CN116888127A - Tri-fused ring HPK1 inhibitor and application thereof - Google Patents
Tri-fused ring HPK1 inhibitor and application thereof Download PDFInfo
- Publication number
- CN116888127A CN116888127A CN202280012271.1A CN202280012271A CN116888127A CN 116888127 A CN116888127 A CN 116888127A CN 202280012271 A CN202280012271 A CN 202280012271A CN 116888127 A CN116888127 A CN 116888127A
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- CN
- China
- Prior art keywords
- alkyl
- amino
- hydroxy
- alkoxy
- membered
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229940125962 HPK1 kinase inhibitor Drugs 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 235
- 150000003839 salts Chemical class 0.000 claims abstract description 56
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 16
- -1 hydroxy, mercapto, amino Chemical group 0.000 claims description 583
- 125000000217 alkyl group Chemical group 0.000 claims description 265
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 115
- 125000003545 alkoxy group Chemical group 0.000 claims description 112
- 229910052736 halogen Inorganic materials 0.000 claims description 103
- 150000002367 halogens Chemical class 0.000 claims description 103
- 229910052739 hydrogen Inorganic materials 0.000 claims description 94
- 239000001257 hydrogen Substances 0.000 claims description 94
- 125000005843 halogen group Chemical group 0.000 claims description 84
- 150000002431 hydrogen Chemical class 0.000 claims description 79
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 72
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 64
- 125000001424 substituent group Chemical group 0.000 claims description 64
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 63
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 61
- 125000000623 heterocyclic group Chemical group 0.000 claims description 58
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 57
- 229910052757 nitrogen Inorganic materials 0.000 claims description 55
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 51
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 43
- 125000003566 oxetanyl group Chemical group 0.000 claims description 36
- 125000006413 ring segment Chemical group 0.000 claims description 32
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 29
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- 229910052801 chlorine Inorganic materials 0.000 claims description 29
- 229910052731 fluorine Inorganic materials 0.000 claims description 29
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 28
- 229910052794 bromium Inorganic materials 0.000 claims description 28
- 239000000460 chlorine Substances 0.000 claims description 28
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- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- 125000002393 azetidinyl group Chemical group 0.000 claims description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 17
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 17
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- 206010028980 Neoplasm Diseases 0.000 claims description 16
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- 125000004193 piperazinyl group Chemical group 0.000 claims description 16
- 125000003386 piperidinyl group Chemical group 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 15
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 14
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- 238000011282 treatment Methods 0.000 claims description 10
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- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 9
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- 125000006001 difluoroethyl group Chemical group 0.000 claims description 8
- 125000003652 trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
- 125000006225 propoxyethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
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- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 6
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- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 6
- 239000003112 inhibitor Substances 0.000 claims description 6
- 125000006229 isopropoxyethyl group Chemical group [H]C([H])([H])C([H])(OC([H])([H])C([H])([H])*)C([H])([H])[H] 0.000 claims description 6
- 125000006233 propoxy propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])OC([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
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- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 4
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- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
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- 125000004076 pyridyl group Chemical group 0.000 claims description 4
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 108090000623 proteins and genes Proteins 0.000 claims description 3
- 102000004169 proteins and genes Human genes 0.000 claims description 3
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 3
- TVEXGJYMHHTVKP-UHFFFAOYSA-N 6-oxabicyclo[3.2.1]oct-3-en-7-one Chemical group C1C2C(=O)OC1C=CC2 TVEXGJYMHHTVKP-UHFFFAOYSA-N 0.000 claims description 2
- 208000036764 Adenocarcinoma of the esophagus Diseases 0.000 claims description 2
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- FDBYIYFVSAHJLY-UHFFFAOYSA-N resmetirom Chemical compound N1C(=O)C(C(C)C)=CC(OC=2C(=CC(=CC=2Cl)N2C(NC(=O)C(C#N)=N2)=O)Cl)=N1 FDBYIYFVSAHJLY-UHFFFAOYSA-N 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
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 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
- 230000002269 spontaneous effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- CTEOEMPYRPQTDU-UHFFFAOYSA-N tert-butyl 1h-azepine-3-carboxylate Chemical compound CC(C)(C)OC(=O)C1=CNC=CC=C1 CTEOEMPYRPQTDU-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
- 150000003866 tertiary ammonium salts Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 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
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000002992 thymic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000009258 tissue cross reactivity Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
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- 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
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- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a tricyclic HPK1 inhibitor compound, a pharmaceutically acceptable salt or stereoisomer thereof, a pharmaceutical composition and a preparation containing the compound, the pharmaceutically acceptable salt or stereoisomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt or stereoisomer thereof, and application of the compound, the pharmaceutically acceptable salt or stereoisomer thereof.
Description
The invention belongs to the technical field of medicines, and in particular relates to a tricyclic HPK1 compound shown in a general formula (I), pharmaceutically acceptable salts thereof and stereoisomers thereof, a pharmaceutical composition and a preparation containing the compound, the pharmaceutically acceptable salts thereof and stereoisomers thereof, a method for preparing the compound, the pharmaceutically acceptable salts thereof and stereoisomers thereof, and application of the compound, the pharmaceutically acceptable salts thereof and stereoisomers thereof.
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. TCRs recognize MHC (major histocompatibility complex) on the surface of antigen presenting cells, and thus recognize signals transmitted to the interior of the cell. The signal transmission is followed by activation of the downstream signal pathway. Typical intracellular signals for TCR activation include MAPK (mitogen activated protein kinase), PKC (protein kinase C), and calcium ion signaling pathways. Activation of these signals ultimately activates specific gene expression of T cells, causing proliferation of the cells and differentiation of the T cells into effector T cells. Endogenous or adoptive transfer of effector T cells is an important mediator of anti-tumor immunity. Continued antigen exposure results in progressive differentiation of T cells into depleted states characterized by a hierarchical loss of effector function and proliferative capacity, as well as significant transcriptional, epigenetic and metabolic changes. How to prevent T cell depletion and expand effector T cell function is one of the most urgent problems in tumor immunology at present.
Hematopoietic progenitor kinase HPK1 (HematopoieticProgenitor Kinase 1) is an immunosuppressive regulatory kinase that is expressed restrictively in hematopoietic stem cells. HPK1 is a negative signal modulator of T Cell Receptor (TCR). Upon TCR activation, cytoplasmic HPK1 is recruited to the vicinity of the cell membrane, and activated HPK1 phosphorylates the adaptor protein SLP76, thereby activating SLP76 as a docking site for negative regulator protein 14-3-3, ultimately leading to destabilization of the TCR signaling complex, thereby down-regulating TCR signaling. Literature (Shu et al, nature Immunology (2007) 8:84-91) discloses that HPK1 deficiency results in increased TCR-induced SLP-76 and Erk phosphorylation, increased Ca flux and increased production of cytokines and antigen-specific antibodies, indicating that HPK1 down regulates TCR signaling and T cell mediated immune responses. In addition, sawasdi kosol et al found HPK1 (-/-) T cells to be resistant to prostaglandin PGE2 inhibition and apoptosis (Sawasdi kosol et al Cancer immunol. Immunother. (2010) 59:419-429). The university of Qinghua Liao Xue topic group 2020 reports the functional significance of HPK1 in T Cell immunotherapy, [ Siet al, hematopoietic Progenitor Kinase1 (HPK 1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies, cancer Cell (2020) ] researchers first analyzed in published tumor databases that MAP4K1 (encoding HPK 1) exhibited strong positive correlation with signaling molecules associated with T Cell depletion (e.g., PDCD1, TIGIT, CTLA4, LAG3, etc.). Patients with low expression of MAP4K1 have a longer survival period, which is significantly shown in Low Grade Glioma (LGG), invasive breast cancer (BRAC) and other tumors. Next, researchers selected multiple myeloma tissue biopsies, and sorted to measure the protein expression of HPK1 and immunosuppressive molecules in T cells, and experimental results revealed that expression of HPK1 was up-regulated in depleted T cells. The experimental results show that HPK1 has a positive correlation with tumor-infiltrating T cell depletion, and HPK1 may be an important kinase for regulating T cell depletion and inhibiting anti-tumor immune response.
HPK1 is also known as MAP4K1, a member belonging to the MAP4K family, among which are other members, MAP4K2 (GCK kinase), MAP4K3 (GLK kinase), MAP4K4 (HGK kinase), MAP4K5 (KHS kinase) and MAP4K6 (MINK kinase). Wherein the biological effects of GLK kinase are directly opposite to those of HPK1, GLK may promote activation of the TCR pathway by binding to a downstream adaptor protein. Whereas the loss of HGK kinase has been found in the literature [ Huai-Chia Chuang et al, chapter Seven-MAP4K Family Kinases in Immunity and Inflammation, advances in Immunology,2016 (129) 277-314 ] to lead to spontaneous systemic inflammation and type 2 diabetes in mice, the role of other kinases in the family is temporarily unclear. To ensure better safety, it is desirable to find HPK1 kinase inhibitors with high selectivity for other members of the MAP4K family.
At present, the research of the target drug is still in the clinical experimental stage, no drug is marketed yet, and the development of the HPK1 kinase inhibitor with high selectivity, high activity and high safety has important clinical significance for better meeting clinical requirements.
Disclosure of Invention
The invention aims to provide an HPK1 inhibitor compound with a novel structure and good inhibition activity on HPK 1. Furthermore, the compounds can be used for inhibiting HPK1 kinase activity, thereby enhancing the immunity of organisms to tumors. Furthermore, the compounds are useful for the treatment or prophylaxis of diseases which are mediated by HPK1, in particular cancer. The compound has good inhibition effect on various cancer cells and good drug-forming property.
The technical scheme of the invention is as follows:
in one aspect, the present invention provides a compound of the following formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
wherein,
X 1 、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 、Y 4 Are each independently selected from-C (R) 2 ) or-N-;
Y 3 selected from-C (R) 5 ) or-N-;
Y 5 selected from-C (R) 6 );
Y 6 Selected from-C (R) 7 ) or-N-;
each R is 2 、R 3 Each R is 4 Are each independently selected from hydrogen, halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 An alkoxy group;
R 5 and R is 7 One of which is with R 6 Together with the ring atoms to which they are each attached form a 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl group optionally substituted with 1-5Q 1; r not forming a ring 5 Or R is 7 Selected from hydrogen, halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 An alkoxy group;
R 1 selected from hydrogen, halogen, hydroxy, 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 the following groups optionally substituted with substituents: - (CH) 2 ) p -3-10 membered cycloalkyl, - (CH) 2 ) p -3-10 membered heterocyclyl, - (CH) 2 ) p -5-to 10-membered heteroaryl, - (CH) 2 ) p -6-10 membered aryl; the substituents are selected fromHalogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1- 6 Alkoxy or halo C 1-6 An alkyl group;
each Q1 is independently selected from halogen, hydroxy, nitro, amino, cyano, carboxy, -NR a R b 、-OR a 、-SR a 、-C(O)R a 、-C(O)OR a 、-C(O)NR a Or optionally substituted with 1-3Q 2: c (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-to 10-membered heteroaryl or- (CH) 2 ) m -6-10 membered aryl; the Q2 groups are each independently selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1- 6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl;
each R is a Each R is b Are each independently selected from hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1- 6 Alkoxy, C 1-6 Alkylamino, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo 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 optionally substituted with substituents: - (CH) 2 ) m -3-10 membered cycloalkyl, - (CH) 2 ) m -3-10Membered heterocyclyl, - (CH) 2 ) m -5-to 10-membered heteroaryl, - (CH) 2 ) m -6-10 membered aryl; the substituents are selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 An alkyl group;
each m, each p is independently selected from 0, 1, 2, 3, 4 or 5.
In certain embodiments, the compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, has a structure of formula (II-1) or formula (II-2)
Wherein,
X 1 、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 、Y 4 are each independently selected from-C (R) 2 ) or-N-;
Y 3 selected from-C (R) 5 ) or-N-;
Y 6 selected from-C (R) 7 ) or-N-;
each R is 2 Each R is 3 Each R is 4 、R 5 、R 7 Are each independently selected from hydrogen, halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 An alkoxy group;
R 1 selected from hydrogen, halogen, hydroxyNitro, 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 the following groups optionally substituted with substituents: - (CH) 2 ) p -3-10 membered cycloalkyl, - (CH) 2 ) p -3-10 membered heterocyclyl, - (CH) 2 ) p -5-to 10-membered heteroaryl, - (CH) 2 ) p -6-10 membered aryl; the substituents are selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1- 6 Alkoxy or halo C 1-6 An alkyl group;
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, hydroxy, nitro, amino, cyano, carboxy, -NR a R b 、-OR a 、-SR a 、- C(O)R a 、-C(O)OR a 、-C(O)NR a Or optionally substituted with 1-3Q 2: c (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-to 10-membered heteroaryl or- (CH) 2 ) m -6-10 membered aryl; the Q2 groups are each independently selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1- 6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl;
each R is a Each R is b Are each independently selected from hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1- 6 Alkoxy, C 1-6 Alkylamino, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo 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 optionally substituted with substituents: - (CH) 2 ) m -3-10 membered cycloalkyl, - (CH) 2 ) m -3-10 membered heterocyclyl, - (CH) 2 ) m -5-to 10-membered heteroaryl, - (CH) 2 ) m -6-10 membered aryl; the substituents are selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 An alkyl group;
each m, each n, each p is independently selected from 0, 1, 2, 3, 4, or 5.
In certain embodiments, a compound of formula (I), formula (II-1) or formula (II-2), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
X 1 、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 、Y 4 are each independently selected from-C (R) 2 ) or-N-;
Y 3 selected from-C (R) 5 ) or-N-; y is Y 6 Selected from-C (R) 7 ) or-N-;
each R is 2 、R 3 Each R is 4 、R 5 、R 7 Are each independently selected from hydrogen, halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy or halo C 1-4 An alkoxy group;
R 1 selected from hydrogen, halogen, hydroxy, 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 the following groups optionally substituted with substituents: - (CH) 2 ) p -3-6 membered cycloalkyl, - (CH) 2 ) p -3-6 membered heterocyclyl, - (CH) 2 ) p -5-8 membered heteroaryl, - (CH) 2 ) p -phenyl; the substituents are selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 An alkyl group;
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, hydroxy, nitro, amino, cyano, carboxy, -NR a R b 、-OR a 、-SR a 、-C(O)R a 、-C(O)OR a 、-C(O)NR a Or optionally substituted with 1-3Q 2: c (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 groups are each independently selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl or phenyl;
each R is a Each R is b Are each independently selected from hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1- 4 Alkoxy, C 1-4 Alkylamino, di (C) 1-4 Alkyl) amino, halo C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkylthio, halo C 1-4 Alkoxy, halo 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 optionally substituted with substituents: - (CH) 2 ) m -3-8 membered cycloalkyl, - (CH) 2 ) m -3-8 membered heterocyclyl, - (CH) 2 ) m -5-8 membered heteroaryl, - (CH) 2 ) m -phenyl; the substituents are selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 An alkyl group;
each m, each n, each p is independently selected from 0, 1, 2, or 3.
In certain embodiments, a compound of formula (II-1) or formula (II-2), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
X 1 、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 、Y 4 are each independently selected from-C (R) 2 ) -or-N-;
Y 3 selected from-C (R) 5 ) or-N-;
Y 6 selected from-C (R) 7 ) or-N-;
each R is 2 、R 3 Each R is 4 、R 5 、R 7 Are independently selected from hydrogen, halogen, C 1-4 Alkyl or halo C 1-4 An alkyl group;
R 1 selected from hydrogen, halogen, hydroxy, 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 are selected from halogen, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 An alkyl group;
ring A is selected from 5-10 membered cycloalkyl or 5-10 membered heterocyclyl;
each Q1 is independently selected from halogen, hydroxy, nitro, amino, cyano, carboxy, -NR a R b 、-OR a 、-C(O)R a 、-C(O)OR a 、-C(O)NR a Or optionally substituted with 1-3Q 2: c (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 groups are each independently selected from halogen, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl or phenyl;
each R is a Each R is b Are each independently selected from hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1- 4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy or optionally substituted with: - (CH) 2 ) m -3-8 membered cycloalkyl, - (CH) 2 ) m -3-8 membered heterocyclyl; the substituents are selected from halogen, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1- 4 Alkoxy or halo C 1-4 An alkyl group;
each m, each n, each p is independently selected from 0, 1, 2, or 3.
In certain embodiments, X 1 、Y 1 Are each independently selected from-C (R) 2 )(R 3 )-、-O-、-N(R 4 ) -or-S-; each R is 2 Each R is 3 Each R is 4 Are independently selected from hydrogen, halogen, C 1-6 Alkyl or halo C 1-6 An alkyl group.
In certain embodiments, X 1 、Y 1 Are each independently selected from-C (R) 2 )(R 3 ) -, -O-or-N (R) 4 ) -; each R is 2 Each R is 3 Each R is 4 Each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, or trifluoromethyl.
In certain embodiments, X 1 、Y 1 Are each independently selected from CH 2 O or NH.
In certain embodiments, Y 2 、Y 4 Are each independently selected from-C (R) 2 ) or-N-; each R is 2 Are independently selected from hydrogen, halogen, C 1-6 Alkyl or halo C 1-6 An alkyl group.
In certain embodiments, Y 2 、Y 4 Are each independently selected from-C (R) 2 ) or-N-; each R is 2 Each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, or trifluoromethyl.
In certain embodiments, R 7 Selected from hydrogen, halogen, C 1-6 Alkyl or halo C 1-6 An alkyl group.
In certain embodiments, R 7 Selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
In certain embodiments, R 5 Is hydrogen.
In certain embodiments, Y 2 Is N.
In certain embodiments, Y 3 、Y 4 Each independently selected from CH or N.
In certain embodiments, X 2 、X 3 、X 4 Are each independently selected from-C (R) 2 )-、-O-、-N-、-N(R 4 ) -or-S-; each R is 2 Each R is 4 Are independently selected from hydrogen, halogen, C 1-6 Alkyl or halo C 1-6 An alkyl group.
In certain embodiments, X 2 、X 3 、X 4 Are each independently selected from-C (R) 2 )-、-O-、-N-、-N(R 4 ) -or-S-; each R is 2 Each R is 4 Each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, or trifluoromethyl.
In certain embodiments, X 2 、X 3 、X 4 One of them is selected from S, O, N or-N (R 4 ) Two other are each independently-C (R 2 ) -; each R is 2 Each R is 4 Are independently selected from hydrogen, halogen, C 1-6 Alkyl or halo C 1-6 An alkyl group.
In certain embodiments, X 2 、X 3 、X 4 One of them is selected from S, O, N or-N (R 4 ) Two other are each independently-C (R 2 ) -; each R is 2 Each R is 4 Each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, or trifluoromethyl.
In certain embodiments, X 2 、X 3 、X 4 One of them is selected from-C (R 2 ) Two other are each independently S, O, N or-N (R 4 ) -; each R is 2 Each R is 4 Are independently selected from hydrogen, halogen, C 1-6 Alkyl or halo C 1-6 An alkyl group.
In certain embodiments, X 2 、X 3 、X 4 One of them is selected from-C (R 2 ) Two other are each independently S, O, N or-N (R 4 ) -; each R is 2 Each R is 4 Each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, or trifluoromethyl.
In certain embodiments, X 2 、X 3 、X 4 One of them is selected from S or O, and the other two are each independently-C (R 2 ) -; each R is 2 Are independently selected from hydrogen, halogen, C 1-6 Alkyl or halo C 1-6 An alkyl group.
In certain embodiments, X 2 、X 3 、X 4 One of them is selected from S or O, and the other two are each independently-C (R 2 ) -; each R is 2 Are each independently selected from hydrogen, fluorine, chlorine,Bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.
In certain embodiments, X 3 Selected from-C (R) 2 ) -, wherein R is 2 Selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl. In certain embodiments, X 2 、X 3 、X 4 One of them is selected from-C (R 2 ) Two other are each independently N or-N (R 4 ) -; each R is 4 Are independently selected from hydrogen, halogen, C 1-6 Alkyl or halo C 1-6 An alkyl group.
In certain embodiments, X 3 Is N, X 2 And X 4 One of them is-N (R 4 ) -, the other is-C (R 2 )-;R 2 And R is 4 Are independently selected from hydrogen, halogen, C 1-6 Alkyl or halo C 1-6 An alkyl group.
In certain embodiments, R 1 Selected from hydrogen, halogen, nitro, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, - (CH) 2 ) p -3-6 membered cycloalkyl, - (CH) 2 ) p -3-6 membered heterocyclyl, -NR a -C(O)-R b -、-NR a R b OR-OR a The method comprises the steps of carrying out a first treatment on the surface of the Each p is independently selected from 0, 1, 2 or 3.
In certain embodiments, R 1 Selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -NR a -C(O)-R b -、-NR a R b 、-OR a Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, oxetanyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl or tetrahydrothiophenyl.
In certain embodiments, ring A is selected from 5-8 membered cycloalkyl or 5-8 membered heterocyclyl.
In certain embodiments, ring A is selected from a 5-8 membered cycloalkyl or a 5-8 membered nitrogen containing heterocyclyl.
In certain embodiments, ring A is selected from 5-8 membered monocycloalkyl, 5-8 membered monocycloheterocyclyl, 6-8 membered fused heterocyclyl, 6-8 membered bridged heterocyclyl, or 6-8 membered spiroheterocyclyl.
In certain embodiments, ring A is selected from 7-8 membered monocycloalkyl, 7-8 membered monocycloheterocyclyl or 8 membered nitrogen-containing bridged heterocyclyl.
In certain embodiments, ring A is selected from a 7-8 membered nitrogen containing mono-heterocyclyl or a 7-8 membered oxygen containing mono-heterocyclyl.
In certain embodiments, each Q1 is independently selected from halogen, hydroxy, nitro, hydroxy, amino, cyano, carboxy, -C (O) R a 、-C(O)OR a 、-C(O)NR a Or optionally substituted with 1-3Q 2: c (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 groups are each independently selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, hydroxy C 1-4 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl or phenyl.
In certain embodiments, each Q1 is independently selected from the group consisting of-C (O) R a 、-C(O)OR a 、-C(O)NR a Or optionally substituted with 1-3Q 2 groups: c (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 groups are each independently selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or hydroxy C 1-4 An alkyl group.
In certain embodiments, each Q1 is independently selected from fluorine, chlorine, bromine, amino, cyano, hydroxyl, carboxyl, nitro, -C (O) R a 、-C(O)OR a 、-C(O)NR a Or optionally substituted with 1-3Q 2 groups: 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 -an oxetanyl, - (CH) 2 ) m -oxetanyl, - (CH) 2 ) m Tetrahydrofuranyl, - (CH) 2 ) m -an oxetanyl, - (CH) 2 ) m Tetrahydropyranyl, - (CH) 2 ) m Azacyclopropyl, - (CH) 2 ) m Azacyclobutyl, - (CH) 2 ) m Pyrrolidinyl, - (CH) 2 ) m Piperidinyl, - (CH) 2 ) m Piperazinyl, - (CH) 2 ) m Tetrahydropyrrolyl, - (CH) 2 ) m Pyrazolidinyl, - (CH) 2 ) m Imidazolidinyl radical, - (CH) 2 ) m Piperazinyl, - (CH) 2 ) m Piperidinyl, - (CH) 2 ) m Pyrazolyl, - (CH) 2 ) m Pyrrolyl, - (CH) 2 ) m Imidazolyl, - (CH) 2 ) m -pyridinyl, - (CH) 2 ) m Pyrimidinyl, - (CH) 2 ) m Pyridazinyl, - (CH) 2 ) m Pyrazinyl or- (CH) 2 ) m -phenyl; the Q2 groups are each independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoromethyl or trifluoromethyl.
In certain embodiments, each Q1 is independently selected from the group consisting of-C (O) R a 、-C(O)OR a 、-C(O)NR a Or optionally substituted with 1-3Q 2 groups: 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 -an oxetanyl, - (CH) 2 ) m -oxetanyl, - (CH) 2 ) m Tetrahydrofuranyl, - (CH) 2 ) m -an oxetanyl, - (CH) 2 ) m Tetrahydropyranyl, - (CH) 2 ) m Azacyclopropyl, - (CH) 2 ) m Azacyclobutyl, - (CH) 2 ) m Pyrrolidinyl, - (CH) 2 ) m Piperidinyl, - (CH) 2 ) m Piperazinyl, - (CH) 2 ) m -pyridinyl, - (CH) 2 ) m Pyrimidinyl, - (CH) 2 ) m Pyridazinyl, - (CH) 2 ) m -pyrazinyl; the Q2 groups are each independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano,Carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoromethyl or trifluoromethyl.
In certain embodiments, each R a Each R is b Are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di (C) 1-4 Alkyl) amino, halo 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 optionally substituted with: - (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, hydroxy, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy or halo C 1-4 An alkyl group.
In certain embodiments, each R a Are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy or optionally substituted with: - (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 halo C 1-4 An alkyl group; each R is b Independently selected from hydrogen or C 1-4 An alkyl group.
In certain embodiments, each R a Independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, monofluoroethyl, difluoroethyl, trifluoroethylA trifluoroethoxy group or a group optionally substituted with a substituent such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, azetidinyl, aziridinyl, tetrahydropyrrolyl, pyrazolidinyl, imidazolidinyl, piperazinyl or piperidinyl; the substituent is selected from fluorine, chlorine, bromine, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, isopropyl, methoxy, ethoxy or trifluoromethyl; each R is b Each independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.
In certain embodiments, each R a Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, or a group optionally substituted with a substituent: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl or pyrrolidinyl; the substituent is selected from fluorine, chlorine, bromine, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, isopropyl, methoxy, ethoxy or trifluoromethyl; each R is b Each independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.
In certain embodiments, the compounds of formula (I), formula (II-1), formula (II-2), pharmaceutically acceptable salts thereof, or stereoisomers thereof, have the structure shown in formula (III-1) or formula (III-2) below:
wherein Y is 1 Selected from-C (R) 2 )(R 3 )-、-O-、-N(R 4 ) -or-S-;
Y 4 selected from-C (R) 2 ) or-N-;
Y 3 selected from-C (R) 5 ) or-N-;
Y 6 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 is 2 、R 3 、R 4 、R 5 、R 7 Are independently selected from hydrogen, halogen, C 1-4 Alkyl or halo C 1-4 An alkyl group;
R 1 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 heterocyclyl; the substituents are selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy or halo C 1-4 An alkyl group;
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 substituted with 1-2Q 2 groups: c (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 groups are each independently selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or hydroxy C 1-4 An alkyl group;
each R is a Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoromethoxy, or the following groups optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidinyl or imidazolidinyl; the substituent is selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl;
each R is b Independently selected from hydrogen or C 1-4 An alkyl group;
each m, each n, each p is independently selected from 0, 1, 2, or 3.
In certain embodiments, a compound of formula (I), formula (II-1), formula (II-2), formula (III-1) or formula (III-2), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
Y 1 Selected from-C (R) 2 )(R 3 )-、-O-、-N(R 4 ) -or-S-;
Y 4 selected from-C (R) 2 ) or-N-;
Y 3 selected from-C (R) 5 ) or-N-;
Y 6 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 is 2 、R 3 Each R is 4 、R 5 、R 7 Each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, or trifluoromethyl;
R 1 selected from the group consisting of 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 optionally substituted with 1-2Q 2 groups: 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 -an oxetanyl, - (CH) 2 ) m -oxetanyl, - (CH) 2 ) m Azacyclopropyl, - (CH) 2 ) m Azacyclobutyl, - (CH) 2 ) m Tetrahydrofuranyl, - (CH) 2 ) m -an oxetanyl, - (CH) 2 ) m Tetrahydropyranyl, - (CH) 2 ) m Pyrrolidinyl, - (CH) 2 ) m Piperidinyl, - (CH) 2 ) m Piperazinyl, - (CH) 2 ) m -pyridinyl, - (CH) 2 ) m Pyrimidinyl, - (CH) 2 ) m Pyridazinyl, - (CH) 2 ) m -pyrazinyl; the Q2 groups are each independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl or hydroxypropyl; each R is a Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoromethoxy, or the following groups optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidinyl or imidazolidinyl; the substituent is selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl;
Each R is b Each independently selected from hydrogen, methyl, ethyl, propyl or isopropyl;
each m, each n is independently selected from 0, 1, 2 or 3.
In certain embodiments, ring a is selected from Wherein each ring atom in ring a is optionally oxo;
each Q1 is independently selected from the group consisting of-C (O) R a 、-C(O)OR a Or optionally substituted with 1-2Q 2 groups: 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 -an oxetanyl, - (CH) 2 ) m -oxetanyl, - (CH) 2 ) m Tetrahydrofuranyl, - (CH) 2 ) m -an oxetanyl, - (CH) 2 ) m Tetrahydropyranyl, - (CH) 2 ) m Azacyclopropyl, - (CH) 2 ) m Azacyclobutyl, - (CH) 2 ) m Pyrrolidinyl, - (CH) 2 ) m Piperidinyl, - (CH) 2 ) m Piperazinyl, - (CH) 2 ) m -pyridinyl, - (CH) 2 ) m Pyrimidinyl, - (CH) 2 ) m Pyridazinyl, - (CH) 2 ) m -pyrazinyl; the Q2 groups are each independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl or hydroxypropyl;
Each m, each n is independently selected from 0, 1, 2 or 3.
In certain embodiments, ring a is selected from Preferably selected fromPreferably 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 optionally substituted with 1-2Q 2 groups: 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 -an oxetanyl, - (CH) 2 ) m -oxetanyl, - (CH) 2 ) m Tetrahydrofuranyl, - (CH) 2 ) m -an oxetanyl, - (CH) 2 ) m Tetrahydropyranyl, - (CH) 2 ) m Azacyclopropyl, - (CH) 2 ) m Azacyclobutyl, - (CH) 2 ) m Pyrrolidinyl, - (CH) 2 ) m Piperidinyl, - (CH) 2 ) m Piperazinyl, - (CH) 2 ) m -pyridinyl, - (CH) 2 ) m Pyrimidinyl, - (CH) 2 ) m Pyridazinyl, - (CH) 2 ) m -pyrazinyl; the Q2 groups are each independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl or hydroxypropyl;
Each m, each n is independently selected from 0, 1, 2 or 3.
