WO2021254493A1 - 一种具有抗肿瘤活性的并环类化合物及其用途 - Google Patents
一种具有抗肿瘤活性的并环类化合物及其用途 Download PDFInfo
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- WO2021254493A1 WO2021254493A1 PCT/CN2021/100967 CN2021100967W WO2021254493A1 WO 2021254493 A1 WO2021254493 A1 WO 2021254493A1 CN 2021100967 W CN2021100967 W CN 2021100967W WO 2021254493 A1 WO2021254493 A1 WO 2021254493A1
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- amino
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- 0 CCCC*C[C@](CCC)[C@](C)(CC)CC(C)(C)C1[C@]2[C@@]1CCCC2 Chemical compound CCCC*C[C@](CCC)[C@](C)(CC)CC(C)(C)C1[C@]2[C@@]1CCCC2 0.000 description 35
- BWZXSKCCTBMXOB-NRFANRHFSA-N CC(N(CC1)CCC1Nc(nc(C)nc12)c1[nH]nc2NC[C@@H](CN(CC1)Cc2c1cccc2)O)=O Chemical compound CC(N(CC1)CCC1Nc(nc(C)nc12)c1[nH]nc2NC[C@@H](CN(CC1)Cc2c1cccc2)O)=O BWZXSKCCTBMXOB-NRFANRHFSA-N 0.000 description 2
- BYWDGTKESWRSML-UHFFFAOYSA-N NCC(CN(CC1)Cc2c1cccc2)O Chemical compound NCC(CN(CC1)Cc2c1cccc2)O BYWDGTKESWRSML-UHFFFAOYSA-N 0.000 description 2
- BYWDGTKESWRSML-LBPRGKRZSA-N NC[C@@H](CN(CC1)Cc2c1cccc2)O Chemical compound NC[C@@H](CN(CC1)Cc2c1cccc2)O BYWDGTKESWRSML-LBPRGKRZSA-N 0.000 description 2
- BYWDGTKESWRSML-GFCCVEGCSA-N NC[C@H](CN(CC1)Cc2c1cccc2)O Chemical compound NC[C@H](CN(CC1)Cc2c1cccc2)O BYWDGTKESWRSML-GFCCVEGCSA-N 0.000 description 2
- JLIJFJUDUPDCOP-MRXNPFEDSA-N O[C@H](CNc1n[nH]c2c1ncnc2NC1COC1)CN(CC1)Cc2c1cccc2 Chemical compound O[C@H](CNc1n[nH]c2c1ncnc2NC1COC1)CN(CC1)Cc2c1cccc2 JLIJFJUDUPDCOP-MRXNPFEDSA-N 0.000 description 2
- OBDIDGKANKNXDV-UHFFFAOYSA-N C(C1OC1)N(CC1)Cc2c1cccc2 Chemical compound C(C1OC1)N(CC1)Cc2c1cccc2 OBDIDGKANKNXDV-UHFFFAOYSA-N 0.000 description 1
- KEHJHUYPQDSGAY-UHFFFAOYSA-N C/C(/N(CC1)CCC1Nc1ncnc2c1[n](C)nc2NCC(CN(CC1)Cc2c1cccc2)O)=[O]\C Chemical compound C/C(/N(CC1)CCC1Nc1ncnc2c1[n](C)nc2NCC(CN(CC1)Cc2c1cccc2)O)=[O]\C KEHJHUYPQDSGAY-UHFFFAOYSA-N 0.000 description 1
- FKWCOLABSDFLKU-WQLSENKSSA-N C1O/C1=C\N(CC1)Cc2c1cccc2 Chemical compound C1O/C1=C\N(CC1)Cc2c1cccc2 FKWCOLABSDFLKU-WQLSENKSSA-N 0.000 description 1
- UWYZHKAOTLEWKK-UHFFFAOYSA-N C1c2ccccc2CNC1 Chemical compound C1c2ccccc2CNC1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 1
- NNFOVLFUGLWWCL-UHFFFAOYSA-N CC(N(CC1)CCC1=O)=O Chemical compound CC(N(CC1)CCC1=O)=O NNFOVLFUGLWWCL-UHFFFAOYSA-N 0.000 description 1
- NLHBHVGPMMXWIM-UHFFFAOYSA-N CC(N(CC1)CCC1N)=O Chemical compound CC(N(CC1)CCC1N)=O NLHBHVGPMMXWIM-UHFFFAOYSA-N 0.000 description 1
- ZHWNUWHHZWNSBM-NDEPHWFRSA-N CC(N(CC1)CCC1Nc(cc(cc12)-c3ccccc3)c1[nH]nc2NC[C@@H](CN(CC1)Cc2c1cccc2)O)=O Chemical compound CC(N(CC1)CCC1Nc(cc(cc12)-c3ccccc3)c1[nH]nc2NC[C@@H](CN(CC1)Cc2c1cccc2)O)=O ZHWNUWHHZWNSBM-NDEPHWFRSA-N 0.000 description 1
- NRIFNUKQXYRAHN-IBGZPJMESA-N CC(N(CC1)CCC1Nc(nc(C(F)(F)F)nc12)c1[nH]nc2NC[C@@H](CN(CC1)Cc(cc2)c1cc2F)O)=O Chemical compound CC(N(CC1)CCC1Nc(nc(C(F)(F)F)nc12)c1[nH]nc2NC[C@@H](CN(CC1)Cc(cc2)c1cc2F)O)=O NRIFNUKQXYRAHN-IBGZPJMESA-N 0.000 description 1
- ZFXXHWZZOFLNGE-KRWDZBQOSA-N CC(N(CC1)CCC1Nc(nc(C(F)(F)F)nc12)c1[nH]nc2NC[C@@H](CN(CC1)Cc2c1c(cccc1)c1[nH]2)O)=O Chemical compound CC(N(CC1)CCC1Nc(nc(C(F)(F)F)nc12)c1[nH]nc2NC[C@@H](CN(CC1)Cc2c1c(cccc1)c1[nH]2)O)=O ZFXXHWZZOFLNGE-KRWDZBQOSA-N 0.000 description 1
- CCTDDBVVUQCIPP-FQEVSTJZSA-N CC(N(CC1)CCC1Nc(nc12)ncc1[nH]nc2NC[C@@H](CN(CC1)Cc2c1cccc2)O)=O Chemical compound CC(N(CC1)CCC1Nc(nc12)ncc1[nH]nc2NC[C@@H](CN(CC1)Cc2c1cccc2)O)=O CCTDDBVVUQCIPP-FQEVSTJZSA-N 0.000 description 1
- XFIWDZAALUISGS-IBGZPJMESA-N CC(N(CC1)CCC1Nc1nc(C(F)(F)F)nc2c1[nH]nc2NC[C@@H](CN(CC1)Cc2c1cccc2)O)=O Chemical compound CC(N(CC1)CCC1Nc1nc(C(F)(F)F)nc2c1[nH]nc2NC[C@@H](CN(CC1)Cc2c1cccc2)O)=O XFIWDZAALUISGS-IBGZPJMESA-N 0.000 description 1
- VHONGVDISBFSTE-HXUWFJFHSA-N CC(N(CC1)CCC1Nc1ncc(c(NC[C@H](CN(CC2)Cc3c2cccc3)O)n[nH]2)c2n1)=O Chemical compound CC(N(CC1)CCC1Nc1ncc(c(NC[C@H](CN(CC2)Cc3c2cccc3)O)n[nH]2)c2n1)=O VHONGVDISBFSTE-HXUWFJFHSA-N 0.000 description 1
- JNPFKKDFWOAKAA-UHFFFAOYSA-N CC(N(CC1)CCC1Nc1ncnc2c1[n](C)nc2I)=O Chemical compound CC(N(CC1)CCC1Nc1ncnc2c1[n](C)nc2I)=O JNPFKKDFWOAKAA-UHFFFAOYSA-N 0.000 description 1
- UWOMLUIOZZSCPN-UHFFFAOYSA-N CC(N1CC(CN)CCC1)=O Chemical compound CC(N1CC(CN)CCC1)=O UWOMLUIOZZSCPN-UHFFFAOYSA-N 0.000 description 1
- PRWRTUFQDOKEKT-CQSZACIVSA-N CC(SC[C@@H](CN(CC1)Cc2c1cccc2)O)=O Chemical compound CC(SC[C@@H](CN(CC1)Cc2c1cccc2)O)=O PRWRTUFQDOKEKT-CQSZACIVSA-N 0.000 description 1
- QOLRTLYESQWHKE-UHFFFAOYSA-N CCCNC(C)N(NC)[N]1(C(C)C)NC1 Chemical compound CCCNC(C)N(NC)[N]1(C(C)C)NC1 QOLRTLYESQWHKE-UHFFFAOYSA-N 0.000 description 1
- NDYWONMXYXWAMH-UHFFFAOYSA-N C[n](c1c(NC2COC2)ncnc11)nc1I Chemical compound C[n](c1c(NC2COC2)ncnc11)nc1I NDYWONMXYXWAMH-UHFFFAOYSA-N 0.000 description 1
- FFGSHRAEJQRETG-UHFFFAOYSA-N Cc(nc12)nc(O)c1[nH]nc2I Chemical compound Cc(nc12)nc(O)c1[nH]nc2I FFGSHRAEJQRETG-UHFFFAOYSA-N 0.000 description 1
- OOCSKEXXKUMJCX-UHFFFAOYSA-N Cc1n[nH]c2c1ncc(C)n2 Chemical compound Cc1n[nH]c2c1ncc(C)n2 OOCSKEXXKUMJCX-UHFFFAOYSA-N 0.000 description 1
- KJGPQVNCQAEOSM-UHFFFAOYSA-N Cc1nc(O)c2[nH]ncc2n1 Chemical compound Cc1nc(O)c2[nH]ncc2n1 KJGPQVNCQAEOSM-UHFFFAOYSA-N 0.000 description 1
- RWUJQGGETPUNFP-UHFFFAOYSA-N Cc1ncnc2c1ccnc2C Chemical compound Cc1ncnc2c1ccnc2C RWUJQGGETPUNFP-UHFFFAOYSA-N 0.000 description 1
- DQNDDUOCVSWTOW-UHFFFAOYSA-N Cc1ncncc1N Chemical compound Cc1ncncc1N DQNDDUOCVSWTOW-UHFFFAOYSA-N 0.000 description 1
- XNFHPIJXLWEVLH-JTQLQIEISA-N NC[C@@H](CN(CC1)Cc2c1c1ccccc1[nH]2)O Chemical compound NC[C@@H](CN(CC1)Cc2c1c1ccccc1[nH]2)O XNFHPIJXLWEVLH-JTQLQIEISA-N 0.000 description 1
- MLIALYPHULZCOY-IBGZPJMESA-N Nc1cccc2c1[o]nc2NCS[C@@H](CCCN(CC1)Cc2c1cccc2)O Chemical compound Nc1cccc2c1[o]nc2NCS[C@@H](CCCN(CC1)Cc2c1cccc2)O MLIALYPHULZCOY-IBGZPJMESA-N 0.000 description 1
- JLIJFJUDUPDCOP-UHFFFAOYSA-N OC(CNc1n[nH]c2c1ncnc2NC1COC1)CN(CC1)Cc2c1cccc2 Chemical compound OC(CNc1n[nH]c2c1ncnc2NC1COC1)CN(CC1)Cc2c1cccc2 JLIJFJUDUPDCOP-UHFFFAOYSA-N 0.000 description 1
- LBJZKDNEYKDXMG-INIZCTEOSA-N O[C@@H](CNc1n[nH]c2c1ncnc2Nc1cnccn1)CN1CC(C=CCC2)=C2CC1 Chemical compound O[C@@H](CNc1n[nH]c2c1ncnc2Nc1cnccn1)CN1CC(C=CCC2)=C2CC1 LBJZKDNEYKDXMG-INIZCTEOSA-N 0.000 description 1
- MKHMBZSAGIAGRG-ZDUSSCGKSA-N O[C@@H](CNc1n[nH]c2c1ncnc2O)CN(CC1)Cc2c1cccc2 Chemical compound O[C@@H](CNc1n[nH]c2c1ncnc2O)CN(CC1)Cc2c1cccc2 MKHMBZSAGIAGRG-ZDUSSCGKSA-N 0.000 description 1
- SALRVBZVLBVPBW-OAHLLOKOSA-N O[C@H](CNc1nccc2c1ncnc2O)CN(CC1)Cc2c1cccc2 Chemical compound O[C@H](CNc1nccc2c1ncnc2O)CN(CC1)Cc2c1cccc2 SALRVBZVLBVPBW-OAHLLOKOSA-N 0.000 description 1
- GMCYWTLYEGOCBF-GOSISDBHSA-N O[C@H](CNc1ncnc2c1ccnc2NC1COC1)CN(CC1)Cc2c1cccc2 Chemical compound O[C@H](CNc1ncnc2c1ccnc2NC1COC1)CN(CC1)Cc2c1cccc2 GMCYWTLYEGOCBF-GOSISDBHSA-N 0.000 description 1
- ISUILBBWIFGVFS-UHFFFAOYSA-N Oc1ncnc2c1[nH]nc2I Chemical compound Oc1ncnc2c1[nH]nc2I ISUILBBWIFGVFS-UHFFFAOYSA-N 0.000 description 1
- BUERZTTWXDSSIY-UHFFFAOYSA-N Oc1ncnc2c1ccnc2Cl Chemical compound Oc1ncnc2c1ccnc2Cl BUERZTTWXDSSIY-UHFFFAOYSA-N 0.000 description 1
- AIHIHVZYAAMDPM-MRVPVSSYSA-N [O-][N+](c1cc(S(OC[C@@H]2OC2)(=O)=O)ccc1)=O Chemical compound [O-][N+](c1cc(S(OC[C@@H]2OC2)(=O)=O)ccc1)=O AIHIHVZYAAMDPM-MRVPVSSYSA-N 0.000 description 1
- APXRHPDHORGIEB-UHFFFAOYSA-N c1n[nH]c2cncnc12 Chemical compound c1n[nH]c2cncnc12 APXRHPDHORGIEB-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to the field of medical technology, in particular, to a compound as a PRMT5 inhibitor and a preparation method and application of the compound.
- PRMT5 is a type of protein arginine methyltransferase, an abbreviation of the English name Protein arginine N-methyltransferase 5, and is a new anti-tumor target related to epigenetic modification. It has several aliases, namely Hsl7, Jbp1, Skb1, Capsuleen, or Dart5. PRMT5 is the main enzyme for arginine monomethylation and symmetric dimethylation. More and more documents prove that protein arginine methyltransferases (PRMTs) play a key role in different biological processes, such as cell growth and proliferation, apoptosis, and metastasis.
- PRMTs protein arginine methyltransferases
- PRMTs protein arginine methyltransferases
- PRMTs can be divided into three types: Type I PRMTs include PRMT1, PRMI2, PRMT3, PRMT4, PRMT6 and PRM8 catalyze monomethylarginine (MMA) and asymmetric dimethylarginine (aDMA); type II PRMTs including PRMT5 and PRMT9 catalyze MMA and symmetric dimethylarginine (sDMA); type III PRMTs PRMT7 can only be monomethylated.
- PRMT5 can symmetrically methylate the arginine residues of histones or non-histone substrates, affecting multiple target genes and multiple signaling pathways, and is involved in protein methylation.
- JNJ-64619178 is a selective PRMT5 inhibitor developed by Johnson & Johnson, which can inhibit the growth of a variety of tumor cells in vitro.
- Johnson & Johnson chose a large number of xenograft animal models to prove its effective anti-tumor effects, such as small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), acute myeloid leukemia (AML), and non-small cell lung cancer (NSCLC).
- SCLC small cell lung cancer
- NSCLC non-small cell lung cancer
- AML acute myeloid leukemia
- NSCLC non-small cell lung cancer
- the Xenograft model of non-Hodgkin lymphoma was used for anti-tumor experiments. Significant tumor growth inhibition of up to 99% was observed in the model, and tumor growth continued to be inhibited within a few weeks after stopping the drug.
- JNJ-64619178 can inhibit the Sym-Arg dimethylation of SMD1/3 protein, the core component of tumor spliceosome, and inhibit the Sym-Arg dimethylation of serum protein. These can be used as pharmacodynamic markers for PRMT5 to inhibit tumor growth in the Xenograft model.
- PRMT5 can be used as pharmacodynamic markers for PRMT5 to inhibit tumor growth in the Xenograft model.
- SCLC model the effective and long-term inhibitory effect of PRMT5 on SMD1/3 dimethylation was observed during and after the administration. Based on these high selectivity and efficiency, good pharmacokinetics and safety, and obvious preclinical efficacy and pharmacodynamic results, JNJ-64619178 began a phase one clinical trial in 2018.
- GSK-3326595 is optimized from EPZ015666 (structure as follows). It is a highly selective, oral small molecule and the first generation PRMT5 inhibitor. EPZ015666 shows significant in vivo and in vitro activities in mantle cell lymphoma.
- GlaxoSmithKline (GSK) announced in September 2016 that GSK-3326595 was the first to enter the clinic for the first time through two years of optimization and preclinical research.
- GlaxoSmithKline announced the Phase I clinical data of GSK-3326595.
- the Phase I clinical selection of GSK-3326595 is for adult patients with solid tumors. The main purpose is to conduct safety, tolerability and PK/PD tests, and to collect efficacy data (ORR and DCR). The data show that GSK3326595PK is dose-dependent in plasma.
- the present invention designs a series of compounds with a new structure represented by the general formula, and finds that compounds with such a structure exhibit excellent effects and effects, which are of positive significance for the development of PRMT5 inhibitors.
- the purpose of the present invention is to provide a compound with a novel structure as a PRMT5 inhibitor, a preparation method of the compound, and its use in treating diseases mediated by a PRMT5 inhibitor.
- the first aspect of the present invention provides a compound represented by the following formula (I), and its stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, and solvents Compound or isotope-labeled analogue.
- Z can be independently selected from C or N;
- Z 2 can be independently selected from CH, C(R 2 ), N, O, S or N(R 1 ); wherein, R 1 can be selected from hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl ; Wherein, each C 1-6 alkyl group and C 3-6 cycloalkyl group may be optionally substituted by halogen, cyano, optionally substituted R 1a , optionally substituted -OR 1a , optionally substituted -SR 1a , Optionally substituted -N(R 1a )R 1a , optionally substituted -NHR 1a , optionally substituted 5-6 membered heteroaryl or optionally substituted phenyl substitution; wherein each occurrence of R 1a is independent Is selected from one of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic group; the optional substitution means that the H on the substituted group is unsubstituted or One or more substitutable positions of the substituted group
- p can be selected from 0 or 1;
- the ring represented is a five-membered ring;
- Z 3 and Z 5 can be independently selected from N, S, O, CH(R 2 ), C(R 2 ), N(R 1 );
- the ring represented is a six-membered ring;
- Z 3 , Z 4 , Z 5 can be independently selected from N, S, O, N(R 1 ), CH(R 2 ), C(R 2 );
- X is selected from -O-, -S-, -CO-, -N(R 5 )-, -S(O)N(R 5 )-, -S(O) 2 N(R 5 )-, -N (R 5 )SO-, -N(R 5 )S(O) 2 -, -C(O)N(R 5 )-, -N(R 5 )C(O)-, -N(R 5 ) One of C(O)N(R 5 )-, -CH(R 5 )-; wherein each occurrence of R 5 is independently selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted One of the C 3-6 cycloalkyl group and the optionally substituted 4-6 membered heterocyclic group; the optional substitution refers to one of the H on the substituted group or the substituted group Multiple substitutable sites are independently selected from halogen, hydroxyl, mercapto, amino, cyano, C 1-6
- Y is selected from bond, -H, -OH, -NH 2 , halogen, -O-, -S-, -CO-, -C(R 6 )F-, -CF 2 -, -SO-, -SO 2 -, -N(R 6 )-, -S(O)N(R 6 )-, -S(O) 2 N(R 6 )-, -N(R 6 )SO-, -N(R 6 ) One of S(O) 2 -, -C(O)N(R 6 )-, -N(R 6 )C(O)-, -CH(R 6 )-; wherein R 6 can be selected from hydrogen One of an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, and an optionally substituted 4-6 membered heterocyclic group; the optional substitution refers to a substituted group The H on the group is unsubstitute
- G 1 and G 3 can be selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 4 One of the -6-membered heterocyclic groups; or G 1 and G 3 are connected to form an optionally substituted C 3-8 carbocyclic structure; the optional substitution means that the H on the substituted group is not One or more substitutable positions of the substituted or substituted group are independently selected from halogen, hydroxyl, mercapto, amino, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl substituted;
- G 2 is selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, optionally substituted R 7 , optionally substituted O (R 7 ), S (R 7 ), optionally substituted NH (R 7 ), One of the optionally substituted N(R 7 )(R 7 ); wherein R 7 is selected from one of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic group Species; the optional substitution means that the H on the substituted group is unsubstituted or one or more substitutable positions of the substituted group are independently selected from halogen, hydroxyl, mercapto, amino, cyano, C Substituted by 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl;
- G 4 is selected from the following groups: optionally substituted C 1-12 alkyl, optionally substituted C 2-12 alkenyl, optionally substituted C 2-12 alkynyl, optionally substituted C 3-6 ring One of an alkyl group, an optionally substituted 4-6 membered heterocyclic group, an optionally substituted C 6-10 aryl group, and an optionally substituted 5-10 membered heteroaryl group; the optional substitution means
- the H on the substituent group is unsubstituted or one or more substitutable positions of the substituted group are independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, -R 3 , -OR 3 ,- NH-R 3 , -N(R 3 )R 3 , Where each occurrence of R 3 is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycle One or more
- B can be selected from -N- or -CH-;
- R 10 is selected from hydrogen, hydroxyl, halogen, C 1-6 alkyl, C 3- One of 6 cycloalkyl and 4-6 membered heterocyclic group;
- At least one of A, B, and C is a substituted N atom that meets their respective definitions
- H ring is selected from one of C 6-10 aryl ring and 5-10 membered heteroaryl ring; the aryl ring or heteroaryl ring can be independently substituted by one or more of the following substituents: hydrogen, halogen , Hydroxyl, mercapto, amino, cyano, optionally substituted -R 4 , optionally substituted -OR 4 , optionally substituted -NH-R 4 , optionally substituted -N(R 4 )R 4 ; wherein , Each occurrence of R 4 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5- 6-membered heteroaryl; the optional substitution means that the hydrogen on the substituted group is unsubstituted or one or more substitutable positions of the substituted group are independently selected from halogen, hydroxyl, mercapto, amino, Substituted by
- the connecting bond between two atoms is a double bond or a single bond, which makes the structure of the merged ring appear aromatic as a whole.
- the connecting bond between two atoms is a double bond or a single bond, so that the ring where Z 2 is located in the fused ring structure is an aromatic ring, and the ring where Z 5 is located is a non-aromatic ring.
- the connecting bond between two atoms is a double bond or a single bond, so that the ring where Z 2 is located in the fused ring structure is a non-aromatic ring, and the ring where Z 5 is located is an aromatic ring.
- the connecting bond between two atoms is a double bond or a single bond, so that the ring where Z 2 is located and the ring where Z 5 is located in the merged ring structure are both non-aromatic rings.
- X is selected from -O-, -S-, -CO-, -NH-, -SONH-, -S(O) 2 NH-, -NHSO-, -NHS(O) 2 -, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -CH 2 -one of them; for example, -O-, -S-, -CO-,- NH-, -SONH-, -S(O) 2 NH-, -NHSO-, -NHS(O) 2 -, -C(O)NH-, -NHC(O)-, -NHC(O)NH- One of them; another example is -O-, -S-, -CO-, -NH-, -S(O) 2 NH-, -NHS(O) 2 -, -C(O)NH-,- One of NHC(O)
- Y is selected from bond, -H, -OH, -NH 2 , halogen, -O-, -S- , -CO-, -CHF-, -CF 2 -, -SO- , -SO 2 -, -NH-, -S(O)NH-, -S(O) 2 NH-, -NHS(O)-, -NHS(O) 2 -, -C(O)NH-, -NHC(O)-, -CH 2 -one of them; for example, bond, H, OH, NH 2 , halogen, -O-, -S- , -CO-, -SO 2 -, -NH-, -S(O) 2 NH-, -NHS(O) 2 -, -C(O)NH-, -NHC(O)-, -CH 2 -.
- o 0,1,2.
- G 1 and G 3 are each independently selected from hydrogen or methyl; or G 1 and G 3 are connected to form an optionally substituted C 5-6 carbocyclic ring structure.
- G 1 and G 3 are joined to form an optionally substituted C 5-6 cycloalkyl structure.
- G 2 is selected from one of hydrogen, fluorine, hydroxyl, amino, methyl, cyclopropyl, methoxy, methylthio, methylamino; for example, fluorine, hydroxyl, One of the amino groups.
- each occurrence of R 2 is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, n-propyl Base, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl.
- R 3 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered hetero One or more optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec Butyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl.
- D is selected from bond and -NH-, and f is selected from 0,1,2,3.
- G 4 is selected from the following groups: optionally substituted C 1-12 alkyl, optionally substituted C 2-12 alkenyl, optionally substituted C 2-12 alkynyl, One of optionally substituted C 3-6 cycloalkyl, optionally substituted 4-6 membered heterocyclic group, optionally substituted C 6-10 aryl group, and optionally substituted 5-10 membered heteroaryl group ;
- the optional substitution means that the hydrogen on the substituted group is unsubstituted or one or more substitutable positions of the substituted group are independently selected from halogen, hydroxyl, mercapto, amino, cyano, trifluoro Methyl, difluoromethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, n-propoxy , Isopropoxy, n-
- G 4 is selected from:
- R 3 is independently selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl , Phenyl, 5-6 membered heteroaryl, one or more optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, Cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl.
- D is selected from bond and -NH-, and f is selected from 0,1,2,3.
- D is selected from a bond, a -NH- where, f is selected from 0,1,2,3; R 3 is selected from hydrogen, halo, hydroxy, mercapto, amino, cyano Group, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, one or more optionally substituted hydrogen, methyl, One of ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl kind.
- D is selected from bond, -NH-, f is selected from 0,1,2,3;
- R 3 is selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C
- D is selected from one of bond and -NH-, f is selected from 0, 1, 2, 3; R 3 is selected from those that can be optionally substituted by one or more of hydrogen, halogen, and hydroxyl.
- Hydrogen methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, One of the pyridyl groups.
- D is selected from one of bond and -NH-, f is selected from 0, 1, 2, 3; R 3 is independently selected from hydrogen, halogen, hydroxyl, mercapto, and amino. , Cyano, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, one or more optionally substituted furyl groups, Thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl; for example, R 3 is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-3 alkyl One or more optionally substituted furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl; for example, R 3 is independently selected from one of hydrogen, halogen, methyl Or
- the H ring is selected from:
- R 13 is selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, optionally substituted -R 4 , optionally substituted -OR 4 , optionally substituted -NH-R 4 , optionally substituted- N(R 4 )R 4 ; where each occurrence of R 4 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 4-6 member Heterocyclyl, phenyl, 5-6 membered heteroaryl; the optional substitution means that the H on the substituted group is unsubstituted or one or more substitutable positions of the substituted group are independently selected From halogen, hydroxy, mercapto, amino, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic group, phenyl, Substituted by 5-6
- R 13 is selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, optionally substituted -R 4 , optionally substituted -OR 4 , optionally substituted -NH-R 4 , any Optional substituted -N(R 4 )R 4 ; wherein each occurrence of R 4 is independently selected from C 1-6 alkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl;
- the optional substitution means that the H on the substituted group is unsubstituted or one or more substitutable positions of the substituted group are independently selected from halogen, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, phenyl substituted.
- formula (II) A can be selected from:
- formula (II) B can be selected from:
- formula (II) C can be selected from:
- formula (II) A is selected from:
- each Rx is independently selected from hydrogen, C 1-6 alkyl optionally substituted by halogen (such as CH 3 , -CF 3 ), halogen (such as fluorine), cyano or 6-10 membered aryl (such as Phenyl);
- halogen such as CH 3 , -CF 3
- halogen such as fluorine
- cyano or 6-10 membered aryl such as Phenyl
- Formula (II) B is selected from
- Formula (II) c is selected from
- each R13 is independently selected from hydrogen or halogen (such as fluorine) when it appears;
- X is selected from -O-, -S-, -CH2-, -N(R 5 )-, R 5 is independently selected from hydrogen or optionally substituted C 1-6 alkyl (such as methyl);
- G1 is selected from hydrogen
- G2 is selected from hydroxyl or amino
- G3 is selected from hydrogen
- Y is selected from bond, -NH 2 , -OH, -NH-;
- formula (II) A is selected from Wherein, each Rx is independently selected from hydrogen, C 1-6 alkyl optionally substituted by halogen, or 6-10 membered aryl;
- Formula (II) B is selected from
- Formula (II) c is selected from
- X is selected from S or NH
- G1 is selected from hydrogen
- G2 is selected from hydroxyl
- G3 is selected from hydrogen
- Y is selected from -NH-;
- the isotope-labeled analogue is selected from the following compounds:
- the object of the present invention also includes providing the preparation of compounds represented by general formula (I), and their stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, solvates or isotopic labels Method of analogues.
- the method can be prepared by using the method shown in Scheme 2, for example, by connecting LG b (leaving group b) of the fused ring structure with the side chain of XH, and then connecting the LG a of the fused ring structure to the side chain of XH. (Leaving group a) is connected with G 4 -YH to synthesize the target compound.
- Scheme 2 is as follows:
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound (I) shown in the present invention, or its stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, Solvates or isotope-labeled analogs, and pharmaceutically acceptable excipients.
- the pharmaceutical composition includes, but is not limited to, an oral dosage form, a parenteral dosage form, a topical dosage form, and a rectal dosage form.
- the administration amount of the compound is, for example, in the range of about 0.001 mg/kg body weight/day to about 10 g/kg body weight/day.
- dosage levels below the lower limit of the aforementioned range may already be sufficient.
- dosage levels above the upper limit of the aforementioned range may be required.
- the individual to which the pharmaceutical composition is administered is a mammal, such as a human.
- the object of the present invention also includes providing the compound (I) shown in the present invention, or its stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate or isotope label
- the object of the present invention also includes providing the compound (I) shown in the present invention, or its stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotopic labels It is used to treat diseases mediated by PRMT5 inhibitors.
- the object of the present invention also includes providing a method for preventing and/or treating diseases mediated by PRMT5 inhibitors, which comprises administering to a patient a therapeutically effective dose of the compound represented by general formula (I), or its stereoisomers, Geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, solvates, isotope-labeled analogs or the pharmaceutical composition of the present invention.
- a method for preventing and/or treating diseases mediated by PRMT5 inhibitors which comprises administering to a patient a therapeutically effective dose of the compound represented by general formula (I), or its stereoisomers, Geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, solvates, isotope-labeled analogs or the pharmaceutical composition of the present invention.
- the PRMT5 inhibitor-mediated disease described in this application is cancer.
- alkyl refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (ie C 1-10 Alkyl), further preferably containing 1-8 carbon atoms (C 1-8 alkyl), more preferably containing 1-6 carbon atoms (ie C 1-6 alkyl), such as "C 1-6 alkyl” It means that the group is an alkyl group, and the number of carbon atoms on the carbon chain is between 1 and 6 (specifically, 1, 2, 3, 4, 5, or 6).
- Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl , N-octyl and so on.
- cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group with a specific number of carbon atoms, preferably containing 3-12 carbon atoms (ie C 3-12 cycloalkyl), more preferably containing 3-10 carbon atoms (C 3-10 cycloalkyl), more preferably 3-6 carbon atoms (C 3-6 cycloalkyl), 4-6 carbon atoms (C 4-6 cycloalkyl), 5-6 carbon atoms (C 5-6 cycloalkyl).
- Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.
- alkoxy refers to -O-alkyl, which is defined as above, that is, contains 1-20 carbon atoms, preferably 1-10 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6).
- Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy Oxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2 , 2-Dimethylpropoxy, 1-ethylpropoxy, etc.
- alkenyl refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms with at least one double bond.
- the alkenyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (ie C 2-10 alkenyl), further preferably 2-8 carbon atoms (C 2-8 alkenyl), more preferably 2-6 carbon atoms (i.e. C 2-6 alkenyl), 2-5 carbon atoms (i.e. C 2-5 alkenyl), 2-4 carbon atoms (i.e.
- C 2-6 alkenyl means that the group is alkenyl, and the carbon chain The number of carbon atoms is between 2-6 (specifically 2, 3, 4, 5 or 6).
- alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
- alkynyl refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms with at least one triple bond.
- the alkynyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (ie C 2-10 alkynyl), further preferably 2-8 carbon atoms (C 2-8 alkynyl), more preferably 2-6 carbon atoms (i.e. C 2-6 alkynyl), 2-5 carbon atoms (i.e. C 2-5 alkynyl), 2-4 carbon atoms (i.e.
- C 2-4 alkynyl 2- 3 carbon atoms (ie C 2-3 alkynyl), 2 carbon atoms (ie C 2 alkynyl), for example, "C 2-6 alkynyl” means that the group is an alkynyl, and the carbon chain The number of carbon atoms is between 2-6 (specifically 2, 3, 4, 5 or 6).
- alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and the like.
- halogen refers to F, Cl, Br, I.
- haloalkyl means that one, two or more hydrogen atoms or all hydrogen atoms in an alkyl group as defined above are replaced by halogen.
- Representative examples of haloalkyl include CCl 3 , CF 3 , CHCl 2 , CH 2 Cl, CH 2 Br, CH 2 I, CH 2 CF 3 , CF 2 CF 3 and the like.
- heterocyclic group refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon substituent. It is a non-aromatic structure and contains 3-20 ring atoms, of which 1, 2 , 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. It preferably contains 3-12 ring atoms, more preferably 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms .
- the heteroatoms are preferably 1 to 4, more preferably 1 to 3 (ie 1, 2, or 3).
- Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl and the like.
- Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
- the heterocyclic group also includes the case where an aromatic group (such as a phenyl group) is condensed with a saturated heterocyclic group.
- the term "heterocycloalkyl" refers to the above-mentioned saturated "heterocyclyl".
- carbocyclic group refers to a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C 3-14 carbocyclic group”) and in There are no heteroatoms in this non-aromatic ring system.
- carbocyclyl groups have 3-12 ring carbon atoms ("C 3-12 carbocyclyl”), or 4-12 ring carbon atoms ("C 4-12 carbocyclyl”) , Or 3 to 10 ring carbon atoms ("C 3-10 carbocyclyl”).
- a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 carbocyclyl”).
- a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4-6 carbocyclyl”). In some embodiments, carbocyclyl groups have 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”), or 5 to 7 ring carbon atoms ("C 5-7 carbocyclyl”) .
- Exemplary C 3-6 carbocyclic groups include, but are not limited to cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclo Pentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), etc.
- Exemplary C 3-8 carbocyclic groups include, but are not limited to the aforementioned C 3-6 carbocyclic groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptanyl Alkenyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1] heptyl (C 7 ), two Cyclo[2.2.2]octyl (C 8 ) and the like.
- Exemplary C 3-10 carbocyclic groups include, but are not limited to the aforementioned C 3-8 carbocyclic groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ), and the like.
- the carbocyclic group is monocyclic ("monocyclic carbocyclyl") or a fused (fused ring group), bridged (bridged ring group) ) Or spiro-fused (spirocyclyl) ring system, such as a bicyclic ring system (“bicyclic carbocyclyl”) and may be saturated or may be partially unsaturated.
- Carbocyclyl also includes a ring system in which the carbocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring and in In such cases, the number of carbons continues to indicate the number of carbons in the carbocyclic ring system.
- each instance of a carbocyclyl group is independently optionally substituted, for example, unsubstituted (an "unsubstituted carbocyclyl") or substituted by one or more Substituted (a "substituted carbocyclyl").
- the carbocyclyl group is an unsubstituted C 3-10 carbocyclyl group.
- the carbocyclyl group is a substituted C 3-10 carbocyclyl.
- aryl means monocyclic, bicyclic and tricyclic rings containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms.
- the aromatic carbocyclic ring system preferably 6-10 carbon atoms, the term “aryl” can be used interchangeably with the term “aromatic ring”.
- aryl groups may include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, or pyrenyl, and the like.
- heteroaryl means an aromatic monocyclic or polycyclic ring containing a 5-12 membered structure, or preferably a 5-10 membered structure, a 5-8 membered structure, and more preferably a 5-6 membered structure
- the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2, or 3. Piece.
- heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl , Tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pterridinyl, purinyl, indino Dole, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrole O[2,3-b]pyridyl,
- the terms “pharmaceutically acceptable salt”, “pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” refer to the application within the scope of reasonable medical judgment for contact with mammalian, especially human tissue, without excessive Salts with toxicity, irritation, allergic reactions, etc. and commensurate with a reasonable benefit/risk ratio, such as medically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art.
- salt includes salts derived from inorganic acids and also includes salts derived from organic acids. If the compound of the present invention is acidic, pharmaceutically acceptable non-toxic bases include inorganic bases and salts prepared with organic bases.
