WO2021254483A1 - 布鲁顿酪氨酸激酶抑制剂及其制备方法 - Google Patents
布鲁顿酪氨酸激酶抑制剂及其制备方法 Download PDFInfo
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- WO2021254483A1 WO2021254483A1 PCT/CN2021/100901 CN2021100901W WO2021254483A1 WO 2021254483 A1 WO2021254483 A1 WO 2021254483A1 CN 2021100901 W CN2021100901 W CN 2021100901W WO 2021254483 A1 WO2021254483 A1 WO 2021254483A1
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- Prior art keywords
- methyl
- amino
- dimethyl
- pyrrolo
- cyclopenta
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- 230000037361 pathway Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 125000005498 phthalate group Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940093625 propylene glycol monostearate Drugs 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 150000004040 pyrrolidinones Chemical class 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000004202 respiratory function Effects 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000012354 sodium borodeuteride Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960001462 sodium cyclamate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- RCOSUMRTSQULBK-UHFFFAOYSA-N sodium;propan-1-olate Chemical compound [Na+].CCC[O-] RCOSUMRTSQULBK-UHFFFAOYSA-N 0.000 description 1
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- WGRQANOPCQRCME-PMACEKPBSA-N teneligliptin Chemical compound O=C([C@H]1NC[C@H](C1)N1CCN(CC1)C1=CC(=NN1C=1C=CC=CC=1)C)N1CCSC1 WGRQANOPCQRCME-PMACEKPBSA-N 0.000 description 1
- JJXVPQLHSUHZBA-NSHDSACASA-N tert-butyl (3s)-3-methyl-4-(6-nitropyridin-3-yl)piperazine-1-carboxylate Chemical compound C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C([N+]([O-])=O)N=C1 JJXVPQLHSUHZBA-NSHDSACASA-N 0.000 description 1
- SUWKOEMQNOBJEQ-UHFFFAOYSA-N tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C([N+]([O-])=O)N=C1 SUWKOEMQNOBJEQ-UHFFFAOYSA-N 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention belongs to the field of medicine, and relates to a class of compounds as Bruton's tyrosine kinase inhibitors and their preparation methods and applications in the field of medicine.
- the compounds provided by the present invention can be used to prevent and/or treat autoimmune diseases, Cancer or inflammatory diseases, etc.
- BTK Bruton's tyrosine kinase belongs to the Tec family of cytoplasmic tyrosine kinases (TFK). There are 5 members in this family, they are BTK, ITK, TEC, BMX and TXK. Among them, BTK is mainly expressed in B cells and myeloid cells, and is distributed in the lymphatic system, hematopoietic and blood system, but lower levels of BTK expression are also found in T cells and plasma cells.
- BTK is mainly responsible for the transmission and amplification of signals inside and outside the cell, which is necessary for the maturation of B cells.
- the upstream signal receptors include growth factor and cytokine receptors, G protein-coupled receptors such as chemokine receptors, antigen receptors (especially B cell receptors (BCR) and integrins, etc.).
- BTK activated Downstream signaling pathways include phosphoinositide-3 kinase (PI3K)-AKT pathway, phospholipase-C (PLC), protein kinase C and nuclear factor kappa B (NF- ⁇ B), etc.
- BTK is the B cell antigen receptor (BCR) ) A key kinase in the signaling pathway, which can regulate the proliferation, differentiation and apoptosis of normal B cells.
- BCR B cell antigen receptor
- Overexpression of BTK causes abnormal activation of the BCR signaling pathway, which can cause B cell dysfunction, changes in immune tolerance, and transform into self-reaction Sex B cells secrete a large amount of autoantibodies to induce autoimmune diseases. Of course, it can also affect the proliferation, differentiation and apoptosis of B cells, which can lead to various malignant lymphomas.
- RA rheumatoid arthritis
- systemic lupus erythematosus psoriasis
- urticaria rhinitis and Asthma etc.
- the binding modes of BTK inhibitors and protein kinases are divided into covalent binding and non-covalent binding.
- Ibrutinib which was launched in 2013, is the representative of covalent binding and is mainly used for the treatment of various lymphomas;
- the BTK inhibitor (GDC-0853) (WO2013/067274, WO2013/067260) developed by Genentech Inc., represented by covalent binding, is mainly used to treat various immune diseases, such as rheumatoid Arthritis (RA), systemic lupus erythematosus, etc., are currently in clinical phase II.
- RA rheumatoid Arthritis
- systemic lupus erythematosus etc.
- BTK inhibitors such as BTK inhibitors (GDC-0853)
- GDC-0853 BTK inhibitors
- Src, Bmx, Fgr, etc. kinases
- the invention newly designs and synthesizes a class of BTK inhibitors. Through experimental research, this class of compounds has high selectivity to BTK targets, and in vivo animal experiments can show excellent pharmacological effects.
- the object of the present invention is to provide a compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, diastereomer, and Its mixture form, and its pharmaceutically acceptable salts, polymorphs, solvates, prodrugs, metabolites, isotope derivatives,
- R a is hydrogen or cyano
- R 0 is hydrogen, halogen, hydroxyl, C 1-6 alkyl, cyano or C 1-6 alkoxy;
- R 0 When X is N, R 0 is hydrogen; when X is CR a, R a is cyano time, R 0 is hydrogen;
- R 1 is hydrogen, deuterium, halogen, cyano, trifluoromethyl, C 0-6 substituted amino, C 1-6 alkyl; C 1-6 alkoxy;
- R 2 and R 3 are each independently a C 1-3 alkyl group
- R is hydroxy or halogen, preferably hydroxy
- R 4 is a linear C 1-6 alkyl group or a branched C 3-6 alkyl group
- R 5 is hydrogen or C 1-3 alkyl
- X 1 is CH or N
- T and T 0 are each independently a nitrogen-containing 5-6 membered heterocycloalkyl group or a nitrogen-containing 9-11 membered spirocycloalkyl group, wherein the 5-6 membered heterocycloalkyl group is not substituted, or Is it replaced by one T 1 or T 2 , or is replaced by T 1 and T 2 at the same time;
- spirocycloalkyl is not substituted, or is substituted by one T 3 or T 4 , or is substituted by T 3 and T 4 at the same time;
- T 1 is C 1-6 alkyl
- T 2 is C 1-6 alkyl or 3-6 membered heterocycloalkyl
- T 3 is hydroxy or C 1-6 alkyl
- T 4 is C 1-6 alkyl or 3-6 membered heterocycloalkyl.
- T and T 0 may be further preferably
- T and T 0 can be specifically
- the compounds represented by the general formula of the present invention can be synthesized according to a variety of reaction schemes, and those skilled in the art can easily design reaction schemes for other compounds through some of the preparation methods provided in the examples herein.
- the present invention relates to a method for preparing a compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof.
- the compound represented by the general formula (I) is prepared by the following scheme:
- the catalyst described in Scheme 1 includes tris(dibenzylideneacetone)dipalladium, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, palladium acetate, and tetrakis(triphenylphosphine)palladium , [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl, 1,1'-biphenyl Naphthalene-2,2'-bisdiphenylphosphine, 1,10-phenanthroline, cuprous iodide;
- the reducing agent 1 is tetrahydrolithium aluminum, borane tetrahydrofuran, borane dimethyl sulfide, reduced iron powder ;
- the reducing agent 2 is sodium borohydride, potassium borohydride, sodium triacetyl borohydride,
- the catalysts described in Scheme 2 and Scheme 3 include tris(dibenzylideneacetone)dipalladium, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, palladium acetate, tetrakis(triphenyl) Phosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl, 1,1 '-Binaphthyl-2,2'-bisdiphenylphosphine, 1,10-phenanthroline, cuprous iodide; the reducing agent 1 is tetrahydrolithium aluminum, borane tetrahydrofuran, borane dimethyl sulfide, Reduced iron powder; the reagent for alkaline conditions can be selected from potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydrox
- the compound represented by the general formula (I) and the pharmaceutically acceptable salt thereof according to the present invention is specifically:
- the pharmaceutically acceptable salts in the present invention refer to inorganic base salts, such as sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, ammonium salt, quaternary ammonium salt or aluminum salt; organic base salt, such as lysine Amino acid salt, arginine salt, diethylamine salt, triethylamine salt, ethanolamine salt, trimethylamine salt, dicyclohexylamine salt, choline salt, dibenzylamine salt, piperidine salt and other pharmaceutically acceptable salts The organic amine salt.
- organic base salt such as sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, ammonium salt, quaternary ammonium salt or aluminum salt
- organic base salt such as lysine Amino acid salt, arginine salt, diethylamine salt, triethylamine salt, ethanolamine salt, trimethylamine salt, dicyclohexylamine salt, choline salt, dibenzylamine salt, piperidine salt and other pharmaceutical
- the compound of the present invention contains at least one salt-forming nitrogen atom, it can be converted into the corresponding salt by reacting with the corresponding organic or inorganic acid in an organic solvent such as acetonitrile or tetrahydrofuran.
- organic acids are oxalic acid, tartaric acid, maleic acid, succinic acid, methanesulfonic acid, benzoic acid, benzenesulfonic acid, toluenesulfonic acid, sulfamic acid, citric acid, glutamic acid, pyroglutamic acid, aspartic acid Acid, glucuronic acid, naphthalenesulfonic acid, glutaric acid, acetic acid, trifluoroacetic acid, malic acid, fumaric acid, salicylic acid, 4-aminosalicylic acid, lactic acid, palmitate, stearic acid, laurel Acid, cinnamic acid, alginic acid, ascorbic acid, typical inorganic acids are
- the compound of the present invention has one or more asymmetric carbon atoms, they can exist in the following forms: optically pure enantiomers, pure diastereomers, mixtures of enantiomers, diastereomers Mixtures of enantiomers, racemic mixtures of enantiomers, racemates or mixtures of racemates. All possible isomers, stereoisomers and mixtures of the compound of formula (II) are also within the scope of the present invention.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising at least one of the above-mentioned compounds and optionally one or more pharmaceutically acceptable carriers and/or diluents.
- the pharmaceutical composition provided by the present invention can be prepared in any form, such as granules, powders, tablets, coated tablets, capsules, pills, syrups, drops, solutions, suspensions and emulsions, or sustained release of active ingredients
- capsules include hard or soft gelatin capsules
- granules and powders may be in non-effervescent or effervescent forms.
- the pharmaceutical composition of the present invention may further include one or more pharmaceutically or physiologically acceptable carriers, and these carriers will be appropriately formulated to facilitate administration.
- the pharmaceutically or physiologically acceptable carrier may be saline, hot-pressed water, Ringer's solution, buffered saline, dextrose, maltodextrin, glycerol, ethanol, and mixtures thereof.
- the pharmaceutical composition of the present invention may also include pharmaceutically or physiologically acceptable additives, such as diluents, lubricants, binders, glidants, disintegrants, sweeteners, flavoring agents, wetting agents, and dispersing agents. , Surfactants, solvents, coating agents, foaming agents, or fragrances.
- diluents that can be used include, but are not limited to, lactose, sucrose, starch, kaolin, salt, mannitol, and dicalcium phosphate;
- examples of lubricants include, but are not limited to, talc, starch, magnesium or calcium stearate, lycopodium
- examples of binders include, but are not limited to, microcrystalline cellulose, tragacanth, glucose solution, acacia, gelatin solution, sucrose, and starch paste;
- examples of glidants include, but are not limited to, colloidal two Silicon oxide;
- disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methyl cellulose, agar, and carboxymethyl cellulose;
- sweeteners include, but are not limited to, sucrose, lactose, mannitol, and artificial sweeteners, such as sodium cycla
- composition of the present invention can be administered by various routes according to traditional methods, including oral, intravenous, intraarterial, intraperitoneal, intrathoracic, transdermal, nasal, inhalation, rectal, ocular and subcutaneous administration.
- the pharmaceutically acceptable carriers optionally added to the pharmaceutical composition of the present invention are: water, alcohol, honey, mannitol, sorbitol, dextrin, lactose, caramel, gelatin, calcium sulfate, magnesium stearate , Talc, kaolin, glycerin, tween, agar, calcium carbonate, calcium bicarbonate, surfactants, cyclodextrin and its derivatives, phospholipids, phosphates, starches and their derivatives, silicon derivatives, One or more of celluloses and their derivatives, pyrrolidones, polyethylene glycols, acrylic resins, phthalates, acrylic copolymers, trimellitates.
- the present invention also provides the use of the above-mentioned compound or pharmaceutical composition in the preparation of a medicament for preventing and/or treating Bruton's tyrosine kinase-mediated related diseases.
- Bruton's tyrosine kinase-mediated related diseases include but are not limited to autoimmune disorders, cancer or inflammatory diseases.
- the aforementioned cancers include, but are not limited to, esophageal cancer, lung cancer, rectal cancer, pancreatic cancer, thyroid cancer, lymphoma or leukemia.
- the autoimmune diseases or inflammatory diseases mentioned above can be arthritis, systemic lupus erythematosus, inflammatory bowel disease, Crohn's disease, multiple sclerosis, asthma, thrombocytopenic purpura, chronic obstructive pulmonary disease, psoriasis Disease, organ transplant rejection, allergy or rhinitis.
- Step 9 9-Bromo-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1(6H )-Keto 1b
- the eleventh step 4-chloro-2-(9-fluoro-7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4, 5]Pyrrolo[1,2-a]pyrazin-2-yl)nicotinaldehyde 1e
- the first step 7,7,9-trimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1(6H)- ketone
- Step 4 (S)-2'-((7,7-Dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrole And [1,2-a]pyrazin-2-yl)-1-isopropyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazine-1 -Yl)pyridin-2-yl)amino-6-oxo-1,6-dihydro-[3,4'-bipyridine]-3'-carbaldehyde 4f
- Step 5 (S)-2-(3'-(hydroxymethyl)-1-isopropyl-5-((5-(2-methyl-4-(oxa-3-yl)piperazine- 1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3 ,4,7,8-Tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1(6H)-one 4
- Step 6 (S)-2-(7,7-Dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[ 1,2-a)pyrazin-2-yl)-3-(hydroxymethyl)-4-(1-methyl-5-((5-(2-methyl-4-(oxetan- 3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)benzonitrile 6
- the first step 4-chloro-2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[ 1,2-a)pyrazin-2-yl)nicotinaldehyde 8a
- reaction solution was cooled to room temperature, it was extracted with DCM/MeOH (10:1, 150ml x 2), the organic phase was dried, spin-dried, and separated by column to obtain a pale yellow solid compound 2 (800mg, yield: 47%).
- Step 8 (2-(7,7-Dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2 -a)pyrazin-2-yl)-4-(7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-2-(triisopropylsilane Yl)furan[3,2-b]pyridin-5-yl)pyridin-3-yl)methyl acetate 8i
- Step 9 2-(3-(hydroxymethyl)-4-(7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-2-(triisopropyl) Ylsilyl)furan[3,2-b]pyridin-5-yl)pyridin-2-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta [4,5]pyrrolo[1,2-a]pyrazine-1(6H)8j
- the first step 4-(6-nitropyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 9b
- the compound 9a (2.5g, 12.3mmol), piperazine-1-carboxylic acid tert-butyl ester (1.9g, 10mmol), palladium acetate (110mg, 0.5mmol), BINAP (310mg, 0.5mmol, 0.05eq), K 3 PO 4 (6.3g, 30mmol, 3.0eq) and toluene (20ml) were sequentially added to a 100ml reaction flask. After nitrogen replacement 3 times, the temperature was raised to 95°C. The reaction solution was stirred and reacted for 5 hours under the protection of nitrogen. LCMS detected that the raw material had basically reacted completely.
