WO2022007824A1 - 一种具有降解btk激酶的化合物及其制备方法和药学上的应用 - Google Patents
一种具有降解btk激酶的化合物及其制备方法和药学上的应用 Download PDFInfo
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- WO2022007824A1 WO2022007824A1 PCT/CN2021/104905 CN2021104905W WO2022007824A1 WO 2022007824 A1 WO2022007824 A1 WO 2022007824A1 CN 2021104905 W CN2021104905 W CN 2021104905W WO 2022007824 A1 WO2022007824 A1 WO 2022007824A1
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- WIPO (PCT)
- Prior art keywords
- azetidine
- substituted
- compound
- pyrazolo
- pyrimidin
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- MJWRGADWXLHZAZ-UHFFFAOYSA-N Nc1c(c(-c(cc2F)ccc2Oc2ccccc2)n[n]2C(CC3)CCN3C(CC3)CCN3C3CNC3)c2ncn1 Chemical compound Nc1c(c(-c(cc2F)ccc2Oc2ccccc2)n[n]2C(CC3)CCN3C(CC3)CCN3C3CNC3)c2ncn1 MJWRGADWXLHZAZ-UHFFFAOYSA-N 0.000 description 1
- KIUDGIQIVLMDIS-UHFFFAOYSA-N Nc1ncnc2c1c(-c(cc1)ccc1Oc1ccc(C(F)(F)F)cc1)n[n]2C(CC1)CCN1C(C1)CN1C(C1)CN1c(cc1)cc(C(N2C(CCC(N3)=O)C3=O)=O)c1C2=O Chemical compound Nc1ncnc2c1c(-c(cc1)ccc1Oc1ccc(C(F)(F)F)cc1)n[n]2C(CC1)CCN1C(C1)CN1C(C1)CN1c(cc1)cc(C(N2C(CCC(N3)=O)C3=O)=O)c1C2=O KIUDGIQIVLMDIS-UHFFFAOYSA-N 0.000 description 1
- KJSLFARRNHNNRJ-UHFFFAOYSA-N Nc1ncnc2c1c(-c(cc1)ccc1Oc1ccccc1)n[n]2C(C1)CC1(CC1)CCN1C(C1)CN1C(C1)CN1c(cc1)cc(C(N2C(CCC(N3)=O)C3=O)=O)c1C2=O Chemical compound Nc1ncnc2c1c(-c(cc1)ccc1Oc1ccccc1)n[n]2C(C1)CC1(CC1)CCN1C(C1)CN1C(C1)CN1c(cc1)cc(C(N2C(CCC(N3)=O)C3=O)=O)c1C2=O KJSLFARRNHNNRJ-UHFFFAOYSA-N 0.000 description 1
- NAQBHAHRUAKFPA-UHFFFAOYSA-N Nc1ncnc2c1c(-c(cc1)ccc1Oc1ccccc1)n[n]2C(CC1)CCN1C1CCN(CC2CCNCC2)CC1 Chemical compound Nc1ncnc2c1c(-c(cc1)ccc1Oc1ccccc1)n[n]2C(CC1)CCN1C1CCN(CC2CCNCC2)CC1 NAQBHAHRUAKFPA-UHFFFAOYSA-N 0.000 description 1
- JYSHFOUKGFDRBE-UHFFFAOYSA-N Nc1ncnc2c1c(-c(cc1)ccc1Oc1ccccc1)n[n]2C(CC1)CCN1C1CN(CC(C2)(CN2c(c(F)c2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)F)C1 Chemical compound Nc1ncnc2c1c(-c(cc1)ccc1Oc1ccccc1)n[n]2C(CC1)CCN1C1CN(CC(C2)(CN2c(c(F)c2)cc(C(N3C(CCC(N4)=O)C4=O)=O)c2C3=O)F)C1 JYSHFOUKGFDRBE-UHFFFAOYSA-N 0.000 description 1
- DFPFXSLGYCGFQK-UHFFFAOYSA-N O=C(c1c(C2)cccc1I)N2C(CCC(N1)=O)C1=O Chemical compound O=C(c1c(C2)cccc1I)N2C(CCC(N1)=O)C1=O DFPFXSLGYCGFQK-UHFFFAOYSA-N 0.000 description 1
- BKIUJJLYXXEGFT-UHFFFAOYSA-N O=C(c1cccc(I)c1C1)N1C(CCC(N1)=O)C1=O Chemical compound O=C(c1cccc(I)c1C1)N1C(CCC(N1)=O)C1=O BKIUJJLYXXEGFT-UHFFFAOYSA-N 0.000 description 1
- DDWBRNXDKNIQDY-UHFFFAOYSA-N c1c[s]c2ncncc12 Chemical compound c1c[s]c2ncncc12 DDWBRNXDKNIQDY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- 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
-
- 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 present invention relates to a compound of general formula (I) or its stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and intermediate and preparation method thereof, as well as in Use in BTK-related diseases such as tumors or autoimmune diseases.
- BTK Bruton's tyrosine kinase
- BCR B cell antigen receptor
- BTK mutations cause downstream tumor cell proliferation, differentiation, and activation of signaling pathways such as angiogenesis, leading to X-linked agammaglobulinemia, non-Hodgkin lymphoma (NHL), and many B-cell malignancies, including chronic lymphoid malignancies.
- CLL Cellular leukemia
- mantle cell lymphoma mantle cell lymphoma
- diffuse large B-cell lymphoma Since it is mainly expressed in B cells and myeloid cells, BTK is a target with better targeting and safety.
- PROTAC proteolysis targeting chimera
- PROTAC proteolysis targeting chimera
- the present invention develops a BTK inhibitor with novel structure, good efficacy, high bioavailability and safety, which is used for the treatment of BTK-related diseases such as tumors or autoimmune system diseases.
- the present invention develops a PROTAC compound with novel structure, good efficacy, high bioavailability, safety, BTK inhibitor that can inhibit or degrade BTK and E3 ubiquitin ligase, for treating BTK-related diseases such as tumors or autoimmune disease.
- the present invention relates to a compound of general formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
- L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5- or a bond;
- L is selected -Cy1-CH 2 -Cy2-;
- Ak1, Ak2, Ak3, Ak4 Ak5 are each independently selected from CH 2, O or a bond;
- Cy1, Cy2, Cy3, and Cy4 are each independently selected from a 3- to 12-membered heterocycle, a 3- to 12-membered cycloalkyl, a 6- to 10-membered aryl, or a bond
- the heterocycle contains 1 to 4 selected from O, S, heteroatom of N;
- Cy1, Cy2, Cy3, and Cy4 are each independently selected from bond, 4-7 membered heteromonocycle, 5-10 membered heterocycle, 6-12 membered heterospirocycle, 7-10 membered heterobridge ring, 4-7 membered monocycloalkyl, 5-10 membered cycloalkyl, 6-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl or 6-10 membered aryl, the aryl, Cycloalkyl (monocycloalkyl, p-cycloalkyl, spirocycloalkyl and bridged cycloalkyl), heteromonocycle, heterocycle, heterospiro or heterobridge optionally further selected from 0 to 4 H, F, Cl, Br, I, OH, NH 2 , oxo, CF 3 , COOH, CN, C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, halogen substituted C 1-4 alky
- Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or substituted or unsubstituted one of the following groups: phenyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo Butyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-cyclobutyl , cyclopropyl and cyclopentyl, cyclopropyl and cyclohexyl, cyclobutyl spiro cyclobutyl, cyclobutyl spiro cyclobutyl, cyclobutyl spiro cyclopentyl, cyclobutyl spiro cycl
- Cy1, Cy2, Cy3 and Cy4 cannot be keys at the same time
- Cy1, Cy2, Cy2, Ak3, Cy3, Ak4, Cy4, Ak5 have 4 or more non-bonds, at least one of Cy1, Cy2, Cy3 and Cy4 is not piperidine, piperazine, pyrimidine or pyridine ;
- B is selected from B1-W1-B2-B3-B4-;
- B1 is selected from a 6-membered heteroaromatic ring or phenyl, said heteroaromatic ring or phenyl is further optionally substituted with 0 to 4 R b1 , said heteroaromatic ring containing 1 to 4 a heteroatom selected from O, S, N;
- B1 is selected from phenyl or pyridyl, further optionally substituted with 0 to 4 R b1 ;
- W1 is selected from -O-, -S-, -NH-, -NHCO- or -CONH-;
- W1 is selected from -O-, -NHCO- or -CONH-;
- B2 is selected from a 6-membered heteroaromatic ring or phenyl optionally further optionally substituted with 0 to 4 R b2 , said heteroaromatic ring containing 1 to 4 heteroatoms selected from O, S, N;
- B3 is selected from an 8-10 membered heterocyclic ring optionally further optionally substituted with 0 to 4 R b3 , said heterocyclic ring containing 1 to 4 selected heteroatoms from O, S, N;
- B4 is selected from a 4-10 membered saturated heterocycle
- the saturated heterocycle is selected from a monocycle, a paracycle or a spirocycle
- the saturated heterocycle, monocycle, paracycle or spirocycle is any
- the saturated heterocycle contains 1 to 2 heteroatoms selected from O, S, N;
- B2 is selected from phenyl or pyridyl, further optionally substituted with 0 to 4 R b2 ;
- B3 is selected from one of the following groups, substituted or unsubstituted: imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine, pyrazolopyrazine, imidazotetrahydropyrimidine, pyrazolotetrahydropyrimidine Hydropyrimidine, when substituted, is optionally further optionally substituted with 0 to 4 R b3 ;
- B4 is selected from one of the following groups, substituted or unsubstituted: azetidinyl, azepanyl, piperidine, morpholine, piperazine, cyclopropylazetidinyl , cyclopropylazepine, cyclopropylazepine, cyclopropylpiperidine, cyclobutylazepine, cyclobutylazepine, cyclobutyl Azacyclohexyl, cyclobutylpiperidine, cyclopentylazepinyl, cyclopentylazepinyl, cyclopentylazepinyl, cyclopentylazepinyl, cyclopentylazepinyl, cyclopentylpiperidine , cyclohexyl azetidine, cyclohexyl azetidine, cyclohexyl azetidine, cyclohexyl and piper
- B is selected from
- B is selected from
- B is selected from
- B is selected from Cy1, Cy2, there is at least one selected from 1 to 4 in CF 3 Cy3 and Cy4, COOH, CN, hydroxy-substituted C 1-4 alkyl substituents;
- R b1 , R b2 , R b3 , or R b4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , COOH, CONH 2 , C 1- 4 alkyl, hydroxy substituted C 1-4 alkyl, halogen substituted C 1-4 alkyl or C 1-4 alkoxy, the alkyl and alkoxy are optionally further selected from 0 to 4 Substituted from substituents of H, F, Cl, Br, I, OH, NH 2 , CN, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy, n1, n2, n3, n4 are each independently is selected from 0, 1, 2, 3 or 4;
- R b1 , R b2 , R b3 , or R b4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CONH 2 , CF 3 , COOH, hydroxymethyl , methyl or methoxy, the methyl or methoxy is optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, n1, n2, n3, n4 are each independently is selected from 0, 1, 2, 3 or 4;
- R b1 , R b2 , R b3 , or R b4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , COOH, CONH 2 , C 1- 4 alkyl, hydroxy substituted C 1-4 alkyl, halogen substituted C 1-4 alkyl or C 1-4 alkoxy, the alkyl and alkoxy are optionally further selected from 0 to 4 Substituted from substituents of H, F, Cl, Br, I, OH, NH 2 , CN, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy;
- B is selected from
- B is selected from
- B is selected from
- B is selected from
- B is selected from
- B is selected from
- BL is selected from Cy5 is selected from substituted or unsubstituted one of the following groups: phenyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl cyclohexyl, cyclopentyl and cyclopentyl, cyclopentyl and cyclohexyl, cyclohexyl and cyclohexyl, cyclopropyl and cyclobutyl, cyclopropyl and cyclopentyl, cyclopropyl and cyclohexyl, cyclo Butylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentyl,
- Cy5 is selected from substituted or unsubstituted one of the following groups: When substituted, optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH 2, oxo, CF 3, COOH, CN, methyl, hydroxymethyl or methoxy substituted by a substituent;
- B is selected from B4 is selected from substituted or unsubstituted one of the following groups: azacyclobutyl, azacyclopentyl, When substituted, optionally further optionally substituted by 0 to 4 R b4 ;
- R b4 is each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , CONH 2 , COOH, C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, halogen Substituted C 1-4 alkyl or C 1-4 alkoxy, said alkyl and alkoxy are optionally further selected by 0 to 4 selected from H, F, Cl, Br, I, OH, NH 2 , CN, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent;
- B is selected from B4 is selected from substituted or unsubstituted one of the following groups: When substituted, optionally further optionally substituted with 0-4 of R b4;
- R b4 is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CONH 2 , CF 3 , COOH, hydroxymethyl, methyl or methoxy, said methyl or methyl Oxygen is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I;
- L is selected from bonds, The left side of L is connected to B, and the right side of L is connected to K;
- L is selected from The left side of L is connected to B, and the right side of L is connected to K;
- L is selected from The left side of L is connected to B, and the right side of L is connected to K;
- L is selected from The left side of L is connected to B, and the right side of L is connected to K;
- K is selected from
- K is selected from
- K is selected from
- K is selected from
- K is selected from
- K is selected from
- Ring E is selected from a benzene ring or a 5-6 membered heteroaromatic ring containing 1 to 2 heteroatoms selected from O, S, N;
- Ring E is selected from a benzene ring, pyridine, thiophene, furan, pyrrole, thiazole, oxazole, imidazole, or pyrazole;
- R k1 , R k3 or R k4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CF 3 , CN, COOH, C 1-4 alkyl or C 1 -4 alkoxy;
- n1, n2, n3, and n4 are each independently selected from 0, 1, 2, 3 or 4;
- R k1 , R k3 or R k4 is each independently selected from H, F, Cl, Br, I, OH or NH 2
- p1 or p2 is each independently selected from 0, 1 or 2.
- Ak1, Ak2, Ak3, Ak4 Ak5 are each independently selected from CH 2, O or a bond;
- Cy1, Cy2, Cy3 and Cy4 are each independently selected from 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle, 6-membered heterocycle, 7-membered heterocycle, 8-membered heterocycle, 9-membered heterocycle, 10-membered heterocycle Ring, 11-membered heterocycle, 12-membered heterocycle, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, 8-membered cycloalkyl, 9-membered Cycloalkyl, 10-membered cycloalkyl, 11-membered cycloalkyl, 12-membered cycloalkyl, 6- to 10-membered aryl or bond, the heterocycle, cycloalkyl or aryl optionally further substituted by 0 to 4 Selected from H, F, Cl, Br, I, OH,
- Cy1, Cy2, Cy3 and Cy4 cannot be keys at the same time
- Cy1, Cy2, Cy2, Ak3, Cy3, Ak4, Cy4, Ak5 have 4 or more non-bonds, at least one of Cy1, Cy2, Cy3 and Cy4 is not piperidine, piperazine, pyrimidine or pyridine ;
- B is selected from B1-W1-B2-B3-B4-;
- B1 is selected from 6-membered heteroaromatic ring or phenyl, the heteroaromatic ring or phenyl is further optionally substituted by 0 to 4 R b1 , and the heteroaromatic ring contains 1 to 4 selected from O, S , N heteroatoms;
- W1 is selected from -O-, -S-, -NH-, -NHCO- or -CONH-;
- B2 is selected from 6-membered heteroaromatic ring or phenyl, the heteroaromatic ring or phenyl is optionally further substituted by 0 to 4 R b2 , and the heteroaromatic ring contains 1 to 4 selected from O, S , N heteroatoms;
- B3 is selected from an 8-10 membered heterocyclic ring optionally further substituted by 0 to 4 R b3 , the heterocyclic ring contains 1 to 4 heterocyclic rings selected from O, S, N atom;
- B4 is selected from 4-10 membered saturated heterocycles, and the saturated heterocycles are selected from monocycles, paracycles or spirocycles, and the saturated heterocycles, monocycles, paracycles or spirocycles are optionally further substituted by 0 to 4 substituted with R b4 , the saturated heterocycle contains 1 to 2 heteroatoms selected from O, S, N;
- R b1 , R b2 , R b3 or R b4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , COOH, CONH 2 , C 1-4 alkyl, hydroxy substituted C 1-4 alkyl group, halogen-substituted C 1-4 alkyl group or C 1-4 alkoxy group, the alkyl group and alkoxy group are optionally further selected from 0 to 4 groups selected from H, F, Cl , Br, I, OH, NH 2 , CN, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent;
- Ring E is selected from benzene ring or 5-6 membered heteroaromatic ring, and described heteroaromatic ring contains 1 to 2 heteroatoms selected from O, S, N;
- R k1 , R k3 or R k4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CF 3 , CN, COOH, C 1-4 alkyl or C 1-4 alkoxy;
- n1, n2, n3, and n4 are each independently selected from 0, 1, 2, 3 or 4;
- the compound is not a compound shown in Table A.
- the compound of the above general formula (I) or its stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal wherein
- L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5- or a bond;
- Ak1, Ak2, Ak3, Ak4 Ak5 are each independently selected from CH 2, O or a bond;
- Cy1, Cy2, Cy3 and Cy4 each independent bond, 4-membered heteromonocycle, 5-membered heteromonocycle, 6-membered heteromonocycle, 7-membered heteromonocycle, 5-membered heterocycle, 6-membered heterocycle, 7-membered heterocycle Heterocycle, 8-membered heterocycle, 9-membered heterocycle, 10-membered heterocycle, 6-membered heterospirocycle, 7-membered heterospirocycle, 8-membered heterospirocycle, 9-membered heterospirocycle, 10-membered heterospirocycle Ring, 11-membered heterospirocycle, 12-membered heterospirocycle, 7-membered heterobridged ring, 8-membered heterobridged ring, 9-membered heterobridged ring, 10-membered heterobridged ring, 4-membered monocycloalkyl, 5-membered monocycloalkane base, 6-membered monocycloalkyl, 7-member
- the monocyclic, heterocyclic, heterospirocyclic or heterobridged ring contains 1, 2, 3 or 4 heteroatoms selected from O, S, N;
- B1 is selected from phenyl or pyridyl, and said phenyl or pyridyl is further optionally substituted by 0 to 4 R b1 ;
- W1 is selected from -O-, -NHCO- or -CONH-;
- B2 is selected from phenyl or pyridyl, and said phenyl or pyridyl is further optionally substituted by 0 to 4 R b2 ;
- B3 is selected from one of the following groups, substituted or unsubstituted: imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine, pyrazolopyrazine, imidazotetrahydropyrimidine, pyrazolotetrahydropyrimidine, when substituted , optionally further optionally substituted by 0 to 4 R b3 ;
- B4 is selected from substituted or unsubstituted one of the following groups: azetidine, azetidine, piperidine, morpholine, piperazine, cyclopropylazetidine, cyclopropylazepine Cyclopentyl, cyclopropylazepinyl, cyclopropylpiperidine, cyclobutylazepinyl, cyclobutylazepinyl, cyclobutylazepinyl , cyclobutylazepinyl , cyclobutylpiperidine, cyclopentylazepinyl, cyclopentylazepine, cyclopentylazepine, cyclopentylpiperidine, cyclohexylazepine Heterobutyl, cyclohexylazepine, cyclohexylazepine, cyclohexylpiperidine, azetidine, azetidine, aze
- Ring E is selected from benzene ring, pyridine, thiophene, furan, pyrrole, thiazole, oxazole, imidazole or pyrazole;
- the compound of the above general formula (I) or its stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal wherein
- the compound of the above general formula (I) or its stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal wherein
- Cy1, Cy2, Cy3 and Cy4 are each independently selected from a bond or one of the following groups, substituted or unsubstituted: phenyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutyl and cyclobutyl , cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclohexyl Pentyl, cyclopropylcyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclobutylspirocyclopenty
- R b1 , R b2 , R b3 or R b4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CONH 2 , CF 3 , COOH, hydroxymethyl, methyl or methoxy base, the methyl group or methoxy group is optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I;
- n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, n11, n12 are each independently selected from 0, 1, 2, 3 or 4;
- R k1 , R k3 or R k4 are each independently selected from H, F, Cl, Br, I, OH or NH 2 ;
- p1 or p2 are each independently selected from 0, 1 or 2;
- B4 is selected from substituted or unsubstituted one of the following groups: azetidinyl, azepanyl, morpholine, piperazine, cyclopropylazepine, cyclopropylazepine pentyl, cyclopropylazepinyl, cyclopropylpiperidine, cyclobutylazepinyl, cyclobutylazepinyl, cyclobutylazepinyl, cyclobutylazepinyl, cyclobutyl Butylpiperidine, cyclopentylazepinyl, cyclopentylazepine, cyclopentylazepine, cyclopentylpiperidine, cyclohexylazepine Butyl, cyclohexylazepine, cyclohexylazepine, cyclohexylazepine, cyclohexylpiperidine, azetidine, a
- R b1 , R b2 , R b3 or R b4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , COOH, CONH 2 , C 1-4 alkyl, hydroxy substituted C 1-4 alkyl group, halogen-substituted C 1-4 alkyl group or C 1-4 alkoxy group, the alkyl group and alkoxy group are optionally further selected from 0 to 4 groups selected from H, F, Cl , Br, I, OH, NH 2 , CN, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent;
- n1, n2, n3 are each independently selected from 0, 1, 2, 3 or 4;
- Cy1, Cy2, Cy3 and Cy4 are each independently selected from a bond or one of the following groups, substituted or unsubstituted: phenyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutyl and cyclobutyl , cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclohexyl Pentyl, cyclopropylcyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclobutylspirocyclopenty
- Cy1, Cy2, Cy3 and Cy4 least one by 1 to 4 substituents selected from CF 3, COOH, CN, hydroxy-substituted C 1-4 alkyl substituents;
- R b1 , R b2 , R b3 or R b4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , COOH, CONH 2 , C 1-4 alkyl, hydroxy substituted C 1-4 alkyl group, halogen-substituted C 1-4 alkyl group or C 1-4 alkoxy group, the alkyl group and alkoxy group are optionally further selected from 0 to 4 groups selected from H, F, Cl , Br, I, OH, NH 2 , CN, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent;
- n1, n2, n3, and n4 are each independently selected from 0, 1, 2, 3 or 4;
- the left side of L is connected to B, and the right side of L is connected to K;
- B4 is selected from substituted or unsubstituted one of the following groups: azacyclobutyl, azacyclopentyl, When substituted, optionally further optionally substituted by 0 to 4 R b4 ;
- R b4 is each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , CONH 2 , COOH, C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, halogen Substituted C 1-4 alkyl or C 1-4 alkoxy, said alkyl and alkoxy are optionally further selected by 0 to 4 selected from H, F, Cl, Br, I, OH, NH 2 , CN, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent;
- the left side of L is connected to B, and the right side of L is connected to K;
- B4 is selected from substituted or unsubstituted one of the following groups: When substituted, optionally further optionally substituted with 0-4 of R b4;
- R b4 is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CONH 2 , CF 3 , COOH, hydroxymethyl, methyl or methoxy, said methyl or methyl Oxygen is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I;
- the aforementioned compound of general formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof is a seventeenth embodiment of the present invention.
- Cy5 is selected from substituted or unsubstituted one of the following groups: phenyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl cyclohexyl, cyclopentyl and cyclopentyl, cyclopentyl and cyclohexyl, cyclohexyl and cyclohexyl, cyclopropyl and cyclobutyl, cyclopropyl and cyclopentyl, cyclopropyl and cyclohexyl, cyclo Butylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohe
- Cy5 is selected from substituted or unsubstituted one of the following groups: When substituted, optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH 2, oxo, CF 3, COOH, CN, methyl, hydroxymethyl or methoxy substituted by a substituent;
- Some embodiments of the present invention relate to a compound as described below, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from one of the following structures:
- Some embodiments of the present invention relate to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, optionally, the compound is not is the compound shown in Table A,
- Some embodiments of the present invention relate to a compound of general formula (I), (Ia), (Ib) and (Ic) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic, which
- Ring E is selected from benzene ring or 5-6 membered heteroaromatic ring, and described heteroaromatic ring contains 1 to 2 heteroatoms selected from O, S, N;
- R k1 , R k3 or R k4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CF 3 , CN, COOH, C 1-4 alkyl or C 1-4 alkoxy;
- Some embodiments of the present invention relate to a compound of general formula (I), (Ia), (Ib) and (Ic) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic, which
- Ring E is selected from benzene ring, pyridine, thiophene, furan, pyrrole, thiazole, oxazole, imidazole or pyrazole;
- R k1 , R k3 or R k4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CF 3 , CN, COOH, C 1-4 alkyl or C 1-4 alkoxy;
- Some embodiments of the present invention relate to a compound of general formula (I), (Ia), (Ib) and (Ic) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic, which
- R k1 , R k3 or R k4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CF 3 , CN, COOH, C 1-4 alkyl or C 1-4 alkoxy;
- Some embodiments of the present invention relate to a compound of general formula (I), (Ia), (Ib) and (Ic) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic, which
- Some embodiments of the present invention relate to a compound of general formula (I), (Ia), (Ib) and (Ic) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic, which
- Some embodiments of the present invention relate to a compound of general formula (I), (Ia), (Ib) and (Ic) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic, which
- Some embodiments of the present invention relate to a compound of general formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
- R b1 , R b2 , R b3 or R b4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CONH 2 , CF 3 , COOH, hydroxymethyl, methyl or methoxy base, the methyl group or methoxy group is optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I;
- n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, n11, n12 are each independently selected from 0, 1, 2, 3, or 4.
- Some embodiments of the present invention relate to a compound of general formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
- Some embodiments of the present invention relate to a compound of general formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein B is selected from Cy1, Cy2, Cy3 and Cy4 there is at least one selected from 1-4 CF 3, COOH, CN, hydroxy-substituted C 1-4 alkyl substituents.
- Some embodiments of the present invention relate to a compound of general formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein B is selected from
- Some embodiments of the present invention relate to a compound of general formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
- Cy5 is selected from substituted or unsubstituted one of the following groups: phenyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl cyclohexyl, cyclopentyl and cyclopentyl, cyclopentyl and cyclohexyl, cyclohexyl and cyclohexyl, cyclopropyl and cyclobutyl, cyclopropyl and cyclopentyl, cyclopropyl and cyclohexyl, cyclo Butylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclopent
- Some embodiments of the present invention relate to a compound of general formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
- Cy5 is selected from substituted or unsubstituted one of the following groups: When substituted, optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH 2, oxo, CF 3, COOH, CN, methyl, hydroxymethyl or methoxy Substituents are substituted.
- Some embodiments of the present invention relate to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein B is selected from B4 is selected from substituted or unsubstituted one of the following groups: azacyclobutyl, azacyclopentyl, When substituted, optionally further optionally substituted by 0 to 4 R b4 ;
- R b4 is each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , CONH 2 , COOH, C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, halogen Substituted C 1-4 alkyl or C 1-4 alkoxy, said alkyl and alkoxy are optionally further selected by 0 to 4 selected from H, F, Cl, Br, I, OH, NH 2 , CN, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent.
- Some embodiments of the present invention relate to a compound of general formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein B is selected from B4 is selected from substituted or unsubstituted one of the following groups: When substituted, optionally further optionally substituted with 0-4 of R b4;
- R b4 is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CONH 2 , CF 3 , COOH, hydroxymethyl, methyl or methoxy, said methyl or methyl
- the oxy group is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I.
- Some embodiments of the present invention relate to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
- Some embodiments of the present invention relate to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
- Some embodiments of the present invention relate to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
- Some embodiments of the present invention relate to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
- Some embodiments of the present invention relate to a compound of general formula (I), (Ia), and (Ic) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, in
- Cy1, Cy2, Cy3 and Cy4 are each independently selected from 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle, 6-membered heterocycle, 7-membered heterocycle, 8-membered heterocycle, 9-membered heterocycle, 10-membered heterocycle Ring, 11-membered heterocycle, 12-membered heterocycle, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, 8-membered cycloalkyl, 9-membered Cycloalkyl, 10-membered cycloalkyl, 11-membered cycloalkyl, 12-membered cycloalkyl, 6- to 10-membered aryl or bond, preferably bond, 4-membered heteromonocycle, 5-membered heteromonocycle, 6-membered heteromonocycle Ring, 7-membered heteromono
- Some embodiments of the present invention relate to a compound of general formula (I), (Ia) and (Ic) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
- Cy1, Cy2, Cy3 and Cy4 are each independently selected from substituted or unsubstituted one of the following groups: bond, phenyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutyl and cyclobutyl , cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclohexyl Pentyl, cyclopropylcyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclohexyl,
- Some embodiments of the present invention relate to a compound of general formula (I), (Ia) and (Ic) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
- Some embodiments of the present invention relate to a compound of general formula (Ia) and (Ic) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
- B4 is selected from substituted or unsubstituted one of the following groups: azetidinyl, azepanyl, morpholine, piperazine, cyclopropylazepine, cyclopropylazepine pentyl, cyclopropylazepinyl, cyclopropylpiperidine, cyclobutylazepinyl, cyclobutylazepinyl, cyclobutylazepinyl, cyclobutylazepinyl, cyclobutyl Butylpiperidine, cyclopentylazepinyl, cyclopentylazepine, cyclopentylazepine, cyclopentylpiperidine, cyclohexylazepine Butyl, cyclohexylazepine, cyclohexylazepine, cyclohexylazepine, cyclohexylpiperidine, azetidine, a
- R b4 is each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , COOH, CONH 2 , C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, halogen Substituted C 1-4 alkyl or C 1-4 alkoxy, said alkyl and alkoxy are optionally further selected by 0 to 4 selected from H, F, Cl, Br, I, OH, NH 2 , CN, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent.
- Some embodiments of the present invention relate to a compound of general formula (Ia) and (Ic) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
- B4 is selected from substituted or unsubstituted one of the following groups: azacyclobutyl, azacyclopentyl, When substituted, optionally further optionally substituted by 0 to 4 R b4 ;
- R b4 is each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , CONH 2 , COOH, C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, halogen Substituted C 1-4 alkyl or C 1-4 alkoxy, said alkyl and alkoxy are optionally further selected by 0 to 4 selected from H, F, Cl, Br, I, OH, NH 2 , CN, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent.
- Some embodiments of the present invention relate to a compound of general formula (Ia) and (Ic) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
- B4 is selected from substituted or unsubstituted one of the following groups: When substituted, optionally further optionally substituted with 0-4 of R b4;
- R b4 is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CONH 2 , CF 3 , COOH, hydroxymethyl, methyl or methoxy, said methyl or methyl
- the oxy group is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I.
- Some embodiments of the present invention relate to a compound of general formula (Ib) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
- the left side of L is connected to B, and the right side of L is connected to K.
- Some embodiments of the present invention relate to a compound of general formula (I) and (Ia) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
- Some embodiments of the present invention relate to a compound of general formula (I), (Ia), (Ib) and (Ic) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable of salts or co-crystals, wherein said salts are selected from trifluoroacetic acid salts.
- the present invention relates to a pharmaceutical composition, comprising the compound of the present invention or its stereoisomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and a pharmaceutically acceptable carrier .
- the present invention relates to a compound of the present invention or its stereoisomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals used in the preparation of drugs for the treatment of diseases related to BTK activity or expression. application in medicine.
- the present invention relates to a compound of the present invention or its stereoisomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals for preparing medicines for treating and inhibiting or degrading BTK-related diseases applications in .
- the present invention relates to the use of the compounds of the present invention or their stereoisomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and the diseases are selected from tumors or autoimmune diseases.
- the present invention relates to the application of the compound of the present invention or its stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the tumor is selected from non-Hodgkin's lymphoma, Chronic lymphocytic leukemia, mantle cell lymphoma, B-cell lymphoma, autoimmune disease is selected from rheumatoid arthritis or psoriasis.
- the general formula (Z-1) and the general formula (Z-2) are obtained by reductive amination, nucleophilic substitution reaction or coupling reaction to obtain the corresponding general formula (Z-3), if the general formula (Z-3) has an amino group at the reactive position Protecting group, first remove the amino protecting group and then react with general formula (Z-4) through nucleophilic substitution to obtain the corresponding general formula (II), that is, general formula (I). Step method and deamination protecting group are prepared;
- the general formula (Z-2-1) can be reacted with the general formula (Z-2-2) to obtain the general formula (Z-2-3) by nucleophilic substitution reaction, coupling reaction or reductive amination, and the preparation of longer chains , can be repeatedly prepared according to the above method;
- the general formula (Z-1) and the general formula (Z-2-1) are subjected to nucleophilic substitution reaction, coupling reaction or reductive amination reaction (the length of the chain can be increased by the preparation method of general formula (Z-2-3) obtain) to obtain the corresponding general formula (II), namely the general formula (I), wherein the length of the L chain can be prepared by the preparation method of the general formula (Z-2-3).
- the general formula (Z-2) has an amino protecting group at the reactive position, the amino protecting group is removed first, and then the corresponding general formula (Z-5) is obtained by a nucleophilic substitution reaction or a coupling reaction with the general formula (Z-4), The general formula (Z-5) and the general formula (Z-1) are obtained through a nucleophilic substitution reaction or a coupling reaction to obtain the corresponding general formula (II), that is, the general formula (I);
- Part of chain L can undergo nucleophilic substitution reaction or coupling reaction before general formula (Z-1), and then undergo nucleophilic substitution reaction or coupling reaction with other parts of chain L (see general formula (Z-2 for the synthesis method). -3) Preparation), and so on until the general formula (Z-3) is obtained, and the general formula (Z-3) and the general formula (Z-4) are subjected to nucleophilic substitution reaction or coupling reaction to obtain the corresponding general formula (II) Namely general formula (I);
- the general formula (Z-11) reacts with p-toluenesulfonyl chloride to obtain the general formula (Z-12), and the general formula (Z-12) undergoes a nucleophilic substitution reaction with the general formula (Z-10) to obtain the general formula (Z-13) , if there is an amino protecting group at the reaction position of general formula (Z-13), first remove the amino protecting group and then react with general formula (Z-2) through reductive amination, nucleophilic substitution reaction or coupling reaction to obtain the corresponding general formula ( Z-3), if the general formula (Z-3) has an amino protecting group at the reactive position, first remove the amino protecting group and then react with the general formula (Z-4) to obtain the corresponding general formula (II) through a nucleophilic substitution reaction.
- Formula (I) the preparation of longer chain, can be repeatedly prepared according to the above first step method and deamination protecting group;
- the general formula (Z-2-1) can be reacted with the general formula (Z-2-2) to obtain the general formula (Z-2-3) by nucleophilic substitution reaction, coupling reaction or reductive amination, and the preparation of longer chains , can be repeatedly prepared according to the above method;
- the general formula (Z-1) and the general formula (Z-2-1) are obtained by reductive amination reaction to obtain the corresponding general formula (Z-14). If the general formula (Z-14) has an amino protecting group at the reactive position, remove it first The amino protecting group is then reacted with the general formula (Z-2-2) to obtain the general formula (Z-15) by reductive amination. If there is an amino protecting group at the reaction position of the general formula (Z-15), first remove the amino protecting group And then with the general formula (Z-4) through a nucleophilic substitution reaction to obtain the general formula (Z-16), that is, the general formula (I).
- the general formula (Z-11) is reacted with methylsulfonyl chloride to obtain the general formula (Z-17), and the general formula (Z-17) and the general formula (Z-10) undergo a nucleophilic substitution reaction to obtain the general formula (Z-13) , if the general formula (Z-13) has an amino protecting group at the reactive position, first remove the amino protecting group and then obtain the corresponding general formula (Z-14) by reductive amination with the general formula (Z-2-1).
- Formula (Z-14) has an amino protecting group at the reactive position, first remove the amino protecting group and then react with general formula (Z-2-2) through reductive amination to obtain general formula (Z-15), if general formula (Z-2-2) -15) There is an amino protecting group at the reactive position, and the amino protecting group is removed first, and then the general formula (Z-16) is obtained by nucleophilic substitution reaction with the general formula (Z-4), that is, the general formula (I).
- R 3 is selected from NH 2 , F, Cl, Br, I, OTf, OH;
- the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotopic conditions, and the carbons involved in the groups and compounds of the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include 12 C, 13 C and 14 C, and isotopes of hydrogen include protium (H), deuterium (D, Also known as heavy hydrogen), tritium (T, also known as super-heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
- isotopes of carbon include 12 C, 13 C
- Alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, even more preferably is an alkyl group of 1 to 4 carbon atoms.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched chain isomers; the alkyl group is optionally further selected from 0 to 6 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amide base, alkenyl, alkynyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 3 to 8 membered carbocyclyl, 3 to 8 membered heterocyclyl, 3 to 8 Substituents substituted by a membered carbocyclyloxy group, a 3- to 8-membered heterocyclyloxy group, a carboxyl group or
- Alkoxy refers to -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyl oxy and cyclobutoxy.
- the alkyl group can be optionally further selected from 0 to 5 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyl Substituents of alkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate. Alkoxy groups appearing herein are defined in accordance with this definition.
- Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring
- the aromatic or non-aromatic ring may be a 3- to 8-membered monocyclic, 4- to 12-membered Bicyclic or 10- to 15-membered tricyclic ring system, and contains 1 to 3 heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group, the N, S optionally substituted in the ring of the heterocyclic group can be oxidized into various oxidation states.
- the heterocyclyl group can be attached to a heteroatom or a carbon atom, and the heterocyclyl group can be attached to a bridged ring or a spiro ring, non-limiting examples include oxirane, azetidinyl, oxetanyl, aza Cyclobutyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, pyridyl, furyl, thienyl, pyridine Alkyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiyl, dihydrofuranyl , dihydropyranyl, dithiopenyl, tetrahydrofuranyl, tetrahydropyrrol
- Heterocyclyl groups appearing herein are defined in accordance with this definition.
- R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or bicyclyl.
- Heterocyclyl groups appearing herein are defined in accordance with this definition.
- Paracyclic refers to a polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain zero or more double bonds, and may be
- Non-limiting examples include:
- R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or bicyclyl.
- Heterocyclyl groups appearing herein are defined in accordance with this definition.
- the ring atoms contain 5 to 20 atoms, preferably 5 to 14 atoms, more preferably 5 to 12 atoms, still more preferably 5 to 10 atoms.
- Non-limiting examples include and adamantane.
- R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or bicyclyl.
- Heterocyclyl groups appearing herein are defined in accordance with this definition.
- Heteromonocycle refers to a “heterocyclyl” or “heterocycle” of a monocyclic ring system, and heterocyclyl groups appearing herein are as defined herein.
- Heterocyclic refers to a “heterocyclic” containing a heteroatom. Heterocyclyl groups appearing herein are defined in accordance with this definition.
- Heterospirocycle refers to a “spirocycle” containing a heteroatom. Heterocyclyl groups appearing herein are defined in accordance with this definition.
- Heterobridged ring refers to a “bridged ring” containing a heteroatom. Heterocyclyl groups appearing herein are defined in accordance with this definition.
- heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Piperidinyl, morpholine, thiomorpholine, 1,3-dithiane, benzimidazole, benzimidazole, benzopyridine, pyrrolopyridine, etc.
- the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples include
- R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or bicyclyl.
- Heterocyclyl groups appearing herein are defined in accordance with this definition.
- Constant 1 to 4 heteroatoms selected from O, S, N means containing 1, 2, 3 or 4 heteroatoms selected from O, S, N.
- Substituted with 0 to X substituents means substituted with 0, 1, 2, 3, ..., or X substituents, where X is selected from any integer between 1 and 10.
- substituted with 0 to 4 substituents means substituted with 0, 1, 2, 3 or 4 substituents.
- substituted with 0 to 5 substituents means substituted with 0, 1, 2, 3, 4 or 5 substituents.
- heterobridged ring is optionally further substituted with 0 to 4 substituents selected from H or F” means that the heterobridged ring is optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H or F base substituted.
- the ring of XY members (X is selected from an integer less than Y and greater than or equal to 3, and Y is selected from any integer between 4 and 12) includes X+1, X+2, X+3, X+4, ..., Y members the ring.
- Rings include heterocycles, carbocycles, aromatic rings, aryl, heteroaryl, cycloalkyl, heteromonocycles, heterocycles, heterospirocycles, or heterobridged rings.
- 4--7 membered heteromonocycle refers to a 4-membered, 5-membered, 6-membered or 7-membered heteromonocycle
- 5--10 membered heterocyclic ring refers to 5-membered, 6-membered, 7-membered, 8-membered , 9- or 10-membered heterocyclic ring.
- alkyl optionally substituted by F means that the alkyl group may but not necessarily be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
- “Pharmaceutically acceptable salt” or “a pharmaceutically acceptable salt thereof” means that a compound of the present invention retains the biological effectiveness and properties of a free acid or free base that is treated with a non-toxic inorganic base or Organic bases, said free bases are salts obtained by reacting with non-toxic inorganic or organic acids.
- “Pharmaceutical composition” refers to a mixture of one or more of the compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof and other chemical components, wherein “other chemical components” refers to pharmaceutically acceptable Accepted carriers, excipients and/or one or more other therapeutic agents.
- Carrier refers to a material that is not appreciably irritating to the organism and that does not abrogate the biological activity and properties of the administered compound.
- Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound.
- Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binding agents agent and disintegrant.
- a “prodrug” refers to a compound of the present invention that can be metabolized in vivo into a biologically active compound.
- the prodrugs of the present invention are prepared by modifying the amino or carboxyl groups in the compounds of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
- the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.
- Co-crystal refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure states of API and CCF are both at room temperature solid, and there is a fixed stoichiometric ratio between the components.
- a co-crystal is a multicomponent crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between neutral solids and salts or solvates.
- Animal is meant to include mammals such as humans, companion animals, zoo animals and domestic animals, preferably humans, horses or dogs.
- Steps refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
- IC 50 inhibitor measured half inhibitory concentration: Inhibition of calcium channels and gabapentin binding test required by the test compound concentration of 50%.
- NMR nuclear magnetic resonance
- MS mass spectrometry
- HPLC HPLC-based high pressure liquid chromatograph
- the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm-0.20mm, and the specification used for TLC separation and purification products is 0.4mm -0.5mm;
- the known starting materials of the present invention can be synthesized by using or according to methods known in the art, or can be purchased from Titan Technology, Annagy Chemical, Shanghai Demer, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, etc. company;
- Tf trifluoromethanesulfonyl
- Boc tert-butoxycarbonyl
- Ts p-toluenesulfonyl
- Step 5 5-(2-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-7-azaspiro [3.5] Nonyl-7-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 63)
- the third step 5-(3-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-7- Azaspiro[3.5]nonan-7-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 64)
- the third step 5-(3-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-7- Azaspiro[3.5]nonan-7-yl)-[1,3'-diazetidine]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)iso Indoline-1,3-dione (Compound 65)
- the third step 5-(2'-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-7,7' -Diaza[2,7'-bisspiro[3.5]nonan]-7-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-di Ketone (Compound 66)
- the white solid was dissolved in 900 mL of dichloromethane and 100 mL of methanol, 500 mL of saturated sodium carbonate solution was added and stirred for 30 min, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4-amino-4-(trifluoromethyl) tert-Butyl piperidine-1-carboxylate (70c) (27 g, yield: 89%).
- reaction solution was concentrated under reduced pressure, diluted with 100 mL of ethyl acetate, washed with 100 mL of water, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4-hydroxy-4'-(trifluoromethyl)-[1, 4'-Bipiperidine]-1'-carboxylate tert-butyl ester (70e) (0.9 g, yield: 89%).
- the crude product was dissolved in 20mL DMF was added 3- (4-phenoxyphenyl) lH-pyrazolo [3,4-d] pyrimidin-4-amine (0.61g, 2.0mmol), and Cs 2 CO 3 (1.7 g, 5.2 mmol), the reaction was stirred at 80 °C for 3 h.
- the reaction solution was cooled to room temperature, 100 mL of ethyl acetate was added to dilute the reaction solution, 100 mL of water was added to wash, the organic phase was dried with anhydrous sodium sulfate, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v) after concentration under reduced pressure.
- Step 7 3-(4-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4'-(tri Fluoromethyl)-[1,4'-bispiperidin]-1'-yl)azetidine-1'-carboxylate tert-butyl ester (70h)
- the eighth step 1-(1'-(azetidin-3-yl)-4'-(trifluoromethyl)-[1,4'-bipiperidin]-4-yl)-3-( 4-Phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (70i)
- Step 9 5-(3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4' -(Trifluoromethyl)-[1,4'-bispiperidin-1'-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl ) isoindoline-1,3-dione (Compound 70)
- Step 2 1-[1-(7-Azaspiro[3.5]non-2-yl)-4-piperidinyl]-3-(4-phenoxyphenyl)pyrazolo[3,4 -d] The trifluoroacetate salt of pyrimidin-4-amine (71b)
- the third step 2-((3r,5r,7r)-adamantan-1-yl)-1-(2-(4-(4-amino-3-(4-phenoxyphenyl)-1H- Trifluoro of pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)ethan-1-one (Compound 71) acetate
- reaction solution was cooled to room temperature, sodium triacetoxyborohydride (1.651 g, 7.79 mmol) was added, and the reaction was performed at room temperature overnight after the addition was complete. Saturated sodium bicarbonate solution was added dropwise to the reaction solution to adjust pH to 10.
- Step 2 1-[1-(azetidin-3-yl)-4-piperidinyl]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine- 4-amine (72b)
- reaction solution was concentrated under reduced pressure, 50 mL of dichloromethane was added to the residue, the pH was adjusted to 10 with saturated sodium bicarbonate solution, the layers were separated, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 1-[1 -(azetidin-3-yl)-4-piperidinyl]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (72b) (0.888 g).
- reaction solution was cooled to room temperature, sodium triacetoxyborohydride (0.672 g, 3.17 mmol) was added, and the reaction was performed at room temperature overnight after the addition was complete. Saturated sodium bicarbonate solution was added dropwise to the reaction to adjust the pH to 10.
- Cyclobutan-1-yl]azetidine-1-carboxylic acid tert-butyl ester (72c) (0.8 g, 1.342 mmol) was dissolved in 10 mL of dichloromethane, 30 mL of 4N ethyl acetate solution of hydrochloric acid was added, and the mixture was stirred at room temperature for 2 h.
- reaction solution was concentrated under reduced pressure, 100 mL of dichloromethane was added to the residue, the pH was adjusted to 10 with saturated sodium bicarbonate solution, the layers were separated, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 1-[1 -[1-(Azetidin-3-yl)azetidin-3-yl]-4-piperidinyl]-3-(4-phenoxyphenyl)pyrazolo[3,4- d] Pyrimidine-4-amine (72d) (0.600 g).
- Step 5 2-(1-adamantyl)-1-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)]pyrazolo[3,4- d]pyrimidin-1-yl]-1-piperidinyl]azetidin-1-yl]azetidin-1-yl]ethanone (Compound 72)
- Step 2 3-(4-Phenoxyphenyl)-1-[1-(4-piperidinyl)-4-piperidinyl]pyrazolo[3,4-d]pyrimidin-4-amine (73b)
- reaction solution was concentrated under reduced pressure, 100 mL of dichloromethane was added to the residue, the pH was adjusted to 10 with saturated sodium bicarbonate solution, the layers were separated, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 3-(4- Phenoxyphenyl)-1-[1-(4-piperidinyl)-4-piperidinyl]pyrazolo[3,4-d]pyrimidin-4-amine (73b) (0.83 g).
- reaction solution was concentrated under reduced pressure, the residue was adjusted to pH 10 with saturated sodium bicarbonate solution, extracted with dichloromethane (40 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 1-( 1'-(azetidin-3-yl)-[1,4'-bipiperidin]-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3, 4-d]pyrimidin-4-amine (73d) (0.3 g).
- Step 5 2-(1-adamantyl)-1-(3-(4-(4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine- 1-yl)-[1,4'-bispiperidin]-1'-yl)azetidin-1-yl)ethan-1-one (Compound 73)
- 2-(1-Adamantyl)acetic acid (0.02 g, 0.103 mmol) was dissolved in 2 mL of dichloromethane, and the above crude product 1-(1'-(azetidin-3-yl)-[1, 4'-Bipiperidin]-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (73d) (0.0594g), HATU (0.0431 g, 0.113 mmol) and diisopropylethylamine (0.0266 g, 0.206 mmol) were added and reacted at room temperature for 3 hours.
- reaction solution was quenched with 10 mL of water, the aqueous phase was extracted with dichloromethane (20 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 7-((methylsulfonyl)oxy) - 2-Azaspiro[3.5]nonan-2-carboxylic acid tert-butyl ester (75c) (461 mg, yield: 97%).
- reaction solution was adjusted to 10 with 2N aqueous sodium hydroxide solution, the aqueous phase was extracted with dichloromethane (10 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-(4-phenoxy Phenyl)-1-(2-azaspiro[3.5]nonan-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (75e) (209 mg, yield: 85 %).
- the pH of the reaction solution was adjusted to 10 with 2N aqueous sodium hydroxide solution, the aqueous phase was extracted with dichloromethane (10 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1-(2-(aza) Cyclobutan-3-yl)-2-azaspiro[3.5]non-7-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-4 - Amine (75 g) (95 mg, yield: 90%).
- Step 7 5-(3-(7-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2- Azaspiro[3.5]nonan-2-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 75)
- reaction solution was cooled to room temperature, 50 mL of water was added, filtered, the solid was collected, washed with 50 mL of water, the solid was dissolved in 100 mL of dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane).
- Step 2 3-(4-phenoxyphenyl)-1-(1-(pyrrol-3-ylmethyl)piperidin-4-yl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine (78b)
- the third step 5-(3-((4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine -1-yl)methyl)pyrrol-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 78)
- reaction solution was cooled to room temperature, 50 mL of water was added, filtered, the solid was collected, washed with 50 mL of water, the solid was dissolved in 100 mL of dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane).
- the third step 5-(3-((4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine -1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 79)
- reaction solution was cooled to room temperature, 50 mL of water was added, filtered, the solid was collected, washed with 50 mL of water, the solid was dissolved in 100 mL of dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane).
- the fifth step (7S)-7-(1-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline -5-yl)azetidin-3-yl)methyl)azetidin-3-yl)piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5, 6,7-Tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 80)
- Step 2 1-(1'-(azetidin-3-ylmethyl)-[1,4'-bispiperidin]-4-yl)-3-(4-phenoxyphenyl) -1H-Pyrazolo[3,4-d]pyrimidin-4-amine (84b)
- the third step 5-(3-((4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[ 1,4'-Bispiperidin-1'-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-Dione (Compound 84)
- the first step 3-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine -1-yl)azetidin-1-yl)methyl)azetidin-1-carboxylate tert-butyl ester (85a)
- the third step 5-(3-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl )piperidin-1-yl)azetidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole Lin-1,3-dione (Compound 85)
- the first step 4-((4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4 '-Bispiperidin]-1'-yl)methyl)piperidine-1-carboxylate tert-butyl ester (86a)
- the third step 5-(4-((4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[ 1,4'-Bispiperidin-1'-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-diketone (compound 86)
- reaction solution was concentrated under reduced pressure, the residue was dissolved in 50 mL of DCM, 50 mL of water was added, 1 mol/L NaOH solution was added dropwise to adjust the pH to 12, the organic layer was separated, and the aqueous layer was extracted with dichloromethane (50 mL ⁇ 3), The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 3-iodo-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (87b ) (1.61 g).
- reaction solution was concentrated under reduced pressure, the residue was dissolved in 50 mL of DCM, 50 mL of water was added, 1 mol/L NaOH solution was added dropwise to adjust the pH to 12, the organic layer was separated, and the aqueous layer was extracted with dichloromethane (50 mL ⁇ 3), The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 1-(1-(azetidin-3-yl)piperidin-4-yl)-3-iodo-1H-pyrazolo[3 ,4-d]pyrimidin-4-amine (87d) (696 mg).
- Step 4 3-(4-(4-Amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'- tert-Butyl diazetidine]-1'-carboxylate (87e)
- the reaction system was concentrated under reduced pressure, the residue was dissolved in 10 mL of DCM, 10 mL of water was added, 1 mol/L NaOH solution was added dropwise to adjust the pH to 12, the organic layer was separated, and the aqueous layer was extracted with dichloromethane (30 mL ⁇ 3), The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 1-(1-([1,3'-diazetidine]-3-yl)piperidin-4-yl)-3-( 4-(4-(Trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (87j) (85 mg).
- Step 9 5-(3-(4-(4-amino-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-d ]pyrimidin-1-yl)piperidin-1-yl]-[1,3'-diazetidine]-1'-yl)-2-(2,6-dioxopiperidin-3-yl ) isoindoline-1,3-dione (compound 87)
- reaction solution was cooled to room temperature, 5 mL of water was added, filtered, the filter cake was collected, washed with 20 mL of water, the solid was dissolved in 30 mL of dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane).
- Step 3 4-(4-Amino-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl )-[1,4'-bispiperidine]-1'-carboxylate tert-butyl ester (88c)
- the reaction system was concentrated under reduced pressure, the residue was dissolved in 30 mL of DCM, 30 mL of water was added, 1 mol/L NaOH solution was added dropwise to adjust the pH to 12, the organic layer was separated, the aqueous layer was extracted with dichloromethane (50 mL ⁇ 3), and the combined The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude 1-([1,4'-bispiperidin]-4-yl)-3-(4-(4-(trifluoromethyl)phenoxy) yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (88d) (280 mg).
- Step 5 3-(4-(4-Amino-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidine- 1-yl)-[1,4'-bispiperidin]-1'-yl)azetidine-1-carboxylate tert-butyl ester (88e)
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Abstract
本发明涉及一种通式(I)所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,及其中间体和制备方法,以及在BTK相关疾病如肿瘤或自身免疫系统疾病中的用途。 B-L-K (I)
Description
本发明涉及一种通式(I)所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,及其中间体和制备方法,以及在BTK相关疾病如肿瘤或自身免疫系统疾病中的用途。
布鲁顿酪氨酸蛋白激酶(BTK,Bruton’s tyrosine kinase)是非受体蛋白酪氨酸激酶Tec家族的成员,是B细胞抗原受体(BCR)信号通路中的关键调节因子,分布在淋巴系统、造血及血液系统中。BTK突变会引起下游肿瘤细胞的增殖、分化以及血管生成等信号通路的激活,会导致X连锁无丙种球蛋白血症、非霍奇金淋巴瘤(NHL)与许多B细胞恶性肿瘤,包括慢性淋巴细胞性白血病(CLL)、套细胞淋巴瘤以及弥漫大B细胞淋巴瘤。由于主要在B细胞和髓细胞中表达,BTK是一种靶向性和安全性较好的靶点。
PROTAC(proteolysis targeting chimera)分子是一类能够同时结合靶向蛋白和E3泛素连接酶的双功能化合物,此类化合物能够被细胞的蛋白酶体识别,引起靶向蛋白的降解,能够有效地降低靶向蛋白在细胞中的含量。通过在PROTAC分子引入能结合不同靶向蛋白的配体,使PROTAC技术应用于各种疾病的治疗成为可能,该技术近年来同时得到了广泛的关注。
发明内容
本发明开发了一种结构新颖的、药效好、生物利用度高、更安全的BTK抑制剂,用于治疗与BTK相关疾病如肿瘤或自身免疫系统疾病。
本发明开发了一种结构新颖的、药效好、生物利用度高、更安全、能抑制或降解BTK的BTK抑制剂与E3泛素连接酶的PROTAC化合物,用于治疗与BTK相关疾病如肿瘤或自身免疫系统疾病。
本发明涉及一种通式(I)所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
B-L-K (I);
在一些实施方案中,L选自-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-或键;
在一些实施方案中,L选自-Cy1-CH
2-Cy2-;
在一些实施方案中,Ak1、Ak2、Ak3、Ak4和Ak5各自独立的选自CH
2、O或者键;
在一些实施方案中,Cy1、Cy2、Cy3和Cy4各自独立的选自3至12元杂环、3至12元环烷基、6至10元芳基或键,所述杂环、环烷基或芳基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、oxo(氧代、O=)、CF
3、COOH、CN、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基的取代基所取代,所述的杂环含有1至4个选自O、S、N的杂原子;
在一些实施方案中,Cy1、Cy2、Cy3和Cy4各自独立的选自键、4-7元杂单环、5-10元杂并环、6-12元杂螺环、7-10元杂桥环、4-7元单环烷基、5-10元并环烷基、6-12元螺环烷基、7-10元桥环烷基或6-10元芳基,所述芳基、环烷基(单环烷基、并环烷基、螺环烷基和桥环烷基)、杂单环、杂并环、杂螺环或杂桥环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、oxo、CF
3、COOH、CN、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基的取代基所取代,所述的杂单环、杂并环、杂螺环或杂桥环含有1至4个选自O、S、N的杂原子;
在一些实施方案中,Cy1、Cy2、Cy3和Cy4各自独立的选自键或者取代的或者未取代的如下基团之一:苯基、萘基、环丁基、环戊基、环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、氮杂环丁基、氮杂环戊基、哌啶、吗啉、哌嗪、吡咯、吡唑、咪唑、噻唑、吡啶、哒嗪、嘧啶、吡嗪、三氮唑、四氮唑、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环已基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊基并哌啶、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环已基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环已基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环已基、环已基螺氮杂环丁 基、环已基螺氮杂环戊基、环已基螺氮杂环已基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、氮杂环已基螺氮杂环已基、环丁基螺哌啶、环戊基螺哌啶、环己基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、氮杂环己基螺哌啶、
当被取代时,任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、oxo、CF
3、COOH、CN、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基的取代基所取代;
在一些实施方案中,Cy1、Cy2、Cy3和Cy4各自独立的选自键、取代或者未取代的如下基团之一:
当被取代时,任选进一步被0至4个选自H、F、CF
3、甲基、=O、羟甲基、COOH、CN或NH
2的取代基所取代;
Cy1、Cy2、Cy3和Cy4不能同时为键;
Ak1、Ak2、Ak3、Ak4或Ak5为O时,不能直接与B连接;
Ak1、Ak2、Ak3、Ak4或Ak5不为键时,互相不能直接连接;
当Ak1、Cy1、Ak2、Cy2、Ak3、Cy3、Ak4、Cy4、Ak5有4个及以上不为键时,Cy1、Cy2、Cy3和Cy4中至少有一个不为哌啶、哌嗪、嘧啶或吡啶;
在一些实施方案中,B选自B1-W1-B2-B3-B4-;
在一些实施方案中,B1选自6元杂芳环或苯基,所述的杂芳环或苯基进一步任选被0至4个R
b1所取代,所述的杂芳环含有1至4个选自O、S、N的杂原子;
在一些实施方案中,B1选自苯基或吡啶基,所述的苯基或吡啶基进一步任选被0至4个R
b1所取代;
在一些实施方案中,W1选自-O-、-S-、-NH-、-NHCO-或-CONH-;
在一些实施方案中,W1选自-O-、-NHCO-或-CONH-;
在一些实施方案中,B2选自6元杂芳环或苯基,所述的杂芳环或苯基任选进一步任选被0至4个R
b2所取代,所述的杂芳环含有1至4个选自O、S、N的杂原子;
在一些实施方案中,B3选自8-10元杂并环,所述的杂并环任选进一步任选被0至4个R
b3所取代,所述的杂并环含有1至4个选自O、S、N的杂原子;
在一些实施方案中,B4选自4-10元饱和杂环,所述的饱和杂环选自单环、并环或螺环,所述的饱和杂环、单环、并环或螺环任选进一步任选被0至4个R
b4所取代,所述的饱和杂环含有1至2个选自O、S、N的杂原子;
在一些实施方案中,B2选自苯基或吡啶基,所述的苯基或吡啶基进一步任选被0至4个R
b2所取代;
在一些实施方案中,B3选自取代或未取代的如下基团之一:咪唑并嘧啶、吡唑并嘧 啶、咪唑并吡嗪、吡唑并吡嗪、咪唑并四氢嘧啶、吡唑并四氢嘧啶,当被取代时,任选进一步任选被0至4个R
b3所取代;
在一些实施方案中,B4选自取代或未取代的如下基团之一:氮杂环丁基、氮杂环戊基、哌啶、吗啉、哌嗪、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环已基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊基并哌啶、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环已基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环已基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环已基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、环丁基螺哌啶、环戊基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、
当被取代时,任选进一步任选被0至4个R
b4所取代;
在一些实施方案中,R
b1、R
b2、R
b3或R
b4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CF
3、COOH、CONH
2、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基,所述的烷基和烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、CN、CONH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代,n1、n2、n3、n4各自独立的选自0、1、2、3或4;
在一些实施方案中,R
b1、R
b2、R
b3或R
b4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CONH
2、CF
3、COOH、羟甲基、甲基或甲氧基,所述的甲基或甲氧基任选进 一步被0至4选自H、F、Cl、Br、I的取代基所取代,n1、n2、n3、n4各自独立的选自0、1、2、3或4;
在一些实施方案中,R
b1、R
b2、R
b3或R
b4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CF
3、COOH、CONH
2、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基,所述的烷基和烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、CN、CONH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代;
在一些实施方案中,B-L选自
Cy5选自取代的或者未取代的如下基团之一:苯基、萘基、环丁基、环戊基、环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基螺环丁基、环丁基螺环戊 基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、氮杂环丁基、氮杂环戊基、哌啶、吗啉、哌嗪、吡咯、吡唑、咪唑、噻唑、吡啶、哒嗪、嘧啶、吡嗪、三氮唑、四氮唑、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环已基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊基并哌啶、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环已基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环已基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环已基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、环已基螺氮杂环已基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、氮杂环已基螺氮杂环已基、环丁基螺哌啶、环戊基螺哌啶、环己基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、氮杂环己基螺哌啶、
当被取代时,任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、oxo、CF
3、COOH、CN、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基的取代基所取代;
在一些实施方案中,Cy5选自取代的或者未取代的如下基团之一:
当被取代时,任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、oxo、CF
3、COOH、CN、甲基、羟甲基或甲氧基的取代基所取代;
R
b4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CF
3、CONH
2、COOH、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基,所述的烷基和烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、CN、CONH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代;
R
b4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CONH
2、CF
3、COOH、羟甲基、甲基或甲氧基,所述的甲基或甲氧基任选进一步被0至4选自H、F、Cl、Br、I的取代基所取代;
在一些实施方案中,环E选自苯环或者5-6元的杂芳环,所述的杂芳环含有1至2个选自O、S、N的杂原子;
在一些实施方案中,环E选自苯环、吡啶、噻吩、呋喃、吡咯、噻唑、恶唑、咪唑或吡唑;
在一些实施方案中,R
k2各自独立的选自CH
2、C=O、S=O、SO
2;
在一些实施方案中,R
k1、R
k3或R
k4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CF
3、CN、COOH、C
1-4烷基或C
1-4烷氧基;
n1、n2、n3、n4各自独立的选自0、1、2、3或4;
在一些实施方案中,R
k2各自独立的选自CH
2或C=O,R
k1、R
k3或R
k4各自独立的选自H、F、Cl、Br、I、OH或NH
2,p1或p2各自独立的选自0、1或2。
作为本发明的第一种实施方案,上述通式(I)所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中L选自-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-或键;
Ak1、Ak2、Ak3、Ak4和Ak5各自独立的选自CH
2、O或者键;
Cy1、Cy2、Cy3和Cy4各自独立的选自3元杂环、4元杂环、5元杂环、6元杂环、7元杂环、8元杂环、9元杂环、10元杂环、11元杂环、12元杂环、3元环烷基、4元环烷基、5元环烷基、6元环烷基、7元环烷基、8元环烷基、9元环烷基、10元环烷基、11元环烷基、12元环烷基、6至10元芳基或键,所述杂环、环烷基或芳基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、oxo、CF
3、COOH、CN、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基的取代基所取代,所述的杂环含有1至4个选自O、S、N的杂原子;
Cy1、Cy2、Cy3和Cy4不能同时为键;
Ak1、Ak2、Ak3、Ak4或Ak5为O时,不能直接与B连接;
Ak1、Ak2、Ak3、Ak4或Ak5不为键时,互相不能直接连接;
当Ak1、Cy1、Ak2、Cy2、Ak3、Cy3、Ak4、Cy4、Ak5有4个及以上不为键时,Cy1、Cy2、Cy3和Cy4中至少有一个不为哌啶、哌嗪、嘧啶或吡啶;
B选自B1-W1-B2-B3-B4-;
B1选自6元杂芳环或苯基,所述的杂芳环或苯基进一步任选被0至4个R
b1所取代,所述的杂芳环含有1至4个选自O、S、N的杂原子;
W1选自-O-、-S-、-NH-、-NHCO-或-CONH-;
B2选自6元杂芳环或苯基,所述的杂芳环或苯基任选进一步被0至4个R
b2所取代,所述的杂芳环含有1至4个选自O、S、N的杂原子;
B3选自8-10元杂并环,所述的杂并环任选进一步被0至4个R
b3所取代,所述的杂并环含有1至4个选自O、S、N的杂原子;
B4选自4-10元饱和杂环,所述的饱和杂环选自单环、并环或螺环,所述的饱和杂环、单环、并环或螺环任选进一步被0至4个R
b4所取代,所述的饱和杂环含有1至2个选自O、S、N的杂原子;
R
b1、R
b2、R
b3或R
b4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CF
3、COOH、CONH
2、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基,所述的烷基和烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、CN、CONH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代;
环E选自苯环或者5-6元的杂芳环,所述的杂芳环含有1至2个选自O、S、N的杂原子;
R
k2各自独立的选自CH
2、C=O、S=O、SO
2;
R
k1、R
k3或R
k4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CF
3、CN、COOH、C
1-4烷基或C
1-4烷氧基;
n1、n2、n3、n4各自独立的选自0、1、2、3或4;
任选地,化合物不为表A所示的化合物。
作为本发明的第二种实施方案,上述通式(I)所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
L选自-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-或键;
Ak1、Ak2、Ak3、Ak4和Ak5各自独立的选自CH
2、O或者键;
Cy1、Cy2、Cy3和Cy4各自独立的键、4元杂单环、5元杂单环、6元杂单环、7元杂单环、5元杂并环、6元杂并环、7元杂并环、8元杂并环、9元杂并环、10元杂并环、6元杂螺环、7元杂螺环、8元杂螺环、9元杂螺环、10元杂螺环、11元杂螺环、12元杂螺环、7元杂桥环、8元杂桥环、9元杂桥环、10元杂桥环、4元单环烷基、5元单环烷基、6元单环烷基、7元单环烷基、5元并环烷基、6元并环烷基、7元并环烷基、8元并环烷基、9元并环烷基、10元并环烷基、6元螺环烷基、7元螺环烷基、8元螺环烷基、9元螺环烷基、10元螺环烷基、11元螺环烷基、12元螺环烷基、7元桥环烷基、8元桥 环烷基、9元桥环烷基、10元桥环烷基或6-10元芳基,所述芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环任选进一步被0、1、2、3或4个选自H、F、Cl、Br、I、OH、NH
2、oxo、CF
3、COOH、CN、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基的取代基所取代,所述的杂单环、杂并环、杂螺环或杂桥环含有1、2、3或4个选自O、S、N的杂原子;
B1选自苯基或吡啶基,所述的苯基或吡啶基进一步任选被0至4个R
b1所取代;
W1选自-O-、-NHCO-或-CONH-;
B2选自苯基或吡啶基,所述的苯基或吡啶基进一步任选被0至4个R
b2所取代;
B3选自取代或未取代的如下基团之一:咪唑并嘧啶、吡唑并嘧啶、咪唑并吡嗪、吡唑并吡嗪、咪唑并四氢嘧啶、吡唑并四氢嘧啶,当被取代时,任选进一步任选被0至4个R
b3所取代;
B4选自取代或未取代的如下基团之一:氮杂环丁基、氮杂环戊基、哌啶、吗啉、哌嗪、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环已基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊基并哌啶、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环已基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环已基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环已基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、环丁基螺哌啶、环戊基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、
当被取代时,任选进一步任选被0至4个R
b4所取代;
环E选自苯环、吡啶、噻吩、呋喃、吡咯、噻唑、恶唑、咪唑或吡唑;
其余基团的定义与第一种实施方案相同。
作为本发明的第三种实施方案,上述通式(I)所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
其余基团定义与第二种实施方案相同。
作为本发明的第四种实施方案,上述通式(I)所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
Cy1、Cy2、Cy3和Cy4各自独立的选自键或者取代的或者未取代的如下基团之一:苯基、萘基、环丁基、环戊基、环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、氮杂环丁基、氮杂环戊基、哌啶、吗啉、哌嗪、吡咯、吡唑、咪唑、噻唑、吡啶、哒嗪、嘧啶、吡嗪、三氮唑、四氮唑、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环已基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊基并哌啶、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环已基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环已基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环已基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、环已基螺氮杂环已基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、 氮杂环已基螺氮杂环已基、环丁基螺哌啶、环戊基螺哌啶、环己基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、氮杂环己基螺哌啶、
当被取代时,任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、oxo、CF
3、COOH、CN、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基的取代基所取代;
R
b1、R
b2、R
b3或R
b4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CONH
2、CF
3、COOH、羟甲基、甲基或甲氧基,所述的甲基或甲氧基任选进一步被0至4选自H、F、Cl、Br、I的取代基所取代;
n1、n2、n3、n4、n5、n6、n7、n8、n9、n10、n11、n12各自独立的选自0、1、2、3或4;
R
k2各自独立的选自CH
2或C=O;
R
k1、R
k3或R
k4各自独立的选自H、F、Cl、Br、I、OH或NH
2;
p1或p2各自独立的选自0、1或2;
其余基团定义与本发明第三种实施方案相同。
作为本发明第五种实施方案,下述通式(Ia)的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
B4选自取代的或者未取代的如下基团之一:氮杂环丁基、氮杂环戊基、吗啉、哌嗪、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环已基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊基并哌啶、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环已基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环已基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环已基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、环丁基螺哌啶、环戊基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、
当被取代时,任选进一步任选被0至4个R
b4所取代;
R
b1、R
b2、R
b3或R
b4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CF
3、COOH、CONH
2、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基,所述的烷基和烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、CN、CONH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代;
n1、n2、n3各自独立的选自0、1、2、3或4;
其余基团定义与本发明第一、二、三或四种实施方案中任意一种相同。
作为本发明第六种实施方案,下述通式(Ib)的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
Cy1、Cy2、Cy3和Cy4各自独立的选自键或者取代的或者未取代的如下基团之一:苯基、萘基、环丁基、环戊基、环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、氮杂环丁基、氮杂环戊基、哌啶、吗啉、哌嗪、吡咯、吡唑、咪唑、噻唑、吡啶、哒嗪、嘧啶、吡嗪、三氮唑、四氮唑、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环已基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊基并哌啶、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环已基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环已基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环已基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、环已基螺氮杂环已基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、氮杂环已基螺氮杂环已基、环丁基螺哌啶、环戊基螺哌啶、环己基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、氮杂环己基螺哌啶、
当被取代时,任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、oxo、CF
3、COOH、CN、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基的取代基所取代;
条件是Cy1、Cy2、Cy3和Cy4中至少有一个被1至4个选自CF
3、COOH、CN、羟基取代的C
1-4烷基的取代基所取代;
R
b1、R
b2、R
b3或R
b4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CF
3、COOH、CONH
2、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基,所述的 烷基和烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、CN、CONH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代;
n1、n2、n3、n4各自独立的选自0、1、2、3或4;
其余基团定义与本发明第一、二、三或四种实施方案中任意一种相同。
作为本发明第七种实施方案,上述通式(I)的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
L左边与B连接,L右边与K连接;
作为本发明第八种实施方案,下述通式(Ic)的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
R
b4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CF
3、CONH
2、COOH、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基,所述的烷基和烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、CN、CONH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代;
其余基团定义与本发明第七种实施方案相同。
作为本发明第九种实施方案,前述通式(Ib)的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
L左边与B连接,L右边与K连接;
其余基团定义与本发明第七种实施方案相同。
作为本发明第十种实施方案,前述通式(Ic)的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
R
b4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CONH
2、CF
3、COOH、羟甲基、甲基或甲氧基,所述的甲基或甲氧基任选进一步被0至4选自H、F、Cl、Br、I的取代基所取代;
其余基团定义与本发明第八种实施方案相同。
作为本发明第十一种实施方案,前述通式(I)、(Ia)、(Ib)或(Ic)的化合物或者其立体 异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
通式(I)其余基团的定义与第七种实施方案相同;
通式(Ic)其余基团的定义与第八或十种实施方案中任意一种相同;
通式(Ib)其余基团的定义与第九种实施方案相同。
