WO2022188823A1 - 三并环类hpk1抑制剂及其用途 - Google Patents
三并环类hpk1抑制剂及其用途 Download PDFInfo
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- WO2022188823A1 WO2022188823A1 PCT/CN2022/080065 CN2022080065W WO2022188823A1 WO 2022188823 A1 WO2022188823 A1 WO 2022188823A1 CN 2022080065 W CN2022080065 W CN 2022080065W WO 2022188823 A1 WO2022188823 A1 WO 2022188823A1
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- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- amino
- alkoxy
- membered
- independently selected
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims abstract description 249
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- -1 mercapto, amino Chemical group 0.000 claims description 471
- 125000000217 alkyl group Chemical group 0.000 claims description 248
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- 239000001257 hydrogen Substances 0.000 claims description 95
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- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- BTZNPZMHENLISZ-UHFFFAOYSA-M fluoromethanesulfonate Chemical compound [O-]S(=O)(=O)CF BTZNPZMHENLISZ-UHFFFAOYSA-M 0.000 description 1
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- 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 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
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- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
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- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
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- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
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- 239000011777 magnesium Substances 0.000 description 1
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- VPYWSRKVRAEDHI-UHFFFAOYSA-N methyl 1h-azepine-2-carboxylate Chemical compound COC(=O)C1=CC=CC=CN1 VPYWSRKVRAEDHI-UHFFFAOYSA-N 0.000 description 1
- YICRPERKKBDRSP-UHFFFAOYSA-N methyl 3-amino-4-methylthiophene-2-carboxylate Chemical compound COC(=O)C=1SC=C(C)C=1N YICRPERKKBDRSP-UHFFFAOYSA-N 0.000 description 1
- FVKMOPIFLCMZMI-UHFFFAOYSA-N methyl 3-amino-5-methylthiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C)=CC=1N FVKMOPIFLCMZMI-UHFFFAOYSA-N 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- OJEOJUQOECNDND-UHFFFAOYSA-N oxetan-3-amine Chemical compound NC1COC1 OJEOJUQOECNDND-UHFFFAOYSA-N 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- CRYATLIDHPPXDV-UHFFFAOYSA-N oxetene Chemical compound C1OC=C1 CRYATLIDHPPXDV-UHFFFAOYSA-N 0.000 description 1
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- 230000037361 pathway Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
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- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
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- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
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- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
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- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- RQGPLDBZHMVWCH-UHFFFAOYSA-N pyrrolo[3,2-b]pyrrole Chemical compound C1=NC2=CC=NC2=C1 RQGPLDBZHMVWCH-UHFFFAOYSA-N 0.000 description 1
- GZTPJDLYPMPRDF-UHFFFAOYSA-N pyrrolo[3,2-c]pyrazole Chemical compound N1=NC2=CC=NC2=C1 GZTPJDLYPMPRDF-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 102000027483 retinoid hormone receptors Human genes 0.000 description 1
- 108091008679 retinoid hormone receptors Proteins 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
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- 229940095064 tartrate Drugs 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- DFVRUHANEXOZGT-UHFFFAOYSA-N tert-butyl n-methyl-n-[2-(methylamino)ethyl]carbamate Chemical compound CNCCN(C)C(=O)OC(C)(C)C DFVRUHANEXOZGT-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- ONCNIMLKGZSAJT-UHFFFAOYSA-N thieno[3,2-b]furan Chemical compound S1C=CC2=C1C=CO2 ONCNIMLKGZSAJT-UHFFFAOYSA-N 0.000 description 1
- GKTQKQTXHNUFSP-UHFFFAOYSA-N thieno[3,4-c]pyrrole-4,6-dione Chemical compound S1C=C2C(=O)NC(=O)C2=C1 GKTQKQTXHNUFSP-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000002992 thymic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—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 invention belongs to the technical field of medicine, and specifically relates to a tricyclic HPK1 compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, and a stereoisomer thereof, comprising the compound, a pharmaceutically acceptable compound thereof
- Pharmaceutical compositions and formulations of salts and stereoisomers thereof, methods for preparing the compounds, pharmaceutically acceptable salts and stereoisomers thereof, and the compounds, pharmaceutically acceptable salts and stereoisomers thereof Use of isomers.
- T cell receptor (TCR)-mediated T cell activation plays an important role in thymic T cell development, T cell subset differentiation, and effector T cell function.
- TCR can recognize the MHC (major histocompatibility complex) on the surface of antigen-presenting cells, and then recognize the signal transmitted to the inside of the cell. Signal transmission leads to activation of downstream signaling pathways.
- Typical intracellular signals activated by TCR include signaling pathways such as MAPK (mitogen-activated protein kinase), PKC (protein kinase C), and calcium ions. Activation of these signals ultimately activates T cell-specific gene expression, causes cell proliferation, and allows T cells to differentiate into effector T cells. Endogenous or adoptively transferred effector T cells are important mediators of antitumor immunity.
- T cells Sustained antigen exposure leads to progressive differentiation of T cells into an exhausted state characterized by a hierarchical loss of effector function and proliferative capacity, as well as marked transcriptional, epigenetic, and metabolic changes. How to prevent T cell exhaustion and expand effector T cell function is one of the most pressing issues in tumor immunology.
- Hematopoietic progenitor kinase HPK1 (HematopoieticProgenitor Kinase1) is an immunosuppressive regulatory kinase with restricted expression in hematopoietic stem cells.
- HPK1 is a negative signaling regulator of the T cell receptor (TCR).
- TCR T cell receptor
- cytoplasmic HPK1 is recruited to the vicinity of the cell membrane, and the activated HPK1 phosphorylates the adaptor protein SLP76, thereby activating SLP76 as a docking site for the negative regulatory protein 14-3-3, which eventually leads to the instability of the TCR signaling complex. thereby downregulating TCR signaling.
- HPK1 also known as MAP4K1
- MAP4K1 is a member of the MAP4K family, which has five other members, MAP4K2 (GCK kinase), MAP4K3 (GLK kinase), MAP4K4 (HGK kinase), MAP4K5 (KHS kinase), and MAP4K6 (MINK kinase) .
- MAP4K2 GCK kinase
- MAP4K3 GLK kinase
- MAP4K4 HGK kinase
- MAP4K5 KHS kinase
- MAP4K6 MINK kinase
- the technical problem to be solved by the present invention is to provide a HPK1 inhibitor compound with novel structure and good inhibitory activity to HPK1. Further, the compounds can be used to inhibit the kinase activity of HPK1, thereby enhancing the immune effect of the body against tumors. Furthermore, the compounds can also be used to treat or prevent related diseases mediated by HPK1, especially cancer. The compounds have good inhibitory effect on various cancer cells and have good druggability.
- the present invention provides a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
- X 1 and Y 1 are each independently selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-;
- X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-;
- Y 2 and Y 4 are independently selected from -C(R 2 ) or -N-;
- Y 3 is selected from -C(R 5 ) or -N-;
- Y 5 is selected from -C(R 6 );
- Y 6 is selected from -C(R 7 ) or -N-;
- Each R 2 , R 3 , and each R 4 are independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1- 6 alkoxy or halogenated C 1-6 alkoxy;
- R 5 and R 7 together with R 6 and the ring atoms to which they are attached respectively form 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered optionally substituted by 1-5 Q1 A membered aryl group or a 5-10 membered heteroaryl group;
- the uncyclic R 5 or R 7 is selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1- 6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy;
- R 1 is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -NR a R b , -OR a , -SR a , -NR a -C(O)-R b -, -C(O)R a , -C(O)NR a , -C(O)OR a or any
- the following groups are selected to be substituted by substituents: -(CH 2 ) p -3-10 membered cycloalkyl, -(CH 2 ) p -3-10 membered heterocyclyl, -(CH 2 ) p -5-10 Heteroaryl, -(CH 2 ) p -6-10-membered aryl ; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxy
- Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR a R b , -OR a , -SR a , -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-3 Q2: C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, -(CH 2 ) m -3-10 membered cycloalkyl, -(CH 2 ) m -3-10 membered heterocyclyl, -(CH 2 ) m -5-10 membered heteroaryl or -( CH 2 ) m -6-10-membered aryl; the Q2 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy , halogen Substi
- Each R a and each R b are independently selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl , C 1-6 alkoxy, C 1-6 alkylamino , di(C 1-6 alkyl)amino, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkylthio, halogenated C 1-6 6 alkoxy, halogenated C 1-6 alkylthio, hydroxy C 1-6 alkoxy, hydroxy C 1-6 alkylthio, amino C 1-6 alkoxy, amino C 1-6 alkylthio Or the following groups optionally substituted by substituents: -(CH 2 ) m -3-10 membered cycloalkyl, -(CH 2 ) m -3-10 membered heterocyclyl, -(CH 2 ) m -5 -10-membered heteroaryl, -(CH 2
- Each m and each p are independently selected from 0, 1, 2, 3, 4, or 5.
- the compound represented by the aforementioned general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof has the following general formula (II-1) or general formula (II-2) the structure shown
- X 1 and Y 1 are each independently selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-;
- X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-;
- Y 2 and Y 4 are independently selected from -C(R 2 ) or -N-;
- Y 3 is selected from -C(R 5 ) or -N-;
- Y 6 is selected from -C(R 7 ) or -N-;
- Each R 2 , each R 3 , each R 4 , R 5 , R 7 is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1- 6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy;
- R 1 is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -NR a R b , -OR a , -SR a , -NR a -C(O)-R b -, -C(O)R a , -C(O)NR a , -C(O)OR a or any
- the following groups are selected to be substituted by substituents: -(CH 2 ) p -3-10 membered cycloalkyl, -(CH 2 ) p -3-10 membered heterocyclyl, -(CH 2 ) p -5-10 Heteroaryl, -(CH 2 ) p -6-10-membered aryl ; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxy
- Ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
- Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR a R b , -OR a , -SR a , -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-3 Q2: C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, -(CH 2 ) m -3-10 membered cycloalkyl, -(CH 2 ) m -3-10 membered heterocyclyl, -(CH 2 ) m -5-10 membered heteroaryl or -( CH 2 ) m -6-10-membered aryl; the Q2 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy , halogen Substi
- Each R a and each R b are independently selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl , C 1-6 alkoxy, C 1-6 alkylamino , di(C 1-6 alkyl)amino, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkylthio, halogenated C 1-6 6 alkoxy, halogenated C 1-6 alkylthio, hydroxy C 1-6 alkoxy, hydroxy C 1-6 alkylthio, amino C 1-6 alkoxy, amino C 1-6 alkylthio Or the following groups optionally substituted by substituents: -(CH 2 ) m -3-10 membered cycloalkyl, -(CH 2 ) m -3-10 membered heterocyclyl, -(CH 2 ) m -5 -10-membered heteroaryl, -(CH 2
- Each m, each n, and each p is independently selected from 0, 1, 2, 3, 4, or 5.
- X 1 and Y 1 are each independently selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-;
- X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-;
- Y 2 and Y 4 are independently selected from -C(R 2 ) or -N-;
- Y 3 is selected from -C(R 5 ) or -N-;
- Y 6 is selected from -C(R 7 ) or -N-;
- Each R 2 , R 3 , each R 4 , R 5 , R 7 is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkoxy;
- R 1 is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, -NR a R b , -OR a , -SR a , -NR a -C(O)-R b -, -C(O)R a , -C(O)NR a , -C(O)OR a or any The following groups are selected substituted by substituents: -( CH2 ) p -3-6 membered cycloalkyl, -( CH2 ) p -3-6 membered heterocyclyl, -( CH2 ) p -5-8 Member heteroaryl, -(CH 2 ) p -phenyl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 alkyl, C
- Ring A is selected from 5-10 membered cycloalkyl, 5-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
- Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR a R b , -OR a , -SR a , -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-3 Q2: C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, -(CH 2 ) m -3-8 membered cycloalkyl, -(CH 2 ) m -3-8 membered heterocyclyl, -(CH 2 ) m -5-8 membered heteroaryl or -( CH 2 ) m -phenyl; the Q2 are independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1- 4 alkyl,
- Each R a and each R b are independently selected from hydrogen, halogen, hydroxyl, nitro , amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino , Di(C 1-4 alkyl)amino, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, C 1-4 alkylthio , halogenated C 1-4 4 alkoxy, halogenated C 1-4 alkylthio, hydroxy C 1-4 alkoxy, hydroxy C 1-4 alkylthio, amino C 1-4 alkoxy, amino C 1-4 alkylthio Or the following groups optionally substituted by substituents: -(CH 2 ) m -3-8 membered cycloalkyl, -(CH 2 ) m - 3-8 membered heterocyclyl, -(CH 2 ) m -5 -8-membered heteroaryl, -(
- Each m, each n, and each p is independently selected from 0, 1, 2, or 3.
- X 1 and Y 1 are each independently selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-;
- X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-;
- Y 2 and Y 4 are independently selected from -C(R 2 )- or -N-;
- Y 3 is selected from -C(R 5 ) or -N-;
- Y 6 is selected from -C(R 7 ) or -N-;
- each R 2 , R 3 , each R 4 , R 5 , R 7 is independently selected from hydrogen, halogen, C 1-4 alkyl or haloC 1-4 alkyl;
- R 1 is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, -NR a -C(O)-R b -, -NR a R b , -OR a or the following groups optionally substituted with substituents: -(CH 2 ) p -3-6 membered cycloalkyl, -(CH 2 ) p -3-6 membered heterocyclyl; the substituents selected from halogen, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;
- Ring A is selected from 5-10 membered cycloalkyl or 5-10 membered heterocyclyl
- Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR a R b , -OR a , -C(O)R a , -C(O)OR a , -C( O) NR a or the following groups optionally substituted by 1-3 Q2: C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, - (CH 2 ) m -3-6 membered cycloalkyl, -(CH 2 ) m -3-6 membered heterocyclyl, -(CH 2 ) m -5-6 membered heteroaryl or -(CH 2 ) m -phenyl; the Q2 are independently selected from halogen, nitro, amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy
- Each R a and each R b are independently selected from hydrogen, halogen, hydroxyl, nitro , amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl group, halogenated C 1-4 alkoxy or the following groups optionally substituted by substituents: -(CH 2 ) m -3-8 membered cycloalkyl, -(CH 2 ) m -3-8 membered heterocyclic cyclic group; the substituent is selected from halogen, nitro , amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl;
- Each m, each n, and each p is independently selected from 0, 1, 2, or 3.
- X 1 , Y 1 are each independently selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-; each R 2 , each R 3 and each R 4 are independently selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
- X 1 , Y 1 are each independently selected from -C(R 2 )(R 3 )-, -O-, or -N(R 4 )-; each R 2 , each R 3 , each R4 is each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
- X 1 , Y 1 are each independently selected from CH 2 , O, or NH.
- Y 2 , Y 4 are each independently selected from -C(R 2 ) or -N-; each R 2 is independently selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
- Y 2 and Y 4 are independently selected from -C(R 2 ) or -N-; each R 2 is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
- R 7 is selected from hydrogen, halogen, C 1-6 alkyl, or haloC 1-6 alkyl.
- R7 is selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, or trifluoromethyl.
- R5 is hydrogen
- Y 2 is N.
- Y 3 , Y 4 are each independently selected from CH or N.
- X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-; each R 2.
- Each R 4 is independently selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
- X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-; each R 2.
- Each R4 is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
- one of X 2 , X 3 , X 4 is selected from S, O, N, or -N(R 4 )-, and the other two are each independently -C(R 2 )-; each R 2 and each R 4 are independently selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
- one of X 2 , X 3 , X 4 is selected from S, O, N, or -N(R 4 )-, and the other two are each independently -C(R 2 )-; each R 2 and each R 4 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
- one of X 2 , X 3 , X 4 is selected from -C(R 2 )-, and the other two are independently S, O, N, or -N(R 4 )-; each R 2 and each R 4 are independently selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
- one of X 2 , X 3 , X 4 is selected from -C(R 2 )-, and the other two are independently S, O, N, or -N(R 4 )-; each R 2 and each R 4 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
- one of X 2 , X 3 , X 4 is selected from S or O, and the other two are each independently -C(R 2 )-; each R 2 is independently selected from hydrogen, halogen , C 1-6 alkyl or halogenated C 1-6 alkyl.
- one of X 2 , X 3 , X 4 is selected from S or O, and the other two are each independently -C(R 2 )-; each R 2 is independently selected from hydrogen, fluoro , chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
- X3 is selected from -C (R2)-, wherein R2 is selected from hydrogen , fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, or trifluoromethyl.
- R2 is selected from hydrogen , fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, or trifluoromethyl.
- one of X 2 , X 3 , X 4 is selected from -C(R 2 )-, and the other two are independently N or -N(R 4 )-; each R 4 is independently is selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
- X 3 is N
- one of X 2 and X 4 is -N(R 4 )- and the other is -C(R 2 )-
- R 2 and R 4 are each independently selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
- R 1 is selected from hydrogen, halogen, nitro, cyano, C 1-4 alkyl, haloC 1-4 alkyl, -(CH 2 ) p -3-6 membered cycloalkane group, -(CH 2 ) p -3-6 membered heterocyclyl, -NR a -C(O)-R b -, -NR a R b or -OR a ; each p is independently selected from 0, 1 , 2 or 3.
- R 1 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl Methyl, -NR a -C(O)-R b -, -NR a R b , -OR a , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclopropyl, oxa propyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl or tetrahydrothienyl.
- Ring A is selected from 5-8 membered cycloalkyl or 5-8 membered heterocyclyl.
- Ring A is selected from 5-8 membered cycloalkyl or 5-8 membered nitrogen-containing heterocyclyl.
- Ring A is selected from 5-8 membered monocycloalkyl, 5-8 membered monoheterocyclyl, 6-8 membered fused heterocyclyl, 6-8 membered bridged heterocyclyl, or 6-8 membered heterocyclyl A membered spiro heterocyclyl.
- Ring A is selected from 7-8 membered monocycloalkyl, 7-8 membered monoheterocyclyl, or 8 membered nitrogen-bridged heterocyclyl.
- Ring A is selected from a 7-8 membered nitrogen-containing monoheterocyclyl group or a 7-8 membered oxygen-containing monoheterocyclyl group.
- each Q1 is independently selected from halogen, hydroxy, nitro, hydroxy, amino, cyano, carboxyl, -C(O)R a , -C(O)OR a , -C(O ) NR a or the following groups optionally substituted by 1-3 Q2: C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, -( CH 2 ) m -3-6 membered cycloalkyl, -(CH 2 ) m -3-6 membered heterocyclyl, -(CH 2 ) m -5-8 membered heteroaryl or -(CH 2 ) m - Phenyl; the Q2 are independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, hydroxyl C 1-4 alkyl, 3-8 membered
- each Q1 is independently selected from -C(O)R a , -C(O)OR a , -C(O)NR a or optionally substituted with 1-3 Q2 Group: C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, -(CH 2 ) m -3-6 membered cycloalkyl, -(CH 2 ) m -3-6-membered heterocyclic group, -(CH 2 ) m -5-6-membered heteroaryl group or -(CH 2 ) m -phenyl; the Q2 is independently selected from halogen, hydroxyl, nitro group, amino group, cyano group, carboxyl group, C 1-4 alkyl group, C 1-4 alkoxy group, halogenated C 1-4 alkyl group or hydroxy C 1-4 alkyl group.
- each Q1 is independently selected from the group consisting of fluorine, chlorine, bromine, amino, cyano, hydroxyl, carboxyl, nitro, -C(O)R a , -C(O)OR a , -C (O) NR a or the following groups optionally substituted by 1-3 Q2: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, methoxy Ethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl radical, isopropoxyethyl, -(CH 2 ) m -cyclopropyl, -(CH 2 ) m -cyclobutyl, -(CH 2 ) m -cyclopentyl, -(CH 2 ) m -
- each Q1 is independently selected from -C(O)R a , -C(O)OR a , -C(O)NR a or optionally substituted with 1-3 Q2 Group: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxy Ethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH 2 ) m -cyclopropyl base, -(CH 2 ) m -cyclobutyl, -(CH 2 ) m -cyclopentyl, -(CH 2 ) m -cyclohexyl, -(CH 2 ) m -oxanyl, -(CH 2 ) m -
- each R a , each R b is independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, bis(C 1-4 Alkyl) amino, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy C 1-4 alkoxy, amino C 1-4 alkoxy or the following groups optionally substituted by substituents: -(CH 2 ) m -3-8 membered cycloalkyl, -(CH 2 ) m -3-8 membered heterocyclyl, - (CH 2 ) m -5-8-membered heteroaryl or -(CH 2 ) m -phenyl; the substituents are selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 alkyl , C 1-4 alkoxy or halogenated C 1-4 alkyl.
- each R a is independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, halo C 1-4 alkoxy Or the following groups optionally substituted by substituents: -(CH 2 ) m -3-8 membered cycloalkyl, -(CH 2 ) m -3-8 membered heterocyclyl; the substituents are selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl; each R b is independently selected from hydrogen or C 1-4 alkyl.
- each R is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoro Methyl, trifluoromethoxy, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy or optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclo pentyl, cyclohexyl, oxetanyl, oxetanyl, tetrahydrofuranyl, azetidinyl, azetidinyl, tetrahydropyrrolyl, pyrazolidine, imidazolidinyl, piperazinyl or piperidinyl; the substituents are selected from fluorine, chlorine, bromine, hydroxyl, nitro, amino, cyano, carboxy
- each R is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy or any
- substituents are selected to be substituted by substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidine or pyrrolidinyl; the substituents are selected from fluorine, chlorine , bromine, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, isopropyl, methoxy, ethoxy or trifluoromethyl; each R b is independently selected from hydrogen, methyl , ethyl, propyl or isopropyl.
- a compound of general formula (I), general formula (II-1), general formula (II-2), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has the following general formula:
- Y 1 is selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-;
- Y 4 is selected from -C(R 2 ) or -N-;
- Y 3 is selected from -C(R 5 ) or -N-;
- Y 6 is selected from -C(R 7 ) or -N-;
- X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-;
- each of R 2 , R 3 , R 4 , R 5 , R 7 is independently selected from hydrogen, halogen, C 1-4 alkyl or halogenated C 1-4 alkyl;
- R 1 is selected from hydrogen, halogen, nitro, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, -NR a - C(O)-R b -, -NR a R b , -OR a or the following groups optionally substituted with substituents: -(CH 2 ) p -3-6 membered cycloalkyl, -(CH 2 ) p -3-6 membered heterocyclic group; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1- 4 alkyl;
- Ring A is selected from wherein each ring atom in Ring A is optionally oxo;
- Each Q1 is independently selected from halogen, nitro, amino, cyano, carboxyl, -C(O)R a , -C(O)OR a , -C(O)NR a or optionally 1-2
- Each R is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl , trifluoroethyl, trifluoroethoxy, trifluoromethoxy, or the following optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxane , oxetanyl, azetidinyl, azetidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidine or imidazolidinyl; the substituents are selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, propyl,
- each R b is independently selected from hydrogen or C 1-4 alkyl
- Each m, each n, and each p is independently selected from 0, 1, 2, or 3.
- Y 1 is selected from -C(R 2 )(R 3 )-, -O-, -N(R 4 )- or -S-;
- Y 4 is selected from -C(R 2 ) or -N-;
- Y 3 is selected from -C(R 5 ) or -N-;
- Y 6 is selected from -C(R 7 ) or -N-;
- X 2 , X 3 , X 4 are each independently selected from -C(R 2 )-, -O-, -N-, -N(R 4 )- or -S-;
- each R 2 , R 3 , each R 4 , R 5 , R 7 is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, or trifluoromethyl;
- R 1 is selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, oxetanyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl , -NR a -C(O)-R b -, -NR a R b or -OR a , preferably selected from -NR a R b ;
- Ring A is selected from wherein each ring atom in Ring A is optionally oxo;
- Each Q1 is independently selected from halogen, -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-2 Q2: methyl, Ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxy propylpropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH 2 ) m -cyclopropyl, -(CH 2 ) m -cyclobutyl, -( CH2 ) m -cyclopentyl, -( CH2 ) m -cyclohexyl, -( CH2 ) m -oxopropyl, -( CH2
- each R b is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl;
- each m, each n is independently selected from 0, 1, 2 or 3.
- Ring A is selected from wherein each ring atom in Ring A is optionally oxo;
- Each Q1 is independently selected from -C(O)R a , -C(O)OR a or the following groups optionally substituted by 1-2 Q2: methyl, ethyl, propyl, isopropyl, Methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, Propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH 2 ) m -cyclopropyl, -(CH 2 ) m -cyclobutyl, -( CH 2 ) m -cyclopentyl, -(CH 2 ) m -cyclohexyl, -(CH 2 ) m -oxetanyl, -(CH 2 ) m -oxetanyl, -(CH 2
- each m, each n is independently selected from 0, 1, 2 or 3.
- Ring A is selected from preferably selected from preferably selected from wherein each ring atom in Ring A is optionally oxo;
- Each Q1 is independently selected from halogen, -C(O)R a , -C(O)OR a or the following groups optionally substituted by 1-2 Q2: methyl, ethyl, propyl, isopropyl methoxy, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl group, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH 2 ) m -cyclopropyl, -(CH 2 ) m -cyclobutyl, -(CH 2 ) m -cyclopentyl, -(CH 2 ) m -cyclohexyl, -(CH 2 ) m -oxopropyl, -(CH 2 ) m -oxet
- each m, each n is independently selected from 0, 1, 2 or 3.
- each Q1 is independently selected from -C(O)R a , -C(O)OR a or the following groups optionally substituted with 1-2 Q2: methyl, ethyl, Propyl, isopropyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxypropyl, propoxymethyl, propoxyethyl, cyclopropyl, cyclobutyl , oxetanyl, oxetanyl, tetrahydrofuranyl, oxanyl, tetrahydropyranyl, azetidinyl, azetidinyl, pyridyl or pyridazinyl; the Q2 are respectively Independently selected from fluoro, chloro, bromo, hydroxy, amino, cyano, carboxy, nitro, methyl, ethyl, propyl, isopropyl, methoxy, e
- the compound of general formula (I), general formula (II-1), general formula (II-2), general formula (III-1) or general formula (III-2), its A pharmaceutically acceptable salt or a stereoisomer thereof has the structure represented by the following general formula (IV-1) or general formula (IV-2):
- X 2 , X 3 , X 4 , ring A, R 1 , R 2 , R 4 , R a , R b , Q1 , Q2 , m, n, and p are as described in any one of the preceding schemes.
- X 3 and X 4 are independently selected from -C(R 2 )-; ring A, R 1 , R 2 , Q1, Q2, R a , R b , m, n, and p are as defined in any of the foregoing plan described.
- X 2 and X 4 are independently selected from -C(R 2 )-; the definitions of ring A, R 1 , R 2 , R 4 , Q1, Q2, R a , R b , m, n, and p are as follows as described in any of the preceding scenarios.
- X 2 and X 3 are independently selected from -C(R 2 )-; ring A, R 1 , R 2 , Q1, Q2, R a , R b , m, n, and p are defined as any of the foregoing plan described.
- X 2 , X 3 , and X 4 are each independently selected from -C(R 2 )-;
- Each R 2 and each R 4 are independently selected from hydrogen, halogen, C 1-4 alkyl or halogenated C 1-4 alkyl;
- R 1 is selected from hydrogen, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR a R b , -OR a , -SR a , -NH-C(O)-R b -, Or the following groups optionally substituted by substituents: -(CH 2 ) p -3-6 membered cycloalkyl, -(CH 2 ) p -3-6 membered heterocyclyl; the substituents are selected from halogen, C 1-4 alkyl or halogenated C 1-4 alkyl;
- Ring A is selected from preferably selected from preferably selected from wherein each ring atom in Ring A is optionally oxo;
- Each Q1 is independently selected from halogen, -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-2 Q2 : C 1- 4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, -(CH 2 ) m -3-6 membered cycloalkyl, -(CH 2 ) m -3 -6-membered heterocyclyl, -(CH 2 ) m -5-6 membered heteroaryl or -(CH 2 ) m -phenyl; the Q2 are independently selected from halogen, hydroxyl, C 1-4 alkyl , C 1-4 alkoxy, halogenated C 1-4 alkyl or hydroxy C 1-4 alkyl;
- Each R a is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, or optionally The following groups substituted by substituents: -(CH 2 ) m -3-6 membered cycloalkyl, -(CH 2 ) m -3-6 membered heterocyclyl; the substituents are selected from halogen, hydroxyl, C 1 -6 alkyl or halogenated C 1-6 alkyl;
- each R b is independently selected from hydrogen or C 1-4 alkyl
- Each m, each n, and each p is independently selected from 0, 1, or 2.
- the compound, its pharmaceutically acceptable salt or its stereoisomer has the structure shown in the following general formula (VII-1) or general formula (VII-2):
- the compound, its pharmaceutically acceptable salt or its stereoisomer has the structure shown in the following general formula (VII-3) or general formula (VII-4):
- the compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof has the structure shown in the following general formula (VII-5) or general formula (VII-6):
- the compound, its pharmaceutically acceptable salt or its stereoisomer has the structure shown in the following general formula (VII-7) or general formula (VII-8):
- R 1 is selected from -NR a R b , -OR a , -SR a , -NH-C(O)-R b -, or the following groups optionally substituted with substituents: -(CH 2 ) p -3 -6-membered cycloalkyl, -(CH 2 ) p -3-6-membered heterocyclyl; the substituent is selected from halogen, C 1-4 alkyl or halogenated C 1-4 alkyl;
- each R 4 is independently selected from hydrogen, halogen, C 1-4 alkyl or halogenated C 1-4 alkyl;
- Ring A is selected from wherein each ring atom in Ring A is optionally oxo;
- Each Q1 is independently selected from -C(O)R a , -C(O)OR a , -C(O)NR a or the following groups optionally substituted by 1-2 Q2: C 1-4 alkane group, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or benzene base; the Q2 is independently selected from halogen, hydroxyl, C 1-4 alkyl or halogenated C 1-4 alkyl;
- Each R a is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, or optionally The following groups substituted by substituents: 3-6-membered cycloalkyl, 3-6-membered heterocyclyl; the substituents are selected from halogen, hydroxyl, C 1-6 alkyl or halogenated C 1-6 alkyl;
- each R b is independently selected from hydrogen or C 1-4 alkyl
- Each n and each p are independently selected from 0, 1 or 2.
- R 1 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl group, azetidine, oxetanyl, -NR a -C(O)-R b -, -NR a R b or -OR a , preferably selected from -NR a R b .
- R 1 is selected from azetidine, oxetanyl, -NR a -C(O)-R b -, -NR a R b or -OR a , each R a is independently selected from hydrogen, methyl radical, ethyl, propyl, isopropyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoromethoxy or optionally substituted with substituents of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidine or imidazolidinyl; the substituents are selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl
- each R is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl , difluoromethyl or trifluoromethyl;
- Ring A is selected from wherein each ring atom in Ring A is optionally oxo;
- Each Q1 is independently selected from -C(O)R a , -C(O)OR a or the following groups optionally substituted by 1-2 Q2: methyl, ethyl, propyl, isopropyl, Methoxymethyl, methoxyethyl, methoxypropyl, ethoxypropyl, propoxymethyl, cyclopropyl, cyclobutyl, oxetanyl, oxetanyl, tetrahydrofuranyl, oxanyl, tetrahydropyranyl, aziridinyl, azetidinyl, pyrrolidinyl, pyridinyl or pyridazinyl; the Q2 is independently selected from fluorine, chlorine, bromine , hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or trifluoromethyl;
- Each R a is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoroethyl Fluoromethoxy or the following optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl , tetrahydropyrrolyl, pyrazolidine or imidazolidinyl; the substituent is selected from halogen, hydroxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl;
- Each R b is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.
- R 1 is selected from -NH 2 ,
- the hydrogen on the ring nitrogen atom in the ring A can be optionally substituted by Q1.
- Q1 substitutes one or more hydrogens on a ring nitrogen atom in Ring A.
- each Q1 is independently selected from methyl, ethyl, cyclopropyl, cyclobutyl,
- the compound of the aforementioned general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from the following compounds:
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound of the present invention, a pharmaceutically acceptable salt or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers and/or diluents; the medicament
- the composition can be made into any clinically or pharmaceutically acceptable dosage form, such as tablet, capsule, pill, granule, solution, suspension, syrup, injection (including injection solution, sterile powder for injection) and concentrated solutions for injection), suppositories, inhalants or sprays, etc.
- the pharmaceutical formulations described above may be administered orally, parenterally, rectally, or via pulmonary administration to a patient or subject in need of such treatment.
- the pharmaceutical composition can be made into oral preparations, for example, can be made into conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; can also be made into oral liquid preparations, such as Oral solution, oral suspension, syrup, etc.
- suitable fillers, binders, disintegrants, lubricants and the like can be added.
- parenteral administration the above-mentioned pharmaceutical preparations can also be prepared into injections, including injection solutions, sterile powders for injection and concentrated solutions for injection.
- the pharmaceutical composition When preparing the injection, it can be produced by the conventional methods in the existing pharmaceutical field. When preparing the injection, no additives can be added, or suitable additives can be added according to the properties of the drug.
- the pharmaceutical composition For rectal administration, the pharmaceutical composition can be formulated into suppositories and the like. When used for pulmonary administration, the pharmaceutical composition can be formulated into an inhaler or a spray or the like.
- the pharmaceutically acceptable carrier and/or diluent usable in the pharmaceutical composition or pharmaceutical formulation of the present invention may be any conventional carrier and/or diluent in the field of pharmaceutical formulations, and the choice of a particular carrier and/or diluent will depend on the Mode of administration or disease type and state to treat a particular patient.
- the preparation of suitable pharmaceutical compositions for a particular mode of administration is well within the knowledge of those skilled in the pharmaceutical arts.
- the present invention also relates to the use of a compound of the present invention, a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a medicament for the prevention and/or treatment of diseases mediated by HPK1 and related diseases,
- the drug can be used in combination with one or more other drugs to prevent or treat diseases and related disorders mediated by HPK1.
- the disease and related conditions are selected from cancers or benign tumors, including carcinomas in situ and metastatic cancers.
- the cancer includes but is not limited to lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, Liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, thyroid cancer, female reproductive tract cancer, lymphoma, neurofibromas, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, small cell Lung cancer, non-small cell lung cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, leukemia, glioma or sarcoma, etc.
- the present invention also relates to the use of a pharmaceutical preparation containing the compound of the present invention, a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a medicament, which can be used in combination with one or more medicaments Treatment and/or prevention of diseases and related disorders mediated by HPK1.
- the present invention relates to a medicament containing a compound of the present invention, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which may be administered alone, or in combination with one or more second therapeutically active agents,
- the second therapeutically active agent is used in combination with the HPK1 inhibitor compounds of the present application for the treatment and/or prevention of diseases and related disorders mediated by HPK1.
- the pharmaceutical composition further contains one or more second therapeutically active agents.
- the second therapeutically active agent is selected from anticancer agents, including mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, antitumor antibiotics, growth factor inhibitors, signaling Conduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormone drugs, angiogenesis inhibitors, cell growth inhibitors agents, targeting antibodies, HMG-CoA reductase inhibitors and isoprenyl protein transferase inhibitors.
- anticancer agents including mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, antitumor antibiotics, growth factor inhibitors, signaling Conduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormone drugs, angiogenesis inhibitors, cell growth inhibitors agents, targeting antibodies, HMG-CoA reductase inhibitors and
- the ingredients to be combined may be administered simultaneously or sequentially and separately .
- the second therapeutically active agent can be administered prior to, concurrently with, or subsequent to administration of a compound of the invention, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
- the components to be combined may also be administered in combination in the same formulation or in separate different formulations.
- the present invention also provides a method for treating diseases and related disorders mediated by HPK1, the method comprising administering to a patient in need an effective amount of the compound of the aforementioned general formula (I), its pharmacy An acceptable salt of the above or a stereoisomer thereof, the aforementioned formulation or pharmaceutical composition; the HPK1-mediated diseases and related disorders are as defined above.
- the "effective amount” refers to a dose of a drug capable of alleviating, delaying, inhibiting or curing a disorder in a subject.
- the size of the administered dose is determined by the mode of drug administration, the pharmacokinetics of the drug, the severity of the disease, and the subject's individual signs (sex, weight, height, age) and the like.
- halogen in the present invention refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
- C 1-6 alkyl group in the present invention refers to a straight-chain or branched alkyl group containing 1-6 carbon atoms, including, for example, “C 1-4 alkyl group” and “C 1-3 alkyl group” , “C 1-2 alkyl”, “C 2-6 alkyl”, “C 2-5 alkyl", “C 2-4 alkyl", “C 2-3 alkyl", “C 3- 6 alkyl”, “C 3-5 alkyl", “C 3-4 alkyl", etc.
- C 1-4 alkyl group in the present invention refers to a specific example of the C 1-6 alkyl group containing 1-4 carbon atoms.
- C 1-6 alkoxy in the present invention refers to “C 1-6 alkyl-O-", and the “C 1-6 alkyl” is as defined above.