- Step 6 (2-(7,7-Dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2 -a)pyrazin-2-yl)-4-(7-((5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-2 -(Triisopropylsilyl)furan[3,2-b]pyridin-5-yl)pyridin-3-yl)methyl acetate 9h
- Step 8 2-(3-(Hydroxymethyl)-4-(7-((5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino )Furan[3,2-b]pyridin-5-yl)pyridin-2-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5] Pyrrolo[1,2-a]pyrazine-1(6H)9
- Example 10 9-Fluoro-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(4-(oxbutan-3-yl)piperazin-1-yl)pyridine -2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8 -Tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1(6H)-one
- Example 12 9-Fluoro-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-2,7-diazaspiro[3.5]nonane- 7-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3, 4,7,8-Tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1(6H)-one
- Example 13 9-Fluoro-2-(5-((5-(2-hydroxy-7-azaspiro[3.5]nonane-7-yl)pyridin-2-yl)amino)-3'-(hydroxyl (Methyl)-1-methyl-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7, 8-Tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1(6H)-one
- Example 14 9-Fluoro-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino) -6-Carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-ring Pentano[4,5]pyrrolo[1,2-a]pyrazine-1(6H)-one
- Example 16 9-Fluoro-2-(3'-(hydroxymethyl)-1-methyl-5-((6-(4-(oxbutan-3-yl)piperazin-1-yl)pyridine -3-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8 -Tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1(6H)-one
- the first step 7,7-dimethyl-1-carbonyl-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a ]Pyrazine-9-carbonitrile
- the first step 7,7-dimethyl-9-(trifluoromethyl)-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyridine Oxazine-1(6H)-one
- the first step 9 9-ethoxy-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1 (6H)-ketone
- the first step 9 9-amino-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine- 1(6H)-ketone
- the first step 7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1(6H) -Keto-9-deuterium
- the mobility change method is used to determine the BTK kinase activity of the compound, and the reaction system is (kinase solution, ATP, kinase substrate2). After the compound was incubated with the enzyme for 30 minutes, the conversion rate was read using Caliper EZ reader, the compound inhibition rate was determined using a calculation formula, and the IC 50 value of the compound of the present invention was obtained by data fitting using Graphad.
- the compound of the present invention has obvious inhibitory effect on BTK kinase, and the 50% inhibitory concentration of BTK is less than 0.75 nM, and the selectivity is better than ibrutinib.
- This experiment measures the effect of the compound on cell proliferation.
- the compound of the present invention can effectively inhibit the proliferation of tumor cells, and the effect is better than that of ibrutinib.
- Rats were immunized twice intracutaneously at the tail root on day 0 and day 7, and were clinically scored. Successfully modeled animals (clinical score> 3 points or more) were randomly assigned to each administration group for treatment. At the same time, various indicators are tested, including clinical scoring, toe volume measurement (twice a week), etc.
- the compound of the present invention can effectively alleviate the clinical score of arthritis in animals and reduce the volume of toes, alleviate the progression of arthritis, and the effect is better than that of ibrutinib after 14 days of administration.
- the purpose of this experiment is to test the effect of the compound on lymphoma.
- the compound of the present invention can effectively reduce the size of animal solid tumors, alleviate the progress of tumors, and can improve the body weight of animals, and the effect is better than that of ibrutinib.
- the purpose of this experiment is to test the effect of the compound on acute pneumonia.
- the animals were anesthetized with chloral hydrate, and lipopolysaccharide was given to chemically induced acute pneumonia models after anesthesia.
- the animals were divided into control and model groups.
- the bronchoalveolar lavage fluid and lung tissues of the animals were collected during each time period after lipopolysaccharide inhalation. Monitor animal lung injury and other indicators through a respiratory function instrument. After the tissues were collected, the tissues were sectioned and stained, and the bronchoalveolar lavage fluid cell count and the corresponding inflammatory factors were determined.
- the compound of the present invention can effectively improve the infiltration of inflammatory cells in HE staining after administration.
- the lymphocytes, mononuclear macrophages and neutrophils in the bronchoalveolar lavage fluid are significantly reduced compared with the control group.
- the IL-1 ⁇ content in the blood was also significantly reduced compared to the control group, and the effect was better than that of ibrutinib.
- the purpose of this experiment is to test the effect of the compound on spontaneous systemic lupus erythematosus in MRL/lpr mice.
- the compound of the present invention can effectively reduce the content of related indexes in animal blood, and effectively alleviate the progress of animal systemic lupus erythematosus.
- the purpose of this experiment is to use electrophysiological manual patch clamp to detect the effect of compounds on hERG potassium channels.
- HEK293 cells overexpressing the hERG potassium channel.
- transfer the cells to the cell bath embedded in the inverted microscope platform, perfuse the extracellular fluid, and stabilize the cell precipitation for 5 minutes before starting the experiment.
- the membrane current was recorded using HEKA EPC-10 patch clamp amplifier and PATCHMASTER acquisition system (HEKA Instruments Inc., D-67466 Lambrcht, Pfalz,
- the experiment was carried out in the whole-cell recording mode, and the current value was recorded according to the preset electrophysiological stimulation scheme. Use the drug to be tested, the concentration from low to high for perfusion and record.
- PATCHMASTER V2X60 HEKA Instruments Inc., D-67466 Lambrecht, Pfalz, Germany
- Origin 8.5 OpinLab Corporation, Northampton, MA
- the purpose of this experiment is to test the content of the compound in plasma and tissues.
- the T 1/2 on the rat is between 3-4 hr.
- the purpose of this experiment is to test the toxic effect of the compound on mice.
- mice were given different doses of the compound at a time and observed for 14 days. The death of the animal, poisoning reaction, weight change, diet, appearance, behavior, etc. were recorded. The animals were dissected at the end point, and organs were taken for histopathological examination.
- the LD 50 of the compound of the invention is >1000mg/kg, and the safety is good. Compared with the mice in the control group, the mice in the administration group had no abnormal body weight and behavior within 14 days from the administration date, no obvious organ lesions were found in the end point anatomy, and the compound of the present invention did not show obvious toxicity. The blood analysis found no obvious abnormality.
- the purpose of this experiment is to test the toxic effect of the compound on rats after long-term administration.
- the rats were given different high-dose compounds for a long period of time for 21 days.
- the animal's weight and related physiological signs were observed every day, and the animal's death, poisoning reaction, weight change, diet, appearance, behavior, etc. were recorded.
- the animals were dissected at the end point, blood samples were collected for four tests of blood routine, blood biochemistry and blood coagulation, and organs were taken for histopathological examination.
- the LD 50 of the compound of the present invention is >100mg/kg, and the safety is good. Compared with the animals in the control group, the animals in the administration group had no body weight, abnormal behavior and physiological changes within 21 days from the administration day, no obvious organ lesions were found in the end point anatomy, and the compound of the present invention did not show obvious toxicity. Blood analysis did not find any abnormality in related indicators in the treatment group.
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Abstract
一类布鲁顿酪氨酸激酶抑制剂及其制备方法和在医药领域的应用,所述布鲁顿酪氨酸激酶抑制剂可用于预防和/或治疗与布鲁顿酪氨酸激酶介导的相关疾病,如自身免疫性疾病、癌症或炎症类疾病等。所提供的化合物,经实验研究,其对布鲁顿酪氨酸激酶靶点的选择性高,体内动物实验能表现出优异的药效作用。
Description
本申请要求于2020年6月18日提交中国专利局、申请号为202010558345.4、发明名称为“布鲁顿酪氨酸激酶抑制剂及其制备方法”的中国专利申请的优先权,其全部内容通过引用结合在本申请中。
本发明属于医药领域,涉及一类作为布鲁顿酪氨酸激酶抑制剂的化合物及其制备方法和在医药领域的应用,本发明所提供的化合物可用于预防和/或治疗自身免疫性疾病、癌症或炎症类疾病等。
布鲁顿酪氨酸激酶(Brutos’s tyrosine kinase,BTK)属于Tec胞质酪氨酸激酶家族(Tec family kinases,TFK)的一员。该家族共有5个成员,它们分别为BTK、ITK、TEC、BMX和TXK。其中BTK主要在B细胞和髓细胞中表达,分布在淋巴系统、造血及血液系统,但在T细胞和浆细胞中也发现了较低水平的BTK表达。
在B细胞中BTK主要负责细胞内外信号的传导与放大,是B细胞成熟所必需的。其上游的信号受体包括生长因子和细胞因子受体、G蛋白偶联受体如趋化因子受体、抗原受体(尤其是B细胞受体(BCR)和整联蛋白等。BTK激活的下游信号通路包括磷酸肌醇-3激酶(PI3K)-AKT通路、磷脂酶-C(PLC)、蛋白激酶C和核因子κB(NF-κB)等等。所以BTK是B细胞抗原受体(BCR)信号通路中的关键激酶,能够调节正常B细胞的增殖、分化与凋亡。BTK过量表达使BCR信号通路异常激活后,可使B细胞功能失调、免疫耐受状态改变,并转化为自身反应性B细胞,分泌大量自身抗体诱发自身免疫性疾病。当然也会影响B细胞的增殖、分化和凋亡,从而引发各种恶性淋巴瘤。
目前大部分BTK抑制剂对自身免疫性疾病的研究尚处于临床一、二期,其主要适应症包括类风湿性关节炎(RA)、系统性红斑狼疮、银屑病、荨麻疹,以及鼻炎和哮喘等。
BTK抑制剂与蛋白激酶的结合方式分为共价结合和非共价结合,其中于2013年上市的依鲁替尼(Ibrutinib)为共价结合代表,主要用于各中淋巴瘤的治疗;非共价结合为代表的由基因泰克公司(Genentech Inc.)开发的BTK抑制剂(GDC-0853)(WO2013/067274,WO2013/067260)主要用于治疗各种的免疫性疾病,如:类风湿性关节炎(RA)、系统性红斑狼疮等,现处于临床二期。由于已知的BTK抑制剂的选择性不理想,如BTK抑制剂(GDC-0853),在选择性上还是对多种激酶(Src、Bmx、Fgr等)存在着抑制作用(J.Med.Chem.2018,61,2227-2245),因此临床上需要开发更多的BTK抑制剂,用于治疗各种的免疫性疾病,同时可以克服在选择性不佳带来的各种副作用。