作为本发明第十二种实施方案,前述通式(I)、(Ia)、(Ib)或(Ic)的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
其余基团定义与第十一种实施方案相同。
作为本发明第十三种实施方案,前述通式(I)的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
B选自
其余基团定义与第十二种实施方案相同。
作为本发明第十四种实施方案,前述通式(I)的化合物或者其立体异构体、溶剂化物、 前药、代谢产物、药学上可接受的盐或共晶,
其余基团定义与第十二种实施方案相同。
作为本发明第十五种实施方案,前述通式(I)的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
其余基团定义与第十二种实施方案相同。
作为本发明第十六种实施方案,前述通式(I)的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
其余基团定义与第十二种实施方案相同。
作为本发明第十七种实施方案,前述通式(I)的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
其余基团定义与第十二种实施方案相同。
作为本发明第十八种实施方案,下述通式(II)的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
Cy5选自取代的或者未取代的如下基团之一:苯基、萘基、环丁基、环戊基、环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、氮杂环丁基、氮杂环戊基、哌啶、吗啉、哌嗪、吡咯、吡唑、咪唑、噻唑、吡啶、哒嗪、嘧啶、吡嗪、三氮唑、四氮唑、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环已基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊基并哌啶、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环已基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环已基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环已基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、环已基螺氮杂环已基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、氮杂环已基螺氮杂环已基、环丁基螺哌啶、 环戊基螺哌啶、环己基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、氮杂环己基螺哌啶、
当被取代时,任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、oxo、CF
3、COOH、CN、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基的取代基所取代;
其余基团的定义与本发明第二、三、四、七、十一、十二种方案种任意一种相同。
作为本发明第十九种实施方案,下述通式(II)的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
其余基团的定义与本发明第一、二、三、四、七、十一、十二种方案种任意一种相同。
本发明的一些实施例涉及一种如下所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中该化合物选自如下结构之一:
本发明的一些实施例涉及一种通式(I)所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,任选地,化合物不为表A所示的化合物,
表A
本发明的一些实施例涉及一种通式(I)、(Ia)、(Ib)和(Ic)化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
环E选自苯环或者5-6元的杂芳环,所述的杂芳环含有1至2个选自O、S、N的杂原子;
R
k2各自独立的选自CH
2、C=O、S=O、SO
2;
R
k1、R
k3或R
k4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CF
3、CN、COOH、C
1-4烷基或C
1-4烷氧基;
本发明的一些实施例涉及一种通式(I)、(Ia)、(Ib)和(Ic)化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
环E选自苯环、吡啶、噻吩、呋喃、吡咯、噻唑、恶唑、咪唑或吡唑;
R
k2各自独立的选自CH
2、C=O、S=O、SO
2;
R
k1、R
k3或R
k4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CF
3、CN、COOH、C
1-4烷基或C
1-4烷氧基;
本发明的一些实施例涉及一种通式(I)、(Ia)、(Ib)和(Ic)化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
R
k2各自独立的选自CH
2、C=O、S=O、SO
2;
R
k1、R
k3或R
k4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CF
3、CN、COOH、C
1-4烷基或C
1-4烷氧基;
本发明的一些实施例涉及一种通式(I)、(Ia)、(Ib)和(Ic)化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
本发明的一些实施例涉及一种通式(I)、(Ia)、(Ib)和(Ic)化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
本发明的一些实施例涉及一种通式(I)、(Ia)、(Ib)和(Ic)化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
本发明的一些实施例涉及一种通式(I)化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
R
b1、R
b2、R
b3或R
b4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CONH
2、CF
3、COOH、羟甲基、甲基或甲氧基,所述的甲基或甲氧基任选进一步被0至4选自H、F、Cl、Br、I的取代基所取代;
n1、n2、n3、n4、n5、n6、n7、n8、n9、n10、n11、n12各自独立的选自0、1、2、3或4。
本发明的一些实施例涉及一种通式(I)化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
本发明的一些实施例涉及一种通式(I)化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中,B选自
Cy1、Cy2、Cy3和Cy4中至少有一个被1至4个选自CF
3、COOH、CN、羟基取代的C
1-4烷基的取代基所取代。
本发明的一些实施例涉及一种通式(I)化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中,
B-L选自
Cy5选自取代的或者未取代的如下基团之一:苯基、萘基、环丁基、环戊基、环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、氮杂环丁基、氮杂环戊基、哌啶、吗啉、哌嗪、吡咯、吡唑、咪唑、噻唑、吡啶、哒嗪、嘧啶、吡嗪、三氮唑、四氮唑、环丙基并氮杂环丁基、环丙 基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环已基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊基并哌啶、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环已基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环已基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环已基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、环已基螺氮杂环已基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、氮杂环已基螺氮杂环已基、环丁基螺哌啶、环戊基螺哌啶、环己基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、氮杂环己基螺哌啶、
当被取代时,任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、oxo、CF
3、COOH、CN、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基的取代基所取代。
本发明的一些实施例涉及一种通式(I)化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中,
本发明的一些实施例涉及一种通式(I)所述的化合物或者其立体异构体、溶剂化物、 前药、代谢产物、药学上可接受的盐或共晶,其中,B选自
B4选自取代的或者未取代的如下基团之一:氮杂环丁基、氮杂环戊基、
当被取代时,任选进一步任选被0至4个R
b4所取代;
R
b4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CF
3、CONH
2、COOH、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基,所述的烷基和烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、CN、CONH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代。
本发明的一些实施例涉及一种通式(I)所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,B选自
B4选自取代的或者未取代的如下基团之一:
当被取代时,任选进一步任选被0至4个R
b4的取代基取代;
R
b4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CONH
2、CF
3、COOH、羟甲基、甲基或甲氧基,所述的甲基或甲氧基任选进一步被0至4选自H、F、Cl、Br、I的取代基所取代。
本发明的一些实施例涉及一种通式(I)所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
本发明的一些实施例涉及一种通式(I)所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
本发明的一些实施例涉及一种通式(I)所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
本发明的一些实施例涉及一种通式(I)所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
本发明的一些实施例涉及一种通式(I)、(Ia)、和(Ic)化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
Cy1、Cy2、Cy3和Cy4各自独立的选自3元杂环、4元杂环、5元杂环、6元杂环、7元杂环、8元杂环、9元杂环、10元杂环、11元杂环、12元杂环、3元环烷基、4元环烷基、5元环烷基、6元环烷基、7元环烷基、8元环烷基、9元环烷基、10元环烷基、 11元环烷基、12元环烷基、6至10元芳基或键,优选键、4元杂单环、5元杂单环、6元杂单环、7元杂单环、5元杂并环、6元杂并环、7元杂并环、8元杂并环、9元杂并环、10元杂并环、6元杂螺环、7元杂螺环、8元杂螺环、9元杂螺环、10元杂螺环、11元杂螺环、12元杂螺环、7元杂桥环、8元杂桥环、9元杂桥环、10元杂桥环、4元单环烷基、5元单环烷基、6元单环烷基、7元单环烷基、5元并环烷基、6元并环烷基、7元并环烷基、8元并环烷基、9元并环烷基、10元并环烷基、6元螺环烷基、7元螺环烷基、8元螺环烷基、9元螺环烷基、10元螺环烷基、11元螺环烷基、12元螺环烷基、7元桥环烷基、8元桥环烷基、9元桥环烷基、10元桥环烷基或6-10元芳基,所述芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环任选进一步被0、1、2、3或4个选自H、F、Cl、Br、I、OH、NH
2、oxo、CF
3、COOH、CN、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基的取代基所取代,所述的杂单环、杂并环、杂螺环或杂桥环含有1、2、3或4个选自O、S、N的杂原子。
本发明的一些实施例涉及一种通式(I)、(Ia)和(Ic)化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
Cy1、Cy2、Cy3和Cy4各自独立的选自取代的或者未取代的如下基团之一:键、苯基、萘基、环丁基、环戊基、环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、氮杂环丁基、氮杂环戊基、哌啶、吗啉、哌嗪、吡咯、吡唑、咪唑、噻唑、吡啶、哒嗪、嘧啶、吡嗪、三氮唑、四氮唑、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环已基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊基并哌啶、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环已基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环已基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环已基、环已基螺氮杂环丁基、环已基螺 氮杂环戊基、环已基螺氮杂环已基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、氮杂环已基螺氮杂环已基、环丁基螺哌啶、环戊基螺哌啶、环己基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、氮杂环己基螺哌啶、
当被取代时,任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、oxo、CF
3、COOH、CN、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基的取代基所取代。
本发明的一些实施例涉及一种通式(I)、(Ia)和(Ic)化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
本发明的一些实施例涉及一种通式(Ia)和(Ic)化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
B4选自取代的或者未取代的如下基团之一:氮杂环丁基、氮杂环戊基、吗啉、哌嗪、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环已基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊基并哌啶、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环已基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环已基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环已基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、环丁基螺哌啶、环戊基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、、
当被取代时,任选进一步任选被0至4个R
b4所取代;
R
b4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CF
3、COOH、CONH
2、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基,所述的烷基和烷氧基 任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、CN、CONH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代。
本发明的一些实施例涉及一种通式(Ia)和(Ic)化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
R
b4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CF
3、CONH
2、COOH、C
1-4烷基、羟基取代的C
1-4烷基、卤素取代的C
1-4烷基或C
1-4烷氧基,所述的烷基和烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、CN、CONH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代。
本发明的一些实施例涉及一种通式(Ia)和(Ic)的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
R
b4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CONH
2、CF
3、COOH、羟甲基、甲基或甲氧基,所述的甲基或甲氧基任选进一步被0至4选自H、F、Cl、Br、I的取代基所取代。
本发明的一些实施例涉及一种通式(Ib)化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
L左边与B连接,L右边与K连接。
本发明的一些实施例涉及一种通式(I)和(Ia)化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
本发明的一些实施例涉及一种通式(I)、(Ia)、(Ib)和(Ic)所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中所述的盐选自三氟乙酸盐。
本发明涉及一种药物组合物,包括本发明所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,以及要学上可接受的载体。
本发明涉及一种本发明所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与BTK活性或表达量相关疾病的药物中的应用。
本发明涉及一种本发明所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与抑制或降解BTK相关疾病的药物中的应用。
本发明涉及的本发明述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的应用,所述的疾病选自肿瘤或自身免疫疾病。
本发明涉及的本发明述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的应用,所述的肿瘤选自非霍奇金淋巴瘤、慢性淋巴细胞性白血病、套细胞淋巴瘤、B细胞淋巴瘤,自身免疫疾病选自内风湿关节炎或银屑病。
合成方法一:
通式(Z-1)与通式(Z-2)通过还原胺化、亲核取代反应或者偶联反应得到对应通式(Z-3),如果通式(Z-3)反应位有氨基保护基,先脱除氨基保护基后再与通式(Z-4)通过亲核取代反应得到对应通式(II)即通式(I),更长链的制备,可以重复按照上面第一步方法及脱氨基保护基制备得到;
R
4-Cy1-R
5(Z-2-1)+R
6-Cy2-R
7(Z-2-2)→R
4-Cy1-Ak2-Cy2-R
7(Z-2-3),
通式(Z-2-1)与通式(Z-2-2)反应可以通过亲核取代反应、偶联反应或者还原胺化得到通式(Z-2-3),更长链的制备,可以重复按照上面方法制备得到;
如果(Z-2-1)反应位有氨基保护基,脱除保护基后与通式(Z-2-2)反应可以通过亲核取代反应或者偶联反应或者还原胺化得到通式(Z-2-3),更长链的制备,可以重复按照上面方法制备得到;
或者通式(Z-1)与通式(Z-2-1)通过亲核取代反应、偶联反应或者还原胺化反应(可以通过通式(Z-2-3)制备方法增加链的长度得到)得到对应通式(II)即通式(I),其中L链的长度可以通过通式(Z-2-3)的制备方法制备。
合成方法二:
如果通式(Z-2)反应位有氨基保护基,先脱除氨基保护基后再与通式(Z-4)通过亲核取代反应或者偶联反应得到对应通式(Z-5),通式(Z-5)与通式(Z-1)通过亲核取代反应或者偶联反应得到对应通式(II)即通式(I);
合成方法三:
部分链L可以先于通式(Z-1)发生亲核取代反应或者偶联反应,然后再与链L的其它部分发生亲核取代反应或者偶联反应(合成方法见通式(Z-2-3)制备),以此类推至得到通式(Z-3),通式(Z-3)与通式(Z-4)通过亲核取代反应或者偶联反应得到对应通式(II)即通式(I);
合成方法四:
或者部分链L可以先于通式(Z-4)发生亲核取代反应或者偶联反应,然后再与链L的其它部分发生亲核取代反应或者偶联反应(合成方法见通式(Z-2-3)制备),以此类推至得到通式(Z-5),通式(Z-5)与通式(Z-1)通过亲核取代反应或者偶联反应得到对应通式(II)即通式(I);
合成方法五:
OH-B4-H(Z-7)→OH-B4-L-R
2(Z-8)→OTs-B4-L-R
2(Z-9)+B1-W1-B2-B3-H(Z-10)→B-L-R
2(Z-3)
通式(Z-7)与通式(Z-2)发生亲核取代反应或者偶联反应得到通式(Z-8)
或者通式(Z-7)与部分链L发生亲核取代反应或者偶联反应,然后再与链L的其它部分发生亲核取代反应或者偶联反应(合成方法见通式(Z-2-3)的制备),得到通式(Z-8),通式(Z-8)与对甲苯磺酰氯反应得到通式(Z-9),通式(Z-9)与通式(Z-10)发生亲核取代反应或者偶联反应得到通式(Z-3);
合成方法六:
通式(Z-11)与对甲苯磺酰氯反应得到通式(Z-12),通式(Z-12)与通式(Z-10)发生亲核取代反应得到通式(Z-13),如果通式(Z-13)反应位有氨基保护基,先脱除氨基保护基后再与通式(Z-2)通过还原胺化、亲核取代反应或者偶联反应得到对应通式(Z-3),如果通式(Z-3)反应位有氨基保护基,先脱除氨基保护基后再与通式(Z-4)通过亲核取代反应得到对应通式(II)即通式(I),更长链的制备,可以重复按照上面第一步方法及脱氨基保护基制备得到;
R
4-Cy1-R
5(Z-2-1)+R
6-Cy2-R
7(Z-2-2)→R
4-Cy1-Ak2-Cy2-R
7(Z-2-3),
通式(Z-2-1)与通式(Z-2-2)反应可以通过亲核取代反应、偶联反应或者还原胺化得到通式(Z-2-3),更长链的制备,可以重复按照上面方法制备得到;
如果(Z-2-1)反应位有氨基保护基,脱除保护基后与通式(Z-2-2)反应可以通过亲核取代反应或者偶联反应或者还原胺化得到通式(Z-2-3),更长链的制备,可以重复按照上面方法制备得到;
或者通式(Z-13)与通式(Z-2-1)通过亲核取代反应、偶联反应或者还原胺化反应(可以通过通式(Z-2-3)制备方法增加链的长度得到)得到对应通式(II)即通式(I),其中L链的长度可以通过通式(Z-2-3)的制备方法制备。
合成方法七:
通式(Z-1)与通式(Z-2-1)通过还原胺化反应得到对应通式(Z-14),如果通式(Z-14) 反应位有氨基保护基,先脱除氨基保护基后再与通式(Z-2-2)通过还原胺化反应得到通式(Z-15),如果通式(Z-15)反应位有氨基保护基,先脱除氨基保护基后再与通式(Z-4)通过亲核取代反应得到通式(Z-16),即通式(I)。
合成方法八:
通式(Z-11)与甲基磺酰氯反应得到通式(Z-17),通式(Z-17)与通式(Z-10)发生亲核取代反应得到通式(Z-13),如果通式(Z-13)反应位有氨基保护基,先脱除氨基保护基后再与通式(Z-2-1)通过还原胺化得到对应通式(Z-14),如果通式(Z-14)反应位有氨基保护基,先脱除氨基保护基后再与通式(Z-2-2)通过还原胺化反应得到通式(Z-15),如果通式(Z-15)反应位有氨基保护基,先脱除氨基保护基后再与通式(Z-4)通过亲核取代反应得到通式(Z-16),即通式(I)。
通式(Z-1)合成方法见J.Med.Chem.2015,58,9625-9638;
通式(Z-4)合成方法见WO2017197056;
R
1选自(=O)、-CHO、F、Cl、Br、I、OTf;
R
2选自H、(=O)、-CHO、F、Cl、Br、I或氨基保护基,优选Boc;
R
3选自NH
2、F、Cl、Br、I、OTf、OH;
R
4、R
5、R
6、R
7各自独立的选自H、(=O)、-CHO、H、F、Cl、Br、I、OTf或氨基保护基。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括
12C、
13C和
14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括
16O、
17O和
18O,硫的同位素包括
32S、
33S、
34S和
36S,氮的同位素包括
14N和
15N,氟的同位素包括
17F和
19F,氯的同位素包括
35Cl和
37Cl,溴的同位素包括
79Br和
81Br。
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基,优选为1至8个碳原子的烷基,更优选为1至6个碳原子的烷基,进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体;所述的烷基任选进一步被0至6个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、C
1-6烷基、C
1-6羟基烷基、C
1-6烷氧基、3至8元碳环基、3至8元杂环基、3至8元碳环基氧基、3至8元杂环基氧基、羧基或者羧酸酯基的取代基所取代,本文中出现的烷基,其定义与本定义一致。
“烷氧基”是指-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷基可以任选进一步被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的烷氧基,其定义与本定义一致。
“杂环基”或”杂环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环,芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系,且包含1至3个选自N、O或S的杂原子,优选3至8元杂环基,杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上,杂环基可以连接有桥环或者螺环,非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的杂环基可以任选进一步被0至5个选自F、Cl、Br、I、=O、羟基、巯基、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的杂环基,其定义与本定 义一致。
“螺环”是指取代的或未取代的单环之间共用一个碳原子(称螺原子)的5至20元多环基团,其可以包含0至5个双键,且可以含有0至5个选自N、O或S(=O)
n的杂原子。优选为6至14元,进一步优选为6至12元,更优选6至10元,其非限定性实例包括:
当被取代时,取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、甲酸酯、-(CH
2)
m-C(=O)-R
a、-O-(CH
2)
m-C(=O)-R
a、-(CH
2)
m-C(=O)-NR
bR
c、-(CH
2)
mS(=O)
nR
a、-(CH
2)
m-烯基-R
a、OR
d或-(CH
2)
m-炔基-R
a(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NR
bR
c等基团,其中R
b与R
c独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基,作为选择,R
b与R
c可形成五或六元环烷基或杂环基。R
a与R
d各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的杂环基,其定义与本定义一致。
“并环”是指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的多环基团,其中一个或多个环可以含有0个或多个双键,且可以是取代的或未取代,并环体系中的各个环可以含0至5个选自N、S(=O)
n或O的杂原子。优选为5至20元,进一步优选为5至14元,更优选5至12元,再进一步优选5至10元。非限定性实例包括:
当被取代时,取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、甲酸酯、-(CH
2)
m-C(=O)-R
a、-O-(CH
2)
m-C(=O)-R
a、-(CH
2)
m-C(=O)-NR
bR
c、-(CH
2)
mS(=O)
nR
a、-(CH
2)
m-烯基-R
a、OR
d或-(CH
2)
m-炔基-R
a(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NR
bR
c等基团,其中R
b与R
c独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基,作为选择,R
b与R
c可形成五或六元环烷基或杂环基。R
a与R
d各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的杂环基,其定义与本定义一致。
“桥环”是指任意两个不直接连接的碳原子的多环基团,可以含有0个或多个双键,且可以是取代的或未取代的,并环体系中的任意环可以含0至5个选自N、S(=O)
n或O杂原子或基团(其中n为1、1、2)。环原子包含5至20个原子,优选为5至14个原子,进一步优选5至12个,在进一步优选5至10个。非限定性实例包括
和金刚烷。当被取代时,取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、甲酸酯、-(CH
2)
m-C(=O)-R
a、-O-(CH
2)
m-C(=O)-R
a、-(CH
2)
m-C(=O)-NR
bR
c、-(CH
2)
mS(=O)
nR
a、-(CH
2)
m-烯基-R
a、OR
d或-(CH
2)
m-炔基-R
a(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NR
bR
c等基团,其中R
b与R
c独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基,作为选择,R
b与R
c可形成五或六元环烷基或杂环基。R
a与R
d各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的杂环基,其定义与本定义一致。
“杂单环”是指单环体系的“杂环基”或“杂环”,本文中出现的杂环基,其定义与 本定义一致。
“杂并环”是指含有杂原子的“并环”。本文中出现的杂环基,其定义与本定义一致。
“杂螺环”是指含有杂原子的“螺环”。本文中出现的杂环基,其定义与本定义一致。
“杂桥环”是指含有杂原子的“桥环”。本文中出现的杂环基,其定义与本定义一致。
“杂芳基”或“杂芳环”是指取代或未取代的5至14元芳香环,且含有1至5个选自N、O或S(=O)
n杂原子或基团,优选5至10元杂芳香环,进一步优选5至6元。杂芳基的非限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉、硫代吗啉、1,3-二噻烷、苯并咪唑、苯并咪唑、苯并吡啶、吡咯并吡啶等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,非限制性实施例包含
当被取代时,取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、甲酸酯、-(CH
2)
m-C(=O)-R
a、-O-(CH
2)
m-C(=O)-R
a、-(CH
2)
m-C(=O)-NR
bR
c、-(CH
2)
mS(=O)
nR
a、-(CH
2)
m-烯基-R
a、OR
d或-(CH
2)
m-炔基-R
a(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NR
bR
c等基团,其中R
b与R
c独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基,作为选择,R
b与R
c可形成五或六元环烷基或杂环基。R
a与R
d各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的杂环基,其定义与本定义一致。
“含有1至4个选自O、S、N的杂原子”是指含有1、2、3或4个选自O、S、N的杂原子。
“0至X个取代基所取代”是指被0、1、2、3、…、或X个取代基所取代,X选自1至10之间的任意整数。如“0至4个取代基所取代”是指被0、1、2、3或4个取代基所取代。如“0至5个取代基所取代”是指被0、1、2、3、4或5个取代基所取代。如“杂桥环任选进一步被0至4个选自H或F的取代基所取代”是指杂桥环任选进一步被0、1、2、3或4个选自H或F的取代基所取代。
X-Y元的环(X选自小于Y大于等于3的整数,Y选自4至12之间的任意整数)包括了X+1、X+2、X+3、X+4、…、Y元的环。环包括了杂环、碳环、芳环、芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环。如“4-7元杂单环”是指4元、5元、6元或7元的杂单环,“5-10元杂并环”是指5元、6元、7元、8元、9元或10元的杂并环。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生,该说明包括该事件或环境发生或不发生的场合。如:“任选被F取代的烷基”指烷基可以但不必须被F取代,说明包括烷基被F取代的情形和烷基不被F取代的情形。
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或者有机碱,所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物,其中,“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备,该修饰可以通过常规的操作或者在体内被除去,而得到母体化合物。当本发明的前药被施予哺乳动物个体时,前药被割裂形成游离的氨基或者羧基。
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体,其中API和CCF的纯态在室温下均为固体,并且各组分间存在固定的化学计量比。共晶是一种多组分晶体,既包含两种中性固体之间形成的二元共晶,也包含中性固体与盐或溶剂化物形成的多元共晶。
“动物”是指包括哺乳动物,例如人、陪伴动物、动物园动物和家畜,优选人、马或者犬。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反 异构体、对映异构体和构象异构体。
IC
50(被测量的抑制剂的半抑制浓度):通过测试受试化合物50%抑制gabapentin与钙离子通道结合所需的浓度。
以下结合实施例详细说明本发明的技术方案,但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10
-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d
6),氘代氯仿(CDCl
3),氘代甲醇(CD
3OD),内标为四甲基硅烷(TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm,薄层层析分离纯化产品采用的规格是0.4mm-0.5mm;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体;
本发明的己知起始原料可以采用或按照本领域已知的方法来合成,或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司;
P13I:
(合成参考文献:Y.Sun,X.Zhao,N.Ding,H.Gao,Y.Wu,Y.Yang,M.Zhao,J.Hwang,Y.Song,W.Liu,Y.Rao,Cell Res.2018,28,779-781.)
Tf:三氟甲磺酰基;
Boc:叔丁氧基羰基;
Ts:对甲苯磺酰基;
Cbz:苄氧羰基;
TMS:三甲基硅基;
实施例63:
5-(2-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7-氮杂螺[3.5]壬基-7-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物63)
5-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:2-羟基-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯(63b)
tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate
将2-氧代-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯(18g,75.22mmol)溶解于200ml无水甲醇中,缓慢分批加入硼氢化钠(5.7g,150.0mmol),加完后室温搅拌30min。向反应液中加入250ml饱和碳酸氢钠水溶液,用100mL DCM萃取,有机相用100mL水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=2:1),得2-羟基-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯(63b)(12g,收率:66%)。
LCMS m/z=242.3[M+1]
+。
第二步:2-((甲基磺酰基)氧基)-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯(63c)
tert-butyl 2-((methylsulfonyl)oxy)-7-azaspiro[3.5]nonane-7-carboxylate
将2-羟基-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯(63b)(3.0g,12.43mmol)溶解于80mL二氯甲烷中,加入DIPEA(4.82g,42.10mmol),然后缓慢滴加MsCl(1.71g,14.93mmol),加完后室温搅拌0.5h。将反应液用150mL水淬灭,用100mL DCM萃取,有机相用100mL水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=5:1),得2-((甲基磺酰基)氧基)-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯(63c)(3.5g,收率:88.5%)。
LCMS m/z=320.3[M+1]
+。
第三步:2-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯(63d)
tert-butyl 2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate
将2-((甲基磺酰基)氧基)-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯(63c)(2.5g,7.83mmol)和3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(2.0g,6.60mmol)溶于40毫升DMF中,加入碳酸铯(6.45g,19.80mmol),反应于100℃搅拌6h。将反应液冷却至室温,加入80mL水,用100mL乙酸乙酯萃取,有机相用100mL水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得2-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯(63d)(3.25g,收率:78.6%)。
LCMS m/z=527.6[M+1]
+。
第四步:3-(4-苯氧基苯基)-1-(7-氮杂螺[3.5]壬-2-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(63e)
3-(4-phenoxyphenyl)-1-(7-azaspiro[3.5]nonan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将2-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯(63d)(1.0g,1.90mmol)溶解到20mL DCM中,加入8mL三氟乙酸,室温搅拌4小时。将体系直接旋干,残留物用5N氢氧化钠水溶液溶解,用100mL二氯甲烷萃取,有机相用100mL水洗涤,无水硫酸钠干燥,减压浓缩,得3-(4-苯氧基苯基)-1-(7-氮杂螺[3.5]壬-2-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(63e)(780mg,收率:96.2%)。
LCMS m/z=427.6[M+1]
+。
第五步:5-(2-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7-氮杂螺[3.5]壬基-7-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物63)
5-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将3-(4-苯氧基苯基)-1-(7-氮杂螺[3.5]壬-2-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(63e)(260mg,0.61mmol)溶于25毫升DMSO中,加入1.5mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(252mg,0.91mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入50mL水,用100mL乙酸乙酯萃取,有机相用100mL水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(2-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7-氮杂螺[3.5]壬基-7-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物63)(150mg,收率:36.0%)。
1H NMR(400MHz,CDCl
3)δ8.92(s,1H),8.38(s,1H),7.72–7.63(m,3H),7.44–7.36(m,2H),7.30(d,1H),7.22–7.13(m,3H),7.12–7.04(m,3H),5.89(br.s,2H),5.55–5.43(m,1H),4.94(dd,1H),3.56–3.36(m,4H),2.94–2.62(m,5H),2.56–2.46(m,2H),2.20–2.08(m,1H),1.96–1.85(m,4H)。
LCMS m/z=683.3[M+1]
+。
实施例64:
5-(3-(2-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7-氮杂螺[3.5]壬-7-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物64)
5-(3-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:3-(2-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7-氮杂螺[3.5]壬-7-基)氮杂环丁-1-甲酸叔丁酯(64a)
tert-butyl 3-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)azetidine-1-carboxylate
将3-(4-苯氧基苯基)-1-(7-氮杂螺[3.5]壬-2-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(63e)(520mg,1.22mmol)溶于30mL DCE(1,2-二氯乙烷)中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(416mg,2.43mmol),室温搅拌10分钟后,加入三乙酰氧基硼氢化钠(1.03g,4.86mmol),室温搅拌过夜。向反应体系中缓慢加入100mL碳酸氢钠水溶液,用DCM萃取(30mL×3),有机相用50毫升水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得3-(2-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7-氮杂螺[3.5]壬-7-基)氮杂环丁-1-甲酸叔丁酯(64a)(630mg,收率:88.8%)。
LCMS m/z=582.4[M+1]
+。
第二步:1-(7-(氮杂环丁烷-3-基)-7-氮杂螺[3.5]壬-2-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(64b)
1-(7-(azetidin-3-yl)-7-azaspiro[3.5]nonan-2-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(2-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7-氮杂螺[3.5]壬-7-基)氮杂环丁-1-甲酸叔丁酯(64a)(610mg,1.05mmol)溶解在20毫升DCM中,加入4毫升三氟乙酸,室温搅拌4小时。将反应体系直接旋干,残留物用30mL 5N氢氧化钠水溶液溶解,用DCM萃取(30mL×4),合并有机相,用1N氢氧化钠水溶液洗涤(30mL×2),无水硫酸钠干燥,减压浓缩,得1-(7-(氮杂环丁烷-3-基)-7-氮杂螺[3.5]壬-2-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(64b)(0.43g,收率:85.0%)。
LCMS m/z=482.5[M+1]
+。
第三步:5-(3-(2-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7-氮杂螺[3.5]壬-7-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物64)
5-(3-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将1-(7-(氮杂环丁烷-3-基)-7-氮杂螺[3.5]壬-2-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(64b)(150mg,0.31mmol)溶于15毫升DMSO中,加入1.5mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(130mg,0.47mmol),反应于80℃搅拌5小时。将反应液冷却,加入50毫升水,用100毫升乙酸乙酯萃取,有机相用100毫升水洗涤,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-(2-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7-氮杂螺[3.5]壬-7-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物64)(95mg,收率:41.5%)。
1H NMR(400MHz,CDCl
3)δ9.09(s,1H),8.39(s,1H),7.70–7.61(m,3H),7.43–7.35(m,2H),7.22–7.12(m,3H),7.12–7.05(m,2H),6.79(d,1H),6.53(dd,1H),5.67(br.s,2H),5.49–5.37(m,1H),4.92(dd,1H),4.15–4.07(m,2H),4.00–3.89(m,2H),3.43–3.31(m,1H),2.93–2.66(m,3H),2.66–2.57(m,2H),2.55–2.25(m,6H),2.16–2.08(m,1H),1.93–1.81(m,4H)。
LCMS m/z=738.3[M+1]
+。
实施例65:
5-(3-(2-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7-氮杂螺[3.5]壬-7-基)-[1,3'-联氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物65)
5-(3-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-[1,3'-biazetidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:3-(2-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7-氮杂螺[3.5]壬-7-基)-[1,3'-二氮杂环丁基]-1'-甲酸叔丁酯(65a)
tert-butyl 3-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-[1,3'-biazetidine]-1'-carboxylate
将1-(7-(氮杂环丁烷-3-基)-7-氮杂螺[3.5]壬-2-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(64b)(330mg,0.69mmol)溶于30mL DCE中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(234mg,1.37mmol),室温搅拌10分钟后,加入三乙酰氧基硼氢化钠(581mg,2.74mmol),室温搅拌过夜。向反应体系中缓慢加入100mL饱和碳酸氢钠水溶液,用DCM萃取(30mL×3),有机相用50毫升水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得3-(2-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7-氮杂螺[3.5]壬-7-基)-[1,3'-二氮杂环丁基]-1'-甲酸叔丁酯(65a)(350mg,收率:79.6%)。
LCMS m/z=637.5[M+1]
+。
第二步:1-(7-([1,3'-联氮杂环丁]-3-基)-7-氮杂螺[3.5]壬-2-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(65b)
1-(7-([1,3'-biazetidin]-3-yl)-7-azaspiro[3.5]nonan-2-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(2-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7-氮杂螺[3.5]壬-7-基)-[1,3'-二氮杂环丁基]-1'-甲酸叔丁酯(65a)(340mg,0.53mmol)溶解在20毫升DCM中,加入8毫升三氟乙酸,室温搅拌4小时。将反应体系直接旋干,残留物用30mL 5N氢氧化钠水溶液溶解,用DCM萃取(30mL×4),有机相用1N氢氧化钠水溶液洗涤(30ml×2),无水硫酸钠干燥,减压浓缩,得1-(7-([1,3'-联氮杂环丁]-3-基)-7-氮杂螺[3.5]壬-2-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(65b)(260mg,收率:91.3%)。
LCMS m/z=537.5[M+1]
+。
第三步:5-(3-(2-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7-氮杂螺[3.5]壬-7-基)-[1,3'-联氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物65)
5-(3-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-7-azaspiro[3.5 ]nonan-7-yl)-[1,3'-biazetidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将1-(7-([1,3'-联氮杂环丁]-3-基)-7-氮杂螺[3.5]壬-2-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(65b)(250mg,0.47mmol)溶于15毫升DMSO中,加入1.5mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(130mg,0.47mmol),反应于80℃搅拌5小时。将反应液冷却至室温,加入50毫升水,用100毫升乙酸乙酯萃取,有机相用100毫升水洗涤,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-(2-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7-氮杂螺[3.5]壬-7-基)-[1,3'-联氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物65)(130mg,收率:34.9%)。
1H NMR(400MHz,CDCl
3)δ9.61(s,1H),8.38(s,1H),7.70–7.59(m,3H),7.43–7.35(m,2H),7.21–7.11(m,3H),7.11–7.05(m,2H),6.77(d,1H),6.50(dd,1H),5.70(br.s,2H),5.46–5.35(m,1H),4.92(dd,1H),4.07–3.97(m,2H),3.90–3.81(m,2H),3.73–3.63(m,1H),3.58–3.50(m,2H),3.20–2.92(m,3H),2.92–2.65(m,3H),2.63–2.53(m,2H),2.48–2.06(m,7H),1.90–1.74(m,4H)。
LCMS m/z=793.3[M+1]
+。
实施例66:
5-(2'-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7,7'-二氮杂[2,7'-双螺[3.5]壬]-7-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物66)
5-(2'-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-7,7'-diaza[2,7'-bispiro[3.5]nonan]-7-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:2'-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7,7'-二氮杂[2,7'-双螺[3.5]壬烷]-7-甲酸叔丁酯(66a)
tert-butyl 2'-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-7,7'-diaza[2,7'-bispiro[3.5]nonane]-7-carboxylate
将3-(4-苯氧基苯基)-1-(7-氮杂螺[3.5]壬-2-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(63e)(250mg,0.59mmol)溶于20mL DCE中,加入2-氧代-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯(280mg,1.17mmol),室温搅拌10分钟后,加入三乙酰氧基硼氢化钠(496mg,2.34mmol),室温搅拌过夜。向反应体系中缓慢加入100ml饱和碳酸氢钠水溶液,用DCM(30ml×3)萃取,有机相用50毫升水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得2'-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7,7'-二氮杂[2,7'-双螺[3.5]壬烷]-7-甲酸叔丁酯(66a)(310mg,收率:80.8%)。
LCMS m/z=650.3[M+1]
+。
第二步:1-(7,7'-二氮杂[2,7'-双螺[3.5]壬]-2'-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(66b)
1-(7,7'-diaza[2,7'-bispiro[3.5]nonan]-2'-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将2'-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7,7'-二氮杂[2,7'-双螺[3.5]壬烷]-7-甲酸叔丁酯(66a)(300mg,0.46mmol)溶解在20毫升DCM中,加入8毫升三氟乙酸,室温搅拌4小时。将反应体系直接旋干,残留物用30mL 5N氢氧化钠水溶液溶解,用DCM萃取(30mL×4),有机相用1N氢氧化钠水溶液洗涤(30mL×4),无水硫酸钠干燥,减压浓缩,得1-(7,7'-二氮杂[2,7'-双螺[3.5]壬]-2'-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(66b)(240mg,收率:94.9%)。
LCMS m/z=550.3[M+1]
+。
第三步:5-(2'-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7,7'-二氮杂[2,7'-双螺[3.5]壬]-7-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物66)
5-(2'-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-7,7'-diaza[2,7'-bispiro[3.5]nonan]-7-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将1-(7,7'-二氮杂[2,7'-双螺[3.5]壬]-2'-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(66b)(230mg,0.42mmol)溶于15毫升DMSO中,加入1.5mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(196mg,0.71mmol),反应于80℃搅拌5小时。将反应液冷却至室温,加入50毫升水,用100毫升乙酸乙酯萃取,有机相用100毫升水洗涤,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(2'-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-7,7'-二氮杂[2,7'-双螺[3.5]壬]-7-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物66)(160mg,收率:47.3%)。
1H NMR(400MHz,CDCl
3)δ9.48(br.s,1H),8.38(s,1H),7.71–7.62(m,3H),7.43–7.35(m,2H),7.29–7.24(m,1H),7.20–7.12(m,3H),7.11–7.06(m,2H),7.03(dd,1H),5.71(br.s,2H),5.48–5.35(m,1H),4.93(dd,1H),3.48–3.28(m,4H),2.93–2.66(m,4H),2.65–2.54(m,2H),2.53–2.18(m,5H),2.17–2.02(m,4H),2.00–1.65(m,10H)。
LCMS m/z=806.3[M+1]
+。
实施例67:
5-(3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物67)
5-(3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将1-[1-(氮杂环丁-3-基)-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(17b)(合成方法见WO2020239103)(0.45g,1.02mmol)溶于8毫升DMSO中,室温下加入2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(0.28g,1.01mmol)和二异丙基乙基胺(0.66g,5.10mmol),升温至80℃反应3h。将反应液倒入20毫升水中,水相用混合溶剂二氯甲烷/甲醇(v/v)=10:1萃取(30mL×3),合并有机相,有机相用50毫升水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=10:1-8:1),得到5-(3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物67)(554mg,产率:78%)。
1H NMR(400MHz,DMSO-d
6)δ11.04(br.s,1H),8.24(s,1H),7.72–7.61(m,3H),7.50–7.36(m,2H),7.23–7.07(m,5H),6.81(d,1H),6.67(dd,1H),5.06(dd,1H),4.80–4.66(m,1H),4.19–4.11(m,2H),3.93–3.84(m,2H),3.48–3.37(m,1H),3.05–2.80(m,3H),2.64–2.52(m,2H),2.30–2.07(m,4H),2.07–1.88(m,3H)。
LCMS m/z=698.3[M+1]
+。
实施例68:
5-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-联哌啶]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物68)
5-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将3-(4-苯氧基苯基)-1-[1-(4-哌啶基)-4-哌啶基]吡唑并[3,4-d]嘧啶-4-胺(2b)(合成方法见WO2020239103)(400mg,0.85mmol)溶于4毫升DMSO中,室温下加入2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(0.23g,0.84mmol)和二异丙基乙基胺(0.44g,3.40mmol),升温至80℃反应4小时。将反应液倒入10毫升水中,水相用混合溶剂二氯甲烷/甲醇(v/v)=10:1萃取(30mL×3),合并有机相,有机相用20毫升水洗涤,无水硫酸钠干燥,减压浓缩后,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1-8:1),得到5-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-联哌啶]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物68)(469mg,产率:65%)。
1H NMR(400MHz,DMSO-d
6)δ11.05(s,1H),8.26–8.20(m,1H),7.97(dd,1H),7.66(d,1H),7.57–7.49(m,2H),7.36–7.29(m,1H),7.29–7.17(m,3H),7.14(d,1H),6.30(s,2H),5.06(dd,1H),4.18–4.03(m,3H),3.10–2.81(m,5H),2.70–2.46(m,3H),2.37–2.20(m,2H),2.10–1.74(m,7H),1.61–1.44(m,2H)。
LCMS m/z=363.8[M/2+1]
+。
实施例69:
5-(7-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-2-氮杂螺[3.5]壬-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物69)
5-(7-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-(1-(2-氮杂螺[3.5]壬-7-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺盐酸盐(55b)(合成方法见WO2020239103)(100mg)溶于3毫升DMSO中,室温下加入2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(58mg,0.21mmol)和二异丙基乙基胺(129mg,1.00mmol),升温至80℃反应5小时。将反应液倒入9毫升水中,水相用混合溶剂二氯甲烷/甲醇(v/v)=10:1萃取(30mL×3),合并有机相,有机相用50毫升水洗涤,无水硫酸钠干燥,减压浓缩后,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1-8:1),得到5-(7-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-2-氮杂螺[3.5]壬-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物69)(92mg)。
1H NMR(400MHz,CDCl
3)δ8.38(s,1H),8.27(br.s,1H),7.74–7.50(m,3H),7.43–7.33(m,2H),7.22–7.11(m,3H),7.11–7.04(m,2H),6.77(d,1H),6.50(dd,1H),5.50(br.s,2H),4.93(dd,1H),4.85–4.70(m,1H),3.77–3.68(m,4H),3.68–3.64(m,4H),3.63–3.59(m,1H),3.23–3.04(m,2H),2.93–2.65(m,3H),2.54–2.34(m,4H),2.13–1.97(m,5H),1.97–1.84(m,2H),
LCMS m/z=766.3[M+1]
+。
实施例70:
5-(3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-4'-(三氟甲基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物70)
