WO2022253311A1 - Hpk1抑制剂及其应用 - Google Patents
Hpk1抑制剂及其应用 Download PDFInfo
- Publication number
- WO2022253311A1 WO2022253311A1 PCT/CN2022/096831 CN2022096831W WO2022253311A1 WO 2022253311 A1 WO2022253311 A1 WO 2022253311A1 CN 2022096831 W CN2022096831 W CN 2022096831W WO 2022253311 A1 WO2022253311 A1 WO 2022253311A1
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- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- substituted
- methyl
- cycloalkyl
- membered
- Prior art date
Links
- 229940125962 HPK1 kinase inhibitor Drugs 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 151
- 238000002360 preparation method Methods 0.000 claims abstract description 32
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 13
- 229940079593 drug Drugs 0.000 claims abstract description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 164
- 229910052736 halogen Inorganic materials 0.000 claims description 112
- 150000002367 halogens Chemical class 0.000 claims description 111
- -1 -O-(C 1 -C 6 alkyl) Chemical group 0.000 claims description 108
- 229910052757 nitrogen Inorganic materials 0.000 claims description 86
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 75
- 102100028199 Mitogen-activated protein kinase kinase kinase kinase 1 Human genes 0.000 claims description 70
- 101001059991 Homo sapiens Mitogen-activated protein kinase kinase kinase kinase 1 Proteins 0.000 claims description 68
- 125000001424 substituent group Chemical group 0.000 claims description 57
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 51
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 45
- 238000006467 substitution reaction Methods 0.000 claims description 44
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 36
- 239000000651 prodrug Substances 0.000 claims description 34
- 229940002612 prodrug Drugs 0.000 claims description 34
- 229910052801 chlorine Inorganic materials 0.000 claims description 32
- 229910052731 fluorine Inorganic materials 0.000 claims description 32
- 229910052799 carbon Inorganic materials 0.000 claims description 28
- 239000012453 solvate Substances 0.000 claims description 27
- 210000004027 cell Anatomy 0.000 claims description 26
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 26
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims description 24
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 24
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 21
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 201000010099 disease Diseases 0.000 claims description 18
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 229910052794 bromium Inorganic materials 0.000 claims description 16
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 16
- 229910052740 iodine Inorganic materials 0.000 claims description 16
- 125000002757 morpholinyl group Chemical group 0.000 claims description 16
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 14
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
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- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 12
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- 206010028980 Neoplasm Diseases 0.000 claims description 12
- 125000002393 azetidinyl group Chemical group 0.000 claims description 12
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 11
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 9
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
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- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 7
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- 208000030808 Clear cell renal carcinoma Diseases 0.000 claims description 6
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims description 6
- 206010073251 clear cell renal cell carcinoma Diseases 0.000 claims description 6
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- 201000011330 nonpapillary renal cell carcinoma Diseases 0.000 claims description 6
- 125000003386 piperidinyl group Chemical group 0.000 claims description 6
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- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 5
- 150000004677 hydrates Chemical class 0.000 claims description 5
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- 229940045513 CTLA4 antagonist Drugs 0.000 claims description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 4
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 201000003708 skin melanoma Diseases 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000005942 tetrahydropyridyl group Chemical group 0.000 claims description 4
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 claims description 3
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
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- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
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- 125000004306 triazinyl group Chemical group 0.000 claims description 3
- 125000001698 2H-pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 2
- 125000001826 4H-pyranyl group Chemical group O1C(=CCC=C1)* 0.000 claims description 2
- 108010021064 CTLA-4 Antigen Proteins 0.000 claims description 2
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- 239000012271 PD-L1 inhibitor Substances 0.000 claims description 2
- 229940121656 pd-l1 inhibitor Drugs 0.000 claims description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- 201000009030 Carcinoma Diseases 0.000 claims 4
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 210000000716 merkel cell Anatomy 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 261
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 28
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- VUSWCWPCANWBFG-UHFFFAOYSA-N cyclohex-3-ene-1-carboxylic acid Chemical compound OC(=O)C1CCC=CC1 VUSWCWPCANWBFG-UHFFFAOYSA-N 0.000 description 1
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- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
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- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
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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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to HPK1 inhibitors and applications thereof. More specifically, the present invention relates to a pyrrolopyridine compound, a preparation method thereof, and an application thereof in the preparation of medicines.
- Hematopoietic progenitor kinase I Hematopoietic progenitor kinase I
- HPK1 also known as MAP4K1
- gene ID: 11184 located at: 19q13.1-q13.4
- MAP4K MAP kinase kinase kinase kinases
- HPK1 is a negative regulator of TCR (T cell receptor) signaling and T cell-mediated immune responses.
- TCR T cell receptor
- cytoplasmic HPK1 Upon TCR activation, cytoplasmic HPK1 is recruited to the plasma membrane, fully activated through its phosphorylation of Y381, S171, and T165, and activated HPK1 phosphorylates the adapter protein SLP76, providing a binding site for the negative regulator 14-3-3 point, ultimately destabilizing the TCR signaling complex (Lat-Gads-SLP76), blocking downstream mitogen-activated protein (MAP) kinase (MAPK) signaling required for T cell activation and proliferation (Hernandez S et al., Cell Reports, 2018, 25(1):80-94.).
- MAP mitogen-activated protein
- HPK1 negatively regulates T cell MAPK signaling pathway and AP-1 (activator protein-1) transcription (Liou J et al.Immunity,2000,12(4):399-408. ).
- HPK1 -/- mice showed enhanced T cell proliferation, increased secretion of IL-2, IL-4 and interferon (IFN)- ⁇ , decreased sensitivity to prostaglandin inhibitory effects, and decreased T cell activation threshold.
- IFN interferon
- HPK1 Similar to the mechanism of T cells, HPK1 also negatively regulates BCR (B cell receptor) signaling, and B cells in HPK1 -/- mice showed a high response to a series of stimuli, and the loss of HPK1 activity was associated with higher titers in the immune response. Degree of IgG1 and IgG2b correlation. In addition, HPK1 also plays an inhibitory role in the release of neoantigens mediated by NK (natural killer) cells, inhibiting lipopolysaccharide (LPS)-stimulated dendritic cell (DC) maturation and other multiple effects (Liu J et al.PLoS ONE , 2019, 14(3):e0212670.). HPK1 not only negatively regulates the function of T cells, but also negatively regulates a variety of immune cells, inhibits their activity, and can promote immune responses from multiple nodes.
- BCR B cell receptor
- MAP4K1 has a strong positive correlation with the signaling molecules related to T cell exhaustion (such as: PD-1, TIGIT, CTLA4, LAG3, etc.), and it has a strong positive correlation in low-grade glioma (LGG), invasive breast cancer (BRAC, etc.). ) and other tumors that significantly exhibited low expression of MAP4K1 had longer survival.
- the protein expression of HPK1 and immunosuppressive molecules in T cells was measured, and the expression of HPK1 was found to be upregulated in exhausted T cells.
- HPK1 is also an important kinase that regulates T cell exhaustion and suppresses anti-tumor immune responses in humans (Sawasdikosol S et al. Immunologic Research,2012,54(1-3):262-265.), and its small molecule inhibitory agents may be used in the treatment of tumors.
- HPK1 The immunosuppressive pathway regulated by HPK1 is different from that of PD-1/L1 (programmed death receptor 1/programmed death receptor-ligand 1), suggesting that small molecule inhibitors of HPK1 can interact with PD-1/L1 inhibitors/ combination of antibodies.
- the combination of HPK1 inhibitors and anti-PD-1/L1 antibodies can enhance antiviral and anti-tumor effects.
- HPK1 inhibitors can inhibit tumor growth and enhance the efficacy of PD-L1.
- Another study showed that combined blocking of HPK1 and PD -L1 can enhance anti-tumor T cell response (Hernandez S et al., Cell Reports, 2018, 25(1):80-94.). These all prove that small molecule inhibitors of HPK1 can be used in combination with anti-PD-1/L1 antibodies to obtain better antiviral and antitumor efficacy.
- MAP4K In addition to MAP4K1/HPK1, MAP4K also includes MAP4K2/GCK, MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS and MAP4K6/MINK, a total of 6 subtypes with similar structures (Chuang H C et al. Advances in Immunology, 2016 , 129:277-314.).
- HPK1 is mainly in hematopoietic related cells Expression, such as hematopoietic progenitor cells, T cells, B cells, macrophages, dendritic cells, neutrophils and mast cells (Kiefer F et al.The EMBO Journal,1996,15(24):7013-7025. ), the expression of other tissues and organs is quite limited, which reduces its safety risk.
- HPK1 inhibitors CFI-402411, BGB-15025
- HPK1 inhibition may be a promising tumor immunotherapy.
- the present invention aims to provide a novel HPK1 inhibitor, which can be used to prepare medicines for treating HPK1-related diseases.
- the present invention proposes a compound, which is a compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
- R 1 is independently H, cyano, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or - O-(C 1 -C 6 alkyl);
- Ring A is independently 6-10 membered aryl, 5-8 membered heteroaryl, 4-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl or C 3 -C 10 cycloalkenyl;
- R2 is independently
- R 21 and R 22 are each independently unsubstituted or substituted by R 211 C 1 -C 6 alkyl, or, unsubstituted or substituted by R 211 C 3 -C 6 cycloalkyl; said R 211 In the substituted C 1 -C 6 alkyl group or the C 3 -C 6 cycloalkyl group substituted by R 211 , the R 211 substitution can be one or more substitutions, and each of the R 211 is independently the following substitutions Group: hydroxyl, halogen, -O-(C 1 -C 6 alkyl), C 1 -C 6 alkylamino or C 3 -C 6 cycloalkyl; when there are multiple substituents, the substituents are the same or different; at least one of R 21 and R 22 is C 1 -C 6 alkyl substituted by R 211 or C 3 -C 6 cycloalkyl substituted by R 211 ;
- Ring B is independently unsubstituted or substituted by R 23 4-8 membered heterocycloalkyl, or, unsubstituted or substituted by R 23 6-11 membered heterospirocycloalkyl; said substituted by R 23 In a 4-8 membered heterocycloalkyl group or a 6-11 membered heterospirocycloalkyl group substituted by R 23 , the R 23 can be substituted by one or more substitutions, and each of the R 23 is independently the following substituents : Hydroxy, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl substituted by 1-5 identical or different halogens; when the substituent is multiple When, the substituents are the same or different;
- R 24 is independently a C 3 -C 6 cycloalkyl group that is unsubstituted or substituted by R 241 ; in the C 3 -C 6 cycloalkyl group substituted by R 241 , the substitution of R 241 can be one or Multiple substitutions, each of the R 241 is independently the following substituents: cyano, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; when there are multiple substituents, the substituents are the same or different;
- R 3 is independently halogen, CN, C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by 1-5 identical or different halogens;
- n 0, 1, 2 or 3;
- R 4 and R 5 are each independently C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by 1-5 identical or different halogens; or the carbon atoms to which R 4 and R 5 are jointly connected may be A 4-8 membered cycloalkyl group or a 4-8 membered heterocycloalkyl group is formed.
- the present invention provides a compound, which is a compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug :
- R 1 is independently H, cyano, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or - O-(C 1 -C 6 alkyl);
- Ring A is independently 6-10 membered aryl, 5-8 membered heteroaryl, 4-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl or C 3 -C 10 cycloalkenyl;
- R2 is independently
- R 21 and R 22 are each independently unsubstituted or substituted by R 211 C 1 -C 6 alkyl, or, unsubstituted or substituted by R 211 C 3 -C 6 cycloalkyl; said R 211 In the substituted C 1 -C 6 alkyl group or the C 3 -C 6 cycloalkyl group substituted by R 211 , the R 211 substitution can be one or more substitutions, and each of the R 211 is independently the following substitutions Group: hydroxyl, halogen, -O-(C 1 -C 6 alkyl), C 1 -C 6 alkylamino or C 3 -C 6 cycloalkyl; when there are multiple substituents, the substituents are the same or different; at least one of R 21 and R 22 is C 1 -C 6 alkyl substituted by R 211 or C 3 -C 6 cycloalkyl substituted by R 211 ;
- Ring B is independently unsubstituted or substituted by R 23 4-8 membered heterocycloalkyl, or, unsubstituted or substituted by R 23 6-11 membered heterospirocycloalkyl; said substituted by R 23 In a 4-8 membered heterocycloalkyl group or a 6-11 membered heterospirocycloalkyl group substituted by R 23 , the R 23 can be substituted by one or more substitutions, and each of the R 23 is independently the following substituents : Hydroxy, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl substituted by 1-5 identical or different halogens; when the substituent is multiple When, the substituents are the same or different;
- R 24 is independently a C 3 -C 6 cycloalkyl group that is unsubstituted or substituted by R 241 ; in the C 3 -C 6 cycloalkyl group substituted by R 241 , the substitution of R 241 can be one or Multiple substitutions, each of the R 241 is independently the following substituents: cyano, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; when there are multiple substituents, the substituents are the same or different;
- R 3 is independently halogen, C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by 1-5 identical or different halogens;
- n 0, 1, 2 or 3;
- R 4 and R 5 are each independently C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by 1-5 identical or different halogens; or the carbon atoms to which R 4 and R 5 are jointly connected may be A 4-8 membered heterocycloalkyl group is formed.
- R3 is CN
- R 4 and R 5 can form a 4-8 membered cycloalkyl group with the carbon atom to which they are jointly connected.
- the compound is the structure shown in formula II, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.
- R 2 , R 4 , R 5 and ring A are as described in the present invention.
- the compound is a structure as shown in formula III or IV, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug .
- R 2 , R 24 , R 4 and R 5 are as described in the present invention.
- Ring C is independently a 5-8 membered heteroaryl group, a 4-8 membered heterocycloalkyl group or a 4-8 membered heterocycloalkenyl group.
- the compound is a structure shown in formula (V) or formula (VI), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.
- ring D is 6-10 membered aryl or C 3 -C 10 cycloalkenyl
- R 2 is
- Ring A is a 6-10 membered aryl group
- the 6-10 membered aryl group is benzene or naphthalene, preferably benzene.
- the 5-8 membered heteroaryl group is pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl , thiadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl or triazinyl, preferably pyrrolyl, oxazolyl, thiazolyl or pyridyl.
- the 4-8 membered heterocycloalkyl group is azetidinyl, oxetanyl, pyrrolidinyl, Tetrahydrofuryl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, morpholinyl or piperazinyl, preferably azetidinyl, morpholinyl or morpholinyl .
- the 4-8 membered heterocyclenyl group is 4H-pyranyl, 2H-pyranyl, tetrahydropyridyl , 2,5-dihydro-1H-pyrrolyl, 2,5-dihydrofuryl, 2,3-dihydrofuryl, 2,5-dihydrothienyl, 2,3-dihydrothienyl or 4 , 5-dihydrooxazolyl, preferably tetrahydropyridyl.
- ring A is C 3 -C 10 cycloalkenyl
- said C 3 -C 10 cycloalkenyl is cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexyl Alkenyl or cycloheptenyl, preferably cyclohexenyl.
- R 2 is
- R 2 is
- the C 1 -C 6 alkyl is methyl, ethyl, n- Propyl, isopropyl, n-butyl, isobutyl or sec-butyl, preferably methyl, ethyl, n-propyl or isobutyl.
- the C 3 -C 6 cycloalkyl is cyclopropyl, cyclo Butyl, cyclopentyl or cyclohexyl, preferably cyclopropyl or cyclobutyl.
- R 21 and R 22 are C 1 -C 6 alkyl substituted by R 211 or C 3 -C 6 cycloalkyl substituted by R 211 , the number of substitutions of R 211 1, 2, 3, 4 or 5, preferably 1 or 2.
- R 211 is hydroxyl
- R 211 when R 211 is halogen, said halogen is F, Cl, Br or I, preferably F or Cl.
- the C 1 -C 6 alkyl is methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl, n-propyl or isopropyl.
- R 211 is -O-(C 1 -C 6 alkyl)
- said -O-(C 1 -C 6 alkyl) is -O-methyl, -O -Ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-isobutyl, -O-sec-butyl or -O-tert-butyl, preferably -O-methyl, -O-ethyl, -O-n-propyl or -O-isopropyl.
- the C 1 -C 6 alkylamino is -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 or -NHCH 2 (CH 3 ) 2 , preferably -NHCH 3 , -N(CH 3 ) 2 or -NHCH 2 CH 3 .
- R 211 is C 3 -C 6 cycloalkyl
- said C 3 -C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, more Preferably it is cyclopropyl or cyclobutyl.
- R 2 is
- the 4-8 membered heterocycloalkyl group is aziridyl, aza Cyclobutyl, azacyclopentyl, azacyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl, compared Preferably it is azetidinyl, azetidinyl or morpholinyl.
- Ring B is a 4-8 membered heterocycloalkyl group
- the 4-8 membered heterocycloalkyl group is aziridyl, azetidinyl, azetidinyl Base, azacyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl, preferably azetidinyl , azacyclopentyl or morpholinyl.
- the 6-11 membered heterospirocycloalkyl group is preferably azaspiro [3.3]heptyl, oxazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl or oxazaspiro[5.3]nonyl, more preferably oxazaspiro[3.3] Heptyl.
- the 6-11 membered heterospirocycloalkyl group is preferably azaspiro[3.3]heptyl, oxa Azaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl or oxazaspiro[5.3]nonyl, more preferably oxazaspiro[3.3]heptyl.
- Ring B is a 4-8 membered heterocycloalkyl group substituted by R 23 or a 6-11 membered heterospirocycloalkyl group substituted by R 23
- the number of substitutions of R 23 is 1, 2, 3, 4 or 5, preferably 1 or 2.
- R 23 is hydroxyl
- R 23 is cyano
- halogen when R23 is halogen, said halogen is F, Cl, Br or I, preferably F or Cl.
- R 23 is C 1 -C 6 alkyl substituted by 1-5 identical or different halogens
- said C 1 -C 6 alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl.
- R 23 is C 1 -C 6 alkyl substituted by 1-5 identical or different halogens
- said halogen is F, Cl, Br or I, preferably F or Cl.
- R 23 is C 1 -C 6 alkyl substituted by 1-5 identical or different halogens
- the number of said halogens is 1, 2, 3, 4 or 5, preferably 1, 2 or 3.
- R 23 when R 23 is C 1 -C 6 alkyl, said C 1 -C 6 alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl.
- R 23 when R 23 is C 3 -C 6 cycloalkyl, said C 3 -C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, more Preferably it is cyclopropyl or cyclobutyl.
- R 2 is
- R 24 is a C 3 -C 6 cycloalkyl group that is unsubstituted or substituted by R 241
- the C 3 -C 6 cycloalkyl group is cyclopropyl, cyclobutyl, Cyclopentyl or cyclohexyl, preferably cyclopropyl or cyclobutyl.
- R 24 is a C 3 -C 6 cycloalkyl group that is unsubstituted or substituted by R 241
- the number of substitutions of R 241 is 1, 2, 3, or 4 Or 5, preferably 1 or 2.
- R 241 is cyano
- halogen when R 241 is halogen, said halogen is F, Cl, Br or I, preferably F or Cl.
- R 241 is C 1 -C 6 alkyl substituted by 1-5 identical or different halogens
- said C 1 -C 6 alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl.
- R 241 is C 1 -C 6 alkyl substituted by 1-5 identical or different halogens
- said halogen is F, Cl, Br or I, preferably F or Cl.
- R 241 is C 1 -C 6 alkyl substituted by 1-5 identical or different halogens
- the number of said halogens is 1, 2, 3, 4 or 5, preferably 1, 2 or 3.
- R 241 when R 241 is C 1 -C 6 alkyl, said C 1 -C 6 alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl.
- R 241 is C 3 -C 6 cycloalkyl
- said C 3 -C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, more Preferably it is cyclopropyl or cyclobutyl.
- n 0, 1 or 2.
- halogen when R 3 is halogen, said halogen is F, Cl, Br or I, preferably F or Cl.
- R 3 is C 1 -C 6 alkyl substituted by 1-5 identical or different halogens
- said C 1 -C 6 alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl.
- R 3 is C 1 -C 6 alkyl substituted by 1-5 identical or different halogens
- said halogen is F, Cl, Br or I, preferably F or Cl.
- R 3 is C 1 -C 6 alkyl substituted by 1-5 identical or different halogens
- the number of said halogens is 1, 2, 3, 4 or 5, preferably 1, 2 or 3.
- R 3 when R 3 is C 1 -C 6 alkyl, said C 1 -C 6 alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl.
- R 4 and R 5 are C 1 -C 6 alkyl
- said C 1 -C 6 alkyl is methyl, ethyl, n-propyl or isopropyl, more Preferably it is methyl.
- R 4 and R 5 are C 1 -C 6 alkyl substituted by 1-5 identical or different halogens
- the C 1 -C 6 alkyl is methyl, Ethyl, n-propyl or isopropyl, preferably methyl or ethyl.
- halogens are F, Cl, Br or I, more Preferably F or Cl.
- R 4 and R 5 are C 1 -C 6 alkyl substituted by 1-5 identical or different halogens
- the number of said halogens is 1, 2, 3, 4 or 5, preferably 1, 2 or 3.
- the 4-8 membered heterocycloalkyl group is aziridyl, oxa Cyclopropyl, Azetidinyl, Azacyclopentyl, Azacyclohexyl, Oxetanyl, Pyrrolidinyl, Tetrahydrofuranyl, Pyrazolidinyl, Imidazolidinyl, Oxazolidinyl, Morpholine group, pyrrolidinyl, piperidinyl or piperazinyl, preferably oxetanyl.
- R1 is H.
- R 2 is
- R4 and R5 are methyl.
- R 4 and R 5 The heterocyclic ring formed by the carbon atom they are connected to is
- the compound is a structure as shown in formula III, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
- R2 is independently
- R 21 and R 22 are each independently unsubstituted or substituted by R 211 C 1 -C 6 alkyl, or, unsubstituted or substituted by R 211 C 3 -C 6 cycloalkyl; said R 211 In the substituted C 1 -C 6 alkyl group or the C 3 -C 6 cycloalkyl group substituted by R 211 , the R 211 substitution can be one or more substitutions, and each of the R 211 is independently the following substitutions Group: hydroxyl, halogen, -O-(C 1 -C 6 alkyl), C 1 -C 6 alkylamino or C 3 -C 6 cycloalkyl; when there are multiple substituents, the substituents are the same or different; at least one of R 21 and R 22 is C 1 -C 6 alkyl substituted by R 211 or C 3 -C 6 cycloalkyl substituted by R 211 ;
- Ring B is independently unsubstituted or substituted by R 23 4-8 membered heterocycloalkyl, or, unsubstituted or substituted by R 23 6-11 membered heterospirocycloalkyl; said substituted by R 23 In a 4-8 membered heterocycloalkyl group or a 6-11 membered heterospirocycloalkyl group substituted by R 23 , the R 23 can be substituted by one or more substitutions, and each of the R 23 is independently the following substituents : Hydroxy, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl substituted by 1-5 identical or different halogens; when the substituent is multiple When, the substituents are the same or different;
- R 4 and R 5 are each independently C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by 1-5 identical or different halogens; or the carbon atoms to which R 4 and R 5 are jointly connected may be A 4-8 membered heterocycle is formed.
- the compound is a structure as shown in formula IV, and its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are:
- Ring C is independently a 4-8 membered heterocycloalkenyl group
- R 24 is independently a C 3 -C 6 cycloalkyl group that is unsubstituted or substituted by R 241 ; in the C 3 -C 6 cycloalkyl group substituted by R 241 , the substitution of R 241 can be one or Multiple substitutions, each of the R 241 is independently the following substituents: cyano, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; when there are multiple substituents, the substituents are the same or different;
- R 4 and R 5 are each independently C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by 1-5 identical or different halogens; or the carbon atoms to which R 4 and R 5 are jointly connected may be A 4-8 membered heterocycle is formed.