- isotope-labeled analog means that one or more protons in the compounds of Formula I to Formula II can be replaced by deuterium atoms, thereby providing deuterated analogs that may have improved pharmacological activity.
- prodrug refers to a drug that is converted into the parent drug in the body.
- Prodrugs are often useful because in some cases they may be easier to administer than the parent drug. For example, they can be bioavailable through oral administration, while the parent body cannot. Compared with the parent drug, the solubility of the prodrug in the pharmaceutical composition is also improved.
- An example, but not limited to, a prodrug can be any compound of formula I, which is administered as an ester ("prodrug") to promote transmission across the cell membrane, where water solubility is harmful to mobility, but once it enters Intracellular water solubility is beneficial, which is subsequently metabolized and hydrolyzed into carboxylic acid, the active entity.
- Another example of a prodrug may be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to show the active part.
- solvate and “solvate” mean the physical association of the compound of the present invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be able to be separated.
- the solvent molecules in the solvate can be arranged in regular and/or disordered arrangements.
- Solvates can contain stoichiometric or non-stoichiometric solvent molecules.
- “Solvate” encompasses both solution-phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
- stereoisomers refers to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space.
- Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis/trans) isomers, atropisomers and the like. Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physical and chemical properties of the components, for example, by chromatography Method and/or fractional crystallization method.
- tautomers refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached.
- proton tautomers also called proton transfer tautomers
- Valence tautomers include interconversion through the recombination of some bond-forming electrons.
- the structural formula described in the present invention includes all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, those containing asymmetric centers R and S configurations, (Z) and (E) isomers of the double bond, and (Z) and (E) conformational isomers. Therefore, a single stereochemical isomer of the compound of the present invention or a mixture of its enantiomers, diastereomers, or geometric isomers (or conformational isomers) all belong to the scope of the present invention.
- the term "optionally substituted” means that the hydrogen at the substitutable position of the group is unsubstituted or substituted by one or more substituents, which are preferably selected from the following group of substitutions Group: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo, carboxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1 -6 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 aryl or 5-10 membered heteroaromatic ring group, wherein , The C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkylsulfonyl , 3-10 membered heterocycloalkyl,
- the present invention designs a class of compounds with novel structures, which provides a new direction for the development of PRMT5 inhibitor drugs.
- In vitro enzyme activity inhibitory activity studies have shown that these compounds have a strong inhibitory effect on PRMT5 enzyme, and can be used as prospective compounds for the treatment of PRMT5 inhibitor-mediated diseases.
- the present invention studies a specific synthesis method, which has simple process and convenient operation, which is beneficial to large-scale industrial production and application.
- the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography (LC-MS) or/and liquid chromatography (HPLC).
- NMR nuclear magnetic resonance
- LC-MS liquid chromatography
- HPLC liquid chromatography
- the starting materials in the examples of the present invention are known and can be bought on the market, or can be synthesized by using or following methods known in the art.
- the first step the preparation of 2-(oxirane-2-methyl)-1,2,3,4-tetrahydroisoquinoline (Intermediate 1-a)
- Step 2 Preparation of 1-amino-3-(3,4dihydroisoquinoline-2(1H)-yl)-propan-2-ol (Intermediate 1-b)
- LCMS: [M+H] + 352.14.
- Step 2 Preparation of (S)-1-amino-3-(3,4dihydroisoquinolin-2(1H)-yl)-propan-2-ol (Intermediate 2-b)
- Step 2 Preparation of (R)-1-amino-3-(3,4dihydroisoquinolin-2(1H)-yl)-propan-2-ol (Intermediate 3-b)
- reaction solution was poured into 10ml of water , Ethyl acetate extraction three times, 5 ml each time, combine the ethyl acetate phases, wash once with 10 ml saturated brine, dry with anhydrous sodium sulfate for 10 minutes, filter, and concentrate to obtain the crude product.
- Preparative-HPLC obtains 40 mg of the target molecule with a yield of 18.2 %.
- reaction solution was poured Pour into 10 ml water, extract with ethyl acetate three times, 5 ml each time, combine the ethyl acetate phase, wash once with 10 ml saturated brine, dry with anhydrous sodium sulfate for 10 minutes, filter and concentrate to obtain the crude product.
- Preparative-HPLC obtains the target molecule 40 mg , The yield is 18.2%.
- reaction solution was poured Pour into 10 ml water, extract with ethyl acetate three times, 5 ml each time, combine the ethyl acetate phases, wash once with 10 ml saturated brine, dry with anhydrous sodium sulfate for 10 minutes, filter and concentrate to obtain the crude product.
- Preparative HPLC obtains 40 mg of the target molecule. The yield was 18.2%.
- the compound (26 mg, 0.044 mmol, 1.0 eq) obtained in the fourth step was dissolved in a 1,4-dioxane solution (4M, 1.2 mL) of hydrochloric acid, and the reaction was carried out at 20° C. for 1.5 hours. After the completion of the reaction detected by TLC, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and dried over anhydrous sodium sulfate.
- reaction solution was quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, extracted with chloroform/isopropanol (7:3), and dried with anhydrous sodium sulfate.
- the organic phase was concentrated and purified by preparative HPLC to obtain 6 mg of the target compound with a yield of 22.2%.
- methyl iodide (96 mg, 4.2 mmol, 1.1 eq) was added, and after the addition was completed, the temperature was raised to room temperature, and stirring was continued for two hours. Add 5 mL of saturated ammonium chloride solution and 50 mL of water to the reaction system.
- Example 19 According to the method of Example 19, using the compound (4-((3-iodo-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)amino)piperidin-1-yl) Ethan-1-one (180mg, 0.45mmol, 1.0eq) (ie Intermediate 19-c, see Example 19 for the preparation method) and the raw material compound (R)-1-amino-3-(3,4-dihydroiso Quinoline-2(1H)-yl)propan-2-ol (141mg, 0.672mmol, 1.5eq) (i.e.
- Example 19 According to the method of Example 19, using the compound (4-((3-iodo-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)amino)piperidin-1-yl) Ethan-1-one (180mg, 0.45mmol, 1.0eq) (ie Intermediate 19-c, see Example 19 for the preparation method) and the raw material compound (R)-1-amino-3-(3,4-dihydroiso Quinoline-2(1H)-yl)propan-2-ol (141mg, 0.672mmol, 1.5eq) (i.e.
- reaction solution was extracted with ethyl acetate and dried over anhydrous sodium sulfate.
- the organic phase was concentrated and purified by column chromatography to obtain 7-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4- c] Pyridine, 920 mg of transparent crystalline solid, with a yield of 62.7%.
- reaction solution was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and dried over anhydrous sodium sulfate.
- organic phase was concentrated and purified by preparative HPLC to obtain 40 mg of the target compound with a yield of 30%.
- Example 25 the raw material compound 1-amino-3-(3,4-dihydroisoquinoline-2(1H)-yl)propan-2-ol (ie Intermediate 1-b) was used.
- Example 1 For the preparation method, see Example 1) as starting material, and 7-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4- c] Pyridine (ie Intermediate 25-b, see Example 25 for the preparation method) is synthesized and coupled with the compound 1-(4-aminopiperidin-1-yl)ethane-1-one hydrochloric acid, Remove the SEM to obtain the target molecule 1-(4-((3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)amino)-1H- Pyrazolo[3,4-c]pyridin-7-yl)amino)piperidin-1-yl)ethan
- 1,8-diazabicycloundec-7-ene (173 mg, 1.14 mmol, 1.5 eq) was added, and the mixture was stirred at room temperature for 0.5 h. TLC detected that the raw material had reacted completely.
- Example 28 using the raw material compound (1-amino-3-(3,4-dihydroisoquinoline-2(1H)-yl)propan-2-ol (ie intermediate 1-b, preparation method See Example 1) as starting material, and 1-(4-((3-iodo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H -Pyrazolo[4,3-d]pyrimidin-7-yl)amino)piperidin-1-yl)ethane-1-one (ie intermediate 28d, see Example 28 for the preparation method) for coupling reaction, Then remove the SEM to obtain the target molecule 1-(4-((3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)amino)-5 -Methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)amino)piperidin-1-yl)
- Example 28 the raw material compound (R)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (ie intermediate 3-b , The preparation method see Example 3) as the starting material, and 1-(4-((3-iodo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-pyrazolo[4,3-d]pyrimidin-7-yl)amino)piperidin-1-yl)ethane-1-one (i.e.
- the raw material compound (R)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol i.e. intermediate 3-b , The preparation method see Example 3) as starting material, and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3- d] pyrimidine (ie intermediate 31-c, see Example 31 for the preparation method) for coupling reaction, and then removing SEM to prepare the target compound (R)-1-((1H-pyrazolo[4,3- d] Pyrimidine-3-yl)amino)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol.
- Example 31 using the raw material compound (1-amino-3-(3,4-dihydroisoquinoline-2(1H)-yl)propan-2-ol (ie intermediate 1-b, preparation method See Example 1) as starting material, and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine (I.e. Intermediate 31-c, refer to Example 31 for the preparation method).
- reaction solution was quenched with saturated sodium bicarbonate aqueous solution, extracted with chloroform: isopropanol (7:3), and dried with anhydrous sodium sulfate.
- organic phase was concentrated, and the crude product was separated and purified by preparative HPLC (C18, 10mmol/L NH 4 HCO 3 in water, MeCN) to obtain the target compound (S)-1-((7-amino-1H-pyrazolo[4, 3-d]pyrimidin-3-yl)amino)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (31.6 mg, 36.3%).
- Example 34 using the raw material compound (R)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (ie intermediate 3-b , The preparation method see Example 3) as starting material, and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3- d] Pyrimidine-7-amine (ie intermediate 34-d, see Example 34 for the preparation method) for coupling reaction, remove SEM, and separate and purify by preparative HPLC (C18, 10mmol/L NH 4 HCO 3 in water, MeCN ) To obtain the target compound (R)-1-((7-amino-1H-pyrazolo[4,3-d]pyrimidin-3-yl)amino)-3-(3,4-dihydroisoquinoline -2(1H)-yl)propan-2-ol.
- the raw material compound 1-amino-3-(3,4-dihydroisoquinoline-2(1H)-yl)propan-2-ol (ie intermediate 1-b) was used.
- the preparation method see Example 1
- the 7-amine ie intermediate 34-d, see Example 34 for the preparation method
- SEM was removed
- preparative HPLC separation and purification C18, 10mmol/L NH 4 HCO 3 in water, MeCN
- the raw material compound (R)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (ie intermediate 3-b , The preparation method see Example 3) as starting material, and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3- d] Pyrimidine-7-ol (ie intermediate 37-b, see Example 37 for the preparation method) for coupling reaction, and then remove the SEM to obtain the target molecule (R)-3-((3-(3,4- Dihydroisoquinoline-2(1H)-yl)-2-hydroxypropyl)amino)-1H-pyrazolo[4,3-d]pyrimidin-7-ol.
- Example 37 using the raw material compound (1-amino-3-(3,4-dihydroisoquinoline-2(1H)-yl)propan-2-ol (ie intermediate 1-b, preparation method See Example 1) as starting material, and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine -7-alcohol (ie intermediate 37-b, see Example 37 for the preparation method) for coupling reaction, and then remove the SEM to obtain the target molecule 3-((3-(3,4-dihydroisoquinoline-2 (1H)-yl)-2-hydroxypropyl)amino)-1H-pyrazolo[4,3-d]pyrimidin-7-ol.
- Example 40 the raw material compound 1-amino-3-(3,4-dihydroisoquinoline-2(1H)-yl)propan-2-ol (ie intermediate 1-b) was used.
- Example 1 For the preparation method, see Example 1) as a starting material, and 1-(4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4, 3-d]pyrimidin-7-yl)piperazin-1-yl)ethane-1-one (ie Intermediate 40-c, see Example 40 for the preparation method), carry out the coupling reaction, and then remove the SEM to obtain the target Molecule 1-(4-(3-((3-(3,4-dihydroisoquinoline-2(1H)-yl)-2-hydroxypropyl)amino)-1H-pyrazolo[4,3 -d]pyrimidin-7-yl)piperazin-1-yl)ethane-1-one.
- the raw material compound (R)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol i.e. intermediate 3-b , See Example 3 for the preparation method) as starting material, and 1-(4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole And [4,3-d]pyrimidin-7-yl)piperazin-1-yl)ethane-1-one (ie intermediate 40-c, see Example 40 for the preparation method) for coupling reaction, and then remove SEM is the target molecule (R)-1-(4-(3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)amino)-1H -Pyrazolo[4,3-d]pyrimidin-7-yl)piperazin-1-yl)ethane-1-one.
- the compound 5-chloro-1H-pyrazolo[4,3-d]pyrimidine (600mg, 3.88mmol, 1.0eq) was dissolved in DMF(N,N-dimethylformamide) (40mL), and NIS( N-iodosuccinimide) (1.1 g, 4.66 mmol, 1.2 eq), the reaction was carried out at 60° C. for 2 hours under the protection of nitrogen. After the completion of the reaction detected by TLC, the reaction solvent was spin-dried, the mixture was dissolved in water, stirred for 30 minutes, and filtered with suction.
- reaction solution was extracted three times with 10 ml of ethyl acetate each time, and the organic phases were combined and dried with anhydrous sodium sulfate.
- the organic phase was concentrated and purified by column chromatography to obtain 5-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3- d] Pyrimidine, colorless crystalline solid 580mg, yield 79.2%.
- reaction solution was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, 10 ml each time, the organic phases were combined, and dried over anhydrous sodium sulfate.
- the organic phase was concentrated and purified by preparative HPLC to obtain the target compound, 19.6 mg, with a yield of 32%.
- Example 43 using the raw material compound (1-amino-3-(3,4-dihydroisoquinoline-2(1H)-yl)propan-2-ol (ie intermediate 1-b, preparation method See Example 1) as a starting material, and 1-(4-((3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[ 4,3-d]pyrimidin-5-yl)amino)piperidin-1-yl)ethane-1-one (i.e.
- the raw material compound (R)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol i.e. intermediate 3-b , See Example 3 for the preparation method
- 1-(4-((3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyridine Azolo[4,3-d]pyrimidin-5-yl)amino)piperidin-1-yl)ethane-1-one i.e.
- the raw material compound (R)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol i.e. intermediate 3-b , See Example 3 for the preparation method) as starting material, and 1-(4-((3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyridine Azolo[3,4-d]pyrimidin-6-yl)amino)piperidin-1-yl)ethane-1-one (ie intermediate 46-c, see Example 46 for the preparation method) for coupling reaction, Then remove the SEM to obtain the target molecule (R)-1-(4-((3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) Amino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)piperidin-1-
- Example 46 using the raw material compound (1-amino-3-(3,4-dihydroisoquinoline-2(1H)-yl)propan-2-ol (ie intermediate 1-b, preparation method See Example 1) as a starting material, and 1-(4-((3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[ 3,4-d]pyrimidin-6-yl)amino)piperidin-1-yl)ethane-1-one (i.e.
- reaction solution was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and dried over anhydrous sodium sulfate.
- organic phase was concentrated, and the crude product was separated and purified by preparative HPLC (C18, 10mmol/L NH 4 HCO 3 aqueous solution, MeCN) to obtain (S)-1-(3,4-dihydroisoquinolin-2(1H)-yl )-3-((7-(pyridazin-4-ylamino)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)amino)propan-2-ol (14 mg, 29.8%).
- Example 49 the raw material compound (R)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (ie intermediate 3-b , For the preparation method, see Example 3) as starting material, and 3-iodo-N-(pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -1H-pyrazolo[4,3-d]pyrimidine-7-amine (i.e.
- Example 49 using the raw material compound (1-amino-3-(3,4-dihydroisoquinoline-2(1H)-yl)propan-2-ol (ie intermediate 1-b, preparation method See Example 1) as the starting material, and 3-iodo-N-(pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- Pyrazolo[4,3-d]pyrimidine-7-amine (ie intermediate 49-d, see Example 49 for the preparation method) was subjected to coupling reaction, and then the SEM was removed to obtain the target molecule 1-(3,4- Dihydroisoquinoline-2(1H)-yl)-3-((7-(pyridazin-4-ylamino)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)amino) Propan-2-ol.
- the seventh step (S)-1-(4-((3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)amino)-5 -(Trifluoromethyl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl)amino)piperidin-1-yl)ethane-1-one (the compound of Example 52)
- the raw material compound (R)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol i.e. intermediate 3-b , The preparation method see Example 3) as starting material, and 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-pyrazolo[4 ,3-d]pyrimidine-7-phenol (ie intermediate 52-d, see Example 52 for the preparation method) for coupling reaction, and then with 1-(4-aminopiperidin-1-yl)ethane-1- The ketone hydrochloride undergoes condensation reaction, and then THP is removed to obtain the target product (R)-1-(4-((3-((3-(3,4-dihydroisoquinolin-2(1H)-yl )-2-hydroxypropyl)amino)-5-(trifluoromethyl)-1H-
- Example 52 using the raw material compound (1-amino-3-(3,4-dihydroisoquinoline-2(1H)-yl)propan-2-ol (ie intermediate 1-b, preparation method See Example 1) as starting material, and 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-pyrazolo[4,3- d] Pyrimidine-7-phenol (ie intermediate 52-d, see Example 52 for the preparation method) for coupling reaction, and then with 1-(4-aminopiperidin-1-yl)ethane-1-one hydrochloric acid The salt undergoes condensation reaction, and then THP is removed to obtain the target molecule 1-(4-((3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropane Yl)amino)-5-(trifluoromethyl)-1H-pyrazolo[4,3-d]
- Step 2 Synthesis of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine-7-ol:
- the third step 7-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-3-iodo-1-((2-(trimethylsilyl )Ethoxy)Methyl)-1H-pyrazolo[4,3-d]pyrimidine synthesis:
- reaction solution was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and dried over anhydrous sodium sulfate.
- organic phase was concentrated, and the crude product was separated and purified by Prep-HPLC (C18, 10 mmol/L NH 4 HCO 3 in water, MeCN) to obtain the target compound (7 mg, yield 31.8%).
- reaction solution was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and dried over anhydrous sodium sulfate.
- organic phase was concentrated, and the crude product was separated and purified by Prep-HPLC (C18, 10 mmol/L NH 4 HCO 3 in water, MeCN) to obtain the target compound (2.5 mg, yield 28.9%).
- the second step is the preparation of (S)-1-amino-3-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol:
- the fourth step 1- (4-((3-(((S)-3-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)amino )-1-(Tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl)amino)piperidine- Preparation of 1-yl)ethane-1-one:
- 1,8-diazabicycloundec-7-ene 134 mg, 0.88 mmol, 3.0 equiv.
- TLC detected that the raw material had reacted completely.
- Water (10mL) was added to the reaction system, extracted three times with ethyl acetate (3 ⁇ 20mL), the organic phases were combined, washed once with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered with suction, and the solvent was concentrated.
- the third step 3-(((S)-3-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)amino)-1-(tetra)-1H-pyran-2-yl)-5-(trifluoromethyl)-1H-pyrazolo[4,3-d]pyrimidine-7-phenol:
- the fourth step 1-(4-((3-(((S)-3-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) Amino)-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl)amino)piperidine -1-yl) ethane-1-one preparation:
- the fifth step (S)-1-(4-((3-((3-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) Preparation of (amino)-5-(trifluoromethyl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl)amino)piperidin-1-yl)ethane-1-one:
- the third step 3-(((S)-2-hydroxy-3-(1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propyl )Amino)-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-pyrazolo[4,3-d]pyrimidine-7-phenol preparation:
- the fourth step 1-(4-((3-(((S)-2-hydroxy-3-(1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole -2-yl)propyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-pyrazolo[4,3-d]pyrimidine- Preparation of 7-yl)amino)piperidin-1-yl)ethane-1-one:
- TLC detects that the raw material has reacted completely.
- Water 60mL was added to the reaction system, extracted three times with ethyl acetate (3 ⁇ 20mL), the organic phases were combined, washed once with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered with suction, and the solvent was concentrated.
- the third step 3-(((S)-3-(4,5-dihydro-1H-benzo[d]azepine-3(2H)-yl)-2-hydroxypropyl)amino)- Preparation of 1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-pyrazolo[4,3-d]pyrimidine-7-ol:
- the fourth step 1-(4-((3-(((S)-3-(4,5-dihydro-1H-benzo[d]azepine-3(2H)-yl)-2- Hydroxypropyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl)
- (amino)piperidin-1-yl)ethanone 1-(4-((3-(((S)-3-(4,5-dihydro-1H-benzo[d]azepine-3(2H)-yl)-2- Hydroxypropyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl)
- the first step 3-(((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)amino)-1-(tetrahydro-2H-
- pyran-2-yl -5-(trifluoromethyl)-1H-pyrazolo[4,3-d]pyrimidine-7-phenol:
- Step 2 1-(3,4-Dihydroisoquinolin-2(1H)-yl)-4-(4-(3,4-Dihydroisoquinolin-2(1H)-yl)-1H -Preparation of pyrazolo[3,4-d]pyrimidin-1 yl)butan-2-ol:
- the first step the first step: (2S)-1-((7-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)amino)-3- Preparation of (3,4-Dihydroisoquinoline-2(1H)-yl)propan-2-ol:
- the second step 1-(4-((3-(((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)amino)-1 -(Tetrahydro-2H-pyran-2-yl)-1H-indazol-7-yl)amino)piperidin-1-yl)ethane-1-one:
- the first step 4-((3-(((S)-3-(3,4-dihydroisoquinoline-2(1H)-yl)-2-hydroxypropyl)amino)-1-(tetra Preparation of hydrogen-2H-pyran-2-yl)-1H-indazol-7-yl)amino)piperidine-1-carboxylic acid tert-butyl ester:
- the reaction was quenched by adding water (40mL), extracted with ethyl acetate (3*15mL), the combined organic phase was washed with 10% sodium sulfite solution (3*20mL) and saturated brine (3*20mL), dried with anhydrous sodium sulfate, filtered, Concentrate to obtain a crude product.
- Step 2 Preparation of 3-iodo-7-nitro-5-phenyl-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole:
- the reaction was quenched by adding water (20 mL), extracted with ethyl acetate (3*10 mL), the combined organic phase was washed with saturated brine (3*15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product.
- the third step Preparation of 3-iodo-5-phenyl-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-amine:
- the reaction was quenched by adding water (20mL), and extracted with ethyl acetate (3*10mL), The combined organic phase was washed with saturated sodium bicarbonate solution (3*20mL) and saturated brine (20mL), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product.
- the first step the preparation of 3-tert-butoxycarbonylamino-2-fluorobenzonitrile:
- the molecular weight was not detected by LCMS, and the reaction was completed by dot plate.
- the reaction solution was filtered directly, the filter cake was washed with ethyl acetate (100 mL), the filtrate was extracted with water (500 mL), the aqueous phase was washed with ethyl acetate (3*100 mL), and the organic phases were combined. Wash with saturated brine (3*200mL), dry with anhydrous sodium sulfate, filter, and concentrate to obtain a crude product.
- Step 2 Preparation of tert-butyl (3-aminobenzo[d]isoxazol-7-yl) carbamate:
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Abstract
提供了一种作为PRMT5抑制剂的具有全新结构的化合物、其化合物的制备方法及其治疗由PRMT5抑制剂介导的疾病方面的用途。实验证实这些化合物对PRMT5酶都具有较强的抑制作用。还提供了化合物的合成方法,其工艺简单,操作便捷,利于规模化工业生产和应用。
Description
本发明涉及医药技术领域,具体而言,涉及作为PRMT5抑制剂的化合物以及所述化合物的制备方法及用途。
PRMT5是蛋白质精氨酸甲基转移酶的一种,是英文名字Protein arginine N-methyltransferase 5的缩写,是表观遗传(epigenetic)修饰相关的新型抗肿瘤靶标。它有好几个别名,分别是Hsl7,Jbp1,Skb1,Capsuleen,或Dart5。PRMT5是精氨酸单甲基化、对称二甲基化的主要酶。越来越多的文献证明蛋白质精氨酸甲基转移酶(PRMTs)在不同的生物过程中起关键作用,如细胞生长增殖、凋亡、转移等。
蛋白质精氨酸甲基转移酶(PRMTs)的作用是从S-腺苷甲硫氨酸(S-adenosylmethionine,或AdoMet或SAM)转移一个甲基到组蛋白或其他蛋白质上精氨酸残基,形成甲基精氨酸和S-腺苷同型半胱氨酸(S-adenosylhomocysteine,或SAH)。目前,已经鉴定出9种该家族的成员(PRMT1~9),根据其催化精氨酸甲基化方式的不同,PRMTs可分为三种类型:Ⅰ型PRMTs包括PRMT1、PRMI2、PRMT3、PRMT4、PRMT6和PRM8催化单甲基精氨酸(MMA)和不对称二甲基精氨酸(aDMA);Ⅱ型PRMTs包括PRMT5及PRMT9催化MMA和对称二甲基精氨酸(sDMA);Ⅲ型PRMTs为PRMT7只能单甲基化。PRMT5作为一种表观遗传酶,能对称性地甲基化组蛋白或者非组蛋白底物的精氨酸残基,影响多个靶基因及多条信号通路途径,在蛋白质的甲基化中起着重要的作用,如参与可变剪切、转录后调节、RNA的加工、细胞增殖、细胞分化、细胞凋亡和肿瘤形成等。选择性抑制PRMT5,可作为一个潜在地强有力的抗癌新药。研究以PRMT5为靶点的新药开发对解决未满足的临床需求有积极的填补空白的作用。
在过去几年内,有不少有关PRMT5抑制剂的报道,此类报道可参见:WO2014100719A、WO2019102494A、WO2015200677A、WO2015200680A、WO2014100764A、WO2014100730A、WO2014100716A、WO2014100695A、WO2019173804A、CN108570059A、WO2018167269A等。并且已经有两例化合物:JNJ-64619178和GSK-3326595进入了临床治疗实体瘤和套细胞淋巴瘤。
JNJ-64619178是强生研发的一种具有选择性的PRMT5抑制剂,在体外对多种肿瘤细胞的生长具有抑制作用。强生公司选择了大量的异种移植(Xenograft)动物模型来证明其有效的抗肿瘤作用,例如:选择了小细胞肺癌(SCLC)、非小细胞肺癌(NSCLC)、急性髓系白血病(AML)和非霍奇金淋巴瘤(non-Hodgkin lymphoma)的Xenograft模型进行抗肿瘤实验。在模型中观察到高达99%的显著的肿瘤生长抑制,停药后数周内肿瘤生长持续受到抑制。JNJ-64619178可抑制SMD1/3蛋白,肿瘤剪接体的核心成分的Sym-Arg二甲基化以及抑制血清蛋白的Sym-Arg二甲基化。这些可以作为在Xenograft模型中PRMT5抑制肿瘤生长的药效学标记物。在SCLC模型中,在给药期间和给药后都观察到PRMT5对SMD1/3二甲基化的有效和长期抑制作用。基于这些高选择性和高效性、良好的药代动力学和安全性、明显的临床前疗效和药效结果,JNJ-64619178于2018年开始进行一期临床试验。
GSK-3326595是由EPZ015666(结构如下)优化而来,是一种高选择性、可口服的小分子,是第一代PRMT5抑制剂。EPZ015666在套细胞淋巴瘤体现出显著的体内外活性,葛兰素史克公司(GSK)通过两年的优化和临床前研究,于2016年9月宣布GSK-3326595首次率先进入了临床。在2019年的ESMO大会上,葛兰素史克公司公布了GSK-3326595的临床一期数据。GSK-3326595的I期临床选择的是成年实体瘤病人,主要目的是进行安全性,耐受性以及PK/PD测试,并收集药效数据(ORR和DCR)。数据显示GSK3326595PK在血浆中呈剂量依赖性。
尽管已公开了一些PRMT5抑制剂小分子,但目前还没有PRMT5抑制剂开发上市,因此开发新的具有上市潜力的,具有更好药效、药代结果的化合物仍是迫切需要的。本发明设计了系列具有通式所示的新结构的化合物,并发现具有此类结构的化合物呈现出优异的效果和作用,对PRMT5抑制剂的开发具有积极意义。
发明内容
本发明的目的在于提供一种作为PRMT5抑制剂的具有全新结构的化合物、其化合物的制备方法及其治疗由PRMT5抑制剂介导的疾病方面的用途。
本发明的第一方面,提供了一种如下式(I)所示的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物。
Z可独立地选自C或N;
q可选自0或1,q=0代表所在的环为五元环,q=1代表所在的环为六元环;
Z
1可独立地选自CH、N、C(R
2),但当q=1时,三个位置的Z
1不同时为N;R
2每次出现时,独立选自氢、卤素、羟基、巯基、氨基、氰基、任选取代的-R
2a、任选取代的-OR
2a、任选取代的-NH-R
2a、任选取代的-N(R
2a)R
2a,其中,R
2a每次出现独立地选自C
1-6烷基、C2-6烯基、C2-6炔基、C
3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基;所述任选取代是指被取代基团上的H未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、巯基、氨基、氰基、C
1-6烷基、C2-6烯基、C2-6炔基、C
3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基所取代;
Z
2可独立地选自CH、C(R
2)、N、O、S或N(R
1);其中,R
1可选自氢、C
1-6烷基或C
3-6环烷基;其中,每个C
1-6烷基和C
3-6环烷基可任选被卤素、氰基、任选取代的R
1a、任选取代的-OR
1a、任选取代的-SR
1a、任选取代的-N(R
1a)R
1a、任选取代的-NHR
1a、任选取代的5-6元杂芳基或任选取代的苯基取代;其中R
1a每次出现时独立地选自氢、C
1-6烷基、C
3-6环烷基、4-6元杂环基其中的一种;所述任选取代是指被取代基团上的H未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、巯基、氨基、氰基、C
1-6烷基、C2-6烯基、C2-6炔基、C
3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基所取代;
p可选自0或1;
p=0时,代表所在的环为五元环;Z
3、Z
5可分别独立地选自N、S、O、CH(R
2)、C(R
2)、N(R
1);
p=1时,代表所在的环为六元环;Z
3、Z
4、Z
5可分别独立地选自N、S、O、N(R
1)、CH(R
2)、C(R
2);
X选自-O-、-S-、-CO-、-N(R
5)-、-S(O)N(R
5)-、-S(O)
2N(R
5)-、-N(R
5)SO-、-N(R
5)S(O)
2-、-C(O)N(R
5)-、-N(R
5)C(O)-、-N(R
5)C(O)N(R
5)-、-CH(R
5)-其中的一种;其中R
5每次出现时独立地选自氢、任选取代的C
1-6烷基、任选取代的C
3-6环烷基、任选取代的4-6元杂环基其中的一种;所述任选取代是指被取代基团上的H未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、巯基、氨基、氰基、C
1-6烷基、C2-6烯基、C2-6炔基、C
3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基所取代;
Y选自键、-H、-OH、-NH
2、卤素、-O-、-S-、-CO-、-C(R
6)F-、-CF
2-、-SO-、-SO
2-、-N(R
6)-、-S(O)N(R
6)-、-S(O)
2N(R
6)-、-N(R
6)SO-、-N(R
6)S(O)
2-、-C(O)N(R
6)-、-N(R
6)C(O)-、-CH(R
6)-其中的一种;其中R
6可选自氢、任选取代的C
1-6烷基、任选取代的C
3-6环烷基、任选取代的4-6元杂环基其中的一种;所述任选取代是指被取代基团上的H未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、巯基、氨基、氰基、C
1-6烷基、C2-6烯基、C2-6炔基、C
3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基所取代;当Y选自-H、-OH、-NH
2、卤素其中的一种时,G
4不存在;
o=0,1,2,3,4,5;
G
1和G
3可分别选自氢、卤素、羟基、巯基、氨基、氰基、任选取代的C
1-6烷基、任选取代的C
3-6环烷基、任选取代的4-6元杂环基其中的一种;或者G
1和G
3连接起来形成一个任选取代的C
3-8的碳环结构;所述任选取代是指被取代基团上的H未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、巯基、氨基、氰基、C
1-6烷基、C2-6烯基、C2-6炔基、C
3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基所取代;
G
2选自氢、卤素、羟基、巯基、氨基、氰基、任选取代的R
7、任选取代的O(R
7)、S(R
7)、任选取代的NH(R
7)、任选取代的N(R
7)(R
7)其中的一种;其中R
7选自氢、C
1-6烷基、C
3-6环烷基、4-6元杂环基其中的一种;所述任选取代是指被取代基团上的H未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、巯基、氨基、氰基、C
1-6烷基、C2-6烯基、C2-6炔基、C
3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基所取代;
G
4选自以下基团:任选取代的C
1-12烷基、任选取代的C
2-12烯基、任选取代的C
2-12炔基、任选取代的C
3-6环烷基、任选取代的4-6元杂环基、任选取代的C
6-10芳基、任选取代的5-10元杂芳基中的一种;所述任选取代是指被取代基团上的H未被取代或被取代基团的一个或多个可取代位点独立地被选自氢、卤素、羟基、巯基、氨基、氰基、-R
3、-OR
3、-NH-R
3、-N(R
3)R
3、
所取代,其中,R
3每次出现独立地选自可被氢、卤素、羟基、巯基、氨基、氰基、C
1-6烷基、C
3-6环烷基、4-6元杂环烷基、苯基、5-6元杂芳基中的一个或多个任意取代的C
1-6烷基、C2-6烯基、C2-6炔基、C
3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基;D选自键、NH、N(CH
3)、O、S其中的一种,f=0,1,2,3,4,5,6,7,8;
A可选自-N(R
9)-、-CH(R
9)-或-CH(NHR
9)-,m=0或1;其中,R
9可选自氢、羟基、卤素、C
1-6烷基、C
3-6环烷基、4-6元杂环基其中的一种;
B可选自-N-或-CH-;
C可选自-NR
10-或-CHR
10-,n=0或1(或者n=0、1或2);R
10选自氢、羟基、卤素、C
1-6烷基、C
3-6环烷基、4-6元杂环基其中的一种;
A,B,C至少有一个为符合各自定义的取代的N原子;
H环选自C
6-10芳基环、5-10元杂芳基环其中的一种;所述芳基环或杂芳基环可被一个或多个以下取代基独立取代:氢、卤素、羟基、巯基、氨基、氰基、任选取代的-R
4、任选取代的-OR
4、任选取代的-NH-R
4、任选取代的-N(R
4)R
4;其中,R
4每次出现独立地选自C
1-6烷基、C2-6烯基、C2-6炔基、C
3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基;所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、巯基、氨基、氰基、C
1-6烷基、C2-6烯基、C2-6炔基、C
3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基所取代。
在本发明的一些实施方案中,X选自-O-、-S-、-CO-、-NH-、-SONH-、-S(O)
2NH-、-NHSO-、-NHS(O)
2-、-C(O)NH-、-NHC(O)-、-NHC(O)NH-、-CH
2-其中的一种;例如为-O-、-S-、-CO-、-NH-、-SONH-、-S(O)
2NH-、-NHSO-、-NHS(O)
2-、-C(O)NH-、-NHC(O)-、-NHC(O)NH-其中的一种;再例如为-O-、-S-、-CO-、-NH-、-S(O)
2NH-、-NHS(O)
2-、-C(O)NH-、-NHC(O)-、-NHC(O)NH-其中的一种。
在本发明的一些实施方案中,Y选自键、-H、-OH、-NH
2、卤素、-O-、-S-、-CO-、-CHF-、-CF
2-、-SO-、-SO
2-、-NH-、-S(O)NH-、-S(O)
2NH-、-NHS(O)-、-NHS(O)
2-、-C(O)NH-、-NHC(O)-、-CH
2-其中的一种;例如为键、H、OH、NH
2、卤素、-O-、-S-、-CO-、-SO
2-、-NH-、-S(O)
2NH-、-NHS(O)
2-、-C(O)NH-、-NHC(O)-、-CH
2-其中的一种。
在本发明的一些实施方案中,o=0,1,2。
在本发明的一些实施方案中,G
1和G
3分别独立地选自氢或甲基;或者G
1和G
3连接起来形成一个任选取代的C
5-6的碳环结构。
在进一步的实施方案中,G
1和G
3连接起来形成一个任选取代的C
5-6环烷基结构。
在本发明的一些实施方案中,G
2选自氢、氟、羟基、氨基、甲基、环丙基、甲氧基、甲硫基、甲胺基其中的一种;例如为氟、羟基、氨基其中的一种。
在本发明的一些实施方案中,R
2每次出现时,独立选自氢、卤素、羟基、巯基、氨基、氰基、甲基、乙基、三氟甲基、二氟甲基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、环丙基、环丁基、环己基、环戊基、苯基、吡啶基、嘧啶基。
在本发明的一些实施方案中,R
3独立地选自可被氢、卤素、羟基、巯基、氨基、氰基、C
1-6烷基、C
3-6环烷基、4-6元杂环烷基、苯基、5-6元杂芳基中的一个或多个任意取代的甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、环丙基、环丁基、环己基、环戊基、苯基、吡啶基、嘧啶基。
在本发明的一些实施方案中,D选自键、-NH-其中的一种,f选自0,1,2,3。
在本发明的一些实施方案中,G
4选自以下基团:任选取代的C
1-12烷基、任选取代的C
2-12烯基、任选取代的C
2-12炔基、任选取代的C
3-6环烷基、任选取代的4-6元杂环基、任选取代的C
6-10芳基、任选取代的5-10元杂芳基中的一种;所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、 巯基、氨基、氰基、三氟甲基、二氟甲基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、甲胺基、乙胺基、正丙胺基、异丙胺基、正丁胺基、异丁胺基、叔丁胺基、仲丁胺基的取代基所取代。
在本发明的一些实施方案中,G
4选自:
其中,R
11和R
12独立选自氢、卤素、羟基、巯基、氨基、氰基、-R
3、-OR
3、-NH-R
3、-N(R
3)R
3、
其中,R
3每次出现独立地选自可被氢、卤素、羟基、巯基、氨基、氰基、C
1-6烷基、C
3-6环烷基、4-6元杂环烷基、苯基、5-6元杂芳基中的一个或多个任意取代的C
1-6烷基、C2-6烯基、C2-6炔基、C
3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基;D选自键、NH、N(CH
3)、O、S其中的一种,f=0,1,2,3,4,5,6,7,8。
在上述实施方案中,R
3独立地选自可被氢、卤素、羟基、巯基、氨基、氰基、C
1-6烷基、C
3-6环烷基、4-6元杂环烷基、苯基、5-6元杂芳基中的一个或多个任意取代的甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、环丙基、环丁基、环己基、环戊基、苯基、吡啶基、嘧啶基。
在上述实施方案中,D选自键、-NH-其中的一种,f选自0,1,2,3。
在本发明的一些实施方案中,D选自键、-NH-其中的一种,f选自0,1,2,3;R
3选自可被氢、卤素、羟基、巯基、氨基、氰基、C
1-6烷基、C
3-6环烷基、4-6元杂环烷基、苯基、5-6元杂芳基中的一个或多个任意取代的氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、环丙基、环丁基、环戊基、环己基、苯基、吡啶基中的一种。
在上述实施方案中,D选自键、-NH-其中的一种,f选自0,1,2,3;R
3选自可被氢、卤素、羟基、巯基、氨基、氰基、C
1-6烷基、C
3-6环烷基中的一个或多个任意取代的氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、环丙基、环丁基、环戊基、环己基、苯基、吡啶基中的一种。
在上述实施方案中,D选自键、-NH-其中的一种,f选自0,1,2,3;R
3选自可被氢、卤素、羟基中的一个或多个任意取代的氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、环丙基、环丁基、环戊基、环己基、苯基、吡啶基中的一种。
在本发明的一些实施方案中,D选自键、-NH-其中的一种,f选自0,1,2,3;R
3独立地选自可被氢、卤素、羟基、巯基、氨基、氰基、C
1-6烷基、C
3-6环烷基、4-6元杂环烷基、苯基、5-6元杂芳基中的一个或多个任意取代的呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基、噁唑基;例如,R
3独立地选自可被氢、卤素、羟基、巯基、氨基、氰基、C
1-3烷基中的一个或多个任意取代的呋喃基、噻吩基、吡咯基、吡唑基、 咪唑基、噻唑基、噁唑基;例如,R
3独立地选自可被氢、卤素、甲基中的一个或多个任意取代的吡唑基。
在本发明的一些实施方案中,A可独立选自-NH-、-CH
2-或-CH(NH
2)-,m=0或1;B可独立选自-N-或-CH-;C可独立选自-NH-或-CH
2-,n=0或1;A,B,C至少有一个为符合各自定义的取代的N原子。
在本发明的一些实施方案中,H环选自:
其中,R
13选自氢、卤素、羟基、巯基、氨基、氰基、任选取代的-R
4、任选取代的-OR
4、任选取代的-NH-R
4、任选取代的-N(R
4)R
4;其中,R
4每次出现独立地选自C
1-6烷基、C2-6烯基、C2-6炔基、C
3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基;所述任选取代是指被取代基团上的H未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、巯基、氨基、氰基、C
1-6烷基、C2-6烯基、C2-6炔基、C
3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基所取代。
在上述实施方案中,R
13选自氢、卤素、羟基、巯基、氨基、氰基、任选取代的-R
4、任选取代的-OR
4、任选取代的-NH-R
4、任选取代的-N(R
4)R
4;其中,R
4每次出现独立地选自C
1-6烷基、4-6元杂环基、苯基、5-6元杂芳基;所述任选取代是指被取代基团上的H未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、巯基、氨基、氰基、C
1-6烷基、C
3-6环烷基、苯基所取代。
在更进一步的实施方案中,式(II)
A可选自:
在更进一步的实施方案中,式(II)
B可选自:
在更进一步的实施方案中,式(II)
C可选自:
在本发明的一些实施方案中,式(II)
A选自:
O=1或2;
X选自-O-、-S-、-CH2-、-N(R
5)-,R
5独立地选自氢或任选取代的C
1-6烷基(如甲基);
G1选自氢,
G2选自羟基或氨基;
G3选自氢;
Y选自键、-NH
2、-OH、-NH-;和
G4选自任选取代的4-6元杂环基、任选取代的5-10元杂芳基(如
);其中,R11选自氢或C
1-6烷基(如甲基);R12选自
其中D选自键;f=0;每个R3均独立选自C
1-6烷基、任选被C
1-6烷基(如甲基)取代的5-6元杂芳基(如5元含氮杂芳基)。
O=1;
X选自S或NH;
G1选自氢;
G2选自羟基;
G3选自氢;
Y选自-NH-;和
在本发明的一些实施方案中,式(I)所示的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物选自如下化合物:
本发明目的还包括提供制备通式(I)所示化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物的方法。
所述方法例如可以使用方案1中示出的方法来制备,可以通过先将并环结构的LG
a(离去基团a)与G
4-YH连接,再将并环结构的LG
b(离去基团b)与XH的侧链进行连接,合成得到目标化合物。方案1如下:
所述方法例如可以使用方案2中示出的方法来制备,可以通过先将并环结构的LG
b(离去基团b)与XH的侧链进行连接,再将将并环结构的LG
a(离去基团a)与G
4-YH连接,合成得到目标化合物。方案2如下:
其中,上述制备方法中,所示化合物中各取代基定义如前所述。
本发明还提供一种药用组合物,其包含本发明所示(I)化合物,或其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物,以及药学上可接受的辅料。所述药物组合物包括但不限于口服剂型、胃肠外给药剂型、外用剂型和直肠给药剂型。在一些实施方式中,所述化合物的施用量例如在约0.001mg/kg体重/天-约10g/kg体重/天的范围内。在其它实施方式中,低于上述范围下限的剂量水平可能已经是足够的。在一些实施方式中,可能需要高于上述范围上限的剂量水平。在一些实施方式中,所述药物组合物施用的个体为哺乳动物,例如人。
本发明的目的还包括提供本发明所示(I)化合物,或其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物在制备治疗由PRMT5抑制剂介导的疾病的药物中的用途。
本发明的目的还包括提供本发明所示(I)化合物,或其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物,其用于治疗PRMT5抑制剂介导的疾病。
本发明的目的还包括提供一种预防和/或治疗由PRMT5抑制剂介导的疾病的方法,其包括向患者施用治疗有效剂量的通式(I)所示化合物,或其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物、同位素标记的类似物或本发明所述药物组合物。
在一些实施例中,本申请所述PRMT5抑制剂介导的疾病为癌症。
定义
除另有规定外,术语“烷基”指一价饱和脂肪族烃基团,包含1-20个碳原子的直链或支链基团,优选包含1-10个碳原子(即C
1-10烷基),进一步优选包含1-8个碳原子(C
1-8烷基),更优选包含1-6个碳原子(即C
1-6烷基),例如“C
1-6烷基”指的是该基团为烷基,且碳链上的碳原子数量在1-6之间(具体地为1个、2个、3个、4个、5个或6个)。实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、新戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、正庚基、正辛基等。
除另有规定外,术语“环烷基”指的是具有特定碳原子数的单环饱和脂烃基,优选地包含3-12个碳原子(即C
3-12环烷基),更优选包含3-10个碳原子(C
3-10环烷基), 进一步优选3-6个碳原子(C
3-6环烷基)、4-6个碳原子(C
4-6环烷基)、5-6个碳原子(C
5-6环烷基)。实例包括但不限于环丙基、环丁基、环戊基、环己基、甲基环丙基、2-乙基-环戊基、二甲基环丁基等。
除另有规定外,术语“烷氧基”指-O-烷基,所述烷基的定义同上,即包含1-20个碳原子,优选地,包含1-10个碳原子,较佳地1-8个碳原子,更佳地1-6个碳原子(具体地为1个、2个、3个、4个、5个或6个)。代表的例子包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、1-甲基丙氧基、2-甲基丙氧基、叔丁氧基、戊氧基、1-甲基丁氧基、2-甲基丁氧基、3-甲基丁氧基、1,1-二甲基丙氧基、1,2-二甲基丙氧基、2,2-二甲基丙氧基、1-乙基丙氧基等。
除另有规定外,术语“烯基”是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂肪族烃基。烯基可以包含2-20个碳原子,优选包含2-10个碳原子(即C
2-10烯基),进一步优选包含2-8个碳原子(C
2-8烯基),更优选包含2-6个碳原子(即C
2-6烯基)、2-5个碳原子(即C
2-5烯基)、2-4个碳原子(即C
2-4烯基)、2-3个碳原子(即C
2-3烯基)、2个碳原子(即C
2烯基),例如“C
2-6烯基”指的是该基团为烯基,且碳链上的碳原子数量在2-6之间(具体地为2个、3个、4个、5个或6个)。烯基的非限制性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基和1,3-丁二烯基等。
除另有规定外,术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个叁键的不饱和脂肪族烃基。炔基可以包含2-20个碳原子,优选包含2-10个碳原子(即C
2-10炔基),进一步优选包含2-8个碳原子(C
2-8炔基),更优选包含2-6个碳原子(即C
2-6炔基)、2-5个碳原子(即C
2-5炔基)、2-4个碳原子(即C
2-4炔基)、2-3个碳原子(即C
2-3炔基)、2个碳原子(即C
2炔基),例如“C
2-6炔基”指的是该基团为炔基,且碳链上的碳原子数量在2-6之间(具体地为2个、3个、4个、5个或6个)。炔基的非限制性实例包括但不限于乙炔基、1-丙炔基、2-丙炔基和1-丁炔基等。
除另有规定外,术语“卤素”或“卤代”是指F、Cl、Br、I。术语“卤代烷基”是指如上所定义的烷基中一个、两个或多个氢原子或全部氢原子被卤素取代。卤代烷基的代表性例子包括CCl
3、CF
3、CHCl
2、CH
2Cl、CH
2Br、CH
2I、CH
2CF
3、CF
2CF
3等。
除另有规定外,术语“杂环基”指饱和或部分不饱和单环、双环或多环环状烃取代基,为非芳香结构,包含3-20个环原子,其中1个、2个、3个或更多个环原子选自N、O或S,其余环原子为C。优选包含3-12个环原子,进一步优选包含3-10个环原子,或 3-8个环原子,或3-6个环原子,或4-6个环原子,或5-6个环原子。杂原子优选1-4个,更优选1-3个(即1个、2个或3个)。单环杂环基的实例包括吡咯烷基、咪唑烷基、四氢呋喃基、二氢吡咯基、哌啶基、哌嗪基、吡喃基等。多环杂环基包括螺环、稠环和桥环的杂环基。杂环基也包括芳香基(如苯基)稠合饱和杂环基的情形。除另有规定外,术语“杂环烷基”指饱和的上述“杂环基”。
除另有规定外,术语“碳环基”或“碳环”是指具有从3到14个环碳原子的一种非芳香族环状烃基(“C
3-14碳环基”)并且在该非芳香族环系统中不具有杂原子。在一些实施例中,碳环基基团具有3-12个环碳原子(“C
3-12碳环基”)、或4-12个环碳原子(“C
4-12碳环基”)、或3到10个环碳原子(“C
3-10碳环基”)。在一些实施例中,碳环基基团具有3到8个环碳原子(“C
3-8碳环基”)。在一些实施例中,碳环基基团具有3到7个环碳原子(“C
3-7碳环基”)。在一些实施例中,碳环基基团具有4到6个环碳原子(“C
4-6碳环基”)。在一些实施例中,碳环基基团具有5到10个环碳原子(“C
5-10碳环基”)、或5到7个环碳原子(“C
5-7碳环基”)。示例性C
3-6碳环基基团包括,但不限于环丙基(C
3)、环丙烯基(C
3)、环丁基(C
4)、环丁烯基(C
4)、环戊基(C
5)、环戊烯基(C
5)、环己基(C
6)、环己烯基(C
6)、环己二烯基(C
6)等。示例性C
3-8碳环基基团包括,但不限于前面提到的C
3-6碳环基基团以及环庚基(C
7)、环庚烯基(C
7)、环庚二烯基(C
7)、环庚三烯基(C
7)、环辛基(C
8)、环辛烯基(C
8)、二环[2.2.1]庚烷基(C
7)、二环[2.2.2]辛烷基(C
8)等。示例性C
3-10碳环基基团包括,但不限于前面提到的C
3-8碳环基基团以及环壬基(C
9)、环壬烯基(C
9)、环癸基(C
10)、环癸烯基(C
10)、八氢-1H-茚基(C
9)、十氢萘基(C
10)、螺[4.5]癸烷基(C
10)等。如上述实例说明,在某些实施例中,该碳环基基团是单环的(“单环碳环基”)或是一种稠合的(稠环基)、桥接的(桥环基)或螺接-稠合(螺环基)的环系统,如一个双环系统(“双环碳环基”)并且可以是饱和的或可以是部分不饱和的。“碳环基”还包括其中如上所定义的该碳环基环被一个或多个芳基或杂芳基基团稠合的环系统,其中附接点是在该碳环基环上,并且在此类情况下,碳的数目继续指示该碳环系统中的碳的数目。在某些实施例中,碳环基基团的每个例子独立地是可任选取代的,例如,未取代的(一种“未取代的碳环基”)或被一个或多个取代基取代的(一种“取代的碳环基”)。在某些实施例中,该碳环基基团是未取代的C
3-10碳环基。在某些实施例中,该碳环基基团是一种取代的C
3-10碳环基。
除另有规定外,术语“芳基”表示含有6-16个碳原子,或6-14个碳原子,或6-12 个碳原子,或6-10个碳原子的单环、双环和三环的芳香碳环体系,优选6-10个碳原子,术语“芳基”可以和术语“芳香环”交换使用。芳基基团的实例可以包括但不限于苯基、萘基、蒽基、菲基或芘基等。
除另有规定外,术语“杂芳基”表示含有5-12元结构,或优选5-10元结构,5-8元结构,更优选5-6元结构的芳香单环或者多环环状系统,其中1个、2个、3个或更多个环原子为杂原子且其余原子为碳,杂原子独立地选自O、N或S,杂原子数量优选为1个、2个或3个。杂芳基的实例包括但不限于呋喃基、噻吩基、噁唑基、噻唑基、异噁唑基、噁二唑基、噻二唑基、吡咯基、吡唑基、咪唑基、三唑基、四唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、硫代二唑基、三嗪基、酞嗪基、喹啉基、异喹啉基、喋啶基、嘌呤基、吲哚基、异吲哚基、吲唑基、苯并呋喃基、苯并噻吩基、苯并吡啶基、苯并嘧啶基、苯并吡嗪基、苯并咪唑基、苯并酞嗪基、吡咯并[2,3-b]吡啶基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基等。
除另有规定外,术语“药物上可接受的盐”、“药用盐”或“可药用盐”是指在合理医学判断范围内适用于与哺乳动物特别是人的组织接触而无过度毒性、刺激、过敏反应等并与合理的效益/风险比相称的盐,比如胺、羧酸和其他类型化合物的医学上可接受的盐在所属领域中是被熟知的。
除另有规定外,术语“盐”包含得自无机酸的盐,也包括自有机酸的盐。如果本发明的化合物为酸性的,则药学上可接受的无毒碱包括无机碱及有机碱制备的盐。
除另有规定外,术语“同位素标记的类似物”是指式I至式II化合物中的一个或一个以上质子可被氘原子取代,从而提供可能具有改善的药理活性的氘代类似物。
除另有规定外,术语“前药”是指在体内转化为母体药物的药物。前药通常是有用的,因为在某些情况下,它们可能比母体药物更容易给药。例如,它们可以通过口服而被生物利用,而母体则不能。与母体药物相比,前药在药物组合物中的溶解度也有所提高。前药的一个例子,但不限于此,可以是任何式I的化合物,其作为酯(“前药”)给药,以促进穿过细胞膜的传递,其中水溶性对迁移性有害,但一旦进入细胞内水溶性是有益的,其随后被代谢水解成羧酸,即活性实体。前药的另一个例子可以是与酸基团结合的短肽(聚氨基酸),其中肽被代谢以显示活性部分。
除另有规定外,术语“溶剂合物”、“溶剂化物”意指本发明化合物与一个或多个溶剂 分子(无论有机的还是无机的)的物理缔合。该物理缔合包括氢键。在某些情形中,例如当一个或多个溶剂分子纳入结晶固体的晶格中时,溶剂化物将能够被分离。溶剂化物中的溶剂分子可按规则排列和/或无序排列存在。溶剂合物可包含化学计量或非化学计量的溶剂分子。“溶剂合物”涵盖溶液相和可分离的溶剂合物。示例性溶剂合物包括但不限于水合物、乙醇合物、甲醇合物和异丙醇合物。溶剂化方法是本领域公知的。
除另有规定外,术语“立体异构体”是指具有相同化学构造,但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体等。所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体,对映异构体,非对映异构体,例如,通过色谱法和/或分步结晶法。
除另有规定外,术语“互变异构体”是指具有不同能量的可通过低能垒互相转化的结构异构体。若互变异构是可能的(如在溶液中),则可以达到互变异构体的化学平衡。例如,质子互变异构体(也称为质子转移互变异构体)包括通过质子迁移来进行的互相转化,如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体包括通过一些成键电子的重组来进行的互相转化。
除非其他方面表明,本发明所描述的结构式包括所有的同分异构形式(如对映异构,非对映异构,和几何异构(或构象异构)):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体,和(Z)、(E)的构象异构体。因此,本发明的化合物的单个立体化学异构体或其对映异构体,非对映异构体,或几何异构体(或构象异构体)的混合物都属于本发明的范围。
除另有规定外,术语“任选取代”指所述基团的可取代位点的氢未被取代,或被一个或多个取代基所取代,所述取代基优先选自下组的取代基:卤素、羟基、巯基、氰基、硝基、氨基、叠氮基、氧代基、羧基、C
2-6链烯基、C
2-6炔基、C
1-6烷基、C
1-6烷氧基、C
3-10环烷基、C
3-10环烷基磺酰基、3-10元杂环烷基、C
6-14芳基或5-10元杂芳环基,其中,所述C
2-6链烯基、C
2-6炔基、C
1-6烷基、C
1-6烷氧基、C
3-10环烷基、C
3-10环烷基磺酰基、3-10元杂环烷基、C
6-14芳基或5-10元杂芳环基可任选地被选自卤素、羟基、氨基、氰基、C
1-6烷基或C
1-6烷氧基中的一个或多个所取代,所述氧代基是指相同取代位的两个H被同一个O替代形成双键。
本发明的有益效果至少在于以下之一:
本发明设计了一类结构新颖的化合物,为PRMT5抑制剂类的药物的发展提供了一个新的方向。体外酶活抑制活性研究显示,这些化合物对PRMT5酶都具有较强的抑制作用,可作为治疗PRMT5抑制剂介导的疾病的前景化合物。此外,本发明研究了特定的合成方法,该合成方法工艺简单,操作便捷,利于规模化工业生产和应用。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件或者按照制造厂商所建议的条件。除非另行定义,文中所使用的所有专业与科学用语与本领域专业人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法之中。文中所示的较佳实施方法与材料仅做示范之用。
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)或/和液相色谱(HPLC)来确定的。NMR的测定使用的仪器是Bruker AVANCE NEO 400MHz,LC-MS使用的仪器是LCMS WATERS ACQUITY UPLC H-Class PLUS或/和SQD2;HPLC使用的仪器是WATERS ACQUITYUPLC或/和Agilent 1260。
本发明实施例中的起始原料是已知的并且可以在市场上买到,或者可以采用或按照本领域已知的方法来合成。
实施例1
1-(3,4-二氢异喹啉-2(1H)-基)-3-((4-(3-氧杂环丁基氨基)吡啶[3,4-d]并嘧啶-8-基)氨基)丙-2-醇的制备
第一步:2-(环氧乙烷-2-甲基)-1,2,3,4-四氢异喹啉(中间体1-a)的制备
将化合物四氢异喹啉(4g,30.04mmol,1.0eq)溶于四氢呋喃(150ml)中, 冷至0℃,氮气保护状态下,加入KF(3.48g,60.08mmol,2.0eq),0℃反1h后,加入化合物间硝基苯磺酸缩水甘油酯(8.8g,33.95mmol,1.13eq),反应液升至室温(20-25℃)反应18小时。检测反应完成后,过滤,浓缩母液,得2-(环氧乙烷-2-甲基)-1,2,3,4-四氢异喹啉粗品6.02g,收率100%。
1H NMR(400MHz,CDCl
3)δ:7.16–7.07(m,3H),7.07–7.00(m,1H),3.85–3.66(m,2H),3.21(tt,J=6.8,2.3Hz,1H),2.99–2.88(m,4H),2.87–2.77(m,2H),2.56(dd,J=5.0,2.7Hz,1H),2.46(dd,J=13.3,6.7Hz,1H)。
第二步:1-氨基-3-(3,4二氢异喹啉-2(1H)-基)-丙-2-醇(中间体1-b)的制备
2-(环氧乙烷-2-甲基)-1,2,3,4-四氢异喹啉(5.6g,29.62mmol,1.0eq)溶于甲醇(150ml)中,加入25%(质量分数)氨水(45.6ml,296.2mmol,10.0eq),反应液升至45℃搅拌过夜。反应完成后,加入二氯甲烷萃取三次,每次40毫升,无水硫酸钠干燥10分钟,过滤,浓缩,粗品柱层析分离得到中间体1-氨基-3-(3,4二氢异喹啉-2(1H)-基)-丙-2-醇3g,收率49%。LCMS:[M+1]
+=207.11。
第三步:3-氨基-2-氯异烟酰胺(中间体1-c)的制备
将原料3-氨基-2-氯异烟酸甲酯(3g,16.1mmol)溶于7摩尔氨气甲醇溶液(120mL),室温(20-25℃)搅拌2天。TLC检测反应完成后,直接浓缩得粗品,加入15毫升乙酸乙酯,15℃打浆10分钟,过滤得到白色固体2.1g,即3-氨基-2-氯异烟酰胺,收率76.14%。LCMS:[M+H]
+=171.95。
第四步:8-氯-3H-吡啶并[3,4-d]嘧啶-4-酮(中间体1-d)的制备
将原料3-氨基-2-氯异烟酰胺(2.1g,12.3mmol)溶于原甲酸三甲酯(60mL),加热回流16小时,检测反应完成后,冷至室温,过滤得粗品固体,加5毫升乙酸乙酯 室温打浆,过滤,干燥得8-氯-3H-吡啶并[3,4-d]嘧啶-4-酮,1.4g白色固体,收率62.9%。LCMS:[M+H]
+=182.06;
1H NMR(400MHz,DMSO)δ:12.85(s,1H),8.44(d,J=5.1Hz,1H),8.32(s,1H),7.97(d,J=5.1Hz,1H)。
第五步:8-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]嘧啶-4-醇(中间体1-e)的制备
将8-氯-3H-吡啶并[3,4-d]嘧啶-4-酮(200mg,1.1mmol)和1-氨基-3-(3,4二氢异喹啉-2(1H)-基)-丙-2-醇(340mg,1.65mmol)溶于NMP(N-甲基吡咯烷酮)(6mL)后,加入三乙胺(0.55g,5.5mmol),反应液升至130℃反应过夜(18小时)。反应完成后将反应液倒入50毫升水中,乙酸乙酯萃取三次,每次15毫升,合并乙酸乙酯相,20毫升水洗一次,20毫升饱和食盐水洗一次,无水硫酸钠干燥10分钟,过滤,浓缩,柱层析分离(MeOH:DCM=1:15)得到8-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]嘧啶-4-醇330mg白色固体,收率85.7%。LCMS:[M+H]
+=352.14。
第六步:1-(3,4-二氢异喹啉-2(1H)-基)-3-((4-(3-氧杂环丁基氨基)吡啶[3,4-d]并嘧啶-8-基)氨基)丙-2-醇(实施例1化合物)的制备
将化合物8-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]嘧啶-4-醇(90mg,0.255mmol)、氧杂环丁烷-3-胺(28mg,0.385mmol)和PyBOP(六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷)(172.5mg,0.33mmol)溶于DMF(N,N-二甲基甲酰胺)(1.5mL)后,加入DBU(1,8-二氮杂二环十一碳-7-烯)(58mg,0.385mmol),室温(10-15℃)搅拌2小时,反应液倒入10毫升水中,乙酸乙酯萃取三次,每次6毫升,合并乙酸乙酯相,10毫升水洗一次,10毫升饱和食盐水洗一次,无水硫酸钠干燥5分钟,过滤,浓缩,制备HPLC纯化得到目标化合物62mg,收率59%。LCMS:[M+H]+=407.44;
1H NMR(400MHz,DMSO-d
6)δ:8.63(d,J=5.3Hz,1H),8.38(s,1H),7.88(s,1H),7.43(t,J=5.5Hz,1H),7.18(d,J=6.0Hz,1H),7.12–7.06 (m,3H),7.04–6.97(m,1H),5.22–5.09(m,1H),5.09(s,1H),4.86(t,J=6.9Hz,2H),4.65(t,J=6.4Hz,2H),4.09–3.89(m,1H),3.73–3.55(m,3H),3.49–3.38(m,1H),2.84(t,J=5.4Hz,2H),2.76(dt,J=11.2,5.5Hz,1H),2.68(dd,J=11.3,6.1Hz,1H),2.58–2.52(m,2H)。
实施例2
(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((4-(3-氧杂环丁基氨基)吡啶[3,4-d]并嘧啶-8-基)氨基)丙-2-醇的制备
第一步:(R)-2-(环氧乙烷-2-甲基)-1,2,3,4-四氢异喹啉(中间体2-a)的制备
将化合物四氢异喹啉(1g,7.51mmol,1.0eq)溶于四氢呋喃(38mL)中,冷至0℃,氮气保护状态下,加入KF(870mg,15.02mmol,2.0eq),0℃反应1h后,加入化合物(S)-(+)-间硝基苯磺酸缩水甘油酯(2.2g,8.49mmol,1.13eq),反应液升至室温反应过夜。检测反应完成后,过滤,浓缩母液,得(R)-2-(环氧乙烷-2-甲基)-1,2,3,4-四氢异喹啉粗品1.5g,收率100%。
1H NMR(400MHz,CDCl
3)δ:7.16–7.07(m,3H),7.07–7.00(m,1H),3.85–3.66(m,2H),3.21(tt,J=6.8,2.3Hz,1H),2.99–2.88(m,4H),2.87–2.77(m,2H),2.56(dd,J=5.0,2.7Hz,1H),2.46(dd,J=13.3,6.7Hz,1H)。
第二步:(S)-1-氨基-3-(3,4二氢异喹啉-2(1H)-基)-丙-2-醇(中间体2-b)的制备
(R)-2-(环氧乙烷-2-甲基)-1,2,3,4-四氢异喹啉(280mg,1.481mmol,1.0eq)溶于甲醇(7.4ml)中,加入25%(质量分数)氨水(2.3ml,14.81mmol,10.0eq),反应液升至45℃搅拌过夜。反应完成后,加入二氯甲烷萃取三次,每次10毫升,无水硫酸 钠干燥10分钟,过滤,浓缩,粗品柱层析分离得到中间体(S)-1-氨基-3-(3,4二氢异喹啉-2(1H)-基)-丙-2-醇147mg,收率48.2%。LCMS:[M+1]
+=207.11。
第三步:(S)-8-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]嘧啶-4-醇(中间体2-c)的制备
将8-氯-3H-吡啶并[3,4-d]嘧啶-4-酮(400mg,2.2mmol)(即中间体1-d,制备方法参见实施例1)和(S)-1-氨基-3-(3,4二氢异喹啉-2(1H)-基)-丙-2-醇(680mg,3.3mmol)溶于NMP(N-甲基吡咯烷酮)(11mL)后,加入三乙胺(1.1g,11mmol),反应液升至130℃反应过夜。反应完成后将反应液倒入50毫升水中,乙酸乙酯萃取三次,每次15毫升,合并乙酸乙酯相,20毫升水洗一次,20毫升饱和食盐水洗一次,无水硫酸钠干燥10分钟,过滤,浓缩,柱层析分离(MeOH:DCM=1:15)得到(S)-8-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]嘧啶-4-醇660mg白色固体,收率85.7%。LCMS:[M+H]
+=352.14。
第四步:(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((4-(3-氧杂环丁基氨基)吡啶[3,4-d]并嘧啶-8-基)氨基)丙-2-醇(实施例2化合物)的制备
将化合物(S)-8-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]嘧啶-4-醇(180mg,0.51mmol)、氧杂环丁烷-3-胺(56mg,0.77mmol)和PyBOP(六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷)(345mg,0.66mmol)溶于DMF(N,N-二甲基甲酰胺)(2.5mL)后,加入DBU(1,8-二氮杂二环十一碳-7-烯)(116mg,0.77mmol),室温(10-15℃)搅拌2小时,反应液倒入10毫升水中,乙酸乙酯萃取三次,每次6毫升,合并乙酸乙酯相,10毫升水洗一次,10毫升饱和食盐水洗一次,无水硫酸钠干燥5分钟,过滤,浓缩,制备HPLC纯化得到目标化合物122mg,收率58.6%。LCMS:[M+H]
+=407.44;
1H NMR(400MHz,DMSO-d
6)δ:8.63(d,J=5.3Hz,1H),8.38(s,1H),7.88(s,1H),7.43(t,J=5.5Hz,1H),7.18(d,J=6.0Hz,1H),7.12–7.06(m,3H),7.04–6.97(m,1H),5.22–5.09(m,1H),5.09(s,1H),4.86 (t,J=6.9Hz,2H),4.65(t,J=6.4Hz,2H),4.09–3.89(m,1H),3.73–3.55(m,3H),3.49–3.38(m,1H),2.84(t,J=5.4Hz,2H),2.76(dt,J=11.2,5.5Hz,1H),2.68(dd,J=11.3,6.1Hz,1H),2.58–2.52(m,2H)。
实施例3
(R)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((4-(3-氧杂环丁基氨基)吡啶[3,4-d]并嘧啶-8-基)氨基)丙-2-醇的制备