- C 1-4 alkoxy in the present invention refers to “C 1-4 alkyl-O-”, and the “C 1-4 alkyl” is as defined above.
- C 1-6 alkylthio in the present invention refers to “C 1-6 alkyl-S-", and the “C 1-6 alkyl” is as defined above.
- C 1-4 alkylthio in the present invention refers to “C 1-4 alkyl-S-”, and the “C 1-4 alkyl” is as defined above.
- hydroxyl C 1-6 alkyl, amino C 1-6 alkyl, halogenated C 1-6 alkyl in the present invention means that one or more hydrogens in the C 1-6 alkyl are replaced by one or more Multiple hydroxy, amino or halogen substituted.
- C 1-6 alkyl is as defined above
- Hydrogen is replaced with one or more hydroxy, amino or halogen.
- hydroxyl C 1-6 alkylthio, amino C 1-6 alkylthio, halogenated C 1-6 alkylthio refers to one or more of "C 1-6 alkylthio" Hydrogen is replaced with one or more hydroxy, amino or halogen.
- C 1-6 alkylamino, di(C 1-6 alkyl) amino in the present invention refer to C 1-6 alkyl-NH-
- C 2-6 alkenyl in the present invention refers to a straight-chain, branched or cyclic alkenyl containing at least one double bond and having 2-6 carbon atoms, including, for example, "C 2-4 alkenyl""Wait.
- Examples include, but are not limited to: vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl Alkenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,4-hexenyl Dienyl, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadienyl and the like.
- C 2-6 alkynyl in the present invention refers to a straight-chain or branched alkynyl group containing at least one triple bond and having 2-6 carbon atoms, including, for example, "C 2-4 alkynyl” and the like. Examples include, but are not limited to: ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3 -hexynyl, 5-methyl-2-hexynyl, etc.
- the "3-10 membered cycloalkyl” in the present invention refers to a saturated or partially saturated monocyclic or polycyclic group containing 3-10 carbon atoms and not having aromaticity.
- the "monocyclic cycloalkyl group” is preferably “3-8 membered monocyclic alkyl group”
- the "polycyclic cycloalkyl group” includes "fused ring group, bridged ring group and spirocyclic group”, preferably "7-10 membered fused cycloalkyl", "7-10-membered bridged cyclic group” and "7-10-membered spirocyclic group”.
- the "3-8 membered monocyclic alkyl group” mentioned in the present invention refers to a saturated or partially saturated monocyclic cyclic alkyl group containing 3-8 carbon atoms without aromaticity, including "3-8 membered saturated monocyclic cyclic alkyl group”.
- 3-8 membered saturated monocycloalkyl include but are not limited to: cyclopropanyl (cyclopropyl), cyclobutanyl (cyclobutyl), cyclopentyl (cyclopentyl) , cyclohexyl (cyclohexyl), cycloheptyl (cycloheptyl), cyclooctyl (cyclooctyl), etc.; specific examples of the "3-8 membered partially saturated monocycloalkyl” include but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1,3-diene, cyclohex-1,4-diene, cycloheptyl Alkenyl, cyclohept-1,3-dienyl, cyclohept-1,4-dienyl, cyclohept-1,3,5
- the "7-10-membered fused ring group” in the present invention refers to a saturated or partially containing 7-10 ring atoms formed by two or more ring structures sharing two adjacent carbon atoms with each other.
- Saturated, non-aromatic cyclic group one of the fused rings can be an aromatic ring, but the fused ring as a whole does not have aromaticity; including "8-9 membered fused ring group", "9-10 "Condensed ring group” etc., the condensing mode can be: 5-6-membered cycloalkyl, 5-6-membered cycloalkyl, benzo 5-6-membered cycloalkyl, benzo 5-6-membered saturated cycloalkyl etc., optionally, ring atoms in the ring structure can be oxo.
- Examples include, but are not limited to: bicyclo[3.1.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl , bicyclo[4.2.0]octyl, octahydrocyclopentadienyl, octahydro-1H-indenyl, decalinyl, tetrahydrophenanthryl, bicyclo[3.1.0]hex-2- Alkenyl, Bicyclo[4.1.0]hept-3-enyl, Bicyclo[3.2.0]hept-3-enyl, Bicyclo[4.2.0]oct-3-enyl, 1,2,3,3a- Tetrahydrocyclopentadienyl, 2,3,3a,4,7,7a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8a-octahydronaphthyl, 1,2,4a,
- the "7-10-membered bridged cyclic group" in the present invention refers to a cyclic ring containing 7-10 ring carbon atoms formed by two or more cyclic structures sharing two non-adjacent carbon atoms with each other. structure.
- carbon atoms in the ring structure can be oxo. Specific examples include but are not limited to: Wait.
- the "7-10 membered spiroheterocyclyl" in the present invention refers to a cyclic structure containing 7-10 ring carbon atoms formed by two or more cyclic structures sharing one carbon atom with each other.
- carbon atoms in the ring structure can be oxo. Specific examples include but are not limited to: Wait.
- the "3-10-membered heterocyclic group” in the present invention refers to a saturated or partially saturated (containing 1 or 2 double bonds) consisting of 3-10 carbon atoms and heteroatoms selected from nitrogen, oxygen or sulfur.
- Non-aromatic cyclic group this cyclic group can be a monocyclic or polycyclic group, in the present invention, the number of heteroatoms in the heterocyclic group is preferably 1, 2, 3 or 4, the nitrogen in the heterocyclic group is preferably 1, 2, 3 or 4.
- carbon or sulfur atoms can be optionally oxidized.
- the nitrogen atom may be optionally further substituted with other groups to form tertiary amines or quaternary ammonium salts.
- the monocyclic heterocyclic group is preferably a "3-8 membered monoheterocyclic group", which means at least one heteroatom (for example, containing 1, 2, 3, 4 or 5) and the number of ring atoms is 3 -8 saturated or partially saturated and non-aromatic monocyclic cyclic groups, the heteroatoms are nitrogen atoms, oxygen atoms and/or sulfur atoms, optionally, ring atoms in the ring structure ( For example carbon atoms, nitrogen atoms or sulfur atoms) can be oxo.
- the "3-8 membered monoheterocyclic group" in the present invention includes "3-8 membered saturated monoheterocyclic group” and "3-8 membered partially saturated monoheterocyclic group”.
- the "3-8-membered heterocyclic group" of the present invention contains 1-3 heteroatoms; preferably, the "3-8-membered monoheterocyclic group” of the present invention contains 1-2 heteroatoms atom, and the heteroatom is selected from nitrogen atom and/or oxygen atom; preferably, the "3-8-membered monoheterocyclic group" of the present invention contains one nitrogen atom.
- the "3-8 membered monoheterocyclic group” is preferably "3-7 membered monoheterocyclic group", "3-6 membered monoheterocyclic group”, “4-7 membered monoheterocyclic group”, “4-6 membered monoheterocyclic group” "Mono-heterocyclic group”, “6-8-membered mono-heterocyclic group”, “5-7-membered mono-heterocyclic group”, "5-6-membered mono-heterocyclic group”, “3-6-membered saturated mono-heterocyclic group” ", "5-6 membered saturated monoheterocyclic group”, “3-6 membered nitrogen-containing monoheterocyclic group”, “3-6 membered saturated nitrogen-containing monoheterocyclic group”, “5-6 membered nitrogen-containing monoheterocyclic group” ring group”, “5-6 membered saturated nitrogen-containing monoheterocyclic group”, etc.
- 3-8 membered monoheterocyclyl include, but are not limited to: aziridyl, 2H-aziridinyl, diaziridinyl, 3H-diaziridenyl, aza Cyclobutanyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolane, 1,4-dioxanyl Dialkenyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydro thienyl, tetrahydrothienyl, 4,5-
- Polycyclic heterocyclic groups include "fused heterocyclic group", “spiro heterocyclic group” and “bridged heterocyclic group”, preferably "7-10 membered fused heterocyclic group", “7-10 membered spiro heterocyclic group” and “7-10 membered bridged heterocyclyl”.
- the "7-10-membered fused heterocyclic group” in the present invention refers to at least one ring formed by two or more cyclic structures sharing two adjacent atoms with each other and containing 7-10 ring atoms
- the atom is a heteroatom, saturated or partially saturated, non-aromatic cyclic group
- one of the rings in the fused ring can be an aromatic ring, but the fused ring as a whole is not aromatic
- the heteroatom is nitrogen Atoms, oxygen atoms and/or sulfur atoms, optionally, ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the ring structure can be oxo, including but not limited to "8-9 membered fused heterocyclic group" ", "9-10-membered fused heterocyclic group", etc.
- the condensing mode can be 5-6-membered heterocyclic group and 5-6-membered heterocyclic group, 5-6-membered heterocyclic group and 5-6-
- benzocyclopentyl the structure of which refers to (also referred to as 2,3-dihydro-1H-indenyl); the term “benzopyrrolidine” whose structure includes etc.; the term “pyridotetrahydrofuranyl” whose structure includes Specific examples of other "other fused heterocyclic groups as defined” previously defined have cyclic structures similar to them.
- the "7-10 membered spiroheterocyclyl" in the present invention refers to a ring formed by two or more cyclic structures sharing one ring atom with each other, containing 7-10 ring atoms (at least one ring atom is A cyclic structure of a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom), includes "7-10 membered saturated spiroheterocyclyl” and "7-10 membered partially saturated spiroheterocyclyl".
- ring atoms eg, carbon, nitrogen, or sulfur atoms
- Specific examples include but are not limited to:
- the "7-10-membered bridged heterocyclyl” in the present invention refers to a group formed by two or more cyclic structures sharing two non-adjacent ring atoms with each other, containing 7-10 ring atoms (wherein A cyclic structure in which at least one ring atom is a heteroatom such as a nitrogen atom, an oxygen atom or a sulfur atom) includes "7-10 membered saturated bridged heterocyclyl" and "7-10 membered partially saturated bridged heterocyclyl".
- ring atoms eg, carbon, nitrogen, or sulfur atoms
- Specific examples include but are not limited to:
- the "6-10-membered aryl group" in the present invention includes “6-8-membered monocyclic aryl group” and "8-10-membered fused-ring aryl group”.
- the "6-8-membered monocyclic aryl group" in the present invention refers to a monocyclic aryl group containing 6-8 ring carbon atoms, examples of which include but are not limited to: phenyl, cyclooctatetraenyl, etc.; preferably benzene base.
- the "8-10-membered fused-ring aryl group” mentioned in the present invention refers to a group formed by two or more cyclic structures sharing two adjacent atoms with each other, containing 8-10 ring carbon atoms, not
- the saturated and aromatic cyclic group is preferably a "9-10-membered fused-ring aryl group", and specific examples are naphthyl and the like.
- the "5-10-membered heteroaryl” in the present invention includes “5-8-membered monoheteroaryl” and "8-10-membered condensed heteroaryl”.
- the "5-8-membered heteroaryl group” in the present invention refers to an aromatic mono-heteroaryl group containing 5-8 ring atoms (at least one of which is a heteroatom, such as nitrogen atom, oxygen atom or sulfur atom). Cyclic ring group.
- ring atoms eg, carbon, nitrogen, or sulfur atoms
- ring structure may be oxo.
- 5-8-membered monoheteroaryl includes, for example, "5-7-membered monoheteroaryl", “5-6-membered monoheteroaryl”, “5-6-membered nitrogen-containing monoheteroaryl", “6-membered monoheteroaryl”
- Nitrogen-containing monoheteroaryl group etc., the heteroatom in the "nitrogen-containing heteroaryl group” contains at least one nitrogen atom, for example, only contains 1 or 2 nitrogen atoms, or, contains one nitrogen atom and other nitrogen atoms 1 or 2 heteroatoms (eg oxygen and/or sulphur atoms), alternatively 2 nitrogen atoms and 1 or 2 other heteroatoms (eg oxygen and/or sulphur atoms).
- 5-8 membered monocyclic heteroaryl include, but are not limited to, furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadi azolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazole base, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-Triazinyl, 1,3,5-Triazinyl, 1,2,4,5-Tetrazinyl, Azacyclotrienyl, 1,3-Diazepinyl Alkenyl,
- the "8-10-membered fused heteroaryl group” in the present invention refers to a group formed by two or more cyclic structures sharing two adjacent atoms with each other, containing 8-10 ring atoms (at least one of which is Ring atoms are heteroatoms, such as nitrogen atoms, oxygen atoms or sulfur atoms), unsaturated aromatic ring structures.
- Ring atoms are heteroatoms, such as nitrogen atoms, oxygen atoms or sulfur atoms
- unsaturated aromatic ring structures such as nitrogen atoms, oxygen atoms or sulfur atoms
- ring atoms eg, carbon, nitrogen, or sulfur atoms
- ring atoms eg, carbon, nitrogen, or sulfur atoms
- Including "9-10-membered condensed heteroaryl", “8-9-membered condensed heteroaryl”, etc., and the condensing method can be benzo-5-6-membered heteroaryl, 5-6-membered heteroaryl and 5- 6-membered heteroaryl, etc.; specific examples include, but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furanothiophene, pyrazolooxazole, benzofuranyl, benziso furanyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinone, 4 -quinolinone, 1-isoquinolinone, isoquinolinyl, acridine, phenanthridine, benzopyri
- substituted refers to two situations in which one or more hydrogen atoms on the substituted group may be "substituted” or “unsubstituted” by one or more substituent groups.
- the "pharmaceutically acceptable salt” in the present invention refers to a salt formed by an acidic functional group (such as -COOH, -OH, -SO 3 H, etc.) existing in a compound and an appropriate inorganic or organic cation (base), including Salts formed by alkali metals or alkaline earth metals, ammonium salts, and salts formed with nitrogen-containing organic bases; and salts formed by basic functional groups (such as -NH2, etc.) present in compounds with appropriate inorganic or organic anions (acids), Included are salts formed with inorganic or organic acids such as carboxylic acids and the like.
- an acidic functional group such as -COOH, -OH, -SO 3 H, etc.
- Examples include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, bismuth, hydrochloride, sulfate, nitrate, phosphate, hydrobromide, hydroiodide, formate , acetate, propionate, oxalate, malonate, succinate, maleate, fumarate, lactate, malate, citrate, tartrate, methanesulfonate salt, ethanesulfonate, benzenesulfonate, tosylate, tetrafluoroborate, arginine, aspartate and glutamic acid, etc.
- isomer refers to when the compound of the present invention contains one or more asymmetric centers, and thus can be used as racemates and racemic mixtures, single enantiomers, diastereomers mixtures and single diastereomers.
- the compounds of the present invention may have asymmetric centers, each of which independently produces two optical isomers.
- the scope of the present invention includes all possible optical isomers and mixtures thereof. If the compound of the present invention contains an olefinic double bond, unless otherwise specified, cis-isomer and trans-isomer are included.
- the compounds described in the present invention may exist as tautomers (a type of functional group isomer) that have different hydrogen attachment points by displacement of one or more double bonds, eg, ketones and their alkenes
- the alcohol form is the keto-enol tautomer.
- the compound of the present invention contains a spiro ring structure, and under the influence of the steric space structure of the ring, the substituents on the ring can exist on both sides of the ring to form relative cis (cis) and trans (trans) isomers.
- cis cis
- trans trans
- Each tautomer and mixtures thereof are included within the scope of the present invention.
- Enantiomers, diastereomers, racemates, mesomers, cis-trans isomers, tautomers, geometric isomers, epimers and the like are included in the scope of the present invention.
- the compounds of the present invention can be prepared in the form of individual enantiomers by enantiospecific synthesis or by resolution from enantiomeric mixtures.
- Conventional resolution techniques include the use of optically active acids to form salts of the free base of each isomer of the enantiomeric pair (followed by fractional crystallization and free base regeneration), the use of optically active amines to form Acid form salts of each enantiomer (followed by fractional crystallization and free acid regeneration), each enantiomer of an enantiomer pair formed using optically pure acids, amines, or alcohols esters or amides of the species (followed by chromatographic separation and removal of chiral auxiliary agents) or resolution of mixtures of enantiomers of the starting material or final product using various well-known chromatographic methods.
- stereochemistry of a disclosed compound is named or depicted by structure
- the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% by weight relative to other stereoisomers or 99.9% by weight pure.
- the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure.
- Optical purity weight % is the ratio of the weight of the enantiomer to the weight of the enantiomer plus its optical isomer.
- the "dosage form” referred to in the present invention refers to the form that the drug is made into suitable for clinical use, including but not limited to powders, tablets, granules, capsules, solutions, emulsions, suspensions, injections (including injections) , sterile powders for injection and concentrated solutions for injection), sprays, aerosols, powders, lotions, liniments, ointments, plasters, pastes, patches, gargles or suppositories, more preferably Powder, tablet, granule, capsule, solution, injection, ointment, gargle or suppository.
- the compounds of the present invention have excellent inhibitory effect on HPK1 activity, good pharmacokinetic properties in vivo, long-lasting effects, and good liver microsome stability Sex, exposure and bioavailability, can treat and/or prevent diseases mediated by HPK1.
- the compound of the present invention has the advantages of simple preparation process, high drug purity and stable quality, and is easy to carry out large-scale industrial production.
- LiAlH 4 lithium aluminum hydride
- 2,2'-(1,2-phenylene)diacetic acid (10.0 g, 51.5 mmol) was dissolved in tetrahydrofuran (200 mL).
- LiAlH 4 (5.9 g, 0.15 mol) was added in batches at 0° C., the addition was completed, and the reaction was carried out at 15° C. for 18 hours.
- LCMS detected the end of the reaction, 5.9 mL of water was added at 0°C to quench the reaction, a solid was precipitated, filtered through celite, the solid was washed with tetrahydrofuran, and the filtrate was dried and concentrated to obtain 7.0 g of the title compound, yield: 81.8%.
- N-(3-Methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (1.9 g, 8.7 mmol) was dissolved in concentrated sulfuric acid (16 mL) ), fuming nitric acid (799.0 mg, 11.3 mmol) was added dropwise at 0 °C, and the reaction was carried out at 0 °C for 10 min.
- 2,3,5,6-Tetrahydrobenzo[d]azepin-4(1H)-one (5.0 g, 28.5 mmol) was dissolved in tetrahydrofuran (200 mL), and lithium tetrahydroaluminum (4.3 mmol) was added at 0°C. g, 113.2 mmol), reacted at 75°C for 1 hour.
- Water (4.3 mL) was added to quench the reaction, 10% sodium hydroxide (4.3 mL) solution and water (12.9 mL) were added, the solid was removed by filtration, and extracted with water (100 mL) and ethyl acetate (200 mL) to obtain 4.2 g of crude product.
- 1,2,3,4,5,6-hexahydrobenzo[d]azepine (2.0 g) was dissolved in formic acid (10 mL), formaldehyde (37%) (20 mL) was added, and the mixture was reacted at 70° C. for 1 hour. The pH was adjusted to 9 with saturated sodium bicarbonate (200 mL), and extracted with ethyl acetate (200 mL) to obtain 2.0 g of crude product.
- 1,4-Dimethyl-8-nitro-1,2,3,4,5,6-hexahydrobenzo[e][1,4]dioxin-9-amine 300 mg, 1.2 mmol was dissolved in ethanol (10 mL), Pd/C (150 mg) was added, the addition was completed, and the reaction was carried out at 10° C. for 2 hours under nitrogen protection.
- LCMS detected the end of the reaction. Filter through diatomaceous earth, concentrate the solvent to obtain the target compound and directly put it into the next step.
- N-(3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (2.3 g , 7.7 mmol) was dissolved in concentrated sulfuric acid (16 mL), at 0 °C, fuming nitric acid (700.0 mg, 10.0 mmol) was added, the addition was completed, and the reaction was carried out at 0 °C for 2 hours.
- LCMS detected the end of the reaction. It was poured into ice water, extracted with dichloromethane, and the organic phase was dried and concentrated to obtain 2.3 g of the target compound, yield: 86.9%.
- 2,3,4,5-Tetrahydro-1H-benzo[d]azepine (5.0 g, 34.0 mmol) was dissolved in trifluoroacetic acid (20 mL), cooled to 0 °C, and concentrated sulfuric acid (7.5 mL) was added and potassium nitrate (5.5 g, 56.7 mmol), react at 0°C for 2 hours.
- N-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (1.5 g, 6.5 mmol) was dissolved in concentrated sulfuric acid (30 mL) ), fuming nitric acid (470 mg, 7.5 mmol) was added dropwise at 0 °C, and the reaction was completed at 0 °C for 10 min.
- 3-Ethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (1.0 g, 4.2 mmol) was dissolved in ethanol (100 mL), Pd/C (300 mg) was added, the mixture was purged with hydrogen 3 times, and hydrogenated at 15° C. for 4 hours under hydrogen.
- 3-Ethoxy-3-iminopropionic acid ethyl ester hydrochloride 2.0 g. 10.2 mmol was added, and the temperature was raised to 50° C. to react for 2 hours.
- reaction solution was quenched by adding water (100 mL), extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain 300 mg of the target compound with a two-step yield of 39.6%.
- N-(3-Cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (2.12 g, 8.65 mmol) was dissolved in concentrated sulfuric acid ( 22mL), fuming nitric acid (849mg, 13mmol) was added at 0°C, reacted at 25°C for 0.5h, the reaction was completed by LCMS, the pH was adjusted to 8-9 with 5M sodium hydroxide solution, extracted with DCM, and the organic phase was anhydrous sulfuric acid. Sodium-drying, spin-dried to obtain 2 g of product with a yield of 79.7%.
- N-(3-Cyclopropyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (1.96 g, 6.76 mmol) It was dissolved in methanol (35 mL), potassium carbonate (4.6 g, 33.4 mmol) was added, and the reaction was carried out at 65 °C for 8 h.
- the reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate (15 mL), added with methanol (1 mL) and ethyl acetate (1 mL), filtered and dried to obtain 7.5 mg of the target compound, yield: 3.5%.
- N-(3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (5.5 g , 18.3 mmol) was dissolved in concentrated sulfuric acid (50 mL), fuming nitric acid (1.5 g, 22.0 mmol) was added dropwise at 0 °C, the addition was completed, and the reaction was carried out at 0 °C for 1.5 hours. LCMS detected the end of the reaction.
- 6-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine 400 mg, 1.9 mmol was dissolved in methanol (10 mL), and formaldehyde (37%) was added ) (791.2 mg, 9.7 mmol), acetic acid (114.0 mg, 1.9 mmol), react at 15° C. for 1 hour, add sodium cyanoborohydride (601.4 mg, 9.7 mmol), complete the addition, and react at 15° C. for 1 hour. LCMS detected the end of the reaction.
- the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain a solid.
- the solid was slurried with methanol to obtain 16.2 mg of the title compound with a yield of 12.7%.
- the crude product from the previous step was dissolved in 10 mL of methanol, 150 mg of potassium carbonate was added, and the reaction was carried out at 25° C. for 1 h. After the reaction was completed, the solvent was concentrated, and 16 mg of the target product was obtained by column chromatography, with a two-step yield of 7.9%.
- Methyl 3-amino-4-methylthiophene-2-carboxylate (1.71 g, 10 mmol) and potassium hydroxide (1.12 g, 20 mmol) were dissolved in water (20 mL) and reacted at 90° C. for 1 hour. The reaction solution was directly used in the next step.
- reaction solution was poured into water (100 mL), suction filtered, the solid was collected, spin-dried, and purified by silica gel column (dichloromethane) to obtain 1.5 g of the target compound with a yield of 64.7%.
- the reaction was quenched by adding saturated aqueous ammonium chloride solution at 0°C, extracted with dichloromethane, and the organic phase was concentrated to obtain a crude product mixed with the intermediate.
- the crude product in the previous step was dissolved in tetrahydrofuran (20 mL), and under nitrogen protection, LDA (9.7 mL, 19.3 mmol) was added at 40° C., the addition was completed, and the reaction was carried out at 40° C. for 2 hours.
- the reaction was quenched with saturated aqueous ammonium chloride solution, the organic phase was concentrated, and purified by silica gel column (100% ethyl acetate) to obtain 710 mg of the title compound in a yield of 31%.
- N-(3-(6-Chloropyrazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide 400 mg, 1.26 mmol
- concentrated sulfuric acid 4 mL
- Fuming nitric acid 95 mg, 1.52 mmol was added dropwise at 0° C., the dropping was completed, and the reaction was carried out at 0° C. for 1 hour.
- the solvent was concentrated, dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate solution, the organic phase was dried, and purified by reversed-phase purification under medium pressure (40% methanol/water (0.5% concentrated hydrochloric acid)) to obtain 40 mg of the target compound with a yield of 41.4%.
- reaction solution was poured into saturated aqueous ammonium chloride solution for quenching, extracted with ethyl acetate, the organic phase was spin-dried, and 18.5 mg of the target compound was obtained after beating with methanol, with a yield of 14.7%.
- the target compound was 19 mg, and the yield was 37.8%.
- N-(8-Nitro-1,2,4,5-tetrahydrobenzo[d]oxazol-7-yl)acetamide (N/A, 0.49 mmol) was dissolved in methanol (5 mL) and added Potassium carbonate (166 mg, 1.2 mmol) was added and reacted at 55°C for 8 hours.
- N-(7-(azetidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]rotaxen-2-yl)acetamide (1.5 g, 5.9 mmol) was dissolved in concentrated sulfuric acid (15 mL), stirred at 0 °C for 1 hour, potassium nitrate (656 mg, 6.5 mmol) was added in batches, the addition was completed, and the reaction was carried out at 0 °C for 1 hour. LCMS detected the end of the reaction.
- the reaction was quenched by pouring into saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried and concentrated, and slurried with methanol and dichloromethane to obtain 10 mg of the target compound with a yield of 8.1%.
- Test substance some compounds of the present invention, the structural formulas and preparation methods of which are shown in the preparation examples of the present invention.
- DMSO dimethyl sulfoxide
- HEPES hydroxyethylpiperazine ethanethiosulfonic acid
- Inhibition percentage (max-Lantha signal)/(max-min)*100
- the “minimum” is the negative control well reading without enzyme; the “maximum” is the positive control well reading without compound.
- the compounds of the present invention have good inhibitory activity on MAP4K1/HPK1, and the compounds of the present invention have excellent selectivity for HPK1.
- Test substance some compounds of the present invention, the structural formulas and preparation methods of which are shown in the preparation examples of the present invention.
- ELISA enzyme-linked immunosorbent assay
- Jurkat human acute T-cell leukemia cells
- SLP76 76kDa leukocyte protein with SH2 domain
- CD3 cluster of differentiation 3 (leukocyte differentiation antigen);
- PBS buffer Phosphate-balanced saline
- TMB 3,3',5,5'-tetramethylbenzidine.
- ELISA method was used to detect the inhibitory level of compounds on the phosphorylation of serine 376 of SLP76 in Jurkat cells in vitro.
- Cell preparation Harvest Jurkat cells in logarithmic growth phase and adjust to an appropriate cell concentration; add 81 ⁇ L of cell suspension per well to a 96-well plate.
- the experimental results show that the compounds of the present invention have good inhibitory activity on the phosphorylation of serine 376 of the downstream protein SLP76 of MAP4K1/HPK1, such as compound 1, compound 10, compound 11, compound 12, compound 14-1, compound 15, compound 23 -1.
- the IC 50 values of compound 26, compound 49, compound 50, compound 53, compound 55, compound 58, compound 63, compound 64, etc. are all less than 100 nM, that is, the compounds of the present invention have good inhibitory activity on HPK1.