In certain embodiments, each Q1 is independently selected from the group consisting of-C (O) R a 、-C(O)OR a Or optionally substituted with 1-2Q 2 groups: methyl, ethyl, propyl, isopropyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxypropyl, propoxymethyl, propoxyethyl, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, oxetanyl, tetrahydropyranyl, aziridinyl, azetidinyl, pyridinyl or pyridazinyl; the Q2 groups are each independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, or trifluoromethyl.
In certain embodiments, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1) or formula (III-2), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, has a structure represented by formula (IV-1) or formula (IV-2) as follows:
wherein X is 2 、X 3 、X 4 Ring A, R 1 、R 2 、R 4 、R a 、R b Q1, Q2, m, n, p are as defined in any of the preceding schemes.
In certain embodiments, the compounds of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1) or formula (IV-2), pharmaceutically acceptable salts thereof, or stereoisomers thereof, have the structure shown by formula (V-1) or formula (V-2) below:
Wherein X is 3 、X 4 Are each independently selected from-C (R) 2 ) -; ring A, R 1 、R 2 、Q1、Q2、R a 、R b The definition of m, n and p is as in any one of the previous schemes.
In certain embodiments, the compounds of formula (I), formula (II-1), formula (II-2), formula (III-1) or formula (III-2), formula (IV-1) or formula (IV-2), pharmaceutically acceptable salts thereof, or stereoisomers thereof, have the structure shown by formula (V-3) or formula (V-4) below:
wherein X is 2 、X 4 Are each independently selected from-C (R) 2 ) -; ring A, R 1 、R 2 、R 4 、Q1、Q2、R a 、R b The definition of m, n and p is as in any one of the previous schemes.
In certain embodiments, the compounds of formula (I), formula (II-1), formula (II-2), formula (III-1) or formula (III-2), formula (IV-1) or formula (IV-2), pharmaceutically acceptable salts thereof, or stereoisomers thereof, have the structure shown in formula (VI-1) or formula (VI-2) below:
wherein X is 2 、X 3 Are each independently selected from-C (R) 2 ) -; ring A, R 1 、R 2 、Q1、Q2、R a 、R b The definition of m, n and p is as in any one of the previous schemes.
In certain embodiments, a compound of formula (V-1), formula (V-2), formula (V-3), formula (V-4), formula (VI-1) or formula (VI-2), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
X 2 、X 3 、X 4 are each independently selected from-C (R) 2 )-;
Each R is 2 Each R is 4 Are independently selected from hydrogen, halogen, C 1-4 Alkyl or halo C 1-4 An alkyl group;
R 1 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 with 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 halo C 1-4 An alkyl group;
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 optionally substituted with 1-2Q 2 groups: c (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 is independently selected from halogen, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or hydroxy C 1-4 An alkyl group;
each R is a Are independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, or the following optionally substituted with substituents: - (CH) 2 ) m -3-6 membered cycloalkyl, - (CH) 2 ) m -3-6 membered heterocyclyl; the substituents are selected from halogen, hydroxy, C 1-6 Alkyl or halo C 1-6 An alkyl group;
each R is b Independently selected from hydrogen or C 1-4 An alkyl group;
each m, each n, each p is independently selected from 0, 1 or 2.
In certain embodiments, the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, has a structure represented by the following formula (VII-1) or formula (VII-2):
wherein the ring A, R 1 、Q1、Q2、R a 、R b The definition of m, n and p is as in any one of the previous schemes.
In certain embodiments, the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, has a structure represented by the following formula (VII-3) or formula (VII-4):
wherein the ring A, R 1 、Q1、Q2、R a 、R b The definition of m, n and p is as in any one of the previous schemes.
In certain embodiments, the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, has a structure represented by the following formula (VII-5) or formula (VII-6):
wherein the ring A, R 1 、R 4 、Q1、Q2、R a 、R b The definition of m, n and p is as in any one of the previous schemes.
In certain embodiments, the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof, has a structure represented by the following formula (VII-7) or formula (VII-8):
wherein the ring A, R 1 、R 4 、Q1、Q2、R a 、R b The definition of m, n and p is as in any one of the previous schemes.
In certain embodiments, a compound represented by formula (VII-1), formula (VII-2), formula (VII-3), formula (VII-4), formula (VII-5), formula (VII-6), formula (VII-7) or formula (VII-8), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
R 1 Selected from-NR a R b 、-OR a 、-SR a 、-NH-C(O)-R b -, or optionally substitutedThe substituted following groups: - (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 halo C 1-4 An alkyl group;
each R is 4 Are independently selected from hydrogen, halogen, C 1-4 Alkyl or halo C 1-4 An alkyl group;
ring A is selected from Wherein each ring atom in ring a is optionally oxo;
each Q1 is independently selected from the group consisting of-C (O) R a 、-C(O)OR a 、-C(O)NR a Or optionally substituted with 1-2Q 2 groups: c (C) 1-4 Alkyl, 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 phenyl; the Q2 is independently selected from halogen, hydroxy, C 1-4 Alkyl or halo C 1-4 An alkyl group;
each R is a Are independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, or the following optionally substituted with substituents: 3-6 membered cycloalkyl, 3-6 membered heterocyclyl; the substituents are selected from halogen, hydroxy, C 1-6 Alkyl or halo C 1-6 An alkyl group;
each R is b Independently selected from hydrogen or C 1-4 An alkyl group;
each n and each p is independently selected from 0, 1 or 2.
In certain embodiments, R 1 Selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, azetidinyl, oxetanyl, -NR a -C(O)-R b -、-NR a R b OR-OR a Preferably selected from-NR a R b 。
In certain embodiments, a compound represented by formula (VII-1), formula (VII-2), formula (VII-3), formula (VII-4), formula (VII-5), formula (VII-6), formula (VII-7) or formula (VII-8), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
R 1 selected from the group consisting of azetidinyl, oxetanyl, -NR a -C(O)-R b -、-NR a R b OR-OR a Each R is a Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoromethoxy, or the following groups optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidinyl or imidazolidinyl; the substituent is selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl; each R is b Each independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.
Each R is 4 Each 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 the group consisting of-C (O) R a 、-C(O)OR a Or optionally substituted with 1-2Q 2 groups: methyl, ethyl, propyl, isopropyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxypropyl, propoxymethyl, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, oxetanyl, tetrahydropyranyl, aziridinyl, azetidinyl, pyrrolidinyl, pyridinyl or pyridazinyl; the Q2 groups are each independently selected from fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, or trifluoromethyl;
each R is a Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoromethoxy, or the following groups optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidinyl or imidazolidinyl; the substituent is selected from halogen, hydroxy, methyl, ethyl, propyl, isopropyl or trifluoromethyl;
Each R is b Each independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.
In certain embodiments, R 1 Selected from the group consisting of-NH 2 、
In the present embodiments, the hydrogen on the ring nitrogen atom in ring a may be optionally substituted with Q1. In certain embodiments, Q1 replaces one or more hydrogens on the ring nitrogen atom in ring a.
In certain embodiments, each Q1 is independently selected from methyl, ethyl, cyclopropyl, cyclobutyl,
the technical schemes in the invention can be mutually combined to form new technical schemes, and the formed new technical schemes are also included in the scope of the invention.
In certain embodiments, the compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, is selected from the group consisting of:
the present invention also provides a pharmaceutical composition comprising a compound of the present invention, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers and/or diluents; the pharmaceutical composition can be prepared into any clinically or pharmaceutically acceptable dosage form, such as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injection and concentrated solutions for injection), suppositories, inhalants or sprays and the like.
In certain embodiments of the present invention, the above-described pharmaceutical formulations may be administered orally, parenterally, rectally, or pulmonary, etc., to a patient or subject in need of such treatment. For oral administration, the pharmaceutical composition may be formulated into oral preparations, for example, into conventional oral solid preparations such as tablets, capsules, pills, granules, etc.; can also be made into oral liquid preparation such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. may be added. For parenteral administration, the pharmaceutical preparations may also be formulated as injections, including injectable solutions, injectable sterile powders and injectable concentrated solutions. When the injection is prepared, the conventional method in the existing pharmaceutical field can be adopted for production, and when the injection is prepared, no additive can be added, and the proper additive can be added according to the property of the medicine. For rectal administration, the pharmaceutical composition may be formulated as suppositories and the like. For pulmonary administration, the pharmaceutical composition may be formulated as an inhalant or spray, etc.
The pharmaceutically acceptable carrier and/or diluent useful in the pharmaceutical composition or pharmaceutical formulation of the present invention may be any conventional carrier and/or diluent in the pharmaceutical formulation arts, and the choice of the particular carrier and/or diluent will depend on the mode of administration or type and state of disease for the particular patient being treated. The preparation of suitable pharmaceutical compositions for specific modes of administration is well within the knowledge of those skilled in the pharmaceutical arts.
In a further aspect, the invention also relates to the use of a compound of the invention, a pharmaceutically acceptable salt or stereoisomer thereof, for the manufacture of a medicament for the prevention and/or treatment of diseases and related disorders mediated by HPK1, which medicament may be used in combination with one or more other medicaments for the prevention or treatment of diseases and related disorders mediated by HPK 1. The disease and related conditions are selected from cancers, including carcinoma in situ and metastatic cancers, or benign tumors. Further, the cancers include, but are 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 genital 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, and the like.
Further, the present invention also relates to the use of a pharmaceutical formulation comprising a compound of the present invention, a pharmaceutically acceptable salt or a stereoisomer thereof, for the manufacture of a medicament for use in combination with one or more medicaments for the treatment and/or prophylaxis of diseases and related conditions mediated by HPK 1.
In another aspect, the application relates to a medicament comprising a compound of the application, a pharmaceutically acceptable salt or stereoisomer thereof, for use alone or in combination with one or more second therapeutically active agents for use in combination with an HPK1 inhibitor compound of the application in the treatment and/or prevention of diseases and related conditions mediated by HPK 1. Thus, in certain embodiments, the pharmaceutical composition further comprises one or more second therapeutically active agents. In certain embodiments, the second therapeutically active agent is selected from the group consisting of anticancer agents including mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, antitumor antibiotics, growth factor inhibitors, signaling inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormonal agents, angiogenesis inhibitors, cytostatic agents, targeting antibodies, HMG-CoA reductase inhibitors, and prenyl protein transferase inhibitors.
In certain embodiments, the individual components to be combined (e.g., a compound of the application, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and a second therapeutically active agent) can be administered simultaneously or sequentially and separately administered in sequence. For example, the second therapeutically active agent may be administered before, simultaneously with, or after administration of the compound of the application, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Furthermore, the individual components to be combined can also be administered jointly in the form of the same formulation or in the form of separate different formulations.
In another aspect, the invention also provides a method of treating diseases and conditions mediated by HPK1, comprising administering to a patient in need thereof an effective amount of a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, a formulation or a pharmaceutical composition as described above; the diseases and related conditions mediated by HPK1 are as defined above.
By "effective amount" is meant an amount of a drug capable of alleviating, delaying, inhibiting or curing a condition in a subject. The size of the dose administered is determined by the mode of administration of the drug, the pharmacokinetics of the agent, the severity of the disease, the individual sign (sex, weight, height, age) of the subject, etc.
[ detailed description of the invention ]
In the present invention, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art, however, for a better understanding of the present invention, the following definitions of some terms are provided. When the definition and interpretation of terms provided by the present invention are not identical to the meanings commonly understood by those skilled in the art, the definition and interpretation of terms provided by the present invention is in control.
"halogen" as used herein refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
"C" as described in the present invention 1-6 Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms and includes, for example," C 1-4 Alkyl "," C 1-3 Alkyl "," 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 ", and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. "C" as described in the present invention 1-4 Alkyl "means C 1-6 Specific examples of the alkyl group include 1 to 4 carbon atoms.
"C" as described in the present invention 1-6 Alkoxy "means" C 1-6 alkyl-O- ", said" C 1-6 Alkyl "is as defined above. "C" as described in the present invention 1-4 Alkoxy "means" C 1-4 alkyl-O- ", said" C 1-4 Alkyl "is as defined above.
"C" as described in the present invention 1-6 Alkylthio "means" C 1-6 alkyl-S- ", described as" C 1-6 Alkyl "is as defined above. "C" as described in the present invention 1-4 Alkylthio "means" C 1-4 alkyl-S- ", described as" C 1-4 Alkyl "is as defined above.
The invention relates to a hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halogenated C 1-6 Alkyl "means C 1-6 One or more hydrogens in the alkyl group are substituted with one or more hydroxy, amino, or halogen groups, respectively. C (C) 1-6 Alkyl is as defined above
The invention relates to the hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, halo C 1-6 Alkoxy "means" C 1-6 One or more hydrogens in the alkoxy "are substituted with one or more hydroxy, amino, or halogen groups.
The invention relates to the hydroxy C 1-6 Alkylthio, amino C 1-6 Alkylthio, halo C 1-6 Alkylthio "means" C 1-6 One or more hydrogens in the alkylthio group "are substituted with one or more hydroxy, amino, or halogen groups.
"C" as described in the present invention 1-6 Alkylamino, di (C) 1-6 Alkyl) amino "means C respectively 1-6 alkyl-NH-,
"C" as described in the present invention 2-6 Alkenyl "means a straight-chain, branched or cyclic alkenyl group having at least one double bond and having 2 to 6 carbon atoms, and includes, for example," C 2-4 Alkenyl ", and the like. Examples include, but are not limited to: vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1, 3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1, 3-pentadienyl, 1, 4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1, 4-hexadienyl, cyclopentenyl, 1, 3-cyclopentadienyl, cyclohexenyl, 1, 4-cyclohexadienyl and the like.
"C" as described in the present invention 2-6 Alkynyl "refers to straight or branched chain alkynyl groups containing at least one triple bond and having 2 to 6 carbon atoms and includes, 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, and the like.
"3-10 membered cycloalkyl" as used herein refers to a saturated or partially saturated, non-aromatic, monocyclic or polycyclic group containing 3 to 10 carbon atoms. The "monocyclic cycloalkyl" is preferably "3-8 membered monocyclic alkyl", and the "polycyclic cycloalkyl" includes "fused ring group, bridged ring group and spiro ring group", preferably "7-10 membered fused ring alkyl", "7-10 membered bridged ring group" and "7-10 membered spiro ring group".
"3-8 membered monocycloalkyl" as used herein refers to a saturated or partially saturated and non-aromatic monocycloalkyl group containing 3-8 carbon atoms, and includes "3-8 membered saturated monocycloalkyl" and "3-8 membered partially saturated monocycloalkyl"; preferably "3-4 membered monocycloalkyl", "3-5 membered monocycloalkyl", "3-6 membered monocycloalkyl", "3-7 membered monocycloalkyl", "4-5 membered monocycloalkyl", "4-6 membered monocycloalkyl", "4-7 membered monocycloalkyl", "4-8 membered monocycloalkyl", "5-6 membered monocycloalkyl", "5-7 membered monocycloalkyl", "5-8 membered monocycloalkyl", "6-7 membered monocycloalkyl", "6-8 membered monocycloalkyl", "3-6 membered saturated monocycloalkyl", "5-8 membered saturated monocycloalkyl", "5-7 membered saturated monocycloalkyl", "5-6 membered saturated monocycloalkyl", etc., optionally, the ring carbon atoms in the cyclic structure may be oxo. Specific examples of the "3-8 membered saturated monocyclic alkyl group" include, but are not limited to: cyclopropane (cyclopropyl), cyclobutane (cyclobutyl), cyclopentane (cyclopentyl), cyclohexane (cyclohexyl), cycloheptane (cycloheptyl), cyclooctyl (cyclooctyl), and the like; specific examples of the "3-8 membered partially saturated monocyclic alkyl group" include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1, 3-diene, cyclohex-1, 4-diene, cycloheptenyl, cyclohepta-1, 3-dienyl, cyclohepta-1, 4-dienyl, cyclohepta-1, 3, 5-trienyl, cyclooctenyl, cycloocta-1, 3-dienyl, cycloocta-1, 4-dienyl, cycloocta-1, 5-dienyl, cycloocta-1, 3, 5-trienyl, cyclooctatetraenyl and the like.
The 7-10 membered condensed ring group refers to a saturated or partially saturated non-aromatic cyclic group containing 7-10 ring atoms and formed by sharing two or more adjacent carbon atoms by two or more cyclic structures, wherein one ring in the condensed ring can be an aromatic ring, but the whole condensed ring does not have aromaticity; including "8-9 membered fused ring group", "9-10 membered fused ring group", etc., the manner of fusion may be: 5-6 membered cycloalkyl and 5-6 membered cycloalkyl, benzo 5-6 membered saturated cycloalkyl, and the like, optionally, a ring atom in the cyclic structure may be oxo. Examples include, but are not limited to: bicyclo [3.1.0] hexyl, bicyclo [4.1.0] heptyl, bicyclo [2.2.0] hexyl, bicyclo [3.2.0] heptyl, bicyclo [4.2.0] octyl, octahydropentalenyl, octahydro-1H-indenyl, decahydronaphthyl, decatetrahydrophenanthryl, bicyclo [3.1.0] hex-2-enyl, bicyclo [4.1.0] hept-3-enyl, bicyclo [3.2.0] hept-3-enyl, bicyclo [4.2.0] oct-3-enyl, 1,2,3 a-tetrahydropentalenyl, 2, 3a,4,7 a-hexahydro-1H-indenyl, 1,2,3, 4a,5,6, 4 a-octahydronaphthyl, 1,2,4a,5,6,8 a-hexahydronaphthyl, 1,2,3,4, 6,7,8, 10-benzopentalenyl, benzocyclohexyl, benzopentalenyl, and the like.
The term "7-to 10-membered bridged ring radical" as used herein refers to a ring structure having 7 to 10 ring carbon atoms formed by two or more ring structures sharing two non-adjacent carbon atoms with each other. Optionally, carbon atoms in the cyclic structure may be oxo. Specific examples include, but are not limited to: etc.
The "7-to 10-membered spiroheterocyclic group" as used herein refers to a cyclic structure having 7 to 10 ring carbon atoms formed by sharing one carbon atom with two or more cyclic structures. Optionally, carbon atoms in the cyclic structure may be oxo. Specific examples thereof include, but are not limited to: etc.
The "3-to 10-membered heterocyclic group" as used herein means a saturated or partially saturated (containing 1 or 2 double bonds) non-aromatic cyclic group consisting of 3 to 10 carbon atoms and hetero atoms selected from nitrogen, oxygen and sulfur, and the cyclic group may be a single ring or a multi-ring group, in the present invention, the number of hetero atoms in the heterocyclic group is preferably 1,2, 3 or 4, and the nitrogen, carbon or sulfur atoms in the heterocyclic group may be optionally oxidized. The nitrogen atom may optionally be further substituted with other groups to form tertiary or quaternary ammonium salts.
A monocyclic heterocyclic group is preferably a "3-8 membered monocyclic heterocyclic group", which means a saturated or partially saturated and non-aromatic monocyclic ring group containing at least one heteroatom (e.g., containing 1,2, 3,4 or 5) and having 3 to 8 ring atoms, the heteroatom being a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally, a ring atom (e.g., a carbon atom, a nitrogen atom or a sulfur atom) in the ring structure may be oxo. The "3-8 membered monocyclic group" described in the present invention includes "3-8 membered saturated monocyclic group" and "3-8 membered partially saturated monocyclic group". Preferably, the "3-8 membered mono-heterocyclic group" according to the present invention contains 1-3 heteroatoms; preferably, the "3-8 membered mono-heterocyclic group" according to the present invention contains 1-2 hetero atoms, and the hetero atoms are selected from nitrogen atoms and/or oxygen atoms; preferably, the "3-8 membered mono-heterocyclic group" according to the present invention contains 1 nitrogen atom. The "3-8 membered mono-heterocyclic group" is preferably "3-7 membered mono-heterocyclic group", "3-6 membered mono-heterocyclic group", "4-7 membered mono-heterocyclic group", "4-6 membered 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 mono-heterocyclic group", "3-6 membered nitrogen-containing mono-heterocyclic group", "3-6 membered saturated nitrogen-containing mono-heterocyclic group", "5-6 membered saturated nitrogen-containing mono-heterocyclic group", or the like. For example, containing only 1 or 2 nitrogen atoms, or containing one nitrogen atom and 1 or 2 other heteroatoms (e.g., oxygen and/or sulfur atoms). Specific examples of "3-8 membered mono-heterocyclyl" include, but are not limited to: aziridine, 2H-aziridine, diazacyclopropane, 3H-diazapropenyl, azetidinyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, 1, 4-dioxadienyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, thiazolidinyl, piperidinyl, and the like tetrahydropyridinyl, piperidonyl, tetrahydropyridinonyl, dihydropyridinonyl, piperazinyl, morpholinyl, 4, 5-dihydro-oxazolyl, 4, 5-dihydro-isoxazolyl, 2, 3-dihydro-isoxazolyl, oxazolidinyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, 4H-1, 3-thiazinyl, 6H-1, 3-thiazinyl, 2H-pyranyl, 2H-pyran-2-onyl, 3, 4-dihydro-2H-pyranyl, and the like.
Polycyclic heterocyclic groups include "fused heterocyclic groups", "spiroheterocyclic groups" and "bridged heterocyclic groups", preferably "7-10 membered fused heterocyclic groups", "7-10 membered spiroheterocyclic groups" and "7-10 membered bridged heterocyclic groups".
The "7-10 membered fused heterocyclic group" as used herein refers to a saturated or partially saturated, non-aromatic cyclic group containing 7-10 ring atoms and at least one ring atom being a heteroatom, formed by two or more cyclic structures sharing two adjacent atoms with each other, one of which may be an aromatic ring but the whole of which is not aromatic, and the heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally, a ring atom (e.g., a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxo-substituted, including, but not limited to, "8-9 membered fused heterocyclic group", "9-10 membered fused heterocyclic group" and the like, and the manner of the fusion may be 5-6 membered heterocyclic group and 5-6 membered heterocyclic group, 5-6 membered cycloalkyl, benzo 5-6 membered saturated heterocyclic group, 5-6 membered heteroaryl and 5-6 membered saturated heterocyclic group; a 5-6 membered heteroaryl group as defined hereinbefore; specific examples of the "8-to 10-membered fused heterocyclic group" include, but are not limited to: pyrrolidinyl, cyclopentylazacyclopropyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinyl-piperidinyl, pyrrolidinyl-piperazinyl, pyrrolidinyl-pentalinyl, piperidinyl-pentalinyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, benzimidazolidinyl, benzoxazolidinyl, benzothiazolidinyl, benzisoxazolidinyl, benzisothiazolidinyl, benzopiperidinyl, benzomorpholinyl, benzopiperazinyl, benzopyranyl, pyridocyclopentyl, pyridocyclohexyl, benzofuranyl-pentalinyl, and benzopiperidinyl-pentalinyl pyridotetrahydrofuranyl, pyridopyrrolidinyl, pyridoimidazolidinyl, pyridooxazolidinyl, pyridothiazolidinyl, pyridoisoxazolidinyl, pyridoisothiazolidinyl, pyridopiperidinyl, pyridomorpholinyl, pyridopiperazinyl, pyridotetrahydropyranyl, pyrimidocyclopentyl, pyrimidocyclohexyl, pyrimidoethylphenyl, pyrimidopyrrolidinyl, pyrimidoimidazolidinyl, pyrimidooxazolidinyl, pyrimidoidinyl, pyrimidoidithiazolidinyl, pyrimidopiperidyl, pyrimidomomorpholinyl, pyrimidopiperidinyl, pyrimidoetetrahydropyranyl; tetrahydroimidazo [4,5-c ] pyridinyl, 3, 4-dihydroquinazolinyl, 1, 2-dihydroquinoxalinyl, benzo [ d ] [1,3] dioxolyl, 2H-chromene-2-onyl, 4H-chromene, 4H-chromen-4-onyl, 4H-1, 3-benzoxazolyl, 4, 6-dihydro-1H-furo [3,4-d ] imidazolyl, 3a,4,6 a-tetrahydro-1H-furo [3,4-d ] imidazolyl, 4, 6-dihydro-1H-thieno [3,4-d ] imidazolyl, 4, 6-dihydro-1H-pyrrolo [3,4-d ] imidazolyl, octahydro-benzo [ d ] imidazolyl, decahydroquinolinyl, hexahydrothienoimidazoyl, hexahydrofuroimidazoyl, 4,5,6, 7-tetrahydro-1H-benzo [3,4-d ] imidazolyl, octahydro-pyrrolo [3,4-d ] pyrrolyl, and the like.
The term "benzocyclopentyl" refers to its structure(also known as 2, 3-dihydro-1H-indenyl); the term "benzopyrrolidine" includes the structure thereofEtc.; the term "pyridotetrahydrofuranyl" includes structures thereof Specific examples of other "defined other fused heterocyclic groups" defined hereinbefore have a cyclic structure similar thereto.
The "7-10 membered spiroheterocyclic group" as used herein refers to a cyclic structure containing 7 to 10 ring atoms (at least one of which is a heteroatom such as nitrogen atom, oxygen atom or sulfur atom) formed by two or more cyclic structures sharing one ring atom with each other, and includes "7-10 membered saturated spiroheterocyclic group" and "7-10 membered partially saturated spiroheterocyclic group". Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. Specific examples thereof include, but are not limited to:
etc.
The "7-10 membered bridged heterocyclic group" as used herein refers to a cyclic structure containing 7 to 10 ring atoms (wherein at least one ring atom is a heteroatom such as nitrogen atom, oxygen atom or sulfur atom) formed by two or more cyclic structures sharing two non-adjacent ring atoms with each other, and includes "7-10 membered saturated bridged heterocyclic group" and "7-10 membered partially saturated bridged heterocyclic group". Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. Specific examples include, but are not limited to:
Etc.
The "6-10 membered aryl" described herein includes "6-8 membered monocyclic aryl" and "8-10 membered condensed ring aryl".
"6-8 membered monocyclic aryl" as used herein refers to monocyclic aryl groups containing 6-8 ring carbon atoms, examples of which include, but are not limited to: phenyl, cyclooctatetraenyl, and the like; phenyl is preferred.
The term "8-to 10-membered condensed ring aryl" as used herein refers to an unsaturated, aromatic cyclic group containing 8 to 10 ring carbon atoms, preferably "9-to 10-membered condensed ring aryl", which is formed by sharing two or more adjacent atoms with each other by two or more cyclic structures, and specific examples thereof are naphthyl and the like.
The "5-to 10-membered heteroaryl" as used herein includes "5-to 8-membered single heteroaryl" and "8-to 10-membered fused heteroaryl".
"5-8 membered mono-heteroaryl" as used herein refers to an aromatic monocyclic ring group containing 5-8 ring atoms, at least one of which is a heteroatom, such as nitrogen, oxygen or sulfur. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. "5-8 membered mono-heteroaryl" includes, for example, "5-7 membered mono-heteroaryl", "5-6 membered nitrogen containing mono-heteroaryl", "6 membered nitrogen containing mono-heteroaryl", etc., wherein the heteroatom in the "nitrogen containing heteroaryl" contains at least one nitrogen atom, e.g., contains only 1 or 2 nitrogen atoms, or contains one nitrogen atom and 1 or 2 other heteroatoms (e.g., oxygen and/or sulfur atoms), or contains 2 nitrogen atoms and 1 or 2 other heteroatoms (e.g., oxygen and/or sulfur atoms). Specific examples of "5-8 membered monocyclic heteroaryl" include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 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, azepanyl, 1, 3-diazinoheptenyl, azocyclotetraenyl and the like. The "5-6 membered single heteroaryl" refers to a specific example in which 5-8 membered heteroaryl contains 5-6 ring atoms.
The "8-to 10-membered fused heteroaryl group" as used herein refers to an unsaturated aromatic ring structure containing 8 to 10 ring atoms (at least one of which is a heteroatom such as a nitrogen atom, an oxygen atom or a sulfur atom) formed by two or more ring structures sharing two adjacent atoms with each other. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. Including "9-10 membered fused heteroaryl", "8-9 membered fused heteroaryl", and the like, which may be fused in such a manner as to be benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, and the like; specific examples include, but are not limited to: pyrrolopyrroles, pyrrolofurans, pyrazolopyrroles, pyrazolothiophenes, furanthiophenes, pyrazolooxazoles, benzofuranyl, benzisofuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolonyl, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, and the like.
The invention relates to a carbon atom, a nitrogen atom or a sulfur atom Sub-oxo "means forming c= O, N = O, S =o or SO 2 Is a structure of (a).
"optionally substituted" as used herein refers to both cases where one or more hydrogen atoms on the substituted group may be "substituted" or "unsubstituted" with one or more substituents.
The term "pharmaceutically acceptable salt" as used herein refers to the acidic functional groups present in the compound (e.g., -COOH, -OH, -SO) 3 H, etc.) with suitable inorganic or organic cations (bases), including salts with alkali metals or alkaline earth metals, ammonium salts, and salts with nitrogen-containing organic bases; and salts of basic functional groups (e.g., -NH2, etc.) present in the compounds with suitable inorganic or organic anions (acids), including salts with inorganic or organic acids (e.g., carboxylic acids, 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, ethanesulfonate, benzenesulfonate, toluenesulfonate, tetrafluoroborate, arginate, aspartate, glutamate, and the like.
