压浓缩,柱层析分离得到产品(400mg)。m/z=350[M+1]
+。
步骤B:6-溴-2-氟-4-羟基吡唑[1,5-a]吡啶-3-甲醛
室温下,向4-(苄氧基)-6-溴-2-氟吡唑[1,5-a]吡啶-3-甲醛(100mg,0.28mmol)和钯碳(10mg)中加入甲醇(10.0mL),用氢气球置换氢气三次,室温反应过夜。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品,m/z=259[M+1]
+。
1HNMR(400MHz,DMSO-d
6)δ11.96(s,1H),10.03(s,1H),8.76(d,1H),7.13(d,1H).
步骤C:6-溴-2-氟-3-甲醛吡唑[1,5-a]吡啶-4-基三氟乙基磺酸酯
向6-溴-2-氟-4-羟基吡唑[1,5-a]吡啶-3-甲醛(52mg,0.2mmol)的DMF(5ml)溶液中加入N-苯基双(三氟甲烷磺酸亚胺)(71mg,0.2mmol),二异丙基乙基胺(78mg,0.6mmol)室温反应12h,加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(85mg),m/z=392[M+1]
+。
步骤D:6-溴-2-氟-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)吡唑[1,5-a]吡啶-3-甲醛
操作同实施例7步骤F得到产品(10mg)。m/z=537[M+1]
+。
步骤E:6-溴-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3- 基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶
操作同实施例7步骤H,得产品(5.4mg)。m/z=531[M+1]
+。
1H NMR(400MHz,DMSO-d
6)δ12.96(s,1H),9.67(d,1H),8.717(d,1H),8.12-8.13(m,2H),7.87-7.88(m,2H),7.74(dd,1H),6.92(d,1H),6.71(d,1H),3.74-3.88(m,5H),3.72(d,2H),3.48(s,2H),3.34(s,2H),2.49(d,1H),1.58(d,1H).
实施例3
6-(苄氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物3)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入苄氯(38mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至60℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(35mg)。m/z=559[M+1]
+。
1H NMR(400MHz,DMSO-d
6)δ12.65(s,1H),8.60-8.63(dd,2H),8.08-8.10(m,2H),7.69(dd,1H),7.67(s,1H),7.51-7.53(m,2H),7.40-7.44(m,2H),7.34-7.37(m,2H),6.91(d,1H),6.77(d,1H),5.25(s,2H),3.74-3.80(m,5H),3.68(brs,2H),3.51-3.58(m,4H),2.51(d,1H),1.58(d,1H).
实施例4
4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物4)
向6-溴-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(30mg,0.056mmol)的四氢呋喃溶液中加入钯碳(3mg),1个大气压氢气室温反应,过滤,减压浓缩,柱层析分离得到产品(1.6mg)。m/z=453[M+1]
+。
1H NMR(400MHz,DMSO-d
6)δ12.71(s,1H),8.81(d,1H),8.64(d,1H),8.11(d,2H),7.70(s, 2H),7.52(d,1H),7.21(m,1H),6.92(d,1H),6.79(d,1H),3.81(s,3H),3.73-3.79(m,2H),3.65-3.70(m,2H),3.55-3.62(m,2H),3.49-3.53(s,2H),2.53(d,1H),1.61(d,1H).
实施例5
4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-氰基(化合物5)
向6-溴-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(30mg,0.057mmol)的DMF(5mL)溶液中加入四三苯基磷钯(6.6mg,0.006mol),氰化锌(6.7mg,0.057mol),加热至100℃反应12小时,减压浓缩,柱层析分离得到产品(14mg),m/z=478[M+1]
+。
1H NMR(400MHz,DMSO-d
6)δ13.01(s,1H),9.66(d,1H),8.67(d,1H),8.10-8.15(m,2H),7.81-7.82(m,2H),7.72(dd,1H),6.95(d,1H),6.79(d,1H),3.77-3.83(m,5H),3.70(d,2H),3.53(s,2H),3.33(s,2H),2.52(d,1H),1.61(d,1H).
实施例6
4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-氨基(化合物6)
步骤A:6-((二苯基亚甲基)氨基)-2-氟-4-(6-((6-甲氧吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑[1,5-a]吡啶-3-甲醛
向6-溴-2-氟-4-(6-((6-甲氧吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑[1,5-a]吡啶-3-甲醛(180mg,0.34mmol)的二氧六环溶液(30ml)中加入二苯甲酮亚胺(60mg,0.34mmol),三(二亚苄基丙酮)二钯氯仿(5.1mg,0.005mmol),Xantphos(11mg,0.005mmol),碳酸铯(330mg,1.0mmol),加热100℃反应12小时,减压浓缩,柱层析分离得到产品(130mg),m/z=638[M+1]
+。
步骤B:6-氨基-2-氟-4-(6-((6-甲氧吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑[1,5-a]吡啶-3-甲醛
向6-((二苯基亚甲基)氨基)-2-氟-4-(6-((6-甲氧吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑[1,5-a]吡啶-3-甲醛(30mg,0.05mmol)的四氢呋喃(3ml)溶液中,加入3N盐酸(2ml),室温搅拌12h,减压浓缩,柱层析分离得到产品(22mg),m/z=474[M+1]
+。步骤C:4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-氨基
操作同实施例7步骤H,得目标产品(2.7mg),m/z=468[M+1]
+。
1H NMR(400MHz,DMSO-d
6)δ12.43(s,1H),8.56(d,1H),8.11(d,1H),8.03(m,2H),7.69-7.72(m,1H),7.50(s,1H),7.01(s,1H),6.92(d,1H),6.79(d,1H),5.24(s,2H),3.75-3.83(m,5H),3.70(d,2H),3.53(m,4H),2.51(d,1H),1.61(d,1H).
实施例7
6-(2-甲氧基乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物7)
步骤A:叔丁基((甲磺酰基)氧基)氨基甲酸酯
冰浴搅拌下向盛有2,4,6-三甲基苯磺酰氯(20.0g,91.5mmol)和N-羟基氨基甲酸叔丁酯(12.2g,91.5mmol)的甲基叔丁基醚(500mL)溶液中,恒压滴液漏斗缓慢滴加三乙胺(13.0mL,93.3mmol),滴加过程中保持反应体系温度小于5℃。在冰浴下,反应体系搅拌4.0小时,减压过滤移去三乙胺盐酸盐,并用甲基叔丁基醚冲洗三次,所有滤液在小于15℃水浴温度下减压浓缩除去大部分甲基叔丁基醚;在冰浴下,向浓缩的残留物中加入正己烷,强烈搅拌10分钟,析出大量白色固体,减压过滤,滤饼用正己烷冲洗两次,真空干燥得到产品(26.1g)。m/z=316[M+1]
+。
步骤B:2-[(氨基氧基)磺酰]-1,3,5-三甲基苯
零度下,向三氟乙酸(80mL)中分批次加入叔丁基((甲磺酰基)氧基)氨基甲酸酯(10.0g,31.7mmol)。完毕后,反应体系在零度下继续搅拌3小时;TLC点板确认反应完毕,将反应体系倒入大量的冰水中,并搅拌15分钟,析出大量白色固体,减压过滤,大量水洗涤滤饼直到固体pH值为中性,减压抽滤至固体含水量20%左右即可,无须再次纯化,直接用于下一步反应。
步骤C:2,4,6-三甲基苯磺酸1-氨基-3-溴-5-苯甲氧基吡啶-1-鎓
零度下,向2-[(氨基氧基)磺酰]-1,3,5-三甲基苯(6.8g,31.7mmol)的二氯甲烷(50mL)溶液中加入3-溴-5-苯甲氧基吡啶(6.0g,32.0mmol),并在零度下继续搅拌3小时,析出大量白色固体;反应完毕后,零度下向反应体系中加入乙醚(50mL)并搅拌10分钟,减压过滤,乙醚冲洗,真空干燥得到产品(15g),无须再次纯化,直接用于下一步反应。m/z=281[M+1]
+。
步骤D:6-(苄氧基)-4-溴-2-氟吡唑[1,5-a]吡啶和4-(苄氧基)-6-溴-2-氟吡唑[1,5-a]吡啶
室温下,向装有2,4,6-三甲基苯磺酸1-氨基-3-溴-5-苯甲氧基吡啶-1-鎓(1.0g,2.3mmol)的DMF(30mL)溶液中加入碳酸钾(1.4g,10.0mmol);反应体系冷却至0℃,分批次加入对甲苯磺酸2,2-二氟乙烯基酯(0.5g,2.3mmol),升至室温下搅拌1小时,再90℃下搅拌1小时;反应完毕并冷却至室温,加水淬灭,用乙酸乙酯萃取,合并有机相,并用水洗涤,减压浓缩,柱层析分离得到6-(苄氧基)-4-溴-2-氟吡唑[1,5-a]吡啶(118mg),
1HNMR(400MHz,CDCl
3)δ7.90(s,1H),7.34-7.44(m,5H),7.32(s,1H),6.08(d,1H),5.02(s,2H),m/z=322[M+1]
+,4-(苄氧基)-6-溴-2-氟吡唑[1,5-a]吡啶(280mg),
1HNMR(400MHz,CDCl
3)δ8.07(s,1H),7.80-7.82(m,5H),6.61(s,1H),6.18(d,1H),5.15(s,2H),m/z=322[M+1]
+。
步骤E:6-(苄氧基)-4-溴-2-氟吡唑[1,5-a]吡啶-3-甲醛
零度下,向装有6-(苄氧基)-4-溴-2-氟吡唑[1,5-a]吡啶(380mg,1.2mmol)的DMF(10mL)溶液中滴加入三氯氧磷(1.0g,6.5mmol),滴完后自然升至室温反应过夜。将反应液倒入100mL冰水中,用2N NaOH溶液调节pH=7,用乙酸乙酯萃取,合并有机相,减压浓缩,柱层析分离得到产品(400mg)。m/z=350[M+1]
+;
1HNMR(400MHz,DMSO-d
6)δ10.49(s,1H),8.80-8.87(m,1H),8.09(d,1H),7.45-7.58(m,2H),7.36-7.44(m,3H),5.20(s,2H).
步骤F:6-(苄氧基)-2-氟-4-(6-((6-甲氧吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑[1,5-a]吡啶-3-甲醛
向6-(苄氧基)-4-溴-2-氟吡唑[1,5-a]吡啶(23mg,0.067mmol),6-((6-甲氧基吡啶-3-基)亚甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧代环戊硼烷-2-基)吡啶-2-基)3,6-二氮杂双环[3.1.1]庚烷(28mg,0.067mmol)(参考文献WO2018/71447中的方法制备),四三苯基磷钯(15mg,0.013mol),碳酸钾(36mg,0.264mol),1,4-二氧六环(2mL),H
2O(1mL),氮气置换三次,90℃反应2小时,LCMS确认原料反应完,有产品生成。加入水,用乙酸乙酯萃取,合并有机相,并用水 洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(25mg)。m/z=565[M+1]
+。
步骤G:2-氟-6-羟基-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂[3.1.1]庚烷-3-基)吡啶-3-基)吡唑[1,5-a]吡啶-3-甲醛
室温下,向6-(苄氧基)-2-氟-4-(6-((6-甲氧吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑[1,5-a]吡啶-3-甲醛(100mg,0.18mmol)和钯碳(5mg)中加入甲醇(10.0mL),用氢气球置换氢气三次,室温反应过夜。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品。
1HNMR(400MHz,DMSO-d
6)δ10.42(s,1H),9.37(s,1H),8.32(s,1H),8.23(s,1H),8.09(s,1H),7.79(d,1H),7.70(d,1H),7.25(s,1H),6.78(t,2H),3.82(s,3H),3.64-3.75(m,4H),3.48-3.60(m,4H),2.51(d,1H),1.60(d,1H).m/z=475[M+1]
+。
步骤H:4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇
向2-氟-6-羟基-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂[3.1.1]庚烷-3-基)吡啶-3-基)吡唑[1,5-a]吡啶-3-甲醛(250mg,0.53mmol)的DMF(5.0mL)溶液中加入水合肼(0.5mL),加热至100℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(170mg)。m/z=469[M+1]
+,
1HNMR(400MHz,DMSO-d
6)δ12.59(s,1H),9.97(s,1H),8.61(s,1H),8.24(d,2H),8.06-8.11(m,2H),7.72(dd,1H),7.58(s,1H),7.15(d,1H),6.93(d,1H),6.79(d,1H),3.72-3.83(m,5H),3.69(s,2H),3.35(brs,3H),2.51(d,1H),1.61(d,1H).