- the compound is a structure as shown in formula II, and its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are:
- Ring A is independently C 3 -C 10 cycloalkenyl
- R2 is independently
- R 21 and R 22 are each independently unsubstituted or substituted by R 211 C 1 -C 6 alkyl, or, unsubstituted or substituted by R 211 C 3 -C 6 cycloalkyl; said R 211 In the substituted C 1 -C 6 alkyl group or the C 3 -C 6 cycloalkyl group substituted by R 211 , the R 211 substitution can be one or more substitutions, and each of the R 211 is independently the following substitutions Group: hydroxyl, halogen, -O-(C 1 -C 6 alkyl), C 1 -C 6 alkylamino or C 3 -C 6 cycloalkyl; when there are multiple substituents, the substituents are the same or different; at least one of R 21 and R 22 is C 1 -C 6 alkyl substituted by R 211 or C 3 -C 6 cycloalkyl substituted by R 211 ;
- Ring B is independently unsubstituted or substituted by R 23 4-8 membered heterocycloalkyl, or, unsubstituted or substituted by R 23 6-11 membered heterospirocycloalkyl; said substituted by R 23 In a 4-8 membered heterocycloalkyl group or a 6-11 membered heterospirocycloalkyl group substituted by R 23 , the R 23 can be substituted by one or more substitutions, and each of the R 23 is independently the following substituents : Hydroxy, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl substituted by 1-5 identical or different halogens; when the substituent is multiple When, the substituents are the same or different;
- R 4 and R 5 are each independently C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by 1-5 identical or different halogens; or the carbon atoms to which R 4 and R 5 are jointly connected may be A 4-8 membered heterocycle is formed.
- the compound is a structure shown in formula V, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug,
- ring D is 6-10 membered aryl or C 3 -C 10 cycloalkenyl
- R 2 is
- Ring B is independently unsubstituted or substituted by R 23 4-8 membered heterocycloalkyl, or, unsubstituted or substituted by R 23 6-11 membered heterospirocycloalkyl; said substituted by R 23 In a 4-8 membered heterocycloalkyl group or a 6-11 membered heterospirocycloalkyl group substituted by R 23 , the R 23 can be substituted by one or more substitutions, and each of the R 23 is independently the following substituents : Hydroxy, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl substituted by 1-5 identical or different halogens; when the substituent is multiple When, the substituents are the same or different;
- R 21 and R 22 are each independently unsubstituted or substituted by R 211 C 1 -C 6 alkyl, or unsubstituted or substituted by R 211 C 3 -C 6 cycloalkyl; said substituted by R 211 In the C 1 -C 6 alkyl group or the C 3 -C 6 cycloalkyl group substituted by R 211 , the R 211 substitution may be one or more substitutions, and each of the R 211 is independently the following substituents : hydroxyl, halogen, -O-(C 1 -C 6 alkyl), C 1 -C 6 alkylamino or C 3 -C 6 cycloalkyl; when there are multiple substituents, the substituents are the same or Different; at least one of R 21 and R 22 is C 1 -C 6 alkyl substituted by R 211 or C 3 -C 6 cycloalkyl substituted by R 211 ;
- R 24 is independently a C 3 -C 6 cycloalkyl group that is unsubstituted or substituted by R 241 ; in the C 3 -C 6 cycloalkyl group substituted by R 241 , the substitution of R 241 can be one or Multiple substitutions, each of the R 241 is independently the following substituents: cyano, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; when there are multiple substituents, the substituents are the same or different;
- R 4 and R 5 are each independently C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by 1-5 identical or different halogens; or the carbon atoms to which R 4 and R 5 are jointly connected may be A 4-8 membered cycloalkyl group or a 4-8 membered heterocycloalkyl group is formed.
- the compound is a structure as shown in formula VI, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug,
- R 4 and R 5 are each independently C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by 1-5 identical or different halogens; or the carbon atoms to which R 4 and R 5 are jointly connected may be A 4-8 membered cycloalkyl group or a 4-8 membered heterocycloalkyl group is formed.
- the compound is a structure shown in formula V-1 or V-2, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrugs,
- R 21 and R 22 are each independently unsubstituted or substituted by R 211 C 1 -C 6 alkyl;
- Ring D is 6-10 membered aryl or C 3 -C 10 cycloalkenyl
- Ring B is independently unsubstituted or substituted by R 23 4-8 membered heterocycloalkyl, or, unsubstituted or substituted by R 23 6-11 membered heterospirocycloalkyl; said substituted by R 23 In a 4-8 membered heterocycloalkyl group or a 6-11 membered heterospirocycloalkyl group substituted by R 23 , the R 23 can be substituted by one or more substitutions, and each of the R 23 is independently the following substituents : Hydroxy, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl substituted by 1-5 identical or different halogens; when the substituent is multiple When, the substituents are the same or different;
- R 4 and R 5 are each independently C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by 1-5 identical or different halogens; or the carbon atoms to which R 4 and R 5 are jointly connected may be A 4-8 membered cycloalkyl group or a 4-8 membered heterocycloalkyl group is formed.
- the compound is a structure such as formula V-1a, V-1b, V-2a or V-2b, its tautomers, stereoisomers, hydrates, solvents compounds, pharmaceutically acceptable salts or prodrugs,
- R 21 and R 22 are each independently unsubstituted or substituted by R 211 C 1 -C 6 alkyl;
- R 41 and R 51 are each independently C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by 1-5 identical or different halogens;
- Ring E is 4-8 membered cycloalkyl or 4-8 membered heterocycloalkyl
- Ring D is 6-10 membered aryl or C 3 -C 10 cycloalkenyl
- Ring B is independently unsubstituted or substituted by R 23 4-8 membered heterocycloalkyl, or, unsubstituted or substituted by R 23 6-11 membered heterospirocycloalkyl; said substituted by R 23 In a 4-8 membered heterocycloalkyl group or a 6-11 membered heterospirocycloalkyl group substituted by R 23 , the R 23 can be substituted by one or more substitutions, and each of the R 23 is independently the following substituents : Hydroxy, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl substituted by 1-5 identical or different halogens; when the substituent is multiple In each case, the substituents are the same or different.
- the compound has the structure shown below, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:
- the present invention proposes a pharmaceutical composition, which includes a therapeutically effective dose of the above compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically Acceptable salts or prodrugs and pharmaceutically acceptable excipients.
- the pharmaceutical composition of the present invention may include a therapeutically effective dose of the above compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt Or prodrugs and pharmaceutically acceptable pharmaceutical carriers, diluents or excipients are mixed to prepare pharmaceutical preparations, which are suitable for oral or parenteral administration.
- Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal and oral routes.
- the formulation can be administered by any route, for example, by infusion or bolus injection, by absorption through the epithelium or mucocutaneous (eg, oral mucosa or rectum, etc.).
- Administration can be systemic or local.
- formulations for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like.
- the formulations can be prepared by methods known in the art, and contain carriers, diluents or excipients commonly used in the field of pharmaceutical formulations.
- the present invention proposes the above compound, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug and PD-1/PD-L1
- the drug can be used for the treatment or prevention of solid tumors, blood Cancer, non-small cell lung cancer, small cell lung cancer, melanoma of the skin, Merkel cell carcinoma, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the anal canal or skin, urothelial carcinoma, clear cell or opaque cell Renal cell carcinoma, triple negative breast cancer, endometrial cancer, cervical cancer, gastroesophageal cancer, or hepatocellular carcinoma.
- the present invention proposes the above-mentioned compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition in the preparation of Use in medicines for treating or preventing diseases related to HPK1.
- the above-mentioned compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition is used in the preparation of treatment or prevention with HPK1 Use in related disease medicines for the treatment of solid tumors, blood cancers, non-small cell lung cancer, small cell lung cancer, melanoma of the skin, Merkel cell carcinoma, squamous cell carcinoma of the head and neck, anal canal or skin Squamous cell carcinoma, urothelial carcinoma, clear cell or non-clear cell renal cell carcinoma, triple negative breast cancer, endometrial cancer, cervical cancer, gastroesophageal cancer, or hepatocellular carcinoma.
- the present invention provides a method for treating or preventing HPK1-related diseases.
- the method includes administering to the patient the above-mentioned compound pharmaceutically acceptable, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or The above-mentioned pharmaceutical composition.
- the above-mentioned compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition is used in the preparation of treatment or prevention with HPK1 Use in related disease medicines for the treatment of solid tumors, blood cancers, non-small cell lung cancer, small cell lung cancer, melanoma of the skin, Merkel cell carcinoma, squamous cell carcinoma of the head and neck, anal canal or skin Squamous cell carcinoma, urothelial carcinoma, clear cell or non-clear cell renal cell carcinoma, triple negative breast cancer, endometrial cancer, cervical cancer, gastroesophageal cancer, or hepatocellular carcinoma.
- the present invention provides the aforementioned compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or pharmaceutical composition , for treating or preventing diseases related to HPK1.
- the HPK1-related diseases include at least one selected from the following: solid tumors, blood cancers, non-small cell lung cancer, small cell lung cancer, skin melanoma, Merkel cell carcinoma, head and neck cancer Squamous cell carcinoma, squamous cell carcinoma of the anal canal or skin, urothelial carcinoma, clear cell or non-clear cell renal cell carcinoma, triple negative breast cancer, endometrial cancer, cervical cancer, gastroesophageal cancer, and hepatocellular carcinoma .
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salt refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
- salts are contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be useful in the identification, characterization or purification of compounds of the invention.
- composition means a mixture of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components such as a physiologically/pharmaceutically acceptable carrier and excipients.
- the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
- excipient refers to a pharmaceutically acceptable inert ingredient.
- examples of categories of the term “excipient” include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flow and/or cohesiveness.
- prodrug refers to a compound of the invention that can be converted to biological activity under physiological conditions or by solvolysis.
- the prodrugs of the present invention are prepared by modifying functional groups in the compounds which can be removed routinely or in vivo to yield the parent compound.
- Prodrugs include compounds formed by linking a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is split to form free hydroxyl, free of amino.
- stereoisomer refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereoisomers and conformers.
- the compounds according to the invention may exist as one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as mixtures of isomers, for example as racemic and non- A mixture of enantiomers, depending on the number of asymmetric carbon atoms.
- the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule.
- the prefixes D and L or (+) and (-) are symbols used to designate the rotation of plane polarized light by a compound, where (-) or L indicates that the compound is levorotatory.
- Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques.
- Compounds of the invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic form. Resolution of racemic mixtures of compounds can be performed by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolving acid that is an optically active, salt-forming organic acid.
- Suitable resolving agents for the fractional recrystallization process are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as ⁇ - D and L forms of camphorsulfonic acid.
- optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as ⁇ - D and L forms of camphorsulfonic acid.
- resolving agents suitable for fractional crystallization methods include ⁇ -methyl-benzylamine in stereomerically pure form (e.g., S and R forms or in diastereomerically pure form), 2-phenylglycinol, Norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc.
- Resolution of racemic mixtures can also be performed by elution on a chromatographic column packed with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). It can be carried out by high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC).
- HPLC high performance liquid chromatography
- SFC supercritical fluid chromatography
- any enantiomer or diastereomer of the compounds described in the present invention can also be obtained by stereoorganic synthesis using optically pure starting materials or reagents of known configuration.
- tautomer refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions.
- the compounds of the present invention may exhibit tautomerism.
- Tautomeric compounds can exist in two or more interconvertible species.
- Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms.
- Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
- the keto form predominates
- the enol form predominates.
- the present invention encompasses all tautomeric forms of the compounds.
- the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
- compounds can be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
- the term "effective amount” or “therapeutically effective amount” refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect.
- the "effective amount” of one active substance in the composition refers to the amount needed to achieve the desired effect when used in combination with another active substance in the composition.
- the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
- active ingredient refers to a chemical entity that is effective in treating the disorder, disease or condition of interest.
- substituted refers to the replacement of any one or more hydrogen atoms on a specified atom with a substituent, including deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable .
- Keto substitution does not occur on aromatic groups.
- optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.
- C 1 -C 6 alkyl is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
- the alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl
- -O-(C 1 -C 6 alkyl) is to be understood as meaning that an alkyl group is attached to the rest of the molecule via an oxygen atom, wherein "C 1 -C 6 alkyl” has the above definition. Such as -O-(methyl), -O-(ethyl).
- C 1 -C 6 alkylamino denotes those alkyl groups containing 1 to 6 carbon atoms attached to the rest of the molecule through an amino group.
- Examples of the C 1 -C 6 alkylamino include, but are not limited to -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 ) (CH 2 CH 3 ), -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 , -NHCH 2 CH 2 CH 2 CH 3 and the like.
- C 3 -C 6 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
- C 3 -C 10 cycloalkenyl refers to a monovalent monocyclic hydrocarbon ring which contains one double bond and which contains 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms ("C 3 -C 10 -cycloalkenyl").
- the C 3 -C 10 -cycloalkenyl group is for example a monocyclic hydrocarbon ring, for example cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononyl alkenyl or cyclodecenyl.
- the cycloalkenyl group contains 5, 6 or 7 carbon atoms (“C 5 -C 7 -cycloalkenyl”) and is, for example, cyclopentenyl, cyclohexenyl or cycloheptenyl.
- 4-8 membered heterocyclyl is understood to mean a saturated monocyclic, bicyclic or tricyclic ring having 4 to 8 atoms , wherein 1, 2, 3, 4 or 5 ring atoms are selected from N, O and S, unless otherwise stated, which may be attached via carbon or nitrogen, wherein the -CH2- group is optionally replaced by -C(O) - replace; and wherein unless otherwise stated to the contrary, ring nitrogen atom or ring sulfur atom is optionally oxidized to form N-oxide or S-oxide or ring nitrogen atom is optionally quaternized; wherein -NH in the ring optionally substituted with acetyl, formyl, methyl or methanesulfonyl; and the ring is optionally substituted with one or more halogens.
- heterocyclyl when the total number of S atoms and O atoms in the heterocyclyl exceeds 1, these heteroatoms are not adjacent to each other.
- the heterocyclyl is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic or aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclyl is monocyclic, it must not be aromatic.
- heterocyclic groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl , piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydroindolyl, tetrahydropyranyl, dihydro -2H-pyranyl, tetrahydrofuryl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one and 2,5 - dioxoimidazolidinyl.
- 4-8 membered heterocycloalkenyl should be understood as a non-aromatic monocyclic or polycyclic group containing 4 to 8 ring atoms, preferably 5 to 6 ring atoms, wherein the 4-8 membered heterocycle
- the cycloalkenyl group contains 1 to 3 heteroatoms selected from N, O, S and P and contains at least one carbon-carbon double bond or carbon-nitrogen double bond.
- the inclusion of aza, oxa or thia in the group name means at least one nitrogen, oxygen or sulfur atom respectively as a ring atom.
- the nitrogen or sulfur atom of the 4-8 membered heterocycloalkenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S-dioxide.
- Preferred 4-8 membered heterocyclenyl groups include but are not limited to 1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3 ,6-tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl , dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorinated dihydrofuranyl and their oxides, etc. "4-8 member
- 6-10 membered aryl should be understood as a monovalent group having 6-10 carbon atoms, at least one ring having an aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring, especially a ring having 6 carbon atoms (" C 6 aryl"), such as phenyl; when the 6-10 membered aryl is substituted, it can be monosubstituted or polysubstituted. Also, there is no limitation on the substitution site, for example, it may be an ortho, para or meta substitution.
- heterospirocycloalkyl refers to a bicyclic saturated heterocyclic ring having a total of 6, 7, 8, 9, 10 or 11 ring atoms, wherein both rings share a common ring carbon atom, said "Heterospirocycloalkyl” contains one or two identical or different ring heteroatoms or heteroatom-containing groups selected from the group consisting of N, NH, O, S, SO and SO 2 ; the heterospirocycloalkane
- the radical can be connected to the rest of the molecule through any carbon atom (except the spiro carbon atom) or (if present) nitrogen atom.
- the heterospirocycloalkyl group is for example azaspiro[2.3]hexyl, azaspiro[ 3.3]heptyl, oxazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, oxazaspiro[5.3]nonyl, oxazepine Spiro[4.3]octyl, azaspiro[4,5]decyl, oxazaspiro[5.5]undecyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3] Heptyl, thiazaspiro[4.3]octyl, or one of the other homologue backbones such as spiro[3.4]-, spiro[4.4]-, spiro[2.4]-, spiro[2.5]-, spiro[2.6 ]-, Spiro[3.5]
- 5-8 membered heteroaryl is understood as a monovalent group having 5-8 ring atoms, especially 5 or 6 ring atoms, and containing 1-5 heteroatoms independently selected from N, O and S Monocyclic, bicyclic or tricyclic aromatic ring groups.
- a monovalent monocyclic, bicyclic or tricyclic aromatic ring group preferably having 1 to 3 heteroatoms independently selected from N, O and S, and, in addition, also includes aromatic ring-fused non-aromatic ring situation.
- heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, Diazolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridyl, pteridine carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.
- halo or halogen refers to fluoro, chloro, bromo and iodo.
- the present invention has at least one of the following technical effects:
- HPK1 inhibitors with novel structure, excellent pharmacokinetic properties, and good efficacy or druggability, which can be used to effectively treat or prevent HPK1-related diseases and diseases.
- the compound of the present invention in the in vitro enzyme test, has a good inhibitory effect on the HPK1 enzyme, and the inhibitory activity is significantly better than that of the reference compound, and in the cell test, the compound of the present invention also has a good inhibitory effect on the HPK1 enzyme Inhibitory effect, the inhibitory activity was significantly better than that of the reference compound.
- the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
- NMR nuclear magnetic resonance
- MS mass spectrometry
- the unit of NMR shift is 10 -6 (ppm).
- the solvents determined by NMR are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
- M molar concentration, such as 1M hydrochloric acid means 1mol/L hydrochloric acid solution
- IC 50 half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
- the third step 4-(2,6-difluoro-4-nitrophenoxy)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H -Synthesis of pyrrolo[2,3-b]pyridine
- the filtrate was concentrated to obtain a crude product, ethyl acetate (100 mL) and water (50 mL) were added to the crude product, the organic phase and the aqueous phase were separated, and the aqueous phase was extracted with ethyl acetate (50 mL ⁇ 3).
- the organic phase was collected, filtered with anhydrous Na 2 SO 4 , and concentrated to obtain crude product 3,5-difluoro-4-((3-iodo-1-((2-(trimethylsilyl)ethoxy) Methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)aniline, directly used in the next reaction.
- the seventh step N-(3,5-difluoro-4-((3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2 ,3-b]pyridin-4-yl)oxy)phenyl)-5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-amine (A1) synthesis
- reaction solution was concentrated and spin-dried to obtain a crude product.
- the first step 1-(3,5-difluoro-4-((3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2 ,3-b]pyridin-4-yl)oxy)phenyl)-3-((3-(hydroxymethyl)oxetan-3-yl)methyl)thiourea
- the second step methyl-N-(3,5-difluoro-4-((3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole[ Synthesis of 2,3-b]pyridin-4-yl)oxy)phenyl)-N'-((3-(hydroxymethyl)oxoalk-3-yl)methyl)carbamoylthioester
- the third step N-(3,5-difluoro-4-((3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2 Synthesis of ,3-b]pyridin-4-yl)oxy)phenyl)-2,6-dioxa-8-azaspiro[3.5]non-7-en-7-amine (A2)
- reaction solution was diluted with 50 mL of water, and the mixture was extracted with ethyl acetate (30 mL ⁇ 3). The collected organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product.
- the synthesis method refers to the synthesis of A1, and the bromination reagent is N-bromosuccinimide.
- Embodiment 1 the preparation of target compound I-1
- Target compound I-1 route is as follows:
- the first step the synthesis of 4-bromo-N-(3-methoxypropyl)-N-methylbenzamide
- the third step the synthesis of 4-(2,6-difluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine
- the fourth step 4-(2,6-difluoro-4-nitrophenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[ Synthesis of 2,3-b]pyridine
- the fifth step 4-(2,6-difluoro-4-nitrophenoxy)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H -Synthesis of pyrrolo[2,3-b]pyridine
- the sixth step 4-(4-(2,6-difluoro-4-nitrophenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- Synthesis of pyrrolo[2,3-b]pyridin-3-yl)-N-(3-methoxypropyl)-N-methylbenzamide
- the reaction solution was stirred at 80° C. for 18 hours under nitrogen protection.
- the reaction solution was filtered with celite, and the filtrate was concentrated to obtain a crude product.
- the seventh step 4-(4-(4-amino-2,6-difluorophenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole Synthesis of [2,3-b]pyridin-3-yl)-N-(3-methoxypropyl)-N-methylbenzamide
- the eighth step o-phenyl (3,5-difluoro-4-((3-(4-((3-methoxypropyl)(methyl)carbamoyl)phenyl)-1-(( Synthesis of 2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole[2,3-b]pyridin-4-yl)oxy)phenyl)carbamate
- the reaction solution was kept stirring at 0°C for 3 hours.
- the reaction solution was diluted with dichloromethane (50 mL), and then washed with water (50 mL ⁇ 3).
- the organic phase was collected, dried over anhydrous Na2SO4 , filtered, and the filtrate was concentrated to give crude o-phenyl(3,5-difluoro-4-((3-(4-((3-methoxypropyl)( Methyl)carbamoyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole[2,3-b]pyridin-4-yl)oxy base) phenyl) carbamate.
- the crude product was directly used in the next reaction.
- the ninth step 4-(4-(2,6-difluoro-4-(3-(3-hydroxyl-2,2-dimethylpropyl)thioureido)phenoxy)-1-(( 2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-N-(3-methoxypropyl)-N-methyl Synthesis of phenylbenzamides
- Step 10 4-(4-(4-((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl)amino)-2,6-di Fluorophenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(3 Synthesis of -methoxypropyl)-N-methylbenzamide
- reaction mixture was stirred at 45°C for 18 hours. After the reaction was completed, the reaction was cooled to room temperature, and the reaction solution was slowly introduced into 60 mL of ice-water mixture. The mixture was extracted with ethyl acetate (60 mL ⁇ 3), the combined organic phases were washed with saturated brine (50 mL). The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
- the eleventh step 4-(4-(4-((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl)amino)-2,6- Synthesis of Difluorophenoxy)-1H-pyrrole[2,3-b]pyridin-3-yl)-N-(3-methoxypropyl)-N-methylbenzamide (I-1)
- reaction solution was concentrated to dryness, and then the concentrated mixture was dissolved in acetonitrile (5 mL), then 5 mL of ammonia water (25%) was added to the reaction solution, and the reaction solution was stirred at 25° C. for 0.5 hours. After the reaction, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (10 mL ⁇ 3), and the organic phase was collected, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain a crude product.
- Embodiment 2 the preparation of target compound 1-2
- the first step the synthesis of (4-bromophenyl) (morpholino) ketone
- the second step Synthesis of morpholino(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone
- the third step (4-(4-(4-((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl)amino)-2,6- Difluorophenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)( Synthesis of morpholino)methanone
- the reaction mixture was stirred at 80°C under nitrogen protection for 18 hours. After the reaction, the reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated to obtain a crude product.
- the fourth step (4-(4-(4-((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl)amino)-2,6- Synthesis of Difluorophenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)(morpholino)methanone (I-2)
- reaction solution was concentrated to obtain a crude product, which was then dissolved in acetonitrile (5 mL), and 5 mL of ammonia water (25%) was added to the reaction solution.
- the reaction solution was stirred at 25°C for 1 hour.
- the reaction solution was diluted with 20 mL of dichloromethane, and the organic phase was washed with water (10 mL ⁇ 3). The organic phase was collected, dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
- Embodiment 3 the preparation of target compound 1-3
- reaction solution was filtered with diatomaceous earth, the filter cake was washed with methanol (20 mL), and the filtrate was concentrated to obtain a crude product.
- the third step (4-(4-(4-((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl)amino)-2,6- Difluorophenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)( Synthesis of cis-2,6-dimethylmorpholino)methanone
- the fourth step (4-(4-(4-((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl)amino)-2,6- Synthesis of difluorophenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)(cis-2,6-dimethylmorpholino)methanone (I-3)
- reaction solution was concentrated to obtain a crude product, which was then dissolved in acetonitrile (5 mL), and 5 mL of ammonia water (25%) was added to the reaction solution.
- the reaction solution was stirred at 25°C for 1 hour.
- the reaction solution was diluted with 20 mL of dichloromethane, and the organic phase was washed with water (10 mL ⁇ 3). The organic phase was collected, dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
- Embodiment 4 the preparation of target compound 1-4
- reaction solution was filtered with diatomaceous earth, the filter cake was washed with methanol (20 mL), and the filtrate was concentrated to obtain a crude product.
- the third step (4-(4-(4-((2,6-dioxa-8-azaspiro[3.5]non-7-en-7-yl)amino)-2,6-difluoro Phenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)(cis- Synthesis of 2,6-Dimethylmorpholino)methanone
- K 2 CO 3 0.086g, 0.623mmol
- [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride 0.023 g, 0.031
- reaction mixture was stirred at 80°C under nitrogen protection for 18 hours. After the reaction, the reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated to obtain a crude product.