"isomers" as used herein refers to compounds of the present invention which contain one or more asymmetric centers and are therefore useful as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention may have asymmetric centers that each independently produce two optical isomers. The scope of the present invention includes all possible optical isomers and mixtures thereof. The compounds of the present invention, if they contain olefinic double bonds, include cis-isomers and trans-isomers unless specified otherwise. The compounds described herein may exist in tautomeric (one of the functional group isomers) forms having different points of attachment of hydrogen through displacement of one or more double bonds, for example, the keto and enol forms thereof are keto-enol tautomers. The compounds of the invention contain spiro structures, which are affected by the steric structure of the ring, and substituents on the ring may be present on both sides of the ring to form the opposite cis (cis) and trans (trans) isomers. Each tautomer and mixtures thereof are included within the scope of the present invention. Enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof and the like of all compounds are included within the scope of the present invention.
The compounds of the invention may be prepared by enantiospecific synthesis or resolution from mixtures of enantiomers to give the individual enantiomers. Conventional resolution techniques include formation of a salt of the free base of each enantiomer of an enantiomer pair using an optically active acid (followed by fractional crystallization and free base regeneration), formation of an acid form salt of each enantiomer of an enantiomer pair using an optically active amine (followed by fractional crystallization and free acid regeneration), formation of an ester or amide of each enantiomer of an enantiomer pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and chiral auxiliary removal) or resolution of mixtures of enantiomers of the starting material or end product using various well known chromatographic methods.
When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60 wt%, 70 wt%, 80 wt%, 90 wt%, 99 wt%, or 99.9 wt% pure relative to the other stereoisomers. When a single isomer is named or depicted by structure, the depicted or named enantiomer is at least 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight, or 99.9% by weight pure. Optical purity wt% is the ratio of the weight of an enantiomer to the weight of the enantiomer plus the weight of its optical isomer.
The term "dosage form" as used herein refers to a form of a medicament formulated for clinical use, including, but not limited to, powders, tablets, granules, capsules, solutions, emulsions, suspensions, injections (including injectable solutions, injectable sterile powders and injectable concentrated solutions), sprays, aerosols, powder sprays, lotions, liniments, ointments, plasters, pastes, patches, gargles or suppositories, more preferably powders, tablets, granules, capsules, solutions, injections, ointments, gargles or suppositories.
Advantageous effects of the invention
1. The compound, the pharmaceutically acceptable salt or the stereoisomer thereof has excellent HPK1 activity inhibition effect, has good pharmacokinetic property in organisms, lasting effect, good liver microsome stability, exposure and bioavailability, and can treat and/or prevent diseases mediated by HPK 1.
2. The compound, the pharmaceutically acceptable salt or the stereoisomer thereof has better treatment effect on HPK1 mediated cancers.
3. The compound has the advantages of simple preparation process, high purity of the medicine, stable quality and easy mass industrial production.
The technical scheme of the present invention will be described in detail below with reference to specific embodiments, but the scope of the subject matter of the present invention should not be construed as being limited to the following examples. All techniques implemented based on the above description of the invention are within the scope of the invention.
Abbreviations used in the following experiments represent the following meanings:
LiAlH 4 : lithium aluminum hydride
LDA: lithium diisopropylamide
DCC: dicyclohexylcarbodiimide
Preparation example 1: preparation of 7-amino-6- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 1)
Preparation of 1.2,2' - (1, 2-phenylene) bis (ethane-1-ol)
2,2' - (1, 2-phenylene) diacetic acid (10.0 g,51.5 mmol) was dissolved in tetrahydrofuran (200 mL). LiAlH is added in portions at 0 DEG C 4 (5.9 g,0.15 mol) was added and reacted at 15℃for 18 hours. After completion of the LCMS test, 5.9mL of water was added at 0deg.C to quench the reaction, the solid was separated out, filtered through celite, the solid was washed with tetrahydrofuran, and the filtrate was dried and concentrated to give the title compound, 7.0g, yield: 81.8%.
Preparation of 1, 2-phenylenedi (ethane-2, 1-diyl) dimethyl sulfonate
2,2' - (1, 2-phenylene) bis (ethan-1-ol) (7.0 g,42.2 mmol) was dissolved in dichloromethane (150 mL), triethylamine (8.5 g,84.4 mmol) and methanesulfonyl chloride (9.8 g,84.4 mmol) were added at 0℃and reacted at 0℃for 1 hour. The reaction is quenched by 1M dilute hydrochloric acid, separated, and concentrated by organic phase drying to be directly used in the next step.
Preparation of 3.2,3,4,5-tetrahydro-1H-benzo [ d ] azepine
1, 2-phenylenedi (ethane-2, 1-diyl) dimethyl sulfonate (N/A, 42.2 mmol) was dissolved in acetonitrile (50 mL), aqueous ammonia (50 mL) was added, and the mixture was reacted in a closed pot at 90℃for 2 hours. Cooling to 15 ℃, concentrating the solvent, adding water for dilution, adjusting pH to be 4 by concentrated hydrochloric acid, extracting by ethyl acetate, adjusting pH to be 11 by aqueous sodium hydroxide solution, extracting by a mixed solvent (dichloromethane: methanol=10:1), and drying and concentrating the organic phase to obtain the target compound 3.0g, wherein the yield of the two steps is: 48.4%.
Preparation of 4.2,2,2-trifluoro-1- (1, 2,4, 5-tetrahydro-3H-benzo [ d ] azepin-3-yl) ethyl-1-one
2,3,4, 5-tetrahydro-1H-benzo [ d ] azepine (3.0 g,20.4 mmol) was dissolved in dichloromethane (100 mL), pyridine (2.4 g,30.6 mmol) was added, trifluoroacetic anhydride (5.4 g,25.5 mmol) was added dropwise at 0deg.C, and the reaction was carried out at 15deg.C for 15 hours. LCMS detected the end of the reaction, quenched with water, extracted with dichloromethane, and purified by organic phase dry concentration on silica gel column (petroleum ether: ethyl acetate=3:1) to give 4.0g of the target compound, yield: 80.8%.
Preparation of 5.2,2,2-trifluoro-1- (7-nitro-1, 2,4, 5-tetrahydro-3H-benzo [ d ] azepin-3-yl) ethan-1-one
2, 2-trifluoro-1- (1, 2,4, 5-tetrahydro-3H-benzo [ d ] azepin-3-yl) ethyl-1-one (4.0 g,16.5 mmol) was dissolved in concentrated sulfuric acid (30 mL), potassium nitrate (1.7 g,16.5 mmol) was added in portions at 0deg.C, and the mixture was reacted at 15deg.C for 16 hours. LCMS detects the end of the reaction. The reaction solution was poured into ice water, extracted with ethyl acetate, concentrated by organic phase drying, and purified by silica gel column (petroleum ether: ethyl acetate=5:1) to give 3.0g of the target compound, yield: 63.3%.
Preparation of 7-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepine
2, 2-trifluoro-1- (7-nitro-1, 2,4, 5-tetrahydro-3H-benzo [ d ] azepin-3-yl) ethan-1-one (3.0 g,10.4 mmol) was dissolved in methanol (50 mL), potassium carbonate (2.9 g,20.8 mmol) was added and the addition was completed for 15 hours at 15 ℃. LCMS detects the end of the reaction. Diatomaceous earth filtration, concentration of solvent, C18 column purification (methanol=0-70%) gave the title compound 1.9g, yield: 95.5%.
Preparation of 3-methyl-7-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepine
7-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepine (65 mg,0.19 mmol) was dissolved in formaldehyde (37%) (10 mL), formic acid (5 mL) was reacted at 15℃for 1 hour, and the temperature was raised to 70℃for 1 hour. LCMS detects the end of the reaction. Saturated sodium bicarbonate solution adjusted ph=9, ethyl acetate extraction organic phase drying concentration to obtain the target compound 1.9g, yield: 93.1%.
Preparation of 3-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine
3-methyl-7-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepine (1.9 g,9.2 mmol) was dissolved in methanol (30 mL), pd/C (1.0 g) was added and hydrogenation was carried out at 15℃for 1 hour. LCMS detects the end of the reaction. The mixture is filtered by diatomite, and the filtrate is dried and concentrated to obtain 1.6g of target compound with yield: 98.6%.
9. Preparation of N- (3-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide
3-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine (1.6 g,9.1 mmol) was dissolved in acetic acid (5 mL), acetic anhydride (1.5 mL) was added, and the reaction was continued for 12 hours at 15 ℃. LCMS detects the end of the reaction. Diluting with water, adjusting pH to 9 with saturated sodium bicarbonate aqueous solution, extracting with dichloromethane, concentrating the aqueous phase, and purifying with C18 column (methanol=0-80%) to obtain 1.9g of the target compound, yield: 96.0%.
10. Preparation of N- (3-methyl-8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide
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 0deg.C, and the reaction was carried out for 10min at 0deg.C. LCMS detects the end of the reaction. Pouring into ice water, adjusting pH to 7 with sodium hydroxide aqueous solution, concentrating the solvent, washing the solid with dichloromethane and methanol, and concentrating the organic phase to obtain crude product which is directly used in the next step.
Preparation of 3-methyl-8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine
N- (3-methyl-8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide (N/A, 8.7 mmol) was dissolved in methanol (20 mL), potassium carbonate (2.4 g,17.4 mmol) was added, and the reaction was completed at 55℃for 36 hours. LCMS detects the end of the reaction. Filtration through celite, concentration of the filtrate on C18 column purification (methanol=0-80%) gave the title compound 1.6g, yield: 83.2%.
Preparation of ethyl 2- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate
3-methyl-8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine (1.6 g,7.2 mmol) was dissolved in ethanol (30 mL), pd/C (1.0 g) was added and the addition was hydrogenated at 15℃for 2 hours. LCMS detects the end of the reaction. Ethyl 3-ethoxy-3-iminopropionate hydrochloride (3.4 g.17.4 mmol) was added and the mixture was allowed to react at 50℃for 2 hours. LCMS detects the end of the reaction. Diatomaceous earth filtration, concentration of the filtrate, column purification on silica gel (dichloromethane: methanol=8:1) gave 1.2g of the target compound, yield: 57.7%.
Preparation of 7-hydroxy-4- (4-methoxybenzyl) -6- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) 1-one
Ethyl 2- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [1,2-d ] azepin-2-yl) acetate (200 mg,0.7 mmol), 1- (4-methoxybenzyl) -2H-thieno [3,2-d ] [1,3] oxazine-2, 4 (1H) -dione (221.5 mg,0.77 mmol) was dissolved in tetrahydrofuran (5 mL), LDA (1.4 mL,2.8 mmol) was added, and the reaction was continued for 2 hours at 40 ℃. LCMS detects the end of the reaction. Saturated ammonium chloride is quenched, dichloromethane is extracted, and organic phase is dried, concentrated and purified by a silica gel column (dichloromethane: methanol=4:1) to obtain 60mg of a target compound, and the yield is: 17.7%.
Preparation of 4- (4-methoxybenzyl) -6- (7-methyl-1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -5-oxo-4, 5-dihydrothieno [3,2-b ] pyridin-7-yl trifluoromethanesulfonate
7-hydroxy-4- (4-methoxybenzyl) -6- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) 1-one (60 mg,0.12 mmol) was dissolved in dichloromethane (10 mL) and pyridine (189.8 mg,2.4 mmol), trifluoromethanesulfonic anhydride (203.1 mg,0.72 mmol) was added at 0deg.C. The reaction was carried out at 0℃for 1 hour. LCMS detects the end of the reaction. Dichloromethane was added for dilution, aqueous sodium bicarbonate was used for washing, and the organic phase was concentrated by drying and used directly in the next step.
Preparation of 7- (((2, 4-dimethoxybenzyl) amino) -4- (4-methoxybenzyl) -6- (1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -1-one
4- (4-methoxybenzyl) -6- (7-methyl-1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -5-oxo-4, 5-dihydrothieno [3,2-b ] pyridin-7-yl trifluoromethanesulfonate (N/A, 0.12 mmol) was dissolved in acetonitrile (5 mL), 2, 4-dimethoxybenzylamine (60.1 mg,0.36 mmol) was added and the addition was warmed to 45℃for 2 hours. LCMS detects the end of the reaction. The solvent was concentrated and purified by column chromatography on silica gel (dichloromethane: methanol=10:1) to give 90.0mg of the title compound in 95.0% yield in two steps.
Preparation of 7-amino-6- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
7- (((2, 4-dimethoxybenzyl) amino) -4- (4-methoxybenzyl) -6- (1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -1-one (90 mg,0.12 mmol) was dissolved in concentrated hydrochloric acid (1 mL), trifluoroacetic acid (7 mL) and added to raise the temperature to 110℃for 24 hours.
Molecular formula C 19 H 19 N 5 OS molecular weight 365.5 LC-MS (M/e): 366.1 (M+H) + )
1 H-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).
Preparation example 2: preparation of 4-amino-5- (7-methyl-1,5,6,7,8,9-hexahydroimidazolyl [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [2,3-b ] pyridin-6 (7H) -one (Compound 2)
Ethyl 2- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (100 mg,0.35 mmol), 2-aminothiophene-3-carbonitrile (47.5 mg,0.38 mmol) was dissolved in tetrahydrofuran (5 mL), heated to 40℃and LDA (0.53 mL,1.05 mmol) was added dropwise, and the mixture was reacted at 40℃for 2 hours. LCMS detects the end of the reaction. Saturated ammonium chloride quench reaction, ethyl acetate extraction, organic phase drying concentration C18 column purification (acetonitrile=0-60%) to give the target compound 6.6mg, yield: 5.2%.
Molecular formula C 19 H 19 N 5 OS molecular weight 365.5 LC-MS (M/e): 366.1 (M+H) + )
1 H-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).
Preparation example 3: preparation of 4-amino-5- (7-methyl-5, 6,7,8,9, 10-hexahydro-1H-imidazo [4',5':4,5] benzo [1,2-d ] azacine-2-yl) thieno [2,3-b ] pyridin-6 (7H) -one (Compound 4)
Preparation of 1.2,3,5,6-tetrahydrobenzo [ d ] azacine-4 (1H) -one
5,6,8, 9-tetrahydro-7H-benzo [7] chromen-7-one (8.0 g,49.9 mmol) was dissolved in trifluoroacetic acid (60 mL) and sodium azide (4.9 g,75.4 mol) was added. The reaction was carried out at 65℃for 7 hours. Extraction with saturated sodium bicarbonate (200 mL) and ethyl acetate (100 mL), drying and concentration of the organic phase, purification on a silica gel column (dichloromethane: methanol=20:1) gave the title compound 5.0g, yield: 57.1%.
Preparation of 2.1,2,3,4,5,6-hexahydrobenzo [ d ] az Xin Yin
2,3,5, 6-tetrahydrobenzo [ d ] azepin-4 (1H) -one (5.0 g,28.5 mmol) was dissolved in tetrahydrofuran (200 mL), lithium aluminum hydride (4.3 g,113.2 mmol) was added at 0deg.C, and the reaction was carried out at 75deg.C for 1 hour. The reaction was quenched with water (4.3 mL), 10% sodium hydroxide (4.3 mL) and water (12.9 mL) were added, the solids were removed by filtration, and extracted with water (100 mL) and ethyl acetate (200 mL) to give 4.2g of crude product.
Preparation of 3.3-methyl-1, 2,3,4,5, 6-hexahydrobenzo [ d ] az Xin Yin
1,2,3,4,5, 6-hexahydrobenzo [ d ] azacine (2.0 g) was dissolved in formic acid (10 mL), formaldehyde (37%) was added (20 mL), and the mixture was reacted at 70℃for 1 hour. The pH was adjusted to 9 with saturated sodium bicarbonate (200 mL) and extracted with ethyl acetate (200 mL) to give 2.0g of crude product.
Preparation of 3-methyl-8-nitro-1, 2,3,4,5, 6-hexahydrobenzo [ d ] az Xin Yin
3-methyl-1, 2,3,4,5, 6-hexahydrobenzo [ d ] azacine (2.0 g) was dissolved in concentrated sulfuric acid (15 mL), cooled to 0℃and potassium nitrate (1.2 g,11.9 mmol) was added thereto, and reacted at 15℃for 15 hours. The pH was adjusted to 12 with 2N sodium hydroxide, extracted with dichloromethane/methanol=9:1 (100 mL), and organic phase was concentrated by dry-column purification on silica gel (dichloromethane: methanol=9:1) to give 1.3g of the title compound.
Preparation of 3-methyl-1, 2,3,4,5, 6-hexahydrobenzo [ d ] azepin-8-amine
3-methyl-8-nitro-1, 2,3,4,5, 6-hexahydrobenzo [ d ] azacine (1.2 g,5.4 mmol) was dissolved in methanol (40 mL), pd/C (1.0 g) was added, and hydrogenation was carried out at 15℃for 1 hour. The mixture was filtered through celite, and the filtrate was dried and concentrated to give 1.0g of the objective compound in 96.46% yield.
6. Preparation of N- (3-methyl-1, 2,3,4,5, 6-hexahydrobenzo [ d ] azocine-8-yl) acetamide
3-methyl-1, 2,3,4,5, 6-hexahydrobenzo [ d ] azepin-8-amine (1.0 g,5.2 mmol) was dissolved in acetic acid (8 mL), acetic anhydride (2 mL) was added, and the addition was completed and reacted at 15℃for 12 hours. LCMS detects the end of the reaction. Diluting with water, adjusting pH to be 9 with saturated sodium bicarbonate aqueous solution, extracting with dichloromethane/methanol=9:1 (100 mL), and concentrating and purifying with C18 column (methanol=0-60%) to obtain 1.0g of the target compound, yield: 81.9%.
7. Preparation of N- (3-methyl-9-nitro-1, 2,3,4,5, 6-hexahydrobenzo [ d ] azepin-8-yl) acetamide
N- (3-methyl-1, 2,3,4,5, 6-hexahydrobenzo [ d ] azepin-8-yl) acetamide (1.0 g,4.3 mmol) was dissolved in concentrated sulfuric acid (15 mL), fuming nitric acid (399 mg,5.4 mmol) was added dropwise at 0deg.C, and the mixture was reacted at 0deg.C for 10min. LCMS detects the end of the reaction. Poured into ice water, adjusted to ph=10 with 2N aqueous sodium hydroxide solution, extracted with dichloromethane/methanol=9:1 (100 mL), and the organic phase concentrated to give 1.8g of crude product.
Preparation of 3-methyl-9-nitro-1, 2,3,4,5, 6-hexahydrobenzo [ d ] azepin-8-amine
N- (3-methyl-9-nitro-1, 2,3,4,5, 6-hexahydrobenzo [ d ] azepin-8-yl) acetamide (1.8 g) was dissolved in methanol (50 mL), and potassium carbonate (1.7 g,12.3 mmol) was added thereto and reacted at 55℃for 48 hours. Concentration, extraction with dichloromethane/methanol=9:1 (100 mL), C18 column purification (methanol=0-70%) gave 800mg of the title compound in two steps yield: 79.0%.
Preparation of ethyl 2- (7-methyl-5, 6,7,8,9, 10-hexahydro-1H-imidazo [4',5':4,5] benzo [1,2-d ] azacine-2-yl) acetate
3-methyl-9-nitro-1, 2,3,4,5, 6-hexahydrobenzo [ d ] azepin-8-amine (800 mg,3.4 mmol) was dissolved in ethanol (30 mL), pd/C (320 mg) was added, and hydrogenation was carried out at 15℃for 1 hour. Ethyl 3-ethoxy-3-iminopropionate hydrochloride (1.66 g,8.5 mmol) was added and the reaction was continued at 50℃for 2 hours. Diatomaceous earth was filtered, the filtrate was concentrated, and purified by silica gel column (dichloromethane: methanol=6:1) to give 500mg of the target compound, yield: 48.8%.
Preparation of 4-amino-5- (7-methyl-5, 6,7,8,9, 10-hexahydro-1H-imidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [2,3-b ] pyridin-6 (7H) -one
Ethyl 2- (7-methyl-5, 6,7,8,9, 10-hexahydro-1H-imidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (70 mg,0.23 mmol) and 2-aminothiophene-3-carbonitrile (32 mg,0.26 mmol) were dissolved in tetrahydrofuran (10 mL), LDA (0.3 mL,0.9 mmol) was added at 40℃and reacted for 2 hours at 40 ℃. The saturated ammonium chloride quenched reaction, ethyl acetate (50 mL) extracted, the organic phase was dried, concentrated, and purified by preparative plate (dichloromethane: methanol=6:1) to give 40mg of crude target compound, and purified again by preparative plate (dichloromethane: methanol=6:1) to give 2.8mg of target compound, yield: 3.2%.
Molecular formula C 20 H 21 N 5 OS molecular weight 379.5 LC-MS (M/e): 380.1 (M+H+)
1 H-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).
Preparation example 4 preparation of 7-amino-6- (5, 8-dimethyl-5, 6,7,8,9, 10-hexahydro-3H-imidazo [4',5':4,5] benzo [1,2-e ] [1,4] diazinon-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 7)
1.2 preparation of 2- (2-chloro-4- ((3, 4-dimethylbenzyl) amino) -5-nitrophenyl) ethan-1-ol
2- (2-chloro-4-fluoro-5-nitrophenyl) ethan-1-ol (4.0 g,18.3 mmol) was dissolved in NMP (50 mL), 2, 4-dimethoxybenzylamine (3.7 g,21.9 mmol) and N, N-diisopropylethylamine (4.7 g,36.4 mmol) were added and reacted at 50℃for 0.5 hours. LCMS detected the end of the reaction, quenched with water, extracted with ethyl acetate, and purified by organic phase dry concentrated silica gel column (petroleum ether: ethyl acetate=3:1) to give 4.0g of the target compound, yield: 68.1%.
2.preparation of 2- (2-chloro-4- ((3, 4-dimethylbenzyl) amino) -5-nitrophenyl) acetaldehyde
2- (2-chloro-4- ((3, 4-dimethylbenzyl) amino) -5-nitrophenyl) ethan-1-ol (4.0 g,10.9 mmol) was dissolved in dichloromethane (100 mL), and dess-Martin reagent (5.6 g,13.1 mmol) was added at 0deg.C and reacted at 15deg.C for 1 hour. LCMS detects the end of the reaction. The reaction solution was quenched by adding dichloromethane and then saturated aqueous sodium bicarbonate, extracted with dichloromethane, concentrated by organic phase drying, and purified by silica gel column (petroleum ether: ethyl acetate=5:1) to give 3.9g of the target compound, yield: 98.3%.
3. Preparation of tert-butyl (2- ((2-chloro-4- ((3, 4-dimethylbenzyl) amino) -5-nitrophenyl) (methyl) amino) ethyl) (methyl) carbamate
2- (2-chloro-4- ((3, 4-dimethylbenzyl) amino) -5-nitrophenyl) acetaldehyde (2.5 g,6.9 mmol) was dissolved in dichloromethane (50 mL), tert-butyl methyl (2- (methylamino) ethyl) carbamate (1.6 g,8.2 mmol) was added, and after reaction at 15℃for 10 minutes. Sodium borohydride acetate (3.2 g,15.0 mmol) and acetic acid (900 mg,15.0 mmol) were added and reacted at 15℃for 16 hours. LCMS detects the end of the reaction. After addition of 1M aqueous sodium hydroxide solution, extraction with dichloromethane, collection of the organic phase, drying and concentrated solvent column chromatography (methanol/dichloromethane=0-8%) gave 3.1g of the title compound, yield: 83.8%.
4. N 1 - (4-amino-2-chloro-5-nitrophenylethyl) -N 1 ,N 2 Preparation of-dimethylethane-1, 2-diamine
Tert-butyl (2- ((2-chloro-4- ((3, 4-dimethylbenzyl) amino) -5-nitrophenyl) (methyl) amino) ethyl) (methyl) carbamate (3.1 g,5.8 mmol) was dissolved in dichloromethane (30 mL), trifluoroacetic acid (10 mL), and the addition was completed and reacted at 10℃for 1 hour. LCMS detects the end of the reaction. Concentrating and then directly feeding into the next step.
Preparation of 5.1,4-dimethyl-8-nitro-1, 2,3,4,5, 6-hexahydrobenzo [ e ] [1,4] diazinon-9-amine
N1- (4-amino-2-chloro-5-nitrophenyl ethyl) -N1, N2-dimethylethane-1, 2-diamine crude product was dissolved in N, N-dimethylacetamide (50 mL), and potassium carbonate (3.3 g,23.8 mmol) was added thereto to react at 110℃for 2 hours. LCMS detects the end of the reaction. Water quenching reaction is added, ethyl acetate extraction is carried out, an organic phase is collected, drying and concentrated solvent column chromatography (methanol/dichloromethane=0-8%) is carried out to obtain 0.3g of target compound, and the two-step yield is as follows: 20.6%.
Preparation of 6.1,4-dimethyl-1, 2,3,4,5, 6-hexahydrobenzo [ e ] [1,4] diazepine-8, 9-diamine
1, 4-dimethyl-8-nitro-1, 2,3,4,5, 6-hexahydrobenzo [ e ] [1,4] diazinon-9-amine (300 mg,1.2 mmol) was dissolved in ethanol (10 mL), pd/C (150 mg) was added, and the mixture was reacted at 10℃for 2 hours under nitrogen. LCMS detects the end of the reaction. Filtering with diatomite, concentrating the solvent to obtain the target compound, and directly feeding the target compound into the next step.
Preparation of ethyl 2- (5, 8-dimethyl-5, 6,7,8,9, 10-hexahydro-3H-imidazo [4',5':4,5] benzo [1,2-e ] [1,4] diazinon-2-yl) acetate
Crude 1, 4-dimethyl-1, 2,3,4,5, 6-hexahydrobenzo [ e ] [1,4] diazepine-8, 9-diamine was dissolved in ethanol (10 mL), ethyl 3-ethoxy-3-iminopropionate hydrochloride (704 mg,3.6 mmol) was added, and the mixture was reacted at 50℃for 3 hours. LCMS detects the end of the reaction. Concentration of solvent column chromatography (methanol/dichloromethane=0-15%) gave 300mg of the title compound, two-step yield: 79.1%.
8.preparation of 1- (4-methoxybenzyl) -2H-thieno [3,2-d ] [1,3] oxazine-2, 4 (1H) -dione
2H-thieno [3,2-d ] [1,3] oxazine-2, 4 (1H) -dione (5.0 g,29.5 mmol) was dissolved in N, N-dimethylformamide (50 mL), p-methoxybenzyl chloride (7.9 g,50.2 mmol), potassium carbonate (4.9 g,35.5 mmol), potassium iodide (2.0 g,12.0 mmol) was added, and the mixture was reacted at 10℃for 2 hours after the addition. LCMS detects the end of the reaction. Water was added to the reaction mixture, and the solid was precipitated and filtered to give 3.0g of the title compound in 35.1% yield.
9.preparation of 6- (5, 8-dimethyl-5, 6,7,8,9, 10-hexahydro-3H-imidazo [4',5':4,5] benzo [1,2-e ] [1,4] diazinon-2-yl) -7-hydroxy-4- (4-methoxybenzyl) thieno [3,2-b ] pyridin-5 (4H) -1-one
Ethyl 2- (5, 8-dimethyl-5, 6,7,8,9, 10-hexahydro-3H-imidazo [4',5':4,5] benzo [1,2-e ] [1,4] diazinon-2-yl) acetate (350 mg,1.1 mmol), 1- (4-methoxybenzyl) -2H-thieno [3,2-d ] [1,3] oxazine-2, 4 (1H) -dione (418 mg,1.4 mmol) was dissolved in tetrahydrofuran (10 mL), heated to 40 ℃, LDA (1.7 mL,3.3 mmol) was added dropwise under nitrogen, and the reaction was continued for 2 hours at 40 ℃. Saturated ammonium chloride is quenched, dichloromethane is extracted, organic phase is dried and concentrated, column chromatography (methanol/dichloromethane=0-15%) is carried out to obtain an intermediate, tetrahydrofuran (10 mL) is added again, LDA (1.2 mL) is added dropwise under the protection of nitrogen for two hours, the above operation is repeated to obtain 150mg of the target compound, and the yield is: 26.5%.
Preparation of 6- (5, 8-dimethyl-5, 6,7,8,9, 10-hexahydro-3H-imidazo [4',5':4,5] benzo [1,2-e ] [1,4] diazinon-2-yl) -7-hydroxy-4- (4-methoxybenzyl) thieno [3,2-b ] pyridin-5 (4H) -1-one
6- (5, 8-dimethyl-5, 6,7,8,9, 10-hexahydro-3H-imidazo [4',5':4,5] benzo [1,2-e ] [1,4] diazinon-2-yl) -7-hydroxy-4- (4-methoxybenzyl) thieno [3,2-b ] pyridin-5 (4H) -1-one (150 mg,0.29 mmol) was dissolved in dichloromethane (10 mL) and pyridine (460 mg,5.8 mmol), trifluoromethanesulfonic anhydride (490 mg,1.74 mmol) was added at 0deg.C. The reaction was carried out at 0℃for 1 hour. LCMS detects the end of the reaction. Dichloromethane was added for dilution, aqueous sodium bicarbonate was used for washing, and the organic phase was concentrated by drying and used directly in the next step.
Preparation of 6- (5, 8-dimethyl-3- ((trifluoromethyl) sulfonyl) -5,6,7,8,9, 10-hexahydro-3H-imidazo [4',5':4,5] benzo [1,2-e ] [1,4] diazinon-2-yl) -7- ((3, 4-dimethylbenzyl) amino) -4- (4-methoxybenzyl) thieno [3,2-b ] pyridin-5 (4H) -one
6- (5, 8-dimethyl-5, 6,7,8,9, 10-hexahydro-3H-imidazo [4',5':4,5] benzo [1,2-e ] [1,4] diazinon-2-yl) -7-hydroxy-4- (4-methoxybenzyl) thieno [3,2-b ] pyridin-5 (4H) -1-one (N/A, 0.29 mmol) was dissolved in acetonitrile (5 mL), 2, 4-dimethoxybenzylamine (130 mg,0.78 mmol) was added and the addition was warmed to 45℃for 2 hours. LCMS detects the end of the reaction. The solvent was concentrated and purified on a silica gel column (dichloromethane: methanol=20:1) to give 200mg of the title compound in 90.2% yield in two steps.
