CN111518076A - Preparation method of indoleamine-2, 3-dioxygenase (IDO) inhibitor - Google Patents
Preparation method of indoleamine-2, 3-dioxygenase (IDO) inhibitor Download PDFInfo
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- CN111518076A CN111518076A CN202010457571.3A CN202010457571A CN111518076A CN 111518076 A CN111518076 A CN 111518076A CN 202010457571 A CN202010457571 A CN 202010457571A CN 111518076 A CN111518076 A CN 111518076A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- 102000006639 indoleamine 2,3-dioxygenase Human genes 0.000 title abstract description 26
- 108020004201 indoleamine 2,3-dioxygenase Proteins 0.000 title abstract description 26
- 239000003112 inhibitor Substances 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 45
- 238000006243 chemical reaction Methods 0.000 claims description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- -1 sulfoxide iodide Chemical class 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 13
- 239000011541 reaction mixture Substances 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical class NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 claims description 4
- 239000007821 HATU Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 4
- 238000012746 preparative thin layer chromatography Methods 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- DGRGLKZMKWPMOH-UHFFFAOYSA-N 4-methylbenzene-1,2-diamine Chemical compound CC1=CC=C(N)C(N)=C1 DGRGLKZMKWPMOH-UHFFFAOYSA-N 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims 3
- 238000004440 column chromatography Methods 0.000 claims 2
- 238000005406 washing Methods 0.000 claims 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 1
- 238000001816 cooling Methods 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 230000003472 neutralizing effect Effects 0.000 claims 1
- 238000004007 reversed phase HPLC Methods 0.000 claims 1
- 229920006395 saturated elastomer Polymers 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 48
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 43
- 238000004949 mass spectrometry Methods 0.000 description 43
- 239000007787 solid Substances 0.000 description 34
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 150000003254 radicals Chemical class 0.000 description 15
- 206010028980 Neoplasm Diseases 0.000 description 13
- YGPSJZOEDVAXAB-UHFFFAOYSA-N kynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-UHFFFAOYSA-N 0.000 description 13
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 11
- 239000007788 liquid Substances 0.000 description 10
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 9
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
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- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- XHNJFNLTFMAPQB-UHFFFAOYSA-N ethyl 2-(4-oxocyclohexyl)acetate Chemical compound CCOC(=O)CC1CCC(=O)CC1 XHNJFNLTFMAPQB-UHFFFAOYSA-N 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N hydroxymaleic acid group Chemical group O/C(/C(=O)O)=C/C(=O)O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 239000012642 immune effector Substances 0.000 description 1
- 230000008629 immune suppression Effects 0.000 description 1
- 230000006058 immune tolerance Effects 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000008975 immunomodulatory function Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960003987 melatonin Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- LBQAJLBSGOBDQF-UHFFFAOYSA-N nitro azanylidynemethanesulfonate Chemical group [O-][N+](=O)OS(=O)(=O)C#N LBQAJLBSGOBDQF-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing alicyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- 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
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings
-
- 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
Abstract
The invention relates to a preparation method of a compound shown as a formula I, a compound prepared by the method and having the function of inhibiting indoleActivity of the enzyme indoleamine 2, 3-dioxygenase.
Description
The application is a divisional application, and the Chinese application number of the parent case is as follows: 201980004340.2, International application number PCT/CN2019/071704, International application date 2019, month 01 and 15.
The present invention claims priority from chinese patent application CN201810044798.8, and the contents of the specification, drawings and claims of this priority document are incorporated in their entirety into the present specification and are included as part of the original description of the present specification. Applicants further claim that applicants have the right to amend the description and claims of this invention based on this priority document.
Technical Field
The invention relates to the field of medicines, in particular to a preparation method of an indoleamine-2, 3-dioxygenase (IDO) inhibitor.
Background
Tryptophan (TRP) is an α -amino acid used in protein biosynthesis. It contains an alpha-amino group, an alpha-carboxylic acid group and a side chain indole. It is essential for humans, who cannot synthesize it, but must obtain it from the diet. Tryptophan is also a precursor in the synthesis of the neurotransmitter 5-hydroxytryptamine (serotonin) and the hormone N-acetyl-5-methoxytryptamine (melatonin). The heme-dependent enzyme indoleamine 2, 3-dioxygenase (also called IDO, or IDO1) is a metabolic enzyme outside the liver responsible for the conversion of tryptophan to N-formyl-kynurenine, which is the first step in the tryptophan metabolism process and is also the rate-limiting step of the overall process. N-formyl-kynurenine is a precursor of the diverse bioactive molecules kynurenine (kynurenine, or Kyn) that has immunomodulatory functions (Schwarcz et al, Nat. Rev. Neurosci.2012; 13(7): 465).