Abstract
本发明属于医药技术领域,具体涉及一类三并环类HPK1抑制剂化合物、其药学上可接受的盐或其立体异构体,含有所述化合物、其药学上可接受的盐或其异构体的药物组合物及制剂,制备所述化合物、其药学上可接受的盐或其立体异构体的方法,以及所述化合物、其药学上可接受的盐或其立体异构体的用途。
Description
本发明属于医药技术领域,具体涉及通式(I)所示的三并环类HPK1化合物、其药学上可接受的盐、及其立体异构体,含有所述化合物、其药学上可接受的盐及其立体异构体的药物组合物及制剂,制备所述化合物、其药学上可接受的盐及其立体异构体的方法,以及所述化合物、其药学上可接受的盐及其立体异构体的用途。
T细胞受体(TCR)介导的T细胞活化在胸腺T细胞发育、T细胞亚群分化以及效应T细胞功能发挥过程中均起着重要的作用。TCR可以识别抗原提呈细胞表面的MHC(主要组织相容性复合物),进而识别向细胞内部传递的信号。信号传递后引起下游信号通路的活化。TCR活化的典型胞内信号包括MAPK(丝裂原活化蛋白激酶)、PKC(蛋白激酶C)以及钙离子等信号通路。这些信号的活化最终激活T细胞的特异性基因表达,引起细胞的增殖,并使得T细胞分化为效应T细胞。内源性或过继转移的效应T细胞是抗肿瘤免疫的重要介质。持续性的抗原暴露会导致T细胞逐渐分化为耗竭状态,其特征是效应器功能和增殖能力的层次性丧失,以及明显的转录、表观遗传和代谢变化。如何预防T细胞耗竭并拓展效应T细胞功能是目前肿瘤免疫学中最紧迫的问题之一。
造血祖细胞激酶HPK1(HematopoieticProgenitor Kinase1)是一种免疫抑制调节激酶,在造血干细胞中限制性表达。HPK1是T细胞受体(TCR)的负信号调节剂。TCR激活后,胞质HPK1被募集到细胞膜附近,活化的HPK1磷酸化衔接蛋白SLP76,以此激活SLP76作为负调节蛋白14-3-3的停靠位点,最终导致TCR信号复合物的不稳定,从而下调TCR信号。文献(Shui等,Nature Immunology(2007)8:84-91)披露HPK1缺乏导致TCR诱导的SLP-76和Erk磷酸化增强,Ca通量增加以及细胞因子和抗原特异性抗体的产生增加,表明HPK1负调节TCR信号传导和T细胞介导的免疫反应。此外,Sawasdikosol等发现HPK1(-/-)T细胞对***素PGE2的抑制和凋亡作用有抵抗力(Sawasdikosol等人,Cancer Immunol.Immunother.(2010)59:419-429)。2020年清华大学廖学斌课题组报道了HPK1在T细胞免疫疗法中的功能意义,【Siet al.,Hematopoietic Progenitor Kinase1(HPK1)Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies,Cancer Cell(2020)】研究人员首先在公开的肿瘤数据库中分析得知MAP4K1(编码HPK1)与T细胞耗竭相关的信号分子(如:PDCD1、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。接下来,研究人员选取多发性骨髓瘤组织活检,分选测量T细胞中HPK1与免疫抑制分子的蛋白表达情况,实验结果可知在耗竭的T细胞中,HPK1的表达上调。此实验结果表明HPK1与肿瘤浸润性T细胞耗竭的正相关性,HPK1可能是调节T细胞耗竭并抑制抗肿瘤免疫反应的一个重要激酶。
HPK1又称为MAP4K1,属于MAP4K家族的成员,该家族中还有其他5位成员MAP4K2(GCK激酶)、MAP4K3(GLK激酶)、MAP4K4(HGK激酶)、MAP4K5(KHS激酶)和MAP4K6(MINK激酶)。其中GLK激酶的生物学作用与HPK1的作用正好相反,GLK 可以通过与下游接头蛋白结合,促进TCR通路的激活。而文献【Huai-Chia Chuang等,Chapter Seven-MAP4K Family Kinases in Immunity and Inflammation,Advances in Immunology,2016(129)277-314】发现HGK激酶的丢失会导致小鼠自发性全身炎症和2型糖尿病,家族中其他激酶的作用暂时不详。为了保证更好的安全性,需要找到对MAP4K家族其他成员具有高选择性的HPK1激酶抑制剂。
目前,该靶点药物的研究仍处于临床实验阶段,尚无药物上市,为了更好的满足临床需求,开发一款选择性高、活性高、安全性强的HPK1激酶抑制剂具有重要的临床意义。
发明内容
本发明要解决的技术问题是提供一种结构新颖的、对HPK1有良好抑制活性的HPK1抑制剂化合物。进一步的,该类化合物可用于抑制HPK1激酶活性,从而增强机体对肿瘤的免疫作用。更进一步的,该类化合物还可用于治疗或预防由HPK1所介导的相关疾病,尤其是癌症。该类化合物对多种癌细胞具有良好的抑制作用,并具有良好的成药性。
本发明的技术方案如下:
在一方面,本发明提供了如下通式(I)所示的化合物、其药学上可接受的盐或其立体异构体,
其中,
X
1、Y
1分别独立地选自-C(R
2)(R
3)-、-O-、-N(R
4)-或-S-;
X
2、X
3、X
4分别独立地选自-C(R
2)-、-O-、-N-、-N(R
4)-或-S-;
Y
2、Y
4分别独立地选自-C(R
2)或-N-;
Y
3选自-C(R
5)或-N-;
Y
5选自-C(R
6);
Y
6选自-C(R
7)或-N-;
各R
2、R
3、各R
4分别独立地选自氢、卤素、羟基、巯基、氨基、硝基、氰基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基或卤代C
1-6烷氧基;
R
5和R
7中有一个与R
6以及和它们各自相连的环原子一起形成任选被1-5个Q1取代的3-10元环烷基、3-10元杂环基、6-10元芳基或5-10元杂芳基;未成环的R
5或R
7选自氢、卤素、羟基、巯基、氨基、硝基、氰基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基或卤代C
1-6烷氧基;
R
1选自氢、卤素、羟基、硝基、氰基、C
1-6烷基、卤代C
1-6烷基、羟基C
1-6烷基、氨基C
1-6烷基、-NR
aR
b、-OR
a、-SR
a、-NR
a-C(O)-R
b-、-C(O)R
a、-C(O)NR
a、-C(O)OR
a或任选被取代基取代的以下基团:-(CH
2)
p-3-10元环烷基、-(CH
2)
p-3-10元杂环基、-(CH
2)
p-5-10元杂芳基、 -(CH
2)
p-6-10元芳基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C
1-6烷基、C
1-
6烷氧基或卤代C
1-6烷基;
各Q1分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、-NR
aR
b、-OR
a、-SR
a、-C(O)R
a、-C(O)OR
a、-C(O)NR
a或任选被1-3个Q2取代的以下基团:C
1-6烷基、C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、-(CH
2)
m-3-10元环烷基、-(CH
2)
m-3-10元杂环基、-(CH
2)
m-5-10元杂芳基或-(CH
2)
m-6-10元芳基;所述Q2分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、C
1-
6烷基、C
1-6烷氧基、卤代C
1-6烷基、卤代C
1-6烷氧基、羟基C
1-6烷基、3-10元环烷基、3-10元杂环基、5-10元杂芳基或6-10元芳基;
各R
a、各R
b分别独立地选自氢、卤素、羟基、硝基、氨基、氰基、羧基、C
1-6烷基、C
1-
6烷氧基、C
1-6烷基氨基、二(C
1-6烷基)氨基、卤代C
1-6烷基、羟基C
1-6烷基、氨基C
1-6烷基、C
1-6烷硫基、卤代C
1-6烷氧基、卤代C
1-6烷硫基、羟基C
1-6烷氧基、羟基C
1-6烷硫基、氨基C
1-6烷氧基、氨基C
1-6烷硫基或任选被取代基取代的以下基团:-(CH
2)
m-3-10元环烷基、-(CH
2)
m-3-10元杂环基、-(CH
2)
m-5-10元杂芳基、-(CH
2)
m-6-10元芳基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C
1-6烷基、C
1-6烷氧基或卤代C
1-6烷基;
各m、各p分别独立地选自0、1、2、3、4或5。
在某些实施方案中,前述通式(I)所示的化合物、其药学上可接受的盐或其立体异构体,具有如下通式(II-1)或通式(II-2)所示的结构
其中,
X
1、Y
1分别独立地选自-C(R
2)(R
3)-、-O-、-N(R
4)-或-S-;
X
2、X
3、X
4分别独立地选自-C(R
2)-、-O-、-N-、-N(R
4)-或-S-;
Y
2、Y
4分别独立地选自-C(R
2)或-N-;
Y
3选自-C(R
5)或-N-;
Y
6选自-C(R
7)或-N-;
各R
2、各R
3、各R
4、R
5、R
7分别独立地选自氢、卤素、羟基、巯基、氨基、硝基、氰基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基或卤代C
1-6烷氧基;
R
1选自氢、卤素、羟基、硝基、氰基、C
1-6烷基、卤代C
1-6烷基、羟基C
1-6烷基、氨基C
1-6烷基、-NR
aR
b、-OR
a、-SR
a、-NR
a-C(O)-R
b-、-C(O)R
a、-C(O)NR
a、-C(O)OR
a或任选被取代基取代的以下基团:-(CH
2)
p-3-10元环烷基、-(CH
2)
p-3-10元杂环基、-(CH
2)
p-5-10元杂芳基、-(CH
2)
p-6-10元芳基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C
1-6烷基、C
1-
6烷氧基或卤代C
1-6烷基;
环A选自3-10元环烷基、3-10元杂环基、6-10元芳基或5-10元杂芳基;
各Q1分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、-NR
aR
b、-OR
a、-SR
a、- C(O)R
a、-C(O)OR
a、-C(O)NR
a或任选被1-3个Q2取代的以下基团:C
1-6烷基、C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、-(CH
2)
m-3-10元环烷基、-(CH
2)
m-3-10元杂环基、-(CH
2)
m-5-10元杂芳基或-(CH
2)
m-6-10元芳基;所述Q2分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、C
1-
6烷基、C
1-6烷氧基、卤代C
1-6烷基、卤代C
1-6烷氧基、羟基C
1-6烷基、3-10元环烷基、3-10元杂环基、5-10元杂芳基或6-10元芳基;
各R
a、各R
b分别独立地选自氢、卤素、羟基、硝基、氨基、氰基、羧基、C
1-6烷基、C
1-
6烷氧基、C
1-6烷基氨基、二(C
1-6烷基)氨基、卤代C
1-6烷基、羟基C
1-6烷基、氨基C
1-6烷基、C
1-6烷硫基、卤代C
1-6烷氧基、卤代C
1-6烷硫基、羟基C
1-6烷氧基、羟基C
1-6烷硫基、氨基C
1-6烷氧基、氨基C
1-6烷硫基或任选被取代基取代的以下基团:-(CH
2)
m-3-10元环烷基、-(CH
2)
m-3-10元杂环基、-(CH
2)
m-5-10元杂芳基、-(CH
2)
m-6-10元芳基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C
1-6烷基、C
1-6烷氧基或卤代C
1-6烷基;
各m、各n、各p分别独立地选自0、1、2、3、4或5。
在某些实施方案中,通式(I)、通式(II-1)或通式(II-2)所示的化合物、其药学上可接受的盐或其立体异构体,其中,
X
1、Y
1分别独立地选自-C(R
2)(R
3)-、-O-、-N(R
4)-或-S-;
X
2、X
3、X
4分别独立地选自-C(R
2)-、-O-、-N-、-N(R
4)-或-S-;
Y
2、Y
4分别独立地选自-C(R
2)或-N-;
Y
3选自-C(R
5)或-N-;Y
6选自-C(R
7)或-N-;
各R
2、R
3、各R
4、R
5、R
7分别独立地选自氢、卤素、羟基、巯基、氨基、硝基、氰基、C
1-4烷基、卤代C
1-4烷基、C
1-4烷氧基或卤代C
1-4烷氧基;
R
1选自氢、卤素、羟基、硝基、氰基、C
1-4烷基、卤代C
1-4烷基、羟基C
1-4烷基、氨基C
1-4烷基、-NR
aR
b、-OR
a、-SR
a、-NR
a-C(O)-R
b-、-C(O)R
a、-C(O)NR
a、-C(O)OR
a或任选被取代基取代的以下基团:-(CH
2)
p-3-6元环烷基、-(CH
2)
p-3-6元杂环基、-(CH
2)
p-5-8元杂芳基、-(CH
2)
p-苯基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C
1-6烷基、C
1-6烷氧基或卤代C
1-6烷基;
环A选自5-10元环烷基、5-10元杂环基、6-10元芳基或5-10元杂芳基;
各Q1分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、-NR
aR
b、-OR
a、-SR
a、-C(O)R
a、-C(O)OR
a、-C(O)NR
a或任选被1-3个Q2取代的以下基团:C
1-4烷基、C
1-4烷氧基、C
1-4烷氧基-C
1-4烷基、-(CH
2)
m-3-8元环烷基、-(CH
2)
m-3-8元杂环基、-(CH
2)
m-5-8元杂芳基或-(CH
2)
m-苯基;所述Q2分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、C
1-4烷基、C
1-4烷氧基、卤代C
1-4烷基、卤代C
1-4烷氧基、羟基C
1-4烷基、3-8元环烷基、3-8元杂环基、5-8元杂芳基或苯基;
各R
a、各R
b分别独立地选自氢、卤素、羟基、硝基、氨基、氰基、羧基、C
1-4烷基、C
1-
4烷氧基、C
1-4烷基氨基、二(C
1-4烷基)氨基、卤代C
1-4烷基、羟基C
1-4烷基、氨基C
1-4烷基、C
1-4烷硫基、卤代C
1-4烷氧基、卤代C
1-4烷硫基、羟基C
1-4烷氧基、羟基C
1-4烷硫基、氨基C
1-4烷氧基、氨基C
1-4烷硫基或任选被取代基取代的以下基团:-(CH
2)
m-3-8元环烷基、-(CH
2)
m- 3-8元杂环基、-(CH
2)
m-5-8元杂芳基、-(CH
2)
m-苯基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C
1-6烷基、C
1-6烷氧基或卤代C
1-6烷基;
各m、各n、各p分别独立地选自0、1、2或3。
在某些实施方案中,通式(II-1)或通式(II-2)所示的化合物、其药学上可接受的盐或其立体异构体,其中,
X
1、Y
1分别独立地选自-C(R
2)(R
3)-、-O-、-N(R
4)-或-S-;
X
2、X
3、X
4分别独立地选自-C(R
2)-、-O-、-N-、-N(R
4)-或-S-;
Y
2、Y
4分别独立地选自-C(R
2)-或-N-;
Y
3选自-C(R
5)或-N-;
Y
6选自-C(R
7)或-N-;
各R
2、R
3、各R
4、R
5、R
7分别独立地选自氢、卤素、C
1-4烷基或卤代C
1-4烷基;
R
1选自氢、卤素、羟基、硝基、氰基、C
1-4烷基、卤代C
1-4烷基、-NR
a-C(O)-R
b-、-NR
aR
b、-OR
a或任选被取代基取代的以下基团:-(CH
2)
p-3-6元环烷基、-(CH
2)
p-3-6元杂环基;所述取代基选自卤素、羟基、氨基、C
1-6烷基、C
1-6烷氧基或卤代C
1-6烷基;
环A选自5-10元环烷基或5-10元杂环基;
各Q1分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、-NR
aR
b、-OR
a、-C(O)R
a、-C(O)OR
a、-C(O)NR
a或任选被1-3个Q2取代的以下基团:C
1-4烷基、C
1-4烷氧基、C
1-4烷氧基-C
1-4烷基、-(CH
2)
m-3-6元环烷基、-(CH
2)
m-3-6元杂环基、-(CH
2)
m-5-6元杂芳基或-(CH
2)
m-苯基;所述Q2分别独立地选自卤素、硝基、氨基、氰基、羧基、C
1-4烷基、C
1-4烷氧基、卤代C
1-4烷基、卤代C
1-4烷氧基、羟基C
1-4烷基、3-8元环烷基、3-8元杂环基、5-8元杂芳基或苯基;
各R
a、各R
b分别独立地选自氢、卤素、羟基、硝基、氨基、氰基、羧基、C
1-4烷基、C
1-
4烷氧基、卤代C
1-4烷基、卤代C
1-4烷氧基或任选被取代基取代的如下基团:-(CH
2)
m-3-8元环烷基、-(CH
2)
m-3-8元杂环基;所述取代基选自卤素、硝基、氨基、氰基、羧基、C
1-4烷基、C
1-
4烷氧基或卤代C
1-4烷基;
各m、各n、各p分别独立地选自0、1、2或3。
在某些实施方案中,X
1、Y
1分别独立地选自-C(R
2)(R
3)-、-O-、-N(R
4)-或-S-;各R
2、各R
3、各R
4分别独立地选自氢、卤素、C
1-6烷基或卤代C
1-6烷基。
在某些实施方案中,X
1、Y
1分别独立地选自-C(R
2)(R
3)-、-O-或-N(R
4)-;各R
2、各R
3、各R
4分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基或三氟甲基。
在某些实施方案中,X
1、Y
1分别独立地选自CH
2、O或NH。
在某些实施方案中,Y
2、Y
4分别独立地选自-C(R
2)或-N-;各R
2分别独立地选自氢、卤素、C
1-6烷基或卤代C
1-6烷基。
在某些实施方案中,Y
2、Y
4分别独立地选自-C(R
2)或-N-;各R
2分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基或三氟甲基。
在某些实施方案中,R
7选自氢、卤素、C
1-6烷基或卤代C
1-6烷基。
在某些实施方案中,R
7选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基或三氟甲基。
在某些实施方案中,R
5为氢。
在某些实施方案中,Y
2为N。
在某些实施方案中,Y
3、Y
4分别独立地选自CH或N。
在某些实施方案中,X
2、X
3、X
4分别独立地选自-C(R
2)-、-O-、-N-、-N(R
4)-或-S-;各R
2、各R
4分别独立地选自氢、卤素、C
1-6烷基或卤代C
1-6烷基。
在某些实施方案中,X
2、X
3、X
4分别独立地选自-C(R
2)-、-O-、-N-、-N(R
4)-或-S-;各R
2、各R
4分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基或三氟甲基。
在某些实施方案中,X
2、X
3、X
4中的一个选自S、O、N或-N(R
4)-,另两个分别独立地是-C(R
2)-;各R
2、各R
4分别独立地选自氢、卤素、C
1-6烷基或卤代C
1-6烷基。
在某些实施方案中,X
2、X
3、X
4中的一个选自S、O、N或-N(R
4)-,另两个分别独立地是-C(R
2)-;各R
2、各R
4分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基或三氟甲基。
在某些实施方案中,X
2、X
3、X
4中的一个选自-C(R
2)-,另两个分别独立地是S、O、N或-N(R
4)-;各R
2、各R
4分别独立地选自氢、卤素、C
1-6烷基或卤代C
1-6烷基。
在某些实施方案中,X
2、X
3、X
4中的一个选自-C(R
2)-,另两个分别独立地是S、O、N或-N(R
4)-;各R
2、各R
4分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基或三氟甲基。
在某些实施方案中,X
2、X
3、X
4中的一个选自S或O,另两个分别独立地是-C(R
2)-;各R
2分别独立地选自氢、卤素、C
1-6烷基或卤代C
1-6烷基。
在某些实施方案中,X
2、X
3、X
4中的一个选自S或O,另两个分别独立地是-C(R
2)-;各R
2分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基或三氟甲基。
在某些实施方案中,X
3选自-C(R
2)-,其中R
2选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基或三氟甲基。在某些实施方案中,X
2、X
3、X
4中的一个选自-C(R
2)-,另两个分别独立地是N或-N(R
4)-;各R
4分别独立地选自氢、卤素、C
1-6烷基或卤代C
1-6烷基。
在某些实施方案中,X
3为N,X
2和X
4中的一个为-N(R
4)-,另一个为-C(R
2)-;R
2和R
4分别独立地选自氢、卤素、C
1-6烷基或卤代C
1-6烷基。
在某些实施方案中,R
1选自氢、卤素、硝基、氰基、C
1-4烷基、卤代C
1-4烷基、-(CH
2)
p-3-6元环烷基、-(CH
2)
p-3-6元杂环基、-NR
a-C(O)-R
b-、-NR
aR
b或-OR
a;各p分别独立地选自0、1、2或3。
在某些实施方案中,R
1选自氢、氟、氯、溴、氰基、硝基、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基、三氟甲基、-NR
a-C(O)-R
b-、-NR
aR
b、-OR
a、环丙基、环丁基、环戊基、环己基、氮杂环丙基、氧杂环丙基、氮杂环丁基、氧杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基或四氢噻吩基。
在某些实施方案中,环A选自5-8元环烷基或5-8元杂环基。
在某些实施方案中,环A选自5-8元环烷基或5-8元含氮杂环基。
在某些实施方案中,环A选自5-8元单环烷基、5-8元单杂环基、6-8元稠杂环基、6-8元桥杂环基或6-8元螺杂环基。
在某些实施方案中,环A选自7-8元单环烷基、7-8元单杂环基或8元含氮桥杂环基。
在某些实施方案中,环A选自7-8元含氮单杂环基或7-8元含氧单杂环基。
在某些实施方案中,各Q1分别独立地选自卤素、羟基、硝基、羟基、氨基、氰基、羧基、-C(O)R
a、-C(O)OR
a、-C(O)NR
a或任选被1-3个Q2取代的以下基团:C
1-4烷基、C
1-4烷氧基、C
1-4烷氧基-C
1-4烷基、-(CH
2)
m-3-6元环烷基、-(CH
2)
m-3-6元杂环基、-(CH
2)
m-5-8元杂芳基或-(CH
2)
m-苯基;所述Q2分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、C
1-4烷基、C
1-4烷氧基、卤代C
1-4烷基、羟基C
1-4烷基、3-8元环烷基、3-8元杂环基、5-8元杂芳基或苯基。
在某些实施方案中,各Q1分别独立地选自-C(O)R
a、-C(O)OR
a、-C(O)NR
a或任选被1-3个Q2取代的如下基团:C
1-4烷基、C
1-4烷氧基、C
1-4烷氧基-C
1-4烷基、-(CH
2)
m-3-6元环烷基、-(CH
2)
m-3-6元杂环基、-(CH
2)
m-5-6元杂芳基或-(CH
2)
m-苯基;所述Q2分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、C
1-4烷基、C
1-4烷氧基、卤代C
1-4烷基或羟基C
1-4烷基。
在某些实施方案中,各Q1分别独立地选自氟、氯、溴、氨基、氰基、羟基、羧基、硝基、-C(O)R
a、-C(O)OR
a、-C(O)NR
a或任选被1-3个Q2取代的如下基团:甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、丙氧基丙基、异丙氧基甲基、异丙氧基乙基、-(CH
2)
m-环丙基、-(CH
2)
m-环丁基、-(CH
2)
m-环戊基、-(CH
2)
m-环己基、-(CH
2)
m-氧杂环丙基、-(CH
2)
m-氧杂环丁基、-(CH
2)
m-四氢呋喃基、-(CH
2)
m-氧杂环己基、-(CH
2)
m-四氢吡喃基、-(CH
2)
m-氮杂环丙基、-(CH
2)
m-氮杂环丁基、-(CH
2)
m-吡咯烷基、-(CH
2)
m-哌啶基、-(CH
2)
m-哌嗪基、-(CH
2)
m-四氢吡咯基、-(CH
2)
m-吡唑烷基、-(CH
2)
m-咪唑烷基、-(CH
2)
m-哌嗪基、-(CH
2)
m-哌啶基、-(CH
2)
m-吡唑基、-(CH
2)
m-吡咯基、-(CH
2)
m-咪唑基、-(CH
2)
m-吡啶基、-(CH
2)
m-嘧啶基、-(CH
2)
m-哒嗪基、-(CH
2)
m-吡嗪基或-(CH
2)
m-苯基;所述Q2分别独立地选自氟、氯、溴、羟基、氨基、氰基、羧基、硝基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、一氟甲基、二氟甲基或三氟甲基。
在某些实施方案中,各Q1分别独立地选自-C(O)R
a、-C(O)OR
a、-C(O)NR
a或任选被1-3个Q2取代的如下基团:甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、丙氧基丙基、异丙氧基甲基、异丙氧基乙基、-(CH
2)
m-环丙基、-(CH
2)
m-环丁基、-(CH
2)
m-环戊基、-(CH
2)
m-环己基、-(CH
2)
m-氧杂环丙基、-(CH
2)
m-氧杂环丁基、-(CH
2)
m-四氢呋喃基、-(CH
2)
m-氧杂环己基、-(CH
2)
m-四氢吡喃基、-(CH
2)
m-氮杂环丙基、-(CH
2)
m-氮杂环丁基、-(CH
2)
m-吡咯烷基、-(CH
2)
m-哌啶基、-(CH
2)
m-哌嗪基、-(CH
2)
m-吡啶基、-(CH
2)
m-嘧啶基、-(CH
2)
m-哒嗪基、-(CH
2)
m-吡嗪基;所述Q2分别独立地选自氟、氯、溴、羟基、氨基、氰基、羧基、硝基、甲 基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、一氟甲基、二氟甲基或三氟甲基。
在某些实施方案中,各R
a、各R
b分别独立地选自氢、C
1-4烷基、C
1-4烷氧基、C
1-4烷基氨基、二(C
1-4烷基)氨基、卤代C
1-4烷基、羟基C
1-4烷基、氨基C
1-4烷基、卤代C
1-4烷氧基、羟基C
1-4烷氧基、氨基C
1-4烷氧基或任选被取代基取代的如下基团:-(CH
2)
m-3-8元环烷基、-(CH
2)
m-3-8元杂环基、-(CH
2)
m-5-8元杂芳基或-(CH
2)
m-苯基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C
1-4烷基、C
1-4烷氧基或卤代C
1-4烷基。
在某些实施方案中,各R
a分别独立地选自氢、C
1-4烷基、C
1-4烷氧基、卤代C
1-4烷基、卤代C
1-4烷氧基或任选被取代基取代的如下基团:-(CH
2)
m-3-8元环烷基、-(CH
2)
m-3-8元杂环基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C
1-4烷基、C
1-4烷氧基或卤代C
1-4烷基;各R
b分别独立地选自氢或C
1-4烷基。
在某些实施方案中,各R
a分别独立地选自氢、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、一氟甲基、二氟甲基、三氟甲基、三氟甲氧基、一氟乙基、二氟乙基、三氟乙基、三氟乙氧基或任选被取代基取代的如下基团:环丙基、环丁基、环戊基、环己基、氧杂环丙基、氧杂环丁基、四氢呋喃基、氮杂环丁基、氮杂环丙基、四氢吡咯基、吡唑烷基、咪唑烷基、哌嗪基或哌啶基;所述取代基选自氟、氯、溴、羟基、硝基、氨基、氰基、羧基、甲基、乙基、异丙基、甲氧基、乙氧基或三氟甲基;各R
b分别独立地选自氢、甲基、乙基、丙基或异丙基。
在某些实施方案中,各R
a分别独立地选自氢、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、三氟甲基、三氟甲氧基或任选被取代基取代的如下基团:环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基或吡咯烷基;所述取代基选自氟、氯、溴、羟基、硝基、氨基、氰基、羧基、甲基、乙基、异丙基、甲氧基、乙氧基或三氟甲基;各R
b分别独立地选自氢、甲基、乙基、丙基或异丙基。
在某些实施方案中,通式(I)、通式(II-1)、通式(II-2)所述的化合物、其药学上可接受的盐或其立体异构体,具有如下通式(III-1)或通式(III-2)所示的结构:
其中,Y
1选自-C(R
2)(R
3)-、-O-、-N(R
4)-或-S-;
Y
4选自-C(R
2)或-N-;
Y
3选自-C(R
5)或-N-;
Y
6选自-C(R
7)或-N-;
X
2、X
3、X
4分别独立地选自-C(R
2)-、-O-、-N-、-N(R
4)-或-S-;
各R
2、R
3、R
4、R
5、R
7分别独立地选自氢、卤素、C
1-4烷基或卤代C
1-4烷基;
R
1选自氢、卤素、硝基、氰基、C
1-4烷基、卤代C
1-4烷基、3-6元环烷基、3-6元杂环基、-NR
a-C(O)-R
b-、-NR
aR
b、-OR
a或任选被取代基取代的以下基团:-(CH
2)
p-3-6元环烷基、-(CH
2)
p-3-6元杂环基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C
1-4烷基、C
1-4烷氧 基或卤代C
1-4烷基;
各Q1分别独立地选自卤素、硝基、氨基、氰基、羧基、-C(O)R
a、-C(O)OR
a、-C(O)NR
a或任选被1-2个Q2取代的如下基团:C
1-4烷基、C
1-4烷氧基、C
1-4烷氧基-C
1-4烷基、-(CH
2)
m-3-6元环烷基、-(CH
2)
m-3-6元杂环基、-(CH
2)
m-5-6元杂芳基或-(CH
2)
m-苯基;所述Q2分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、C
1-4烷基、C
1-4烷氧基、卤代C
1-4烷基或羟基C
1-4烷基;
各R
a分别独立地选自氢、甲基、乙基、丙基、异丙基、甲氧基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、三氟乙氧基、三氟甲氧基或任选被取代基取代的以下基团:环丙基、环丁基、环戊基、环己基、氧杂环丙基、氧杂环丁基、氮杂环丙基、氮杂环丁基、四氢呋喃基、哌啶基、哌嗪基、四氢吡咯基、吡唑烷基或咪唑烷基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、甲基、乙基、丙基、异丙基或三氟甲基;
各R
b分别独立地选自氢或C
1-4烷基;
各m、各n、各p分别独立地选自0、1、2或3。
在某些实施方案中,通式(I)、通式(II-1)、通式(II-2)、通式(III-1)或通式(III-2)所示的化合物、其药学上可接受的盐或其立体异构体,其中,
Y
1选自-C(R
2)(R
3)-、-O-、-N(R
4)-或-S-;
Y
4选自-C(R
2)或-N-;
Y
3选自-C(R
5)或-N-;
Y
6选自-C(R
7)或-N-;
X
2、X
3、X
4分别独立地选自-C(R
2)-、-O-、-N-、-N(R
4)-或-S-;
各R
2、R
3、各R
4、R
5、R
7分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基或三氟甲基;
R
1选自氢、氟、氯、溴、氰基、硝基、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基、三氟甲基、环丙基、环丁基、环戊基、环己基、氮杂环丙基、氧杂环丙基、氮杂环丁基、氧杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、-NR
a-C(O)-R
b-、-NR
aR
b或-OR
a,优选选自-NR
aR
b;
各Q1分别独立地选自卤素、-C(O)R
a、-C(O)OR
a、-C(O)NR
a或任选被1-2个Q2取代的如下基团:甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、丙氧基丙基、异丙氧基甲基、异丙氧基乙基、-(CH
2)
m-环丙基、-(CH
2)
m-环丁基、-(CH
2)
m-环戊基、-(CH
2)
m-环己基、-(CH
2)
m-氧杂环丙基、-(CH
2)
m-氧杂环丁基、-(CH
2)
m-氮杂环丙基、-(CH
2)
m-氮杂环丁基、-(CH
2)
m-四氢呋喃基、-(CH
2)
m-氧杂环己基、-(CH
2)
m-四氢吡喃基、-(CH
2)
m-吡咯烷基、-(CH
2)
m-哌啶基、-(CH
2)
m-哌嗪基、-(CH
2)
m-吡啶基、-(CH
2)
m-嘧啶基、-(CH
2)
m-哒嗪基、-(CH
2)
m-吡嗪基;所述Q2分别独立地选自氟、氯、溴、羟基、氨基、氰基、羧基、硝基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、羟基甲基、羟基乙基或羟基丙基;各R
a分别独立地选自氢、甲基、乙基、丙基、异丙基、甲氧基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、三氟乙氧基、三氟甲氧基或任选被取代基取代的以下基团:环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、哌啶基、哌嗪基、四氢吡咯基、吡唑烷基或咪唑烷基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、甲基、乙基、丙基、异丙基或三氟甲基;
各R
b分别独立地选自氢、甲基、乙基、丙基或异丙基;
各m、各n分别独立地选自0、1、2或3。
各Q1分别独立地选自-C(O)R
a、-C(O)OR
a或任选被1-2个Q2取代的如下基团:甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、丙氧基丙基、异丙氧基甲基、异丙氧基乙基、-(CH
2)
m-环丙基、-(CH
2)
m-环丁基、-(CH
2)
m-环戊基、-(CH
2)
m-环己基、-(CH
2)
m-氧杂环丙基、-(CH
2)
m-氧杂环丁基、-(CH
2)
m-四氢呋喃基、-(CH
2)
m-氧杂环己基、-(CH
2)
m-四氢吡喃基、-(CH
2)
m-氮杂环丙基、-(CH
2)
m-氮杂环丁基、-(CH
2)
m-吡咯烷基、-(CH
2)
m-哌啶基、-(CH
2)
m-哌嗪基、-(CH
2)
m-吡啶基、-(CH
2)
m-嘧啶基、-(CH
2)
m-哒嗪基、-(CH
2)
m-吡嗪基;所述Q2分别独立地选自氟、氯、溴、羟基、氨基、氰基、羧基、硝基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、一氟甲基、二氟甲基、三氟甲基、羟基甲基、羟基乙基或羟基丙基;
各m、各n分别独立地选自0、1、2或3。
各Q1分别独立地选自卤素、-C(O)R
a、-C(O)OR
a或任选被1-2个Q2取代的如下基团:甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、丙氧基丙基、异丙氧基甲基、异丙氧基乙基、-(CH
2)
m-环丙基、-(CH
2)
m-环丁基、-(CH
2)
m-环戊基、-(CH
2)
m-环己基、-(CH
2)
m-氧杂环丙基、-(CH
2)
m-氧杂环丁基、-(CH
2)
m-四氢呋喃基、-(CH
2)
m-氧杂环己基、-(CH
2)
m-四氢吡喃基、-(CH
2)
m-氮杂环丙基、-(CH
2)
m-氮杂环丁基、-(CH
2)
m-吡咯烷基、-(CH
2)
m-哌啶基、-(CH
2)
m-哌嗪基、-(CH
2)
m-吡啶基、-(CH
2)
m-嘧啶基、-(CH
2)
m-哒嗪基、-(CH
2)
m-吡嗪基;所述Q2分别独立地选自氟、氯、溴、羟基、氨基、氰基、羧基、硝基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、一氟甲基、二氟甲基、三氟甲基、羟基甲基、羟基乙基或羟基丙基;
各m、各n分别独立地选自0、1、2或3。
在某些实施方案中,各Q1分别独立地选自-C(O)R
a、-C(O)OR
a或任选被1-2个Q2取代的如下基团:甲基、乙基、丙基、异丙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、四氢呋喃基、氧杂环己基、四氢吡喃基、氮杂环丙基、氮杂环丁基、吡啶基或哒嗪基;所述Q2分别独立地选自氟、氯、溴、羟基、氨基、氰基、羧基、硝基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或三氟甲基。
在某些实施方案中,通式(I)、通式(II-1)、通式(II-2)、通式(III-1)或通式(III-2)所述的化合物、其药学上可接受的盐或其立体异构体,具有如下通式(IV-1)或通式(IV-2)所示的结构:
其中,X
2、X
3、X
4、环A、R
1、R
2、R
4、R
a、R
b、Q1、Q2、m、n、p的定义如前文任一方案所述。
在某些实施方案中,通式(I)、通式(II-1)、通式(II-2)、通式(III-1)、通式(III-2)、通式(IV-1)或通式(IV-2)所述的化合物、其药学上可接受的盐或其立体异构体,具有如下通式(V-1)或通式(V-2)所示的结构:
其中,X
3、X
4分别独立地选自-C(R
2)-;环A、R
1、R
2、Q1、Q2、R
a、R
b、m、n、p的定义如前文任一方案所述。
在某些实施方案中,通式(I)、通式(II-1)、通式(II-2)、通式(III-1)或通式(III-2)、通式(IV-1)或通式(IV-2)所述的化合物、其药学上可接受的盐或其立体异构体,具有如下 通式(V-3)或通式(V-4)所示的结构:
其中,X
2、X
4分别独立地选自-C(R
2)-;环A、R
1、R
2、R
4、Q1、Q2、R
a、R
b、m、n、p的定义如前文任一方案所述。
在某些实施方案中,通式(I)、通式(II-1)、通式(II-2)、通式(III-1)或通式(III-2)、通式(IV-1)或通式(IV-2)所述的化合物、其药学上可接受的盐或其立体异构体,具有如下通式(VI-1)或通式(VI-2)所示的结构:
其中,X
2、X
3分别独立地选自-C(R
2)-;环A、R
1、R
2、Q1、Q2、R
a、R
b、m、n、p的定义如前文任一方案所述。
在某些实施方案中,通式(V-1)、通式(V-2)、通式(V-3)、通式(V-4)、通式(VI-1)或通式(VI-2)所示的化合物、其药学上可接受的盐或其立体异构体,其中,
X
2、X
3、X
4分别独立地选自-C(R
2)-;
各R
2、各R
4分别独立地选自氢、卤素、C
1-4烷基或卤代C
1-4烷基;
R
1选自氢、卤素、C
1-6烷基、卤代C
1-6烷基、-NR
aR
b、-OR
a、-SR
a、-NH-C(O)-R
b-、或任选被取代基取代的以下基团:-(CH
2)
p-3-6元环烷基、-(CH
2)
p-3-6元杂环基;所述取代基选自卤素、C
1-4烷基或卤代C
1-4烷基;
各Q1分别独立地选自卤素、-C(O)R
a、-C(O)OR
a、-C(O)NR
a或任选被1-2个Q2取代的如下基团:C
1-4烷基、C
1-4烷氧基、C
1-4烷氧基-C
1-4烷基、-(CH
2)
m-3-6元环烷基、-(CH
2)
m-3-6元杂环基、-(CH
2)
m-5-6元杂芳基或-(CH
2)
m-苯基;所述Q2分别独立地选自卤素、羟基、C
1-4烷基、C
1-4烷氧基、卤代C
1-4烷基或羟基C
1-4烷基;
各R
a分别独立地选自氢、卤素、C
1-4烷基、C
1-4烷氧基、卤代C
1-4烷基、卤代C
1-4烷氧基、或任选被取代基取代的以下基团:-(CH
2)
m-3-6元环烷基、-(CH
2)
m-3-6元杂环基;所述取代基选自卤素、羟基、C
1-6烷基或卤代C
1-6烷基;
各R
b分别独立地选自氢或C
1-4烷基;
各m、各n、各p分别独立地选自0、1或2。
在某些实施方案中,所述的化合物、其药学上可接受的盐或其立体异构体,具有如下通式(VII-1)或通式(VII-2)所示的结构:
其中,环A、R
1、Q1、Q2、R
a、R
b、m、n、p的定义如前文任一方案所述。
在某些实施方案中,所述的化合物、其药学上可接受的盐或其立体异构体,具有如下通式(VII-3)或通式(VII-4)所示的结构:
其中,环A、R
1、Q1、Q2、R
a、R
b、m、n、p的定义如前文任一方案所述。
在某些实施方案中,所述的化合物、其药学上可接受的盐或其立体异构体,具有如下通式(VII-5)或通式(VII-6)所示的结构:
其中,环A、R
1、R
4、Q1、Q2、R
a、R
b、m、n、p的定义如前文任一方案所述。
在某些实施方案中,所述的化合物、其药学上可接受的盐或其立体异构体,具有如下通式(VII-7)或通式(VII-8)所示的结构:
其中,环A、R
1、R
4、Q1、Q2、R
a、R
b、m、n、p的定义如前文任一方案所述。
在某些实施方案中,通式(VII-1)、通式(VII-2)、通式(VII-3)、通式(VII-4)、通式(VII-5)、通式(VII-6)、通式(VII-7)或通式(VII-8)所示的化合物、其药学上可接受的盐或其立体异构体,其中,
R
1选自-NR
aR
b、-OR
a、-SR
a、-NH-C(O)-R
b-、或任选被取代基取代的以下基团:-(CH
2)
p-3-6元环烷基、-(CH
2)
p-3-6元杂环基;所述取代基选自卤素、C
1-4烷基或卤代C
1-4烷基;
各R
4分别独立地选自氢、卤素、C
1-4烷基或卤代C
1-4烷基;
各Q1分别独立地选自-C(O)R
a、-C(O)OR
a、-C(O)NR
a或任选被1-2个Q2取代的如下基团:C
1-4烷基、C
1-4烷氧基、C
1-4烷氧基-C
1-4烷基、3-6元环烷基、3-6元杂环基、5-6元杂芳基或苯基;所述Q2分别独立地选自卤素、羟基、C
1-4烷基或卤代C
1-4烷基;
各R
a分别独立地选自氢、卤素、C
1-4烷基、C
1-4烷氧基、卤代C
1-4烷基、卤代C
1-4烷氧基、或任选被取代基取代的以下基团:3-6元环烷基、3-6元杂环基;所述取代基选自卤素、羟基、C
1-6烷基或卤代C
1-6烷基;
各R
b分别独立地选自氢或C
1-4烷基;
各n、各p分别独立地选自0、1或2。
在某些实施方案,R
1选自氢、氟、氯、溴、氰基、硝基、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基、三氟甲基、氮杂环丁基、氧杂环丁基、-NR
a-C(O)-R
b-、-NR
aR
b或-OR
a,优选选自-NR
aR
b。
在某些实施方案中,通式(VII-1)、通式(VII-2)、通式(VII-3)、通式(VII-4)、通式(VII- 5)、通式(VII-6)、通式(VII-7)或通式(VII-8)所示的化合物、其药学上可接受的盐或其立体异构体,其中,