Preparation of 7-amino-6- (5, 8-dimethyl-5, 6,7,8,9, 10-hexahydro-3H-imidazo [4',5':4,5] benzo [1,2-e ] [1,4] diazocine-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
6- (5, 8-dimethyl-3- ((trifluoromethyl) sulfonyl) -5,6,7,8,9, 10-hexahydro-3H-imidazo [4',5':4,5] benzo [1,2-e ] [1,4] diazinon-2-yl) -7- ((3, 4-dimethylbenzyl) amino) -4- (4-methoxybenzyl) thieno [3,2-b ] pyridin-5 (4H) -one (200 mg,0.25 mmol) was dissolved in concentrated hydrochloric acid (1 mL), trifluoroacetic acid (7 mL) and the addition was warmed to 110℃for 24 hours. LCMS detects the end of the reaction. Ph=7, solvent concentration, pre-HPLC purification (acetonitrile=0-40%) gave the title compound 20mg, yield 20.1%.
Molecular formula C 20 H 22 N 6 OS molecular weight 394.5 LC-MS (M/e): 395.1 (M+H) + )
1 H-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).
PREPARATION EXAMPLE 5 preparation of 4-amino-5- (5, 8-dimethyl-5, 6,7,8,9, 10-hexahydro-3H-imidazo [4',5':4,5] benzo [1,2-e ] [1,4] diazinon-2-yl) thieno [2,3-b ] pyridin-6 (7H) -one (Compound 8)
Ethyl 2- (5, 8-dimethyl-5, 6,7,8,9, 10-hexahydro-3H-imidazo [4',5':4,5] benzo [1,2-e ] [1,4] oxadiazol-2-yl) acetate (100 mg,0.32 mmol) was dissolved in tetrahydrofuran (5 mL), 2-aminothiophene-3-carbonitrile (40 mg,0.32 mmol) was added under nitrogen, LDA (0.32 mL,0.64 mmol) was added, and the reaction was continued for 2 hours at 40 ℃. LCMS detects the end of the reaction. Saturated ammonium chloride was quenched, extracted with dichloromethane, concentrated, and purified by reverse column chromatography (methanol/water=0-45%) to afford the title compound 30.0mg, 23.7% yield.
Molecular formula C 20 H 22 N 6 OS molecular weight 394.5 LC-MS (M/e): 395.1 (M+H) + )
1 H-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).
Preparation example 6 preparation of 4-amino-5- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [2,3-b ] pyridin-6 (7H) -one hydrochloride (hydrochloride of Compound 9)
Preparation of 1- (7-amino-1, 2,4, 5-tetrahydro-3H-benzo [ d ] azepin-3-yl) -2, 2-trifluoroethan-1-one
2, 2-trifluoro-1- (7-nitro-1, 2,4, 5-tetrahydro-3H-benzo [ d ] azepin-3-yl) ethan-1-one (3.0 g,10.4 mmol) was dissolved in methanol (50 mL), pd/C (1.0 g) was added and reacted at 15℃for 15 hours. LCMS detects the end of the reaction. The mixture was filtered through celite, and the solvent was concentrated to give 2.6g of the target compound, yield: 96.7%.
2. Preparation of N- (3- (2, 2-trifluoroacetyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide
1- (7-amino-1, 2,4, 5-tetrahydro-3H-benzo [ d ] azepin-3-yl) -2, 2-trifluoroethan-1-one (2.6 g,10.1 mmol) was dissolved in acetic acid (30 mL), and acetic anhydride (1.5 mL) was added to react at 15℃for 16 hours. LCMS detects the end of the reaction. Adding water, stirring for 1 hour, separating out solid, filtering, washing the solid with water, and drying to obtain 2.3g of target compound, yield: 76.2%.
3. Preparation of N- (8-nitro-3- (2, 2-trifluoroacetyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide
N- (3- (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), fuming nitric acid (700.0 mg,10.0 mmol) was added at 0deg.C, and the addition was completed and reacted at 0deg.C for 2 hours. LCMS detects the end of the reaction. Pouring into ice water, extracting with dichloromethane, drying and concentrating the organic phase to obtain 2.3g of target compound, and obtaining the yield: 86.9%.
Preparation of tert-butyl 4.7-amino-8-nitro-1, 2,4, 5-tetrahydro-3H-benzo [ d ] azepin-3-carboxylate
N- (8-nitro-3- (2, 2-trifluoroacetyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ]]Azepin-7-yl) acetamide (2.3 g,6.7 mmol) was dissolved in methanol (30 mL), warmed to 55deg.C, potassium carbonate (2.8 g,20.1 mmol) was added and reacted at 55deg.C for 16 hours. Filtering through celite, adding Boc to the filtrate 2 O (2.2 g,10.1 mmol) was reacted at 15℃for 2 hours after the addition. Purification by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1) afforded the title compound 1.7g, yield: 82.9%.
Preparation of tert-butyl 2- (2-ethoxy-2-oxoethyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylate
7-amino-8-nitro-1, 2,4, 5-tetrahydro-3H-benzo [ d ] azepine-3-carboxylic acid tert-butyl ester (1.7 g,5.5 mmol) was dissolved in ethanol (100 mL), pd/C (800 mg) was added and the mixture was hydrogenated at 15℃for 2 hours. LCMS detects the end of the reaction. Ethyl 3-ethoxy-3-iminopropionate hydrochloride (2.6 g.13.3 mmol) was added, and the reaction was continued for 2 hours at 50 ℃. LCMS detects the end of the reaction. Diatomite is filtered, and the filtrate is concentrated and purified by a silica gel column (ethyl acetate) to obtain 1.6g of target compound, yield: 60.4%
Preparation of tert-butyl 2- (4-amino-6-oxo-6, 7-dihydrothieno [2,3-b ] pyridin-5-yl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin 7 (1H) -carboxylate
2- (2-ethoxy-2-oxoethyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylic acid tert-butyl ester (300 mg,0.8 mmol), 2-aminothiophene-3-carbonitrile (109.9 mg,0.88 mmol) was dissolved in tetrahydrofuran (5 mL), heated to 40℃under nitrogen protection, LDA (1.2 mL,2.4 mmol) was added dropwise and reacted at 40℃for 2 hours. LCMS detects the end of the reaction. Saturated ammonium chloride, ethyl acetate extraction, organic phase drying concentration and silica gel column purification (petroleum ether: ethyl acetate=5:1) to obtain 260mg of the target compound, yield: 71.7%
Preparation of 4-amino-5- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [2,3-b ] pyridin-6 (7H) -one hydrochloride
2- (4-amino-6-oxo-6, 7-dihydrothieno [2,3-b ] pyridin-5-yl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepine 7 (1H) -carboxylic acid tert-butyl ester (45.0 mg,0.1 mmol) was dissolved in ethanol (2 mL), HCl/ethanol (1.5 mL) was added and reacted at 15℃for 4 hours. LCMS detects the end of the reaction. 0.5mL of water was added, filtered, and the solid was dried to give 12.0mg of the title compound, yield: 31.0%.
Molecular formula C 18 H 17 N 5 OS molecular weight 351.4 LC-MS (M/e): 352.1 (M+H) + )
1 H-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).
Preparation example 7: preparation of 7-amino-6- (7-ethyl-1,5,6,7,8,9-hexahydroimidazolyl [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 10)
Preparation of 1, 7-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepine
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℃and concentrated sulfuric acid (7.5 mL) and potassium nitrate (5.5 g,56.7 mmol) were added and reacted at 0℃for 2 hours. The reaction solution was poured into ice water, the pH was adjusted to 11 with 2N sodium hydroxide, and extracted with dichloromethane/methanol=9:1 (100 mL), yielding 5.0g of crude product.
Preparation of 2, 3-ethyl-7-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepine
7-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepine (5.0 g, crude) was dissolved in tetrahydrofuran (100 mL), aqueous acetaldehyde (40%) (15.75 g,142.9 mmol), acetic acid (3.1 g,51.6 mmol) and sodium triacetoxyborohydride (9.65 g,45.5 mmol) were added and reacted at 15℃for 2 hours. The pH was adjusted to about 10 with 1N sodium hydroxide, extracted with dichloromethane/methanol=9:1 (200 mL), and concentrated by organic phase drying on silica gel column (dichloromethane: methanol=10:1) to give 2.0g of the target compound, with a two-step reaction yield of 26.8%.
Preparation of 3.3-ethyl-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine
3-Ethyl-7-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepine (2.0 g,9.1 mmol) was dissolved in methanol (40 mL), pd/C (500 mg) was added and the mixture was sparged with hydrogen 3 times and hydrogenated at 15℃for 2 hours under hydrogen. The mixture was filtered through celite, and the filtrate was dried and concentrated to give 1.9g of the objective compound.
4. Preparation of N- (3-ethyl-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide
3-Ethyl-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine (1.9 g, crude) was dissolved in acetic acid (16 mL), acetic anhydride (4 mL) was added, and the reaction was carried out at 15℃for 1 hour. Dilution with water, pH=11 with sodium hydroxide, extraction with dichloromethane/methanol=9:1 (100 mL), and purification with C18 column (methanol=0-60%) gave the title compound in 1.5g, two-step yield 71.4%.
5. Preparation of N- (3-ethyl-8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide
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 0deg.C, and the reaction was carried out for 10min at 0deg.C. LCMS detects the end of the reaction. Poured into ice water, adjusted ph=10 with 2N aqueous sodium hydroxide solution, extracted with dichloromethane/methanol=9:1 (100 mL), and purified by C18 column (methanol=0-65%) to give 1.2g of the title compound, yield: 66.7%.
Preparation of 3-ethyl-8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine
N- (3-ethyl-8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide (1.2 g,4.33 mmol) was dissolved in methanol (150 mL), potassium carbonate (2.3 g,16.6 mmol) was added and the reaction was completed at 50℃for 2 hours. Concentration and purification by column chromatography on silica gel (dichloromethane: methanol=8:1) gave 1.0g of the title compound, yield: 98.2%.
Preparation of ethyl 2- (7-ethyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate
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 sparged with hydrogen 3 times, and hydrogenation was carried out at 15℃for 4 hours under hydrogen. Ethyl 3-ethoxy-3-iminopropionate hydrochloride (2.0 g.10.2 mmol) was added and the mixture was allowed to react at 50℃for 2 hours. Diatomaceous earth was filtered, the filtrate was concentrated, extracted with saturated sodium bicarbonate (10 mL), water (20 mL) and dichloromethane/methanol=9:1 (100 mL), and purified on a silica gel column (dichloromethane: methanol=15:1) to give 800mg of the title compound in yield: 63.5%.
Preparation of 7-amino-6- (7-ethyl-1,5,6,7,8,9-hexahydroimidazolyl [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
Ethyl 2- (7-ethyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (50 mg,0.17 mmol), 3-aminothiophene-2-carbonitrile (21 mg,0.17 mmol) was dissolved in tetrahydrofuran (10 mL), LDA (0.43 mL,0.86 mmol) was added at 40℃and reacted at 40℃for 3 hours. The reaction was quenched with saturated ammonium chloride, extracted with water (15 mL) and ethyl acetate (15 mL), methanol (3 mL) was added, filtered, and dried to give 21mg of the title compound, yield: 32.6%.
Molecular formula C 20 H 21 N 5 OS molecular weight 379.5 LC-MS (M/e): 380.1 (M+H) + )
1 H-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).
Preparation example 8: preparation of 7-amino-6- (7-cyclobutyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 11)
Preparation of 1.8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine
N- (8-nitro-3- (2, 2-trifluoroacetyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide (1.0 g,2.9 mmol) was dissolved in methanol (10.0 mL), potassium carbonate (600.0 mg,4.3 mmol) was added and reacted at 20℃for 2.0H, after the reaction was completed, the crude product was directly used for the next reaction after filtration, water washing, dichloromethane extraction concentration.
Preparation of 2, 3-cyclobutyl-8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine
8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine (crude product of the above step) was dissolved in 10.0mL of methanol, sodium cyanoborohydride (550.0 mg,8.8 mmol), acetic acid (1.7 g,28.3 mmol) and cyclobutanone (410.0 mg,5.8 mmol) were added dropwise at 0deg.C and reacted for 2.0H at 20deg.C. To the reaction solution was added water (100 mL), which was quenched, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and dried by spinning to give 300mg of the objective compound in 39.6% yield in two steps.
Preparation of 3, 3-cyclobutyl-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepine-7, 8-diamine
3-cyclobutyl-8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine (250 mg) was dissolved in ethanol (10 mL), pd/C (50.0 mg) was added, and the reaction was completed at 25℃for 1.5H under hydrogen atmosphere, and the reaction solution was directly used for the next reaction.
Preparation of ethyl 2- (7-cyclobutyl-1,5,6,7,8,9-hexahydroimidazolyl [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate
To the reaction mixture of the above step was added ethyl 3-ethoxy-3-iminopropionate hydrochloride (330.0 mg,1.7 mmol), and the reaction was completed after the system had been heated to 80℃for 2 hours. After filtration, the pH was adjusted to 8 with saturated sodium bicarbonate solution, and column chromatography (dichloromethane: methanol=10:1) after concentration gave 200mg of the target compound in a two-step yield of 63.9%.
Preparation of 7-amino-6- (7-cyclobutyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
Ethyl 2- (7-cyclobutyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (30.0 mg,0.09 mmol) and 3-aminothiophene-2-carbonitrile (13.0 mg,0.10 mmol) were dissolved in tetrahydrofuran (3.0 mL), LDA (0.3 mL,0.60 mmol) was added dropwise at 40℃under nitrogen protection, and the reaction was continued for 2.0h. After the reaction was completed, the system was quenched by pouring into saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase was spin-dried, and the crude product was purified by column chromatography on silica gel (DCM: meoh=10:1), slurried with methanol, and purified to yield 12.0mg of product in 32.3%.
Molecular formula C 22 H 23 N 5 OS molecular weight 405.5 LC-MS (M/e): 406.0 (M+H) + )
1 H-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).
Preparation example 9: preparation of 7-amino-6- (7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazolyl [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 12)
Preparation of 3-cyclopropyl-7-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepine
7-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepine (4.2 g,21.8 mmol), sodium cyanoborohydride (8.7 g,139.5 mmol), acetic acid (13.6 g,230.6 mmol) were dissolved in methanol (120 mL), 1-ethoxycyclopropoxy) trimethylsilane (8.7 g,50.1 mmol) was added dropwise at 0deg.C, the reaction was completed for 4H at 60deg.C, LCMS detection reaction was completed, water (100 mL) was added to the reaction solution to quench, ethyl acetate extraction, and the organic phase was dried over anhydrous sodium sulfate, and dried to give 4g of the target compound in 78.7% yield.
Preparation of 2, 3-cyclopropyl-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine
3-cyclopropyl-7-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepine (3.8 g,16.3 mmol) was dissolved in methanol (50 mL), pd/C (1.9 g) was added, the reaction was carried out at 25℃for 16H under hydrogen, LCMS detection was complete, suction filtration was carried out, and the filtrate was spun dry to give crude 3.5g.
3. Preparation of N- (3-cyclopropyl-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide
3-cyclopropyl-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine (3.5 g, crude product) is dissolved in acetic acid (20 mL), acetic anhydride (3 mL) is added, the reaction is carried out for 4H at 25 ℃, LCMS detection reaction is completed, the reaction solution is dried by spinning, the pH value of saturated sodium bicarbonate aqueous solution is adjusted to 8-9, dichloromethane extraction is carried out, the organic phase is dried by spinning, and silica gel column chromatography separation (dichloromethane: methanol=20:1) is carried out to obtain 2.12g of target compound, and the yield is 53.1%.
4. Preparation of N- (3-cyclopropyl-8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide
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 (22 mL), fuming nitric acid (849 mg,13 mmol) was added at 0deg.C, the reaction was carried out for 0.5H at 25deg.C, LCMS detection was completed, pH was adjusted to 8-9 with 5M sodium hydroxide solution, DCM extraction, the organic phase dried over anhydrous sodium sulfate, and spin-dried to give 2g of product with 79.7% yield.
Preparation of 3-cyclopropyl-8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine
N- (3-cyclopropyl-8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide (1.96 g,6.76 mmol) was dissolved in methanol (35 mL), potassium carbonate (4.6 g,33.4 mmol) was added, the reaction was allowed to react at 65℃for 8H, LCMS detection was completed, celite was filtered, and the title compound was isolated by silica gel column chromatography (methanol: dichloromethane=1:15) in 65.1 g yield.
Preparation of ethyl 2- (7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate
3-cyclopropyl-8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine (1.1 g,4.4 mmol) was dissolved in ethanol (25 mL), reacted under hydrogen for 2H at 25℃and ethyl 3-ethoxy-3-iminopropionate hydrochloride (1.7 g,8.8 mmol) was added, LCMS detection reaction was complete, filtration, spin-dry filtrate, silica gel column chromatography (dichloromethane: methanol=10:1) to give 900mg of product in 65.1% yield.
Preparation of 7.7-amino-6- (7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazolyl [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
Ethyl 2- (7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (200 mg,0.64 mmol) and 3-aminothiophene-2-carbonitrile (76 mg,0.61 mmol) were dissolved in tetrahydrofuran (5 mL), LDA (1.5 mL,2.88 mmol) was added dropwise at 40℃under nitrogen, and the reaction continued for 6h, and LCMS detection was complete. Pouring into saturated ammonium chloride solution for quenching, extracting with ethyl acetate, spinning dry the organic phase, purifying the crude product by silica gel column chromatography (dichloromethane: methanol=10:1), pulping and purifying the methanol to obtain 77mg of product with the yield of 30.7%.
Molecular formula C 21 H 21 N 5 OS molecular weight 391.5 LC-MS (M/e): 392.0 (M+H) + )
1 H-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).
Preparation example 10: preparation of 6- (7-acetyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7-aminothiophene [3,2-b ] pyridine-5 (4H) (Compound 13)
Preparation of ethyl 2- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate hydrochloride
2- (2-ethoxy-2-oxoethyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylic acid tert-butyl ester (373 mg,1.0 mmol) was dissolved in 4M HCl/dioxane (10 mL), reacted at 15℃for 2 hours, concentrated to 241mg for the next step.
2. Preparation of ethyl (7-acetyl-1,5,6,7,8,9-hexahydroimidazolyl [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate
Ethyl 2- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (210 mg, crude) was dissolved in dichloromethane (10 mL), acetic anhydride (86 mg,0.85 mmol) was added dropwise at 0℃and the reaction was carried out at 0℃for 2 hours. Concentration, organic phase drying concentration silica gel column purification (dichloromethane: methanol=10:1) gave 200mg of the target compound, two step yield: 63.5%
Preparation of 6- (7-acetyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7-aminothiophene [3,2-b ] pyridine-5 (4H)
Ethyl 7-acetyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (170 mg,0.54 mmol) and 3-aminothiophene-2-carbonitrile (74 mg,0.59 mmol) were dissolved in tetrahydrofuran (10 mL), LDA (1.1 mL,2.16 mmol) was added at 40℃and reacted at 40℃for 5 hours. 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 give the title compound 7.5mg, yield: 3.5%.
Molecular formula C 20 H 19 N 5 O 2 S molecular weight 393.13 LC-MS (M/e): 394.47 (M+H) + )
1 H-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).
Preparation example 11: preparation of 7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) -6- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 14-1)
Preparation of 7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) -4- (4-methoxybenzyl) -6- (7-methyl-1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
4- (4-methoxybenzyl) -6- (7-methyl-1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -5-oxo-4, 5-dihydrothieno [3,2-b ] pyridin-7-yl trifluoromethanesulfonate (N/A, 0.37 mmol) was dissolved in acetonitrile (20 mL), and (1 s,4 s) -4-aminocyclohex-1-ol (170.5 mg,1.48 mmol) was added and reacted at 45℃for 2 hours. LCMS detects the end of the reaction. The reaction solution was concentrated and purified by silica gel column (dichloromethane: methanol=10:1) to give 216mg of the target compound, yield in two steps: 81.8%.
Preparation of 7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) -6- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) -4- (4-methoxybenzyl) -6- (7-methyl-1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (216 mg,0.3 mmol) was dissolved in concentrated hydrochloric acid (2 mL), trifluoroacetic acid (14 mL), and the mixture was reacted at 110℃for 24 hours. LCMS detects the end of the reaction. The solvent was concentrated, dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate, and concentrated by organic phase dryness to give Pre-TLC purification (dichloromethane: methanol=7:1) as the title compound 12.7mg in 9.1% yield.
Molecular formula C 25 H 29 N 5 O 2 S molecular weight 463.6 LC-MS (M/e): 464.0 (M+H) + )
1 H-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).
Preparation example 12: preparation of 7- (isopropylamino) -6- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 15)
1.preparation of 7- (isopropylamino) -4- (4-methoxybenzyl) -6- (7-methyl-1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
4- (4-methoxybenzyl) -6- (7-methyl-1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -5-oxo-4, 5-dihydrothieno [3,2-b ] pyridin-7-yl trifluoromethanesulfonate (N/A, 0.23 mmol) was dissolved in acetonitrile (10 mL), isopropylamine (54.3 mg,0.92 mmol) was added and the reaction was carried out at 40℃for 2 hours. LCMS detects the end of the reaction. The reaction mixture was purified by column chromatography on silica gel (dichloromethane: methanol=20:1) to give 100mg of the objective compound.
Preparation of 7- (isopropylamino) -6- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
7- (isopropylamino) -4- (4-methoxybenzyl) -6- (7-methyl-1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (100 mg,0.15 mmol) was dissolved in concentrated hydrochloric acid (1.5 mL), trifluoroacetic acid (10.5 mL), and the addition was completed and reacted to 110℃for 24 hours. LCMS detects the end of the reaction. The solvent was concentrated, dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate, and concentrated by organic phase dryness to give Pre-TLC purification (dichloromethane: methanol=7:1) as the title compound 12.5mg in 20.2% yield.
Molecular formula C 22 H 25 N 5 OS molecular weight 407.5 LC-MS (M/e): 408.0 (M+H) + )
1 H-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).
Preparation example 13: preparation of 4-amino-5- (8-methyl-1,6,7,8,9,10-hexahydroimidazo [4',5':3,4] benzo [1,2-d ] azepin-2-yl) thieno [2,3-b ] pyridin-6 (7H) -one (Compound 19)
1. Preparation of N- (6-nitro-3- (2, 2-trifluoroacetyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide
N- (3- (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 0deg.C, and the addition was completed, and the reaction was carried out at 0deg.C for 1.5 hours. LCMS detects the end of the reaction. Pouring into ice water, extracting with dichloromethane, drying and concentrating the organic phase, and separating by silica gel column chromatography (petroleum ether: ethyl acetate=2:1) to obtain the title compound 800mg, with a yield of 12.6%.
Preparation of 2, 6-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine
N- (6-nitro-3- (2, 2-trifluoroacetyl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide (800 mg,2.3 mmol) was dissolved in methanol (20 mL), potassium carbonate (960 mg,6.9 mmol) was added, and the mixture was reacted at 55℃for 24 hours. Filtration through celite, concentration of the filtrate, and purification by C18 column (methanol=0-50%) gave the title compound 400mg, yield 83.3%.
Preparation of 3-methyl-6-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine
6-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine (400 mg,1.9 mmol) was dissolved in methanol (10 mL), formaldehyde (37%) (791.2 mg,9.7 mmol), acetic acid (114.0 mg,1.9 mmol) were added, reacted at 15℃for 1 hour, sodium cyanoborohydride (601.4 mg,9.7 mmol) was added, and the mixture was reacted at 15℃for 1 hour. LCMS detects the end of the reaction. The solvent was concentrated, the solid was dissolved in dichloromethane, washed with saturated sodium chloride and saturated aqueous sodium bicarbonate, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, and dried by spin-drying, and the title compound was obtained in 280mg by silica gel column chromatography (methanol: dichloromethane=1:10) in 65.6% yield.
Preparation of ethyl 2- (8-methyl-1,6,7,8,9,10-hexahydroimidazo [4',5':3,4] benzo [1,2-d ] azepin-2-yl) acetate
3-methyl-6-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine (280 mg,1.3 mmol) was dissolved in ethanol (10 mL), pd/C (100 mg) was added, hydrogenation was carried out at 15℃for 1 hour after the addition, 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (594.8 mg,3.0 mmol) was added, and reaction was carried out at 55℃for 1 hour after the addition. LCMS detects the end of the reaction. Diatomaceous earth was filtered, the filtrate was concentrated to give a solid which was dissolved in methylene chloride, washed with saturated aqueous sodium bicarbonate, separated, extracted with methylene chloride, and separated by organic phase dry concentration on silica gel column chromatography (methanol: methylene chloride=1:4) to give 250mg of the title compound in 68.8% yield.
Preparation of 4-amino-5- (8-methyl-1,6,7,8,9,10-hexahydroimidazo [4',5':3,4] benzo [1,2-d ] azepin-2-yl) thieno [2,3-b ] pyridin-6 (7H) -one
Ethyl 2- (8-methyl-1,6,7,8,9,10-hexahydroimidazo [4',5':3,4] benzo [1,2-d ] azepin-2-yl) acetate (100 mg,0.35 mmol) and 2-amino-3-cyanothiophene (43.4 mg,0.35 mmol) were dissolved in tetrahydrofuran (10 mL), LDA (0.7 mL,1.4 mmol) was added dropwise under nitrogen protection at 40℃and the mixture was reacted at 40℃for 2 hours. LCMS detects the end of the reaction. The reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, and concentrated in vacuo to give a solid, which was slurried with methanol to give 16.2mg of the title compound in 12.7% yield.
Molecular formula C 19 H 19 N 5 OS molecular weight 365.5 LC-MS (M/e): 366.0 (M+H) + )
1 H-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).
Preparation example 14:6- (7- (2-hydroxyethyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (isopropylamino) thieno [3,2-b ] pyridin-5 (4H) -one hydrochloride (hydrochloride of Compound 20)
Preparation of tert-butyl 2- (7- (isopropylamino) -4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrothieno [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylate
2- (4- (4-methoxybenzyl) -5-oxo-7- (((trifluoromethyl) sulfonyl) oxy) -4, 5-dihydrothieno [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylic acid tert-butyl ester (500 mg,0.60 mmol) was dissolved in acetonitrile (10 mL), isopropylamine (141.8 mg,2.4 mmoles) was added and reacted at 40℃for 2 hours. LCMS detects the end of the reaction. The reaction solution was concentrated and purified by silica gel column (ethyl acetate: petroleum ether=1:1) to give 180mg of the objective compound in 40.2% yield.
Preparation of 6- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (isopropylamino) thieno [3,2-b ] pyridin-5 (4H) -one
2- (7- (isopropylamino) -4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrothieno [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepine-7 (1H) -carboxylic acid tert-butyl ester (180 mg,0.24 mmol) was dissolved in concentrated hydrochloric acid (1.0 mL) and trifluoroacetic acid (7.0 mL) and reacted at 110℃for 48 hours. LCMS detects the end of the reaction. The solvent was concentrated and used directly in the next reaction.
Preparation of 6- (7- (2- (((tert-butyldimethylsilyl) oxy) ethyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (isopropylamino) thieno [3,2-b ] pyridin-5 (4H) -one
6- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (isopropylamino) thieno [3,2-b ] pyridin-5 (4H) -one (N/A, 0.51 mmol) was dissolved in methanol (10 mL), 2- ((tert-butyldimethylsilyl) oxy) acetaldehyde (266.7 mg,1.5 mmol) and acetic acid (30.6 mg,0.51 mmol)) were added at 25℃and sodium cyanoborohydride (96.1 mg,1.5 mmol)) was added and the reaction was continued for 4 hours. The reaction was quenched with water, extracted with dichloromethane (50 mL) and the organic phase was purified on a column of concentrated silica gel (methanol/dichloromethane=1:10) to give 170.0mg of the target compound in a two-step yield of 60.5%.
Preparation of 6- (7- (2-hydroxyethyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (isopropylamino) thieno [3,2-b ] pyridin-5 (4H) -one hydrochloride
6- (7- (2- (((tert-Butyldimethylsilyl) oxy) ethyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (isopropylamino) thieno [3,2-b ] pyridin-5 (4H) -one (160.0 mg,0.29 mmol) was dissolved in tetrahydrofuran (4 mL) and concentrated hydrochloric acid (4 mL) and reacted for 1 hour after the reaction was completed, the filter cake was collected and washed with ethyl acetate and dichloromethane to give 19.4mg of the title compound in 15.3% yield.
Molecular formula C 23 H 27 N 5 O 2 S molecular weight 437.6 LC-MS (M/e): 438.2 (M+H) + )
1 H-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).
Preparation example 15: preparation of 7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) -6- (7- (oxetan-3-yl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 21-1)
6- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) thieno [3,2-b ] pyridin-5 (4H) -one (80 mg,0.18 mmol) was dissolved in methanol (10 mL), 3-oxetanone (38.5 mg,0.54 mmol) \acetic acid (10.8 mg,0.18 mmol) was added and reacted at 20℃for 30 minutes, sodium cyanoborohydride (33.5 mg,0.54 mmol) was added and reacted at 20℃for 17 hours. LCMS detects the end of the reaction. The solvent was concentrated, the solid was dissolved in methylene chloride, washed with saturated sodium chloride and saturated aqueous sodium bicarbonate, extracted with methylene chloride, the organic phase was dried over anhydrous sodium sulfate, and dried by spin-drying, and the target compound was obtained by column chromatography on silica gel (methanol: methylene chloride=1:15) in 15.1% yield.