第一步:(S)-2-(环氧乙烷-2-甲基)-1,2,3,4-四氢异喹啉(中间体3-a)的制备
将化合物四氢异喹啉(1.8g,13.518mmol,1.0eq)溶于四氢呋喃(75mL)中,冷至0℃,氮气保护状态下,加入KF(1.566g,27.03mmol,2.0eq),0℃反应1h后,加入化合物(R)-氧化乙烯-2-基甲基3-硝基苯磺酸酯(3.96g,15.273mmol,1.13eq),反应液升至室温反应过夜。检测反应完成后,过滤,浓缩母液,得(R)-2-(环氧乙烷-2-甲基)-1,2,3,4-四氢异喹啉粗品2.7g,收率100%。
1H NMR(400MHz,CDCl
3)δ:7.16–7.07(m,3H),7.07–7.00(m,1H),3.85–3.66(m,2H),3.21(tt,J=6.8,2.3Hz,1H),2.99–2.88(m,4H),2.87–2.77(m,2H),2.56(dd,J=5.0,2.7Hz,1H),2.46(dd,J=13.3,6.7Hz,1H)。
第二步:(R)-1-氨基-3-(3,4二氢异喹啉-2(1H)-基)-丙-2-醇(中间体3-b)的制备
(S)-2-(环氧乙烷-2-甲基)-1,2,3,4-四氢异喹啉(1.4g,7.405mmol,1.0eq)溶于甲醇(74mL)中,加入25%(质量分数)氨水(11.3ml,74.05mmol,10.0eq),反应液升至45℃搅拌过夜。反应完成后,加入二氯甲烷萃取三次,每次30毫升,无水硫酸钠干燥10分钟,过滤,浓缩,粗品柱层析分离得到中间体(R)-1-氨基-3-(3,4二氢异 喹啉-2(1H)-基)-丙-2-醇735mg,收率48.2%。LCMS:[M+1]
+=207.11。
第三步:(R)-8-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]嘧啶-4-醇(中间体3-c)的制备
将8-氯-3H-吡啶并[3,4-d]嘧啶-4-酮(400mg,2.2mmol)(即中间体1-d,制备方法参见实施例1)和(R)-1-氨基-3-(3,4二氢异喹啉-2(1H)-基)-丙-2-醇(680mg,3.3mmol)溶于NMP(N-甲基吡咯烷酮)(11mL)后,加入三乙胺(1.1g,11mmol),反应液升至130℃反应过夜。反应完成后将反应液倒入50毫升水中,乙酸乙酯萃取三次,每次15毫升,合并乙酸乙酯相,20毫升水洗一次,20毫升饱和食盐水洗一次,无水硫酸钠干燥10分钟,过滤,浓缩,柱层析分离(MeOH:DCM=1:15)得到(R)-8-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]嘧啶-4-醇660mg白色固体,收率85.7%。LCMS:[M+H]
+=352.14。
第四步:(R)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((4-(3-氧杂环丁基氨基)吡啶[3,4-d]并嘧啶-8-基)氨基)丙-2-醇(实施例3化合物)的制备
将化合物(R)-8-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]嘧啶-4-醇(180mg,0.51mmol)、氧杂环丁烷-3-胺(56mg,0.77mmol)和PyBOP(六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷)(345mg,0.66mmol)溶于DMF(N,N-二甲基甲酰胺)(2.5mL)后,加入DBU(1,8-二氮杂二环十一碳-7-烯)(116mg,0.77mmol),室温(10-15℃)搅拌2小时,反应液倒入10毫升水中,乙酸乙酯萃取三次,每次6毫升,合并乙酸乙酯相,10毫升水洗一次,10毫升饱和食盐水洗一次,无水硫酸钠干燥5分钟,过滤,浓缩,制备HPLC纯化得到目标化合物122mg,收率58.6%。LCMS:[M+H]
+=407.44;
1H NMR(400MHz,DMSO-d
6)δ:8.63(d,J=5.3Hz,1H),8.38(s,1H),7.88(s,1H),7.43(t,J=5.5Hz,1H),7.18(d,J=6.0Hz,1H),7.12–7.06(m,3H),7.04–6.97(m,1H),5.22–5.09(m,1H),5.09(s,1H),4.86(t,J=6.9Hz,2H),4.65(t,J=6.4Hz,2H),4.09–3.89(m,1H),3.73– 3.55(m,3H),3.49–3.38(m,1H),2.84(t,J=5.4Hz,2H),2.76(dt,J=11.2,5.5Hz,1H),2.68(dd,J=11.3,6.1Hz,1H),2.58–2.52(m,2H)。
实施例4
1-(4-((8-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]嘧啶-4-基)氨基)哌啶-1-基)乙-1酮的制备
将化合物8-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]嘧啶-4-醇(180mg,0.51mmol)(即中间体1-e,制备方法参见实施例1)、1-(4-氨基哌啶-1-基)乙-1-酮(56mg,0.77mmol)和PyBOP(六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷)(345mg,0.66mmol)溶于DMF(N,N-二甲基甲酰胺)(2.5mL)后,加入DBU(1,8-二氮杂二环十一碳-7-烯)(116mg,0.77mmol),10-15℃搅拌2小时,反应液倒入10毫升水中乙酸乙酯萃取三次,每次6毫升,合并乙酸乙酯相,10毫升水洗一次,10毫升饱和食盐水洗一次,无水硫酸钠干燥10分钟,过滤,浓缩,制备HPLC制备得到目标化合物24mg,收率9.8%。LCMS:[M+H]
+=476.37;
1H NMR(400MHz,DMSO-d
6)δ:8.57(s,1H),8.11(d,J=6.5Hz,1H),7.83(m,1H),7.44–7.08(m,6H),4.58–4.26(m,5H),3.89(m,1H),3.70–3.49(m,4H),3.42–2.97(m,6H),2.67(t,J=11.7Hz,1H),2.15–1.83(m,5H),1.50(m,2H)。
实施例5
(S)-1-(4-((8-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]嘧啶-4-基)氨基)哌啶-1-基)乙-1酮的制备
将化合物(S)-8-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]嘧啶-4-醇(90mg,0.255mmol)(即中间体2-c,制备方法参见实施例2)、1-(4-氨基哌啶-1-基)乙-1-酮(28mg,0.385mmol)和PyBOP(六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷)(172mg,0.33mmol)溶于DMF(N,N-二甲基甲酰胺)(2.5mL)后,加入DBU(58mg,0.385mmol),10-15℃搅拌2小时,反应液倒入10毫升水中乙酸乙酯萃取三次,每次6毫升,合并乙酸乙酯相,10毫升水洗一次,10毫升饱和食盐水洗一次,无水硫酸钠干燥10分钟,过滤,浓缩,制备-HPLC制备得到目标化合物13mg,收率10%。
LCMS:[M+H]
+=476.37;
1H NMR(400MHz,DMSO-d
6)δ:8.57(s,1H),8.11(d,J=6.5Hz,1H),7.83(m,1H),7.44–7.08(m,6H),4.58–4.26(m,5H),3.89(m,1H),3.70–3.49(m,4H),3.42–2.97(m,6H),2.67(t,J=11.7Hz,1H),2.15–1.83(m,5H),1.50(m,2H)。
实施例6
(R)-1-(4-((8-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]嘧啶-4-基)氨基)哌啶-1-基)乙-1酮的制备
将化合物(R)-8-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]嘧啶-4-醇(180mg,0.51mmol)(即中间体3-c,制备方法参见实施例3)、1-(4-氨基哌啶-1-基)乙-1-酮(56mg,0.77mmol)和PyBOP(六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷)(345mg,0.66mmol)溶于DMF(N,N-二甲基甲酰胺)(2.5mL)后,加入DBU(116mg,0.77mmol),10-15℃搅拌2小时,反应液倒入10毫升水中乙酸乙酯萃取 三次,每次6毫升,合并乙酸乙酯相,10毫升水洗一次,10毫升饱和食盐水洗一次,无水硫酸钠干燥10分钟,过滤,浓缩,制备HPLC制备得到目标化合物26mg,收率10.5%。
LCMS:[M+H]
+=476.37;
1H NMR(400MHz,DMSO-d
6)δ:8.57(s,1H),8.11(d,J=6.5Hz,1H),7.83(m,1H),7.44–7.08(m,6H),4.58–4.26(m,5H),3.89(m,1H),3.70–3.49(m,4H),3.42–2.97(m,6H),2.67(t,J=11.7Hz,1H),2.15–1.83(m,5H),1.50(m,2H)。
实施例7
1-(3,4-二氢异喹啉-2(1H)-基)-3-((8-(3-氧杂环丁基氨基)吡啶[3,4-d]并嘧啶-4基)氨基)丙-2-醇的制备
第一步:1-((8-氯吡啶[3,4-d]嘧啶-4-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(中间体7-a)的制备
将化合物8-氯-3H-吡啶并[3,4-d]嘧啶-4-酮(300mg,1.65mmol)(即中间体1-d,制备方法参见实施例1)、1-氨基-3-(3,4二氢异喹啉-2(1H)-基)-丙-2-醇(512mg,2.49mmol)(即中间体1-b,制备方法参见实施例1)和PyBOP(六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷)(1.12g,2.15mmol)溶于DMF(N,N-二甲基甲酰胺)(8mL)后,加入DBU(377mg,2.49mmol),室温搅拌2小时,反应液倒入10毫升水中,乙酸乙酯萃取三次,每次6毫升,合并乙酸乙酯相,10毫升水洗一次,10毫升饱和食盐水洗一次,无水硫酸钠干燥10分钟,过滤、浓缩得粗品,柱层析分离(MeOH:DCM=1:15)得到550mg 1-((8-氯吡啶[3,4-d]嘧啶-4-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇,收率90%。LCMS:[M+H]
+=370.29。
第二步:1-(3,4-二氢异喹啉-2(1H)-基)-3-((8-(3-氧杂环丁基氨基)吡啶[3,4-d]并嘧啶-4基)氨基)丙-2-醇(实施例7化合物)的制备
将化合物1-((8-氯吡啶[3,4-d]嘧啶-4-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(200mg,0.54mmol)、氧杂环丁烷-3-胺(395mg,5.42mmol),Brettphos(二环己基[3,6-二甲氧基-2',4',6'-三异丙基[1,1'-联苯]-2-基]膦)(30mg,0.05mmol)、Brettphos-Pd-G3(甲磺酸(2-二环己基膦基-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2-氨基-1,1'-联苯-2-基)钯(II))(49mg,0.05mmol)溶于THF(四氢呋喃)(3mL)后,依次加入t-BuONa(叔丁醇钠)(78mg,0.81mmol),升温60℃反应两个小时,反应结束后,反应液倒入10毫升水中,乙酸乙酯萃取三次,每次5毫升,合并乙酸乙酯相,10毫升饱和食盐水洗一次,无水硫酸钠干燥10分钟,过滤、浓缩得到粗品,制备-HPLC得到目标分子40mg,收率18.2%。LCMS:[M+H]
+=407.27;
1H NMR(400MHz,DMSO-d
6)δ:8.49(s,1H),8.32(t,J=5.3Hz,1H),7.84(d,J=5.8Hz,1H),7.78(d,J=5.8Hz,1H),7.15–7.08(m,3H),7.04(t,J=6.3Hz,2H),5.06(dq,J=13.4,6.7Hz,1H),4.98(d,J=4.7Hz,1H),4.79(t,J=6.7Hz,2H),4.64(t,J=6.0Hz,2H),4.09(dd,J=11.2,5.2Hz,1H),3.74–3.66(m,2H),3.61(m,1H),3.50–3.45(m,1H),2.82(d,J=5.6Hz,2H),2.79–2.70(m,2H),2.64–2.53(m,2H)。
实施例8
(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((8-(3-氧杂环丁基氨基)吡啶[3,4-d]并嘧啶-4基)氨基)丙-2-醇的制备
第一步:(S)-1-((8-氯吡啶[3,4-d]嘧啶-4-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(中间体8-a)的制备
将化合物8-氯-3H-吡啶并[3,4-d]嘧啶-4-酮(300mg,1.65mmol)(即中间体1-d, 制备方法参见实施例1)、(S)-1-氨基-3-(3,4二氢异喹啉-2(1H)-基)-丙-2-醇(512mg,2.49mmol)(即中间体2-b,制备方法参见实施例2)和PyBOP(六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷)(1.12g,2.15mmol)溶于DMF(N,N-二甲基甲酰胺)(8mL)后,加入DBU(377mg,2.49mmol),室温搅拌2小时,反应液倒入10毫升水中,乙酸乙酯萃取三次,每次6毫升,合并乙酸乙酯相,10毫升水洗一次,10毫升饱和食盐水洗一次,无水硫酸钠干燥10分钟,过滤、浓缩得粗品,柱层析分离(MeOH:DCM=1:15)得到550mg(S)-1-((8-氯吡啶[3,4-d]嘧啶-4-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇,收率90%。LCMS:[M+H]
+=370.29。
第二步:(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((8-(3-氧杂环丁基氨基)吡啶[3,4-d]并嘧啶-4基)氨基)丙-2-醇(实施例8化合物)的制备
将化合物(S)-1-((8-氯吡啶[3,4-d]嘧啶-4-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(200mg,0.54mmol)、氧杂环丁烷-3-胺(395mg,5.42mmol),Brettphos(二环己基[3,6-二甲氧基-2',4',6'-三异丙基[1,1'-联苯]-2-基]膦)(30mg,0.05mmol)、Brettphos-Pd-G3(甲磺酸(2-二环己基膦基-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2-氨基-1,1'-联苯-2-基)钯(II))(49mg,0.05mmol)溶于THF(四氢呋喃)(3mL)后,依次加入t-BuONa(叔丁醇钠)(78mg,0.81mmol),升温60℃反应两个小时,反应结束后,反应液倒入10毫升水中,乙酸乙酯萃取三次,每次5毫升,合并乙酸乙酯相,10毫升饱和食盐水洗一次,无水硫酸钠干燥10分钟,过滤、浓缩得到粗品,制备-HPLC得到目标分子40mg,收率18.2%。LCMS:[M+H]
+=407.27;
1H NMR(400MHz,DMSO-d
6)δ:8.49(s,1H),8.32(t,J=5.3Hz,1H),7.84(d,J=5.8Hz,1H),7.78(d,J=5.8Hz,1H),7.15–7.08(m,3H),7.04(t,J=6.3Hz,2H),5.06(dq,J=13.4,6.7Hz,1H),4.98(d,J=4.7Hz,1H),4.79(t,J=6.7Hz,2H),4.64(t,J=6.0Hz,2H),4.09(dd,J=11.2,5.2Hz,1H),3.74–3.66(m,2H),3.61(m,1H),3.50–3.45(m,1H),2.82(d,J=5.6Hz,2H),2.79–2.70(m,2H),2.64–2.53(m,2H)。
实施例9
(R)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((8-(3-氧杂环丁基氨基)吡啶[3,4-d]并嘧啶-4基)氨基)丙-2-醇的制备
第一步:(R)-1-((8-氯吡啶[3,4-d]嘧啶-4-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(中间体9-a)的制备
将化合物8-氯-3H-吡啶并[3,4-d]嘧啶-4-酮(300mg,1.65mmol)(即中间体1-d,制备方法参见实施例1)、(R)-1-氨基-3-(3,4二氢异喹啉-2(1H)-基)-丙-2-醇(512mg,2.49mmol)(即中间体3-b,制备方法参见实施例3)和PyBOP(六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷)(1.12g,2.15mmol)溶于DMF(N,N-二甲基甲酰胺)(8mL)后,加入DBU(377mg,2.49mmol),室温搅拌2小时,反应液倒入10毫升水中,乙酸乙酯萃取三次,每次6毫升,合并乙酸乙酯相,10毫升水洗一次,10毫升饱和食盐水洗一次,无水硫酸钠干燥10分钟,过滤、浓缩得粗品,柱层析分离(MeOH:DCM=1:15)得到550mg(S)-1-((8-氯吡啶[3,4-d]嘧啶-4-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇,收率90%。LCMS:[M+H]
+=370.29。
第二步:(R)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((8-(3-氧杂环丁基氨基)吡啶[3,4-d]并嘧啶-4基)氨基)丙-2-醇(实施例9化合物)的制备
将化合物(R)-1-((8-氯吡啶[3,4-d]嘧啶-4-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(200mg,0.54mmol)、氧杂环丁烷-3-胺(395mg,5.42mmol),Brettphos(二环己基[3,6-二甲氧基-2',4',6'-三异丙基[1,1'-联苯]-2-基]膦)(30mg,0.05mmol)、Brettphos-Pd-G3(甲磺酸(2-二环己基膦基-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2-氨基-1,1'-联苯-2-基)钯(II))(49mg,0.05mmol)溶于 THF(四氢呋喃)(3mL)后,依次加入t-BuONa(叔丁醇钠)(78mg,0.81mmol),升温60℃反应两个小时,反应结束后,反应液倒入10毫升水中,乙酸乙酯萃取三次,每次5毫升,合并乙酸乙酯相,10毫升饱和食盐水洗一次,无水硫酸钠干燥10分钟,过滤、浓缩得到粗品,制备HPLC得到目标分子40mg,收率18.2%。LCMS:[M+H]
+=407.27;
1H NMR(400MHz,DMSO-d
6)δ:8.49(s,1H),8.32(t,J=5.3Hz,1H),7.84(d,J=5.8Hz,1H),7.78(d,J=5.8Hz,1H),7.15–7.08(m,3H),7.04(t,J=6.3Hz,2H),5.06(dq,J=13.4,6.7Hz,1H),4.98(d,J=4.7Hz,1H),4.79(t,J=6.7Hz,2H),4.64(t,J=6.0Hz,2H),4.09(dd,J=11.2,5.2Hz,1H),3.74–3.66(m,2H),3.61(m,1H),3.50–3.45(m,1H),2.82(d,J=5.6Hz,2H),2.79–2.70(m,2H),2.64–2.53(m,2H)。
实施例10
1-(4-((4-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]并嘧啶-8-基)氨基)哌啶-1-基)乙-1-酮的制备
按实施例7第二步的合成方法,利用化合物1-((8-氯吡啶[3,4-d]嘧啶-4-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(400mg,1.08mmol)(即中间体7-a,制备方法参见实施例7)和1-(4-氨基哌啶-1-基)乙-1-酮(990mg,5.42mmol),合成得到60mg目标分子1-(4-((4-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]并嘧啶-8-基)氨基)哌啶-1-基)乙-1-酮,收率11.6%。LCMS:[M+H]
+=476.34;
1H NMR(400MHz,DMSO-d
6)δ:8.44(s,1H),8.28(t,J=5.3Hz,1H),7.81(d,J=5.8Hz,1H),7.14–7.06(m,3H),7.05–6.96(m,3H),4.97(d,J=4.1Hz,1H),4.34(d,J=13.6Hz,1H),4.25–4.13(m,1H),4.08(d,J=5.4Hz,1H),3.83(d,J=13.6Hz,1H),3.65(m,3H),3.54–3.41(m,1H),3.16(t,J=11.7Hz,1H),2.75(m,5H),2.57(m,2H),2.05–1.84(m,5H),1.63–1.34 (m,2H)。
实施例11
(S)-1-(4-((4-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]并嘧啶-8-基)氨基)哌啶-1-基)乙-1-酮的制备
按照实施例8的方法,利用化合物(S)-1-((8-氯吡啶[3,4-d]嘧啶-4-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(200mg,0.54mmol)(即中间体8-a,制备方法参见实施例8)和1-(4-氨基哌啶-1-基)乙-1-酮(485mg,2.71mmol),得到22mg目标分子(S)-1-(4-((4-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]并嘧啶-8-基)氨基)哌啶-1-基)乙-1-酮,收率8.5%。LCMS:[M+H]
+=476.34;
1H NMR(400MHz,DMSO-d
6)δ:8.44(s,1H),8.28(t,J=5.3Hz,1H),7.81(d,J=5.8Hz,1H),7.14–7.06(m,3H),7.05–6.96(m,3H),4.97(d,J=4.1Hz,1H),4.34(d,J=13.6Hz,1H),4.25–4.13(m,1H),4.08(d,J=5.4Hz,1H),3.83(d,J=13.6Hz,1H),3.65(m,3H),3.54–3.41(m,1H),3.16(t,J=11.7Hz,1H),2.75(m,5H),2.57(m,2H),2.05–1.84(m,5H),1.63–1.34(m,2H)。
实施例12
(R)-1-(4-((4-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]并嘧啶-8-基)氨基)哌啶-1-基)乙-1-酮的制备
按照实施例9的方法,利用化合物(R)-1-((8-氯吡啶[3,4-d]嘧啶-4-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(200mg,0.54mmol)(即中间体9-a,制备方法参见实施例9)和1-(4-氨基哌啶-1-基)乙-1-酮(485mg,2.71mmol),得到33mg目标分子(R)-1-(4-((4-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)吡啶[3,4-d]并嘧啶-8-基)氨基)哌啶-1-基)乙-1-酮,收率12.8%。LCMS:[M+H]
+=476.34;
1H NMR(400MHz,DMSO-d
6)δ:8.44(s,1H),8.28(t,J=5.3Hz,1H),7.81(d,J=5.8Hz,1H),7.14–7.06(m,3H),7.05–6.96(m,3H),4.97(d,J=4.1Hz,1H),4.34(d,J=13.6Hz,1H),4.25–4.13(m,1H),4.08(d,J=5.4Hz,1H),3.83(d,J=13.6Hz,1H),3.65(m,3H),3.54–3.41(m,1H),3.16(t,J=11.7Hz,1H),2.75(m,5H),2.57(m,2H),2.05–1.84(m,5H),1.63–1.34(m,2H)。
实施例13
(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮的制备
第一步:3-碘-1H-吡唑并[4,3-d]嘧啶-7-醇(中间体13-a)的合成
将化合物7-羟基吡唑并[4,3-d]嘧啶(2g,14.694mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(40mL)中,加入NIS(N-碘丁二酰亚胺)(4.96g,22.041mmol,1.5eq),反应在N
2保护下60℃反应5小时。TLC检测反应完毕后,旋干反应溶剂,将混合物溶于甲醇,抽滤。滤饼用甲醇淋洗,干燥,得到3-碘-1H-吡唑并[4,3-d]嘧啶-7-醇3.46g,收率89.9%。LCMS:[M+1]
+=262.87;
1H NMR(400MHz,DMSO-d
6)δ:14.55(s,1H), 12.41(s,1H),7.92(d,J=3.3Hz,1H)。
第二步:3-碘-1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇(中间体13-b)的合成
将化合物3-碘-1H-吡唑并[4,3-d]嘧啶-7-醇(1.50g,5.725mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(28mL)中,加入碳酸铯(2.24g,6.870mmol,1.2eq),0℃下滴加SEMCl(
2-(三甲基硅烷基)乙氧甲基氯)(1.0mL,5.725mmol,1.0eq),反应在20℃过夜反应16小时。TLC检测反应完毕后,反应液用二氯甲烷萃取,无水硫酸钠干燥。有机相浓缩,柱层析纯化,得到3-碘-1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇1.21g,收率53.8%。LCMS:[M+1]
+=393.12。
第三步:1-(4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮(中间体13-c)的合成
将化合物3-碘-1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇(0.60g,1.530mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(8mL)中,加入化合物1-乙酰基哌啶-4-胺盐酸盐(0.41g,2.294mmol,1.5eq)、PyBOP(六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷)(1.03g,1.988mmol,1.3eq)及DBU(1,8-二氮杂二环十一碳-7-烯)(0.69mL,4.589mmol,3.0eq),反应在20℃反应1小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取,无水硫酸钠干燥。有机相浓缩,柱层析纯化,得到1-(4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮598mg,收率75.7%。LCMS:[M+1]
+=517.21。
第四步:(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮(中间体13-d)的合成
将化合物1-(4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮(200mg,0.387mmol,1.0eq)溶于DMSO(二甲基亚砜)(4mL)中,加入化合物(S)-1-氨基-3-(3,4二氢异喹啉-2(1H)-基)-丙-2-醇(160mg,0.775mmol,2.0eq)(即中间体2-b,制备方法参见实施例2)、CuI(碘化亚铜)(15mg,0.077mmol,0.2eq)、碳酸钾(268mg,1.936mmol,5.0eq)及L-Prolinol(L-脯氨醇)(16mg,0.155mmol,0.4eq),反应在N
2保护下80℃反应20小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取,无水硫酸钠干燥。有机相浓缩,柱层析纯化,得到(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮32mg,收率13.9%。LCMS:[M+1]
+=595.39。
第五步:(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮(实施例13化合物)的合成
将第四步得到的化合物(26mg,0.044mmol,1.0eq)溶于盐酸的1,4-二氧六环溶液(4M,1.2mL)中,反应在20℃反应1.5小时。TLC检测反应完毕后,反应液用饱和碳酸氢钠水溶液淬灭,二氯甲烷萃取,无水硫酸钠干燥。有机相浓缩,制备HPLC纯化,得到18mg目标化合物(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮,收率90.0%。LCMS:[M+1]
+=465.20;
1H NMR(400MHz,CDCl
3)δ:11.13(s,1H),8.27(s,1H),7.13(ddt,J=12.9,6.7,3.1Hz,3H),7.02–6.97(m,1H),6.83(s,1H),4.63(d,J=13.6Hz,1H),4.48(s,1H),4.19(dd,J=9.2,5.4Hz,1H),3.88(t,J=12.4Hz,2H),3.73(d,J=15.0Hz,1H),3.66(dd,J=13.4,3.5Hz,1H),3.45(dd,J=13.6,5.8Hz,1H),3.32(t,J=12.9Hz,1H),3.03–2.96(m,1H),2.93(dd,J=7.3,4.7Hz,2H),2.90–2.82(m,2H),2.79(dd,J=12.5,9.6Hz,1H),2.69(dd,J=12.5,3.9Hz,1H),2.35(d,J=13.1Hz,2H),2.14(s, 3H),2.08(d,J=12.5Hz,2H),1.38(dd,J=23.1,12.0Hz,2H)。
实施例14
(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮的制备
按实施例13的方法,利用1-(4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮(400mg,0.774mmol,1.0eq)(即中间体13-c,制备方法参见实施例13)和原料(R)-1-氨基-3-(3,4二氢异喹啉-2(1H)-基)-丙-2-醇(320mg,1.55mmol,2.0eq)(即中间体3-b,制备方法参见实施例3)进行偶联反应得到中间体(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮(97mg,收率21%)(中间体14-a),脱掉SEM保护基得到64mg目标分子(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮,收率85%。LCMS:[M+1]
+=465.20;
1H NMR(400MHz,CDCl
3)δ:11.13(s,1H),8.27(s,1H),7.13(ddt,J=12.9,6.7,3.1Hz,3H),7.02–6.97(m,1H),6.83(s,1H),4.63(d,J=13.6Hz,1H),4.48(s,1H),4.19(dd,J=9.2,5.4Hz,1H),3.88(t,J=12.4Hz,2H),3.73(d,J=15.0Hz,1H),3.66(dd,J=13.4,3.5Hz,1H),3.45(dd,J=13.6,5.8Hz,1H),3.32(t,J=12.9Hz,1H),3.03–2.96(m,1H),2.93(dd,J=7.3,4.7Hz,2H),2.90–2.82(m,2H),2.79(dd,J=12.5,9.6Hz,1H),2.69(dd,J=12.5,3.9Hz,1H),2.35(d,J=13.1Hz,2H),2.14(s,3H),2.08(d,J=12.5Hz,2H),1.38(dd,J=23.1,12.0Hz,2H)。
实施例15
1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1H-吡唑并[4,3-d]嘧啶 -7-基)氨基)哌啶-1-基)乙酮的制备
按实施例13的方法,利用1-(4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮(600mg,1.161mmol,1.0eq)(即中间体13-c,制备方法参见实施例13)和1-氨基-3-(3,4二氢异喹啉-2(1H)-基)-丙-2-醇(480mg,2.322mmol,2.0eq)(即中间体1-b,制备方法参见实施例1)进行偶联反应得到消旋中间体1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮(172.7mg,收率25%)(中间体15-a),脱掉SEM保护基得到115mg目标分子1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮,收率85%。LCMS:[M+1]
+=465.20;
1H NMR(400MHz,CDCl
3)δ:11.13(s,1H),8.27(s,1H),7.13(ddt,J=12.9,6.7,3.1Hz,3H),7.02–6.97(m,1H),6.83(s,1H),4.63(d,J=13.6Hz,1H),4.48(s,1H),4.19(dd,J=9.2,5.4Hz,1H),3.88(t,J=12.4Hz,2H),3.73(d,J=15.0Hz,1H),3.66(dd,J=13.4,3.5Hz,1H),3.45(dd,J=13.6,5.8Hz,1H),3.32(t,J=12.9Hz,1H),3.03–2.96(m,1H),2.93(dd,J=7.3,4.7Hz,2H),2.90–2.82(m,2H),2.79(dd,J=12.5,9.6Hz,1H),2.69(dd,J=12.5,3.9Hz,1H),2.35(d,J=13.1Hz,2H),2.14(s,3H),2.08(d,J=12.5Hz,2H),1.38(dd,J=23.1,12.0Hz,2H)。
实施例16
(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(噁丁环-3-基氨基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙烷-2-醇的制备
第一步:3-碘-N-(噁丁环-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-胺(中间体16-a)的合成
将化合物3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(590mg,1.504mmol,1.0eq)(即中间体13-b,制备方法参见实施例13)溶于DMF(N,N-二甲基甲酰胺)(8mL)中,加入化合物噁丁环-3-胺(165mg,2.256mmol,1.5eq)、PyBOP(六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷)(1.02g,1.955mmol,1.3eq)及DBU(1,8-二氮杂二环十一碳-7-烯)(0.34mL,2.256mmol,1.5eq),反应在20℃反应1小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取,无水硫酸钠干燥。有机相浓缩,柱层析纯化,得到3-碘-N-(噁丁环-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-胺(中间体16-a)402mg,收率59.7%。LCMS:[M+1]
+=448.03。
第二步:(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(噁丁环-3-基氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙烷-2-醇(中间体16-b)的合成
将化合物3-碘-N-(噁丁环-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-胺(190mg,0.425mmol,1.0eq)溶于DMSO(二甲基亚砜)(4mL)中,加入化合物(S)-1-氨基-3-(3,4二氢异喹啉-2(1H)-基)-丙-2-醇(175mg,0.849mmol,2.0eq)(即中间体2-b,制备方法参见实施例2)、CuI(碘化亚铜)(16mg,0.085mmol,0.2eq)、碳酸钾(293mg,2.124mmol,5.0eq)及L-Prolinol(L-脯氨醇)(17mg,0.170mmol,0.4eq),反应在N
2保护下80℃反应18小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取,无水硫酸钠干燥。有机相浓缩,柱层析纯化,得到36mg化合物(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(噁丁环-3-基氨基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙烷-2-醇,收率16.1%。LCMS:[M+1]
+=526.32。
第三步:(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(噁丁环-3-基氨基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙烷-2-醇(实施例16化合物)的合成
将化合物(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(噁丁环-3-基氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙烷-2-醇(36mg,0.068mmol,1.0eq)溶于盐酸的1,4-二氧六环溶液(摩尔浓度:4摩尔/升)(2mL)中,反应在20℃反应1小时。TLC检测反应完毕后,反应液用饱和碳酸氢钠水溶液淬灭,二氯甲烷萃取,氯仿/异丙醇(7:3)萃取,无水硫酸钠干燥。有机相浓缩,制备HPLC纯化,得到目标化合物6mg,收率22.2%。LCMS:[M+1]
+=396.18;
1H NMR(400MHz,DMSO-d
6)δ:12.39(s,1H),7.69(s,1H),7.15–7.06(m,3H),7.05–6.99(m,1H),5.20(s,1H),4.88–4.67(m,2H),4.25(dtd,J=10.6,6.7,4.0Hz,1H),4.13–4.04(m,1H),3.99–3.89(m,2H),3.64–3.54(m,2H),3.44–3.35(m,3H),3.19–3.11(m,1H),2.81(t,J=5.8Hz,2H),2.70(dq,J=17.2,5.6Hz,2H),2.60–2.43(m,2H)。
实施例17
(R)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(噁丁环-3-基氨基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙烷-2-醇的制备
按实施例16的方法,利用原料化合物3-碘-N-(噁丁环-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-胺(380mg,0.85mmol,1.0eq)(中间体16-a,制备方法参见实施例16)和原料(R)-1-氨基-3-(3,4二氢异喹啉-2(1H)-基)-丙-2-醇(350mg,1.7mmol,2.0eq)(中间体3-b,制备方法参见实施例3)进行偶 联反应得到中间体(R)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(噁丁环-3-基氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙烷-2-醇(42.4mg,收率19%)(中间体17-a),脱掉SEM保护基得到4.8mg目标分子(R)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(噁丁环-3-基氨基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙烷-2-醇,收率15%。LCMS:[M+1]
+=396.18,;
1H NMR(400MHz,DMSO-d
6)δ12.39(s,1H),7.69(s,1H),7.15–7.06(m,3H),7.05–6.99(m,1H),5.20(s,1H),4.88–4.67(m,2H),4.25(dtd,J=10.6,6.7,4.0Hz,1H),4.13–4.04(m,1H),3.99–3.89(m,2H),3.64–3.54(m,2H),3.44–3.35(m,3H),3.19–3.11(m,1H),2.81(t,J=5.8Hz,2H),2.70(dq,J=17.2,5.6Hz,2H),2.60–2.43(m,2H)。
实施例18
1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(噁丁环-3-基氨基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙烷-2-醇的制备
按实施例16的方法,利用原料化合物3-碘-N-(噁丁环-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-胺(760mg,1.7mmol,1.0eq)(即中间体16-a,制备方法参见实施例16)和原料1-氨基-3-(3,4二氢异喹啉-2(1H)-基)-丙-2-醇(700mg,3.4mmol,2.0eq)(即中间体1-b,制备方法参见实施例1)进行偶联反应得到消旋中间体1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(噁丁环-3-基氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙烷-2-醇(134mg,收率15%)(中间体18-a),脱掉SEM保护基得到20mg目标分子1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(噁丁环-3-基氨基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙烷-2-醇,收率20%。LCMS:[M+1]
+=396.18;
1H NMR(400MHz,DMSO-d
6)δ:12.39(s,1H),7.69(s,1H),7.15–7.06(m,3H),7.05–6.99(m,1H),5.20(s,1H),4.88–4.67(m,2H),4.25(dtd,J=10.6,6.7,4.0Hz,1H),4.13–4.04(m, 1H),3.99–3.89(m,2H),3.64–3.54(m,2H),3.44–3.35(m,3H),3.19–3.11(m,1H),2.81(t,J=5.8Hz,2H),2.70(dq,J=17.2,5.6Hz,2H),2.60–2.43(m,2H)。
实施例19
(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备
第一步:3-碘-1-甲基-1H-吡唑并[4,3-d]嘧啶-7-酚(中间体19-a)和3-碘-2-甲基-2H-吡唑并[4,3-d]嘧啶-7-酚(中间体19-b)的制备
将氢化钠(质量分数60%)(230mg,5.73mmol,1.5eq)加到100mL三口烧瓶中,在0℃,氮气保护条件下加入20mL无水DMF(N,N-二甲基甲酰胺),搅拌15min后,加入化合物3-碘-1氢-吡唑并[3,4-d]嘧啶-4(5H)-酮(1g,3.82mmol,1.0eq)(即中间体13-a,制备方法参见实施例13)缓慢滴加。在此条件下搅拌30min后,加入碘甲烷(596mg,4.2mmol,1.1eq),滴加完毕后,升温至室温,继续搅拌两小时。向反应体系加入5mL饱和氯化铵溶液和50mL水。用乙酸乙酯萃取三次(3×20mL),合并有机相,用20mL饱和氯化钠溶液洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩,柱层析分离(MeOH:DCM=1:20)得两个中间体3-碘-1-甲基-1H-吡唑并[4,3-d]嘧啶-7-酚(440mg淡黄色固体,收率27.8%,LCMS:[M+H]
+=277.09。)和3-碘-2-甲基-2H-吡唑并[4,3-d]嘧啶-7-酚(150mg淡黄色固体,收率9.5%,LCMS:[M+H]
+=277.09)。
第二步:1-(4-((3-碘-1-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙-1-酮(中间体19-c)的制备
将化合物3-碘-1-甲基-1H-吡唑并[4,3-d]嘧啶-7-酚(100mg,0.364mmol,1.0eq)、1-(4-氨基哌啶-1-基)乙-1-酮(97.5mg,545mmol,1.5eq)和六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(246mg,0.473mmol,1.3eq)溶于1.8mL DMF(N,N-二甲基甲酰胺),置换氮气三次。再加入DBU(1,8-二氮杂二环十一碳-7-烯)(166mg,1.092mmol,3eq),在室温(20-25℃)下搅拌1h,TLC检测原料反应完全。向反应体系加入20mL水,用乙酸乙酯萃取三次(3×20mL),合并有机相,用20mL饱和氯化钠溶液洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩,制备HPLC提纯得60mg(4-((3-碘-1-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙-1-酮,白色固体,收率41.3%。LCMS:[M+H]
+=401.15;
1H NMR(400MHz,DMSO-d
6)δ:8.31–8.20(m,1H),6.91(d,J=7.8Hz,1H),4.45(ddd,J=10.3,8.8,5.2Hz,1H),4.39(d,J=13.3Hz,1H),4.26(s,3H),3.87(d,J=14.0Hz,1H),3.22–3.12(m,1H),2.69(td,J=12.8,2.6Hz,1H),2.02(d,J=10.9Hz,3H),2.00–1.88(m,2H),1.7–1.48(m,2H)。
第三步:(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(实施例19化合物)的制备
将化合物(4-((3-碘-1-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙-1-酮(60mg,0.149mmol,1.0eq)溶于DMSO(二甲亚砜)(0.7mL)中,加入化合物(S)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(46.2mg,0.224mmol,1.5eq)(即中间体2-b,制备方法参见实施例2)、CuI(碘化亚铜)(5.6mg,0.0298mmol,0.2eq)、碳酸钾(102.8mg,0.745mmol,5.0eq)及L-prolinol(L-脯氨醇)(6mg,0.0596mmol,0.4eq),反应在N
2保护下80℃反应20小时。TLC检测反应完毕后,向反应 体系加入15mL水,用乙酸乙酯萃取三次(3×20mL),合并有机相,用20mL饱和氯化钠溶液洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩,制备-HPLC提纯得12mg目标分子(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮,收率16.8%。LCMS:[M+1]
+=479.31;
1H NMR(400MHz,CDCl
3)δ:8.29(s,1H),7.24–7.10(m,3H),7.02(dd,J=9.2,6.9Hz,1H),4.86(d,J=7.4Hz,2H),4.64(d,J=13.7Hz,1H),4.52–4.40(m,1H),4.24(s,1H),4.06–3.82(m,5H),3.65(d,J=13.1Hz,1H),3.46(s,1H),3.35–3.24(m,1H),2.88(dd,J=39.2,26.6Hz,6H),2.31(d,J=12.7Hz,1H),2.23–2.10(m,4H),1.48(tt,J=16.6,8.2Hz,2H)。
实施例20
(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备
按实施例19的方法,利用化合物(4-((3-碘-1-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙-1-酮(180mg,0.45mmol,1.0eq)(即中间体19-c,制备方法参见实施例19)和原料化合物(R)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(141mg,0.672mmol,1.5eq)(即中间体3-b,制备方法参见实施例3)进行偶联反应得到36mg目标分子(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮,收率17%。LCMS:[M+1]
+=479.31;
1H NMR(400MHz,CDCl
3)δ:8.29(s,1H),7.24–7.10(m,3H),7.02(dd,J=9.2,6.9Hz,1H),4.86(d,J=7.4Hz,2H),4.64(d,J=13.7Hz,1H),4.52–4.40(m,1H),4.24(s,1H),4.06–3.82(m,5H),3.65(d,J=13.1Hz,1H),3.46(s,1H),3.35–3.24(m,1H),2.88(dd,J=39.2,26.6Hz,6H),2.31(d,J=12.7Hz,1H),2.23–2.10(m,4H),1.48(tt,J=16.6,8.2Hz,2H)。
实施例21
(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备
按实施例19的方法,利用化合物(4-((3-碘-1-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙-1-酮(180mg,0.45mmol,1.0eq)(即中间体19-c,制备方法参见实施例19)和原料化合物(R)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(141mg,0.672mmol,1.5eq)(即中间体1-b,制备方法参见实施例1)进行偶联反应得到36mg目标分子(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮,收率17%。LCMS:[M+1]
+=479.31;
1H NMR(400MHz,CDCl