步骤I:6-(2-甲氧基乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入2-溴乙基甲基醚(40mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至80℃反应12小时。加入水,用乙酸 乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(84mg)。
1HNMR(400MHz,DMSO-d
6)δ12.66(s,1H),8.65(d,1H),8.56(d,1H),8.13(m,2H),7.69-7.72(m,1H),7.63(s,1H),7.30(s,1H),6.93(d,1H),6.79(d,1H),4.26-4.28(m,2H),3.83(s,3H),3.72-3.79(m,6H),3.47-3.70(m,7H),2.51(d,1H),1.61(d,1H),m/z=527[M+1]
+。
实施例8
1-((4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-基)氧基)-2-甲基丙烷-2-醇(化合物8)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.32mmol),2-甲基环氧丙烷(350mg,4.8mmol),碳酸钾(133mg,0.96mmol)中加入DMF(5.0mL)加热至80℃反应12h。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,反相柱层析分离得到产品三氟乙酸盐(78mg).m/z=541[M+1]
+。
实施例9
6-乙氧基-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物9)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入2-碘乙烷(47mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至60℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(125mg)。
1H NMR(400MHz,DMSO-d
6)δ12.66(s,1H),8.65(d,1H),8.53(d,1H),8.10-8.12(m,2H),7.62-7.72(m,2H),7.27(s,1H),6.93(d,1H),6.79(d,1H),4.16-4.21(m,2H),3.82(s,3H),3.77(d,2H),3.67(d,2H),3.56(m,2H),3.51(s,2H),2.51(d,1H),1.61(d,1H),1.39-1.42(m,3H),m/z=497[M+1]
+。
实施例10
2-((4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-基)氧基)乙烷-1-醇(化合物10)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入碳酸乙烯酯(26mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至80℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(30mg),m/z=513[M+1]
+。
1H NMR(400MHz,DMSO-d
6)δ12.64(s,1H),8.62(d,1H),8.53(d,1H),8.09(dt,2H),7.72-7.63(m,1H),7.60(s,1H),7.26(d,1H),6.90(d,1H),6.75(dd,1H),4.96(t,1H),4.14(t,2H),3.80(s,3H),3.80-3.73(m,4H),3.67(d,2H),3.58(s,1H),3.51(s,2H),2.51(d,1H),1.57(t,1H),1.23(d,1H)。
实施例11
6-丁氧基-((4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-基)氧基)乙烷-1-醇(化合物11)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入溴丁烷(41mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至80℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(43mg),m/z=525[M+1]
+,
1H NMR(400MHz,DMSO-d
6)δ12.63(s,1H),8.63(d,1H),8.51(d,1H),8.09(dt,2H),7.68(dd,1H),7.60(s,1H),7.25(d,1H),6.89(d,1H),6.76(d,1H),4.11(t,2H),3.81(s,3H),3.80-3.79(m,2H),3.76(d,1H),3.67(d,2H),3.51(s,2H),2.51(d,1H),1.79-1.69(m,2H),1.58(d,1H),1.53-1.42(m,2H),1.22(d,1H),0.95(t,3H).
实施例12
6-(3-氟丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物12)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入1-溴-3-氟丙烷(42mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至80℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(35mg),m/z=529[M+1]
+,
1H NMR(400MHz,DMSO-d
6)δ12.65(s,1H),8.63(d,1H),8.57(d,1H),8.09(dd,1H),8.08(s,1H),7.68(dd,1H),7.61(s,1H),7.28(d,1H),6.90(d,1H),6.76(d,1H),4.71(t,1H),4.59(t,1H),4.23(t,2H),3.81(s,3H),3.80-3.72(m,2H),3.67(d,2H),3.57(s,2H),3.51(s,2H),2.51(d,1H),2.16(dt,2H),1.58(d,1H)。
实施例13
6-(4-氟丁氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物13)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入1-溴-4-氟丁烷(47mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至80℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(60mg),m/z=543[M+1]
+,
1H NMR(400MHz,DMSO-d
6)δ12.64(s,1H),8.63(d,1H),8.53(d,1H),8.13–8.05(m,2H),7.68(dd,1H),7.61(s,1H),7.27(d,1H),6.90(d,1H),6.76(d,1H),4.59(s,1H),4.47(t,1H),4.20-4.12(m,2H),3.81(s,3H),3.80-3.71(m,2H),3.67(d,2H),3.58(s,2H),3.51(s,2H),2.52(d,1H),1.87(s,2H),1.86-1.76(m,2H),1.58(d,1H).
实施例14
6-(2-氯乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物14)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入1-氯-2碘乙烷(57mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至80℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(6mg),m/z=531[M+1]
+,
1H NMR(400MHz,DMSO-d
6)δ12.67(s,1H),8.62(dd,2H),8.10(dd,1H),8.09(s,1H),7.68(dd,1H),7.63(s,1H),7.30(d,1H),6.90(d,1H),6.76(d,1H), 4.46-4.39(m,2H),4.01(dd,2H),3.81(s,3H),3.76(d,2H),3.67(d,2H),3.57(s,2H),3.51(s,2H),2.58-2.50(m,1H),1.58(d,1H)。
实施例15
6-(2-溴乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物15)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入三氟甲磺酸(2-溴乙基)酯(77mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至80℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(16mg),m/z=575[M+1]
+,
1H NMR(400MHz,DMSO-d
6)δ12.68(s,1H),8.61-8.67(dd,2H),8.11-8.15(m,2H),7.71(d,1H),7.64(s,1H),7.32(d,1H),6.93(d,1H),6.80(d,1H),4.53(t,2H),3.87-3.90(m,2H),3.53-3.82(m,11H),2.51(d,1H),1.51-1.62(m,1H).
实施例16
6-(2-氟乙氧基)-4-(5-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡嗪-2-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物16)
步骤A:3-(5-氯吡嗪-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-碳酸叔丁酯
室温下,向250mL单口瓶中加入2-氯-5-氟吡嗪(6.9g,0.052mol),3,6-二氮杂双环[3.1.1]庚烷-6-碳酸叔丁酯(11.5g,0.058mol),加入DMSO(20mL)中,120℃下反应过夜。减压除去DMSO,加入甲醇使其溶解,冰水浴下慢慢加入饱和氢氧化钠溶液,调节pH至13左右,再搅拌2小时。减压浓缩出甲醇,二氯甲烷萃取,无水硫酸钠干燥,减压浓缩,柱层析分离得到产品(12g,74%收率)。m/z=311[M+1]
+。
步骤B:3-(5-氯吡嗪-2-基)-3,6-二氮杂双环[3.1.1]庚烷二盐酸盐
向100mL单口瓶中,加入3-(5-氯吡嗪-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-碳酸叔丁酯(5.0g,14mmol),氯化氢二氧六环溶液(15mL),室温搅拌2h,直接浓缩后用于下步反应。 m/z=211[M+1]
+。
步骤C:3-(5-氯吡嗪-2-基)-6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷
向100mL单口瓶中,加入6-甲氧基烟醛(0.21g,1.9mmol),3-(5-氯吡嗪-2-基)-3,6-二氮杂双环[3.1.1]庚烷二盐酸盐(0.4g,1.9mmol),醋酸硼氢化钠(1.2g,5.8mmol),二氯甲烷20mL,室温搅拌12小时。TLC点板反应完毕,加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品3-(5-氯吡嗪-2-基)-6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷(0.5g,收率80%)。m/z=332[M+1]
+。
1HNMR(400MHz,DMSO-d
6)δ8.25(d,1H),8.09(s,1H),7.99(d,1H),7.69(dd,1H),6.78(d,1H),3.83(s,3H),3.71(m,4H),3.51(m,4H),2.51(d,1H),1.59(d,1H).
步骤D:6-((6-甲氧基吡啶-3-基)甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡嗪-2-基)-3,6-二氮杂双环[3.1.1]庚烷
向10mL封管中,加入3-(5-氯吡嗪-2-基)-6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷(44mg,0.132mmol),双联频哪醇硼酸酯(50mg,0.198mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(10mg,0.013mmol),醋酸钾(39mg,0.396mmol),1,4-二氧六环(20mL),氮气置换三次,100℃反应3小时,无须后处理,直接进行下一步反应。
步骤E:6-(苄氧基)-2-氟-4-(5-(6-((6-甲氧吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)吡唑[1,5-a]吡啶-3-甲醛
向6-(苄氧基)-4-溴-2-氟吡唑[1,5-a]吡啶(23mg,0.067mmol),6-((6-甲氧基吡啶-3-基)甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡嗪-2-基)-3,6-二氮杂双环[3.1.1]庚烷(28mg,0.067mmol),四三苯基磷钯(15mg,0.013mol),碳酸钾(36mg,0.264mol),1,4-二氧六环(2mL),H
2O(1mL),氮气置换三次,90℃反应2小时,LCMS确认原料反应完,有产品生成。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(20mg)。m/z=566[M+1]
+。
步骤F:2-氟-6-羟基-4-(5-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂[3.1.1]庚烷-3-基)吡嗪-2-基)吡唑[1,5-a]吡啶-3-甲醛
室温下,向6-(苄氧基)-2-氟-4-(5-(6-((6-甲氧吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)吡唑[1,5-a]吡啶-3-甲醛(100mg,0.18mmol)和钯碳(5mg)中加入甲醇(10.0mL),用氢气球置换氢气三次,室温反应过夜。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品,m/z=476[M+1]
+。
步骤G:4-(5-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇
向2-氟-6-羟基-4-(5-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂[3.1.1]庚烷-3-基)吡嗪-2-基)吡唑[1,5-a]吡啶-3-甲醛(250mg,0.53mmol)的DMF(5.0mL)溶液中加入水合肼(0.5mL),加热至100℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(75mg),m/z=470[M+1]
+。
步骤H:6-(2-氟乙氧基)-4-(5-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡嗪-2-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶
向4-(5-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入1-氟-2-碘乙基(52mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至80℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(34mg),m/z=516[M+1]
+,H NMR(400MHz,DMSO-d
6)δ12.51(s,1H),8.99(s,1H),8.64(d,1H),8.55(s,1H),8.05-8.13(m,2H),7.80(d,1H),7.72(dd,1H),6.79(d,1H),4.90(dd,1H),4.77(d,1H),4.49(dd,2H),3.83-3.87(m,5H),3.65-3.71(m,4H),3.56(s,2H),2.56(d,1H),1.62(d,1H).
实施例17
(2S)-2-(((4-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-基)氧基)甲基)吗啉(化合物17)
向4-(5-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入(2S)-2-(溴甲基)-4-吗啉羧酸叔丁酯(82mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至80℃反应12小时。加入氯化氢二氧六环溶液(1.5mL,4.0M)继续反应2h。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(4.2mg),m/z=567[M+1]
+,
1H NMR(400MHz,DMSO-d
6):12.65(s,1H),8.65(s,1H),8.54(s,1H),8.10-8.12(m,2H),7.63-7.72(m,2H),7.30(s,1H),6.90(d,1H),6.76(d,1H),4.10(d,2H),3.76-3.83(m,8H),3.64-3.72(m,3H),3.48-3.63(m,6H),2.58-2.76(m,2H),1.58-1.61(m,1H)。
实施例18
N,N-二乙基-4-(5-(6-(2-氟乙氧基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-4-基)吡啶-2-基)哌嗪-1-甲酰胺(化合物18)
步骤A:4-(5-(6-(苄氧基)-2-氟-3-甲醛吡唑[1,5-a]吡啶-4-基)吡啶-2-基)哌嗪-1-碳酸叔丁酯
向6-(苄氧基)-4-溴-2-氟吡唑[1,5-a]吡啶(23mg,0.067mmol),4-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-2-基)哌嗪-1-碳酸叔丁酯(26mg,0.067mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(10mg,0.013mmol),碳酸钾(36mg,0.264mol),1,4-二氧六环(2mL),H
2O(1mL),氮气置换三次,90℃反应2小时,LCMS确认原料反应完,有产品生成。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(18mg),m/z=532[M+1]
+。
步骤B:4-(5-(2-氟-3-甲醛-6-羟基吡唑[1,5-a]吡啶-4-基)吡啶-2-基)哌嗪-1-碳酸叔丁酯
室温下,向4-(5-(6-(苄氧基)-2-氟-3-甲醛吡唑[1,5-a]吡啶-4-基)吡啶-2-基)哌嗪-1-碳酸叔丁酯(96mg,0.18mmol)和钯碳(5mg)中加入甲醇(10.0mL),用氢气球置换氢气三次,室温反应过夜。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品,m/z=442[M+1]
+。
步骤C:4-(5-(6-羟基-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-4-基)吡啶-2-基)哌嗪-1-碳酸叔丁酯
向4-(5-(2-氟-3-甲醛-6-羟基吡唑[1,5-a]吡啶-4-基)吡啶-2-基)哌嗪-1-碳酸叔丁酯(234mg,0.53mmol)的DMF(5.0mL)溶液中加入水合肼(0.5mL),加热至100℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(82mg),m/z=436[M+1]
+。
步骤D:4-(5-(6-(2-氟乙氧基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-4-基)吡啶-2-基)哌嗪-1-碳酸叔丁酯
向4-(5-(6-羟基-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-4-基)吡啶-2-基)哌嗪-1-碳酸叔丁酯(130mg,0.3mmol)的DMF(10.0mL)溶液中加入1-氟-2-碘乙基(52mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至80℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(60mg),m/z=482[M+1]
+,
1HNMR(400MHz,DMSO-d
6)δ12.70(brs,1H),8.61(d,2H),8.11(dd,1H),7.60(s,1H),7.33(d,1H),7.10(d,1H),4.88(q,1H),4.76(q,1H),4.46(t,1H),4.39(t,1H),3.65(t,4H),3.49(d,4H),1.44(d,9H).
步骤E:6-(2-氟乙氧基)-4-(6-(哌嗪-1-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶
向4-(5-(6-(2-氟乙氧基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-4-基)吡啶-2-基)哌嗪-1-碳酸叔丁酯(63mg,0.13mmol)的二氧六环溶液(2ml)中加入氯化氢二氧六环溶液(0.5mL,4.0M),室温反应12h,减压浓缩直接用于下步反应。m/z=382[M+1]
+,
1HNMR(400MHz,DMSO-d
6)δ12.68(s,1H),8.61(t,2H),8.09(d,1H),7.59(s,1H),7.33(d,1H),7.08(d,1H),4.88(t,1H),4.76(q,1H),4.47(t,1H),4.39(t,1H),3.62(s,4H),2.93(s,4H),1.15(s,1H).