Molecular formula C 27 H 31 N 5 O 3 S molecular weight 505.6 LC-MS (M/e): 506.0 (M+H) + )
1 H-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).
Preparation example 16: preparation of 7- (((1 s,3 s) -3-hydroxycyclobutyl) amino) -6- (7- (oxetan-3-yl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -1-one (Compound 22-1)
Preparation of tert-butyl 2- (7- (((1 s,3 s) -3-hydroxycyclobutyl) amino) -4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrothieno [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylate
2- (4- (4-methoxybenzyl) -5-oxo-7- (((trifluoromethyl) sulfonyl) oxy) -4, 5-dihydrothieno [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylic acid tert-butyl ester (500 mg,0.6 mmol) was dissolved in acetonitrile (10 mL), cis-3-aminocyclobutanol hydrochloride (295.7 mg,2.4 mmol) was added and the mixture was reacted at 40℃for 2 hours. LCMS detects the end of the reaction. The solvent was concentrated and separated by column chromatography on silica gel (methanol: dichloromethane=1:20) to give 400mg of the target compound in 86.6% yield.
2.6- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (((1 s,3 s) -3-hydroxycyclobutyl) amino) thieno [3,2-b ] pyridin-5 (4H) -one preparation
2- (7- (((1 s,3 s) -3-hydroxycyclobutyl) amino) -4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrothieno [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylic acid tert-butyl ester (400 mg,0.52 mmol) was dissolved in concentrated hydrochloric acid (2 mL) and trifluoroacetic acid (14 mL) and reacted at 110℃for 20 hours. The solvent was concentrated, the solid was dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, and subjected to C18 column chromatography (methanol=0 to 60%) to give 150mg of the title compound in 68.8% yield.
Preparation of 7- (((1 s,3 s) -3-hydroxycyclobutyl) amino) -6- (7- (oxetan-3-yl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -1-one
6- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (((1 s,3 s) -3-hydroxycyclobutyl) amino) thieno [3,2-b ] pyridin-5 (4H) -one (150 mg,0.36 mmol) was dissolved in methanol (15 mL), 3-oxetanone (77.1 mg,1.1 mmol) and acetic acid (21.6 mg,0.36 mmol) were added, reacted at 20℃for 30 minutes, sodium cyanoborohydride (68.2 mg,1.1 mmol) was added, and reacted at 20℃for 17 hours. LCMS detects the end of the reaction. The solvent was concentrated, the solid was dissolved in methylene chloride, washed with saturated sodium chloride and saturated aqueous sodium bicarbonate, extracted with methylene chloride, the organic phase was dried over anhydrous sodium sulfate, and dried by spin-drying, and the target compound was obtained in a yield of 9.9% by silica gel column chromatography (methanol: methylene chloride=1:15).
Molecular formula C 25 H 27 N 5 O 3 S molecular weight 477.6 LC-MS (M/e): 478.0 (M+H) + )
1 H-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).
Preparation example 17: preparation of 6- (7- (cyclopropanecarbonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 23-1)
Preparation of ethyl 2- (7- (cyclopropanecarbonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate
Ethyl 2- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate hydrochloride (1.7 g5.5 mmol), triethylamine (3.9 g,38.5 mmol) and cyclopropanecarbonyl chloride (600 mg,5.7 mmol) were dissolved in 40mL dichloromethane and reacted at 0℃for 1.5 hours. After the reaction, the mixture was concentrated and purified by silica gel column (methanol: dichloromethane=10%) to obtain 1.5g of the target compound, yield: 71.8%.
2. (E) Preparation of ethyl-2- (7- (cyclopropanecarbonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -3-hydroxy-3- (3- ((4-methoxybenzyl) amino) thiophen-2-yl) propionate
Ethyl 2- (7- (cyclopropanecarbonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (850 mg,2.5 mmol) and 1- (4-methoxybenzyl) -2H-thieno [3,2-d ] [1,3] oxazine-2, 4 (1H) -dione (780 mg,2.7 mmol) were dissolved in tetrahydrofuran (10 mL), LDA (5.0 mL,10.0 mmol) was added at 40℃and reacted for 2 hours. After the reaction, saturated ammonium chloride aqueous solution is added for quenching, dichloromethane extraction is carried out, the organic phase is concentrated, and the crude product is directly used in the next step.
Preparation of 6- (7- (cyclopropanecarbonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7-hydroxy-4- (4-methoxybenzyl) thieno [3,2-b ] pyridin-5 (4H) -one
The crude product of the previous step is dissolved in 15mL tetrahydrofuran, LDA (5.0 mL) is added dropwise at 40 ℃ and the reaction is completed for 1.5h, after the completion, saturated ammonium chloride aqueous solution is added for quenching, dichloromethane extraction is carried out, and the organic phase is concentrated to obtain 650mg of crude product of the target compound.
Preparation of 6- (7- (cyclopropanecarbonyl) -1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrothiophen [3,2-b ] pyridin-7-yl trifluoromethanesulfonate
6- (7- (cyclopropanecarbonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7-hydroxy-4- (4-methoxybenzyl) thieno [3,2-b ] pyridin-5 (4H) -one (600 mg,1.1 mmol) was dissolved in dichloromethane (15 mL), cooled to-15 ℃, pyridine (1.8 g,22.8 mmol) and trifluoromethanesulfonic anhydride (3.0 g,10.6 mmol) were added and the reaction was completed for 1.0 hour, quenched with saturated sodium bicarbonate solution, dichloromethane extracted, and the organic phase was dried and concentrated to give crude target compound, which was used directly in the next step.
5.6- (7- (cyclopropanecarbonyl) -1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) -4- (4-methoxybenzyl) thieno [3,2-b ] pyridin-5 (4H) -one preparation
The crude product of the above step was dissolved in 10mL of acetonitrile, and (1 s,4 s) -4-aminocyclohex-1-ol (160 mg, 1.4 mmol) was added thereto, and the reaction was carried out at 50℃for 1 hour. The target compound was obtained by filtration through celite, drying, concentration and column chromatography (methanol: dichloromethane=10%) in a yield of 35.1% in two steps.
6. Preparation of (1 s,4 s) -4- ((6- (7- (cyclopropanecarbonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -5-oxo-4, 5-dihydrothieno [3,2-b ] pyridin-7-yl) amino) cyclohexyl-2, 2-trifluoroacetate
6- (7- (cyclopropanecarbonyl) -1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) -4- (4-methoxybenzyl) thieno [3,2-b ] pyridin-5 (4H) -one (300 mg,0.39 mmol) is dissolved in trifluoroacetic acid (3 mL) and concentrated hydrochloric acid 1mL and reacted at 115℃for 22H before proceeding with the next reaction.
7.6- (7- (cyclopropanecarbonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) thieno [3,2-b ] pyridin-5 (4H) -one preparation
The crude product of the above step was dissolved in 10mL of methanol, 150mg of potassium carbonate was added thereto, and the mixture was reacted at 25℃for 1 hour. After the reaction, the solvent was concentrated, and the target product was 16mg by column chromatography, with a yield of 7.9% in two steps.
Molecular formula C 28 H 31 N 5 O 3 S molecular weight 517.6. 517.6 LC-MS (M/e): 518.0 (M+H) + )
1 H-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).
Preparation example 18: preparation of 7-amino-6- (7- (3-hydroxycyclobutyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (bromate of Compound 24)
Preparation of ethyl 2- (7- (3- (benzyloxy) cyclobutyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate)
Ethyl 2- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate hydrochloride (230 mg,0.74 mmol), 3- (benzyloxy) cyclobutan-1-one (196 mg,1.11 mmol), acetic acid (44 mg,0.74 mmol) were dissolved in dichloromethane (10 mL), sodium borohydride acetate (314 mg,1.48 mmol) was added at 0deg.C, the reaction was allowed to proceed for 8h at 25deg.C, and LCMS detection was complete. The reaction solution was poured into a saturated aqueous sodium hydroxide solution (50 mL), extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, dried by spin-drying, and separated by silica gel column chromatography (methanol: dichloromethane=1:10) to give 260mg of the objective compound in a yield of 81.0%.
Preparation of 7-amino-6- (7- (3- (benzyloxy) cyclobutyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
Ethyl 2- (7- (3- (benzyloxy) cyclobutyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (150 mg,0.35 mmol) and 3-aminothiophene-2-carbonitrile (43 mg,0.35 mmol) were dissolved in tetrahydrofuran (5 mL), LDA (1.05 mL,2.1 mmol) was added dropwise at 40℃and the reaction was continued for 4h, LCMS detection was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution and quenched, dichloromethane extraction, the organic phase was dried over anhydrous sodium sulfate, dried, and silica gel column chromatography (methanol: dichloromethane=1:10) gave the title compound in 55.8% yield.
Preparation of 7-amino-6- (7- (3-hydroxycyclobutyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one bromate
7-amino-6- (7- (3- (benzyloxy) cyclobutyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (50 mg,0.10 mmol) was dissolved in dichloromethane (5 mL), boron tribromide (100 mg,0.40 mmol) was added dropwise at-40℃and the reaction was carried out for 1H at 25℃and completion of LCMS detection. Adding methanol for quenching, spin-drying the solvent, and pulping the crude product by methanol to obtain 19mg of the target compound with the yield of 37.8%.
Molecular formula C 22 H 24 BrN 5 O 2 S molecular weight 502.4 LC-MS (M/e): 422.0 (M+H) + )
1 H-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).
Preparation example 19: preparation of 7-amino-6- (7- (2-hydroxyethyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-pyridin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one hydrochloride (hydrochloride of Compound 25)
Preparation of ethyl 2- (7- (2- ((tert-butyldimethylsilyl) oxy) ethyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate
Ethyl 2- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (240 mg,0.88 mmol) was dissolved in methanol (10 mL), 2- ((tert-butyldimethylsilyl) oxy) acetaldehyde (352 mg,2.0 mmol) and acetic acid (560 mg,9.3 mmol) were added at 20℃and reacted for 5 minutes at 20℃followed by sodium cyanoborohydride (352 mg,6.4 mmol) and reacted for 6 hours at 20 ℃. After the reaction, the solvent was dried by spinning, saturated aqueous sodium bicarbonate (20 mL) was added to quench the reaction, ethyl acetate (50 mL) was extracted, the organic phase was concentrated, and purified by silica gel column (methanol/dichloromethane=1:20) to give 250mg of the target compound in 65.8% yield.
Preparation of 7-amino-6- (7- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
Ethyl 2- (7- (2- ((tert-butyldimethylsilyl) oxy) ethyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (250 mg,0.58 mmol) and 3-aminothiophene-2-carbonitrile (71 mg,0.57 mmol) are dissolved in anhydrous tetrahydrofuran (5 mL) and LDA (1.2 mL,2.3 mmol) is added at 40 ℃. After the reaction, the reaction was quenched by addition of saturated aqueous ammonium chloride at 0 ℃, the organic phase was dried, concentrated, and purified on a silica gel column (dichloromethane: methanol=10:1) to give 80mg of the title compound, yield: 27.0%.
Preparation of 7-amino-6- (7- (2-hydroxyethyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-pyridin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one hydrochloride
7-amino-6- (7- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (50 mg,0.1 mmol) was dissolved in 1ml tetrahydrofuran and 1ml concentrated hydrochloric acid and reacted for 0.5 hours. After the reaction was completed, a filter cake was collected by filtration, and washed with ethyl acetate and methylene chloride to give 12.4mg of the objective compound in a yield of 26.4%.
Molecular formula C 20 H 22 ClN 5 O 2 S molecular weight 431.9 LC-MS (M/e): 396.5 (M+H) + )
1 H-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).
Preparation example 20: preparation of 7-amino-6- (7- (oxetan-3-yl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 26)
Preparation of ethyl 2- (7- (oxetan-3-yl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -acetate
Ethyl 2- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate hydrochloride (309.1 mg,1.0 mmol) was dissolved in methanol (30 mL), 3-oxetanone (216.3 mg,3.0 mmol), acetic acid (60.0 mg,1.0 mmol) was added, and the mixture was reacted at 20℃for 30 minutes, sodium cyanoborohydride (186.0 mg,3.0 mmol) was added, and the mixture was reacted at 20℃for 17 hours. LCMS detects the end of the reaction. The solvent was concentrated, the solid was dissolved in dichloromethane, washed with saturated sodium chloride and saturated aqueous sodium bicarbonate, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, and dried by spin-drying, and separated by silica gel column chromatography (methanol: dichloromethane=1:15) to give 200mg of the title compound in 60.8% yield.
Preparation of 7-amino-6- (7- (oxetan-3-yl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
6- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (((1 s,3 s) -3-hydroxycyclobutyl) amino) thieno [3,2-b ] pyridin-5 (4H) -one (150 mg,0.36 mmol) was dissolved in methanol (15 mL), 3-oxetanone (77.1 mg,1.1 mmol) and acetic acid (21.6 mg,0.36 mmol) were added, reacted at 20℃for 30 minutes, sodium cyanoborohydride (68.2 mg,1.1 mmol) was added, and reacted at 20℃for 17 hours. LCMS detects the end of the reaction. The solvent was concentrated, the solid was dissolved in methylene chloride, washed with saturated sodium chloride and saturated aqueous sodium bicarbonate, extracted with methylene chloride, the organic phase was dried over anhydrous sodium sulfate, and dried by spin-drying, and the target compound was obtained by column chromatography on silica gel (methanol: methylene chloride=1:15) in a yield of 9.1%.
Molecular formula C 21 H 21 N 5 O 2 S molecular weight 407.5 LC-MS (M/e): 408.1 (M+H) + )
1 H-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).
Preparation example 21:7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) -3-methyl-6- (7-methyl-1- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one hydrochloride (hydrochloride of compound 27-1)
Preparation of 3-amino-4-methylthiophene-2-carboxylic acid
3-amino-4-methylthiophene-2-carboxylic acid methyl ester (1.71 g,10 mmol) and potassium hydroxide (1.12 g,20 mmol) were dissolved in water (20 mL) and reacted at 90℃for 1 hour. The reaction solution was used directly in the next step.
Preparation of 2.7-methyl-2H-thieno [3,2-d ] [1,3] oxazine-2, 4 (1H) -dione
3-amino-4-methylthiophene-2-carboxylic acid (reaction solution in the previous step) was cooled to 0℃and trichloromethyl chloroformate (2.37 g,12 mol) was added thereto, followed by a reaction at 20℃for 2 hours. Suction filtration and collection of solid spin-drying gave the title compound 1.6g, yield 87.3%.
Preparation of 1- (4-methoxybenzyl) -7-methyl-2H-thieno [3,2-d ] [1,3] oxazine-2, 4- (1H) -dione
7-methyl-2H-thieno [3,2-d ] [1,3] oxazine-2, 4 (1H) -dione (1.6 g,8.7 mmol), 1- (chloromethyl) -4-methoxybenzene (1.65 g,10.5 mmol), potassium carbonate (1.45 g,10.5 mmol) and potassium iodide (282 mg,1.7 mmol) were dissolved in N, N-dimethylformamide (23 mL) and reacted at 20℃for 16 hours. The reaction solution was poured into water (100 mL), suction filtration was performed, and the solid was collected, dried by spin-drying, and purified by a silica gel column (dichloromethane) to give 1.5g of the objective compound in a yield of 64.7%.
Preparation of ethyl 3- (3- (((4-methoxybenzyl) amino) -4-methylthiophene-2-yl) -2- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -3-oxopropionate
Ethyl 2- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (470 mg,1.65 mmol) and 1- (4-methoxybenzyl) -7-methyl-2H-thieno [3,2-d ] [1,3] oxazine-2, 4 (1H) -dione (500 mg,1.65 mmol) are dissolved in tetrahydrofuran (20 mL). LDA (3.3 mL,6.6 mmol) was added at 40℃under nitrogen protection, and the reaction was completed at 40℃for 4 hours. The reaction was quenched with saturated aqueous ammonium chloride at 0deg.C, the organic phase was dried, concentrated, and purified on a silica gel column (dichloromethane: methanol=10:1) to give 480mg of the title compound in 53.3% yield.
Preparation of 7-hydroxy-4- (4-methoxybenzyl) -3-methyl-6- (7-methyl-1,5,6,7,8,9-hexahydroimidazolyl [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
Ethyl 3- (3- (((4-methoxybenzyl) amino) -4-methylthiophene-2-yl) -2- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -3-oxopropionate (480 mg,0.88 mmol) was dissolved in tetrahydrofuran (8 mL), LDA (1.76 mL,3.52 mol) was added at 40 ℃ under nitrogen protection, and the addition was completed and reacted at 40 ℃ for 2 hours, quenched with saturated aqueous ammonium chloride (8 mL), the organic phase was concentrated, and the silica gel column was purified (dichloromethane: methanol=4:1) to give 390mg of the title compound in 88.7% yield.
Preparation of 4- (4-methoxybenzyl) -3-methyl-6- (7-methyl-1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -5-oxo-4, 5-dihydro-thieno [3,2-b ] pyridin-7-yl trifluoromethanesulfonate
7-hydroxy-4- (4-methoxybenzyl) -3-methyl-6- (7-methyl-1,5,6,7,8,9-hexahydroimidazolyl [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (390 mg,0.78 mmol) was dissolved in dichloromethane (8 mL), pyridine (1232 mg,15.6 mmol) was added at 0deg.C, and trifluoromethanesulfonic anhydride (1318 mg,4.68 mmol) was reacted at 0deg.C for 1 hour. The reaction was quenched with saturated aqueous sodium bicarbonate, extracted with dichloromethane, and the organic phase was concentrated by drying and used directly in the next step.
Preparation of 7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) -4- (4-methoxybenzyl) -3-methyl-6- (7-methyl-1- (((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
4- (4-methoxybenzyl) -3-methyl-6- (7-methyl-1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -5-oxo-4, 5-dihydrothieno [3,2-b ] pyridin-7-yl trifluoromethanesulfonate (N/A, 0.39 mmol) was dissolved in acetonitrile (5 mL), and (1 s,4 s) -4-aminocyclohex-1-ol (178 mg,1.56 mmol) was added and reacted at 40℃for 2 hours. The reaction mixture was purified by column chromatography on silica gel (dichloromethane: methanol=10:1) to give 180mg of the target compound in two steps with a yield of 63.3%.
Preparation of 7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) -3-methyl-6- (7-methyl-1- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one hydrochloride
7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) -4- (4-methoxybenzyl) -3-methyl-6- (7-methyl-1- (((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (180 mg,0.25 mmol) was dissolved in concentrated hydrochloric acid (1 mL) and trifluoroacetic acid (7 mL), and then allowed to react for 24 hours at 110℃after addition, the solvent was concentrated, dichloromethane (20 mL) was added, naOH (1N, 20 mL) solution was added and stirred for 0.2 hours, the organic phase was concentrated, and then prepared by medium-pressure reverse phase (0-50% methanol/water (0.5% concentrated hydrochloric acid)) to give 70mg of the title compound in 59.4% yield.
Molecular formula C 26 H 32 ClN 5 O 2 S molecular weight 514.1 LC-MS (M/e): 478.0 (M+H) + )
1 H-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).
Preparation example 22:7- (((1S, 4S) -4-hydroxycyclohexyl) amino) -2-methyl-6- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 28-1)
Preparation of 7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) -4- (4-methoxybenzyl) -2-methyl-6- (7-methyl-1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
Using 3-amino-5-methylthiophene-2-carboxylic acid methyl ester as a starting material, 7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) -4- (4-methoxybenzyl) -2-methyl-6- (7-methyl-1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one was prepared according to the method of preparation example 21.
2. Preparation of (1 s,4 s) -4- ((2-methyl-6- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -5-oxo-4, 5-dihydrothieno [3,2-b ] pyridin-7-yl) amino) cyclohexyl 2, 2-trifluoroacetate
7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) -4- (4-methoxybenzyl) -2-methyl-6- (7-methyl-1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (150 mg,0.21 mmol) was dissolved in concentrated hydrochloric acid (1 mL) and trifluoroacetic acid (4 mL) and the addition was completed to 115℃for 5.0 hours. The solvent was concentrated and used directly in the next reaction.
Preparation of 7- (((1S, 4S) -4-hydroxycyclohexyl) amino) -2-methyl-6- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
The crude product of the above step was dissolved in 5mL of methanol, potassium carbonate (300 mg,2.2 mmol) was added, the solvent was concentrated after reacting at 25℃for 1 hour, and the target compound 15mg was obtained by column chromatography (dichloromethane: methanol=10:1) in two steps with a yield of 15.3%.
Molecular formula C 26 H 31 N 5 O 2 S molecular weight 477.6 LC-MS (M/e): 478.0 (M+H) + )
1 H-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).
Preparation example 23:7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) -2, 3-dimethyl-6- (7-methyl-1- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one hydrochloride (hydrochloride of compound 29-1)
3-amino-4, 5-dimethylthiophene-2-carboxylic acid was used as the starting material, and 7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) -2, 3-dimethyl-6- (7-methyl-1- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one hydrochloride was prepared according to the method of preparation example 21.
Molecular formula C 27 H 34 ClN 5 O 2 S molecular weight 528.1 LC-MS(M/e):492.0(M+H + )
1 H-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).
Preparation example 24:7- ((1 s,4 s) -4-hydroxycyclohexyl) amino) -4-methyl-6- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 30-1)
Preparation of tert-butyl 2- (7-hydroxy-4-methyl-5-oxo-4, 5-dihydrothien [3,2-b ] pyridin-6-yl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylate
2- (2-ethoxy-2-oxoethyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylic acid tert-butyl ester (1.8 g,4.83 mmol) and 1-methyl-2H-thieno [3,2-d ] [1,3] oxazine-2, 4 (1H) -dione (972 mg,5.3 mmol) are dissolved in tetrahydrofuran (50 mL). LDA (9.7 mL,19.3 mmol) was added at 40℃under nitrogen, and the reaction was completed at 40℃for 4 hours. Adding saturated ammonium chloride water solution at 0 ℃ to quench the reaction, extracting the separated liquid by using dichloromethane, and concentrating the organic phase to obtain a product and an intermediate mixed crude product. The crude product of the above step was dissolved in tetrahydrofuran (20 mL), LDA (9.7 mL,19.3 mmol) was added at 40℃under nitrogen protection, and the reaction was carried out for 2 hours at 40 ℃. The reaction was quenched with saturated aqueous ammonium chloride, the organic phase was concentrated, and purified by silica gel column (100% ethyl acetate) to give 710mg of the title compound in 31% yield.
Preparation of tert-butyl 2- (4-methyl-5-oxo-7- ((trifluoromethyl) sulfonyl) oxy) -4, 5-dihydrothien [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepine-7 (1H) -carboxylate
2- (7-hydroxy-4-methyl-5-oxo-4, 5-dihydrothien [3,2-b ] pyridin-6-yl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylic acid tert-butyl ester (710 mg,1.52 mmol) was dissolved in dichloromethane (15 mL), pyridine (2.4 g,30.4 mmol) and trifluoromethanesulfonic anhydride (2.6 g,9.12 mmol) were added at 0deg.C and reacted for 1 hour at 0deg.C. The reaction solution was concentrated, extracted with dichloromethane, washed with saturated aqueous sodium bicarbonate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, and column chromatography (ethyl acetate/n-heptane=0-60%) to give 450mg of the target compound in 41% yield.
Preparation of tert-butyl 2- (7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) -4-methyl-5-oxo-4, 5-dihydrothien [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylate
2- (4-methyl-5-oxo-7- ((trifluoromethyl) sulfonyl) oxy) -4, 5-dihydrothiophen [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepine-7 (1H) -carboxylic acid tert-butyl ester (450 mg,0.62 mmol) was dissolved in acetonitrile (10 mL), and (1 s,4 s) -4-aminocyclohex-1-ol (284 mg,2.5 mmol) was added and reacted at 40℃for 2 hours. The reaction solution was concentrated and purified by silica gel column (dichloromethane: methanol=10:1) to give 430mg of the objective compound in 99% yield.
Preparation of 6- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- ((1 s,4 s) -4-hydroxycyclohexyl) amino) -4-methylthiophene [3,2-b ] pyridin-5 (4H) -one
Tert-butyl 2- (7- (((1 s,4 s) -4-hydroxycyclohexyl) amino) -4-methyl-5-oxo-4, 5-dihydrothiophene [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepine-7 (1H) -carboxylate (120 mg,0.17 mmol) was dissolved in trifluoroacetic acid (4 mL), reacted at 25℃for 1 hour and concentrated. Tetrahydrofuran/water (5/5 mL) mixed solvent was added to the reaction solution, naOH was added to adjust ph=10, and the reaction was carried out at 25 ℃ for 1 hour, and the mixture was concentrated and used directly in the next reaction.
5.7- ((1 s,4 s) -4-hydroxycyclohexyl) amino) -4-methyl-6- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one preparation
6- (1,5,6,7,8,9-hexahydro)Imidazo [4',5':4,5]Benzo [1,2-d]Azepin-2-yl) -7- ((1 s,4 s) -4-hydroxycyclohexyl) amino) -4-methylthiophene [3,2-b]Pyridin-5 (4H) -one (crude product of the above step) was dissolved in 10mL of methanol, 40% aqueous formaldehyde (0.1 mL) and sodium cyanoborohydride (70 mg,1.1 mmol) were added, the solvent was concentrated after 3 hours reaction at 20℃and purified by column chromatography (dichloromethane: methanol=7:1), (0.3% TFA in MeOH/H 2 O=0-75%) to give 40mg of the target compound in 49% yield in two steps.
Molecular formula C 26 H 31 N 5 O 2 S molecular weight 477.6 LC-MS (M/e): 478.2 (M+H) + )
1 H-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).
Preparation example 25: preparation of 7-amino-6- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 33)
Preparation of tert-butyl 2- (7- (((2, 4-dimethoxybenzyl) amino) -4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrothieno [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylate
2- (4- (4-methoxybenzyl) -5-oxo-7- (((trifluoromethyl) sulfonyl) oxy) -4, 5-dihydrothieno [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylic acid tert-butyl ester (N/A, 0.26 mmol) was dissolved in acetonitrile (10 mL), 2, 4-dimethoxybenzylamine (130.3 mg,0.78 mmoL) was added and reacted at 40℃for 2 hours. LCMS detects the end of the reaction. The reaction mixture was purified by column chromatography on silica gel (dichloromethane: methanol=20:1) to give 80mg of the target compound in two steps: 37.4%.
Preparation of 7-amino-6- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
2- (7- (((2, 4-dimethoxybenzyl) amino) -4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrothieno [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepine-7 (1H) -carboxylic acid tert-butyl ester (80 mg, 98.3. Mu. Mol) was dissolved in concentrated hydrochloric acid (0.5 mL), trifluoroacetic acid (3.5 mL), and reacted at 110℃for 48 hours.
Molecular formula C 18 H 17 N 5 OS molecular weight 351.4 LC-MS (M/e): 352.1 (M+H) + )
1 H-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).
Preparation example 26: preparation of isopropyl 2- (7-amino-5-oxo-4, 5-dihydrothiophene [3,2-b ] pyridin-6-yl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylate (Compound 37)
Preparation of isopropyl 2- (2-ethoxy-2-oxoethyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylate
Ethyl 2- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (330 mg,1.2 mmol), triethylamine (607 mg,6.0 mmol) were dissolved in dichloromethane (10 mL), cooled to-10 ℃, isopropyl chloroformate (111 mg,0.91 mmol) was added, and the reaction was allowed to react at-10℃for 2h, and the system was quenched with methanol (1 mL). The system was dried by spin and separated by column chromatography on silica gel (methanol: dichloromethane=1:15) to give 110mg of the target compound in 25.5% yield.
Preparation of isopropyl 2- (7-amino-5-oxo-4, 5-dihydrothiophene [3,2-b ] pyridin-6-yl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylate
Isopropyl 2- (2-ethoxy-2-oxoethyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylate (90 mg,0.25 mmol) and 3-aminothiophene-2-carbonitrile (32 mg,0.26 mmol) were dissolved in tetrahydrofuran (8 mL) and LDA (2M, 0.63mL,1.26 mmol) was added dropwise at 40℃and the reaction continued for 2H. After the reaction, adding saturated ammonium chloride aqueous solution (5 mL) for quenching, then adding ethyl acetate (20 mL) and water (10 mL) for extraction and separation, drying an organic phase by using anhydrous sodium sulfate, spin-drying to obtain 80mg of crude product, then adding methanol (5 mL) for ultrasonic pulping, separating out solid, and then carrying out vacuum suction filtration to obtain 40mg of target compound with the yield of 36.6%.
Molecular formula C 22 H 23 N 5 O 3 S molecular weight 437.5-LC-MS (M/e): 438.0 (M+H) + )
1 H-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).
Preparation example 27: preparation of methyl 2- (7-amino-5-oxo-4, 5-dihydrothiophene [3,2-b ] pyridin-6-yl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylate (Compound 40)
Preparation of methyl 2- (2-ethoxy-2-oxoethyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylate
Ethyl 2- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (300 mg,1.1 mmol), triethylamine (445 mg,4.4 mmol) were dissolved in dichloromethane (40 mL), cooled to 0℃and then methyl chloroformate solution (0.3M/L, 3.7mL,1.1 mmol) was added and reacted at 0℃for 2h, the system was quenched with methanol (2 mL). The system was dried by spin, and after separation by silica gel column chromatography (methanol: dichloromethane=1:20), 220mg of the target compound was obtained, with a yield of 60.4%.
Preparation of methyl 2- (7-amino-5-oxo-4, 5-dihydrothiophene [3,2-b ] pyridin-6-yl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylate
Methyl 2- (2-ethoxy-2-oxoethyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylate (100 mg,0.30 mmol) and 3-aminothiophene-2-carbonitrile (45 mg,0.36 mmol) were dissolved in tetrahydrofuran (15 mL) and LDA (2M, 0.75mL,1.5 mmol) was added dropwise at 40℃and the reaction continued for 2H. The reaction solution was quenched by adding saturated aqueous ammonium chloride (3 mL), then extracted with ethyl acetate (20 mL) and water (10 mL), the organic phase was dried over anhydrous sodium sulfate, the crude product was obtained by spin-drying, methanol (10 mL) was added for ultrasonic pulping, and after precipitation of the solid, 35mg of the target compound was obtained by suction filtration under reduced pressure, with a yield of 28.5%.