5-(3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4'-(trifluoromethyl)-[1,4'-bipiperidin]-1'-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:4-(苄基氨基)-4-(三氟甲基)哌啶-1-甲酸叔丁酯(70b)
tert-butyl 4-(benzylamino)-4-(trifluoromethyl)piperidine-1-carboxylate
将4-氧代哌啶-1-甲酸叔丁酯(70a)(40g,0.2mol)溶解于500mL甲苯中,加入苯甲胺(21.4g,0.2mol),回流反应6h,将反应液冷却至室温,减压浓缩后加入500mL乙腈及DMF(46mL),加入KHF
2(1.2g,0.15mol),冷却至0℃,继续在该条件下滴加三氟乙酸(20mL,0.25mol),滴加完成后继续反应5min,0℃条件下滴加TMSCF
3(44mL,0.3mol),升至室温继续搅拌16h。向反应液中缓慢加入100mL饱和碳酸钠溶液,用800mL乙酸乙酯稀释反应液,分液,有机相用1000mL水洗涤,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=10:1),得到4-(苄基氨基)-4-(三氟甲基)哌啶-1-甲酸叔丁酯(70b)(40g,收率:56%)。
第二步:4-氨基-4-(三氟甲基)哌啶-1-甲酸叔丁酯(70c)
tert-butyl 4-amino-4-(trifluoromethyl)piperidine-1-carboxylate
将4-(苄基氨基)-4-(三氟甲基)哌啶-1-甲酸叔丁酯(70b)(40g,0.112mol)溶解到1000mL甲醇中,加入甲酸(25mL,0.66mol)及10%钯/碳(10g),反应于45℃搅拌16h。将反应液冷却至室温,过滤,将滤液减压浓缩,得到白色固体。将该白色固体用900mL二氯甲烷及100mL甲醇溶解,加入500mL饱和碳酸钠溶液搅拌30min,分离有机相,无水硫酸钠干燥,减压浓缩,得到4-氨基-4-(三氟甲基)哌啶-1-甲酸叔丁酯(70c)(27g,产率:89%)。
第三步:4-氧代-4'-(三氟甲基)-[1,4'-联哌啶]-1'-甲酸叔丁酯(70d)
tert-butyl 4-oxo-4'-(trifluoromethyl)-[1,4'-bipiperidine]-1'-carboxylate
向4-氨基-4-(三氟甲基)哌啶-1-甲酸叔丁酯(70c)(2.7g,0.01mol)加入15mL DMF,分别加入碳酸钾(5.5g,0.05mol)和1,5-二氯-3-戊酮(3.1g,0.02mol),升温至90℃反应16h。将反应液冷却至室温,用200mL乙酸乙酯稀释反应液,用200mL纯化水洗涤,有机相用无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=5:1),得到4-氧代-4'-(三氟甲基)-[1,4'-联哌啶]-1'-甲酸叔丁酯(70d)(1.0g,收率:28.6%)。
第四步:4-羟基-4'-(三氟甲基)-[1,4'-联哌啶]-1'-甲酸叔丁酯(70e)
tert-butyl 4-hydroxy-4'-(trifluoromethyl)-[1,4'-bipiperidine]-1'-carboxylate
向4-氧代-4'-(三氟甲基)-[1,4'-联哌啶]-1'-甲酸叔丁酯(70d)(1.0g,2.86mmol)加入20mL甲醇,冷却至0℃,缓慢加入硼氢化钠(0.2g,5.7mol),室温反应2h。将反应液减 压浓缩,用100mL乙酸乙酯稀释,加入100mL水洗涤,有机相用无水硫酸钠干燥,减压浓缩,得到4-羟基-4'-(三氟甲基)-[1,4'-联哌啶]-1'-甲酸叔丁酯(70e)(0.9g,收率:89%)。
第五步:4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-4'-(三氟甲基)-[1,4'-联哌啶]-1'-甲酸叔丁酯(70f)
tert-butyl 4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4'-(trifluoromethyl)-[1,4'-bipiperidine]-1'-carboxylate
将4-羟基-4'-(三氟甲基)-[1,4'-联哌啶]-1'-甲酸叔丁酯(70e)(0.9g,2.57mmol)加入15mL无水吡啶中,加入TsCl(1.0g,5.2mmol),60℃下反应3h。将反应液冷却至室温,减压浓缩,用100mL乙酸乙酯稀释反应液,加入100mL饱和碳酸氢钠水溶液洗涤,有机相用无水硫酸钠干燥,减压浓缩后得粗品。将该粗品溶于20mL DMF中,加入3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(0.61g,2.0mmol)和Cs
2CO
3(1.7g,5.2mmol),反应于80℃搅拌3h。将反应液冷却至室温,加入100mL乙酸乙酯稀释反应液,加入100mL水洗涤,有机相用无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=1:1),得到4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-4'-(三氟甲基)-[1,4'-联哌啶]-1'-甲酸叔丁酯(70f)(0.4g,总收率:24%)。
1H NMR(400MHz,CDCl
3)δ8.37(s,1H),7.70–7.63(m,2H),7.42–7.34(m,2H),7.20–7.12(m,3H),7.11–7.04(m,2H),5.58(br.s,2H),4.92–4.79(m,1H),4.08–3.75(m,2H),3.37–3.22(m,2H),3.20–2.92(m,2H),2.79–2.65(m,2H),2.35–2.19(m,2H),2.14–2.98(m,4H),1.74–1.61(m,2H),1.48(s,9H)。
LCMS m/z=638.3[M+1]
+。
第六步3-(4-苯氧基苯基)-1-(4'-(三氟甲基)-[1,4'-双哌啶]-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(70g)
3-(4-phenoxyphenyl)-1-(4'-(trifluoromethyl)-[1,4'-bipiperidin]-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-4'-(三氟甲基)-[1,4'-联哌啶]-1'-甲酸叔丁酯(70f)(0.4g,0.63mmol)溶解到10mL DCM中,加入3mL三氟乙酸,室温搅拌3h。向反应液中缓慢滴加30mL饱和碳酸氢钠水溶液,用50mL二氯甲烷萃取和50mL水洗涤,有机相用无水硫酸钠干燥,减压浓缩,得3-(4-苯氧基苯基)-1-(4'-(三氟甲基)-[1,4'-双哌啶]-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(70g)(0.32g,产率:95%)。
LCMS m/z=538.6[M+1]
+。
第七步:3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-4'-(三氟甲基)-[1,4'-双哌啶]-1'-基)氮杂环丁烷-1'-甲酸叔丁酯(70h)
tert-butyl 3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4'-(trifluoromethyl)-[1,4'-bipiperidin]-1'-yl)azetidine-1-carboxylate
将3-(4-苯氧基苯基)-1-(4'-(三氟甲基)-[1,4'-双哌啶]-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(70g)(0.32g,0.6mmol)溶于20mL DCE中,加入3-氧杂氮杂环丁-1-甲酸叔丁酯(0.2g,1.2mmol),室温搅拌1h后,加入三乙酰氧基硼氢化钠(0.6g,3.0mmol),室温搅拌16h。向反应液中缓慢滴加30mL饱和碳酸氢钠溶液,加入30mL二氯甲烷萃取,有机相用50mL水洗涤,分离有机相,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得到3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-4'-(三氟甲基)-[1,4'-双哌啶]-1'-基)氮杂环丁烷-1'-甲酸叔丁酯(70h)(0.3g,收率:70%)。
LCMS m/z=693.3[M+1]
+。
第八步:1-(1'-(氮杂环丁-3-基)-4'-(三氟甲基)-[1,4'-联哌啶]-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(70i)
1-(1'-(azetidin-3-yl)-4'-(trifluoromethyl)-[1,4'-bipiperidin]-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-4'-(三氟甲基)-[1,4'-双哌啶]-1'-基)氮杂环丁烷-1'-甲酸叔丁酯(70h)(0.3g,0.43mmol)溶解到10mL DCM中,加入3mL三氟乙酸,室温搅拌3h。向反应液中缓慢滴加30mL饱和碳酸氢钠溶液,加入50mL二氯甲烷萃取,有机相用50mL水洗涤,分离有机相,无水硫酸钠干燥,减压浓缩,得1-(1'-(氮杂环丁-3-基)-4'-(三氟甲基)-[1,4'-联哌啶]-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(70i)(0.25g,产率:96%)。
LCMS m/z=593.3[M+1]
+。
第九步:5-(3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-4'-(三氟甲基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物70)
5-(3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4'-(trifluoromethyl)-[1,4'-bipiperidin]-1'-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将1-(1'-(氮杂环丁-3-基)-4'-(三氟甲基)-[1,4'-联哌啶]-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(70i)(0.12g,0.2mmol)溶于5mL DMSO中,加入DIPEA(0.13g,0.1mmol)和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(90mg,0.30mmol),升温至90℃反应5h。将反应液冷却至室温,加入50mL乙酸乙酯和50mL水,分离有机相,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得5-(3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-4'-(三氟甲基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物70)(20mg,收率:11%)。
1H NMR(400MHz,CDCl
3)δ8.50–8.28(m,2H),7.69–7.60(m,3H),7.43–7.35(m, 2H),7.21–7.12(m,3H),7.11–7.04(m,2H),6.80(d,1H),6.53(dd,1H),5.78(br.s,2H),4.98–4.78(m,2H),4.16–4.07(m,2H),3.93–3.85(m,2H),3.52–3.43(m,1H),3.36–3.24(m,2H),2.94–2.62(m,7H),2.42–2.21(m,4H),2.18–2.10(m,3H),2.08–2.02(m,2H),1.92–1.81(m,2H)。
LCMS m/z=849.3[M+1]
+。
实施例71:
2-((3r,5r,7r)-金刚烷-1-基)-1-(2-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-7-氮杂螺[3.5]壬-7-基)乙-1-酮(化合物71)的三氟乙酸盐
2-((3r,5r,7r)-adamantan-1-yl)-1-(2-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)ethan-1-one trifluoroacetate
第一步:2-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]-7-氮杂螺[3.5]壬-7-甲酸叔丁酯(71a)
Tert-butyl 2-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]-7-azaspiro[3.5]nonane-7-carboxylate
将3-(4-苯氧基苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(1a)(合成方法见J.Med.Chem.2015,58,9625-9638)(1.1g,2.85mmol)溶解在30mL 1,2-二氯乙烷中,加入 2-氧代-7-氮杂螺[3.5]壬-7-甲酸叔丁酯(0.67g,3.92mmol)和冰醋酸(0.342g,5.70mmol),室温搅拌1h,再加入三乙酰氧基硼氢化钠(1.068g,5.04mmol),加完后室温反应过夜。向反应液滴加饱和碳酸氢钠溶液调节pH至10,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=100:0-9:1),得到2-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]-7-氮杂螺[3.5]壬-7-甲酸叔丁酯(71a)(1.11g,产率:64%)。
LCMS m/z=610.3[M+1]
+。
第二步:1-[1-(7-氮杂螺[3.5]壬-2-基)-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(71b)的三氟乙酸盐
1-[1-(7-Azaspiro[3.5]nonan-2-yl)-4-piperidyl]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate
将2-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]-7-氮杂螺[3.5]壬-7-甲酸叔丁酯(71a)(1.1g,1.81mmol)溶解在15mL二氯甲烷中,加入40mL 4N的盐酸乙酸乙酯溶液,室温搅拌2h。将反应液减压浓缩,得粗品1-[1-(7-氮杂螺[3.5]壬-2-基)-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(71b)的三氟乙酸盐(0.65g)。
LCMS m/z=510.3[M+1]
+。
第三步:2-((3r,5r,7r)-金刚烷-1-基)-1-(2-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-7-氮杂螺[3.5]壬-7-基)乙-1-酮(化合物71)的三氟乙酸盐
2-((3r,5r,7r)-adamantan-1-yl)-1-(2-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)ethan-1-one trifluoroacetate
将金刚烷乙酸(92mg,0.47mmol)溶解于15mL DCM中,依次加入DIPEA(152mg,1.18mmol)与HATU(224mg,0.59mmol),室温下搅拌30min,加入上述粗品1-[1-(7-氮杂螺[3.5]壬-2-基)-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(71b)的三氟乙 酸盐(200mg),室温搅拌18h。将反应体系减压浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得2-((3r,5r,7r)-金刚烷-1-基)-1-(2-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-7-氮杂螺[3.5]壬-7-基)乙-1-酮(化合物71)的三氟乙酸盐(100mg)。
1H NMR(400MHz,CDCl
3)δ8.36(s,1H),7.68–7.60(m,2H),7.44–7.35(m,2H),7.22–7.05(m,5H),5.52(s,2H),4.90–4.71(m,1H),3.66–3.30(m,4H),3.18–3.00(m,2H),2.94–2.73(m,1H),2.52–2.34(m,2H),2.18–2.00(m,8H),1.96(s,3H),1.85–1.73(m,2H),1.73–1.46(m,16H)。
LCMS m/z=686.4[M+1]
+。
实施例72:
2-(1-金刚烷基)-1-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)]吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]乙酮(化合物72)
2-(1-adamantyl)-1-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]azetidin-1-yl]azetidin-1-yl]ethanone
第一步:3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-甲酸叔丁酯(72a)
tert-butyl 3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]azetidine-1-carboxylate
将3-(4-苯氧基苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(1a)(合成方法见J.Med.Chem.2015,58,9625-9638)(1.5g,3.88mmol)溶解在15mL 1,2-二氯乙烷中,依次加入3-氧代氮杂环丁-1-甲酸叔丁酯(0.797g,4.66mmol)和冰醋酸(1.24g,20.63mmol),加完后反应于65℃搅拌3h。将反应液冷却至室温,加入三乙酰氧基硼氢化钠(1.651g,7.79mmol),加完后室温反应过夜。向反应液中滴加饱和碳酸氢钠溶液调pH至10,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=100:0-19:1),得到3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-甲酸叔丁酯(72a)(1.932g,产率:92%)。
LCMS m/z=542.3[M+1]
+。
第二步:1-[1-(氮杂环丁-3-基)-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(72b)
1-[1-(azetidin-3-yl)-4-piperidyl]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine
将3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-甲酸叔丁酯(72a)(1.6g,2.96mmol)溶解在5mL二氯甲烷中,加入12mL 4N盐酸乙酸乙酯溶液,室温搅拌2h。将反应液减压浓缩,向残留物中加入50mL二氯甲烷,用饱和碳酸氢钠溶液调pH至10,分液,有机层用无水硫酸钠干燥,减压浓缩,得粗品1-[1-(氮杂环丁-3-基)-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(72b)(0.888g)。
LCMS m/z=442.2[M+1]
+。
第三步:3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环 丁-1-基]氮杂环丁-1-甲酸叔丁酯(72c)
tert-butyl 3-[3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]azetidin-1-yl]azetidine-1-carboxylate
将上述粗品1-[1-(氮杂环丁-3-基)-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(72b)(0.7g)溶解在20mL 1,2-二氯乙烷中,依次加入3-氧代氮杂环丁-1-甲酸叔丁酯(0.407g,2.38mmol)和冰醋酸(0.190g,3.17mmol),加完后反应于65℃搅拌3h。将反应液冷却至室温,加入三乙酰氧基硼氢化钠(0.672g,3.17mmol),加完后室温反应过夜。向反应液滴加饱和碳酸氢钠溶液调pH至10,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=100:0-19:1),得到3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-甲酸叔丁酯(72c)(0.918g,从化合物72a算两步产率:66%)。
LCMS m/z=597.3[M+1]
+。
第四步:1-[1-[1-(氮杂环丁-3-基)氮杂环丁-3-基]-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(72d)
1-[1-[1-(azetidin-3-yl)azetidin-3-yl]-4-piperidyl]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine
将3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-甲酸叔丁酯(72c)(0.8g,1.342mmol)溶解在10mL二氯甲烷中,加入30mL4N盐酸乙酸乙酯溶液,室温搅拌2h。将反应液减压浓缩,向残留物中加入100mL二氯甲烷,用饱和碳酸氢钠溶液调pH至10,分液,有机层用无水硫酸钠干燥,减压浓缩,得粗品1-[1-[1-(氮杂环丁-3-基)氮杂环丁-3-基]-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(72d)(0.600g)。
LCMS m/z=497.3[M+1]
+。
第五步:2-(1-金刚烷基)-1-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)]吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]乙酮(化合物72)
2-(1-adamantyl)-1-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]azetidin-1-yl]azetidin-1-yl]ethanone
将2-(1-金刚烷基)乙酸(0.050g,0.257mmol)溶解在2mL二氯甲烷中,依次加入上述粗品1-[1-[1-(氮杂环丁-3-基)氮杂环丁-3-基]-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(72d)(0.141g)、HATU(0.108g,0.284mmol)和二异丙基乙胺(0.0665g,0.515mmol),加完后室温反应3小时。向反应液中加入10mL水和20mL二氯甲烷,分液,有机层用无水硫酸钠干燥,减压浓缩所得粗品硅胶柱色谱分离纯化(二氯甲烷/甲醇(v/v)=98:2-92:8),得2-(1-金刚烷基)-1-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)]吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]乙酮(化合物72)(0.102g,从化合物72c算两步产率:48%)。
1H NMR(400MHz,CDCl
3)δ8.36(s,1H),7.69–7.60(m,2H),7.44–7.35(m,2H),7.21–7.11(m,3H),7.10–7.04(m,2H),5.57(s,2H),4.89–4.73(m,1H),4.14–4.06(m,1H),4.05–3.91(m,2H),3.83–3.72(m,1H),3.59–3.50(m,2H),3.50–3.40(m,1H),3.22–2.84(m,5H),2.53–2.37(m,2H),2.29–1.99(m,4H),1.99–1.91(m,3H),1.85(s,2H),1.73–1.57(m,12H)。
LCMS m/z=673.4[M+1]
+。
实施例73:
2-(1-金刚烷基)-1-(3-(4-(4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)乙-1-酮(化合物73)
2-(1-adamantyl)-1-(3-(4-(4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)azetidin-1-yl)ethan-1-one
第一步:4-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]哌啶-1-甲酸叔丁酯(73a)
Tert-butyl 4-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]piperidine-1-carboxylate
将3-(4-苯氧基苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(1a)(合成方法见J.Med.Chem.2015,58,9625-9638)(1.72g,4.45mmol)溶解在18mL 1,2-二氯乙烷中,向其加入4-氧代哌啶-1-甲酸叔丁酯(1.065g,5.35mmol)和冰醋酸(1.42g,23.66mmol),加完后反应于65℃搅拌3h,再冷却至室温,加入三乙酰氧基硼氢化钠(1.894g,8.93mmol),加完后室温反应过夜。向反应液滴加饱和碳酸氢钠溶液调节pH至10,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=100:0-19:1),得到4-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]哌啶-1-甲酸叔丁酯(73a)(1.22g,产率:48%)。
第二步:3-(4-苯氧基苯基)-1-[1-(4-哌啶基)-4-哌啶基]吡唑并[3,4-d]嘧啶-4-胺(73b)
3-(4-phenoxyphenyl)-1-[1-(4-piperidyl)-4-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine
将4-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]哌啶-1-甲酸叔丁酯(73a)(1.05g,1.84mmol)溶解在5mL二氯甲烷中,加入17mL 4N盐酸乙酸乙酯溶液,室温搅拌2h。将反应液减压浓缩,向残留物中加入100mL二氯甲烷,用饱和碳酸氢钠溶液调节pH至10,分液,有机层用无水硫酸钠干燥,减压浓缩得粗品3-(4-苯氧基苯基)-1-[1-(4-哌啶基)-4-哌啶基]吡唑并[3,4-d]嘧啶-4-胺(73b)(0.83g)。
第三步:3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(73c)
Tert-butyl 3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)azetidine-1-carboxylate
将上述粗品3-(4-苯氧基苯基)-1-[1-(4-哌啶基)-4-哌啶基]吡唑并[3,4-d]嘧啶-4-胺(73b)(0.8g)溶解在60mL 1,2-二氯乙烷中,依次加入冰醋酸(0.154g,2.56mmol)和3-氧代氮杂环丁-1-甲酸叔丁酯(0.408g,2.38mmol),氮气氛围下反应加热至65℃搅拌3h,将反应液冷却至室温,加入三乙酰氧基硼氢化钠(2.166g,10.22mmol),室温搅拌过夜。向反应液中加入70mL饱和碳酸氢钠溶液淬灭反应,搅拌,静置分层,水相用二氯甲烷萃取(50mL x 2),合并有机相,用100mL饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=100/1-15/1),得3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(73c)(0.897g,从化合物73a算两步产率:81%)。
第四步:1-(1'-(氮杂环丁-3-基)-[1,4'-联哌啶]-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(73d)
1-(1'-(azetidin-3-yl)-[1,4'-bipiperidin]-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(73c)(0.5g,0.80mmol)用3mL甲醇溶解,滴加18mL 4N盐酸乙酸乙酯溶液,室温反应过夜。将反应液减压浓缩,残留物用饱和碳酸氢钠溶液调pH至10,用二氯甲烷萃取(40mL x 3),合并有机相,无水硫酸钠干燥,减压浓缩,得到粗品1-(1'-(氮杂环丁-3-基)-[1,4'-联哌啶]-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(73d)(0.3g)。
第五步:2-(1-金刚烷基)-1-(3-(4-(4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)乙-1-酮(化合物73)
2-(1-adamantyl)-1-(3-(4-(4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)azetidin-1-yl)ethan-1-one
将2-(1-金刚烷基)乙酸(0.02g,0.103mmol)溶解在2mL二氯甲烷中,依次加入上述粗品1-(1'-(氮杂环丁-3-基)-[1,4'-联哌啶]-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(73d)(0.0594g)、HATU(0.0431g,0.113mmol)和二异丙基乙胺(0.0266g,0.206mmol),加完后室温反应3小时。向反应液中加入10mL水和20mL二氯甲烷,分液,有机层用无水硫酸钠干燥,减压浓缩所得粗品硅胶柱色谱分离纯化(二氯甲烷/甲醇(v/v)=98:2-92:8),得2-(1-金刚烷基)-1-(3-(4-(4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)乙-1-酮(化合物73)(0.052g,从化合物73c算两步产率:47%)。
1H NMR(400MHz,CDCl
3)δ8.37(s,1H),7.70–7.62(m,2H),7.45–7.35(m,2H),7.22–7.12(m,3H),7.12–7.05(m,2H),5.52(s,2H),4.81–4.70(m,1H),4.17–4.07(m,1H),4.07–3.94(m,2H),3.90–3.79(m,1H),3.15–3.02(m,3H),2.96–2.81(m,2H),2.54–2.33(m,5H),2.10–2.00(m,2H),2.00–1.93(m,3H),1.93–1.82(m,6H),1.74–1.60(m, 14H)。
LCMS m/z=701.5[M+1]
+。
实施例74:
2-((3r,5r,7r)-金刚烷-1-基)-1-(3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)乙酮(化合物74)
2-((3r,5r,7r)-adamantan-1-yl)-1-(3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)ethanone
将金刚烷乙酸(66mg,0.34mmol)溶解于15mL DCM中,依次加入DIPEA(58mg,0.45mmol)与HATU(172mg,0.45mmol),室温下搅拌30min,加入上述粗品1-[1-(氮杂环丁-3-基)-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(72b)(100mg),室温搅拌18h。将反应体系减压浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得2-((3r,5r,7r)-金刚烷-1-基)-1-(3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)乙酮(化合物74)(50mg,从化合物72a算两步收率:24%)。
1H NMR(400MHz,CDCl
3)δ8.36(s,1H),7.65(d,2H),7.44–7.33(m,2H),7.22–7.02(m,5H),5.57(s,2H),4.88–4.74(m,1H),4.20–4.10(m,1H),4.09–3.96(m,2H),3.92–3.83(m,1H),3.24–3.13(m,1H),3.06–2.88(m,2H),2.53–2.37(m,2H),2.20–2.02(m,4H),2.01–1.92(m,3H),1.87(s,2H),1.76–1.58(m,12H)。
LCMS m/z=618.3[M+1]
+。
实施例75:
5-(3-(7-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-2-氮杂螺[3.5]壬-2-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物75)
5-(3-(7-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azaspiro[3.5 ]nonan-2-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:7-羟基-2-氮杂螺[3.5]壬-2-甲酸叔丁酯(75b)
tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate
将7-氧代-2-氮杂螺[3.5]壬-2-甲酸叔丁酯(75a)(380mg,1.59mmol)溶于8毫升甲醇中,加入硼氢化钠(120mg,3.18mmol),室温反应0.5小时。将反应液用5mL水淬灭反应,水相用乙酸乙酯萃取(20mL×3),合并有机相,无水硫酸钠干燥,减压浓缩,得到7-羟基-2-氮杂螺[3.5]壬-2-甲酸叔丁酯(75b)(360mg,产率:94%)。
第二步:7-((甲基磺酰基)氧基)-2-氮杂螺[3.5]壬-2-甲酸叔丁酯(75c)
Tert-butyl 7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate
将7-羟基-2-氮杂螺[3.5]壬-2-甲酸叔丁酯(75b)(360mg,1.49mmol)溶于10毫升二氯甲烷中,降温至0℃,依次加入三乙胺(302mg,2.98mmol)和甲基磺酰氯(0.17mL, 2.24mmol),反应回到室温搅拌1.5小时。将反应液用10mL水淬灭反应,水相用二氯甲烷萃取(20mL×3),合并有机相,无水硫酸钠干燥,减压浓缩,得到7-((甲基磺酰基)氧基)-2-氮杂螺[3.5]壬-2-甲酸叔丁酯(75c)(461mg,产率:97%)。
第三步:7-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-2-氮杂螺[3.5]壬烷-2-甲酸叔丁酯(75d)
tert-butyl 7-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azaspiro[3.5]nonane-2-carboxylate
将7-((甲基磺酰基)氧基)-2-氮杂螺[3.5]壬-2-甲酸叔丁酯(75c)(461mg,1.44mmol)溶于10毫升DMF中,依次加入3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(524mg,1.73mmol)和碳酸铯(1.4g,4.32mmol),反应升温至80℃搅拌5小时。将反应液冷却至室温,用10mL水稀释反应液,水相用二氯甲烷萃取(20mL×3),合并有机相,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=10:1-8:1),得到7-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-2-氮杂螺[3.5]壬烷-2-甲酸叔丁酯(75d)(305mg,产率:40%)。
LCMS m/z=527.3[M+1]
+。
第四步:3-(4-苯氧基苯基)-1-(2-氮杂螺[3.5]壬烷-7-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(75e)
3-(4-phenoxyphenyl)-1-(2-azaspiro[3.5]nonan-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将7-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-2-氮杂螺[3.5]壬烷-2-甲酸叔丁酯(75d)(305mg,0.58mmol)溶于6毫升二氯甲烷中,加入3毫升三氟乙酸,室温反应2.5小时。将反应液用2N氢氧化钠水溶液调pH至10,水相用二氯甲烷萃取(10mL×3),合并有机相,无水硫酸钠干燥,减压浓缩,得到3-(4-苯氧基苯基)-1-(2-氮杂螺[3.5] 壬烷-7-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(75e)(209mg,产率:85%)。
LCMS m/z=427.3[M+1]
+。
第五步:3-(7-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-2-氮杂螺[3.5]壬-2-基)氮杂环丁-1-甲酸叔丁酯(75f)
tert-butyl 3-(7-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)azetidine-1-carboxylate
将3-(4-苯氧基苯基)-1-(2-氮杂螺[3.5]壬烷-7-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(75e)(115mg,0.27mmol)溶于5毫升DCE中,室温下依次加入1-Boc-3-氮杂环丁酮(92mg,0.54mmol)、冰乙酸(0.04mL,0.68mmol)和无水硫酸钠(200mg),搅拌5分钟后加入三乙酰氧基硼氢化钠(172mg,0.81mmol),室温搅拌过夜。向反应液中加入20毫升水,用2N氢氧化钠水溶液调pH为10,用二氯甲烷萃取(30mL×3),合并有机相,有机相用水洗涤(20mL×2),无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=10:1-8:1),得到3-(7-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-2-氮杂螺[3.5]壬-2-基)氮杂环丁-1-甲酸叔丁酯(75f)(130mg,产率:83%)。
LCMS m/z=582.3[M+1]
+。
第六步:1-(2-(氮杂环丁-3-基)-2-氮杂螺[3.5]壬-7-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(75g)
1-(2-(azetidin-3-yl)-2-azaspiro[3.5]nonan-7-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(7-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-2-氮杂螺[3.5]壬-2-基)氮杂环丁-1-甲酸叔丁酯(75f)(130mg,0.22mmol)溶于4毫升二氯甲烷中,加入2毫升三氟乙酸,室温反应2.5小时。将反应液用2N氢氧化钠水溶液调pH至10,水相用二氯甲烷萃取(10mL×3),合并有机相,无水硫酸钠干燥,减压浓缩,得到1-(2-(氮杂环丁 -3-基)-2-氮杂螺[3.5]壬-7-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(75g)(95mg,产率:90%)。
第七步:5-(3-(7-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-2-氮杂螺[3.5]壬-2-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物75)
5-(3-(7-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将1-(2-(氮杂环丁-3-基)-2-氮杂螺[3.5]壬-7-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(75g)(95mg,0.20mmol)溶于5毫升DMSO中,室温下加入2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(55mg,0.20mmol)和二异丙基乙基胺(129mg,1.00mmol),升温至80℃反应4小时。将反应液冷却至室温,倒入20毫升水中,水相用混合溶剂二氯甲烷/甲醇(v/v)=10:1萃取(30mL×3),合并有机相,有机相用50毫升水洗涤,无水硫酸钠干燥,减压浓缩后,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=10:1-5:1),得到5-(3-(7-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-2-氮杂螺[3.5]壬-2-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物75)(81mg,产率:55%)。
1H NMR(400MHz,CDCl
3)δ8.82(br.s,1H),8.37(s,1H),7.69–7.59(m,3H),7.43–7.34(m,2H),7.21–7.03(m,5H),6.79(d,1H),6.53(dd,1H),5.60(br.s,2H),4.92(dd,1H),4.81–4.70(m,1H),4.11–4.03(m,2H),3.95–3.86(m,2H),3.80–3.71(m,1H),3.32(s,2H),3.19(s,2H),2.93–2.65(m,3H),2.24–2.06(m,5H),2.06–1.95(m,2H),1.78–1.67(m,2H)。
LCMS m/z=738.3[M+1]
+。
实施例76:
3-(2-(3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-基)-5-氧代-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)哌啶-2,6-二酮(化合物76)
3-(2-(3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione
将3-(2-氯-5-氧代-7H-吡咯并[3,4-b]吡啶-6-基)哌啶-2,6-二酮(合成方法见WO2017197056)(0.1g,0.36mmol)溶于8mL DMSO中,加入0.5mL DIPEA和1-[1-[1-(氮杂环丁-3-基)氮杂环丁-3-基]-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(17d)(合成方法见WO2020239103)(0.53g,1.07mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入10mL水,用乙酸乙酯萃取(40mL×3),有机相用饱和食盐水洗涤(20mL×3),无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=100:0-10:1),得到3-(2-(3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-基)-5-氧代-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)哌啶-2,6-二酮(化合物76)(0.1g,收率:38%)。
1H NMR(400MHz,CDCl
3)δ9.33(s,1H),8.38(s,1H),7.81(d,1H),7.68–7.60(m,2H),7.43–7.34(m,2H),7.20–7.03(m,5H),6.26(d,1H),5.69(s,2H),5.17(dd,1H),4.90–4.73(m,1H),4.36–4.08(m,4H),4.02–3.94(m,2H),3.77–3.65(m,1H),3.63–3.52(m,2H),3.26–3.03(m,3H),3.03–2.73(m,4H),2.53–1.75(m,8H)。
LC-MS m/z=740.3[M+1]
+。
实施例77:
5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物77)
5-(4-((4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将3-(4-苯氧基苯基)-1-(1-(哌啶-4-基甲基)哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(6b)(合成方法见WO2020239103)(150mg,0.31mmol)溶于10mL DMSO中,加入1.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(128mg,0.46mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入50mL水,过滤,收集固体,用50mL水洗涤,固体用100mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物77)(160mg,收率:70%)。
1H NMR(400MHz,CDCl
3)δ9.18(s,1H),8.40(s,1H),7.71–7.61(m,3H),7.43–7.34(m,2H),7.28(d,1H),7.21–7.11(m,3H),7.11-7.01(m,3H),5.72(br.s,2H),4.94(dd,1H),4.88–4.70(m,1H),4.01–3.87(m,2H),3.10–2.66(m,7H),2.52–2.37(m,2H),2.34–2.20(m,2H),2.17–2.08(m,1H),2.07–1.66(m,7H),1.37–1.22(m,2H)。
LCMS m/z=740.3[M+1]
+。
实施例78:
5-(3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)甲基)吡咯-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物78)
5-(3-((4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)甲基)吡咯-1-甲酸叔丁酯(78a)
tert-butyl 3-((4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate
将3-(4-苯氧基苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(1a)(合成方法见J.Med.Chem.2015,58,9625-9638)(310mg,0.80mmol)溶于15mL DCE中,加入3-甲酰基吡咯-1-甲酸叔丁酯(240mg,1.20mmol),室温搅拌10min后,加入三乙酰氧基硼氢化钠(340mg,1.60mmol),室温搅拌16h。向反应体系中缓慢加入20mL碳酸氢钠水溶液,用DCM萃取(50mL×3),有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)甲基)吡咯-1-甲酸叔丁酯(78a)(460mg,收率:>99%)。
LCMS m/z=570.3[M+1]
+。
第二步:3-(4-苯氧基苯基)-1-(1-(吡咯-3-基甲基)哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(78b)
3-(4-phenoxyphenyl)-1-(1-(pyrrolidin-3-ylmethyl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)甲基)吡咯-1-甲酸叔丁酯(78a)(460mg,0.8mmol)溶解在10mL二氯甲烷中,加入5mL三氟乙酸,室温搅拌2h。将反应体系减压浓缩,残留物用30mL 4mol/L NaOH水溶液溶解,用DCM 萃取(40mL×3),有机相用40mL水洗涤,无水硫酸钠干燥,减压浓缩,得3-(4-苯氧基苯基)-1-(1-(吡咯-3-基甲基)哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(78b)(360mg,收率:96%)。
LCMS m/z=470.2[M+1]
+。
第三步:5-(3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)甲基)吡咯-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物78)
5-(3-((4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将3-(4-苯氧基苯基)-1-(1-(吡咯-3-基甲基)哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(78b)(150mg,0.32mmol)溶于10mL DMSO中,加入1.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(132mg,0.478mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入50mL水,过滤,收集固体,用50mL水洗涤,固体用100mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)甲基)吡咯-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物78)(120mg,收率:52%)。
1H NMR(400MHz,CDCl
3)δ9.12(s,1H),8.40(s,1H),7.69–7.61(m,3H),7.43–7.35(m,2H),7.20–7.11(m,3H),7.11–7.04(m,2H),6.96(d,1H),6.70(dd,1H),5.71(br.s,2H),4.94(dd,1H),4.89–4.75(m,1H),3.64–3.55(m,1H),3.54–3.46(m,1H),3.46–3.37(m,1H),3.27–3.00(m,3H),2.94–2.62(m,4H),2.58–2.40(m,4H),2.36–2.18(m,2H),2.18–1.97(m,3H),1.93–1.80(m,2H)。
LCMS m/z=726.3[M+1]
+。
实施例79:
5-(3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物79)
5-(3-((4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)甲基)氮杂环丁-1-甲酸叔丁酯(79a)
tert-butyl 3-((4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)methyl)azetidine-1-carboxylate
将3-(4-苯氧基苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(1a)(合成方法见J.Med.Chem.2015,58,9625-9638)(775mg,2.00mmol)溶于25mL DCE中,加入3-甲酰基氮杂环丁-1-甲酸叔丁酯(555mg,3.00mmol),室温搅拌10min后,加入三乙酰氧基硼氢化钠(850mg,4.01mmol),室温搅拌15h。向反应体系中缓慢加入40mL碳酸氢钠水溶液,用DCM萃取(50mL×3),有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)甲基)氮杂环丁-1-甲酸叔丁酯(79a)(1.1g,收率:99%)。
LCMS m/z=556.3[M+1]
+。
第二步:1-(1-(氮杂环丁-3-基甲基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(79b)
1-(1-(azetidin-3-ylmethyl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)甲基)氮杂环丁-1-甲酸叔丁酯(79a)(1.1g,1.98mmol)溶解在20mL二氯甲烷中,加入9mL三氟乙酸,室温搅拌2h。将反应体系减压浓缩,残留物用30mL 4mol/L NaOH水溶液溶解,用DCM萃取(40mL×3),有机相用40mL水洗涤,无水硫酸钠干燥,减压浓缩,得1-(1-(氮杂环丁-3-基甲基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(79b)(0.9g,收率:>99%)。
LCMS m/z=456.2[M+1]
+。
第三步:5-(3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物79)
5-(3-((4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将1-(1-(氮杂环丁-3-基甲基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(79b)(180mg,0.40mmol)溶于10mL DMSO中,加入1.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(163mg,0.59mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入50mL水,过滤,收集固体,用50mL水洗涤,固体用100mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物79)(80mg,收率:28%)。
1H NMR(400MHz,CDCl
3)δ9.07(s,1H),8.40(s,1H),7.69–7.61(m,3H),7.43–7.35(m,2H),7.21–7.12(m,3H),7.11–7.05(m,2H),6.79(d,1H),6.50(dd,1H),5.66(br.s,2H),4.93(dd,1H),4.89–4.75(m,1H),4.21–4.09(m,2H),3.80–3.68(m,2H),3.18–3.00(m,3H),2.93–2.66(m,5H),2.54–2.26(m,4H),2.18–1.98(m,3H)。
LCMS m/z=712.3[M+1]
+。
实施例80:
(7S)-7-(1-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氮杂环丁-3-基)甲基)氮杂环丁-3-基)哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(化合物80)
(7S)-7-(1-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)azetidin-3-yl)piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide
第一步:(S)-3-((3-(4-(3-氨基甲酰基-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-7-基)哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-甲酸叔丁酯(80a)
tert-butyl(S)-3-((3-(4-(3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)azetidin-1-yl)methyl)azetidine-1-carboxylate
将(7S)-7-[1-(氮杂环丁-3-基)-4-哌啶基]-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(31b)(合成方法见WO2020239103)(140mg,0.30mmol)溶于15mL DCE中,加入3-甲酰基氮杂环丁-1-甲酸叔丁酯(100mg,0.54mmol),室温搅拌10min后,加入三乙酰氧基硼氢化钠(191mg,0.90mmol),室温搅拌16h。向反应体系中缓慢加入20mL饱和碳酸氢钠水溶液,用DCM萃取(50mL×3),有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=10:1-4:1),得 (S)-3-((3-(4-(3-氨基甲酰基-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-7-基)哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-甲酸叔丁酯(80a)(140mg,收率:73%)。
LCMS m/z=642.3[M+1]
+。
第二步:(S)-7-(1-(1-(1-(氮杂环丁-3-基甲基)氮杂环丁-3-基)哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(80b)的三氟乙酸盐
(S)-7-(1-(1-(azetidin-3-ylmethyl)azetidin-3-yl)piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate
将(S)-3-((3-(4-(3-氨基甲酰基-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-7-基)哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-甲酸叔丁酯(80a)(140mg,0.22mmol)溶解在10mL二氯甲烷中,加入5mL三氟乙酸,室温搅拌2h。将反应体系减压浓缩,得粗品(S)-7-(1-(1-(1-(氮杂环丁-3-基甲基)氮杂环丁-3-基)哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(80b)的三氟乙酸盐(190mg)。
LCMS m/z=542.3[M+1]
+。
第五步:(7S)-7-(1-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氮杂环丁-3-基)甲基)氮杂环丁-3-基)哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(化合物80)
(7S)-7-(1-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)azetidin-3-yl)piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide
将上述粗品(S)-7-(1-(1-(1-(氮杂环丁-3-基甲基)氮杂环丁-3-基)哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(80b)的三氟乙酸盐(190mg)溶于10mL DMSO中,加入固体碳酸氢钠(67mg,0.80mmol),室温搅拌10min后,加入1.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056) (83mg,0.30mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入50mL水,过滤,收集固体,用50mL水洗涤,固体用100mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=10:1),得(7S)-7-(1-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氮杂环丁-3-基)甲基)氮杂环丁-3-基)哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(化合物80)(80mg,从化合物80a算两步收率:46%)。
1H NMR(400MHz,CDCl
3)δ9.45(br.s,1H),7.62(d,1H),7.53–7.46(m,2H),7.40–7.32(m,2H),7.18–7.11(m,1H),7.10–7.01(m,4H),6.87–6.82(m,1H),6.58(s,1H),6.47(dd,1H),5.17(br.s,2H),4.91(dd,1H),4.12–4.04(m,3H),3.73–3.66(m,2H),3.66–3.54(m,2H),3.46–3.36(m,2H),3.07–2.92(m,2H),2.90–2.64(m,7H),2.25–2.00(m,4H),1.95–1.65(m,6H),1.64–1.53(m,2H)。
LCMS m/z=798.3[M+1]
+。
实施例81:
(7S)-7-(1'-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)甲基)-[1,4'-联哌啶]-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(化合物81)
(7S)-7-(1'-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-[1,4'-bipiperidin]-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide
第一步:(S)-4-((4-(3-氨基甲酰基-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-7-基)-[1,4'-联哌啶]-1'-基)甲基)哌啶-1-甲酸叔丁酯(81a)
tert-butyl(S)-4-((4-(3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)-[1,4'-bipiperidin]-1'-yl)methyl)piperidine-1-carboxylate
将(7S)-2-(4-苯氧基苯基)-7-[1-(4-哌啶基)-4-哌啶基]-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(30c)(合成方法见WO2020239103)(230mg,0.46mmol)溶于15mL DCE中,加入4-甲酰基哌啶-1-甲酸叔丁酯(150mg,0.70mmol),室温搅拌10min后,加入三乙酰氧基硼氢化钠(195mg,0.92mmol),室温搅拌16h。向反应体系中缓慢加入20mL碳酸氢钠水溶液,用DCM萃取(50mL×3),有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=10:1-4:1),得(S)-4-((4-(3-氨基甲酰基-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-7-基)-[1,4'-联哌啶]-1'-基)甲基)哌啶-1-甲酸叔丁酯(81a)(250mg,收率:78%)。
LCMS m/z=698.5[M+1]
+。
第二步:(S)-2-(4-苯氧基苯基)-7-(1'-(哌啶-4-基甲基)-[1,4'-联哌啶]-4-基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(81b)的三氟乙酸盐
(S)-2-(4-phenoxyphenyl)-7-(1'-(piperidin-4-ylmethyl)-[1,4'-bipiperidin]-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate
将(S)-4-((4-(3-氨基甲酰基-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-7-基)-[1,4'-联哌啶]-1'-基)甲基)哌啶-1-甲酸叔丁酯(81a)(230mg,0.33mmol)溶解在10mL二氯甲烷中,加入5mL三氟乙酸,室温搅拌2h。将反应体系直接减压浓缩,得粗品(S)-2-(4-苯氧基苯基)-7-(1'-(哌啶-4-基甲基)-[1,4'-联哌啶]-4-基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(81b)的三氟乙酸盐(270mg)。
LCMS m/z=598.3[M+1]
+。
第三步:(7S)-7-(1'-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)甲基)-[1,4'-联哌啶]-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(化 合物81)
(7S)-7-(1'-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-[1,4'-bipiperidin]-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide
将上述粗品(S)-2-(4-苯氧基苯基)-7-(1'-(哌啶-4-基甲基)-[1,4'-联哌啶]-4-基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(81b)的三氟乙酸盐(270mg)溶于10mL DMSO中,加入固体碳酸氢钠(143mg,1.70mmol),室温搅拌10min后,加入1.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(142mg,0.51mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入50mL水,过滤,收集固体,用50mL水洗涤,固体用100mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=10:1),得(7S)-7-(1'-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)甲基)-[1,4'-联哌啶]-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(化合物81)(140mg,从化合物81a算两步收率:50%)。
1H NMR(400MHz,CDCl
3)δ7.66(d,1H),7.54–7.47(m,2H),7.40–7.32(m,2H),7.29–7.26(m,1H),7.18–7.11(m,1H),7.10–6.98(m,5H),6.57(s,1H),5.18(br.s,2H),4.93(dd,1H),4.11–4.03(m,1H),3.98–3.87(m,2H),3.47–3.35(m,2H),3.06–2.65(m,9H),2.35–2.00(m,9H),1.96–1.68(m,8H),1.64–1.52(m,4H),1.50–1.40(m,1H),1.32–1.19(m,2H)。