R
1选自氮杂环丁基、氧杂环丁基、-NR
a-C(O)-R
b-、-NR
aR
b或-OR
a,各R
a分别独立地选自氢、甲基、乙基、丙基、异丙基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、三氟乙氧基、三氟甲氧基或任选被取代基取代的以下基团:环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、哌啶基、哌嗪基、四氢吡咯基、吡唑烷基或咪唑烷基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、甲基、乙基、丙基、异丙基或三氟甲基;各R
b分别独立地选自氢、甲基、乙基、丙基或异丙基。
各R
4分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基或三氟甲基;
各Q1分别独立地选自-C(O)R
a、-C(O)OR
a或任选被1-2个Q2取代的如下基团:甲基、乙基、丙基、异丙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基丙基、丙氧基甲基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、四氢呋喃基、氧杂环己基、四氢吡喃基、氮杂环丙基、氮杂环丁基、吡咯烷基、吡啶基或哒嗪基;所述Q2分别独立地选自氟、氯、溴、羟基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或三氟甲基;
各R
a分别独立地选自氢、甲基、乙基、丙基、异丙基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、三氟乙氧基、三氟甲氧基或任选被取代基取代的以下基团:环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、哌啶基、哌嗪基、四氢吡咯基、吡唑烷基或咪唑烷基;所述取代基选自卤素、羟基、甲基、乙基、丙基、异丙基或三氟甲基;
各R
b分别独立地选自氢、甲基、乙基、丙基或异丙基。
在本发明技术方案中,所述环A中环氮原子上的氢可任选的被Q1取代。在某些实施方案,Q1对环A中环氮原子上的一个或多个氢进行取代。
本发明中各技术方案之间可以相互组合形成新的技术方案,所形成的新的技术方案同样包括在本发明的范围之内。
在某些实施方案中,前述通式(I)所述的化合物、其药学上可接受的盐或其立体异构体,选自如下化合物:
本发明还提供了一种药物组合物,其含有本发明的化合物、其药学上可接受的盐或其立体异构体,及一种或多种药用载体和/或稀释剂;所述药物组合物可以制成临床上或药学上可接受的任一剂型,如片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂等。
在本发明的某些实施方案中,上述药物制剂可以以口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时,所述药物组合物可制成口服制剂,例如可以制成常规的口服固体制剂,如片剂、胶囊剂、丸剂、颗粒剂等;也可制成口服液体制剂,如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时,可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时,上述药物制剂也可制成注射剂、包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时,可采用现有制药领域中的常规方法生产,配置注射剂时,可以不加入附加剂,也可以根据药物的性质加入适宜的附加剂。用于直肠给药时,所述药物组合物可制成栓剂等。用于经肺给药时,所述药物组合物可制成吸入剂或喷雾剂等。
本发明的药物组合物或药物制剂中可用的药用载体和/或稀释剂可以是药物制剂领域中任何常规的载体和/或稀释剂,特定载体和/或稀释剂的选择将取决于用于治疗特定患者的给药方式或疾病类型和状态。用于特定给药模式的合适药物组合物的制备方法完全在药物领域技术人员的知识范围内。
在另一方面,本发明还涉及本发明的化合物、其药学上可接受的盐或其立体异构体在制备预防和/或治疗由HPK1所介导的疾病及相关疾病的药物中的用途,所述药物可与一种或多种其他药物联用以预防或治疗由HPK1所介导的疾病及相关病症。所述疾病及相关病症选自癌症或良性肿瘤,所述癌症包括原位癌和转移的癌症。进一步的,所述癌症包括但不限于肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子***、子宫内膜癌、直肠癌、肝癌、肾癌、食管腺癌、食管鳞状细胞癌、***癌、甲状腺癌、雌性生殖道癌、淋巴瘤、神经纤维瘤、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、小细胞肺癌、非小细胞肺癌、胃肠道间质瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、白血病、胶质瘤或肉瘤等。
进一步的,本发明还涉及含有本发明的化合物、其药学上可接受的盐或其立体异构体的药物制剂在制备药物中的用途,所述药物可与一种或多种药物联用以治疗及/或预防由HPK1所介导的疾病及相关病症。
在另一方面,本发明涉及的含有本发明的化合物、其药学上可接受的盐或其立体异构体 的药物可以单独给药,或者与一种或多种第二治疗活性剂联合使用,所述第二治疗活性剂与本申请的HPK1抑制剂化合物组合用于治疗和/或预防由HPK1所介导的疾病和相关病症。因此,在某些实施方案中,所述的药物组合物还含有一种或多种第二治疗活性剂。在某些实施方案中,所述的第二治疗活性剂选自抗癌剂,包括有丝***抑制剂、烷化剂、抗代谢物、反义DNA或RNA、抗肿瘤抗生素、生长因子抑制剂、信号传导抑制剂、细胞周期抑制剂、酶抑制剂、类维生素A受体调控剂、蛋白酶体抑制剂、拓扑异构酶抑制剂、生物应答调节剂、激素类药物、血管再生抑制剂、细胞生长抑制剂、靶向抗体、HMG-CoA还原酶抑制剂和异戊二烯基蛋白质转移酶抑制剂。
在某些实施方案中,待组合的各成分(例如,本发明的化合物、其药学上可接受的盐、其立体异构体与第二治疗活性剂)可同时给药或依次顺序地分开用药。例如,可以在施用本发明化合物、其药学上可接受的盐或其立体异构体之前、同时或之后,施用第二治疗活性剂。此外,待组合的各成分还可以以同一制剂形式或以分开的不同制剂的形式联合给药。
在另一方面,本发明还提供了一种治疗由HPK1介导的疾病及相关病症的方法,该方法包括向有需要的患者施用有效量的前述通式(I)所述的化合物、其药学上可接受的盐或其立体异构体,前述制剂或药物组合物;所述由HPK1介导的疾病及相关病症如上定义。
所述的“有效量”是指能够减轻、延缓、抑制或治愈受试者病症的药物剂量。给药剂量的大小与药物给药方式、药剂的药代动力学、疾病的严重程度、受试者的个性体征(性别、体重、身高、年龄)等来确定。
【发明详述】
在本发明中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员通常理解的含义,然而为了更好的理解本发明,下面提供了部分术语的定义。当本发明所提供的术语的定义和解释与本领域技术人员所通常理解的含义不符的时候,以本发明所提供的术语的定义和解释为准。
本发明所述的“卤素”是指氟原子、氯原子、溴原子或碘原子。
本发明所述的“C
1-6烷基”表示直链或支链的含有1-6个碳原子的烷基,包括例如“C
1-4烷基”、“C
1-3烷基”、“C
1-2烷基”、“C
2-6烷基”、“C
2-5烷基”、“C
2-4烷基”、“C
2-3烷基”、“C
3-6烷基”、“C
3-5烷基”、“C
3-4烷基”等,具体实例包括但不限于:甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。本发明所述的“C
1-4烷基”指C
1-6烷基中的含有1-4个碳原子的具体实例。
本发明所述的“C
1-6烷氧基”是指“C
1-6烷基-O-”,所述的“C
1-6烷基”如前文所定义。本发明所述的“C
1-4烷氧基”是指“C
1-4烷基-O-”,所述的“C
1-4烷基”如前文所定义。
本发明所述的“C
1-6烷硫基”是指“C
1-6烷基-S-”,所述的“C
1-6烷基”如前文所定义。本发明所述的“C
1-4烷硫基”是指“C
1-4烷基-S-”,所述的“C
1-4烷基”如前文所定义。
本发明所述的“羟基C
1-6烷基、氨基C
1-6烷基、卤代C
1-6烷基”是指C
1-6烷基中的一个或多个氢分别被一个或多个羟基、氨基或卤素所取代。C
1-6烷基如前文所定义
本发明所述“羟基C
1-6烷氧基、氨基C
1-6烷氧基、卤代C
1-6烷氧基”是指“C
1-6烷氧基”中的一个或多个氢被一个或多个羟基、氨基或卤素所取代。
本发明所述“羟基C
1-6烷硫基、氨基C
1-6烷硫基、卤代C
1-6烷硫基”是指“C
1-6烷硫基”中的一个或多个氢被一个或多个羟基、氨基或卤素所取代。
本发明所述的“C
2-6烯基”是指含有至少一个双键且碳原子数为2-6的直链、支链或环状的烯基,包括例如“C
2-4烯基”等。其实例包括但不限于:乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、1,3-丁二烯基、1-戊烯基、2-戊烯基、3-戊烯基、1,3-戊二烯基、1,4-戊二烯基、1-己烯基、2-己烯基、3-己烯基、1,4-己二烯基、环戊烯基、1,3-环戊二烯基、环己烯基、1,4-环己二烯基等。
本发明所述的“C
2-6炔基”是指含有至少一个三键且碳原子数为2-6的直链或支链的炔基,包括例如“C
2-4炔基”等。其实例包括但不限于:乙炔基、丙炔基、2-丁炔基、2-戊炔基、3-戊炔基、4-甲基-2-戊炔基、2-己炔基、3-己炔基、5-甲基-2-己炔基等。
本发明所述的“3-10元环烷基”是指包含3-10个碳原子的饱和或部分饱和的且不具有芳香性的单环或多环基团。所述“单环环烷基”优选“3-8元单环烷基”,所述“多环环烷基”包括“稠环基、桥环基和螺环基”,优选“7-10元稠环烷基”、“7-10元桥环基”和“7-10元螺环基”。
本发明所述的“3-8元单环烷基”是指含有3-8个碳原子的饱和或部分饱和的且不具有芳香性的单环环状烷基,包括“3-8元饱和单环烷基”和“3-8元部分饱和单环烷基”;优选“3-4元单环烷基”、“3-5元单环烷基”、“3-6元单环烷基”、“3-7元单环烷基”、“4-5元单环烷基”、“4-6元单环烷基”、“4-7元单环烷基”、“4-8元单环烷基”、“5-6元单环烷基”、“5-7元单环烷基”、“5-8元单环烷基”、“6-7元单环烷基”、“6-8元单环烷基”、“7-8元单环烷基”、“3-6元饱和单环烷基”、“5-8元饱和单环烷基”、“5-7元饱和单环烷基”、“5-6元饱和单环烷基”等,任选地,环状结构中的环碳原子可以被氧代。所述的“3-8元饱和单环烷基”的具体实例包括但不限于:环丙烷基(环丙基)、环丁烷基(环丁基)、环戊烷基(环戊基)、环己烷基(环己基)、环庚烷基(环庚基)、环辛烷基(环辛基)等;所述的“3-8元部分饱和单环烷基”的具体实例包括但不限于环丙烯基、环丁烯基、环戊烯基、环戊二烯基、环己烯基、环己-1,3-二烯、环己-1,4-二烯、环庚烯基、环庚-1,3-二烯基、环庚-1,4-二烯基、环庚-1,3,5-三烯基,环辛烯基、环辛-1,3-二烯基、环辛-1,4-二烯基、环辛-1,5-二烯基、环辛-1,3,5-三烯基、环辛四烯基等。
本发明所述的“7-10元稠环基”是指由两个或两个以上环状结构彼此共用两个相邻的碳原子所形成的含有7-10个环原子的、饱和或部分饱和的、非芳香性环状基团,所述的稠环中的一个环可以为芳香性环,但稠环整体不具备芳香性;包括“8-9元稠环基”、“9-10元稠环基”等,其稠和方式可以为:5-6元环烷基并5-6元环烷基、苯并5-6元环烷基、苯并5-6元饱和环烷基等,任选地,环状结构中的环原子可以被氧代。其实例包括但不限于:二环[3.1.0]己烷基、 二环[4.1.0]庚烷基、二环[2.2.0]己烷基、二环[3.2.0]庚烷基、二环[4.2.0]辛烷基、八氢并环戊二烯基、八氢-1H-茚基、十氢化萘基、十四氢菲基、双环[3.1.0]己-2-烯基、双环[4.1.0]庚-3-烯基、双环[3.2.0]庚-3-烯基、双环[4.2.0]辛-3-烯基、1,2,3,3a-四氢并环戊二烯基、2,3,3a,4,7,7a-六氢-1H-茚基、1,2,3,4,4a,5,6,8a-八氢化萘基、1,2,4a,5,6,8a-六氢化萘基、1,2,3,4,5,6,7,8,9,10-十氢菲基、苯并环戊基、苯并环己基、苯并环己烯基、苯并环戊烯基等。
本发明所述的“3-10元杂环基”是指由3-10个碳原子以及选自氮、氧或硫等杂原子组成的饱和或部分饱和(包含1或2个双键)的非芳香环状基团,此环状基团可为单环或多环基团,在本发明中,杂环基中杂原子个数优选1、2、3或4,杂环基中的氮、碳或硫原子可任选地被氧化。氮原子可任选进一步被其他基团取代而形成叔胺或季铵盐。
单环杂环基优选“3-8元单杂环基”,是指至少含有一个杂原子(例如,含有1个、2个、3个、4个或5个)的且环原子数为3-8个的饱和或部分饱和的且不具有芳香性的单环环状基团,所述杂原子为氮原子、氧原子和/或硫原子,任选地,环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。本发明所述的“3-8元单杂环基”包括“3-8元饱和单杂环基”和“3-8元部分饱和单杂环基”。优选地,本发明所述的“3-8元单杂环基”含有1-3个杂原子;优选地,本发明所述的“3-8元单杂环基”含有1-2个杂原子,且所述的杂原子选自氮原子和/或氧原子;优选地,本发明所述的“3-8元单杂环基”含有1个氮原子。所述“3-8元单杂环基”优选“3-7元单杂环基”、“3-6元单杂环基”、“4-7元单杂环基”、“4-6元单杂环基”、“6-8元单杂环基”、“5-7元单杂环基”、“5-6元单杂环基”、“3-6元饱和单杂环基”、“5-6元饱和单杂环基”、“3-6元含氮单杂环基”、“3-6元饱和含氮单杂环基”、“5-6元含氮单杂环基”、“5-6元饱和含氮单杂环基”等。例如,仅包含1个或2个氮原子,或者,包含一个氮原子和其他的1个或2个杂原子(例如氧原子和/或硫原子)。“3-8元单杂环基”的具体实例包括但不仅限于:氮杂环丙烷基、2H-氮杂环丙烷基、二氮杂环丙烷基、3H-二氮杂环丙烯基、氮杂环丁烷基、1,4-二氧杂环己烷基、1,3-二氧杂环己烷基、1,3-二氧杂环戊烷基、1,4-二氧杂环己二烯基、四氢呋喃基、二氢吡 咯基、吡咯烷基、咪唑烷基、4,5-二氢咪唑基、吡唑烷基、4,5-二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二氢噻唑基、噻唑烷基、哌啶基、四氢吡啶基、哌啶酮基、四氢吡啶酮基、二氢哌啶酮基、哌嗪基、吗啉基、4,5-二氢噁唑基、4,5-二氢异噁唑基、2,3-二氢异噁唑基、噁唑烷基、2H-1,2-噁嗪基、4H-1,2-噁嗪基、6H-1,2-噁嗪基、4H-1,3-噁嗪基、6H-1,3-噁嗪基、4H-1,4-噁嗪基、4H-1,3-噻嗪基、6H-1,3-噻嗪基、2H-吡喃基、2H-吡喃-2-酮基、3,4-二氢-2H-吡喃基等。
多环杂环基包括“稠杂环基”、“螺杂环基”和“桥杂环基”,优选“7-10元稠杂环基”、“7-10元螺杂环基”和“7-10元桥杂环基”。
本发明所述“7-10元稠杂环基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的含有7-10个环原子的、且至少一个环原子为杂原子的、饱和或部分饱和的、非芳香性环状基团,所述的稠环中其中一个环可以为芳香性环,但稠环整体不具备芳香性,所述杂原子为氮原子、氧原子和/或硫原子,任选地,环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代,包括但不限于“8-9元稠杂环基”、“9-10元稠杂环基”等,其稠和方式可以为5-6元杂环基并5-6元杂环基、5-6元杂环基并5-6元环烷基、苯并5-6元杂环基、苯并5-6元饱和杂环基、5-6元杂芳基并5-6元杂环基、5-6元杂芳基并5-6元饱和杂环基;5-6元杂芳基如前文所定义;所述“8-10元稠杂环基”具体实例包括但不仅限于:吡咯烷基并环丙基、环戊基并氮杂环丙基、吡咯烷基并环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、吡咯烷基并哌嗪基、吡咯烷基并吗啉基、哌啶基并吗啉基、苯并吡咯烷基、苯并环戊基、苯并环己基、苯并四氢呋喃基、苯并吡咯烷基、苯并咪唑烷基、苯并噁唑烷基、苯并噻唑烷基、苯并异噁唑烷基、苯并异噻唑烷基、苯并哌啶基、苯并吗啉基、苯并哌嗪基、苯并四氢吡喃基、吡啶并环戊基、吡啶并环己基、吡啶并四氢呋喃基、吡啶并吡咯烷基、吡啶并咪唑烷基、吡啶并噁唑烷基、吡啶并噻唑烷基、吡啶并异噁唑烷基、吡啶并异噻唑烷基、吡啶并哌啶基、吡啶并吗啉基、吡啶并哌嗪基、吡啶并四氢吡喃基、嘧啶并环戊基、嘧啶并环己基、嘧啶并四氢呋喃基、嘧啶并吡咯烷基、嘧啶并咪唑烷基、嘧啶并噁唑烷基、嘧啶并噻唑烷基、嘧啶并异噁唑烷基、嘧啶并异噻唑烷基、嘧啶并哌啶基、嘧啶并吗啉基、嘧啶并哌嗪基、嘧啶并四氢吡喃基;四氢咪唑并[4,5-c]吡啶基、3,4-二氢喹唑啉基、1,2-二氢喹喔啉基、苯并[d][1,3]二氧杂环戊烯基、2H-色原烯基、2H-色原烯-2-酮基、4H-色烯基、4H-色烯-4-酮基、4H-1,3-苯并噁嗪基、4,6-二氢-1H-呋喃并[3,4-d]咪唑基、3a,4,6,6a-四氢-1H-呋喃并[3,4-d]咪唑基、4,6-二氢-1H-噻吩并[3,4-d]咪唑基、4,6-二氢-1H-吡咯并[3,4-d]咪唑基、八氢-苯并[d]咪唑基、十氢喹啉基、六氢噻吩并咪唑基、六氢呋喃并咪唑基、4,5,6,7-四氢-1H-苯并[d]咪唑基、八氢环戊烯并[c]吡咯基、4H-1,3-苯并噁嗪基等。
术语“苯并环戊基”,其结构是指
(亦可称之为2,3-二氢-1H-茚基);术语“苯并吡咯烷”其结构包括
等;术语“吡啶并四氢呋喃基”其结构包括
前文所定义的其他“定义的其它稠杂环基”的具体实例具有与之类似的环状结构。
本发明所述的“7-10元螺杂环基”是指由两个或两个以上环状结构彼此共用一个环原子所形成的、含有7-10个环原子(其中至少一个环原子为杂原子,例如氮原子、氧原子或硫原子)的环状结构,包括“7-10元饱和螺杂环基”和“7-10元部分饱和螺杂环基”。任选地,环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。其具体实例包括但不仅限于:
本发明所述的“7-10元桥杂环基”是指由两个或两个以上环状结构彼此共用两个非相邻的环原子所形成的、含有7-10个环原子(其中至少一个环原子为杂原子,例如氮原子、氧原子或硫原子)的环状结构,包括“7-10元饱和桥杂环基”和“7-10元部分饱和桥杂环基”。任选地,环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。具体实例包括但不仅限于:
本发明所述的“6-10元芳基”包括“6-8元单环芳基”和“8-10元稠环芳基”。
本发明所述的“6-8元单环芳基”是指含有6-8个环碳原子的单环芳基,其实例包括但不限于:苯基、环辛四烯基等;优选苯基。
本发明所述的“8-10元稠环芳基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的、含有8-10个环碳原子的、不饱和的、具有芳香性的环状基团,优选“9-10元稠环芳基”,具体实例如萘基等。
本发明所述的“5-10元杂芳基”包括“5-8元单杂芳基”和“8-10元稠杂芳基”。
本发明所述的“5-8元单杂芳基”是指含有5-8个环原子(其中至少一个环原子为杂原子,例如氮原子、氧原子或硫原子)的具有芳香性的单环环状基团。任选地,环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。“5-8元单杂芳基”包括例如“5-7元单杂芳基”、“5-6元单杂芳基”、“5-6元含氮单杂芳基”、“6元含氮单杂芳基”等,所述的“含氮杂芳基”中的杂 原子至少含有一个氮原子,例如,仅包含1个或2个氮原子,或者,包含一个氮原子和其他的1个或2个杂原子(例如氧原子和/或硫原子),或者,包含2个氮原子和其他的1个或2个杂原子(例如氧原子和/或硫原子)。“5-8元单环杂芳基”的具体实例包括但不仅限于呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-***基、1,2,4-***基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基、氮杂环庚三烯基、1,3-二氮杂环庚三烯基、氮杂环辛四烯基等。所述“5-6元单杂芳基”是指5-8元杂芳基中含有5-6个环原子的具体实例。
本发明所述的“8-10元稠杂芳基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的、含有8-10个环原子(其中至少一个环原子为杂原子,例如氮原子、氧原子或硫原子)的、不饱和的具有芳香性的环状结构。任选地,环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。包括“9-10元稠杂芳基”,“8-9元稠杂芳基”等,其稠和方式可以为苯并5-6元杂芳基、5-6元杂芳基并5-6元杂芳基等;具体实例包括但不限于:吡咯并吡咯、吡咯并呋喃、吡唑并吡咯、吡唑并噻吩、呋喃并噻吩、吡唑并噁唑、苯并呋喃基、苯并异呋喃基、苯并噻吩基、吲哚基、异吲哚基、苯并噁唑基、苯并咪唑基、吲唑基、苯并***基、喹啉基、2-喹啉酮基、4-喹啉酮基、1-异喹啉酮基、异喹啉基、吖啶基、菲啶基、苯并哒嗪基、酞嗪基、喹唑啉基、喹喔啉基、嘌呤基、萘啶基等。
本发明所述的“碳原子、氮原子或硫原子被氧代”是指形成C=O、N=O、S=O或SO
2的结构。
本发明所述“任选被取代”是指被取代基上的一个或多个氢原子可以被一个或多个取代基“取代”或“不取代”的两种情形。
本发明所述的“药学上可接受的盐”指化合物中存在的酸性官能团(例如-COOH、-OH、-SO
3H等)与适当的无机或者有机阳离子(碱)形成的盐,包括与碱金属或碱土金属形成的盐、铵盐,以及与含氮有机碱形成的盐;以及化合物中存在的碱性官能团(例如-NH2等)与适当的无机或者有机阴离子(酸)形成的盐,包括与无机酸或有机酸(例如羧酸等)形成的盐。其实例包括但不限于锂盐、钠盐、钾盐、钙盐、镁盐、铋盐、盐酸盐、硫酸盐、硝酸盐、磷酸盐、氢溴酸盐、氢碘酸盐、甲酸盐、乙酸盐、丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、马来酸盐、富马酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、甲苯磺酸盐、四氟硼酸盐、精氨酸盐、天冬氨酸盐和谷氨酸等。
本发明所述的“异构体”是指当本发明化合物含有一个或多个不对称中心,因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物可以有不对称中心,这类不对称中心各自独立地产生两个光学异构体。本发明的范围包括所有可能的光学异构体和它们的混合物。本发明所述的化合物若含有烯烃双键,除非特别说明,包括顺式异构体和反式异构体。本发明所述的化合物可以以互变异构体(官能团异构体的一种)形式存在,其通过一个或多个双键位移而具有不同的氢的连接点,例如,酮和它的烯醇形式是酮-烯醇互变异构体。本发明化合物含有螺环结构,受环的立体空间结构的 影响,环上的取代基可存在于环两侧从而形成相对的顺式(cis)和反式(trans)异构体。各互变异构体及其混合物都包括在本发明的范围中。所有化合物的对映异构体、非对映异构体、外消旋体、内消旋体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物等,均包括在本发明范围中。
本发明化合物可通过对映体特异性合成或从对映异构体混合物拆分以得到个别对映异构体的形式制备。常规拆分技术包括使用光学活性酸形成对映异构体对的每一异构体的游离碱的盐(接着分步结晶和游离碱再生)、使用光学活性胺形成对映异构体对的每一对映异构体的酸形式的盐(接着分步结晶和游离酸再生)、使用光学纯酸、胺或醇形成对映异构体对的每一对映异构体中的每一种的酯或酰胺(接着为色谱分离和手性助剂去除)或使用各种众所周知的色谱方法拆分起始物质或最终产物的对映异构体的混合物。
当公开的化合物的立体化学通过结构命名或描绘时,命名或描绘的立体异构体相对于其他立体异构体为至少60%重量、70%重量、80%重量、90%重量、99%重量或99.9%重量纯。当单一异构体通过结构命名或描绘时,所描绘或命名的对映异构体为至少60%重量、70%重量、80%重量、90%重量、99%重量或99.9%重量纯。光学纯度重量%为对映异构体的重量与对映异构体重量加上其光学异构体的重量比率。
本发明所述的“剂型”指将药物制成的适用于临床使用的形式,包括但不限于散剂、片剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、喷雾剂、气雾剂、粉雾剂、洗剂、搽剂、软膏剂、硬膏剂、糊剂、贴剂、含漱剂或栓剂,更优选散剂、片剂、颗粒剂、胶囊剂、溶液剂、注射剂、软膏剂、含漱剂或栓剂。
发明的有益效果
1、本发明化合物、其药学上可接受的盐或其立体异构体具有优异的HPK1活性抑制作用,其在生物体内具有良好的药代动力学性质,作用持久,具有良好的肝微粒体稳定性、暴露量和生物利用度,能够治疗和/或预防由HPK1介导的疾病。
2、本发明化合物、其药学上可接受的盐或其立体异构体对HPK1介导的癌症具有较好的治疗作用。
3、本发明化合物制备工艺简单,药品纯度高,质量稳定,易于进行大规模工业生产。
下面将结合具体实施方式对本发明技术方案进行描述,对本发明的上述内容作进一步的详细说明,但不应将此理解为本发明上述主题的范围仅限于以下实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
下述实验中所用缩写代表的含义如下:
LiAlH
4:氢化铝锂
LDA:二异丙基胺基锂
DCC:二环己基碳二亚胺
制备例1:7-氨基-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮制备(化合物1)
1. 2,2'-(1,2-亚苯基)双(乙烷-1-醇)的制备
将2,2'-(1,2-亚苯基)二乙酸(10.0g,51.5mmol)溶于四氢呋喃(200mL)。0℃下分批次加入LiAlH
4(5.9g,0.15mol),加毕,15℃下反应18小时。LCMS检测反应结束,0℃下加入5.9mL水淬灭反应,有固体析出,硅藻土过滤,固体用四氢呋喃洗涤,滤液干燥浓缩得标题化合物7.0g,收率:81.8%。
2. 1,2-亚苯基双(乙烷-2,1-二基)二甲磺酸酯的制备
将2,2'-(1,2-亚苯基)双(乙烷-1-醇)(7.0g,42.2mmol)溶于二氯甲烷(150mL),0℃下加入三乙胺(8.5g,84.4mmol)和甲基磺酰氯(9.8g,84.4mmol),加毕,0℃下反应1小时。1M稀盐酸淬灭反应,分液,有机相干燥浓缩直接用于下一步。
3. 2,3,4,5-四氢-1H-苯并[d]氮杂卓的制备
将1,2-亚苯基双(乙烷-2,1-二基)二甲磺酸酯(N/A,42.2mmol)溶于乙腈(50mL),加入氨水(50mL),闷罐90℃反应2小时。降温至15℃,浓缩溶剂,加水稀释,浓盐酸调pH=4,乙酸乙酯萃取,水相用氢氧化钠水溶液调pH=11,混合溶剂(二氯甲烷:甲醇=10:1)萃取,有机相干燥浓缩得目标化合物3.0g,两步收率:48.4%。
4. 2,2,2-三氟-1-(1,2,4,5-四氢-3H-苯并[d]氮杂卓-3-基)乙基-1-酮的制备
将2,3,4,5-四氢-1H-苯并[d]氮杂卓(3.0g,20.4mmol)溶于二氯甲烷(100mL),加入吡啶(2.4g,30.6mmol),0℃下滴加三氟乙酸酐(5.4g,25.5mmol),加毕,15℃下反应15小时。LCMS检测反应结束,加水淬灭反应,二氯甲烷萃取,有机相干燥浓缩硅胶柱纯化(石油醚:乙酸乙酯=3:1)得目标化合物4.0g,收率:80.8%。
5. 2,2,2-三氟-1-(7-硝基-1,2,4,5-四氢-3H-苯并[d]氮杂卓-3-基)乙烷-1-酮的制备
将2,2,2-三氟-1-(1,2,4,5-四氢-3H-苯并[d]氮杂卓-3-基)乙基-1-酮(4.0g,16.5mmol)溶于浓硫酸(30mL),0℃下,分批次加入硝酸钾(1.7g,16.5mmol),加毕,15℃下反应16小时。 LCMS检测反应结束。反应液倒入冰水中,乙酸乙酯萃取,有机相干燥浓缩,硅胶柱纯化(石油醚:乙酸乙酯=5:1)得目标化合物3.0g,收率:63.3%。
6. 7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓的制备
将2,2,2-三氟-1-(7-硝基-1,2,4,5-四氢-3H-苯并[d]氮杂卓-3-基)乙烷-1-酮(3.0g,10.4mmol)溶于甲醇(50mL),加入碳酸钾(2.9g,20.8mmol),加毕15℃反应15小时。LCMS检测反应结束。硅藻土过滤,浓缩溶剂,C18柱纯化(甲醇=0-70%)得目标化合物1.9g,收率:95.5%。
7. 3-甲基-7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓的制备
将7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓(65mg,0.19mmol)溶于甲醛(37%)(10mL),甲酸(5mL)加毕15℃反应1小时,升温至70℃反应1小时。LCMS检测反应结束。饱和碳酸氢钠溶液调pH=9,乙酸乙酯萃取有机相干燥浓缩得目标化合物1.9g,收率:93.1%。
8. 3-甲基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备
将3-甲基-7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓(1.9g,9.2mmol)溶于甲醇(30mL),加入Pd/C(1.0g),加毕15℃氢化反应1小时。LCMS检测反应结束。硅藻土过滤,滤液干燥浓缩得目标化合物1.6g,收率:98.6%。
9. N-(3-甲基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备
将3-甲基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(1.6g,9.1mmol)溶于乙酸(5mL),加入乙酸酐(1.5mL),加毕15℃反应12小时。LCMS检测反应结束。加水稀释,饱和碳酸氢钠水溶液调pH=9,二氯甲烷萃取,水相浓缩C18柱纯化(甲醇=0-80%)得目标化合物1.9g,收率:96.0%。
10. N-(3-甲基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备
将N-(3-甲基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(1.9g,8.7mmol)溶于浓硫酸(16mL),0℃下滴加发烟硝酸(799.0mg,11.3mmol),加毕0℃下反应10min。LCMS检测反应结束。倒入冰水中,氢氧化钠水溶液调pH=7,浓缩溶剂,固体用二氯甲烷和甲醇洗涤,有机相浓缩得粗品直接用于下一步。
11. 3-甲基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备
将N-(3-甲基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(N/A,8.7mmol)溶于甲醇(20mL),加入碳酸钾(2.4g,17.4mmol),加毕,55℃下反应36小时。LCMS检测反应结束。硅藻土过滤,滤液浓缩C18柱纯化(甲醇=0-80%)得目标化合物1.6g,收率:83.2%。
12. 2-(7-甲基-1,5,6,7,8,9-六氢咪唑基并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备
将3-甲基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(1.6g,7.2mmol)溶于乙醇(30mL),加入Pd/C(1.0g),加毕15℃下氢化反应2小时。LCMS检测反应结束。加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(3.4g.17.4mmol),升至50℃反应2小时。LCMS检测反应结束。硅藻土过滤,滤液浓缩硅胶柱柱纯化(二氯甲烷:甲醇=8:1)得目标化合物1.2g,收率:57.7%。
13. 7-羟基-4-(4-甲氧基苄基)-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂 卓-2-基)噻吩并[3,2-b]吡啶-5(4H)1-酮的制备
将2-(7-甲基-1,5,6,7,8,9-六氢咪唑基苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(200mg,0.7mmol),1-(4-甲氧基苄基)-2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮(221.5mg,0.77mmol)溶于四氢呋喃(5mL),加入LDA(1.4mL,2.8mmol),加毕40℃下反应2小时。LCMS检测反应结束。饱和氯化铵淬灭反应,二氯甲烷萃取,有机相干燥浓缩硅胶柱纯化(二氯甲烷:甲醇=4:1)得目标化合物60mg,收率:17.7%。
14. 4-(4-甲氧基苄基)-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-7-基三氟甲磺酸酯的制备
将7-羟基-4-(4-甲氧基苄基)-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)1-酮(60mg,0.12mmol)溶于二氯甲烷(10mL),0℃下加入吡啶(189.8mg,2.4mmol),三氟甲磺酸酐(203.1mg,0.72mmol),加毕。0℃下反应1小时。LCMS检测反应结束。加入二氯甲烷稀释,碳酸氢钠水溶液洗涤,有机相干燥浓缩直接用于下一步。
15. 7-(((2,4-二甲氧基苄基)氨基)-4-(4-甲氧基苄基)-6-(1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-1-酮制备
将4-(4-甲氧基苄基)-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-7-基三氟甲磺酸酯(N/A,0.12mmol)溶于乙腈(5mL),加入2,4-二甲氧基苄胺(60.1mg,0.36mmol),加毕升至45℃反应2小时。LCMS检测反应结束。浓缩溶剂,硅胶柱纯化(二氯甲烷:甲醇=10:1)得标题化合物90.0mg,两步收率95.0%。
16. 7-氨基-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮制备
将7-(((2,4-二甲氧基苄基)氨基)-4-(4-甲氧基苄基)-6-(1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-1-酮(90mg,0.12mmol)溶于浓盐酸(1mL),三氟乙酸(7mL),加毕升至110℃反应24小时。LCMS检测反应结束。饱和碳酸氢钠水溶液调节pH=7,浓缩溶剂,Pre-HPLC纯化(乙腈=0-40%)得标题化合物10.0mg,收率23.4%。
分子式:C
19H
19N
5OS 分子量:365.5 LC-MS(M/e):366.1(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:11.83(s,1H),9.67(m,1H),7.96(d,J=5.2Hz,1H),7.51(s,2H),7.02(d,J=5.6Hz,1H),3.55-3.95(m,4H),2.95-3.28(m,4H),2.88(s,3H).
制备例2:4-氨基-5-(7-甲基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮的制备(化合物2)
将2-(7-甲基-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(100mg,0.35mmol),2-氨基噻吩-3-甲腈(47.5mg,0.38mmol)溶于四氢呋喃(5mL),加热至40℃,滴加LDA(0.53mL,1.05mmol),加毕40℃下反应2小时。LCMS检测反应结束。饱和氯化铵淬灭反应,乙酸乙酯萃取,有机相干燥浓缩C18柱纯化(乙腈=0-60%)得目标化合物6.6mg,收率:5.2%。
分子式:C
19H
19N
5OS 分子量:365.5 LC-MS(M/e):366.1(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:9.91(m,1H),7.57(m,2H),7.23(m,2H),4.45(m,2H),3.20-3.34(m,4H),3.17(s,3H),2.98-3.14(m,4H).
制备例3:4-氨基-5-(7-甲基-5,6,7,8,9,10-六氢-1H-咪唑并[4',5':4,5]苯并[1,2-d]吖辛因-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮的制备(化合物4)
1. 2,3,5,6-四氢苯并[d]吖辛因-4(1H)-酮的制备
将5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮(8.0g,49.9mmol)溶于三氟乙酸(60mL),加入叠氮化钠(4.9g,75.4mol)。65℃下反应7小时。用饱和碳酸氢钠(200mL)和乙酸乙酯(100mL)萃取,有机相干燥浓缩,硅胶柱纯化(二氯甲烷:甲醇=20:1)得目标化合物5.0g,收率:57.1%。
2. 1,2,3,4,5,6-六氢苯并[d]吖辛因的制备
将2,3,5,6-四氢苯并[d]吖辛因-4(1H)-酮(5.0g,28.5mmol)溶于四氢呋喃(200mL),0℃下加入四氢铝锂(4.3g,113.2mmol),75℃下反应1小时。加水(4.3mL)淬灭反应,加入10%氢氧化钠(4.3mL)溶液和水(12.9mL),过滤除去固体,用水(100mL)和乙酸乙酯(200mL)萃取,得粗品4.2g。
3. 3-甲基-1,2,3,4,5,6-六氢苯并[d]吖辛因的制备
将1,2,3,4,5,6-六氢苯并[d]吖辛因(2.0g)溶于甲酸(10mL),加入甲醛(37%)(20mL),70℃反应1小时。用饱和碳酸氢钠(200mL)调节pH至9,乙酸乙酯(200mL)萃取,得粗品2.0g。
4. 3-甲基-8-硝基-1,2,3,4,5,6-六氢苯并[d]吖辛因的制备
将3-甲基-1,2,3,4,5,6-六氢苯并[d]吖辛因(2.0g)溶于浓硫酸(15mL),降温至加入0℃加入硝酸钾(1.2g,11.9mmol),15℃下反应15小时。用2N氢氧化钠调节pH至12,用二 氯甲烷/甲醇=9:1(100mL)萃取,有机相干燥浓缩硅胶柱纯化(二氯甲烷:甲醇=9:1)得目标化合物1.3g。
5. 3-甲基-1,2,3,4,5,6-六氢苯并[d]吖辛因-8-胺制备
将3-甲基-8-硝基-1,2,3,4,5,6-六氢苯并[d]吖辛因(1.2g,5.4mmol)溶于甲醇(40mL),加入Pd/C(1.0g),加毕,15℃氢化反应1小时。硅藻土过滤,滤液干燥浓缩得目标化合物1.0g,收率96.46%。
6. N-(3-甲基-1,2,3,4,5,6-六氢苯并[d]吖辛因-8-基)乙酰胺的制备
将3-甲基-1,2,3,4,5,6-六氢苯并[d]吖辛因-8-胺(1.0g,5.2mmol)溶于乙酸(8mL),加入乙酸酐(2mL),加毕,15℃反应12小时。LCMS检测反应结束。加水稀释,饱和碳酸氢钠水溶液调pH=9,二氯甲烷/甲醇=9:1(100mL)萃取,浓缩C18柱纯化(甲醇=0-60%)得目标化合物1.0g,收率:81.9%。
7. N-(3-甲基-9-硝基-1,2,3,4,5,6-六氢苯并[d]吖辛因-8-基)乙酰胺的制备
将N-(3-甲基-1,2,3,4,5,6-六氢苯并[d]吖辛因-8-基)乙酰胺(1.0g,4.3mmol)溶于浓硫酸(15mL),0℃下滴加发烟硝酸(339mg,5.4mmol),加毕,0℃下反应10min。LCMS检测反应结束。倒入冰水中,用2N氢氧化钠水溶液调pH=10,二氯甲烷/甲醇=9:1(100mL)萃取,有机相浓缩得粗品1.8g。
8. 3-甲基-9-硝基-1,2,3,4,5,6-六氢苯并[d]吖辛因-8-胺的制备
将N-(3-甲基-9-硝基-1,2,3,4,5,6-六氢苯并[d]吖辛因-8-基)乙酰胺(1.8g)溶于甲醇(50mL),加入碳酸钾(1.7g,12.3mmol),加毕,55℃下反应48小时。浓缩,用二氯甲烷/甲醇=9:1(100mL)萃取,C18柱纯化(甲醇=0-70%)得目标化合物800mg,两步收率:79.0%。
9. 2-(7-甲基-5,6,7,8,9,10-六氢-1H-咪唑并[4',5':4,5]苯并[1,2-d]吖辛因-2-基)乙酸乙酯的制备
将3-甲基-9-硝基-1,2,3,4,5,6-六氢苯并[d]吖辛因-8-胺(800mg,3.4mmol)溶于乙醇(30mL),加入Pd/C(320mg),加毕,15℃下氢化反应1小时。加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(1.66g,8.5mmol),升温至50℃反应2小时。硅藻土过滤,滤液浓缩,经硅胶柱柱纯化(二氯甲烷:甲醇=6:1)得目标化合物500mg,收率:48.8%。
10. 4-氨基-5-(7-甲基-5,6,7,8,9,10-六氢-1H-咪唑并[4',5':4,5]苯并[1,2-d]吖辛因-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮的制备
将2-(7-甲基-5,6,7,8,9,10-六氢-1H-咪唑并[4',5':4,5]苯并[1,2-d]吖辛因-2-基)乙酸乙酯(70mg,0.23mmol)、2-氨基噻吩-3-甲腈(32mg,0.26mmol)溶于四氢呋喃(10mL),40℃下加入LDA(0.3mL,0.9mmol),加毕40℃下反应2小时。饱和氯化铵淬灭反应,乙酸乙酯(50mL)萃取,有机相经干燥、浓缩、制备板纯化(二氯甲烷:甲醇=6:1)得目标化合物粗品40mg,再次经制备板纯化(二氯甲烷:甲醇=6:1)得目标化合物2.8mg,收率:3.2%。
分子式:C
20H
21N
5OS 分子量:379.5 LC-MS(M/e):380.1(M+H+)
1H-NMR(400MHz,DMSO-d
6)δ:7.45(s,1H),7.32(s,1H),7.22-7.17(m,2H),4.20(s,2H),3.15-3.07(m,4H),2.95-2.87(m,4H),2.70-2.54(m,3H),1.95-1.79(m,2H).