Indoleamine 2, 3-dioxygenase (IDO) is widely expressed in solid tumors (Uyttenhove et al, nat. med. 2003; 10:1269), and is also expressed in both primary and metastatic cancer cells. IDO is induced in tumors by pro-inflammatory factors, including type I and type II interferons produced by infiltrating lymphocytes (Tnani and Bayard, biochimbiophysis acta.1999; 1451(l): 59; Mellor and Munn, nat. rev. immunol. 2004; 4(10): 762; Munn, Front biosci.2012; 4:734) and transforming growth factor-beta (TGF-beta) (Pallotta et al, nat. immunol.2011; 12(9): 870). In recent years, there has been increasing evidence that IDO plays an important role in immune cell regulation as an inducible enzyme. A decrease in tryptophan levels and an increase in kynurenine suppress immune effector cells and promote adaptive immune suppression by inducing and maintaining regulatory T cells; the concentration of tryptophan in the immune system is positively correlated with T cells. In the tumor immune microenvironment, activated or overexpressed IDO leads to tryptophan depletion, which in turn leads to T cell death, immune system inactivation, and ultimately to the development of tumor immune tolerance and immune escape. The existing research shows that the immune balance disorder caused by IDO is deeply involved in the generation and the progression of tumors. Therefore, IDO becomes an important target for immunotherapy of tumors and the like. IDO is associated with, in addition to tumors, viral infections, depression, organ transplant rejection or autoimmune diseases (Johnson and Munn, immunol. invest.2012; 41(6-7): 765). Therefore, agents targeting IDO are also of great value for the treatment of the above mentioned diseases. In conclusion, it is necessary to develop an IDO inhibitor having activity and selectivity to effectively treat diseases due to harmful substances in the kynurenine pathway by modulating the kynurenine pathway and maintaining tryptophan levels in the body, either as a single agent or a combination therapy.
Numerous published preclinical data also further confirm the role of IDO in antitumor immune responses. IDO inhibitors may be used to activate T cells, thereby increasing T cell activation when the T cells are suppressed by viruses such as pregnancy, malignancy, or HIV. Forced induction of IDO in cancer cells has proven to be a survival advantage (Uyttenhove et al, Nat Med.2003; 10: 1269). Another in vivo study showed that IDO inhibitors reduce lymphocyte dependence by reducing kynurenine levels in tumor growth (Liu et al, blood.2010; 115(17): 3520). Preclinical studies have also shown that IDO inhibitors have synergistic effects if combined with other tumor drugs, such as radiation therapy, chemotherapy, or vaccines, etc. (koblissh et al, mol. Cancer ther.2010; 9(2): 489; Hou et al, Cancer res.2007; 67(2): 792; Sharma et al, blood.2009; 113(24): 6102).
Research on IDO inhibitor antitumor drugs has currently made significant progress worldwide, such as INCB024360, NLG919 and BMS-986205 all entering the clinic. However, the INCB024360 has the problem of toxic and side effects, so that the dosage (50mg bid or 100mg bid) of the existing clinical research is about 30 percent of the optimal dosage (300mg bid or 600mg bid), and the clinical activity is greatly limited; meanwhile, the toxic group of INCB024360 is a pharmacophore, and the INCB024360 and derivatives thereof have the problem of high toxicity. The safety of NLG919 is good, but the bioactivity of NLG919 is poor. BMS-986205 has also entered the clinic at present, but clinical data are limited. There is also a need for better IDO inhibitors for tumor therapy.