本发明新设计合成了一类BTK抑制剂,经实验研究,该类化合物对BTK靶点的选择性高,体内动物实验能表现出优异的药效作用。
发明内容
本发明的目的在于提供一种通式(I)所示的化合物,或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、及其混合物形式、及其可药用盐、多晶型物、溶剂合物、前药、代谢物、同位素衍生物,
其中X为C-R
a或N;
R
a为氢或氰基;
R
0为氢、卤素、羟基、C
1-6烷基、氰基或C
1-6烷氧基;
当X为N时,R
0为氢;当X为C-R
a,R
a为氰基时,R
0为氢;
R
1为氢、氘、卤素、氰基、三氟甲基、C
0-6取代氨基、C
1-6烷基;C
1-6烷氧基;
R
2和R
3分别独立地为C
1-3烷基;
R为羟基或卤素,优选羟基;
R
4为直链的C
1-6烷基或是带支链的C
3-6烷基;
R
5为氢或C
1-3烷基;
X
1为CH或N;
T和T
0分别独立地为含氮的5-6元杂环烷基或是含氮的9-11元螺环烷基,其中所述的5-6元杂环烷基不被取代,或是被1个T
1或T
2取代,或是同时被T
1和T
2取代;
其中所述的螺环烷基不被取代,或是被1个T
3或T
4取代,或是同时被T
3和T
4取代;
T
1为C
1-6烷基;
T
2为C
1-6烷基或是3-6元杂环烷基;
T
3为羟基或C
1-6烷基;
T
4为C
1-6烷基或是3-6元杂环烷基。
本发明所提供化合物的合成流程:
本发明的通式表示的化合物可以按照多种反应流程加以合成,本领域技术人员可以很容易的通过本文在实施例中所提供的一些制备方法设计其他化合物的反应流程。
本发明涉及一种通式(1)所示化合物或其可药用的盐的制备方法,所述通式(I)所示的化合物通过以下方案制备,
方案1:
方案2:
方案3:
方案1所述的催化剂包括三(二亚苄基丙酮)二钯、4,5-双二苯基膦-9,9-二 甲基氧杂蒽、醋酸钯、四(三苯基膦)钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、2-二环己基磷-2,4,6-三异丙基联苯、1,1'-联萘-2,2'-双二苯膦、1,10-菲罗啉、碘化亚铜;所述还原剂1为四氢锂铝、硼烷四氢呋喃、硼烷二甲硫醚、还原铁粉;所述还原剂2为硼氢化钠、硼氢化钾、三乙酰基硼氢化钠、氰基硼氢化钠。
方案2和方案3所述的催化剂包括三(二亚苄基丙酮)二钯、4,5-双二苯基膦-9,9-二甲基氧杂蒽、醋酸钯、四(三苯基膦)钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、2-二环己基磷-2,4,6-三异丙基联苯、1,1'-联萘-2,2'-双二苯膦、1,10-菲罗啉、碘化亚铜;所述还原剂1为四氢锂铝、硼烷四氢呋喃、硼烷二甲硫醚、还原铁粉;所述碱性条件的试剂可选自碳酸钾、碳酸铯、氢氧化钾、氢氧化钠或氟化铯。
根据本发明通式(I)所示的化合物及其可药用的盐,其中该化合物具体为:
(S)-9-氟-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶基-2-基)氨基)-6-氧代-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;
(S)-9-氯-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶基-2-基)氨基)-6-氧代-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;
(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶基-2-基)氨基)-6-氧代-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7,9-三甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;
(S)-2-(3'-(羟甲基)-1-异丙基-5-((5-(2-甲基-4-(氧杂-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-氧代-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;
(S)-3-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)-4-(羟甲基)-5-(1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶 -2-基)氨基)-6-氧代-1,6-二氢吡啶-3-基)苄腈;
(S)-2-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)-3-(羟甲基)-4-(1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-氧代-1,6-二氢吡啶-3-基)苄腈;
(S)-4-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)-3-(羟甲基)-2-(1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-氧代-1,6-二氢吡啶-3-基)苄腈;
2-(3-(羟甲基)-4-(7-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)呋喃[3,2-b]吡啶-5-基)吡啶-2-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H);
2-(3-(羟甲基)-4-(7-((5-(4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)呋喃[3,2-b]吡啶-5-基)吡啶-2-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H);
9-氟-2-(3'-(羟甲基)-1-甲基-5-((5-(4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;
2-(5-((5-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)吡啶-2-基)氨基)-3'-(羟甲基)-1-甲基-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-9-氟-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;
9-氟-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-2,7-二氮杂螺[3.5]壬烷-7-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;
9-氟-2-(5-((5-(2-羟基-7-氮杂螺[3.5]壬烷-7-基)吡啶-2-基)氨基)-3'-(羟甲基)-1-甲基-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;
9-氟-2-(3'-(羟甲基)-1-甲基-5-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;
9-氟-2-(3'-(羟甲基)-1-甲基-5-((4-(4-(噁丁环-3-基)哌嗪-1-基)苯基)氨基)-6- 羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;
9-氟-2-(3'-(羟甲基)-1-甲基-5-((6-(4-(噁丁环-3-基)哌嗪-1-基)吡啶-3-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;
(S)-9-溴-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;
(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-1-羰基-1,3,4,6,7,8-六氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-9-甲腈;
(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-1-羰基-1,3,4,6,7,8-六氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-9-甲腈;
(S)-9-乙氧基-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶基-2-基)氨基)-6-氧代-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;
(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-9-甲氧基-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;
(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-9-丙氧基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;
(S)-9-环丙氧基-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;
(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-9-异丙氧基-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;
(S)-9-氨基-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;
(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-9-异丙氧基-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮。
本发明所述的药用可接受的盐的是指无机碱盐,如钠盐、钾盐、钙盐、镁盐、锌盐、铵盐、季铵盐或铝盐;有机碱盐,如赖氨酸盐、精氨酸盐、二乙胺盐、三乙胺盐、乙醇胺盐、三甲胺盐、二环己基胺盐、胆碱盐、二苄胺盐、哌啶盐及其他药学上可接受的有机胺盐。
在本发明的化合物分子中包含至少一个可成盐的氮原子时,可以通过在有机溶剂如乙腈、四氢呋喃中与相应的有机酸或无机酸反应,从而转化为相应的盐。典型的有机酸有草酸、酒石酸、马来酸、琥珀酸、甲磺酸、苯甲酸、苯磺酸、甲苯磺酸、氨基磺酸、柠檬酸、谷氨酸、焦谷氨酸、天冬氨酸、葡糖醛酸、萘磺酸、戊二酸、乙酸、三氟乙酸、苹果酸、富马酸、水杨酸、4-氨基水杨酸、乳酸、棕榈酸盐、硬脂酸、月桂酸、肉桂酸、海藻酸、抗坏血酸,典型的无机酸有硝酸、盐酸、硫酸、磷酸。
本发明的化合物中具有一个或多个不对称碳原子时,它们能够以如下形式存在:光学纯的对映异构体、纯的非对映异构体、对映异构体混合物、非对映异构体混合物、对映异构体外消旋混合物、外消旋物或外消旋物混合物。式(II)的化合物的全部可能的异构体、立体异构体和其混合物也在本发明的范围内。
本发明还提供了一种药物组合物,其包含上述至少一个化合物以及任选一种或多种医药上可接受的载剂和/或稀释剂。
本发明所提供的药物组合物可以制备为任何形式,例如颗粒、粉末、片剂、包衣片剂、胶囊、药丸、糖浆、滴剂、溶液、混悬剂和乳剂,或者活性成分的缓释制剂,其中胶囊剂的实例包括硬或软明胶胶囊剂,颗粒剂和粉剂可以是非泡腾或泡腾形式。
本发明的药物组合物可进一步包括一种或多种医药或生理上可接受的载 体,这些载体将适当配制以便于给药。例如,医药或生理上可接受的载体可以是盐水、热压水、林格氏液、缓冲盐水、葡萄糖、麦芽糖糊精、甘油、乙醇及其混合物。本发明的药物组成物还可以包括医药或生理上可接受的添加剂,例如稀释剂、润滑剂、粘合剂、助流剂、崩解剂、甜味剂、矫味剂、湿润剂、分散剂、表面活性剂、溶剂、涂层剂、发泡剂、或芳香剂。
可以使用的稀释剂的实例包括但不限于乳糖、蔗糖、淀粉、高岭土、盐、甘露糖醇和磷酸二钙;润滑剂的实例包括但不限于滑石、淀粉、镁或钙的硬脂酸盐、石松子和硬脂酸;粘合剂的实例包括但不限于微晶纤维素、黄蓍胶、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖和淀粉糊;助流剂的实例包括但不限于胶体二氧化硅;崩解剂的实例包括但不限于交联羧甲基纤维素钠、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、膨润土、甲基纤维素、琼脂和羧甲基纤维素;甜味剂的实例包括但不限于蔗糖、乳糖、甘露糖醇和人工甜味剂,例如环磺酸钠和糖精,和任意数量的喷雾干燥矫味剂;矫味剂的实例包括但不限于从植物提取的天然矫味剂,例如果实,和味道较好的化合物,例如但不限于薄荷和水杨酸甲酯;湿润剂的实例包括但不限于丙二醇一硬脂酸酯、脱水山梨醇一油酸酯、二甘醇一月桂酸酯和聚氧乙烯月桂基醚。
本发明的药物组合物可以根据传统方法来通过各种途径给药,包括口服、静脉内、动脉内、腹腔内、胸腔内、透皮、鼻腔、吸入、直肠、眼部和皮下导入。
任选地添加到本发明的药物组合物中的医药上可接受的载体是:水、醇、蜂蜜、甘露醇、山梨醇、糊精、乳糖、焦糖、明胶、硫酸钙、硬脂酸镁、滑石粉、高岭土、甘油、吐温、琼脂、碳酸钙、碳酸氢钙、表面活性剂、环糊精及其衍生物、磷脂类、磷酸盐类、淀粉类及其衍生物、硅衍生物、纤维素类及其衍生物、吡咯烷酮类、聚乙二醇类、丙烯酸树脂类、酞酸酯类、丙烯酸共聚物、苯三酸酯类中的一种或几种。
本发明还提供了上述化合物或者药物组合物在制备用于预防和/或治疗布鲁顿酪氨酸激酶介导的相关疾病的药物中的用途。
如上所述的布鲁顿酪氨酸激酶介导的相关疾病包括但不限于自身免疫失调、癌症或炎症类疾病。
上述所提到的癌症包括但不限于食道癌、肺癌、直肠癌、胰腺癌、甲状腺癌、淋巴瘤或白血病。上述所提到的自身免疫性疾病或炎症类疾病可以是关节炎、系统性红斑狼疮、炎症性肠炎、克罗恩病、多发性硬化、哮喘、血小板减少性紫癜、慢性阻塞性肺病、银屑病、器官移植排斥、变态反应或鼻炎。
为使本发明的目的、技术方案、及优点更加清楚明白,以下参照附图并举实施例,对本发明进一步详细说明。显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。本领域普通技术人员基于本发明中的实施例所获得的所有其他实施例,都属于本发明保护的范围。
本发明中使用的缩写总结如表1所示。
表1
序号 | 缩写 | 中文名称 |
1 | XPhos | 2-二环己基磷-2',4',6'-三异丙基联苯 |
2 | Xantphos | 4,5-双(二苯基膦)-9,9-二甲基氧杂蒽 |
3 | BINAP | 1,1'-联萘-2,2'-双二苯膦 |
4 | DME | 二甲醚 |
5 | DMF | N,N-二甲基甲酰胺 |
6 | DIPEA | N,N-二异丙基乙胺 |
7 | NMP | N-甲基吡咯烷酮 |
8 | NBS | N-溴代琥珀酰亚胺 |
9 | DCM | 二氯甲烷 |
10 | TEA | 三乙醇胺 |
11 | LDA | 二异丙基氨基锂 |
12 | TFA | 三氟乙酸 |
13 | TBAF | 四丁基氟化铵 |
实施例1(S)-9-氟-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶基-2-基)氨基)-6-氧代-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
第一步 叔丁基(S)-3-甲基-4-(6-硝基吡啶-3-基)哌嗪-1-羧酸盐1-2b
化合物1-2a(20g,100mmol)、Int-1(24g,150mmol)和碳酸钾(50g,235mmol)溶于甲苯(250mL),充分搅拌后加入醋酸钯(0.68g,3mmol)和BINAP(2.0g,3mmol),随后氮气条件下抽换气三次,将反应升温至90℃下搅拌3小时。加水淬灭,二氯甲烷萃取,有机相依次用水(100mL)和饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,浓缩,所得粗品经柱层析纯化得标题化合物1-2b(19.5g,58.7mmol),收率58.7%。
MS m/z(ESI):323.2[M+H]
+。
第二步 (S)-5-(2-甲基哌嗪-1-基)吡啶-2-胺1-2c
化合物1-2b(10.0g,32.2mmol)溶于盐酸甲醇溶液中(100mL),后加入20mL浓盐酸搅拌24小时后,有大量金黄色固体析出,抽滤,将固体用二氯甲烷溶解后,再用饱和碳酸钾溶液游离。随后用二氯甲烷萃取,有机相依次用水(100mL)和饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,浓缩,得标题化合物1-2c(7.0g,31.5mmol),收率98.0%。
MS m/z(ESI):223.1[M+H]
+。
第三步 (S)-2-甲基-1-(6-硝基吡啶-3-基)-4-(氧乙烷-3-基)哌嗪1-2d
化合物1-2c(7.0g,31.5mmol)溶于THF(50mL)中,加入2mL醋酸 后,加入Int 2(3.0g,41mmol)。常温下搅拌15min后,分批加入醋酸硼氢化钠(10.0g,47.3mmol)。常温搅拌3小时后,加水淬灭,二氯甲烷萃取。有机相依次用水(150mL)和饱和食盐水(150mL)洗涤,无水硫酸钠干燥,过滤,浓缩,所得粗品经柱层析纯化(纯乙酸乙酯)得标题化合物1-2d(3.5g,12.5mmol)收率40.0%。
MS m/z(ESI):279.1[M+H]
+。
第四步 (S)-5-(2-甲基-4-(氧乙烷-3-基)哌嗪-1-基)吡啶-2-胺1-2e
化合物1-2d(3.5g,12.5mmol)溶于甲醇搅拌均匀后,加入钯碳(1.7g,16.0mmol)氢气球抽换气3次,室温条件下搅拌约12小时。抽滤,将滤液旋干,得粗品1-2e(2.8g,11.3mmol),收率70.5%。MS m/z(ESI):249.1[M+H]
+。
第五步 (S)-5-溴-1-甲基-3-((5-(2-甲基-4-(氧乙烷-3-基)哌嗪-1-基)吡啶-2-基)氨基)吡啶-2(1H)-酮1-2f
化合物1-2e(2.8g,11.3mmol)与化合物Int 3(3.2g,12.0mmol)溶于甲苯(25mL),搅拌条件下加入醋酸钯(0.27g,1.1mmol)、Xantphos(1.4g,2.2mmol)和碳酸钾(4.8g,34mmol),在氮气条件下抽换气三次,105℃回流3.0小时。降温后加入饱和氯化铵溶液淬灭。二氯甲烷萃取,有机相多次用水(100mL)和饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,浓缩,经柱层析(DCM:MeOH=97:3)得标题化合物1-2f(2.8g,6.5mmol),收率57.1%。
MS m/z(ESI):434.2[M+H]
+。
第六步 (S)-1-甲基-3-((5-(2-甲基-4-(氧乙烷-3-基)哌嗪-1-基)吡啶-2-基)氨基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂醇-2-基)吡啶-2(1H)-酮1f
化合物1-2f(2.8g,6.5mmol)溶于THF(25mL),加入频那醇硼酸酯(B
2pin
2)2.5g搅拌均匀后,加入Pd
2(dba)
3(0.19g,0.33mmol)、XPhos(0.62g,1.3mmol)和碳酸钾(4.8g,34mmol),在氮气条件下抽换气三次,65℃反应6.0小时后加入饱和氯化铵溶液淬灭。二氯甲烷萃取,有机相多次用水(100mL)和饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,浓缩,经柱层析(DCM:MeOH=98:2)得标题化合物1f(1.4g,3.2mmol),收率50%。
MS m/z(ESI):560.4[M+H]
+。
第七步 2-氯-4,4-二甲基环戊-1-烯-1-甲醛1-2
在1L反应瓶中,将化合物1-1(20g,0.177mmol)溶解于二氯甲烷(350ml),在冰浴条件下加入DMF(32.5g,0.44mol)至,再将POCl
3(57.0g,0.375mol,2.1eq)慢慢滴加到上述反应体系。加完后反应液慢慢升温到30℃并保持在室温下搅拌30分钟后,再将3,3-二甲基-环戊酮(20g,0.178mol)慢慢滴加到上述反应液中,将反应液逐渐升温至回流状态反应5小时。待反应液冷却至室温后,在冰浴条件下,将K
3PO
4(10%w aq,300ml)滴加到反应液中淬灭反应搅拌后静置,水相用二氯甲烷(200ml)反萃一遍,合并有机相,干燥旋干得到粗品30g,直接用于下一步反应。
第八步 2-氯-4,4-二甲基环戊-1-烯-1-甲醛1a
将上一步反应得到的粗品1-2和2-哌嗪酮(18.5g,0.19mol)、NMP(300ml)以及DIPEA(46g,0.36mol)依次加入到反应瓶中,氮气保护下,升温至120℃反应5小时。LCMS检测反应完全。降温后向反应液中加入水(1000ml),大量固体析出,过滤固体再用石油醚:乙酸乙酯(5:1,200ml)打浆,过滤并干燥,得到产物1-3
1H NMR(400MHz,CDCl
3)δ6.73–6.67(m,1H),5.97(s,1H),4.01–3.88(m,2H),3.70–3.60(m,2H),2.51–2.49(m,2H),2.47(q,J=0.7Hz,2H),1.23(s,6H).