步骤F:N,N-二乙基-4-(5-(6-(2-氟乙氧基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-4-基)吡啶-2-基)哌嗪-1-甲酰胺
向6-(2-氟乙氧基)-4-(6-(哌嗪-1-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(106mg,0.28mmol)的二氯甲烷溶液(5ml)中加入二乙基氨基甲酰氯(40mg,0.3mmol),三乙胺(85mg,0.84mmol),室温反应12h,加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(32.4mg),m/z=481[M+1]
+,
1H NMR(400MHz,DMSO-d
6)δ12.68(s,1H),8.62(d,2H),8.10(dd,1H),7.58(s,1H),7.34(d,1H),7.09(d,1H),4.88(t,1H),4.76(dd,1H),4.47(t,1H),4.39(t,1H),3.66(t,4H),3.16-3.25(m,8H),1.10(t,6H).
实施例19
1-(4-(5-(6-(2-氟乙氧基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-4-基)吡啶-2-基)哌嗪-1-基)-2-(吡啶-2-基)乙烷-1-酮(化合物19)
向6-(2-氟乙氧基)-4-(6-(哌嗪-1-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(106mg,0.28mmol)的二氯甲烷溶液(5ml)中加入2-(吡啶-2-基)乙酸(41mg,0.3mmol),2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(114mg,0.3mmol),三乙胺(85mg,0.84mmol),室温反应12h,加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(32.4mg),m/z=501[M+1]
+,
1H NMR(400MHz,DMSO-d
6)δ12.68(s,1H),8.62(d,2H),8.51(t,1H),8.10(dd,1H),7.73-7.78(m,1H),7.58(s,1H),7.34(t,2H),7.28(dd,1H),7.10(d,1H),4.88(t,1H),4.76(t,1H),4.47(d,1H),4.45(d,1H),3.96(s,2H),3.72(m,2H),3.34(s,6H).
实施例20
(R)-1-(4-(5-(6-(2-氟乙氧基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-4-基)吡啶-2-基)哌嗪-1-基)-2-羟基-2-苯乙烷-1-酮(化合物20)
向6-(2-氟乙氧基)-4-(6-(哌嗪-1-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(106mg, 0.28mmol)的二氯甲烷溶液(5ml)中加入(R)-2-羟基-2-苯乙酸(46mg,0.3mmol),2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(114mg,0.3mmol),三乙胺(85mg,0.84mmol),室温反应12h,加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(33mg),m/z=516[M+1]
+,
1H NMR(400MHz,DMSO-d
6)δ12.68(s,1H),8.61(dd,2H),8.07(dd,1H),7.56(s,1H),7.29-7.43(m,6H),7.04(d,1H),5.78(d,1H),5.51(d,1H),4.88(t,1H),4.76(t,1H),4.46(t,1H),4.38(t,1H),3.38-3.68(m,7H),3.26-3.29(m,1H)。
实施例21
(R)-1-(4-(5-(6-(2-氟乙氧基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-4-基)吡啶-2-基)哌嗪-1-基)-2-甲氧基-2-苯乙烷-1-酮(化合物21)
向6-(2-氟乙氧基)-4-(6-(哌嗪-1-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(106mg,0.28mmol)的二氯甲烷溶液(5ml)中加入(R)-2-甲氧基-2-苯乙酸(46mg,0.3mmol),2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(114mg,0.3mmol),三乙胺(85mg,0.84mmol),室温反应12h,加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(35mg),m/z=530[M+1]
+,
1H NMR(400MHz,DMSO-d
6)δ12.69(s,1H),8.61(dd,2H),8.08(dd,1H),7.58(s,1H),7.32-7.44(m,6H),7.05(d,1H),5.28(s,1H),4.88(t,1H),4.76(t,1H),4.46(t,1H),4.39(d,1H),3.36-3.65(m,7H),3.34(s,3H),3.28(brs,1H).
实施例22
(4-(5-(6-(2-氟乙氧基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-4-基)吡啶-2-基)哌嗪-1-基)(6-甲氧基吡啶-3-基)甲酮(化合物22)
向6-(2-氟乙氧基)-4-(6-(哌嗪-1-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(106mg,0.28mmol)的二氯甲烷溶液(5ml)中加入6-甲氧基烟酸(46mg,0.3mmol),2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(114mg,0.3mmol),三乙胺(85mg,0.84mmol),室温反应12h,加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(43mg),m/z=517[M+1]
+,
1H NMR(400MHz,DMSO-d
6)δ12.69(s,1H),8.63(dd,2H),8.34(d,1H),8.12(dd,1H),7.86(dd,1H),7.59(s,1H),7.34(d,1H),7.11(d,1H),6.93(d,1H),4.87(d,1H),4.75(d,1H),4.47(d,1H),4.39(d,1H),3.92(s,3H),3.73 (m,8H).
实施例23
(3-(5-(6-(2-氟乙氧基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-4-基)吡啶-2-基)-3,6-二氮杂双环[3.3.1]庚烷-6-基)(6-甲氧基吡啶-3-基)甲基酮(化合物23)
步骤A:3-(5-溴吡啶-2-基)-3,6-二氮杂双环[3.3.1]庚烷-6-碳酸叔丁酯
向5-溴-2-氟吡啶(5.3g,30mmol)的二甲基甲酰胺溶液(50ml)中加入6-(叔丁基羰基)-3,-6-二氮杂双环[3,1,1]庚烷(6.0g,30mmol),碳酸钾(7.0g,50mmol)加热至120℃反应16h。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(6.0g),m/z=354[M+1]
+。
步骤B:3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-2-基)-3,6-二氮杂双环[3.3.1]庚烷-6-碳酸叔丁酯
向10mL封管中,加入3-(5-溴吡啶-2-基)-3,6-二氮杂双环[3.3.1]庚烷-6-碳酸叔丁酯(47mg,0.132mmol),双联频哪醇硼酸酯(50mg,0.198mmol),四三苯基磷钯(15mg,0.013mol),醋酸钾(39mg,0.396mmol),二甲基亚砜(5mL),氮气置换三次,100℃反应3小时,LCMS确认原料反应完,加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩直接用于下步反应。
1H NMR(400MHz,DMSO-d
6)δ8.35(d,1H),7.73(q,1H),6.63(d,1H),4.20(d,2H),3.39-3.42(m,4H),3.97(s,2H),1.47(d,1H),1.27-1.30(m,20H).
步骤C:3-(5-(6-(苄氧基)-2-氟-3-甲醛吡唑[1,5-a]吡啶-4-基)吡啶-2-基)-3,6-二氮杂双环[3.3.1]庚烷-6-碳酸叔丁酯
向6-(苄氧基)-4-溴-2-氟吡唑[1,5-a]吡啶(23mg,0.067mmol),3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-2-基)-3,6-二氮杂双环[3.3.1]庚烷-6-碳酸叔丁酯(27mg,0.067mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(10mg,0.013mmol),碳酸铯(86mg,0.264mol),1,4-二氧六环(2mL),H
2O(1mL),氮气置换三次,90℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(21mg)。m/z=544[M+1]
+。
步骤D:3-(5-(2-氟-3-甲醛-6-羟基吡唑[1,5-a]吡啶-4-基)吡啶-2-基)-3,6-二氮杂双环[3.3.1]庚烷-6-碳酸叔丁酯
室温下,向3-(5-(6-(苄氧基)-2-氟-3-甲醛吡唑[1,5-a]吡啶-4-基)吡啶-2-基)-3,6-二氮杂双环[3.3.1]庚烷-6-碳酸叔丁酯(98mg,0.18mmol)和钯碳(5mg)中加入甲醇(10.0mL),用氢气球置换氢气三次,室温反应过夜。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品,m/z=454[M+1]
+。
步骤E:3-(5-(6-羟基-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-4-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-碳酸叔丁酯
向3-(5-(2-氟-3-甲醛-6-羟基吡唑[1,5-a]吡啶-4-基)吡啶-2-基)-3,6-二氮杂双环[3.3.1]庚烷-6-碳酸叔丁酯(240mg,0.53mmol)的DMF(5.0mL)溶液中加入水合肼(0.5mL),加热至100℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(92mg),m/z=448[M+1]
+。
步骤F:3-(5-(6-(2-氟乙氧基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-4-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-碳酸叔丁酯
向3-(5-(6-羟基-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-4-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-碳酸叔丁酯(134mg,0.3mmol)的DMF(10.0mL)溶液中加入1-氟-2-碘乙基(52mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至80℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(60mg),m/z=494[M+1]
+,
1H NMR(400MHz,DMSO-d
6)δ12.67(s,1H),8.60-8.63(m,2H),8.07-8.10(m,1H),7.57(s,1H),7.33(d,1H),6.92(d,1H),4.86-4.88(q,1H),4.74-4.76(t,1H),4.37-4.39(t,1H),4.26(d,2H),4.00-4.07(m,2H),3.54(d,2H),2.59(d,1H),1.99(s,1H),1.53(d,1H),1.29(s,9H).
步骤H:4-(6-(3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-6-(2-氟乙氧基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶
向4-(5-(6-(2-氟乙氧基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-4-基)吡啶-2-基)哌嗪-1-碳酸叔丁酯(63mg,0.13mmol)的二氧六环溶液(2ml)中加入氯化氢二氧六环溶液(0.5mL,4.0M),室温反应12h,减压浓缩直接用于下步反应,m/z=394[M+1]
+,
1H NMR(400MHz,DMSO-d
6)δ12.70(s,1H),8.68(s,1H),8.63(s,1H),8.17(s,1H),7.58(s,1H),7.35(s,1H),6.96(s,1H),4.75-4.89(m,2H),4.39-4.47(m,2H),3.91-4.05(m,4H),2.91(brs,2H),1.92(s,1H),1.15(s,2H).
步骤I:(3-(5-(6-(2-氟乙氧基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-4-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)(6-甲氧基吡啶-3-基)甲基酮
向4-(6-(3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-6-(2-氟乙氧基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(110mg,0.28mmol)的二氯甲烷溶液(5ml)中加入6-甲氧基烟酸(46mg,0.3mmol),2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(114mg,0.3mmol),三乙胺(85mg,0.84mmol),室温反应12h,加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(3mg),m/z=529[M+1]
+,
1HNMR(400MHz,DMSO-d
6)δ12.66(s,1H),8.55-8.60(m,3H),8.08(dd,1H),8.00(dd,1H),7.58(s,1H),7.31(d,1H),6.84-6.90(m,2H),4.94(brs,1H),4.86(dd,1H),4.74(dd,1H),4.61(brs,1H),4.42-4.44(m,1H),4.35-4.36(m,1H),4.20(d,1H),3.71(d,3H),3.57(m,3H),2.84(q,1H),1.72(d,1H).
实施例24
6-甲氧基-4-(5-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡嗪-2-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物24)
步骤A:2,4,6-三甲基苯磺酸1-氨基-3-溴-5-甲氧基吡啶-1-鎓
零度下,向2-[(氨基氧基)磺酰]-1,3,5-三甲基苯(6.8g,31.7mmol)的二氯甲烷(50mL)溶液中加入3-溴-5-甲氧基吡啶(6.0g,32.0mmol),并在零度下继续搅拌3小时,析出大量白色固体;反应完毕后,零度下向反应体系中加入乙醚(50mL)并搅拌10分钟,减压过滤,乙醚冲洗,真空干燥得到产品(15g),无须再次纯化,直接用于下一步反应。m/z=204[M+1]
+。
步骤B:4-溴-2-氟-6-甲氧基吡唑[1,5-a]吡啶
室温下,向装有2,4,6-三甲基苯磺酸1-氨基-3-溴-5-甲氧基吡啶-1-鎓(1.0g,2.3mmol)的DMF(30mL)溶液中加入碳酸钾(1.4g,10.0mmol);反应体系冷却至0℃,分批次加入对甲苯磺酸2,2-二氟乙烯基酯(0.5g,2.3mmol),升至室温下搅拌1小时,再90℃下搅拌1小时;反应完毕并冷却至室温,加水淬灭,用乙酸乙酯萃取,合并有机相,并用水洗涤,减压浓缩,柱层析分离得到产品(80mg),m/z=245[M+1]
+,
1HNMR(400MHz,CDCl
3)δ8.07(s,1H),6.61(s,1H),6.18(d,1H),3.85(s,3H)。
步骤C:4-溴-2-氟-6-甲氧基吡唑[1,5-a]吡啶-3-甲醛
零度下,向装有4-溴-2-氟-6-甲氧基吡唑[1,5-a]吡啶(294mg,1.2mmol)的DMF(10mL)溶液中滴加入三氯氧磷(1.0g,6.5mmol),滴完后自然升至室温反应过夜。将反应液倒入100mL冰水中,用2N NaOH溶液调节pH=7,用乙酸乙酯萃取,合并有机相,减压浓缩,柱层析分离得到产品(240mg)。m/z=273[M+1]
+。
1HNMR(400MHz,DMSO-d
6)δ10.51(s,1H),8.72(d,1H),8.04(d,1H),3.87(s,3H).
步骤D:4-溴-6-甲氧基-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶
操作同时实施例22步骤E,m/z=267[M+1]
+,
1HNMR(400MHz,DMSO-d
6)δ12.82(s,1H),8.67(d,1H),7.92(s,1H),7.62(d,1H),3.89(s,3H).