Disclosure of Invention
In one aspect, the present invention provides a compound represented by formula (I), a salt, a solvate, a prodrug, a metabolite, a nitrogen oxide, a stereoisomer, or an isotopic derivative thereof:
wherein
Represents: - (O) b,
Or
Cy1Selected from 5-15 membered rings optionally substituted with a substituent selected from: halogen, hydroxy, C1-6Alkyl, amino, halo C1-6Alkyl, mercapto, C1-6Alkyl mercapto group, C1-6Alkylamino radical, di (C)1-6Alkyl) amino and cyano;
Cy2selected from optionally substituted by one, two or more R2Substituted C6-10Cycloalkyl having a ring system of6-10A heterocyclic radical, C6-10Aryl radicals or C6-10A membered heteroaryl group; preferably by one, two or more R2Substituted phenyl, pyridyl, cyclohexyl, piperidinyl, piperazinyl, pyrazinyl, pyrimidinyl, morpholinyl; a pyridazinyl group;
R1and R2Independently selected from hydrogen atom, halogen, hydroxyl, nitro, cyano, sulfonic acid group, C1-6Alkyl radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, halo C1-C6Alkyl, halo C1-C6Alkoxy, halo C3-C6Cycloalkyl radical, C1-6Alkylthio radical, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl, di (C)1-6Alkyl) amino C2-6Alkoxycarbonyl, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, carbamoyl, C1-6Alkylcarbamoyl, di (C)1-6Alkyl) carbamoyl, di (C)1-6Alkyl) amino C2-6Alkylcarbamoyl, sulfamoyl, C1-6Alkylsulfamoyl, di (C)1-6Alkyl) sulfamoyl, di (C)1-6Alkyl) amino C2-6Alkylsulfamoyl, C1-6Alkylsulfonyl radical, C1-6Alkylsulfinyl, di (C)1-6Alkyl) phosphono group,Hydroxy radical C1-6Alkyl, hydroxy carbonyl C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylsulfonyl radical C1-6Alkyl radical, C1-6Alkylsulfinyl C1-6Alkyl, di (C)1-6Alkyl) phosphono C1-6Alkyl, hydroxy C2-6Alkoxy radical, C1-6Alkoxy radical C2-6Alkoxy, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, di (C)1-6Alkyl) amino C1-6Alkyl, di (C)1-6Alkyl) aminoacetyl, amino C2-6Alkoxy radical, C1-6Alkylamino radical C2-6Alkoxy, di (C)1-6Alkyl) amino C2-6Alkoxy, hydroxy C2-6Alkylamino radical, C1-6Alkoxy radical C2-6Alkylamino radical, amino radical C2-6Alkylamino radical, C1-6Alkylamino radical C2-6Alkylamino radical, di (C)1-6Alkyl) amino C2-6An alkylamino group; or two adjacent R1Or R2Mutually cyclized to form a 3-8 membered ring, and the ring contains 0-3 heteroatoms;
m, n are integers selected from 0, 1,2, 3 and 4;
Ra、Rbeach independently selected from hydrogen and C1-C6Alkyl or C3-6A cycloalkyl group;
x is selected from CRaRb、NReOr O;
y is selected from CReOr N; wherein R iseRepresents hydrogen, C1-6Alkyl or C3-6Cycloalkyl radical, C1-6A haloalkyl group.
In another aspect, the present invention provides a compound represented by formula (II), a salt, a solvate, a prodrug, a metabolite, a nitrogen oxide, a stereoisomer, or an isotopic derivative thereof:
wherein, W1、W2、W3、W4Are respectively independentIs selected from CReC ═ O or N; p is an integer selected from 0, 1,2, 3 and 4; r1、R2、Cy1、Ra、Rb、ReX, Y, m, n are as defined for formula I; the dotted line represents a single bond or a double bond.
In one embodiment of the invention, Cy1Selected from the following groups:
wherein R is3Selected from hydrogen, C1-C6Alkyl radical, C3-C6A cycloalkyl group;
the above groups may be substituted by one or more groups selected from halogen, hydroxy, C1-6Alkyl, amino, halo C1-6Alkyl, mercapto, C1-6Alkyl mercapto group, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, cyano.
In one aspect, the present invention provides a compound represented by formula (III), a salt, a solvate, a prodrug, a metabolite, a nitrogen oxide, a stereoisomer, or an isotopic derivative thereof:
wherein R is1、R2、Ra、Rb、X、Y、W1、W2、W3、W4M, n, p are as defined for formula II.
In one aspect, the present invention provides a compound represented by formula (IV), a salt, a solvate, a prodrug, a metabolite, a nitrogen oxide, a stereoisomer, or an isotopic derivative thereof:
wherein Q1And Q2Are each independently selected from CRaRb、NReOr O;Q3selected from the group consisting of CRaOr N; wherein R is1、R2、Ra、Rb、Re、X、Y、W1、W2、W3、W4M, p are as defined for formula II;
in another embodiment of the present invention, the compound of formula II has the structure of formula (V):
wherein R is1、R2、Ra、Rb、X、Y、W1、W2、W3、W4M, p are as defined above for formula II.
In the context of the present disclosure, it is,
is shown to,
Or
In the context of the present disclosure, it is,
preferably, it is
Unless otherwise indicated, all compound structures of the present invention also include stereoisomers (including enantiomers, diastereomers, stereoisomers, conformations, and enantiomers) that may exist. For example, the R and S configurations of each chiral center, and the E and Z isomers of each olefinic double bond are included in the invention. For some freely rotatable bonds, the position of the substituent may also follow the free rotation, for example:
structural formula (I)
The method also represents the following steps:
also representative of tautomers thereof:
thus, a single stereochemical isomer, as well as enantiomeric mixtures, geometric isomer mixtures, conformational isomer mixtures, tautomers thereof, are all within the scope of the present application.