- the fourth step (4-(4-(4-((2,6-dioxo-8-azaspiro[3.5]non-7-en-7-yl)amino)-2,6-difluorobenzene Synthesis of oxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)(cis-2,6-dimethylmorpholino)methanone (I-4)
- reaction solution was concentrated to obtain a crude product, which was then dissolved in acetonitrile (5 mL), and 5 mL of ammonia water (25%) was added to the reaction solution.
- the reaction solution was stirred at 25°C for 1 hour.
- the reaction solution was diluted with 20 mL of dichloromethane, and the organic phase was washed with water (10 mL ⁇ 3). The organic phase was collected, dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
- Embodiment 5 the preparation of target compound 1-5
- the synthetic route of target compound 1-5 is as follows:
- the first step the synthesis of 4-bromo-N-(2-hydroxy-2-methylpropyl)-N methylbenzamide
- reaction solution was filtered with diatomaceous earth, the filter cake was washed with methanol (10 mL), and the filtrate was concentrated to obtain a crude product.
- the third step 4-(4-(4-((2,6-dioxa-8-azaspiro[3.5]non-7-en-7-yl)amino-2,6-difluorophenoxy Base)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(2-hydroxyl-2 Synthesis of -methylpropyl)-N-methylbenzamide
- the fourth step 4-(4-(4-((2,6-dioxa-8-azaspiro[3.5]non-7-en-7-yl)amino-2,6-difluorophenoxy Base)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(2-hydroxyl-2-methylpropyl)-N-methylbenzamide (target compound I-5) Synthesis
- the reaction solution was concentrated to obtain the crude product, then the crude product was dissolved in acetonitrile (3mL), and 3mL of ammonia water (25%) was added to the reaction solution.
- the reaction solution was stirred at 25° C. for 1 hour.
- the reaction solution was diluted with 10 mL of dichloromethane, organic
- the phase was washed with water (5mL ⁇ 3).
- the organic phase was collected, dried with anhydrous Na 2 SO 4 , filtered, and concentrated to obtain the crude product.
- Embodiment 6 the preparation of target compound 1-6
- the reaction mixture was stirred at 25°C for 18 hours under nitrogen protection.
- the reaction solution was diluted with dichloromethane (10mL), the organic phase was washed with saturated aqueous sodium bicarbonate (10mL ⁇ 3), the organic phase was collected, washed with 1M aqueous hydrochloric acid (10mL ⁇ 3), the organic phase was collected, washed with anhydrous Na2 Dried over SO 4 , filtered and concentrated to give (4-bromophenyl)(2-oxa-6-azaspiro[3.3]hept-6-yl)methanone (0.6 g, 85% yield) as a yellow oil.
- the third step (4-(4-(4-(4-((2,6-dioxa-8-azaspiro[3.5]non-7-en-7-yl)amino)-2,6-difluoro Phenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)(2- Synthesis of oxa-6-azaspiro[3.3]hept-6-yl)methanone
- reaction solution was concentrated to obtain a crude product, which was then dissolved in acetonitrile (3 mL), and 3 mL of ammonia water (25%) was added to the reaction solution.
- the reaction solution was stirred at 25°C for 1 hour.
- the reaction solution was diluted with 10 mL of dichloromethane, and the organic phase was washed with water (5 mL ⁇ 3). The organic phase was collected, dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
- Embodiment 7 the preparation of target compound 1-7
- the synthetic route of target compound 1-7 is as follows:
- the first step the synthesis of 4-bromo-N-(2-hydroxyethyl)-N-methylbenzamide
- the reaction mixture was stirred at 25°C for 3 hours under nitrogen protection.
- the reaction solution was diluted with dichloromethane (20 mL), the organic phase was washed with saturated aqueous sodium bicarbonate (20 mL), the organic phase was collected, washed with 0.5M aqueous hydrochloric acid (20 mL), the organic phase was collected, and dried with anhydrous Na 2 SO 4 , filtered, and concentrated to give yellow oil 4-bromo-N-(2-hydroxyethyl)-N-methylbenzamide (650 mg, yield 96%).
- the third step 4-(4-(4-((2,6-dioxa-8-azaspiro[3.5]non-7-en-7-yl)amino)-2,6-difluorobenzene Oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(2-methoxy Synthesis of (ethylethyl)-N-methylbenzamide
- the fourth step 4-(4-(4-((2,6-dioxa-8-azaspiro[3.5]non-7-en-7-yl)amino)-2,6-difluorobenzene Synthesis of oxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(2-methoxyethyl)-N-methylbenzamide (I-7)
- reaction solution was concentrated to obtain a crude product, which was then dissolved in acetonitrile (3 mL), and 3 mL of ammonia water (25%) was added to the reaction solution.
- the reaction solution was stirred at 25°C for 1 hour.
- the reaction solution was diluted with 10 mL of dichloromethane, and the organic phase was washed with water (5 mL ⁇ 3). The organic phase was collected, dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
- Embodiment 8 the preparation of target compound 1-8
- the synthetic route of target compound 1-8 is as follows:
- the first step (4-(4-(4-((2,6-dioxa-8-azaspiro[3.5]non-7-en-7-yl)amino)-2,6-difluoro Phenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)(morpholine Synthesis of methanone
- reaction mixture was stirred at 80°C under nitrogen protection for 18 hours. After the reaction, the reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated to obtain a crude product.
- reaction solution was concentrated to obtain a crude product, which was then dissolved in acetonitrile (3 mL), and 3 mL of ammonia water (25%) was added to the reaction solution.
- the reaction solution was stirred at 25°C for 1 hour.
- the reaction solution was diluted with 10 mL of dichloromethane, and the organic phase was washed with water (5 mL ⁇ 3). The organic phase was collected, dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
- Embodiment 9 the preparation of target compound 1-9
- the first step the synthesis of (4-bromophenyl)(3-hydroxy-3-methylazetidin-1-yl)methanone
- 1-Ethyl-(3-dimethylaminopropyl)carbodiimide was added to a solution of 4-bromobenzoic acid (0.5g, 2.487mmol) in dichloromethane (10mL) at 25°C under nitrogen protection Hydrochloride (0.715g, 3.73mmol), 1-hydroxybenzotriazole (0.504g, 3.73mmol) and triethylamine (0.693ml, 4.97mmol). The reaction mixture was stirred at 25°C for 10 minutes under nitrogen protection. Then, 3-methylazetidin-3-ol hydrochloride (0.369 g, 2.98 mmol) was added to the reaction solution under nitrogen protection at 25°C.
- reaction mixture was stirred at 25°C for 3 hours under nitrogen protection. After the reaction, the reaction solution was diluted with dichloromethane (20 mL), and the organic phase was washed with saturated NaHCO 3 (20 mL) aqueous solution. The organic phase was collected and washed with aqueous 0.5N HCl (20 mL). The organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give (4-bromophenyl)(3-hydroxy-3-methylazetidin-1-yl)methanone (650 mg, yielding rate 97%).
- reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated to obtain a crude product.
- the third step (4-(4-(4-(4-((2,6-dioxa-8-azaspiro[3.5]non-7-en-7-yl)amino)-2,6-difluoro Phenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)(3- Synthesis of hydroxy-3-methylazetidin-1-yl)methanone
- the fourth step (4-(4-(4-((2,6-dioxa-8-azaspiro[3.5]non-7-en-7-yl)amino)-2,6-difluoro Phenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)(3-hydroxy-3-methylazetidin-1-yl)methanone (target compound I -9)
- reaction solution was concentrated to obtain a crude product, which was then dissolved in acetonitrile (3 mL), and 3 mL of ammonia water (25%) was added to the reaction solution.
- the reaction solution was stirred at 25°C for 1 hour.
- the reaction solution was diluted with 10 mL of dichloromethane, and the organic phase was washed with water (5 mL ⁇ 3). The organic phase was collected, dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
- Embodiment 10 the preparation of target compound I-10
- the synthetic route of target compound 1-10 is as follows:
- the first step 4-(4-(4-((2,6-dioxa-8-azaspiro[3.5]non-7-en-7-yl)amino)-2,6-difluorobenzene Oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(3-methoxy Synthesis of propyl)-N-methylbenzamide (3)
- the second step 4-(4-(4-((2,6-dioxa-8-azaspiro[3.5]non-7-en-7-yl)amino)-2,6-difluorobenzene Synthesis of oxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(3-methoxypropyl)-N-methylbenzamide (target compound I-10)
- reaction solution was concentrated to obtain a crude product, which was then dissolved in acetonitrile (3 mL), and 3 mL of ammonia water (25%) was added to the reaction solution.
- the reaction solution was stirred at 25°C for 1 hour.
- the reaction solution was diluted with 10 mL of dichloromethane, and the organic phase was washed with water (5 mL ⁇ 3). The organic phase was collected, dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
- Embodiment 11 Preparation of target compound I-11
- the first step (4-(4-(4-((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl)amino)-2,6- Difluorophenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)di Synthesis of Methylphosphine Oxide
- reaction mixture was stirred at 80°C under nitrogen protection for 18 hours. After the reaction, the reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated to obtain a crude product.
- the second step (4-(4-(4-((2,6-dioxa-8-azaspiro[3.5]non-7-en-7-yl)amino)-2,6-difluoro Phenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)(3-hydroxy-3-methylazetidin-1-yl)methanone (target compound I -11)
- the reaction solution was concentrated to obtain a crude product, and then The crude product was dissolved in acetonitrile (3 mL), and 3 mL of ammonia (25%) was added to the reaction solution. The reaction solution was stirred at 25° C. for 1 hour. The reaction solution was diluted with 10 mL of dichloromethane, and the organic phase was washed with water (5 mL ⁇ 3) The organic phase was collected, dried with anhydrous Na 2 SO 4 , filtered, and concentrated to obtain the crude product.
- Embodiment 12 Preparation of target compound 1-12
- the synthetic route of target compound 1-12 is as follows:
- the first step the synthesis of (S)-(4-bromophenyl)(3-fluoropyrrolidin-1-yl)methanone
- reaction mixture was stirred at 25°C for 18 hours under nitrogen protection.
- the reaction solution was diluted with dichloromethane (10mL), the organic phase was washed with saturated aqueous sodium bicarbonate (10mL ⁇ 3), the organic phase was collected, washed with 1M aqueous hydrochloric acid (10mL ⁇ 3), the organic phase was collected, washed with anhydrous Na2 Dried over SO 4 , filtered and concentrated to give (S)-(4-bromophenyl)(3-fluoropyrrolidin-1-yl)methanone (0.65 g, 96% yield) as a yellow oil.
- the third step (S)-(4-(4-(4-(4-((2,6-dioxa-8-azaspiro[3.5]non-7-en-7-yl)amino)-2, 6-difluorophenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl ) Synthesis of (3-fluoropyrrolidin-1-yl)methanone
- the fourth step (S)-(4-(4-(4-(4-((2,6-dioxa-8-azaspiro[3.5]non-7-en-7-yl)amino)-2, 6-difluorophenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)(3-fluoropyrrolidin-1-yl)methanone (target compound I-12)
- reaction solution was concentrated to obtain a crude product, which was then dissolved in acetonitrile (3 mL), and 3 mL of ammonia water (25%) was added to the reaction solution.
- the reaction solution was stirred at 25°C for 1 hour.
- the reaction solution was diluted with 10 mL of dichloromethane, and the organic phase was washed with water (5 mL ⁇ 3). The organic phase was collected, dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
- Embodiment 13 Preparation of target compound 1-13
- the synthetic route of target compound 1-13 is as follows:
- the first step (4-(4-(4-((2,6-dioxa-8-azaspiro[3.5]non-7-en-7-yl)amino)-2,6-difluoro Phenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)(3, Synthesis of 3-difluoroazetidin-1-yl)methanone
- the second step (4-(4-(4-((2,6-dioxa-8-azaspiro[3.5]non-7-en-7-yl)amino)-2,6-difluoro Phenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)(3,3-difluoroazetidin-1-yl)methanone (target compound I-13 )
- reaction solution was concentrated to obtain a crude product, which was then dissolved in acetonitrile (3 mL), and 3 mL of ammonia water (25%) was added to the reaction solution.
- the reaction solution was stirred at 25°C for 1 hour.
- the reaction solution was diluted with 10 mL of dichloromethane, and the organic phase was washed with water (5 mL ⁇ 3). The organic phase was collected, dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
- Embodiment 14 Preparation of Target Compound I-14
- the synthetic route of target compound 1-14 is as follows:
- the first step (4-(4-(4-((2,6-dioxa-8-azaspiro[3.5]non-7-en-7-yl)amino)-2,6-difluoro Phenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)(3, Synthesis of 3-Difluoropyrrolidin-1-yl)methanone
- the reaction mixture was stirred at 80°C under nitrogen protection for 18 hours. After the reaction, the reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated to obtain a crude product.
- the second step (4-(4-(4-((2,6-dioxa-8-azaspiro[3.5]non-7-en-7-yl)amino)-2,6-difluoro Phenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)(3,3-difluoropyrrolidin-1-yl)methanone (target compound I-14)
- reaction solution was concentrated to obtain a crude product, which was then dissolved in acetonitrile (3 mL), and 3 mL of ammonia water (25%) was added to the reaction solution.
- the reaction solution was stirred at 25°C for 1 hour.
- the reaction solution was diluted with 10 mL of dichloromethane, and the organic phase was washed with water (5 mL ⁇ 3). The organic phase was collected, dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
- Embodiment 15 Preparation of target compound I-15
- the synthetic route of target compound 1-15 is as follows:
- the first step the synthesis of azetidin-1-yl (4-bromophenyl) ketone
- the reaction solution was diluted with dichloromethane (10mL), the organic phase was washed with saturated aqueous sodium bicarbonate (10mL ⁇ 3), the organic phase was collected, washed with 1M aqueous hydrochloric acid (10mL ⁇ 3), the organic phase was collected, washed with anhydrous Na2 Dried over SO 4 , filtered and concentrated to give azetidin-1-yl(4-bromophenyl)methanone (0.7 g, 98% yield) as a yellow oil.
- the third step azetidin-1-yl (4-(4-(4-((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazine-2- Base)amino)-2,6-difluorophenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine Synthesis of -3-yl)phenyl)methanone
- the fourth step azetidin-1-yl (4-(4-(4-((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazine-2- Base) amino)-2,6-difluorophenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (target compound I-15)
- reaction solution was concentrated to obtain a crude product, which was then dissolved in acetonitrile (3 mL), and 3 mL of ammonia water (25%) was added to the reaction solution.
- the reaction solution was stirred at 25°C for 1 hour.
- the reaction solution was diluted with 10 mL of dichloromethane, and the organic phase was washed with water (5 mL ⁇ 3). The organic phase was collected, dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
- Embodiment 16 Preparation of Target Compound I-16
- the synthetic route of target compound 1-16 is as follows:
- the first step cyclopropyl (4-(4-(4-(((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl)amino)- 2,6-difluorophenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl) Synthesis of -3,6-dihydropyridin-1(2H)-yl)methanone
- the second step cyclopropyl (4-(4-(4-((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl)amino)-2 ,6-difluorophenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydropyridin-1(2H)-yl)methanone (target compound I- 16)
- the reaction solution was concentrated to obtain a crude product, which was then dissolved in acetonitrile (3 mL), and 3 mL of ammonia water (25%) was added to the reaction solution.
- the reaction solution was stirred at 25°C for 1 hour.
- the reaction solution was diluted with 10 mL of dichloromethane, and the organic phase was washed with water (5 mL ⁇ 3).
- the organic phase was collected , dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
- Embodiment 17 Preparation of target compound I-17
- the target compound I-17 line is shown below:
- the first step 4-(4-(((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl)amino)-2,6-difluorobenzene Oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclohex-3-ene- Synthesis of methyl 1-carboxylate
- the second step 4-(4-(4-(((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl)amino)-2,6- Difluorophenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclohexyl-3 Synthesis of -ene-1-carboxylic acid
- the reaction solution was concentrated to a crude product. Dissolve the crude product in 20 mL of water, then extract with ethyl acetate (10 mL), collect the aqueous phase, adjust the pH to 3-4, then extract the aqueous phase with ethyl acetate (10 mL ⁇ 3), collect the organic phase, and wash with anhydrous sodium sulfate Dry, filter, and concentrate the filtrate to give a yellow solid 4-(4-(4-(((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl)amino) -2,6-Difluorophenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl ) cyclohex-3-ene-1-carboxylic acid (500 mg, 51.1% yield).
- the third step azetidin-1-yl (4-(4-(4-((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazine-2- Base)amino)-2,6-difluorophenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine Synthesis of -3-yl)cyclohex-3-en-1-yl)methanone
- reaction mixture was stirred at 25°C under nitrogen for 18 hours.
- the fourth step azetidin-1-yl (4-(4-(4-((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazine-2- Base) amino)-2,6-difluorophenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclohexyl-3-en-1-yl)methanone (target compound I -17)
- reaction solution was concentrated to obtain a crude product, which was then dissolved in acetonitrile (3 mL), and 3 mL of ammonia water (25%) was added to the reaction solution.
- the reaction solution was stirred at 25°C for 1 hour.
- the reaction solution was diluted with 10 mL of dichloromethane, and the organic phase was washed with water (5 mL ⁇ 3). The organic phase was collected, dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
- Test Example 1 In vitro enzyme activity inhibition IC50 evaluation test of recombinant HPK1 enzyme
- HPK1 kinase reaction system is 10 ⁇ L, and the final concentrations of each component are as follows: 0.5 nM HPK1 recombinase (Carna, Cat.NO.07-410), small molecule inhibitors with different concentration gradients, 10 mM MgCl 2 , 4 mM DTT, 2.5 ⁇ M ATP , 0.1 ⁇ M FITC-PKC (Invitrogen, Cat. NO. PV3506), 0.01% Tween-20, 0.01% BSA and 50 mM HEPES pH 7.5.
- Inhibition% (max-Lantha signal ratio)/(max-min)*100
- test compound IC 50 (nM) Control compound 1 18.1 I-1 0.70 I-2 0.40 I-3 0.72 I-4 0.66 I-5 0.74 I-6 0.63 I-7 0.82 I-8 0.41 I-9 0.62 I-10 0.81 I-11 2.28
- Test Example 2 Jurkat phospho-SLP76(Ser376) ELISA test
- Jurkat cells were used to evaluate the inhibitory activity of the compounds synthesized in Examples 1-17 on intracellular HPK1 enzyme activity.
- the cells were cultured with RPMI1640 complete medium (RPMI-1640, 10% fetal bovine serum, 1% Pen/Strep).
- the inhibition rate was calculated by the following formula, and then the log value of the concentration of the compound was plotted on the X axis, and the inhibition rate was drawn on the Y axis, and the IC 50 was calculated with Graphpad 7.0.
- Inhibition% (max-compound well absorbance value)/(max-min)*100
- test compound IC 50 (nM) Control compound 1 656 I-1 182 I-2 49.1 I-3 174 I-4 386 I-5 366
- the result of cell test shows that the compound of the invention has good inhibitory effect on HPK1 enzyme, and the inhibitory activity is significantly better than that of the control compound.