制备例4:7-氨基-6-(5,8-二甲基-5,6,7,8,9,10-六氢-3H-咪唑并[4',5':4,5]苯并[1,2-e][1,4]二吖辛因-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物7)
1. 2-(2-氯-4-((3,4-二甲基苄基)氨基)-5-硝基苯基)乙-1-醇的制备
将2-(2-氯-4-氟-5-硝基苯基)乙-1-醇(4.0g,18.3mmol)溶于NMP(50mL)中,加入2,4-二甲氧基苄基胺(3.7g,21.9mmol),和N,N-二异丙基乙胺(4.7g,36.4mmol),加毕,50℃下反应0.5小时。LCMS检测反应结束,加水淬灭反应,乙酸乙酯萃取,有机相干燥浓缩硅胶柱纯化(石油醚:乙酸乙酯=3:1)得目标化合物4.0g,收率:68.1%。
2. 2-(2-氯-4-((3,4-二甲基苄基)氨基)-5-硝基苯基)乙醛的制备
将2-(2-氯-4-((3,4-二甲基苄基)氨基)-5-硝基苯基)乙-1-醇(4.0g,10.9mmol)溶于二氯甲烷(100mL),0℃下加入戴斯-马丁试剂(5.6g,13.1mmol),加毕,15℃下反应1小时。LCMS检测反应结束。反应液加入二氯甲烷,然后加入饱和碳酸氢钠水溶液淬灭反应,二氯甲烷萃取,有机相干燥浓缩,硅胶柱纯化(石油醚:乙酸乙酯=5:1)得目标化合物3.9g,收率:98.3%。
3. (2-((2-氯-4-((3,4-二甲基苄基)氨基)-5-硝基苯乙基)(甲基)氨基)乙基)(甲基)氨基甲酸叔丁酯的制备
将2-(2-氯-4-((3,4-二甲基苄基)氨基)-5-硝基苯基)乙醛(2.5g,6.9mmol)溶于二氯甲烷(50mL),加入甲基(2-(甲基氨基)乙基)氨基甲酸叔丁酯(1.6g,8.2mmol),加毕15℃反应10分钟后。加入醋酸硼氢化钠(3.2g,15.0mmol)和醋酸(900mg,15.0mmol),15℃反应16小时。LCMS检测反应结束。加入1M氢氧化钠水溶液后用二氯甲烷萃取,收集有机相,干燥,浓缩溶剂柱层析(甲醇/二氯甲烷=0-8%)得目标化合物3.1g,收率:83.8%。
4. N
1-(4-氨基-2-氯-5-硝基苯乙基)-N
1,N
2-二甲基乙烷-1,2-二胺的制备
将(2-((2-氯-4-((3,4-二甲基苄基)氨基)-5-硝基苯乙基)(甲基)氨基)乙基)(甲基)氨基甲酸叔丁酯(3.1g,5.8mmol)溶于二氯甲烷(30mL),三氟乙酸(10mL),加毕,10℃反应1小时。LCMS检测反应结束。浓缩后直接投入下一步。
5. 1,4-二甲基-8-硝基-1,2,3,4,5,6-六氢苯并[e][1,4]二吖辛因-9-胺的制备
将N1-(4-氨基-2-氯-5-硝基苯乙基)-N1,N2-二甲基乙烷-1,2-二胺粗品溶于N,N-二甲基 乙酰胺(50mL),加入碳酸钾(3.3g,23.8mmol),加毕110℃反应2小时。LCMS检测反应结束。加入水淬灭反应,乙酸乙酯萃取,收集有机相,干燥,浓缩溶剂柱层析(甲醇/二氯甲烷=0-8%)得目标化合物0.3g,两步收率:20.6%。
6. 1,4-二甲基-1,2,3,4,5,6-六氢苯并[e][1,4]二吖辛因-8,9-二胺的制备
将1,4-二甲基-8-硝基-1,2,3,4,5,6-六氢苯并[e][1,4]二吖辛因-9-胺(300mg,1.2mmol)溶于乙醇(10mL),加入Pd/C(150mg),加毕,在氮气保护下10℃反应2小时。LCMS检测反应结束。硅藻土过滤,浓缩溶剂得目标化合物直接投入下一步。
7. 2-(5,8-二甲基-5,6,7,8,9,10-六氢-3H-咪唑并[4',5':4,5]苯并[1,2-e][1,4]二吖辛因-2-基)乙酸乙酯的制备
将1,4-二甲基-1,2,3,4,5,6-六氢苯并[e][1,4]二吖辛因-8,9-二胺粗品溶于乙醇(10mL),加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(704mg,3.6mmol),加毕50℃下反应3小时。LCMS检测反应结束。浓缩溶剂柱层析(甲醇/二氯甲烷=0-15%)得目标化合物300mg,两步收率:79.1%。
8. 1-(4-甲氧基苄基)-2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮的制备
将2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮(5.0g,29.5mmol)溶于N,N-二甲基甲酰胺(50mL),加入对甲氧基苯甲基氯(7.9g,50.2mmol),碳酸钾(4.9g,35.5mmol),碘化钾(2.0g,12.0mmol),加毕10℃下反应2小时。LCMS检测反应结束。反应液中加入水,固体析出,过滤得标题化合物3.0g,收率35.1%。
9. 6-(5,8-二甲基-5,6,7,8,9,10-六氢-3H-咪唑并[4',5':4,5]苯并[1,2-e][1,4]二吖辛因-2-基)-7-羟基-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-1-酮的制备
将2-(5,8-二甲基-5,6,7,8,9,10-六氢-3H-咪唑并[4',5':4,5]苯并[1,2-e][1,4]二吖辛因-2-基)乙酸乙酯(350mg,1.1mmol),1-(4-甲氧基苄基)-2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮(415mg,1.4mmol)溶于四氢呋喃(10mL),加热至40℃,在氮气保护下,滴加LDA(1.7mL,3.3mmol),加毕40℃下反应2小时。饱和氯化铵淬灭反应,二氯甲烷萃取,有机相干燥浓缩柱层析(甲醇/二氯甲烷=0-15%)得中间体,复加入四氢呋喃(10mL)在氮气保护下滴加LDA(1.2mL)反应两个小时重复上面操作得目标化合物150mg,收率:26.5%。
10. 6-(5,8-二甲基-5,6,7,8,9,10-六氢-3H-咪唑并[4',5':4,5]苯并[1,2-e][1,4]二吖辛因-2-基)-7-羟基-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-1-酮的制备
将6-(5,8-二甲基-5,6,7,8,9,10-六氢-3H-咪唑并[4',5':4,5]苯并[1,2-e][1,4]二吖辛因-2-基)-7-羟基-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-1-酮(150mg,0.29mmol)溶于二氯甲烷(10mL),0℃下加入吡啶(460mg,5.8mmol),三氟甲磺酸酐(490mg,1.74mmol),加毕。0℃下反应1小时。LCMS检测反应结束。加入二氯甲烷稀释,碳酸氢钠水溶液洗涤,有机相干燥浓缩直接用于下一步。
11. 6-(5,8-二甲基-3-((三氟甲基)磺酰基)-5,6,7,8,9,10-六氢-3H-咪唑并[4',5':4,5]苯并[1,2-e][1,4]二吖辛因-2-基)-7-((3,4-二甲基苄基)氨基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将6-(5,8-二甲基-5,6,7,8,9,10-六氢-3H-咪唑并[4',5':4,5]苯并[1,2-e][1,4]二吖辛因-2-基)-7-羟基-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-1-酮(N/A,0.29mmol)溶于乙腈(5mL),加入2,4-二甲氧基苄胺(130mg,0.78mmol),加毕升至45℃反应2小时。LCMS检测反应结束。浓缩溶剂,硅胶柱纯化(二氯甲烷:甲醇=20:1)得标题化合物200mg,两步收率90.2%。
12. 7-氨基-6-(5,8-二甲基-5,6,7,8,9,10-六氢-3H-咪唑并[4',5':4,5]苯并[1,2-e][1,4]二吖辛因-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将6-(5,8-二甲基-3-((三氟甲基)磺酰基)-5,6,7,8,9,10-六氢-3H-咪唑并[4’,5’:4,5]苯并[1,2-e][1,4]二吖辛因-2-基)-7-((3,4-二甲基苄基)氨基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮(200mg,0.25mmol)溶于浓盐酸(1mL),三氟乙酸(7mL),加毕升至110℃反应24小时。LCMS检测反应结束。调节pH=7,浓缩溶剂,Pre-HPLC纯化(乙腈=0-40%)得标题化合物20mg,收率20.1%。
分子式:C
20H
22N
6OS 分子量:394.5 LC-MS(M/e):395.1(M+H
+)
1H-NMR(400MHz,MeOD)δ:7.83(d,J=5.2Hz,1H),7.37-7.52(m,2H),7.08(d,J=5.2Hz,1H),3.10-3.12(m,2H),2.89-2.90(m,7H),2.48(s,3H),2.21-2.37(m,2H).
制备例5:4-氨基-5-(5,8-二甲基-5,6,7,8,9,10-六氢-3H-咪唑并[4’,5’:4,5]苯并[1,2-e][1,4]二吖辛因-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮的制备(化合物8)
将2-(5,8-二甲基-5,6,7,8,9,10-六氢-3H-咪唑并[4’,5’:4,5]苯并[1,2-e][1,4]二唑-2-基)乙酸乙酯(100mg,0.32mmol)溶于四氢呋喃(5mL),在氮气保护下加入2-氨基噻吩-3-甲腈(40mg,0.32mmol),加入LDA(0.32mL,0.64mmol),加毕40℃下反应2小时。LCMS检测反应结束。饱和氯化铵淬灭反应,二氯甲烷萃取,有机相干燥浓缩C18拌样,反向柱层析纯化(甲醇/水=0-45%)得标题化合物30.0mg,收率23.7%。
分子式:C
20H
22N
6OS 分子量:394.5 LC-MS(M/e):395.1(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:7.34-7.41(m,1H),7.28(s,1H),6.95(d,J=5.6Hz,1H),6.84(d,J=5.6Hz,1H),4.10(s,2H),3.03-3.09(m,2H),2.90-2.91(m,2H),2.84-2.88(m,5H),2.41-2.46(m,3H),2.02-2.04(m,2H).
制备例6:4-氨基-5-(1,5,6,7,8,9-六氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮盐酸盐的制备(化合物9的盐酸盐)
1. 1-(7-氨基-1,2,4,5-四氢-3H-苯并[d]氮杂卓-3-基)-2,2,2-三氟乙烷-1-酮的制备
将2,2,2-三氟-1-(7-硝基-1,2,4,5-四氢-3H-苯并[d]氮杂卓-3-基)乙-1-酮(3.0g,10.4mmol)溶于甲醇(50mL),加入Pd/C(1.0g),加毕15℃反应15小时。LCMS检测反应结束。硅藻土过滤,浓缩溶剂得目标化合物2.6g,收率:96.7%。
2. N-(3-(2,2,2-三氟乙酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备
将1-(7-氨基-1,2,4,5-四氢-3H-苯并[d]氮杂卓-3-基)-2,2,2-三氟乙烷-1-酮(2.6g,10.1mmol)溶于乙酸(30mL),加入乙酸酐(1.5mL)加毕15℃反应16小时。LCMS检测反应结束。加水,继续搅拌1小时,固体析出,过滤,固体用水洗涤,干燥得目标化合物2.3g,收率:76.2%。
3. N-(8-硝基-3-(2,2,2-三氟乙酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备
将N-(3-(2,2,2-三氟乙酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(2.3g,7.7mmol)溶于浓硫酸(16mL),0℃下,加入发烟硝酸(700.0mg,10.0mmol),加毕,0℃下反应2小时。LCMS检测反应结束。倒入冰水中,二氯甲烷萃取,有机相干燥浓缩得目标化合物2.3g,收率:86.9%。
4. 7-氨基-8-硝基-1,2,4,5-四氢-3H-苯并[d]氮杂卓-3-羧酸叔丁酯的制备
将N-(8-硝基-3-(2,2,2-三氟乙酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(2.3g,6.7mmol)溶于甲醇(30mL),升温至55℃,加入碳酸钾(2.8g,20.1mmol),加毕55℃反应16小时。硅藻土过滤,滤液中加入Boc
2O(2.2g,10.1mmol),加毕,15℃反应2小时。浓缩硅胶柱纯化(石油醚:乙酸乙酯=5:1)得目标化合物1.7g,收率:82.9%。
5. 2-(2-乙氧基-2-氧乙基)-5,6,8,9-四氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯的制备
将7-氨基-8-硝基-1,2,4,5-四氢-3H-苯并[d]氮杂卓-3-羧酸叔丁酯(1.7g,5.5mmol)溶于乙醇(100mL),加入Pd/C(800mg),加毕15℃下氢化反应2小时。LCMS检测反应结束。加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(2.6g.13.3mmol),加毕,升温至50℃反应2小时。LCMS检测反应结束。硅藻土过滤,滤液浓缩硅胶柱纯化(乙酸乙酯)得目标化合物1.6g,收率:60.4%
6. 2-(4-氨基-6-氧代-6,7-二氢噻吩并[2,3-b]吡啶基-5-基)-5,6,8,9-四氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓7(1H)-羧酸叔丁酯的制备
将2-(2-乙氧基-2-氧乙基)-5,6,8,9-四氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(300mg,0.8mmol),2-氨基噻吩-3-甲腈(109.9mg,0.88mmol)溶于四氢呋喃(5mL),氮气保护下加热至40℃,滴加LDA(1.2mL,2.4mmol),加毕40℃下反应2小时。LCMS检测反应结束。饱和氯化铵淬灭反应,乙酸乙酯萃取,有机相干燥浓缩硅胶柱纯化(石油醚:乙酸乙酯=5:1)得目标化合物260mg,收率:71.7%
7. 4-氨基-5-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮盐酸盐的制备
将2-(4-氨基-6-氧代-6,7-二氢噻吩并[2,3-b]吡啶基-5-基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓7(1H)-羧酸叔丁酯(45.0mg,0.1mmol)溶于乙醇(2mL),加入HCl/乙醇(1.5mL),加毕15℃下反应4小时。LCMS检测反应结束。加入0.5mL水,过滤,固体干燥得目标化合物12.0mg,收率:31.0%。
分子式:C
18H
17N
5OS 分子量:351.4 LC-MS(M/e):352.1(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:9.39(m,2H),7.67(s,2H),7.23-7.26(m,2H),4.64(s,2H),3.26-3.36(m,4H),3.15-3.25(m,4H).
制备例7:7-氨基-6-(7-乙基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物10)
1. 7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓的制备
将2,3,4,5-四氢-1H-苯并[d]氮杂卓(5.0g,34.0mmol)溶于三氟乙酸(20mL),降温至0℃,加入浓硫酸(7.5mL)和硝酸钾(5.5g,56.7mmol),0℃下反应2小时。将反应液倾入冰水中,用2N氢氧化钠调节pH至11,用二氯甲烷/甲醇=9:1(100mL)萃取,得粗品5.0g。
2. 3-乙基-7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓的制备
将7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓(5.0g,粗品)溶于四氢呋喃(100mL),加入 乙醛水溶液(40%)(15.75g,142.9mmol),醋酸(3.1g,51.6mmol)和三乙酰氧基硼氢化钠(9.65g,45.5mmol),15℃下反应2小时。用1N氢氧化钠调节pH至10左右,用二氯甲烷/甲醇=9:1(200mL)萃取,有机相干燥浓缩硅胶柱纯化(二氯甲烷:甲醇=10:1)得目标化合物2.0g,两步反应收率26.8%。
3. 3-乙基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备
将3-乙基-7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓(2.0g,9.1mmol)溶于甲醇(40mL),加入Pd/C(500mg),用氢气换气3次,在氢气下15℃氢化反应2小时。硅藻土过滤,滤液干燥浓缩得目标化合物1.9g。
4. N-(3-乙基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备
将3-乙基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(1.9g,粗品)溶于乙酸(16mL),加入乙酸酐(4mL),加毕15℃反应1小时。加水稀释,用氢氧化钠调pH=11,二氯甲烷/甲醇=9:1(100mL)萃取,C18柱纯化(甲醇=0-60%)得目标化合物1.5g,两步收率71.4%。
5. N-(3-乙基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备
将N-(3-乙基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(1.5g,6.5mmol)溶于浓硫酸(30mL),0℃下滴加发烟硝酸(470mg,7.5mmol),加毕0℃下反应10min。LCMS检测反应结束。倒入冰水中,用2N氢氧化钠水溶液调pH=10,二氯甲烷/甲醇=9:1(100mL)萃取,C18柱纯化(甲醇=0-65%)得目标化合物1.2g,收率:66.7%。
6. 3-乙基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备
将N-(3-乙基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(1.2g,4.33mmol)溶于甲醇(150mL),加入碳酸钾(2.3g,16.6mmol),加毕,50℃下反应2小时。浓缩,用硅胶柱层析纯化(二氯甲烷:甲醇=8:1)得目标化合物1.0g,收率:98.2%。
7. 2-(7-乙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备
将3-乙基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(1.0g,4.2mmol)溶于乙醇(100mL),加入Pd/C(300mg),用氢气换气3次,在氢气下15℃氢化反应4小时。加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(2.0g.10.2mmol),升至50℃反应2小时。硅藻土过滤,滤液浓缩,用饱和碳酸氢钠(10mL),水(20mL)和二氯甲烷/甲醇=9:1(100mL)萃取,硅胶柱柱纯化(二氯甲烷:甲醇=15:1)得目标化合物800mg,收率:63.5%。
8. 7-氨基-6-(7-乙基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将2-(7-乙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(50mg,0.17mmol),3-氨基噻吩-2-甲腈(21mg,0.17mmol)溶于四氢呋喃(10mL),40℃下加入LDA(0.43mL,0.86mmol),加毕40℃下反应3小时。饱和氯化铵淬灭反应,用水(15mL)和乙酸乙酯(15mL)萃取,加入甲醇(3mL),过滤,干燥,得目标化合物21mg,收率:32.6%。
分子式:C
20H
21N
5OS 分子量:379.5 LC-MS(M/e):380.1(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.77(s,1H),11.80(s,1H),10.85-10.51(brs,1H),7.94(s, 1H),7.98-7.71(brs,1H),7.40-7.34(m,2H),7.02(s,1H),2.98-2.86(m,4H),2.72-2.44(m,6H),1.02(t,J=7.2Hz,3H).
制备例8:7-氨基-6-(7-环丁基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物11)
1. 8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备
将N-(8-硝基-3-(2,2,2-三氟乙酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(1.0g,2.9mmol)溶于甲醇(10.0mL)中,加入碳酸钾(600.0mg,4.3mmol),20℃反应2.0h,反应结束后,经过滤、水洗、二氯甲烷萃取浓缩后,粗品直接用于下一步反应。
2. 3-环丁基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备
将8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(上步粗品)溶于10.0mL甲醇中,加入氰基硼氢化钠(550.0mg,8.8mmol)、醋酸(1.7g,28.3mmol),0℃下滴加环丁酮(410.0mg,5.8mmol),20℃下反应2.0h。向反应液中加水(100mL)淬灭,乙酸乙酯萃取,有机相经无水硫酸钠干燥、旋干,得目标化合物300mg,两步收率39.6%。
3. 3-环丁基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7,8-二胺的制备
将3-环丁基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(250mg)溶于乙醇(10mL)中,加入Pd/C(50.0mg),氢气条件下25℃下反应1.5h结束,反应液直接用于下一步反应。
4. 2-(7-环丁基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备
向上步反应液中加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(330.0mg,1.7mmol),体系升至80℃后反应2h结束。过滤后用饱和碳酸氢钠溶液调pH至8,经浓缩后柱层析(二氯甲烷:甲醇=10:1)得目标化合物200mg,两步收率为63.9%。
5. 7-氨基-6-(7-环丁基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将2-(7-环丁基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(30.0mg,0.09mmol)和3-氨基噻吩-2-腈(13.0mg,0.10mmol)溶于四氢呋喃(3.0mL)中,氮气保护下,40℃下滴加LDA(0.3mL,0.60mmol),继续反应2.0h。反应完成后,将体系倒入饱和氯化铵溶液中淬灭,乙酸乙酯萃取,有机相旋干,粗品经硅胶柱层析分离(DCM:MeOH=10:1)纯化,甲醇打浆纯化得产品12.0mg,产率32.3%。
分子式:C
22H
23N
5OS 分子量:405.5 LC-MS(M/e):406.0(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.73(s,1H),11.76(s,1H),10.80-10.55(br s,1H),7.91(s,1H),7.90-7.75(br s,1H),7.40(s,1H),7.31(s,1H),7.00(s,1H),2.95-2.85(m,4H),2.81-2.71(m,1H),2.47-2.35(m,4H),2.08-1.98(m,2H),1.90-1.85(m,2H),1.65-1.51(m,2H).
制备例9:7-氨基-6-(7-环丙基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物12)
1. 3-环丙基-7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓的制备
将7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓(4.2g,21.8mmol)、氰基硼氢化钠(8.7g,139.5mmol)、醋酸(13.6g,230.6mmol)溶于甲醇(120mL)中,0℃下滴加(1-乙氧基环丙氧基)三甲基硅烷(8.7g,50.1mmol),60℃下反应4h,LCMS检测反应完成,向反应液中加水(100mL)淬灭,乙酸乙酯萃取,有机相无水硫酸钠干燥,旋干,得目标化合物4g,收率78.7%。
2. 3-环丙基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备
将3-环丙基-7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓(3.8g,16.3mmol)溶于甲醇(50mL)中,加入Pd/C(1.9g),氢气条件下25℃下反应16h,LCMS检测反应完成,抽滤,滤液旋干得粗品3.5g。
3. N-(3-环丙基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备
将3-环丙基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(3.5g,粗品)溶于醋酸(20mL)中,加入乙酸酐(3mL),25℃下反应4h,LCMS检测反应完成,反应液旋干,饱和碳酸氢钠水溶液调pH至8-9,二氯甲烷萃取,有机相旋干,硅胶柱层析分离(二氯甲烷:甲醇=20:1)得目标化合物2.12g,收率53.1%。
4. N-(3-环丙基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备
将N-(3-环丙基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(2.12g,8.65mmol)溶于浓硫酸(22mL)中,0℃下加入发烟硝酸(849mg,13mmol),25℃下反应0.5h,LCMS检测反应完成,用5M氢氧化钠溶液调pH至8-9,DCM萃取,有机相无水硫酸钠干燥,旋干得产品2g,收率79.7%。
5. 3-环丙基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备
将N-(3-环丙基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(1.96g,6.76mmol)溶于甲醇(35mL)中,加入碳酸钾(4.6g,33.4mmol),65℃反应8h,LCMS检测反应完成,硅藻土过滤,硅胶柱层析分离(甲醇:二氯甲烷=1:15)得目标化合物1.1g,收率65.1%。
6. 2-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备
将3-环丙基-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(1.1g,4.4mmol)溶于乙醇(25mL)中,氢气条件下25℃下反应2h,加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(1.7g,8.8mmol),LCMS检测反应完成,过滤,滤液旋干,硅胶柱层析分离(二氯甲烷:甲醇=10:1)得产品900mg,收率65.1%。
7. 7-氨基-6-(7-环丙基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将2-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(200mg,0.64mmol)和3-氨基噻吩-2-腈(76mg,0.61mmol)溶于四氢呋喃(5mL)中,氮气保护,40℃下滴加LDA(1.5Ml,2.88mmol),继续反应6h,LCMS检测反应完成。倒入饱和氯化铵溶液中淬灭,乙酸乙酯萃取,有机相旋干,粗品经硅胶柱层析分离(二氯甲烷:甲醇=10:1)纯化,甲醇打浆纯化得产品77mg,产率30.7%。
分子式:C
21H
21N
5OS 分子量:391.5 LC-MS(M/e):392.0(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.96(s,1H),11.79(s,1H),10.55-10.80(br s,1H),7.98(s,1H),7.75-7.95(br s,1H),7.40(s,1H),7.38(s,1H),7.02(s,1H),2.85-2.95(m,4H),2.70-2.84(m,4H),1.75-1.85(m,1H),0.30-0.50(m,4H).
制备例10:6-(7-乙酰基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-氨基噻吩并[3,2-b]吡啶-5(4H)的制备(化合物13)
1. 2-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯盐酸盐的制备
将2-(2-乙氧基-2-氧乙基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(373mg,1.0mmol)溶于4M HCl/二氧六环(10mL),15℃反应2小时,浓缩得241mg,用于下一步。
2.(7-乙酰基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备
将2-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(210mg,粗品)溶于二氯甲烷(10mL),0℃下滴加乙酸酐(86mg,0.85mmol),0℃反应2小时。浓缩, 有机相干燥浓缩硅胶柱纯化(二氯甲烷:甲醇=10:1)得目标化合物200mg,两步收率:63.5%
3. 6-(7-乙酰基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-氨基噻吩并[3,2-b]吡啶-5(4H)的制备
将7-乙酰基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(170mg,0.54mmol)、3-氨基噻吩-2-甲腈(74mg,0.59mmol)溶于四氢呋喃(10mL),40℃下加入LDA(1.1mL,2.16mmol),加毕40℃下反应5小时。饱和氯化铵淬灭反应,乙酸乙酯(15mL)萃取,加入甲醇(1mL)和乙酸乙酯(1mL),过滤,干燥,得目标化合物7.5mg,收率:3.5%。
分子式:C
20H
19N
5O
2S 分子量:393.13 LC-MS(M/e):394.47(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.81(s,1H),11.80(s,1H),10.85-10.51(brs,1H),7.95(s,1H),7.94-7.71(brs,1H),7.46-7.40(m,2H),7.02(s,1H),3.59-3.57(m,4H),3.05-2.97(m,2H),2.99-2.90(m,2H),2.08(s,3H).
制备例11:7-(((1s,4s)-4-羟基环己基)氨基)-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物14-1)
1. 7-(((1s,4s)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将4-(4-甲氧基苄基)-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-7-基三氟甲磺酸酯(N/A,0.37mmol)溶于乙腈(20mL),加入(1s,4s)-4-氨基环己-1-醇(170.5mg,1.48mmol),加毕45℃反应2小时。LCMS检测反应结束。反应液浓缩硅胶柱纯化(二氯甲烷:甲醇=10:1)得目标化合物216mg,两步收率:81.8%。
2. 7-(((1s,4s)-4-羟基环己基)氨基)-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将7-(((1s,4s)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(216mg,0.3mmol)溶于浓盐酸(2mL),三氟乙酸(14mL),加毕,升至110℃反应24小时。LCMS检测反应结束。浓缩溶剂,二氯甲烷溶解,饱和碳酸氢钠水溶液洗涤,有机相干燥浓缩Pre-TLC纯化(二氯甲烷:甲醇=7:1)得标题化合物12.7mg,收率9.1%。
分子式:C
25H
29N
5O
2S 分子量:463.6 LC-MS(M/e):464.0(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:13.08(s,1H),12.24(d,J=8.4Hz 1H),11.87(s,1H),8.03(d,J=5.2Hz,1H),7.50(s,1H),7.42(s,1H),7.05(d,J=5.2Hz,1H),4.65(d,J=3.2Hz,1H),4.31(m,1H),3.73(m,1H),3.05-3.17(m,4H),2.56-2.72(m,4H),2.51(s,3H),1.81-1.95(m,4H),1.65-1.80(m,4H).
制备例12:7-(异丙基氨基)-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物15)
1. 7-(异丙氨基)-4-(4-甲氧基苄基)-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将4-(4-甲氧基苄基)-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-7-基三氟甲磺酸酯(N/A,0.23mmol)溶于乙腈(10mL),加入异丙胺(54.3mg,0.92mmol),加毕40℃反应2小时。LCMS检测反应结束。反应液浓缩硅胶柱纯化(二氯甲烷:甲醇=20:1)得目标化合物100mg。
2. 7-(异丙基氨基)-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将7-(异丙氨基)-4-(4-甲氧基苄基)-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(100mg,0.15mmol)溶于浓盐酸(1.5mL),三氟乙酸(10.5mL),加毕,升至110℃反应24小时。LCMS检测反应结束。浓缩溶剂,二氯甲烷溶解,饱和碳酸氢钠水溶液洗涤,有机相干燥浓缩Pre-TLC纯化(二氯甲烷:甲醇=7:1)得标题化合物12.5mg,收率20.2%。
分子式:C
22H
25N
5OS 分子量:407.5 LC-MS(M/e):408.0(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:13.05(s,1H),12.14(d,J=8.0Hz 1H),11.87(s,1H),8.04(d,J=5.2Hz,1H),7.45(s,1H),7.39(s,1H),7.05(d,J=5.2Hz,1H),4.45-4.54(m,1H),3.04-3.14(m,4H),2.74-2.83(m,4H),2.51(s,3H),1.45(d,J=6.0Hz,6H).
制备例13:4-氨基-5-(8-甲基-1,6,7,8,9,10-六氢咪唑并[4',5':3,4]苯并[1,2-d]氮杂卓-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮的制备(化合物19)
1. N-(6-硝基-3-(2,2,2-三氟乙酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备
将N-(3-(2,2,2-三氟乙酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(5.5g,18.3mmol)溶于浓硫酸(50mL)中,0℃下滴加发烟硝酸(1.5g,22.0mmol),加毕,0℃反应1.5小时。LCMS检测反应结束。倒入冰水中,二氯甲烷萃取,有机相干燥浓缩,硅胶柱层析分离(石油醚:乙酸乙酯=2:1)得标题化合物800mg,收率12.6%。
2. 6-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备
将N-(6-硝基-3-(2,2,2-三氟乙酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(800mg,2.3mmol)溶于甲醇(20mL),加入碳酸钾(960mg,6.9mmol),加毕,55℃反应24小时。硅藻土过滤,滤液浓缩,C18柱纯化(甲醇=0-50%)得标题化合物400mg,收率83.3%。
3. 3-甲基-6-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备
将6-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(400mg,1.9mmol)溶于甲醇(10mL)中,加入甲醛(37%)(791.2mg,9.7mmol)、乙酸(114.0mg,1.9mmol),15℃反应1小时,加入氰基硼氢化钠(601.4mg,9.7mmol),加毕,15℃反应1小时。LCMS检测反应结束。浓缩溶剂,固体用二氯甲烷溶解,饱和氯化钠和饱和碳酸氢钠水溶液洗涤,二氯甲烷萃取,有机相用无水硫酸钠干燥,旋干,硅胶柱层析分离(甲醇:二氯甲烷=1:10)得标题化合物有280mg,收率65.6%。
4. 2-(8-甲基-1,6,7,8,9,10-六氢咪唑并[4',5':3,4]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备
将3-甲基-6-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(280mg,1.3mmol)溶于乙醇(10mL)中,加入Pd/C(100mg),加毕15℃下氢化反应1小时,加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(594.8mg,3.0mmol),加毕,55℃反应1小时。LCMS检测反应结束。硅藻土过滤,滤液浓缩,得固体用二氯甲烷溶解,饱和碳酸氢钠水溶液洗涤,分液,二氯甲烷萃取,有机相干燥浓缩硅胶柱层析分离(甲醇:二氯甲烷=1:4)得标题化合物250mg,收率68.8%。
5. 4-氨基-5-(8-甲基-1,6,7,8,9,10-六氢咪唑并[4',5':3,4]苯并[1,2-d]氮杂卓-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮的制备
将2-(8-甲基-1,6,7,8,9,10-六氢咪唑并[4',5':3,4]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(100mg,0.35mmol)和2-氨基-3-氰基噻吩(43.4mg,0.35mmol)溶于四氢呋喃(10mL)中,氮气保护下40℃下滴加LDA(0.7mL,1.4mmol),加毕,40℃下反应2小时。LCMS检测反应结束。饱和氯化铵水溶液淬灭反应,乙酸乙酯萃取,有机相干燥浓缩得固体,固体用甲醇打浆得标题化合物16.2mg,收率12.7%。
分子式:C
19H
19N
5OS 分子量:365.5 LC-MS(M/e):366.0(M+H
+)
1H-NMR(400MHz,MeOD)δ:7.28(d,J=8.0Hz,1H),7.03-7.06(m,3H),3.31-3.34(m,3H),3.07-3.10(m,2H),2.20-2.35(m,4H),2.47(s,3H),2.47(s,3H).
制备例14:6-(7-(2-羟乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙氨基)噻吩并[3,2-b]吡啶-5(4H)-酮盐酸盐(化合物20的盐酸盐)
1. 2-(7-(异丙基氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯的制备
将2-(4-(4-甲氧基苄基)-5-氧代-7-(((三氟甲基)磺酰基)氧基)-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(500mg,0.60mmol)溶于乙腈(10mL),加入异丙胺(141.8mg,2.4mmoL),加毕,40℃反应2小时。LCMS检测反应结束。反应液浓缩,经硅胶柱纯化(乙酸乙酯:石油醚=1:1)得目标化合物180mg,收率40.2%。
2. 6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将2-(7-(异丙基氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(180mg,0.24mmol)溶于浓盐酸(1.0mL)和三氟乙酸(7.0mL),110℃下反应48小时。LCMS检测反应结束。浓缩溶剂,直接用于下一步反应。
3. 6-(7-(2-(((叔丁基二甲基甲硅烷基)氧基)乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮(N/A,0.51mmol)溶于甲醇(10mL),25℃下加入2-((叔丁基二甲基甲硅烷基)氧基)乙醛(266.7mg,1.5mmol)和醋酸(30.6mg,0.51mmol)),加入氰基硼氢化钠(96.1mg,1.5mmol)),继续反应4小时。反应加入水淬灭反应,二氯甲烷(50mL)萃取,有机相浓缩硅胶柱纯化(甲醇/二氯甲烷=1:10)得目标化合物170.0mg,两步收率60.5%。
4. 6-(7-(2-羟乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙氨基)噻吩并[3,2-b]吡啶-5(4H)-酮盐酸盐的制备
将6-(7-(2-(((叔丁基二甲基甲硅烷基)氧基)乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮(160.0mg,0.29mmol)溶于四氢呋喃(4mL)和浓盐酸(4mL)中,反应1小时。反应完毕后,过滤,收集滤饼,乙酸乙酯和二氯甲烷洗涤,得目标化合物19.4mg,收率15.3%。
分子式:C
23H
27N
5O
2S 分子量:437.6 LC-MS(M/e):438.2(M+H
+)
1H-NMR(400MHz,MeOD)8.01(d,J=5.6Hz,1H),7.63(s,2H),7.09(d,J=5.6Hz,1H),4.33-4.27(m,1H),3.96-3.86(m,4H),3.53-3.47(m,2H),3.40-3.36(m,5H),3.29-3.17(m,2H),1.35(s,6H).
制备例15:7-(((1s,4s)-4-羟基环己基)氨基)-6-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物21-1)
将6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(((1s,4s)-4-羟基环己基)氨基)噻吩并[3,2-b]吡啶-5(4H)-酮(80mg,0.18mmol),溶于甲醇(10mL)中,加入3-氧杂环丁酮(38.5mg,0.54mmol)\乙酸(10.8mg,0.18mmol),20℃反应30分钟,加入氰基硼氢化钠(33.5mg,0.54mmol),加毕,20℃反应17小时。LCMS检测反应结束。浓缩溶剂,固体用二氯甲烷溶解,饱和氯化钠和饱和碳酸氢钠水溶液洗涤,二氯甲烷萃取,有机相用无水硫酸钠干燥,旋干,硅胶柱层析分离(甲醇:二氯甲烷=1:15)得目标化合物13.6mg,收率15.1%。
分子式:C
27H
31N
5O
3S 分子量:505.6 LC-MS(M/e):506.0(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.97(s,1H),12.24(d,J=4.0Hz,1H),11.80(s,1H),7.98(d,J=5.2Hz,1H),7.39(s,1H),7.30(s,1H),7.01(d,J=5.6Hz,1H),4.60(s,1H),4.45-4.52(m,4H),4.20-4.30(m,1H),3.65-3.72(m,1H),3.45-3.48(m,1H),3.14-3.29(m,4H),2.90-3.01(m,4H),1.65-1.86(m,8H).