步骤E:6-甲氧基-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶
操作同实施例16步骤E,m/z=484[M+1]
+,
1H NMR(400MHz,DMSO-d
6)δ12.50(s,1H),8.98(d,1H),8.59(dd,2H),8.13(d,1H),8.03(s,1H),7.70-7.74(m,2H),6.79(d,1H),3.94(s,3H),3.82-3.87(m,5H),3.65-3.71(m,4H),3.56(s,2H),2.49-2.56(m,1H),1.64(d,1
实施例25
6-(2,2-二氟乙氧基)-4-(5-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡嗪-2-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物25)
向4-(5-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入1,1-二氟-2-碘乙基(58mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至80℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(12mg),m/z=534[M+1]
+,H NMR(400MHz,DMSO-d
6)δ12.55(s,1H),9.01(s,1H),8.73(s,1H),8.55(s,1H),8.12(s,1H),8.07(s,1H),7.83(s,1H),7.72(d,1H),6.77(d,1H),6.35-6.66(m,1H),4.50-4.57(m,2H),3.82-3.87(m,5H),3.65-3.84(m,4H),3.56-3.64(m,2H),1.62-1.64(m,1H)。
实施例26
2-((4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-基)氧基)乙腈(化合物26)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入溴乙腈(36mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至90℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(62mg)。m/z=508[M+1]
+,
1H NMR(400MHz,DMSO-d
6)δ12.76(s,1H),8.81(s,1H),8.67(s,1H),8.10-8.14(m,2H),7.68-7.71(m,2H),7.43(s,1H),6.92(d,1H),6.76(d,1H),5.37(s,2H),3.68-3.82(m,8H),3.53-3.68(m,3H),2.51(d,1H),1.58-1.61(m,1H).
实施例27
6-(2-(二氟甲氧基)乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物27)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑 [3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入2-(二氟甲氧基)乙基对甲苯磺酸酯(80mg,0.3mmol,制备方法参考文献WO2016/123706),碳酸钾(83mg,0.6mmol),加热至90℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(143mg)。m/z=563[M+1]
+。
1H NMR(400MHz,DMSO-d
6)δ12.67(s,1H),8.60-8.66(dd,2H),8.10-8.13(m,2H),7.63-7.72(m,2H),7.32(s,1H),6.91(d,1H),6.76-6.80(m,1H),4.37(d,2H),4.23(d,2H),3.76-3.83(m,5H),3.68-3.70(m,3H),3.53-3.69(m,4H),2.51(d,1H),1.61(d,1H).
实施例28
6-(2-(环丙基甲氧基)乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物28)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入2-(环丙基甲氧基)乙基对甲苯磺酸酯(81mg,0.3mmol,制备方法参考文献US4406907),碳酸钾(83mg,0.6mmol),加热至90℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(127mg)。m/z=567[M+1]
+。
实施例29
6-异丙氧基-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物29)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入碘代异丙烷(51mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至80℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(133mg)。m/z=511[M+1]
+。
1H NMR(400MHz,DMSO-d
6)δ12.65(s,1H),8.65(d,1H),8.55(d,1H),8.11(d,2H),7.63-7.72(m,1H),7.62(s,1H),7.26(d,1H),6.92(d,1H),6.79(d,1H),4.75(m,1H),3.72-3.83(m,5H),3.70(d,2H),3.53-3.60(m,4H),2.51(d,1H),1.59(d,1H),1.36(d,6H),。
实施例30
4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-6-(2,2,2-三氟乙氧基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物30)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入三氟乙基对甲苯磺酸酯(76mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至120℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(20mg)。m/z=551[M+1]
+。
1HNMR(400MHz,DMSO-d
6)δ12.72(s,1H),8.75(d,1H),8.66(d,1H),8.08-8.13(m,2H),7.65-7.71(m,2H),7.41(d,1H),6.92(d,1H),6.74-6.77(m,1H),4.92-4.98(m,2H),3.75-3.81(m,5H),3.64-3.68(m,2H),3.52-3.68(m,4H),2.51(d,1H),1.55-1.59(m,1H).
实施例31
6-(2-氟乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物31)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入1-溴-2-氟乙烷(38mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至70℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(139mg)。
1HNMR(400MHz,DMSO-d
6)δ12.68(s,1H),8.61-8.66(d,2H),8.10-8.13(m,2H),7.64-7.12(m,2H),7.33(d,1H),6.93(d,2H),6.79(d,2H),4.89(t,1H),4.76(t,1H),4.47(t,1H),4.39(t,1H),3.76-3.83(m,5H),3.70(d,2H),3.53-3.60(m,4H),2.51(d,1H),1.61(d,1H).m/z=515[M+1]
+。
实施例32
6-(2,2-二氟乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物32)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑 [3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入1,1-二氟-2-碘乙烷(58mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至70℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(118mg)。
1HNMR(400MHz,DMSO-d
6)δ12.69(s,1H),8.69(d,1H),8.66(d,1H),8.10-8.13(m,2H),7.71(d,1H),7.65(s,1H),7.57(s,1H),6.91(d,1H),6.76(d,1H),6.38-6.62(m,1H),4.52(t,2H),3.80-3.83(m,5H),3.68(m,2H),3.53-3.62(m,4H),2.51(d,1H),1.58(d,1H),m/z=533[M+1]
+。
实施例33
6-(二氟甲氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物33)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入二氟氯乙酸钠(46mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至80℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,反相柱层析分离得到产品的三氟乙酸盐(118mg),m/z=519[M+1]
+,
1H NMR(400MHz,DMSO-d
6):8.64(s,1H),8.54(s,1H),8.10-8.26(m,2H),7.80-7.89(m,2H),7.56(s,1H),7.28-7.34(m,1H),7.06-7.09(m,1H),6.89-6.97(m,1H),3.76-3.93(m,11H),2.51(d,1H),2.02-2.08(m,1H).
实施例34
6-(2-环丙氧基乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物34)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入2-(环丙基氧基)乙基对甲苯磺酸酯(77mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至70℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,反相柱层析分离得到产品的三氟乙酸盐(132mg)。m/z=553[M+1]
+。
1H NMR(400MHz,DMSO-d
6):8.73(s,1H),8.69(s,1H),8.15-8.19(m,2H),7.85-7.89(m,2H),7.48-7.52(m,1H),6.93-6.98(m,2H),4.61-4.65(m,2H),4.48-4.50(m,2H),4.02-4.12(m,4H),3.79-3.98(m,8H),3.48-3.53(m,1H),2.08-2.12(m,2H),1.68-1.80(m,1H).
实施例35
6-乙氧基-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-3-甲基-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物35)
步骤A:1-(6-(苄氧基)-4-溴-2-氟吡唑[1,5-a]吡啶-3-基)乙烷-1-酮
零度下,向6-(苄氧基)-4-溴-2-氟吡唑[1,5-a]吡啶(220mg,0.69mmol)中加入醋酸酐(2.0mL),再加入磷酸(0.2mL),室温搅拌12h,直接减压浓缩,柱层析分离得到产品(100mg)。m/z=364[M+1]
+。
步骤B:1-(4-溴-2-氟-6-羟基吡唑[1,5-a]吡啶-3-基)乙烷-1-酮
室温下,向1-(6-(苄氧基)-4-溴-2-氟吡唑[1,5-a]吡啶-3-基)乙烷-1-酮(100mg,0.28mmol)和钯碳(5mg)中加入甲醇(10.0mL),用氢气球置换氢气三次,室温反应过夜。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(65mg)。m/z=274[M+1]
+。
步骤C:1-(4-溴-6-乙氧基-2-氟吡唑[1,5-a]吡啶-3-基)乙烷-1-酮
向1-(4-溴-2-氟-6-羟基吡唑[1,5-a]吡啶-3-基)乙烷-1-酮(110mg,0.36mmol)和碘乙烷(56mg,0.4mmol),碳酸钾(167mg,1.2mmol)中加入DMF(2.0mL),加热至60℃反应12h。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(100mg)。m/z=302[M+1]
+。
步骤D:4-溴-6-乙氧基-3-甲基-1氢-吡唑[3',4':3,4]吡唑[1,5-a]吡啶
将1-(4-溴-6-乙氧基-2-氟吡唑[1,5-a]吡啶-3-基)乙烷-1-酮(110mg,0.37mmol)溶于DMF(5.0mL)中,加入水合肼(0.5mL),加热至120℃反应。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(72mg)。m/z=296[M+1]
+。
步骤E:6-乙氧基-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-3-甲基-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶
向4-溴-6-乙氧基-3-甲基-1氢-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(72mg,0.24mmol),6-((6-甲氧基吡啶-3-基)亚甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧代环戊硼烷-2-基)吡啶-2-基)3,6-二氮杂双环[3.1.1]庚烷(101mg,0.24mmol)(参考文献WO2018/71447中的方法制备),四三苯基磷钯(18mg,0.013mol),碳酸钾(66mg,0.48mol),1,4-二氧六环(2mL),H
2O(1mL),氮气置换三次,90℃反应2小时,LCMS确认原料反应完,有产品生成。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(36mg)。
1HNMR(400MHz,DMSO-d
6)δ12.11(s,1H),8.49(d,2H),8.06(s,1H),7.88(d,1H),7.69(d,1H),7.03(s,1H),6.85(dd,2H),4.17(d,2H),3.67-3.82(m,3H),3.49-3.56(m,4H),3.44-3.54(m,4H),2.51(d,1H),1.98(s,3H),1.60(d,1H),1.40(t,3H).m/z=511[M+1]
+。
实施例36
6-甲氧基-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物36)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入碘甲烷(43mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至60℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(137mg)。
1HNMR(400MHz,DMSO-d
6)δ12.66(s,1H),8.64-8.65(m,1H),8.55(d,1H),7.63-7.71(m,3H),7.28(d,1H),6.93(d,1H),6.79(d,2H),3.88-3.96(m,3H),3.76-3.82(m,5H),3.71(brs,2H),3.49-3.55(m,4H),2.51(d,1H),1.61(d,1H).m/z=483[M+1]
+。
实施例37
6-(环丙甲氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物37)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入环丙基溴甲烷(41mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至60℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(66mg),1H NMR(400MHz,DMSO-d6)δ12.63(s,1H),8.63(s,1H),8.47(s,1H),8.10(m,2H),7.65(m,1H),7.60(s,1H),7.29(s,1H),6.90(d,1H),6.77(d,1H),3.96(d,2H),3.81(s,3H),3.4-3.75(m,8H),2.51(d,1H),1.60(d,1H),0.75-0.85(m,1H),0.59(m,2H),0.36(m,2H),m/z=523[M+1]
+。
实施例38
4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-6-丙氧基-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物38)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入1-溴丙烷(37mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至60℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(96mg)。m/z=511[M+1]
+。
1H NMR(400MHz,DMSO-d
6)δ12.63(s,1H),8.63(d,1H),8.51(d,1H),8.08(s,2H),7.77–7.65(m,1H),7.60(s,1H),7.26(d,1H),6.90(d,1H),6.76(d,1H),4.08(t,2H),3.81(s,3H),3.76(d,2H),3.67(d,2H),3.58(s,1H),3.52(s,2H),2.51(d,1H),1.78(p,2H),1.58(d,1H),1.22(s,1H),1.02(t,3H).
实施例39
6-异丁氧基-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物39)
向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入1-溴-2-甲基丙烷(41mg,0.3mmol),碳酸钾(83mg,0.6mmol),加热至60℃反应12小时。加入水,用乙酸乙酯萃取,合并有机相,并用水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱层析分离得到产品(33mg)。m/z=525[M+1]
+。
1H NMR(400MHz,DMSO-d
6)δ12.63(s,1H),8.64(d,1H),8.51(d,1H),8.12-8.07(m,2H),7.69(dd,1H),7.60(s,1H),7.27(d,1H),6.90(d,1H),6.76(d,1H),3.90(d,2H),3.81(s,3H),3.76(d,2H),3.67(d,2H),3.51(s,2H),2.51(d,1H),2.07(dq,1H),1.58 (d,1H),1.24(d,2H),1.02(d,6H).