3)δ:8.29(s,1H),7.24–7.10(m,3H),7.02(dd,J=9.2,6.9Hz,1H),4.86(d,J=7.4Hz,2H),4.64(d,J=13.7Hz,1H),4.52–4.40(m,1H),4.24(s,1H),4.06–3.82(m,5H),3.65(d,J=13.1Hz,1H),3.46(s,1H),3.35–3.24(m,1H),2.88(dd,J=39.2,26.6Hz,6H),2.31(d,J=12.7Hz,1H),2.23–2.10(m,4H),1.48(tt,J=16.6,8.2Hz,2H)。
实施例22
(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-2-甲基-2H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备
按实施例19的方法,利用3-碘-2-甲基-2H-吡唑并[4,3-d]嘧啶-7-酚(即中间体19-b,制备方法参见实施例19)做起始原料,合成得到目标分子(S) -1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-2-甲基-2H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮。LCMS:[M+1]
+=479.31。
实施例23
(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-2-甲基-2H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备
按实施例19的方法,利用3-碘-2-甲基-2H-吡唑并[4,3-d]嘧啶-7-酚(即中间体19-b,制备方法参见实施例19)做起始原料,合成得到目标分子(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-2-甲基-2H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮。LCMS:[M+1]
+=479.31。
实施例24
1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-2-甲基-2H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备
按实施例19的方法,利用3-碘-2-甲基-2H-吡唑并[4,3-d]嘧啶-7-酚(即中间体19-b,制备方法参见实施例19)做起始原料,合成得到目标分子1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-2-甲基-2H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮。LCMS:[M+1]
+=479.31。
实施例25
(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[3,4-c]吡啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备
第一步:7-氯-3-碘-1H-吡唑并[3,4-c]吡啶(中间体25-a)的制备
将化合物7-氯-1H-吡唑并[3,4-c]吡啶(2g,13mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(40mL)中,加入NIS(N-碘代丁二酰亚胺)(4.4g,19.5mmol,1.5eq),反应在N
2保护下60℃反应4小时。TLC检测反应完毕后,旋干反应溶剂,将混合物溶于乙醇,15-20度搅拌30分钟,抽滤。滤饼用乙醇淋洗,干燥,得到7-氯-3-碘-1H-吡唑并[3,4-c]吡啶,黄色固体3g,收率82.4%。LCMS:[M+H]
+=279.84;
1H NMR(400MHz,DMSO)δ:14.64(s,1H),8.10(d,J=5.6Hz,1H),7.52(d,J=5.6Hz,1H)。
第二步:7-氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-c]吡啶(中间体25-b)的制备
将化合物7-氯-3-碘-1H-吡唑并[3,4-c]吡啶(1g,3.58mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(4mL)中,0℃下滴加到氢化钠(215mg,5.37mmol,1.5eq)的DMF(N,N-二甲基甲酰胺)悬浊液中(4mL),并搅拌30分钟。0℃下滴加SEMCl(2-(三甲硅烷基)乙氧甲基氯)(776mg,4.65mmol,1.3eq),室温搅拌1小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取,无水硫酸钠干燥。有机相浓缩,柱层析纯化,得到7-氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-c]吡啶,透明结晶固体920mg,收率62.7%。LCMS:[M+H]
+=409.95:
1H NMR(400MHz,DMSO-d
6)δ:8.38–8.24(m,1H),7.87–7.48(m,1H),6.12(s,2H),3.70(t,J=7.8Hz,2H),0.91(t,J=7.8Hz,2H),0.04–-0.06(m,9H)。
第三步:(S)-1-((7-氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-c]吡啶-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(中间体25-c)的制备
将化合物7-氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-c]吡啶(500mg,1.22mmol,1.0eq)化合物(S)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(302mg,1.46mmol,1.2eq)、碘化亚铜(93mg,0.49mmol,0.4eq)、碳酸钾(840mg,6.1mmol,5.0eq)及L-脯氨酸(56mg,0.49mmol,0.4eq)溶于DMSO(6mL)中,反应在N
2保护下80℃反应18小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取,无水硫酸钠干燥。有机相浓缩,柱层析纯化,得到(S)-1-((7-氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-c]吡啶-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇,黄色固体360mg,收率60%。LCMS:[M+H]
+=488.24;
1H NMR(400MHz,DMSO-d
6)δ:8.10(d,J=5.3Hz,1H),8.00(d,J=5.3Hz,1H),7.24(dd,J=5.5,3.6Hz,3H),7.17(d,J=4.5Hz,1H),6.80(s,1H),5.91–5.85(m,2H),4.94(d,J=4.0Hz,1H),4.21(s,1H),3.87–3.72(m,2H),3.68(dd,J=14.2,6.3Hz,3H),3.38–3.27(m,1H),3.00–2.82(m,5H),2.73(s,1H),0.90(t,J=7.8Hz,2H),0.06–-0.15(m,9H)。
第四步:(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-c]吡啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(中间体25-d)的制备
将化合物(S)-1-((7-氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-c]吡啶-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(300mg,0.616mmol,1.0eq),化合物1-(4-氨基哌啶-1-基)乙烷-1-酮盐酸(132mg,0.74mmol,1.2eq)、Ru-phos(29mg,0.06mmol,0.1eq)、Ru-phos-G3(52mg,0.06mmol,0.1eq)及叔丁醇钠(178mg,1.85mmol,3.0eq),溶于四氢呋喃(3mL)中,反应在N
2保护下60℃反应1小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取,无水硫酸钠干燥。 有机相浓缩,柱层析纯化,得到(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-c]吡啶-7-基)氨基)哌啶-1-基)乙烷-1-酮,黄色固体170mg,收率46.6%。LCMS:[M+1]
+=594.37。
第五步:(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[3,4-c]吡啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(实施例25化合物)的制备
将化合物(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-c]吡啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(170mg,0.286mmol,1.0eq)溶于盐酸的1,4-二氧六环溶液(4M,3mL)中,反应在室温反应2小时。TLC检测反应完毕后,反应液用饱和碳酸氢钠水溶液淬灭,二氯甲烷萃取,无水硫酸钠干燥。有机相浓缩,制备HPLC纯化,得到目标化合物40mg,收率30%。LCMS:[M+H]
+=464.31;
1H NMR(600MHz,DMSO-d
6)δ:11.20(s,1H),7.42(d,J=5.8Hz,1H),7.13–7.07(m,3H),7.02(d,J=6.7Hz,1H),6.82(d,J=5.8Hz,1H),6.25(d,J=7.1Hz,1H),5.82(t,J=5.9Hz,1H),4.77(d,J=4.5Hz,1H),4.28–4.12(m,2H),4.01(d,J=5.6Hz,1H),3.80(d,J=13.1Hz,1H),3.63(m,2H),3.46–3.40(m,1H),3.19(m,3H),2.90–2.79(m,3H),2.73(m,2H),2.59(dd,J=12.5,5.7Hz,1H),2.09–1.95(m,5H),1.48–1.36(m,1H),1.33–1.24(m,1H)。
实施例26
1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[3,4-c]吡啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备
按实施例25的方法,利用原料化合物1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2- 醇(即中间体1-b,制备方法参见实施例1)做起始原料,与7-氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-c]吡啶(即中间体25-b,制备方法参见实施例25)合成进行偶联反应,再与化合物1-(4-氨基哌啶-1-基)乙烷-1-酮盐酸连接后,脱除SEM即得到目标分子1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[3,4-c]吡啶-7-基)氨基)哌啶-1-基)乙烷-1-酮。LCMS:[M+H]
+=464.31;
1H NMR(600MHz,DMSO-d
6)δ:11.20(s,1H),7.42(d,J=5.8Hz,1H),7.13–7.07(m,3H),7.02(d,J=6.7Hz,1H),6.82(d,J=5.8Hz,1H),6.25(d,J=7.1Hz,1H),5.82(t,J=5.9Hz,1H),4.77(d,J=4.5Hz,1H),4.28–4.12(m,2H),4.01(d,J=5.6Hz,1H),3.80(d,J=13.1Hz,1H),3.63(m,2H),3.46–3.40(m,1H),3.19(m,3H),2.90–2.79(m,3H),2.73(m,2H),2.59(dd,J=12.5,5.7Hz,1H),2.09–1.95(m,5H),1.48–1.36(m,1H),1.33–1.24(m,1H)。
实施例27
(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[3,4-c]吡啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备
按实施例25的方法,利用原料化合物(R)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(即中间体3-b,制备方法参见实施例3)做起始原料,与7-氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-c]吡啶(即中间体25-b,制备方法参见实施例25)合成进行偶联反应,再与化合物1-(4-氨基哌啶-1-基)乙烷-1-酮盐酸连接后,脱除SEM即得到目标分子(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[3,4-c]吡啶-7-基)氨基)哌啶-1-基)乙烷-1-酮。LCMS:[M+H]
+=464.31;
1H NMR(600MHz,DMSO-d
6)δ:11.20(s,1H),7.42(d,J=5.8Hz,1H),7.13–7.07(m,3H),7.02(d,J=6.7Hz,1H),6.82(d,J=5.8Hz,1H),6.25(d,J=7.1Hz,1H),5.82(t,J=5.9Hz,1H),4.77(d,J=4.5Hz,1H),4.28–4.12(m,2H),4.01(d,J=5.6Hz,1H),3.80(d,J=13.1Hz,1H),3.63(m, 2H),3.46–3.40(m,1H),3.19(m,3H),2.90–2.79(m,3H),2.73(m,2H),2.59(dd,J=12.5,5.7Hz,1H),2.09–1.95(m,5H),1.48–1.36(m,1H),1.33–1.24(m,1H)。
实施例28
(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备
第一步:5-甲基-1H-吡唑并[4,3-d]嘧啶-7-酚(中间体28-a)的制备
将化合物4-氨基-1H-吡唑-5-甲酸乙酯(500mg,3.23mmol,1.0eq)和化合物苄基硫代乙酰亚胺盐酸盐(648mg,3.23mmol,1.0eq)加到100mL圆底烧瓶中,加入16mL吡啶,置换氮气三次,加热到115℃,搅拌12小时。冷却至室温(15-20度),减压蒸馏除去吡啶,加入9mL乙醇和3mL水,用1M(摩尔浓度)NaOH溶液调节pH至中性。过滤得滤饼,78℃烘干得310mg 5-甲基-1H-吡唑并[4,3-d]嘧啶-7-酚,白色固体,收率64.04%。
1H NMR(400MHz,DMSO-d
6)δ:13.97(s,1H),12.10(s,1H),7.94(s,1H),2.31(s,3H)。
第二步:3-碘-5-甲基-1H-吡唑并[4,3-d]嘧啶-7-酚(中间体28-b)的制备
将化合物5-甲基-1H-吡唑并[4,3-d]嘧啶-7-酚(200mg,1.33mmol,1.0eq)和化合物N-碘代丁二酰亚胺(447mg,1.99mmol,1.5eq)加到微波管中,加入6mL DMF(N,N-二甲基甲酰胺),置换氮气三次,加热到60℃,四个小时反应结束。冷却至室 温(15-20度),加入100mL水和30mL乙酸乙酯,搅拌2分钟后分层。有机相分别用水、饱和氯化钠溶液洗涤一次,无水硫酸钠干燥,旋干溶剂,用10毫升乙醇打浆,得392mg白色固体,3-碘-5-甲基-1H-吡唑并[4,3-d]嘧啶-7-酚(粗品)。
1H NMR(400MHz,DMSO-d
6)δ:14.43(s,1H),12.32(s,1H),2.35(s,3H)。
第三步:3-碘-5-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(中间体28-c)的制备
将化合物3-碘-5-甲基-1H-吡唑并[4,3-d]嘧啶-7-酚(100mg,0.362mmol,1.0eq)和碳酸铯(141mg,0.434mmol,1.2eq)加到无水1.8mL DMF(N,N-二甲基甲酰胺)中,置换氮气三次。在冰浴条件下,滴加SEMCl(2-(三甲基硅烷基)乙氧甲基氯)(60mg,0.362mmol,1.0eq),在此条件下搅拌十分钟后恢复至室温(15-20度),继续搅拌一个小时,TLC检测原料反应完。加入20mL水和15mL乙酸乙酯。有机相分别用水、饱和氯化钠溶液洗涤一次,无水硫酸钠干燥,旋干溶剂,制备HPLC纯化得52mg白色固体,3-碘-5-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚,收率35.6%。LCMS:[M+H]
+=407.14;
1H NMR(400MHz,DMSO-d
6)δ:5.83(s,2H),3.69–3.63(m,2H),2.44(s,3H),0.92–0.86(m,2H),0.02–0.05(m,9H)。
第四步:1-(4-((3-碘-5-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(中间体28-d)的制备
将化合物3-碘-5-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(310mg,0.763mmol,1.0eq)、1-(4-氨基哌啶-1-基)乙烷-1-酮(204mg,1.14mmol,1.5eq)和六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(516mg,0.992mmol,1.3eq)溶于3.8mL DMF(N,N-二甲基甲酰胺),置换氮气三次。再加入1,8-二氮杂二环十一碳-7-烯(173mg,1.14mmol,1.5eq),在室温下搅拌0.5h,TLC检测原料反 应完全。向反应体系加入40mL水,用乙酸乙酯萃取三次(3×20mL),合并有机相,用20mL饱和氯化钠溶液洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩,柱层析提纯得180mg 1-(4-((3-碘-5-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮,白色固体,收率44.6%。LCMS:[M+H]
+=531.24。
第五步:(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(中间体28-e)的制备
将化合物1-(4-((3-碘-5-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(170mg,0.32mmol,1.0eq)溶于DMSO(二甲亚砜)(1.6mL)中,加入化合物(S)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(98.8mg,0.48mmol,1.5eq)(即中间体2-b,制备方法参见实施例2)、碘化亚铜(12.2mg,0.064mmol,0.2eq)、碳酸钾(221.1mg,1.6mmol,5.0eq)及L-脯氨酸(14.7mg,0.128mmol,0.4eq),反应在N
2保护下80℃反应16小时。TLC检测反应完毕后,向反应体系加入15mL水,用乙酸乙酯萃取三次(3×20mL),合并有机相,用20mL饱和氯化钠溶液洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩,制备HPLC提纯得104mg白色固体,(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮,收率53.6%。LCMS:[M+1]
+=609.49。
第六步:(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(实施例28化合物)的制备
向化合物(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(81mg)中,加入4M(摩尔浓度)盐酸的二氧六环溶液(0.9mL),反应在室温(15-20度),N
2保护下反应1小时。TLC检测反应完毕后,向反应体系加入饱和碳酸氢钠溶液至pH=7-8,用20mL乙酸乙酯萃取,有机相用20mL饱和氯化钠溶液洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩,制备HPLC提纯得30mg,(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮,收率47.2%。LCMS:[M+1]
+=479.31;
1H NMR(400MHz,CDCl
3)δ:7.20–7.04(m,3H),7.04–6.95(m,1H),6.71(s,1H),4.61(d,J=13.5Hz,1H),4.51(s,1H),4.15(d,J=3.8Hz,1H),3.84(d,J=15.0Hz,2H),3.68(d,J=15.0Hz,1H),3.61(dd,J=13.5,3.3Hz,1H),3.42(dd,J=13.2,5.7Hz,1H),3.31(t,J=11.7Hz,1H),2.98–2.84(m,4H),2.79(dd,J=13.4,7.6Hz,1H),2.75–2.69(m,1H),2.64(dd,J=12.5,4.0Hz,1H),2.55(d,J=14.0Hz,3H),2.33(d,J=11.9Hz,1H),2.13(s,3H),2.06(d,J=10.1Hz,1H),1.35(dt,J=24.5,12.2Hz,2H)。
实施例29
1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备
按实施例28的方法,利用原料化合物(1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(即中间体1-b,制备方法参见实施例1)做起始原料,与1-(4-((3-碘-5-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(即中间体28d,制备方法参见实施例28)进行偶联反应,再脱除SEM即得到目标分子1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮。LCMS:[M+1]
+=479.31;
1H NMR(400MHz,CDCl
3)δ:7.20–7.04(m,3H),7.04–6.95(m,1H),6.71(s,1H),4.61(d,J=13.5Hz,1H),4.51(s,1H),4.15(d,J=3.8Hz,1H),3.84(d,J =15.0Hz,2H),3.68(d,J=15.0Hz,1H),3.61(dd,J=13.5,3.3Hz,1H),3.42(dd,J=13.2,5.7Hz,1H),3.31(t,J=11.7Hz,1H),2.98–2.84(m,4H),2.79(dd,J=13.4,7.6Hz,1H),2.75–2.69(m,1H),2.64(dd,J=12.5,4.0Hz,1H),2.55(d,J=14.0Hz,3H),2.33(d,J=11.9Hz,1H),2.13(s,3H),2.06(d,J=10.1Hz,1H),1.35(dt,J=24.5,12.2Hz,2H)。
实施例30
(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备
按实施例28的方法,利用原料化合物(R)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(即中间体3-b,制备方法参见实施例3)做起始原料,与1-(4-((3-碘-5-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(即中间体28d,制备方法参见实施例28)进行偶联反应,再脱除SEM即得到目标分子(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮。LCMS:[M+1]
+=479.31;
1H NMR(400MHz,CDCl
3)δ7.20–7.04(m,3H),7.04–6.95(m,1H),6.71(s,1H),4.61(d,J=13.5Hz,1H),4.51(s,1H),4.15(d,J=3.8Hz,1H),3.84(d,J=15.0Hz,2H),3.68(d,J=15.0Hz,1H),3.61(dd,J=13.5,3.3Hz,1H),3.42(dd,J=13.2,5.7Hz,1H),3.31(t,J=11.7Hz,1H),2.98–2.84(m,4H),2.79(dd,J=13.4,7.6Hz,1H),2.75–2.69(m,1H),2.64(dd,J=12.5,4.0Hz,1H),2.55(d,J=14.0Hz,3H),2.33(d,J=11.9Hz,1H),2.13(s,3H),2.06(d,J=10.1Hz,1H),1.35(dt,J=24.5,12.2Hz,2H)。
实施例31
(S)-1-((1H-吡唑并[4,3-d]嘧啶-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇的制备
第一步:1H-吡唑并[4,3-d]嘧啶(中间体31-a)的制备
将化合物4-甲基-5-氨基嘧啶(3.17g,29.0mmol,1.0eq)溶于甲苯(40mL)中,室温18℃下依次加入Ac
2O(乙酐)(6.23g,61.0mmol,2.1eq),HOAc(冰醋酸)(6.03g,101.5mmol,3.5eq),AcOK(乙酸钾)(5.68g,58.0mmol,2.0eq),Isoamyl nitrite(亚硝酸异戊酯)(4.24g,36.0mmol,1.25eq),110℃反应3h后,LCMS检测反应完成,冷却至室温18℃,加入水(300mL),然后加入Na
2CO
3(碳酸钠)固体颗粒,调节pH=9~10,加入乙酸乙酯(60mL×3)萃取三次,饱和食盐水(50mL)洗涤,无水硫酸钠干燥10分钟,过滤,粗产物用快速色谱法分离纯化(Silica gel,乙酸乙酯:石油醚=1/1),得标题化合物1H-吡唑并[4,3-d]嘧啶(400mg,11.5%),为黄色固体。LCMS(ESI)[M+H]
+=120.90;
1H NMR(400MHz,DMSO-d
6)δ:13.92(s,1H),9.36(s,1H),9.04(s,1H),8.47(s,1H)。
第二步:3-碘-1H-吡唑并[4,3-d]嘧啶(中间体31-b)的制备
室温20℃下将原料1H-吡唑并[4,3-d]嘧啶(400mg,3.33mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(5mL),加入NIS(N-碘代丁二酰亚胺)(970mg,4.33mmol,1.3eq),反应升至60℃搅拌15小时。LCMS检测反应完成后,冷却至室温18℃,加入水(20mL),然后加入二氯甲烷:甲醇(V/V=10/1)(10mL×3)萃取三次,饱和食盐水(5mL)洗涤,无水硫酸钠干燥10分钟,过滤,粗产物用快速色谱法分离纯化(Silica gel,乙酸乙酯:石油醚(V/V=1/1))得标题化合3-碘-1H-吡唑并[4,3-d]嘧啶(600mg,73.2%),为黄色固体。LCMS(ESI)[M+H]
+=246.9。
1H NMR(400MHz,DMSO-d
6)δ:14.35 (s,1H),9.34(s,1H),9.08(s,1H)。
第三步:3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶(中间体31-c)的制备
将原料3-碘-1H-吡唑并[4,3-d]嘧啶(300mg,1.22mmol,1.0eq)溶解到无水DMF(N,N-二甲基甲酰胺)(5mL),冰水浴冷确,加入NaH(氢化钠)(质量分数60%)(98mg,2.44mmol,2.0eq),搅拌0.5h,然后缓慢滴加溶解在无水DMF(N,N-二甲基甲酰胺)(1mL)的化合物SEMCl(2-(三甲基硅烷基)乙氧甲基氯)(243mg,1.46mmol,1.2eq),0℃缓慢升至室温20℃搅拌4h,LCMS检测反应完成后,加到水(25mL)中,用乙酸乙酯(10mL×3)萃取三次,饱和食盐水(10mL)洗涤,无水硫酸钠干燥10分钟,过滤,粗产物用快速色谱法分离纯化(Silica gel,乙酸乙酯:石油醚(V/V=1/5))得标题化合物3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶(400mg,87.2%)为黄色固体。LCMS(ESI)[M+H]
+=377.0。
第四步:(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙烷-2-醇(中间体31-d)的制备
将原料3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶(170mg,0.45mmol,1.0eq)加入到DMSO(二甲基亚砜)(4mL)中,然后氮气保护下加入(S)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(112mg,0.54mmol,1.2eq)(即中间体2-b,制备方法参见实施例2),K
2CO
3(碳酸钾)(312mg,2.26mmol,5.0eq),L-proline(L-脯氨酸)(21mg,0.18mmol,0.4eq),CuI(碘化亚铜)(17mg,0.09mmol,0.2eq),80℃搅拌4h。LCMS检测反应完成后,冷却至室温20℃,加到水(25mL)中, 加入乙酸乙酯(10mL×3)萃取三次,饱和食盐水(5mL)洗涤,无水硫酸钠干燥10分钟,过滤,粗产物用快速色谱法分离纯化(Silica gel,乙酸乙酯:石油醚(V/V=1/4))得标题化合物(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙烷-2-醇(160mg,78.0%)为黄色固体。LCMS(ESI)[M+H]
+=455.3。
第五步:(S)-1-((1H-吡唑并[4,3-d]嘧啶-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(实施例31化合物)的制备
室温20℃,将原料(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙烷-2-醇(150mg,0.34mmol)溶入到DCM(二氯甲烷)(4mL),加入4M(摩尔浓度)HCL-二氧六环(2mL),室温20℃搅拌5h。将反应液用10%NaHCO
3水溶液调节pH=7~8,加入DCM(二氯甲烷)(10mL×3)萃取三次,饱和食盐水(5mL)洗涤,浓缩,粗产物用Prep-HPLC分离纯化(C18,10mmol/l NH
4HCO
3in water,MeCN),得目标化合物(S)-1-((1H-吡唑并[4,3-d]嘧啶-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(9mg,8.1%)。LCMS(ESI)[M+H]
+=325.30;
1H NMR(400MHz,CD
3OD)δ:8.99(s,1H),8.83(s,1H),7.11-7.03(m,4H),4.27-4.24(m,1H),3.76(s,2H),3.68-3.64(m,2H),3.50-3.45(m,2H),2.94-2.87(m,4H),2.76-2.72(m,2H)。
实施例32
(R)-1-((1H-吡唑并[4,3-d]嘧啶-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇的制备
按实施例31的方法,利用原料化合物(R)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(即中间体3-b,制备方法参见实施例3)做起始原料,与3-碘-1-((2-(三甲 基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶(即中间体31-c,制备方法参见实施例31)进行偶联反应,再脱除SEM,制备得目标化合物(R)-1-((1H-吡唑并[4,3-d]嘧啶-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇。LCMS(ESI)[M+H]
+=325.30;
1H NMR(400MHz,CD
3OD)δ:8.99(s,1H),8.83(s,1H),7.11-7.03(m,4H),4.27-4.24(m,1H),3.76(s,2H),3.68-3.64(m,2H),3.50-3.45(m,2H),2.94-2.87(m,4H),2.76-2.72(m,2H)。
实施例33
1-((1H-吡唑并[4,3-d]嘧啶-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇的制备
按实施例31的方法,利用原料化合物(1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(即中间体1-b,制备方法参见实施例1)做起始原料,与3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶(即中间体31-c,制备方法参见实施例31)进行偶联反应,再脱除SEM,制备得目标化合物1-((1H-吡唑并[4,3-d]嘧啶-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇。LCMS(ESI)[M+H]
+=325.30;
1H NMR(400MHz,CD
3OD)δ:8.99(s,1H),8.83(s,1H),7.11-7.03(m,4H),4.27-4.24(m,1H),3.76(s,2H),3.68-3.64(m,2H),3.50-3.45(m,2H),2.94-2.87(m,4H),2.76-2.72(m,2H)。
实施例34
(S)-1-((7-氨基-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇的制备
第一步:3-碘-1H-吡唑并[4,3-d]嘧啶-7-醇(中间体34-a)的制备
将7-羟基吡唑并[4,3-d]嘧啶(2.00g,14.69mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(40mL)中,加入NIS(N-碘代丁二酰亚胺)(4.96g,22.04mmol,1.5eq),反应在氮气保护下60℃反应5小时。TLC检测反应完毕后,旋干反应溶剂,将混合物溶于甲醇,抽滤。滤饼用甲醇淋洗,干燥,得到目标化合物(3.46g,89.9%),为紫灰色固体。LCMS(ESI)[M+H]
+=262.87;
1H NMR(400MHz,DMSO-d
6)δ:14.55(s,1H),12.41(s,1H),7.92(d,J=3.3Hz,1H)。
第二步:3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇(中间体34-b)的制备
将3-碘-1H-吡唑并[4,3-d]嘧啶-7-醇(1.50g,5.72mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(28mL)中,加入Cs
2CO
3(碳酸铯)(2.24g,6.87mmol,1.2eq),0℃下滴加SEMCl(2-(三甲基硅烷基)乙氧甲基氯)(0.95g,5.72mmol,1.0eq),反应在20℃过夜反应16小时。TLC检测反应完毕后,反应液用二氯甲烷萃取,无水硫酸钠干燥。有机相浓缩,粗产物用快速色谱法分离纯化(Silica gel,DCM:MeOH=15:1),得到目标中间体3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇(1.21g,53.8%),为黄色固体。LCMS(ESI)[M+H]
+=393.12。
第三步:7-((1H-苯并[d][1,2,3]三唑-1-基)氧基)-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶(中间体34-c)的制备
将3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇(2.00g,5.10mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(26mL)中,加入PyBOP(1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐)(3.45g,6.63mmol,1.3eq)和DBU(1,8-二氮杂双环[5.4.0]十一碳-7-烯)(1.16g,7.65mmol,1.5eq),反应在20℃反应0.5小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取,无水硫酸钠干燥。有机相浓缩,粗产物用快速色谱法分离纯化(Silica gel,PE:EA=5:1),得到目标化合物(1.25g,48.1%),为白色固体。LCMS(ESI)[M+H]
+=510.16。
第四步:3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-胺(中间体34-d)的制备
将7-((1H-苯并[d][1,2,3]三唑-1-基)氧基)-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶(300mg,0.59mmol,1.0eq)溶于0.4M(摩尔浓度)氨的1,4-二氧六环溶液(12mL)中,反应在100℃反应2小时。TLC检测反应完毕后,反应液浓缩,得到目标化合物粗品(230mg,100.0%),为黄色固体。LCMS(ESI)[M+H]
+=392.09。
第五步:(S)-1-((7-氨基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(中间体34-e)的制备
将3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-胺(230mg,0.59mmol,1.0eq)溶于DMSO(二甲基亚砜)(6mL)中,加入化合物(S)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(182mg,0.88mmol,1.5eq)(即中间体2-b,制备方法参见实施例2)、CuI(碘化亚铜)(22mg,0.12mmol,0.2eq)、K
2CO
3 (碳酸钾)(406mg,2.94mmol,5.0eq)及L-Proline(L-脯氨酸)(27mg,0.24mmol,0.4eq),反应在氮气保护下80℃反应18小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取,无水硫酸钠干燥。有机相浓缩,粗产物用快速色谱法分离纯化(Silica gel,DCM:MeOH=15:1),得到目标化合物(140mg,50.5%),为黄色固体。LCMS(ESI)[M+H]
+=470.26。
第六步:(S)-1-((7-氨基-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(实施例34化合物)的制备
将(S)-1-((7-氨基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(120mg,0.26mmol,1.0eq)溶于4M(摩尔浓度)盐酸的1,4-二氧六环溶液(5mL)中,反应在20℃反应1小时。TLC检测反应完毕后,反应液用饱和碳酸氢钠水溶液淬灭,氯仿:异丙醇(7:3)萃取,无水硫酸钠干燥。有机相浓缩,粗产物用制备HPLC分离纯化(C18,10mmol/L NH
4HCO
3in water,MeCN),得目标化合物(S)-1-((7-氨基-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(31.6mg,36.3%)。LCMS(ESI)[M+H]
+=340.3;
1H NMR(400MHz,DMSO-d
6)δ:11.19(s,1H),8.04(s,1H),7.13–6.98(m,6H),5.45(t,J=5.9Hz,1H),4.87(d,J=4.6Hz,1H),4.00(q,J=5.5Hz,1H),3.68–3.56(m,2H),3.48(ddd,J=12.2,7.1,4.7Hz,1H),3.21(ddd,J=12.5,7.0,5.0Hz,1H),2.81(t,J=5.9Hz,2H),2.71(dtd,J=17.5,11.4,5.6Hz,2H),2.58(dd,J=12.5,5.8Hz,1H),2.54–2.45(m,1H)。
实施例35
(R)-1-((7-氨基-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇的制备
按实施例34的方法,利用原料化合物(R)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(即中间体3-b,制备方法参见实施例3)做起始原料,与3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-胺(即中间体34-d,制备方法参见实施例34)进行偶联反应,再脱除SEM,制备HPLC分离纯化(C18,10mmol/L NH
4HCO
3in water,MeCN),得目标化合物(R)-1-((7-氨基-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇。LCMS(ESI)[M+H]
+=340.3;
1H NMR(400MHz,DMSO-d
6)δ:11.19(s,1H),8.04(s,1H),7.13–6.98(m,6H),5.45(t,J=5.9Hz,1H),4.87(d,J=4.6Hz,1H),4.00(q,J=5.5Hz,1H),3.68–3.56(m,2H),3.48(ddd,J=12.2,7.1,4.7Hz,1H),3.21(ddd,J=12.5,7.0,5.0Hz,1H),2.81(t,J=5.9Hz,2H),2.71(dtd,J=17.5,11.4,5.6Hz,2H),2.58(dd,J=12.5,5.8Hz,1H),2.54–2.45(m,1H)。
实施例36
1-((7-氨基-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇的制备
按实施例34的方法,利用原料化合物1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(即中间体1-b,制备方法参见实施例1)做起始原料,与3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-胺(即中间体34-d,制备方法参见实施例34)进行偶联反应,再脱除SEM,制备HPLC分离纯化(C18,10mmol/L NH
4HCO
3in water,MeCN),得目标化合物1-((7-氨基-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇。LCMS(ESI)[M+H]
+=340.3;
1H NMR(400MHz,DMSO-d
6)δ:11.19(s,1H),8.04(s,1H),7.13–6.98(m,6H),5.45(t,J=5.9Hz,1H),4.87(d,J=4.6Hz,1H),4.00(q,J=5.5Hz,1H),3.68–3.56(m,2H),3.48(ddd,J=12.2,7.1,4.7Hz,1H),3.21(ddd,J=12.5,7.0,5.0Hz,1H),2.81(t,J=5.9Hz,2H),2.71(dtd,J=17.5,11.4,5.6Hz,2H),2.58(dd,J=12.5,5.8Hz,1H),2.54–2.45(m,1H)。
实施例37
(S)-3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1H-吡唑并[4,3-d]嘧啶-7-醇的制备
第一步:3-碘-1H-吡唑并[4,3-d]嘧啶-7-醇(中间体37-a)的制备
将化合物7-羟基-吡唑并[4,3-d]嘧啶(2g,14.694mmol,1.0eq)溶于N,N-二甲基甲酰胺(40mL)中,加入N-碘代丁二酰亚胺(4.96g,22.041mmol,1.5eq),反应在氮气保护下60℃反应5小时。TLC检测反应完毕后,旋干反应溶剂,将混合物溶于甲醇,抽滤。滤饼用甲醇淋洗,干燥,得到3-碘-1H-吡唑并[4,3-d]嘧啶-7-醇3.46g,收率89.9%。LCMS:[M+1]
+=262.87;
1H NMR(400MHz,DMSO-d
6)δ14.55(s,1H),12.41(s,1H),7.92(d,J=3.3Hz,1H)。
第二步:3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇(中间体37-b)的制备
将3-碘-1H-吡唑并[4,3-d]嘧啶-7-醇(1.50g,5.725mmol,1.0eq)溶于N,N-二甲基甲酰胺(28mL)中,加入碳酸铯(2.24g,6.870mmol,1.2eq),0℃下滴加2-(三甲基硅烷基)乙氧甲基氯(1.0mL,5.725mmol,1.0eq),反应在20℃过夜反应16小时。TLC检测反应完毕后,反应液用二氯甲烷萃取,无水硫酸钠干燥。有机相浓缩,柱层析纯化,得到3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇1.21g,收率53.8%。LCMS:[M+1]
+=393.12。
第三步:(S)-3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇(中间体37-c)的制备
将化合物3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇(600mg,1.530mmol,1.0eq)溶于DMSO(二甲基亚砜)(10mL)中,加入化合物(S)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(473mg,2.294mmol,1.5eq)(即中间体2-b,制备方法参见实施例2)、碘化亚铜(58mg,0.306mmol,0.2eq)、碳酸钾(1.06g,7.648mmol,5.0eq)及L-脯氨酸(70mg,0.612mmol,0.4eq),反应在氮气保护下80℃反应18小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取,无水硫酸钠干燥。有机相浓缩,柱层析纯化得到230mg,(S)-3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇,收率31.9%。LCMS:[M+1]
+=471.37。
第四步:(S)-3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1H-吡唑并[4,3-d]嘧啶-7-醇(实施例37化合物)的制备
将化合物(S)-3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇(30mg,0.064mmol,1.0eq)溶于4M(摩尔浓度)盐酸的1,4-二氧六环溶液(1mL)中,反应在20℃反应1小时。TLC检测反应完毕后,反应液用饱和碳酸氢钠水溶液淬灭,二氯甲烷萃取,无水硫酸钠干燥。有机相浓缩,制备HPLC纯化,得到目标化合物(S)-3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1H-吡唑并[4,3-d]嘧啶-7-醇1.8mg,收率8.3%。LCMS:[M+1]
+=341.2;
1H NMR(400MHz,DMSO-d
6)δ12.65(s,1H),12.07(s,1H),7.70(s,1H),7.15–7.06(m,3H),7.03(d,J=6.6Hz,1H),5.41(s,1H),4.84(s,1H),4.00(s,1H),3.54(s,2H),3.26–3.13(m,2H),2.89–2.65(m,6H)。
实施例38
(R)-3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1H-吡唑并[4,3-d]嘧啶-7-醇的制备
按实施例37的方法,利用原料化合物(R)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(即中间体3-b,制备方法参见实施例3)做起始原料,与3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇(即中间体37-b,制备方法参见实施例37)进行偶联反应,再脱除SEM即得到目标分子(R)-3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1H-吡唑并[4,3-d]嘧啶-7-醇。LCMS:[M+1]
+=341.2;
1H NMR(400MHz,DMSO-d
6)δ12.65(s,1H),12.07(s,1H),7.70(s,1H),7.15–7.06(m,3H),7.03(d,J=6.6Hz,1H),5.41(s,1H),4.84(s,1H),4.00(s,1H),3.54(s,2H),3.26–3.13(m,2H),2.89–2.65(m,6H)。
实施例39
3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1H-吡唑并[4,3-d]嘧啶-7-醇的制备
按实施例37的方法,利用原料化合物(1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(即中间体1-b,制备方法参见实施例1)做起始原料,与3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇(即中间体37-b,制备方法参见实施例37)进行偶联反应,再脱除SEM即得到目标分子3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1H-吡唑并[4,3-d]嘧啶-7-醇。LCMS:[M+1]
+=341.2;
1H NMR(400MHz,DMSO-d
6)δ:12.65(s,1H),12.07(s,1H),7.70(s,1H),7.15–7.06(m,3H),7.03(d,J=6.6Hz,1H),5.41(s,1H),4.84(s,1H),4.00(s,1H),3.54(s,2H),3.26–3.13(m,2H),2.89–2.65(m,6H)。
实施例40
(S)-1-(4-(3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[4,3-d]嘧啶-7-基)哌嗪-1-基)乙烷-1-酮的制备
第一步:3-碘-1H-吡唑并[4,3-d]嘧啶-7-醇(中间体40-a)的制备
将7-羟基吡唑并[4,3-d]嘧啶(2.00g,14.69mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(40mL)中,加入NIS(N-碘代丁二酰亚胺)(4.96g,22.04mmol,1.5eq),反应在氮气保护下60℃反应5小时。TLC检测反应完毕后,旋干反应溶剂,将混合物溶于甲醇,抽滤。滤饼用甲醇淋洗,干燥,得到目标化合物(3.46g,89.9%),为紫灰色固体。LCMS(ESI)[M+H]
+=262.87;
1H NMR(400MHz,DMSO-d
6)δ:14.55(s,1H),12.41(s,1H),7.92(d,J=3.3Hz,1H)。
第二步:3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇(中间体40-b)的制备