The compounds of the present invention may also be prepared in the form of pharmaceutically acceptable salts formed using, for example, inorganic or organic acids such as: hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, mandelic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, methanesulfonic, benzenesulfonic and toluenesulfonic acids. When referring to the compounds of the present invention, these pharmaceutically acceptable salts of the compounds of the present invention are also encompassed.
The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent (e.g., acetone, methanol, ethanol and acetonitrile), adding thereto an excess of an organic acid or an aqueous solution of an inorganic acid to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid therefrom, and then separating the precipitated salt.
Design and reaction examples
The compound of the present invention can be synthesized by known procedures with reference to the following descriptions. All solvents and reagents purchased were used directly without treatment. All synthesized compounds can be analytically validated by, but not limited to, the following methods: LCMS (liquid chromatography mass spectrometry) and NMR (nuclear magnetic resonance). Nuclear Magnetic Resonance (NMR) was measured by Bruker AVANCE-500 nuclear magnetic resonance, and the deuterated solvents used for the measurement were deuterated dimethyl sulfoxide (d6-DMSO) and deuterated chloroform (CDC)l3), Tetramethylsilane (TMS) as internal standard. The following abbreviations represent various types of split peaks: singlet(s), doublet (d), triplet (t), multiplet (m), broad (br). Mass Spectrometry (MS) determination Using Thermo Fisher-MSQ Plus LC Mass spectrometer, of xylonite for resolution of chiral Compounds
AD-H chiral column (0.46cm i.d. × 15cm L, HEP: ETOH (0.1% DEA) ═ 60:40 (V/V)).
The compounds of the invention can be prepared as follows.
General route one:
synthesis of intermediate F (mixture of cis and trans, racemic Compound)
The first step is as follows: ethyl 4-oxocyclohexaneacetate (2.0g,10.86mmol) was dissolved in 60mL of ultra-dry tetrahydrofuran, and to this solution was added dropwise sodium bis (trimethylsilyl) amide (2mol/L tetrahydrofuran solution) (6.5mL,13.03mmol) under a nitrogen atmosphere at-78 ℃. The reaction solution was stirred at this temperature for 1 hour. A solution of N-phenylbis (trifluoromethanesulfonyl) imide (4.65g,13.03mmol) in tetrahydrofuran (20mL) was then added. After the addition was complete, the reaction mixture was stirred at room temperature overnight until complete consumption of the starting material by TLC. The reaction solution was quenched with 5mL of an aqueous potassium hydrogen sulfate solution, filtered to remove solids, and the filtrate was concentrated. To the residue was added 50mL of methyl t-butyl ether, and the organic layer was washed with 1.0mol/L sodium hydroxide solution (3X20mL) and with 20mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate a (3.12g) as an orange oily liquid in 91% yield.1H NMR(500MHz,CDCl3)5.74–5.70(m,1H),4.15(q,J＝7.0Hz,2H),2.48–2.40(m,1H),2.38–2.32(m,2H),2.30(d,J＝7.0Hz,2H),2.18–2.10(m,1H),1.97–1.89(m,2H),1.57–1.48(m,1H),1.27(t,J＝7.0Hz,3H).
The second step is that: intermediate A (3.12g,9.86mmol) was dissolved in 15mL dioxane, followed by the addition of pinacol diboron (3.26g,12.82 g)mmol), potassium acetate (2.90g,29.59mmol), sodium bromide (406mg,3.95mmol) and Pd (dppf) Cl2(722mg,0.98 mmol). The reaction mixture was refluxed overnight under nitrogen atmosphere. The reaction solvent dioxane was then evaporated to dryness, ethyl acetate was added, filtration was carried out over celite, the filtrate was concentrated and then separated by flash column chromatography to give intermediate B (1.66g) as a colourless liquid in 57% yield.1H NMR(500MHz,CDCl3)6.54–6.48(m,1H),4.12(q,J＝6.5Hz,2H),2.30–2.02(m,7H),1.84–1.72(m,2H),1.27–1.23(m,15H).