实施例40
6-(2-甲氧基-2-甲基丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)亚甲基)-3,6-二氮杂双环[3.3.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶(化合物40)
生物活性测试例
测试例1
转染重组基因(RET)是一个已经确认的原癌基因。它编码的单次跨膜受体酪氨酸激酶,是许多组织和细胞类型的发育,成熟和维持所必需的。在正常条件下,神经胶质细胞系衍生的神经营养因子(GDNF)家族配体与细胞表面上的RET的结合导致细胞内酪氨酸残基的二聚化和自磷酸化,进而导致下游RAS-MAPK,PI3K-AKT和磷脂酶Cγ(PLCγ)通路的激活,并增加细胞存活和增殖。激活RET突变的实例包括C634W,M918T和关守突变V804L、V804M,以及溶剂前沿突变G810R等。
该试验将肽底物和单一专有单克隆抗体与HTRF技术相结合,HTRF技术是一种高灵敏度和稳定的技术,用于检测蛋白质的分子相互作用。酶将底物磷酸化,然后Eu标记的抗体结合磷酸化底物,链霉抗生物素蛋白-XL665结合所有底物。TR-FRET信号由HTRF原理产生。一旦添加抑制剂(受试化合物),就获得较弱的TR-FRET信号。据此,评估抑制效果。
表1.激酶活性测试试剂和耗材
1.2配制溶液
将所有的化合物都溶解在DMSO中的配制成10mM的储液。
用DMSO将卡博替尼(Cabozantinib)从2mM和0.2mM分别梯度稀释3倍,共10个浓度。
其他化合物从10mM的原液用DMSO梯度稀释3倍,共10个浓度。
制备1000×阳性对照(0.1mM Cabozantinib)和1000×阴性对照(100%DMSO)。
在平板振荡器上振荡5分钟。
1.3制备1×激酶缓冲液
将4体积蒸馏水加入1体积酶缓冲液5×;5mM MgCl
2;1mM DTT。
1.4筛选方法
a)将1μl化合物稀释液转移到测试板的每个孔中;
b)在1000g下将化合物板离心1分钟。
c)密封测试板。
d)制备1×激酶缓冲液中的2×Ret wt(0.04ng/μl)和2×Ret V804M(0.2ng/μl)和2×RET G810R(2ng/μl)。
e)加入5μl的2×Ret wt或Ret V804M或RET G810R至384孔测试板。
f)在1000g下离心样品板30秒,在室温放置10分钟。
g)用1×激酶缓冲液制备激酶缓冲液中的5×TK-底物-生物素(5μM)和激酶缓冲液中的5×ATP(50μM)的溶液。
h)通过加入2μl STK-底物-生物素和2μlATP(步骤g中制备的)开始反应。
i)在1000g下离心样品板30秒。密封测试板,室温放置30分钟。
j)制备在HTRF检测缓冲液中的4×Sa-XL 665(250nM)。
k)将5μl的Sa-XL 665和5μl的TK-antibody-Cryptate(在步骤i中制备的)加入到测试板的每个孔中。
l)在1000g下离心30秒,室温放置1小时。
m)在Envision 2104读板仪或BioTek酶标仪上读取620nm(Cryptate)和665nm(XL665)的荧光信号值。
1.5数据分析
计算每个孔的比率(665nm/620nm)。
抑制率%通过如下方式计算:
抑制率%=[1-(受试化合物比率-阳性对照平均比率)/(阴性对照平均比率-阳性对照平均比率)]*100%
比率:由测得的荧光信号值产生
阳性对照平均比率为样品板中阳性对照(20μM Cabozantinib)的平均比率;
阴性对照平均比率为样品板中阴性对照(0.1%DMSO)的平均比率。
利用一些非线性拟合公式来得到化合物的IC
50(半数抑制浓度):用GraphPad 6.0软件进行数据分析。
Y=Bottom+(Top-Bottom)/(1+10^((LogIC
50-X)*Hill Slope))
X:化合物浓度Log值 Y:抑制率(%inhibition)
Z’因子技术方程:
Z’=1-3(SDmin+SDmax)/(AVEmax-AVEmin)
Min为阳性对照药20μM Cabozantinib Ratio(665/620nM*10000)至,Max为阴性对照药DMSO Ration(665/620nM*10000)。
SD为标准误差,AVE为Ration(665/620nM*10000)平均值。
激酶结果如表2、表3和表4所示:表2.
表3.
表4.
表2、表3和表4所示的的实验结果表明:化合物1,7,9,12,27,31,32,36,38,39对RET wt的抑制活性均显著优于Cabozantinib。化合物1,7,9,12,16,17,23,27,31,32,36,38,39对RET V804M的抑制活性均显著优于Cabozantinib。化合物3,5,7,9,10,11,12,13,14,15,16,18,19,20,21,22,24,25,26,27,30,31,32,36,38,39对RET G810R的抑制活性均显著优于Cabozantinib及Selpercatinib(LOXO-292)。
测试例2
表2.1细胞活性测试试剂和耗材
试剂和耗材 | 供应商 | 型号 |
Ham’s F-12K | Procell | PM150910 |
FBS | Invitrogen | 10099141 |
Penicillin-streptomycin | Invitrogen | 15140-122 |
DMSO | Sigma | D8418-1L |
Cabozantinib | MCE | HY-13016 |
384well cell seeding plate | Corning | 3570 |
CelltiterGlo assay kit(CTG) | Promega | G7573 |
Instrumentation: | Vendor | Model |
Echo550 | Echo | 550 |
Biological Safety Cabinet(Class II) | Thermo Scientific | 1300Series A2 |
Centrifuge | Eppendorf | 5702 |
CO 2Incubator | Thermo Scientific | 1300SERIES A2 |
EnVision | PerkinElmer | EnVision 2104 |
2.2实验步骤
a)用100%DMSO将Cabozantinib和测试化合物(10mM储液)稀释5倍至2mM,在384孔稀释板中以1:3进行等比稀释10个浓度。
b)用Echo转移200nL(a步骤中准备)到384细胞培养板。Cabozantinib和测试化合物的梯度浓度为10000,3333.3,1111.1,370.4,123.4,41.1,13.7,4.5,1.5,0.5nM,DMSO终浓度为0.5%。
c)TT细胞系养基是含有10%FBS,1%Penicillin-streptomycin。
d)将细胞悬液加入含有化合物的384孔板(b步骤中准备),每孔含有800个细胞,体积为40μL,在细胞培养箱中继续孵育72h。
e)取出384孔细胞培养板,加20μl CTG试剂。
f)放置快速振荡器振荡2min,然后在室温放30min。
用Envision仪器读取荧光信号值。
2.3数据处理
%inhibition(抑制率)=100*(HC-测试化合物孔读值)/(HC-LC)
◆High control(HC,没有抑制的读值对照)是:0.5%DMSO
◆Low control(LC,有化合物抑制的对照)是:1μMCEP-32496
用GraphPad Prism 6software计算IC
50。
Y=Bottom+(Top-Bottom)/(1+10^((LogIC
50-X)*HillSlope));
X:log of cpd concentration;
Y:%inhibition;
Top and Bottom:Plateaus in same units as Y;
logIC
50:same log units as X;
HillSlope:Slope factor
细胞结果如表5所示:
表5.
表5所示的实验结果表明:化合物2、3、5、6、7、8、9、10、11、12、13、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、34、36、37、38、39对TT细胞的抑制活性均显著优于Cabozantinib。
测试例3 TT细胞人源甲状腺髓样癌异种移植模型药效测试
3.1细胞培养
用含有灭活的10%胎牛血清,100U/mL的青霉素和100μg/mL的链霉素以及2mM谷氨酰胺的F12K培养基在37℃、5%CO
2的培养箱中培养TT肿瘤细胞。细胞培养起始浓度为1×10
6个/毫升,每隔3至4天待细胞长满后分瓶传代。将处于对数生长期的肿瘤细胞用于体内肿瘤的接种。
3.2肿瘤细胞的接种与分组
将无血清F12K培养液重悬的TT肿瘤细胞1×10
7+胶/100μL接种于实验动物的右侧胁肋部皮下。待肿瘤生长至224mm
3左右时进行分组给药,每组6只动物。
3.3给药,肿瘤测量及实验指标
小鼠每天两次经口给予测试化合物,连续给药28天。
肿瘤体积:使用游标卡尺对肿瘤的长径和短径进行测量,其体积计算公式为:体积=0.5×长径×短径
2。要求给药期间对动物体重和肿瘤大小进行测量,每周2次。
动物给药后的反应:在进行肿瘤测量的同时,称量实验动物体重。记录动物体重的变化与给药时间的关系。同时观察小鼠的存活情况和健康状况如给药期间动物活动、进食等一般状态。
相对肿瘤增殖率T/C(%)=TRTV/CRTV×100%。(TRTV:治疗组RTV;CRTV:阴性对照组RTV),其中相对肿瘤体积(relative tumor volume,RTV),计算公式为:RTV=Vt/V0。其中V0为分组给药时(即给药第1天)测量所得肿瘤体积,Vt为每一次测量时的 肿瘤体积。肿瘤生长抑制率TGI(%)=(1-T/C)×100%。
在TT人源甲状腺髓样癌异种移植模型中,化合物9、化合物31、化合物32给药剂量为10mg/kg,均表现出非常显著的肿瘤抑制作用(TGI=88.5%、TGI=87.4%和TGI=86.9%),且三组之间药效相当。给药期间,各组实验动物活动和进食等一般状态均良好,无明显体重下降及不良反应,具体结果请见图1。
测试例4 Ba/F3细胞KIF5B-RET-V804M融合异种移植模型的药效测试
4.1细胞培养
Ba/F3 KIF5B-RET-V804M肿瘤细胞,用含有灭活的10%胎牛血清,100U/ml的青霉素和100μg/ml的链霉素以及2mM谷氨酰胺的RPMI-1640培养基在37℃、5%CO
2的培养箱中培养肿瘤细胞,每隔3至4天待细胞长满后分瓶传代,将处于对数生长期的肿瘤细胞用于体内肿瘤的接种。
4.2肿瘤细胞接种与分组
PBS与Matrigel等体积重悬的Ba/F3KIF5B-RET-V804M肿瘤细胞,浓度为5×10
7/ml,接种于BALB/c nude小鼠的右侧胁肋部皮下,100μl/只,在肿瘤生长至194mm
3左右时分组给药,每组6只动物。
4.3给药,肿瘤测量及实验指标
小鼠每天两次经口给予测试化合物,连续给药14天。
肿瘤体积:使用游标卡尺对肿瘤的长径和短径进行测量,其体积计算公式为:体积=0.5×长径×短径
2。要求给药期间对动物体重和肿瘤大小进行测量,每周2次。
动物给药后的反应:在进行肿瘤测量的同时,称量实验动物体重。记录动物体重的变化与给药时间的关系。同时观察小鼠的存活情况和健康状况如给药期间动物活动、进食等一般状态。
相对肿瘤增殖率T/C(%)=TRTV/CRTV×100%。(TRTV:治疗组RTV;CRTV:阴性对照组RTV),其中相对肿瘤体积(relative tumor volume,RTV),计算公式为:RTV=Vt/V0。其中V0为分组给药时(即给药第1天)测量所得肿瘤体积,Vt为每一次测量时的肿瘤体积。肿瘤生长抑制率TGI(%)=(1-T/C)×100%。
Selpercatinib,化合物9,化合物31,化合物32给药剂量均为10mg/kg,对照组实验结束(给药第8天)时,肿瘤生长抑制率分别为49%,94%、92%、96%,各治疗组肿瘤体积均显著低于对照组(p<0.05);化合物9,化合物31,化合物32组肿瘤体积均显著低于Selpercatinib组(p<0.05)。实验结束(给药第14天)时,化合物9,化合物31,化合物32组肿瘤体积均显著低于Selpercatinib组(p<0.05)。治疗期间,荷瘤鼠对测试物均表现出很好的耐受性,各组小鼠体重正常,无异常表现,一般状态良好,具体结果请见图2。
本发明涉及药物化学领域,具体涉及式I所示含氮多环稠环类化合物,其药物组合物、制备方法和用途。本发明的化合物可以作为一种高度选择性和非常有效的RET抑制剂,此类化合物对RET看门残基突变体RET V804M突变、RET溶剂前沿残基突变体RET G810R和其他临床相关RET突变体以及RET wt均有较强的抑制作用,该化合物还能显著抑制甲状腺癌来源的TT细胞系和各种RET突变体转化的Ba/F3细胞的生长,并能显著诱导TT细胞死亡。
本文对本发明示例性的实施方案进行了说明。但是应当理解,本发明的保护范围不拘囿于上述实施方案。在本发明的精神和原则之内,所作出的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (107)
- 式I所示的化合物或其药学上可接受的盐:其特征在于:X 1、X 2、X 3、X 4、X 5、X 6、X 7相同或不同,彼此独立地选自CR 1或N;X 8选自CR 1R 1’或NR 1;其中:每个R 1和R 1’相同或不同,彼此独立地选自H、卤素、CN、NH 2或OH,或者每个R 1和R 1’相同或不同,彼此独立地选自无取代或任选地被1个、2个或3个R a取代的下列基团:C 1-6烷基、C 3-6环烷基、C 1-6烷氧基或C 3-6环烷基氧基;每个R a相同或不同,彼此独立地选自卤素、CN、OH、C 1-6烷基、C 3-6环烷基或C 1-6烷氧基;A选自H、卤素、CN、OH或NH 2,或者A选自无取代或任选地被1个、2个或3个R b取代的下列基团:C 1-6烷基、C 2-6烯基、C 3-6环烷基、C 1-6烷氧基或C 3-6环烷基氧基;每个R b相同或不同,彼此独立地选自卤素、CN、OH、C 1-6烷基、C 3-6环烷基或C 1-6烷氧基;D、E相同或不同,彼此独立地选自H、卤素、CN、OH或NH 2,或者D、E相同或不同,彼此独立地选自无取代或任选地被1个、2个或3个R c取代的下列基团:-C 1-6烷基、-C 1-6烷氧基、-O(CH 2) nO(CH 2) nC 3-6碳环、-O(CH 2) n-3-8元的杂环或-O(CH 2) nC 6-10芳香环;每个R c相同或不同,彼此独立地选自卤素、CN、OH、氧代(=O)、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3-10元杂环基、5-7元杂芳基、6-10元芳基、C 1-6烷氧基、3-6元环烷基氧基或3-8元杂环基氧基;每个n相同或不同,彼此独立选自0、1、2或3;上述D、E和R c中的每个杂环、杂环基、杂芳基中的杂原子个数和种类相同或不同,彼此独立地含有1、2或3个杂原子,所述杂原子选自N、O或S;G选自下列基团:(1)饱和的4-8元的含有2个杂原子的杂环;(2)饱和的7-10元的含有2个杂原子的桥杂环;(3)饱和的7-11元的含有2个杂原子的杂螺环;或(4)饱和的7-10元的含有两个杂原子的双环稠合的杂环;上述杂原子选自N或O,每个环彼此 独立地任选地不被取代或被1、2、3或4个R G取代,每个R G相同或不同,且每个R G独立地选自H、卤素、OH、NH 2、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基或卤素取代的C 1-6烷氧基;K选自无取代或任选地被1个、2个、3个或4个R K取代的下列基团:C 1-6烷基、C 3-6环烷基、C 6-10芳基、-C 1-6亚烷基C 6-10芳环、-COC 1-6亚烷基C 6-10芳环、-C 1-6亚烷基5-10元芳杂环、-COC 1-6亚烷基5-10元芳杂环、-CONR K1R K2、3-10元杂环基、C 1-6烷氧基、C 3-6环烷基氧基、C 6-10芳基氧基、5-10元杂芳基氧基或3-10元杂环基氧基;每个R K相同或不同,彼此独立地选自下列基团:-CN、OH、-NH 2、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、卤素取代的C 1-6烷基或卤素取代的C 1-6烷氧基;R K1和R K2相同或不同,彼此独立地选自下列基团:-CN、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、卤素取代的C 1-6烷基或卤素取代的C 1-6烷氧基;所述K中的每个芳杂环、杂环、杂环基相同或不同,彼此独立地含1或2个N原子。
- 根据权利要求1所述的式I所示的化合物或药学上可接受的盐,其特征在于:X 1、X 3和X 4均独立地选自CR 1。
- 根据权利要求1或2所述所述的式I所示的化合物或药学上可接受的盐,其特征在于:X 5选自CR 1。
- 根据权利要求1-3任一项的式I所示的化合物或药学上可接受的盐,其特征在于:X 8选自NR 1。