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Abstract
式I所示的作为HPK1抑制剂的化合物、包含该化合物的药物组合物以及该化合物在制备药物中的用途。
Description
本发明属于医药化学领域,具体的,本发明涉及HPK1抑制剂及其应用,更具体的,本发明涉及一种吡咯并吡啶类化合物及其制备方法,以及其在制备药物中的用途。
造血祖细胞激酶(Hematopoietic progenitor kinase I)HPK1,也称MAP4K1,基因ID:11184,位于:19q13.1-q13.4,属于哺乳动物Ste20样丝氨酸/苏氨酸激酶家族中的MAP激酶激酶激酶激酶(MAP4K,MAP kinase kinase kinase kinases)。
HPK1是TCR(T细胞受体)信号和T细胞介导的免疫应答的负调节因子。在TCR激活时,细胞质HPK1被募集到质膜,通过其Y381、S171和T165的磷酸化被完全激活,激活的HPK1磷酸化衔接蛋白SLP76,为负性调节因子14-3-3提供一个结合位点,最终破坏TCR信号复合物(Lat-Gads-SLP76)的稳定,阻断T细胞活化和增殖所需的下游丝裂原活化蛋白(MAP)激酶(MAPK)信号(Hernandez S et al.,Cell Reports,2018,25(1):80-94.)。在HPK1过表达和基因敲除研究中,HPK1负性调节T细胞MAPK信号通路和AP-1(激活蛋白-1)转录(Liou J et al.Immunity,2000,12(4):399-408.)。HPK1
-/-小鼠表现出T细胞增殖能力增强,IL-2、IL-4和干扰素(IFN)–γ分泌增加,对前列腺素的抑制效果敏感性降低,T细胞激活的阈值降低等效应(Shui,JW.,Boomer,J.,Han,J.et al.Nat Immunol 8,84–91(2007).)。
与T细胞机制类似,HPK1同样负性调节BCR(B细胞受体)信号,HPK1
-/-小鼠B细胞对一系列刺激表现出高度反应,HPK1活性的丧失与免疫应答中产生的更高滴度的IgG1和IgG2b相关。另外,HPK1还发挥在NK(自然杀伤)细胞介导的新抗原释放中具有抑制作用,抑制脂多糖(LPS)刺激的树突状细胞(DC)成熟等多重效应(Liu J et al.PLoS ONE,2019,14(3):e0212670.)。HPK1不仅负性调节T细胞功能,对多种免疫细胞都有负性调节作用,抑制其活性,能从多个节点促进免疫反应。
基于HPK1对免疫反应的负调控作用,抑制其活力将具有明显的抗肿瘤作用。野生型和HPK1
-/-小鼠分别静脉注射给予Lewis肺癌肿瘤细胞株(3LL)后,与野生型小鼠相比,HPK1
-/-小鼠的肿瘤数量和大小较小,这种肿瘤抑制作用是由T细胞介导的;当HPK1
-/-小鼠脾细胞与3LL细胞共培养时,其对3LL细胞的杀伤效果是野生型脾细胞的5倍;在向T细胞缺陷型小鼠静脉注射野生型或HPK1
-/-的T细胞后,注射HPK1
-/-T细胞的小鼠的肺部肿瘤数量和大小
相比注射野生型T细胞的小鼠明显减少(Si J,Shi X,Sun S,et al.Cancer Cell,2020,38(4).)。这些试验结果都表明,降低HPK1水平可增强T细胞的抗肿瘤反应,HPK1的抑制剂具有作为抗肿瘤药物的潜力。
另外,MAP4K1表达与T细胞耗竭相关的信号分子(如:PD-1、TIGIT、CTLA4、LAG3等)呈现很强的正相关性,在低级别胶质瘤(LGG)、浸润性乳腺癌(BRAC)等肿瘤中显著的表现出MAP4K1低表达的患者有着更长的生存期。在临床上的多发性骨髓瘤组织活检中测量T细胞中HPK1与免疫抑制分子的蛋白表达情况,发现在耗竭的T细胞中,HPK1的表达上调。这些结果表明HPK1在人体上也是调节T细胞耗竭并抑制抗肿瘤免疫反应的一个重要激酶(Sawasdikosol S et al.Immunologic Research,2012,54(1-3):262-265.),其小分子抑制剂可能可用于肿瘤的治疗。
HPK1调控的免疫抑制途径与PD-1/L1(程序性死亡受体1/程序性死亡受体-配体1)不同,提示HPK1的小分子抑制剂可以与PD-1/L1的抑制剂/抗体联合使用。HPK1的抑制剂和抗PD-1/L1抗体联用能增强抗病毒和抗肿瘤作用,HPK1抑制剂能够抑制肿瘤生长并增强PD-L1的药效,另一项研究表明联合阻断HPK1和PD-L1能够增强抗肿瘤T细胞应答(Hernandez S et al.,Cell Reports,2018,25(1):80-94.)。这些都证明了HPK1的小分子抑制剂能与抗PD-1/L1抗体联用,以获得更优的抗病毒和抗肿瘤药效。
MAP4K中除了MAP4K1/HPK1外,还包括MAP4K2/GCK、MAP4K3/GLK、MAP4K4/HGK、MAP4K5/KHS和MAP4K6/MINK,共6个结构相近的亚型(Chuang H C et al.Advances in Immunology,2016,129:277-314.)。研究表明抑制MAP4K3、MAP4K5等亚型存在明显的毒副作用,因此选择性HPK1抑制剂具有更好的安全性;另外,对HPK1的Northern印迹分析表明,除胚胎期以外,HPK1主要在造血相关细胞中表达,如造血祖细胞、T细胞、B细胞、巨噬细胞、树突状细胞、中性粒细胞和肥大细胞(Kiefer F et al.The EMBO Journal,1996,15(24):7013-7025.),其他组织器官的表达相当有限,这降低了其安全性风险。
目前一些HPK1抑制剂(CFI-402411、BGB-15025)已进入临床阶段,HPK1抑制可能是有希望的肿瘤免疫疗法。
发明内容
本发明旨在提出一种新的HPK1抑制剂,可用于制备治疗HPK1相关疾病的药物。
本发明的第一方面,本发明提出了一种化合物,为式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:
其中,
R
1独立地为H、氰基、卤素、被1-5个相同或不同的卤素取代的C
1-C
6烷基、C
1-C
6烷基、C
3-C
6环烷基或-O-(C
1-C
6烷基);
环A独立地为6-10元芳基、5-8元杂芳基、4-8元杂环烷基、4-8元杂环烯基或C
3-C
10环烯基;
R
21和R
22各自独立地为未取代或被R
211取代的C
1-C
6烷基、或、未取代或被R
211取代的C
3-C
6环烷基;所述的被R
211取代的C
1-C
6烷基或被R
211取代的C
3-C
6环烷基中,所述的R
211取代可以是一个或多个取代,所述的R
211各自独立地为下列取代基:羟基、卤素、-O-(C
1-C
6烷基)、C
1-C
6烷氨基或C
3-C
6环烷基;当取代基为多个时,所述的取代基相同或不同;所述R
21和R
22至少一个为被R
211取代的C
1-C
6烷基或被R
211取代的C
3-C
6环烷基;
环B独立地为未取代或被R
23取代的4-8元杂环烷基、或、未取代或被R
23取代的6-11元杂螺环烷基;所述的被R
23取代的4-8元杂环烷基或被R
23取代的6-11元杂螺环烷基中,所述的R
23取代可以是一个或多个取代,所述R
23各自独立地为下列取代基:羟基、氰基、卤素、被1-5个相同或不同的卤素取代的C
1-C
6烷基、C
1-C
6烷基或C
3-C
6环烷基;当取代基为多个时,所述的取代基相同或不同;
R
24独立地为未取代或被R
241取代的C
3-C
6环烷基;所述的被R
241取代的C
3-C
6环烷基中,所述的R
241取代可以是一个或多个取代,所述R
241各自独立地为下列取代基:氰基、卤素、被1-5个相同或不同的卤素取代的C
1-C
6烷基、C
1-C
6烷基或C
3-C
6环烷基;当取代基为多个时,所述的取代基相同或不同;
R
3独立地为卤素、CN、被1-5个相同或不同的卤素取代的C
1-C
6烷基或C
1-C
6烷基;
n为0、1、2或3;
R
4和R
5各自独立地为被1-5个相同或不同的卤素取代的C
1-C
6烷基或C
1-C
6烷基;或R
4 和R
5与其共同相连的碳原子可以形成4-8元环烷基或4-8元杂环烷基。
在本发明一些实施方案中,本发明提出了一种化合物,为式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:
其中,
R
1独立地为H、氰基、卤素、被1-5个相同或不同的卤素取代的C
1-C
6烷基、C
1-C
6烷基、C
3-C
6环烷基或-O-(C
1-C
6烷基);
环A独立地为6-10元芳基、5-8元杂芳基、4-8元杂环烷基、4-8元杂环烯基或C
3-C
10环烯基;
R
21和R
22各自独立地为未取代或被R
211取代的C
1-C
6烷基、或、未取代或被R
211取代的C
3-C
6环烷基;所述的被R
211取代的C
1-C
6烷基或被R
211取代的C
3-C
6环烷基中,所述的R
211取代可以是一个或多个取代,所述的R
211各自独立地为下列取代基:羟基、卤素、-O-(C
1-C
6烷基)、C
1-C
6烷氨基或C
3-C
6环烷基;当取代基为多个时,所述的取代基相同或不同;所述R
21和R
22至少一个为被R
211取代的C
1-C
6烷基或被R
211取代的C
3-C
6环烷基;
环B独立地为未取代或被R
23取代的4-8元杂环烷基、或、未取代或被R
23取代的6-11元杂螺环烷基;所述的被R
23取代的4-8元杂环烷基或被R
23取代的6-11元杂螺环烷基中,所述的R
23取代可以是一个或多个取代,所述R
23各自独立地为下列取代基:羟基、氰基、卤素、被1-5个相同或不同的卤素取代的C
1-C
6烷基、C
1-C
6烷基或C
3-C
6环烷基;当取代基为多个时,所述的取代基相同或不同;
R
24独立地为未取代或被R
241取代的C
3-C
6环烷基;所述的被R
241取代的C
3-C
6环烷基中,所述的R
241取代可以是一个或多个取代,所述R
241各自独立地为下列取代基:氰基、卤素、被1-5个相同或不同的卤素取代的C
1-C
6烷基、C
1-C
6烷基或C
3-C
6环烷基;当取代基为多个时,所述的取代基相同或不同;
R
3独立地为卤素、被1-5个相同或不同的卤素取代的C
1-C
6烷基或C
1-C
6烷基;
n为0、1、2或3;
R
4和R
5各自独立地为被1-5个相同或不同的卤素取代的C
1-C
6烷基或C
1-C
6烷基;或R
4和R
5与其共同相连的碳原子可以形成4-8元杂环烷基。
在本发明一些实施方案中,R
3为CN。
在本发明一些实施方案中,R
4和R
5与其共同相连的碳原子可以形成4-8元环烷基。
在本发明一优选实施方案中,所述化合物为如式II所示的结构、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药。
其中,R
2、R
4、R
5和环A的定义如本发明所述。
在本发明一优选实施方案中,所述化合物为如式III或IV所示的结构、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药。
其中,R
2、R
24、R
4和R
5的定义如本发明所述;
环C独立地为5-8元杂芳基、4-8元杂环烷基或4-8元杂环烯基。
在本发明一优选实施方案中,所述化合物为如式(V)或式(VI)所示结构、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药。
环B、R
4、R
5、R
21、R
22和R
24的定义如本发明所述。
在本发明一优选实施方案中,当环A为6-10元芳基时,所述6-10元芳基为苯或萘,较佳地为苯。
在本发明一优选实施方案中,当环A为5-8元杂芳基时,所述5-8元杂芳基为吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、噻唑基、噻二唑基、吡啶基、吡嗪基、吡唑基、哒嗪基、嘧啶基或三嗪基,较佳地为吡咯基、噁唑基、噻唑基或吡啶基。
在本发明一优选实施方案中,当环A为4-8元杂环烷基时,所述4-8元杂环烷基为氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、吡唑烷基、咪唑烷基、噁唑烷基、吗啉基、吡咯烷基、吗啉基或哌嗪基,较佳地为氮杂环丁基、吗啉基或吗啉基。
在本发明一优选实施方案中,当环A为4-8元杂环烯基时,所述4-8元杂环烯基为4H-吡喃基、2H-吡喃基、四氢吡啶基、2,5-二氢-1H-吡咯基、2,5-二氢呋喃基、2,3-二氢呋喃基、2,5-二氢噻吩基、2,3-二氢噻吩基或4,5-二氢噁唑基,较佳地为四氢吡啶基。
在本发明一优选实施方案中,当环A为C
3-C
10环烯基时,所述C
3-C
10环烯基为环丙烯基、环丁烯基、环戊烯基、环己烯基或环庚烯基,较佳地为环己烯基。
在本发明一优选实施方案中,当R
21和R
22为未取代或被R
211取代的C
1-C
6烷基时,所述C
1-C
6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或仲丁基,较佳地为甲基、乙基、正丙基或异丁基。
在本发明一优选实施方案中,当R
21和R
22为未取代或被R
211取代的C
3-C
6环烷基时,所述C
3-C
6环烷基为环丙基、环丁基、环戊基或环己基,较佳地为环丙基或环丁基。
在本发明一优选实施方案中,R
21和R
22为被R
211取代的C
1-C
6烷基或被R
211取代的C
3-C
6环烷基时,所述R
211取代个数为1个、2个、3个、4个或5个,较佳地为1个或2个。
在本发明一优选实施方案中,R
211为羟基。
在本发明一优选实施方案中,当R
211为卤素时,所述卤素为F、Cl、Br或I,较佳地为F或Cl。
在本发明一优选实施方案中,当R
211为-O-(C
1-C
6烷基)时,所述C
1-C
6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,较佳地为甲基、乙基、正丙基或异丙基。
在本发明一优选实施方案中,当R
211为-O-(C
1-C
6烷基)时,所述-O-(C
1-C
6烷基)为-O-甲基、-O-乙基、-O-正丙基、-O-异丙基、-O-正丁基、-O-异丁基、-O-仲丁基或-O-叔丁基,较佳地为-O-甲基、-O-乙基、-O-正丙基或-O-异丙基。
在本发明一优选实施方案中,当R
211为C
1-C
6烷氨基时,所述C
1-C
6烷氨基为-NHCH
3、-N(CH
3)
2、-NHCH
2CH
3、-N(CH
3)CH
2CH
3、-NHCH
2CH
2CH
3或-NHCH
2(CH
3)
2,较佳地为-NHCH
3、-N(CH
3)
2或-NHCH
2CH
3。
在本发明一优选实施方案中,当R
211为C
3-C
6环烷基时,所述C
3-C
6环烷基为环丙基、环丁基、环戊基或环己基,较佳地为环丙基或环丁基。
在本发明一优选实施方案中,当环B为未取代或被R
23取代的4-8元杂环烷基时,所述4-8元杂环烷基为氮杂环丙基、氮杂环丁基、氮杂环戊基、氮杂环己基、吡咯烷基、吡唑烷基、咪唑烷基、噁唑烷基、吗啉基、吡咯烷基、哌啶基或哌嗪基,较佳地为氮杂环丁基、氮杂环戊基或吗啉基。
在本发明一优选实施方案中,当环B为4-8元杂环烷基时,所述4-8元杂环烷基为氮杂环丙基、氮杂环丁基、氮杂环戊基、氮杂环己基、吡咯烷基、吡唑烷基、咪唑烷基、噁唑烷基、吗啉基、吡咯烷基、哌啶基或哌嗪基,较佳地为氮杂环丁基、氮杂环戊基或吗啉基。
在本发明一优选实施方案中,当环B为未取代或被R
23取代的6-11元杂螺环烷基时,所述6-11元杂螺环烷基较佳地为氮杂螺[3.3]庚基、氧杂氮杂螺[3.3]庚基、硫杂氮杂螺[3.3]庚基 或氧氮杂螺[5.3]壬基,更佳地为氧杂氮杂螺[3.3]庚基。
在本发明一优选实施方案中,当环B为6-11元杂螺环烷基时,所述6-11元杂螺环烷基较佳地为氮杂螺[3.3]庚基、氧杂氮杂螺[3.3]庚基、硫杂氮杂螺[3.3]庚基或氧氮杂螺[5.3]壬基,更佳地为氧杂氮杂螺[3.3]庚基。
在本发明一优选实施方案中,环B为被R
23取代的4-8元杂环烷基或被R
23取代的6-11元杂螺环烷基时,所述R
23取代个数为1个、2个、3个、4个或5个,较佳地为1个或2个。
在本发明一优选实施方案中,R
23为羟基。
在本发明一优选实施方案中,R
23为氰基。
在本发明一优选实施方案中,当R
23为卤素时,所述卤素为F、Cl、Br或I,较佳地为F或Cl。
在本发明一优选实施方案中,当R
23为被1-5个相同或不同的卤素取代的C
1-C
6烷基时,所述C
1-C
6烷基为甲基、乙基、正丙基或异丙基,较佳地为甲基或乙基。
在本发明一优选实施方案中,当R
23为被1-5个相同或不同的卤素取代的C
1-C
6烷基时,所述卤素为F、Cl、Br或I,较佳地为F或Cl。
在本发明一优选实施方案中,当R
23为被1-5个相同或不同的卤素取代的C
1-C
6烷基时,所述卤素的个数为1个、2个、3个、4个或5个,较佳地为1个、2个或3个。
在本发明一优选实施方案中,当R
23为C
1-C
6烷基时,所述C
1-C
6烷基为甲基、乙基、正丙基或异丙基,较佳地为甲基。
在本发明一优选实施方案中,当R
23为C
3-C
6环烷基时,所述C
3-C
6环烷基为环丙基、环丁基、环戊基或环己基,较佳地为环丙基或环丁基。
在本发明一优选实施方案中,当R
24为未取代或被R
241取代的C
3-C
6环烷基时,所述C
3-C
6环烷基为环丙基、环丁基、环戊基或环己基,较佳地为环丙基或环丁基。
在本发明一优选实施方案中,当R
24为未取代或被R
241取代的C
3-C
6环烷基时,所述R
241取代个数为1个、2个、3个、4个或5个,较佳地为1个或2个。
在本发明一优选实施方案中,R
241为氰基。
在本发明一优选实施方案中,当R
241为卤素时,所述卤素为F、Cl、Br或I,较佳地为F或Cl。
在本发明一优选实施方案中,当R
241为被1-5个相同或不同的卤素取代的C
1-C
6烷基时,所述C
1-C
6烷基为甲基、乙基、正丙基或异丙基,较佳地为甲基或乙基。
在本发明一优选实施方案中,当R
241为被1-5个相同或不同的卤素取代的C
1-C
6烷基时,所述卤素为F、Cl、Br或I,较佳地为F或Cl。
在本发明一优选实施方案中,当R
241为被1-5个相同或不同的卤素取代的C
1-C
6烷基时,所述卤素的个数为1个、2个、3个、4个或5个,较佳地为1个、2个或3个。
在本发明一优选实施方案中,当R
241为C
1-C
6烷基时,所述C
1-C
6烷基为甲基、乙基、正丙基或异丙基,较佳地为甲基或乙基。
在本发明一优选实施方案中,当R
241为C
3-C
6环烷基时,所述C
3-C
6环烷基为环丙基、环丁基、环戊基或环己基,较佳地为环丙基或环丁基。
在本发明一优选实施方案中,n为0、1或2。
在本发明一优选实施方案中,当R
3为卤素时,所述卤素为F、Cl、Br或I,较佳地为F或Cl。
在本发明一优选实施方案中,当R
3为被1-5个相同或不同的卤素取代的C
1-C
6烷基时,所述C
1-C
6烷基为甲基、乙基、正丙基或异丙基,较佳地为甲基或乙基。
在本发明一优选实施方案中,当R
3为被1-5个相同或不同的卤素取代的C
1-C
6烷基时,所述卤素为F、Cl、Br或I,较佳地为F或Cl。
在本发明一优选实施方案中,当R
3为被1-5个相同或不同的卤素取代的C
1-C
6烷基时,所述卤素的个数为1个、2个、3个、4个或5个,较佳地为1个、2个或3个。
在本发明一优选实施方案中,当R
3为C
1-C
6烷基时,所述C
1-C
6烷基为甲基、乙基、正丙基或异丙基,较佳地为甲基或乙基。
在本发明一优选实施方案中,当R
4和R
5为C
1-C
6烷基时,所述C
1-C
6烷基为甲基、乙基、正丙基或异丙基,较佳地为甲基。
在本发明一优选实施方案中,当R
4和R
5为被1-5个相同或不同的卤素取代的C
1-C
6烷基时,所述C
1-C
6烷基为甲基、乙基、正丙基或异丙基,较佳地为甲基或乙基。
在本发明一优选实施方案中,当R
4和R
5为被1-5个相同或不同的卤素取代的C
1-C
6烷基时,所述卤素为F、Cl、Br或I,较佳地为F或Cl。
在本发明一优选实施方案中,当R
4和R
5为被1-5个相同或不同的卤素取代的C
1-C
6烷基时,所述卤素的个数为1个、2个、3个、4个或5个,较佳地为1个、2个或3个。
在本发明一优选实施方案中,R
4和R
5与其共同相连的碳原子形成4-8元杂环烷基时,所述4-8元杂环烷基为氮杂环丙基、氧杂环丙基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、吡咯烷基、四氢呋喃基、吡唑烷基、咪唑烷基、噁唑烷基、吗啉基、吡咯烷基、哌啶基或哌嗪基,较佳地为氧杂环丁基。
在本发明一优选实施方案中,R
1为H。
在本发明一优选实施方案中,R
4和R
5为甲基。
在本发明一优选实施方案中,所述化合物为如式III所示结构、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:
R
21和R
22各自独立地为未取代或被R
211取代的C
1-C
6烷基、或、未取代或被R
211取代的C
3-C
6环烷基;所述的被R
211取代的C
1-C
6烷基或被R
211取代的C
3-C
6环烷基中,所述的R
211取代可以是一个或多个取代,所述的R
211各自独立地为下列取代基:羟基、卤素、-O-(C
1-C
6烷基)、C
1-C
6烷氨基或C
3-C
6环烷基;当取代基为多个时,所述的取代基相同或不同;所述R
21和R
22至少一个为被R
211取代的C
1-C
6烷基或被R
211取代的C
3-C
6环烷基;
环B独立地为未取代或被R
23取代的4-8元杂环烷基、或、未取代或被R
23取代的6-11元杂螺环烷基;所述的被R
23取代的4-8元杂环烷基或被R
23取代的6-11元杂螺环烷基中,所述的R
23取代可以是一个或多个取代,所述R
23各自独立地为下列取代基:羟基、氰基、卤素、被1-5个相同或不同的卤素取代的C
1-C
6烷基、C
1-C
6烷基或C
3-C
6环烷基;当取代基为多个 时,所述的取代基相同或不同;
R
4和R
5各自独立地为被1-5个相同或不同的卤素取代的C
1-C
6烷基或C
1-C
6烷基;或R
4和R
5与其共同相连的碳原子可以形成4-8元杂环。
在本发明一优选实施方案中,所述化合物为如式IV所示结构、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药为:
环C独立地为4-8元杂环烯基;
R
24独立地为未取代或被R
241取代的C
3-C
6环烷基;所述的被R
241取代的C
3-C
6环烷基中,所述的R
241取代可以是一个或多个取代,所述R
241各自独立地为下列取代基:氰基、卤素、被1-5个相同或不同的卤素取代的C
1-C
6烷基、C
1-C
6烷基或C
3-C
6环烷基;当取代基为多个时,所述的取代基相同或不同;
R
4和R
5各自独立地为被1-5个相同或不同的卤素取代的C
1-C
6烷基或C
1-C
6烷基;或R
4和R
5与其共同相连的碳原子可以形成4-8元杂环。
在本发明一优选实施方案中,所述化合物为如式II所示结构、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药为:
环A独立地为C
3-C
10环烯基;
R
21和R
22各自独立地为未取代或被R
211取代的C
1-C
6烷基、或、未取代或被R
211取代的 C
3-C
6环烷基;所述的被R
211取代的C
1-C
6烷基或被R
211取代的C
3-C
6环烷基中,所述的R
211取代可以是一个或多个取代,所述的R
211各自独立地为下列取代基:羟基、卤素、-O-(C
1-C
6烷基)、C
1-C
6烷氨基或C
3-C
6环烷基;当取代基为多个时,所述的取代基相同或不同;所述R
21和R
22至少一个为被R
211取代的C
1-C
6烷基或被R
211取代的C
3-C
6环烷基;
环B独立地为未取代或被R
23取代的4-8元杂环烷基、或、未取代或被R
23取代的6-11元杂螺环烷基;所述的被R
23取代的4-8元杂环烷基或被R
23取代的6-11元杂螺环烷基中,所述的R
23取代可以是一个或多个取代,所述R
23各自独立地为下列取代基:羟基、氰基、卤素、被1-5个相同或不同的卤素取代的C
1-C
6烷基、C
1-C
6烷基或C
3-C
6环烷基;当取代基为多个时,所述的取代基相同或不同;
R
4和R
5各自独立地为被1-5个相同或不同的卤素取代的C
1-C
6烷基或C
1-C
6烷基;或R
4和R
5与其共同相连的碳原子可以形成4-8元杂环。
在本发明一优选实施方案中,所述化合物为如式V所示结构、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,
环B独立地为未取代或被R
23取代的4-8元杂环烷基、或、未取代或被R
23取代的6-11元杂螺环烷基;所述的被R
23取代的4-8元杂环烷基或被R
23取代的6-11元杂螺环烷基中,所述的R
23取代可以是一个或多个取代,所述R
23各自独立地为下列取代基:羟基、氰基、卤素、被1-5个相同或不同的卤素取代的C
1-C
6烷基、C
1-C
6烷基或C
3-C
6环烷基;当取代基为多个时,所述的取代基相同或不同;
R
21和R
22各自独立地为未取代或被R
211取代的C
1-C
6烷基、或未取代或被R
211取代的C
3-C
6环烷基;所述的被R
211取代的C
1-C
6烷基或被R
211取代的C
3-C
6环烷基中,所述的R
211取代可以是一个或多个取代,所述的R
211各自独立地为下列取代基:羟基、卤素、-O-(C
1-C
6烷基)、C
1-C
6烷氨基或C
3-C
6环烷基;当取代基为多个时,所述的取代基相同或不同;所述R
21和R
22 至少一个为被R
211取代的C
1-C
6烷基或被R
211取代的C
3-C
6环烷基;
R
24独立地为未取代或被R
241取代的C
3-C
6环烷基;所述的被R
241取代的C
3-C
6环烷基中,所述的R
241取代可以是一个或多个取代,所述R
241各自独立地为下列取代基:氰基、卤素、被1-5个相同或不同的卤素取代的C
1-C
6烷基、C
1-C
6烷基或C
3-C
6环烷基;当取代基为多个时,所述的取代基相同或不同;
R
4和R
5各自独立地为被1-5个相同或不同的卤素取代的C
1-C
6烷基或C
1-C
6烷基;或R
4和R
5与其共同相连的碳原子可以形成4-8元环烷基或4-8元杂环烷基。
在本发明一优选实施方案中,所述化合物为如式VI所示结构、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,
R
4和R
5各自独立地为被1-5个相同或不同的卤素取代的C
1-C
6烷基或C
1-C
6烷基;或R
4和R
5与其共同相连的碳原子可以形成4-8元环烷基或4-8元杂环烷基。
在本发明一优选实施方案中,所述化合物为如式V-1或V-2所示结构、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,
其中,R
21和R
22各自独立地为未取代或被R
211取代的C
1-C
6烷基;
环D为6-10元芳基或C
3-C
10环烯基;
环B独立地为未取代或被R
23取代的4-8元杂环烷基、或、未取代或被R
23取代的6-11元杂螺环烷基;所述的被R
23取代的4-8元杂环烷基或被R
23取代的6-11元杂螺环烷基中,所述的R
23取代可以是一个或多个取代,所述R
23各自独立地为下列取代基:羟基、氰基、卤素、 被1-5个相同或不同的卤素取代的C
1-C
6烷基、C
1-C
6烷基或C
3-C
6环烷基;当取代基为多个时,所述的取代基相同或不同;
R
4和R
5各自独立地为被1-5个相同或不同的卤素取代的C
1-C
6烷基或C
1-C
6烷基;或R
4和R
5与其共同相连的碳原子可以形成4-8元环烷基或4-8元杂环烷基。
在本发明一优选实施方案中,所述化合物为如式V-1a、V-1b、V-2a或V-2b所示结构、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,
其中,R
21和R
22各自独立地为未取代或被R
211取代的C
1-C
6烷基;
R
41和R
51各自独立地为被1-5个相同或不同的卤素取代的C
1-C
6烷基或C
1-C
6烷基;
环E为4-8元环烷基或4-8元杂环烷基;
环D为6-10元芳基或C
3-C
10环烯基;
环B独立地为未取代或被R
23取代的4-8元杂环烷基、或、未取代或被R
23取代的6-11元杂螺环烷基;所述的被R
23取代的4-8元杂环烷基或被R
23取代的6-11元杂螺环烷基中,所述的R
23取代可以是一个或多个取代,所述R
23各自独立地为下列取代基:羟基、氰基、卤素、被1-5个相同或不同的卤素取代的C
1-C
6烷基、C
1-C
6烷基或C
3-C
6环烷基;当取代基为多个时,所述的取代基相同或不同。
在本发明一优选实施方案中,所述化合物具有如下所示结构、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:
本发明的第二方面,本发明提出了一种药物组合物,所述药物组合物包括治疗有效剂量的上述化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药以及药学上可接受的赋形剂。
根据本发明的具体实施例,可以将本发明的所述药物组合物包括治疗有效剂量的上述化合物,其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药以及药学上可接受的药用载体、稀释剂或赋形剂混合制备成药物制剂,以适合于经口或胃肠外给药。给药方法包括,但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内和经口途径。所述制剂可以通过任何途径施用,例如通过输注或推注,通过经上皮或皮肤粘膜(例如口腔粘膜或直肠等)吸收的途径施用。给药可以是全身的或局部的。经口施用制剂的实例包括固体或液体剂型,具体而言,包括片剂、丸剂、粒剂、粉剂、胶囊剂、糖浆、乳剂、混悬剂等。所述制剂可通过本领域已知的方法制备,且包含药物制剂领域常规使用的载体、稀释剂或赋形剂。
本发明的第三方面,本发明提出了上述化合物、或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药与PD-1/PD-L1/CTLA-4抗体或者PD-1/PD-L1/CTLA-4抑制剂联用在制备用于治疗或预防与HPK1相关疾病药物中的用途,所述药物可用于治疗或与预防实体瘤、血液癌症、非小细胞肺癌、小细胞肺癌、皮肤黑色素瘤、梅克尔细胞癌、头颈部鳞状细胞癌、肛管或皮肤的鳞状细胞癌、尿路上皮癌、透明细胞或非透明细胞肾细胞癌、三阴性乳腺癌、子宫内膜癌、宫颈癌、胃食管癌或肝细胞癌。
本发明的第四方面,本发明提出了上述化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或上述药物组合物在制备用于治疗或预防与HPK1相关疾病药物中的用途。
根据本发明的具体实施例,上述化合物或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或上述药物组合物在制备治疗或预防与HPK1相关疾病药物中的用途,所述药物可用于治疗实体瘤、血液癌症、非小细胞肺癌、小细胞肺癌、皮肤黑色素瘤、梅克尔细胞癌、头颈部鳞状细胞癌、肛管或皮肤的鳞状细胞癌、尿路上皮癌、透明细胞或非透明细胞肾细胞癌、三阴性乳腺癌、子宫内膜癌、宫颈癌、胃食管癌或肝细胞癌。
本发明的第五方面,本发明提出了一种治疗或预防HPK1相关疾病的方法。根据本发明的实施例,所述方法包括给与患者药学上可接受的上述化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或上述药物组合物。
根据本发明的具体实施例,上述化合物或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或上述药物组合物在制备治疗或预防与HPK1相关疾病药物中的用途,所述药物可用于治疗实体瘤、血液癌症、非小细胞肺癌、小细胞肺癌、皮肤黑色素瘤、梅克尔细胞癌、头颈部鳞状细胞癌、肛管或皮肤的鳞状细胞癌、尿路上皮癌、透明细胞或非透明细胞肾细胞癌、三阴性乳腺癌、子宫内膜癌、宫颈癌、胃食管癌或肝细胞癌。
在本发明的第六方面,本发明提出了前面所述的化合物、其互变异构体、立体异构体、 水合物、溶剂化物、药学上可接受的盐或前药、或药物组合物,用于治疗或预防与HPK1相关疾病。
根据本发明的具体实施例,所述HPK1相关疾病包括选自下列的至少之一:实体瘤、血液癌症、非小细胞肺癌、小细胞肺癌、皮肤黑色素瘤、梅克尔细胞癌、头颈部鳞状细胞癌、肛管或皮肤的鳞状细胞癌、尿路上皮癌、透明细胞或非透明细胞肾细胞癌、三阴性乳腺癌、子宫内膜癌、宫颈癌、胃食管癌和肝细胞癌。
术语和定义