Molecular formula C 20 H 19 N 5 O 3 S molecular weight 409.5 LC-MS (M/e): 409.9 (M+H) + )
1 H-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).
Preparation example 28: preparation of 6- (7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (oxa-3-cyclobutylamino) thiophene [3,2-b ] pyridin-5 (4H) -one (Compound 42)
Preparation of 7-chloro-6- (7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thiophene [3,2-b ] pyridin-5 (4H) -one
7-chloro-5-oxo-4, 5-dihydrothiophene [3,2-b ] pyridine-6-carbaldehyde (500 mg,2.35 mmol), 3-cyclopropyl-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepine-7, 8-diamine (510 mg,2.35 mmol), and ferric trichloride (1.5 g,9.4 mmol) were dissolved in 1, 4-dioxane (30 mL), and the temperature was raised to 110℃for 1 hour. LCMS detects the end of the reaction. The temperature is reduced to 25 ℃, the pH of the system is adjusted to be 9 by saturated sodium bicarbonate aqueous solution, dichloromethane is used for extraction, and the organic phase is dried, concentrated and purified by a silica gel column (dichloromethane: methanol=10:1) to obtain 220g of target compound, and the yield is 22.9%.
Preparation of 6- (7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (oxa-3-cyclobutylamino) thiophen [3,2-b ] pyridin-5 (4H) -one
7-chloro-6- (7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thiophen [3,2-b ] pyridin-5 (4H) -one (220 mg,0.54 mmol), 3-aminooxetan (59.2 mg,0.81 mmol), sodium bicarbonate (136.1 mg,1.6 mmol) and tetrabutylammonium iodide (19.9 mg, 54.0. Mu. Mol) were dissolved in water (3 mL) and chloroform (18 mL), warmed to 60℃and reacted for 16 hours. LCMS detects the end of the reaction. Cooling to 25deg.C, adding dichloromethane for dilution, adding water for washing, drying and concentrating the organic phase to obtain solid, pulping the solid with methanol to obtain 14.5mg of target compound with a yield of 6.0%.
Molecular formula C 24 H 25 N 5 O 2 S molecular weight 447.6 LC-MS (M/e): 448.0 (M+H) + )
1 H-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).
Preparation example 29: preparation of 7- (((1 r,4 r) -4-hydroxycyclohexyl) amino) -6- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 44)
1.2- (((1 r,4 r) -4-hydroxycyclohexyl) amino) -4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrothiophene [3, 2-b)]Pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -1,5,7,8,9-hexahydro-7λ 4 Imidazole [4',5':4,5]Benzo [1,2-d]Preparation of tert-butyl azepine-7-carboxylate
2- (4- (4-methoxybenzyl) -5-oxo-7- (((trifluoromethyl) sulfonyl) oxy) -4, 5-dihydrothiophene [3, 2-b)]Pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -1,5,7,8,9-hexahydro-7λ 4 Imidazole [4',5':4,5]Benzo [1,2-d]Azepine-7-carboxylic acid tert-butyl ester (200.0 mg,0.24 mmol) was dissolved in acetonitrile (5 mL), and (1 r,4 r) -4-aminocyclohexane-1-ol (110.1 mg,0.96 mmol) was added and reacted at 45℃for 2 hours. The reaction solution was concentrated and purified by a silica gel column (dichloromethane: methanol=10:1) to give 200.0mg of the crude product of the objective compound.
Preparation of 6- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- ((1 r,4 r) -4-hydroxycyclohexyl) amino) thiophen [3,2-b ] pyridin-5 (4H) -one
2- (((1 r,4 r) -4-hydroxycyclohexyl) amino) -4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrothiophene [3, 2-b)]Pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -1,5,7,8,9-hexahydro-7λ 4 Imidazole [4',5':4,5]Benzo [1,2-d]Azepine-7-carboxylic acid tert-butyl ester (200.0 mg crude, N/A) was dissolved in concentrated hydrochloric acid (4 mL) and trifluoroacetic acid (28 mL), and the mixture was heated to 110℃for 24 hours. The solvent was concentrated, dissolved in dichloromethane (20 mL), 1N NaOH (20 mL) was stirred for 0.2 h, the organic phase was concentrated and prepared in medium pressure reverse phase (0-50% methanol/water (0.5% concentrated hydrochloric acid)) to give the title compound 75.0mg in two steps at a yield of 70.8%.
Preparation of 7- (((1 r,4 r) -4-hydroxycyclohexyl) amino) -6- (7-methyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
6- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- ((1 r,4 r) -4-hydroxycyclohexyl) amino) thiophen [3,2-b ] pyridin-5 (4H) -one (75.0 mg,0.17 mmol) was dissolved in 10.0mL of methanol, 1.0mL of formaldehyde, sodium cyanoborohydride (21.0 mg,0.33 mmol) was added, stirred at 25℃for 1H, the solvent was concentrated, and 7.6mg was isolated by normal phase column (methanol: dichloromethane=1:99) to yield 9.8%.
Molecular formula C 25 H 29 N 5 O 2 S molecular weight 463.2. 463.2 LC-MS (M/e): 464.0 (M+H) + )
1 H-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).
Preparation example 30: preparation of 7- (azetidin-1-yl) -6- (7- (oxetan-3-yl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 45)
Preparation of tert-butyl 2- (7- (azetidin-1-yl) -4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrothien [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylate
2- (4- (4-methoxybenzyl) -5-oxo-7- (((trifluoromethyl) sulfonyl) oxy) -4, 5-dihydrothiophene [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepine-7-carboxylic acid tert-butyl ester (200 mg,0.24 mmol) was dissolved in acetonitrile (5 mL), azetidine (55 mg,0.96 mmol) was added and reacted at 40℃for 2 hours. LCMS detects the end of the reaction. The reaction solution was concentrated and purified by a silica gel column (dichloromethane: methanol=10:1) to obtain a crude product of the target compound.
Preparation of 7- (azetidin-1-yl) -6- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
2- (7- (azetidin-1-yl) -4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrothien [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylic acid tert-butyl ester (crude) was dissolved in concentrated hydrochloric acid (1 mL) and trifluoroacetic acid (7 mL), and after addition, the reaction was carried out at 110℃for 24 hours. LCMS detects the end of the reaction. The solvent was concentrated, dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate, and concentrated by organic phase dryness to give the target compound 40mg, 43% yield in two steps, as purified by Pre-TLC (dichloromethane: methanol=7:1).
Preparation of 7- (azetidin-1-yl) -6- (7- (oxetan-3-yl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
7- (azetidin-1-yl) -6- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (40 mg,0.1 mmol) was dissolved in methanol (6 mL), 3-oxetan (22 mg,0.3 mmol) and glacial acetic acid (6 mg,0.1 mmol) were added and reacted at 20℃for 30min, sodium cyanoborohydride (19 mg,0.3 mmol) was added and reacted at 20℃for 4H. After the reaction, dichloromethane and saturated sodium bicarbonate solution were added and extracted three times, the organic phase was dried by spinning, and the target compound was obtained by forward preparative separation (dichloromethane: methanol=5:1).
Molecular formula C 24 H 25 N 5 O 2 S molecular weight 447.5 LC-MS (M/e): 448.2 (M+H) + )
1 H-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).
Preparation example 31: preparation of 7-amino-6- (7- (6-chloropyrazin-3-yl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thiophen [3,2-b ] pyridin-5 (4H) -one (Compound 46)
Preparation of 3- (6-chloropyrazin-3-yl) -7-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepine
7-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepine (961 mg,5 mmol), triethylamine (1012 mg,10 mmol) and 3, 6-dichloropyrazine (894 mg,6 mmol) were dissolved in dimethyl sulfoxide (50 mL) and reacted at 110℃for 1 hour. After completion of the reaction, the reaction was quenched with water (50 mL), extracted with dichloromethane (50 mL), and the organic phase was concentrated and purified by silica gel column (ethyl acetate/dichloromethane=1:9) to give 500mg of the objective compound in a yield of 32.8%.
Preparation of 3- (6-chloropyrazin-3-yl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine
3- (6-Chloropyrazin-3-yl) -7-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepine (500 mg,1.64 mmol), ammonium chloride (351 mg,6.56 mmol) and iron powder (275 mg,4.92 mmol) were dissolved in ethanol (15 mL) and water (15 mL) and reacted at 95℃for 3 hours. Dichloromethane (50 mL) was extracted and the organic phase was concentrated directly for the next step.
3. Preparation of N- (3- (6-chloropyrazin-3-yl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide
3- (6-Chloropyrazin-3-yl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine (crude in the above step) was dissolved in acetic anhydride (2 mL) and acetic acid (5 mL) and reacted at 25℃for 1 hour. The reaction was quenched by addition of water (50 mL), extracted with dichloromethane (50 mL) and the organic phase concentrated to give 400mg of the title compound in a two-step reaction yield of 76.9%.
4. Preparation of N- (3- (6-chloropyrazin-3-yl) -8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide
N- (3- (6-chloropyrazin-3-yl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide (400 mg,1.26 mmol) was dissolved in concentrated sulfuric acid (4 mL). Fuming nitric acid (95 mg,1.52 mmol) was added dropwise at 0deg.C, and the mixture was reacted at 0deg.C for 1 hour. After the completion of the reaction, the reaction mixture was diluted with dichloromethane (50 mL), washed with water (50 mL), and the organic phase was concentrated and purified by silica gel column (ethyl acetate/dichloromethane=1:4) to give 230mg of the objective compound in a yield of 50.3%.
Preparation of 3- (6-chloropyrazin-3-yl) -8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine
N- (3- (6-chloropyrazin-3-yl) -8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide (230 mg,0.64 mol) was reacted with potassium carbonate (263 mg,1.91 mol) in methanol (6 mL) at 50℃for 2 hours. Quenched with water (30 mL), filtered with suction, and the solid collected was spun-dried to give 200mg of the title compound in 98.4% yield.
Preparation of 3- (6-chloropyrazin-3-yl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7, 8-diamine
3- (6-Chloropyrazin-3-yl) -8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine (200 mg,0.63 mmol), ammonium chloride (167 mg,3.13 mmol) and iron powder (105 mg,1.88 mmol) were dissolved in ethanol (10 mL) and water (10 mL) and reacted at 95℃for 2 hours. Dichloromethane (50 mL) was extracted, water (20 mL) was used for washing, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 180mg of the target compound, with a yield of 99.3%.
Preparation of ethyl 2- (7- (6-chloropyrazin-3-yl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate
3- (6-Chloropyrazin-3-yl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7, 8-diamine (180 mg,0.62 mmol) and ethyl 3-ethoxy-3-iminopropionate hydrochloride (292 mg,1.49 mmol) were dissolved in ethanol (10 mL). The reaction was carried out at 55℃for 1 hour. Spin-drying, dilution with dichloromethane (50 mL), washing with aqueous ammonia (10 mL), drying the organic phase, concentrating, and purifying with silica gel column (dichloromethane: methanol=19:1) to give the target compound 160mg, yield 66.8%.
Preparation of 7-amino-6- (7- (6-chloropyrazin-3-yl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thiophen [3,2-b ] pyridin-5 (4H) -one
Ethyl 2- (7- (6-chloropyrazin-3-yl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (60 mg,0.16 mmol) was dissolved in tetrahydrofuran (4 mL), LDA (0.32 mL,0.64 mol) was added at 40℃under nitrogen protection, and the mixture was reacted at 40℃for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride (8 mL), the organic phase was concentrated and purified by reverse phase column (acetonitrile: water (0.5% hydrochloric acid) =30%) to give the target compound 7mg in 9.7% yield.
Molecular formula C 22 H 18 ClN 7 OS molecular weight 463.9 LC-MS (M/e): 464.0 (M+H) + )
1 H-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)
Preparation example 32: preparation of 7-amino-6- (7-methyl-6, 7,8, 9-tetrahydro-5H-oxazolo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thiophen [3,2-b ] pyridin-5 (4H) -one (Compound 47)
Preparation of ethyl 2- (7-methyl-6, 7,8, 9-tetrahydro-5H-oxazolo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate
To an ethanol solution of 3-methyl-8-amino-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-ol was added ethyl 3-ethoxy-3-iminopropionate hydrochloride (3.75 g.19.3 mmol), and the mixture was reacted at 50℃for 16 hours. After the reaction, the mixture was filtered through celite, the pH of the filtrate was adjusted to about 8 by adding sodium bicarbonate solution, extracted with methylene chloride (100 mL), and the organic phase was concentrated by drying and purified by silica gel column (methylene chloride: methanol=10:1) to give 820mg of the target compound, with a reaction yield of 59.0%.
Preparation of 2- (7-methyl-6, 7,8, 9-tetrahydro-5H-oxazolo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetic acid
Ethyl 2- (7-methyl-6, 7,8, 9-tetrahydro-5H-oxazolo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (750 mg,2.6 mmol) was dissolved in methanol (10 mL) and water (10 mL), sodium hydroxide (312.0 mg,7.8 mmol) was added, and the mixture was reacted at 25℃for 3 hours. After the reaction is finished, adding 2M dilute hydrochloric acid solution into the system to adjust the pH to be neutral, concentrating and spin-drying the system to obtain a crude product of the target compound, and directly using the crude product of the target compound in the next reaction.
3. Preparation of N- (2-cyanothiophen-3-yl) -2- (7-methyl-6, 7,8, 9-tetrahydro-5H-oxazolo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetamide
2- (7-methyl-6, 7,8, 9-tetrahydro-5H-oxazolo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetic acid (N/A, 2.6 mmol) was dissolved in dichloromethane (50 mL), 2-aminothiophene-3-carbonitrile (387.5 mg,3.1 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (1.5 g,3.9 mmol) and triethylamine (526.2 mg,5.2 mmol) were added sequentially and the system was reacted at 25℃for 8 hours. After the reaction, the system was quenched with water, extracted with dichloromethane (100 mL), concentrated by organic phase drying, and purified by silica gel column (dichloromethane: methanol=9:1) to give 700mg of crude target compound, which was directly used in the next reaction.
Preparation of 7-amino-6- (7-methyl-6, 7,8, 9-tetrahydro-5H-oxazolo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thiophen [3,2-b ] pyridin-5 (4H) -one
N- (2-Cyanothiophen-3-yl) -2- (7-methyl-6, 7,8, 9-tetrahydro-5H-oxazolo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetamide (600 mg,1.6 mmol) was dissolved in methanol (50 mL), sodium methoxide (5.2 g,28.9 mmol) was added and the system was reacted at 70℃for 2 hours. After the reaction, adding 2M dilute hydrochloric acid solution to adjust the pH of the system to be neutral, concentrating and spin-drying, purifying by a silica gel column (dichloromethane: methanol=7:3), spin-drying the solvent, pulping by methanol, filtering, washing and drying to obtain the target compound 19.0mg, wherein the three-step reaction yield is 2.3%.
Molecular formula C 19 H 18 N 4 O 2 S molecular weight 366.4 LC-MS (M/e): 367.4.1 (M+H) + )
1 H-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).
Preparation example 33: preparation of 6- (7- (2, 2-difluoroethyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (isopropylamino) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 48)
Preparation of tert-butyl 2- (7- (isopropylamino) -4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrothieno [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylate
2- (4- (4-methoxybenzyl) -5-oxo-7- (((trifluoromethyl) sulfonyl) oxy) -4, 5-dihydrothieno [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylic acid tert-butyl ester (500 mg,0.60 mmol) was dissolved in acetonitrile (10 mL), isopropylamine (106 mg,1.80 mmoL) was added and the temperature was raised to 40℃for 2 hours. LCMS detects the end of the reaction. The reaction solution was concentrated and purified by silica gel column (dichloromethane: methanol=20:1) to give 300mg of the objective compound, yield: 67.1%.
Preparation of 7- (isopropylamino) -4- (4-methoxybenzyl) -6- (1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
2- (7- (isopropylamino) -4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrothieno [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylic acid tert-butyl ester (300 mg,0.4 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (2 mL) was added for reaction for 1 hour. LCMS detects the end of the reaction. Dilute in methylene chloride, wash with saturated aqueous sodium bicarbonate and dry concentrate the organic phase for the next step.
Preparation of 6- (7- (2, 2-difluoroethyl) -1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (isopropylamino) -4- (4-methoxybenzyl) thieno [3,2-b ] pyridin-5 (4H) -one
7- (isopropylamino) -4- (4-methoxybenzyl) -6- (1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (N/A, 0.4 mmoL) was dissolved in acetonitrile (5 mL), N diisopropylethylamine (155 mg,1.2 mmoL) and 2, 2-difluoroethyl trifluoromethanesulfonate (256 mg,1.2 mmoL) were added and the reaction was completed for 2 hours. LCMS detects the end of the reaction. The reaction solution was concentrated and purified by silica gel column (ethyl acetate: petroleum ether=1:1) to give 150mg of the target compound, yield in two steps: 52.9%.
Preparation of 6- (7- (2, 2-difluoroethyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (isopropylamino) thieno [3,2-b ] pyridin-5 (4H) -one
6- (7- (2, 2-difluoroethyl) -1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (isopropylamino) -4- (4-methoxybenzyl) thieno [3,2-b ] pyridin-5 (4H) -one (180 mg,0.25 mmol) was dissolved in concentrated hydrochloric acid (0.5 mL), trifluoroacetic acid (3.5 mL) was added and reacted at 110℃for 48 hours. LCMS detects the end of the reaction. The solvent was concentrated, the system pH was adjusted to 8 with saturated aqueous sodium bicarbonate and purified by Pre-TLC plate (dichloromethane: methanol=7:1) to give 17mg of the title compound, yield: 14.9%.
Molecular formula C 23 H 25 F 2 N 5 OS molecular weight 457.5 LC-MS (M/e): 458.0 (M+H) + )
1 H-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).
Preparation example 34: preparation of 6- (7- (2, 2-difluoroethyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (isopropylamino) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 49)
Preparation of 7-amino-6- (7- (2, 2-difluoroethyl) -1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -4- (4-methoxybenzyl) thieno [3,2-b ] pyridin-5 (4H) -one
7- ((3, 4-dimethylbenzyl) amino) -4- (4-methoxybenzyl) -6- (1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (400 mg,0.53 mmoL) was dissolved in acetonitrile (5 mL), N diisopropylethylamine (206 mg,1.6 mmoL), 2-difluoroethyl trifluoromethanesulfonate (342 mg,1.6 mmoL) was added and the addition was reacted for 2 hours. LCMS detects the end of the reaction. The reaction solution was concentrated and purified by silica gel column (ethyl acetate: petroleum ether=1:1) to give 250mg of the objective compound, yield: 70.7%.
Preparation of 6- (7- (2, 2-difluoroethyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (isopropylamino) thieno [3,2-b ] pyridin-5 (4H) -one
7-amino-6- (7- (2, 2-difluoroethyl) -1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -4- (4-methoxybenzyl) thieno [3,2-b ] pyridin-5 (4H) -one (180 mg,0.27 mmol) was dissolved in concentrated hydrochloric acid (0.5 mL), trifluoroacetic acid (3.5 mL) was added and reacted at 110℃for 48 hours. LCMS detects the end of the reaction. The solvent was concentrated, the system pH was adjusted to 8 with saturated aqueous sodium bicarbonate and purified by Pre-TLC plate (dichloromethane: methanol=7:1) to give 20mg of the title compound, yield: 17.8%.
Molecular formula C 20 H 19 F 2 N 5 OS molecular weight 415.5 LC-MS (M/e): 416.0 (M+H) + )
1 H-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).
Preparation example 35: preparation of 6- (7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- ((2, 2-difluoroethyl) amino) thiophene [3,2-b ] pyridin-5 (4H) -one (Compound 50)
Preparation of 6- (7-cyclopropyl-1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5:4,5] benzo [1,2-d ] azepin-2-yl) -4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrothiophen [3,2-b ] pyridin-7-yl trifluoromethanesulfonate
6- (7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7-hydroxy-4- (4-methoxybenzyl) thiophen [3,2-b ] pyridin-5 (4H) -one (600 mg,1.2 mmol) was dissolved in dichloromethane (12 mL), pyridine (1.90 g,24 mmol) and trifluoromethanesulfonic anhydride (2.03 g,7.2 mmol) were added at 0deg.C and reacted for 30 minutes at 0deg.C. The reaction was quenched with saturated aqueous sodium bicarbonate, extracted with dichloromethane, and the organic phase was concentrated by drying and used directly in the next step.
Preparation of 6- (7-cyclopropyl-1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5:4,5] benzo [1,2-d ] azepin-2-yl) -7- ((2, 2-difluoroethyl) amino) -4- (4-methoxybenzyl) thiophen [3,2-b ] pyridin-5 (4H) -one
6- (7-cyclopropyl-1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5:4,5] benzo [1,2-d ] azepin-2-yl) -4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrothiophene [3,2-b ] pyridin-7-yl trifluoromethanesulfonate (crude product of the above step) was dissolved in acetonitrile (10 mL), and 2, 2-difluoroethylamine (389 mg,4.8 mmol) was added and reacted at 40℃for 1 hour after the addition. The reaction solution was concentrated and purified by silica gel column (dichloromethane: methanol=13:1) to give 300mg of the objective compound in a two-step yield of 36.2%.
Preparation of 6- (7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- ((2, 2-difluoroethyl) amino) thiophen [3,2-b ] pyridin-5 (4H) -one
6- (7-cyclopropyl-1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5:4,5] benzo [1,2-d ] azapyridin-2-yl) -7- ((2, 2-difluoroethyl) amino) -4- (4-methoxybenzyl) thiophen [3,2-b ] pyridin-5 (4H) -one (150 mg,0.21 mmol) is dissolved in concentrated hydrochloric acid (1 mL), trifluoroacetic acid (7 mL) is added, and the mixture is warmed to 110℃and reacted for 24 hours. Concentrating the solvent, dissolving with dichloromethane, washing with saturated sodium bicarbonate aqueous solution, drying the organic phase, and purifying with medium pressure reversed phase (40% methanol/water (0.5% concentrated hydrochloric acid)) to obtain the target compound 40mg, with a yield of 41.4%.
Molecular formula C 23 H 23 F 2 N 5 OS molecular weight 455.5 LC-MS (M/e): 456.1 (M+H) + )
1 H-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).
Preparation example 36: preparation of 6- (7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (isopropylamino) thiophene [3,2-b ] pyridin-5 (4H) -one hydrochloride (hydrochloride salt of Compound 52)
Preparation of 6- (7-cyclopropyl-1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5:4,5] benzo [1,2-d ] azepin-2-yl) -7-isopropylamino-4- (4-methoxybenzyl) -thieno [3,2-b ] pyridin-5 (4H) one
6- (7-cyclopropyl-1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazo [4',5:4,5] benzo [1,2-d ] azepin-2-yl) -4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrothiophene [3,2-b ] pyridin-7-yl trifluoromethanesulfonate was dissolved in acetonitrile (30 mL), isopropylamine (141.6 mg,2.4 mmol) was added, and the mixture was reacted at 45℃for 1 hour. The reaction solution was concentrated and purified by silica gel column (dichloromethane: methanol=20:1) to give 200mg of the objective compound.
Preparation of 6- (7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (isopropylamino) thiophene [3,2-b ] pyridin-5 (4H) -one hydrochloride
6- (7-cyclopropyl-1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydroimidazole [4',5:4,5 ]Benzo [1,2-d]Azepin-2-yl) -7-isopropylamino-4- (4-methoxybenzyl) -thieno [3,2-b]Pyridin-5 (4H) one (200 mg,0.29 mmol) was dissolved in concentrated hydrochloric acid (2 mL), trifluoroacetic acid (14 mL) was added, and the mixture was reacted at 110℃for 16 hours. Concentrating the solvent, passing through C 18 Column purification (B)Nitrile=0-30%) to give 11.5mg of the target compound, yield 8.4%.
Molecular formula C 24 H 28 N 5 OSCl molecular weight 469.2 LC-MS (M/e): 434.0 (M+H) + )
1 H-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).
Preparation example 37: preparation of 7-amino-6- (7-ethyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thiophene [3,2-b ] pyridin-5 (4H) -one (Compound 53)
Preparation of 1, 5-dihydrobenzo [ d ] oxazepin-2, 4-dione
2,2' - (1, 2-phenylene) diacetic acid (12 g,61.9 mmol) was dissolved in dichloromethane (200 mL), DCC (12.8 g,61.9 mmol) was added at 25℃and reacted for 4h at 25℃and the completion of LCMS detection reaction was filtered and the filter cake was dried to give 12g of crude title compound.
2.preparation of 2- (2- (2- (ethylamino) -2-oxyethyl) phenyl) acetic acid
1, 5-Dihydrobenzo [ d ] oxazepine-2, 4-dione (12 g, crude product) was dissolved in dichloromethane (200 mL), ethylamine hydrochloride (2.7 g,33 mmol) and triethylamine (13.7 g,136 mmol) were added at 0deg.C, the reaction was completed at 25deg.C, LCMS was examined to complete the reaction, water quench the system was added, the organic phase was extracted with dichloromethane, and the organic phase was concentrated and purified by silica gel column (methanol/dichloromethane=1:10) to give the target compound 7g in 50.9% two-step yield.
3. Preparation of N-ethyl-2- (2- (2-hydroxyethyl) phenyl) acetamide
2- (2- (2- (ethylamino) -2-oxyethyl) phenyl) acetic acid (7 g,31.5 mmol) was dissolved in tetrahydrofuran (10 mL), borane (37.8 mL,37.8 mmol) was added dropwise at 0deg.C, the system was reacted at 25deg.C for 3h, LCMS detected completion of the reaction, the system was quenched with methanol, and the target compound 5g was obtained in 76.3% yield by water washing, ethyl acetate extraction, concentration of the organic phase, and purification on silica gel column (methanol/dichloromethane=1:10).
4.preparation of 2- (2- (ethylamino) -2-oxoethyl) phenethyl mesylate
N-ethyl-2- (2- (2-hydroxyethyl) phenyl) acetamide (5 g,24 mmol) was dissolved in tetrahydrofuran (10 mL), methanesulfonyl chloride (5.6 g,48 mmol) and triethylamine (7.3 g,72 mmol) were added dropwise at 0deg.C, the system reacted at 0deg.C for 3h, LCMS detection was completed, water quench reaction was added to the system, extraction by ethyl acetate, concentration of organic phase, purification by silica gel column (methanol/dichloromethane=1:10) to give the target compound 4.9g, yield 71.4%.
Preparation of 3-ethyl-1, 3,4, 5-tetrahydro-2H-benzo [ d ] azepin-2-one
2- (2- (ethylamino) -2-oxoethyl) phenethyl methanesulfonate (4.5 g,15.7 mmol) was dissolved in N, N-dimethylformamide (10 mL), sodium hydride (1.2 g,31.4 mmol) was added dropwise at 0deg.C, after the addition was completed, the system was reacted at 0deg.C for 2h, LCMS detection was completed, the system was quenched with water, extracted with ethyl acetate, and the organic phase was purified by column chromatography on silica gel (ethyl acetate/petroleum ether=1:1) to give crude 2.35g.
Preparation of 3-ethyl-8-nitro-1, 3,4, 5-tetrahydro-2H-benzo [ d ] azepin-2-one
3-Ethyl-1, 3,4, 5-tetrahydro-2H-benzo [ d ] azepin-2-one (2.35 g, crude product) was dissolved in concentrated sulfuric acid (10 mL), potassium nitrate (1.4 g,13.8 mmol) was added at 0deg.C, after the addition was completed, the system was reacted at 0deg.C for 2H, and the completion of the reaction was detected by LCMS. The reaction was quenched by dropwise addition to ice water, extracted with ethyl acetate, concentrated in organic phase, and purified on silica gel column (ethyl acetate/petroleum ether=1:3) to give 1g of the target compound in a two-step yield of 27.1%
Preparation of 7.8-amino-3-ethyl-1, 3,4, 5-tetrahydro-2H-benzo [ d ] azepin-2-one
3-Ethyl-8-nitro-1, 3,4, 5-tetrahydro-2H-benzo [ d ] azepin-2-one (1 g,4.3 mmol) was dissolved in methanol (20 mL), pd/C (500 mg) was added, the reaction was continued at 25℃for 2H, and completion of the reaction was detected by LCMS. Filtering, and spin-drying the filtrate to obtain 860mg of the target compound with a yield of 90.4%.