- 根据权利要求1-4任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:每个R 1和R 1’相同或不同,彼此独立地选自H、F、Cl、Br、CN、NH 2或OH,或者每个R 1和R 1’相同或不同,彼此独立地选自无取代或任选地被1个、2个或3个R a取代的下列基团:C 1-3烷基、C 4-6环烷基、C 1-3烷氧基或C 4-6环烷基氧基。
- 根据权利要求1-5任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:每个R 1和R 1’相同或不同,彼此独立地选自H、F、Cl、CN或NH 2,或者每个R 1和R 1’相同或不同,彼此独立地选自无取代或任选地被1个、2个或3个R a取代的下列基团:甲基、乙基、丙基、5元环烷基、6元环烷基、甲氧基、乙氧基、丙氧基、5元环烷基氧基或6元环烷基氧基。
- 根据权利要求1-6任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:每个R a相同或不同,彼此独立地选自F、Cl、Br、CN、OH、C 1-3烷基、C 4-6环烷基或C 1-3烷氧基;
- 根据权利要求1-7任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:每个R a相同或不同,彼此独立地选自F、Cl、CN、OH、甲基、乙基、丙基、5元环烷基、6元环烷基、甲氧基、乙氧基、丙氧基、5元环烷基氧基或6元环烷基氧基。
- 根据权利要求1-8任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:X 1选自CH。
- 根据权利要求1-9任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:X 3选自CH。
- 根据权利要求1-10任一项所述的式I所示的化合物或药学上可接受的盐,其特征在 于:X 5选自-CH。
- 根据权利要求1-11任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:X 5选自CH。
- 根据权利要求1-12任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:X 8选自NH。
- 根据权利要求1-13任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:X 1、X 3、X 4和X 5均选自CH,X 8选自NH。
- 根据权利要求1-14任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:X 2选自N。
- 根据权利要求1-15任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:X 6选自N。
- 根据权利要求1-16任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:X 7选自N。
- 根据权利要求1-17任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:X 1、X 3、X 4和X 5均选自CH,X 2、X 6和X 7均选自N,X 8选自NH。
- 根据权利要求1-18任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:A选自H、F、Cl、Br、CN、OH或NH 2,或者A选自无取代或任选地被1个、2个或3个R b取代的下列基团:C 1-3烷基、C 4-6环烷基、C 1-3烷氧基或C 4-6环烷基氧基;每个R b相同或不同,彼此独立地选自F、Cl、Br、CN、OH、C 1-3烷基或C 1-3烷氧基。
- 根据权利要求1-19任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:A选自H、F、Cl、CN、OH或NH 2,或者A选自无取代或任选地被1个、2个或3个R b取代的下列基团:甲基、乙基、丙基、5元环烷基、6元环烷基、甲氧基、乙氧基、丙氧基、5元环烷基氧基或6元环烷基氧基;每个Rb相同或不同,彼此独立地选自F、Cl、甲基、乙基、甲氧基或乙氧基。
- 根据权利要求1-20任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:A选自H、-F、-Cl、-CN、-OH、-NH 2或-CH 3、。
- 根据权利要求1-21任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:D、E相同或不同,彼此独立地选自H、F、Cl、Br、CN、OH或NH 2,或者D、E相同或不同,彼此独立地选自无取代或任选地被1、2或3个R c取代的下列基团:-C 1-3烷基、-C 1-3烷氧基、-O(CH 2) nO(CH 2) nC 3-6碳环、-O(CH 2) n-4-6元的杂环、-O(CH 2) nC 6芳香环或-O(CH 2) nC 10芳香环。
- 根据权利要求1-22任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:D、E相同或不同,彼此独立地选自H、F、Cl、Br、、CN、OH或NH 2,或者D、E相同或不同,彼此独立地选自无取代或任选地被1、2或3个R c取代的下列基团:甲基、乙基、丙基、甲氧基、乙氧基、丙氧基、-O(CH 2) nO(CH 2) n-3元碳环、-O(CH 2) nO(CH 2) n-4元碳环、-O(CH 2) nO(CH 2) n-5元碳环、-O(CH 2) n-5元的杂环、-O(CH 2) n-6元的杂环或-O(CH 2) n-苯环。
- 根据权利要求1-23任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:D、E相同或不同,彼此独立地选自H、F、Cl、Br、CN、OH或NH 2,或者D、E相同或不同,彼此独立地选自无取代或任选地被1、2或3个R c取代的下列基团:甲基、甲氧基、-O(CH 2) nO(CH 2) n-3元碳环、-O(CH 2) n-6元的杂环或-O(CH 2) n-苯环。
- 根据权利要求1-24任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:每个n相同或不同,彼此独立选自0、1或2。
- 根据权利要求1-25任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:每个n相同或不同,彼此独立选自1或2。
- 根据权利要求1-26任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:每个R c相同或不同,彼此独立地选自F、Cl、Br、CN、OH、C 1-3烷基、C 3-5环烷基、4-6元杂环基、5-6元杂芳基、苯基、C 1-3烷氧基、3-5元环烷基氧基或4-6元饱和杂环基氧基。
- 根据权利要求1-27任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:每个R c相同或不同,彼此独立地选自F、Cl、Br、CN、OH、甲基、乙基、丙基、3元环烷基、4元环烷基、4元饱和杂环基、5元饱和杂环基、6元饱和的杂环基、5元杂芳基、6元杂芳基、苯基、甲氧基、乙氧基、丙氧基、3元环烷基氧基、4元环烷基氧基、5元饱和的杂环基氧基或6元饱和的杂环基氧基。
- 根据权利要求1-28任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:每个R c相同或不同,彼此独立地选自F、Cl、Br、CN、OH、甲基、乙基、丙基、3元环烷基、4元环烷基、4元饱和杂环基、5元饱和杂环基、6元饱和的杂环基、5元杂芳基、6元杂芳基、苯基、甲氧基、乙氧基、丙氧基、3元环烷基氧基、4元环烷基氧基、5元饱和的杂环基氧基或6元饱和的杂环基氧基。
- 根据权利要求1-29任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:所述D、E和R c中的每个杂环、杂环基、杂芳基中的杂原子个数和种类相同或不同,彼此独立地含有1或2个杂原子,所述杂原子选自N或O。
- 根据权利要求1-30任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:所述D、E和R c中的每个杂环、杂环基、杂芳基中的杂原子个数和种类相同或不同,彼此独立地含有1个N原子和/或1个O原子。
- 根据权利要求1-35任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:G选自下列基团:饱和的5、6、7或8元的含有2个N原子的杂环。
- 根据权利要求1-6任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:G选自下列基团:饱和的5元的含有2个N原子的杂环、饱和的6元的含有2个N原子的杂环、饱和的7元的含有2个N原子的杂环和饱和的8元的含有2个N原子的杂环。
- 根据权利要求1-38任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:G选自下列基团:饱和的7、8或9元的含有2个N或O原子的桥杂环。
- 根据权利要求1-35或39任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:G选自下列基团:饱和的8元的含有2个N或O原子的桥杂环或饱和的9元的含有2个N原子的桥杂环。
- 根据权利要求1-35或39-40任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:G选自下列基团:饱和的8元的含有2个N原子的桥杂环或饱和的9元的含有2个N原子的桥杂环。
- 根据权利要求1-43任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:每个R G相同或不同,且每个R G独立地选自H、F、Cl、Br、OH、NH 2、C 1-3烷基、F或Cl取代的C 1-3烷基或C 1-3烷氧基。
- 根据权利要求1-44任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:每个R G相同或不同,且每个R G独立地选自H、NH 2、甲基、乙基、丙基、F取代的甲基、F取代的乙基、F取代的丙基、甲氧基、乙氧基或丙氧基。
- 根据权利要求1-45任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:每个R G相同或不同,且每个R G独立地选自H、NH 2、甲基、F取代的甲基或甲氧基。
- 根据权利要求1-46任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:K选自无取代或任选地被一个、两个或多个R K取代的下列基团:K选自无取代或任选地被1、2或3个R K取代的下列基团:C 1-3烷基、C 5-6环烷基、苯基、-C 1-3亚烷基苯环、-COC 1-3亚烷基苯环、-COC 1-3亚烷基联苯环、-C 1-3亚烷基5-8元芳杂环、-COC 1-3亚烷基5-8元芳杂环、-CONR K1R K2、5-6元杂环基、C 1-3烷氧基、C 3-6环烷基氧基、C 6-10芳基氧基、5-8元杂芳基氧基或5-8元杂环基氧基;
- 根据权利要求1-47任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:K选自无取代或任选地被一个、两个或多个R K取代的下列基团:K选自无取代或任选地被1或2个R K取代的下列基团:C 1-3烷基、C 5-6环烷基、苯基、-C 1-3亚烷基苯环、-COCH 2苯环、-COCH 2CH 2苯环、-COCH 2联苯环、-CH 2-6元芳杂环、-CH 2CH 2-6元芳杂环、-CO CH 2-6元芳杂环、-COCH 2CH 2-6元芳杂环、-CONR K1R K2、5元杂环基、6元杂环基、甲氧基、C 5环烷基氧基、苯基氧基、6元杂芳基氧基或6元杂环基氧基;
- 根据权利要求1-48任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:所述K中的每个芳杂环、杂环、杂环基、芳环、芳基、环烷基相同或不同,其中每个芳杂环、杂环或杂环基中含有1个N原子。
- 根据权利要求1-49任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:每个R K彼此独立地选自下列基团:-CN、OH、-NH 2、C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、F取代的C 1-3烷基、Cl取代的C 1-3烷基、F取代的C 1-3烷氧基或Cl取代的C 1-3烷氧基。
- 根据权利要求1-50任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:每个R K彼此独立地选自下列基团:-CN、OH、-NH 2、甲基、乙基、甲氧基或乙氧基。
- 根据权利要求1-51任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:R K1和R K2相同或不同,彼此独立地选自下列基团:-CN、C 1-3烷基、C 1-3烷氧基、C 4-5环烷基、F取代的C 1-3烷基、Cl取代的C 1-3烷基、F取代的C 1-3烷氧基或Cl取代的C 1-3烷氧基。
- 根据权利要求1-52任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:R K1和R K2相同或不同,彼此独立地选自下列基团:-CN、OH、-NH 2、甲基、乙基、甲氧基或乙氧基。
- 根据权利要求1-54任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:所述杂环基、杂环、芳杂环、杂芳基或芳杂基含有1、2或3个杂原子,所述杂原子选自N或O。
- 根据权利要求1-55任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:所述杂环基、杂环、芳杂环、杂芳基或芳杂基含有1或2个杂原子,所述杂原子选自N或O。
- 根据权利要求1-56任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:所述杂环基、杂环、芳杂环、杂芳基或芳杂基是含有1个杂原子的4、5、6、7或8元的环,所述杂原子选自N或O。
- 根据权利要求1-57任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:所述杂环基、杂环、芳杂环、杂芳基或芳杂基是含有2个杂原子4、5、6、7或8元的杂环,所述杂原子选自N或O。
- 根据权利要求1-58任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:所述杂环基、杂环、芳杂环、杂芳基或芳杂基是含有2个杂原子4、5、6、7或8元的环,所述杂原子选自N。
- 根据权利要求1-59任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:所述杂环基、杂环、芳杂环、杂芳基或芳杂基是含有2个杂原子5或6元的环,所述杂原子选自N。
- 根据权利要求1-60任一项所述的式I所示的化合物或药学上可接受的盐,其特征在于:所述杂环基、杂环、芳杂环、杂芳基或芳杂基是含有2个杂原子6元的环,所述杂原子选自N。
- 根据权利要求62所述的式II所示的化合物或药学上可接受的盐,其特征在于:R 22选自H、F、Cl、Br、、CN、-C 1-3烷基、-C 1-3烷氧基、-O(CH 2) m-C 1-3烷基或-O(CH 2) m-C 1-3烷氧基,每个C 1-3烷基和每个C 1-3烷氧基均可不取代或者被F、Cl、Br、C 1-3烷基或C 1-3烷氧基取代;R 21选自H、NH 2或甲基;R 23选自H、NH 2、甲基或甲氧基。
- 根据权利要求62或63所述的式II所示的化合物或药学上可接受的盐,其特征在于:R 22选自H、F、Cl、Br、、CN、-C 1-3烷基、-C 1-3烷氧基、-O(CH 2) m-C 1-3烷基或-O(CH 2) m-C 1-3烷氧基,每个C 1-3烷基和每个C 1-3烷氧基均可不取代或者被F、Cl、Br、C 1-3烷基或C 1-3烷氧基取代;R 21选自H;R 23选自甲氧基。
- 根据权利要求62-64任一项所述的式II所示的化合物或药学上可接受的盐,其特征在于:R 22选自H、F、Cl、CN、甲基、乙基、甲氧基、乙氧基、-O(CH 2) m甲基、-O(CH 2) m乙基、-O(CH 2) m甲氧基或-O(CH 2) m乙氧基,每个甲基、乙基、甲氧基和乙氧基均可不取代或者被F、Cl、Br、甲基、乙基、甲氧基或乙氧基取代;
- 权利要求62-65任一项所述的式II所示的化合物或药学上可接受的盐,其特征在于:m=1或2。
- 一种药物组合物,包含有治疗有效量的权利要求1-68任一项所述的化合物或其药学上可接受的盐,和至少一种药学上可接受的辅料。
- 权利要求1-68任一项所述的化合物或其药学上可接受的盐及权利要求69所述的药物组合物用于制备药物的用途.