除非另有说明,用于本发明申请,包括本申请说明书和权利要求书中记载的术语和定义如下。
术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
术语“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐,包括无机酸和碱、有机酸和碱的盐。
除了药学可接受的盐外,本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。
术语“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐或前体药物与其它化学组分的混合物,其它组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药。
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性,即通过增加流动性和/或粘着性使制剂更适于直接压缩。
术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备,该修饰可以按常规的操作或者在体内被除去,而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物,当本发明化合物的前药被施予哺乳动物个体时,前药被割裂而分别形成游离的羟基、游离的氨基。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体、非对应异构体和构象异构体。
依据原料和方法的选择,本发明化合物可以以可能的异构体中的一个或它们的混合物的形式存在,例如作为纯旋光异构体,或作为异构体混合物,如作为外消旋和非对映异构体混合物,这取决于不对称碳原子的数量。当描述具有光学活性的化合物时,使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号,其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。就给定的化学结构而言,除了这些立体异构体互为镜像外,这些立体异构体是相同的。具体的立体异构体也可称为对映异构体,并且所述异构体的混合物通常称作对映异构体的混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体,当在化学反应或方法中没有立体选择性或立体特异性时,可出现所述外消旋混合物或外消旋体。烯烃、C=N双键等的许多几何异构体也可以存在于本文所述的化合物中,且所有这种稳定的异构体在本发明中均被考虑。当本文所描述化合物含有烯双键时,除非另外说明,否则,这种双键包括E和Z几何异构体。如果化合物中含有二取代的环烷基,环烷基的取代基可能为顺式或反式(cis-或trans-)构型。
当将本发明式中与手性碳的键描写直成线时,应当理解为,手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。本文中消旋体或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。除非另有说明,用楔形键和虚线键表示一个立体中心的绝对构型。
旋光性的(R)-或(S)-异构体可使用手性合成子或手性制剂制备,或使用常规技术拆分。含有不对称取代的碳原子的本发明化合物能够以旋光活性形式或外消旋形式分离。化合物的外消旋混合物的拆分可以通过本领域已知的许多方法中的任一种来进行。示例性方法包括使用手性拆分酸的分级重结晶,该手性拆分酸是旋光活性的成盐有机酸。用于分级重结晶方法的适合的拆分剂例如是旋光活性酸,例如酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、扁桃酸、苹果酸、乳酸或各种旋光活性樟脑磺酸如β-樟脑磺酸的D和L形式。适合于分级结晶方法的其它的拆分剂包括立体异构纯形式的α-甲基-苄胺(例如,S和R形式或者非对映异构纯形式)、2-苯基甘氨醇、降麻黄碱、麻黄碱、N-甲基麻黄碱、环己基乙胺、1,2-二氨基环己烷等。外消旋混合物的拆分还可以通过在填充有旋光活性拆分剂(例如,二硝基苯甲酰基苯基甘氨酸)的色谱柱上洗脱来进行。可以采用高效液相色谱(HPLC)法也可以采用超临界流体色谱法(SFC)进行。具体方法的选择以及洗脱条件、色谱柱的选择可以由本领域技术人员根据化合物的结构以及试验结果选择。进一步的,还可以使用已知构型的光学纯的起始原料或试剂,通 过立体有机合成,获得本发明所描述化合物的任何对映体或非对映体。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在,尝试分离单一互变异构体时通常产生一种混合物,其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如,在很多脂族醛和酮如乙醛中,酮型占优势;而在酚中,烯醇型占优势。本发明包含化合物的所有互变异构形式。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氘(
2H),氚(
3H),碘-125(
125I)或C-14(
14C)。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
针对药物或药理学活性剂而言,术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型,组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异,取决于受体的年龄和一般情况,也取决于具体的活性物质,个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”,“活性物质”或“活性剂”是指一种化学实体,它可以有效地治疗目标紊乱、疾病或病症。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代,包括重氢和氢的变体,只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即=O)时,意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代,也可以不被取代,除非另有规定,取代基的种类和数目在化学上可以实现的基础上可以是任意的。
前缀“C
u-C
v”表示接下来的基团具有从u至v个碳原子。例如,“C
1-C
6烷基”表示该烷基具有1至6个碳原子。
术语“C
1-C
6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地,所述基团具有1、2或3个碳原子(“C
1-C
3烷基”), 例如甲基、乙基、正丙基或异丙基。
术语“-O-(C
1-C
6烷基)”应理解为烷基基团通过氧原子与分子其余部分相连,其中“C
1-C
6烷基”具有上述定义。如-O-(甲基)、-O-(乙基)。
术语“C
1-C
6烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C
1-C
6烷氨基的实例包括但不限于-NHCH
3、-N(CH
3)
2、-NHCH
2CH
3、-N(CH
3)CH
2CH
3、-N(CH
2CH
3)(CH
2CH
3)、-NHCH
2CH
2CH
3、-NHCH
2(CH
3)
2、-NHCH
2CH
2CH
2CH
3等。
术语“C
3-C
6环烷基”应理解为表示饱和的一价单环或双环烃环,其具有3~6个碳原子,包括稠合或桥接的多环系统。如环丙基、环丁基、环戊基、环己基。
术语“C
3-C
10环烯基”是指一价单环烃环,其含有一个双键并且其含有3、4、5、6、7、8、9或10个碳原子(“C
3-C
10-环烯基”)。所述C
3-C
10-环烯基是例如单环烃环,例如环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基、环壬烯基或环癸烯基。特别地,所述环烯基含有5、6或7个碳原子(“C
5-C
7-环烯基”)并且是例如环戊烯基、环己烯基或环庚烯基。
术语“4-8元杂环基”、“4-8元杂环”或“4-8元杂环烷基”应理解为表示具有4至8个原子的饱和单环、二环或三环,其中1、2、3、4或5个环原子选自N、O和S,除非另有说明,其可通过碳或氮连接,其中-CH
2-基团任选被-C(O)-代替;及其中除非另有相反说明,环氮原子或环硫原子任选被氧化以形成N-氧化物或S-氧化物或环氮原子任选被季铵化;其中环中的-NH任选被乙酰基、甲酰基、甲基或甲磺酰基取代;及环任选被一个或多个卤素取代。应该理解的是,当杂环基中S原子和O原子的总数超过1时,这些杂原子不彼此相邻。若所述杂环基为二环或三环,则至少一个环可任选为杂芳族环或芳族环,条件是至少一个环是非杂芳族的。若所述杂环基为单环,则其一定不是芳族的。杂环基的实例包括但不限于哌啶基、N-乙酰基哌啶基、N-甲基哌啶基、N-甲酰基哌嗪基、N-甲磺酰基哌嗪基、高哌嗪基、哌嗪基、氮杂环丁烷基、氧杂环丁烷基、吗啉基、四氢异喹啉基、四氢喹啉基、二氢吲哚基、四氢吡喃基、二氢-2H-吡喃基、四氢呋喃基、四氢噻喃基、四氢噻喃-1-氧化物、四氢噻喃-1,1-二氧化物、1H-吡啶-2-酮和2,5-二氧代咪唑烷基。
术语“4-8元杂环烯基”应理解为含有4至8个环原子,优选5至6个环原子的非芳族单环或多环基团,其中,所述4-8元杂环烯基包含选自N、O、S和P中的1至3个杂原子并且含有至少一个碳-碳双键或碳-氮双键。在基团名称中包含的氮杂、氧杂或硫杂是指至少一个氮、氧或硫原子分别地作为环原子。4-8元杂环烯基的氮或硫原子可以任选被氧化成相应的N-氧化物、S-氧化物或S-二氧化物。优选的4-8元杂环烯基包含但不限于1,2,3,4-四氢吡啶基、1,2-二氢吡啶基、1,4-二氢吡啶基、1,2,3,6-四氢吡啶基、1,4,5,6-四氢嘧啶基、2-吡咯啉基、3-吡咯 啉基、2-咪唑啉基、2-吡唑啉基、二氢咪唑基、二氢噁唑基、二氢噁二唑基、二氢噻唑基、3,4-二氢-2H-吡喃基、二氢呋喃基、氟代二氢呋喃基基及其氧化物等。“4-8元杂环烯基”还可包括环上相同碳原子上的两个可用氢原子同时被单一的基团=O取代(即形成羰基)。
术语“6-10元芳基”应理解为具有6-10个碳原子的一价至少有一个环具有芳香性单环、双环或三环烃环,特别是具有6个碳原子的环(“C
6芳基”),例如苯基;当所述6-10元芳基被取代时,其可以为单取代或者多取代。并且,对其取代位点没有限制,例如可以为邻位、对位或间位取代。
术语“6-11元杂螺环烷基”是指总共具有6、7、8、9、10或11个环原子的双环饱和杂环,其中两个环共有一个共同的环碳原子,所述―杂螺环烷基”包含一个或两个相同或不同的选自以下的环杂原子或含杂原子的基团:N、NH、O、S、SO和SO
2;所述杂螺环烷基可通过任何一个碳原子(除了螺碳原子之外)或(如果存在)氮原子与分子的其余部分连接。所述杂螺环烷基为例如氮杂螺[2.3]己基、氮杂螺[3.3]庚基、氧杂氮杂螺[3.3]庚基、硫杂氮杂螺[3.3]庚基、氧杂螺[3.3]庚基、氧杂氮杂螺[5.3]壬基、氧杂氮杂螺[4.3]辛基、氮杂螺[4,5]癸基、氧杂氮杂螺[5.5]十一烷基、二氮杂螺[3.3]庚基、硫杂氮杂螺[3.3]庚基、硫杂氮杂螺[4.3]辛基,或其他同系物骨架之一,例如螺[3.4]-、螺[4.4]-、螺[2.4]-、螺[2.5]-、螺[2.6]-、螺[3.5]-、螺[3.6]-和螺[4.5]-。
术语“5-8元杂芳基”应理解为具有5-8个环原子,特别是5或6个环原子,且包含1-5个独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团。优选1-3个且独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团,并且,另外,还包含具有芳香性的环稠合非芳香性的环的情况。特别地,杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基等;或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等;或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。
术语“卤代基”或“卤素”为氟、氯、溴和碘。
另外,需要说明的是,除非以其他方式明确指出,在本发明中所采用的描述方式“……独立地”应作广义理解,是指所描述的各个个体之间是相互独立的,可以独立地为相同或不同的具体基团。更详细地,描述方式“……独立地”既可以是指在不同基团中,相同符合之间所表达的具体选项之间互相不影响,也可以表示在相同的基团中,相同符号之间所表达的具体选项之间互相不影响。
根据本发明的实施例,本发明至少具有如下技术效果至少之一:
1)提供了结构新颖、药代动力学性质优良、药效或成药性好的HPK1抑制剂,可以用于有效治疗或预防HPK1相关的疾病、病症。
2)根据本发明的实施例,在体外酶试验中,本发明化合物对HPK1酶具有良好的抑制作用,抑制活性显著优于对照化合物,而在细胞试验中,本发明化合物对HPK1酶也具有良好的抑制作用,抑制活性显著优于对照化合物。
本发明的附加方面和优点将在下面的描述中部分给出,部分将从下面的描述中变得明显,或通过本发明的实践了解到。
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解,下面的实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体技术或条件的,按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
如无特别说明,本发明的化合物均是通过核磁共振(NMR)和/或质谱(MS)来确定其结构的。NMR位移的单位为10
-6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等,内标为四甲基硅烷(TMS)。
本发明的缩写定义如下:
M:摩尔浓度,如1M盐酸表示1mol/L盐酸溶液
DCM:二氯甲烷
DMF:N,N-二甲基甲酰胺
DMSO:二甲基亚砜
HEPES:(4-(2-羟乙基)-1-哌嗪乙磺酸)
LC-MS:液质联用色谱
IC
50:半数抑制浓度,指达到最大抑制效果一半时的浓度。
测试例1:对照化合物1的制备
5-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-噁嗪-2-基)氨基)-2,6-二氟苯氧基)-1H-吡咯[2,3-b]吡啶-3-基)-2-异丙氧基苄腈(对照化合物1)
对照化合物1
参考专利WO2019016071A方法制备。
1H NMR(400MHz,CDCl
3)δ9.25(br s,1H),8.19(d,J=5.2Hz,1H),7.91-7.90(m,1H),7.85-7.83(m,1H),731(s,1H),7.09-7.07(m,2H),7.02-6.99(m,1H),6.34(d,J=5.6Hz,1H),4.70-4.66(m,1H),4.19(s,2H),3.29(s,2H),1.45(s,3H),1.43(s,3H),1.20(s,6H).
LC-MS,M/Z(ESI):532.2[M+H]
+。
下文所述“对照化合物1”均指测试例1所述化合物。
制备例1:中间体A1
N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-胺(A1)的合成
合成路线:
第一步:4-(2,6-二氟-4-硝基苯氧基)-1H-吡咯并[2,3-b]吡啶的合成
在25℃下,向4-羟基-7-氮杂吲哚(10g,74.6mmol)的二甲基亚砜(100mL)溶液中加入K
2CO
3(20.61g,149mmol)。反应混合物在25℃下搅拌10分钟。然后将1,2,3-三氟-5-硝基苯(15.84g,89mmol)分批加入到反应液中。反应混合物在25℃下搅拌2小时。将反应液缓慢倒入500mL冰水混合物中。混合物用乙酸乙酯(100mL×3)萃取。收集有机相用无水Na
2SO
4干燥,然后过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=10:1-3:1)得到4-(2,6-二氟-4-硝基苯氧基)-1H-吡咯并[2,3-b]吡啶(12g,产率55.3%)。
第二步:4-(2,6-二氟-4-硝基苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶的合成
在25℃下,向4-(2,6-二氟-4-硝基苯氧基)-1H-吡咯并[2,3-b]吡啶(12g,41.2mmol)的MeCN(20mL)溶液中加入N,N-二异丙基乙胺(9.59g,74.2mmol)和2-(氯甲氧基)乙基三甲硅烷(9.62g, 57.7mmol)。反应混合物在25℃下搅拌18小时。将反应混合物浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-5:1)得到黄色油状物4-(2,6-二氟-4-硝基苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶(15g,产率86%)。
第三步:4-(2,6-二氟-4-硝基苯氧基)-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶的合成
在25℃下,向4-(2,6-二氟-4-硝基苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶(15g,35.6mmol)的DMF(150mL)溶液中加入N-碘代丁二酰亚胺(8.81g,39.1mmol)。反应混合物在25℃下搅拌18小时。将反应液缓慢倒入500mL冰水混合物中。混合物用乙酸乙酯(100mL×3)。结合有机相,用饱和食盐水(100mL)洗涤。有机相用无水Na
2SO
4干燥,过滤,浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-5:1)得到4-(2,6-二氟-4-硝基苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶(15g,产率77%)。
第四步:3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯胺的合成
在80℃下,向4-(2,6-二氟-4-硝基苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶(5g,9.13mmol)的乙醇(50mL)和水(5.00mL)的混合溶剂中分批加入氯化铵(2.93g,54.8mmol)和铁粉(3.06g,54.8mmol)。反应混合物在80℃下搅拌3小时。将反应液冷却到室温,反应液用硅藻土过滤,滤饼有50mL乙醇淋洗。滤液浓缩得到粗品,向粗品中加入乙酸乙酯(100mL)和水(50mL),分离有机相和水相,水相用乙酸乙酯(50mL×3)萃取。收集有机相,用无水Na
2SO
4,过滤,浓缩得到粗品3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯胺,直接用于下一步反应。
第五步:邻苯基(3,5-二氟-4-((3-碘-1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)硫代氨基甲酸酯的合成
在0℃下,将上一步得到的粗品3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯胺溶解在四氢呋喃(50mL)中,然后将吡啶(7.39mL,1mmol)加到反应液中,随后将硫代氯甲酸苯酯(2.367g,13.71mmol)缓慢滴加到反应液中。反应液在0℃下搅拌5小时。反应结束后向反应液中加入二氯甲烷(100mL),有机相用水(100mL×3)洗。收集有机相用无水Na
2SO
4,过滤,浓缩得到粗品邻苯基(3,5-二氟-4-((3-碘-1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)硫代氨基甲酸酯,直接用于下一步反应。
第六步:1-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-3-(3-羟基-2,2-二甲基丙基)硫脲的合成
在25℃下,取上一步粗品的一半溶解在DMF(30mL)中,向反应液中加入3-氨基-2,2-二甲基丙烷-1-醇(0.916g,8.87mmol)。将反应液加热到60℃,搅拌2小时。反应结束后将反应液缓慢倒入150mL冰水混合物中,混合物用乙酸乙酯(80mL×3)萃取,收集有机相用饱和食盐水洗,然后用无水Na
2SO
4干燥,过滤浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-0:1)得到粗品黄色固体1-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-3-(3-羟基-2,2-二甲基丙基)硫脲(2.8g)。
第七步:N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-胺(A1)的合成
在25℃下,向粗品1-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-3-(3-羟基-2,2-二甲基丙基)硫脲(2.8g)的乙腈(30mL)溶液中加入 三乙胺(0.88mL,6.34mmol)和1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(1.620g,8.45mmol)。反应混合物在50℃下搅拌18小时。反应结束后,将反应液浓缩旋干得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-0:1)得到粗品黄色固体N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-胺(A1)(1.0g,1.591mmol)。
制备例2:中间体A2
N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-胺(A2)的合成
合成路线:
第一步:1-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-3-((3-(羟甲基)氧杂环丁-3-基)甲基)硫脲的合成
在25℃下,取上一步粗品的一半溶解在DMF(30mL)中,向反应液中加入(3-(氨基甲基) 氧杂环丁烷-3-基)甲醇盐酸盐(1.401g,9.12mmol)和三乙胺(1.271ml,9.12mmol)。将反应液加热到60℃,搅拌6小时。反应结束后将反应液缓慢倒入150mL冰水混合物中,混合物用乙酸乙酯(80mL×3)萃取,收集有机相用饱和食盐水洗,然后用无水Na
2SO
4干燥,过滤浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-0:1)得到粗品黄色固体1-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-3-((3-(羟甲基)氧杂环丁-3-基)甲基)硫脲(2.7g)。
第二步:甲基-N-(3,5-二氟-4-((3-碘-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯[2,3-b]吡啶-4-基)氧基)苯基)-N'-((3-(羟甲基)氧代烷-3-基)甲基)氨基甲酰硫代酯的合成
在25℃下,向1-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-3-((3-(羟甲基)氧杂环丁-3-基)甲基)硫脲(2.7g,3.99mmol)的丙酮(30ml)溶液中加入N-乙基-N-二异丙基-2-胺(2.321g,17.96mmol)和碘甲烷(2.266g,15.96mmol)。反应混合物在密封条件55℃下搅拌3小时。将反应混合物浓缩得到粗品黄色固体甲基-N-(3,5-二氟-4-((3-碘-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯[2,3-b]吡啶-4-基)氧基)苯基)-N'-((3-(羟甲基)氧代烷-3-基)甲基)氨基甲酰硫代酯直接用于下一步反应。
第三步:N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-胺(A2)的合成
在25℃下,向上一步得到的粗品甲基-N-(3,5-二氟-4-((3-碘-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯[2,3-b]吡啶-4-基)氧基)苯基)-N'-((3-(羟甲基)氧代烷-3-基)甲基)氨基甲酰硫代酯的四氢呋喃(30mL)溶液中加入NaOH(0.398g,9.96mmol)。反应混合物在25℃下搅拌5小时。反应结束后,反应液用50mL水稀释,混合物用乙酸乙酯萃取(30mL×3)。收集有机相用无水硫酸钠干燥,过滤,浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-0:1)得到粗品黄色固体N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-胺(A2)(1.1g)。
制备例3:中间体A3
N-(4-((3-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-3,5-二氟苯基)-5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-胺
合成方法参照A1的合成,溴化试剂选用N-溴代丁二酰亚胺。
实施例1:目标化合物I-1的制备
4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺(目标化合物I-1)
目标化合物I-1路线如下所示:
第一步:4-溴-N-(3-甲氧基丙基)-N-甲基苯甲酰胺的合成
在0℃氮气保护下,向4-溴苯甲酸(2g,9.95mmol)的二氯甲烷(30mL)溶液中加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(5.67g,14.92mmol)和N,N-二异丙基乙胺(4.34ml,24.87mmol)。反应混合物在0℃氮气保护下搅拌0.5小时。然后将3-甲氧基-N-甲基-1-丙胺盐酸盐(1.528g,10.94mmol)分批加入到反应液中。反应混合物在25℃氮气保护下搅拌18小时。反应结束后将反应液倒入到冰水混合物(50mL)中。混合物用乙酸乙酯(50mL×3)萃取。有机层用无水硫酸钠干燥,过滤,浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=20:1-5:1)得到黄色油状物4-溴-N-(3-甲氧基丙基)-N-甲基苯甲酰胺(2.4g,产率84%)。
第二步:N-(3-甲氧基丙基)-N-甲基4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酰胺的合成
在25℃氮气保护下,向4-溴-N-(3-甲氧基丙基)-N-甲基苯甲酰胺(1g,3.49mmol),双联频那醇硼酸酯(1.331g,5.24mmol)的1,4-二氧六环(10ml)溶液中加入无水醋酸钾(0.686g,6.99mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.256g,0.349mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应混合物用硅藻土过滤,滤液浓缩干得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=10:1-1:1)得到棕色油状物N-(3-甲氧基丙基)-N-甲基4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酰胺(1.1g,产率94%)。
第三步:4-(2,6-二氟-4-硝基苯氧基)-1H-吡咯并[2,3-b]吡啶的合成
在25℃下,向4-羟基-7-氮杂吲哚(10g,74.6mmol)的二甲基亚砜(100mL)溶液中加入K
2CO
3(20.61g,149mmol)。反应混合物在25℃下搅拌10分钟。然后将1,2,3-三氟-5-硝基苯(15.84g,89mmol)分批加入到反应液中。反应混合物在25℃下搅拌2小时。将反应液缓慢倒入500mL冰水混合物中。混合物用乙酸乙酯(100mL×3)萃取。收集有机相用无水Na
2SO
4干 燥,然后过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=10:1-3:1)得到黄色固体4-(2,6-二氟-4-硝基苯氧基)-1H-吡咯并[2,3-b]吡啶(12g,产率55.3%)。
第四步:4-(2,6-二氟-4-硝基苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶的合成
在25℃下,向4-(2,6-二氟-4-硝基苯氧基)-1H-吡咯并[2,3-b]吡啶(12g,41.2mmol)的MeCN(20mL)溶液中加入N,N-二异丙基乙胺(9.59g,74.2mmol)和2-(氯甲氧基)乙基三甲硅烷(9.62g,57.7mmol)。反应混合物在25℃下搅拌18小时。将反应混合物浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-5:1)得到黄色油状物4-(2,6-二氟-4-硝基苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶(15g,产率86%)。
第五步:4-(2,6-二氟-4-硝基苯氧基)-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶的合成
在25℃下,向4-(2,6-二氟-4-硝基苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶(15g,35.6mmol)的DMF(150mL)溶液中加入N-碘代丁二酰亚胺(8.81g,39.1mmol)。反应混合物在25℃下搅拌18小时。将反应液缓慢倒入500mL冰水混合物中。混合物用乙酸乙酯(100mL×3)。结合有机相,用饱和食盐水(100mL)洗涤。有机相用无水Na
2SO
4干燥,过滤,浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-5:1)得到黄色固体4-(2,6-二氟-4-硝基苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶(15g,产率77%)。
第六步:4-(4-(2,6-二氟-4-硝基苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺的合成
在25℃氮气保护下,向4-(2,6-二氟-4-硝基苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶(1.2g,2.192mmol)和N-(3-甲氧基丙基)-N-甲基4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酰胺(1.096g,3.29mmol)的1,4-二氧六环(15mL)和水(1.5mL)的混合溶液中加入碳酸铯(1.429g,4.38mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.160g,0.219mmol)。反应液在80℃氮气保护下搅拌18小时。反应液用硅藻土过滤,滤液浓缩后得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-0:1)得到黄色固体4-(4-(2,6-二氟-4-硝基苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺(1.17g,产率85%)。
第七步:4-(4-(4-氨基-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺的合成
在25℃下,将4-(4-(2,6-二氟-4-硝基苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺(1.17g,1.867mmol)溶解在MeOH(15mL)中,将湿Pd/C(0.2g,0.188mmol,10%)加入到反应液中,然后用氢气球置换三次氢气,反应液在25℃在氢气球下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液旋干得到粗品4-(4-(4-氨基-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺(1.1g),直接用于下一步反应。