LCMS m/z=854.4[M+1]
+。
实施例82:
(7S)-7-(1'-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氮杂环丁-3-基)甲基)-[1,4'-联哌啶]-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(化合物82)
(7S)-7-(1'-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)-[1,4'-bipiperidin]-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide
第一步:(S)-3-((4-(3-氨基甲酰基-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-7-基)-[1,4'-联哌啶]-1'-基)甲基)氮杂环丁-1-甲酸叔丁酯(82a)
tert-butyl(S)-3-((4-(3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)-[1,4'-bipiperidin]-1'-yl)methyl)azetidine-1-carboxylate
将(7S)-2-(4-苯氧基苯基)-7-[1-(4-哌啶基)-4-哌啶基]-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(30c)(合成方法见WO2020239103)(230mg,0.46mmol)溶于15mL DCE中,加入3-甲酰基氮杂环丁-1-甲酸叔丁酯(128mg,0.69mmol),室温搅拌10min后,加入三乙酰氧基硼氢化钠(195mg,0.92mmol),室温搅拌16h。向反应体系中缓慢加入20mL碳酸氢钠水溶液,用DCM萃取(50mL×3),有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=10:1-4:1),得(S)-3-((4-(3-氨基甲酰基-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-7-基)-[1,4'-联哌啶]-1'-基)甲基)氮杂环丁-1-甲酸叔丁酯(82a)(280mg,收率:91%)。
LCMS m/z=670.5[M+1]
+。
第二步:(S)-7-(1'-(氮杂环丁-3-基甲基)-[1,4'-联哌啶]-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(82b)的三氟乙酸盐
(S)-7-(1'-(azetidin-3-ylmethyl)-[1,4'-bipiperidin]-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra hydropyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate
将(S)-3-((4-(3-氨基甲酰基-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-7-基)-[1,4'-联哌啶]-1'-基)甲基)氮杂环丁-1-甲酸叔丁酯(82a)(260mg,0.39mmol)溶解在10mL二氯甲烷中,加入5mL三氟乙酸,室温搅拌2h。将反应体系直接减压浓缩,得粗品(S)-7-(1'-(氮杂环丁-3-基甲基)-[1,4'-联哌啶]-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(82b)的三氟乙酸盐(320mg)。
LCMS m/z=570.3[M+1]
+。
第三步:(7S)-7-(1'-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氮杂环丁-3-基)甲基)-[1,4'-联哌啶]-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(化合物82)
(7S)-7-(1'-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)-[1,4'-bipiperidin]-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide
将上述粗品(S)-7-(1'-(氮杂环丁-3-基甲基)-[1,4'-联哌啶]-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(82b)的三氟乙酸盐(320mg)溶于10mL DMSO中,加入固体碳酸氢钠(173mg,2.06mmol),室温搅拌10min,加入1.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(168mg,0.61mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入50mL水,过滤,收集固体,用50mL水洗涤,固体用100mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=10:1),得(7S)-7-(1'-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氮杂环丁-3-基)甲基)-[1,4'-联哌啶]-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(化合物82)(140mg,从化合物82a算两步收率:43%)。
1H NMR(400MHz,CDCl
3)δ7.63(d,1H),7.55–7.47(m,2H),7.41–7.32(m,2H),7.18–7.11(m,1H),7.10–7.01(m,4H),6.82(d,1H),6.57(s,1H),6.48(dd,1H),5.19(br.s,2H),4.92(dd,1H),4.16–4.04(m,3H),3.73–3.63(m,2H),3.47–3.35(m,2H),3.08–2.68(m,8H),2.68–2.59(m,2H),2.35–1.94(m,10H),1.91–1.79(m,4H),1.75–1.71(m,1H),1.65–1.50(m,4H),1.48–1.39(m,1H)。
LCMS m/z=826.4[M+1]
+。
实施例83:
(7S)-7-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)甲基)哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(化合物83)
(7S)-7-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide
第一步:(S)-4-((4-(3-氨基甲酰基-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-7-基)哌啶-1-基)甲基)哌啶-1-甲酸叔丁酯(83a)
tert-butyl(S)-4-((4-(3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate
将(S)-2-(4-苯氧基苯基)-7-(哌啶-4-基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(30a)(95%ee)(合成方法见WO2018033853)(417mg,1.00mmol)溶于15mL氯仿中,室温下依次加入1-叔丁氧羰基哌啶-4-甲醛(1.07g,5.00mmol)、冰乙酸(0.23mL,4.00mmol)和无水硫酸钠(800mg),60℃下搅拌2h后加入三乙酰氧基硼氢化钠(1.27g,6.00mmol),室温搅拌16h。向反应液中加入50mL水,用2mol/L氢氧化钠水溶液调水相pH至10,用二氯甲烷萃取(30mL×3),合并有机相,有机相用水洗涤(20mL×2),无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=10:1-8:1),得到(S)-4-((4-(3-氨基甲酰基-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-7-基)哌啶-1-基)甲基)哌啶-1-甲酸叔丁酯(83a)(240mg,产率:39%)。
LCMS m/z=615.3[M+1]
+。
第二步:(S)-2-(4-苯氧基苯基)-7-(1-(哌啶-4-基甲基)哌啶-4-基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(83b)
(S)-2-(4-phenoxyphenyl)-7-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide
将(S)-4-((4-(3-氨基甲酰基-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-7-基)哌啶-1-基)甲基)哌啶-1-甲酸叔丁酯(83a)(240mg,0.39mmol)溶于4mL二氯甲烷中,加入2mL三氟乙酸,室温反应1.5h。将反应液用2mol/L氢氧化钠溶液调pH至10,水相用二氯甲烷萃取(10mL×3),合并有机相,用无水硫酸钠干燥,减压浓缩,得到(S)-2-(4-苯氧基苯基)-7-(1-(哌啶-4-基甲基)哌啶-4-基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(83b)(190mg,产率:95%)。
LCMS m/z=515.3[M+1]
+。
第三步:(7S)-7-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)甲基)哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(化合物83)
(7S)-7-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide
将(S)-2-(4-苯氧基苯基)-7-(1-(哌啶-4-基甲基)哌啶-4-基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(83b)(190mg,0.37mmol)溶于5mL DMSO中,室温下加入2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(129mg,0.47mmol)和二异丙基乙基胺(255mg,1.97mmol),升温至80℃反应4h。将反应液冷却至室温,倒入20mL水中,水相用二氯甲烷/甲醇(v/v)=10:1萃取(30mL×3),合并有机相,有机相用40mL水洗涤,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1-8:1),得到(7S)-7-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)甲基)哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(化合物83)(90mg,产率:32%)。
1H NMR(400MHz,CDCl
3)δ8.66(br.s,1H),7.66(d,1H),7.55–7.47(m,2H),7.40–7.32(m,2H),7.29–7.25(m,1H),7.20–6.98(m,6H),6.59(s,1H),5.23(br.s,2H),4.93(dd,1H),4.11–4.03(m,1H),3.99–3.88(m,2H),3.46–3.37(m,2H),3.05–2.65(m,7H),2.26–2.02(m,6H),2.01–1.84(m,4H),1.83–1.41(m,5H),1.33–1.20(m,2H)。
LCMS m/z=771.3[M+1]
+。
实施例84:
5-(3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物84)
5-(3-((4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)甲基)氮杂环丁-1-甲酸叔丁酯(84a)
tert-butyl 3-((4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)methyl)azetidine-1-carboxylate
将3-(4-苯氧基苯基)-1-[1-(4-哌啶基)-4-哌啶基]吡唑并[3,4-d]嘧啶-4-胺(2b)(合成方法见WO2020239103)(0.52g,1.11mmol)溶解于20mL DCE中,加入3-甲酰基氮杂环丁-1-甲酸叔丁酯(0.37g,2.0mmol),室温搅拌10min后,向其加入三乙酰氧基硼氢化钠(0.7g,3.3mmol),室温搅拌反应12h。向反应液中缓慢滴加50mL饱和碳酸氢钠溶液,水相用30mL二氯甲烷萃取,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得到3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)甲基)氮杂环丁-1-甲酸叔丁酯(84a)(0.5g,收率:71%)。
LC-MS m/z=639.4[M+1]
+。
第二步:1-(1'-(氮杂环丁-3-基甲基)-[1,4'-双哌啶]-4-基)-3-(4-苯氧基苯基)-1H-吡唑并 [3,4-d]嘧啶-4-胺(84b)
1-(1'-(azetidin-3-ylmethyl)-[1,4'-bipiperidin]-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)甲基)氮杂环丁-1-甲酸叔丁酯(84a)(0.5g,0.78mmol)溶解到15mL DCM中,加入5mL三氟乙酸,室温搅拌3h。向反应液中缓慢滴加30mL饱和碳酸氢钠溶液,水相用30mL二氯甲烷萃取,无水硫酸钠干燥,减压浓缩,得粗品1-(1'-(氮杂环丁-3-基甲基)-[1,4'-双哌啶]-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(84b)(0.4g)。
LCMS m/z=539.3[M+1]
+。
第三步:5-(3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物84)
5-(3-((4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-(1'-(氮杂环丁-3-基甲基)-[1,4'-双哌啶]-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(84b)(0.4g)溶于10mL DMSO中,加入1.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(0.35g,1.27mmol),反应于90℃搅拌5h。将反应液冷却至室温,用50mL乙酸乙酯稀释,有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得5-(3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物84)(50mg,从化合物84a算两步收率:8%)。
1H NMR(400MHz,CDCl
3)δ8.37(s,1H),7.69–7.60(m,3H),7.43–7.34(m,2H),7.21–7.03(m,5H),6.81(d,1H),6.49(dd,1H),5.60(br.s,2H),4.93(dd,1H),4.82–4.70(m, 1H),4.19–4.09(m,2H),3.75–3.65(m,2H),3.17–3.07(m,2H),3.07–2.91(m,3H),2.91–2.68(m,3H),2.68–2.61(m,2H),2.51–2.31(m,5H),2.17–2.08(m,1H),2.08–1.99(m,4H),1.88–1.79(m,2H),1.68–1.55(m,2H)。
LCMS m/z=795.4[M+1]
+。
实施例85:
5-(3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物85)
5-(3-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-甲酸叔丁酯(85a)
tert-butyl 3-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)azetidine-1-carboxylate
将1-[1-(氮杂环丁-3-基)-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(17b)(合成方法见WO2020239103)(0.7g,1.59mmol)溶解于20mL DCE中,加入3-甲酰基氮 杂环丁-1-甲酸叔丁酯(0.37g,2.0mmol),室温搅拌10min后,向其加入三乙酰氧基硼氢化钠(0.7g,3.3mmol),室温搅拌反应12h。向反应液中缓慢滴加50mL饱和碳酸氢钠溶液,水相用30mL二氯甲烷萃取,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得到3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-甲酸叔丁酯(85a)(0.6g,收率:62%)。
LC-MS m/z=611.3[M+1]
+。
第二步:1-(1-(1-(氮杂环丁烷-3-基甲基)氮杂环丁-3-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(85b)
1-(1-(1-(azetidin-3-ylmethyl)azetidin-3-yl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-甲酸叔丁酯(85a)(0.6g,0.98mmol)溶解到15mL DCM中,加入5mL三氟乙酸,室温搅拌3h。向反应液中缓慢滴加30mL饱和碳酸氢钠溶液,水相用30mL二氯甲烷萃取,无水硫酸钠干燥,减压浓缩,得粗品1-(1-(1-(氮杂环丁烷-3-基甲基)氮杂环丁-3-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(85b)(0.45g)。
LCMS m/z=511.3[M+1]
+。
第三步:5-(3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物85)
5-(3-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-(1-(1-(氮杂环丁烷-3-基甲基)氮杂环丁-3-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(85b)(0.45g)溶于10mL DMSO中,加入1.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(0.35g,1.27mmol),反应于90℃搅拌5h。将反应液冷却至室温,用50mL乙酸乙酯稀释,有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得5-(3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物85)(0.11g,从化合物85a算两步收率:15%)。
1H NMR(400MHz,CDCl
3)δ11.24(br.s,1H),8.38(s,1H),7.69–7.59(m,3H),7.42–7.34(m,2H),7.21–7.03(m,5H),6.93(d,1H),6.46(dd,1H),5.82(br.s,2H),4.94(dd,1H),4.84–4.71(m,1H),4.14–4.03(m,2H),3.76–3.53(m,4H),3.12–2.97(m,3H),2.96–2.66(m,8H),2.48–2.31(m,2H),2.16–1.94(m,5H)。
LCMS m/z=767.3[M+1]
+。
实施例86:
5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物86)
5-(4-((4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'- 基)甲基)哌啶-1-甲酸叔丁酯(86a)
tert-butyl 4-((4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)methyl)piperidine-1-carboxylate
将3-(4-苯氧基苯基)-1-[1-(4-哌啶基)-4-哌啶基]吡唑并[3,4-d]嘧啶-4-胺(2b)(合成方法见WO2020239103)(0.7g,1.49mmol)溶解于20mL DCE中,加入4-甲酰基哌啶-1-甲酸叔丁酯(0.5g,2.34mmol),室温搅拌10min后,向其加入三乙酰氧基硼氢化钠(0.7g,3.3mmol),室温搅拌反应12h。向反应液中缓慢滴加50mL饱和碳酸氢钠溶液,水相用30mL二氯甲烷萃取,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得到4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)甲基)哌啶-1-甲酸叔丁酯(86a)(0.55g,收率:55%)。
LC-MS m/z=667.4[M+1]
+。
第二步:3-(4-苯氧基苯基)-1-(1'-(哌啶-4-基甲基)-[1,4'-联哌啶]-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(86b)
3-(4-phenoxyphenyl)-1-(1'-(piperidin-4-ylmethyl)-[1,4'-bipiperidin]-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)甲基)哌啶-1-甲酸叔丁酯(86a)(0.55g,0.83mmol)溶解到15mL DCM中,加入5mL三氟乙酸,室温搅拌3h。向反应液中缓慢滴加30mL饱和碳酸氢钠溶液,水相用30mL二氯甲烷萃取,无水硫酸钠干燥,减压浓缩,得粗品3-(4-苯氧基苯基)-1-(1'-(哌啶-4-基甲基)-[1,4'-联哌啶]-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(86b)(0.43g)。
LCMS m/z=567.3[M+1]
+。
第三步:5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物86)
5-(4-((4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品3-(4-苯氧基苯基)-1-(1'-(哌啶-4-基甲基)-[1,4'-联哌啶]-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(86b)(0.43g)溶于10mL DMSO中,加入1.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(0.35g,1.27mmol),反应于90℃搅拌5h。将反应液冷却至室温,用50mL乙酸乙酯稀释,有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物86)(40mg,从化合物86a算两步收率:6%)。
1H NMR(400MHz,CDCl
3)δ8.39(s,1H),7.70–7.60(m,3H),7.42–7.34(m,2H),7.30–7.26(m,1H),7.20–6.99(m,6H),5.78(br.s,2H),4.94(dd,1H),4.83–4.69(m,1H),3.99–3.89(m,2H),3.17–3.05(m,2H),3.02–2.89(m,4H),2.89–2.65(m,3H),2.50–2.29(m,5H),2.23–2.15(m,2H),2.15–2.08(m,1H),2.03–1.99(m,1H),1.99–1.93(m,3H),1.93–1.88(m,2H),1.88–1.84(m,1H),1.84–1.76(m,2H),1.68–1.54(m,2H),1.34–1.19(m,2H)。
LCMS m/z=823.4[M+1]
+。
实施例87:
5-(3-(4-(4-氨基-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]-[1,3'-双氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物87)
5-(3-(4-(4-amino-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:3-碘-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(87b)
3-iodo-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将4-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(87a)(合成方法见CN110627796)(2g,4.50mmol)溶于20mL DCM中,加入7.0mL三氟乙酸,反应于室温搅拌4h。将反应液减压浓缩,将残余物溶于50mL DCM中,加入50mL水,滴加1mol/L NaOH溶液调pH到12,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品3-碘-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(87b)(1.61g)。
LCMS m/z=345.0[M+1]
+。
第二步:3-(4-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-甲酸叔丁酯(87c)
tert-butyl 3-(4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl) azetidine-1-carboxylate
将上述粗品3-碘-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(87b)(1.61g)溶于20mL DCE中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(1.31g,7.66mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠(2.44g,11.5mmol),反应于室温搅拌16h。向反应液中加入50mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(70mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得3-(4-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-甲酸叔丁酯(87c)(1.00g,从化合物87a算两步收率:45%)。
LCMS m/z=500.1[M+1]
+。
第三步:1-(1-(氮杂环丁-3-基)哌啶-4-基)-3-碘-1H-吡唑并[3,4-d]嘧啶-4-胺(87d)
1-(1-(azetidin-3-yl)piperidin-4-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(4-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-甲酸叔丁酯(87c)(1g,2.0mmol)溶于15mL DCM中,加入6.0mL三氟乙酸,反应于室温搅拌4h。将反应液减压浓缩,将残余物溶于50mL DCM中,加入50mL水,滴加1mol/L NaOH溶液调pH到12,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-(1-(氮杂环丁-3-基)哌啶-4-基)-3-碘-1H-吡唑并[3,4-d]嘧啶-4-胺(87d)(696mg)。
LCMS m/z=400.1[M+1]
+。
第四步:3-(4-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(87e)
tert-butyl 3-(4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidine]-1'-carboxylate
将上述粗品1-(1-(氮杂环丁-3-基)哌啶-4-基)-3-碘-1H-吡唑并[3,4-d]嘧啶-4-胺(87d) (696mg)溶于20mL DCE中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(596mg,3.48mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠(1.1g,5.19mmol),反应于室温搅拌16h。向反应液中加入30mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得3-(4-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(87e)(120mg,从化合物87c算两步收率:11%)。
LCMS m/z=555.2[M+1]
+。
第五步:1-溴-4-(4-(三氟甲基)苯氧基)苯(87g)
1-bromo-4-(4-(trifluoromethyl)phenoxy)benzene
向1-氯-4-(三氟甲基)苯(87f)(5g,27.7mmol)的DMSO(70mL)溶液中加入叔丁醇钾(3.26g,29.1mmol)和4-溴苯酚(5.03g,29.1mmol),并将反应体系升至160℃,加热反应28h。将反应冷却至室温,缓慢倒入100mL冰水中,用乙酸乙酯萃取(100mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(石油醚),得1-溴-4-(4-(三氟甲基)苯氧基)苯(87g)(3.1g,收率:35%)。
第六步:(4-(4-(三氟甲基)苯氧基)苯基)硼酸(87h)
(4-(4-(trifluoromethyl)phenoxy)phenyl)boronic acid
向充满氮气的三口瓶中加入1-溴-4-(4-(三氟甲基)苯氧基)苯(87g)(1g,3.15mmol)和干燥的四氢呋喃(20mL),冷却至-78℃,缓慢滴加2.5mol/L正丁基锂溶液(1.89mL),加完后在-78℃反应30min,滴加硼酸三异丙酯(0.88mL,3.81mmol),缓慢升至室温反应3h。反应完毕,用2mol/L盐酸溶液(50mL)淬灭反应,用乙酸乙酯萃取(50mL×3),有机相用饱和氯化钠溶液洗涤(50mL),无水硫酸钠干燥,减压浓缩得粗品(4-(4-(三氟甲基)苯氧基)苯基)硼酸(87h)(100mg)。
第七步:3-(4-(4-氨基-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(87i)
tert-butyl 3-(4-(4-amino-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidine]-1'-carboxylate
将3-(4-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(87e)(132mg,0.24mmol)、Pd(dppf)Cl
2(9mg,0.012mmol)、碳酸钾(100mg,0.72mmol)、上述粗品(4-(4-(三氟甲基)苯氧基)苯基)硼酸(87h)(100mg)依次加入到三口瓶中,置换氮气三次,加入10mL 1,4-二氧六环和水(v/v)=7:3的混合溶剂,将反应升至120℃搅拌回流4h。将反应体系冷却至室温,加入30mL乙酸乙酯和30mL水,分离有机相,水相用乙酸乙酯萃取(30mL×3),合并有机相,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱柱提纯(二氯甲烷/甲醇(v/v)=20:1),得3-(4-(4-氨基-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(87i)(100mg,从化合物87e算收率:63%)。
LCMS m/z=665.3[M+1]
+。
第八步:1-(1-([1,3'-双氮杂环丁]-3-基)哌啶-4-基)-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(87j)
1-(1-([1,3'-biazetidin]-3-yl)piperidin-4-yl)-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(4-(4-氨基-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(87i)(100mg,0.15mmol)溶于10mL DCM中,加入2.0mL三氟乙酸,反应于室温搅拌4h。将反应体系减压浓缩,将残余物溶于10mL DCM中,加入10mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(30mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-(1-([1,3'-双氮杂环丁]-3-基)哌啶-4-基)-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(87j)(85mg)。
第九步:5-(3-(4-(4-氨基-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]-[1,3'-双氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物 87)
5-(3-(4-(4-amino-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-(1-([1,3'-双氮杂环丁]-3-基)哌啶-4-基)-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(87j)(85mg)溶于5mL DMSO中,加入0.3mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(42mg,0.15mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入5mL水,过滤,收集滤饼,用20mL水洗涤,固体用30mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-(4-(4-氨基-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]-[1,3'-双氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物87)(20mg,从化合物87i算两步收率:16%)。
1H NMR(400MHz,CDCl
3)δ8.32(s,1H),7.68–7.60(m,2H),7.60–7.52(m,3H),7.13(d,2H),7.06(d,2H),6.74–6.69(m,1H),6.45(dd,1H),5.59(br.s,2H),4.85(dd,1H),4.79–4.66(m,1H),4.02–3.91(m,2H),3.84–3.75(m,2H),3.66–3.58(m,1H),3.54–3.43(m,2H),3.09–2.94(m,3H),2.91–2.81(m,2H),2.81–2.58(m,3H),2.46–2.27(m,2H),2.09–1.90(m,5H)。
LCMS m/z=821.3[M+1]
+。
实施例88:
5-(3-(4-(4-氨基-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物88)
5-(3-(4-(4-amino-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:4-(4-氨基-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(88a)
tert-butyl 4-(4-amino-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate
将4-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(87a)(合成方法见CN110627796)(0.88g,2mmol)、Pd(dppf)Cl
2(73mg,0.1mmol)、碳酸钾(0.83g,6.0mmol)、上述粗品(4-(4-(三氟甲基)苯氧基)苯基)硼酸(87h)(0.62g)加入到三口瓶中,置换氮气三次,加入22mL 1,4-二氧六环和水(v/v)=8:3的混合溶剂,将反应升至120℃搅拌回流4h。将反应体系冷却至室温,加入50mL乙酸乙酯和50mL水,分离出有机相,水相用乙酸乙酯萃取(50mL×3),合并有机相,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得4-(4-氨基-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(88a)(450mg,从化合物87a算收率:41%)。
第二步:1-(哌啶-4-基)-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(88b)
1-(piperidin-4-yl)-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将4-(4-氨基-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(88a)(450mg,0.81mmol)溶于15mL DCM中,加入5.0mL三氟乙酸,反应于室温搅拌4h。将反应体系减压浓缩,将残余物溶于20mL DCM中,加入20mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-(哌啶-4-基)-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(88b)(370mg)。
第三步:4-(4-氨基-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-甲酸叔丁酯(88c)
tert-butyl 4-(4-amino-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidine]-1'-carboxylate
将上述粗品1-(哌啶-4-基)-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(88b)(370mg)溶于30mL DCE中,加入4-氧代哌啶-1-甲酸叔丁酯(320mg,1.61mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠(520mg,2.45mmol),反应于室温搅拌16h。向反应液中加入30mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得4-(4-氨基-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-甲酸叔丁酯(88c)(330mg,从化合物88a算两步收率:64%)。
LCMS m/z=638.3[M+1]
+。
第四步:1-([1,4'-双哌啶]-4-基)-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(88d)
1-([1,4'-bipiperidin]-4-yl)-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将4-(4-氨基-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-甲酸叔丁酯(88c)(330mg,0.52mmol)溶于20mL DCM中,加入8.0mL三氟乙酸,反应于室温搅拌2h。将反应体系减压浓缩,将残余物溶于30mL DCM,加入30mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-([1,4'-双哌啶]-4-基)-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(88d)(280mg)。
第五步:3-(4-(4-氨基-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(88e)
tert-butyl 3-(4-(4-amino-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)azetidine-1-carboxylate
将上述粗品1-([1,4'-双哌啶]-4-基)-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(88d)(280mg)溶于20mL DCE中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(178mg,1.04mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠(331mg,1.56mmol),反应于室温搅拌16h。向反应液中加入20mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(30mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得3-(4-(4-氨基-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(88e)(100mg,从化合物88c算两步收率:28%)。
第六步:1-(1'-(氮杂环丁-3-基)-[1,4'-双哌啶]-4-基)-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(88f)
1-(1'-(azetidin-3-yl)-[1,4'-bipiperidin]-4-yl)-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(4-(4-氨基-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(88e)(100mg,0.14mmol)溶于10mL DCM中,加入3mL三氟乙酸,反应于室温搅拌2h。将反应体系减压浓缩,将残余物溶于15mL DCM,加入15mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(30mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-(1'-(氮杂环丁-3-基)-[1,4'-双哌啶]-4-基)-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(88f)(83mg)。
第七步:5-(3-(4-(4-氨基-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物88)
5-(3-(4-(4-amino-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-(1'-(氮杂环丁-3-基)-[1,4'-双哌啶]-4-基)-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(88f)(83mg)溶于5mL DMSO中,加入0.5mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(43mg,0.16mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入5mL水,过滤,收集滤饼,用20mL水洗涤,固体用30mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-(4-(4-氨基-3-(4-(4-(三氟甲基)苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物88)(81mg,从化合物88e算两步收率:68%)。
1H NMR(400MHz,CDCl
3)δ8.84(s,1H),8.39(s,1H),7.76–7.67(m,2H),7.67–7.58 (m,3H),7.19(d,2H),7.13(d,2H),6.81–6.76(m,1H),6.52(dd,1H),5.61(br.s,2H),4.93(dd,1H),4.86–4.68(m,1H),4.16–4.04(m,2H),3.94–3.83(m,2H),3.41–3.31(m,1H),3.21–3.03(m,2H),3.01–2.92(m,2H),2.92–2.64(m,3H),2.62–2.30(m,5H),2.20–1.82(m,7H),1.78–1.54(m,2H)。
LCMS m/z=849.3[M+1]
+。
实施例89:
5-(3-(4-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物89)
5-(3-(4-(4-amino-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:1-溴-4-(4-氟苯氧基)苯(89b)
1-bromo-4-(4-fluorophenoxy)benzene
向干燥三口瓶中依次加入4-氟苯酚(89a)(0.87g,7.8mmol)、1-溴-4-碘苯(2.0g,7.07mmol)、CuI(27mg,0.142mmol)、N,N′-二甲基甘氨酸(55mg,0.53mmol)和Cs
2CO
3(4.6g,14.1mmol),置换氮气3次,加入50mL 1,4-二氧六环,将反应升至90℃搅拌12h。将反应体系冷却至室温,加入50mL乙酸乙酯和50mL水,分离出有机层,水层用乙酸乙酯萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(石油醚),得1-溴-4-(4-氟苯氧基)苯(89b)(1.27g,收率:67%)。
第二步:(4-(4-氟苯氧基)苯基)硼酸(89c)
(4-(4-fluorophenoxy)phenyl)boronic acid
向充满氮气的三口瓶中加入1-溴-4-(4-氟苯氧基)苯(89b)(0.5g,1.87mmol)和30mL干燥的四氢呋喃,冷却至-78℃,缓慢滴加2.5mol/L正丁基锂溶液(1.12mL),加完后在-78℃反应30min,滴加硼酸三异丙酯(0.52mL,2.24mmol),缓慢升至室温后反应3h。反应完毕,用2mol/L盐酸溶液(40mL)淬灭反应,用乙酸乙酯萃取(40mL×3),有机相用饱和氯化钠溶液(40mL)洗涤,无水硫酸钠干燥,减压浓缩,得粗品(4-(4-氟苯氧基)苯基)硼酸(89c)(0.26g)。
第三步:4-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(89d)
tert-butyl 4-(4-amino-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate
将4-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(87a)(合成方法见CN110627796)(0.44g,1mmol)、Pd(dppf)Cl
2(37mg,0.05mmol)、碳酸钾(0.41g,3.0mmol)、上述粗品(4-(4-氟苯氧基)苯基)硼酸(89c)(0.26g)依次加入到三口瓶中,置换氮气3次,加入10mL 1,4-二氧六环和水(v/v)=7:3的混合溶剂,将反应升至120℃搅拌回 流4h。将反应体系冷却至室温,加入30mL乙酸乙酯和30mL水,分离出有机相,水相用乙酸乙酯萃取(30mL×3),合并有机相,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得4-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(89d)(340mg,从化合物87a算收率:67%)。
LCMS m/z=505.2[M+1]
+。
第四步:3-(4-(4-氟苯氧基)苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(89e)
3-(4-(4-fluorophenoxy)phenyl)-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将4-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(89d)(342mg,0.68mmol)溶于10mL DCM中,加入2.0mL三氟乙酸,反应于室温搅拌4h。将反应体系减压浓缩,将残余物溶于10mL DCM中,加入10mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(30mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品3-(4-(4-氟苯氧基)苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(89e)(320mg)。
第五步:4-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-甲酸叔丁酯(89f)
tert-butyl 4-(4-amino-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidine]-1'-carboxylate
将上述粗品3-(4-(4-氟苯氧基)苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(89e)(320mg)溶于20mL DCE中,加入4-氧代哌啶-1-甲酸叔丁酯(310mg,1.56mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠(500mg,2.36mmol),反应于室温搅拌16h。向反应液中加入30mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得4-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H- 吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-甲酸叔丁酯(89f)(230mg,从化合物89d算两步收率:58%)。
第六步:1-([1,4'-双哌啶]-4-基)-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(89g)
1-([1,4'-bipiperidin]-4-yl)-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将4-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-甲酸叔丁酯(89f)(226mg,0.38mmol)溶于10mL DCM中,加入3.0mL三氟乙酸,反应于室温搅拌2h。将反应体系减压浓缩,将残余物溶于20mL DCM,加入20mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(30mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-([1,4'-双哌啶]-4-基)-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(89g)(190mg)。
第七步:3-(4-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(89h)
tert-butyl 3-(4-(4-amino-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)azetidine-1-carboxylate
将上述粗品1-([1,4'-双哌啶]-4-基)-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(89g)(190mg)溶于20mL DCE中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(130mg,0.76mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠(240mg,1.13mmol),反应于室温搅拌16h。向反应液中加入20mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(30mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得3-(4-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(89h) (120mg,从化合物89f算两步收率:49%)。
第八步:1-(1'-(氮杂环丁-3-基)-[1,4'-双哌啶]-4-基)-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(89i)
1-(1'-(azetidin-3-yl)-[1,4'-bipiperidin]-4-yl)-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(4-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(89h)(120mg,0.19mmol)溶于10mL DCM中,加入3mL三氟乙酸,反应于室温搅拌2h。将反应体系减压浓缩,将残余物溶于15mL DCM,加入15mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(30mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-(1'-(氮杂环丁-3-基)-[1,4'-双哌啶]-4-基)-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(89i)(100mg)。
第九步:5-(3-(4-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物89)
5-(3-(4-(4-amino-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-(1'-(氮杂环丁-3-基)-[1,4'-双哌啶]-4-基)-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(89i)(100mg)溶于5mL DMSO中,加入0.5mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(58mg,0.21mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入5mL水,过滤,收集滤饼,用20mL水洗涤,固体用30mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-(4-(4-氨基-3-(4-(4-氟苯氧基)苯 基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物89)(81mg,从化合物89h算两步收率:53%)。
1H NMR(400MHz,CDCl
3)δ8.71(s,1H),8.41–8.35(m,1H),7.68–7.32(m,3H),7.26–7.00(m,6H),6.79(d,1H),6.52(dd,1H),5.59(br.s,2H),4.93(dd,1H),4.86–4.66(m,1H),4.14–4.06(m,2H),3.93–3.83(m,2H),3.40–3.31(m,1H),3.23–3.03(m,2H),3.01–2.92(m,2H),2.92–2.65(m,3H),2.62–2.26(m,5H),2.18–1.80(m,7H),1.78–1.57(m,2H)。
LCMS m/z=799.3[M+1]
+。
实施例90:
5-(3-(4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物90)
5-(3-(4-(4-amino-3-(4-(4-methoxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:1-溴-4-(4-甲氧基苯氧基)苯(90b)
1-bromo-4-(4-methoxyphenoxy)benzene
向干燥三口瓶中依次加入4-甲氧基苯酚(90a)(2.41g,19.4mmol)、1-溴-4-碘苯(5.0g,17.67mmol)、CuI(67mg,0.35mmol)、N,N′-二甲基甘氨酸(140mg,1.36mmol)和Cs
2CO
3(11.51g,35.33mmol),置换氮气三次,然后加入50mL 1,4-二氧六环,将反应体系升至90℃反应12h。将反应体系冷却至室温,加入100mL乙酸乙酯和100mL水,分离出有机层,水层用乙酸乙酯萃取(100mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(石油醚),得1-溴-4-(4-甲氧基苯氧基)苯(90b)(2.0g,收率:37%)。
第二步:(4-(4-甲氧基苯氧基)苯基)硼酸(90c)
(4-(4-methoxyphenoxy)phenyl)boronic acid
向充满氮气的三口瓶中加入1-溴-4-(4-甲氧基苯氧基)苯(90b)(2.0g,7.17mmol)和30mL干燥的四氢呋喃,将反应液冷却至-78℃,缓慢滴加1.6mol/L正丁基锂溶液(6.72mL),加完后在-78℃反应30min,滴加硼酸三异丙酯(2.00mL,8.61mmol),反应缓慢升至室温搅拌3h。反应完毕,用2mol/L盐酸溶液(50mL)淬灭反应,用乙酸乙酯萃取(50mL×3),有机相用饱和氯化钠溶液(50mL)洗涤,无水硫酸钠干燥,减压浓缩,得粗品(4-(4-甲氧基苯氧基)苯基)硼酸(90c)(0.94g)。
第三步:4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(90d)
tert-butyl 4-(4-amino-3-(4-(4-methoxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate
将4-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(87a)(合成方法见CN110627796)(1.55g,3.49mmol)、Pd(dppf)Cl
2(130mg,0.18mmol)、碳酸钾(1.45g,10.49 mmol)、上述粗品(4-(4-甲氧基苯氧基)苯基)硼酸(90c)(0.94g)依次加入到三口瓶中,置换氮气三次,加入50mL 1,4-二氧六环和水(v/v)=7:3的混合溶剂,将反应升至120℃搅拌回流4h。将反应体系冷却至室温,加入100mL乙酸乙酯和100mL水,分离出有机相,水相用乙酸乙酯萃取(100mL×3),合并有机相,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(90d)(1.54g,从化合物87a算收率:85%)。
第四步:3-(4-(4-甲氧基苯氧基)苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(90e)
3-(4-(4-methoxyphenoxy)phenyl)-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(90d)(1.54g,2.98mmol)溶于30mL DCM中,加入11.0mL三氟乙酸,反应于室温搅拌4h。将反应体系减压浓缩,将残余物溶于30mL DCM中,加入30mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品3-(4-(4-甲氧基苯氧基)苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(90e)(600mg)。
第五步:3-(4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-甲酸叔丁酯(90f)
tert-butyl 3-(4-(4-amino-3-(4-(4-methoxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidine-1-carboxylate
将上述粗品3-(4-(4-甲氧基苯氧基)苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(90e)(600mg)溶于20mL DCE中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(490mg,2.87mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠 (920mg,4.34mmol),反应于室温搅拌16h。向反应液中加入30mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得3-(4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-甲酸叔丁酯(90f)(800mg,从化合物90d算两步收率:47%)。
LCMS m/z=572.3[M+1]
+。
第六步:1-(1-(氮杂环丁-3-基)哌啶-4-基)-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(90g)
1-(1-(azetidin-3-yl)piperidin-4-yl)-3-(4-(4-methoxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-甲酸叔丁酯(90f)(800mg,1.40mmol)溶于20mL DCM中,加入7.0mL三氟乙酸,反应于室温搅拌2h。将反应体系减压浓缩,将残余物溶于30mL DCM,加入30mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-(1-(氮杂环丁-3-基)哌啶-4-基)-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(90g)(660mg)。
LCMS m/z=472.2[M+1]
+。
第七步:3-(4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(90h)
tert-butyl 3-(4-(4-amino-3-(4-(4-methoxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidine]-1'-carboxylate
将上述粗品1-(1-(氮杂环丁-3-基)哌啶-4-基)-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(90g)(660mg)溶于30mL DCE中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(480mg,2.80mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧 基硼氢化钠(890mg,4.20mmol),反应于室温搅拌16h。向反应液中加入30mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得3-(4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(90h)(430mg,从化合物90f算两步收率:49%)。
第八步:1-(1-([1,3'-双氮杂环丁]-3-基)哌啶-4-基)-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(90i)
1-(1-([1,3'-biazetidin]-3-yl)piperidin-4-yl)-3-(4-(4-methoxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(90h)(430mg,0.69mmol)溶于20mL DCM中,加入5.5mL三氟乙酸,反应于室温搅拌2h。将反应体系减压浓缩,将残余物溶于30mL DCM,加入30mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-(1-([1,3'-双氮杂环丁]-3-基)哌啶-4-基)-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(90i)(320mg)。
第九步:5-(3-(4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物90)
5-(3-(4-(4-amino-3-(4-(4-methoxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-(1-([1,3'-双氮杂环丁]-3-基)哌啶-4-基)-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(90i)(320mg)溶于10mL DMSO中,加入1mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(190mg,0.69mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入20mL水,过滤,收集滤饼, 用50mL水洗涤,固体用50mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-(4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物90)(200mg,从化合物90h算两步收率:37%)。
1H NMR(400MHz,CDCl
3)δ9.51(s,1H),8.38(s,1H),7.68–7.56(m,3H),7.10–6.99(m,4H),6.96–6.89(m,2H),6.78(d,1H),6.52(dd,1H),5.70(br.s,2H),4.92(dd,1H),4.86–4.71(m,1H),4.09–3.99(m,2H),3.92–3.85(m,2H),3.83(s,3H),3.76–3.65(m,1H),3.62–3.52(m,2H),3.20–3.00(m,3H),3.00–2.64(m,5H),2.51–2.35(m,2H),2.18–1.96(m,5H)。