The third step: intermediate B (1.66g,5.64mmol) was dissolved in 12mL/3mL dioxane/water and 4-chloro-6-fluoroquinoline (860mg,4.74mmol), potassium carbonate (1.96g,14.21mmol) and Pd (PPh) were added sequentially3)4(274mg,0.24 mmol). The reaction mixture was refluxed overnight under nitrogen atmosphere. The reaction was then concentrated, diluted with 50mL of water, extracted with ethyl acetate (3 × 50mL), and the organic phase was concentrated and then separated by flash column chromatography to give intermediate C (1.48g) as a pale yellow liquid in 100% yield. MS (ESI) M/z313.9(M + H)+.1H NMR(500MHz,CDCl3)8.81(d,J＝4.5Hz,1H),8.16(dd,J＝8.5,5.5Hz,1H),7.62(dd,J＝10.0,2.5Hz,1H),7.52–7.46(m,1H),7.22(d,J＝4.5Hz,1H),5.86–5.81(m,1H),4.19(q,J＝7.0Hz,2H),2.56–2.26(m,6H),2.08–1.98(m,2H),1.64–1.55(m,1H),1.30(t,J＝7.0Hz,3H).
The fourth step: intermediate C (1.48g,4.72mmol) was dissolved in 30mL ethanol and 10% palladium on carbon (300mg) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere overnight. The palladium on carbon was then filtered off with celite and the filtrate was concentrated. The residue was isolated by flash column chromatography to give intermediate D (1.31g) as a pale yellow liquid in 88% yield. MS (ESI) M/z316.0(M + H)+.1H NMR(500MHz,CDCl3)8.84–8.79(m,1H),8.13(dd,J＝9.0,5.5Hz,1H),7.66(dd,J＝10.5,2.5Hz,1H),7.51–7.44(m,1H),7.34(d,J＝4.5Hz,1H),4.20–4.14(m,2H),3.26–3.18(m,1H),2.53–2.43(m,2H),2.31(d,J＝7.0Hz,1H),2.07–1.97(m,2H),1.90–1.70(m,5H),1.68–1.58(m,1H),1.31–1.25(m,3H).
The fifth step: diisopropylamine (1.54g,15.22mmol) was dissolved in 18mL tetrahydrofuran. Under nitrogen atmosphere and-78 deg.C, adding into the solutionTo the mixture was added dropwise a 2.5M n-butyllithium (6.1mL,15.22mmol) in n-hexane. A solution of intermediate D (2.4g,7.61mmol) in tetrahydrofuran (6mL) was then added dropwise. The reaction mixture was stirred at-78 ℃ for 1.5 hours. Methyl iodide (2.16g,15.22mmol) was then added dropwise and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate (3 × 50mL), the organic phases combined, washed with 50mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was isolated by flash column chromatography to give intermediate E (1.96g) as a pale yellow liquid in 78% yield. MS (ESI) M/z330.5(M + H)+.1H NMR(500MHz,CDCl3)8.84–8.79(m,1H),8.16–8.10(dd,1H),7.66(d,J＝10.5Hz,1H),7.51–7.44(m,1H),7.35(d,J＝4.5Hz,1H),4.22–4.14(m,2H),3.32–3.23(m,1H),2.82–2.72(m,1H),2.12–1.98(m,2H),1.96–1.55(m,7H),1.32–1.24(m,3H),1.20(d,J＝6.5Hz,3H).
And a sixth step: intermediate E (400mg,1.21mmol) was dissolved in 4mL/4mL tetrahydrofuran/ethanol and 2mL water was added. Sodium hydroxide (243mg,6.07mmol) was then added to the solution. The reaction mixture was stirred at 50 ℃ overnight and concentrated. After dilution with 3mL of water, pH was adjusted to 3 with 4mol/L hydrochloric acid solution, and the mixture was filtered to obtain intermediate F (330mg) as a white solid with a yield of 90%. MS (ESI) M/z302.6(M + H)+.1H NMR(500MHz,d6-DMSO)12.22(s,1H),8.81(d,J＝4.5Hz,1H),8.14–8.06(m,1H),8.01–7.94(m,1H),7.66(t,J＝8.5Hz,1H),7.52(s,1H),3.32–3.23(m,1H),2.76–2.66(m,1H),1.97–1.62(m,7H),1.61–1.51(m,1H),1.49–1.31(m,1H),1.09(d,J＝6.5Hz,3H).
General route two: asymmetric synthetic route
The asymmetric synthesis method of the intermediate K' adopts a synthesis method reported in the literature (WO2016073774A2)
A general route III:
the first step is as follows: intermediate F (or K', 1.0eq) was dissolved in N, N-dimethylformamide and HATU (1.1eq) and diisopropylethylamine (3.0eq) were added. Further, a substituted 1, 2-diamine or a substituted o-aminoaniline (1.5eq) was added to the reaction solution. The reaction mixture was stirred at 30 ℃ overnight. Then, water and ethyl acetate were added to the reaction solution, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude intermediate which was used in the next step without purification.