将3-碘-1H-吡唑并[4,3-d]嘧啶-7-醇(1.50g,5.72mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(28mL)中,加入Cs
2CO
3(碳酸铯)(2.24g,6.87mmol,1.2eq),0℃下滴加SEMCl(2-(三甲基硅烷基)乙氧甲基氯)(0.95g,5.72mmol,1.0eq),反应在20℃过夜反应16小时。TLC检测反应完毕后,反应液用二氯甲烷萃取,无水硫酸钠干燥。有机相浓缩,粗产物用快速色谱法分离纯化(Silica gel,DCM:MeOH=15:1),得到目标中间体3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇(1.21g,53.8%),为黄色固体。LCMS(ESI)[M+H]
+=393.12。
第三步:1-(4-(3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)哌嗪-1-基)乙烷-1-酮(中间体40-c)的制备
将化合物3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(100mg,0.255mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(1.3mL)中,加入化合物1-(哌嗪-1-基)乙烷-1-酮(49mg,0.382mmol,1.5eq)、PyBOP(六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷)(173mg,0.331mmol,1.3eq)及DBU(1,8-二氮杂二环十一碳-7-烯)(116.2mg,0.765mmol,3.0eq),反应在20℃反应0.5小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取,无水硫酸钠干燥。有机相浓缩,柱层析纯化,得到1-(4-(3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)哌嗪-1-基)乙烷-1-酮115mg,收率89.8%。LCMS:[M+1]
+=503.23。
第四步:(S)-1-(4-(3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)哌嗪-1-基)乙烷-1-酮(中间体40-d)的制备
将化合物1-(4-(3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)哌嗪-1-基)乙烷-1-酮(115mg,0.229mmol,1.0eq)溶于DMSO(2mL)中,加入化合物(S)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(71mg,0.344mmol,1.5eq)、碘化亚铜(17mg,0.092mmol,0.4eq)、碳酸钾(158.3mg,1.145mmol,5.0eq)及L-脯氨酸(10.5mg,0.092mmol,0.4eq),反应在N
2保护下80℃反应10小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取,无水硫酸钠干燥。有机相浓缩,柱层析纯化,(S)-1-(4-(3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)哌嗪-1-基)乙烷-1-酮得到81mg,收率61.0%。LCMS:[M+1]
+=581.48。
第五步:(S)-1-(4-(3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[4,3-d]嘧啶-7-基)哌嗪-1-基)乙烷-1-酮(实施例40化合物)的制备
将化合物(S)-1-(4-(3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)哌嗪-1-基)乙烷-1-酮(80mg,0.138mmol,1.0eq)溶于盐酸的1,4-二氧六环溶液(4M,0.7mL)中,反应在20℃反应1.5小时。TLC检测反应完毕后,反应液用饱和碳酸氢钠水溶液淬灭,二氯甲烷萃取,无水硫酸钠干燥。有机相浓缩,制备HPLC纯化,得到目标化合物(S)-1-(4-(3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[4,3-d]嘧啶-7-基)哌嗪-1-基)乙烷-1-酮18.9mg,收率30.4%。LCMS:[M+1]
+=451.26;1H NMR(400MHz,CDCl
3)δ:8.23(s,1H),7.20–7.09(m,3H),7.03–6.97(m,1H),5.27(brs,1H),4.15(s,5H),3.87(d,J=14.9Hz,1H),3.78(t,J=5.3Hz,2H),3.72–3.58(m,4H),3.39(dd,J=15.3,4.5Hz,1H),3.04–2.92(m,3H),2.85–2.72(m,2H),2.63(dd,J=12.4,4.2Hz,1H),2.16(s,3H)。
实施例41
1-(4-(3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[4,3-d]嘧啶-7-基)哌嗪-1-基)乙烷-1-酮的制备
按实施例40的方法,利用原料化合物1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(即中间体1-b,制备方法参见实施例1)做起始原料,与1-(4-(3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)哌嗪-1-基)乙烷-1-酮(即中间体40-c,制备方法参见实施例40)进行偶联反应,再脱除SEM即得到目标分子1-(4-(3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[4,3-d]嘧啶 -7-基)哌嗪-1-基)乙烷-1-酮。LCMS:[M+1]
+=451.26;
1H NMR(400MHz,CDCl
3)δ8.23(s,1H),7.20–7.09(m,3H),7.03–6.97(m,1H),5.27(brs,1H),4.15(s,5H),3.87(d,J=14.9Hz,1H),3.78(t,J=5.3Hz,2H),3.72–3.58(m,4H),3.39(dd,J=15.3,4.5Hz,1H),3.04–2.92(m,3H),2.85–2.72(m,2H),2.63(dd,J=12.4,4.2Hz,1H),2.16(s,3H)。
实施例42
(R)-1-(4-(3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[4,3-d]嘧啶-7-基)哌嗪-1-基)乙烷-1-酮的制备
按实施例40的方法,利用原料化合物(R)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(即中间体3-b,制备方法参见实施例3)做起始原料,与1-(4-(3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)哌嗪-1-基)乙烷-1-酮(即中间体40-c,制备方法参见实施例40)进行偶联反应,再脱除SEM即得到目标分子(R)-1-(4-(3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[4,3-d]嘧啶-7-基)哌嗪-1-基)乙烷-1-酮。LCMS:[M+1]
+=451.26;
1H NMR(400MHz,CDCl
3)δ:8.23(s,1H),7.20–7.09(m,3H),7.03–6.97(m,1H),5.27(brs,1H),4.15(s,5H),3.87(d,J=14.9Hz,1H),3.78(t,J=5.3Hz,2H),3.72–3.58(m,4H),3.39(dd,J=15.3,4.5Hz,1H),3.04–2.92(m,3H),2.85–2.72(m,2H),2.63(dd,J=12.4,4.2Hz,1H),2.16(s,3H)。
实施例43
(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[3,4-c]吡啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备
第一步:5-氯-3-碘-1H-吡唑并[4,3-d]嘧啶(中间体43-a)的合成
将化合物5-氯-1H-吡唑并[4,3-d]嘧啶(600mg,3.88mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(40mL)中,加入NIS(N-碘代丁二酰亚胺)(1.1g,4.66mmol,1.2eq),反应在氮气保护下60℃反应2小时。TLC检测反应完毕后,旋干反应溶剂,将混合物溶于水搅拌30分钟,抽滤。滤饼用水淋洗,干燥,得到5-氯-3-碘-1H-吡唑并[4,3-d]嘧啶,黄色固体950mg,收率87.4%。LCMS:[M+H]
+=280.90;
1H NMR(400MHz,DMSO-d
6)δ:14.59(s,1H),9.31(s,1H)。
第二步:5-氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶(中间体43-b)的制备
将化合物5-氯-3-碘-1H-吡唑并[4,3-d]嘧啶(500mg,1.78mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(3mL)中,0℃下滴加到NaH(氢化钠)(110mg,2.67mmol,1.5eq)的DMF(N,N-二甲基甲酰胺)悬浊液中(3mL),并搅拌30分钟。0℃下滴加SEMCl(2-(三甲硅烷基)乙氧甲基氯)(387mg,2.32mmol,1.3eq),室温(15-20度)搅拌1小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取三次,每次10毫升,合并有机相,无水硫酸钠干燥。有机相浓缩,柱层析纯化,得到5-氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶,无色结晶固体580mg,收率79.2%。LCMS:[M+H]
+=410.92;
1H NMR(400MHz,DMSO-d
6)δ9.66(s,1H),5.99(s,2H),3.77–3.61(m,2H),1.02–0.85(m,2H),0.01(s,9H)。
第三步:1-(4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-5-基)氨基)哌啶-1-基)乙烷-1-酮(中间体43-c)的制备
将化合物5-氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶(500mg,1.22mmol,1.0eq)、化合物1-(4-氨基哌啶-1-基)乙烷-1-酮盐酸(261mg,1.46mmol,1.2eq),DIEA(N,N-二异丙基乙胺)(550mg,4.27mmol,3.5eq)溶到NMP(N-甲基吡咯烷酮)(6mL)中,氮气保护下,微波180℃反应1小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取,每次10毫升,合并有机相,无水硫酸钠干燥。有机相浓缩,柱层析纯化,得到1-(4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-5-基)氨基)哌啶-1-基)乙烷-1-酮,黄色油状220mg,收率35%。LCMS:[M+H]
+=517.14。
第四步:(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-5-基)氨基)哌啶-1-基)乙烷-1-酮(中间体43-d)的制备
将化合物1-(4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-5-基)氨基)哌啶-1-基)乙烷-1-酮(220ng,0.42mmol,1.0eq),化合物(S)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(105mg,0.51mmol,1.2eq)、CuI(碘化亚铜)(32mg,0.168mmol,0.4eq)、碳酸钾(290mg,2.1mmol,5.0eq)及L-脯氨酸(20mg,0.168mmol,0.4eq)溶于DMSO(二甲基亚砜)(2mL)中,反应在氮气保护下80℃反应18小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取,每次10毫升,合并有机相,无水硫酸钠干燥。有机相浓缩,柱层析纯化,得到(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-5-基)氨基)哌啶-1-基)乙烷-1-酮,黄色固体90mg,收率35.6%。LCMS:[M+1]
+=595.43。
第五步:(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[3,4-c]吡啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(实施例43化合物)的制备
将化合物(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-c]吡啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(80mg,0.13mmol,1.0eq)溶于4M(摩尔浓度)盐酸的1,4-二氧六环溶液(2mL)中,反应在室温(15-20度)反应4小时。TLC检测反应完毕后,反应液用饱和碳酸氢钠水溶液淬灭,二氯甲烷萃取,每次10毫升,合并有机相,无水硫酸钠干燥。有机相浓缩,制备HPLC纯化,得到目标化合物,19.6mg,收率32%。LCMS:[M+H]
+=465.41;
1H NMR(600MHz,CDCl
3)δ:8.55(s,1H),7.20–7.12(m,3H),7.03(d,J=7.5Hz,1H),4.92(m,2H),4.50(d,J=13.1Hz,1H),4.32(s,1H),4.14–3.98(m,2H),3.90–3.76(m,2H),3.67(d,J=13.0Hz,1H),3.47(dd,J=12.6,6.1Hz,1H),3.26(t,J=11.1Hz,1H),3.13(s,1H),3.01(s,3H),2.88(m,3H),2.17(s,1H),2.12(s,3H),2.09(s,1H),1.42(s,2H)。
实施例44
1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[3,4-c]吡啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备
按实施例43的方法,利用原料化合物(1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(即中间体1-b,制备方法参见实施例1)做起始原料,与1-(4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-5-基)氨基)哌啶-1-基)乙烷-1-酮(即中间体43-c,合成方法参见实施例43)进行偶联反应,再脱除SEM即得到目标分子1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[3,4-c]吡啶-7-基)氨基)哌啶-1-基)乙烷-1-酮。LCMS:[M+H]
+=465.41;
1H NMR(600 MHz,CDCl
3)δ:8.55(s,1H),7.20–7.12(m,3H),7.03(d,J=7.5Hz,1H),4.92(m,2H),4.50(d,J=13.1Hz,1H),4.32(s,1H),4.14–3.98(m,2H),3.90–3.76(m,2H),3.67(d,J=13.0Hz,1H),3.47(dd,J=12.6,6.1Hz,1H),3.26(t,J=11.1Hz,1H),3.13(s,1H),3.01(s,3H),2.88(m,3H),2.17(s,1H),2.12(s,3H),2.09(s,1H),1.42(s,2H)。
实施例45
(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[3,4-c]吡啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备
按实施例43的方法,利用原料化合物(R)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(即中间体3-b,制备方法参见实施例3)做起始原料,与1-(4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-5-基)氨基)哌啶-1-基)乙烷-1-酮(即中间体43-c,合成方法参见实施例43)进行偶联反应,再脱除SEM即得到目标分子(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[3,4-c]吡啶-7-基)氨基)哌啶-1-基)乙烷-1-酮。LCMS:[M+H]
+=465.41;
1H NMR(600MHz,CDCl
3)δ8.55(s,1H),7.20–7.12(m,3H),7.03(d,J=7.5Hz,1H),4.92(m,2H),4.50(d,J=13.1Hz,1H),4.32(s,1H),4.14–3.98(m,2H),3.90–3.76(m,2H),3.67(d,J=13.0Hz,1H),3.47(dd,J=12.6,6.1Hz,1H),3.26(t,J=11.1Hz,1H),3.13(s,1H),3.01(s,3H),2.88(m,3H),2.17(s,1H),2.12(s,3H),2.09(s,1H),1.42(s,2H)。
实施例46
(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)哌啶-1-基)乙烷-1-酮的制备
第一步:6-氯-3-碘-1H-吡唑并[3,4-d]嘧啶(中间体46-a)的制备
将化合物6-氯-1H-吡唑并[3,4-D]嘧啶(0.85g,5.52mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(10mL),加入NIS(N-碘代丁二酰亚胺)(1.48g,6.62mmol,1.2eq),反应升至120℃,微波条件下搅拌1小时。LCMS检测反应完成后,冷却至室温,加入水(30mL),然后加入二氯甲烷:甲醇(V/V=10/1)(20mL×3)萃取三次,饱和食盐水(25mL)洗涤,无水硫酸钠干燥10分钟,过滤,浓缩,粗产物用快速色谱法分离纯化(Silica gel,DCM:MeOH=50:1)得标题化合物6-氯-3-碘-1H-吡唑并[3,4-d]嘧啶(1.10g,71.42%)为黄色固体。LCMS(ESI)[M+H]
+=280.9;1H NMR(400MHz,DMSO-d6)δ14.64(s,1H),9.02(s,1H)。
第二步:6-氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶(中间体46-b)的制备
将原料6-氯-3-碘-1H-吡唑并[3,4-d]嘧啶(1.0g,3.58mmol,1.0eq)溶解到无水THF(四氢呋喃)(15mL),冰水浴冷却,加入氢化钠(质量分数60%)(286mg,27.16mmol,2.0eq),搅拌0.5h,然后缓慢滴加溶解在无水THF(四氢呋喃)(2mL)的化合物SEMCl(2-(三甲基硅烷基)乙氧甲基氯)(654mg,3.94mmol,1.1eq),0℃到室温20℃搅拌10h,LCMS检测反应完成后,加到水(25mL)中,用乙酸乙酯(20mL×3)萃取三次,饱和食盐水(15mL)洗涤,无水硫酸钠干燥10分钟,过滤,浓缩,粗产物用快速色谱法分离纯化(Silica gel,EA:Pe=1:5)得标题化合物6-氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶(670mg,产率45.64%)为黄色固体。LCMS(ESI)[M+H]
+=411.04;
1H NMR(400MHz,DMSO-d
6)δ:9.08(s,1H),5.71(s,2H),3.63-3.59(t,J=8.0Hz,2H),3.63-3.59(t,J=8.0Hz,2H),0.83-0.87(t,J=8.4Hz,2H),-0.07(s,9H)。
第三步:1-(4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d] 嘧啶-6-基)氨基)哌啶-1-基)乙烷-1-酮(中间体46-c)的制备
将中间体6-氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶(400mg,0.97mmol,1.0eq)加入到ACN(乙腈)(10mL)中,然后加入1-乙酰基哌啶-4-胺盐酸盐(208mg,1.17mmol,1.2eq)和DIEA(N,N-二异丙基乙胺)(275mg,2.13mmol,2.2eq),90℃搅拌5h,LCMS检测反应完成后,浓缩,残留物加入水(15mL)中,用乙酸乙酯(20mL×3)萃取三次,合并有机相,用无水硫酸钠干燥10分钟,过滤,浓缩,粗产物用快速色谱法分离纯化(Silica gel,乙酸乙酯:石油醚=1:5)得标题化合物1-(4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)哌啶-1-基)乙烷-1-酮(400mg,79.9%),为黄色固体。LCMS(ESI)[M+H]
+=517.2。
第四步:(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)哌啶-1-基)乙烷-1-酮(中间体46-d)的制备
将1-(4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)哌啶-1-基)乙烷-1-酮(52mg,0.1mmol,1.0eq)加入到DMSO(二甲基亚砜)(2mL)中,然后氮气保护下加入(S)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(25mg,0.12mmol,1.2eq),K
2CO
3(碳酸钾)(55mg,0.4mmol,4.0eq),L-Proline(L-脯氨酸)(9mg,0.08mmol,0.8eq),CuI(碘化亚铜)(8mg,0.04mmol,0.04eq),80℃搅拌12h。LCMS检测反应完成后,冷却至室温20℃,加到水(10mL)中,加入乙酸乙酯(10mL×3)萃取三次,饱和食盐水(5mL)洗涤,无水硫酸钠干燥10分钟,过滤,浓缩,粗产物用快速色谱法分离纯化(Silica gel,二氯甲烷:甲醇= 10:1)得标题化合物(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)哌啶-1-基)乙烷-1-酮(30mg,77.96%)为黄色固体。LCMS(ESI)[M+H]
+=455.3。
第五步:(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)哌啶-1-基)乙烷-1-酮(实施例46化合物)的制备
室温20℃,将原料(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)哌啶-1-基)乙烷-1-酮(150mg,0.34mmol)溶入到Dioxane(1,4-二氧六环)(4mL),加入4M(摩尔浓度)HCl-Dioxane(HCl-1,4-二氧六环溶液)(2mL),室温搅拌5h。将反应液用10%NaHCO
3水溶液调节pH=7~8,加入二氯甲烷(10mL×3)萃取三次,饱和食盐水(5mL)洗涤,浓缩,残留物用粗产物用制备HPLC分离纯化(C18,10mmol/L NH
4HCO
3水溶液,MeCN)(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)哌啶-1-基)乙烷-1-酮(55mg,34.7%)。LCMS(ESI)[M+H]
+=465.4;1H NMR(400MHz,CD
3OD)δ:11.52(s,1H),8.65(s,1H),7.12-7.03(m,5H),6.30-6.27(t,J=2.6Hz,1H),4.80(s,1H),4.30-4.26(d,J=12.4Hz,1H),4.00-3.97(m,2H),3.83-3.79(d,J=13.6Hz,1H),3.68-3.59(q,J=14.8Hz,J=6.0Hz,1H),3.42-3.60(m,1H),3.16-3.09(m,2H),2.83-2.80(m,2H),2.77-2.68(m,3H),2.59-2.54(m,2H),2.01(s,3H),1.93-1.84(m,2H),1.43-1.28(m,2H)。
实施例47
(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)哌啶-1-基)乙烷-1-酮的制备
按实施例46的方法,利用原料化合物(R)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(即中间体3-b,制备方法参见实施例3)做起始原料,与1-(4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)哌啶-1-基)乙烷-1-酮(即中间体46-c,制备方法参见实施例46)进行偶联反应,再脱除SEM即得到目标分子(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)哌啶-1-基)乙烷-1-酮。LCMS(ESI)[M+H]
+=465.4;
1H NMR(400MHz,CD
3OD)δ:11.52(s,1H),8.65(s,1H),7.12-7.03(m,5H),6.30-6.27(t,J=2.6Hz,1H),4.80(s,1H),4.30-4.26(d,J=12.4Hz,1H),4.00-3.97(m,2H),3.83-3.79(d,J=13.6Hz,1H),3.68-3.59(q,J=14.8Hz,J=6.0Hz,1H),3.42-3.60(m,1H),3.16-3.09(m,2H),2.83-2.80(m,2H),2.77-2.68(m,3H),2.59-2.54(m,2H),2.01(s,3H),1.93-1.84(m,2H),1.43-1.28(m,2H)。
实施例48
1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)哌啶-1-基)乙烷-1-酮的制备
按实施例46的方法,利用原料化合物(1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(即中间体1-b,制备方法参见实施例1)做起始原料,与1-(4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)哌啶-1-基)乙烷-1-酮(即中间体46-c,制备方法参见实施例46)进行偶联反应,再脱除SEM即得到目标分子1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)哌啶-1-基)乙烷-1-酮。LCMS(ESI)[M+H]
+=465.4;1H NMR(400MHz,CD
3OD)δ:11.52(s,1H),8.65(s,1H),7.12-7.03(m,5H),6.30-6.27(t,J=2.6Hz,1H),4.80(s,1H),4.30-4.26(d,J=12.4Hz,1H),4.00-3.97(m,2H),3.83-3.79(d,J=13.6Hz,1H),3.68-3.59(q,J=14.8Hz,J=6.0Hz,1H),3.42-3.60(m,1H),3.16-3.09(m,2H),2.83-2.80(m,2H),2.77-2.68(m,3H),2.59-2.54(m,2H),2.01(s,3H),1.93-1.84(m,2H),1.43-1.28(m,2H)。
实施例49
(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(哒嗪-4-基氨基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙-2-醇的制备
第一步:3-碘-1H-吡唑并[4,3-d]嘧啶-7-醇(中间体49-a)的制备
将7-羟基吡唑并[4,3-d]嘧啶(2.00g,14.69mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(40mL)中,加入NIS(N-碘代丁二酰亚胺)(4.96g,22.04mmol,1.5eq),反应在氮气保护下60℃反应5小时。TLC检测反应完毕后,旋干反应溶剂,将混合物溶于甲醇,抽滤。滤饼用甲醇淋洗,干燥,得到目标化合物(3.46g,89.9%),为紫灰色固体。LCMS(ESI)[M+H]
+=262.87;
1H NMR(400MHz,DMSO-d
6)δ14.55(s,1H),12.41(s,1H),7.92(d,J=3.3Hz,1H)。
第二步:3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇(中间体49-b)的制备
将3-碘-1H-吡唑并[4,3-d]嘧啶-7-醇(1.50g,5.72mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(28mL)中,加入Cs
2CO
3(碳酸铯)(2.24g,6.87mmol,1.2eq),0℃下滴加SEMCl(2-(三甲基硅烷基)乙氧甲基氯)(0.95g,5.72mmol,1.0eq),反应在20℃过夜反应16小时。TLC检测反应完毕后,反应液用二氯甲烷萃取,无水硫酸钠干燥。有机相浓缩,粗产物用快速色谱法分离纯化(Silica gel,DCM:MeOH=15:1),得到目标化合物(1.21g,53.8%),为黄色固体。LCMS(ESI)[M+H]
+=393.12。
第三步:7-((1H-苯并[d][1,2,3]三唑-1-基)氧基)-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶(中间体49-c)的制备
将3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇(2.00g,5.10mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(26mL)中,加入PyBOP(1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐)(3.45g,6.63mmol,1.3eq)及DBU(1,8-二氮杂双环[5.4.0]十一碳-7-烯)(1.16g,7.65mmol,1.5eq),反应在20℃反应0.5小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取,无水硫酸钠干燥。有机相浓缩,粗产物用快速色谱法分离纯化(Silica gel,PE:EA=6:1),得到目标化合物(1.25g,48.1%),为白色固体。LCMS(ESI)[M+H]
+=510.16。
第四步:3-碘-N-(哒嗪-4-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-胺(中间体49-d)的制备
4-氨基哒嗪(140mg,1.47mmol,1.5eq)的DMF(N,N-二甲基甲酰胺)(3mL)溶液中,0℃下加入NaH(氢化钠)(118mg,2.94mmol,3.0eq),氮气保护下搅拌10分钟。再加入7-((1H-苯并[d][1,2,3]三唑-1-基)氧基)-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶(500mg,0.98mmol,1.0eq)的DMF(N,N-二甲基甲酰胺)(4mL)溶液,反应在20℃反应0.5小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取,无水硫酸钠干燥。有机相浓缩,粗产物用快速色谱法分离纯化(Silica gel,EA),得到目标化合物(430mg,93.3%),为黄色固体。LCMS(ESI)[M+H]
+=470.21。
第五步:(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(哒嗪-4-基氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙-2-醇(中间体49-e)的制备
将3-碘-N-(哒嗪-4-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-胺(320mg,0.68mmol,1.0eq)溶于DMSO(二甲基亚砜)(7mL)中,加入(S)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(169mg,0.82mmol,1.2eq)、CuI(碘化亚铜)(26mg,0.14mmol,0.2eq)、K
2CO
3(碳酸钾)(471mg,3.41mmol,5.0eq)及L-Proline(L-脯氨酸)(31mg,0.27mmol,0.4eq),反应在氮气保护下80℃反应16小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取,无水硫酸钠干燥。有机相浓缩,粗产物用快速色谱法分离纯化(Silica gel,DCM:MeOH=30:1),得到目标化合物(82mg,22.0%),为黄色固体。LCMS(ESI)[M+H]
+=548.34。
第六步:(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(哒嗪-4-基氨基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙-2-醇(实施例49化合物)的制备
将(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(哒嗪-4-基氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙-2-醇(62mg,0.11mmol,1.0eq)溶于MeOH(甲醇)(3mL)中,加入盐酸的1,4-二氧六环溶液(3mL,4M),反应在40℃反应3小时。TLC检测反应完毕后,反应液用饱和碳酸氢钠水溶液淬灭,二氯甲烷萃取,无水硫酸钠干燥。有机相浓缩,粗产物用制备HPLC分离纯化(C18,10mmol/L NH
4HCO
3水溶液,MeCN),得到(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(哒嗪-4-基氨基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙-2-醇(14mg,29.8%)。LCMS(ESI)[M+H]
+=418.3;
1H NMR(400MHz,DMSO-d
6)δ:11.48(s,1H),10.19(s,1H),9.51(s,1H),9.04(d,J=6.0Hz,1H),8.39(d,J=48.8Hz,2H),7.08(dd,J=5.1,3.3Hz,3H),7.04–6.97(m,1H),5.80(s,1H),4.89(s,1H),4.19–3.96(m,1H),3.70–3.57(m,2H),3.56–3.48(m,1H),3.31–3.23(m,1H),2.81(d,J=5.8Hz,2H),2.72(td,J=11.3,5.5Hz,2H),2.61(dd,J=12.6,5.7Hz,1H),2.54(d,J=6.5Hz,1H)。
实施例50
(R)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(哒嗪-4-基氨基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙-2-醇的制备
按实施例49的方法,利用原料化合物(R)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(即中间体3-b,制备方法参见实施例3)做起始原料,与3-碘-N-(哒嗪-4-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-胺(即中间体49-d,制备方法参见实施例49)进行偶联反应,再脱除SEM即得到目标分子(R)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(哒嗪-4-基氨基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙-2-醇。LCMS(ESI)[M+H]
+=418.3;
1H NMR(400MHz,DMSO-d
6)δ:11.48(s,1H),10.19(s,1H),9.51(s,1H),9.04(d,J=6.0Hz,1H),8.39(d,J=48.8Hz,2H),7.08(dd,J=5.1,3.3Hz,3H),7.04–6.97(m,1H),5.80(s,1H),4.89(s,1H),4.19–3.96(m,1H),3.70–3.57(m,2H),3.56–3.48(m,1H),3.31–3.23(m,1H),2.81(d,J=5.8Hz,2H),2.72(td,J=11.3,5.5Hz,2H),2.61(dd,J=12.6,5.7Hz,1H),2.54(d,J=6.5Hz,1H)。
实施例51
1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(哒嗪-4-基氨基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙-2-醇的制备
按实施例49的方法,利用原料化合物(1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(即中间体1-b,制备方法参见实施例1)做起始原料,与3-碘-N-(哒嗪-4-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-胺(即中间体49-d,制备方法参见实施例49)进行偶联反应,再脱除SEM即得到目标分子1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(哒嗪-4-基氨基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙-2-醇。LCMS(ESI)[M+H]
+=418.3;
1H NMR(400MHz,DMSO-d
6)δ:11.48(s,1H),10.19(s,1H),9.51(s,1H),9.04(d,J=6.0Hz,1H),8.39(d,J=48.8Hz,2H),7.08(dd,J=5.1,3.3Hz,3H),7.04–6.97(m,1H),5.80(s,1H),4.89(s,1H),4.19–3.96(m,1H),3.70–3.57(m,2H),3.56–3.48(m,1H),3.31–3.23(m,1H),2.81(d,J=5.8Hz,2H),2.72(td,J=11.3,5.5Hz,2H),2.61 (dd,J=12.6,5.7Hz,1H),2.54(d,J=6.5Hz,1H)。
实施例52
(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备
第一步:苯甲基2,2,2-三氟乙酰亚胺酸酯(中间体52-a)的制备
将化合物2,2,2-三氟乙酰胺(5.0g,44.2mmol,1.06eq)溶于二氯甲烷(220mL),加入二甲基亚砜(10.4g,133.4mmol,3.2eq),氮气保护下降温至-75℃。在此温度下,分别滴加草酰氯(5.25g,41.69mmol,1.0eq)和三乙胺(10.6g,105.5mmol,2.5eq),控制内温在-75℃左右,继续搅拌0.5h。加入DBU(1,8-二氮杂二环十一碳-7-烯)(4.25g,27.93mmol,0.67eq)和苄醇(4.5g,41.7mmol,1.0eq),在-75℃条件下搅拌15min后升至15℃搅拌16h。向反应体系加入水(100mL),水相用乙酸乙酯萃取三次(3×50mL),有机相分别用水、饱和氯化钠溶液洗涤一次,无水硫酸钠干燥,将溶剂浓缩,柱层析分离(Silica gel,PE:EA=100:0-92:8),得1.5g苯甲基2,2,2-三氟乙酰亚胺酸酯,无色透明油状,产率16.7%。
1H NMR(400MHz,DMSO-d
6)δ:10.13(s,1H),7.45–7.39(m,5H),5.29(s,2H)。
第二步:5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(中间体52-b)的制备
将化合物苯甲基2,2,2-三氟乙酰亚胺酸酯(65.0mg,0.322mmol,1.0eq)和乙基 4-氨基-1H-吡唑-5-羧酸酯(50.0mg,0.322mmol,1.0eq)溶于吡啶(1.6mL),升温至115℃搅拌16h。冷却至室温,减压蒸馏除去吡啶,用二氯甲烷打浆得31mg 5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚,白色固体,产率46.9%。LCMS(ESI)[M+H]
+=205.05;
1H NMR(400MHz,DMSO-d
6)δ:13.13(s,1H),7.77(s,1H)。
第三步:3-碘-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(中间体52-c)的制备
将化合物5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(2.0g,9.8mmol,1.0eq)和化合物N-碘代丁二酰亚胺(3.3g,14.7mmol,1.5eq)加入N,N-二甲基甲酰胺(48mL),置换氮气三次,加热到60℃,16h反应结束。冷却至室温。减压蒸馏除去溶剂,粗品用二氯甲烷打浆,得1.9g白色固体,即3-碘-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚,收率58.6%。LCMS(ESI)[M+H]
+=331.02;
1H NMR(400MHz,DMSO-d
6)δ:14.92(s,1H),13.73(s,1H)。
第四步:3-碘-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(中间体52-d)的制备
将化合物3-碘-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(50mg,0.151mmol,1.0eq)和对甲基苯磺酸(3.9mg,0.023mmol,0.15eq)加到二氯甲烷(0.8mL),加入DHP(3,4-二氢-2H-吡喃)(19mg,0.226mmol,1.5eq),室温下搅拌20min,TLC检测反应完全。过滤得滤饼,3-碘-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚,33mg白色固体。LCMS(ESI)[M+H]
+=415.21;
1H NMR(400MHz,DMSO-d
6)δ:13.97(s,1H),6.15(dd,J=10.1,2.3Hz,1H),3.96(d,J=11.1Hz,1H),3.70–3.58(m,1H),2.30(ddd,J=23.0,12.6,4.0Hz,1H),2.06–1.82(m,2H),1.78–1.63(m,1H),1.61–1.44(m,2H)。
第五步:3-(((S)-3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1-(四氢-2H- 吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(中间体52-e)的制备
将化合物3-碘-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(30mg,0.073mmol,1.0eq)溶于二甲基亚砜(0.36mL)中,加入化合物(S)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(15.0mg,0.073mmol,1.0eq)、碘化亚铜(2.7mg,0.0145mmol,0.2eq)、碳酸钾(280mg,2.03mmol,3.0eq)及L-脯氨酸(31.0mg,0.27mmol,0.4eq),反应在N
2保护下80℃反应16小时。TLC检测反应完毕后,向反应体系加入水(15mL),用乙酸乙酯萃取三次(3×20mL),合并有机相,用饱和氯化钠溶液(20mL)洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩,HPLC(DCM:MeOH=20:1)提纯得66.0mg 3-(((S)-3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚,淡黄色固体,收率53.6%。LCMS(ESI)[M+H]
+=493.41。
第六步:(S)-1-(4-((3-(((S)-3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(中间体52-f)的制备
将化合物3-(((S)-3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(60.0mg,0.122mmol,1.0eq)、1-(4-氨基哌啶-1-基)乙烷-1-酮盐酸盐(32.6mg,0.183mmol,1.5eq)和PyBOP(六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷)(82.5mg,0.158mmol,1.3eq)溶于N,N-二甲基甲酰胺(0.6mL),置换氮气三次。再加入DBU(1,8-二氮杂二环十一碳-7-烯)(27.8mg,0.183mmol,1.5eq),在室温下搅拌0.5h,TLC检测原料反应完全。向反应体系加入水(10mL),用乙酸乙酯萃取三次(3×20mL),合并有机相,用饱和氯化钠溶液(20mL)洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩,HPLC(DCM:MeOH =20:1)提纯得40.0mg目标中间体1-(4-((3-(((S)-3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮,淡黄色油状,收率53.3%。LCMS(ESI)[M+H]
+=617.43。
第七步:(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(实施例52化合物)的制备
向化合物1-(4-((3-(((S)-3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(40mg,0.06mmol,1.0eq)中,加入4M(摩尔浓度)盐酸二氧六环溶液(0.2mL),反应在室温,N
2保护下反应1小时。TLC检测反应完毕后,向反应体系加入饱和碳酸氢钠溶液至pH=7-8,用乙酸乙酯(20mL)萃取,有机相用饱和氯化钠溶液(20mL)洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩,制备HPLC分离纯化(C18,0.08%NH
4HCO
3水溶液/乙腈)提纯得6mg目标产物(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮,收率17.8%。LCMS(ESI)[M+1]
+=533.25;
1H NMR(400MHz,DMSO-d
6)δ:11.62(s,1H),7.82(s,1H),7.07(dd,J=28.1,5.3Hz,4H),5.80(s,1H),4.89(s,1H),4.25(s,2H),4.11–3.97(m,1H),3.82(d,J=14.0Hz,1H),3.76–3.39(m,3H),3.26(s,2H),3.01–2.53(m,7H),2.06(d,J=10.1Hz,1H),2.03(s,3H),1.44(dd,J=47.5,10.2Hz,2H)。
实施例53
(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备
按实施例52的方法,利用原料化合物(R)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(即中间体3-b,制备方法参见实施例3)做起始原料,与3-碘-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(即中间体52-d,制备方法参见实施例52)进行偶联反应,再与1-(4-氨基哌啶-1-基)乙烷-1-酮盐酸盐发生缩合反应,然后脱除THP即得到目标产物(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮。LCMS(ESI)[M+1]
+=533.25;
1H NMR(400MHz,DMSO-d
6)δ:11.62(s,1H),7.82(s,1H),7.07(dd,J=28.1,5.3Hz,4H),5.80(s,1H),4.89(s,1H),4.25(s,2H),4.11–3.97(m,1H),3.82(d,J=14.0Hz,1H),3.76–3.39(m,3H),3.26(s,2H),3.01–2.53(m,7H),2.06(d,J=10.1Hz,1H),2.03(s,3H),1.44(dd,J=47.5,10.2Hz,2H)。
实施例54
1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备
按实施例52的方法,利用原料化合物(1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(即中间体1-b,制备方法参见实施例1)做起始原料,与3-碘-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(即中间体52-d,制备方法参见实施例52)进行偶联反应,再与1-(4-氨基哌啶-1-基)乙烷-1-酮盐酸盐发生缩合反应,然后脱除THP即得到到目标分子1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮。LCMS(ESI)[M+1]
+=533.25;
1H NMR(400MHz,DMSO-d
6)δ:11.62(s,1H),7.82(s,1H),7.07(dd,J=28.1,5.3Hz,4H),5.80(s,1H),4.89(s,1H),4.25(s,2H),4.11–3.97(m,1H),3.82(d,J=14.0Hz,1H),3.76–3.39(m,3H),3.26(s,2H),3.01–2.53(m,7H),2.06(d,J=10.1Hz,1H),2.03(s,3H),1.44(dd,J=47.5,10.2Hz,2H)。
实施例55
(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(吡嗪-2-基氨基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙-2-醇的制备:
第一步:3-碘-1H-吡唑并[4,3-d]嘧啶-7-醇的合成:
将7-羟基吡唑并[4,3-d]嘧啶(2.00g,14.69mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(40mL)中,加入NIS(N-碘代丁二酰亚胺,CAS:516-12-1)(4.96g,22.04mmol,1.5eq),反应在氮气保护下60℃反应5小时。TLC检测反应完毕后,旋干反应溶剂,将混合物溶于甲醇,抽滤。滤饼用甲醇淋洗,干燥,得到目标化合物(3.46g,收率89.9%)。LCMS(ESI)[M+H]
+=262.87;
1H NMR(400MHz,DMSO-d
6)δ14.55(s,1H),12.41(s,1H),7.92(d,J=3.3Hz,1H).