8. Preparation of N- (3-ethyl-4-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide
8-amino-3-ethyl-1, 3,4, 5-tetrahydro-2H-benzo [ d ] azepin-2-one (860 mg,4.20 mmol) was dissolved in acetic acid (10 mL), acetic anhydride (2 mL) was added, the reaction was allowed to proceed at 25℃for 2H, and completion of the reaction was detected by LCMS. The reaction solution is dried by spinning, diluted by methylene dichloride, washed by saturated sodium bicarbonate solution, dried by spinning of an organic phase and separated and purified by silica gel column chromatography (methanol/methylene dichloride=1:1) to obtain 650mg of target compound with the yield of 62.7 percent
9. Preparation of N- (3-ethyl-8-nitro-4-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide
N- (3-ethyl-4-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide (580 mg,2.35 mmol) was dissolved in concentrated sulfuric acid (10 mL), fuming nitric acid (181 mg,2.82 mmol) was added dropwise at 0deg.C for 2H at 25deg.C, LCMS detection was completed, the reaction was added dropwise to ice-in water quenching, the organic phase was extracted with dichloromethane, and the organic phase was concentrated by silica gel column purification (methanol/dichloromethane=1:10) to give 230mg of the target compound in 33.5% yield
Preparation of 7-amino-3-ethyl-8-nitro-1, 3,4, 5-tetrahydro-2H-benzo [ d ] azepin-2-one
N- (3-ethyl-8-nitro-4-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-yl) acetamide (230 mg,0.79 mmol) was dissolved in methanol (10 mL), potassium carbonate (327 mg,2.37 mmol) was added, the reaction was allowed to react at 25℃for 4H, LCMS detection was completed, the reaction solution was dried by spin, and the crude product was purified by silica gel column (methanol/dichloromethane=1:10) to give 190mg of the target compound with a yield of 96.54%
Preparation of ethyl 2- (7-ethyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate
7-amino-3-ethyl-8-nitro-1, 3,4, 5-tetrahydro-2H-benzo [ d ] azepin-2-one (190 mg,0.76 mmol) was dissolved in ethanol (10 mL), pd/C (120 mg) was added, reaction was performed at 25℃for 2H, LCMS detection was complete, ethyl 3-ethoxy-3-iminopropionate hydrochloride (297 mg,1.52 mmol), reaction was performed at 50℃for 2H, LCMS detection was complete. Filtration, spin-drying of the filtrate, dilution with dichloromethane, washing with saturated aqueous sodium bicarbonate, spin-drying of the organic phase, and column chromatography on silica gel (methanol/dichloromethane=1:10) gave 150mg of the title compound in 62.4% yield.
Preparation of 7-amino-6- (7-ethyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thiophen [3,2-b ] pyridin-5 (4H) -one
Ethyl 2- (7-ethyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (100 mg,0.32 mmol) and 3-aminothiophene-2-carbonitrile (40 mg,0.32 mmol) are dissolved in tetrahydrofuran (10 mL), LDA (1 mL,1.92 mmol) is added at 40℃and the reaction is allowed to proceed for 2h at 40℃and LCMS detection is complete. The reaction solution was poured into a saturated aqueous ammonium chloride solution to quench, extracted with ethyl acetate, dried by spinning, and slurried with methanol to give 18.5mg of the target compound in a yield of 14.7%.
Molecular formula C 20 H 19 N 5 O 2 S molecular weight 393.5 LC-MS (M/e): 394.0 (M+H+)
1 H-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).
Preparation example 38: preparation of 7-amino-6- (7-cyclopropyl-1,5,6,7,8,9-hexahydro-5, 9-methanoimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thiophen [3,2-b ] pyridin-5 (4H) -one (Compound 54)
1.7,8-dinitro-2, 3,4, 5-tetrahydro-1H-1, 5-methanolbenzo [ d ] aza Zhuo Zhibei
1- (7, 8-dinitro-1, 2,4, 5-tetrahydro-3H-1, 5-methoxybenzo [ d ] azepin-3-yl) -2, 2-trifluoroethan-1-one (200.0 mg,0.58 mol) was dissolved in methanol (8 mL) and water (3 mL), and sodium carbonate (127.2 mg,1.2 mmol) was added to continue the reaction for 16 hours. Water is added to the system to quench the reaction, dichloromethane (100 mL) is used for extraction, and the organic phase is dried and concentrated to obtain 170mg of crude target compound, which is directly used for the next reaction.
Preparation of 2, 3-cyclopropyl-7, 8-dinitro-2, 3,4, 5-tetrahydro-1H-1, 5-methylbenzo [ d ] azepine
7, 8-dinitro-2, 3,4, 5-tetrahydro-1H-1, 5-methanobenzo [ d ] azepine (crude) (170.0 mg,0.68 mmol) was dissolved in methanol (10.0 mL) and acetic acid (432.0 mg,7.2 mmol), sodium cyanoborohydride (276.3 mg,4.4 mmol) and (1-ethoxycyclopropyloxy) trimethylsilane (278.9 mg,1.6 mmol) were added and the system reacted at 65℃for 3H. The reaction was quenched by adding water to the system, the organic phase was extracted with dichloromethane, and the organic phase was concentrated and purified by a silica gel column (ethyl acetate/petroleum ether=2:3) to give 127.0mg of the target compound, with a two-step yield of 75.7%.
Preparation of 3, 3-cyclopropyl-7, 8-diamino-2, 3,4, 5-tetrahydro-1H-1, 5-methylbenzo [ d ] azepine
3-cyclopropyl-7, 8-dinitro-2, 3,4, 5-tetrahydro-1H-1, 5-methylbenzo [ d ] azepine (320.0 mg,1.1 mmol) was dissolved in ethanol (10 mL), pd/C (200.0 mg) was added and the system was subjected to hydrogenation at 25℃for 40 minutes under hydrogen atmosphere. The reaction solution was directly used for the next reaction.
Preparation of ethyl 2- (7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate
To the reaction mixture of the above step was added ethyl 3-ethoxy-3-iminopropionate hydrochloride (508.6 mg.2.6 mmol), and the mixture was reacted at 50℃for 2 hours. Diatomaceous earth was filtered, the filtrate was concentrated to dryness, diluted with water, PH adjusted to alkaline with sodium bicarbonate solution, extracted with dichloromethane (100 mL), concentrated to dryness, and purified on a silica gel column (dichloromethane: methanol=10:1) to give 250.0mg of the title compound, yield (two steps): 69.4%.
Preparation of 7-amino-6- (7-cyclopropyl-1,5,6,7,8,9-hexahydro-5, 9-methanoimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thiophen [3,2-b ] pyridin-5 (4H) -one
Ethyl 2- (7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (250 mg,0.66 mmol) was dissolved in tetrahydrofuran (15 mL), 2-aminothiophene-3-carbonitrile (113.1 mg,0.91 mmol) was added, the mixture was placed under nitrogen at 40℃and lithium diisopropylamide (1.5 mL,3.0 mmol) was added and stirring continued for 1 hour. The reaction was quenched with aqueous ammonium chloride, extracted with ethyl acetate (100 mL), and the organic phase was concentrated by drying and purified on a silica gel column (ethyl acetate=100%) to give the title compound 19.0mg, yield: 7.1%.
Molecular formula C 22 H 21 N 5 OS molecular weight 403.5 LC-MS (M/e): 404.0 (M+H) + )
1 H-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).
Preparation example 39: preparation of 7-amino-6- (7-cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo [4',5]:4,5] benzo [1,2-d ] azepin-2-yl) thiophene [3,2-b ] pyridin-5 (4H) -one (Compound 55)
Preparation of ethyl 2- (7-cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate
1, 5-dihydrobenzo [ d ] oxazepin-2, 4-dione and cyclopropylamine are selected as starting materials, and ethyl 2- (7-cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate is prepared by referring to the preparation method of preparation example 37.
Preparation of 7-amino-6- (7-cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo [4',5]:4,5] benzo [1,2-d ] azepin-2-yl) thiophen [3,2-b ] pyridin-5 (4H) -one
Ethyl 2- (7-cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin Zhuo Biding-2-yl) acetate (32.7 mg,0.1 mmol), 2-cyano-3-aminothiophene (12.4 mg,0.1 mmol) were dissolved in tetrahydrofuran (5 mL), heated to 40℃under nitrogen protection, and a 2M lithium diisopropylamide solution (0.25 mL,0.5 mmol) was added dropwise at 40℃and reacted at 40℃for 3 hours. LCMS detects the end of the reaction. Cooling to 25 ℃, quenching reaction with saturated ammonium chloride aqueous solution, extracting with ethyl acetate, drying and concentrating the organic phase, pulping the obtained solid with methanol, filtering to obtain solid, and drying the solid to obtain 14.5mg of the title compound, wherein the yield is as follows: 35.8%.
Molecular formula C 21 H 19 N 5 O 2 S molecular weight 405.5 LC-MS (M/e) 406.1 (M+H) + )
1 H-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).
Preparation example 40: preparation of 7- ((2, 2-difluoroethyl) amino) -6- (7- (oxetan-3-yl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one trifluoroacetate (trifluoroacetate of Compound 58)
Preparation of tert-butyl 2- (7- ((2, 2-difluoroethyl) amino) -4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrothieno [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylate
2- (4- (4-methoxybenzyl) -5-oxo-7- (((trifluoromethyl) sulfonyl) oxy) -4, 5-dihydrothieno [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepine-7 (1H) -carboxylic acid tert-butyl ester (500 mg,0.60 mmol) was dissolved in acetonitrile (5 mL), and 2, 2-difluoroethyl-1-amine (3838 mg,4.78 mmol) was added and reacted at 40℃for 2H. LCMS detection of reaction completed, spin-drying of solvent, and column chromatography over silica gel (ethyl acetate: petroleum ether=1:1) gave 300mg of the target compound in 65.4% yield.
2.7- ((2, 2-difluoroethyl) amino) -6- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one preparation
2- (7- ((2, 2-difluoroethyl) amino) -4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrothieno [3,2-b ] pyridin-6-yl) -1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-7 (1H) -carboxylic acid tert-butyl ester (300 mg,0.39 mmol) was dissolved in trifluoroacetic acid (3.5 mL) and hydrochloric acid (0.5 mL), the reaction was warmed to 110℃for 24H and the LCMS detection was complete. The reaction solution was dried by spin-drying, the system ph=8 was adjusted with saturated aqueous sodium bicarbonate, and 200mg of the crude target compound was obtained by extraction with methylene chloride, drying, and concentration.
Preparation of 7- ((2, 2-difluoroethyl) amino) -6- (7- (oxetan-3-yl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one trifluoroacetate
7- ((2, 2-difluoroethyl) amino) -6- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (200 mg, N/A) was dissolved in methanol (5 mL), oxetan-3-one (30 mg,0.40 mmol) and acetic acid (144 mg,2.4 mmol) were added, after 1 hour of reaction at 25℃sodium cyanoborohydride (150 mg,2.4 mmol) was added and the reaction was continued for 8 hours, LCMS detection was complete. Adding sodium bicarbonate aqueous solution into the system, extracting with dichloromethane, collecting organic phase solvent, spin-drying, and performing reverse phase column chromatography (methanol/water=0-40% wherein two phases each contain 0.3% trifluoroacetic acid) to obtain 19mg of target compound with a yield of 37.8%.
Molecular formula C 25 H 24 F 5 N 5 O 3 Molecular weight of S569.15 LC-MS (M/e): 472.5 (M+H) + )
1 H-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).
Preparation example 41: preparation of 6- (7- (azetidin-1-yl) -1,5,6,7,8,9-hexahydrocycloheptyl [4,5] benzo [1,2-d ] imidazol-2-yl) -7- ((2, 2-difluoroethyl) amino) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 59)
Preparation of 6- (7- (azetidin-1-yl) -1,5,6,7,8,9-hexahydrocycloheptyl [4,5] benzo [1,2-d ] imidazol-2-yl) -7-hydroxy-4- (4-methoxybenzyl) thieno [3,2-b ] pyridin-5 (4H) -one
Ethyl 2- (7- (azetidin-1-yl) -1,5,6,7,8,9-hexahydrocyclohepta [4,5] benzo [1,2-d ] imidazol-2-yl) acetate (130 mg,0.4 mmol) and 1- (4-methoxybenzyl) -2H-thieno [3,2-d ] [1,3] oxazine-2, 4 (1H) -dione (173 mg,0.6 mmol) were dissolved in tetrahydrofuran (20 mL), warmed to 40℃and LDA (2 mL,4 mmol) was added under nitrogen protection, and the reaction was carried out for 2 hours after the addition. LCMS detects the end of the reaction. Saturated ammonium chloride solution was added to quench, extraction was performed with a mixed solution of ethyl acetate and methanol (ethyl acetate: methanol=10:1 (100 ml×4)), the organic phase was concentrated by drying, and the title compound was obtained by silica gel column purification (dichloromethane: methanol=10:1) in a yield of 90%.
Preparation of 6- (7- (azetidin-1-yl) -1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydrocycloheptyl [4,5] benzo [1,2-d ] imidazol-2-yl) -4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrothieno [3,2-b ] pyridin-7-yl triflate
6- (7- (azetidin-1-yl) -1,5,6,7,8,9-hexahydrocycloheptyl [4,5] benzo [1,2-d ] imidazol-2-yl) -7-hydroxy-4- (4-methoxybenzyl) thieno [3,2-b ] pyridin-5 (4H) -one (190 mg,0.36 mmol) was dissolved in dichloromethane (100 mL) and pyridine (284 mg,3.3 mmol) and trifluoromethanesulfonic anhydride (620 mg,2 mmol) were added to react for 1 hour. LCMS detects the end of the reaction. The solvent was concentrated, quenched with saturated sodium bicarbonate, extracted with dichloromethane (100 mL. Times.4), and concentrated by organic phase drying to yield 390mg of crude title compound, which was taken to the next step without further treatment.
Preparation of 6- (7- (azetidin-1-yl) -1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydrocycloheptyl [4,5] benzo [1,2-d ] imidazol-2-yl) -7- ((2, 2-difluoroethyl) amino) -4- (4-methoxybenzyl) thieno [3,2-b ] pyridin-5 (4H) -one
6- (7- (azetidin-1-yl) -1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydrocycloheptyl [4,5] benzo [1,2-d ] imidazol-2-yl) -4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrothieno [3,2-b ] pyridin-7-yl triflate (390 mg) was dissolved in acetonitrile (100 mL), and difluoroethylamino (29 mg,3.6 mmol) was added and the temperature was raised to 40℃for 4 hours. LCMS detects the end of the reaction. The organic phase was concentrated by drying and purified by column chromatography on silica gel (dichloromethane: methanol=10:1) to give 140mg of the title compound in 66% yield in two steps.
4.6- (7- (azetidin-1-yl) -1,5,6,7,8,9-hexahydrocycloheptyl [4,5] benzo [1,2-d ] imidazol-2-yl) -7- ((2, 2-difluoroethyl) amino) thieno [3,2-b ] pyridin-5 (4H) -one preparation
6- (7- (azetidin-1-yl) -1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydrocycloheptyl [4,5] benzo [1,2-d ] imidazol-2-yl) -7- ((2, 2-difluoroethyl) amino) -4- (4-methoxybenzyl) thieno [3,2-b ] pyridin-5 (4H) -one (140 mg,0.24 mmol) was placed in a 100mL single-port flask, trifluoroacetic acid (6 mL) and concentrated hydrochloric acid (1 mL) were added, and the temperature was raised to 110℃for reaction for 24 hours. LCMS detects the end of the reaction. The organic phase was concentrated and purified by reverse phase column chromatography (water: methanol=10:3) to give 52mg of the title compound in 57% yield.
Molecular formula C 24 H 25 F 2 N 5 OS molecular weight 469.6 LC-MS (M/e): 470.2 (M+H) + )
1 H-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).
Preparation example 42: preparation of 7-amino-6- (5, 6,8, 9-tetrahydro-1H-oxazepino [4',5':4,5] benzo [1,2-d ] imidazol-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 60)
Preparation of 1, 7-amino-1, 2,4, 5-tetrahydrobenzo [ d ] oxazepine
7-nitro-1, 2,4, 5-tetrahydrobenzo [ d ] oxazepine (140 mg,0.73 mmol) was dissolved in methanol (5 mL), palladium on carbon (100 mg, N/A) was added and reacted under a hydrogen atmosphere for 2 hours. LCMS detects the end of the reaction. Filtering, collecting filtrate, concentrating to obtain crude target compound, and directly using in the next step.
2. Preparation of N- (1, 2,4, 5-tetrahydrobenzo [ d ] oxazepin-7-yl) acetamide
7-amino-1, 2,4, 5-tetrahydrobenzo [ d ] oxazepine (crude product of the previous step) was dissolved in acetic acid (2 mL), acetic anhydride (2 mL) was added, and the reaction was carried out at 15℃for 1 hour after the addition. LCMS detects the end of the reaction. Diluting with water, adjusting pH to=9 with saturated sodium bicarbonate aqueous solution, extracting with dichloromethane, concentrating the aqueous phase, and purifying with C18 column (methanol=0-80%) to obtain 100mg of the target compound, with a two-step yield of 66.8%.
3. Preparation of N- (8-nitro-1, 2,4, 5-tetrahydrobenzo [ d ] oxazepin-7-yl) acetamide
N- (1, 2,4, 5-tetrahydrobenzo [ d ] oxazepin-7-yl) acetamide (100 mg,0.49 mmol) was dissolved in concentrated sulfuric acid (2 mL), fuming nitric acid (38 mg,0.61 mmol) was added dropwise at 0deg.C, and the reaction was carried out for 10min at 0deg.C. LCMS detects the end of the reaction. Pouring into ice water, adjusting pH to 7 with sodium hydroxide aqueous solution, concentrating the solvent, washing the solid with dichloromethane and methanol, and concentrating the organic phase to obtain crude product of the target compound, which is directly used in the next step.
Preparation of 8-nitro-1, 2,4, 5-tetrahydrobenzo [ d ] oxazepin-7-amine
N- (8-nitro-1, 2,4, 5-tetrahydrobenzo [ d ] oxazepin-7-yl) acetamide (N/A, 0.49 mmol) was dissolved in methanol (5 mL), potassium carbonate (166 mg,1.2 mmol) was added, and the reaction was continued at 55℃for 8 hours. LCMS detects the end of the reaction. The mixture was filtered through celite, and the filtrate was concentrated and purified by C18 column (methanol=0 to 80%) to give 80mg of the target compound in 78.1% yield.
Preparation of ethyl 2- (5, 6,8, 9-tetrahydro-1H-oxazepino [4',5':4,5] benzo [1,2-d ] imidazol-2-yl) acetate
8-nitro-1, 2,4, 5-tetrahydrobenzo [ d ] oxazepin-7-amine (80 mg,0.38 mmol) was dissolved in ethanol (3 mL), pd/C (100 mg) was added and hydrogenation was carried out at 15℃for 2 hours. LCMS detects the end of the reaction. Ethyl 3-ethoxy-3-iminopropionate hydrochloride (149 mg,0.76 mmol) was added and the mixture was allowed to react at 50℃for 2 hours. LCMS detects the end of the reaction. Diatomite is filtered, the filtrate is concentrated and purified by a silica gel column (dichloromethane: methanol=15:1) to obtain 100mg of the target compound with a yield of 94.9%.
Preparation of 7-amino-6- (5, 6,8, 9-tetrahydro-1H-oxazepino [4',5':4,5] benzo [1,2-d ] imidazol-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
Ethyl 2- (5, 6,8, 9-tetrahydro-1H-oxazepino [4',5':4,5] benzo [1,2-d ] imidazol-2-yl) acetate (50 mg,0.18 mmol) and 3-aminothiophene-2-carbonitrile (27 mg,0.22 mmol) were dissolved in tetrahydrofuran (2 mL), LDA (0.41 mL,0.81 mmol) was added, and the mixture was reacted at 40℃for 2 hours. LCMS detects the end of the reaction. Saturated ammonium chloride is added for quenching reaction, dichloromethane extraction is carried out, and an organic phase is dried, concentrated and pulped by methanol to obtain 5mg of target compound, and the yield is 7.98%.
Molecular formula C 18 H 16 N 4 O 2 S molecular weight 352.1 LC-MS (M/e): 353.1 (M+H) + )
1 H-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).
Preparation example 43: preparation of 7- ((2, 2-difluoroethyl) amino) -6- (5, 6,8, 9-tetrahydro-1H-oxazepino [4',5':4,5] benzo [1,2-d ] imidazol-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 61)
Preparation of 7-hydroxy-4- (4-methoxybenzyl) -6- (5, 6,8, 9-tetrahydro-1H-oxazepino [4',5':4,5] benzo [1,2-d ] imidazol-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
Ethyl 2- (5, 6,8, 9-tetrahydro-1H-oxazepino [4',5':4,5] benzo [1,2-d ] imidazol-2-yl) acetate (500 mg,1.8 mmol) and 1- (4-methoxybenzyl) -2H-thieno [3,2-d ] [1,3] oxazine-2, 4 (1H) -dione (686 mg,2.4 mmol) were dissolved in tetrahydrofuran (10 mL). LDA (4.5 mL,5 mol) was added at 40℃under nitrogen protection, and the reaction was completed at 40℃for 1 hour. And after the LCMS detection reaction is finished, cooling to 15 ℃, quenching the reaction by using saturated ammonium chloride aqueous solution, extracting by using dichloromethane, drying an organic phase, and concentrating to obtain a crude product of the target compound. The crude target compound was added again to tetrahydrofuran (10 mL), LDA (4.5 mL,5 mol) was added under nitrogen, and the reaction was continued at 40℃for 1 hour. Cooling to 15 ℃, adding saturated ammonium chloride aqueous solution for quenching reaction, extracting with dichloromethane, drying, concentrating and purifying an organic phase by a silica gel column (dichloromethane: methanol=20:1) to obtain 320mg of target compound, wherein the yield is 37.1%.
Preparation of 4- (4-methoxybenzyl) -5-oxo-6- (1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydro-1H-oxazepino [4',5':4,5] benzo [1,2-d ] imidazol-2-yl) -4, 5-dihydrothieno [3,2-b ] pyridin-7-yl trifluoromethanesulfonate
7-hydroxy-4- (4-methoxybenzyl) -6- (5, 6,8, 9-tetrahydro-1H-oxazepino [4',5':4,5] benzo [1,2-d ] imidazol-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (320 mg,0.68 mmol) was dissolved in dichloromethane (10 mL), pyridine (1.1 g,13.6 mmol) and trifluoromethanesulfonic anhydride (1.2 g,4.1 mmol) were added at 0deg.C and reacted for 30 min at 0deg.C. LCMS detects the end of the reaction. The reaction was quenched by addition of saturated aqueous sodium bicarbonate, extracted with dichloromethane, and the organic phase was concentrated by drying and used directly in the next step.
3.7- ((2, 2-difluoroethyl) amino) -4- (4-methoxybenzyl) -6- (1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydro-1H-oxazepino [4',5':4,5] benzo [1,2-d ] imidazol-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one preparation
4- (4-methoxybenzyl) -5-oxo-6- (1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydro-1H-oxazepino [4',5':4,5] benzo [1,2-d ] imidazol-2-yl) -4, 5-dihydrothieno [3,2-b ] pyridin-7-yl trifluoromethanesulfonate (N/A, 0.68 mmol) was dissolved in acetonitrile (10 mL), 2-difluoroethyl-1-amine (440 mg,5.4 mmol) was added and reacted at 40℃for 2 hours. LCMS detects the end of the reaction. The reaction mixture was purified by concentration on a silica gel column (dichloromethane: methanol=20:1) to give 130mg of the target compound in a two-step yield of 28.6%
4.7- ((2, 2-difluoroethyl) amino) -6- (5, 6,8, 9-tetrahydro-1H-oxazepino [4',5':4,5] benzo [1,2-d ] imidazol-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one preparation
7- ((2, 2-difluoroethyl) amino) -4- (4-methoxybenzyl) -6- (1- ((trifluoromethyl) sulfonyl) -5,6,8, 9-tetrahydro-1H-oxazepino [4',5':4,5] benzo [1,2-d ] imidazol-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (130 mg,0.19 mmol) was dissolved in concentrated hydrochloric acid (1.5 mL), trifluoroacetic acid (10.5 mL) was added, and the addition was completed and the temperature was raised to 110℃for 24 hours. LCMS detects the end of the reaction. Concentrating the solvent, dissolving in dichloromethane, adding saturated sodium bicarbonate aqueous solution, filtering, pulping the filter cake with methanol to obtain 40mg of target compound with a yield of 50.5%.
Molecular formula C 20 H 18 F 2 N 4 O 2 S molecular weight 416.4 LC-MS (M/e): 417.1 (M+H) + )
1 H-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).
Preparation example 44: preparation of 7-amino-6- (7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -1-methyl-1, 4-dihydro-5H-pyrazolo [4,3-b ] pyridin-5-one (Compound 62)
Ethyl 2- (7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (50 mg,0.16 mmol) was dissolved in tetrahydrofuran (3 mL), 4-amino-1-methyl-1H-pyrazole-5-carbonitrile (20 mg,0.16 mmol) was added under nitrogen, lithium diisopropylamide (0.40 mL,0.80 mmol) was added at 40℃and reacted for 2 hours at 40 ℃. LCMS detects the end of the reaction. Saturated ammonium chloride is added to quench the reaction, ethyl acetate is used for extraction, and the organic phase is dried, concentrated and pulped with methanol to obtain the title compound 33mg, and the yield is 53.0%.
Molecular formula C 21 H 23 N 7 Molecular weight of O389.5 LC-MS (M/e) 390.2 (M+H) + )
1 H-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).
Preparation example 45: preparation of 7-amino-6- (7- (azetidin-1-yl) -1,5,6,7,8,9-hexahydrocycloheptyl [4,5] benzo [1,2-d ] imidazol-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 63)
Preparation of 2-nitro-5, 6,8, 9-tetrahydro-7H-benzo [7] rotaen-7-one
5,6,8, 9-tetrahydro-7H-benzo [7] chromen-7-one (2.0 g,12.4 mmol) was dissolved in concentrated sulfuric acid (20 mL), and after stirring for 1H, potassium nitrate (1.5 g,14.9 mmol) was slowly added in portions and reacted at 0℃for 2 hours. LCMS detects the end of the reaction. Poured into ice water (200 mL), extracted with ethyl acetate (100 mL x 4 times), concentrated by organic phase drying and purified by silica gel column (n-heptane: ethyl acetate=5:1) to give the title compound 2.0g, yield 79%.
Preparation of 1- (2-nitro-6, 7,8, 9-tetrahydro-5H-benzo [7] cyclohex-7-yl) azetidine
2-nitro-5, 6,8, 9-tetrahydro-7H-benzo [7] chromen-7-one (2.0 g,9.7 mmol) was dissolved in methanol (100 mL), sodium cyanoborohydride (1.6 g,23.5 mmol) and azetidine (673 mg,11.8 mmol) were added, and the mixture was reacted at 35℃for 12 hours. LCMS detects the end of the reaction. The solvent was concentrated, quenched with saturated sodium bicarbonate, extracted with ethyl acetate (100 ml×4 times), concentrated by organic phase drying, and purified by silica gel column (dichloromethane: methanol=10:1) to give the title compound 2.3g in 96% yield.
Preparation of 7- (azetidin-1-yl) -6,7,8, 9-tetrahydro-5H-benzo [7] chromen-2-amine
1- (2-nitro-6, 7,8, 9-tetrahydro-5H-benzo [7] chromen-7-yl) azetidine (2.3 g,9.3 mmol) was dissolved in methanol (100 mL), raney nickel (79mg, 9.3 mmol) was added and reacted at 30℃for 4 hours. LCMS detects the end of the reaction. The title compound 1.6g was obtained by suction filtration through celite and 80% yield of crude product.
4. Preparation of N- (7- (azetidin-1-yl) -6,7,8, 9-tetrahydro-5H-benzo [7] chromen-2-yl) acetamide
7- (azetidin-1-yl) -6,7,8, 9-tetrahydro-5H-benzo [7] chromen-2-amine (1.6 g,7.5 mmol) was placed in a 100mL single-necked flask, acetic acid (5 mL) and acetic anhydride (5 mL) were added, and reacted at 25℃for 1 hour. LCMS detects the end of the reaction. Concentrate to dryness, quench with saturated sodium bicarbonate, extract with ethyl acetate and methanol mixed solution (ethyl acetate: methanol=5:1) (100 ml×4 times), dry concentrate the organic phase, purify on silica gel column (dichloromethane: methanol=10:1) to give the title compound 1.5g, yield 78%.
5. Preparation of N- (7- (azetidin-1-yl) -3-nitro-6, 7,8, 9-tetrahydro-5H-benzo [7] chromen-2-yl) acetamide
N- (7- (azetidin-1-yl) -6,7,8, 9-tetrahydro-5H-benzo [7] chromen-2-yl) acetamide (1.5 g,5.9 mmol) was dissolved in concentrated sulfuric acid (15 mL), stirred at 0deg.C for 1 hour, potassium nitrate (650 mg,6.5 mmol) was added in portions, and the mixture was reacted at 0deg.C for 1 hour. LCMS detects the end of the reaction. Poured into ice water, quenched with saturated sodium carbonate, extracted with a mixed solution of ethyl acetate and methanol (ethyl acetate: methanol=10:1) (200 ml×4 times), concentrated by organic phase drying, and purified by silica gel column (dichloromethane: methanol=10:1) to give the title compound 1.6g in 89% yield.
Preparation of 7- (azetidin-1-yl) -3-nitro-6, 7,8, 9-tetrahydro-5H-benzo [7] chromen-2-amine
N- (7- (azetidin-1-yl) -3-nitro-6, 7,8, 9-tetrahydro-5H-benzo [7] chromen-2-yl) acetamide (1.6 g,5.3 mmol) was dissolved in methanol (100 mL), potassium carbonate (2.2 g,15.8 mmol) was added and the reaction was continued at 50℃for 4 hours. LCMS detects the end of the reaction. The title compound 854mg was obtained in 62% yield by suction filtration through celite and purification through an organic phase dry concentrated silica gel column (dichloromethane: methanol ester=10:1).
Preparation of ethyl 2- (7- (azetidin-1-yl) -1,5,6,7,8,9-hexahydrocycloheptyl [4,5] benzo [1,2-d ] imidazol-2-yl) acetate
7- (azetidin-1-yl) -3-nitro-6, 7,8, 9-tetrahydro-5H-benzo [7] cyclo-en-2-amine (854 mg,3.3 mmol) was dissolved in ethanol (50 mL), pd/C (4819 mg,1.7 mmol) was added and the addition was completed and hydrogenated at 25℃for 8 hours. LCMS detects the end of the reaction. Ethyl 3-ethoxy-3-iminopropionate hydrochloride (1.5 g,7.9 mmol) was added, the temperature was raised to 50℃and the reaction was stirred at reflux for 3 hours, and the reaction was terminated by LCMS. Celite was added for filtration, and the organic phase was concentrated by column purification on silica gel (dichloromethane: methanol ester=10:1) to give 755mg of the title compound in 70.6% yield in two steps.