制备例16:7-(((1s,3s)-3-羟基环丁基)氨基)-6-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-1-酮的制备(化合物22-1)
1. 2-(7-(((1s,3s)-3-羟基环丁基)氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯的制备
将2-(4-(4-甲氧基苄基)-5-氧代-7-(((三氟甲基)磺酰基)氧基)-4,5-二氢噻吩并[3,2-b]吡 啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(500mg,0.6mmol)溶于乙腈(10mL)中,加入顺式-3-氨基环丁醇盐酸盐(295.7mg,2.4mmol),加毕,40℃反应2小时。LCMS检测反应结束。浓缩溶剂,经硅胶柱层析分离(甲醇:二氯甲烷=1:20)得目标化合物400mg,收率86.6%。
2. 6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(((1s,3s)-3-羟基环丁基)氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将2-(7-(((1s,3s)-3-羟基环丁基)氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(400mg,0.52mmol)溶于浓盐酸(2mL)和三氟乙酸(14mL)中,110℃反应20小时。浓缩溶剂,固体用二氯甲烷溶解,饱和碳酸氢钠水溶液洗涤,二氯甲烷萃取,有机相用无水硫酸钠干燥,旋干,C18柱层析分离(甲醇=0-60%)得目标化合物150mg,收率68.8%。
3. 7-(((1s,3s)-3-羟基环丁基)氨基)-6-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-1-酮的制备
将6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(((1s,3s)-3-羟基环丁基)氨基)噻吩并[3,2-b]吡啶-5(4H)-酮(150mg,0.36mmol)溶于甲醇(15mL)中,加入3-氧杂环丁酮(77.1mg,1.1mmol)、乙酸(21.6mg,0.36mmol),20℃反应30分钟,加入氰基硼氢化钠(68.2mg,1.1mmol),加毕,20℃反应17小时。LCMS检测反应结束。浓缩溶剂,固体用二氯甲烷溶解,饱和氯化钠和饱和碳酸氢钠水溶液洗涤,二氯甲烷萃取,有机相用无水硫酸钠干燥,旋干,硅胶柱层析分离(甲醇:二氯甲烷=1:15)得目标化合物16.9mg,收率9.9%。
分子式:C
25H
27N
5O
3S 分子量:477.6 LC-MS(M/e):478.0(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.93(s,1H),12.26(d,J=6.8Hz,1H),11.83(s,1H),8.01(d,J=5.2Hz,1H),7.39(s,1H),7.35(s,1H),7.01(d,J=5.6Hz,1H),4.60(s,1H),4.43-4.53(m,4H),4.19-4.21(m,1H),3.96-4.06(m,1H),3.45-3.48(m,1H),2.91-3.15(m,8H),2.33(m,4H).
制备例17:6-(7-(环丙烷羰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(((1s,4s)-4-羟基环己基)氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物23-1)
1. 2-(7-(环丙烷羰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备
将2-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯盐酸盐(1.7g5.5mmol)、三乙胺(3.9g,38.5mmol)和环丙酰氯(600mg,5.7mmol)溶于40mL二氯甲烷中,在0℃下反应1.5小时。反应结束后,浓缩,经硅胶柱纯化(甲醇:二氯甲烷=10%)得目标化合物1.5g,收率:71.8%。
2. (E)-2-(7-(环丙烷羰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-3-羟基-3-(3-((4-甲氧基苄基)氨基)噻吩-2-基)丙酸乙酯的制备
将2-(7-(环丙烷羰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(850mg,2.5mmol)和1-(4-甲氧基苄基)-2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮(790mg,2.7mmol)溶于四氢呋喃(10mL),40℃下加入LDA(5.0mL,10.0mmol),并反应2小时。反应结束后,加入饱和氯化铵水溶液淬灭,二氯甲烷萃取,浓缩有机相,粗品直接用于下一步。
3. 6-(7-(环丙烷羰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-羟基-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将上步粗品溶于15mL四氢呋喃中,在40℃下滴加LDA(5.0mL),并反应1.5h结束,结束后加入饱和氯化铵水溶液淬灭,二氯甲烷萃取,浓缩有机相,得目标化合物粗品650mg。
4. 6-(7-(环丙烷羰基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-7-基三氟甲磺酸酯的制备
将6-(7-(环丙烷羰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-羟基-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮(600mg,1.1mmol)溶于二氯甲烷(15mL),降温至-15℃,加入吡啶(1.8g,22.8mmol)和三氟甲磺酸酐(3.0g,10.6mmol),并反应1.0小时结束,加入饱和碳酸氢钠溶液淬灭反应,二氯甲烷萃取,有机相经干燥浓缩得目标化 合物粗品,直接用于下一步反应。
5. 6-(7-(环丙烷羰基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(((1s,4s)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮制备
将上步粗品溶于10mL乙腈中,加入(1s,4s)-4-氨基环己-1-醇(160mg 1.4mmol),加毕,50℃反应1小时。硅藻土过滤,滤液干燥、浓缩、经柱层析(甲醇:二氯甲烷=10%)得目标化合物300mg,两步收率为35.1%。
6.(1s,4s)-4-((6-(7-(环丙烷羰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-7-基)氨基)环己基-2,2,2-三氟乙酸酯的制备
将6-(7-(环丙烷羰基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(((1s,4s)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮(300mg,0.39mmol)溶于三氟乙酸(3mL)和浓盐酸1mL中,在115℃下反应22h后,浓缩,直接进行下一步反应。
7. 6-(7-(环丙烷羰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(((1s,4s)-4-羟基环己基)氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将上步粗品溶于甲醇10mL中,加入碳酸钾150mg,在25℃下反应1h。反应结束后,浓缩溶剂,经柱层析得目标产物16mg,两步收率为7.9%。
分子式:C
28H
31N
5O
3S 分子量:517.6 LC-MS(M/e):518.0(M+H
+)
1H-NMR(400MHz,CDCl
3)δ:12.99(s,1H),12.22(s,1H),11.92-11.82(m,1H),8.0(s,1H),7.51-7.41(m,2H),7.01(s,1H),4.61(s,1H),4.41-4.31(m,1H),3.81(s,2H),3.80(s,1H),3.71-3.61(m,2H),3.08-2.96(m,2H),2.91-2.86(m,2H),2.01(s,1H),1.91-1.61(m,8H),0.88-0.71(m,4H).
制备例18:7-氨基-6-(7-(3-羟基环丁基)-1,5,6,7,8,9-六氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物24的溴酸盐)
1. 2-(7-(3-(苄氧基)环丁基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯)的制备
将2-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯盐酸盐(230mg,0.74mmol)、3-(苄氧基)环丁-1-酮(196mg,1.11mmol)、乙酸(44mg,0.74mmol)溶于二氯甲烷(10mL)中,0℃下加入醋酸硼氢化钠(314mg,1.48mmol),25℃下反应8h, LCMS检测反应完成。反应液倒入饱和氢氧化钠水溶液(50mL)中,二氯甲烷萃取,有机相用无水硫酸钠干燥,旋干,硅胶柱层析分离(甲醇:二氯甲烷=1:10)得目标化合物260mg,收率81.0%。
2. 7-氨基-6-(7-(3-(苄氧基)环丁基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将2-(7-(3-(苄氧基)环丁基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(150mg,0.35mmol)和3-氨基噻吩-2-腈(43mg,0.35mmol)溶于四氢呋喃(5mL)中,40℃下滴加LDA(1.05mL,2.1mmol),继续反应4h,LCMS检测反应完成,反应液倒入饱和氯化铵水溶液中淬灭,二氯甲烷萃取,有机相用无水硫酸钠干燥,旋干,硅胶柱层析分离(甲醇:二氯甲烷=1:10)得目标化合物100mg,收率55.8%。
3. 7-氨基-6-(7-(3-羟基环丁基)-1,5,6,7,8,9-六氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮溴酸盐的制备
将7-氨基-6-(7-(3-(苄氧基)环丁基)-1,5,6,7,8,9-六氢咪唑[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(50mg,0.10mmol)溶于二氯甲烷(5mL)中,-40℃下滴加三溴化硼(100mg,0.40mmol),25℃下反应1h,LCMS检测反应完成。加入甲醇淬灭,溶剂旋干,粗品经甲醇打浆得目标化合物19mg,收率37.8%。
分子式:C
22H
24BrN
5O
2S 分子量:502.4 LC-MS(M/e):422.0(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:11.81(s,1H),9.71(s,1H),7.95(d,J=5.2Hz,1H),7.51(s,2H),6.99(d,J=5.2Hz,1H),3.82-3.92(m,1H),3.52-3.62(m,2H),3.18-3.32(m,3H),3.02-3.17(m,2H),2.75-2.90(m,2H),2.58-2.62(m,2H),2.02-2.18(m,2H).
制备例19:7-氨基-6-(7-(2-羟乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-吡啶-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮盐酸盐的制备(化合物25的盐酸盐)
1. 2-(7-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)乙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备
将2-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(240mg,0.88mmol)溶于甲醇(10mL),20℃下加入2-((叔丁基二甲基甲硅烷基)氧基)乙醛(352mg,2.0mmol)和醋酸(560mg,9.3mmol)),20℃下反应5分钟后,加入氰基硼氢化钠(352mg,6.4mmol),加毕20℃反应6小时。反应完毕后,旋干溶剂,加入饱和碳酸氢钠水溶液(20mL)淬灭反应,乙酸乙酯(50mL)萃取,有机相浓缩,经硅胶柱纯化(甲醇/二氯甲烷=1:20)得目 标化合物250mg,收率65.8%。
2. 7-氨基-6-(7-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将2-(7-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)乙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(250mg,0.58mmol)与3-氨基噻吩-2-腈(71mg,0.57mmol)溶于无水四氢呋喃(5mL),40℃下加入LDA(1.2ml,2.3mmol)。反应结束后,0℃下加入饱和氯化铵水溶液淬灭反应,有机相干燥,浓缩,硅胶柱纯化(二氯甲烷:甲醇=10:1)得标题化合物80mg,收率:27.0%。
3. 7-氨基-6-(7-(2-羟乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-吡啶-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮盐酸盐的制备
将7-氨基-6-(7-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(50mg,0.1mmol)溶于1ml四氢呋喃和1ml浓盐酸中,反应0.5小时。反应完毕后,过滤收集滤饼,乙酸乙酯和二氯甲烷洗涤,得目标化合物12.4mg,收率26.4%。
分子式:C
20H
22ClN
5O
2S 分子量:431.9 LC-MS(M/e):396.5(M+H
+)
1H-NMR(400MHz,MeOD)δ:7.98-7.96(m,1H),7.65(s,2H),7.09-7.08(m,1H),3.97-3.90(m,4H),3.55-3.48(m,2H),3.40-3.30(m,4H),3.24-3.18(m,2H).
制备例20:7-氨基-6-(7-(氧杂环丁-3-基)-1,5,6,7,8,9-六氢咪唑[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物26)
1. 2-(7-(氧杂环丁-3-基)-1,5,6,7,8,9-六氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)-乙酸乙酯的制备
将2-(1,5,6,7,8,9-六氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯盐酸盐(309.1mg,1.0mmol)溶于甲醇(30mL)中,加入3-氧杂环丁酮(216.3mg,3.0mmol),乙酸(60.0mg,1.0mmol),20℃反应30分钟,加入氰基硼氢化钠(186.0mg,3.0mmol),加毕,20℃反应17小时。LCMS检测反应结束。浓缩溶剂,固体用二氯甲烷溶解,饱和氯化钠和饱和碳酸氢钠水溶液洗涤,二氯甲烷萃取,有机相用无水硫酸钠干燥,旋干,硅胶柱层析分离(甲醇:二氯甲烷=1:15)得标题化合物200mg,收率60.8%。
2. 7-氨基-6-(7-(氧杂环丁-3-基)-1,5,6,7,8,9-六氢咪唑[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将6-(1,5,6,7,8,9-六氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)-7-(((1s,3s)-3-羟基环丁基)氨基)噻吩并[3,2-b]吡啶-5(4H)-酮(150mg,0.36mmol)溶于甲醇(15mL)中,加入3-氧杂环丁酮(77.1mg,1.1mmol)、乙酸(21.6mg,0.36mmol),20℃反应30分钟,加入氰基硼氢化 钠(68.2mg,1.1mmol),加毕,20℃反应17小时。LCMS检测反应结束。浓缩溶剂,固体用二氯甲烷溶解,饱和氯化钠和饱和碳酸氢钠水溶液洗涤,二氯甲烷萃取,有机相用无水硫酸钠干燥,旋干,硅胶柱层析分离(甲醇:二氯甲烷=1:15)得目标化合物16.9mg,收率9.1%。
分子式:C
21H
21N
5O
2S 分子量:407.5 LC-MS(M/e):408.1(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.74(s,1H),11.76(s,1H),10.54-10.62(m,1H),7.91(d,J=5.2Hz,1H),7.72-7.91(m,1H),7.38(s,1H),7.33(s,1H),6.98(d,J=5.2Hz,1H),4.44-4.53(m,4H),3.44-3.50(m,1H),2.88-2.95(m,4H),2.25-2.40(m,4H).
制备例21:7-(((1s,4s)-4-羟基环己基)氨基)-3-甲基-6-(7-甲基-1-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮盐酸盐(化合物27-1的盐酸盐)
1. 3-氨基-4-甲基噻吩-2-羧酸的制备
将3-氨基-4-甲基噻吩-2-羧酸甲酯(1.71g,10mmol)和氢氧化钾(1.12g,20mmol)溶于水(20mL)中,90℃下反应1小时。反应液直接用于下一步。
2. 7-甲基-2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮的制备
将3-氨基-4-甲基噻吩-2-羧酸(上步反应液)降温至0℃,加入氯甲酸三氯甲酯(2.37g,12mol),加毕,20℃下反应2小时。抽滤,收集固体旋干得标题化合物1.6g,收率87.3%。
3. 1-(4-甲氧基苄基)-7-甲基-2H-噻吩并[3,2-d][1,3]恶嗪-2,4-(1H)-二酮的制备
将7-甲基-2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮(1.6g,8.7mmol)、1-(氯甲基)-4-甲氧基苯(1.65g,10.5mmol)、碳酸钾(1.45g,10.5mmol)和碘化钾(282mg,1.7mmol)溶于N,N-二甲基甲酰胺(23mL),20℃下反应16小时。将反应液倒入水(100mL)中,抽滤,收集固体,旋干,硅胶柱纯化(二氯甲烷)得目标化合物1.5g,收率64.7%。
4. 3-(3-(((4-甲氧基苄基)氨基)-4-甲基噻吩-2-基)-2-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-3-氧代丙酸乙酯的制备
将2-(7-甲基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(475mg,1.65mmol)和1-(4-甲氧基苄基)-7-甲基-2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮(500mg,1.65mmol)溶于四氢呋喃(20mL)。氮气保护下,40℃下加入LDA(3.3mL,6.6mmol),加毕,40℃下反应4小时。0℃下饱和氯化铵水溶液淬灭反应,有机相干燥,浓缩,硅胶柱纯化(二氯甲烷:甲醇=10:1)得标题化合物480mg,收率53.3%。
5. 7-羟基-4-(4-甲氧基苄基)-3-甲基-6-(7-甲基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将3-(3-(((4-甲氧基苄基)氨基)-4-甲基噻吩-2-基)-2-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-3-氧代丙酸乙酯(480mg,0.88mmol)溶于四氢呋喃(8mL),氮气保护下,40℃下加入LDA(1.76mL,3.52mol),加毕,40℃下反应2小时。用饱和氯化铵水溶液(8mL)淬灭反应,有机相浓缩,硅胶柱纯化(二氯甲烷:甲醇=4:1)得标题化合物390mg,收率88.7%。
6. 4-(4-甲氧基苄基)-3-甲基-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-7-基三氟甲磺酸酯的制备
将7-羟基-4-(4-甲氧基苄基)-3-甲基-6-(7-甲基-1,5,6,7,8,9-六氢咪唑基[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(390mg,0.78mmol)溶于二氯甲烷(8mL),0℃下加入吡啶(1232mg,15.6mmol),三氟甲磺酸酐(1318mg,4.68mmol),加毕,0℃下反应1小时。饱和碳酸氢钠水溶液淬灭反应,二氯甲烷萃取,有机相干燥浓缩直接用于下一步。
7. 7-(((1s,4s)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)-3-甲基-6-(7-甲基-1-(((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将4-(4-甲氧基苄基)-3-甲基-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-7-基三氟甲磺酸酯(N/A,0.39mmol)溶于乙腈(5mL),加入(1s,4s)-4-氨基环己-1-醇(179mg,1.56mmol),加毕40℃反应2小时。反应液浓缩硅胶柱纯化(二氯甲烷:甲醇=10:1)得目标化合物180mg,两步收率63.3%。
8. 7-(((1s,4s)-4-羟基环己基)氨基)-3-甲基-6-(7-甲基-1-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮盐酸盐的制备
将7-(((1s,4s)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)-3-甲基-6-(7-甲基-1-(((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(180mg,0.25mmol)溶于浓盐酸(1mL)与三氟乙酸(7mL),加毕升至110℃反应24小时。浓缩溶剂,加入二氯甲烷(20mL)溶解,加入NaOH(1N,20mL)溶液搅拌0.2小时, 有机相浓缩,经中压反相制备(0-50%甲醇/水(0.5%浓盐酸))得标题化合物70mg,收率59.4%。
分子式:C
26H
32ClN
5O
2S 分子量:514.1 LC-MS(M/e):478.0(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:13.08(s,1H),12.08(s,1H),11.47(s,1H),10.39(s,1H),7.66(s,1H),7.47(s,2H),4.28-4.26(m,1H),3.75-3.65(m,2H),3.40-3.25(m,4H),3.10-2.90(m,4H),2.81(s,3H),2.28(s,3H),1.91-1.75(m,4H),1.75-1.60(m,4H).
制备例22:7-(((1S,4S)-4-羟基环己基)氨基)-2-甲基-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(化合物28-1)
1. 7-(((1s,4s)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)-2-甲基-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
选用3-氨基-5-甲基噻吩-2-羧酸甲酯作为起始原料,参照制备例21的方法制备得到7-(((1s,4s)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)-2-甲基-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮。
2.(1s,4s)-4-((2-甲基-6-(7-甲基-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-7-基)氨基)环己基2,2,2-三氟乙酸盐的制备
将7-(((1s,4s)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)-2-甲基-6-(7-甲基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(150mg,0.21mmol)溶于浓盐酸(1mL)与三氟乙酸(4mL),加毕升至115℃反应5.0小时。浓缩溶剂,直接用于下一步反应。
3. 7-(((1S,4S)-4-羟基环己基)氨基)-2-甲基-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将上步粗品溶于5mL甲醇中,加入碳酸钾(300mg,2.2mmol),在25℃反应1小时后浓缩溶剂,经柱层析(二氯甲烷:甲醇=10:1)得目标化合物15mg,两步收率为15.3%。
分子式:C
26H
31N
5O
2S 分子量:477.6 LC-MS(M/e):478.0(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:13.00(s,1H),12.13(s,1H),11.74(s,1H),10.39(s,1H),7.42(s,1H),7.33(s,1H),6.77(s,1H),4.62-4.4.58(s,1H),4.28-4.21(m,1H)3.75-3.65(m,1H),3.10-3.25(m,8H),2.48(m,3H),1.91-1.75(m,4H),1.75-1.60(m,4H).
制备例23:7-(((1s,4s)-4-羟基环己基)氨基)-2,3-二甲基-6-(7-甲基-1-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮盐酸盐(化合物29-1的盐酸盐)
选用3-氨基-4,5-二甲基噻吩-2-羧酸作为起始原料,参照制备例21的方法制备得到7-(((1s,4s)-4-羟基环己基)氨基)-2,3-二甲基-6-(7-甲基-1-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮盐酸盐。
分子式:C
27H
34ClN
5O
2S 分子量:528.1 LC-MS(M/e):492.0(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:13.08(s,1H),11.98(s,1H),11.33(s,1H),10.64(s,1H),7.47(s,2H),4.25-4.15(m,1H),3.80-3.70(m,4H),3.40-3.30(m,2H),3.10-2.90(m,4H),2.80(s,3H),2.41(s,3H),2.18(s,3H),1.80-1.60(m,8H).
制备例24:7-((1s,4s)-4-羟基环己基)氨基)-4-甲基-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(化合物30-1)
1. 2-(7-羟基-4-甲基-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯的制备
将2-(2-乙氧基-2-氧乙基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(1.8g,4.83mmol)和1-甲基-2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮(972mg,5.3mmol)溶于四氢呋喃(50mL)。氮气保护下,40℃下加入LDA(9.7mL,19.3mmol),加 毕,40℃下反应4小时。0℃下加入饱和氯化铵水溶液淬灭反应,用二氯甲烷萃取分液,有机相浓缩得到产物与中间体混合粗品。将上步粗品溶于四氢呋喃(20mL),氮气保护下,40℃下加入LDA(9.7mL,19.3mmol),加毕,40℃下反应2小时。饱和氯化铵水溶液淬灭反应,有机相浓缩,硅胶柱纯化(100%乙酸乙酯)得标题化合物710mg,收率31%。
2. 2-(4-甲基-5-氧代-7-((三氟甲基)磺酰基)氧基)-4,5-二氢噻吩[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯的制备
将2-(7-羟基-4-甲基-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(710mg,1.52mmol)溶于二氯甲烷(15mL),0℃下加入吡啶(2.4g,30.4mmol),三氟甲磺酸酐(2.6g,9.12mmol),加毕,0℃下反应1小时。浓缩反应液,二氯甲烷萃取,饱和碳酸氢钠水溶液洗,饱和食盐水洗,有机相经无水硫酸钠干燥,柱层析(乙酸乙酯/正庚烷=0-60%)得到目标化合物450mg,收率41%。
3. 2-(7-(((1s,4s)-4-羟基环己基)氨基)-4-甲基-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯的制备
将2-(4-甲基-5-氧代-7-((三氟甲基)磺酰基)氧基)-4,5-二氢噻吩[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(450mg,0.62mmol)溶于乙腈(10mL),加入(1s,4s)-4-氨基环己-1-醇(284mg,2.5mmol),加毕40℃反应2小时。反应液浓缩,经硅胶柱纯化(二氯甲烷:甲醇=10:1)得目标化合物430mg,收率99%。
4. 6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-((1s,4s)-4-羟基环己基)氨基)-4-甲基噻吩[3,2-b]吡啶-5(4H)-酮的制备
将2-(7-(((1s,4s)-4-羟基环己基)氨基)-4-甲基-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(120mg,0.17mmol)溶于三氟乙酸(4mL),25℃反应1小时,浓缩。将四氢呋喃/水(5/5mL)混合溶剂加入反应液,加入NaOH调节pH=10,25℃反应1小时,浓缩直接用于下步反应。
5. 7-((1s,4s)-4-羟基环己基)氨基)-4-甲基-6-(7-甲基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-((1s,4s)-4-羟基环己基)氨基)-4-甲基噻吩[3,2-b]吡啶-5(4H)-酮(上步粗品)溶于10mL甲醇中加入40%甲醛水溶液(0.1mL)和氰基硼氢化钠(70mg,1.1mmol),在20℃反应3小时后浓缩溶剂,经柱层析(二氯甲烷:甲醇=7:1),(0.3%TFA in MeOH/H
2O=0-75%)得目标化合物40mg,两步收率为49%。
分子式:C
26H
31N
5O
2S 分子量:477.6 LC-MS(M/e):478.2(M+H
+)
1H-NMR(400MHz,MeOD)δ:7.95(m,1H),7.49(s,2H),7.31(m,1H),7.4(m,1H),3.87-3.68(m,6H),3.38-2.95(m,9H),2.12-1.73(m,8H).
制备例25:7-氨基-6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物33)
1. 2-(7-(((2,4-二甲氧基苄基)氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯的制备
将2-(4-(4-甲氧基苄基)-5-氧代-7-(((三氟甲基)磺酰基)氧基)-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(N/A,0.26mmol)溶于乙腈(10mL),加入2,4-二甲氧基苄胺(130.3mg,0.78mmoL),加毕40℃反应2小时。LCMS检测反应结束。反应液浓缩硅胶柱纯化(二氯甲烷:甲醇=20:1)得目标化合物80mg,两步收率:37.4%。
2. 7-氨基-6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将2-(7-(((2,4-二甲氧基苄基)氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(80mg,98.3μmol)溶于浓盐酸(0.5mL),三氟乙酸(3.5mL),110℃下反应48小时。LCMS检测反应结束。浓缩溶剂,饱和碳酸氢钠水溶液调节pH=8,Pre-TLC板纯化(二氯甲烷:甲醇=7:1)得目标化合物4.2mg,收率:12.8%。
分子式:C
18H
17N
5OS 分子量:351.4 LC-MS(M/e):352.1(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.85(s,1H),11.83(m,1H),7.95(d,J=5.2Hz,1H),7.49(s,1H),7.44(s,1H),7.02(d,J=5.6Hz,1H),4.07-4.11(m,2H),3.18-3.23(m,4H),3.13-3.17(m,4H).
制备例26:2-(7-氨基-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸异丙酯的制备(化合物37)
1. 2-(2-乙氧基-2-氧乙基)-5,6,8,9-四氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸异丙酯的制备
将2-(1,5,6,7,8,9-六氢咪唑并[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(330mg,1.2mmol),三乙胺(607mg,6.0mmol)溶于二氯甲烷(10mL)中,降温至-10℃,加入氯甲酸异丙酯(111mg,0.91mmol),-10℃下反应2h,体系用甲醇(1mL)淬灭反应。体系旋干,经硅胶柱层析分离(甲醇:二氯甲烷=1:15)得目标化合物110mg,收率25.5%。
2. 2-(7-氨基-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸异丙酯的制备
将2-(2-乙氧基-2-氧乙基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸异丙酯(90mg,0.25mmol)和3-氨基噻吩-2-腈(32mg,0.26mmol)溶于四氢呋喃(8mL)中,40℃下滴加LDA(2M,0.63mL,1.26mmol),继续反应2h。反应结束后,加入饱和氯化铵水溶液(5mL)淬灭,后加入乙酸乙酯(20mL)和水(10mL)萃取分液,有机相用无水硫酸钠干燥,旋干得粗品80mg,后加入甲醇(5mL)超声打浆,析出固体后经减压抽滤得目标化合物40mg,收率36.6%。
分子式:C
22H
23N
5O
3S 分子量:437.5 LC-MS(M/e):438.0(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.77(s,1H),11.76(s,1H),10.70-10.55(m,1H),7.92(d,J=2.8Hz,1H),7.84-7.71(m,1H),7.42(s,1H),7.37(s,1H),6.99(d,J=2.8Hz,1H),4.82-4.75(m,1H),3.52-3.46(m,4H),2.96-2.89(m,4H),1.22-1.18(m,6H).
制备例27:2-(7-氨基-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸甲酯的制备(化合物40)
1. 2-(2-乙氧基-2-氧乙基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸甲酯的制备
将2-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(300mg,1.1mmol),三乙胺(445mg,4.4mmol)溶于二氯甲烷(40mL)中,降温至0℃后,加入氯甲酸甲酯溶液(0.3M/L,3.7mL,1.1mmol),0℃下反应2h,体系用甲醇(2mL)淬灭反应。体系旋干,经硅胶柱层析分离后(甲醇:二氯甲烷=1:20)得目标化合物220mg,收率60.4%。
2. 2-(7-氨基-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸甲酯的制备
将2-(2-乙氧基-2-氧乙基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸甲酯(100mg,0.30mmol)和3-氨基噻吩-2-腈(45mg,0.36mmol)溶于四氢呋喃(15mL)中,40℃下滴加LDA(2M,0.75mL,1.5mmol),继续反应2h。反应液加入饱和氯化铵水溶液(3mL)淬灭,后加入乙酸乙酯(20mL)和水(10mL)萃取分液,有机相用无水硫酸钠干燥,旋干得粗品,加入甲醇(10mL)超声打浆,析出固体后经减压抽滤得目标化合物35mg,收率28.5%。
分子式:C
20H
19N
5O
3S 分子量:409.5 LC-MS(M/e):409.9(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.77(s,1H),11.77(s,1H),10.70-10.55(m,1H),7.92-7.85(m,2H),7.45-7.32(m,2H),6.99-6.93(m,1H),3.60(s,3H),3.52–3.46(m,4H),2.96-2.89(m,4H).
制备例28:6-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(氧杂 -3-环丁氨基)噻吩[3,2-b]吡啶-5(4H)-酮的制备(化合物42)
1. 7-氯-6-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备
将7-氯-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-甲醛(500mg,2.35mmol)、3-环丙基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7,8-二胺(510mg,2.35mmol)、三氯化铁(1.5g,9.4mmol)溶于1,4-二氧六环(30mL),升温至110℃,反应1小时。LCMS检测反应结束。降至25℃,饱和碳酸氢钠水溶液调节体系pH=9,用二氯甲烷萃取,有机相经干燥、浓缩、硅胶柱纯化(二氯甲烷:甲醇=10:1)得目标化合物220g,收率22.9%。
2. 6-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(氧杂-3-环丁氨基)噻吩[3,2-b]吡啶-5(4H)-酮的制备
将7-氯-6-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮(220mg,0.54mmol)、3-氨基氧杂环丁烷(59.2mg,0.81mmol)、碳酸氢钠(136.1mg,1.6mmol)和四丁基碘化铵(19.9mg,54.0μmol)溶于水(3mL)和氯仿(18mL)中,升温至60℃,反应16小时。LCMS检测反应结束。降温至25℃,加入二氯甲烷稀释,加水洗涤,有机相经干燥、浓缩得固体,固体用甲醇打浆得目标化合物14.5mg,收率6.0%。
分子式:C
24H
25N
5O
2S 分子量:447.6 LC-MS(M/e):448.0(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.91(s,1H),12.74(d,J=6.0Hz,1H),11.96(s,1H),8.05(d,J=5.6Hz,1H),7.43(s,1H),7.42(s,1H),7.06(d,J=5.2Hz,1H),5.70-5.80(m,1H),5.06-5.10(m,2H),4.67-4.70(m,2H),2.90-2.92(m,4H),2.76-2.90(m,4H),1.75-1.85(m,1H),0.48-0.49(m,2H),0.35-0.40(m,2H).
制备例29:7-(((1r,4r)-4-羟基环己基)氨基)-6-(7-甲基-1,5,6,7,8,9-六氢咪唑[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物44)
1. 2-(((1r,4r)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-1,5,7,8,9-六氢-7λ
4-咪唑[4’,5’:4,5]苯并[1,2-d]氮杂卓-7-羧酸叔丁酯的制备
将2-(4-(4-甲氧基苄基)-5-氧代-7-(((三氟甲基)磺酰基)氧)-4,5-二氢噻吩[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-1,5,7,8,9-六氢-7λ
4-咪唑[4’,5’:4,5]苯并[1,2-d]氮杂卓-7-羧酸叔丁酯(200.0mg,0.24mmol)溶于乙腈(5mL)中,加入(1r,4r)-4-氨基环己烷-1-醇(110.1mg,0.96mmol),加毕,45℃下反应2小时。反应液经浓缩、硅胶柱纯化(二氯甲烷:甲醇=10:1)得目标化合物200.0mg粗品。
2. 6-(1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-((1r,4r)-4-羟基环己基)氨基)噻吩[3,2-b]吡啶-5(4H)-酮的制备
将2-(((1r,4r)-4-羟基环己基)氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-1,5,7,8,9-六氢-7λ
4-咪唑[4’,5’:4,5]苯并[1,2-d]氮杂卓-7-羧酸叔丁酯(200.0mg粗品,N/A)溶于浓盐酸(4mL)与三氟乙酸(28mL)中,加毕,升温至110℃反应24小时。浓缩溶剂,用二氯甲烷(20mL)溶解,1N NaOH(20mL)搅拌0.2小时,有机相浓缩,经中压反相制备(0-50%甲醇/水(0.5%浓盐酸))得目标化合物75.0mg,两步收率70.8%。
3. 7-(((1r,4r)-4-羟基环己基)氨基)-6-(7-甲基-1,5,6,7,8,9-六氢咪唑[4’,5’:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将6-(1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-((1r,4r)-4-羟基环己基)氨基)噻吩[3,2-b]吡啶-5(4H)-酮(75.0mg,0.17mmol)溶于10.0mL甲醇中,加入1.0mL甲醛,氰基硼氢化钠(21.0mg,0.33mmol),25℃搅拌1h,浓缩溶剂,过正相柱分离(甲醇:二氯甲烷=1:99)得7.6mg,收率9.8%。
分子式:C
25H
29N
5O
2S 分子量:463.2 LC-MS(M/e):464.0(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.99(s,1H),12.17(s,1H),11.85(s,1H),8.02(d,1H),7.40(s,1H),7.32(s,1H),7.05(d,1H),4.66-4.65(m,1H),4.21-4.12(m,1H),3.80-3.60(m,1H),3.32(d,4H),2.95(s,4H),2.27(s,3H),2.17-2.16(m,2H),1.99-1.96(m,2H),1.58-1.56(m,2H),1.45-1.42(m,2H).
制备例30:7-(氮杂环丁烷-1-基)-6-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物45)
1. 2-(7-(氮杂环丁烷-1-基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯的制备
将2-(4-(4-甲氧基苄基)-5-氧代-7-(((三氟甲基)磺酰基)氧)-4,5-二氢噻吩[3,2-b]吡啶-6- 基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑[4’,5’:4,5]苯并[1,2-d]氮杂卓-7-羧酸叔丁酯(200mg,0.24mmol)溶于乙腈(5mL),加入氮杂环丁烷(55mg,0.96mmol),加毕,40℃下反应2小时。LCMS检测反应结束。反应液经浓缩、硅胶柱纯化(二氯甲烷:甲醇=10:1)得目标化合物粗品。
2. 7-(氮杂环丁烷-1-基)-6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将2-(7-(氮杂环丁烷-1-基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(粗品)溶于浓盐酸(1mL)和三氟乙酸(7mL)中,加毕,升温至110℃反应24小时。LCMS检测反应结束。浓缩溶剂,用二氯甲烷溶解,经饱和碳酸氢钠水溶液洗涤,有机相干燥浓缩Pre-TLC纯化(二氯甲烷:甲醇=7:1)得目标化合物40mg,两步反应收率43%。
3. 7-(氮杂环丁烷-1-基)-6-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将7-(氮杂环丁烷-1-基)-6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(40mg,0.1mmol)溶于甲醇(6mL)中,加入3-氧杂环丁酮(22mg,0.3mmol)和冰醋酸(6mg,0.1mmol),20℃下反应30min,加入氰基硼氢化钠(19mg,0.3mmol),20℃下反应4h。反应完毕,加入二氯甲烷和饱和碳酸氢钠溶液分液萃取三次,有机相旋干,经正向制备分离(二氯甲烷:甲醇=5:1)得目标化合物5mg。
分子式:C
24H
25N
5O
2S 分子量:447.5 LC-MS(M/e):448.2(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.10(s,1H),11.50(s,1H),7.90-7.91(d,J=4Hz,1H),7.32(s,1H),7.19(s,1H),6.97-6.98(d,J=4Hz,1H),4.46-4.55(m,4H),3.94(s,4H),3.48-3.51(t,1H),2.96(s,4H),2.36(s,4H),2.09-2.11(m,2H).