MS m/z(ESI):205(M+1)
+
第九步 9-溴-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮1b
化合物1a(1g,4.9mmol)溶解在二氯甲烷(30mL)中,冷却至-20℃,向溶液中加入NBS(1.05g,5.88mmol),反应液升至室温搅拌过夜。反应完全后反应液用二氯甲烷(50mL)稀释,并用饱和Na
2S
2O
3水溶液洗涤,有机相用无水硫酸钠干燥,过滤旋干得到粗产品,经过硅胶柱层析纯化后得到化合物1b(960mg),收率69%。
第十步 9-氟-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮1c
化合物1b(560mg,2.0mmol)溶解在四氢呋喃(15mL)中,然后在-78℃下搅拌的同时滴加正丁基锂(30mL,7.0mmol),将所得溶液在-40℃搅拌3小时, 然后冷却至-78℃,向溶液中滴加N-氟苯磺酰亚胺(1.26g,4.0mmol)的四氢呋喃(10mL)溶液,将所得溶液在室温搅拌3小时,通过添加水(15mL)来淬灭反应,并用乙酸乙酯(50×2mL)萃取。将合并后的有机相用无水硫酸钠干燥,过滤旋干得到粗产品,经过硅胶柱层析纯化后得到化合物1c(310mg),收率70%。
第十一步 4-氯-2-(9-氟-7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)烟醛1e
化合物1c(250mg,1.12mmol)、化合物1d(246.4mg,1.12mmol)、Pd
2(dba)
3(211mg,0.23mmol)、XantPhos(266mg,0.46mmol)和碳酸钾(309mg,2.24mmol)悬浮在四氢呋喃(15mL)中,通过两次氮气置换后反应液加热至65℃搅拌2小时,反应完全后将反应液旋干,得到的残渣经过硅胶柱层析纯化后得到化合物1e(170mg),收率42%。
第十二步 (S)-2'-(9-氟-7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)-1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-氧代-1,6-二氢-[3,4'-联吡啶]-3'-甲醛1g
化合物1e(130mg,0.36mmol)、化合物1f(173mg,0.36mmol)、Pd(dppf)Cl
2(26.3mg,0.036mmol)和磷酸钾(114.5mg,0.54mmol)溶于四氢呋喃(16mL)和水(4mL)的混合溶液中,通过两次氮气置换后反应液加热至65℃搅拌3小时,反应完全后将溶液旋干,加水(30mL)稀释,用二氯甲烷(30×2mL)萃取,合并后的有机相用无水硫酸钠干燥,过滤旋干得到粗产品,经过硅胶柱层析纯化后的化合物1g(40mg),收率16%。
第十三步 (S)-9-氟-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶基-2-基)氨基)-6-氧代-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
化合物1g(40mg,0.06mmol)溶解在四氢呋喃(10mL)和水(3mL)的混合溶液中,加入K
2HPO
4(10.4mg,0.06mmol)和NaOH(2.4mg,0.06mmol),然后加入硼氢化钠(6.7mg,0.18mmol),反应液在常温下搅拌2小时,加入水(20mL)稀释,用二氯甲烷(30×2mL)萃取,合并后的有机相用无水硫酸钠干燥,过滤旋干得到粗产品,经过硅胶柱层析纯化后的化合物1(5mg)。
1H NMR(400MHz,DMSO-d6)δ8.61(d,J=2.3Hz,1H),8.48(d,J=5.0 Hz,1H),8.44(s,1H),7.83(d,J=2.8Hz,1H),7.45(d,J=2.3Hz,1H),7.40–7.32(m,2H),7.24(d,J=9.0Hz,1H),4.94(t,J=5.1Hz,1H),4.55(td,J=6.5,2.9Hz,2H),4.49-4.39(m,4H),4.25-4.12(m,3H),3.82(d,J=11.1Hz,1H),3.67(d,J=5.5Hz,1H),3.60(s,3H),3.40(q,J=6.2Hz,1H),3.13–3.06(m,1H),2.94(t,J=8.9Hz,1H),2.58-2.53(m,3H),2.45(s,2H),2.36-2.28(m,2H),2.19(t,J=9.1Hz,1H),1.22(s,6H),0.93(d,J=6.3Hz,3H).MS m/z(ESI):683[M+H]
+。
实施例2(S)-9-氯-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶基-2-基)氨基)-6-氧代-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
采用与实施例1类似的合成方法,将N-溴代丁二酰亚胺替换为N-氯代丁二酰亚胺,得到9-氯-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮中间体直接进行实施例1类似第三步以后的反应,制得标题产物2,收率13%。
1H NMR(400MHz,DMSO-d6)δ8.61(d,J=2.3Hz,1H),8.48(d,J=5.0Hz,1H),8.44(s,1H),7.83(d,J=2.8Hz,1H),7.45(d,J=2.3Hz,1H),7.40–7.32(m,2H),7.24(d,J=9.0Hz,1H),4.94(t,J=5.1Hz,1H),4.55(td,J=6.5,2.9Hz,2H),4.49-4.39(m,4H),4.25-4.12(m,3H),3.82(d,J=11.1Hz,1H),3.67(d,J=5.5Hz,1H),3.60(s,3H),3.40(q,J=6.2Hz,1H),3.13–3.06(m,1H),2.94(t,J=8.9Hz,1H),2.58-2.53(m,3H),2.42(s,2H),2.38-2.29(m,2H),2.19(t,J=9.1Hz,1H),1.21(s,6H),0.93(d,J=6.3Hz,3H).MS m/z(ESI):699(M+1)
+.
实施例3(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶基-2-基)氨基)-6-氧代-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7,9-三甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
第一步 7,7,9-三甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
化合物1a(0.5g,2.45mmol)溶于醋酸(10mL)中,再加入氢碘酸(10mL)和多聚甲醛(0.5g),反应液在氮气保护下及25℃搅拌3小时后,用次磷酸(50%,0.8mL)滴加至反应液无色。在冰浴下加入饱和氯化铵,再用乙酸乙酯(50×2mL)萃取。将合并后的有机相用无水硫酸钠干燥,过滤旋干得到粗产品,经过硅胶柱层析纯化后得到化合物3b(280mg),收率52.4%。
MS m/z(ESI):215(M+1)
+
此后步骤采用与实施例1类似第五步以后的反应,制得标题产物3,收率19%。
1H NMR(400MHz,DMSO-d6)δ8.60(d,J=2.4Hz,1H),8.46–8.42(m,2H),7.81(d,J=2.8Hz,1H),7.46(d,J=2.4Hz,1H),7.36–7.30(m,2H),7.23–7.21(m,1H),4.95(t,J=5.2Hz,1H),4.55–4.38(m,6H),4.18–4.10(m,3H),3.78–3.75(m,1H),3.65(s,1H),3.58(s,3H),3.40–3.35(m,2H),3.09–3.06(m,1H),2.95–2.90(m,1H),2.57–2.51(m,2H),2.34–2.30(m,4H),2.17(s,4H),1.19(s,6H),0.91(d,J=6.4Hz,3H).
实施例4(S)-2-(3'-(羟甲基)-1-异丙基-5-((5-(2-甲基-4-(氧杂-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-氧代-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮4
第一步 3,5-二溴-1-异丙基吡啶-2(1H)-酮4b
化合物4a(2.52g,10mmol)溶解在DME(30mL)中,加入2-碘丙烷(2.04g,1.2mmol)和碳酸铯(3.9g,1.2mmol),反应液在80℃回流3小时,冷却后反应液用乙酸乙酯(60mL)稀释,并用NaHCO
3水溶液洗涤,有机相用无水硫酸钠干燥,过滤旋干得到粗产品,经过硅胶柱层析纯化后得到化合物4b(1.7g),收率58%。
第二步 (S)-5-溴-1-异丙基-3-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)吡啶-2(1H)-酮4d
化合物4b(1g,3.4mmol)、化合物4c(843mg,3.4mmol)、醋酸钯(152mg,0.68mmol),Xantphos(786mg,1.36mmol)和碳酸钾(1.41g,10.2mmol)悬浮在甲苯(30mL)中,通过两次氮气置换后反应液加热至100℃搅拌2小时,反应完全后将反应液旋干,将得到的残渣溶解在二氯甲烷(60mL)中,用饱和食盐水(30mL)洗涤,有机相用无水硫酸钠干燥,过滤旋干得到粗产品,经过硅胶柱层析纯化后得到化合物4d(670mg),收率43%。
第三步 (S)-1-异丙基-3-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)硼烷基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)吡啶-2(1H)-酮4e
化合物1d(560mg,1.2mmol)、联硼酸频那醇酯(309mg,1.2mmol)、Pd
2(dba)
3(220mg,0.24mmol)、XPhos(228mg,0.48mmol)和醋酸钾(235mg,2.4mmol)悬浮在四氢呋喃(20mL)中,通过两次氮气置换后反应液加热至70℃搅拌2小时,反应完全后将反应液旋干后得到的残渣经过硅胶柱层析纯化后得到化合物4e(500mg),收率81%。
第四步 (S)-2'-((7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)-1-异丙基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基-6-氧代-1,6-二氢-[3,4'-联吡啶]-3'-甲醛4f
化合物4e(506mg,1mmol)、化合物8a(343mg,1mmol)、Pd(dppf)Cl
2(73.1mg,0.1mmol)和磷酸钾(424mg,2.0mmol)溶于四氢呋喃(10mL)中,通过两次氮气置换后反应液加热至50℃搅拌3小时,反应完全后将溶液旋干,加水(30mL)稀释,用二氯甲烷(50×2mL)萃取,合并后的有机相用无水硫酸钠干燥,过滤旋干得到粗产品,经过硅胶柱层析纯化后的化合物4g(350mg),收率51%。
第五步 (S)-2-(3'-(羟甲基)-1-异丙基-5-((5-(2-甲基-4-(氧杂-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-氧代-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮4
化合物4g(250mg,0.36mmol)溶解在四氢呋喃(15mL)和水(3mL)的混合溶液中,加入K
2HPO
4(62.6mg,0.36mmol)和NaOH(14.4mg,0.36mmol),然后加入硼氢化钠(38mg,1mmol),反应液在常温下搅拌2小时,加入水(30mL)稀释,用二氯甲烷(30×2mL)萃取,合并后的有机相用无水硫酸钠干燥,过滤旋干得到粗产品,经过硅胶柱层析纯化后的化合物4(80mg),收率32%。
1H NMR(400MHz,DMSO-d6)δ8.59(d,J=2.2Hz,1H),8.52–8.40(m,2H),7.81(d,J=3.0Hz,1H),7.61(d,J=2.3Hz,1H),7.40–7.29(m,2H),7.21(d,J=9.0Hz,1H),6.53(s,1H),5.21(p,J=6.8Hz,1H),5.07(s,1H),4.52(td,J=6.4,2.9Hz,2H),4.40(dt,J=21.9,5.9Hz,4H),4.18(t,J=8.7Hz,3H),3.87–3.73(m,1H),3.65(s,1H),3.36(q,J=6.3Hz,1H),3.14–3.00(m,1H),2.91(t,J=10.3Hz,1H),2.61–2.48(m,2H),2.39(s,2H),2.28(d,J=3.9Hz,2H),2.14(t, J=9.2Hz,1H),1.34(d,J=6.8Hz,6H),1.27–1.12(m,7H),0.89(d,J=6.3Hz,3H).
MS m/z(ESI):693[M+H]
+。
实施例5(S)-3-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)-4-(羟甲基)-5-(1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-氧代-1,6-二氢吡啶-3-基)苄腈
第一步 3,5-二溴-4-甲基苯甲酰氯5b
将3,5-二溴-4-甲基苯甲酸(5.0g,17.0mmol,1.0eq)溶解于DCM(50ml)中,冰水浴冷却下滴加草酰氯(7.2ml,85.0mmol,5.0eq)和DMF(2滴),室温反应过夜,减压蒸干得粗品5b,直接用于下步反应。
第二步 3,5-二溴-4-甲基苯甲酰胺5c
将化合物5b(5.3g,17.0mmol,1.0eq)溶于无水THF(5ml)中,加至25%氨 水,室温反应30min,加入乙酸乙酯(50ml)萃取,有机层依次经盐水洗涤和无水硫酸钠干燥,浓缩至干得白色固体(4.9g)5c。
MS m/z(ESI):293[M+1]
+
第三步 3,5-二溴-4-甲基苄腈5d
将化合物5c(4.6g,15.7mmol)、三苯氧磷(45mg,0.16mmol)和TEA(6.5ml,47.1mmol)投于DCM(100ml)中,冰水浴冷却下,加入草酰氯(2.7ml,31.4mmol),升至室温,反应30min。浓缩,flash柱纯化得白色固体(HHT0130-180-1A,3.0g)。
MS m/z(ESI):275[M+1]+
第四步 3,5-二溴-4-(溴甲基)苄腈5e
将化合物5d(1.0g,3.6mmol,1.0eq)溶于DCM(30ml)和水(6ml)中,依次加入NBS(0.64g,3.6mmol)和双氧水(0.12g,3.6mmol),回流反应4h。冷却至室温,分出有机层,经无水硫酸钠干燥,浓缩,flash柱纯化得白色固体(1.1g)。
MS m/z(ESI):354[M+1]
+
第五步 2,6-二溴-4-氰基乙酸苄酯5f
将化合物5e(1.0g,2.8mmol,1.0eq)溶于DMF(10ml)中,加入醋酸钾(0.33g,3.4mmol,1.2eq),80℃反应1h。冷至室温,加入乙酸乙酯(50ml)稀释,依次用水(20ml)和盐水(15ml×3)洗涤,经无水硫酸钠干燥,浓缩,flash柱纯化(PE~PA/EA=10:1)得白色固体(HHT0130-158-1A,590mg)。
MS m/z(ESI):333[M+1]
+
第六步 2-溴-4-氰基-6-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)乙酸苄酯5g
将化合物5f(540mg,1.6mmol,1.5eq)和7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮(7)(0.22g,1.1mmol,1.0eq)投于无水1,4-二氧六环(30ml)中,依次加入碳酸铯(0.72g,2.2mmol,2.0eq)、Pd
2(dba)
3(0.10g,0.11mmol,0.1eq)和Xantphos(0.13g,0.22mmol,0.2eq),回流反应8h。减压蒸干,加入乙酸乙酯(50ml),依次用水(20ml)和盐水(20ml)洗涤,浓缩,flash柱纯化得黄色固体(290mg)。
MS m/z(ESI):457[M+1]
+
第七步 (S)-3-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并 [1,2-a]吡嗪-2-基)-4-(羟甲基)-5-(1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-氧代-1,6-二氢吡啶-3-基)苄腈5
将化合物5g(100mg,0.22mmol,1.0eq)和(S)-1-甲基-3-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)吡啶-2(1H)-酮(0.11g,0.22mmol,1.0eq)投于正丁醇(20ml)和水(4ml)中,依次加入磷酸钾(93mg,0.44mmol)、Pd
2(dba)
3(20mg,0.022mmol)和XPhos(21mg,0.044mmol),回流反应8h。减压蒸干,加入乙酸乙酯(50ml),依次用水(20ml)和饱和盐水(20ml)洗涤,浓缩,flash柱纯化得近白色固体(60mg)。
MS m/z(ESI):689[M+1]
+
1H NMR(400MHz,DMSO-d6)δ8.56(t,J=2.5Hz,1H),8.44(s,1H),7.94(d,J=1.7Hz,1H),7.83(d,J=2.9Hz,1H),7.79(d,J=1.7Hz,1H),7.40–7.33(m,2H),7.24(d,J=9.0Hz,1H),6.51(s,1H),5.09(q,J=4.2Hz,1H),4.60–4.35(m,6H),4.17(dq,J=25.9,7.8,6.8Hz,3H),3.92–3.81(m,1H),3.67(s,1H),3.58(s,3H),3.39(q,J=6.2Hz,1H),3.09(d,J=12.1Hz,1H),2.93(t,J=9.7Hz,1H),2.56(d,J=3.8Hz,2H),2.41(s,2H),2.32(d,J=3.8Hz,2H),2.19(d,J=10.0Hz,1H),1.21(s,6H),0.92(dd,J=6.4,2.3Hz,3H).
实施例6(S)-2-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)-3-(羟甲基)-4-(1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-氧代-1,6-二氢吡啶-3-基)苄腈
第一步 2-溴-4-氯-3-甲酰基苄腈6b
将化合物6a(5.00g,23.1mmol)溶于THF(50mL)中,在-78℃下滴加LDA(15.0mL,30.1mmol),在-78℃搅拌0.5小时。-78℃下滴加DMF(1.89mL,25.5mmol),-78℃搅拌2小时。LCMS显示反应完全。饱和NH
4Cl溶液(50mL)淬灭反应,EA(50mL×3)萃取。合并有机相,饱和食盐水(50mL)洗涤,无水Na
2SO
4干燥,过滤,浓缩。残余物经柱层析(PE/EA=100/1至1/100)得白色固体化合物6b(0.60g,收率10%)。
LCMS(ESI-MS)m/z:245.9(M+H)
+.
第二步 2-溴-4-氯-3-(羟甲基)苄腈6c
将化合物6b(0.60g,2.46mmol)溶于无水MeOH(10mL),在0℃下加入NaBH
4(0.19g,4.92mmol)。恢复常温搅拌2小时。LCMS显示反应完全。反应液加水(20mL)淬灭,EA(20mL×3)萃取。合并有机相,饱和食盐水(20mL)洗涤,无水Na
2SO
4干燥,过滤,浓缩。残余物经柱层析(PE/EA=100/1至1/100)得白色固体化合物6c(0.50g,收率82%)。
LCMS(ESI-MS)m/z:247.9(M+H)
+.