- 根据权利要求70所述的用途,所述药物用于治疗、阻止或预防由RET基因、RET激酶蛋白或其任何一种或几种的突变、表达、活性或水平的失调导致的疾病或不适。
- 根据权利要求71所述的用途,其中,RET基因中的一个或多个点突变导致在以下一个或多个氨基酸位置具有一个或多个氨基酸替换的RET蛋白的翻译:2、3、4、5、6、7、8、11、12、13、20、32、34、40、56、64、67、114、136、145、180、200、292、294、321、330、338、360、373、393、423、432、446、505、506、510、511、513、515、525、531、532、533、550、591、593、595、600、602、603、606、609、611、616、618、619、620、623、624、630、631、632、633、634、635、636、640、641、648、649、664、665、666、 675、686、689、691、694、700、706、713、732、736、748、750、765、766、768、769、770、771、777、778、781、788、790、791、802、804、805、806、810、818、819、823、836、841、843、844、848、852、865、870、873、876、881、882、883、884、886、891、897、898、900、901、904、905、907、908、911、912、918、919、921、922、930、961、972、981、982、1009、1015、1017、1041、1062、1064和1096。
- 根据权利要求71所述的用途,其中,RET基因中的一个或多个点突变导致在以下一个或多个氨基酸位置具有一个或多个氨基酸替换的RET蛋白的翻译:32、34、40、56、64、67、114、145、292、321、330、338、360、393、423、446、510、511、513、515、525、531、532、533、550、591、593、595、600、602、603、606、609、611、616、618、619、620、623、624、630、631、632、634、635、636、640、641、648、649、664、665、666、675、686、689、691、694、700、706、713、732、736、748、750、765、766、768、769、770、771、777、778、781、788、790、791、804、805、806、810、818、819、823、826、833、836、841、843、844、848、852、865、870、873、876、881、883、884、886、891、897、898、900、901、904、905、907、908、911、912、918、919、921、922、930、961、972、981、982、1009、1015、1017、1041、1064和1096。
- 根据权利要求71所述的用途,其中RET基因中的一个或多个点突变导致含有以下一个或多个氨基酸取代的RET蛋白的转译:S32L、D34S、L40P、L56M、P64L、R67H、R114H、V145G、V292M、G321R、R330Q、T338I、R360W、F393L、G423R、G446R、A510V、E511K、G513D、C515S、C515W、R525W、C531R、G533C、G533S、G550E、V591I、G593E、E595D、E595A、R600Q、I602V、K603Q、K603E、Y606C、C609C、C609Y、C609S、C609G、C609R、C609F、C609W、C611R、C611S、C611G、C611Y、C611F、C611W、E616Q、C618S、C618Y、C618R、C618G、C618F、C618W、F619F、C620S、C620W、C620R、C620G、C620L、C620Y、C620F、E623K、D624N、C630A、C630R、C630S、C630Y、C630F、C630W、D631N、D631Y、D631A、D631G、D631V、D631E、E632K、E632G、C634W、C634Y、C634S、C634R、C634F、C634G、C634L、C634A、C634T、R635G、T636P、T636M、A640G、A641S、A641T、V648I、S649L、A664D、H665Q、K666E、K666M、K666N、K666R、T675T S686N、S689T、G691S、R694Q、M700L、V706M、V706A、E713K、E732K、G736R、G748C、A750P、S765P、P766S、P766M、E768Q、E768D、L769L、R770Q、D771N、N777S、V778I、Q781R、I788I、L790F、Y791F、Y791N、V804L、V804M、V804E、E805K、Y806E、Y806F、Y806S、Y806G、Y806C、Y806H、Y806N、Y806Y、G810R、G810S、G810A、E818K、S819I、G823E、Y826M、Y826S、R833C、S836S、P841L、P841P、E843D、R844W、R844Q、R844L、M848T、I852M、L865V、L870F、R873W、A876V、L881V、A883F、A883S、A883T、E884K、R886W、S891A、S891S、R897Q、D898V、Y900F、E901K、S904F、S904S、S904C、Y905F、K907E、K907M、R908K、G911D、R912P、R912Q、M918T、M918V、M918L、A919V、E921K、S922P、S922Y、T930M、F961L、R972G、Y981F、R982C、Ml009V、Y1015F、D1017N、V1041G、M1064T和Y1096F。
- 根据权利要求71所述的用途,其中,RET基因中的一个或多个点突变发生在人类RET基因的一个或多个外显子10、11、13、14、15和16中。
- 根据权利要求75所述的用途,其中,所述RET基因融合选自:BCR-RET、CLIP 1-RET、 KIF5B-RET、CCDC6-RET、NCOA4-RET、TRIM33-RET、ERC1-RET、FGFR1OP-RET、RET-MBD1、RET-RAB61P2、RET-PRKAR1A、RET-TRIM24、RET-GOLGA5、HOOGA5。KIAA1217-RET、MPRIP-RET、HRH4-RET、RIA-RET、RET-PTC4、FRMD4A-RET、SQSTM1-RET、AFAP1L2-RET、PPFIBP2-RET、EML4-RET、PARD3-RET、MYH10-RET、HTIF1/RET、AFAP1-RET、RASGEF1A-RET、TEL-RET。
- 根据权利要求71-76任一项所述的用途,,RET基因、RET激酶蛋白或其任何一种或几种的突变、表达、活性或水平的失调是RET基因融合。
- 根据权利要求70-77任一项所述的用途,所述由RET基因、RET激酶蛋白或其任何一种或的表达、活性或水平的失调导致的疾病或不适是癌症或癌转移。
- 根据权利要求70-78任一项所述的用途,所述由RET基因、RET激酶蛋白或其任何一种的表达、活性或水平的失调导致的疾病或不适选自以下一种或多种下列病症:肺癌、乳头状甲状腺癌、髓样甲状腺癌、分化型甲状腺癌、复发性甲状腺癌、难分化甲状腺癌、2A或2B型多发性内分泌肿瘤(分别为MEN2A或MEN2B)、嗜铬细胞瘤、甲状旁腺增生、乳腺癌、结直肠癌、乳头状肾细胞癌、胃肠道神经节细胞瘤病(分别为MEN2A或MEN2B型)、嗜铬细胞瘤、甲状旁腺增生、乳腺癌、结直肠癌、乳头状肾细胞癌、胃肠道神经节细胞瘤病及其组合。
- 一种治疗、阻止或预防由RET活性介导的疾病或病症的方法,其包括:(1)确定疾病或不适是否与RET基因、RET激酶或其任何一种或多种的表达、活性或水平失调有关;以及(2)如果确定确定疾病或不适与RET基因、RET激酶或其任何一种或多种的表达、活性或水平的失调有关,则向患者给予有效剂量的权利要求1-68中任一项所述的化合物或其药学上可接受的盐或权利要求69中所述的药物组合物。
- 根据权利要求73中所述的方法,其中:所述由RET活性介导的疾病或病症是癌症和/或癌转移。
- 根据权利要求80或81所述的方法,其中,RET基因中的一个或多个点突变导致在以下一个或多个氨基酸位置具有一个或多个氨基酸替换的RET蛋白的翻译:2、3、4、5、6、7、8、11、12、13、20、32、34、40、56、64、67、114、136、145、180、200、292、294、321、330、338、360、373、393、423、432、446、505、506、510、511、513、515、525、531、532、533、550、591、593、595、600、602、603、606、609、611、616、618、619、620、623、624、630、631、632、633、634、635、636、640、641、648、649、664、665、666、675、686、689、691、694、700、706、713、732、736、748、750、765、766、768、769、770、771、777、778、781、788、790、791、802、804、805、806、810、818、819、823、836、841、843、844、848、852、865、870、873、876、881、882、883、884、886、891、897、898、900、901、904、905、907、908、911、912、918、919、921、922、930、961、972、981、982、1009、1015、1017、1041、1062、1064和1096。
- 根据权利要求80-82任一项所述的方法,其中,RET基因中的一个或多个点突变导致在以下一个或多个氨基酸位置具有一个或多个氨基酸替换的RET蛋白的翻译:32、34、40、56、64、67、114、145、292、321、330、338、360、393、423、446、510、511、513、515、525、531、532、533、550、591、593、595、600、602、603、606、609、611、616、618、619、620、623、624、630、631、632、634、635、636、640、641、648、649、664、665、666、675、686、689、691、694、700、706、713、732、736、748、750、765、766、768、 769、770、771、777、778、781、788、790、791、804、805、806、810、818、819、823、826、833、836、841、843、844、848、852、865、870、873、876、881、883、884、886、891、897、898、900、901、904、905、907、908、911、912、918、919、921、922、930、961、972、981、982、1009、1015、1017、1041、1064和1096。
- 根据权利要求80-83任一项所述的方法,其中RET基因中的一个或多个点突变导致含有以下一个或多个氨基酸取代的RET蛋白的转译:S32L、D34S、L40P、L56M、P64L、R67H、R114H、V145G、V292M、G321R、R330Q、T338I、R360W、F393L、G423R、G446R、A510V、E511K、G513D、C515S、C515W、R525W、C531R、G533C、G533S、G550E、V591I、G593E、E595D、E595A、R600Q、I602V、K603Q、K603E、Y606C、C609C、C609Y、C609S、C609G、C609R、C609F、C609W、C611R、C611S、C611G、C611Y、C611F、C611W、E616Q、C618S、C618Y、C618R、C618G、C618F、C618W、F619F、C620S、C620W、C620R、C620G、C620L、C620Y、C620F、E623K、D624N、C630A、C630R、C630S、C630Y、C630F、C630W、D631N、D631Y、D631A、D631G、D631V、D631E、E632K、E632G、C634W、C634Y、C634S、C634R、C634F、C634G、C634L、C634A、C634T、R635G、T636P、T636M、A640G、A641S、A641T、V648I、S649L、A664D、H665Q、K666E、K666M、K666N、K666R、T675T S686N、S689T、G691S、R694Q、M700L、V706M、V706A、E713K、E732K、G736R、G748C、A750P、S765P、P766S、P766M、E768Q、E768D、L769L、R770Q、D771N、N777S、V778I、Q781R、I788I、L790F、Y791F、Y791N、V804L、V804M、V804E、E805K、Y806E、Y806F、Y806S、Y806G、Y806C、Y806H、Y806N、Y806Y、G810R、G810S、G810A、E818K、S819I、G823E、Y826M、Y826S、R833C、S836S、P841L、P841P、E843D、R844W、R844Q、R844L、M848T、I852M、L865V、L870F、R873W、A876V、L881V、A883F、A883S、A883T、E884K、R886W、S891A、S891S、R897Q、D898V、Y900F、E901K、S904F、S904S、S904C、Y905F、K907E、K907M、R908K、G911D、R912P、R912Q、M918T、M918V、M918L、A919V、E921K、S922P、S922Y、T930M、F961L、R972G、Y981F、R982C、Ml009V、Y1015F、D1017N、V1041G、M1064T和Y1096F。
- 根据权利要求80-84任一项所述的方法,其中,RET基因中的一个或多个点突变发生在人类RET基因的一个或多个外显子10、11、13、14、15和16中。
- 根据权利要求80-85任一项所述的方法,其中,所述RET基因融合选自:BCR-RET、CLIP 1-RET、KIF5B-RET、CCDC6-RET、NCOA4-RET、TRIM33-RET、ERC1-RET、FGFR1OP-RET、RET-MBD1、RET-RAB61P2、RET-PRKAR1A、RET-TRIM24、RET-GOLGA5、HOOGA5。KIAA1217-RET、MPRIP-RET、HRH4-RET、RIA-RET、RET-PTC4、FRMD4A-RET、SQSTM1-RET、AFAP1L2-RET、PPFIBP2-RET、EML4-RET、PARD3-RET、MYH10-RET、HTIF1/RET、AFAP1-RET、RASGEF1A-RET、TEL-RET。
- 根据权利要求80-86任一项所述的方法,RET基因、RET激酶蛋白或其任何一种或几种的突变、表达、活性或水平的失调是RET基因融合。
- 根据权利要求80-87任一项所述的方法,其中:所述由RET活性介导的疾病选自一种或多种下列疾病:肺癌、乳头状甲状腺癌、髓样甲状腺癌、分化型甲状腺癌、复发性甲状腺癌、难分化甲状腺癌、2A或2B型多发性内分泌肿瘤(分别为MEN2A或MEN2B)、嗜铬细胞瘤、甲状旁腺增生、乳腺癌、结直肠癌、乳头状肾细胞癌、胃肠道神经节细胞瘤病(分别 为MEN2A或MEN2B型)、嗜铬细胞瘤、甲状旁腺增生、乳腺癌、结直肠癌、乳头状肾细胞癌、胃肠道神经节细胞瘤病及其组合。