制备例31:7-氨基-6-(7-(6-氯吡嗪-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备(化合物46)
1. 3-(6-氯吡嗪-3-基)-7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓的制备
将7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓(961mg,5mmol),三乙胺(1012mg,10mmol)与3,6-二氯吡嗪(894mg,6mmol)溶于二甲基亚砜(50mL),110℃下反应1小时。反应结 束后使用水(50mL)淬灭反应,二氯甲烷(50mL)萃取,有机相浓缩经硅胶柱纯化(乙酸乙酯/二氯甲烷=1:9)得目标化合物500mg,收率32.8%。
2. 3-(6-氯吡嗪-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备
将3-(6-氯吡嗪-3-基)-7-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓(500mg,1.64mmol)、氯化铵(351mg,6.56mmol)与铁粉(275mg,4.92mmol)溶于乙醇(15mL)和水(15mL)中,95℃下反应3小时。二氯甲烷(50mL)萃取,有机相浓缩直接用于下一步。
3. N-(3-(6-氯吡嗪-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备
将3-(6-氯吡嗪-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(上步粗品)溶于乙酸酐(2mL)和乙酸(5mL)中,25℃反应1小时。加入水(50mL)淬灭反应,二氯甲烷(50mL)萃取,有机相浓缩得目标化合物400mg,两步反应收率76.9%。
4. N-(3-(6-氯吡嗪-3-基)-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备
将N-(3-(6-氯吡嗪-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(400mg,1.26mmol)溶于浓硫酸(4mL)。0℃下滴加发烟硝酸(95mg,1.52mmol),滴毕,0℃下反应1小时。反应结束后使用二氯甲烷(50mL)稀释,水(50mL)洗涤,有机相浓缩经硅胶柱纯化(乙酸乙酯/二氯甲烷=1:4)得目标化合物230mg,收率50.3%。
5. 3-(6-氯吡嗪-3-基)-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备
将N-(3-(6-氯吡嗪-3-基)-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(230mg,0.64mol)与碳酸钾(263mg,1.91mol)溶于甲醇(6mL),50℃下反应2小时。水(30mL)淬灭,抽滤,收集固体旋干得目标化合物200mg,收率98.4%。
6. 3-(6-氯吡嗪-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7,8-二胺的制备
将3-(6-氯吡嗪-3-基)-8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(200mg,0.63mmol)、氯化铵(167mg,3.13mmol)与铁粉(105mg,1.88mmol)溶于乙醇(10mL)和水(10mL)中,95℃下反应2小时。二氯甲烷(50mL)萃取,水(20mL)洗涤,有机相用无水硫酸钠干燥,经过滤、浓缩得目标化合物180mg,收率99.3%。
7. 2-(7-(6-氯吡嗪-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备
将3-(6-氯吡嗪-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7,8-二胺(180mg,0.62mmol)和3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(292mg,1.49mmol)溶于乙醇(10mL)。55℃下反应1小时。旋干,二氯甲烷(50mL)稀释,氨水(10mL)洗涤,有机相干燥,浓缩,硅胶柱纯化(二氯甲烷:甲醇=19:1)得目标化合物160mg,收率66.8%。
8. 7-氨基-6-(7-(6-氯吡嗪-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备
将2-(7-(6-氯吡嗪-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(60mg,0.16mmol)与3-氨基噻吩-2-甲腈(20mg,0.16mmol)溶于四氢呋喃(4mL),氮气保护下,40℃下加入LDA(0.32mL,0.64mol),加毕,40℃下反应2小时。饱和氯化铵水溶液(8mL)淬灭反应,有机相浓缩,经反相柱纯化(乙腈:水(0.5%盐酸)=30%)得目 标化合物7mg,收率9.7%。
分子式:C
22H
18ClN
7OS 分子量:463.9 LC-MS(M/e):464.0(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:11.92(s,2H),8.25-8.09(m,1H),8.02(d,J=5.2,1H),7.60-7.50(m,4H),7.03(d,J=5.2,1H),3.95-3.85(m,4H),3.15-3.05(m,4H)
制备例32:7-氨基-6-(7-甲基-6,7,8,9-四氢-5H-恶唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备(化合物47)
1. 2-(7-甲基-6,7,8,9-四氢-5H-恶唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备
于3-甲基-8-氨基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-酚的乙醇溶液中加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(3.75g.19.3mmol),升至50℃反应16小时。反应结束后,用硅藻土过滤,滤液加入碳酸氢钠溶液调节pH至8左右,用二氯甲烷(100mL)萃取,有机相干燥浓缩,经硅胶柱纯化(二氯甲烷:甲醇=10:1),得目标化合物820mg,反应收率59.0%。
2. 2-(7-甲基-6,7,8,9-四氢-5H-恶唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸的制备
将2-(7-甲基-6,7,8,9-四氢-5H-恶唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(750mg,2.6mmol)溶于甲醇(10mL)和水(10mL)中,加入氢氧化钠(312.0mg,7.8mmol),25℃下反应3小时。反应结束后,向体系中加入2M稀盐酸溶液调节pH至中性,体系经浓缩旋干得到目标化合物粗品直接用于下一步反应。
3. N-(2-氰基噻吩-3-基)-2-(7-甲基-6,7,8,9-四氢-5H-恶唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酰胺的制备
将2-(7-甲基-6,7,8,9-四氢-5H-恶唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸(N/A,2.6mmol)溶于二氯甲烷(50mL)中,依次加入2-氨基噻吩-3-甲腈(387.5mg,3.1mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.5g,3.9mmol)和三乙胺(526.2mg,5.2mmol),体系于25℃下反应8小时。反应结束后,体系加水淬灭反应,用二氯甲烷(100mL)萃取,有机相干燥浓缩,硅胶柱纯化(二氯甲烷:甲醇=9:1)得目标化合物粗品700mg,直接用于下一步反应。
4. 7-氨基-6-(7-甲基-6,7,8,9-四氢-5H-恶唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备
将N-(2-氰基噻吩-3-基)-2-(7-甲基-6,7,8,9-四氢-5H-恶唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酰胺(600mg,1.6mmol)溶于甲醇(50mL)中,加入甲醇钠(5.2g,28.9mmol)后将体系置于70℃下反应2小时。反应结束后,加入2M稀盐酸溶液调节体系pH至中性,浓缩 旋干,经硅胶柱纯化(二氯甲烷:甲醇=7:3)、旋干溶剂、甲醇打浆、过滤、洗涤、干燥后得目标化合物19.0mg,三步反应收率2.3%。
分子式:C
19H
18N
4O
2S 分子量:366.4 LC-MS(M/e):367.4.1(M+H
+)
1H-NMR(400MHz,CDCl
3)δ:11.51(s,1H),9.30-8.40(m,2H),7.95(d,J=5.2HZ,1H),7.47(s,2H),6.94(d,J=5.2HZ,1H),3.30-3.20(m,4H),3.10-2.90(m,4H),2.28(s,3H).
制备例33:6-(7-(2,2-二氟乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物48)
1. 2-(7-(异丙基氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯的制备
将2-(4-(4-甲氧基苄基)-5-氧代-7-(((三氟甲基)磺酰基)氧基)-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(500mg,0.60mmol)溶于乙腈(10mL),加入异丙胺(106mg,1.80mmoL),升温至40℃反应2小时。LCMS检测反应结束。反应液浓缩经硅胶柱纯化(二氯甲烷:甲醇=20:1)得目标化合物300mg,收率:67.1%。
2. 7-(异丙基氨基)-4-(4-甲氧基苄基)-6-(1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将2-(7-(异丙基氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(300mg,0.4mmol)溶于二氯甲烷(10mL),加入三氟乙酸(2ml)反应1小时。LCMS检测反应结束。二氯甲烷稀释,饱和碳酸氢钠水溶液洗涤,有机相干燥浓缩直接用于下一步。
3. 6-(7-(2,2-二氟乙基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将7-(异丙基氨基)-4-(4-甲氧基苄基)-6-(1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(N/A,0.4mmoL)溶于乙腈(5mL),加入N,N二异丙基乙胺(155mg,1.2mmoL)、2,2-二氟乙基三氟甲磺酸酯(256mg,1.2mmoL),加毕反应2小时。LCMS检测反应结束。反应液浓缩经硅胶柱纯化(乙酸乙酯:石油醚=1:1)得目标化合物150mg,两步收率:52.9%。
4. 6-(7-(2,2-二氟乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙 基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将6-(7-(2,2-二氟乙基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮(180mg,0.25mmol)溶于浓盐酸(0.5mL),加入三氟乙酸(3.5mL),110℃下反应48小时。LCMS检测反应结束。浓缩溶剂,用饱和碳酸氢钠水溶液调节体系pH=8,经Pre-TLC板纯化(二氯甲烷:甲醇=7:1)得目标化合物17mg,收率:14.9%。
分子式:C
23H
25F
2N
5OS 分子量:457.5 LC-MS(M/e):458.0(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:13.00(s,1H),11.14(d,J=8.4Hz,1H),11.84(s,1H),8.03(d,J=5.6Hz,1H),7.40(s,1H),7.33(s,1H),7.05(d,J=5.6Hz,1H),6.18-6.14(m,1H),4.50-4.48(m,1H),2.95-2.90(m,6H),2.87-2.78(m,4H),1.45-1.44(m,6H).
制备例34:6-(7-(2,2-二氟乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物49)
1. 7-氨基-6-(7-(2,2-二氟乙基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将7-((3,4-二甲基苄基)氨基)-4-(4-甲氧基苄基)-6-(1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(400mg,0.53mmoL)溶于乙腈(5mL),加入N,N二异丙基乙胺(206mg,1.6mmoL)、2,2-二氟乙基三氟甲磺酸酯(342mg,1.6mmoL),加毕反应2小时。LCMS检测反应结束。反应液浓缩硅胶柱纯化(乙酸乙酯:石油醚=1:1)得目标化合物250mg,收率:70.7%。
2. 6-(7-(2,2-二氟乙基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将7-氨基-6-(7-(2,2-二氟乙基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮(180mg,0.27mmol)溶于浓盐酸(0.5mL),加入三氟乙酸(3.5mL),110℃下反应48小时。LCMS检测反应结束。浓缩溶剂,用饱和碳酸氢钠水溶液调节体系pH=8,经Pre-TLC板纯化(二氯甲烷:甲醇=7:1)得目标化合物20mg,收率:17.8%。
分子式:C
20H
19F
2N
5OS 分子量:415.5 LC-MS(M/e):416.0(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.99(s,1H),7.92(d,J=5.6Hz,1H),7.39-7.34(m,2H),7.01(d,J=5.2Hz,1H),6.19-6.23(m,1H),2.95-2.90(m,6H),2.87-2.78(m,4H).
制备例35:6-(7-环丙基-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-((2,2-二氟乙基)氨基)噻吩[3,2-b]吡啶-5(4H)-酮的制备(化合物50)
1. 6-(7-环丙基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5:4,5]苯并[1,2-d]氮杂卓-2-基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-7-基三氟甲磺酸酯的制备
将6-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-羟基-4-(4-甲氧基苄基)噻吩[3,2-b]吡啶-5(4H)-酮(600mg,1.2mmol)溶于二氯甲烷(12mL),0℃下加入吡啶(1.90g,24mmol)、三氟甲磺酸酐(2.03g,7.2mmol),加毕,0℃下反应30分钟。用饱和碳酸氢钠水溶液淬灭反应,二氯甲烷萃取,有机相干燥浓缩直接用于下一步。
2. 6-(7-环丙基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5:4,5]苯并[1,2-d]氮杂卓-2-基)-7-((2,2-二氟乙基)氨基)-4-(4-甲氧基苄基)噻吩[3,2-b]吡啶-5(4H)-酮的制备
将6-(7-环丙基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5:4,5]苯并[1,2-d]氮杂卓-2-基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-7-基三氟甲磺酸盐酯(上步粗品)溶于乙腈(10mL),加入2,2-二氟乙胺(389mg,4.8mmol),加毕,40℃反应1小时。反应液浓缩,经硅胶柱纯化(二氯甲烷:甲醇=13:1)得目标化合物300mg,两步收率36.2%。
3. 6-(7-环丙基-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-((2,2-二氟乙基)氨基)噻吩[3,2-b]吡啶-5(4H)-酮的制备
将6-(7-环丙基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5:4,5]苯并[1,2-d]氮杂吡啶-2-基)-7-((2,2-二氟乙基)氨基)-4-(4-甲氧基苄基)噻吩[3,2-b]吡啶-5(4H)-酮(150mg,0.21mmol)溶于浓盐酸(1mL),加入三氟乙酸(7mL),加毕,升温至110℃反应24小时。浓缩溶剂,二氯甲烷溶解,饱和碳酸氢钠水溶液洗涤,有机相干燥,经中压反相纯化(40%甲醇/水(0.5%浓盐酸))得目标化合物40mg,收率41.4%。
分子式:C
23H
23F
2N
5OS 分子量:455.5 LC-MS(M/e):456.1(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.21(s,1H),12.05(s,1H),10.38(s,1H),8.08(d,J=5.6Hz,1H),7.50(s,2H),7.09(d,J=5.6Hz,1H),6.46(t,J=14.8Hz,1H),4.40-4.30(m,2H),3.80-3.70(m,2H),3.60-3.50(m,2H),3.30-3.05(m,4H),2.95-2.85(m,1H),1.25-1.20(m,2H),0.90-0.80(m,2H).
制备例36:6-(7-环丙基-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)噻吩[3,2-b]吡啶-5(4H)-酮盐酸盐的制备(化合物52的盐酸盐)
1. 6-(7-环丙基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5:4,5]苯并[1,2-d]氮杂卓-2- 基)-7-异丙基氨基-4-(4-甲氧基苄基)-噻吩并[3,2-b]吡啶-5(4H)酮的制备
将6-(7-环丙基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5:4,5]苯并[1,2-d]氮杂卓-2-基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩[3,2-b]吡啶-7-基三氟甲磺酸酯溶于乙腈(30mL),加入异丙胺(141.6mg,2.4mmol),加毕,45℃下反应1小时。反应液浓缩,经硅胶柱纯化(二氯甲烷:甲醇=20:1)得目标化合物200mg。
2. 6-(7-环丙基-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)噻吩[3,2-b]吡啶-5(4H)-酮盐酸盐的制备
将6-(7-环丙基-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢咪唑[4',5:4,5]苯并[1,2-d]氮杂卓-2-基)-7-异丙基氨基-4-(4-甲氧基苄基)-噻吩并[3,2-b]吡啶-5(4H)酮(200mg,0.29mmol)溶于浓盐酸(2mL),加入三氟乙酸(14mL),加毕,升至110℃反应16小时。浓缩溶剂,经C
18柱纯化(乙腈=0-30%)得目标化合物11.5mg,收率8.4%。
分子式:C
24H
28N
5OSCl 分子量:469.2 LC-MS(M/e):434.0(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:13.11(m,1H),12.09(m,1H),11.87(s,1H),9.03(m,1H),8.04(d,J=5.2Hz,1H),7.51(s,2H),7.05(d,J=5.2Hz,1H),4.47-4.52(m,1H),3.70-3.85(m,2H),3.14-3.24(m,4H),2.96-3.05(m,2H),1.45(d,J=6.4Hz,6H),1.20-1.30(m,1H),1.02-1.10(m,2H),0.89-0.91(m,2H).
制备例37:7-氨基-6-(7-乙基-6-氧代-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备(化合物53)
1. 1,5-二氢苯并[d]氧杂卓-2,4-二酮的制备
将2,2'-(1,2-亚苯基)二乙酸(12g,61.9mmol)溶于二氯甲烷(200mL)中,25℃下加入DCC(12.8g,61.9mmol),25℃下反应4h,LCMS检测反应完成,过滤,滤饼干燥得目标化合物粗品12g。
2. 2-(2-(2-(乙氨基)-2-氧乙基)苯基)乙酸的制备
将1,5-二氢苯并[d]氧杂卓-2,4-二酮(12g,粗品)溶于二氯甲烷(200mL)中,0℃下加入乙胺盐酸盐(2.7g,33mmol)和三乙胺(13.7g,136mmol),25℃下反应4h,LCMS检 测反应完成,体系加入水淬灭反应,二氯甲烷萃取有机相,有机相浓缩经硅胶柱纯化(甲醇/二氯甲烷=1:10)得目标化合物7g,两步收率50.9%。
3. N-乙基-2-(2-(2-羟乙基)苯基)乙酰胺的制备
将2-(2-(2-(乙氨基)-2-氧乙基)苯基)乙酸(7g,31.5mmol)溶于四氢呋喃(10mL)中,0℃下滴加硼烷(37.8mL,37.8mmol),滴加完毕,体系于25℃下反应3h,LCMS检测反应完成,体系加入甲醇淬灭反应,经水洗、乙酸乙酯萃取、有机相浓缩、硅胶柱纯化(甲醇/二氯甲烷=1:10)得目标化合物5g,收率76.3%。
4. 2-(2-(乙基氨基)-2-氧乙基)苯乙基甲磺酸盐的制备
将N-乙基-2-(2-(2-羟乙基)苯基)乙酰胺(5g,24mmol)溶于四氢呋喃(10mL)中,0℃下滴加甲磺酰氯(5.6g,48mmol)和三乙胺(7.3g,72mmol),滴加完毕,体系于0℃下反应3h,LCMS检测反应完成,体系加入水淬灭反应,经乙酸乙酯萃取、有机相浓缩、硅胶柱纯化(甲醇/二氯甲烷=1:10)得目标化合物4.9g,收率71.4%。
5. 3-乙基-1,3,4,5-四氢-2H-苯并[d]氮杂卓-2-酮的制备
将2-(2-(乙基氨基)-2-氧乙基)苯乙基甲磺酸盐(4.5g,15.7mmol)溶于N,N-二甲基甲酰胺(10mL)中,0℃下滴加氢化钠(1.2g,31.4mmol),滴加完毕后,体系于0℃下反应2h,LCMS检测反应完成,体系加入水淬灭反应,乙酸乙酯萃取,有机相浓缩硅胶柱纯化(乙酸乙酯/石油醚=1:1)得粗品2.35g。
6. 3-乙基-8-硝基-1,3,4,5-四氢-2H-苯并[d]氮杂卓-2-酮的制备
将3-乙基-1,3,4,5-四氢-2H-苯并[d]氮杂卓-2-酮(2.35g,粗品)溶于浓硫酸(10mL)中,0℃下加入硝酸钾(1.4g,13.8mmol),滴加完毕后,体系于0℃下反应2h,LCMS检测反应完成。将反应液滴加到冰水中淬灭反应,经乙酸乙酯萃取、有机相浓缩、硅胶柱纯化(乙酸乙酯/石油醚=1:3)得目标化合物1g,两步收率27.1%
7. 8-胺基-3-乙基-1,3,4,5-四氢-2H-苯并[d]氮杂卓-2-酮的制备
将3-乙基-8-硝基-1,3,4,5-四氢-2H-苯并[d]氮杂卓-2-酮(1g,4.3mmol)溶于甲醇(20mL)中,加入Pd/C(500mg),25℃反应2h,LCMS检测反应完成。过滤,滤液旋干得目标化合物860mg,收率90.4%。
8. N-(3-乙基-4-氧代-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备
将8-胺基-3-乙基-1,3,4,5-四氢-2H-苯并[d]氮杂卓-2-酮(860mg,4.20mmol)溶于乙酸(10mL)中,加入乙酸酐(2mL),25℃下反应2h,LCMS检测反应完成。反应液旋干,经二氯甲烷稀释、饱和碳酸氢钠溶液洗、有机相旋干、硅胶柱层析分离纯化(甲醇/二氯甲烷=1:1)得目标化合物650mg,收率62.7%
9. N-(3-乙基-8-硝基-4-氧代-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺的制备
将N-(3-乙基-4-氧代-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(580mg,2.35mmol)溶于浓硫酸(10mL)中,0℃下滴加发烟硝酸(181mg,2.82mmol)25℃反应2h,LCMS检测反应完成,反应液滴加到冰入水淬灭反应,二氯甲烷萃取有机相,有机相浓缩硅胶柱纯化(甲醇/二氯甲烷=1:10)得目标化合物230mg,收率33.5%
10. 7-胺基-3-乙基-8-硝基-1,3,4,5-四氢-2H-苯并[d]氮杂卓-2-酮的制备
将N-(3-乙基-8-硝基-4-氧代-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-基)乙酰胺(230mg,0.79mmol)溶于甲醇(10mL)中,加入碳酸钾(327mg,2.37mmol),25℃反应4h,LCMS检测反应完成,反应液旋干,粗品经硅胶柱纯化(甲醇/二氯甲烷=1:10)得目标化合物190mg,收率96.54%
11. 2-(7-乙基-6-氧代-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)醋酸乙酯的制备
将7-胺基-3-乙基-8-硝基-1,3,4,5-四氢-2H-苯并[d]氮杂卓-2-酮(190mg,0.76mmol)溶于乙醇(10mL)中,加入Pd/C(120mg),25℃下反应2h,LCMS检测反应完成,加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(297mg,1.52mmol),50℃下反应2h,LCMS检测反应完成。过滤,滤液旋干,用二氯甲烷稀释,饱和碳酸氢钠水溶液洗涤,有机相旋干,经硅胶柱层析分离(甲醇/二氯甲烷=1:10)得目标化合物150mg,收率62.4%。
12. 7-氨基-6-(7-乙基-6-氧代-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备
将2-(7-乙基-6-氧代-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)醋酸乙酯(100mg,0.32mmol)和3-氨基噻吩-2-甲腈(40mg,0.32mmol)溶于四氢呋喃(10mL)中,40℃下加入LDA(1mL,1.92mmol),40℃下反应2h,LCMS检测反应完成。将反应液倒入饱和氯化铵水溶液中淬灭,经乙酸乙酯萃取,有机相旋干,甲醇打浆后得目标化合物18.5mg,收率14.7%。
分子式:C
20H
19N
5O
2S 分子量:393.5 LC-MS(M/e):394.0(M+H+)
1H-NMR(400MHz,DMSO-d
6)δ:12.80(d,J=6.0Hz,1H),11.79(d,J=6.8Hz,1H),10.50-10.70(br s,1H),7.94(d,J=4.2Hz,1H),7.80-7.94(br s,1H),7.30-7.45(m,2H),7.03(d,J=4.2Hz,1H),3.88(d,J=9.2Hz,2H),3.71(t,J=5.2Hz,1H),3.35-3.40(m,2H),3.21(s,2H),1.03(t,J=7.2Hz,3H).
制备例38:7-氨基-6-(7-环丙基-1,5,6,7,8,9-六氢-5,9-桥亚甲基咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备(化合物54)
1. 7,8-二硝基-2,3,4,5-四氢-1H-1,5-甲醇苯并[d]氮杂卓制备
将1-(7,8-二硝基-1,2,4,5-四氢-3H-1,5-甲氧基苯并[d]氮杂卓-3-基)-2,2,2-三氟乙烷-1-酮(200.0mg,0.58mol)溶于甲醇(8mL)和水(3mL)中,加入碳酸钠(127.2mg,1.2mmol), 继续反应16小时。向体系中加水淬灭反应,用二氯甲烷(100mL)萃取,有机相经干燥浓缩得目标化合物粗品170mg,直接用于下一步反应。
2. 3-环丙基-7,8-二硝基-2,3,4,5-四氢-1H-1,5-甲基苯并[d]氮杂卓的制备
将7,8-二硝基-2,3,4,5-四氢-1H-1,5-甲醇苯并[d]氮杂卓(粗品)(170.0mg,0.68mmol)溶于甲醇(10.0mL)中,加入乙酸(432.0mg,7.2mmol)、氰基硼氢化钠(276.3mg,4.4mmol)和(1-乙氧基环丙氧基)三甲基硅烷(278.9mg,1.6mmol),体系于65℃下反应3h。向体系中加入水淬灭反应,用二氯甲烷萃取有机相,有机相浓缩经硅胶柱纯化(乙酸乙酯/石油醚=2:3)得目标化合物127.0mg,两步收率75.7%。
3. 3-环丙基-7,8-二氨基-2,3,4,5-四氢-1H-1,5-甲基苯并[d]氮杂卓的制备
将3-环丙基-7,8-二硝基-2,3,4,5-四氢-1H-1,5-甲基苯并[d]氮杂卓(320.0mg,1.1mmol)溶于乙醇(10mL)中,加入Pd/C(200.0mg),氢气氛围下将体系置于25℃氢化反应40分钟。反应液直接用于下一步反应。
4. 2-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备
于上一步反应液中加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(508.6mg.2.6mmol),升至50℃反应2小时。硅藻土过滤,滤液浓缩旋干,加入水稀释,用碳酸氢钠溶液调节PH至碱性,用二氯甲烷(100mL)萃取,有机相干燥浓缩,硅胶柱纯化(二氯甲烷:甲醇=10:1),得目标化合物250.0mg,收率(两步):69.4%。
5. 7-氨基-6-(7-环丙基-1,5,6,7,8,9-六氢-5,9-桥亚甲基咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备
将2-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(250mg,0.66mmol)溶于四氢呋喃(15mL)中,加入2-氨基噻吩-3-甲腈(113.1mg,0.91mmol),氮气氛围下将混合物置于40℃下,加入二异丙基氨基锂(1.5mL,3.0mmol),继续搅拌1小时。体系加氯化铵水溶液淬灭反应,用乙酸乙酯(100mL)萃取,有机相经干燥浓缩、硅胶柱纯化(乙酸乙酯=100%)得目标化合物19.0mg,产率:7.1%。
分子式:C
22H
21N
5OS 分子量:403.5 LC-MS(M/e):404.0(M+H
+)
1H-NMR(400MHz,CDCl
3)δ:12.75(s,1H),11.75(s,1H),10.72-10.52(m,1H),7.94(d,J=8.8HZ,1H),7.91-7.67(m,1H),7.36(s,1H),7.28(s,1H),7.01(d,J=5.2HZ,1H),3.20-3.10(m,2H),2.92-2.82(m,2H),2.64-2.50(m,2H),2.25-2.15(m,1H),1.85-1.75(m,1H),1.70-1.60(m,1H),0.30-0.20(m,2H),-0.1--0.2(m,2H).
制备例39:7-氨基-6-(7-环丙基-6-氧代-1,5,6,7,8,9-六氢咪唑[4',5]:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备(化合物55)
1. 2-(7-环丙基-6-氧代-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备
选用1,5-二氢苯并[d]氧杂卓-2,4-二酮和环丙胺作为起始原料,参照制备例37的制备方法,制备得到2-(7-环丙基-6-氧代-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯。
2. 7-氨基-6-(7-环丙基-6-氧代-1,5,6,7,8,9-六氢咪唑[4',5]:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备
将2-(7-环丙基-6-氧代-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓吡啶-2-基)乙酸乙酯(32.7mg,0.1mmol)、2-氰基-3-氨基噻吩(12.4mg,0.1mmol)溶于四氢呋喃(5mL)中,氮气保护下升温至40℃,40℃下滴加2M的二异丙基氨基锂溶液(0.25mL,0.5mmol),加毕,40℃反应3小时。LCMS检测反应结束。降温至25℃,饱和氯化铵水溶液淬灭反应,乙酸乙酯萃取,有机相干燥浓缩,得到的固体用甲醇打浆,过滤得固体,固体干燥得标题化合物14.5mg,收率:35.8%。
分子式:C
21H
19N
5O
2S 分子量:405.5 LC-MS(M/e):406.1(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.80(s,1H),11.81(m,1H),7.94(d,J=5.2Hz,1H),7.89(m,1H),7.41(s,1H),7.36(s,1H),7.01(d,J=5.2Hz,1H),3.87(s,2H),3.72-3.70(m,2H),3.15-3.20(m,2H),2.65-2.75(m,1H),0.69-0.71(m,2H),0.60-0.62(m,2H).
制备例40:7-((2,2-二氟乙基)氨基)-6-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮三氟乙酸盐的制备(化合物58的三氟乙酸盐)
1. 2-(7-((2,2-二氟乙基)氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯的制备
将2-(4-(4-甲氧基苄基)-5-氧代-7-(((三氟甲基)磺酰基)氧基)-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧 酸叔丁酯(500mg,0.60mmol),溶于乙腈(5mL)中,加入2,2-二氟乙基-1-胺(388mg,4.78mmol),40℃下反应2h。LCMS检测反应完成,旋干溶剂,经硅胶柱层析分离(乙酸乙酯:石油醚=1:1)得目标化合物300mg,收率65.4%。
2. 7-((2,2-二氟乙基)氨基)-6-(1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将2-(7-((2,2-二氟乙基)氨基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-6-基)-1-((三氟甲基)磺酰基)-5,6,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-7(1H)-羧酸叔丁酯(300mg,0.39mmol)溶于三氟乙酸(3.5ml)和盐酸(0.5mL)中,升温至110℃反应24h,LCMS检测反应完成。将反应液旋干,用饱和碳酸氢钠水溶液调节体系pH=8,经二氯甲烷萃取、干燥、浓缩得目标化合物粗品200mg。
3. 7-((2,2-二氟乙基)氨基)-6-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮三氟乙酸盐的制备
将7-((2,2-二氟乙基)氨基)-6-(1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(200mg,N/A)溶于甲醇(5mL)中,加入氧杂环丁烷-3-酮(30mg,0.40mmol)和乙酸(144mg,2.4mmol),25℃下反应1小时后,加入氰基硼氢化钠(150mg,2.4mmol),继续反应8小时,LCMS检测反应完成。向体系中加入碳酸氢钠水溶液,用二氯甲烷萃取,收集有机相溶剂旋干,经反相柱层析(甲醇/水=0-40%其中两相各含有0.3%的三氟乙酸)得目标化合物19mg,收率37.8%。
分子式:C
25H
24F
5N
5O
3S 分子量:569.15 LC-MS(M/e):472.5(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:13.06(s,1H),12.35-12.33(m,1H),12.04(s,1H),11.07(s,1H),8.09-8.07(d,J=5.6Hz,1H),7.54-7.47(m,2H),7.10-7.08(d,J=5.6Hz,1H),6.46-6.33(m,1H),4.91-4.89(m,2H),4.75-4.72(m,2H),4.47-4.41(m,3H),3.54-3.48(m,4H),3.12-3.10(m,2H),2.88-2.86(m,2H).
制备例41:6-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚烷基[4,5]苯并[1,2-d]咪唑-2-基)-7-((2,2-二氟乙基)氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物59)
1. 6-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚烷基[4,5]苯并[1,2-d]咪唑-2-基)-7-羟基-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将2-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚烷基[4,5]苯并[1,2-d]咪唑-2-基)乙酸 乙酯(130mg,0.4mmol)和1-(4-甲氧基苄基)-2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮(173mg,0.6mmol)溶于四氢呋喃(20mL),升温至40℃,氮气保护下加入LDA(2mL,4mmol),加入完毕后反应2小时。LCMS检测反应结束。加入饱和氯化铵溶液淬灭,用乙酸乙酯和甲醇混合溶液萃取(乙酸乙酯:甲醇=10:1(100mL×4))萃取,有机相干燥浓缩,硅胶柱纯化(二氯甲烷:甲醇=10:1)得标题化合物190mg,收率90%。
2. 6-(7-(氮杂环丁烷-1-基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢环庚烷基[4,5]苯并[1,2-d]咪唑-2-基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-7-基三氟甲磺酸盐的制备
0℃下,将6-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚烷基[4,5]苯并[1,2-d]咪唑-2-基)-7-羟基-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮(190mg,0.36mmol)溶于二氯甲烷(100mL)中,加入吡啶(285mg,3.3mmol)和三氟甲磺酸酐(620mg,2mmol),反应1小时。LCMS检测反应结束。浓缩溶剂,加入饱和碳酸氢钠淬灭反应,二氯甲烷(100mL×4次)萃取,有机相干燥浓缩,得标题化合物粗品390mg,不作进一步处理,投入下一步。
3. 6-(7-(氮杂环丁烷-1-基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢环庚烷基[4,5]苯并[1,2-d]咪唑-2-基)-7-((2,2-二氟乙基)氨基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将6-(7-(氮杂环丁烷-1-基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢环庚烷基[4,5]苯并[1,2-d]咪唑-2-基)-4-(4-甲氧基苄基)-5-氧代-4,5-二氢噻吩并[3,2-b]吡啶-7-基三氟甲磺酸盐(390mg)溶于乙腈(100mL),加入二氟乙氨(291mg,3.6mmol),升温至40℃下反应4小时。LCMS检测反应结束。有机相干燥浓缩,硅胶柱纯化(二氯甲烷:甲醇=10:1)得标题化合物140mg,两步收率66%。
4. 6-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚烷基[4,5]苯并[1,2-d]咪唑-2-基)-7-((2,2-二氟乙基)氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将6-(7-(氮杂环丁烷-1-基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢环庚烷基[4,5]苯并[1,2-d]咪唑-2-基)-7-((2,2-二氟乙基)氨基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮(140mg,0.24mmol)置于100mL单口瓶中,加入三氟乙酸(6mL)和浓盐酸(1mL),升温至110℃反应24小时。LCMS检测反应结束。有机相浓缩,反相柱层析纯化(水:甲醇=10:3)得标题化合物52mg,收率57%。
分子式:C
24H
25F
2N
5OS 分子量:469.6 LC-MS(M/e):470.2(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.22(s,1H),7.99(d,J=5.6Hz 1H),7.37(s,1H),7.28(s,1H),7.07(d,J=5.6Hz 1H),6.57-6.29(t,J=15.2Hz,1H),4.37-4.28(m,2H),3.12-3.08(m,4H),2.95-2.90(m,2H),2.71-2.65(m,2H),2.34(s,1H),2.26-2.23(m,1H),2.00-1.90(m,1H),1.89-1.75(m,4H),1.15-1.08(m,2H).
制备例42:7-氨基-6-(5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物60)
1. 7-胺基-1,2,4,5-四氢苯并[d]氧杂卓的制备
将7-硝基-1,2,4,5-四氢苯并[d]氧杂卓(140mg,0.73mmol)溶于甲醇(5mL),加入钯碳(100mg,N/A),在氢气氛围下反应2小时。LCMS检测反应结束。过滤,收集滤液浓缩得目标化合物粗品,直接用于下一步。
2. N-(1,2,4,5-四氢苯并[d]氧杂卓-7-基)乙酰胺的制备
将7-胺基-1,2,4,5-四氢苯并[d]氧杂卓(上一步粗品)溶于乙酸(2mL),加入乙酸酐(2mL),加毕15℃反应1小时。LCMS检测反应结束。加水稀释,饱和碳酸氢钠水溶液调pH=9,二氯甲烷萃取,水相浓缩,经C18柱纯化(甲醇=0-80%)得目标化合物100mg,两步收率66.8%。
3. N-(8-硝基-1,2,4,5-四氢苯并[d]氧杂卓-7-基)乙酰胺的制备
将N-(1,2,4,5-四氢苯并[d]氧杂卓-7-基)乙酰胺(100mg,0.49mmol)溶于浓硫酸(2mL),0℃下滴加发烟硝酸(38mg,0.61mmol),加毕,0℃下反应10min。LCMS检测反应结束。倒入冰水中,氢氧化钠水溶液调pH=7,浓缩溶剂,固体用二氯甲烷和甲醇洗涤,有机相浓缩得目标化合物粗品,直接用于下一步。
4. 8-硝基-1,2,4,5-四氢苯并[d]氧杂卓-7-胺的制备
将N-(8-硝基-1,2,4,5-四氢苯并[d]氧杂卓-7-基)乙酰胺(N/A,0.49mmol)溶于甲醇(5mL),加入碳酸钾(166mg,1.2mmol),加毕,55℃下反应8小时。LCMS检测反应结束。硅藻土过滤,滤液浓缩,经C18柱纯化(甲醇=0-80%)得目标化合物80mg,收率78.1%。
5. 2-(5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)乙酸乙酯的制备
将8-硝基-1,2,4,5-四氢苯并[d]氧杂卓-7-胺(80mg,0.38mmol)溶于乙醇(3mL),加入Pd/C(100mg),加毕,15℃下氢化反应2小时。LCMS检测反应结束。加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(149mg,0.76mmol),升至50℃反应2小时。LCMS检测反应结束。硅藻土过滤,滤液浓缩,经硅胶柱柱纯化(二氯甲烷:甲醇=15:1)得目标化合物100mg,收率94.9%。
6. 7-氨基-6-(5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将2-(5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)乙酸乙酯(50mg,0.18mmol)、3-氨基噻吩-2-腈(27mg,0.22mmol)溶于四氢呋喃(2mL),加入LDA(0.41mL,0.81mmol),加毕,40℃下反应2小时。LCMS检测反应结束。加入饱和氯化铵淬灭反应,二氯甲烷萃取,有机相经干燥、浓缩、甲醇打浆得目标化合物5mg,收率7.98%。
分子式:C
18H
16N
4O
2S 分子量:352.1 LC-MS(M/e):353.1(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.78(s,1H),11.81(s,1H),10.60(s,1H),7.98-7.93(m,2H),742(d,J=5.2Hz,2H),7.02-7.00(m,1H),3.92-3.88(m,4H),3.17-3.00(m,4H).
制备例43:7-((2,2-二氟乙基)氨基)-6-(5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物61)
1. 7-羟基-4-(4-甲氧基苄基)-6-(5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将2-(5,6,8,9-四氢-1H-氧杂卓并[4’,5’:4,5]苯并[1,2-d]咪唑-2-基)乙酸乙酯(500mg,1.8mmol)和1-(4-甲氧基苄基)-2H-噻吩并[3,2-d][1,3]恶嗪-2,4(1H)-二酮(686mg,2.4mmol)溶于四氢呋喃(10mL)。氮气保护下,40℃下加入LDA(4.5mL,5mol),加毕,40℃下反应1小时。LCMS检测反应结束,降温至15℃,饱和氯化铵水溶液淬灭反应,二氯甲烷萃取,有机相干燥,浓缩,得目标化合物粗品。将目标化合物粗品再次加入四氢呋喃(10mL)中,在氮气保护下加入LDA(4.5mL,5mol),加毕,40℃下反应1小时。降温至15℃,加入饱和氯化铵水溶液淬灭反应,二氯甲烷萃取,有机相经干燥、浓缩、硅胶柱纯化(二氯甲烷:甲醇=20:1)得目标化合物320mg,收率37.1%。
2. 4-(4-甲氧基苄基)-5-氧代-6-(1-((三氟甲基)磺酰基)-5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)-4,5-二氢噻吩并[3,2-b]吡啶-7-基三氟甲基磺酸酯的制备
将7-羟基-4-(4-甲氧基苄基)-6-(5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(320mg,0.68mmol)溶于二氯甲烷(10mL)中,0℃下加入吡啶(1.1g,13.6mmol)和三氟甲磺酸酐(1.2g,4.1mmol),加毕,0℃下反应30分钟。LCMS检测反应结束。加入饱和碳酸氢钠水溶液淬灭反应,二氯甲烷萃取,有机相干燥浓缩,直接用于下一步。
3. 7-((2,2-二氟乙基)氨基)-4-(4-甲氧基苄基)-6-(1-((三氟甲基)磺酰基)-5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将4-(4-甲氧基苄基)-5-氧代-6-(1-((三氟甲基)磺酰基)-5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)-4,5-二氢噻吩并[3,2-b]吡啶-7-基三氟甲基磺酸酯(N/A,0.68mmol)溶于乙腈(10mL),加入2,2-二氟乙-1-胺(440mg,5.4mmol),加毕40℃反应2小时。LCMS检测反应结束。反应液浓缩硅胶柱纯化(二氯甲烷:甲醇=20:1)得目标化合物 130mg,两步收率28.6%
4. 7-((2,2-二氟乙基)氨基)-6-(5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将7-((2,2-二氟乙基)氨基)-4-(4-甲氧基苄基)-6-(1-((三氟甲基)磺酰基)-5,6,8,9-四氢-1H-氧杂卓并[4',5':4,5]苯并[1,2-d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(130mg,0.19mmol)溶于浓盐酸(1.5mL),加入三氟乙酸(10.5mL),加毕,升至110℃反应24小时。LCMS检测反应结束。浓缩溶剂,二氯甲烷溶解,加入饱和碳酸氢钠水溶液,过滤,滤饼用甲醇打浆得目标化合物40mg,收率50.5%。
分子式:C
20H
18F
2N
4O
2S 分子量:416.4 LC-MS(M/e):417.1(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.96(s,1H),12.38(s,1H),12.03(s,1H),8.04(d,J=5.2Hz,1H),7.44(s,1H),7.32(s,1H),7.07(d,J=4.8Hz,1H),6.75-6.38(m,1H),4.38-4.31(m,2H),3.88-3.74(m,4H),3.02-2.98(m,4H).