The second step is that: the crude intermediate (1.0eq) obtained in the previous step was dissolved in acetic acid, and the mixture was reacted with stirring at 100 ℃ for 19 hours, followed by concentrating the reaction solution. The residue was purified by reverse phase high performance liquid preparative chromatography to give the final compound.
The general route is four:
the first step is as follows: triethyl phosphonoacetate (968mg,4.32mmol) was dissolved in 16mL of ultra dry tetrahydrofuran and sodium tert-butoxide (415mg,4.32mmol) was added at 0 ℃ in an ice bath. After 10 min, a solution of intermediate E' (1g,4.12mmol) in tetrahydrofuran (4mL) was added to the reaction. After 2 hours of reaction, quench with water. The aqueous solution was extracted three times with 20mL of ethyl acetate, the organic phases were combined, washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was isolated by flash column chromatography to give intermediate F "(1.18 g) as a white solid in 92% yield. MS (ESI) M/z314.0(M + H)+.1H NMR(500MHz,CDCl3)8.81(d,J＝4.5Hz,1H),8.17(dd,J＝9.0,5.5Hz,1H),7.72(dd,J＝10.0,2.5Hz,1H),7.53–7.47(m,1H),7.28(d,J＝4.5Hz,1H),5.75(s,1H),4.19(q,J＝7.0Hz,2H),3.52–3.42(m,1H),2.54–2.48(m,2H),2.26–2.11(m,4H),1.80–1.68(m,2H),1.30(t,J＝7.0Hz,3H).
The second step is that: NaH (383mg,9.57mmol) was added to 15mL of dimethyl sulfoxide, and trimethyl sulfoxide iodide (2.11g,9.57mmol) was added to the suspension. The mixture was stirred at room temperature for 1.5 hours. Then, a solution of intermediate F "(1.0 g,3.19mmol) in dimethyl sulfoxide (5mL) was added to the reaction mixture. The reaction was stirred at room temperature overnight. It was then quenched with water, extracted with ethyl acetate and isolated by flash column chromatography to give intermediate G "(820 mg) as a colorless oily liquid in 78% yield. MS (ESI) M/z328.1(M + H)+.1H NMR(500MHz,CDCl3)8.83(d,J＝4.5Hz,1H),8.24(dd,J＝9.0,5.5Hz,1H),7.71(dd,J＝10.0,2.5Hz,1H),7.55–7.49(m,1H),7.35(d,J＝4.5Hz,1H),4.19(q,J＝7.0Hz,2H),3.32–3.24(m,1H),2.17(td,J＝13.0,3.5Hz,1H),2.07–1.90(m,4H),1.87–1.78(m,1H),1.58(dd,J＝8.0,5.5Hz,1H),1.46–1.37(m,1H),1.30(t,J＝7.0Hz,3H),1.28–1.24(m,2H),1.16–1.11(m,1H),1.00(dd,J＝8.0,4.5Hz,1H).
The third step: intermediate G "(200 mg,0.61mmol) was dissolved in 10mL ethanol and 4mL of 2mol/L sodium hydroxide solution was added. The reaction solution was heated to 50 ℃ and reacted for 2 hours. After the reaction solution was cooled to room temperature, it was neutralized with a 4mol/L hydrochloric acid solution to pH 1. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was isolated by preparative thin layer chromatography to give intermediate H "(150 mg) as a white solid in 83% yield. MS (ESI) M/z300.0(M + H)+.1H NMR(500MHz,d6-DMSO)12.02(br,1H),8.83(d,J＝4.5Hz,1H),8.10(dd,J＝9.0,5.5Hz,1H),8.03(dd,J＝10.0,2.5Hz,1H),7.71–7.64(m,1H),7.38(d,J＝4.5Hz,1H),3.48–3.41(m,1H),2.21–2.13(m,1H),2.01–1.80(m,4H),1.75–1.65(m,1H),1.51(dd,J＝8.0,5.5Hz,1H),1.38–1.32(m,1H),1.11–1.05(m,1H),1.04–0.99(m,1H),0.95(dd,J＝7.5,4.0Hz,1H).
The fourth step: intermediate H "(1.0 eq) was dissolved in N, N-dimethylformamide and HATU (1.1eq) and diisopropylethylamine (3.0eq) were added. Further, a substituted 1, 2-diamine or a substituted o-aminoaniline (1.5eq) was added to the reaction solution. The reaction mixture was stirred at 30 ℃ overnight. Then, water and ethyl acetate were added to the reaction solution, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude intermediate obtained was dissolved in acetic acid, and the mixture was stirred at 100 ℃ for reaction for 19 hours, followed by concentrating the reaction solution. The residue was purified by reverse phase high performance liquid preparative chromatography to give the final compound.