LCMS m/z=783.3[M+1]
+。
实施例91:
5-(3-(4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物91)
5-(3-(4-(4-amino-3-(4-(4-methoxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-甲酸叔丁酯(91a)
tert-butyl 4-(4-amino-3-(4-(4-methoxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidine]-1'-carboxylate
将上述粗品3-(4-(4-甲氧基苯氧基)苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(90e)(700mg)溶于20mL DCE中,加入4-氧代哌啶-1-甲酸叔丁酯(670mg,3.37mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠(1.07g,5.05mmol),反应于室温搅拌16h。向反应液中加入30mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-甲酸叔丁酯(91a)(330mg,从化合物90d算两步收率:16%)。
LCMS m/z=600.3[M+1]
+。
第二步:1-([1,4'-双哌啶]-4-基)-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(91b)
1-([1,4'-bipiperidin]-4-yl)-3-(4-(4-methoxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-甲酸叔丁酯(91a)(330mg,0.55mmol)溶于10mL DCM中,加入3.0mL三氟乙酸,反应于室温搅拌2h。将反应液减压浓缩,将残余物溶于20mL DCM,加入20mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(30mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-([1,4'-双哌啶]-4-基)-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(91b)(280mg)。
LCMS m/z=500.3[M+1]
+。
第三步:3-(4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(91c)
tert-butyl 3-(4-(4-amino-3-(4-(4-methoxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)azetidine-1-carboxylate
将粗品1-([1,4'-双哌啶]-4-基)-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(91b)(280mg)溶于30mL DCE中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(190mg,1.11mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠(360mg,1.70mmol),反应于室温搅拌16h。向反应液中加入30mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得3-(4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(91c)(360mg,从化合物91a算两步收率:>99%)。
第四步:1-(1'-(氮杂环丁-3-基)-[1,4'-双哌啶]-4-基)-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(91d)
1-(1'-(azetidin-3-yl)-[1,4'-bipiperidin]-4-yl)-3-(4-(4-methoxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(91c)(360mg,0.55mmol)溶于20mL DCM中,加入8.2mL三氟乙酸,反应于室温搅拌2h。将反应体系减压浓缩,将残余物溶于30mL DCM,加入30mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-(1'-(氮杂环丁-3-基)-[1,4'-双哌啶]-4-基)-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(91d) (310mg)。
第五步:5-(3-(4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物91)
5-(3-(4-(4-amino-3-(4-(4-methoxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-(1'-(氮杂环丁-3-基)-[1,4'-双哌啶]-4-基)-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(91d)(310mg)溶于10mL DMSO中,加入1mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(170mg,0.62mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入10mL水,过滤,收集滤饼,用30mL水洗涤,固体用50mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-(4-(4-氨基-3-(4-(4-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物91)(130mg,从化合物91c算两步收率:29%)。
1H NMR(400MHz,CDCl
3)δ8.56(s,1H),8.37(s,1H),7.70–7.55(m,3H),7.12–6.98(m,4H),6.96–6.89(m,2H),6.79(d,1H),6.52(dd,1H),5.54(br.s,2H),4.93(dd,1H),4.84–4.67(m,1H),4.15–4.05(m,2H),3.94–3.84(m,2H),3.83(s,3H),3.40–3.32(m,1H),3.21–3.03(m,2H),3.02–2.65(m,5H),2.60–2.30(m,5H),2.18–1.83(m,7H),1.79–1.55(m,2H)。
LCMS m/z=811.4[M+1]
+。
实施例92:
5-(3-(4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物92)
5-(3-(4-(4-amino-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piper idin-1-yl)-[1,3'-biazetidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:1-(4-溴苯氧基)-2-氟苯(92b)
1-(4-bromophenoxy)-2-fluorobenzene
向干燥三口瓶中依次加入2-氟苯酚(92a)(2.38g,21.23mmol)、1-溴-4-碘苯(4.0g,14.14mmol)、CuI(54mg,0.28mmol)、N,N′-二甲基甘氨酸(110mg,1.07mmol)和Cs
2CO
3(9.2g,28.24mmol),置换氮气三次,然后加入50mL 1,4-二氧六环,并将反应升至90℃搅拌12h。将反应体系冷却至室温,加入50mL乙酸乙酯和50mL水,分离出有机层,水层用乙酸乙酯萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅 胶柱色谱分离提纯(石油醚),得1-(4-溴苯氧基)-2-氟苯(92b)(1.23g,收率:33%)。
第二步:(4-(2-氟苯氧基)苯基)硼酸(92c)
(4-(2-fluorophenoxy)phenyl)boronic acid
向充满氮气的三口瓶中加入1-(4-溴苯氧基)-2-氟苯(92b)(2.3g,8.61mmol)和30mL干燥的四氢呋喃,冷却至-78℃,缓慢滴加1.6mol/L正丁基锂溶液(8mL),加完后在-78℃反应30min,滴加硼酸三异丙酯(2.4mL,10.33mmol),缓慢升至室温反应3h。反应完毕,用2mol/L盐酸溶液(50mL)淬灭反应,用乙酸乙酯萃取(50mL×3),有机相用饱和氯化钠溶液(40mL)洗涤,无水硫酸钠干燥,减压浓缩,得粗品(4-(2-氟苯氧基)苯基)硼酸(92c)(890mg)。
第三步:4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(92d)
tert-butyl 4-(4-amino-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate
将4-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(87a)(合成方法见CN110627796)(1.55g,3.49mmol)、Pd(dppf)Cl
2(130mg,0.18mmol)、碳酸钾(1.45g,10.49mmol)和上述粗品(4-(2-氟苯氧基)苯基)硼酸(92c)(890mg)依次加入到三口瓶中,置换氮气三次,加入50mL 1,4-二氧六环和水(v/v)=7:3的混合溶剂,将反应升至120℃搅拌回流4h。将反应体系冷却至室温,加入100mL乙酸乙酯和100mL水,分离出有机相,水相用乙酸乙酯萃取(100mL×3),合并有机相,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(92d)(1.6g,从化合物87a算收率:91%)。
第四步:3-(4-(2-氟苯氧基)苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(92e)
3-(4-(2-fluorophenoxy)phenyl)-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(92d)(1.6g,3.17mmol)溶于30mL DCM中,加入10.0mL三氟乙酸,反应于室温搅拌4h。将反应体系减压浓缩,将残余物溶于30mL DCM中,加入30mL水,滴加1mol/L NaOH溶液调pH至12,分离有机层,水层用二氯甲烷萃取(500mL×4),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品3-(4-(2-氟苯氧基)苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(92e)(700mg)。
第五步:3-(4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-甲酸叔丁酯(92f)
tert-butyl 3-(4-(4-amino-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidine-1-carboxylate
将上述粗品3-(4-(2-氟苯氧基)苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(92e)(700mg)溶于30mL DCE中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(590mg,3.45mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠(1.10g,5.19mmol),反应于室温搅拌16h。向反应液中加入30mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得3-(4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-甲酸叔丁酯(92f)(600mg,从化合物92d算两步收率:34%)。
LCMS m/z=560.2[M+1]
+。
第六步:1-(1-(氮杂环丁-3-基)哌啶-4-基)-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(92g)
1-(1-(azetidin-3-yl)piperidin-4-yl)-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-甲酸叔丁酯(92f)(600mg,1.07mmol)溶于30mL DCM中,加入10.0mL三氟乙酸,反应于室温搅拌2h。将反应体系减压浓缩,将残余物溶于30mL DCM,加入30mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(50mL×4),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-(1-(氮杂环丁-3-基)哌啶-4-基)-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(92g)(490mg)。
第七步:3-(4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(92h)
tert-butyl 3-(4-(4-amino-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidine]-1'-carboxylate
将上述粗品1-(1-(氮杂环丁-3-基)哌啶-4-基)-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(92g)(490mg)溶于30mL DCE中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(370mg,2.16mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠(680mg,3.21mmol),反应于室温搅拌16h。向反应液中加入30mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得3-(4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(92h)(600mg,从化合物92f算两步收率:91%)。
LCMS m/z=615.4[M+1]
+。
第八步:1-(1-([1,3'-双氮杂环丁]-3-基)哌啶-4-基)-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(92i)
1-(1-([1,3'-biazetidin]-3-yl)piperidin-4-yl)-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(92h)(600mg,0.98mmol)溶于20mL DCM中,加入7mL三氟乙酸,反应于室温搅拌2h。将反应体系减压浓缩,将残余物溶于30mL DCM,加入30mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(50mL×4),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-(1-([1,3'-双氮杂环丁]-3-基)哌啶-4-基)-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(92i)(450mg)。
第九步:5-(3-(4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物92)
5-(3-(4-(4-amino-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-(1-([1,3'-双氮杂环丁]-3-基)哌啶-4-基)-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(92i)(450mg)溶于10mL DMSO中,加入1mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(260mg,0.94mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入20mL水,过滤,收集滤饼,用50mL水洗涤,固体用50mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-(4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物92)(215mg,从化合物92h算两步收率:28%)。
1H NMR(400MHz,CDCl
3)δ8.70(s,1H),8.38(s,1H),7.68–7.30(m,3H),7.28–7.02(m,6H),6.78(d,1H),6.53(dd,1H),5.55(br.s,2H),4.92(dd,1H),4.87–4.71(m,1H),4.08–4.00(m,2H),3.96–3.83(m,2H),3.78–3.65(m,1H),3.64–3.52(m,2H),3.25–3.03(m,3H),3.03–2.63(m,5H),2.54–2.36(m,2H),2.24–1.94(m,5H)。
LCMS m/z=771.3[M+1]
+。
实施例93:
5-(3-(4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮(化合物93)
5-(3-(4-(4-amino-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-甲酸叔丁酯(93a)
tert-butyl 4-(4-amino-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidine]-1'-carboxylate
将上述粗品3-(4-(2-氟苯氧基)苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(92e)(700mg)溶于20mL DCE中,加入4-氧代哌啶-1-甲酸叔丁酯(690mg,3.46mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠(1.10g,5.19mmol),反应于室温搅拌16h。向反应液中加入30mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-甲酸叔丁酯(93a)(560mg,从化合物92d算两步收率:30%)。
LCMS m/z=588.3[M+1]
+。
第二步:1-([1,4'-双哌啶]-4-基)-3-(4-(2-氟苯氧基)苯基)-1H-吡唑[3,4-d]嘧啶-4-胺(93b)
1-([1,4'-bipiperidin]-4-yl)-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-甲酸叔丁酯(93a)(560mg,0.95mmol)溶于30mL DCM中,加入10.0mL三氟乙酸,反应于室温搅拌2h。将反应体系减压浓缩,将残余物溶于30mL DCM,加入30mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-([1,4'-双哌啶]-4-基)-3-(4-(2-氟苯氧基)苯基)-1H-吡唑[3,4-d]嘧啶-4-胺(93b)(460mg)。
第三步:3-(4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(93c)
tert-butyl 3-(4-(4-amino-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)azetidine-1-carboxylate
将上述粗品1-([1,4'-双哌啶]-4-基)-3-(4-(2-氟苯氧基)苯基)-1H-吡唑[3,4-d]嘧啶-4-胺(93b)(460mg)溶于30mL DCE中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(330mg,1.9mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠(600mg,2.83mmol),反应于室温搅拌16h。向反应液中加入30mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得3-(4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(93c)(530mg,从化合物93a算两步收率:87%)。
LCMS m/z=643.4[M+1]
+。
第四步:1-(1'-(氮杂环丁-3-基)-[1,4'-双哌啶]-4-基)-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(93d)
1-(1'-(azetidin-3-yl)-[1,4'-bipiperidin]-4-yl)-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(93c)(500mg,0.78mmol)溶于30mL DCM中,加入8.2mL三氟乙酸,反应于室温搅拌2h。将反应体系减压浓缩,将残余物溶于30mL DCM,加入30mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-(1'-(氮杂环丁-3-基)-[1,4'-双哌啶]-4-基)-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(93d)(420mg)。
第五步:5-(3-(4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮(化合物93)
5-(3-(4-(4-amino-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4' -bipiperidin]-1'-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-(1'-(氮杂环丁-3-基)-[1,4'-双哌啶]-4-基)-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(93d)(420mg)溶于10mL DMSO中,加入1mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(240mg,0.87mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入10mL水,过滤,收集滤饼,用30mL水洗涤,固体用50mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-(4-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮(化合物93)(130mg,从化合物93c算两步收率:21%)。
1H NMR(400MHz,CDCl
3)δ8.82(s,1H),8.38(s,1H),7.70–7.30(m,3H),7.28–6.99(m,6H),6.78(d,1H),6.52(dd,1H),5.59(br.s,2H),4.93(dd,1H),4.85–4.67(m,1H),4.16–4.04(m,2H),3.93–3.82(m,2H),3.41–3.31(m,1H),3.28–3.03(m,2H),3.03–2.92(m,2H),2.92–2.65(m,3H),2.65–2.25(m,5H),2.18–1.84(m,7H),1.77–1.57(m,2H)。
LCMS m/z=799.3[M+1]
+。
实施例94:
5-(3-(4-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物94)
5-(3-(4-(4-amino-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:3-(4-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-甲酸叔丁酯(94a)
tert-butyl 3-(4-(4-amino-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidine-1-carboxylate
将上述粗品3-(4-(4-氟苯氧基)苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(89e)(280mg)溶于10mL DCE中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(240mg,1.40mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠(430mg,2.03mmol),反应于室温搅拌16h。向反应液中加入10mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(30mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得3-(4-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-甲酸叔丁酯(94a)(170mg,从化合物89d算两步收率:51%)。
LCMS m/z=560.2[M+1]
+。
第二步:1-(1-(氮杂环丁-3-基)哌啶-4-基)-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(94b)
1-(1-(azetidin-3-yl)piperidin-4-yl)-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(4-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-甲酸叔丁酯(94a)(170mg,0.30mmol)溶于5mL DCM中,加入1.0mL三氟乙酸,反应于室温搅拌2h。将反应体系减压浓缩,将残余物溶于10mL DCM,加入10mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(20mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-(1-(氮杂环丁-3-基)哌啶-4-基)-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(94b)(124mg)。
LCMS m/z=460.2[M+1]
+。
第三步:3-(4-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(94c)
tert-butyl 3-(4-(4-amino-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidine]-1'-carboxylate
将粗品1-(1-(氮杂环丁-3-基)哌啶-4-基)-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(94b)(124mg)溶于10mL DCE中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(92mg,0.54mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠(151mg,0.71mmol),反应于室温搅拌16h。向反应液中加入10mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(30mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得3-(4-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(94c)(65mg,从化合物94a算两步收率:35%)。
LCMS m/z=615.3[M+1]
+。
第四步:1-(1-([1,3'-双氮杂环丁]-3-基)哌啶-4-基)-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(94d)
1-(1-([1,3'-biazetidin]-3-yl)piperidin-4-yl)-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrazolo[3, 4-d]pyrimidin-4-amine
将3-(4-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(94c)(65mg,0.11mmol)溶于5mL DCM中,加入0.5mL三氟乙酸,反应于室温搅拌2h。将反应体系减压浓缩,将残余物溶于10mL DCM,加入10mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(20mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-(1-([1,3'-双氮杂环丁]-3-基)哌啶-4-基)-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(94d)(56mg)。
第五步:5-(3-(4-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物94)
5-(3-(4-(4-amino-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-(1-([1,3'-双氮杂环丁]-3-基)哌啶-4-基)-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(94d)(56mg)溶于2mL DMSO中,加入0.2mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(30mg,0.11mmol),反应于80℃搅拌5h。将反应液冷却至室温,加5mL水,过滤,收集滤饼,用20mL水洗涤,固体用30mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-(4-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物94)(20mg,从化合物94c算两步收率:24%)。
1H NMR(400MHz,CDCl
3)δ8.40–8.34(m,1H),7.67–7.34(m,3H),7.27–6.99(m,6H),6.78(d,1H),6.52(dd,1H),5.56(br.s,2H),4.92(dd,1H),4.84–4.72(m,1H),4.08–3.99(m,2H),3.91–3.83(m,2H),3.74–3.63(m,1H),3.60–3.52(m,2H),3.15–3.02(m,3H),2.98–2.64(m,5H),2.51–2.33(m,2H),2.17–1.95(m,5H)。
LCMS m/z=771.3[M+1]
+。
实施例95:
5-(3-(4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]-[1,3'-二氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物95)
5-(3-(4-(4-amino-3-(3-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:4-溴-2-氟-1-苯氧基苯(95b)
4-bromo-2-fluoro-1-phenoxybenzene
向4-溴-2-氟苯酚(95a)(1.2g,6.3mmol)和溴化二苯基碘(2.5g,6.9mmol)的水溶液 (20mL)中加入1mol/L NaOH溶液(6.9mL),将反应混合物升至110℃搅拌5h。将反应体系冷却至室温,加入50mL甲基叔丁基醚稀释,过滤,滤液分离出有机层,用30mL饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(石油醚),得4-溴-2-氟-1-苯氧基苯(95b)(1.2g,收率:71%)。
第二步:(3-氟-4-苯氧基苯基)硼酸(95c)
(3-fluoro-4-phenoxyphenyl)boronic acid
向充满氮气的三口瓶中加入4-溴-2-氟-1-苯氧基苯(95b)(1.18g,4.42mmol)和干燥的四氢呋喃(30mL),冷却至-78℃,缓慢滴加1.6mol/L正丁基锂溶液(4.1mL),加完后在-78℃反应30min,滴加硼酸三异丙酯(1.23mL,5.33mmol),缓慢升至室温反应3h。反应完毕,用2mol/L盐酸溶液(50mL)淬灭反应,用乙酸乙酯萃取(50mL×3),有机相用饱和氯化钠溶液(50mL)洗涤,无水硫酸钠干燥,减压浓缩,得粗品(3-氟-4-苯氧基苯基)硼酸(95c)(0.57g)。
第三步:4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(95d)
tert-butyl 4-(4-amino-3-(3-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate
将4-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(87a)(合成方法见CN110627796)(1.0g,2.25mmol)、Pd(dppf)Cl
2(82mg,0.11mmol)、碳酸钾(0.93g,6.73mmol)、粗品(3-氟-4-苯氧基苯基)硼酸(95c)(0.57g)依次加入到三口瓶中,置换氮气3次,加入30mL 1,4-二氧六环和水(v/v)=7:3的混合溶剂,升至120℃搅拌回流4h。将反应体系冷却至室温,加入100mL乙酸乙酯和100mL水,分离出有机相,水相用乙酸乙酯萃取(100mL×3),合并有机相,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(95d)(920mg,从化合物87a算收率:81%)。
LCMS m/z=505.3[M+1]
+。
第四步:3-(3-氟-4-苯氧基苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(95e)
3-(3-fluoro-4-phenoxyphenyl)-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(95d)(920mg,1.82mmol)溶于20mL DCM中,加入7.0mL三氟乙酸,反应于室温搅拌4h。将反应体系减压浓缩,将残余物溶于30mL DCM中,加入30mL水后,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品3-(3-氟-4-苯氧基苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(95e)(370mg)。
第五步:3-(4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-甲酸叔丁酯(95f)
tert-butyl 3-(4-(4-amino-3-(3-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidine-1-carboxylate
将上述粗品3-(3-氟-4-苯氧基苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(95e)(370mg)溶于20mL DCE中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(310mg,1.81mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠(580mg,2.74mmol),反应于室温搅拌16h。向反应液中加入20mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得3-(4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-甲酸叔丁酯(95f)(350mg,从化合物95d算两步收率:34%)。
LCMS m/z=560.3[M+1]
+。
第六步:1-(1-(氮杂环丁-3-基)哌啶-4-基)-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(95g)
1-(1-(azetidin-3-yl)piperidin-4-yl)-3-(3-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-甲酸叔丁酯(95f)(350mg,0.63mmol)溶于10mL DCM中,加入3.0mL三氟乙酸,反应于室温搅拌2h。将反应体系减压浓缩,将残余物溶于10mL DCM,加入10mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(20mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-(1-(氮杂环丁-3-基)哌啶-4-基)-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(95g)(290mg)。
第七步:3-(4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(95h)
tert-butyl 3-(4-(4-amino-3-(3-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidine]-1'-carboxylate
将上述粗品1-(1-(氮杂环丁-3-基)哌啶-4-基)-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(95g)(290mg)溶于20mL DCE中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(220mg,1.29mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠(400mg,1.89mmol),反应于室温搅拌16h。向反应液中加入10mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(50mL×4),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得3-(4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(95h)(300mg,从化合物95f算两步收率:77%)。
第八步:1-(1-([1,3'-双氮杂环丁]-3-基)哌啶-4-基)-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(95i)
1-(1-([1,3'-biazetidin]-3-yl)piperidin-4-yl)-3-(3-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3, 4-d]pyrimidin-4-amine
将3-(4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(95h)(300mg,0.49mmol)溶于10mL DCM中,加入3mL三氟乙酸,反应于室温搅拌2h。将反应体系减压浓缩,将残余物溶于10mL DCM,加入10mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(30mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-(1-([1,3'-双氮杂环丁]-3-基)哌啶-4-基)-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(95i)(220mg)。
第九步:5-(3-(4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]-[1,3'-二氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物95)
5-(3-(4-(4-amino-3-(3-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-(1-([1,3'-双氮杂环丁]-3-基)哌啶-4-基)-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(95i)(220mg)溶于5mL DMSO中,加入1.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(130mg,0.47mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入20mL水,过滤,收集滤饼,用30mL水洗涤,固体用30mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-(4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]-[1,3'-二氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物95)(100mg,从化合物95h算两步收率:26%)。
1H NMR(400MHz,CDCl
3)δ8.68(br.s,1H),8.37(s,1H),7.64(d,1H),7.55(dd,1H),7.44–7.34(m,3H),7.20–7.13(m,2H),7.09–7.03(m,2H),6.79(d,1H),6.53(dd,1H),5.74(br.s,2H),4.97–4.72(m,2H),4.10–4.01(m,2H),3.95–3.86(m,2H),3.79–3.68(m,1H),3.65–3.55(m,2H),3.30–2.92(m,5H),2.92–2.64(m,3H),2.52–2.37(m,2H),2.33 –2.00(m,5H)。
LCMS m/z=771.3[M+1]
+。
实施例96:
5-(3-(4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物96)
5-(3-(4-(4-amino-3-(3-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-甲酸叔丁酯(96a)
tert-butyl 4-(4-amino-3-(3-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidine]-1'-carboxylate
将上述粗品3-(3-氟-4-苯氧基苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(95e)(370mg)溶于20mL DCE中,加入4-氧代哌啶-1-甲酸叔丁酯(360mg,1.81mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠(580mg,2.74mmol),反应于室温搅拌16h。向反应液中加入30mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-甲酸叔丁酯(96a)(250mg,从化合物95d算两步收率:23%)。
LCMS m/z=588.3[M+1]
+。
第二步:1-([1,4'-双哌啶]-4-基)-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(96b)
1-([1,4'-bipiperidin]-4-yl)-3-(3-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-甲酸叔丁酯(96a)(250mg,0.43mmol)溶于10mL DCM中,加入3.0mL三氟乙酸,反应于室温搅拌2h。将反应体系减压浓缩,将残余物溶于10mL DCM,加入10mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(30mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-([1,4'-双哌啶]-4-基)-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(96b)(210mg)。
第三步:3-(4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(96c)
tert-butyl 3-(4-(4-amino-3-(3-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)azetidine-1-carboxylate
将上述粗品1-([1,4'-双哌啶]-4-基)-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(96b)(210mg)溶于10mL DCE中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(150mg,0.88mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠(270mg,1.27mmol),反应于室温搅拌16h。向反应液中加入20mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(30mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得3-(4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(96c)(200mg,从化合物96a算两步收率:72%)。
第四步:1-(1'-(氮杂环丁-3-基)-[1,4'-双哌啶]-4-基)-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(96d)
1-(1'-(azetidin-3-yl)-[1,4'-bipiperidin]-4-yl)-3-(3-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(96c)(200mg,0.31mmol)溶于10mL DCM中,加入3.0mL三氟乙酸,反应于室温搅拌2h。将反应体系减压浓缩,将残余物溶于10mL DCM,加入10mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(30mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-(1'-(氮杂环丁-3-基)-[1,4'-双哌啶]-4-基)-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(96d)(170mg)。
第五步:5-(3-(4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物96)
5-(3-(4-(4-amino-3-(3-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-(1'-(氮杂环丁-3-基)-[1,4'-双哌啶]-4-基)-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(96d)(170mg)溶于10mL DMSO中,加入0.6mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(94mg,0.34mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入10mL水,过滤,收集滤饼,用30mL水洗涤,固体用50mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-(4-(4-氨基-3-(3-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-双哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物96)(66mg,从化合物96c算两步收率:27%)。
1H NMR(400MHz,CDCl
3)δ8.36(s,1H),7.64(d,1H),7.54(dd,1H),7.43–7.34(m,3H),7.20–7.12(m,2H),7.10–7.03(m,2H),6.79(d,1H),6.53(dd,1H),6.05–5.60(m,2H),4.98–4.78(m,2H),4.15–4.06(m,2H),3.92–3.84(m,2H),3.42–3.33(m,1H),3.32–3.18(m,2H),3.03–2.93(m,2H),2.93–2.60(m,5H),2.57–2.39(m,3H),2.29–2.16(m,2H),2.20–2.08(m,1H),2.06–1.93(m,4H),1.81–1.65(m,2H)。
LCMS m/z=799.3[M+1]
+。
实施例97:
5-(3-(4-(4-氨基-3-(6-苯氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]-[1,3'-双氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物97)
5-(3-(4-(4-amino-3-(6-phenoxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:5-溴-2-苯氧基吡啶(97b)
5-bromo-2-phenoxypyridine
向干燥三口瓶中依次加入2,5-二溴吡啶(97a)(5.0g,21.1mmol)、苯酚(2.38g,25.29mmol)、CuI(401mg,2.11mmol)、TMEDA(244mg,2.10mmol)和Cs
2CO
3(13.7g,42.0mmol),置换氮气3次,加入100mL DMSO,并将反应混合物升至110℃搅拌24h。将反应体系冷却至室温,缓慢倒入200mL冰水中,加入300mL乙酸乙酯萃取,分离出有机层,有机层用水洗涤(50mL×3),无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(石油醚),得5-溴-2-苯氧基吡啶(97b)(4.0g,收率:76%)。
第二步:(6-苯氧基吡啶-3-基)硼酸(97c)
(6-phenoxypyridin-3-yl)boronic acid
向充满氮气的三口瓶中加入5-溴-2-苯氧基吡啶(97b)(2.0g,8.00mmol)和干燥的四氢呋喃(30mL),冷却至-78℃,缓慢滴加1.6mol/L正丁基锂溶液(7.5mL),加完后在-78℃反应30min,滴加硼酸三异丙酯(2.2mL,9.5mmol),缓慢升至室温反应3h。反应 完毕,用2mol/L盐酸溶液(50mL)淬灭反应,乙酸乙酯萃取(50mL×3),有机相用饱和氯化钠溶液(50mL)洗涤,无水硫酸钠干燥,减压浓缩,得粗品(6-苯氧基吡啶-3-基)硼酸(97c)(0.83g)。
第三步:4-(4-氨基-3-(6-苯氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(97d)
tert-butyl 4-(4-amino-3-(6-phenoxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate
将4-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(87a)(合成方法见CN110627796)(1.55g,3.38mmol)、Pd(dppf)Cl
2(130mg,0.18mmol)、碳酸钾(1.45g,10.49mmol)和上述粗品(6-苯氧基吡啶-3-基)硼酸(97c)(0.83g)依次加入到三口瓶中,置换氮气3次,加入50mL 1,4-二氧六环和水(v/v)=7:3的混合溶剂,将反应混合物升至120℃搅拌回流4h。将反应体系冷却至室温,加入100mL乙酸乙酯和100mL水,分离出有机相,水相用乙酸乙酯萃取(100mL×3),合并有机相,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得4-(4-氨基-3-(6-苯氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(97d)(584mg,从化合物87a算收率:35%)。
LCMS m/z=488.2[M+1]
+。
第四步:3-(6-苯氧基吡啶-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(97e)
3-(6-phenoxypyridin-3-yl)-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将4-(4-氨基-3-(6-苯氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(97d)(487mg,1.0mmol)溶于10mL DCM中,加入3.0mL三氟乙酸,反应于室温搅拌4h。将反应体系减压浓缩,将残余物溶于10mL DCM中,加入10mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(30mL×3),合并有机层, 无水硫酸钠干燥,减压浓缩,得粗品3-(6-苯氧基吡啶-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(97e)(390mg)。
第五步:3-(4-(4-氨基-3-(6-苯氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-甲酸叔丁酯(97f)
tert-butyl 3-(4-(4-amino-3-(6-phenoxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidine-1-carboxylate
将上述粗品3-(6-苯氧基吡啶-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(97e)(390mg)溶于20mL DCE中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(340mg,2.0mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠(640mg,3.0mmol),反应于室温搅拌16h。向反应液中加入20mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(50mL×3),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得3-(4-(4-氨基-3-(6-苯氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-甲酸叔丁酯(97f)(175mg,从化合物97d算两步收率:32%)。
LCMS m/z=543.3[M+1]
+。
第六步:1-(1-(氮杂环丁-3-基)哌啶-4-基)-3-(6-苯氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(97g)
1-(1-(azetidin-3-yl)piperidin-4-yl)-3-(6-phenoxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(4-(4-氨基-3-(6-苯氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-甲酸叔丁酯(97f)(175mg,0.32mmol)溶于10mL DCM中,加入3.0mL三氟乙酸,反应于室温搅拌2h。将反应体系减压浓缩,将残余物溶于10mL DCM,加入10mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(20mL×3), 合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-(1-(氮杂环丁-3-基)哌啶-4-基)-3-(6-苯氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(97g)(140mg)。
第七步:3-(4-(4-氨基-3-(6-苯氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(97h)
tert-butyl 3-(4-(4-amino-3-(6-phenoxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidine]-1'-carboxylate
将上述粗品1-(1-(氮杂环丁-3-基)哌啶-4-基)-3-(6-苯氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(97g)(140mg)溶于10mL DCE中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(110mg,0.64mmol)和乙酸(0.05mL,0.875mmol),反应于室温搅拌1h,加入三乙酰氧基硼氢化钠(200mg,0.94mmol),反应于室温搅拌16h。向反应液中加入10mL水淬灭反应,分离出有机层,水层用二氯甲烷萃取(20mL×4),合并有机层,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得3-(4-(4-氨基-3-(6-苯氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(97h)(44mg,从化合物97f算两步收率:23%)。
第八步:1-(1-([1,3'-双氮杂环丁]-3-基)哌啶-4-基)-3-(6-苯氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(97i)
1-(1-([1,3'-biazetidin]-3-yl)piperidin-4-yl)-3-(6-phenoxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(4-(4-氨基-3-(6-苯氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-甲酸叔丁酯(97h)(44mg,0.074mmol)溶于5mL DCM中,加入2mL三氟乙酸,反应于室温搅拌2h。将反应体系减压浓缩,将残余物溶于10mL DCM,加入10mL水,滴加1mol/L NaOH溶液调pH至12,分离出有机层,水层用二氯甲烷萃取(20mL×3),合并有机层,无水硫酸钠干燥,减压浓缩,得粗品1-(1-([1,3'-双氮杂环丁]-3-基)哌啶 -4-基)-3-(6-苯氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(97i)(32mg)。
第九步:5-(3-(4-(4-氨基-3-(6-苯氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]-[1,3'-双氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物97)
5-(3-(4-(4-amino-3-(6-phenoxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-(1-([1,3'-双氮杂环丁]-3-基)哌啶-4-基)-3-(6-苯氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(97i)(32mg)溶于3mL DMSO中,加入0.1mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(20mg,0.07mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入5mL水,过滤,收集滤饼,用10mL水洗涤,固体用10mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-(4-(4-氨基-3-(6-苯氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]-[1,3'-双氮杂环丁]-1'-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物97)(17mg,从化合物97h算两步收率:30%)。
1H NMR(400MHz,CDCl
3)δ8.51(s,1H),8.45–8.41(m,1H),8.32(s,1H),7.96(dd,1H),7.57(d,1H),7.42–7.34(m,2H),7.22–7.15(m,1H),7.15–7.09(m,2H),7.01(d,1H),6.72(d,1H),6.46(dd,1H),5.46(br.s,2H),4.93–4.70(m,2H),4.05–3.93(m,2H),3.90–3.78(m,2H),3.75–3.62(m,1H),3.59–3.50(m,2H),3.28–3.02(m,3H),3.02–2.85(m,2H),2.85–2.58(m,3H),2.46–2.30(m,2H),2.26–1.90(m,5H)。
LCMS m/z=754.3[M+1]
+。
实施例98:
5-(4-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物98)的三氟乙酸盐
5-(4-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate
第一步:4-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)哌啶-1-甲酸叔丁酯(98a)
tert-butyl 4-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)piperidine-1-carboxylate
将1-[1-(氮杂环丁-3-基)-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(17b)(合成方法见WO2020239103)(100mg,0.23mmol)溶于15mL DCE中,依次加入4-甲酰基哌啶-1-甲酸叔丁酯(74mg,0.35mmol)和0.05mL醋酸,室温搅拌60min后,加入三乙酰氧基硼氢化钠(97mg,0.46mmol),室温反应16h。向反应体系中缓慢加入20mL饱和碳酸氢钠溶液,用80mL DCM萃取,有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=8:1),得4-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)哌啶-1-甲酸叔丁酯(98a)(100mg,收率:68%)。
LCMS m/z=639.5[M+1]
+。
第二步:3-(4-苯氧基苯基)-1-(1-(1-(哌啶-4-基甲基)氮杂环丁-3-基)哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(98b)的三氟乙酸盐
3-(4-phenoxyphenyl)-1-(1-(1-(piperidin-4-ylmethyl)azetidin-3-yl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate
将4-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)哌啶-1-甲酸叔丁酯(98a)(100mg,0.16mmol)溶解在5mL DCM中,加入2mL三氟乙酸,室温搅拌2h。将反应液减压浓缩,得粗品3-(4-苯氧基苯基)-1-(1-(1-(哌啶-4-基甲基)氮杂环丁-3-基)哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(98b)的三氟乙酸盐(120mg)。
LCMS m/z=539.3[M+1]
+。
第三步:5-(4-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物98)的三氟乙酸盐
5-(4-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate
将上述粗品3-(4-苯氧基苯基)-1-(1-(1-(哌啶-4-基甲基)氮杂环丁-3-基)哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(98b)的三氟乙酸盐(120mg)溶于4mL DMSO中,加入固体碳酸氢钠(71mg,0.85mmol),室温搅拌10min,加入0.2mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(94mg,0.34mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入50mL水,过滤,收集固体,用20mL水洗涤,固体用100mL DCM溶解,无水硫酸钠干燥,减压浓缩后粗品过Pre-HPLC(仪器及制备柱:采用Glison GX-281制备液相,制备柱型号是Sunfire C18,5μm,内径×长度=30mm×150mm)。制备方法:粗品用甲醇和二甲亚砜溶解,并用0.45μm滤膜过滤,制备成样品液。流动相体系:乙腈/水(含0.1%TFA)。梯度洗脱方法:乙腈由5%梯度洗脱60%(洗脱时间15min),冻干得到5-(4-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物98)的三氟乙酸盐(40mg)。
1H NMR(400MHz,DMSO-d
6)δ11.06(s,1H),8.36(s,1H),7.72–7.63(m,3H),7.50–7.41(m,2H),7.38–7.32(m,1H),7.30–7.24(m,1H),7.24–7.19(m,1H),7.19–7.11(m,4H),5.07(dd,1H),5.00–4.86(m,1H),4.52–4.34(m,2H),4.34–4.20(m,2H),4.14–4.04(m,2H),3.92–3.80(m,1H),3.34–3.22(m,2H),3.22–3.13(m,2H),3.04–2.82(m,3H),2.80–2.52(m,4H),2.45–2.28(m,2H),2.20–2.08(m,2H),2.08–1.98(m,1H),1.98–1.86(m,1H),1.83–1.69(m,2H),1.34–1.20(m,2H)。
LCMS m/z=795.4[M+1]
+。.