制备例44:7-氨基-6-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-1-甲基-1,4-二氢-5H-吡唑并[4,3-b]吡啶-5-酮的制备(化合物62)
将2-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(50mg,0.16mmol)溶于四氢呋喃(3mL)中,在氮气保护下加入4-氨基-1-甲基-1H-吡唑-5-腈(20mg,0.16mmol),40℃下加入二异丙基氨基锂(0.40mL,0.80mmol),加毕,40℃下反应2小时。LCMS检测反应结束。加入饱和氯化铵淬灭反应,用乙酸乙酯萃取,有机相经干燥、浓缩、甲醇打浆得标题化合物33mg,收率53.0%。
分子式:C
21H
23N
7O 分子量:389.5 LC-MS(M/e):390.2(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.90(s,1H),11.23(s,1H),7.40-7.35(m,3H),4.27(s,3H),2.90-2.85(m,4H),2.75-2.65(m,4H),1.78-1.76(m,1H),0.49-0.43(m,4H).
制备例45:7-氨基-6-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚基[4,5]苯并[1,2-d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备(化合物63)
1. 2-硝基-5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮的制备
将5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮(2.0g,12.4mmol)溶于浓硫酸(20mL),搅拌1h后,分批次缓慢加入硝酸钾(1.5g,14.9mmol),加毕,0℃下反应2小时。LCMS检测反应结束。倒入冰水(200mL)中,乙酸乙酯(100mL×4次)萃取,有机相干燥浓缩,硅胶柱纯化(正庚烷:乙酸乙酯=5:1)得标题化合物2.0g,收率79%。
2. 1-(2-硝基-6,7,8,9-四氢-5H-苯并[7]轮烯-7-基)氮杂环丁烷的制备
将2-硝基-5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮(2.0g,9.7mmol)溶于甲醇(100mL)中,加入氰基硼氢化钠(1.6g,23.5mmol)和氮杂环丁烷(673mg,11.8mmol),加毕,35℃下反应12小时。LCMS检测反应结束。浓缩溶剂,加入饱和碳酸氢钠淬灭反应,乙酸乙酯(100mL×4次)萃取,有机相干燥浓缩,硅胶柱纯化(二氯甲烷:甲醇=10:1)得标题化合物2.3g,收率96%。
3. 7-(氮杂环丁烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-胺的制备
将1-(2-硝基-6,7,8,9-四氢-5H-苯并[7]轮烯-7-基)氮杂环丁烷(2.3g,9.3mmol)溶于甲醇(100mL),加入雷尼镍(790mg,9.3mmol),30℃下反应4小时。LCMS检测反应结束。硅藻土抽滤,浓缩得标题化合物1.6g,粗品收率80%。
4. N-(7-(氮杂环丁烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)乙酰胺的制备
将7-(氮杂环丁烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-胺(1.6g,7.5mmol)置于100mL单口瓶中,加入乙酸(5mL)和乙酸酐(5mL),25℃反应1小时。LCMS检测反应结束。浓缩半干,用饱和碳酸氢钠淬灭,用乙酸乙酯和甲醇混合溶液(乙酸乙酯:甲醇=5:1)(100mL×4次)萃取,有机相干燥浓缩,硅胶柱纯化(二氯甲烷:甲醇=10:1)得标题化合物1.5g,收率78%。
5. N-(7-(氮杂环丁烷-1-基)-3-硝基-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)乙酰胺的制备
将N-(7-(氮杂环丁烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)乙酰胺(1.5g,5.9mmol)溶于浓硫酸(15mL)中,0℃下搅拌1小时,分批次加入硝酸钾(656mg,6.5mmol),加毕,0℃反应1小时。LCMS检测反应结束。倒入冰水中,用饱和碳酸钠淬灭反应,用乙酸乙酯和甲醇混合溶液(乙酸乙酯:甲醇=10:1)(200mL×4次)萃取,有机相干燥浓缩,硅胶柱纯化(二氯甲烷:甲醇=10:1)得标题化合物1.6g,收率89%。
6. 7-(氮杂环丁烷-1-基)-3-硝基-6,7,8,9-四氢-5H-苯并[7]轮烯-2-胺的制备
将N-(7-(氮杂环丁烷-1-基)-3-硝基-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)乙酰胺(1.6g,5.3mmol)溶于甲醇(100mL),加入碳酸钾(2.2g,15.8mmol),加毕,50℃下继续反应4小时。LCMS检测反应结束。硅藻土抽滤,有机相干燥浓缩硅胶柱纯化(二氯甲烷:甲醇酯=10:1)得标题化合物854mg,收率62%。
7. 2-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚基[4,5]苯并[1,2-d]咪唑-2-基)乙酸乙酯的制备
将7-(氮杂环丁烷-1-基)-3-硝基-6,7,8,9-四氢-5H-苯并[7]环烯-2-胺(854mg,3.3mmol) 溶于乙醇(50mL),加入Pd/C(489mg,1.7mmol),加毕,25℃下氢化反应8小时。LCMS检测反应结束。加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(1.5g,7.9mmol),升温至50℃,搅拌回流反应3小时,LCMS检测反应结束。加入硅藻土过滤,有机相干燥浓缩硅胶柱纯化(二氯甲烷:甲醇酯=10:1)得标题化合物755mg,两步收率70.6%。
8. 7-氨基-6-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚基[4,5]苯并[1,2-d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将2-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚基[4,5]苯并[1,2-d]咪唑-2-基)乙酸乙酯(755mg,2.3mmol)和2-氰基-3-氨基噻酚(682mg,5.5mmol)溶于四氢呋喃(15mL)中,氮气保护下升温至40℃,缓慢加入LDA(1.2mmol,0.6mL),加毕,40℃下反应2小时。LCMS检测反应结束。加入饱和氯化铵水溶液淬灭反应,乙酸乙酯萃取,有机相干燥浓缩,用乙酸乙酯和甲醇混合溶液(乙酸乙酯:甲醇=10:1)(200mL×4次)萃取,有机相干燥浓缩,硅胶柱纯化(二氯甲烷:甲醇=10:1)得标题化合物401mg,收率:43%。
分子式:C
22H
23N
5OS 分子量:405.5 LC-MS(M/e):406.1(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.73(s,1H),11.79(s,1H),7.94-7.93(d,J=5.2Hz,1H),7.38(s,1H),7.33(s,1H),7.01-7.00(d,J=5.2Hz,1H),3.12-3.09(m,4H),2.93-2.92(m,2H),2.70-2.63(m,2H),2.49-2.51(m,1H),1.90-1.80(m,4H),1.30-1.23(m,2H).
制备例46:7-(异丙基氨基)-6-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5:4,5]苯并[1,2-d]氮杂卓-2-基)噻吩[3,2-b]吡啶-5(4H)-酮的制备(化合物64)
将6-(1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-7-(异丙基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮(120mg,0.30mmol)溶于甲醇(10mL)中,加入3-氧杂环丁酮(90mg,0.54mmol)和乙酸(186mg,0.18mmol),25℃反应30分钟后,加入氰基硼氢化钠(96mg,0.54mmol),加毕,35℃反应16小时。LCMS检测反应结束。加入饱和碳酸氢钠调节pH=8,用二氯甲烷(40mL)萃取,用硅胶柱层析分离(甲醇:二氯甲烷=1:15)得目标化合物60mg,收率43.8%。
分子式:C
24H
27N
5O
2S 分子量:449.6 LC-MS(M/e):450.2(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:13.00(s,1H),12.15(d,J=8.2,1H),11.86(s,1H),8.03(d,J=5.2,1H),7.40(s,1H),7.34(s,1H),7.04(s,1H),4.54-4.45(m,5H),3.49-3.47(m,1H),3.01-2.85(m,4H),2.49-2.25(m,4H),1.50-1.40(m,6H).
制备例47:6-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚基[4,5]苯并[1,2-d]咪唑-2-基)-7-(异丙基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮(化合物65)
1. 6-(7-(氮杂环丁烷-1-基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢环庚基[4,5]苯并[1,2-d]咪唑-2-基)-7-(异丙基氨基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将6-(7-(氮杂环丁烷-1-基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢环庚[4,5]苯并[1,2-d]咪唑-2-基)-4-(4-甲氧基苄基)-5-氧代-2,3,4,5-四氢噻吩并[3,2-b]吡啶-7-基三氟甲磺酸盐(315mg,0.4mmol)和异丙胺(235mg,4mmol)溶于乙腈(50mL),升温至40℃后反应3小时。LCMS检测反应结束。柱层析分离,硅胶柱纯化(二氯甲烷:甲醇=10:1)得标题化合物157mg,收率56.5%。
2. 6-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚基[4,5]苯并[1,2-d]咪唑-2-基)-7-(异丙基氨基)噻吩并[3,2-b]吡啶-5(4H)-酮的制备
将6-(7-(氮杂环丁烷-1-基)-1-((三氟甲基)磺酰基)-1,5,6,7,8,9-六氢环庚基[4,5]苯并[1,2-d]咪唑-2-基)-7-(异丙基氨基)-4-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-5(4H)-酮(157mg,0.22mmol)置于100mL单口瓶中,加入三氟乙酸(6mL)和浓盐酸(1mL),升温至110℃反应24小时。LCMS检测反应结束。有机相浓缩,经反相柱层析纯化(水:甲醇=10:3)得目标化合物38mg,收率39%。
分子式:C
25H
29N
5OS 分子量:447.6 LC-MS(M/e):480.2(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:13.08-13.03(d,J=5.2Hz,1H),12.15-12.13(d,J=5.2Hz,1H),8.02-8.00(d,J=5.2Hz,1H),7.43-7.37(d,J=5.2Hz,1H),7.30(s,1H),7.06(s,1H),7.04(s,1H),4.43-4.48(m,1H),3.08-3.30(m,4H),2.6-2.7(m,2H),2.49-2.51(m,2H),2.32-2.30(m,1H),2.24-2.23(m,4H),2.22-2.00(m,6H),1.89-1.97(m,2H).
制备例48:2-(7-氨基-1-甲基-5-氧代-4,5-二氢-1H-吡唑并[4,3-b]吡啶-6-基)-7-环丙基-5,7,8,9-四氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-6(1H)-酮(化合物66)
将2-(7-环丙基-6-氧代-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)醋酸乙酯(200mg,0.61mmol)溶于四氢呋喃(10mL)中,加入4-氨基-1-甲基-1H-吡唑-5-甲腈(89mg,0.73mmol),40℃滴加LDA(2.44mL,4.88mmol),继续反应6h,LCMS检测反应完成。倒入饱和氯化铵水溶液中淬灭,乙酸乙酯萃取,有机相旋干,甲醇打浆得目标化合物粗品40mg,经反相色谱纯化(甲醇:水=0-50%)得目标化合物2.4mg,收率1.0%。
分子式:C
21H
21N
7O
2 分子量:403.4 LC-MS(M/e):404.1(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.93(d,J=10.4Hz,1H),11.23(d,J=7.9Hz,1H),7.35-7.45 (m,3H),4.46(s,3H),4.26(s,3H),3.88(d,J=11.6Hz,2H),3.71(t,J=5.4Hz,2H),3.15-3.19(m,2H),2.68-2.72(m,1H),0.68-0.73(m,2H),0.50-0.60(m,2H).
制备例49:7-氨基-1-甲基-6-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-1,4-二氢-5H-吡唑并[4,3-b]吡啶-5-酮的制备(化合物67)
1. 8-硝基-3-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺的制备
将8-硝基-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(500mg,5.42mmol)、氧杂环丁酮(523mg,7.26mmol)溶于甲醇(20mL)中,加入乙酸(1.5g,24.2mmol)和氰基硼氢化钠(900mg,14.5mmol),25℃下反应16h,LCMS检测反应完成。用饱和碳酸氢钠水溶液调节pH=7-8,二氯甲烷萃取,有机相旋干,硅胶柱纯化(二氯甲烷:甲醇=15:1)得目标化合物420mg,收率66.0%。
2. 2-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯的制备
将8-硝基-3-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂卓-7-胺(420mg,1.6mmol)溶于乙醇(10mL)中,加入Pd/C(200mg),25℃下氢化反应2小时。加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(657mg,3.36mmol),升温至50℃继续反应4h。LCMS检测反应完成。硅藻土过滤,滤液旋干,二氯甲烷稀释,饱和碳酸氢钠洗涤,有机相旋干,经硅胶柱纯化(二氯甲烷:甲醇=10:1)得目标化合物370mg,收率70.1%。
3. 7-氨基-1-甲基-6-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-1,4-二氢-5H-吡唑并[4,3-b]吡啶-5-酮的制备
将2-(7-(氧杂环丁烷-3-基)-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(80mg,0.24mmol)溶于四氢呋喃(5mL)中,加入4-氨基-1-甲基-1H-吡唑-5-甲腈(29mg,0.24mmol),45℃下滴加LDA(0.96mL,1.92mmol),继续反应5h,LCMS检测反应完成。倒入饱和氯化铵水溶液中淬灭,乙酸乙酯萃取,有机相旋干,甲醇打浆得目标化合物17.5mg,收率17.8%。
分子式:C
21H
23N
7O
2 分子量:405.5 LC-MS(M/e):406.2(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.90(s,1H),11.23(s,1H),7.30-7.45(m,3H),4.40-4.58(m,4H),4.26(s,3H),3.40-3.50(m,1H),2.85-2.95(m,4H),2.35-2.45(m,4H).
制备例50:7-氨基-6-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚基并[4,5]苯并[1,2-d]咪唑-2-基)-1-甲基-1,4-二氢-5H-吡唑并[4,3-b]吡啶-5-酮的制备(化合物68)
将2-(7-(氮杂环丁烷-1-基)-1,5,6,7,8,9-六氢环庚基[4,5]苯并[1,2-d]咪唑-2-基)乙酸乙酯(200mg,0.61mmol)和3-氨基-1,5-二甲基-1氢-吡咯-2-氰基(112mg,0.92mmol)溶于四氢呋喃(50mL)中,氮气保护下升温至40℃,缓慢加入LDA(3.1mL,6.1mmoL),加毕,40℃下反应2小时。LCMS检测反应结束。加入饱和氯化铵水溶液淬灭反应,乙酸乙酯萃取,有机相干燥浓缩,用乙酸乙酯/甲醇混合溶剂(乙酸乙酯:甲醇=10:1,200mL×4次)萃取,有机相干燥浓缩,经反相柱层析纯化(水:甲醇=10:4)得目标化合物100mg,收率40.6%。
分子式:C
22H
25N
7O 分子量:403.5 LC-MS(M/e):404.2(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.87(s,1H),11.21(s,1H),7.39-7.33(m,3H),4.27(s,3H),7.33(s,1H),3.17-3.08(m,4H),2.98-2.94(m,2H),2.67-2.56(m,2H),2.33-2.26(m,1H),1.99-1.85(m,4H),1.23-1.4(m,2H).
制备例51:4-氨基-5-(7-环丙基-1,5,6,7,8,9-六氢咪唑[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)-1-甲基-1,7-二氢-6H-吡唑[3,4-b]吡啶-6-酮的制备(化合物69)
将2-(7-环丙基-1,5,6,7,8,9-六氢咪唑并[4',5':4,5]苯并[1,2-d]氮杂卓-2-基)乙酸乙酯(100mg,0.32mmol)溶于四氢呋喃(5mL),在氮气保护下加入6-甲基-1-甲基-1H-吡唑-4-腈(39mg,0.32mmol),40℃下加入LDA(2M,1.3mL,2.6mmol),加毕,40℃下反应3小时。LCMS检测反应结束。倒入饱和氯化铵溶液中淬灭反应,乙酸乙酯萃取,有机相经干燥、浓缩后,经甲醇和二氯甲烷打浆得目标化合物10mg,收率8.1%。
分子式:C
21H
23N
7O
2 分子量:389.5 LC-MS(M/e):390.2(M+H
+)
1H-NMR(400MHz,DMSO-d
6)δ:12.17(s,1H),10.71(s,1H),10.55(s,1H),7.60(s,1H),7.33(s,1H),7.25(s,1H),7.10(s,1H),2.92(s,3H),2.91(s,4H),4.40-2.72(s,4H),1.75(s,1H),0.37-0.46(d,4H).
使用与上述制备例相同或相似的方法制备了以下表格所示的化合物:
实验方案
以下提供本发明部分化合物的示例性实验方案,以显示本发明化合物有利活性和有益技术效果。但是应当理解,下述实验方案仅仅是对本发明内容的示例,而不是对本发明范围的限制。
实验例1本发明化合物对体外激酶活性的抑制实验
测试物:本发明部分化合物,其结构式和制备方法见本发明制备例。
下述实验中所用缩写代表的含义如下:
DMSO:二甲基亚砜;
HEPES:羟乙基哌嗪乙硫磺酸
实验方法:用Lantha screen Assay方法,在体外6个激酶上对化合物进行评价。
实验步骤:
1.制备含50mM HEPES溶液,10mM氯化镁,4mM二硫苏糖醇,0.01%牛血清白蛋白和0.01%吐温-20的1×激酶缓冲液:
2.化合物稀释:
1)取90μl的100%DMSO,再加入10μl 10mM化合物溶液,即配制成1mM化合物溶液。在96孔板上第二个孔中加入90μl的100%DMSO,再加入10μl 1mM化合物溶液,即配制成100μM化合物溶液,其他孔加入60μl的100%DMSO。从第二孔中取30μl化合物加入第三孔中,依次往下做3倍稀释,共稀释10个浓度。
转移40μl上述配制的100μM化合物溶液到384孔Echo板中;
2)转移40μl 100%DMSO到两个空孔中作为不加化合物的阳性对照和不加酶的阴性对照;
3)使用Echo 550转移100nl化合物到384孔测试板中,化合物的检测起始浓度为1μM。
3.用1×激酶缓冲液配置2×激酶溶液,转移5μl 2×激酶溶液到384孔板反应孔中,阴性对照孔加入1×激酶缓冲液,450转/分钟振荡混匀,室温下静置孵育10分钟。
4.用1×激酶缓冲液配置2×底物溶液,转移5μl 2×底物溶液到384孔板反应孔中,450转/分钟振荡混匀。
5.室温进行反应90分钟。
6.配置2×含抗体的终止反应液,转移10μl 2×终止反应液到384孔板反应孔中,1000转/分钟离心1分钟,室温放置60分钟,检测。
7.数据读取:Envision2104 Multilable Reader上读取在340nm处激发,520nm和495nm处发射的数值。
8.数据计算
1)将荧光读数的数值比(Lantha signal(520nm/495nm))通过公式转换为抑制百分率:
抑制百分率=(最大值-Lantha signal)/(最大值-最小值)*100
“最小值”为不加酶的阴性对照样孔读数;“最大值”为不加化合物的阳性对照孔读数。
2)将数据导入MS Excel,IC
50结果使用XLFit excel add-in version 5.4.0.8进行曲线拟合。
实验结果
表1本发明化合物体外酶学抑制活性
实验结论
本发明化合物对MAP4K1/HPK1有很好的抑制活性,并且本发明化合物对HPK1具有优异的选择性。
实验例2本发明化合物对体外细胞学活性的抑制实验
测试物:本发明部分化合物,其结构式和制备方法见本发明制备例。
下述实验中所用缩写代表的含义如下:
ELISA:酶联免疫吸附试验;
Jurkat:人急性T细胞白血病细胞;
SLP76:含SH2结构域的76kDa白细胞蛋白;
CD3:分化簇3(白细胞分化抗原);
PBS缓冲液:磷酸盐平衡生理盐水;
TMB:3,3',5,5'-四甲基联苯胺。
实验方法:用ELISA方法,在体外Jurkat细胞上检测化合物对SLP76的376位丝氨酸磷酸化的抑制水平。
实验步骤:
1.细胞准备:收获对数生长期的Jurkat细胞,调整至合适的细胞浓度;每孔81μL细胞悬液加至96孔板中。
2.药物稀释和加药:
1)配制10倍药物溶液,最高浓度为3μM,3倍稀释,6个浓度;
2)在接种有细胞的96孔板中每孔加入9μL药物溶液,每个药物浓度设置两个复孔。将96孔板中的细胞置于37℃、5%CO
2条件下培养1h。
3.细胞刺激:每孔加入10μL 50μg/mL的CD3抗体处理30min,裂解细胞进行pSLP76检测。
4.细胞收集、裂解
1)将细胞吹起转移到离心管中,3000rpm 4℃离心3min;
2)弃上清液,加入100μL/孔预冷的PBS缓冲液重悬,3000rpm 4℃离心3min;
3)弃上清液,加入100μL/管细胞裂解液;
4)超声裂解5min,14000rpm离心5min。
5.pSLP76检测
1)转移50μL/孔样品上清液到96孔板中;
2)加入50μL/孔混合抗体;
3)室温震荡1h;
4)弃上清液,用清洗液清洗3次,200μL/孔;
5)加入100μL/孔TMB底物,室温震荡15min;
6)加入100μL/孔终止液,30min内在450nm下检测。
6、数据处理
使用GraphPad Prism 5.0软件分析数据,利用非线性S曲线回归来拟合数据得出剂量-效应曲线,并由此计算IC
50值。
pSLP76抑制(%)=(测试物孔读数-细胞不加CD3孔读数均值)/(细胞加CD3孔读数均值-细胞不加CD3孔读数均值)×100%
实验结论
实验结果证明,本发明化合物对MAP4K1/HPK1下游蛋白SLP76的376位丝氨酸磷酸化有很好的抑制活性,例如化合物1、化合物10、化合物11、化合物12、化合物14-1、化合物15、化合物23-1、化合物26、化合物49、化合物50、化合物53、化合物55、化合物58、化合物63、化合物64等的IC
50值均小于100nM,即本发明化合物对HPK1具有很好的抑制活性。
Claims (14)
- 式(I)所示化合物、其药学上可接受的盐或其立体异构体,其中,X 1、Y 1分别独立地选自-C(R 2)(R 3)-、-O-、-N(R 4)-或-S-;X 2、X 3、X 4分别独立地选自-C(R 2)-、-O-、-N-、-N(R 4)-或-S-;Y 2、Y 4分别独立地选自-C(R 2)或-N-;Y 3选自-C(R 5)或-N-;Y 5选自-C(R 6);Y 6选自-C(R 7)或-N-;各R 2、R 3、各R 4分别独立地选自氢、卤素、羟基、巯基、氨基、硝基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基;R 5和R 7中有一个与R 6以及和它们各自相连的环原子一起形成任选被1-5个Q1取代的3-10元环烷基、3-10元杂环基、6-10元芳基或5-10元杂芳基;未成环的R 5或R 7选自氢、卤素、羟基、巯基、氨基、硝基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基;R 1选自氢、卤素、羟基、硝基、氰基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、-NR aR b、-OR a、-SR a、-NR a-C(O)-R b-、-C(O)R a、-C(O)NR a、-C(O)OR a或任选被取代基取代的以下基团:-(CH 2) p-3-10元环烷基、-(CH 2) p-3-10元杂环基、-(CH 2) p-5-10元杂芳基、-(CH 2) p-6-10元芳基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1- 6烷氧基或卤代C 1-6烷基;各Q1分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、-NR aR b、-OR a、-SR a、-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-3个Q2取代的以下基团:C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基、-(CH 2) m-3-10元环烷基、-(CH 2) m-3-10元杂环基、-(CH 2) m-5-10元杂芳基或-(CH 2) m-6-10元芳基;所述Q2分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、C 1- 6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、3-10元环烷基、3-10元杂环基、5-10元杂芳基或6-10元芳基;各R a、各R b分别独立地选自氢、卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1- 6烷氧基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷硫基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、羟基C 1-6烷氧基、羟基C 1-6烷硫基、氨基C 1-6烷氧基、氨基C 1-6烷硫基或任选被取代基取代的以下基团:-(CH 2) m-3-10元环烷基、-(CH 2) m-3-10元杂环基、-(CH 2) m-5-10元杂芳基、-(CH 2) m-6-10元芳基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷基;各m、各p分别独立地选自0、1、2、3、4或5。
- 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体,其具有通式(II-1)或通式(II-2)所示的结构:其中,各R 2、各R 3、各R 4、R 5、R 7分别独立地选自氢、卤素、羟基、巯基、氨基、硝基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基;R 1选自氢、卤素、羟基、硝基、氰基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、-NR aR b、-OR a、-SR a、-NR a-C(O)-R b-、-C(O)R a、-C(O)NR a、-C(O)OR a或任选被取代基取代的以下基团:-(CH 2) p-3-10元环烷基、-(CH 2) p-3-10元杂环基、-(CH 2) p-5-10元杂芳基、-(CH 2) p-6-10元芳基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1- 6烷氧基或卤代C 1-6烷基;环A选自3-10元环烷基、3-10元杂环基、6-10元芳基或5-10元杂芳基;各Q1分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、-NR aR b、-OR a、-SR a、-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-3个Q2取代的以下基团:C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基、-(CH 2) m-3-10元环烷基、-(CH 2) m-3-10元杂环基、-(CH 2) m-5-10元杂芳基或-(CH 2) m-6-10元芳基;所述Q2分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、C 1- 6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、3-10元环烷基、3-10元杂环基、5-10元杂芳基或6-10元芳基;各R a、各R b分别独立地选自氢、卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1- 6烷氧基、C 1-6烷基氨基、二(C 1-6烷基)氨基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷硫基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、羟基C 1-6烷氧基、羟基C 1-6烷硫基、氨基C 1-6烷氧基、氨基C 1-6烷硫基或任选被取代基取代的以下基团:-(CH 2) m-3-10元环烷基、-(CH 2) m-3-10元杂环基、-(CH 2) m-5-10元杂芳基、-(CH 2) m-6-10元芳基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷基;各m、各n、各p分别独立地选自0、1、2、3、4或5;X 1、X 2、X 3、X 4、Y 1、Y 2、Y 3、Y 4、Y 5、Y 6如权利要求1所定义。
- 如权利要求2所述的化合物、其药学上可接受的盐或其立体异构体,其中,各R 2、R 3、各R 4、R 5、R 7分别独立地选自氢、卤素、羟基、巯基、氨基、硝基、氰基、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基或卤代C 1-4烷氧基;R 1选自氢、卤素、羟基、硝基、氰基、C 1-4烷基、卤代C 1-4烷基、羟基C 1-4烷基、氨基C 1-4烷基、-NR aR b、-OR a、-SR a、-NR a-C(O)-R b-、-C(O)R a、-C(O)NR a、-C(O)OR a或任选被取代基取代的以下基团:-(CH 2) p-3-6元环烷基、-(CH 2) p-3-6元杂环基、-(CH 2) p-5-8元杂芳基、-(CH 2) p-苯基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1-6烷氧基 或卤代C 1-6烷基;环A选自5-10元环烷基、5-10元杂环基、6-10元芳基或5-10元杂芳基;各Q1分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、-NR aR b、-OR a、-SR a、-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-3个Q2取代的以下基团:C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基-C 1-4烷基、-(CH 2) m-3-8元环烷基、-(CH 2) m-3-8元杂环基、-(CH 2) m-5-8元杂芳基或-(CH 2) m-苯基;所述Q2分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、3-8元环烷基、3-8元杂环基、5-8元杂芳基或苯基;各R a、各R b分别独立地选自氢、卤素、羟基、硝基、氨基、氰基、羧基、C 1-4烷基、C 1- 4烷氧基、C 1-4烷基氨基、二(C 1-4烷基)氨基、卤代C 1-4烷基、羟基C 1-4烷基、氨基C 1-4烷基、C 1-4烷硫基、卤代C 1-4烷氧基、卤代C 1-4烷硫基、羟基C 1-4烷氧基、羟基C 1-4烷硫基、氨基C 1-4烷氧基、氨基C 1-4烷硫基或任选被取代基取代的以下基团:-(CH 2) m-3-8元环烷基、-(CH 2) m-3-8元杂环基、-(CH 2) m-5-8元杂芳基、-(CH 2) m-苯基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷基;各m、各n、各p分别独立地选自0、1、2或3。
- 如权利要求1-3任一项所述的化合物、其药学上可接受的盐或其立体异构体,其具有通式(III-1)或通式(III-2)所示的结构:其中,Y 1选自-C(R 2)(R 3)-、-O-、-N(R 4)-或-S-;Y 4选自-C(R 2)或-N-;Y 3选自-C(R 5)或-N-;Y 6选自-C(R 7)或-N-;X 2、X 3、X 4分别独立地选自-C(R 2)-、-O-、-N-、-N(R 4)-或-S-;各R 2、R 3、R 4、R 5、R 7分别独立地选自氢、卤素、C 1-4烷基或卤代C 1-4烷基;R 1选自氢、卤素、硝基、氰基、C 1-4烷基、卤代C 1-4烷基、3-6元环烷基、3-6元杂环基、-NR a-C(O)-R b-、-NR aR b、-OR a或任选被取代基取代的以下基团:-(CH 2) p-3-6元环烷基、-(CH 2) p-3-6元杂环基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-4烷基、C 1-4烷氧基或卤代C 1-4烷基;各Q1分别独立地选自卤素、硝基、氨基、氰基、羧基、-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-2个Q2取代的如下基团:C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基-C 1-4烷基、-(CH 2) m-3-6元环烷基、-(CH 2) m-3-6元杂环基、-(CH 2) m-5-6元杂芳基或-(CH 2) m-苯基;所述Q2分别独立地选自卤素、羟基、硝基、氨基、氰基、羧基、C 1-4烷基、C 1-4烷氧基或羟基C 1-4烷基;各R a分别独立地选自氢、甲基、乙基、丙基、异丙基、甲氧基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、三氟乙氧基、三氟甲氧基或任选被取代基取代的以下基团:环丙基、环丁基、环戊基、环己基、氧杂环丙基、氧杂环丁基、氮杂环丙基、氮杂环丁基、四氢呋喃基、哌啶基、哌嗪基、四氢吡咯基、吡唑烷基或咪唑烷基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、甲基、乙基、丙基、异丙基或三氟甲基;各R b分别独立地选自氢或C 1-4烷基;各m、各n、各p分别独立地选自0、1、2或3。
- 如权利要求1-3任一项所述的化合物、其药学上可接受的盐或其立体异构体,其中:各R 2、R 3、各R 4、R 5、R 7分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基或三氟甲基;R 1选自氢、氟、氯、溴、氰基、硝基、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基、三氟甲基、环丙基、环丁基、环戊基、环己基、氮杂环丙基、氧杂环丙基、氮杂环丙基、氮杂环丁基、氧杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、-NR a-C(O)-R b-、-NR aR b或-OR a,优选选自-NR aR b;各Q1分别独立地选自卤素、-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-2个Q2取代的如下基团:甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、丙氧基丙基、异丙氧基甲基、异丙氧基乙基、-(CH 2) m-环丙基、-(CH 2) m-环丁基、-(CH 2) m-环戊基、-(CH 2) m-环己基、-(CH 2) m-氧杂环丙基、-(CH 2) m-氧杂环丁基、-(CH 2) m-氮杂环丙基、-(CH 2) m-氮杂环丁基、-(CH 2) m-四氢呋喃基、-(CH 2) m-氧杂环己基、-(CH 2) m-四氢吡喃基、-(CH 2) m-吡咯烷基、-(CH 2) m-哌啶基、-(CH 2) m-哌嗪基、-(CH 2) m-吡啶基、-(CH 2) m-嘧啶基、-(CH 2) m-哒嗪基、-(CH 2) m-吡嗪基;所述Q2分别独立地选自氟、氯、溴、羟基、氨基、氰基、羧基、硝基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、羟基甲基、羟基乙基或羟基丙基;各R a分别独立地选自氢、甲基、乙基、丙基、异丙基、甲氧基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、三氟乙氧基、三氟甲氧基或任选被取代基取代的以下基团:环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、哌啶基、哌嗪基、四氢吡咯基、吡唑烷基或咪唑烷基;所述取代基选自卤素、羟基、硝基、氨基、氰基、羧基、甲基、乙基、丙基、异丙基或三氟甲基;各R b分别独立地选自氢、甲基、乙基、丙基或异丙基;各m、各n分别独立地选自0、1、2或3。
- 如权利要求1-5任一项所述的化合物、其药学上可接受的盐或其立体异构体,其中,X 2、X 3、X 4中的一个选自S、O、N或-N(R 4)-,另两个分别独立地是-C(R 2)-。
- 如权利要求8所述的化合物、其药学上可接受的盐或其立体异构体,其中,R 1选自-NR aR b、-OR a、-SR a、-NH-C(O)-R b-、或任选被取代基取代的以下基团:-(CH 2) p-3-6元环烷基、-(CH 2) p-3-6元杂环基;所述取代基选自卤素、C 1-4烷基或卤代C 1-4烷基;各R 4分别独立地选自氢、卤素、C 1-4烷基或卤代C 1-4烷基;各Q1分别独立地选自-C(O)R a、-C(O)OR a、-C(O)NR a或任选被1-2个Q2取代的如下基团:C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基-C 1-4烷基、3-6元环烷基、3-6元杂环基、5-6元杂芳基或苯基;所述Q2分别独立地选自卤素、羟基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基或羟基C 1-4烷基;各R a分别独立地选自氢、卤素、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、或任选被取代基取代的以下基团:3-6元环烷基、3-6元杂环基;所述取代基选自卤素、羟基、C 1-6烷基或卤代C 1-6烷基;各R b分别独立地选自氢或C 1-4烷基;各n、各p分别独立地选自0、1或2。
- 如权利要求9所述的化合物、其药学上可接受的盐或其立体异构体,其中,R 1选自氮杂环丁基、氧杂环丁基、-NR a-C(O)-R b-、-NR aR b或-OR a;各R 4分别独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基或三氟甲基;各Q1分别独立地选自-C(O)R a、-C(O)OR a或任选被1-2个Q2取代的如下基团:甲基、乙基、丙基、异丙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基丙基、丙氧基甲基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、四氢呋喃基、氧杂环己基、四氢吡喃基、氮杂环丙基、氮杂环丁基、吡咯烷基、吡啶基或哒嗪基;所述Q2分别独立地选自氟、氯、溴、羟基、氨基、氰基、羧基、硝基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或三氟甲基;各R a分别独立地选自氢、甲基、乙基、丙基、异丙基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、三氟乙氧基、三氟甲氧基或任选被取代基取代的以下基团:环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、哌啶基、哌嗪基、四氢吡咯基、吡唑烷基或咪唑烷 基;所述取代基选自卤素、羟基、甲基、乙基、丙基、异丙基或三氟甲基;各R b分别独立地选自氢、甲基、乙基、丙基或异丙基。
- 含有权利要求1-11任一项所述的化合物、其药学上可接受的盐或其立体异构体的药物制剂,其特征在于,包含一种或多种药学上可接受的赋形剂,该药物制剂为药学上可接受的任一剂型。
- 含有权利要求1-11任一项所述的化合物、其药学上可接受的盐或其立体异构体的药物组合物,其特征在于,包含一种或多种第二治疗活性剂,所述的第二活性治疗剂选自有丝***抑制剂、烷化剂、抗代谢物、反义DNA或RNA、抗肿瘤抗生素、生长因子抑制剂、信号传导抑制剂、细胞周期抑制剂、酶抑制剂、类维生素A受体调控剂、蛋白酶体抑制剂、拓扑异构酶抑制剂、生物应答调节剂、激素类药物、血管再生抑制剂、细胞生长抑制剂、靶向抗体、HMG-CoA还原酶抑制剂和异戊二烯基蛋白质转移酶抑制剂。
- 权利要求1-11任一项所述的化合物、其药学上可接受的盐或其立体异构体、权利要求12所述的药物制剂、或权利要求13所述的药物组合物在制备用于治疗和/或预防由HPK1所介导的疾病及相关病症的药物中的应用,所述由HPK1所介导的疾病及相关病症选自癌症或良性肿瘤,所述癌症选自肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子***、子宫内膜癌、直肠癌、肝癌、肾癌、食管腺癌、食管鳞状细胞癌、***癌、甲状腺癌、雌性生殖道癌、淋巴瘤、神经纤维瘤、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、小细胞肺癌、非小细胞肺癌、胃肠道间质瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、白血病、胶质瘤或肉瘤。
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US11925631B2 (en) | 2018-10-31 | 2024-03-12 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds |
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