- 一种如下式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物或药学上可接受的盐:其中,X 1、X 2、X 3、X 4、X 5、X 6、X 7相同或不同,彼此独立地选自CR 1或N;X 8选自CR 1R 1’或NR 1;其中每一个R 1和R 1’相同或不同,彼此独立地选自H、卤素、CN、OH,无取代或任选被一个、两个或更多个R a取代的下列基团:C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7;A选自H、卤素、CN、OH,NH 2,无取代或任选被一个、两个或更多个R b取代的下列基团:C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7;D、E相同或不同,彼此独立地选自H、卤素、CN、OH、-O-R 2,无取代或任选被一个、两个或更多个R c取代的下列基团:C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基,条件是D和E中的至少一个选自-O-R 2;R 2选自H,无取代或任选被一个、两个或更多个R d取代的下列基团:C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基;G选自无取代或任选被一个、两个或更多个R e取代的下列基团:C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基或3-20元杂环基氧基;K选自无取代或任选被一个、两个或更多个R f取代的下列基团:H、卤素、CN、OH,无取代或任选被一个、两个或更多个R g取代的下列基团:C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7;每一个R 2相同或不同,彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、-C(O)R 4、-S(O) 2R 6;每一个R 3相同或不同,彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷 基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、-C(O)R 4、-S(O) 2R 6;或者,R 2和R 3与所连的N原子一起形成5-20元杂芳基或3-20元杂环基;每一个R 4相同或不同,彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3;每一个R 5相同或不同,彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基羰基、C 2-40烯基羰基、C 2-40炔基羰基、C 3-40环烷基羰基、C 3-40环烯基羰基、C 3-40环炔基羰基、C 6-20芳基羰基、5-20元杂芳基羰基、3-20元杂环基羰基;每一个R 6相同或不同,彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3;每一个R 7相同或不同,彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基;每一个R a、R b、R c、R d、R e、R f相同或不同,彼此独立地选自卤素、CN、OH、SH、氧代(=O)、NO 2,无取代或任选被一个、两个或更多个R g取代的下列基团:C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7;每一个R g相同或不同,彼此独立地选自卤素、CN、OH、SH、氧代(=O)、NO 2,无取代或任选被一个、两个或更多个R h取代的下列基团:C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7;或者,当环状基团(包括但不限于C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、3-20元杂环基等)的不同位置被两个或更多个取代基取代时,所述取代基中的两个也可以与所述环状基团形成桥环,其中所述桥环中除桥头原子之外的桥原子可以包含1、2、3、4或5个选自CH 2、O、NH的二价基团;每一个R h相同或不同,彼此独立地选自卤素、CN、OH、SH、氧代(=O)、NO 2、无取代或任选被一个、两个或更多个R g取代的下列基团:C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7;或者,当环状基团(包括但不限于C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、3-20元杂环基等)的不同位置被两个或更多个取代基取代时,所述取代基中的两个也可以与所述环状基团形成桥环,其中所述桥环中除桥头原子之外的桥原子可以包含1、2、3、4或5个选自CH 2、 O、NH的二价基团;或者,当一个原子(如碳原子)被两个或更多个取代基取代时,所述取代基中的两个也可以与其共同连接的原子形成环状基团(包括但不限于C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、3-20元杂环基等)。
- 根据权利要求89所述的化合物,其特征在于,X 1、X 2、X 3、X 4、X 5、X 6、X 7相同或不同,彼此独立地选自CR 1或N;例如,X 1,X 2,X 3,X 4、X 5、X 6、X 7中的至少一个为N,;X 8选自CR 1R 1’或NR 1;每一个R 1和R 1’相同或不同,彼此独立地选自H、卤素、CN、OH、C 1-6烷基、C 3-10环烷基、C 1-6烷基氧基;A选自H、卤素、CN、OH、C 1-6烷基、C 1-6烷基氧基;D、E相同或不同,彼此独立地选自H或-O-R 2,条件是D和E中的至少一个选自-O-R 2;R 2选自无取代或任选被一个、两个或更多个被R d取代的C 1-6烷基;每一个R a、R b、R c、R d、R e、R f相同或不同,彼此独立地选自卤素、CN、OH,无取代或任选被一个、两个或更多个R g取代的下列基团:C 1-6烷基、C 1-6烷基氧基、C 3-10环烷基、C 3-10环烷基氧基;每一个R g相同或不同,彼此独立地选自卤素或C 3-10环烷基;G选自C 3-10环烷基、C 6-14芳基、5-14元杂芳基、3-10元杂环基;K选自-C 1-6烷基-C 3-10环烷基、-C 1-6烷基-C 6-14芳基、-C 1-6烷基-5-14元杂芳基、-C 1-6烷基-3-10元杂环基,其中所述C 3-10环烷基、C 6-14芳基、5-14元杂芳基、3-10元杂环基的环上还任选被一个、两个或更多个C 1-6烷基或C 1-6烷基氧基取代。
- 权利要求94所述式I-1或式I-2所示的化合物用于制备权利要求89-92任一项所述式I所示化合物的用途。
- 一种药物组合物,其包含治疗有效量的权利要求89-92任一项所述式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物或药学上可接受的盐中的至少一种。
- 权利要求89-92任一项所述的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、或药学上可接受的盐中的至少一种在制备用于治疗RET激酶介导的疾病的药物中的用途;或者,用于抑制RET激酶活性的药物中的用途;或者,在制备用于治疗癌症和/或抑制与特定癌症相关的转移的药物中的用途;或者,在制备用于治疗肠易激综合征(IBS)或与IBS相关的疼痛的药物中的用途;或者,在制备用于向癌症患者提供支持护理的药物中的用途;或者,在制备用于治疗RET相关疾病或病症的药物中的用途。
- 一种如下式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物或药学上可接受的盐:其中,X 1、X 2、X 3、X 4、X 5、X 6、X 7相同或不同,彼此独立地选自CR 1或N;X 8选自CR 1R 1’或NR 1;其中每一个R 1和R 1’相同或不同,彼此独立地选自H、卤素、CN、OH,无取代或任选被一个、两个或更多个R a取代的下列基团:C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7;A选自H、卤素、CN、OH,NH 2,无取代或任选被一个、两个或更多个R b取代的下列 基团:C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7;D、E相同或不同,彼此独立地选自H、卤素、CN、OH、-O-R 21,无取代或任选被一个、两个或更多个R c取代的下列基团:C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、NH 2,条件是D和E中的至少一个选自-O-R 21;R 21选自H,无取代或任选被一个、两个或更多个R d取代的下列基团:C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基;G选自无取代或任选被一个、两个或更多个R e取代的下列基团:C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基或3-20元杂环基氧基;K选自无取代或任选被一个、两个或更多个R f取代的下列基团:H、卤素、CN、OH,无取代或任选被一个、两个或更多个R g取代的下列基团:C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7;每一个R 2相同或不同,彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、-C(O)R 4、-S(O) 2R 6;每一个R 3相同或不同,彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、-C(O)R 4、-S(O) 2R 6;或者,R 2和R 3与所连的N原子一起形成5-20元杂芳基或3-20元杂环基;每一个R 4相同或不同,彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3;每一个R 5相同或不同,彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基羰基、C 2-40烯基羰基、C 2-40炔基羰基、C 3-40环烷基羰基、C 3-40环烯基羰基、C 3-40环炔基羰基、C 6-20芳基羰基、5-20元杂芳基羰基、3-20元杂环基羰基;每一个R 6相同或不同,彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3;每一个R 7相同或不同,彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基;每一个R a、R b、R c、R d、R e、R f相同或不同,彼此独立地选自卤素、CN、OH、SH、氧代(=O)、NO 2,无取代或任选被一个、两个或更多个R g取代的下列基团:C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7;每一个R g相同或不同,彼此独立地选自卤素、CN、OH、SH、氧代(=O)、NO 2,无取代或任选被一个、两个或更多个R h取代的下列基团:C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40 环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7;或者,当环状基团(包括但不限于C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、3-20元杂环基等)的不同位置被两个或更多个取代基取代时,所述取代基中的两个也可以与所述环状基团形成桥环,其中所述桥环中除桥头原子之外的桥原子可以包含1、2、3、4或5个选自CH 2、O、NH的二价基团;每一个R h相同或不同,彼此独立地选自卤素、CN、OH、SH、氧代(=O)、NO 2、无取代或任选被一个、两个或更多个R g取代的下列基团:C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7;或者,当环状基团(包括但不限于C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、3-20元杂环基等)的不同位置被两个或更多个取代基取代时,所述取代基中的两个也可以与所述环状基团形成桥环,其中所述桥环中除桥头原子之外的桥原子可以包含1、2、3、4或5个选自CH 2、O、NH的二价基团;或者,当一个原子(如碳原子)被两个或更多个取代基取代时,所述取代基中的两个也可以与其共同连接的原子形成环状基团(包括但不限于C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、3-20元杂环基等)。
- 根据权利要求98所述的化合物,其特征在于,X 1、X 2、X 3、X 4、X 5、X 6、X 7相同或不同,彼此独立地选自CR 1或N;例如,X 1,X 2,X 3,X 4、X 5、X 6、X 7中的至少一个为N,;X 8选自CR 1R 1’或NR 1;每一个R 1和R 1’相同或不同,彼此独立地选自H、卤素、CN、OH、C 1-6烷基、C 3-10环烷基、C 1-6烷基氧基;A选自H、卤素、CN、OH、C 1-6烷基、C 1-6烷基氧基;D、E相同或不同,彼此独立地选自H、卤素、CN、NH 2或-O-R 21,条件是D和E中的至少一个选自-O-R 2;R 21选自无取代或任选被一个、两个或更多个被R d取代的C 1-6烷基;每一个R a、R b、R c、R d、R e、R f相同或不同,彼此独立地选自卤素、CN、OH,无取代或任选被一个、两个或更多个R g取代的下列基团:C 1-6烷基、C 1-6烷基氧基、C 3-10环烷基、C 3-10环烷基氧基;每一个R g相同或不同,彼此独立地选自卤素或C 3-10环烷基;G选自C 3-10环烷基、C 6-14芳基、5-14元杂芳基、3-10元杂环基,例如6-7元具有单环、双环、桥环结构的杂环基,其可包含1、2、3个独立选自N、O和S的杂原子;K选自-C 1-6烷基-C 3-10环烷基、-C 1-6烷基-C 6-14芳基、-C 1-6烷基-5-14元杂芳基、-C 1-6烷基-3-10元杂环基、-C(O)NH 2、-C(O)-C 3-10环烷基、-C(O)-C 6-14芳基、-C(O)-5-14元杂芳基、-C(O)-3-10元杂环基、-C(O)-C 1-6烷基-C 3-10环烷基、-C(O)-C 1-6烷基-C 6-14芳基、-C(O)-C 1-6烷基-5-14元杂芳基、-C(O)-C 1-6烷基-3-10元杂环基,其中所述C 3-10环烷基、C 6-14芳基、5-14元杂芳基、3-10元杂环基、-C(O)-C 3-10环烷基、-C(O)-C 6-14芳基、-C(O)-5-14元杂芳基、-C(O)-3-10元杂环基、-C(O)-C 1-6烷基-C 3-10环烷基、-C(O)-C 1-6烷基-C 6-14芳基、-C(O)-C 1-6烷基-5-14元杂芳基、-C(O)-C 1-6烷基-3-10元杂环基的环上上或非环基团,或-C(O)NH 2还任选被一个、两个或更多个选自OH、卤素、CN、C 1-6烷基、C 1-6烷基氧基的基团取代;其中,所述杂环基可以为吡啶基,芳基可以为苯基。
- 权利要求104所述式I-1或式I-2所示的化合物用于制备权利要求98-101任一项所 述式I所示化合物的用途。
- 一种药物组合物,其包含治疗有效量的权利要求98-101任一项所述式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物或药学上可接受的盐中的至少一种。
- 权利要求98-101任一项所述的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、或药学上可接受的盐中的至少一种在制备用于治疗RET激酶介导的疾病的药物中的用途;或者,用于抑制RET激酶活性的药物中的用途;或者,在制备用于治疗癌症和/或抑制与特定癌症相关的转移的药物中的用途;或者,在制备用于治疗肠易激综合征(IBS)或与IBS相关的疼痛的药物中的用途;或者,在制备用于向癌症患者提供支持护理的药物中的用途;或者,在制备用于治疗RET相关疾病或病症的药物中的用途。
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WO2023280073A1 (zh) | 2021-07-09 | 2023-01-12 | 北京志健金瑞生物医药科技有限公司 | 含氮多环稠环类化合物的制备方法及其中间体和用途 |
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