第八步:邻苯基(3,5-二氟-4-((3-(4-((3-甲氧基丙基)(甲基)氨基甲酰基)苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯[2,3-b]吡啶-4-基)氧基)苯基)氨基甲酸酯的合成
在0℃下,向上一步得到粗品4-(4-(4-氨基-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺(1.1g)的四氢呋喃(10mL)溶液中加入吡啶(1.491mL,18.43mmol)。反应混合物在0℃氮气保护下搅拌0.5小时。然后将硫代氯甲酸苯酯(0.477g,2.77mmol)滴加到反应液中。反应液保持在0℃下搅拌3小时。将反应液用二氯甲烷(50mL)稀释,然后用水(50mL×3)洗。收集有机相,用无水Na
2SO
4干燥,过滤,滤液浓缩得到粗品邻苯基(3,5-二氟-4-((3-(4-((3-甲氧基丙基)(甲基)氨基甲酰基)苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯[2,3-b]吡啶-4-基)氧基)苯基)氨基甲酸酯。粗品直接用于下一步反应。
第九步:4-(4-(2,6-二氟-4-(3-(3-羟基-2,2-二甲基丙基)硫脲基)苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺的合成
将上一步得到的粗品邻苯基(3,5-二氟-4-((3-(4-((3-甲氧基丙基)(甲基)氨基甲酰基)苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯[2,3-b]吡啶-4-基)氧基)苯基)氨基甲酸酯和3-氨基-2,2-二甲基-1-丙醇(0.380g,3.69mmol)溶在DMF(15mL)。反应液在60℃下搅拌5小时。反应结束后,将反应液冷却到室温,然后,将反应液缓慢的倒入60mL冰水混合物中。混合物用乙酸乙酯(50mL×3)萃取,结合有机相,用饱和食盐水(50mL)洗。有机相用无水Na
2SO
4干燥,过滤,浓缩得到粗品。粗品用硅胶柱分离纯化(乙酸乙酯:甲醇=1:0-15:1)得到黄色固体4-(4-(2,6-二氟-4-(3-(3-羟基-2,2-二甲基丙基)硫脲基)苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺(720mg)。
第十步:4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三 甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺的合成
在25℃下,向4-(4-(2,6-二氟-4-(3-(3-羟基-2,2-二甲基丙基)硫脲基)苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺(720mg,0.970mmol)和三乙胺(0.203ml,1.456mmol)的乙腈(15mL)溶液中加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(372mg,1.941mmol)。反应混合物在45℃下搅拌18小时。反应结束后将反应冷却到室温,将反应液缓慢导入到60mL冰水混合物中。混合物用乙酸乙酯(60mL×3)萃取,结合有机相,用饱和食盐水(50mL)洗。有机相用无水Na
2SO
4干燥,过滤,浓缩得到粗品。粗品用硅胶柱分离纯化(乙酸乙酯:甲醇=1:0-15:1)得到黄色固体物4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺(500mg,产率72.8%)。
第十一步:4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1H-吡咯[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺(I-1)的合成
在25℃下,向4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺(500mg,0.706mmol)的DCM(5mL)溶液中滴加三氟乙酸(5.00mL)。反应混合物在25℃搅拌18小时。将反应液浓缩干,然后将浓缩后的混合物溶解在乙腈(5mL)中,随后将5mL氨水(25%)加入到反应液中,反应液在25℃下搅拌0.5小时。反应结束后,反应液用水(20mL)稀释,稀释后用乙酸乙酯(10mL×3)萃取,收集有机相用无水Na
2SO
4干燥,过滤, 浓缩得到粗品。粗品用制备板分离纯化(乙酸乙酯:甲醇=10:0)得到4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1H-吡咯[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺(I-1)(178.7mg,产率43.8%)
1H NMR(400MHz,CDCl
3)δ10.86(br s,1H),8.14(d,J=5.2Hz,1H),7.75(d,J=8.4Hz,2H),7.40(d,J=8.0Hz,2H),7.35(s,1H),6.96(d,J=9.6Hz,2H),6.36(d,J=5.6Hz,1H),3.98(s,2H),3.61(br s,1H),3.49-3.43(m,2H),3.35-3.24(m,3H),3.18(s,3H),3.04(br s,3H),1.94-1.82(m,2H),1.11(s,6H)。
LC-MS,M/Z(ESI):578.3[M+H]
+。
实施例2:目标化合物I-2的制备
4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺(目标化合物I-2)
目标化合物I-2的合成路线如下所示:
第一步:(4-溴苯基)(吗啉代)甲酮的合成
在0℃氮气保护下,向4-溴苯甲酸(5g,24.87mmol)的二氯甲烷(50mL)溶液中加入1-羟基苯并三唑(5.71g,37.3mmol),1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(7.15g,37.3mmol)和三乙胺(6.93ml,49.7mmol)。反应混合物在0℃下搅拌0.5小时。随后在0℃下,吗啡啉(2.82g,32.3mmol)加入到反应混合物中。反应混合物在25℃氮气保护下搅拌18小时。反应结束后,向反应液中加入50mL二氯甲烷,有机相用饱和碳酸氢钠(50mL×3)洗,收集有机相,继续使用1M的盐酸水溶液(50mL×3)洗,收集有机相用无水Na
2SO
4干燥,过滤,浓缩得到(4-溴苯基)(吗啉代)甲酮(6.0g,收率89%)。
第二步:吗啉代(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲酮的合成
在25℃氮气保护下,向(4-溴苯基)(吗啉代)甲酮(1g,3.70mmol)和双联频那醇硼酸酯(1.410g,5.55mmol)的1,4-二氧六环(10mL)溶液中加入无水醋酸钾(0.727g,7.40mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.27g,0.37mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤饼用甲醇(20mL)洗,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-5:1)得到粗品黄色固体吗啉代(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲酮(1.0g,产率85%)。
第三步:(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(吗啉代)甲酮的合成
在25℃氮气保护下,向N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-胺(A1)(0.3g,0.477mmol)和吗啉代(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲酮(0.227g,0.716mmol)的1,4-二氧六环(6mL)和水(1mL)的混合溶液中加入K
2CO
3(0.132g,0.955mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.035g,0.048mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-0:1,然后,乙酸乙酯:甲醇=100:1-10:1)得到粗品黄色固体(4-(4-(4-((5,5-二甲 基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(吗啉代)甲酮(150mg,产率45.4%)。
第四步:(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(吗啉代)甲酮(I-2)的合成
在25℃下,向(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(吗啉代)甲酮(150mg,0.217mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(3.00mL)。反应液在25℃下搅拌18小时。将反应液浓缩得到粗品,然后将粗品溶解在乙腈(5mL)中,向反应液中加入5mL氨水(25%)。反应液在25℃下搅拌1小时。反应液用20mL二氯甲烷稀释,有机相用水(10mL×3)洗。收集有机相,用无水Na
2SO
4干燥,过滤,浓缩得到粗品。粗品用制备硅胶板分离纯化(乙酸乙酯:甲醇=10:1)得到(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(吗啉代)甲酮(I-2)(45.2mg,产率37.1%)。
1H NMR(400MHz,CDCl
3)δ10.01(br s,1H),8.16(d,J=5.6Hz,1H),7.79-7.70(m,2H),7.44-7.42(m,2H),7.35(s,1H),6.98-6.96(m,2H),6.38(d,J=5.6Hz,1H),3.94(s,2H),3.72(br s,9H),3.16(s,2H),1.10(s,6H)。
LC-MS,M/Z(ESI):562.2[M+H]
+。
实施例3:目标化合物I-3的制备
(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)((2R,6S)-2,6-二甲基吗啉代)甲酮(目标化合物I-3)
目标化合物I-3的合成路线如下所示:
第一步:(4-溴苯基)(顺式-2,6-二甲基吗啉代)甲酮的合成
在0℃氮气保护下,向4-溴苯甲酸(5g,24.87mmol)的二氯甲烷(50mL)溶液中加入1-羟基苯并三唑(5.71g,37.3mmol),1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(7.15g,37.3mmol)和三乙胺(6.93ml,49.7mmol)。反应混合物在0℃下搅拌0.5小时。随后在0℃下,顺式-2,6-二甲基吗啉(3.72g,32.3mmol)加入到反应混合物中。反应混合物在25℃氮气保护下搅拌18小时。反应结束后,向反应液中加入50mL二氯甲烷,有机相用饱和碳酸氢钠(50mL×3)洗,收集有机相,继续使用1M的盐酸水溶液(50mL×3)洗,收集有机相用无水Na
2SO
4干燥,过滤,浓缩得到(4-溴苯基)(顺式-2,6-二甲基吗啉代)甲酮(6.0g,收率81%)。
第二步:(顺-2,6-二甲基吗啉代)(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)苯基)甲酮的合成
在25℃氮气保护下,向(4-溴苯基)(顺式-2,6-二甲基吗啉代)甲酮(1g,3.35mmol)和双联频那醇硼酸酯(1.410g,5.55mmol)的1,4-二氧六环(10mL)溶液中加入无水醋酸钾(0.658g,6.71mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.245g,0.335mmol)。反应混合物在80℃氮气 保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤饼用甲醇(20mL)洗,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-1:1)得到粗品黄色固体(顺-2,6-二甲基吗啉代)(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)苯基)甲酮(1.1g,产率95%)。
第三步:(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(顺-2,6-二甲基吗啉代)甲酮的合成
在25℃氮气保护下,向N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-胺(A1)(0.3g,0.477mmol)和(顺-2,6-二甲基吗啉代)(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)苯基)甲酮(0.247g,0.716mmol)的1,4-二氧六环(6mL)和水(1mL)的混合溶液中加入Cs
2CO
3(0.311g,0.955mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.035g,0.048mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-0:1,然后,乙酸乙酯:甲醇=100:1-10:1)得到(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(顺-2,6-二甲基吗啉代)甲酮(150mg,产率43.7%)。
第四步:(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(顺-2,6-二甲基吗啉代)甲酮(I-3)的合成
在25℃下,向(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(顺-2,6-二甲基吗啉代)甲酮(150mg,0.208mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(3.00mL)。反应液在25℃下搅拌18小时。将反应液浓缩得到粗品,然后将粗品溶解在乙腈(5mL)中,向反应液 中加入5mL氨水(25%)。反应液在25℃下搅拌1小时。反应液用20mL二氯甲烷稀释,有机相用水(10mL×3)洗。收集有机相,用无水Na
2SO
4干燥,过滤,浓缩得到粗品。粗品用制备硅胶板分离纯化(乙酸乙酯:甲醇=10:1)得到(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(顺-2,6-二甲基吗啉代)甲酮(I-3)(18.0mg,产率14.65%)。
1H NMR(400MHz,CDCl
3)δ10.31(br s,1H),8.16(d,J=5.6Hz,1H),7.78(d,J=8.0Hz,2H),7.41(d,J=8.4Hz,2H),7.37(s,1H),6.96(d,J=8.4Hz,2H),6.38(d,J=5.6Hz,1H),4.58(br s,1H),3.95(s,2H),3.62(br s,2H),3.16(s,2H),2.83-2.54(m,4H),1.26-1.01(m,12H)。
LC-MS,M/Z(ESI):590.2[M+H]
+。
实施例4:目标化合物I-4的制备
(4-(4-(4-((2,6-二氧-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(顺-2,6-二甲基吗啉代)甲酮(目标化合物I-4)
目标化合物I-4的合成路线如下所示:
第一步:(4-溴苯基)(顺式-2,6-二甲基吗啉代)甲酮的合成
在0℃氮气保护下,向4-溴苯甲酸(5g,24.87mmol)的二氯甲烷(50mL)溶液中加入1-羟基苯并三唑(5.71g,37.3mmol),1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(7.15g,37.3mmol)和三乙胺(6.93ml,49.7mmol)。反应混合物在0℃下搅拌0.5小时。随后在0℃下,顺式-2,6-二甲基吗啉(3.72g,32.3mmol)加入到反应混合物中。反应混合物在25℃氮气保护下搅拌18小时。反应结束后,向反应液中加入50mL二氯甲烷,有机相用饱和碳酸氢钠(50mL×3)洗,收集有机相,继续使用1M的盐酸水溶液(50mL×3)洗,收集有机相用无水Na
2SO
4干燥,过滤,浓缩得到(4-溴苯基)(顺式-2,6-二甲基吗啉代)甲酮(6.0g,收率81%)。
第二步:(顺-2,6-二甲基吗啉代)(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)苯基)甲酮的合成
在25℃氮气保护下,向(4-溴苯基)(顺式-2,6-二甲基吗啉代)甲酮(1g,3.35mmol)和双联频那醇硼酸酯(1.410g,5.55mmol)的1,4-二氧六环(10mL)溶液中加入无水醋酸钾(0.658g,6.71mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.245g,0.335mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤饼用甲醇(20mL)洗,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-1:1)得到(顺-2,6-二甲基吗啉代)(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)苯基)甲酮(1.1g,产率95%)。
第三步:(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(顺-2,6-二甲基吗啉代)甲酮的合成
在25℃氮气保护下,向N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡 咯并[2,3-b]吡啶-4-基)氧基)苯基)-2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-胺(A2)(0.2g,0.311mmol)和(顺-2,6-二甲基吗啉代)(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)苯基)甲酮(0.161g,0.467mmol)的1,4-二氧六环(6mL)和水(1mL)的混合溶液中加入K
2CO
3(0.086g,0.623mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.023g,0.031mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-0:1,然后,乙酸乙酯:甲醇=100:1-10:1)得到黄色固体(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(顺-2,6-二甲基吗啉代)甲酮(130mg,产率56.9%)。
第四步:(4-(4-(4-((2,6-二氧-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(顺-2,6-二甲基吗啉代)甲酮(I-4)的合成
在25℃下,向(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(顺-2,6-二甲基吗啉代)甲酮(130mg,0.177mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(3.00mL)。反应液在25℃下搅拌18小时。将反应液浓缩得到粗品,然后将粗品溶解在乙腈(5mL)中,向反应液中加入5mL氨水(25%)。反应液在25℃下搅拌1小时。反应液用20mL二氯甲烷稀释,有机相用水(10mL×3)洗。收集有机相,用无水Na
2SO
4干燥,过滤,浓缩得到粗品。粗品用制备硅胶板分离纯化(乙酸乙酯:甲醇=10:1)得到(4-(4-(4-((2,6-二氧-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(顺-2,6-二甲基吗啉代)甲酮(I-4)(17.2mg,产率16.09%)。
1H NMR(400MHz,CDCl
3)δ10.34(br s,1H),8.15(d,J=5.6Hz,1H),7.78(d,J=8.0Hz,2H),7.41(d,J=8.4Hz,2H),7.37(s,1H),7.08-7.06(m,2H),6.36(d,J=5.6Hz,1H),4.60-4.54(m,4H),4.44(s,2H),3.69(s,2H),3.61(br s,2H),2.98-2.57(m,4H),1.26-1.15(m,6H)。
LC-MS,M/Z(ESI):604.2[M+H]
+。
实施例5:目标化合物I-5的制备
4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(2-羟基-2-甲基丙基)-N-甲基苯甲酰胺(目标化合物I-5)
目标化合物I-5的合成路线如下所示:
第一步:4-溴-N-(2-羟基-2-甲基丙基)-N甲基苯甲酰胺的合成
在0℃氮气保护下,向4-溴苯甲酸(0.3g,1.492mmol)的二氯甲烷(6mL)溶液中加入1-羟基苯并三唑(0.302g,2.239mmol),1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(0.429g,2.239mmol)和三乙胺(0.416ml,2.98mmol)。反应混合物在0℃下搅拌0.5小时。随后在0℃下,2-甲基-1-(甲基氨基)丙烷-2-醇(0.185g,1.791mmol)加入到反应混合物中。反应混合物在25℃氮气保护下搅拌18小时。反应结束后,向反应液中加入10mL二氯甲烷,有机相用饱和碳酸氢钠(10mL×3)洗,收集有机相,继续使用1M的盐酸水溶液(10mL×3)洗,收集有机相用无水Na
2SO
4干燥,过滤,浓缩得到4-溴-N-(2-羟基-2-甲基丙基)-N甲基苯甲酰胺(0.4g, 收率94%)。
第二步:N-(2-羟基-2-甲基丙基)-N-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酰胺的合成
在25℃氮气保护下,向4-溴-N-(2-羟基-2-甲基丙基)-N甲基苯甲酰胺(0.4g,1.398mmol)和双联频那醇硼酸酯(0.532g,2.097mmol)的1,4-二氧六环(6mL)溶液中加入无水醋酸钾(0.274g,2.80mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.102g,0.140mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤饼用甲醇(10mL)洗,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-1:1)得到粗品黄色油状N-(2-羟基-2-甲基丙基)-N-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酰胺(0.2g,产率42.9%)。
第三步:4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基-2,6-二氟苯氧基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(2-羟基-2-甲基丙基)-N-甲基苯甲酰胺的合成
在25℃氮气保护下,向N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-胺(0.2g,0.311mmol)(A2)和N-(2-羟基-2-甲基丙基)-N-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酰胺(0.156g,0.467mmol)的1,4-二氧六环(6mL)和水(1mL)的混合溶液中加入K
2CO
3(0.086g,0.623mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.023g,0.031mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-0:1,然后,乙酸乙酯:甲醇=100:1-10:1)得到黄色固体4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基-2,6-二氟苯氧基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(2-羟基-2-甲基丙基)-N-甲基苯甲酰胺(200mg,产率89%)。
第四步:4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(2-羟基-2-甲基丙基)-N-甲基苯甲酰胺(目标化合物I-5)的合成
在25℃下,向4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基-2,6-二氟苯氧基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(2-羟基-2-甲基丙基)-N-甲基苯甲酰胺(200mg,0.277mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(3.00mL)。反应液在25℃下搅拌18小时。将反应液浓缩得到粗品,然后将粗品溶解在乙腈(3mL)中,向反应液中加入3mL氨水(25%)。反应液在25℃下搅拌1小时。反应液用10mL二氯甲烷稀释,有机相用水(5mL×3)洗。收集有机相,用无水Na
2SO
4干燥,过滤,浓缩得到粗品。粗品用制备硅胶板分离纯化(乙酸乙酯:甲醇=10:1)得到4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(2-羟基-2-甲基丙基)-N-甲基苯甲酰胺(目标化合物I-5)(15.1mg,产率9.21%)。
1H NMR(400MHz,CDCl
3)δ9.80(br s,1H),8.14(d,J=5.6Hz,1H),7.77(d,J=8.4Hz,2H),7.46(d,J=8.0Hz,2H),7.36(s,1H),7.09-7.07(m,2H),6.35(d,J=5.6Hz,1H),4.60-4.54(m,4H),4.44(s,2H),3.69(s,2H),3.61(s,2H),3.17(s,3H),1.32(s,6H)。
LC-MS,M/Z(ESI):592.1[M+H]
+。
实施例6:目标化合物I-6的制备
(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(2-氧杂-6-氮杂螺[3.3]庚-6-基)甲酮(目标化合物I-6)
目标化合物I-6的合成路线如下所示:
第一步:(4-溴苯基)(2-氧杂-6-氮杂螺[3.3]庚-6-基)甲酮的合成
在0℃氮气保护下,向4-溴苯甲酸(0.5g,2.487mmol)的二氯甲烷(10mL)溶液中加入乙基[3-(二甲胺基)丙基]碳二亚胺盐酸盐(0.715g,3.73mmol),1-羟基苯并三唑(0.504g,3.73mmol)和三乙胺(0.693ml,4.97mmol),反应混合物在0℃下搅拌0.5小时。然后,在0℃下将2-氧杂-6-氮杂螺[3.3]庚烷(0.296g,2.98mmol)分批加入到反应液中。反应混合物在氮气保护下25℃搅拌18小时。反应液用二氯甲烷(10mL)稀释,有机相用饱和碳酸氢钠水溶液(10mL×3)洗,收集有机相,用1M盐酸水溶液(10mL×3)洗,收集有机相,用无水Na
2SO
4干燥,过滤,浓缩得到黄色油状物(4-溴苯基)(2-氧杂-6-氮杂螺[3.3]庚-6-基)甲酮(0.6g,产率85%)。
第二步:(2-氧杂-6-氮杂螺并[3.3]庚-6-基)(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲酮的合成
在25℃氮气保护下,向(4-溴苯基)(2-氧杂-6-氮杂螺[3.3]庚-6-基)甲酮(0.6g,2.127mmol) 和双联频那醇硼酸酯(0.810g,3.19mmol)的1,4-二氧六环(10mL)溶液中加入无水醋酸钾(0.417g,4.25mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.156g,0.213mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-5:1)得到黄色固体(2-氧杂-6-氮杂螺并[3.3]庚-6-基)(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲酮(500mg,产率71.4%)。
第三步:(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(2-氧杂-6-氮杂螺[3.3]庚-6-基)甲酮的合成
在25℃氮气保护下,向N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-胺(A2)(0.3g,0.467mmol),(2-氧杂-6-氮杂螺并[3.3]庚-6-基)(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲酮(0.231g,0.700mmol)的1,4-二氧六环(10mL)和水(1mL)的混合溶液中加入碳酸钾(0.129g,0.934mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.034g,0.047mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-0:1,然后乙酸乙酯:甲醇=100:1-20:1)得到黄色固体(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(2-氧杂-6-氮杂螺[3.3]庚-6-基)甲酮(170mg,产率50.7%)。
第四步:(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(2-氧杂-6-氮杂螺[3.3]庚-6-基)甲酮(I-6)的合成
在25℃下,向(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(2-氧杂-6-氮杂螺[3.3]庚-6-基)甲酮(170mg,0.237mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(3.00mL)。反应 液在25℃下搅拌18小时。将反应液浓缩得到粗品,然后将粗品溶解在乙腈(3mL)中,向反应液中加入3mL氨水(25%)。反应液在25℃下搅拌1小时。反应液用10mL二氯甲烷稀释,有机相用水(5mL×3)洗。收集有机相,用无水Na
2SO
4干燥,过滤,浓缩得到粗品。粗品用制备硅胶板分离纯化(乙酸乙酯:甲醇=10:1)得到(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(2-氧杂-6-氮杂螺[3.3]庚-6-基)甲酮(I-6)(21.4mg,产率43.0%)。
1H NMR(400MHz,DMSO)δ12.21(d,J=2.0Hz,1H),9.11(br s,1H),8.11(d,J=5.6Hz,1H),7.81-7.71(m,4H),7.61(d,J=8.4Hz,2H),7.54(br s,1H),6.33(d,J=5.2Hz,1H),4.67(s,4H),4.53(s,2H),4.44-4.40(m,6H),4.20(s,2H),3.60(s,2H).