第三步 2-溴-6-氯-3-氰基苄基乙酸酯6d
将化合物6c(0.50g,2.03mmol)溶于DCM(5mL)中,在冰浴下加入TEA(0.53mL,4.06mmol)和乙酰氯(0.22mL,3.05mmol)。常温搅拌2小时。LCMS 显示反应完全。反应液加水(10mL)淬灭,DCM(10mL×3)萃取。合并有机相,饱和食盐水(10mL)洗涤,无水Na
2SO
4干燥,过滤,浓缩。残余物柱层析(PE/EA=100/1至1/100)得白色固体化合物6d(0.45g,收率77%)。
LCMS(ESI-MS)m/z:287.9(M+H)
+.
第四步 6-氯-3-氰基-2-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)乙酸苄酯6e
将化合物6d(0.45g,1.56mmol)溶于二氧六环(5mL)中,加入化合物5(0.32g,1.56mmol)、Pd(AcO)
2(35mg,0.16mmol)、Xantphos(90mg,0.16mmol)和Cs
2CO
3(1.02g,3.13mmol)。N
2保护下回流反应2小时。LCMS显示反应完全。加水(10mL),EA(10mL×3)萃取。合并有机相,饱和食盐水(10mL)洗涤,无水Na
2SO
4干燥,过滤,浓缩。残余物经柱层析(PE/EA=100/1至1/100)得浅黄色固体化合物6e(0.21g,收率33%)。
LCMS(ESI-MS)m/z:412.2(M+H)
+.
第五步 (S)-3-氰基-2-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)-6-(1-甲基-5-((5-(2-甲基-4-(氧杂-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-氧代-1,6-二氢吡啶-3-基)乙酸苄酯6f
将化合物6e(0.16g,0.39mmol)溶于二氧六环(3mL)中,加入化合物7(0.19g,0.39mmol)、Pd(dppf)Cl
2(28mg,0.039mmol)和K
3PO
4(0.16g,0.78mmol)。N
2保护下微波反应2小时。LCMS显示反应完全。加水(10mL),EA(10mL×3)萃取。合并有机相,饱和食盐水(10mL)洗涤,无水Na
2SO
4干燥,过滤,浓缩。残余物经柱层析(PE/EA=100/1至1/100)得棕色固体化合物6f(80mg,收率28%)。
LCMS(ESI-MS)m/z:367.1(M+H)
+.
第六步 (S)-2-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)-3-(羟甲基)-4-(1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-氧代-1,6-二氢吡啶-3-基)苄腈6
将化合物6f(80mg,0.11mmol)溶于MeOH(2mL)中,加入NaOH的水溶液(1mL,0.22M)。常温搅拌2小时。LCMS显示反应完全。反应液加水(5mL)稀释,DCM(5mL×3)萃取。合并有机相,饱和食盐水(5mL)洗涤,无水Na
2SO
4 干燥,过滤,浓缩。残余物经反相柱层析(H
2O/MeCN=20/1至1/20)和正相柱层析(DCM/EA=100/1至1/100)得白色固体化合物6(10mg,收率13%)。
LCMS(ESI-MS)m/z:689.5(M+H)
+.
1H NMR(400MHz,CDCl
3)δ8.59(s,1H),7.95–7.86(m,2H),7.77(d,J=4.0Hz,1H),7.56–7.52(m,2H),6.85–6.81(m,2H),4.72–4.47(m,5H),4.39–4.34(m,1H),4.17–3.96(m,3H),3.70(s,2H),3.67–3.29(m,4H),3.12–3.07(m,2H),2.60–2.03(m,7H),1.30–1.25(m,9H),0.96–0.86(m,3H).
实施例7(S)-4-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)-3-(羟甲基)-2-(1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-氧代-1,6-二氢吡啶-3-基)苄腈
第一步 4-溴-2-氯-3-甲酰基苄腈7b
将化合物7a(4.00g,18.5mmol)溶于THF(50mL)中,在-78℃下滴加LDA(12.0mL,24.1mmol),在-78℃搅拌0.5小时,在-78℃下滴加DMF(1.51mL,20.4mmol),-78℃搅拌2小时。LCMS显示反应完全。饱和NH
4Cl溶液(50mL)淬灭反应,EA(50mL×3)萃取。合并有机相,饱和食盐水(50mL)洗涤,无水Na
2SO
4干燥,过滤,浓缩。残余物经柱层析(PE/EA=100/1至1/100)得白色固体化合物2(0.45g,收率10%)。
LCMS(ESI-MS)m/z:243.9(M+H+).
第二步 2-氯-4-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)-3-甲酰基苄腈7c
将化合物7b(0.45g,1.84mmol)溶于DMF(3mL)中,加入化合物1a(0.32g,1.84mmol)、Pd
2(dba)
3(0.17g,0.18mmol)、Xantphos(0.10g,0.18mmol)和Cs
2CO
3(1.20g,3.69mmol)。N
2保护下回流反应2小时。LCMS显示反应完全。加水(10mL)淬灭,EA(10mL×3)萃取。合并有机相,饱和食盐水(10mL)洗涤,无水Na
2SO
4干燥,过滤,浓缩。残余物经柱层析(PE/EA=100/1至1/100)得浅黄色固体化合物7c(0.14g,收率21%)。
LCMS(ESI-MS)m/z:368.2(M+H)
+.
第三步 (S)-4-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)-3-(甲酰基)-2-(1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-氧-1,6-二氢吡啶-3-基)苄腈7d
将化合物7c(0.14g,0.38mmol)溶于二氧六环(3mL)中,加入化合物1f(0.18g,0.38mmol)、Pd(dppf)Cl
2(27mg,0.038mmol)和K
3PO
4(0.16g,0.76mmol)。N
2保护下微波反应2小时。LCMS显示反应完全。加水(10mL)淬灭反应,EA(10mL×3)萃取。合并有机相,饱和食盐水(10mL)洗涤,无水Na
2SO
4干燥,过滤,浓缩。残余物经柱层析(PE/EA=100/1至1/100)得棕色固体化合物7d(20mg,收率7%)。
LCMS(ESI-MS)m/z:687.5(M+H)
+.
第四步 (S)-4-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)-3-(羟甲基)-2-(1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1- 基)吡啶-2-基)氨基)-6-氧代-1,6-二氢吡啶-3-基)苄腈7
将化合物7d(20mg,0.029mmol)溶于MeOH(2mL)中,加入NaBH
4(2.2mg,0.058mmol)。常温搅拌2小时。LCMS显示反应完全。反应液加水(5mL)淬灭,DCM(5mL×3)萃取。合并有机相,饱和食盐水(5mL)洗涤,无水Na
2SO
4干燥,过滤,浓缩。残余物经反相柱层析(H
2O/MeCN=20/1至1/20)和正相柱层析(DCM/EA=100/1至1/100)得白色固体化合物7(2mg,收率10%)。
LCMS(ESI-MS)m/z:689.5(M+H)
+.
1H NMR(400MHz,CDCl
3)δ8.39(s,1H),7.88–7.76(m,3H),7.36–7.29(m,2H),6.81(s,2H),5.38–5.30(m,2H),4.71(s,3H),4.53–4.21(m,4H),4.17–3.99(m,2H),3.70–3.49(m,6H),3.07(s,1H),2.56–2.50(m,3H),2.23–2.19(m,2H),2.03–1.98(m,2H),1.70–1.60(m,5H),0.97–0.86(m,6H).
实施例8 2-(3-(羟甲基)-4-(7-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)呋喃[3,2-b]吡啶-5-基)吡啶-2-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)
第一步 4-氯-2-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)烟碱醛8a
将化合物1a(1.0g,4.9mmol)、2-溴-4-氯烟碱醛(1.1g,4.9mmol)、醋酸钯(60mg,0.25mmol)、Xantphos(140mg,0.25mmol)、碳酸铯(3.2g,10mmol)和二氧六环(20ml)依次加入到100ml反应瓶中。氮气置换3次后升温到85℃。反应液在氮气保护下,搅拌反应5小时。LCMS检测原料基本反应完全。反应液冷却到室温后,用DCM/MeOH(10:1,150ml x 2)萃取,有机相干燥后旋干、过柱分离得到淡黄色固体化合物2(800mg,收率:47%)。
LCMS(ESI-MS)m/z:344.2(M+H)
+.
1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),8.55(d,J=5.4Hz,1H),7.51(d,J=5.4Hz,1H),6.58(s,1H),4.26–4.15(m,4H),2.55(s,2H),2.38(s,2H),1.18(s,6H).
第二步 2-(4-氯-3-(羟甲基)吡啶-2-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)8b
将化合物8a(700mg,2.0mmol)溶解在二氯甲烷(10ml)和甲醇(10ml)的混合溶剂中,冰浴条件下,再将硼氢化钠(160mg,4.0mmol)分批加入到反应体系。室温下搅拌反应2小时后,LCMS检测原料反应完全。向反应液中加入饱和氯化铵溶液淬灭反应,有机相干燥旋干得到白色固体化合物8b(700mg.收率:100%)。
LCMS(ESI-MS)m/z:346.2(M+H)
+.
第三步 (4-氯-2-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)吡啶-3-基)乙酸甲酯8c
将化合物8b(550mg,1.6mmol)溶解在二氯甲烷(10ml)中,冰浴条件下将三乙胺(900mg,9mmol)和乙酸酐(1.6g,16mmol,10eq)滴加到反应体系中,保持室温下搅拌过夜。LCMS检测反应完全。向反应液中加入水和二氯甲烷,有机相干燥旋干过柱得到白色固体化合物8c(600mg,收率:97%)。
LCMS(ESI-MS)m/z:388.2(M+H)
+.
第四步 (3-(乙酰氧基甲基)-2-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊 [4,5]吡咯并[1,2-a]吡嗪-2-基)吡啶-4-基)硼酸8d
将化合物8c(370mg,1.0mmol)、Pd(dppf)(OAc)
2(73mg,0.1mmol)、XPhos(47mg,0.1mmol)、醋酸钾(300mg,3.0mmol)、双联硼(500mg,2.0mmol)和二氧六环依次加入到反应瓶中,氮气置换3次后,升温至70℃反应4小时。LCMS显示原料几乎反应完全。反应液冷却至室温后,向反应液中加入水和乙酸乙酯,有机相干燥浓缩至干得到粗品8d(500mg,纯度:80%),直接用于下一步反应。
LCMS(ESI-MS)m/z:398.3(M+H)
+.
第五步 5-氯-2-(三异丙基甲硅烷基)呋喃并[3,2-b]吡啶8f
将化合物8e(3.0g,11.7mmol)、三异丙基硅基乙炔(4.3g,24mmol)、碘化亚铜(200mg,1.1mmol)、PdCl
2(PPh
3)
2(700mg,1.0mmol)、二氧六环(50ml)和三乙胺(50ml)依次加入到反应瓶中,氮气置换3次后,升温至50℃反应2小时。LCMS显示反应完全。反应冷却至室温后,反应液用水和乙酸乙酯稀释,有机相干燥后浓缩至干过柱得到淡绿色固体化合物(3.6g,收率:100%)。
LCMS(ESI-MS)m/z:310.2(M+H)
+.
1H NMR(400MHz,Chloroform-d)δ7.69(dd,J=8.6,1.0Hz,1H),7.17(d,J=8.6Hz,1H),7.11(d,J=0.9Hz,1H),1.44–1.34(m,3H),1.12(d,J=7.4Hz,18H).
第六步 5-氯-7-碘-2-(三异丙基甲硅烷基)呋喃[3,2-b]吡啶8g
将化合物7(3.1g,10mmol)溶解在无水四氢呋喃(20ml)中,降温至-65℃,将正丁基锂(13mmol,1.3eq)滴加到反应体系中,搅拌1小时后,再将碘(3.8g,15mmol)溶解在无水四氢呋喃(10ml)中后滴加到上述反应体系中,保持低温搅拌反应2小时。LCMS检测反应完全。向反应液中加入饱和氯化铵溶液和亚硫酸钠溶液淬灭反应。乙酸乙酯和水加入,搅拌静置分液。有机相干燥后浓缩至干过柱分离得到黄色固体化合物8g(4.0g,收率:92%)。
1H NMR(400MHz,Chloroform-d)δ7.59(s,1H),7.19(s,1H),1.40(ddd,J=14.8,8.1,6.9Hz,3H),1.14(d,J=7.5Hz,18H).
第七步 5-氯-N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)-2-(三异丙基甲硅烷基)呋喃[3,2-b]吡啶-7-胺8h
将化合物8g(560mg,1.2mmol)、5-(4-甲基哌嗪-1-基)吡啶-2-胺(250mg,1.30mmol)(上海药明康德新药开发有限公司)、醋酸钯(40mg,0.18mmol)、Xantphos(40mg,0.07mmol)、碳酸铯(1.2g,3.6mmol)和二氧六环(15ml)依次加入到反应体系中,氮气置换3次后,升温至85℃反应4小时。LCMS显示原料几乎反应完全。反应液冷却后,加入水和乙酸乙酯稀释反应,有机相干燥后浓缩至干、过柱分离得到黄色固体化合物8h(500mg,收率:78%)。
LCMS(ESI-MS)m/z:500.4(M+H)
+.
1H NMR(400MHz,Chloroform-d)δ8.08(d,J=2.9Hz,1H),7.77(s,1H),7.31(dd,J=8.9,3.0Hz,1H),7.08(s,1H),7.03(dd,J=8.9,0.7Hz,1H),6.91(s,1H),3.34(s,4H),2.84(s,4H),2.53(s,3H),1.42–1.35(m,3H),1.13(d,J=7.4Hz,18H).
第八步 (2-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)-4-(7-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-2-(三异丙基甲硅烷基)呋喃[3,2-b]吡啶-5-基)吡啶-3-基)乙酸甲酯8i
将化合物8h(80mg,0.16mmol)、化合物8d(100mg,粗品,1.0eq)、K
3PO
4(110mg,0.5mmol)、Pd(dppf)Cl
2(12mg,0.016mmol)、DME(5ml)和水(1.5ml)依次加入到反应瓶中,氮气置换3次后,升温至80℃反应4小时。反应液冷却至室温后,加入水和乙酸乙酯稀释,有机相干燥后浓缩至干得到粗品。制备板分离得到油状化合物8i(30mg,纯度:80%)
第九步 2-(3-(羟甲基)-4-(7-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-2-(三异丙基甲硅烷基)呋喃[3,2-b]吡啶-5-基)吡啶基-2-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)8j
将化合物8i(30mg,纯度80%)溶解在四氢呋喃(6ml)和水(2ml)中,氢氧化锂(24mg,1.0mmol)加入到反应体系中,室温搅拌过夜,LCMS显示反应完全。向反应液中加入水和乙酸乙酯,有机相干燥后浓缩至干得粗品8j,直接用于下一步反应。
LCMS(ESI-MS)m/z:775.6(M+H)+.