实施例99:
5-(3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)吡咯烷-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物99)的三氟乙酸盐
5-(3-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate
第一步:3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)吡咯烷-1-甲酸叔丁酯(99a)
tert-butyl 3-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)pyrrolidine-1-carboxylate
将1-[1-(氮杂环丁-3-基)-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(17b)(合成方法见WO2020239103)(100mg,0.23mmol)溶于15mL DCE中,依次加入3-甲酰基吡咯烷-1-甲酸叔丁酯(90mg,0.45mmol)和0.05mL醋酸,室温搅拌60min后,加入三乙酰氧基硼氢化钠(97mg,0.46mmol),室温反应16h。向反应体系中缓慢加入20mL饱和碳酸氢钠溶液,用80mL DCM萃取,有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=8:1),得3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)吡咯烷-1-甲酸叔丁酯(99a)(110mg,收率:77%)。
LCMS m/z=625.4[M+1]
+。
第二步:3-(4-苯氧基苯基)-1-(1-(1-(吡咯烷-3-基甲基)氮杂环丁-3-基)哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(99b)的三氟乙酸盐
3-(4-phenoxyphenyl)-1-(1-(1-(pyrrolidin-3-ylmethyl)azetidin-3-yl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate
将3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)吡咯烷-1-甲酸叔丁酯(99a)(100mg,0.16mmol)溶解在5mL DCM中,加入2mL三氟乙酸,室温搅拌2h。将反应液减压浓缩,得粗品3-(4-苯氧基苯基)-1-(1-(1-(吡咯烷-3-基甲基)氮杂环丁-3-基)哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(99b)的三氟乙酸盐(120mg)。
LCMS m/z=525.3[M+1]
+。
第三步:5-(3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)吡咯烷-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物99)的三氟乙酸盐
5-(3-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate
将上述粗品3-(4-苯氧基苯基)-1-(1-(1-(吡咯烷-3-基甲基)氮杂环丁-3-基)哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(99b)的三氟乙酸盐(120mg)溶于4mL DMSO中,加入固体碳酸氢钠(71mg,0.85mmol),室温搅拌10min,加入0.2mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(94mg,0.34mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入50mL水,过滤,收集固体,用20mL水洗涤,固体用100mL DCM溶解,无水硫酸钠干燥,减压浓缩后粗品过Pre-HPLC(仪器及制备柱:采用Glison GX-281制备液相,制备柱型号是Sunfire C18,5μm,内径×长度=30mm×150mm)。制备方法:粗品用甲醇和二甲亚砜溶解,并用0.45μm滤膜过滤,制备成样品液。流动相体系:乙腈/水(含0.1%TFA)。梯度洗脱方法:乙腈由5%梯度洗脱60%(洗脱时间15min),冻干得到5-(3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)吡咯烷-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物99)的三氟乙酸盐(35mg)。
1H NMR(400MHz,DMSO-d
6)δ11.06(s,1H),8.35(s,1H),7.72–7.63(m,3H),7.51–7.41(m,2H),7.28–7.09(m,5H),6.96–6.90(m,1H),6.83(dd,1H),5.06(dd,1H),5.00–4.82(m,1H),4.50–4.33(m,2H),4.33–4.14(m,2H),3.90–3.65(m,2H),3.50–3.31(m,3H),3.30–3.15(m,4H),2.96–2.81(m,1H),2.74–2.53(m,5H),2.45–2.29(m,2H),2.28–2.07(m,3H),2.07–1.96(m,1H),1.90–1.74(m,1H)。
LCMS m/z=781.3[M+1]
+。.
实施例100:
5-(3-(((3aR,6aS)-5-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)六氢环戊并[c]吡咯-2(1H)-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物100)的三氟乙酸盐
5-(3-(((3aR,6aS)-5-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate
第一步:3-(((3aR,6aS)-5-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)六氢环戊并[c]吡咯-2(1H)-基)甲基)氮杂环丁-1-甲酸叔丁酯(100a)
tert-butyl 3-(((3aR,6aS)-5-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)azetidine-1-carboxylate
将1-(1-((3aR,6aS)-八氢环戊[c]吡咯-5-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺三氟乙酸盐(52b)(合成方法见WO2020239103)(120mg)溶于15mL THF中,依次加入3-甲酰基氮杂环丁-1-甲酸叔丁酯(90mg,0.49mmol)和0.05mL醋酸,室温搅拌60min后,加入三乙酰氧基硼氢化钠(102mg,0.48mmol),室温反应16h。向反应体系中缓慢加入20mL饱和碳酸氢钠溶液,用80mL DCM萃取,有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=8:1),得3-(((3aR,6aS)-5-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)六氢环戊并[c]吡咯-2(1H)-基)甲基)氮杂环丁-1-甲酸叔丁酯(100a)(160mg)。
LCMS m/z=665.4[M+1]
+。
第二步:1-(1-((3aR,6aS)-2-(氮杂环丁-3-基甲基)八氢环戊并[c]吡咯-5-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(100b)的三氟乙酸盐
1-(1-((3aR,6aS)-2-(azetidin-3-ylmethyl)octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl) -3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate
将3-(((3aR,6aS)-5-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)六氢环戊并[c]吡咯-2(1H)-基)甲基)氮杂环丁-1-甲酸叔丁酯(100a)(150mg,0.23mmol)溶解在5mL DCM中,加入2mL三氟乙酸,室温搅拌2h。将反应液减压浓缩,得粗品1-(1-((3aR,6aS)-2-(氮杂环丁-3-基甲基)八氢环戊并[c]吡咯-5-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(100b)的三氟乙酸盐(180mg)。
LCMS m/z=565.3[M+1]
+。
第三步:5-(3-(((3aR,6aS)-5-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)六氢环戊并[c]吡咯-2(1H)-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物100)的三氟乙酸盐
5-(3-(((3aR,6aS)-5-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate
将上述粗品1-(1-((3aR,6aS)-2-(氮杂环丁-3-基甲基)八氢环戊并[c]吡咯-5-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(100b)的三氟乙酸盐(180mg)溶于4mL DMSO中,加入固体碳酸氢钠(85mg,1.0mmol),室温搅拌10min,加入0.2mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(127mg,0.46mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入50mL水,过滤,收集固体,用20mL水洗涤,固体用100mL DCM溶解,无水硫酸钠干燥,减压浓缩后粗品过Pre-HPLC(仪器及制备柱:采用Glison GX-281制备液相,制备柱型号是Sunfire C18,5μm,内径×长度=30mm×150mm)。制备方法:粗品用甲醇和二甲亚砜溶解,并用0.45μm滤膜过滤,制备成样品液。流动相体系:乙腈/水(含0.1%TFA)。梯度洗脱方法:乙腈由5%梯度洗脱60%(洗脱时间15min),冻干得到 5-(3-(((3aR,6aS)-5-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)六氢环戊并[c]吡咯-2(1H)-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物100)的三氟乙酸盐(40mg)。
1H NMR(400MHz,DMSO-d
6)δ11.15–11.00(m,1H),8.38–8.30(m,1H),7.76–7.60(m,3H),7.49–7.41(m,2H),7.25–7.10(m,5H),6.84–6.75(m,1H),6.72–6.60(m,1H),5.23–5.00(m,2H),4.30–4.15(m,2H),3.93–3.68(m,3H),3.68–3.08(m,9H),3.02–2.86(m,2H),2.84–2.68(m,1H),2.68–2.51(m,2H),2.51–2.43(m,4H),2.42–2.28(m,2H),2.28–2.13(m,2H),2.12–1.95(m,1H),1.85–1.60(m,2H)。
LCMS m/z=821.4[M+1]
+。.
实施例101:
5-(3-((2-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-7-氮杂螺[3.5]壬-7-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物101)的三氟乙酸盐
5-(3-((2-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate
第一步:3-((2-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-7-氮杂螺[3.5]壬-7-基)甲基)氮杂环丁-1-甲酸叔丁酯(101a)
tert-butyl 3-((2-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)azetidine-1-carboxylate
将1-(1-(1-(7-氮杂螺[3.5]壬-2-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺三氟乙酸盐(51b)(合成方法见WO2020239103)(120mg)溶于15mL THF中,依次加入3-甲酰基氮杂环丁-1-甲酸叔丁酯(90mg,0.49mmol)和0.05mL醋酸,室温搅拌60min后,加入三乙酰氧基硼氢化钠(102mg,0.48mmol),室温反应16h。向反应体系中缓慢加入20mL饱和碳酸氢钠溶液,用80mL DCM萃取,有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=8:1),得3-((2-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-7-氮杂螺[3.5]壬-7-基)甲基)氮杂环丁-1-甲酸叔丁酯(101a)(160mg)。
LCMS m/z=679.4[M+1]
+。
第二步:1-(1-(7-(氮杂环丁-3-基甲基)-7-氮杂螺[3.5]壬-2-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(101b)的三氟乙酸盐
1-(1-(7-(azetidin-3-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate
将3-((2-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-7-氮杂螺[3.5]壬-7-基)甲基)氮杂环丁-1-甲酸叔丁酯(101a)(150mg,0.22mmol)溶解在5mL DCM中,加入2mL三氟乙酸,室温搅拌2h。将反应液减压浓缩,得粗品1-(1-(7-(氮杂环丁-3-基甲基)-7-氮杂螺[3.5]壬-2-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(101b)的三氟乙酸盐(180mg)。
LCMS m/z=579.4[M+1]
+。
第三步:5-(3-((2-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-7-氮杂螺[3.5]壬-7-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物101)的三氟乙酸盐
5-(3-((2-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1 -yl)-7-azaspiro[3.5]nonan-7-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate
将上述粗品1-(1-(7-(氮杂环丁-3-基甲基)-7-氮杂螺[3.5]壬-2-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(101b)的三氟乙酸盐(180mg)溶于4mL DMSO中,加入固体碳酸氢钠(85mg,1.0mmol),室温搅拌10min,加入0.2mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(127mg,0.46mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入50mL水,过滤,收集固体,用20mL水洗涤,固体用100mL DCM溶解,无水硫酸钠干燥,减压浓缩后粗品过Pre-HPLC(仪器及制备柱:采用Glison GX-281制备液相,制备柱型号是Sunfire C18,5μm,内径×长度=30mm×150mm)。制备方法:粗品用甲醇和二甲亚砜溶解,并用0.45μm滤膜过滤,制备成样品液。流动相体系:乙腈/水(含0.1%TFA)。梯度洗脱方法:乙腈由5%梯度洗脱60%(洗脱时间15min),冻干得到5-(3-((2-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-7-氮杂螺[3.5]壬-7-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物101)的三氟乙酸盐(60mg)。
1H NMR(400MHz,DMSO-d
6)δ11.06(s,1H),8.36(s,1H),7.76–7.62(m,3H),7.50–7.41(m,2H),7.25–7.10(m,5H),6.81(d,1H),6.68(dd,1H),5.24–5.00(m,2H),4.30–4.19(m,2H),3.90–3.80(m,2H),3.80–3.68(m,4H),3.58–3.50(m,2H),3.50–3.43(m,2H),3.43–3.32(m,2H),3.32–3.20(m,1H),3.18–3.04(m,2H),3.04–2.95(m,1H),2.95–2.82(m,1H),2.70–2.52(m,2H),2.50–2.34(m,4H),2.32–2.21(m,2H),2.21–2.13(m,1H),2.13–1.89(m,2H),1.88–1.70(m,2H)。
LCMS m/z=835.3[M+1]
+。.
实施例102:
5-(3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-二氮杂环丁]-1'-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物102)的三氟乙酸盐
5-(3-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate
第一步:3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-二氮杂环丁]-1'-基)甲基)氮杂环丁-1-甲酸叔丁酯(102a)
tert-butyl 3-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)methyl)azetidine-1-carboxylate
将1-[1-[1-(氮杂环丁-3-基)氮杂环丁-3-基]-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(17d)(合成方法见WO2020239103)(200mg,0.40mmol)溶于15mL THF中,依次加入3-甲酰基氮杂环丁-1-甲酸叔丁酯(150mg,0.81mmol)和0.05mL醋酸,室温搅拌60min后,加入三乙酰氧基硼氢化钠(171mg,0.81mmol),室温反应16h。向反应体系中缓慢加入20mL饱和碳酸氢钠溶液,用80mL DCM萃取,有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=8:1),得3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-二氮杂环丁]-1'-基)甲基)氮杂环丁-1-甲酸叔丁酯(102a)(150mg,收率:56%)。
LCMS m/z=666.4[M+1]
+。
第二步:1-(1-(1'-(氮杂环丁-3-基甲基)-[1,3'-二氮杂环丁]-3-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(102b)的三氟乙酸盐
1-(1-(1'-(azetidin-3-ylmethyl)-[1,3'-biazetidin]-3-yl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate
将3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-二氮杂环丁]-1'-基)甲基)氮杂环丁-1-甲酸叔丁酯(102a)(150mg,0.23mmol)溶解在5mL DCM中,加入2mL三氟乙酸,室温搅拌2h。将反应液减压浓缩,得粗品1-(1-(1'-(氮杂环丁-3-基甲基)-[1,3'-二氮杂环丁]-3-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(102b)的三氟乙酸盐(180mg)。
LCMS m/z=566.3[M+1]
+。
第三步:5-(3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-二氮杂环丁]-1'-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物102)的三氟乙酸盐
5-(3-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate
将上述粗品1-(1-(1'-(氮杂环丁-3-基甲基)-[1,3'-二氮杂环丁]-3-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(102b)的三氟乙酸盐(180mg)溶于4mL DMSO中,加入固体碳酸氢钠(85mg,1.0mmol),室温搅拌10min,加入0.2mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(127mg,0.46mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入50mL水,过滤,收集固体,用20mL水洗涤,固体用100mL DCM溶解,无水硫酸钠干燥,减压浓缩后粗品过Pre-HPLC(仪器及制备柱:采用Glison GX-281制备液相,制备柱型号是Sunfire C18,5μm,内径×长度=30mm×150mm)。制备方法:粗品用甲醇和二甲亚砜溶解,并用0.45μm滤膜过滤,制备成样品液。流动相体系:乙腈/水(含0.1%TFA)。梯度洗脱方法:乙腈由5%梯度洗脱60%(洗脱时间15min),冻干得到5-(3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-二氮杂环丁]-1'-基)甲基)氮杂环丁-1- 基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物102)的三氟乙酸盐(20mg)。
1H NMR(400MHz,DMSO-d
6)δ8.36(s,1H),7.73–7.63(m,3H),7.45–7.38(m,2H),7.23–7.07(m,5H),6.83(d,1H),6.67(dd,1H),5.26–5.12(m,1H),5.05(dd,1H),4.37–4.16(m,4H),4.10–3.95(m,3H),3.89–3.75(m,4H),3.74–3.57(m,5H),3.57–3.45(m,2H),3.30–3.18(m,2H),3.16–3.03(m,1H),2.92–2.79(m,1H),2.79–2.56(m,4H),2.45–2.31(m,2H),2.14–2.04(m,1H)。
LCMS m/z=822.4[M+1]
+。.
实施例103:
5-(3-((7-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-2-氮杂螺[3.5]壬-2-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物103)的三氟乙酸盐
5-(3-((7-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate
第一步:3-((7-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-2-氮杂螺[3.5]壬-2-基)甲基)氮杂环丁-1-甲酸叔丁酯(103a)
tert-butyl 3-((7-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)methyl)azetidine-1-carboxylate
将1-(1-(2-氮杂螺[3.5]壬-7-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺盐酸盐(55b)(合成方法见WO2020239103)(120mg)溶于15mL THF中,依次加入3-甲酰基氮杂环丁-1-甲酸叔丁酯(91mg,0.49mmol)和0.05mL醋酸,室温搅拌60min后,加入三乙酰氧基硼氢化钠(105mg,0.50mmol),室温反应16h。向反应体系中缓慢加入20mL饱和碳酸氢钠溶液,用80mL DCM萃取,有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=8:1),得3-((7-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-2-氮杂螺[3.5]壬-2-基)甲基)氮杂环丁-1-甲酸叔丁酯(103a)(150mg)。
LCMS m/z=679.4[M+1]
+。
第二步:1-(1-(2-(氮杂环丁-3-基甲基)-2-氮杂螺[3.5]壬-7-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(103b)的三氟乙酸盐
1-(1-(2-(azetidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate
将3-((7-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-2-氮杂螺[3.5]壬-2-基)甲基)氮杂环丁-1-甲酸叔丁酯(103a)(150mg,0.22mmol)溶解在5mL DCM中,加入2mL三氟乙酸,室温搅拌2h。将反应液减压浓缩,得粗品1-(1-(2-(氮杂环丁-3-基甲基)-2-氮杂螺[3.5]壬-7-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(103b)的三氟乙酸盐(180mg)。
LCMS m/z=579.3[M+1]
+。
第三步:5-(3-((7-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-2-氮杂螺[3.5]壬-2-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物103)的三氟乙酸盐
5-(3-((7-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1 -yl)-2-azaspiro[3.5]nonan-2-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate
将上述粗品1-(1-(2-(氮杂环丁-3-基甲基)-2-氮杂螺[3.5]壬-7-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(103b)的三氟乙酸盐(180mg)溶于4mL DMSO中,加入固体碳酸氢钠(85mg,1.0mmol),室温搅拌10min,加入0.2mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(127mg,0.46mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入50mL水,过滤,收集固体,用20mL水洗涤,固体用100mL DCM溶解,无水硫酸钠干燥,减压浓缩后粗品过Pre-HPLC(仪器及制备柱:采用Glison GX-281制备液相,制备柱型号是Sunfire C18,5μm,内径×长度=30mm×150mm)。制备方法:粗品用甲醇和二甲亚砜溶解,并用0.45μm滤膜过滤,制备成样品液。流动相体系:乙腈/水(含0.1%TFA)。梯度洗脱方法:乙腈由5%梯度洗脱60%(洗脱时间15min),冻干得到5-(3-((7-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-2-氮杂螺[3.5]壬-2-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物103)的三氟乙酸盐(15mg)。
1H NMR(400MHz,DMSO-d
6)δ11.20–11.00(m,1H),8.40–8.33(m,1H),7.75–7.60(m,3H),7.50–7.40(m,2H),7.29–7.08(m,5H),6.83–6.73(m,1H),6.71–6.62(m,1H),5.28–5.01(m,2H),4.25–4.13(m,2H),3.99–3.94(m,2H),3.92–3.84(m,2H),3.80–3.68(m,2H),3.64–3.49(m,2H),3.49–3.40(m,2H),3.40–3.27(m,2H),3.25–3.11(m,1H),2.98–2.81(m,3H),2.65–2.51(m,2H),2.45–2.14(m,5H),2.08–1.95(m,1H),1.95–1.80(m,2H),1.80–1.50(m,4H)。
LCMS m/z=835.3[M+1]
+。.
实施例104:
5-(3-((3-((3R,4S)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物104)
5-(3-((3-((3R,4S)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione
第一步:3-((3-((3R,4S)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-甲酸叔丁酯(104a)
tert-butyl 3-((3-((3R,4S)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)azetidine-1-carboxylate
将1-((3R,4S)-1-(氮杂环丁-3-基)-3-氟哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(41f)(合成方法见WO2020239103)(0.46g,1.0mmol)溶于20mL THF中,加入3-甲酰基氮杂环丁-1-甲酸叔丁酯(0.37g,2.0mmol),室温搅拌1h,加入三乙酰氧基硼氢化钠(0.43g,2.0mmol),室温下反应16h。向反应液中加入50mL二氯甲烷,用饱和碳酸氢钠溶液调pH至9.0,分离有机相,有机相用无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=10:1),得3-((3-((3R,4S)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-甲酸叔丁酯(104a)(0.46g,收率:73%)。
LCMS m/z=629.3[M+1]
+。
第二步:1-((3R,4S)-1-(1-(氮杂环丁-3-基甲基)氮杂环丁-3-基)-3-氟哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(104b)
1-((3R,4S)-1-(1-(azetidin-3-ylmethyl)azetidin-3-yl)-3-fluoropiperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-((3-((3R,4S)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-甲酸叔丁酯(104a)(0.45g,0.72mmol)溶于10mL甲醇中,加入10mL 4mol/L盐酸1,4-二氧六环溶液,常温反应1h。将反应液减压浓缩,加入100mL二氯甲烷,用3mol/L氢氧化钠溶液调pH至12,分离有机相,有机相用无水硫酸钠干燥,减压浓缩,得粗品1-((3R,4S)-1-(1-(氮杂环丁-3-基甲基)氮杂环丁-3-基)-3-氟哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(104b)(0.36g)。
第三步:5-(3-((3-((3R,4S)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物104)
5-(3-((3-((3R,4S)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-((3R,4S)-1-(1-(氮杂环丁-3-基甲基)氮杂环丁-3-基)-3-氟哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(104b)(0.36g)溶于10mL DMSO中,加入1.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(0.37g,1.34mmol),升温至85℃反应3h。将反应液冷却至室温,加入50mL水,过滤,收集固体,用20mL水洗涤,固体用100mL DCM溶解,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-((3-((3R,4S)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物104)(0.18g,从化合物104a算两步收率:32%)。
1H NMR(400MHz,CDCl
3)δ8.38(d,1H),7.70–7.59(m,3H),7.43–7.33(m,2H), 7.21–7.03(m,5H),6.97–6.88(m,1H),6.51–6.41(m,1H),5.64(br.s,2H),5.18–4.98(m,1H),4.98–4.78(m,2H),4.18–4.00(m,2H),3.78–3.48(m,4H),3.25–2.94(m,6H),2.90–2.66(m,6H),2.42–2.22(m,1H),2.22–2.14(m,1H),2.14–2.04(m,2H)。
LCMS m/z=785.3[M+1]
+。
实施例105:
4-(3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物105)
4-(3-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-(1-(1-(氮杂环丁烷-3-基甲基)氮杂环丁-3-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(85b)(110mg)溶于5mL DMSO中,加入0.2mL DIPEA和2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(83mg,0.3mmol),反应于85℃搅拌3h。将反应液冷却至室温,用50mL乙酸乙酯稀释,有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得4-(3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物105)(60mg,从化合物85a算两步收率:33%)。
1H NMR(400MHz,CDCl
3)δ9.29(br.s,1H),8.31(s,1H),7.61–7.53(m,2H),7.40–7.25(m,3H),7.14–6.96(m,6H),6.49(d,1H),5.58(br.s,2H),4.92–4.82(m,1H),4.77–4.64(m,1H),4.35–4.20(m,2H),3.93–3.81(m,2H),3.68–3.52(m,2H),3.10–2.90(m,3H),2.90–2.56(m,8H),2.42–2.27(m,2H),2.12–1.88(m,5H)。
LCMS m/z=767.3[M+1]
+。
实施例106:
5-(3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁 -1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(化合物106)
5-(3-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
将上述粗品1-(1-(1-(氮杂环丁烷-3-基甲基)氮杂环丁-3-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(85b)(150mg)溶于5mL DMSO中,加入0.2mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5,6-二氟异吲哚啉-1,3-二酮(合成方法见WO2020239103)(118mg,0.4mmol),反应于85℃搅拌3h。将反应液冷却至室温,用50mL乙酸乙酯稀释,有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(化合物106)(120mg,从化合物85a算两步收率:47%)。
1H NMR(400MHz,DMSO-d
6)δ11.06(br.s,1H),8.23(s,1H),7.70–7.62(m,2H),7.57(d,1H),7.48–7.40(m,2H),7.23–7.09(m,5H),6.88(d,1H),5.05(dd,1H),4.72–4.59(m,1H),4.27–4.16(m,2H),3.88–3.78(m,2H),3.48–3.39(m,2H),2.98–2.78(m,6H),2.78–2.63(m,3H),2.63–2.51(m,2H),2.27–2.11(m,2H),2.07–1.83(m,5H)。
LCMS m/z=785.3[M+1]
+。
实施例107:
3-(5-3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(化合物107)的三氟乙酸盐
3-(5-(3-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione trifluoroacetate
将1-(1-(1-(氮杂环丁烷-3-基甲基)氮杂环丁-3-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(85b)(510mg)溶于10mL DMSO中,加入碳酸铯(980mg,3.0mmol),碘化亚铜(190mg,1.0mmol)和L-脯氨酸(230mg,2mmol),升温至100℃反应2h。将反应体系冷却至室温,加入100mL乙酸乙酯,过滤,滤液用100mL纯化水洗涤,无水硫酸钠干燥,减压浓缩,粗品过Pre-HPLC(仪器及制备柱:采用Glison GX-281制备液相,制备柱型号是Sunfire C18,5μm,内径×长度=30mm×150mm)。制备方法:粗品用甲醇和二甲亚砜溶解,并用0.45μm滤膜过滤,制备成样品液。流动相体系:乙腈/水(含0.1%TFA)。梯度洗脱方法:乙腈由5%梯度洗脱60%(洗脱时间15min),冻干得到3-(5-3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(化合物107)的三氟乙酸盐(130mg)。
1H NMR(400MHz,DMSO-d
6)δ10.92(br.s,1H),8.33–8.28(m,1H),7.70–7.62(m,2H),7.52(d,1H),7.49–7.41(m,2H),7.25–7.09(m,5H),6.56–6.46(m,2H),5.03(dd,1H),4.93–4.77(m,1H),4.36–4.26(m,3H),4.25–4.16(m,1H),4.16–3.99(m,5H),3.74–3.66(m,2H),3.59–3.49(m,2H),3.24–3.06(m,2H),3.04–2.82(m,2H),2.70–2.50(m,2H),2.45–2.22(m,4H),2.15–2.00(m,2H),2.00–1.87(m,1H)。
LCMS m/z=753.2[M+1]
+。
实施例107-1:
3-(5-3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(化合物107)
3-(5-(3-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
向3-(5-3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(化合物107)的三氟乙酸盐(80mg)加入30mL二氯甲烷,加入30mL 25%氨水,继续搅拌1h至体系变澄清,分离出有机相,无水硫酸钠干燥,减压浓缩,得3-(5-3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(化合物107)(30mg)。
1H NMR(400MHz,CDCl
3)δ8.46–8.30(m,2H),7.72–7.56(m,3H),7.44–7.33(m,2H),7.22–7.03(m,5H),6.43(dd,1H),6.39–6.33(m,1H),5.52(br.s,2H),5.18(dd,1H),4.87–4.72(m,1H),4.42–4.33(m,1H),4.27–4.17(m,1H),4.13–4.01(m,2H),3.96–3.57(m,4H),3.35–3.04(m,3H),3.04–2.70(m,6H),2.51–2.29(m,3H),2.29–1.94(m,6H).
LCMS m/z=753.2[M+1]
+。
实施例108:
5-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物108)的三氟乙酸盐
5-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate
将1-[1-[1-(氮杂环丁-3-基)氮杂环丁-3-基]-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(17d)(合成方法见WO2020239103)(100mg,0.2mmol)加入到10mL 1,2-二氯 乙烷和2mL DMSO的混合溶剂中,加入2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-甲醛(合成方法见Org.Biomol.Chem.,2013,11,4757-4763)(86mg,0.3mmol),室温反应1h,加入三乙酰氧基硼氢化钠(63mg,0.3mmol),室温下继续反应12h。向反应液中加入30mL二氯甲烷,用饱和碳酸氢钠溶液调体系pH至9.0,分离有机相,有机相用无水硫酸钠干燥,减压浓缩后粗品过Pre-HPLC(仪器及制备柱:采用Glison GX-281制备液相,制备柱型号是Sunfire C18,5μm,内径×长度=30mm×150mm)。制备方法:粗品用甲醇和二甲亚砜溶解,并用0.45μm滤膜过滤,制备成样品液。流动相体系:乙腈/水(含0.1%TFA)。梯度洗脱方法:乙腈由5%梯度洗脱60%(洗脱时间15min),冻干得到5-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-[1,3'-双氮杂环丁]-1'-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物108)的三氟乙酸盐(45mg)。
1H NMR(400MHz,DMSO-d
6)δ11.13(br.s,1H),8.37–8.31(m,1H),8.08(s,1H),8.06–7.94(m,2H),7.71–7.63(m,2H),7.49–7.41(m,2H),7.27–7.10(m,5H),5.18(dd,1H),5.14–5.00(m,1H),4.57(s,2H),4.24–4.08(m,2H),4.02–3.86(m,4H),3.76–3.64(m,4H),3.48–3.40(m,2H),3.25–3.10(m,2H),2.97–2.83(m,1H),2.69–2.51(m,2H),2.50–2.38(m,2H),2.30–2.18(m,2H),2.13–2.02(m,1H)。
LCMS m/z=767.3[M+1]
+。
实施例109:
5-((3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物109)的三氟乙酸盐
5-((3-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)azetidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate
将上述粗品1-(1-(1-(氮杂环丁烷-3-基甲基)氮杂环丁-3-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(85b)(110mg)加入到10mL 1,2-二氯乙烷和2mL DMSO的混合溶剂中,加入2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-甲醛(合成方法见Org.Biomol.Chem.,2013,11,4757-4763)(86mg,0.3mmol),室温反应1h,加入三乙酰氧基硼氢化钠(63mg,0.3mmol),室温下搅继续反应12h。向反应液中加入30mL二氯甲烷,用饱和碳酸氢钠溶液调体系pH至9.0,分离有机相,有机相用无水硫酸钠干燥,减压浓缩后粗品过Pre-HPLC(仪器及制备柱:采用Glison GX-281制备液相,制备柱型号是Sunfire C18,5μm,内径×长度=30mm×150mm)。制备方法:粗品用甲醇和二甲亚砜溶解,并用0.45μm滤膜过滤,制备成样品液。流动相体系:乙腈/水(含0.1%TFA)。梯度洗脱方法:乙腈由5%梯度洗脱60%(洗脱时间15min),冻干得到5-((3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物109)的三氟乙酸盐(40mg)。
1H NMR(400MHz,DMSO-d
6)11.13(br.s,1H),8.32(s,1H),8.08–8.01(m,2H),7.98–7.91(m,1H),7.70–7.63(m,2H),7.49–7.41(m,2H),7.27–7.09(m,5H),5.18(dd,1H),4.95–4.80(m,1H),4.59(s,2H),4.32–4.08(m,5H),4.08–3.96(m,4H),3.49–3.39(m,2H),3.22–3.11(m,2H),3.06–2.82(m,2H),2.70–2.51(m,4H),2.40–2.24(m,2H),2.14–2.00(m,3H)。
LCMS m/z=781.3[M+1]
+。
实施例110:
5-(3-((3-((3S,4R)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物110)
5-(3-((3-((3S,4R)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:3-((3-((3S,4R)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基氮杂环丁-1-甲酸叔丁酯(110a)
tert-butyl 3-((3-((3S,4R)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)azetidine-1-carboxylate
将1-((3S,4R)-1-(氮杂环丁-3-基)-3-氟哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑[3,4-d]嘧啶-4-胺(38f)(合成方法见WO2020239103)(1.4g,3.0mmol)加入到50mL 1,2-二氯乙烷中,加入3-甲酰基氮杂环丁-1-甲酸叔丁酯(0.63g,3.4mmol),室温搅拌1h,加入三乙酰氧基硼氢化钠(0.72g,3.4mmol),室温下反应12h。向反应液加入50mL二氯甲烷,用饱和碳酸氢钠溶液调pH至9.0,分离有机相,有机相用无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=10:1),得3-((3-((3S,4R)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基氮杂环丁-1-甲酸叔丁酯(110a)(1.8g,收率:95%)。
LCMS m/z=629.3[M+1]
+。
第二步:1-((3S,4R)-1-(1-(氮杂环丁-3-基甲基)氮杂环丁-3-基)-3-氟哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(110b)
1-((3S,4R)-1-(1-(azetidin-3-ylmethyl)azetidin-3-yl)-3-fluoropiperidin-4-yl)-3-(4-phenoxy phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-((3-((3S,4R)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基氮杂环丁-1-甲酸叔丁酯(110a)(1.8g,2.9mmol)溶于20mL甲醇中,加入20mL 4mol/L盐酸1,4-二氧六环溶液,常温反应1h。将反应液减压浓缩,加入100mL二氯甲烷溶解,用3mol/L氢氧化钠溶液调pH至12,分离有机相,有机相用无水硫酸钠干燥,减压浓缩,得粗品1-((3S,4R)-1-(1-(氮杂环丁-3-基甲基)氮杂环丁-3-基)-3-氟哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(110b)(1.5g)。
第三步:5-(3-((3-((3S,4R)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物110)
5-(3-((3-((3S,4R)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-((3S,4R)-1-(1-(氮杂环丁-3-基甲基)氮杂环丁-3-基)-3-氟哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(110b)(0.62g)溶于10mL DMSO中,加入1.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(0.5g,1.8mmol),升温至85℃反应3h。将反应液冷却至室温,用100mL乙酸乙酯稀释,有机相用100mL水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-((3-((3S,4R)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物110)(0.31g,从化合物110a算两步收率:33%)。
1H NMR(400MHz,CDCl
3)δ8.37(d,1H),7.70–7.59(m,3H),7.42–7.34(m,2H),7.21–7.03(m,5H),6.95–6.86(m,1H),6.51–6.42(m,1H),5.72(br.s,2H),5.18–4.98(m, 1H),4.98–4.78(m,2H),4.14–4.03(m,2H),3.78–3.52(m,4H),3.25–2.94(m,6H),2.91–2.67(m,6H),2.44–2.23(m,1H),2.22–2.04(m,3H)。
LCMS m/z=785.3[M+1]
+。
实施例111:
5-(3-((3-((3R,4R)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物111)
5-(3-((3-((3R,4R)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:3-((3-((3R,4R)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-甲酸叔丁酯(111a)
tert-butyl 3-((3-((3R,4R)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)azetidine-1-carboxylate
将1-((3R,4R)-1-(氮杂环丁-3-基)-3-氟哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(39f)(合成方法见WO2020239103)(2.5g,5.4mmol)加入到80mL 1,2-二氯乙 烷中,加入3-甲酰基氮杂环丁1-甲酸叔丁酯(1.1g,5.9mmol),室温搅拌1h,加入三乙酰氧基硼氢化钠(1.3g,6.1mmol),室温下反应12h。向反应液加入50mL二氯甲烷,用饱和碳酸氢钠溶液调pH至9.0,分离有机相,有机相用无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=10:1),得3-((3-((3R,4R)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-甲酸叔丁酯(111a)(3.3g,收率:97%)。
LCMS m/z=629.3[M+1]
+。
第二步:1-((3R,4R)-1-(1-(氮杂环丁-3-基甲基)氮杂环丁-3-基)-3-氟哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(111b)
1-((3R,4R)-1-(1-(azetidin-3-ylmethyl)azetidin-3-yl)-3-fluoropiperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-((3-((3R,4R)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-甲酸叔丁酯(111a)(3.3g,5.3mmol)溶于50mL甲醇中,加入50mL 4mol/L盐酸1,4-二氧六环溶液,常温反应1h。将反应液减压浓缩,加入100mL二氯甲烷溶解,用3mol/L氢氧化钠溶液调pH至12,分离有机相,有机相用无水硫酸钠干燥,减压浓缩,得粗品1-((3R,4R)-1-(1-(氮杂环丁-3-基甲基)氮杂环丁-3-基)-3-氟哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(111b)(2.7g)。
第三步:5-(3-((3-((3R,4R)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物111)
5-(3-((3-((3R,4R)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-((3R,4R)-1-(1-(氮杂环丁-3-基甲基)氮杂环丁-3-基)-3-氟哌啶-4-基)-3-(4- 苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(111b)(1.95g)溶于20mL DMSO中,加入2.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(1.6g,5.8mmol),升温至85℃反应3h。将反应液冷却至室温,用100mL乙酸乙酯稀释,有机相用100mL水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-((3-((3R,4R)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物111)(1.4g,从化合物111a算两步收率:47%)。
1H NMR(400MHz,CDCl
3)δ11.49(br.s,1H),8.41(s,1H),7.80–7.52(m,3H),7.47–7.25(m,2H),7.24–7.00(m,5H),6.98–6.84(m,1H),6.57–6.37(m,1H),5.98(br.s,2H),5.38–5.06(m,1H),5.04–4.76(m,2H),4.25–3.95(m,2H),3.82–3.48(m,4H),3.35–2.97(m,4H),2.96–2.65(m,7H),2.58–2.30(m,1H),2.25–1.95(m,4H)。
LCMS m/z=785.3[M+1]
+。
实施例112:
5-(3-((3-((3S,4S)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物112)
5-(3-((3-((3S,4S)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
第一步:3-((3-((3S,4S)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-甲酸叔丁酯(112a)
tert-butyl 3-((3-((3S,4S)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)azetidine-1-carboxylate
将1-[(3S,4S)-1-(氮杂环丁-3-基)-3-氟-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(43f)(合成方法见WO2020239103)(1.05g,2.3mmol)加入到50mL 1,2-二氯乙烷中,加入3-甲酰基氮杂环丁-1-甲酸叔丁酯(0.46g,2.5mmol),室温搅拌1h,加入三乙酰氧基硼氢化钠(0.53g,2.5mmol),室温下反应12h。向反应液加入50mL二氯甲烷,用饱和碳酸氢钠溶液调pH至9.0,分离有机相,有机相用无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=10:1),得3-((3-((3S,4S)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-甲酸叔丁酯(112a)(1.35g,收率:93%)。