Preparation of 7-amino-6- (7- (azetidin-1-yl) -1,5,6,7,8,9-hexahydrocycloheptyl [4,5] benzo [1,2-d ] imidazol-2-yl) thieno [3,2-b ] pyridin-5 (4H) -one
Ethyl 2- (7- (azetidin-1-yl) -1,5,6,7,8,9-hexahydrocyclohepta [4,5] benzo [1,2-d ] imidazol-2-yl) acetate (755mg, 2.3 mmol) and 2-cyano-3-aminothiophenol (682 mg,5.5 mmol) were dissolved in tetrahydrofuran (15 mL), warmed to 40℃under nitrogen, and LDA (1.2 mmol,0.6 mL) was slowly added and reacted at 40℃for 2 hours. LCMS detects the end of the reaction. The reaction was quenched by addition of saturated aqueous ammonium chloride, extracted with ethyl acetate, dried and concentrated in organic phase, extracted with a mixture of ethyl acetate and methanol (ethyl acetate: methanol=10:1) (200 ml×4 times), dried and concentrated in organic phase, and purified on a silica gel column (dichloromethane: methanol=10:1) to give the title compound 401mg, yield: 43%.
Molecular formula C 22 H 23 N 5 OS molecular weight 405.5 LC-MS (M/e): 406.1 (M+H) + )
1 H-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).
Preparation example 46: preparation of 7- (isopropylamino) -6- (7- (oxetan-3-yl) -1,5,6,7,8,9-hexahydroimidazo [4',5:4,5] benzo [1,2-d ] azepin-2-yl) thiophene [3,2-b ] pyridin-5 (4H) -one (Compound 64)
6- (1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -7- (isopropylamino) thieno [3,2-b ] pyridin-5 (4H) -one (120 mg,0.30 mmol) was dissolved in methanol (10 mL), 3-oxetanone (90 mg,0.54 mmol) and acetic acid (186 mg,0.18 mmol) were added, and after 30 minutes at 25℃sodium cyanoborohydride (96 mg,0.54 mmol) was added and the mixture was reacted at 35℃for 16 hours. LCMS detects the end of the reaction. Saturated sodium bicarbonate was added to adjust ph=8, extracted with dichloromethane (40 mL), and separated by silica gel column chromatography (methanol: dichloromethane=1:15) to give 60mg of the target compound in 43.8% yield.
Molecular formula C 24 H 27 N 5 O 2 S molecular weight 449.6 LC-MS (M/e): 450.2 (M+H) + )
1 H-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).
Preparation example 47:6- (7- (azetidin-1-yl) -1,5,6,7,8,9-hexahydrocycloheptyl [4,5] benzo [1,2-d ] imidazol-2-yl) -7- (isopropylamino) thieno [3,2-b ] pyridin-5 (4H) -one (Compound 65)
1.6- (7- (azetidin-1-yl) -1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydrocycloheptyl [4,5] benzo [1,2-d ] imidazol-2-yl) -7- (isopropylamino) -4- (4-methoxybenzyl) thieno [3,2-b ] pyridin-5 (4H) -one preparation
6- (7- (azetidin-1-yl) -1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydrocyclohepta [4,5] benzo [1,2-d ] imidazol-2-yl) -4- (4-methoxybenzyl) -5-oxo-2, 3,4, 5-tetrahydrothieno [3,2-b ] pyridin-7-yl trifluoromethanesulfonate (315 mg,0.4 mmol) and isopropylamine (235 mg,4 mmol) were dissolved in acetonitrile (50 mL) and reacted after warming to 40℃for 3 hours. LCMS detects the end of the reaction. Column chromatography, silica gel column purification (dichloromethane: methanol=10:1) gave 157mg of the title compound in a yield of 56.5%.
Preparation of 6- (7- (azetidin-1-yl) -1,5,6,7,8,9-hexahydrocyclohepta [4,5] benzo [1,2-d ] imidazol-2-yl) -7- (isopropylamino) thieno [3,2-b ] pyridin-5 (4H) -one
6- (7- (azetidin-1-yl) -1- ((trifluoromethyl) sulfonyl) -1,5,6,7,8,9-hexahydrocycloheptyl [4,5] benzo [1,2-d ] imidazol-2-yl) -7- (isopropylamino) -4- (4-methoxybenzyl) thieno [3,2-b ] pyridin-5 (4H) -one (157 mg,0.22 mmol) was placed in a 100mL single-necked flask, trifluoroacetic acid (6 mL) and concentrated hydrochloric acid (1 mL) were added, and the temperature was raised to 110℃for 24 hours. LCMS detects the end of the reaction. The organic phase was concentrated and purified by reverse phase column chromatography (water: methanol=10:3) to give 38mg of the title compound in 39% yield.
Molecular formula C 25 H 29 N 5 OS molecular weight 447.6 LC-MS (M/e): 480.2 (M+H) + )
1 H-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).
Preparation example 48:2- (7-amino-1-methyl-5-oxo-4, 5-dihydro-1H-pyrazolo [4,3-b ] pyridin-6-yl) -7-cyclopropyl-5, 7,8, 9-tetrahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-6 (1H) -one (Compound 66)
Ethyl 2- (7-cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (200 mg,0.61 mmol) was dissolved in tetrahydrofuran (10 mL), 4-amino-1-methyl-1H-pyrazole-5-carbonitrile (89 mg,0.73 mmol) was added, LDA (2.44 mL,4.88 mmol) was added dropwise at 40℃and the reaction was continued for 6H, LCMS detection was complete. Pouring into saturated ammonium chloride aqueous solution for quenching, extracting with ethyl acetate, spinning-drying an organic phase, pulping with methanol to obtain 40mg of a crude product of the target compound, and purifying with reversed phase chromatography (methanol: water=0-50%) to obtain 2.4mg of the target compound with a yield of 1.0%.
Molecular formula C 21 H 21 N 7 O 2 Molecular weight 403.4 LC-MS (M/e) 404.1 (M+H) + )
1 H-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).
Preparation example 49: preparation of 7-amino-1-methyl-6- (7- (oxetan-3-yl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -1, 4-dihydro-5H-pyrazolo [4,3-b ] pyridin-5-one (Compound 67)
Preparation of 8-nitro-3- (oxetan-3-yl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine
8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine (500 mg,5.42 mmol), oxetanone (803 mg,7.26 mmol) were dissolved in methanol (20 mL), acetic acid (1.5 g,24.2 mmol) and sodium cyanoborohydride (900 mg,14.5 mmol) were added and reacted at 25℃for 16H, and completion of the reaction was detected by LCMS. The pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate, extracted with dichloromethane, the organic phase was dried by spin-drying and purified on a silica gel column (dichloromethane: methanol=15:1) to give 420mg of the title compound in 66.0% yield.
Preparation of ethyl 2- (7- (oxetan-3-yl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate
8-nitro-3- (oxetan-3-yl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-7-amine (420 mg,1.6 mmol) was dissolved in ethanol (10 mL), pd/C (200 mg) was added and the mixture was hydrogenated at 25℃for 2 hours. Ethyl 3-ethoxy-3-iminopropionate hydrochloride (657 mg,3.36 mmol) was added and the reaction was continued at 50℃for 4h. LCMS detects completion of the reaction. The mixture was filtered through celite, the filtrate was dried by spin, diluted with dichloromethane, washed with saturated sodium bicarbonate, and the organic phase was dried by spin and purified by column on silica gel (dichloromethane: methanol=10:1) to give 370mg of the title compound in 70.1% yield.
Preparation of 7-amino-1-methyl-6- (7- (oxetan-3-yl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -1, 4-dihydro-5H-pyrazolo [4,3-b ] pyridin-5-one
Ethyl 2- (7- (oxetan-3-yl) -1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (80 mg,0.24 mmol) is dissolved in tetrahydrofuran (5 mL), 4-amino-1-methyl-1H-pyrazole-5-carbonitrile (29 mg,0.24 mmol) is added, LDA (0.96 mL,1.92 mmol) is added dropwise at 45℃and the reaction is continued for 5H, LCMS detection is complete. Pouring into saturated ammonium chloride aqueous solution for quenching, extracting by ethyl acetate, spin-drying an organic phase, pulping by methanol to obtain 17.5mg of a target compound, and obtaining the yield of 17.8%.
Molecular formula C 21 H 23 N 7 O 2 Molecular weight 405.5 LC-MS (M/e) 406.2 (M+H) + )
1 H-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).
Preparation example 50: preparation of 7-amino-6- (7- (azetidin-1-yl) -1,5,6,7,8,9-hexahydrocyclohepta [4,5] benzo [1,2-d ] imidazol-2-yl) -1-methyl-1, 4-dihydro-5H-pyrazolo [4,3-b ] pyridin-5-one (Compound 68)
Ethyl 2- (7- (azetidin-1-yl) -1,5,6,7,8,9-hexahydrocyclohepta [4,5] benzo [1,2-d ] imidazol-2-yl) acetate (200 mg,0.61 mmol) and 3-amino-1, 5-dimethyl-1-hydro-pyrrole-2-cyano (112 mg,0.92 mmol) were dissolved in tetrahydrofuran (50 mL), warmed to 40℃under nitrogen, and LDA (3.1 mL,6.1 mmol) was slowly added and reacted at 40℃for 2 hours. LCMS detects the end of the reaction. Adding saturated ammonium chloride aqueous solution to quench the reaction, extracting with ethyl acetate, drying and concentrating the organic phase, extracting with ethyl acetate/methanol mixed solvent (ethyl acetate: methanol=10:1, 200ml×4 times), drying and concentrating the organic phase, purifying by reverse phase column chromatography (water: methanol=10:4) to obtain the target compound 100mg, with a yield of 40.6%.
Molecular formula C 22 H 25 N 7 O molecular weight 403.5 LC-MS (M/e) 404.2 (M+H) + )
1 H-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).
Preparation example 51: preparation of 4-amino-5- (7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) -1-methyl-1, 7-dihydro-6H-pyrazolo [3,4-b ] pyridin-6-one (Compound 69)
Ethyl 2- (7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5] benzo [1,2-d ] azepin-2-yl) acetate (100 mg,0.32 mmol) was dissolved in tetrahydrofuran (5 mL), 6-methyl-1H-pyrazole-4-carbonitrile (39 mg,0.32 mmol) was added under nitrogen, LDA (2M, 1.3mL,2.6 mmol) was added at 40℃and the reaction was carried out for 3 hours at 40 ℃. LCMS detects the end of the reaction. Pouring into saturated ammonium chloride solution for quenching reaction, extracting by ethyl acetate, drying and concentrating an organic phase, and pulping by methanol and dichloromethane to obtain the target compound with the yield of 10mg and 8.1 percent.
Molecular formula C 21 H 23 N 7 O 2 Molecular weight 389.5 LC-MS (M/e) 390.2 (M+H) + )
1 H-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).
Using the same or similar methods as the preparation examples described above, the compounds shown in the following tables were prepared:
experimental protocol
Exemplary protocols for some of the compounds of the present invention are provided below to demonstrate the advantageous activity and beneficial technical effects of the compounds of the present invention. It should be understood that the following experimental schemes are merely illustrative of the present disclosure and are not intended to limit the scope of the present disclosure.
Experimental example 1 inhibition experiment of in vitro kinase Activity by the Compounds of the invention
Test article: the structural formula and the preparation method of part of the compounds are shown in the preparation examples.
Abbreviations used in the following experiments represent the following meanings:
DMSO: dimethyl sulfoxide;
HEPES: hydroxyethyl piperazine ethyl sulfuric acid
The experimental method comprises the following steps: compounds were evaluated on 6 kinases in vitro using the Lantha screen Assay method.
The experimental steps are as follows:
1. preparation of 1 Xkinase buffer containing 50mM HEPES solution, 10mM magnesium chloride, 4mM dithiothreitol, 0.01% bovine serum albumin and 0.01% Tween-20:
2. compound dilution:
1) Mu.l of 100% DMSO was taken and 10. Mu.l of 10mM compound solution was added to prepare a 1mM compound solution. To a second well of a 96-well plate, 90. Mu.l of 100% DMSO was added, and 10. Mu.l of 1mM compound solution was added to prepare 100. Mu.M compound solution, and the other wells were added with 60. Mu.l of 100% DMSO. Mu.l of the compound was taken from the second well and added to the third well, followed by 3-fold dilution down in sequence for a total of 10 concentrations.
Transfer 40 μl of the 100 μM compound solution prepared above to 384 well Echo plates;
2) Transfer 40 μl of 100% dmso into two wells as positive control without compound and negative control without enzyme;
3) Using Echo 550, 100nl of compound was transferred to 384 well test plates at an initial concentration of 1. Mu.M.
3. The 2 Xkinase solution was prepared with 1 Xkinase buffer, 5. Mu.l of the 2 Xkinase solution was transferred to 384-well plate reaction wells, and the 1 Xkinase buffer was added to the negative control wells, mixed by shaking at 450 rpm, allowed to stand at room temperature for 10 minutes.
4. The 2 Xsubstrate solution was prepared with 1 Xkinase buffer, and 5. Mu.l of the 2 Xsubstrate solution was transferred to 384-well plate reaction wells and mixed by shaking at 450 rpm.
5. The reaction was carried out at room temperature for 90 minutes.
6. A2 Xantibody-containing stop reaction solution was prepared, 10. Mu.l of the 2 Xstop reaction solution was transferred to 384-well plate reaction wells, centrifuged at 1000 rpm for 1 minute, left at room temperature for 60 minutes, and detected.
7. Reading data: values emitted at 340nm, 520nm and 495nm were read on Envision2104, multilable Reader.
8. Data computation
1) The numerical ratio of fluorescence readings (Lantha signal (520 nm/495 nm)) was converted to percent inhibition by the formula:
percent inhibition = (max-Lantha signal)/(max-min) ×100
"minimum" is the reading of the negative control well without enzyme; "maximum" is the positive control well reading without compound.
2) Importing data into MS Excel, IC 50 Results were curve fitted using XLFIT excel add-in version 5.4.0.8.
Experimental results
TABLE 1 in vitro enzymatic inhibitory Activity of the Compounds of the invention
Conclusion of the experiment
The compound has good inhibitory activity on MAP4K1/HPK1, and has excellent selectivity on HPK 1.
Experimental example 2 inhibition experiment of the in vitro cytological Activity of the Compounds of the invention
Test article: the structural formula and the preparation method of part of the compounds are shown in the preparation examples.
Abbreviations used in the following experiments represent the following meanings:
ELISA: enzyme-linked immunosorbent assay;
jurkat: human acute T cell leukemia cells;
SLP76: SH2 domain-containing 76kDa albumin;
CD3: cluster of differentiation 3 (leukocyte differentiation antigen);
PBS buffer: phosphate balanced physiological saline;
TMB:3,3', 5' -tetramethylbenzidine.
The experimental method comprises the following steps: the inhibition level of serine phosphorylation at position 376 of SLP76 by the compound was detected on Jurkat cells in vitro by ELISA.
The experimental steps are as follows:
1. cell preparation: harvesting Jurkat cells in logarithmic growth phase, and adjusting to proper cell concentration; mu.L of cell suspension per well was added to 96-well plates.
2. Drug dilution and dosing:
1) Preparing a 10-time drug solution with the highest concentration of 3 mu M, 3-time dilution and 6 concentrations;
2) 9 μl of drug solution was added to each well of a 96-well plate seeded with cells, and two duplicate wells were set for each drug concentration. Cells in 96-well plates were placed at 37℃in 5% CO 2 Culturing for 1h under the condition.
3. Cell stimulation: cells were lysed for pSLP76 detection by adding 10. Mu.L of 50. Mu.g/mL of CD3 antibody per well for 30 min.
4. Cell collection and lysis
1) The cells were blown up and transferred to a centrifuge tube and centrifuged at 3000rpm at 4℃for 3min;
2) The supernatant was discarded, resuspended in 100. Mu.L/Kong Yuleng PBS buffer and centrifuged at 3000rpm for 3min at 4 ℃.
3) Removing the supernatant, and adding 100 mu L/tube cell lysate;
4) Ultrasonic cleavage for 5min and centrifugation at 14000rpm for 5min.
pSLP76 assay
1) Transfer 50 μl/well of sample supernatant into a 96-well plate;
2) Adding 50. Mu.L/well of the mixed antibody;
3) Oscillating for 1h at room temperature;
4) Discarding the supernatant, and cleaning 3 times with a cleaning solution, wherein 200 mu L/hole;
5) Adding 100 mu L/hole TMB substrate, and vibrating for 15min at room temperature;
6) 100. Mu.L/Kong Zhongzhi solution was added and detected at 450nm over 30 min.
6. Data processing
Analysis of data using GraphPad Prism 5.0 software, fitting data to derive dose-response curves using nonlinear S-curve regression, and calculating IC therefrom 50 Values.
pSLP76 inhibition (%) = (assay well read-average of cell plus CD3 well read)/(average of cell plus CD3 well read-average of cell plus CD3 well read) ×100% of
Conclusion of the experiment
Experimental results show that the compound of the invention has good inhibitory activity on serine phosphorylation at 376 position of MAP4K1/HPK1 downstream protein SLP76, such as IC of compound 1, compound 10, compound 11, compound 12, compound 14-1, compound 15, compound 23-1, compound 26, compound 49, compound 50, compound 53, compound 55, compound 58, compound 63, compound 64 and the like 50 The values are all less than 100nM, i.e. the compounds of the invention have very good inhibitory activity on HPK 1.
Claims (14)
- A compound of formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof,wherein,X 1 、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 、Y 4 are each independently selected from-C (R) 2 ) or-N-;Y 3 selected from-C (R) 5 ) or-N-;Y 5 selected from-C (R) 6 );Y 6 Selected from-C (R) 7 ) or-N-;each R is 2 、R 3 Each R is 4 Are each independently selected from hydrogen, halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 An alkoxy group;R 5 and R is 7 One of which is with R 6 Together with the ring atoms to which they are each attached form a 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl group optionally substituted with 1-5Q 1; r not forming a ring 5 Or R is 7 Selected from hydrogen, halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 An alkoxy group;R 1 selected from hydrogen, halogen, hydroxy, 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 the following groups optionally substituted with substituents: - (CH) 2 ) p -3-10 membered cycloalkyl, - (CH) 2 ) p -3-10 membered heterocyclyl, - (CH) 2 ) p -5-to 10-membered heteroaryl, - (CH) 2 ) p -6-10 membered aryl; the substituents are selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1- 6 Alkoxy or halo C 1-6 An alkyl group;each Q1 is independently selected from halogen, hydroxy, nitro, amino, cyano, carboxy, -NR a R b 、-OR a 、-SR a 、-C(O)R a 、-C(O)OR a 、-C(O)NR a Or optionally substituted with 1-3Q 2: c (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-to 10-membered heteroaryl or- (CH) 2 ) m -6-10 membered aryl; the Q2 groups are each independently selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1- 6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl;each R is a Each R is b Are independently selected from hydrogen, halogen,Hydroxy, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1- 6 Alkoxy, C 1-6 Alkylamino, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo 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 optionally substituted with substituents: - (CH) 2 ) m -3-10 membered cycloalkyl, - (CH) 2 ) m -3-10 membered heterocyclyl, - (CH) 2 ) m -5-to 10-membered heteroaryl, - (CH) 2 ) m -6-10 membered aryl; the substituents are selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 An alkyl group;each m, each p is independently selected from 0, 1, 2, 3, 4 or 5.
- The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, having a structure represented by general formula (II-1) or general formula (II-2):wherein,each R is 2 Each R is 3 Each R is 4 、R 5 、R 7 Are each independently selected from hydrogen, halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 An alkoxy group;R 1 selected from hydrogen, halogen, hydroxy, 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 the following groups optionally substituted with substituents: - (CH) 2 ) p -3-10 membered cycloalkyl, - (CH) 2 ) p -3-10 membered heterocyclyl, - (CH) 2 ) p -5-to 10-membered heteroaryl, - (CH) 2 ) p -6-10 membered aryl; the substituents are selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1- 6 Alkoxy or halo C 1-6 An alkyl group;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, hydroxy, nitro, amino, cyano, carboxy, -NR a R b 、-OR a 、-SR a 、-C(O)R a 、-C(O)OR a 、-C(O)NR a Or optionally substituted with 1-3Q 2: c (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-to 10-membered heteroaryl or- (CH) 2 ) m -6-10 membered aryl; the Q2 groups are each independently selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1- 6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl;each R is a Each R is b Are each independently selected from hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1- 6 Alkoxy, C 1-6 Alkylamino, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo 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 optionally substituted with substituents: - (CH) 2 ) m -3-10 membered cycloalkyl, - (CH) 2 ) m -3-10 membered heterocyclyl, - (CH) 2 ) m -5-to 10-membered heteroaryl, - (CH) 2 ) m -6-10 membered aryl; the substituents are selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 An alkyl group;each m, each n, each p is independently selected from 0, 1, 2, 3, 4, or 5;X 1 、X 2 、X 3 、X 4 、Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 as defined in claim 1.
- The compound of claim 2, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,each R is 2 、R 3 Each R is 4 、R 5 、R 7 Are each independently selected from hydrogen, halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy or halo C 1-4 An alkoxy group;R 1 selected from hydrogen, halogen, hydroxy, 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 the following groups optionally substituted with substituents: - (CH) 2 ) p -3-6 membered cycloalkyl, - (CH) 2 ) p -3-6 membered heterocyclyl, - (CH) 2 ) p -5-8 membered heteroaryl, - (CH) 2 ) p -phenyl; the substituents are selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 An alkyl group;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, hydroxy, nitro, amino, cyano, carboxy, -NR a R b 、-OR a 、-SR a 、-C(O)R a 、-C(O)OR a 、-C(O)NR a Or optionally substituted with 1-3Q 2: c (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-to 8-membered heteroaryl or-(CH 2 ) m -phenyl; the Q2 groups are each independently selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl or phenyl;each R is a Each R is b Are each independently selected from hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1- 4 Alkoxy, C 1-4 Alkylamino, di (C) 1-4 Alkyl) amino, halo C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkylthio, halo C 1-4 Alkoxy, halo 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 optionally substituted with substituents: - (CH) 2 ) m -3-8 membered cycloalkyl, - (CH) 2 ) m -3-8 membered heterocyclyl, - (CH) 2 ) m -5-8 membered heteroaryl, - (CH) 2 ) m -phenyl; the substituents are selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 An alkyl group;each m, each n, each p is independently selected from 0, 1, 2, or 3.
- A compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, having a structure according to formula (III-1) or formula (III-2):wherein Y is 1 Selected from-C (R) 2 )(R 3 )-、-O-、-N(R 4 ) -or-S-;Y 4 selected from-C (R) 2 ) or-N-;Y 3 selected from-C (R) 5 ) or-N-;Y 6 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 is 2 、R 3 、R 4 、R 5 、R 7 Are independently selected from hydrogen, halogen, C 1-4 Alkyl or halo C 1-4 An alkyl group;R 1 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 heterocyclyl; the substituents are selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy or halo C 1-4 An alkyl group;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 substituted with 1-2Q 2 groups: c (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 groups are each independently selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy or hydroxy C 1-4 An alkyl group;each R is a Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoromethoxy, or the following groups optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidinyl or imidazolidinyl; the substituent is selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl;each R is b Independently selected from hydrogen or C 1-4 An alkyl group;each m, each n, each p is independently selected from 0, 1, 2, or 3.
- The compound of any one of claims 1-3, pharmaceutically acceptable salt thereof, or stereoisomer thereof, wherein:each R is 2 、R 3 Each R is 4 、R 5 、R 7 Each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, or trifluoromethyl;R 1 selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, oxetanyl, aziridinyl, 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 Preferably 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 optionally substituted with 1-2Q 2 groups: 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 -an oxetanyl, - (CH) 2 ) m -oxetanyl, - (CH) 2 ) m Azacyclopropyl, - (CH) 2 ) m Azacyclobutyl, - (CH) 2 ) m -tetrahydrochyseneFuryl, - (CH) 2 ) m -an oxetanyl, - (CH) 2 ) m Tetrahydropyranyl, - (CH) 2 ) m Pyrrolidinyl, - (CH) 2 ) m Piperidinyl, - (CH) 2 ) m Piperazinyl, - (CH) 2 ) m -pyridinyl, - (CH) 2 ) m Pyrimidinyl, - (CH) 2 ) m Pyridazinyl, - (CH) 2 ) m -pyrazinyl; the Q2 groups are each independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl or hydroxypropyl;each R is a Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoromethoxy, or the following groups optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidinyl or imidazolidinyl; the substituent is selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl;Each R is b Each independently selected from hydrogen, methyl, ethyl, propyl or isopropyl;each m, each n is independently selected from 0, 1, 2 or 3.
- The compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof according to any one of claim 1 to 5, wherein,X 2 、X 3 、X 4 one of them is selected from S, O, N or-N (R 4 ) Two other are each independently-C (R 2 )-。
- The compound of any one of claims 1-5, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, having a structure of formula (IV-1) or formula (IV-2):wherein X is 2 、X 3 、X 4 Ring A, R 1 、R 2 、R 4 、R a 、R b Q1, Q2, m, n, p are as defined in any one of claims 1 to 5.
- A compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, having a structure represented by general formula (VII-1), general formula (VII-2), general formula (VII-3), general formula (VII-4), general formula (VII-5) or general formula (VII-6):wherein the ring A, R 1 、R 4 、R a 、R b Q1, Q2, m, n, p are as defined in any of claims 1 to 3.
- The compound of claim 8, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,R 1 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 substituents are selected from halogen, C 1-4 Alkyl or halo C 1-4 An alkyl group;each R is 4 Are independently selected from hydrogen, halogen, C 1-4 Alkyl or halo C 1-4 An alkyl group;ring A is selected from Wherein each ring atom in ring a is optionally oxo;each Q1 is independently selected from the group consisting of-C (O) R a 、-C(O)OR a 、-C(O)NR a Or optionally substituted with 1-2Q 2 groups: c (C) 1-4 Alkyl, 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 phenyl; the Q2 is independently selected from halogen, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or hydroxy C 1-4 An alkyl group;each R is a Are independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, or the following optionally substituted with substituents: 3-6 membered cycloalkyl, 3-6 membered heterocyclyl; the substituents are selected from halogen, hydroxy, C 1-6 Alkyl or halo C 1-6 An alkyl group;each R is b Independently selected from hydrogen orC 1-4 An alkyl group;each n and each p is independently selected from 0, 1 or 2.
- The compound of claim 9, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,R 1 selected from the group consisting of azetidinyl, oxetanyl, -NR a -C(O)-R b -、-NR a R b OR-OR a ;Each R is 4 Each 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 the group consisting of-C (O) R a 、-C(O)OR a Or optionally substituted with 1-2Q 2 groups: methyl, ethyl, propyl, isopropyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxypropyl, propoxymethyl, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, oxetanyl, tetrahydropyranyl, aziridinyl, azetidinyl, pyrrolidinyl, pyridinyl or pyridazinyl; the Q2 groups are each independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, or trifluoromethyl;each R is a Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoromethoxy, or the following groups optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidinyl or imidazolidinyl; the substituent is selected from halogen, hydroxy, methyl, ethyl, propyl, isopropyl or trifluoromethyl;Each R is b Each independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.
- The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from the group consisting of:
- a pharmaceutical formulation comprising a compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt or stereoisomer thereof, wherein the pharmaceutical formulation comprises one or more pharmaceutically acceptable excipients and is in any one of the pharmaceutically acceptable dosage forms.
- A pharmaceutical composition comprising a compound according to any one of claims 1-11, a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that it comprises one or more second therapeutically active agents selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, antitumor antibiotics, growth factor inhibitors, signaling inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormonal agents, angiogenesis inhibitors, cytostatic agents, targeting antibodies, HMG-CoA reductase inhibitors and prenyl protein transferase inhibitors.
- Use of a compound according to any one of claims 1-11, a pharmaceutically acceptable salt or stereoisomer thereof, a pharmaceutical formulation according to claim 12, or a pharmaceutical composition according to claim 13 for the manufacture of a medicament for the treatment and/or prophylaxis of diseases mediated by HPK1 and related conditions selected from cancers or benign tumors selected from 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, squamous cell carcinoma, prostate cancer, thyroid cancer, female genital 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.
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PCT/CN2022/080065 WO2022188823A1 (en) | 2021-03-10 | 2022-03-10 | Tricyclic hpk1 inhibitor and use thereof |
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CN202280012271.1A Pending CN116888127A (en) | 2021-03-10 | 2022-03-10 | Tri-fused ring HPK1 inhibitor and application thereof |
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CN (1) | CN116888127A (en) |
TW (1) | TW202246284A (en) |
WO (1) | WO2022188823A1 (en) |
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JP7460644B2 (en) | 2018-10-31 | 2024-04-02 | ギリアード サイエンシーズ, インコーポレイテッド | Substituted 6-Azabenzimidazole Compounds as HPK1 Inhibitors |
JP7273172B2 (en) | 2018-10-31 | 2023-05-12 | ギリアード サイエンシーズ, インコーポレイテッド | Substituted 6-azabenzimidazole compounds with HPK1 inhibitory activity |
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MA42456B1 (en) * | 2015-06-25 | 2021-06-30 | Univ Health Network | Hpk1 inhibitors and methods of use |
CN109721620B (en) * | 2017-10-27 | 2022-05-13 | 药捷安康(南京)科技股份有限公司 | HPK1 inhibitors and uses thereof |
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2022
- 2022-03-10 TW TW111108814A patent/TW202246284A/en unknown
- 2022-03-10 CN CN202280012271.1A patent/CN116888127A/en active Pending
- 2022-03-10 WO PCT/CN2022/080065 patent/WO2022188823A1/en active Application Filing
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WO2022188823A1 (en) | 2022-09-15 |
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