第十步 2-(3-(羟甲基)-4-(7-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)呋喃[3,2-b]吡啶-5-基)吡啶-2-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a] 吡嗪-1(6H)8
将化合物8j(25mg,纯度80%)溶解在四氢呋喃(5ml)中,冰浴条件下,将TBAF(1.0M,0.2ml)滴加到反应体系中,继续搅拌反应2小时。LCMS显示反应完全。向反应液中加入乙酸乙酯和饱和氯化按溶液,有机相干燥后浓缩至干,制备板分离得到淡黄色固体化合物8(10mg,收率:60%)。
LCMS(ESI-MS)m/z:619.4(M+H)
+.
1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.61–8.51(m,2H),8.11(d,J=3.0Hz,1H),7.59–7.55(m,1H),7.51(d,J=5.0Hz,1H),7.37(q,J=5.1,4.7Hz,2H),7.23(d,J=5.1Hz,2H),7.12(d,J=5.8Hz,1H),6.56(s,1H),5.32(t,J=4.9Hz,1H),4.43(d,J=8.8Hz,1H),4.27(d,J=12.3Hz,1H),4.21(t,J=5.8Hz,1H),3.92(d,J=12.0Hz,1H),3.80(s,1H),3.14(d,J=8.5Hz,3H),2.79(d,J=4.1Hz,2H),2.58(d,J=8.0Hz,1H),2.42(s,1H),1.99(dd,J=8.5,6.5Hz,2H),1.22(s,6H).
实施例9 2-(3-(羟甲基)-4-(7-((5-(4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)呋喃[3,2-b]吡啶-5-基)吡啶-2-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)
第一步 4-(6-硝基吡啶-3-基)哌嗪-1-羧酸叔丁酯9b
将化合物9a(2.5g,12.3mmol)、哌嗪-1-羧酸叔丁酯(1.9g,10mmol)、醋酸钯(110mg,0.5mmol)、BINAP(310mg,0.5mmol,0.05eq)、K
3PO
4(6.3g,30mmol,3.0eq)和甲苯(20ml)依次加入到100ml反应瓶中。氮气置换3次后升温到95℃。反应液在氮气保护下,搅拌反应5小时。LCMS检测原料基本反应完全。反应液冷却到室温后,用DCM/MeOH(10:1,150ml x 2)萃取,有机相干燥后旋干、过柱分离得到淡黄色固体化合物9b(1.8g,收率:58%)。
1H NMR(400MHz,DMSO-d6)δ8.21(d,J=3.0Hz,1H),8.14(d,J=9.2Hz,1H),7.43(dd,J=9.3,3.1Hz,1H),3.57–3.38(m,8H),1.39(s,9H).
第二步 1-(6-硝基吡啶-3-基)哌嗪9c
将化合物9b(1.0g,3.2mmol)溶解在二氯甲烷(10ml),冰浴条件下,再将TFA(8ml)滴加到反应体系。室温下搅拌反应2小时后,TLC检测原料反应完全。反应液直接旋干得到黄色油状化合物9c,直接用于下一步反应。
第三步 1-(6-硝基吡啶-3-基)-4-(氧杂环丁-3-基)哌嗪9d
将化合物9c(1.2g,10mmol)溶解在甲醇(20ml)中,室温条件下将3-氧杂环丁酮(720mg,10mmol)、氯化锌(870mg,6.4mmol)和氰基硼氢化钠(400mg g,6.4mmol)加到反应体系中,50℃搅拌4小时。LCMS检测反应完全。向反应 液中加入水和二氯甲烷,有机相干燥旋干过柱得到黄色固体化合物9d(800mg,收率:94%)。
1H NMR(400MHz,Chloroform-d)δ8.15(d,J=9.1Hz,1H),8.12(d,J=3.0Hz,1H),7.19(dd,J=9.2,3.0Hz,1H),4.70(t,J=6.5Hz,2H),4.62(t,J=6.1Hz,2H),3.57–3.52(m,1H),3.50–3.45(m,4H),2.53–2.48(m,4H).
第四步 5-(4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-胺9e
将化合物9d(800mg,3.0mmol),溶解在甲醇(20ml)中,将钯碳(10%w,100mg)加入到反应体系中,氢气置换3次后,保持搅拌反应4小时。TLC显示原料反应完全。反应液经硅藻土过滤后旋干得到白色固体化合物9e(700mg,收率:98%)
LCMS(ESI-MS)m/z:235.2(M+H)
+.
第五步 5-氯-N-(5-(4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)-2-(三异丙基甲硅烷基)呋喃[3,2-b]吡啶-7-胺9g
将化合物9e(800mg,1.8mmol)、化合物9f(420mg,1.8mmol,1.0eq)、醋酸钯(20mg,0.09mmol)、Xantphos(50mg,0.09mmol)、碳酸铯(1.1g,3.6mmol)和二氧六环(20ml)依次加入到反应瓶中,氮气置换3次后,升温至85℃反应4小时。LCMS显示原料反应完全。反应液冷却后,加入乙酸乙酯和水稀释反应液,有机相干燥后浓缩至干,过柱分离得到黄色固体化合物9g(800mg,收率:82%)。
LCMS(ESI-MS)m/z:542.4(M+H)
+.
第六步 (2-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)-4-(7-((5-(4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)-2-(三异丙基甲硅烷基)呋喃[3,2-b]吡啶-5-基)吡啶-3-基)乙酸甲酯9h
将化合物9g(150mg,0.28mmol)、(3-(乙酰氧基甲基)-2-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)吡啶-4-基)硼酸(200mg.纯度:87%)、Pd(dppf)Cl
2(20mg,0.028mmol)、K
3PO
4(180mg,0.84mmol)、二氧六环(6ml)和水(2ml)依次加入到反应瓶中,氮气置换3次后,升温至80℃反应4小时。反应液经制备板分离纯化得到化合物9h(20mg,纯度:90%,收率:10%)。
LCMS(ESI-MS)m/z:859.6(M+H)+.
第七步 2-(3-(羟甲基)-4-(7-((5-(4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)-2-(三异丙基甲硅烷基)呋喃[3,2-b]吡啶-5-基)吡啶-2-基-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)9i
将化合物9h(20mg,纯度:90%)溶解在四氢呋喃(6ml)和水(2ml)中,氢氧化锂(24mg,1.0mmol)加入到反应液中,室温反应过夜。TLC显示反应完全。反应液用乙酸乙酯和水稀释后,有机相干燥后旋干得粗品9i,粗品直接用于下一步反应。
第八步 2-(3-(羟甲基)-4-(7-((5-(4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)呋喃[3,2-b]吡啶-5-基)吡啶-2-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)9
将化合物9i(20mg,纯度90%)溶解在四氢呋喃(5ml)中,冰浴条件下,将TBAF(1.0M,0.2ml)滴加到反应体系中,继续搅拌反应2小时。LCMS显示反应完全。向反应液中加入乙酸乙酯和饱和氯化按溶液,有机相干燥后浓缩至干,制备板分离得到淡黄色固体化合物9(5mg,收率:60%)。
LCMS(ESI-MS)m/z:661.4(M+H)
+.
1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.52–8.48(m,2H),8.30(d,J=2.2Hz,1H),7.96(d,J=3.0Hz,1H),7.47–7.40(m,2H),7.21(d,J=9.0Hz,1H),7.17(s,1H),7.10(d,J=2.2Hz,1H),6.63(s,2H),6.52(s,1H),5.32–5.28(m,2H),5.18–5.14(m,1H),4.54(t,J=6.5Hz,2H),4.44(t,J=6.0Hz,2H),4.39(t,J=5.5Hz,2H),4.17(t,J=5.3Hz,2H),3.11(t,J=5.0Hz,4H),2.39(d,J=7.8Hz,4H),1.97(d,J=7.7Hz,4H).1.20(s,6H).
实施例10 9-氟-2-(3'-(羟甲基)-1-甲基-5-((5-(4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
采用与实施例1类似的合成方法,将叔-丁基(S)-3-甲基哌嗪-1-羧酸酯替换为叔-丁基哌嗪-1-羧酸酯,制得标题产物10,收率19%。
1H NMR(400MHz,DMSO-d
6)δ8.61(d,J=2.3Hz,1H),8.48(d,J=5.0Hz,1H),8.44(s,1H),7.83(d,J=2.8Hz,1H),7.45(d,J=2.3Hz,1H),7.40–7.32(m,2H),7.24(d,J=9.0Hz,1H),4.93(t,J=5.1Hz,1H),4.52(t,J=6.5Hz,2H),4.50–4.33(m,4H),4.31–4.12(m,3H),3.89–3.79(m,1H),3.60(s,3H),3.53–3.40(m,1H),3.08(t,J=5.0Hz,4H),2.57(q,J=8.9Hz,2H),2.42–2.35(m,6H),1.22(s,6H).
LCMS(ESI-MS)m/z:668.8(M+H)
+.
实施例11 2-(5-((5-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)吡啶-2-基)氨基)-3'-(羟甲基)-1-甲基-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-9-氟-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
采用与实施例1类似的合成方法,将叔-丁基(S)-3-甲基哌嗪-1-羧酸酯替换为2-氧杂-7-氮杂螺[3.5]壬烷,制得标题产物11,收率26%。
1H NMR(400MHz,DMSO-d
6)δ8.61(d,J=2.3Hz,1H),8.48(d,J=5.0Hz,1H),8.44(s,1H),7.83(d,J=2.8Hz,1H),7.45(d,J=2.3Hz,1H),7.40–7.32(m,2H),7.24(d,J=9.0Hz,1H),4.93(t,J=5.1Hz,1H),4.52(t,J=6.5Hz,2H), 4.50–4.33(m,4H),4.31–4.12(m,3H),3.89–3.79(m,1H),3.60(s,3H),3.08(t,J=5.0Hz,4H),2.57(q,J=8.9Hz,2H),2.42–2.35(m,2H),1.65-1.43(m,4H),1.22(s,6H).
LCMS(ESI-MS)m/z:653.8(M+H)
+.
实施例12 9-氟-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-2,7-二氮杂螺[3.5]壬烷-7-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
采用与实施例1类似的合成方法,将叔-丁基(S)-3-甲基哌嗪-1-羧酸酯替换为2-甲基-2,7-二氮杂螺[3.5]壬烷,制得标题产物12,收率29%。
1H NMR(400MHz,DMSO-d
6)δ8.61(d,J=2.3Hz,1H),8.48(d,J=5.0Hz,1H),8.44(s,1H),7.83(d,J=2.8Hz,1H),7.45(d,J=2.3Hz,1H),7.40–7.32(m,2H),7.24(d,J=9.0Hz,1H),4.93(t,J=5.1Hz,1H),4.52(t,J=6.5Hz,2H),4.31–4.12(m,3H),3.89–3.79(m,1H),3.60(s,3H),3.08(t,J=5.0Hz,4H),2.57(q,J=8.9Hz,2H),2.42–2.35(m,6H),2.21(s,3H),1.65-1.43(m,4H),1.22(s,6H).
LCMS(ESI-MS)m/z:666.8(M+H)
+.
实施例13 9-氟-2-(5-((5-(2-羟基-7-氮杂螺[3.5]壬烷-7-基)吡啶-2-基)氨基)-3'-(羟甲基)-1-甲基-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
采用与实施例1类似的合成方法,将叔-丁基(S)-3-甲基哌嗪-1-羧酸酯替换为2-甲基-2,7-二氮杂螺[3.5]壬烷,制得标题产物13,收率17%。
1H NMR(400MHz,DMSO-d6)δ1H NMR(400MHz,DMSO-d6)δ8.61(d,J=2.3Hz,1H),8.48(d,J=5.0Hz,1H),8.44(s,1H),7.83(d,J=2.8Hz,1H),7.45(d,J=2.3Hz,1H),7.40–7.32(m,2H),7.24(d,J=9.0Hz,1H),4.94(t,J=5.1Hz,1H),4.55(td,J=6.5,2.9Hz,2H),4.29-4.19(m,1H),4.25-4.12(m,3H),3.82(d,J=11.1Hz,1H),3.67(d,J=5.5Hz,1H),3.60(s,3H),3.40(t,J=6.2Hz,4H),2.45(s,2H),2.36-2.28(m,2H),2.09-1.75(m,8H),1.22(s,6H).
LCMS(ESI-MS)m/z:667.8(M+H)
+.
实施例14 9-氟-2-(3'-(羟甲基)-1-甲基-5-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
采用与实施例1类似的合成方法,将叔-丁基(S)-3-甲基哌嗪-1-羧酸酯替换为1-甲基哌嗪,制得标题产物14,收率21%。
1H NMR(400MHz,DMSO-d
6)δ8.61(d,J=2.3Hz,1H),8.48(d,J=5.0Hz, 1H),8.44(s,1H),7.83(d,J=2.8Hz,1H),7.45(d,J=2.3Hz,1H),7.40–7.32(m,2H),7.24(d,J=9.0Hz,1H),4.94(t,J=5.1Hz,1H),4.39(d,J=5.1Hz,2H),3.58(s,3H),3.08(t,4H),2.41-2.30(m,11H),,2.39-2.19(m,4H),1.22(s,6H).
LCMS(ESI-MS)m/z:626.7(M+H)
+.
实施例15 9-氟-2-(3'-(羟甲基)-1-甲基-5-((4-(4-(噁丁环-3-基)哌嗪-1-基)苯基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
采用与实施例1类似的合成方法,将叔-丁基(S)-3-甲基哌嗪-1-羧酸酯替换为叔-丁基哌嗪-1-羧酸酯;5-氯-2-硝基吡啶替换为1-溴-4-氯苯,制得标题产物15,收率19%。
1H NMR(400MHz,DMSO-d
6)δ8.61(d,J=2.3Hz,1H),8.48(d,J=5.0Hz,1H),8.44(s,1H),7.83(d,J=2.8Hz,1H),7.45(d,J=2.3Hz,1H),7.26(d,J=9.0Hz,2H),7.04(d,J=9.0Hz,2H),4.93(t,J=5.1Hz,1H),4.52(t,J=6.5Hz,2H),4.50–4.33(m,4H),4.31–4.12(m,3H),3.89–3.79(m,1H),3.60(s,3H),3.53–3.40(m,1H),3.08(t,J=5.0Hz,4H),2.57(q,J=8.9Hz,2H),2.42–2.35(m,6H),1.22(s,6H).
LCMS(ESI-MS)m/z:667.8(M+H)
+.
实施例16 9-氟-2-(3'-(羟甲基)-1-甲基-5-((6-(4-(噁丁环-3-基)哌嗪-1-基)吡啶-3-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
采用与实施例1类似的合成方法,将叔-丁基(S)-3-甲基哌嗪-1-羧酸酯替换为叔-丁基哌嗪-1-羧酸酯;5-氯-2-硝基吡啶替换为2-溴-5-氯吡啶,制得标题产物16,收率23%。
1H NMR(400MHz,DMSO-d
6)δ8.60(d,J=2.3Hz,1H),8.47(d,J=5.0Hz,1H),8.41(s,1H),7.82(d,J=2.9Hz,1H),7.44(d,J=2.3Hz,1H),7.37–7.30(m,2H),7.21(d,J=9.0Hz,1H),4.93(t,J=5.1Hz,1H),4.52(t,J=6.5Hz,2H),4.50–4.33(m,4H),4.31–4.12(m,3H),3.89–3.79(m,1H),3.60(s,3H),3.53–3.40(m,1H),3.08(t,J=5.0Hz,4H),2.57(q,J=8.9Hz,2H),2.42–2.35(m,6H),1.22(s,6H).