第二步:3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇的合成:
将3-碘-1H-吡唑并[4,3-d]嘧啶-7-醇(1.50g,5.72mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(28mL)中,加入Cs
2CO
3(2.24g,6.87mmol,1.2eq),0℃下滴加SEMCl(2-(三甲基硅烷基)乙氧甲基氯)(0.95g,5.72mmol,1.0eq),反应在20℃过夜反应16小时。TLC检测反应完毕后,反应液用二氯甲烷萃取,无水硫酸钠干燥。有机相浓缩,粗产物用快速色谱法分离纯化(Silica gel,DCM:MeOH=15:1),得到目标化合物(1.21g,收率53.8%)。LCMS(ESI)[M+H]
+=393.12。
第三步:7-((1H-苯并[d][1,2,3]三唑-1-基)氧基)-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶的合成:
将3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇(2.00g,5.10mmol,1.0eq)溶于DMF(N,N-二甲基甲酰胺)(26mL)中,加入PyBOP(1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐)(3.45g,6.63mmol,1.3eq)及DBU(1.16g,7.65mmol,1.5eq),反应在20℃反应0.5小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取,无水硫酸钠干燥。有机相浓缩,粗产物用快速色谱法分离纯化(Silica gel,PE:EA=6:1),得到目标化合物(1.25g,收率48.1%)。LCMS(ESI)[M+H]
+=510.16。
第四步:3-碘-N-(吡嗪-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-胺的合成:
于氨基吡嗪(142mg,1.50mmol,1.5eq)的DMF(N,N-二甲基甲酰胺)(3mL)溶液中,0℃下加入NaH(120mg,2.99mmol,3.0eq),氮气保护下搅拌10分钟。再加入7-((1H-苯并[d][1,2,3]三唑-1-基)氧基)-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶(508mg,1.00mmol,1.0eq)的DMF(N,N-二甲基甲酰胺)(4mL)溶液,反应在20℃反应0.5小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取,无水硫酸钠干燥。有机相浓缩,粗产物用快速色谱法分离纯化(Silica gel,PE:EA=2:1),得到目标化合物(450mg,收率96.2%)。LCMS(ESI)[M+H]
+=470.17。
第五步:(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(吡嗪-2-基氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙-2-醇的合成:
将3-碘-N-(吡嗪-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-胺(70mg,0.15mmol,1.0eq)溶于DMSO(二甲基亚砜)(2mL)中,加入(S)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(46mg,0.22mmol,1.5eq)、CuI(57mg,0.30mmol,2.0eq)、K
2CO
3(103mg,0.75mmol,5.0eq)及L-Proline(34mg,0.30mmol,2.0eq),反应在氮气保护下80℃反应16小时。TLC检测反应完毕后,反应液用乙酸乙酯萃取,无水硫酸钠干燥。有机相浓缩,粗产物用快速色谱法分离纯化(Silica gel,DCM:MeOH=15:1),得到目标化合物(18mg,收率22.0%)。LCMS(ESI)[M+H]
+=548.43。
第六步:(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(吡嗪-2-基氨基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙-2-醇的合成:
将(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(吡嗪-2-基氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙-2-醇(29mg,0.05mmol,1.0eq)溶于MeOH(甲醇)(1mL)中,加入盐酸的1,4-二氧六环溶液(1mL,4M),反应在40℃反应4小时。TLC检测反应完毕后,反应液用饱和碳酸氢钠水溶液淬灭,二氯甲烷萃取,无水硫酸钠干燥。有机相浓缩,粗产物用Prep-HPLC分离纯化(C18,10mmol/L NH
4HCO
3in water,MeCN),得目标化合物(7mg,收率31.8%)。LCMS(ESI)[M+H]
+=418.3;
1H NMR(400MHz,Chloroform-d)δ11.33(s,1H),δ8.90(s,1H),8.44(s,1H),8.23(d,J=16.9Hz,2H),7.17–7.05(m,3H),7.02–6.95(m,1H),5.14(s,1H),4.25(s,1H),3.85(d,J=14.8Hz,1H),3.68(dd,J=26.2,14.2Hz,2H),3.51(s,1H),3.03–2.87(m,3H),2.82–2.71(m,2H),2.65(dd,J=12.3,3.7Hz,1H).
实施例56
(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)硫基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮的制备:
第一步:(R)-S-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)硫代乙酸酯的合成:
将(R)-2-(环氧乙烷-2-基甲基)-1,2,3,4-四氢异喹啉(50mg,0.26mmol,1.0eq)溶于DCM(二氯甲烷)(1.5mL)中,加入thioacetic acid(硫代乙酸)(30mg,0.40mmol,1.5eq)及potassium thioacetate(硫代乙酸钾)(45mg,0.40mmol,1.5eq),20℃反应20小时。TLC检测反应完毕后,反应液抽滤,滤液浓缩得到目标化合物粗品(70mg,收率100%)。LCMS(ESI)[M+H]
+=266.2。
第二步:(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)硫基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮的合成:
将1-(4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮(50mg,0.10mmol,1.0eq)溶于i-PrOH(异丙醇)(1mL)中,加入(R)-S-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)硫代乙酸酯(31mg,0.12mmol,1.2eq)、CuI(18mg,0.10mmol,1.0eq)、K
2CO
3(67mg,0.48mmol,5.0eq)及乙二醇(12mg,0.19mmol,2.0eq),反应在氮气保护下80℃反应17小时,再在100℃反应23小时。TLC检测反应完毕后,反应液抽滤,滤液浓缩,粗产物用PLC纯化(Silica gel,DCM:MeOH=10:1),得到目标化合物(11mg,收率18.5%)。LCMS(ESI)[M+H]
+=612.5。
第三步:(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)硫基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮的合成:
将(R)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)硫基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮(11mg,0.02mmol,1.0eq)溶于盐酸的1,4-二氧六环溶液(0.5mL,4M)中,反应在20℃反应2小时。TLC检测反应完毕后,反应液用饱和碳酸氢钠水溶液淬灭,二氯甲烷萃取,无水硫酸钠干燥。有机相浓缩,粗产物用Prep-HPLC分离纯化(C18,10mmol/L NH
4HCO
3in water,MeCN),得目标化合物(2.5mg,收率28.9%)。LCMS(ESI)[M+H]
+=482.4;
1H NMR(400MHz,Chloroform-d)δ8.39(s,1H),7.18–7.06(m,3H),6.99(d,J=6.8Hz,1H),6.82(s,1H),4.65(d,J=13.5Hz,1H),4.51(s,1H),4.14(s,1H),3.89(d,J=13.9Hz,1H),3.81(d,J=15.0Hz,1H),3.71(d,J=14.9Hz,1H),3.39–3.23(m,2H),3.13(dd,J=14.4,6.6Hz,1H),2.96–2.80(m,5H),2.73(d,J=6.7Hz,2H),2.37(d,J=12.9Hz,1H),2.17(s,3H),2.11(d,J=13.4Hz,1H),1.51–1.33(m,2H).
实施例57
(S)-1-(4-((3-((3-(6-氟-3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备:
第一步:(R)-6-氟-2-(噁丙环-2-基甲基)-1,2,3,4-四氢异喹啉的制备:
将6-氟-1,2,3,4-四氢异喹啉盐酸盐(400mg,2.6mmol,1.0eq)和(R)-2-(氯甲基)噁丙环(294mg,3.2mmol,1.2eq)溶于异丙醇(10mL)中,加入碳酸钾(517mg,13.2mmol,5eq)。将混合物在氮气下在50℃下搅拌16小时。向反应体系加入水(100mL),水相用乙酸乙酯萃取三次(3×50mL),有机相分别用水、饱和氯化钠溶液洗涤一次,无水硫酸钠干燥,将溶剂浓缩,柱层析分离(Silica gel,0-4%MeOH in DCM),得(R)-6-氟-2-(噁丙环-2-基甲基)-1,2,3,4-四氢异喹啉(350mg,收率63.8%)。LCMS(ESI)[M+H]
+=208.09。
第二步(S)-1-氨基-3-(6-氟-3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇的制备:
将(R)-6-氟-2-(噁丙环-2-基甲基)-1,2,3,4-四氢异喹啉(350mg,1.69mmol,1.0eq)溶于NH
3·H
2O(30mL)中,70℃搅拌2小时,用(CHCl
3:i-PrOH=4:1)(3×20mL)萃取。有机相分别用水、饱和氯化钠溶液洗涤一次,无水硫酸钠干燥,将溶剂浓缩,得到粗品产物(S)-1-氨基-3-(6-氟-3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(400mg)。LCMS(ESI)[M+H]+=225.13。
第三步3-(((S)-3-(6-氟-3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚的制备:
将化合物3-碘-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(200mg,0.48mmol,1.0equiv.)溶于二甲基亚砜(3mL)中,加入化合物(S)-1-氨基-3-(6-氟-3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(130mg,0.58mmol,1.2equiv.)、碘化亚铜(37mg,0.19mol,0.4equiv.)、L-脯氨酸(22mg,0.19mmol,0.4equiv.)及碳酸钾(334mg,2.41mol,5.0equiv.),反应在N
2保护下80℃反应16小时。TLC检测反应完毕后,向反应体系加入水(15mL),用乙酸乙酯萃取三次(3×20mL),合并有机相,用饱和氯化钠溶液(20mL)洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩,柱层析分离(Silica gel,0-4%MeOH in DCM),得3-(((S)-3-(6-氟-3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(200mg,收率81.1%)。LCMS(ESI)[M+H]
+=511.41。
第四步1-(4-((3-(((S)-3-(6-氟-3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备:
将化合物3-(((S)-3-(6-氟-3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(150mg,0.29mmol,1.0equiv.)、1-(4-氨基哌啶-1-基)乙烷-1-酮盐酸盐(63mg,0.44mmol,1.5equiv.)和六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(199mg,0.38mmol,1.3eq)溶于N,N-二甲基甲酰胺(1.5mL),置换氮气三次。再加入1,8-二氮杂二环十一碳-7-烯(134mg,0.88mmol,3.0equiv.),在室温下搅拌10分钟,TLC检测原料反应完全。向反应体系加入水(10mL),用乙酸乙酯萃取三次(3×20mL),合并有机相,用饱和氯化钠溶液(20mL)洗涤一次,无水硫酸钠干燥,抽 滤,将溶剂浓缩,PLC(DCM:MeOH=15:1)提纯得1-(4-((3-(((S)-3-(6-氟-3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(62mg,产率33.2%)。LCMS(ESI)[M+H]
+=635.60。
第五步(S)-1-(4-((3-((3-(6-氟-3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备:
向1-(4-((3-(((S)-3-(6-氟-3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮中,加入2mL盐酸(4M二氧六环溶液),反应在室温,N
2保护下反应1小时。TLC检测反应完毕后,向反应体系加入饱和碳酸氢钠溶液至pH=7-8,用乙酸乙酯(20mL)萃取,有机相用饱和氯化钠溶液(20mL)洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩,粗产物用Prep-HPLC分离纯化(C18,10mmol/L NH
4HCO
3in water,MeCN),得到(S)-1-(4-((3-((3-(6-氟-3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(8.9mg,收率17.1%)。LCMS(ESI)[M+H]
+=551.44;
1H NMR(400MHz,CDCl
3)δ6.95(dd,J=8.3,5.7Hz,1H),6.86–6.73(m,2H),4.67(d,J=12.7Hz,1H),4.53(d,J=6.7Hz,1H),4.17(td,J=9.6,3.8Hz,1H),3.75-3.94(m,2H),3.69–3.60(m,2H),3.50–3.40(m,1H),3.36(t,J=12.2Hz,1H),2.98–2.82(m,4H),2.83–2.71(m,2H),2.65(dd,J=12.5,3.9Hz,1H),2.44(d,J=12.9Hz,1H),2.17(s,3H),2.10(d,J=10.3Hz,1H),1.51–1.22(m,2H).
实施例58
(S)-1-(4-((3-((3-(7-氟-3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备:
第一步:(R)-7-氟-2-(噁丙环-2-基甲基)-1,2,3,4-四氢异喹啉的制备:
将7-氟-1,2,3,4-四氢异喹啉盐酸盐(500mg,2.66mmol,1.0eq)和(R)-2-(氯甲基) 噁丙环(296mg,3.20mmol,1.2eq)溶于异丙醇(10mL)中,加入碳酸钾(1.84g,13.32mmol,5.0eq)。将混合物在氮气保护下50℃下搅拌16小时。反应液浓缩,柱层析分离(Silica gel,1%MeOH in DCM),得(R)-7-氟-2-(噁丙环-2-基甲基)-1,2,3,4-四氢异喹啉(360mg,收率65.2%)。LCMS(ESI)[M+H]
+=208.09。
第二步:(S)-1-氨基-3-(7-氟-3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇的制备:
将(R)-7-氟-2-(噁丙环-2-基甲基)-1,2,3,4-四氢异喹啉(360mg,1.74mmol,1.0eq)溶于NH
4OH(氨水)(30mL)中,70℃搅拌2小时。用(氯仿:异丙醇=4:1)(3×20mL)萃取。有机相分别用水、饱和氯化钠溶液洗涤一次,无水硫酸钠干燥,过滤,将滤液浓缩,得到粗产物(S)-1-氨基-3-(7-氟-3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(422mg)。LCMS(ESI)[M+H]
+=225.14。
第三步:3-(((S)-3-(7-氟-3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚的制备:
将化合物3-碘-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(300mg,0.72mmol,1.0equiv)溶于二甲基亚砜(7mL)中,加入化合物(S)-1-氨基-3-(7-氟-3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(211mg,0.94mmol,1.3 0.2equiv.)、碘化亚铜(28mg,0.14mol,0.2equiv.)、L-脯氨酸(33mg,0.29mmol,0.4equiv.)及碳酸钾(501mg,3.62mol,5.0equiv.),反应在N
2保护下80℃反应15小时。TLC检测反应完毕后,向反应体系加入水(100mL),用乙酸乙酯萃取三次(3×20mL),合并有机相,用饱和氯化钠溶液(20mL)洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩,柱层析分离(Silica gel,3%MeOH in DCM),得3-(((S)-3-(7-氟-3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(336mg,收率90.9%)。LCMS(ESI):[M+H]
+=511.2。
第四步:1-(4-((3-(((S)-3-(7-氟-3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备:
将化合物3-(((S)-3-(7-氟-3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(295mg,0.58mmol,1.0eq)、1-(4-氨基哌啶-1-基)乙烷-1-酮盐酸盐(155mg,0.87mmol,1.5eq)和六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(391mg,0.75mmol,1.3eq)及1,8-二氮杂二环十一碳-7-烯(264mg,1.73mmol,3.0eq)溶于N,N-二甲基甲酰胺(4.5mL)中,20℃搅拌10分钟,TLC检测原料反应完全。向反应体系加入水(60mL),用乙酸乙酯萃取三次(3×20mL),合并有机相,用饱和氯化钠溶液(20mL)洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩,PLC(DCM:MeOH=15:1)纯化得1-(4-((3-(((S)-3-(7-氟-3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(100mg,收率27.3%)。LCMS(ESI)[M+H]
+=635.56。
第五步:(S)-1-(4-((3-((3-(7-氟-3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备:
向1-(4-((3-(((S)-3-(7-氟-3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(95mg,0.15mmol,1.0eq)中,加入5mL盐酸的1,4-二氧六环溶液(4M),20℃反应20分钟。TLC检测反应完毕后,反应液用饱和碳酸氢钠水溶液淬灭,二氯甲烷(3×20mL)萃取,有机相浓缩,粗产物用Prep-HPLC分离纯化(C18,10mmol/L NH
4HCO
3in water,MeCN),得到(S)-1-(4-((3-((3-(7-氟-3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(13.7mg,收率16.6%)。LCMS(ESI)[M+H]
+=551.6;
1H NMR(400MHz,CDCl
3)δ7.12(br s,1H),7.04(dd,J=8.5, 5.6Hz,1H),6.85(td,J=8.5,2.7Hz,1H),6.70(dd,J=9.3,2.7Hz,1H),4.59(d,J=13.6Hz,1H),4.49(br s,1H),4.21(br s,1H),3.93–3.83(m,2H),3.74(d,J=15.3Hz,1H),3.63(dd,J=13.7,3.5Hz,1H),3.44(dd,J=13.7,6.0Hz,1H),3.34(t,J=12.8Hz,1H),3.05–2.85(m,5H),2.83–2.69(m,2H),2.36(d,J=12.9Hz,1H),2.15(s,3H),2.08(d,J=11.4Hz,1H),1.53–1.33(m,2H).
实施例59
(S)-1-(4-((3-((2-羟基-3-(1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)丙基)氨基)-5-(三氟甲基)-1H-吡啶并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备:
第一步:(R)-2-(噁丙环-2-亚甲基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚的制备:
将2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚(1g,5.81mmol,1.0eq)和(R)-2-(氯甲基)噁丙环(617mg,6.68mmol,1.15eq)溶于异丙醇(24mL)中,加入碳酸钾(4.01g,29.03mmol,5.0eq)。将混合物在氮气保护下50℃下搅拌5小时。反应液浓缩,用DCM萃取(50mL X 3)。二氯甲烷相用无水硫酸钠干燥后,过滤,浓缩。柱层析分离(Silica gel,1%MeOH in DCM),得(R)-2-(噁丙环-2-亚甲基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚(200mg,收率15%)。
1H NMR(400MHz,Chloroform-d)δ7.78(s,1H),7.47(dq,J=7.5,0.8Hz,1H),7.30(dt,J=8.2,1.0Hz,1H),7.19–7.03(m,2H),3.92(dt,J=14.7,1.6Hz,1H),3.75(dt,J=14.8,1.7Hz,1H),3.24(ddt,J=7.0,4.1,2.8Hz,1H),3.08(dd,J=13.3,2.9Hz,1H),2.99(dd,J=6.5,5.7Hz,2H),2.90–2.78(m,3H),2.55(dd,J=5.0,2.7Hz,1H),2.51(dd,J=13.3,7.1Hz,1H).
第二步:(S)-1-氨基-3-(1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)丙烷-2-醇的制备:
将(R)-2-(噁丙环-2-亚甲基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚(150mg,0.657mmol,1.0eq)溶于NH3/MeOH(7M)(2mL)中,50℃搅拌4小时。直接旋干得到粗产 物(S)-1-氨基-3-(1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)丙烷-2-醇(160mg)。LCMS(ESI)[M+H]
+=246.2
第三步:3-(((S)-2-羟基-3-(1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚的制备:
将化合物3-碘-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(200mg,0.48mmol,1.0equiv)溶于二甲基亚砜(2mL)中,加入化合物(S)-1-氨基-3-(1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)丙烷-2-醇粗品(0.2g,0.72mmol,1.5equiv.)、碘化亚铜(18mg,0.096mol,0.2equiv.)、L-脯氨酸(22mg,0.19mmol,0.4equiv.)及碳酸钾(333mg,2.41mol,5.0equiv.),反应在N
2保护下80℃反应15小时。TLC检测反应完毕后,向反应体系加入水(100mL),用乙酸乙酯萃取三次(3×20mL),合并有机相,用饱和氯化钠溶液(20mL)洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩,柱层析分离(Silica gel,3%MeOH in DCM),得3-(((S)-2-羟基-3-(1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(160mg)。LCMS(ESI)[M+H]
+=532.7。
第四步:1-(4-((3-(((S)-2-羟基-3-(1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备:
将化合物3-(((S)-2-羟基-3-(1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(145mg,0.272mmol,1.0eq)、1-(4-氨基哌啶-1-基)乙烷-1-酮盐酸盐(CAS:214147-48-5)(73mg,0.409mmol, 1.5eq)和六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(183mg,0.353mmol,1.3eq)及1,8-二氮杂二环十一碳-7-烯(124mg,0.818mmol,3.0eq)溶于N,N-二甲基甲酰胺(1.5mL)中,20℃搅拌6分钟,TLC检测原料反应完全。向反应体系加入水(60mL),用乙酸乙酯萃取三次(3×20mL),合并有机相,用饱和氯化钠溶液(20mL)洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩,PLC(DCM:MeOH=10:1)纯化得1-(4-((3-(((S)-2-羟基-3-(1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(100mg,收率67%)。LCMS(ESI)[M+H]
+=656.7。
第五步:(S)-1-(4-((3-((2-羟基-3-(1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)丙基)氨基)-5-(三氟甲基)-1H-吡啶并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备:
向1-(4-((3-(((S)-2-羟基-3-(1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(90mg,0.137mmol,1.0eq)中,加入2mL盐酸的1,4-二氧六环溶液(4M),20℃反应60分钟。TLC检测反应完毕后,反应液用饱和碳酸氢钠水溶液淬灭,二氯甲烷(3×20mL)萃取,有机相浓缩,粗产物用Prep-HPLC分离纯化(C18,10mmol/L NH
4HCO
3in water,MeCN),得到(S)-1-(4-((3-((2-羟基-3-(1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)丙基)氨基)-5-(三氟甲基)-1H-吡啶并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙烷-1-酮(13.4mg,收率17.0%)。LCMS(ESI)[M+H]
+=572.6。
1H NMR(400MHz,DMSO-d
6)δ11.53(br s,1H),10.68(s,1H),7.74(br s,1H),7.34(d,J=7.7Hz,1H),7.26(d,J=7.9Hz,1H),7.00(ddd,J=8.1,6.4,1.3Hz,1H),6.93(td,J=7.5,1.1Hz,1H),5.77(s,1H),4.86(s,1H),4.35–4.14(m,2H),4.10–3.95(m,1H),3.82(d,J=13.8Hz,1H),3.77–3.61(m,2H),3.48(dt,J=12.1,5.9Hz,1H),3.26–3.23(m,2H),2.91-2.69(m,3H),2.69-2.50(m,3H),2.60(dd,J=12.7,6.4Hz,1H),2.16–1.93(m,5H),1.58–1.44(m,1H),1.44–1.31(m,1H).
实施例60
(S)-1-(4-((3-((3-(4,5-二氢-1H-苯并[d]氮杂卓-3(2H)-基)-2-羟丙基)氨基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮的制备:
第一步:(R)-3-(环氧乙烷-2-基甲基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓的制备:
将2,3,4,5-四氢-1H-苯并[d]氮杂卓(500mg,3.40mmol,1equiv.)溶于i-PrOH(异丙醇,17ml)中,加入K
2CO
3(碳酸钾)(2.35g,17.00mmol,5.01equiv.)和(R)-2-(氯甲基)环氧乙烷(380mg,4.11mmol,1.21equiv.)。50℃反应过夜(16h)。TLC和LCMS监测反应完成。将反应液冷却至室温,过滤。滤液旋干,粗产品用快速色谱法分离纯化(Silica gel,100%EA)后得到产品(R)-3-(环氧乙烷-2-基甲基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓(206mg,收率29.8%)。LCMS(ESI)[M+1]
+=204.06;
1H NMR(400MHz,Chloroform-d)δ7.15–7.07(m,4H),3.17–3.13(m,1H),3.01–2.90(m,4H),2.89–2.77(m,4H),2.76–2.68(m,2H),2.52–2.43(m,2H).
第二步:(S)-1-氨基-3-(4,5-二氢-1H-苯并[d]氮杂卓-3(2H)-基)丙-2-醇的制备:
向装有(R)-3-(环氧乙烷-2-基甲基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓(125mg,0.615mmol,1equiv.)的微波管中加入浓氨水(2.5ml),封管于70℃反应5小时。LCMS监测反应完成。反应液冷却至室温,用含30%异丙醇的氯仿溶液萃取三遍,合并有机相,干燥,旋干,得到粗品(S)-1-氨基-3-(4,5-二氢-1H-苯并[d]氮杂卓-3(2H)-基)丙-2-醇(134mg,收率98.9%),并直接用于下一步。LCMS(ESI)[M+H]
+=221.3。
第三步:3-(((S)-3-(4,5-二氢-1H-苯并[d]氮杂卓-3(2H)-基)-2-羟丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇的制备:
称量(S)-1-氨基-3-(4,5-二氢-1H-苯并[d]氮杂卓-3(2H)-基)丙-2-醇(105mg,0.477mmol,1equiv.),3-碘-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇 (198mg,0.478mmol,1equiv.),CuI(碘化亚铜)(36mg,0.189mmol,0.4equiv.),L-Proline(L-脯氨酸)(22mg,0.191mmol,0.4equiv.)和K
2CO
3(碳酸钾)(330mg,2.388mmol,4.99equiv.)加入烘干的微波管中,密封并置换为氮气条件后加入无水二甲基亚砜(2.4ml)。反应于80℃搅拌过夜(20h)。反应液过滤后反向柱纯化(C18,0.1%NH
4OH in water,MeCN0-50%)得到产品3-(((S)-3-(4,5-二氢-1H-苯并[d]氮杂卓-3(2H)-基)-2-羟丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇(87mg,收率34.1%)。LCMS(ESI)[M+1]
+=507.5。
第四步:1-(4-((3-(((S)-3-(4,5-二氢-1H-苯并[d]氮杂卓-3(2H)-基)-2-羟丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮的制备:
将原料3-(((S)-3-(4,5-二氢-1H-苯并[d]嗪-3(2H)-基)-2-羟丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-醇(77mg,0.152mmol,1equiv.)和PyBOP(1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐)(103mg,0.198mmol,1.3equiv.)溶于N,N-二甲基甲酰胺(1.5ml)中,加入DBU(1,8-二氮杂二环十一碳-7-烯)(70mg,0.460mmol,3.0equiv.),室温搅拌5分钟后加入1-乙酰基哌啶-4-胺盐酸盐(33mg,0.185mmol,1.2equiv.)。室温反应2小时,LCMS监测反应完成。将反应液旋干,粗产品用快速色谱法分离纯化(Silica gel,MeOH:DCM=0-5%)后得到产品1-(4-((3-(((S)-3-(4,5-二氢-1H-苯并[d]氮杂卓-3(2H)-基)-2-羟丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮(102mg,收率89.4%)。LCMS(ESI)[M+1]
+=631.7。
第五步:(S)-1-(4-((3-((3-(4,5-二氢-1H-苯并[d]氮杂卓-3(2H)-基)-2-羟丙基)氨基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮的制备:
将原料1-(4-((3-(((S)-3-(4,5-二氢-1H-苯并[d]氮杂卓-3(2H)-基)-2-羟丙基)氨基)-1-(四 氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮(102mg,0.162mmol,1equiv.)溶于二氧六环(1ml)中,加入盐酸二氧六环(4M,0.5ml,2mmol),室温反应5分钟。TLC监测反应完成。加入饱和碳酸氢钠水溶液调节pH至7-8。将溶液旋干,粗品溶于甲醇,过滤,反向柱纯化(C18,0.1%NH
4OH in water,MeCN)后再prep-HPLC反向柱纯化(C18,10mmol/L NH
4HCO
3in water,MeCN)得到产品(S)-1-(4-((3-((3-(4,5-二氢-1H-苯并[d]氮杂卓-3(2H)-基)-2-羟丙基)氨基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-基)氨基)哌啶-1-基)乙酮(13mg,收率14.3%)。LCMS(ESI)[M+1]
+=547.5;
1H NMR(400MHz,Chloroform-d)δ11.26(brs,1H),7.18–7.06(m,4H),6.98(brs,1H),5.00(brs,1H),4.67(d,J=13.6Hz,1H),4.60–4.46(m,1H),4.16–4.05(m,1H),3.89(d,J=13.9Hz,1H),3.64(d,J=13.5Hz,1H),3.48–3.31(m,2H),3.05–2.82(m,7H),2.79–2.57(m,4H),2.43(d,J=13.0Hz,1H),2.17(s,3H),2.11(d,J=13.0Hz,1H),1.49–1.24(m,2H).
实施例61
(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-((1-(甲磺酰)哌啶-4-基)氨基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙烷-2-醇的制备的:
第一步:3-(((S)-3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚的制备:
将化合物3-碘-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(300mg,0.725mmol,1.0equiv.)溶于二甲基亚砜(3.6mL)中,加入化合物(S)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(150mg,0.725mmol,1.0equiv.)、碘化亚铜(27mg,0.145mmol,0.2equiv.)、碳酸钾(300mg,2.18mmol,3.0equiv.)及L-脯氨酸(34mg,0.29mmol,0.4equiv.),反应在N
2保护下80℃反应16小时。TLC检测反应完毕后,向反应体系加入水(36mL),用乙酸乙酯萃取三次(3×30mL),合并有机相,用饱和氯化钠溶液(20mL)洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩, PLC(DCM:MeOH=20:1)提纯得3-(((S)-3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(180mg,收率50.4%)。LCMS(ESI)[M+1]
+=493.46
第二步:(2S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-((1-(甲磺酰)哌啶-4-基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙烷-2-醇的制备:
将化合物3-(((S)-3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-7-酚(100mg,0.2mmol,1.0equiv.)、1-(甲磺酰)哌啶-4-胺(53mg,0.3mmol,1.5equiv.)和六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(155mg,0.3mmol,1.5equiv.)溶于N,N-二甲基甲酰胺(1.0mL),置换氮气三次。再加入1,8-二氮杂二环十一碳-7-烯(91mg,0.6mmol,3equiv.),在室温下搅拌0.2h,TLC检测原料反应完全。向反应体系加入水(10mL),用乙酸乙酯萃取三次(3×20mL),合并有机相,用饱和氯化钠溶液(20mL)洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩,PLC(DCM:MeOH=20:1)提纯得(2S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-((1-(甲磺酰)哌啶-4-基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙烷-2-醇(103mg,收率83.7%)。LCMS(ESI)[M+1]
+=653.53。
第三步:(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-((1-(甲磺酰)哌啶-4-基)氨基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙烷-2-醇的制备:
向化合物(2S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-((1-(甲磺酰)哌啶-4-基)氨基)-1-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙烷-2-醇(100mg,0.153mmol)中,加入盐酸(4M in 1,4-dioxane,1.0mL),在室温下反应,N
2保护下反应0.5小时。TLC检测反应完毕后,向反应体系加入饱和碳酸氢钠溶液至pH=7-8,用乙酸乙酯(20mL)萃取,有机相用饱和氯化钠溶液(20mL)洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩,由Prep-HPLC分离纯化(C18,10mmol/L NH
4HCO
3in water,MeCN)提纯得(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-((1-(甲磺酰)哌啶-4-基)氨基)-5-(三氟甲基)-1H-吡唑并[4,3-d]嘧啶-3-基)氨基)丙烷-2-醇(22.4mg,收率26.1%)。LCMS(ESI)[M+H]
+=569.4;
1H NMR(400MHz,DMSO)δ11.55(s,1H),7.80(s,1H),7.09(m,3H),7.03(m,1H),5.79(brs,1H),4.85(brs,1H),4.09(d,J=49.8Hz,2H),3.58(m,J=12.1Hz,4H),3.47-3.42(m,1H),3.30(m,2H),2.99(t,J=10.9Hz,2H),2.91(s,3H),2.83(m,2H),2.69–2.63(m,3H),2.13(m,2H),1.65-1.59(m,2H).
实施例62
1-(3,4-二氢异喹啉-2(1H)-基)-4-(4-(3,4-二氢异喹啉-2(1H)-基)-1H-吡唑并[3,4-d]嘧啶-1基)丁-2-醇的制备:
第一步:4-氯-1-(2-(环氧乙烷-2-基)乙基)-1H-吡唑并[3,4-d]嘧啶的制备:
将4-氯-1H-吡唑并[3,4-d]嘧啶(100mg,0.647mmol,1.0equiv.)溶于N,N-二甲基甲酰胺(1mL)中,加入碳酸铯(421.6mg,1.29mmol,2.0equiv.)。25℃搅拌4小时。用TLC检测反应完成,将溶剂旋干,并用Prep-TLC分离纯化(PE:EA=8%)得到标题化合物(15mg,收率10.3%)。LCMS(ESI)[M+H]
+=225.1
第二步:1-(3,4-二氢异喹啉-2(1H)-基)-4-(4-(3,4-二氢异喹啉-2(1H)-基)-1H-吡唑并[3,4-d]嘧啶-1基)丁-2-醇的制备:
将4-氯-1-(2-(环氧乙烷-2-基)乙基)-1H-吡唑并[3,4-d]嘧啶(10mg,0.045mmol,1.0equiv.),溶于N,N-二甲基甲酰胺(0.5mL)中,加入1,2,3,4-四氢异喹啉,N-乙基-N-丙-2-基丙-2-胺(8.7mg,0.0675mmol,1.5equiv)100℃搅拌4小时。LCMS检测反应完成后,浓缩,得到粗产物,经过制备得到目标化合物(1.2mg,收率7.5%)。LCMS(ESI)[M+H]
+=456。
实施例63
(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吲唑-7-基)氨基)哌啶-1-基)乙烷-1-酮甲酸盐的制备:
第一步:第一步:(2S)-1-((7-溴-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)氨基)-3-(3,4-二氢异喹啉 -2(1H)-基)丙烷-2-醇的制备:
将7-溴-3-碘-1-(四氢-2H-吡喃-2-基)-1H-吲唑(2.0g,4.91mmol,1equiv.)溶于二甲基亚砜(25mL)中,加入(S)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(1.21g,5.89mmol,1.2equiv.)、碘化亚铜(1.87g,0.982mmol,0.2equiv.)、碳酸钾(3.4g,24.55mmol,5equiv.)及L-脯氨酸(226mg,1.96mmol,0.4equiv.),反应在N
2保护下80℃反应16小时。TLC检测反应完毕后,向反应体系加入水(300mL),用乙酸乙酯萃取三次(3×60mL),合并有机相,用饱和氯化钠溶液(60mL)洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩,柱色谱纯化(DCM:MeOH=98:2)得到标题化合物(0.54g,收率22.6%)。LCMS(ESI)[M+H]
+=485.1。
第二步:1-(4-((3-(((S)-3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-基)氨基)哌啶-1-基)乙烷-1-酮的制备:
将(2S)-1-((7-溴-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(500mg,1.03mmol,1.0equiv.)和1-(4-氨基哌啶-1-基)乙烷-1-酮(219mg,1.55mmol,1.5equiv.),Pd
2(dba)
3(94mg,0.103mmol,0.1equiv.),BINAP(64mg,0.103mmol,0.1equiv.)和Cs
2CO
3(1.68g,5.15mmol,5equiv.)。放至微波管中,氮气置换后加入甲苯(5mL)。110℃加热反应16h。LCMS监测反应完成。冷却至室温,向反应体系加入水(30mL),用乙酸乙酯萃取三次(3×30mL),合并有机相,用饱和氯化钠溶液(300mL)洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩,柱色谱纯化(DCM:MeOH=98:2)得到标题化合物(0.14g,收率25.2%)。LCMS(ESI)[M+H]
+=547.3。
第三步:(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吲唑-7-基)氨基)哌啶-1-基)乙烷-1-酮甲酸盐的制备:
将1-(4-((3-(((S)-3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-基)氨基)哌啶-1-基)乙烷-1-酮(120mg,0.22mmol,1equiv.)加到1,4-二氧六环(1mL)中,再加入0.25mL 4M盐酸的1,4-二氧六环溶液,在16℃下搅拌1h,TLC检测原料反应完全。将溶剂旋干, 粗产物用Prep-HPLC分离纯化(C18,0.1%(V/V)FA in water,MeCN)得目标产物(4.54mg,收率4.5%)。LCMS(ESI)[M+H]
+=463.3;
1H NMR(400MHz,DMSO)δ10.93(s,1H),8.16(s,1H),7.12–7.01(m,4H),6.88(d,J=7.9Hz,1H),6.71(t,J=7.7Hz,1H),6.39(d,J=7.4Hz,1H),5.71(s,1H),5.12(s,1H),4.27–4.19(m,1H),4.07–4.00(m,1H),3.83–3.77(m,1H),3.69–3.61(m,3H),3.44–3.40(m,1H),3.24–3.17(m,2H),2.91–2.71(m,6H),2.68–2.54(m,2H),2.10–2.03(m,1H),2.02(s,3H),2.00–1.90(m,1H),1.39–1.21(m,2H).
实施例64
(S)-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吲唑-7-基)氨基)哌啶-1-基)(1-甲基-1H-吡唑-4-基)甲酮甲酸盐的制备:
第一步:4-((3-(((S)-3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-基)氨基)哌啶-1-羧酸叔丁酯的制备:
将(2S)-1-((7-溴-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(2.25g,4.64mmol,1equiv.)和叔丁基-4-氨基哌啶-1-羧酸酯(1.39g,6.96mmol,1.5equiv.),Pd
2(dba)
3(425mg,0.46mmol,0.1equiv.),BINAP(289mg,0.46mmol,0.1equiv.)和Cs
2CO
3(7.56g,23.2mmol,5equiv.)。放至微波管中,氮气置换后加入甲苯(22mL)。110℃加热反应6h。LCMS监测反应完成。冷却至室温,向反应体系加入水(30mL),用乙酸乙酯萃取三次(3×30mL),合并有机相,用饱和氯化钠溶液(300mL)洗涤一次,无水硫酸钠干燥,抽滤,将溶剂浓缩,柱色谱纯化(DCM:MeOH=98:2),得到标题化合物(1.5g,收率53.5%)。LCMS(ESI)[M+H]
+=605.5。
第二步(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(哌啶-4-基氨基)-1H-吲唑-3-基)氨基)丙烷-2-醇的制备:
将叔丁基-4-((3-(((S)-3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-基)氨基)哌啶-1-羧酸酯(0.75g,1.24mmol,1equiv.)加到二氯甲烷(16mL)中,再加入三氟乙酸(2mL),在16℃下搅拌1h,TLC检测原料反应完全。将溶剂旋干,粗产物用Prep-HPLC分离纯化(C18,0.1%三氟乙酸水溶液,乙腈)得到目标产物(0.33g,收率63.3%)。LCMS(ESI)[M+H]
+=421.3。
第三步(S)-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)氨基)-1H-吲唑-7-基)氨基)哌啶-1-基)(1-甲基-1H-吡唑-4-基)甲酮甲酸盐的制备:
将(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-(哌啶-4-基氨基)-1H-吲唑-3-基)氨基)丙烷-2-醇(0.3g,0.71mmol,1equiv.),1-甲基-1H-吡唑-4-羧酸(108mg,0.852mmol,1.2equiv.),HATU(405mg,1.06mmol,1.5equiv.)溶于DMF(4mL)中,加入DIEA(275mg,2.13mmol,3equiv.)。16℃反应1小时。LCMS检测反应完成后,加入水和乙酸乙酯,粗产物用Prep-HPLC分离纯化(C18,0.1%甲酸水溶液,乙腈)得到标题化合物(46mg,收率12.3%)。LCMS(ESI)[M+H]
+=529.6,
1H NMR(400MHz,(CD
3)
2SO)δ10.93(s,1H),8.15(s,1H),8.05(s,1H),7.65(s,1H),7.12–7.01(m,4H),6.88(d,J=8.0Hz,1H),6.71(t,J=7.7Hz,1H),6.40(d,J=7.4Hz,1H),5.70(s,1H),5.17–5.11(m,1H),4.87(s,1H),4.19(s,2H),4.06–3.99(m,1H),3.85(s,3H),3.72–3.58(m,3H),3.46–3.38(m,2H),3.21–3.12(m,2H),2.84–2.60(m,6H),2.14–2.00(m,2H),1.44–1.29(m,2H).