General route five:
the first step is as follows: n-butyllithium (0.49mL,1.22mmol) was added dropwise to a solution of diisopropylamine (123mg,1.22mmol) in tetrahydrofuran (15mL) at-78 ℃. A solution of intermediate G "(200 mg,0.61mmol) in tetrahydrofuran (5mL) was added dropwise. The reaction was stirred at-78 ℃ for 1 hour. Then, a solution of iodomethane (173mg,1.22mmol) in tetrahydrofuran (2mL) was added dropwise to the reaction mixture, and the reaction was maintained at-78 ℃ for half an hour, then warmed to room temperature, and stirred overnight. Quench with saturated ammonium chloride solution and extract the aqueous phase with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was isolated by preparative thin layer chromatography to give compound intermediate H' "(121 mg) as a colorless oily liquid in 58% yield. MS (ESI) M/z342.4(M + H)+.
The second step is that: intermediate H' (100mg,0.29mmol) was dissolved in 10mL ethanol and 2mL of 2mol/L sodium hydroxide solution was added. The reaction solution was heated to 50 ℃ and reacted for 2 hours. After the reaction solution was cooled to room temperature, it was neutralized with a 4mol/L hydrochloric acid solution to pH 1. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was isolated by preparative thin layer chromatography to give intermediate I "' (76mg) as a white solid in 83% yield. MS (ESI) M/z314.3(M + H)+.
The third step: intermediate I "' (1.0eq) was dissolved in N, N-dimethylformamide and HATU (1.1eq) and diisopropylethylamine (3.0eq) were added. Further, a substituted 1, 2-diamine or a substituted o-aminoaniline (1.5eq) was added to the reaction solution. The reaction mixture was stirred at 30 ℃ overnight. Then, water and ethyl acetate were added to the reaction solution, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude intermediate obtained was dissolved in acetic acid, and the mixture was stirred at 100 ℃ for reaction for 19 hours, followed by concentrating the reaction solution. The residue was purified by reverse phase high performance liquid preparative chromatography to give the final compound.
Example 1: compound 1
Compound 1 was prepared from intermediate F (20mg) and 4-chloro-1, 2-phenylenediamine via general scheme one and general scheme three. Compound 1(10.05mg) was obtained as a white solid in 37% yield. MS (ESI) M/z408.3(M + H)+.1HNMR(500MHz,d6-DMSO)12.40(s,1H),8.79(d,J＝4.5Hz,1H),8.11–8.04(m,1H),7.97(d,J＝10.5Hz,1H),7.65(t,J＝8.5Hz,1H),7.60–7.45(m,2H),7.42(d,J＝4.0Hz,1H),7.15(d,J＝8.5Hz,1H),3.30–3.24(m,1H),2.95–2.88(m,1H),1.95(t,J＝10.5Hz,2H),1.90–1.79(m,2H),1.61–1.47(m,3H),1.45–1.32(m,5H).
Example 2: compound 17 and compound 18
Compound 17 (trans, racemic) and compound 18 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (40mg) and 4-fluoro-1, 2-phenylenediamine.
Compound 17(8.49mg) was obtained as the first eluting isomer in 16% yield as a white solid. MS (ESI) M/z392.5(M + H)+.1H NMR(500MHz,d6-DMSO)12.28(s,1H),8.79(s,1H),8.11–8.04(m,1H),7.97(d,J＝10.5Hz,1H),7.65(t,J＝8.5Hz,1H),7.45–7.39(m,2H),7.34(d,J＝10.0Hz,1H),7.02–6.92(m,1H),3.29–3.23(m,1H),2.93–2.87(m,1H),2.00–1.91(m,2H),1.89–1.79(m,2H),1.61–1.46(m,3H),1.45–1.33(m,5H).
Compound 18(9.24mg), the second eluting isomer, was obtained as a white solid in 18% yield. MS (ESI) M/z392.5(M + H)+.1H NMR(500MHz,d6-DMSO)12.31(s,1H),8.86(s,1H),8.13–8.06(m,1H),7.97(d,J＝11.0Hz,1H),7.66(t,J＝8.5Hz,1H),7.58(s,1H),7.44–7.39(m,1H),7.23(d,J＝9.0Hz,1H),7.01–6.92(m,1H),3.45–3.35(m,2H),2.15–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.53(m,1H),1.34(d,J＝6.5Hz,3H),1.21–1.14(m,1H).