LCMS(ESI-MS)m/z:668.8(M+H)
+.
实施例17(S)-9-溴-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
采用与实施例1类似的合成方法,将中间体1b进行合成,制得标题产物17,收率29%。
1H NMR(400MHz,DMSO-d
6)δ8.59(d,J=2.3Hz,1H),8.46(d,J=5.0Hz, 1H),8.42(s,1H),7.82(d,J=2.9Hz,1H),7.43(d,J=2.3Hz,1H),7.38–7.30(m,2H),7.24–7.20(m,1H),4.93(t,J=5.1Hz,1H),4.62–4.32(m,6H),4.21(d,J=10.2Hz,3H),3.82(d,J=6.4Hz,1H),3.65(d,J=5.9Hz,1H),3.59(s,3H),3.43–3.33(m,1H),3.08(d,J=11.5Hz,1H),2.93(t,J=9.9Hz,1H),2.69–2.50(m,3H),2.37-2.23(m,4H),2.17(t,J=9.7Hz,1H),1.21(d,J=2.9Hz,6H),0.91(d,J=6.3Hz,3H).LCMS(ESI-MS)m/z:743.7(M+H)
+.
实施例18(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-1-羰基-1,3,4,6,7,8-六氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-9-甲腈
第一步 7,7-二甲基-1-羰基-1,3,4,6,7,8-六氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-9-甲腈
化合物1b(0.5g,1.77mmol)溶于甲苯(10mL)中,再加入氰化亚铜(0.16g,1.77mmol)和四三苯基磷钯(50mg),反应液在氮气保护下及100℃搅拌3小时。冷却后用加入饱和食盐水洗,再用乙酸乙酯(50×2mL)萃取。将合并后的有机相用无水硫酸钠干燥,过滤旋干得到粗产品,经过硅胶柱层析纯化后得到化合物18a(280mg),收率69.1%。
MS m/z(ESI):230(M+1)
+
此后步骤采用与实施例1类似第五步以后的反应,制得标题产物18,收率19%。
1H NMR(400MHz,DMSO-d6)δ8.59(d,J=2.4Hz,1H),8.48(d,J=5.2Hz,1H),8.44(s,1H),7.81(d,J=2.8Hz,1H),7.40–7.34(m,3H),7.24–7.22(m,1H),4.99(s,1H),4.55–4.38(m,6H),4.30–4.28(m,3H),3.90(s,1H),3.67–3.65(m,1H),3.59(s,3H),3.38–3.34(m,1H),3.09–3.05(m,1H),2.95–2.90(m,1H),2.66–2.65(m,2H),2.31–2.13(m,6H),1.22(s,6H),0.91(d,J=6.4Hz,3H).
LCMS(ESI-MS)m/z:689.8(M+H)
+.
实施例19(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-1-羰基-1,3,4,6,7,8-六氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-9-甲腈
第一步 7,7-二甲基-9-(三氟甲基)-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
化合物1a(0.5g,2.45mmol)溶于DMF(10mL)中,再加入二碘二氟甲烷(1.48g,4.9mmol),反应液在氮气保护下强光照射及搅拌18小时。冷却后用加入饱和食盐水洗,再用乙酸乙酯(50×2mL)萃取。将合并后的有机相用无水硫酸钠干燥,过滤旋干得到粗产品,经过硅胶柱层析纯化后得到化合物19a(180mg),收率27%。
MS m/z(ESI):230(M+1)
+
此后步骤采用与实施例1类似第五步以后的反应,制得标题产物19,收 率16%。
1H NMR(400MHz,Methanol-d
4)δ7.38(d,J=1.9Hz,1H),7.25(d,J=1.8Hz,1H),7.07(d,J=7.6Hz,1H),6.85(dd,J=7.7,1.6Hz,1H),6.65(d,J=1.5Hz,1H),6.09(s,1H),4.47(s,2H),3.90(d,J=11.0Hz,2H),3.36(d,J=11.7Hz,2H),3.17–3.01(m,6H),2.81(s,3H),2.76(d,J=7.2Hz,2H),2.50(s,1H),2.46(s,3H),2.33(s,3H),2.25(s,3H),2.12(s,3H),1.97(td,J=13.4,12.8,4.0Hz,2H),1.81(d,J=13.9Hz,2H),1.78(d,J=12.5Hz,2H),1.67–1.53(m,3H),1.28–1.22(m,4H),0.86(t,J=7.0Hz,3H).
LCMS(ESI-MS)m/z:732.8(M+H)
+.
实施例20(S)-9-乙氧基-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶基-2-基)氨基)-6-氧代-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
第一步 9-乙氧基-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
化合物1b(0.5g,1.77mmol)溶于二氯甲烷(10mL)中,再加入乙醇钠(0.16g,1.77mmol),反应液在氮气保护下封管、于50℃下搅拌18小时。冷却后用加入饱和食盐水洗,再用乙酸乙酯(50×2mL)萃取。将合并后的有机相用无水硫 酸钠干燥,过滤旋干得到粗产品,经过硅胶柱层析纯化后得到化合物20a(210mg),收率47.8%。
MS m/z(ESI):248.3(M+1)
+
此后步骤采用与实施例1类似第五步以后的反应,制得标题产物20,收率30%。
1H NMR(400MHz,Methanol-d
4)δ7.38(d,J=1.9Hz,1H),7.25(d,J=1.8Hz,1H),7.07(d,J=7.6Hz,1H),6.85(dd,J=7.7,1.6Hz,1H),6.65(d,J=1.5Hz,1H),6.09(s,1H),4.47(s,2H),4.07(m,2H),3.90(d,J=11.0Hz,2H),3.36(d,J=11.7Hz,2H),3.19–3.01(m,6H),2.81(s,3H),2.76(d,J=7.2Hz,2H),2.50(s,1H),2.41(s,3H),2.33(s,3H),2.23(s,3H),2.14(s,3H),1.98(td,J=13.4,12.8,4.0Hz,2H),1.82(d,J=13.9Hz,2H),1.77(d,J=12.5Hz,2H),1.69–1.56(m,3H),1.38(m,2H),1.27–1.21(m,4H),0.86(t,J=7.0Hz,3H).
LCMS(ESI-MS)m/z:708.9(M+H)
+.
实施例21(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-9-甲氧基-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
采用与实施例20类似的合成方法,将乙醇钠替换为甲醇钠,制得标题产物21,收率35%。
1H NMR(400MHz,Methanol-d
4)δ7.38(d,J=1.9Hz,1H),7.25(d,J=1.8Hz,1H),7.07(d,J=7.6Hz,1H),6.85(dd,J=7.7,1.6Hz,1H),6.65(d,J=1.5Hz,1H),6.09(s,1H),4.47(s,2H),3.90(d,J=11.0Hz,2H),3.83(s,3H),3.36(d,J=11.7Hz,2H),3.19–3.01(m,6H),2.81(s,3H),2.76(d,J=7.2Hz,2H),2.50(s,1H),2.41(s,3H),2.33(s,3H),2.23(s,3H),2.14(s,3H),1.98(td,J=13.4, 12.8,4.0Hz,2H),1.82(d,J=13.9Hz,2H),1.77(d,J=12.5Hz,2H),1.69–1.56(m,3H),1.27–1.21(m,4H),0.86(t,J=7.0Hz,3H).
LCMS(ESI-MS)m/z:694.8(M+H)
+.
实施例22(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-9-丙氧基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
采用与实施例20类似的合成方法,将乙醇钠替换为丙醇钠,制得标题产物22,收率26%。
1H NMR(400MHz,Methanol-d
4)δ7.38(d,J=1.9Hz,1H),7.25(d,J=1.8Hz,1H),7.07(d,J=7.6Hz,1H),6.85(dd,J=7.7,1.6Hz,1H),6.65(d,J=1.5Hz,1H),6.09(s,1H),4.47(s,2H),3.99(m,2H),390(d,J=11.0Hz,2H),3.36(d,J=11.7Hz,2H),3.19–3.01(m,6H),2.81(s,3H),2.76(d,J=7.2Hz,2H),2.50(s,1H),2.41(s,3H),2.33(s,3H),2.23(s,3H),2.14(s,3H),1.98(td,J=13.4,12.8,4.0Hz,2H),1.82(d,J=13.9Hz,2H),1.77(d,J=12.5Hz,2H),1.72(m,2H),1.69–1.56(m,3H),1.27–1.21(m,4H),0.99(m,3H),0.86(t,J=7.0Hz,3H).
LCMS(ESI-MS)m/z:722.9(M+H)
+.
实施例23(S)-9-环丙氧基-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
采用与实施例20类似的合成方法,将乙醇钠替换为环丙醇钠,制得标题产物23,收率17%。
1H NMR(400MHz,Methanol-d
4)δ7.38(d,J=1.9Hz,1H),7.25(d,J=1.8Hz,1H),7.07(d,J=7.6Hz,1H),6.85(dd,J=7.7,1.6Hz,1H),6.65(d,J=1.5Hz,1H),6.09(s,1H),4.47(s,2H),390(d,J=11.0Hz,2H),3.37(m,3H),3.19–3.01(m,6H),2.81(s,3H),2.76(d,J=7.2Hz,2H),2.50(s,1H),2.41(s,3H),2.33(s,3H),2.23(s,3H),2.14(s,3H),1.98(td,J=13.4,12.8,4.0Hz,2H),1.82(d,J=13.9Hz,2H),1.77(d,J=12.5Hz,2H),1.69–1.56(m,3H),1.27–1.21(m,4H),0.86(t,J=7.0Hz,3H),0.58(m,2H),0.34(m,2H).
LCMS(ESI-MS)m/z:720.9(M+H)
+.
实施例24(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-9-异丙氧基-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
采用与实施例23类似的合成方法,将乙醇钠替换为异丙醇钠,制得标题产物24,收率25%。
1H NMR(400MHz,Methanol-d
4)δ7.38(d,J=1.9Hz,1H),7.25(d,J=1.8 Hz,1H),7.07(d,J=7.6Hz,1H),6.85(dd,J=7.7,1.6Hz,1H),6.65(d,J=1.5Hz,1H),6.09(s,1H),4.47(s,2H),4.69(m,1H),3.90(d,J=11.0Hz,2H),3.36(d,J=11.7Hz,2H),3.19–3.01(m,6H),2.81(s,3H),2.76(d,J=7.2Hz,2H),2.50(s,1H),2.41(s,3H),2.33(s,3H),2.23(s,3H),2.14(s,3H),1.98(td,J=13.4,12.8,4.0Hz,2H),1.82(d,J=13.9Hz,2H),1.77(d,J=12.5Hz,2H),1.69–1.56(m,3H),1.31(m,6H),1.27–1.21(m,4H),0.99(m,3H),0.86(t,J=7.0Hz,3H).
LCMS(ESI-MS)m/z:722.9(M+H)
+.
实施例25(S)-9-氨基-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
第一步 9-氨基-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
化合物1b(0.5g,1.77mmol)溶于氨的甲醇溶液(10mL)中,反应液在氮气保护下及封管加热80℃搅拌3小时。冷却后用加入饱和食盐水洗,再用乙酸乙酯(50×2mL)萃取。将合并后的有机相用无水硫酸钠干燥,过滤旋干得到粗产品,经过硅胶柱层析纯化后得到化合物25a(156mg),收率40.1%。
MS m/z(ESI):219(M+1)
+
此后步骤采用与实施例1类似第五步以后的反应,制得标题产物25,收率11%。
1H NMR(400MHz,Methanol-d
4)δ7.38(d,J=1.9Hz,1H),7.25(d,J=1.8Hz,1H),7.07(d,J=7.6Hz,1H),6.85(dd,J=7.7,1.6Hz,1H),6.65(d,J=1.5Hz,1H),6.09(s,1H),5.82(s,2H),4.47(s,2H),3.90(d,J=11.0Hz,2H),3.36(d,J=11.7Hz,2H),3.19–3.01(m,6H),2.81(s,3H),2.76(d,J=7.2Hz,2H),2.50(s,1H),2.41(s,3H),2.33(s,3H),2.23(s,3H),2.14(s,3H),1.98(td,J=13.4,12.8,4.0Hz,2H),1.82(d,J=13.9Hz,2H),1.77(d,J=12.5Hz,2H),1.69–1.56(m,3H),1.28–1.21(m,4H),0.88(t,J=7.0Hz,3H).
LCMS(ESI-MS)m/z:679.8(M+H)
+.
实施例26(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-9-异丙氧基-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮
采用与实施例25类似的合成方法,将氨的甲醇溶液替换为甲氨盐酸盐,制得标题产物26,收率24.6%。
1H NMR(400MHz,Methanol-d
4)δ7.38(d,J=1.9Hz,1H),7.25(d,J=1.8Hz,1H),7.07(d,J=7.6Hz,1H),6.85(dd,J=7.7,1.6Hz,1H),6.65(d,J=1.5Hz,1H),6.09(s,1H),4.47(s,2H),3.90(d,J=11.0Hz,2H),3.36(d,J=11.7Hz,2H),3.19–3.01(m,6H),2.81(s,3H),2.76(d,J=7.2Hz,2H),2.72(s,2H),2.50(s,1H),2.41(s,3H),2.33(s,3H),2.23(s,3H),2.14(s,3H),1.98(td,J=13.4,12.8,4.0Hz,2H),1.82(d,J=13.9Hz,2H),1.77(d,J=12.5Hz,2H),1.69–1.56(m,3H),1.28–1.22(m,4H),0.88(t,J=7.0Hz,3H).
LCMS(ESI-MS)m/z:693.9(M+H)
+.
实施例27(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮-9-氘
第一步 7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮-9-氘
化合物1b(0.5g,1.77mmol)溶于四氢呋喃中,反应液在氮气保护下加入氘代硼氢化钠,冰浴下搅拌3小时。用加入饱和食盐水洗,再用乙酸乙酯(50×2mL)萃取。将合并后的有机相用无水硫酸钠干燥,过滤旋干得到粗产品,经过硅胶柱层析纯化后得到化合物27a(160mg),收率44.2%。
MS m/z(ESI):206.3(M+1)
+
此后步骤采用与实施例1类似第五步以后的反应,制得标题产物26,收率21%。
1H NMR(400MHz,DMSO-d6)δ8.64(d,J=22.6Hz,2H),8.47(d,J=5.0Hz,1H),7.92(s,1H),7.45(dd,J=9.7,2.6Hz,2H),7.36–7.24(m,2H),4.83–4.60(m,4H),4.40(q,J=11.7Hz,3H),4.23–4.04(m,3H),3.79(d,J=11.5Hz,1H),3.56(s,3H),3.18–3.05(m,3H),2.54(d,J=8.8Hz,2H),2.42(s,2H),1.18(d,J=5.6Hz,8H),0.90(s,3H).