实施例65
(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-5-苯基-1H-吲唑-7-基)氨基)哌啶-1-基)乙-1-酮的制备:
第一步:3-碘-7-硝基-5-苯基-1H-吲唑的制备:
将7-硝基-5-苯基-1H-吲唑(900mg,3.76mmol,1.0equiv.)和氢氧化钾(633mg,11.3mmol,3.0equiv.)溶于DMF(15mL)中,单质碘(1.43g,5.64mmol,1.5equiv.)加到反应液中,25℃搅拌2小时。加水(40mL)淬灭反应,乙酸乙酯萃取(3*15mL),合并有机相分别用10%亚硫酸钠溶液(3*20mL)和饱和食盐水洗(3*20mL),无水硫酸钠干燥,过滤,浓缩得到粗产品。粗产品快速色谱法分离纯化(100-200目硅胶,石油醚:乙酸乙 酯=0-10%)得到标题化合物(280mg,收率20%)。LCMS(ESI)[M+H]
+=365.75;
1H NMR(400MHz,CDCl
3):δ8.67(d,J=1.4Hz,1H),8.06(d,J=1.4Hz,1H),7.67(d,J=7.5Hz,2H),7.53(t,J=7.5Hz,2H),7.45(t,J=7.3Hz,1H)。
第二步:3-碘-7-硝基-5-苯基-1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑的制备:
将3-碘-7-硝基-5-苯基-1H-吲唑(230mg,63umol,1.0equiv.)溶于DMF(5mL)中,在0℃条件下,NaH(38mg,94umol,1.5equiv.)加到反应液中,然后恢复到25℃搅拌0.5小时。SEMCl(157mg,94umol,1.5equiv.)缓慢滴加到反应液中,25℃搅拌1小时。加水(20mL)淬灭反应,乙酸乙酯萃取(3*10mL),合并有机相用饱和食盐水洗(3*15mL),无水硫酸钠干燥,过滤,浓缩得到粗产品。粗产品快速色谱法分离纯化(100-200目硅胶,石油醚:乙酸乙酯=0-5%)得到标题化合物(220mg,产率70%)。LCMS(ESI)[M+H]
+=496.20;
1H NMR(400MHz,CDCl
3):δ8.43(d,J=1.6Hz,1H),7.97(d,J=1.6Hz,1H),7.66(d,J=7.0Hz,2H),7.51(t,J=7.5Hz,2H),7.44(d,J=7.3Hz,1H),5.96(s,2H),3.36–3.24(m,2H),0.81–0.71(m,2H),-0.12(s,9H)。
第三步:3-碘-5-苯基-1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-7-胺的制备:
将3-碘-7-硝基-5-苯基-1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑(1.16g,2.34mmol,1.0equiv.)、还原铁粉(655mg,11.7mmol,5.0equiv.)及氯化铵(1.25g,23.4mmol,10.0equiv.)溶于乙醇(15mL)和水(3mL)中,80℃搅拌2小时。反应液用硅藻土过滤,乙酸乙酯萃取(3*15mL),合并有机相用饱和食盐水洗(30mL),无水硫酸钠干燥,过滤,浓缩的粗产物,粗产物用快速色谱法分离纯化(100-200目硅胶,石油醚:乙酸乙 酯=0-2%),得到目标化合物(370mg,收率34%)。LCMS(ESI)[M+H]
+=466.10;
1H NMR(400MHz,CDCl
3):δ7.64(d,J=7.6Hz,1H),7.52(s,1H),7.47(d,J=7.0Hz,4H),7.36(d,J=6.4Hz,3H),6.01(s,2H),5.83(s,1H),3.72(d,J=8.7Hz,1H),3.63–3.56(m,2H),1.06–1.01(m,1H),0.95–0.89(m,2H),-0.01(s,4H),-0.05(s,6H)。
第四步:1-(4-((3-碘-5-苯基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-7-基)氨基)哌啶-1-基)乙-1-酮的制备:
将原料3-碘-5-苯基-1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-7-胺(155mg,0.33mmol,1.0equiv.)、N-乙酰基-4-哌啶酮(71mg,0.5mmol,1.5equiv.)和三乙酰基硼氢化钠(211mg,1.0mmol,3.0equiv.)溶于乙酸(10mL)中,然后将四氯化钛溶液(0.67mL,0.67mmol,2.0equiv,1M/DCM)滴加到反应液中,25℃搅拌16小时。加水(20mL)淬灭反应,乙酸乙酯萃取(3*10mL),合并有机相分别用饱和碳酸氢钠溶液(3*20mL)和饱和食盐水洗(20mL),无水硫酸钠干燥,过滤,浓缩得到粗产品。粗产品快速色谱法分离纯化(100-200目硅胶,石油醚:乙酸乙酯=0-60%)得到标题化合物(115mg,收率59%)。LCMS(ESI)[M+1]
+=591.20;
1H NMR(400MHz,CDCl
3):δ7.61(d,J=7.2Hz,2H),7.46(t,J=7.7Hz,2H),7.37(d,J=7.2Hz,1H),7.02(s,1H),6.84(s,1H),5.82(s,2H),3.76(s,2H),3.72–3.67(m,2H),3.30(s,2H),2.13(s,4H),1.76–1.68(m,2H),1.61(s,2H),0.97–0.91(m,2H),-0.01(s,10H)。
第五步:(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-5-苯基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-7-基)氨基)哌啶-1-基)乙-1-酮的制备:
将反应物1-(4-((3-碘-5-苯基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-7-基)氨基)哌啶-1-基)乙-1-酮(370mg,626umol,1.0equiv.)、(S)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙烷-2-醇(258mg,1.25mmol,2.0equiv.)、碘化亚铜(48mg,250umol,0.4equiv.)、L-脯氨酸(57mg,500umol,0.8equiv.)和无水磷酸钾(530mg,2.5mmol,4.0equiv.)溶于DMSO(5mL)。反应液在氮气保护60℃条件下搅拌16小时。加水(20mL)淬灭反应,乙酸乙酯萃取(3*10mL),合并有机相用饱和食盐水洗(3*15mL),无水硫酸钠干燥,过滤,浓缩得到粗产品。粗产品快速色谱法分离纯化(100-200目硅胶,二氯甲烷:甲醇=0-5%)得到标题化合物(42mg,收率10%)。LCMS(ESI)[M+H]
+=669.25。
第六步:(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-5-苯基-1H-吲唑-7-基)氨基)哌啶-1-基)乙-1-酮的制备:
将反应物(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)-5-苯基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-7-基)氨基)哌啶-1-基)乙-1-酮(45mg,67umol,1.0equiv.)溶于二氯甲烷(5mL)。三氟乙酸(0.2mL)加入反应液中,在25℃下搅拌2小时。反应液加氨水中和,然后浓缩,制备板纯化(二氯甲烷:甲醇=15/1)得到目标化合物(12mg,收率3%)。LCMS(ESI)[M+H]
+=539.20;
1H NMR(400MHz,CD
3OD):δ7.55(d,J=7.8Hz,2H),7.37(t,J=7.7Hz,2H),7.26(d,J=7.4Hz,1H),7.14(d,J=4.7Hz,4H),7.07(s,1H),6.76(s,1H),4.39(d,J=15.2Hz,1H),4.28(s,1H),4.04(s,1H),3.91(s,1H),3.82(s,1H),3.46(t,J=8.3Hz,2H),3.34(d,J=10.9Hz,1H),3.14(d,J=26.4Hz,2H),3.02(s,5H),2.22(s,1H),2.11(s,3H),2.02(s,1H),1.61–1.33(m,4H)。
实施例66
(s)-1-(4-(3-(3-(3,4-二氢异喹啉-2(1h)-基)-2羟丙基)氨基)苯并[d]异噁唑-7-基氨基)哌啶-1-基)乙酮的制备:
第一步:3-叔丁氧羰基氨基-2-氟苯腈的制备:
将3-溴-2-氟苯腈(25.00g,125.00mmol,1.0equiv.),氨基甲酸叔丁酯(17.60g,150.00mmol,1.2equiv.),三(二亚苄基丙酮)二钯(2.30g,2.50mmol,0.02equiv.),4,5-双二苯基膦-9,9-二甲基氧杂蒽(3.70g,7.50mmol,0.06equiv.)和碳酸铯(49.00g,150.00mmol,1.2equiv.)溶于甲苯(400mL)中,90℃搅拌16小时。LCMS监测不出分子量,点板监测反应完全,反应液直接过滤,乙酸乙酯冲洗滤饼(100mL),滤液加水(500mL)萃取,水相用乙酸乙酯洗(3*100mL),合并有机相用饱和食盐水洗(3*200mL),无水硫酸钠干燥,过滤,浓缩得到粗产品。粗产品快速色谱法分离纯化(100-200目硅胶,石油醚:乙酸乙酯=0-20%)得到标题化合物(6.60g,收率22.4%)。
1H NMR(400MHz,dmso-d
6)δ9.38(s,1H),7.94(s,1H),7.59–7.54(m,1H),7.30(t,J=8.0Hz,1H),1.43(s,9H)。
第二步:叔丁基(3-氨基苯并[d]异噁唑-7-基)氨基甲酸酯的制备:
将3-叔丁氧羰基氨基-2-氟苯腈(6.60g,28.00mmol,1.0equiv.)和乙酰氧肟酸(6.30g,84.00mmol,3.0equiv.)溶于叔丁醇(100mL)中,在120℃条件下搅拌2小时,然后恢复到25℃,叔丁醇钾(9.40g,84.00mmol,3.0equiv.)缓慢加到反应液中,25℃搅拌16小时。LCMS监测产物生成,加水(200mL)淬灭反应,乙酸乙酯萃取(3*100mL),合并有机相用饱和食盐水洗(3*150mL),无水硫酸钠干燥,过滤,浓缩得到粗产品。粗产品快速色谱法分离纯化(100-200目硅胶,石油醚:乙酸乙酯=0-20%)得到标题化合物(1.20g,收率17.2%)。LCMS(ESI)[M+H]
+=250.10。
第三步:(S)-2-(环氧乙烷-2-基甲基)-1,2,3,4-四氢异喹啉的制备:
将四氢异喹啉(5.00g,37.54mmol,1.0equiv.)、(R)-(+)-间硝基苯磺酸缩水甘油酯(11.70g,45.05mmol,1.2equiv.)和氟化钾(6.50g,112.62mmol,3.0equiv.)溶于四氢呋喃(100mL)中,25℃搅拌16小时。LCMS监测产物不出分子量,点板监测有新点生成,紫外荧光不强,碘显较明显。反应液加水(300mL)淬灭,用乙酸乙酯萃取(3*150mL),合并有机相用饱和食盐水洗(300mL),无水硫酸钠干燥,过滤,浓缩的粗产物,粗产物用快速色谱法分离纯化(100-200目硅胶,石油醚:乙酸乙酯=0-20%),得到目标化合物(2.80g,收率39.5%)。LCMS(ESI)[M+H]
+=190.00。
第四步:(s)-叔丁基(3-(3,4-二氢异喹啉-2(1h)-基)-2-羟丙基)氨基)苯并[d]异噁唑-7-基)氨基甲酸酯的制备:
将原料叔丁基(3-氨基苯并[d]异噁唑-7-基)氨基甲酸酯(900mg,3.60mmol,1.0equiv.)、(S)-2-(环氧乙烷-2-基甲基)-1,2,3,4-四氢异喹啉(888mg,4.70mmol,1.3equiv.)和叔丁醇钾(1212mg,10.80mmol,3.0equiv.)溶于N,N-二甲基甲酰胺(10mL)中,25℃搅拌4小时。LCMS监测有产物生成,原料未反应完,加水(50mL)淬灭反应,乙酸乙酯萃取(3*50mL),合并有机相分别用饱和碳酸氢钠溶液(3*50mL)和饱和食盐水洗(50mL),无水硫酸钠干燥,过滤,浓缩得到粗产品。粗产品快速色谱法分离纯化(100-200目硅胶,二氯甲烷:甲醇=0-5%)得到标题化合物(200mg,收率12.7%)。LCMS(ESI)[M+1]
+=439.20。
第五步:(s)-1-(7-氨基苯并[d]异噁唑-3-基)氨基)-3-(3,4-二氢异喹啉-2(1h)-基)丙烷-2-醇的制备:
将反应物(s)-叔丁基(3-(3,4-二氢异喹啉-2(1h)-基)-2-羟丙基)氨基)苯并[d]异噁唑-7-基)氨基甲酸酯(200mg,0.45mmol,1.0equiv.)溶于乙酸乙酯盐酸气(4M)(5mL)中。反应液在氮气保护25℃条件下搅拌2小时。LCMS监测反应完全,反应液直接旋干得到粗产品。粗产品用制备板分离纯化(二氯甲烷:甲醇=10/1)得到标题化合物(100 mg,收率65.7%)。LCMS(ESI)[M+H]
+=339.10。
第六步:(s)-1-(4-(3-(3-(3,4-二氢异喹啉-2(1h)-基)-2羟丙基)氨基)苯并[d]异噁唑-7-基氨基)哌啶-1-基)乙酮的制备:
将反应物(s)-1-(7-氨基苯并[d]异噁唑-3-基)氨基)-3-(3,4-二氢异喹啉-2(1h)-基)丙烷-2-醇(100mg,0.29mmol,1.0equiv.),N-乙酰基-4-哌啶酮(63mg,0.44mmol,1.5equiv.)和三乙酰氧基硼氢化钠(189mg,0.89mmol,3.0equiv.)溶于醋酸(5mL)中,冰浴下加入四氯化钛溶液(0.59mL,0.59mmol,2.0equiv,1M/DCM)。在25℃下搅拌16小时。反应液加饱和碳酸氢钠溶液(200mL)调PH至碱性,然后乙酸乙酯萃取(3*50mL),合并有机相用饱和食盐水洗(50mL),然后浓缩,制备板纯化(二氯甲烷:甲醇=10/1)得到目标化合物(49mg,收率36.5%)。LCMS(ESI)[M+H]
+=464.25;
1H NMR(400MHz,cd3od)δ7.08(s,3H),6.99(s,2H),6.87(d,J=7.8Hz,1H),6.75(d,J=7.6Hz,1H),4.57(s,1H),4.43(d,J=13.3Hz,1H),4.21(dt,J=11.9,5.9Hz,1H),3.91(d,J=14.0Hz,1H),3.76(t,J=7.3Hz,1H),3.73–3.71(m,2H),3.44(dd,J=13.4,5.3Hz,1H),3.35(dd,J=13.4,6.7Hz,1H),3.27–3.19(m,1H),2.91–2.88(m,2H),2.87–2.80(m,3H),2.73–2.63(m,2H),2.11–2.00(m,5H),1.53–1.34(m,2H)。
实施例67
(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨基)苯并[d]异噻唑-7-基)氨基)哌啶-1-基)乙酮的制备
第一步:2-氯-3-硝基苯甲酰氯的制备:
将2-氯-3-硝基苯甲酸(12.00g,59.53mmol,1.0equiv.)溶于二氯甲烷(200mL)中,加入N,N-二甲基甲酰胺(1.0mL)。草酰氯(15.11g,119.07mmol,2.0equiv.)在0℃下慢慢加入。反应于室温搅拌2h。溶液变澄清。将溶剂旋干,得到粗品目标化合物(13.00 g,收率不计)。
第二步:2-氯-N-(4-甲氧苄基)-3-硝基苯酰胺的制备:
将2-氯-3-硝基苯甲酰氯(12.00g,54.54mmol,1.0equiv.)溶于二氯甲烷(150mL)中,在0℃下加入对甲氧基苄胺(11.22g,81.81mmol,1.5equiv.)。室温搅拌1h。LCMS检测反应完全。加水100mL用二氯甲烷萃取三次,每次100mL。合并有机相,浓缩得到粗品,用柱层析纯化得到标题化合物(10.60g,收率60.6%)。LCMS(ESI)[M+1]
+=321.0。
第三步:2-(4-甲氧苄基)-7-硝基苯并[d]异噻唑-3(2H)-酮的制备:
将2-氯-N-(4-甲氧苄基)-3-硝基苯酰胺(5.00g,15.59mmol,1.0equiv.),硫粉(600mg,18.71mmol,1.2equiv.),碘化亚铜(742mg,3.90mmol,0.25equiv.),1,10-邻菲罗啉(702mg,3.90mmol,0.25equiv.)和碳酸钾(2.80g,20.27mmol,1.3equiv.)溶于N,N-二甲基甲酰胺(60mL)。反应在110℃氮气保护下搅拌3h。点小板监测反应完全。浓缩除去N,N-二甲基甲酰胺。加水50mL用二氯甲烷萃取三次,每次100mL。合并有机相,浓缩得到粗品,用柱层析纯化得到纯品(4.50g,收率91.2%)。
1H NMR(400MHz,CDCl
3)δ8.52–8.50(m,1H),8.42–8.40(m,1H),7.64–7.60(t,1H),7.35–7.33(m,2H),6.91–6.89(m,2H),5.02(s,2H),3.80(s,3H).
第四步:7-硝基苯并[d]异噻唑-3-醇的制备:
将2-(4-甲氧苄基)-7-硝基苯并[d]异噻唑-3(2H)-酮(3.50g,11.06mmol,1.0equiv.),硝酸铈胺(24.26g,44.26mmol,4.0equiv.)溶于乙腈(80mL)和水(20mL)。反应在 25℃下搅拌5h。TLC检测反应完全。浓缩除去溶剂。加水100mL用二氯甲烷萃取三次,每次100mL。合并有机相,浓缩得到粗品,用乙酸乙酯打浆得到纯品(800mg,收率36.9%)。
1H NMR(400MHz,CDCl
3)δ11.93(s,1H),8.66–8.63(m,1H),8.36–8.34(t,1H),8.14–8.10(m,1H).
第五步:(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-硝基苯并[d]异噻唑-3-基)氨基)丙醇:
将7-硝基苯并[d]异噻唑-3-醇(309mg,1.58mmol,1.0equiv.),溶于N,N-二甲基甲酰胺(10mL)中。加入1,8-二氮杂二环十一碳-7-烯(361mg,2.37mmol,1.5equiv.)和六氟磷酸苯并三唑-1-氧基三(二甲氨基)磷(839mg,1.90mmol,1.2equiv.),置换氮气反应在25℃下搅拌半小时。然后加入(S)-1-氨基-3-(3,4-二氢异喹啉-2(1H)-基)丙-2-醇(391mg,1.90mmol,1.2equiv.)置换氮气,先用25℃搅拌16小时,然后在50℃下搅拌2小时,LCMS检测产物生成。加水100mL用乙酸乙酯萃取三次,每次50mL。合并有机相,浓缩得到粗品,用制备板纯化(二氯甲烷:甲醇=20/1)得到标题化合物(170mg,收率27.9%)。LCMS(ESI)[M+1]
+=385.05。
第六步:(S)-1-((7-氨基苯并[d]异噻唑-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙醇的制备:
将(S)-1-(3,4-二氢异喹啉-2(1H)-基)-3-((7-硝基苯并[d]异噻唑-3-基)氨基)丙醇(170mg,0.44mmol,1.0equiv.),铁粉(124mg,2.21mmol,5.0equiv.)和氯化铵(237mg,4.43mmol,10.0equiv.)溶于乙醇(8mL)和水(2mL)中。置换氮气,反应在80℃下搅拌4小时。LCMS检测反应完全。反应液过滤,加水100mL用乙酸乙酯萃取三次,每次50mL。合并有机相,浓缩得到粗品,用制备板纯化(二氯甲烷:甲醇=10/1)得到标题化合物(70mg,收率44.5%)。LCMS(ESI)[M+1]
+=355.30。
第七步:(S)-1-(4-((3-((3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)氨 基)苯并[d]异噻唑-7-基)氨基)哌啶-1-基)乙酮的制备:
将反应物(S)-1-((7-氨基苯并[d]异噻唑-3-基)氨基)-3-(3,4-二氢异喹啉-2(1H)-基)丙醇(70mg,0.19mmol,1.0equiv.),N-乙酰基-4-哌啶酮(42mg,0.29mmol,1.5equiv.)和三乙酰氧基硼氢化钠(126mg,0.59mmol,3.0equiv.)溶于醋酸(4mL)中,冰浴下加入四氯化钛溶液(0.40mL,0.40mmol,2.0equiv,1M/DCM)。在25℃下搅拌16小时。反应液加饱和碳酸氢钠溶液(200mL)调PH至碱性,然后乙酸乙酯萃取(3*50mL),合并有机相用饱和食盐水洗(50mL),然后浓缩,制备板纯化(二氯甲烷:甲醇=10/1)得到目标化合物(20mg,收率21.9%)。LCMS(ESI)[M+H]
+=480.35;
1H NMR(400MHz,cd3od)δ7.14(d,J=3.7Hz,2H),7.08(d,J=6.3Hz,3H),7.01(s,1H),6.75(s,1H),4.61(s,1H),4.46(d,J=13.9Hz,1H),4.26–4.18(m,1H),3.93(d,J=12.3Hz,1H),3.76–3.66(m,3H),3.57(qd,J=13.4,5.8Hz,2H),3.24(d,J=11.4Hz,1H),2.94–2.81(m,5H),2.70(qd,J=12.9,6.0Hz,2H),2.08(t,J=15.3Hz,5H),1.46(ddd,J=30.3,17.9,6.2Hz,2H).
生物学测试评价
以下结合测试例进一步描述解释本发明,但这些实施例并非意味着限制本发明的范围。
测试例1 用放射性同位素的方法测定本发明化合物的PRMT5酶活抑制活性
试验原理:在组蛋白甲基转移酶PRMT5的催化作用下,将同位素标记的[3H]-SAM上的[3H]-CH3基团转移到生物素化的组蛋白多肽底物上,生物素化的组蛋白多肽底物又可以与FlashPlate板结合,这样同位素与FlashPlate板距离足够近,就可以将放射性同位素[3H]的辐射能量转化为光子并被检测到。
试验方法:配制1倍酶反应缓冲液(10mM Tris 8.0(Sigma,Cat.No.T2694-1L),0.01%Tween-20(Sigma,Cat.No.P2287-100ML),1mM DTT(Sigma,Cat.No.D0632-10G))。将PRMT5(Active Motif,Cat.No.31921)加入到1倍酶反应缓冲液中,配制成25/15倍PRMT5酶溶液(PRMT5终浓度为:5nM),转移15μL PRMT5 酶溶液至含有不同浓度化合物(DMSO终浓度1%)的384孔微孔板(
384-well Polypropylene Storage Microplates,Cat.No.3657)中,室温孵育15分钟。将多肽底物GL-27(Ac-SGRGKGGKGLGKGGAKRHRKVGG-K(Biotin)(GL Biochem,Cat.No.342095)和[3H]-SAM(PerkinElmer,Cat.No.NET155V001MC)加入到1倍酶反应缓冲液中,配制成25/10倍底物溶液,然后加入10μL多肽底物溶液(多肽底物终浓度100nM,[3H]-SAM终浓度0.25μM),室温反应120分钟后加入5μL 6倍冰冷的SAM(Sigma,Cat.No.A7007-100MG)溶液终止反应(SAM终浓度:0.125mM)。转移25μL反应体系至FlashPlate(Streptavidin FlashPlate HTS PLUS,High Capacity,384-well,Perkin Elmer,Cat.No.SMP410A001PK),室温孵育1小时,用含有0.1%Tween-20的蒸馏水洗板三次后,微孔板在MicroBeta仪器上读取CPM数据(Counts Per Minute,每分钟计数)。得到化合物不同浓度的CPM原始数据后,按照公式Inh%=(Max-Sample)/(Max-Min)*100%对数据进行标准化处理得到每个浓度点的酶活性抑制率Inh%(其中Max为含酶阳性孔的CPM值,Min为不含酶阴性孔的CPM值,Sample为化合物处理样品孔的CPM值),然后在EXCEL中输入每个浓度(X)对应的抑制率Inh%(Y),用XLfit插件根据内置四参数拟合公式Y=Bottom+(Top-Bottom)/(1+(IC
50/X)*HillSlope)计算出每个化合物的半数抑制浓度IC
50值。
试验结论:通过以上方案得出本发明所示部分实施例化合物在PRMT5酶活抑制试验中显示出如下表1的生物活性
表1:化合物对PRMT5酶活抑制的IC
50值
实施例化合物 | PRMT5/IC 50 |
13 | A |
25 | A |
28 | A |
43 | A |
52 | A |
55 | A |
56 | A |
57 | A |
59 | A |
61 | A |
63 | A |
64 | A |
65 | A |
66 | A |
注:A代表IC
50<100nΜ。
上表所示结果表明,该系列化合物具有较强的PRMT5酶抑制活性。
Claims (27)
- 一种式(I)所示的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物:Z独立地选自C或N;q选自0或1,q=0代表所在的环为五元环,q=1代表所在的环为六元环;Z 1独立地选自CH、N、C(R 2),但当q=1时,三个位置的Z 1不同时为N;R 2每次出现时,独立选自氢、卤素、羟基、巯基、氨基、氰基、任选取代的-R 2a、任选取代的-OR 2a、任选取代的-NH-R 2a、任选取代的-N(R 2a)R 2a,其中,R 2a每次出现独立地选自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基;所述任选取代是指被取代基团上的H未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、巯基、氨基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基所取代;Z 2独立地选自CH、C(R 2)、N、O、S或N(R 1);其中,R 1可选自氢、C 1-6烷基或C 3-6环烷基;其中,每个C 1-6烷基和C 3-6环烷基可任选被卤素、氰基、任选取代的R 1a、任选取代的-OR 1a、任选取代的-SR 1a、任选取代的-N(R 1a)R 1a、任选取代的-NHR 1a、任选取代的5-6元杂芳基或任选取代的苯基取代;其中R 1a每次出现时独立地选自氢、C 1-6烷基、C 3-6环烷基、4-6元杂环基其中的一种;所述任选取代是指被取代基团上的H未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、巯基、氨基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基所取代;p选自0或1;p=0时,代表所在的环为五元环;Z 3、Z 5分别独立地选自N、S、O、CH(R 2)、C(R 2)、N(R 1);p=1时,代表所在的环为六元环;Z 3、Z 4、Z 5分别独立地选自N、S、O、N(R 1)、CH(R 2)、C(R 2);X选自-O-、-S-、-CO-、-N(R 5)-、-S(O)N(R 5)-、-S(O) 2N(R 5)-、-N(R 5)SO-、-N(R 5)S(O) 2-、-C(O)N(R 5)-、-N(R 5)C(O)-、-N(R 5)C(O)N(R 5)-、-CH(R 5)-其中的一种;其中R 5每次出现时独立地选自氢、任选取代的C 1-6烷基、任选取代的C 3-6环烷基、任选取代的4-6元杂环基其中的一种;所述任选取代是指被取代基团上的H未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、巯基、氨基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基所取代;Y选自键、-H、-OH、-NH 2、卤素、-O-、-S-、-CO-、-C(R 6)F-、-CF 2-、-SO-、-SO 2-、-N(R 6)-、-S(O)N(R 6)-、-S(O) 2N(R 6)-、-N(R 6)SO-、-N(R 6)S(O) 2-、-C(O)N(R 6)-、-N(R 6)C(O)-、-CH(R 6)-其中的一种;其中R 6选自氢、任选取代的C 1-6烷基、任选取代的C 3-6环烷基、任选取代的4-6元杂环基其中的一种;所述任选取代是指被取代基团上的H未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、巯基、氨基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基所取代;当Y选自-H、-OH、-NH 2、卤素其中的一种时,G 4不存在;o=0,1,2,3,4,5;G 1和G 3分别选自氢、卤素、羟基、巯基、氨基、氰基、任选取代的C 1-6烷基、任选取代的C 3-6环烷基、任选取代的4-6元杂环基其中的一种;或者G 1和G 3连接起来形成一个任选取代的C 3-8的碳环结构;所述任选取代是指被取代基团上的H未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、巯基、氨基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基所取代;G 2选自氢、卤素、羟基、巯基、氨基、氰基、任选取代的R 7、任选取代的O(R 7)、S(R 7)、任选取代的NH(R 7)、任选取代的N(R 7)(R 7)其中的一种;其中R 7选自氢、C 1-6烷基、C 3-6环烷基、4-6元杂环基其中的一种;所述任选取代是指被取代基团上的H未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、巯基、氨基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基所取代;G 4选自以下基团:任选取代的C 1-12烷基、任选取代的C 2-12烯基、任选取代的C 2-12炔基、任选取代的C 3-6环烷基、任选取代的4-6元杂环基、任选取代的C 6-10芳基、任选取代的5-10元杂芳基中的一种;所述任选取代是指被取代基团上的H未被取代或被取代基团的一个或多个可取代位点独立地被选自氢、卤素、羟基、巯基、氨基、氰基、-R 3、-OR 3、-NH-R 3、-N(R 3)R 3、 所取代,其中,R 3每次出现独立地选自可被氢、卤素、羟基、巯基、氨基、氰基、C 1-6烷基、C 3-6环烷基、4-6元杂环烷基、苯基、5-6元杂芳基中的一个或多个任意取代的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基;D选自键、NH、N(CH 3)、O、S其中的一种,f=0,1,2,3,4,5,6,7,8;A选自-N(R 9)-、-CH(R 9)-或-CH(NHR 9)-,m=0或1;其中,R 9选自氢、羟基、卤素、C 1-6烷基、C 3-6环烷基、4-6元杂环基其中的一种;B选自-N-或-CH-;C选自-NR 10-或-CHR 10-,n=0、1或2;R 10选自氢、羟基、卤素、C 1-6烷基、C 3-6环烷基、4-6元杂环基其中的一种;A,B,C至少有一个为符合各自定义的取代的N原子;H环选自C 6-10芳基环、5-10元杂芳基环其中的一种;所述芳基环或杂芳基环可被一个或多个以下取代基独立取代:氢、卤素、羟基、巯基、氨基、氰基、任选取代的-R 4、任选取代的-OR 4、任选取代的-NH-R 4、任选取代的-N(R 4)R 4;其中,R 4每次出现独立地选自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基;所述任选取代是指被取代基团上的H未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、巯基、氨基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基所取代。
- 根据权利要求1所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物,其特征在于,X选自-O-、-S-、-CO-、-NH-、-SONH-、-S(O) 2NH-、-NHSO-、-NHS(O) 2-、-C(O)NH-、-NHC(O)-、-NHC(O)NH-、-CH 2-其中的一种;更进一步优选为-O-、-S-、-CO-、-NH-、-SONH-、-S(O) 2NH-、-NHSO-、-NHS(O) 2-、-C(O)NH-、-NHC(O)-、-NHC(O)NH-其中的一种;最优选为-O-、-S-、-CO-、-NH-、-S(O) 2NH-、-NHS(O) 2-、-C(O)NH-、-NHC(O)-、-NHC(O)NH-其中的一种。
- 根据权利要求1或2所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物,其特征在于,Y选自键、-H、-OH、-NH 2、卤素、-O-、-S-、-CO-、-CHF-、-CF 2-、-SO-、-SO 2-、-NH-、-S(O)NH-、-S(O) 2NH-、-NHS(O)-、-NHS(O) 2-、-C(O)NH-、-NHC(O)-、-CH 2-其中的一种;更进一步优选为键、H、OH、NH 2、卤素、-O-、-S-、-CO-、-SO 2-、-NH-、-S(O) 2NH-、-NHS(O) 2-、-C(O)NH-、-NHC(O)-、-CH 2-其中的一种。
- 根据权利要求1-3任一项所述的化合物,及其立体异构体、几何异构体、互变异构体、 药用盐、前药、水合物、溶剂合物或同位素标记的类似物,其特征在于,o=0,1或2。
- 根据权利要求1-4任一项所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物,其特征在于,G 1和G 3分别独立地选自氢或甲基,或者G 1和G 3连接起来形成一个任选取代的C 5-6的碳环结构;优选的,G 1和G 3连接起来形成一个任选取代的C 5-6环烷基结构。
- 根据权利要求1-5任一项所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物,其特征在于,G 2选自氢、氟、羟基、氨基、甲基、环丙基、甲氧基、甲硫基、甲胺基其中的一种;更优选为氟、羟基、氨基其中的一种。
- 根据权利要求1-6任一项所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物,其特征在于,R 2每次出现时,独立选自氢、卤素、羟基、巯基、氨基、氰基、甲基、乙基、三氟甲基、二氟甲基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、环丙基、环丁基、环己基、环戊基、苯基、吡啶基、嘧啶基。
- 根据权利要求1-7任一项所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物,其特征在于,G 4选自以下基团:任选取代的C 1-12烷基、任选取代的C 2-12烯基、任选取代的C 2-12炔基、任选取代的C 3-6环烷基、任选取代的4-6元杂环基、任选取代的C 6-10芳基、任选取代的5-10元杂芳基中的一种;所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、巯基、氨基、氰基、三氟甲基、二氟甲基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、甲胺基、乙胺基、正丙胺基、异丙胺基、正丁胺基、异丁胺基、叔丁胺基、仲丁胺基的取代基所取代。
- 根据权利要求1-9任一项所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物,其特征在于,D选自键、-NH-其中的一种;f选自0,1,2或3。
- 根据权利要求1-10任一项所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物,其特征在于,R 3独立地选自可被氢、卤素、羟基、巯基、氨基、氰基、C 1-6烷基、C 3-6环烷基、4-6元杂环烷基、苯基、5-6元杂芳基中的一个或多个任意取代的甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、环丙基、环丁基、环己基、环戊基、苯基、吡啶基、嘧啶基;优选的,R 3选自可被氢、卤素、羟基、巯基、氨基、氰基、C 1-6烷基、C 3-6环烷基、4-6元杂环烷基、苯基、5-6元杂芳基中的一个或多个任意取代的甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔 丁基、仲丁基、环丙基、环丁基、环戊基、环己基、苯基、吡啶基;更优选的,R 3选自可被氢、卤素、羟基中的一个或多个任意取代的甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、环丙基、环丁基、环戊基、环己基、苯基、吡啶基。
- 根据权利要求1-10任一项所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物,其特征在于,R 3独立地选自可被氢、卤素、羟基、巯基、氨基、氰基、C 1-6烷基、C 3-6环烷基、4-6元杂环烷基、苯基、5-6元杂芳基中的一个或多个任意取代的呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基、噁唑基;优选的,R 3独立地选自可被氢、卤素、羟基、巯基、氨基、氰基、C 1-3烷基中的一个或多个任意取代的呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基、噁唑基;更优选的,R 3独立地选自可被氢、卤素、甲基中的一个或多个任意取代的吡唑基。
- 根据权利要求1-12任一项所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物,其特征在于,A可独立选自-NH-、-CH 2-或-CH(NH 2)-,m=0或1;B可独立选自-N-或-CH-;C可独立选自-NH-或-CH 2-,n=0或1;A,B,C至少有一个为符合各自定义的取代的N原子。
- 根据权利要求1-14任一项所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物,所述H环选自:其中,R 13选自氢、卤素、羟基、巯基、氨基、氰基、任选取代的-R 4、任选取代的-OR 4、任选取代的-NH-R 4、任选取代的-N(R 4)R 4;其中,R 4每次出现独立地选自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基;所述任选取代是指被取代基团上的氢未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、巯基、氨基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、4-6元杂环基、苯基、5-6元杂芳基所取代。
- 根据权利要求15所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物,R 13选自氢、卤素、羟基、巯基、氨基、氰基、任选取代的-R 4、任选取代的-OR 4、任选取代的-NH-R 4、任选取代的-N(R 4)R 4;其中,R 4每次出现独立地选自C 1-6烷基、4-6元杂环基、苯基、5-6元杂芳基;所述任选取代是指被取代基团上的H未被取代或被取代基团的一个或多个可取代位点独立地被选自卤素、羟基、巯基、氨基、氰基、C 1-6烷基、C 3-6环烷基、苯基所取代。
- 根据前述任意一项权利要求所述的化合物,及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物,其特征在于,式(II) A选自:O=1或2;X选自-O-、-S-、-CH 2-、-N(R 5)-,R 5独立地选自氢或任选取代的C 1-6烷基;G1选自氢,G2选自羟基或氨基;G3选自氢;Y选自键、-NH 2、-OH、-NH-;和
- 一种药用组合物,其特征在于,所述组合物包含权利要求1-23任一项所示化合物、其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物,以及药学上可接受的辅料。
- 权利要求1-23任一项所述的化合物、其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物在制备治疗由PRMT5抑制剂介导的疾病的药物中的用途。
- 根据权利要求26所述的用途,其中所述PRMT5抑制剂介导的疾病为癌症。
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