LC-MS,M/Z(ESI):588.1[M+H]
+。
实施例7:目标化合物I-7的制备
4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(2-甲氧基乙基)-N-甲基苯甲酰胺(目标化合物I-7)
目标化合物I-7的合成路线如下所示:
第一步:4-溴-N-(2-羟乙基)-N-甲基苯甲酰胺的合成
在0℃氮气保护下,向4-溴苯甲酸(0.5g,2.487mmol)的二氯甲烷(10mL)溶液中加入乙基[3-(二甲胺基)丙基]碳二亚胺盐酸盐(0.715g,3.73mmol),1-羟基苯并三唑(0.504g,3.73mmol)和三乙胺(0.693ml,4.97mmol),反应混合物在0℃下搅拌0.5小时。然后,在0℃下将2-甲氧基-N-甲基乙胺(0.266g,2.98mmol)分批加入到反应液中。反应混合物在氮气保护下25℃搅拌3小时。反应液用二氯甲烷(20mL)稀释,有机相用饱和碳酸氢钠水溶液(20mL)洗,收集有机相,用0.5M盐酸水溶液(20mL)洗,收集有机相,用无水Na
2SO
4干燥,过滤,浓缩得到黄色油状物4-溴-N-(2-羟乙基)-N-甲基苯甲酰胺(650mg,产率96%)。
第二步:N-(2-羟乙基)-N-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酰胺的合成
在25℃氮气保护下,向4-溴-N-(2-羟乙基)-N-甲基苯甲酰胺(650mg,2.388mmol)和双联频那醇硼酸酯(1213mg,4.78mmol)的1,4-二氧六环(10mL)溶液中加入无水醋酸钾(469mg,4.78mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(175mg,0.239mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-5:1)得到黄色固体N-(2-羟乙基)-N-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酰胺(0.5g,产率65.6%)。
第三步:4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(2-甲氧基乙基)-N-甲基苯甲酰胺的合成
在25℃氮气保护下,向N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-胺(A2)(0.3g,0.467 mmol),N-(2-羟乙基)-N-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酰胺(0.224g,0.700mmol)的1,4-二氧六环(8mL)和水(1.5mL)的混合溶液中加入碳酸钾(0.129g,0.934mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.034g,0.047mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-0:1,然后乙酸乙酯:甲醇=100:1-20:1)得到黄色固体4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(2-甲氧基乙基)-N-甲基苯甲酰胺(170mg,产率51.4%)。
第四步:4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(2-甲氧基乙基)-N-甲基苯甲酰胺(I-7)的合成
在25℃下,向4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(2-甲氧基乙基)-N-甲基苯甲酰胺(6)(170mg,0.240mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(3.00mL)。反应液在25℃下搅拌18小时。将反应液浓缩得到粗品,然后将粗品溶解在乙腈(3mL)中,向反应液中加入3mL氨水(25%)。反应液在25℃下搅拌1小时。反应液用10mL二氯甲烷稀释,有机相用水(5mL×3)洗。收集有机相,用无水Na
2SO
4干燥,过滤,浓缩得到粗品。粗品用制备硅胶板分离纯化(乙酸乙酯:甲醇=10:1)得到4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(2-甲氧基乙基)-N-甲基苯甲酰胺(I-7)(40.6mg,产率29.3%)。
1H NMR(400MHz,CDCl
3)δ10.15(br s,1H),8.15(d,J=5.6Hz,1H),7.74(d,J=8.0Hz,2H),7.43(d,J=8.0Hz,2H),7.35(s,1H),7.06(d,J=9.6Hz,2H),6.34(d,J=5.6Hz,1H),4.61-4.55(m,4H),4.51(s,2H),3.72(s,2H),3.67-3.50(m,3H),3.39-3.28(m,4H),3.12(s,3H).
LC-MS,M/Z(ESI):578.1[M+H]
+。
实施例8:目标化合物I-8的制备
(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b] 吡啶-3-基)苯基)(吗啉代)甲酮(目标化合物I-8)
目标化合物I-8的合成路线如下所示:
第一步:(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(吗啉代)甲酮的合成
在25℃氮气保护下,向N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-胺(A2)(0.3g,0.467mmol),吗啉代(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲酮(0.222g,0.700mmol)的1,4-二氧六环(8mL)和水(1.5mL)的混合溶液中加入碳酸钾(0.097g,0.700mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.034g,0.047mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-0:1,然后乙酸乙酯:甲醇=100:1-20:1)得到黄色固体(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(吗啉代)甲酮(200mg,产率60.7%)。
第二步:(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(吗啉代)甲酮(I-8)的合成
在25℃下,向(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(吗啉代)甲酮(0.2g,0.283mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(3.00mL)。反应液在25℃下搅拌18小时。将反应液浓缩得到粗品,然后将粗品溶解在乙腈(3mL)中,向反应液中加入3mL氨水(25%)。反应液在25℃下搅拌1小时。反应液用10mL二氯甲烷稀释,有机相用水(5mL×3)洗。收集有机相,用无水Na
2SO
4干燥,过滤,浓缩得到粗品。粗品用制备硅胶板分离纯化(乙酸乙酯:甲醇=10:1)得到(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(吗啉代)甲酮(I-8)(76.4mg,产率46.8%)。
1H NMR(400MHz,CD
3OD)δ8.08(d,J=5.6Hz,1H),7.82(d,J=8.4Hz,2H),7.53(s,1H),7.44(d,J=8.4Hz,2H),7.14(br s,2H),6.38(d,J=5.6Hz,1H),4.58-4.54(m,4H),4.46(s,2H),3.70-3.59(m,10H).
LC-MS,M/Z(ESI):576.2[M+H]
+。
实施例9:目标化合物I-9的制备
(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3-羟基-3-甲基氮杂环丁烷-1-基)甲酮(目标化合物I-9)
目标化合物I-9的合成路线如下所示:
第一步:(4-溴苯基)(3-羟基-3-甲基氮杂环丁烷-1-基)甲酮的合成
在25℃氮气保护下,向4-溴苯甲酸(0.5g,2.487mmol)的二氯甲烷(10mL)溶液中加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(0.715g,3.73mmol),1-羟基苯并三唑(0.504g,3.73mmol)和三乙胺(0.693ml,4.97mmol)。反应混合物在25℃氮气保护下搅拌10分钟。然后在25℃氮气保护下将3-甲基氮杂环丁烷-3-醇盐酸盐(0.369g,2.98mmol)加入到反应液中。反应混合物在25℃氮气保护下搅拌3小时。反应结束后,反应液用二氯甲烷(20mL)稀释,有机相用饱和NaHCO
3(20mL)水溶液洗。收集有机相再用0.5N HCl(20mL)水溶液洗。有机相用无水Na
2SO
4干燥,过滤,浓缩得到黄色油状物(4-溴苯基)(3-羟基-3-甲基氮杂环丁烷-1-基)甲酮(650mg,产率97%)。
第二步:(3-羟基-3-甲基氮杂环丁烷-1-基)(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲酮的合成
在25℃氮气保护下,向(4-溴苯基)(3-羟基-3-甲基氮杂环丁烷-1-基)甲酮(650mg,2.406mmol)和双联频那醇硼酸酯(1222mg,4.81mmol)的1,4-二氧六环(10mL)溶液中加入无水醋酸钾(472mg,4.81mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(176mg,0.241mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-5:1)得到黄色固体(3-羟基-3-甲基氮杂环丁烷-1-基)(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲酮(0.3g,产率39.3%)。
第三步:(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3-羟基-3-甲基氮杂环丁烷-1-基)甲酮的合成
在25℃氮气保护下,向N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-胺(A2)(0.3g,0.467mmol),(3-羟基-3-甲基氮杂环丁烷-1-基)(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲酮(0.222g,0.700mmol)的1,4-二氧六环(8mL)和水(1.5mL)的混合溶液中加入碳酸钾(0.129g,0.934mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.034g,0.047mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-0:1,然后乙酸乙酯:甲醇=100:1-20:1)得到黄色固体(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3-羟基-3-甲基氮杂环丁烷-1-基)甲酮(0.2g,产率60.7%)。
第四步:(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3-羟基-3-甲基氮杂环丁烷-1-基)甲酮(目标化合物I-9)
在25℃下,向(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3-羟基-3-甲基氮杂环丁烷-1-基)甲酮(0.2g,0.283mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(3.00mL)。反应液在25℃下搅拌18小时。将反应液浓缩得到粗品,然后将粗品溶解在乙腈(3mL)中,向反应液中加入3mL氨水(25%)。反应液在25℃下搅拌1小时。反应液用10mL二氯甲烷稀释,有机相用水(5mL×3)洗。收集有机相,用无水Na
2SO
4干燥,过滤,浓缩得到粗品。粗品用制备硅胶板分离纯化(乙酸乙酯:甲醇=10:1)得到(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3-羟基-3-甲基氮杂环丁烷-1-基)甲酮(目标化合物I-9)(23.4mg,产率14.35%)。
1H NMR(400MHz,CD
3Cl)δ9.59(br s,1H),8.12-8.08(m,1H),7.73(d,J=8.0Hz,2H),7.64(d,J=8.4Hz,2H),7.34(s,1H),7.04(d,J=9.2Hz,2H),6.32(d,J=4.8Hz,1H),4.64-4.58(m,6H),4.30-4.18(m,4H),3.75(s,2H),1.57(s,3H).
LC-MS,M/Z(ESI):576.1[M+H]
+。
实施例10:目标化合物I-10的制备
4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺(目标化合物I-10)
目标化合物I-10的合成路线如下所示:
第一步:4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺(3)的合成
在25℃氮气保护下,向N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-胺(A2)(0.3g,0.467mmol)和N-(3-甲氧基丙基)-N-甲基4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酰胺(0.233g,0.700mmol)的1,4-二氧六环(6mL)和水(1mL)的混合溶液中加入K
2CO
3(0.129g,0.934mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.034g,0.047mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-0:1,然后,乙酸乙酯:甲醇=100:1-10:1)得到4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺(200mg,产率59.3%)。
第二步:4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺(目标化合物I-10)的合成
在25℃下,向4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺(200mg,0.277mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(3.00mL)。反应液在25℃下搅拌18小时。将反应液浓缩得到粗品,然后将粗品溶解在乙腈(3mL)中,向反应液中加入3mL氨水(25%)。反应液在25℃下搅拌1小时。反应液用10mL二氯甲烷稀释,有机相用水(5mL×3)洗。收集有机相,用无水Na
2SO
4干燥,过滤,浓缩得到粗品。粗品用制备硅胶板分离纯化(乙酸乙酯:甲醇=10:1)得到4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)-N-(3-甲氧基丙基)-N-甲基苯甲酰胺(目标化合物I-10)(70.5mg,产率43.0%)。
1H NMR(400MHz,CDCl
3)δ9.81(br s,1H),8.15(d,J=5.6Hz,1H),7.74(d,J=8.4Hz,2H),7.41(d,J=8.0Hz,2H),7.34(s,1H),7.09-7.07(m,2H),6.34(d,J=5.6Hz,1H),4.61-4.55(m,4H),4.48(s,2H),3.71(s,2H),3.62(br s,1H),3.49-3.18(m,6H),3.07-3.04(m,3H),1.98-1.80(m,2H)。
LC-MS,M/Z(ESI):592.2[M+H]
+。
实施例11:目标化合物I-11的制备
(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3-羟基-3-甲基氮杂环丁烷-1-基)甲酮(目标化合物I-11)
目标化合物I-11的合成路线如下所示:
第一步:(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)二甲基氧化膦的合成
在25℃氮气保护下,向N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-胺(A1)(0.3g,0.477mmol)和二甲基(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)氧化膦(0.267g,0.955mmol)的1,4-二氧六环(6mL)和水(1mL)的混合溶液中加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.035g,0.048mmol)和K
2CO
3(0.132g,0.955mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液浓缩得到粗品。粗品通过制备硅胶板分离纯化(乙酸乙酯:甲醇=10:1)得到(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)二甲基氧化膦(0.2g)。
第二步:(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3-羟基-3-甲基氮杂环丁烷-1-基)甲酮(目标化合物I-11)
在25℃下,向(4-(4-(4-(((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)二甲基氧化膦(0.2g,0.305mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(3.00mL)。反应液在25℃下搅拌5小时。将反应液浓缩得到粗品,然后将粗品溶解在乙腈(3mL)中,向反应液中加入3mL氨水(25%)。反应液在25℃下搅拌1小时。反应液用10mL二氯甲烷稀释,有机相用水(5mL×3)洗。收集有机相,用无水Na
2SO
4干燥,过滤,浓缩得到粗品。粗品用制备硅胶板分离纯化(乙酸乙酯:甲醇=10:1)得到(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3-羟基-3-甲基氮杂环丁烷-1-基)甲酮(目标化合物I-11)(79.9mg,产率49.9%)。
1H NMR(400MHz,CD
3OD)δ8.10(d,J=5.6Hz,1H),7.93-7.90(m,2H),7.80-7.75(m,2H),7.58(s,1H),7.01(d,J=10.4Hz,2H),6.42(d,J=5.6Hz,1H),3.97(s,2H),3.11(s,2H),1.82(s,3H),1.78(s,3H),1.08(s,6H).
LC-MS,M/Z(ESI):525.1[M+H]
+。
实施例12:目标化合物I-12的制备
(S)-(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3-氟吡咯烷-1-基)甲酮(目标化合物I-12)
目标化合物I-12的合成路线如下所示:
第一步:(S)-(4-溴苯基)(3-氟吡咯烷-1-基)甲酮的合成
在0℃氮气保护下,向4-溴苯甲酸(0.5g,2.487mmol)的二氯甲烷(10mL)溶液中加入乙基[3-(二甲胺基)丙基]碳二亚胺盐酸盐(0.715g,3.73mmol),1-羟基苯并三唑(0.504g,3.73mmol)和三乙胺(0.693ml,4.97mmol),反应混合物在0℃下搅拌0.5小时。然后,在0℃下将(S)-3-氟吡咯烷(0.332g,3.73mmol)分批加入到反应液中。反应混合物在氮气保护下25℃搅拌18小时。反应液用二氯甲烷(10mL)稀释,有机相用饱和碳酸氢钠水溶液(10mL×3)洗,收集有机相,用1M盐酸水溶液(10mL×3)洗,收集有机相,用无水Na
2SO
4干燥,过滤,浓缩得到黄色油状物(S)-(4-溴苯基)(3-氟吡咯烷-1-基)甲酮(0.65g,产率96%)。
第二步:(S)-(3-氟吡咯烷-1-基)(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲酮的合成
在25℃氮气保护下,向(S)-(4-溴苯基)(3-氟吡咯烷-1-基)甲酮(650mg,2.389mmol)和双联频那醇硼酸酯(910mg,3.58mmol)的1,4-二氧六环(8mL)溶液中加入无水醋酸钾(469mg,4.78mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(175mg,0.239mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-5:1)得到黄色固体(S)-(3-氟吡咯烷-1-基)(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲酮(600mg,产率79%)。
第三步:(S)-(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3-氟吡咯烷-1-基)甲酮的合成
在25℃氮气保护下,向N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-胺(A2)(0.3g,0.467mmol),(S)-(3-氟吡咯烷-1-基)(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲酮(0.194g,0.607mmol)的1,4-二氧六环(10mL)和水(1mL)的混合溶液中加入碳酸钾(0.129g,0.934mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.034g,0.047mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-0:1,然后乙酸乙酯:甲醇=100:1-20:1)得到黄色固体(S)-(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3-氟吡咯烷-1-基)甲酮(170mg,产率51.4%)。
第四步:(S)-(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3-氟吡咯烷-1-基)甲酮(目标化合物I-12)
在25℃下,向(S)-(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3-氟吡咯烷-1-基)甲酮(170mg,0.240mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(3.00mL)。反应液在25℃下搅拌18小时。将反应液浓缩得到粗品,然后将粗品溶解在乙腈(3mL)中,向反应液中加入3mL氨水(25%)。反应液在25℃下搅拌1小时。反应液用10mL二氯甲烷稀释,有机相用水(5mL×3)洗。收集有机相,用无水Na
2SO
4干燥,过滤,浓缩得到粗品。粗品用制备硅胶板分离纯化(乙酸乙酯:甲醇=10:1)得到(S)-(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3-氟吡咯烷-1-基)甲酮(目标化合物 I-12)(50.8mg,产率36.6%)。
1H NMR(400MHz,CD
3OD)δ8.09(d,J=5.6Hz,1H),7.82(d,J=8.4Hz,2H),7.58-7.53(m,3H),7.13(d,J=10.8Hz,2H),6.38(d,J=5.2Hz,1H),5.41-5.17(m,1H),4.58-4.54(m,4H),4.47(s,2H),3.87-3.70(m,4H),3.65(s,2H),2.32-2.04(m,2H).
LC-MS,M/Z(ESI):578.1[M+H]
+。
实施例13:目标化合物I-13的制备
(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3,3-二氟氮杂环丁烷-1-基)甲酮(目标化合物I-13)
目标化合物I-13的合成路线如下所示:
第一步:(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3,3-二氟氮杂环丁烷-1-基)甲酮的合成
在25℃氮气保护下,向N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-胺(A2)(0.3g,0.467mmol),(3,3-二氟氮杂环丁烷-1-基)(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲酮(0.226g,0.700mmol)的1,4-二氧六环(5mL)和水(1mL)的混合溶液中加入碳酸钾(0.129g,0.934mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.034g,0.047mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-0:1,然后乙酸乙酯:甲醇=100:1-20:1)得到粗品黄色固体(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3,3-二氟氮杂环丁烷-1-基)甲酮(310mg,产率93%)。
第二步:(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3,3-二氟氮杂环丁烷-1-基)甲酮(目标化合物I-13)
在25℃下,向(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3,3-二氟氮杂环丁烷-1-基)甲酮(310mg,0.436mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(3.00mL)。反应液在25℃下搅拌18小时。将反应液浓缩得到粗品,然后将粗品溶解在乙腈(3mL)中,向反应液中加入3mL氨水(25%)。反应液在25℃下搅拌1小时。反应液用10mL二氯甲烷稀释,有机相用水(5mL×3)洗。收集有机相,用无水Na
2SO
4干燥,过滤,浓缩得到粗品。粗品用制备硅胶板分离纯化(乙酸乙酯:甲醇=10:1)得到(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3,3-二氟氮杂环丁烷-1-基)甲酮(目标化合物I-13)(10.3mg,产率4.07%)。
1H NMR(400MHz,CD
3OD)δ8.09(d,J=5.6Hz,1H),7.86-7.84(m,2H),7.71-7.69(m,2H),7.56(s,1H),7.14(br s,2H),6.39(d,J=5.6Hz,1H),4.74-4.54(m,8H),4.46(s,2H),3.65 (s,2H).
LC-MS,M/Z(ESI):582.1[M+H]
+。
实施例14:目标化合物I-14的制备
(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3,3-二氟吡咯烷-1-基)甲酮(目标化合物I-14)
目标化合物I-14的合成路线如下所示:
第一步:(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3,3-二氟吡咯烷-1-基)甲酮的合成
在25℃氮气保护下,向N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-胺(A2)(0.3g,0.467 mmol),(3,3-二氟吡咯烷-1-基)(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲酮(0.236g,0.700mmol)的1,4-二氧六环(5mL)和水(1mL)的混合溶液中加入碳酸钾(0.129g,0.934mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.034g,0.047mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-0:1,然后乙酸乙酯:甲醇=100:1-20:1)得到粗品黄色固体(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3,3-二氟吡咯烷-1-基)甲酮(250mg,产率73.8%)。
第二步:(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3,3-二氟吡咯烷-1-基)甲酮(目标化合物I-14)
在25℃下,向(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3,3-二氟吡咯烷-1-基)甲酮(250mg,0.344mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(3.00mL)。反应液在25℃下搅拌18小时。将反应液浓缩得到粗品,然后将粗品溶解在乙腈(3mL)中,向反应液中加入3mL氨水(25%)。反应液在25℃下搅拌1小时。反应液用10mL二氯甲烷稀释,有机相用水(5mL×3)洗。收集有机相,用无水Na
2SO
4干燥,过滤,浓缩得到粗品。粗品用制备硅胶板分离纯化(乙酸乙酯:甲醇=10:1)得到(4-(4-(4-((2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(3,3-二氟吡咯烷-1-基)甲酮(目标化合物I-14)(15.2mg,产率7.41%)。
1H NMR(400MHz,CD
3OD)δ8.09(d,J=5.6Hz,1H),7.83(d,J=8.4Hz,2H),7.55(d,J=8.4Hz,3H),7.14(d,J=10.4Hz,2H),6.38(d,J=5.6Hz,1H),4.58-4.54(m,4H),4.48(s,2H),3.95(t,J=12.8Hz,2H),3.85-3.82(m,2H),3.65(s,2H),2.47-2.40(m,2).
LC-MS,M/Z(ESI):596.2[M+H]
+。
实施例15:目标化合物I-15的制备
氮杂环丁烷-1-基(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)甲酮(目标化合物I-15)
目标化合物I-15的合成路线如下所示:
第一步:氮杂环丁烷-1-基(4-溴苯基)甲酮的合成
在0℃氮气保护下,向4-溴苯甲酸(0.6g,2.98mmol)的二氯甲烷(10mL)溶液中加入乙基[3-(二甲胺基)丙基]碳二亚胺盐酸盐(0.858g,4.48mmol),1-羟基苯并三唑(0.605g,4.48mmol)和三乙胺(0.832ml,5.97mmol),反应混合物在0℃下搅拌0.5小时。然后,在0℃下将氮杂环丁烷盐酸盐(0.419g,4.48mmol)分批加入到反应液中。反应混合物在氮气保护下25℃搅拌18小时。反应液用二氯甲烷(10mL)稀释,有机相用饱和碳酸氢钠水溶液(10mL×3)洗,收集有机相,用1M盐酸水溶液(10mL×3)洗,收集有机相,用无水Na
2SO
4干燥,过滤,浓缩得到黄色油状物氮杂环丁烷-1-基(4-溴苯基)甲酮(0.7g,产率98%)。
第二步:氮杂环丁烷-1-基(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲酮的合成
在25℃氮气保护下,向氮杂环丁烷-1-基(4-溴苯基)甲酮(0.7g,2.92mmol)和双联频那醇硼酸酯(1.111g,4.37mmol)的1,4-二氧六环(8mL)溶液中加入无水醋酸钾(0.572g,5.83mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.213g,0.292mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-5:1)得到黄色固体氮杂环丁烷-1-基(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲酮(800mg,产率96%)。
第三步:氮杂环丁烷-1-基(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)甲酮的合成
在25℃氮气保护下,向N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-胺(A1)(0.5g,0.796mmol),氮杂环丁烷-1-基(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲酮(0.343g,1.193mmol)的1,4-二氧六环(10mL)和水(1mL)的混合溶液中加入碳酸钾(0.220g,1.591mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.058g,0.080mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-0:1,然后乙酸乙酯:甲醇=100:1-20:1)得到粗品黄色固体氮杂环丁烷-1-基(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)甲酮(300mg)。
第四步:氮杂环丁烷-1-基(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)甲酮(目标化合物I-15)
在25℃下,向氮杂环丁烷-1-基(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6- 二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)甲酮(0.3g,0.453mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(3.00mL)。反应液在25℃下搅拌18小时。将反应液浓缩得到粗品,然后将粗品溶解在乙腈(3mL)中,向反应液中加入3mL氨水(25%)。反应液在25℃下搅拌1小时。反应液用10mL二氯甲烷稀释,有机相用水(5mL×3)洗。收集有机相,用无水Na
2SO
4干燥,过滤,浓缩得到粗品。粗品用制备硅胶板分离纯化(乙酸乙酯:甲醇=10:1)得到氮杂环丁烷-1-基(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)甲酮(目标化合物I-15)(70.8mg,产率29.4%)。
1H NMR(400MHz,CD
3OD)δ8.09(d,J=5.6Hz,1H),7.82(d,J=8.0Hz,2H),7.64(d,J=8.4Hz,2H),7.54(s,1H),6.99(d,J=10.8Hz,2H),6.41(d,J=5.6Hz,1H),4.43(t,J=7.6Hz,2H),4.20(t,J=8.0Hz,2H),3.94(s,2H),3.10(s,2H),2.40-2.33(m,2H),1.07(s,6H).