MS m/z(ESI):666.8[M+H]
+。
生物学实验实施例:
实验一、化合物抑制BTK激酶的活性研究
使用迁移率改变法来测定化合物的BTK激酶活性,反应体系为(激酶溶液、ATP、kinase substrate2)。化合物与酶共孵育30分钟后使用Caliper EZ reader读取转化率,使用计算公式测定化合物抑制率,并使用Graphad进行数据拟合得出本发明化合物的IC
50值。
实验结果
本发明化合物对BTK激酶具有具有明显的抑制作用,BTK的50%抑制浓度<0.75nM,选择性优于依鲁替尼。
表2化合物抑制BTK激酶的活性研究
化合物编号 | BTK(IC 50,nM) |
H01 | 0.23 |
H02 | 0.59 |
H03 | 0.14 |
H04 | 0.26 |
H05 | 0.69 |
H06 | 0.41 |
H07 | 0.38 |
H08 | 0.23 |
H09 | 0.71 |
H10 | 0.21 |
H11 | 0.26 |
H12 | 0.49 |
H13 | 0.18 |
H14 | 0.27 |
H15 | 0.68 |
H16 | 0.17 |
H17 | 0.73 |
H18 | 0.65 |
H19 | 0.52 |
H20 | 0.55 |
H21 | 0.38 |
H22 | 0.74 |
H23 | 0.51 |
H24 | 0.65 |
H25 | 0.44 |
H26 | 0.46 |
依鲁替尼 | 0.78 |
实验二、化合物对细胞增殖的抑制效果
1、实验目的和方法
本实验测定化合物对细胞增殖的效果。
测定化合物对肿瘤细胞增殖的抑制效果,培养肿瘤细胞(A20 5E6细胞)至一定数量后进行96孔铺板,根据实验要求在培养板中加入不同浓度的本发明化合物,经过1h、2h、4h、8h、24h观察对于肿瘤细胞的抑制作用,加入CCK8孵育2h后检测其吸光度值,测定化合物对细胞增殖的抑制效果,使用Graphad进行数据拟合得到化合物的IC
50值。
2、实验结果
本发明化合物能有效抑制肿瘤细胞的增殖,效果优于依鲁替尼。
表3化合物对细胞增殖的抑制效果
化合物编号 | IC 50(μM) |
H01 | 0.024 |
H02 | 0.023 |
H03 | 0.061 |
H04 | 0.026 |
H05 | 0.023 |
H06 | 0.031 |
H07 | 0.040 |
H08 | 0.029 |
H09 | 0.031 |
H10 | 0.021 |
H11 | 0.013 |
H12 | 0.013 |
H13 | 0.019 |
H14 | 0.047 |
H15 | 0.023 |
H16 | 0.047 |
依鲁替尼 | 0.087 |
实验三、化合物对类风湿关节炎的缓解效果
1、实验目的和方法
本实验目的是为了测试化合物对II型胶原诱导的大鼠关节炎模型的效果。大鼠在第0天及第7天尾根部皮内两次免疫注射造模,并进行临床评分。造模成功的动物(临床评分>3分以上)随机分配到各个给药组,进行治疗给药。同时进行各种指标的检测,包括临床评分,足趾体积测量(一周两次)等。
2、实验结果
本发明化合物在给药14天后能有效缓解动物的关节炎的临床评分以及减小足趾体积,缓解关节炎的进展,效果优于依鲁替尼。
实验四、化合物对淋巴瘤的作用效果
1、实验目的和方法
本实验目的是为了测试化合物对淋巴瘤的效果。培育A20 5E6细胞,1于皮下接种于SCID裸鼠中,一周两次测量肿瘤体积,待瘤种长至一定体积后,将造模成功的动物随机分配至各剂量给药组,进行治疗给药。同时每天观察其瘤种大小及体重变化等。
2、实验结果
本发明化合物能有效减小动物实体瘤的大小,缓解肿瘤的进程,并且能改善动物体重,效果优于依鲁替尼。
实验五、化合物对急性肺炎的效果
1、实验目的和方法
本实验目的是为了测试化合物对急性肺炎的效果。
动物给予水合氯醛进行麻醉,麻醉后给予脂多糖进行化学诱导急性肺炎模型,动物分为对照及模型组,吸入脂多糖后的各时间段内收集动物的支气管肺泡灌洗液及肺组织,并通过呼吸功能仪监测动物肺损伤等指标。收集组织后进行组织切片及染色,支气管肺泡灌洗液细胞计数及相应炎症因子测定。
2、实验结果
本发明化合物在给药后相较于对照组能有效改善HE染色中炎症细胞浸润,支气管肺泡灌洗液中淋巴细胞、单核巨噬细胞以及中性粒细胞相较于对照组明显减少,组织及血液中IL-1β含量相较于对照组也明显减少,效果优于依鲁替尼。
实验六、化合物对系统性红斑狼疮的效果
1、实验目的和方法
本实验目的是为了测试化合物对MRL/lpr小鼠自发系统性红斑狼疮的药效作用。
MRL/lpr小鼠适应7天后,采集血清,测定血液中抗核抗体含量,并进行分组给药。分别在第4、8、16、20周时进行血样采集,测定其血液中抗核抗体、抗单链变形DNA抗体、抗组织蛋白、尿素氮、肌酐、尿蛋白检测。观察化合物对系统性红斑狼疮的药效结果。
2、实验结果
本发明化合物能有效降低动物血液中相关指标的含量,有效缓解动物系统性红斑狼疮的进程。
实验七、化合物对hERG钾通道电流的抑制效果
1、实验目的和方法
本实验目的是应用电生理手动膜片钳检测化合物对hERG钾通道的作用。
过表达hERG钾离子通道HEK293细胞。使用DMEM/15%胎牛血清/1%青霉素-链霉素组成的培养基培养于37℃5%CO
2培养箱中。实验时,将细胞转移到嵌入倒置显微镜平台的细胞浴槽中,灌流细胞外液,稳定5分钟细胞沉淀后即可开始实验。采用HEKA EPC-10膜片钳放大器和PATCHMASTER采集系统记录膜电流(HEKA Instruments Inc.,D-67466Lambrcht,Pfalz,
Germany)。
实验采用全细胞记录模式进行,按照预设的电生理刺激方案记录电流值。使用含待测药物,浓度由低到高进行灌流及记录。使用PATCHMASTER V2X60(HEKA Instruments Inc.,D-67466Lambrecht,Pfalz,Germany)进行数据 采集,采用Origin 8.5(OriginLab Corporation,Northampton,MA)软件进行分析和统计。
2、实验结果
本发明化合物
hERG IC
50>40μM,心脏安全性较好。
实验八、化合物的药代动力学结果
1、实验目的和方法
本实验目的是为了测试化合物在血浆中和组织中的含量。
SD大鼠给药前,给药后15,30mins,1hr,2hr,4hr,8hr,12hr,24hr,48hr测定血浆中和组织中的化合物含量。
2、实验结果
大鼠上的T
1/2在3-4hr之间。
实验九、化合物的急毒实验结果
1、实验目的和方法
本实验目的是为了测试化合物在小鼠上的毒性效果。
小鼠单次给予不同剂量的化合物,观察14天,记录动物死亡情况,中毒反应,体重变化,饮食,外观,行为等。终点解剖动物,取脏器,进行组织病理学检查。
2、实验结果
本发明化合物的LD
50>1000mg/kg,安全性好。与对照组小鼠比较,给药组小鼠自给药日起14天内未见体重及行为异常,终点解剖学未发现明显脏器病变,本发明化合物并未显示出明显毒性。血液分析未发现有明显指标异常。
实验十、化合物的预长毒实验结果
1、实验目的和方法
本实验目的是为了测试化合物长期给药后在大鼠上的毒性效果。
大鼠长期给予不同高剂量的化合物,给药21天,每天观察动物的体重及 相关生理性体征,记录动物死亡情况,中毒反应,体重变化,饮食,外观,行为等。21天后终点解剖动物,收集血样进行血常规、血生化及凝血四项的检测,取脏器,进行组织病理学检查。
2、实验结果
本发明化合物的LD
50>100mg/kg,安全性较好。与对照组动物比较,给药组动物自给药日起21天内未见体重、行为异常及生理性变化,终点解剖学未发现明显脏器病变,本发明化合物并未显示出明显毒性。血液分析未发现给药组动物出现相关指标异常。
以上所述仅为本发明的较佳实施例,并不用以限制本发明,凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明保护的范围之内。
Claims (12)
- 一种通式(I)所示的化合物,或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、及其混合物形式、及其可药用盐、多晶型物、溶剂合物、前药、代谢物、同位素衍生物,其中X为C-R a或N;R a为氢或氰基;R 0为氢、卤素、羟基、C 1-6烷基、氰基或C 1-6烷氧基;当X为N时,R 0为氢;当X为C-R a,R a为氰基时,R 0为氢;R 1为氢、氘、卤素、氰基、三氟甲基、C 0-6取代氨基、C 1-6烷基;C 1-6烷氧基;R 2和R 3分别独立地为C 1-3烷基;R为羟基或卤素;R 4为直链的C 1-6烷基或是带支链的C 3-6烷基;R 5为氢或C 1-3烷基;X 1为CH或N;T和T 0分别独立地为含氮的5-6元杂环烷基或是含氮的9-11元螺环烷基,其中所述的5-6元杂环烷基不被取代,或是被1个T 1或T 2取代,或是同时被T 1和T 2取代;其中所述的螺环烷基不被取代,或是被1个T 3或T 4取代,或是同时被T 3和T 4取代;T 1为C 1-6烷基;T 2为C 1-6烷基或是3-6元杂环烷基;T 3为羟基或C 1-6烷基;T 4为C 1-6烷基或是3-6元杂环烷基。
- 根据权利要求2所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、及其混合物形式、及其可药用盐、多晶型物、溶剂合物、前药、代谢物、同位素衍生物,其特征在于,R 0为氢或氰基;R为羟基。
- 根据权利要求1所述的化合物,其中所述化合物选自:(S)-9-氟-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶基-2-基)氨基)-6-氧代-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;(S)-9-氯-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶基-2-基)氨基)-6-氧代-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶基-2-基)氨基)-6-氧代-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7,9-三甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;(S)-2-(3'-(羟甲基)-1-异丙基-5-((5-(2-甲基-4-(氧杂-3-基)哌嗪-1-基)吡啶-2- 基)氨基)-6-氧代-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;(S)-3-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)-4-(羟甲基)-5-(1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-氧代-1,6-二氢吡啶-3-基)苄腈;(S)-2-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)-3-(羟甲基)-4-(1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-氧代-1,6-二氢吡啶-3-基)苄腈;(S)-4-(7,7-二甲基-1-氧代-1,3,4,6,7,8-六氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-2-基)-3-(羟甲基)-2-(1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-氧代-1,6-二氢吡啶-3-基)苄腈;2-(3-(羟甲基)-4-(7-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)呋喃[3,2-b]吡啶-5-基)吡啶-2-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H);2-(3-(羟甲基)-4-(7-((5-(4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)呋喃[3,2-b]吡啶-5-基)吡啶-2-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H);9-氟-2-(3'-(羟甲基)-1-甲基-5-((5-(4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;2-(5-((5-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)吡啶-2-基)氨基)-3'-(羟甲基)-1-甲基-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-9-氟-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;9-氟-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-2,7-二氮杂螺[3.5]壬烷-7-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;9-氟-2-(5-((5-(2-羟基-7-氮杂螺[3.5]壬烷-7-基)吡啶-2-基)氨基)-3'-(羟甲基)-1-甲基-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;9-氟-2-(3'-(羟甲基)-1-甲基-5-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;9-氟-2-(3'-(羟甲基)-1-甲基-5-((4-(4-(噁丁环-3-基)哌嗪-1-基)苯基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;9-氟-2-(3'-(羟甲基)-1-甲基-5-((6-(4-(噁丁环-3-基)哌嗪-1-基)吡啶-3-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;(S)-9-溴-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-1-羰基-1,3,4,6,7,8-六氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-9-甲腈;(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-1-羰基-1,3,4,6,7,8-六氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-9-甲腈;(S)-9-乙氧基-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(氧杂环丁-3-基)哌嗪-1-基)吡啶基-2-基)氨基)-6-氧代-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-9-甲氧基-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-9-丙氧基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;(S)-9-环丙氧基-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8- 四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-9-异丙氧基-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;(S)-9-氨基-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮;(S)-2-(3'-(羟甲基)-1-甲基-5-((5-(2-甲基-4-(噁丁环-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-羰基-1,6-二氢-[3,4'-联吡啶]-2'-基)-9-异丙氧基-7,7-二甲基-3,4,7,8-四氢-2H-环戊二烯并[4,5]吡咯并[1,2-a]吡嗪-1(6H)-酮。
- 一种制备如权利要求1至5中任一项所限定的通式(I)所示的化合物的方法,所述通式(I)所示的化合物通过以下方案制备,方案1:方案2:方案3:其中,方案1所述的催化剂包括三(二亚苄基丙酮)二钯、4,5-双二苯基膦-9,9-二甲基氧杂蒽、醋酸钯、四(三苯基膦)钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、2-二环己基磷-2,4,6-三异丙基联苯、1,1'-联萘-2,2'-双二苯膦、1,10-菲罗啉、碘化亚铜;所述还原剂1为四氢锂铝、硼烷四氢呋喃、硼烷二甲硫醚、还原铁粉;所述还原剂2为硼氢化钠、硼氢化钾、三乙酰基硼氢化钠、氰基硼氢化钠;方案2和方案3所述的催化剂包括三(二亚苄基丙酮)二钯、4,5-双二苯基膦-9,9-二甲基氧杂蒽、醋酸钯、四(三苯基膦)钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、2-二环己基磷-2,4,6-三异丙基联苯、1,1'-联萘-2,2'-双二苯膦、1,10-菲罗啉、碘化亚铜;所述还原剂1为四氢锂铝、硼烷四氢呋喃、硼烷二甲硫醚、还原铁粉;所述碱性条件的试剂可选为碳酸钾,碳酸铯,氢氧化钾,氢氧化钠,氟化铯。
- 一种药物组合物,包含治疗有效量的权利要求1-5任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、及其混合物形式、及其可药用盐、多晶型物、溶剂合物、前药、代谢物、同位素衍生物,以及任选一种或多种医药上可接受的载剂和/或稀释剂。
- 根据权利要求1-5任一项所述的化合物或其互变异构体、内消旋体、 外消旋体、对映异构体、非对映异构体、及其混合物形式、及其可药用盐、多晶型物、溶剂合物、前药、代谢物、同位素衍生物,或者根据权利要求7所述的药物组合物在制备用于预防和/或治疗布鲁顿酪氨酸激酶介导的相关疾病的药物中的用途。
- 根据权利要求8所述的用途,其中所述布鲁顿酪氨酸激酶介导的相关疾病包括自身免疫失调、癌症或炎症类疾病。
- 根据权利要求9所述的用途,其中所述的癌症为食道癌、肺癌、直肠癌、胰腺癌、甲状腺癌、淋巴瘤或白血病,所述的自身免疫性疾病或炎症类疾病为关节炎、系统性红斑狼疮、炎症性肠炎、克罗恩病、多发性硬化、哮喘、血小板减少性紫癜、慢性阻塞性肺病、银屑病、器官移植排斥、变态反应或鼻炎。
- 一种用于预防和/或治疗自身免疫失调、癌症或炎症类疾病的方法,所述方法包括对有需要的对象施用治疗有效量的根据权利要求1-5任一项所述的化合物及其药学上可接受的盐或立体异构体或者根据权利要求7所述的药物组合物。
- 根据权利要求1-5任一项所述的化合物及其药学上可接受的盐或立体异构体或者根据权利要求7所述的药物组合物用于预防和/或治疗自身免疫失调、癌症或炎症类疾病。
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