LCMS m/z=629.3[M+1]
+。
第二步:1-((3S,4S)-1-(1-(氮杂环丁-3-基甲基)氮杂环丁-3-基)-3-氟哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(112b)
1-((3S,4S)-1-(1-(azetidin-3-ylmethyl)azetidin-3-yl)-3-fluoropiperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-((3-((3S,4S)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-甲酸叔丁酯(112a)(1.35g,2.15mmol)溶于20mL甲醇中,加入20mL 4mol/L盐酸1,4-二氧六环溶液,常温反应1h。将反应液减压浓缩,加入100mL二氯甲烷溶解,用3mol/L氢氧化钠溶液调pH至12,分离有机相,有机相用无水硫酸钠干燥,减压浓缩,得粗品1-((3S,4S)-1-(1-(氮杂环丁-3-基甲基)氮杂环丁-3-基)-3-氟哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(112b)(1.1g)。
第三步:5-(3-((3-((3S,4S)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3- 氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物112)
5-(3-((3-((3S,4S)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-((3S,4S)-1-(1-(氮杂环丁-3-基甲基)氮杂环丁-3-基)-3-氟哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(112b)(0.7g)溶于10mL DMSO中,加入1.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(0.5g,1.8mmol),升温至85℃反应3h。将反应液冷却至室温,用100mL乙酸乙酯稀释,有机相用100mL水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-((3-((3S,4S)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物112)(0.33g,从化合物112a算两步收率:31%)。
1H NMR(400MHz,CDCl
3)δ8.40(s,1H),7.72–7.58(m,3H),7.44–7.32(m,2H),7.23–7.00(m,5H),6.93–6.83(m,1H),6.53–6.43(m,1H),5.74(br.s,2H),5.34–5.08(m,1H),5.02–4.80(m,2H),4.17–3.97(m,2H),3.80–3.55(m,4H),3.30–2.97(m,4H),2.97–2.66(m,7H),2.52–2.34(m,1H),2.24–1.98(m,4H)。
LCMS m/z=785.3[M+1]
+。
实施例113:
5-(3-((3-((3R,4S)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)-3-氟氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(化合物113)
5-(3-((3-((3R,4S)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)-3-fluoroazetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
第一步:3-((3-((3R,4S)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)-3-氟氮杂环丁-1-甲酸叔丁酯(113a)
tert-butyl 3-((3-((3R,4S)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)-3-fluoroazetidine-1-carboxylate
将1-((3R,4S)-1-(氮杂环丁-3-基)-3-氟哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(41f)(合成方法见WO2020239103)(510mg,1.11mmol)加入到50mL 1,2-二氯乙烷中,加入3-氟-3-甲酰基氮杂环丁-1-甲酸叔丁酯(合成方法见WO2018089355)(304mg,1.5mmol),室温反应1h后,加入三乙酰氧基硼氢化钠(318mg,1.5mmol),室温继续反应12h。向反应体系中加入50mL二氯甲烷,用饱和碳酸氢钠溶液调pH至9.0,分离出有机相,有机相用无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=10:1),得3-((3-((3R,4S)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)-3-氟氮杂环丁-1-甲酸叔丁酯(113a)(600mg,收率:84%)。
LCMS m/z=647.5[M+1]
+。
第二步:1-((3R,4S)-3-氟-1-(1-((3-氟氮杂环丁-3-基)甲基)氮杂环丁-3-基)-哌啶-4- 基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(113b)
1-((3R,4S)-3-fluoro-1-(1-((3-fluoroazetidin-3-yl)methyl)azetidin-3-yl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-((3-((3R,4S)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)-3-氟氮杂环丁-1-甲酸叔丁酯(113a)(600mg,0.93mmol)溶于20mL甲醇中,加入20mL 4mol/L盐酸1,4-二氧六环溶液,室温反应1h。将反应液减压浓缩,加入100mL二氯甲烷溶解,用3mol/L氢氧化钠溶液调pH至12.0,分离有机相,有机相用无水硫酸钠干燥,减压浓缩,得粗品1-((3R,4S)-3-氟-1-(1-((3-氟氮杂环丁-3-基)甲基)氮杂环丁-3-基)-哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(113b)(450mg)。
LCMS m/z=547.3[M+1]
+。
第三步:5-(3-((3-((3R,4S)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)-3-氟氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(化合物113)
5-(3-((3-((3R,4S)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)-3-fluoroazetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
将上述粗品1-((3R,4S)-3-氟-1-(1-((3-氟氮杂环丁-3-基)甲基)氮杂环丁-3-基)-哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(113b)(450mg)溶于10mL DMSO中,加入1.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5,6-二氟异吲哚啉-1,3-二酮(合成方法见WO2020239103)(300mg,1.02mmol),反应于85℃搅拌3h。将反应液冷却至室温,加入200mL水,过滤,滤饼用100mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-((3-((3R,4S)-4-(4-氨基-3-(4- 苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)-3-氟氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(化合物113)(300mg,从化合物113a算两步收率:39%)。
1H NMR(400MHz,CDCl
3)δ8.31(d,1H),7.62–7.56(m,2H),7.35–7.27(m,3H),7.14–7.03(m,3H),7.03–6.98(m,2H),6.98–6.87(m,1H),5.61(br.s,2H),5.12–4.71(m,3H),4.25–4.06(m,4H),3.73–3.53(m,2H),3.38–3.15(m,2H),3.15–3.04(m,2H),3.04–2.88(m,4H),2.84–2.64(m,3H),2.36–2.16(m,1H),2.16–2.07(m,1H),2.07–1.96(m,2H)。
LCMS m/z=821.3[M+1]
+。
实施例114:
5-(3-((3-((3R,4S)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(化合物114)
5-(3-((3-((3R,4S)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
将上述粗品1-((3R,4S)-1-(1-(氮杂环丁-3-基甲基)氮杂环丁-3-基)-3-氟哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(104b)(450mg)溶于10mL DMSO中,加入1.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5,6-二氟异吲哚啉-1,3-二酮(合成方法见WO2020239103)(300mg,1.02mmol),反应于85℃搅拌3h。将反应液冷却至室温,加入200mL水,过滤,滤饼用100mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-((3-((3R,4S)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟哌啶-1-基)氮杂环丁-1-基)甲基)氮杂环丁-1- 基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(化合物114)(200mg,从化合物104a算两步收率:28%)。
1H NMR(400MHz,CDCl
3)δ8.37(d,1H),7.69–7.62(m,2H),7.42–7.30(m,3H),7.20–7.04(m,5H),7.02–6.91(m,1H),5.63(br.s,2H),5.20–4.78(m,3H),4.30–4.17(m,2H),3.94–3.77(m,2H),3.77–3.52(m,2H),3.32–2.97(m,6H),2.97–2.65(m,6H),2.43–2.14(m,2H),2.14–2.02(m,2H)。
LCMS m/z=803.3[M+1]
+。
实施例115:
5-(3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-哌啶-1-基)氮杂环丁-1-基)甲基)-3-氟氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(化合物115)
5-(3-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)-3-fluoroazetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
第一步:3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-哌啶-1-基)氮杂环丁-1-基)甲基)-3-氟氮杂环丁-1-甲酸叔丁酯(115a)
tert-butyl 3-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)-3-fluoroazetidine-1-carboxylate
将1-[1-(氮杂环丁-3-基)-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(17b)(合成方法见WO2020239103)(900mg,2.04mmol)加入到50mL 1,2-二氯乙烷中,加入3-氟-3-甲酰基氮杂环丁-1-甲酸叔丁酯(合成方法见WO2018089355)(610mg,3.0mmol),室温反应1h后,加入三乙酰氧基硼氢化钠(630mg,3.0mmol),室温下继续反应12h。向反应体系中加入50mL二氯甲烷,用饱和碳酸氢钠溶液调pH至9.0,分离出有机相,有机相用无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=10:1),得3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-哌啶-1-基)氮杂环丁-1-基)甲基)-3-氟氮杂环丁-1-甲酸叔丁酯(115a)(1.0g,收率:78%)。
LCMS m/z=629.3[M+1]
+。
第二步:1-(1-(1-((3-氟氮杂环丁-3-基)甲基)氮杂环丁-3-基)-哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(115b)
1-(1-(1-((3-fluoroazetidin-3-yl)methyl)azetidin-3-yl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-哌啶-1-基)氮杂环丁-1-基)甲基)-3-氟氮杂环丁-1-甲酸叔丁酯(115a)(1.0g,1.6mmol)溶于20mL甲醇中,加入20mL 4mol/L盐酸1,4-二氧六环溶液,室温反应1h。将反应液减压浓缩,加入100mL二氯甲烷溶解,用3mol/L氢氧化钠溶液调pH至12.0,分离有机相,有机相用无水硫酸钠干燥,减压浓缩,得粗品1-(1-(1-((3-氟氮杂环丁-3-基)甲基)氮杂环丁-3-基)-哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(115b)(830mg)。
LCMS m/z=529.3[M+1]
+。
第三步:5-(3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-哌啶-1-基)氮杂环丁-1-基)甲基)-3-氟氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(化合物115)
5-(3-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1 -yl)azetidin-1-yl)methyl)-3-fluoroazetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
将上述粗品1-(1-(1-((3-氟氮杂环丁-3-基)甲基)氮杂环丁-3-基)-哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(115b)(400mg)溶于10mL DMSO中,加入1.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5,6-二氟异吲哚啉-1,3-二酮(合成方法见WO2020239103)(300mg,1.02mmol),反应于85℃搅拌3h。将反应液冷却至室温,加入200mL水,过滤,滤饼用100mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-哌啶-1-基)氮杂环丁-1-基)甲基)-3-氟氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(化合物115)(420mg,从化合物115a算两步收率:68%)。
1H NMR(400MHz,CDCl
3)δ10.35(br.s,1H),8.31(s,1H),7.62–7.53(m,2H),7.37–7.26(m,3H),7.14–6.97(m,5H),6.91(d,1H),5.71(br.s,2H),4.92–4.82(m,1H),4.80–4.64(m,1H),4.26–4.00(m,4H),3.69–3.54(m,2H),3.28–3.09(m,2H),3.09–2.95(m,2H),2.95–2.83(m,3H),2.83–2.61(m,3H),2.44–2.26(m,2H),2.16–1.92(m,5H)。
LCMS m/z=803.2[M+1]
+。
实施例116:
5-(3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-哌啶-1-基)氮杂环丁-1-基)甲基)-3-氟氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮(化合物116)
5-(3-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)-3-fluoroazetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-(1-(1-((3-氟氮杂环丁-3-基)甲基)氮杂环丁-3-基)-哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(115b)(430mg)溶于10mL DMSO中,加入1.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(300mg,1.1mmol),反应于85℃搅拌3h。将反应液冷却至室温,加入200mL水,过滤,滤饼用100mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(3-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-哌啶-1-基)氮杂环丁-1-基)甲基)-3-氟氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮(化合物116)(420mg,从化合物115a算两步收率:65%)。
1H NMR(400MHz,CDCl
3)δ9.43(br.s,1H),8.37(s,1H),7.70–7.61(m,3H),7.43–7.35(m,2H),7.21–7.04(m,5H),6.87(d,1H),6.56(dd,1H),5.72(br.s,2H),5.00–4.70(m,2H),4.18–4.01(m,4H),3.74–3.62(m,2H),3.34–3.07(m,3H),3.07–2.67(m,7H),2.53–2.36(m,2H),2.20–1.95(m,5H)。
LCMS m/z=785.3[M+1]
+。
实施例117:
5-(4-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-哌啶-1-基)氮杂环丁-1-基)甲基)-4-氟哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(化合物117)
5-(4-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)-4-fluoropiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
第一步:4-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)-4-氟哌啶-1-甲酸叔丁酯(117a)
tert-butyl 4-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)-4-fluoropiperidine-1-carboxylate
将1-[1-(氮杂环丁-3-基)-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(17b)(合成方法见WO2020239103)(1.5g,3.4mmol)加入到50mL 1,2-二氯乙烷中,加入4-氟-4-甲酰基哌啶-1-甲酸叔丁酯(920mg,4.0mmol),室温反应1h后,加入三乙酰氧基硼氢化钠(844mg,4.0mmol),室温下继续反应12h。向反应体系中加入50mL二氯甲烷,用饱和碳酸氢钠溶液调pH至9.0,分离出有机相,有机相用无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=10:1),得4-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)-4-氟哌啶-1-甲酸叔丁酯(117a)(1.2g,收率:54%)。
LCMS m/z=657.3[M+1]
+。
第二步:1-(1-(1-((4-氟哌啶-4-基)甲基)氮杂环丁-3-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(117b)
1-(1-(1-((4-fluoropiperidin-4-yl)methyl)azetidin-3-yl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将4-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)氮杂环丁-1-基)甲基)-4-氟哌啶-1-甲酸叔丁酯(117a)(1.2g,1.8mmol)溶于20mL甲醇中,加入20mL 4mol/L盐酸1,4-二氧六环溶液,室温反应1h。将反应液减压浓缩,加入100mL二氯甲烷溶解,用3mol/L氢氧化钠溶液调pH至12.0,分离有机相,有机相用无水硫酸钠干燥,减压浓缩,得粗品1-(1-(1-((4-氟哌啶-4-基)甲基)氮杂环丁-3-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(117b)(980mg)。
LCMS m/z=557.3[M+1]
+。
第三步:5-(4-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-哌啶-1-基)氮杂环丁-1-基)甲基)-4-氟哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(化合物117)
5-(4-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)-4-fluoropiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
将上述粗品1-(1-(1-((4-氟哌啶-4-基)甲基)氮杂环丁-3-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(117b)(450mg)溶于10mL DMSO中,加入1.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5,6-二氟异吲哚啉-1,3-二酮(合成方法见WO2020239103)(300mg,1.02mmol),反应于85℃搅拌3h。将反应液冷却至室温,加入200mL水,过滤,滤饼用100mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(4-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-哌啶-1-基)氮杂环丁-1-基)甲基)-4-氟哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(化合物117)(230mg,从化合物117a算两步收率33%)。
1H NMR(400MHz,CDCl
3)δ9.71(br.s,1H),8.31(s,1H),7.62–7.52(m,2H),7.44–7.26(m,4H),7.14–6.96(m,5H),5.69(br.s,2H),4.92–4.81(m,1H),4.78–4.63(m,1H), 3.63–3.49(m,2H),3.46–3.32(m,2H),3.18–3.05(m,2H),3.05–2.92(m,3H),2.92–2.50(m,7H),2.43–2.26(m,2H),2.11–1.90(m,7H),1.79–1.62(m,2H)。
LCMS m/z=831.3[M+1]
+。
实施例118:
5-(4-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-哌啶-1-基)氮杂环丁-1-基)甲基)-4-氟哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮(化合物118)
5-(4-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)azetidin-1-yl)methyl)-4-fluoropiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
将上述粗品1-(1-(1-((4-氟哌啶-4-基)甲基)氮杂环丁-3-基)哌啶-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(117b)(500mg)溶于10mL DMSO中,加入1.0mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(300mg,1.1mmol),反应于85℃搅拌3h。将反应液冷却至室温,加入200mL水,过滤,滤饼用100mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得5-(4-((3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-哌啶-1-基)氮杂环丁-1-基)甲基)-4-氟哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮(化合物118)(300mg,从化合物117a算两步收率:40%)。
1H NMR(400MHz,CDCl
3)δ8.97(br.s,1H),8.31(s,1H),7.65–7.53(m,3H),7.36–7.27(m,2H),7.22(d,1H),7.15–6.95(m,6H),5.56(br.s,2H),4.92–4.82(m,1H),4.80–4.64(m,1H),3.75–3.65(m,2H),3.63–3.52(m,2H),3.32–3.19(m,2H),3.17–2.96(m,3H),2.93–2.56(m,7H),2.44–2.28(m,2H),2.14–1.86(m,7H),1.75–1.53(m,2H)。
LCMS m/z=813.4[M+1]
+。
七:效果
1.细胞增殖抑制实验
SU-DHL-4、Mino、SU-DHL-6培养基为RPMI1640+10%FBS,培养于37℃、5%CO
2孵箱中。细胞铺板96孔板。其中SU-DHL-4细胞20000个/孔,Mino和SU-DHL-6细胞5000个/孔,每孔90μL。每孔加入10μL不同浓度的化合物。每个浓度设3复孔,最后一列为DMSO溶媒对照组,在37℃、5%CO
2条件下继续培养72小时。72小时后,每孔加入100μL检测试剂(Cell Viability Assay,Promega,G7573),混匀2分钟,室温孵育10分钟,用酶标仪(PHERAstar FSX)测定荧光信号值。使用origin9.2软件,计算化合物抑制细胞增殖的IC
50值,并根据式(1)计算在化合物最高浓度下的抑制率Max inhi.%。
Max inhi.%=(1-T72
给药/T72
溶媒)×100% 式(1)。
OCI-LY10、TMD-8细胞培养基为RPMI1640+10%FBS,培养于37℃、5%CO
2孵箱中。细胞铺板96孔板。其中OCI-LY10细胞10000个/孔,TMD-8细胞8000个/孔,每孔90μL,于37℃、5%CO
2条件下培养过夜。第二天每孔加入10μL不同浓度的化合物。每个浓度设3复孔,最后一列为DMSO溶媒对照组,在37℃、5%CO
2条件下继续培养72小时。72小时后,每孔加入100μL检测试剂(Cell Viability Assay,Promega,G7573),混匀2分钟,室温孵育10分钟,Envision2104读板仪(PerkinElmer)测定荧光信号值。抑制率使用式(2)计算,其中RLU
compound为药物处理组的读数,RLU
control为溶剂对照组的平均值,RLU
blank为无细胞孔平均值。应用GraphPad Prism软件,计算IC
50值。
IR(%)=(1–(RLU
compound–RLU
blank)/(RLU
control–RLU
blank))*100% 式(2)
抑制Mino细胞增殖的IC
50值结果见表1.
表1抑制Mino细胞增殖的IC
50值
序号 | 化合物编号 | IC50(nM) |
1 | P13I* | 844 |
2 | 化合物65 | 14 |
3 | 化合物66 | 27 |
4 | 化合物70 | 101 |
5 | 化合物75 | 37 |
6 | 化合物76 | 141 |
7 | 化合物84 | 32 |
8 | 化合物85 | 32 |
9 | 化合物86 | 42 |
10 | 化合物95 | 100 |
11 | 化合物96 | 501 |
12 | 化合物98的三氟乙酸盐 | 20 |
13 | 化合物99的三氟乙酸盐 | 21 |
14 | 化合物100的三氟乙酸盐 | 123 |
15 | 化合物101的三氟乙酸盐 | 77 |
16 | 化合物102的三氟乙酸盐 | 42 |
17 | 化合物104 | 16 |
18 | 化合物105 | 208 |
19 | 化合物106 | 119 |
20 | 化合物107的三氟乙酸盐 | 34 |
21 | 化合物109的三氟乙酸盐 | 356 |
22 | 化合物110 | 35 |
23 | 化合物111 | 50 |
24 | 化合物112 | 39 |
26 | 化合物113 | 61 |
27 | 化合物114 | 66 |
28 | 化合物115 | 166 |
29 | 化合物116 | 29 |
30 | 化合物117 | 119 |
31 | 化合物118 | 52 |
*注:为其三氟乙酸盐。
抑制Mino细胞增殖的Max inhi.%值结果见表1-1。
表1-1抑制Mino细胞增殖的Max inhi.%值
序号 | 化合物编号 | Mino Max inhi.% |
1 | 化合物64 | 83.3 |
2 | 化合物68 | 94.2 |
3 | 化合物69 | 99.9 |
4 | 化合物71的三氟乙酸盐 | 95.2 |
5 | 化合物72 | 88.5 |
6 | 化合物73 | 99.8 |
7 | 化合物74 | 88.3 |
8 | 化合物80 | 99.1 |
9 | 化合物81 | 99.9 |
10 | 化合物82 | 99.9 |
11 | 化合物83 | 99.7 |
抑制SU-DHL-4细胞增殖的IC
50值结果见表1-2。
表1-2抑制SU-DHL-4细胞的IC
50值
序号 | 化合物编号 | IC 50(nM) |
1 | P13I* | 1184 |
2 | 化合物85 | 624 |
*注:为其三氟乙酸盐。
抑制SU-DHL-6细胞增殖的IC
50值结果见表1-3。
表1-3抑制SU-DHL-6细胞的IC
50值
序号 | 化合物编号 | IC 50(nM) |
1 | P13I* | 1638 |
2 | 化合物85 | 26 |
3 | 化合物98的三氟乙酸盐 | 12 |
4 | 化合物99的三氟乙酸盐 | 24 |
5 | 化合物100的三氟乙酸盐 | 99 |
6 | 化合物101的三氟乙酸盐 | 77 |
7 | 化合物102的三氟乙酸盐 | 23 |
4 | 化合物104 | 23 |
5 | 化合物105 | 331 |
6 | 化合物106 | 95 |
7 | 化合物107的三氟乙酸盐 | 22 |
8 | 化合物109的三氟乙酸盐 | 145 |
9 | 化合物110 | 31 |
10 | 化合物111 | 23 |
11 | 化合物112 | 36 |
12 | 化合物113 | 100 |
13 | 化合物114 | 24 |
14 | 化合物115 | 133 |
15 | 化合物116 | 52 |
16 | 化合物117 | 98 |
17 | 化合物118 | 50 |
*注:为其三氟乙酸盐。
结论:运用本发明技术所合成的化合物对SU-DHL-4细胞和SU-DHL-6细胞(人B淋巴瘤细胞)、Mino细胞(套细胞淋巴瘤细胞)、OCI-LY10细胞(弥漫大B细胞淋巴瘤细胞)及TMD-8细胞(人弥漫大B淋巴瘤细胞)增殖有显著的抑制作用,本发明实施例化合物63-70、72、75-79、84-86、95-96、98-102的三氟乙酸盐、104-106、107的三氟乙酸盐、109的三氟乙酸盐、110-118对Mino细胞(套细胞淋巴瘤细胞)的IC
50值为10~1000nM,化合物64、68、69、化合物71的三氟乙酸盐、72-74、80-83对Mino细胞最大抑制率大于80%,化合物85对DHL-4细胞(人B淋巴瘤细胞)的IC
50值为10~1000nM,化合物85、98-102的三氟乙酸盐、104-106、107的三氟乙酸盐、109的三氟乙酸盐、110-118对DHL-6细胞(人B淋巴瘤细胞)的IC
50值为10~1000nM。
2.大鼠药代动力学测试
实验目的:本试验通过单剂量静脉和灌胃给予受试物于SD大鼠,测定大鼠血浆中受试物的浓度,评价受试物在大鼠体内药代特征和生物利用度。
试验动物:雄性SD大鼠,200g左右,6~8周龄,6只/化合物。购于湖南斯莱克景达实验动物有限公司,实验动物生产许可证号SCXK(湘)2019-004。
试验方法:试验当天,6只SD大鼠按体重随机分组。给药前1天禁食不禁水12~14h,给药后4h给食。
*剂量以游离碱计。
取样
于给药前及给药后异氟烷麻醉经眼眶取血0.1mL,置于EDTAK2离心管中。5000rpm,4℃离心10min,收集血浆。
G1&G2组样品采集时间点:
G1:0,5min,15min,30min,1,2,4,6,8,24h;
G2:0,15min,30min,1,2,4,6,8,24h。
分析检测前,所有样品存于-80℃。用HPLC-MS/MS对样品进行检测。
表2化合物在大鼠血浆中药代动力学参数
*注:i.g.(灌胃)给予化合物。
N/A代表未测试。
结论:运用本发明技术所合成的化合物在大鼠体内具有一定的口服吸收性能。
3.Mino细胞中BTK降解检测
Mino人套细胞淋巴瘤细胞株,购自于ATCC,培养条件:RPMI-1640+15%FBS+1%双抗,培养于37℃,5%CO
2孵箱中。细胞铺板6孔板,5×10
5个/孔。铺板后,加入不同浓度化合物,37℃,5%CO
2孵箱中培养48小时。培养结束后,收集细胞,加入RIPA裂解液(beyotime,Cat.P0013B)于冰上裂解15分钟后,12000rpm,4℃离心10分钟,收集上清蛋白样品,用BCA试剂盒(Beyotime,Cat.P0009)进行蛋白定量后,将蛋白稀释为0.25mg/mL,使用全自动蛋白质印迹定量分析仪(Proteinsimple)运用试剂盒(Protein simple,Cat.SM-W004)检测BTK(CST,Cat.8547S)和内参β-actin(CST,Cat.3700S)的表达。使用compass软件计算BTK相对于内参的表达量并使用Origin9.2软件根据式(3)计算DC
50值。其中BTK
给药为不同剂量给药组BTK表达量,BTK
溶媒为溶媒对照组BTK表达量。
BTK%=BTK
给药/BTK
溶媒×100% 式(3)
表3 Mino细胞中BTK降解的DC
50值
序号 | 化合物编号 | DC 50(nM) |
1 | 化合物85 | 1.6 |
结论:运用本发明技术所合成的化合物对Mino细胞中的BTK有显著的降解作用。
4、小鼠脾脏BTK蛋白降解检测
雌性ICR小鼠,6-8周龄,购自于北京维通利华实验动物技术有限公司,适应3天后开始实验。连续3天灌胃给于不同剂量的化合物后,取小鼠脾脏,收集脾脏细胞,加入RIPA裂解液(beyotime,Cat.P0013B)于冰上裂解15分钟后,12000rpm,4℃离心10分钟,收集上清蛋白样品,用BCA试剂盒(Beyotime,Cat.P0009)进行蛋白定量后,将蛋白稀释为0.25mg/mL,使用全自动蛋白质印迹定量分析仪(Proteinsimple)检测BTK(CST,Cat.8547S)和内参β-actin(CST,Cat.3700S)的表达。使用compass软件计算BTK相对于内参的表达量并使用Origin9.2软件根据式(4)计算DD
50值。其中BTK
给药为不同剂量给药组BTK表达量,BTK
溶媒为溶媒对照组BTK表达量。
BTK%=BTK
给药/BTK
溶媒×100% 式(4)
表4化合物小鼠脾脏BTK蛋白降解的DD
50值
序号 | 化合物编号 | DD 50(mg/kg) |
1 | 化合物85 | 3.3 |
结论:运用本发明技术所合成的化合物对小鼠脾脏BTK蛋白有显著的降解作用。
5.Mino细胞中Aiolos降解检测
Mino是人套细胞淋巴瘤细胞株,购自于ATCC,培养条件:RPMI-1640+15%FBS+1%双抗,培养于37℃,5%CO
2孵箱中。细胞铺板6孔板,5×10
5个/孔。铺板后,加入不同浓度化合物,37℃,5%CO
2孵箱中培养48小时。培养结束后,收集细胞,加入RIPA裂解液(beyotime,Cat.P0013B)于冰上裂解15分钟后,12000rpm,4℃离心10分钟,收集上清蛋白样品,用BCA试剂盒(Beyotime,Cat.P0009)进行蛋白定量后,将蛋白稀释为0.25mg/mL,使用全自动蛋白质印迹定量分析仪(Proteinsimple)检测Aiolos(CST,Cat.15103S)和内参GAPDH(CST,Cat.5174S)的表达。使用compass软件计算Aiolos相对于内参的表达量并使用Origen9.2软件根据式(5)计算DC
50值。其中Aiolos
给药为不同剂量给药组Aiolos表达量,Aiolos
溶媒为溶媒对照组Aiolos表达量。
Aiolos%=Aiolos
给药/Aiolos
溶媒×100% (式5)
表5 Mino细胞中Aiolos降解的DC
50值
序号 | 化合物编号 | DC 50(nM) |
1 | 化合物85 | ≥1000 |
结论:运用本发明技术所合成的化合物对Mino细胞中的Aiolos没有明显的降解作用。
6、本发明化合物对hERG钾离子通道作用实验方法及实验结果
实验平台:电生理手动膜片钳系统
细胞系:稳定表达hERG钾离子通道的中国仓鼠卵巢(CHO)细胞
实验方法:稳定表达hERG钾通道的CHO(Chinese Hamster Ovary)细胞,在室温下用全细胞膜片钳技术记录hERG钾通道电流。玻璃微电极由玻璃电极毛胚(BF150-86-10,Sutter)经拉制仪拉制而成,灌注电极内液后的尖端电阻为2-5MΩ左右,将玻璃微电极插入放大器探头即可连接至膜片钳放大器。钳制电压和数据记录由pClamp 10软件通过电脑控制和记录,采样频率为10kHz,滤波频率为2kHz。在得到全细胞记录后,细胞钳制在-80mV,诱发hERG钾电流(I
hERG)的步阶电压从-80mV给予一个2s的去极化电压到+20mV,再复极化到-50mV,持续1s后回到-80mV。每10s给予此电压刺激,确定hERG钾电流稳定后(至少1分钟)开始给药过程。化合物每个测试浓度至少给予1分钟,每个浓度至少测试2个细胞(n≥2)。
数据处理:
数据分析处理采用pClamp 10,GraphPad Prism 5和Excel软件。不同化合物浓度对hERG钾电流(-50mV时诱发的hERG尾电流峰值)的抑制程度用以下公式计算:
Inhibition%=[1–(I/I
o)]×100%
其中,Inhibition%代表化合物对hERG钾电流的抑制百分率,I和I
o分别表示在加药后和加药前hERG钾电流的幅度。
化合物IC
50使用GraphPad Prism 5软件通过以下方程拟合计算得出:
Y=Bottom+(Top-Bottom)/(1+10^((LogIC
50-X)*HillSlope))
其中,X为供试品检测浓度的Log值,Y为对应浓度下抑制百分率,Bottom和Top分别为最小和最大抑制百分率。
本发明的化合物对hERG钾通道电流抑制作用的IC
50值见表6。
表6对hERG钾通道电流抑制作用的IC
50值
序号 | 化合物编号 | IC 50(μM) |
1 | 化合物113 | >40 |
2 | 化合物115 | >40 |
结论:运用本发明技术所合成的化合物对hERG钾通道电流没有明显的抑制作用。
Claims (26)
- 一种通式(I)所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中B-L-K (I);L选自-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-或键;Ak1、Ak2、Ak3、Ak4和Ak5各自独立的选自CH 2、O或者键;Cy1、Cy2、Cy3和Cy4各自独立的选自3至12元杂环、3至12元环烷基、6至10元芳基或键,所述杂环、环烷基或芳基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH 2、oxo、CF 3、COOH、CN、C 1-4烷基、羟基取代的C 1-4烷基、卤素取代的C 1-4烷基或C 1-4烷氧基的取代基所取代,所述的杂环含有1至4个选自O、S、N的杂原子;Cy1、Cy2、Cy3和Cy4不能同时为键;Ak1、Ak2、Ak3、Ak4或Ak5为O时,不能直接与B连接;Ak1、Ak2、Ak3、Ak4或Ak5不为键时,互相不能直接连接;当Ak1、Cy1、Ak2、Cy2、Ak3、Cy3、Ak4、Cy4、Ak5有4个及以上不为键时,Cy1、Cy2、Cy3和Cy4中至少有一个不为哌啶、哌嗪、嘧啶或吡啶;B选自B1-W1-B2-B3-B4-;B1选自6元杂芳环或苯基,所述的杂芳环或苯基进一步任选被0至4个R b1所取代,所述的杂芳环含有1至4个选自O、S、N的杂原子;W1选自-O-、-S-、-NH-、-NHCO-或-CONH-;B2选自6元杂芳环或苯基,所述的杂芳环或苯基任选进一步任选被0至4个R b2所取代,所述的杂芳环含有1至4个选自O、S、N的杂原子;B3选自8-10元杂并环,所述的杂并环任选进一步任选被0至4个R b3所取代,所述的杂并环含有1至4个选自O、S、N的杂原子;B4选自4-10元饱和杂环,所述的饱和杂环选自单环、并环或螺环,所述的饱和杂环、单环、并环或螺环任选进一步任选被0至4个R b4所取代,所述的饱和杂环含有1至2个选自O、S、N的杂原子;R b1、R b2、R b3或R b4各自独立的选自H、F、Cl、Br、I、OH、NH 2、CN、CF 3、COOH、CONH 2、C 1-4烷基、羟基取代的C 1-4烷基、卤素取代的C 1-4烷基或C 1-4烷氧基,所述的烷基和烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH 2、CN、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代;环E选自苯环或者5-6元的杂芳环,所述的杂芳环含有1至2个选自O、S、N的杂原子;R k2各自独立的选自CH 2、C=O、S=O、SO 2;R k1、R k3或R k4各自独立的选自H、F、Cl、Br、I、OH、NH 2、CF 3、CN、COOH、C 1-4烷基或C 1-4烷氧基;n1、n2、n3、n4各自独立的选自0、1、2、3或4;化合物不为表A所示的化合物。
- 根据权利要求1所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中Cy1、Cy2、Cy3和Cy4各自独立的选自键、4-7元杂单环、5-10元杂并环、6-12元杂螺环、7-10元杂桥环、4-7元单环烷基、5-10元并环烷基、6-12元螺环烷基、7-10元桥环烷基或6-10元芳基,所述芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH 2、oxo、CF 3、COOH、CN、C 1-4烷基、羟基取代的C 1-4烷基、卤素取代的C 1-4烷基或C 1-4烷氧基的取代基所取代,所述的杂单环、杂并环、杂螺环或杂桥环含有1至4个选自O、S、N的杂原子;B1选自苯基或吡啶基,所述的苯基或吡啶基进一步任选被0至4个R b1所取代;W1选自-O-、-NHCO-或-CONH-;B2选自苯基或吡啶基,所述的苯基或吡啶基进一步任选被0至4个R b2所取代;B3选自取代或未取代的如下基团之一:咪唑并嘧啶、吡唑并嘧啶、咪唑并吡嗪、吡唑并吡嗪、咪唑并四氢嘧啶、吡唑并四氢嘧啶,当被取代时,任选进一步任选被0至4个R b3所取代;B4选自取代或未取代的如下基团之一:氮杂环丁基、氮杂环戊基、哌啶、吗啉、哌嗪、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环已基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊基并哌啶、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环已基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环已基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环已基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、环丁基螺哌啶、环戊基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、 当被取代时,任选进一步任选被0至4个R b4所取代;环E选自苯环、吡啶、噻吩、呋喃、吡咯、噻唑、恶唑、咪唑或吡唑。
- 根据权利要求3所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中Cy1、Cy2、Cy3和Cy4各自独立的选自键或者取代的或者未取代的如下基团之一: 苯基、萘基、环丁基、环戊基、环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、氮杂环丁基、氮杂环戊基、哌啶、吗啉、哌嗪、吡咯、吡唑、咪唑、噻唑、吡啶、哒嗪、嘧啶、吡嗪、三氮唑、四氮唑、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环已基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊基并哌啶、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环已基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环已基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环已基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、环已基螺氮杂环已基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、氮杂环已基螺氮杂环已基、环丁基螺哌啶、环戊基螺哌啶、环己基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、氮杂环己基螺哌啶、 当被取代时,任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH 2、oxo、CF 3、COOH、CN、C 1-4烷基、羟基取代的C 1-4烷基、卤素取代的C 1-4烷基或C 1-4烷氧基的取代基所取代;R b1、R b2、R b3或R b4各自独立的选自H、F、Cl、Br、I、OH、NH 2、CN、CONH 2、CF 3、COOH、羟甲基、甲基或甲氧基,所述的甲基或甲氧基任选进一步被0至4选自H、F、Cl、Br、I的取代基所取代;n1、n2、n3、n4、n5、n6、n7、n8、n9、n10、n11、n12各自独立的选自0、1、2、3或4;R k2各自独立的选自CH 2或C=O;R k1、R k3或R k4各自独立的选自H、F、Cl、Br、I、OH或NH 2;p1或p2各自独立的选自0、1或2。
- 根据权利要求3所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中,所述的化合物如通式(Ia)所示,B4选自取代的或者未取代的如下基团之一:氮杂环丁基、氮杂环戊基、吗啉、哌嗪、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环已基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊基并哌啶、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环已基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环已基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环已基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、环丁基螺哌啶、环戊基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、 当被取代时,任选进一步任选被0至4个R b4所取代;R b1、R b2、R b3或R b4各自独立的选自H、F、Cl、Br、I、OH、NH 2、CN、CF 3、COOH、CONH 2、C 1-4烷基、羟基取代的C 1-4烷基、卤素取代的C 1-4烷基或C 1-4烷氧基,所述的烷基和烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH 2、CN、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代;L和K的定义与权利要求3一致;n1、n2、n3各自独立的选自0、1、2、3或4。
- 根据权利要求3所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中,所述的化合物如通式(Ib)所示,Cy1、Cy2、Cy3和Cy4各自独立的选自键或者取代的或者未取代的如下基团之一:苯基、萘基、环丁基、环戊基、环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、氮杂环丁基、氮杂环戊基、哌啶、吗啉、哌嗪、吡咯、吡唑、咪唑、噻唑、吡啶、哒嗪、嘧啶、吡嗪、三氮唑、四氮唑、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环已基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊基并哌啶、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环已基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环已基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环已基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、环已基螺氮杂环已基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、氮杂环已基螺氮杂环已基、环丁基螺哌啶、环戊基螺哌啶、环己基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、氮杂环己基螺哌啶、 当被取代时,任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH 2、oxo、CF 3、COOH、CN、C 1-4烷基、羟基取代的C 1-4烷基、卤素取代的C 1-4烷基或C 1-4烷氧基的取代基所取代;条件是Cy1、Cy2、Cy3和Cy4中至少有一个被1至4个选自CF 3、COOH、CN、羟基取代的C 1-4烷基的取代基所取代;R b1、R b2、R b3或R b4各自独立的选自H、F、Cl、Br、I、OH、NH 2、CN、CF 3、COOH、CONH 2、C 1-4烷基、羟基取代的C 1-4烷基、卤素取代的C 1-4烷基或C 1-4烷氧基,所述的烷基和烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH 2、CN、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代;L和K的定义与权利要求3一致;n1、n2、n3、n4各自独立的选自0、1、2、3或4。
- 根据权利要求1所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中,所述的化合物如通式(Ic)所示,L和K的定义与权利要求7一致;R b4各自独立的选自H、F、Cl、Br、I、OH、NH 2、CN、CF 3、CONH 2、COOH、C 1-4烷基、羟基取代的C 1-4烷基、卤素取代的C 1-4烷基或C 1-4烷氧基,所述的烷基和烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH 2、CN、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代。
- 一种通式(II)所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、 药学上可接受的盐或共晶,其中Cy5选自取代的或者未取代的如下基团之一:苯基、萘基、环丁基、环戊基、环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、氮杂环丁基、氮杂环戊基、哌啶、吗啉、哌嗪、吡咯、吡唑、咪唑、噻唑、吡啶、哒嗪、嘧啶、吡嗪、三氮唑、四氮唑、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环已基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊基并哌啶、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环已基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环已基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环已基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、环已基螺氮杂环已基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、氮杂环已基螺氮杂环已基、环丁基螺哌啶、环戊基螺哌啶、环己基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、氮杂环己基螺哌啶、 当被取代时,任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH 2、oxo、CF 3、COOH、CN、C 1-4烷基、羟基取代的C 1-4烷基、卤素取代的C 1-4烷基或C 1-4烷氧基的取代基所取代;K的定义与权利要求2一致。
- 根据权利要求1至20任意一项所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中所述的盐选自三氟乙酸盐。
- 一种药物组合物,包括权利要求1-21任意一项所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,以及要学上可接受的载体。
- 权利要求1-21任意一项所述的化合物或者其立体异构体、溶剂化物、前药、代 谢产物、药学上可接受的盐或共晶在用于制备治疗与BTK活性或表达量相关疾病的药物中的应用。
- 权利要求1-21任意一项所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与抑制或降解BTK相关疾病的药物中的应用。
- 根据权利要求23-24任意一项所述的应用,其特征在于,所述的疾病选自肿瘤或自身免疫疾病。
- 根据权利要求25所述的应用,其特征在于,所述的肿瘤选自非霍奇金淋巴瘤、慢性淋巴细胞性白血病、套细胞淋巴瘤、B细胞淋巴瘤,自身免疫疾病选自内风湿关节炎或银屑病。
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CN114560757A (zh) * | 2022-03-04 | 2022-05-31 | 上海凌凯医药科技有限公司 | 一种二芳基醚化合物的制备方法 |
CN114560757B (zh) * | 2022-03-04 | 2023-09-26 | 上海凌凯医药科技有限公司 | 一种二芳基醚化合物的制备方法 |
WO2023184898A1 (zh) * | 2022-04-02 | 2023-10-05 | 水木未来(北京)科技有限公司 | 一种同时调节btk和ikzf3的双功能化合物 |
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TW202216715A (zh) | 2022-05-01 |
CN116134028A (zh) | 2023-05-16 |
EP4180432A1 (en) | 2023-05-17 |
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