LC-MS,M/Z(ESI):532.2[M+H]
+。
实施例16:目标化合物I-16的制备
环丙基(4-(4-(4-(((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,6-二氢吡啶-1(2H)-基)甲酮(目标化合物I-16)
目标化合物I-16的合成路线如下所示:
第一步:环丙基(4-(4-(4-(((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧 基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,6-二氢吡啶-1(2H)-基)甲酮的合成
在25℃氮气保护下,向N-(3,5-二氟-4-((3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2,6-二氧杂-8-氮杂螺[3.5]壬-7-烯-7-胺(A1)(0.2g,0.318mmol),环丙基(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-5,6-二氢吡啶-1(2H)-基)甲酮(0.097g,0.350mmol)的1,4-二氧六环(5mL)和水(1mL)的混合溶液中加入碳酸钠(0.067g,0.636mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.023g,0.032mmol)。反应混合物在80℃氮气保护下搅拌18小时。反应结束后,反应液用硅藻土过滤,滤液浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-0:1,然后乙酸乙酯:甲醇=100:1-20:1)得到黄色油状物环丙基(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,6-二氢吡啶-1(2H)-基)甲酮(80mg,产率38.6%)。
第二步:环丙基(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,6-二氢吡啶-1(2H)-基)甲酮(目标化合物I-16)
在25℃下,向环丙基(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,6-二氢吡啶-1(2H)-基)甲酮(80mg,0.123mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(3.00mL)。反应液在25℃下搅拌18小时。将反应液浓缩得到粗品,然后将粗品溶解在乙腈(3mL)中,向反应液中加入3mL氨水(25%)。反应液在25℃下搅拌1小时。反应液用10mL二氯甲烷稀释,有机相用水(5mL×3)洗。收集有机相,用无水Na
2SO
4干燥,过滤,浓缩得到粗品。粗品用制备硅胶板分离纯化(乙酸乙酯:甲醇=10:1)得到环丙基(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,6-二氢吡啶-1(2H)-基)甲酮(目标化合物I-16)(27.1mg,产率42.3%)。
1H NMR(400MHz,CD
3OD)δ8.03(d,J=5.6Hz,1H),7.32(d,J=3.6Hz,1H),7.07(d,J=9.6Hz,2H),6.35(d,J=5.6Hz,1H),6.10(d,J=21.6Hz,1H),4.41(d,J=2.0Hz,1H),4.17(d,J=2.4Hz,1H),4.05(s,2H),3.97(t,J=5.6Hz,1H),3.79(t,J=5.6Hz,1H),3.14(s,2H),2.78(s,1H),2.66(s,1H),2.07-2.00(m,1H),1.10(s,6H),0.92-0.87(m,2),084-0.79(m,2).
LC-MS,M/Z(ESI):522.2[M+H]
+。
实施例17:目标化合物I-17的制备
氮杂环丁烷-1-基(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)环己基-3-烯-1-基)甲酮(目标化合物I-17)
目标化合物I-17线如下所示:
第一步:4-(4-(((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)环己-3-烯-1-羧酸甲酯的合成
在25℃氮气保护下,向N-(4-((3-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3,5-二氟苯基)-5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-胺(A3)(1g,1.720mmol)的1,4-二氧六环(10ml)和水(1ml)的混合溶液中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)环己基-3-烯基羧酸甲酯(0.549g,2.064mmol),K
2CO
3(0.475g,3.44mmol)和四(三苯基膦)钯(0.199g,0.172mmol)。反应混合物在氮气保护下100℃搅拌18小时。反应液用硅藻土过滤,滤液浓缩得到粗品,粗品用硅胶色谱柱纯化(PE:EA=10:1-0:1,然后用EA:MeOH=100:1-20:1)得到黄色油状物甲基4-(4-(((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)环己-3-烯-1-羧酸酯(1.0g,产率91%)
第二步:4-(4-(4-(((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)环己-3-烯-1-羧酸的合成
在25℃下,向4-(4-(((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)环己-3-烯-1-羧酸甲酯(1.0g,1.561mmol)的甲醇(10ml)和水(2ml)的混合溶液中加入氢氧化锂一水合物(0.131g,3.12mmol)。反应混合物在25℃下搅拌18小时。反应结束后,将反应液浓缩的到粗品。粗品用20mL水溶解,然后用乙酸乙酯(10mL)萃取,收集水相,调pH到3-4,然后水相用乙酸乙酯(10mL×3)萃取,收集有机相,用无水硫酸钠干燥,过滤,滤液浓缩得到黄色固体4-(4-(4-(((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)环己-3-烯-1-羧酸(500mg,产率51.1%)。
第三步:氮杂环丁烷-1-基(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)环己-3-烯-1-基)甲酮的合成
在25℃氮气保护下,向4-(4-(4-(((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)环己-3-烯-1-羧酸(500mg,0.798mmol)的二氯甲烷(10mL)的溶液中加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(229mg,1.197mmol),1-羟基苯并三唑(162mg,1.197mmol)和三乙胺(0.278ml,1.994mmol),反应混合物在氮气保护下搅拌10分钟,然后将氮杂环丁烷盐酸盐(112mg,1.197mmol)分批加入到反应混合物中。反应混合物在25℃氮气保护下搅拌18小时。反应结束后,反应液用二氯甲烷(10mL)稀释,混合物用先后用饱和碳酸氢钠水溶液(10mL)和0.5M的氯化氢水溶液(10mL)洗,收集有机相,用无水硫酸钠干燥,过滤,浓缩得到粗品,粗品用硅胶柱分离纯化(石油醚:乙酸乙酯=100:1-0:1,然后乙酸乙酯:甲醇=100:1-20:1)得到粗品黄色固体氮杂环丁烷-1-基(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)环己-3-烯-1-基)甲酮(300mg)。
第四步:氮杂环丁烷-1-基(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)环己基-3-烯-1-基)甲酮(目标化合物I-17)
在25℃下,向氮杂环丁烷-1-基(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)环己-3-烯-1-基)甲酮(6)(0.3g,0.451mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(3.00mL)。反应液在25℃下搅拌18小时。将反应液浓缩得到粗品,然后将粗品溶解在乙腈(3mL)中,向反应液中加入3mL氨水(25%)。反应液在25℃下搅拌1小时。反应液用10mL二氯甲烷稀释,有机相用水(5mL×3)洗。收集有机相,用无水Na
2SO
4干燥,过滤,浓缩得到粗品。粗品用制备硅胶板分离纯化(乙酸乙酯:甲醇=10:1)得到氮杂环丁烷-1-基(4-(4-(4-((5,5-二甲基-5,6-二氢-4H-1,3-恶嗪-2-基)氨基)-2,6-二氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)环己基-3-烯-1-基)甲酮(目标化合物I-17)(54.5mg,产率22.59%)。
1H NMR(400MHz,CDCl
3)δ9.14(s,1H),8.07(d,J=5.4Hz,1H),7.11(s,1H),7.00-6.95 (m,2H),7.54(s,1H),6.31(d,J=5.4Hz,1H),6.08-6.07(m,1H),4.21(t,J=7.6Hz,2H),4.03(t,J=8.0Hz,2H),3.92(s,2H),3.16(s,2H),2.71-2.67(m,1H),2.52-2.46(m,3H),2.31-2.20(m,3H),1.92-1.86(m,2H),1.10(s,6H).
LC-MS,M/Z(ESI):536.5[M+H]
+。
测试例1:重组HPK1酶体外酶活抑制IC50评价试验
采用Lantha screen Assay检测实施例1~17所制备的化合物对HPK1激酶的抑制作用。
HPK1激酶反应体系为10μL,各组分终浓度如下:0.5nM HPK1重组酶(Carna,Cat.NO.07-410)、不同浓度梯度的小分子抑制剂、10mM MgCl
2、4mM DTT、2.5μM ATP、0.1μM FITC-PKC(Invitrogen,Cat.NO.PV3506)、0.01%Tween-20、0.01%BSA和PH 7.5的50mM HEPES。具体的,首先将2×的HPK1重组酶与2×的待测化合物加入384孔板中的缓冲液体系中室温孵育10分钟,同时设定不含酶的阴性对照孔、不含化合物的阳性对照孔和加入同样浓度的对照化合物1的对照孔,然后加入2×的多肽底物与ATP,反应开始,室温孵育90分钟后加入10μL相应的2×的磷酸化抗体Tb-pSer(PKC)Antibody(Invitrogen,Cat.NO.PV3536)和EDTA混合液来终止反应,室温放置60分钟。Envision 2104 Multilabel Reader上读取在340nm处激发,520nm和495nm处发射的数值,计算RFU 520nm/RFU 495nm,通过以下公式计算抑制率,然后以抑制剂的浓度Log值为X轴,抑制率为Y轴绘制曲线,用Graphpad 7.0计算得出IC
50。
Inhibition%=(max-Lantha signal ratio)/(max-min)*100
“min”为不加酶进行反应的阴性对照孔读数;“max”为不加入化合物的阳性对照孔读数。
表1:测试化合物对重组HPK1酶体外抑制活性
测试化合物 | IC 50(nM) |
对照化合物1 | 18.1 |
I-1 | 0.70 |
I-2 | 0.40 |
I-3 | 0.72 |
I-4 | 0.66 |
I-5 | 0.74 |
I-6 | 0.63 |
I-7 | 0.82 |
I-8 | 0.41 |
I-9 | 0.62 |
I-10 | 0.81 |
I-11 | 2.28 |
I-12 | 0.37 |
I-13 | 0.65 |
I-14 | 0.55 |
I-15 | 0.35 |
I-16 | 2.45 |
I-17 | 0.53 |
体外酶试验结果表明,本发明化合物对HPK1酶具有良好的抑制作用,抑制活性显著优于对照化合物。
测试例2:Jurkat phospho-SLP76(Ser376)ELISA试验
采用Jurkat细胞来评价实施例1~17合成的化合物对细胞内HPK1酶活抑制活性。细胞用RPMI1640完全培养基(RPMI-1640,10%胎牛血清,1%Pen/Strep)进行培养。300×g离心10分钟收集细胞,使用不含FBS的RPMI-1640重悬细胞,按照1×10
5个细胞每孔接种于96孔细胞培养板中,将稀释好的不同浓度梯度的待测化合物加入96孔板,同时设定不含化合物的阳性对照孔、只含有培养基的空白对照孔和加入与待测化合物同样浓度的对照化合物1的对照孔,然后在37℃、含5%CO
2的培养箱中孵育1小时,然后加入终浓度为1ug/mL的anti-human CD3(OKT-3)刺激30分钟,同时设定不含刺激剂OKT-3的阴性对照孔,将96孔板置于水平离心机中1200rpm离心1分钟,缓慢吸弃上清培养基,之后加入预冷的裂解液至细胞孔中,冰上放置30分钟以充分裂解细胞,将细胞裂解液转移至预包被的ELISA板中,使用
Phospho-SLP76(Ser376)Sandwich ELISA Kit(CST,78222C),按照供应商的操作流程检测细胞内Phospho-SLP76水平。酶标仪检测的450nm下吸光度信号值,通过以下公式计算抑制率,然后以化合物的浓度Log值为X轴,抑制率为Y轴绘制曲线,用Graphpad 7.0计算得出IC
50。
Inhibition%=(max-化合物孔吸光度值)/(max-min)*100
“min”为不加刺激剂OKT-3孵育的阴性对照孔吸光度值;“max”为不加入化合物孵育的阳性对照孔吸光度值。
表2:测试化合物对Jurkat phospho-SLP76(Ser376)体外抑制活性
测试化合物 | IC 50(nM) |
对照化合物1 | 656 |
I-1 | 182 |
I-2 | 49.1 |
I-3 | 174 |
I-4 | 386 |
I-5 | 366 |
I-7 | 210 |
细胞试验结果表明,本发明化合物对HPK1酶具有良好的抑制作用,抑制活性显著优于对照化合物。
Claims (18)
- 式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:其中,R 1独立地为H、氰基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、C 1-C 6烷基、C 3-C 6环烷基或-O-(C 1-C 6烷基);环A独立地为6-10元芳基、5-8元杂芳基、4-8元杂环烷基、4-8元杂环烯基或C 3-C 10环烯基;R 21和R 22各自独立地为未取代或被R 211取代的C 1-C 6烷基、或、未取代或被R 211取代的C 3-C 6环烷基;所述的被R 211取代的C 1-C 6烷基或被R 211取代的C 3-C 6环烷基中,所述的R 211取代可以是一个或多个取代,所述的R 211各自独立地为下列取代基:羟基、卤素、-O-(C 1-C 6烷基)、C 1-C 6烷氨基或C 3-C 6环烷基;当取代基为多个时,所述的取代基相同或不同;所述R 21和R 22至少一个为被R 211取代的C 1-C 6烷基或被R 211取代的C 3-C 6环烷基;环B独立地为未取代或被R 23取代的4-8元杂环烷基、或、未取代或被R 23取代的6-11元杂螺环烷基;所述的被R 23取代的4-8元杂环烷基或被R 23取代的6-11元杂螺环烷基中,所述的R 23取代可以是一个或多个取代,所述R 23各自独立地为下列取代基:羟基、氰基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、C 1-C 6烷基或C 3-C 6环烷基;当取代基为多个时,所述的取代基相同或不同;R 24独立地为未取代或被R 241取代的C 3-C 6环烷基;所述的被R 241取代的C 3-C 6环烷基中,所述的R 241取代可以是一个或多个取代,所述R 241各自独立地为下列取代基:氰基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、C 1-C 6烷基或C 3-C 6环烷基;当取代基为多个时,所述的取代基相同或不同;R 3独立地为卤素、CN、被1-5个相同或不同的卤素取代的C 1-C 6烷基或C 1-C 6烷基;n为0、1、2或3;R 4和R 5各自独立地为被1-5个相同或不同的卤素取代的C 1-C 6烷基或C 1-C 6烷基;或R 4和R 5与其共同相连的碳原子可以形成4-8元环烷基或4-8元杂环烷基。
- 如权利要求1所述的化合物,其特征在于,当环A为6-10元芳基时,所述6-10元芳基为苯或萘,较佳地为苯;和/或,当环A为5-8元杂芳基时,所述5-8元杂芳基为吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、噻唑基、噻二唑基、吡啶基、吡嗪基、吡唑基、哒嗪基、嘧啶基或三嗪基,较佳地为吡咯基、噁唑基、噻唑基或吡啶基;和/或,当环A为4-8元杂环烷基时,所述4-8元杂环烷基为氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、吡唑烷基、咪唑烷基、噁唑烷基、吗啉基、吡咯烷基、吗啉基或哌嗪基,较佳地为氮杂环丁基、吗啉基或吗啉基;和/或,当环A为4-8元杂环烯基时,所述4-8元杂环烯基为4H-吡喃基、2H-吡喃基、四氢吡啶基、2,5-二氢-1H-吡咯基、2,5-二氢呋喃基、2,3-二氢呋喃基、2,5-二氢噻吩基、2,3-二氢噻吩基或4,5-二氢噁唑基,较佳地为四氢吡啶基;和/或,当环A为C 3-C 10环烯基时,所述C 3-C 10环烯基为环丙烯基、环丁烯基、环戊烯基、环己烯基或环庚烯基,较佳地为环己烯基;和/或,当R 21和R 22为未取代或被R 211取代的C 1-C 6烷基时,所述C 1-C 6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或仲丁基,较佳地为甲基、乙基、正丙基或异丁基;和/或,当R 21和R 22为未取代或被R 211取代的C 3-C 6环烷基时,所述C 3-C 6环烷基为环丙基、环丁基、环戊基或环己基,较佳地为环丙基或环丁基;和/或,R 21和R 22为被R 211取代的C 1-C 6烷基或被R 211取代的C 3-C 6环烷基时,所述R 211取代个数为1个、2个、3个、4个或5个,较佳地为1个或2个;和/或,R 211为羟基;和/或,当R 211为卤素时,所述卤素为F、Cl、Br或I,较佳地为F或Cl;和/或,当R 211为-O-(C 1-C 6烷基)时,所述C 1-C 6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,较佳地为甲基、乙基、正丙基或异丙基;和/或,当R 211为C 1-C 6烷氨基时,所述C 1-C 6烷氨基为-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)CH 2CH 3、-NHCH 2CH 2CH 3或-NHCH 2(CH 3) 2,较佳地为-NHCH 3、-N(CH 3) 2或-NHCH 2CH 3;和/或,当R 211为C 3-C 6环烷基时,所述C 3-C 6环烷基为环丙基、环丁基、环戊基或环己基,较佳地为环丙基或环丁基;和/或,当环B为未取代或被R 23取代的4-8元杂环烷基时,所述4-8元杂环烷基为氮杂环丙基、氮杂环丁基、氮杂环戊基、氮杂环己基、吡咯烷基、吡唑烷基、咪唑烷基、噁唑烷基、吗啉基、吡咯烷基、哌啶基或哌嗪基,较佳地为氮杂环丁基、氮杂环戊基或吗啉基;和/或,当环B为未取代或被R 23取代的6-11元杂螺环烷基时,所述6-11元杂螺环烷基较佳地为氮杂螺[3.3]庚基、氧杂氮杂螺[3.3]庚基、硫杂氮杂螺[3.3]庚基或氧氮杂螺[5.3]壬基,更佳地为氧杂氮杂螺[3.3]庚基;和/或,环B为被R 23取代的4-8元杂环烷基或被R 23取代的6-11元杂螺环烷基时,所述R 23取代个数为1个、2个、3个、4个或5个,较佳地为1个或2个;和/或,R 23为羟基;和/或,R 23为氰基;和/或,当R 23为卤素时,所述卤素为F、Cl、Br或I,较佳地为F或Cl;和/或,当R 23为被1-5个相同或不同的卤素取代的C 1-C 6烷基时,所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基,较佳地为甲基或乙基;和/或,当R 23为被1-5个相同或不同的卤素取代的C 1-C 6烷基时,所述卤素为F、Cl、Br或I,较佳地为F或Cl;和/或,当R 23为被1-5个相同或不同的卤素取代的C 1-C 6烷基时,所述卤素的个数为1个、2个、3个、4个或5个,较佳地为1个、2个或3个;和/或,当R 23为C 1-C 6烷基时,所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基,较佳地为甲基;和/或,当R 23为C 3-C 6环烷基时,所述C 3-C 6环烷基为环丙基、环丁基、环戊基或环己基,较佳地为环丙基或环丁基;和/或,当R 24为未取代或被R 241取代的C 3-C 6环烷基时,所述C 3-C 6环烷基为环丙基、环丁基、环戊基或环己基,较佳地为环丙基或环丁基;和/或,当R 24为未取代或被R 241取代的C 3-C 6环烷基时,所述R 241取代个数为1个、2个、3个、4个或5个,较佳地为1个或2个;和/或,R 241为氰基;和/或,当R 241为卤素时,所述卤素为F、Cl、Br或I,较佳地为F或Cl;和/或,当R 241为被1-5个相同或不同的卤素取代的C 1-C 6烷基时,所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基,较佳地为甲基或乙基;和/或,当R 241为被1-5个相同或不同的卤素取代的C 1-C 6烷基时,所述卤素为F、Cl、Br或I,较佳地为F或Cl;和/或,当R 241为被1-5个相同或不同的卤素取代的C 1-C 6烷基时,所述卤素的个数为1个、2个、3个、4个或5个,较佳地为1个、2个或3个;和/或,当R 241为C 1-C 6烷基时,所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基,较佳地为甲基或乙基;和/或,当R 241为C 3-C 6环烷基时,所述C 3-C 6环烷基为环丙基、环丁基、环戊基或环己基,较佳地为环丙基或环丁基;和/或,n为0、1或2;和/或,当R 3为卤素时,所述卤素为F、Cl、Br或I,较佳地为F或Cl;和/或,当R 3为被1-5个相同或不同的卤素取代的C 1-C 6烷基时,所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基,较佳地为甲基或乙基;和/或,当R 3为被1-5个相同或不同的卤素取代的C 1-C 6烷基时,所述卤素为F、Cl、Br或I,较佳地为F或Cl;和/或,当R 3为被1-5个相同或不同的卤素取代的C 1-C 6烷基时,所述卤素的个数为1个、2个、3个、4个或5个,较佳地为1个、2个或3个;和/或,当R 3为C 1-C 6烷基时,所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基,较佳地为甲基或乙基。
- 如权利要求1所述的化合物,其特征在于,当R 4和R 5为C 1-C 6烷基时,所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基,较佳地为甲基;和/或,当R 4和R 5为被1-5个相同或不同的卤素取代的C 1-C 6烷基时,所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基,较佳地为甲基或乙基;和/或,当R 4和R 5为被1-5个相同或不同的卤素取代的C 1-C 6烷基时,所述卤素为F、Cl、Br或I,较佳地为F或Cl;和/或,当R 4和R 5为被1-5个相同或不同的卤素取代的C 1-C 6烷基时,所述卤素的个数为1个、2个、3个、4个或5个,较佳地为1个、2个或3个;和/或,R 4和R 5与其共同相连的碳原子形成4-8元杂环烷基时,所述4-8元杂环烷基为氮杂环丙基、氧杂环丙基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、吡咯烷基、四氢呋喃基、吡唑烷基、咪唑烷基、噁唑烷基、吗啉基、吡咯烷基、哌啶基或哌嗪基,较佳地为氧杂环丁基。
- 一种药物组合物,其特征在于,其包含如权利要求1-9中任一项所述的如式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药。
- 根据权利要要求10所述的药物组合物,其特征在于,进一步包括药学上可接受的赋形剂。
- 根据权利要求1-9中任一项所述的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药与PD-1/PD-L1/CTLA-4抗体或者PD-1/PD-L1/CTLA-4抑制剂联用在制备用于治疗或预防与HPK1相关疾病药物中的用途。
- 根据权利要求1-9中任一项所述的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药、或如权利要求10或11所述的药物组合物在制备用于治疗或预防与HPK1相关疾病药物中的用途。
- 根据权利要求12或13所述的用途,其特征在于,所述HPK1相关疾病包括选自下列的至少之一:实体瘤、血液癌症、非小细胞肺癌、小细胞肺癌、皮肤黑色素瘤、梅克尔细胞癌、头颈部鳞状细胞癌、肛管或皮肤的鳞状细胞癌、尿路上皮癌、透明细胞或非透明细胞肾细胞癌、三阴性乳腺癌、子宫内膜癌、宫颈癌、胃食管癌和肝细胞癌。
- 一种治疗或预防与HPK1相关疾病的方法,其特征在于,给与患者药学上可接受的权利要求1-9中任一项所述的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药、或如权利要求10或11所述的药物组合物。
- 根据权利要求15所述的方法,其特征在于,所述HPK1相关疾病包括选自下列的至少之一:实体瘤、血液癌症、非小细胞肺癌、小细胞肺癌、皮肤黑色素瘤、梅克尔细胞癌、头颈部鳞状细胞癌、肛管或皮肤的鳞状细胞癌、尿路上皮癌、透明细胞或非透明细胞肾细胞癌、三阴性乳腺癌、子宫内膜癌、宫颈癌、胃食管癌和肝细胞癌。
- 权利要求1-9中任一项所述的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药、或如权利要求10或11所述的药物组合物,用于治疗或预防与HPK1相关疾病。
- 根据权利要求17所述的化合物或药物组合物,所述HPK1相关疾病包括选自下列的至少之一:实体瘤、血液癌症、非小细胞肺癌、小细胞肺癌、皮肤黑色素瘤、梅克尔细胞癌、头颈部鳞状细胞癌、肛管或皮肤的鳞状细胞癌、尿路上皮癌、透明细胞或非透明细胞肾细胞癌、三阴性乳腺癌、子宫内膜癌、宫颈癌、胃食管癌和肝细胞癌。
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