Example 3: compound 21 and compound 22
Compound 21 (trans, racemic) and compound 22 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (40mg) and 4-methyl-1, 2-phenylenediamine.
Compound 21(11.40mg) was obtained as the first eluting isomer in 22% yield as a white solid. MS (ESI) M/z388.5(M + H)+.1H NMR(500MHz,d6-DMSO)11.98(s,1H),8.79(s,1H),8.11–8.04(m,1H),7.97(d,J＝10.5Hz,1H),7.65(t,J＝8.5Hz,1H),7.44–7.38(m,2H),7.20(s,1H),6.93(t,J＝9.5Hz,1H),3.30–3.23(m,1H),2.91–2.83(m,1H),2.39(s,3H),2.00–1.91(m,2H),1.89–1.78(m,2H),1.61–1.46(m,3H),1.44–1.33(m,5H).
Compound 22(13.51mg), the second eluting isomer, was obtained as a white solid in 26% yield. MS (ESI) M/z388.5(M + H)+.1H NMR(500MHz,d6-DMSO)12.02(s,1H),8.86(s,1H),8.13–8.06(m,1H),7.97(d,J＝11.0Hz,1H),7.66(t,J＝9.0Hz,1H),7.58(s,1H),7.39(d,J＝8.5Hz,1H),7.20(s,1H),6.93(t,J＝10.0Hz,1H),3.46–3.34(m,2H),2.38(s,3H),2.16–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.70(m,2H),1.67–1.51(m,2H),1.33(d,J＝6.5Hz,3H),1.21–1.14(m,1H).
Example 4: compound 13 and compound 14
Compound 13 (trans, racemic) and compound 14 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (50mg) and 4-chloro-1, 2-phenylenediamine.
Compound 13(7.93mg) was obtained as the first eluting isomer in 12% yield as a white solid. MS (ESI) M/z408.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.36(s,1H),8.80(s,1H),8.11–8.04(m,1H),7.97(d,J＝11.0Hz,1H),7.65(t,J＝8.5Hz,1H),7.60(s,1H),7.46–7.40(m,2H),7.15(t,J＝10.5Hz,1H),3.30–3.23(m,1H),2.95–2.88(m,1H),2.00–1.91(m,2H),1.89–1.79(m,2H),1.61–1.46(m,3H),1.45–1.32(m,5H).
Compound 14(10.25mg), the second eluting isomer, was obtained as a white solid in 15% yield. MS (ESI) M/z408.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.42(s,1H),8.86(d,J＝4.0Hz,1H),8.13–8.07(m,1H),7.98(d,J＝11.0Hz,1H),7.67(t,J＝8.5Hz,1H),7.61–7.56(m,2H),7.45(d,J＝8.5Hz,1H),7.17–7.11(m,1H),3.45–3.37(m,2H),2.16–2.09(m,1H),2.07–2.00(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.19–1.12(m,1H).
Example 5: compound 33 and compound 34
Compound 33 (trans, racemic) and compound 34 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (40mg) and 4-trifluoromethyl-1, 2-phenylenediamine.
Compound 33(5.95mg) was obtained as the first eluting isomer in 10% yield as a white solid. MS (ESI) M/z442.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.63(s,1H),8.79(s,1H),8.10–8.04(m,1H),7.97(d,J＝11.0Hz,1H),7.91(s,1H),7.67–7.61(m,2H),7.49–7.40(m,2H),3.30–3.23(m,1H),3.02–2.94(m,1H),2.00–1.91(m,2H),1.91–1.82(m,2H),1.61–1.47(m,3H),1.46–1.35(m,5H).
Compound 34(4.55mg), the second eluting isomer, was obtained as a white solid in 8% yield. MS (ESI) M/z442.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.66(s,1H),8.87(s,1H),8.12–8.06(m,1H),7.98(d,J＝10.5Hz,1H),7.90(s,1H),7.69–7.62(m,2H),7.59(s,1H),7.48–7.41(m,1H),3.52–3.38(m,2H),2.21–2.11(m,1H),2.09–2.01(m,1H),1.94–1.73(m,4H),1.69–1.61(m,1H),1.60–1.54(m,1H),1.37(d,J＝6.0Hz,3H),1.19–1.13(m,1H).
Example 6: compound 27 and compound 28
Compound 27 (trans, racemic) and compound 28 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (50mg) and 4-methoxy-1, 2-phenylenediamine.
Compound 27(3.67mg) was obtained as the first eluting isomer in 5% yield as a white solid. (ESI): M/z404.4(M + H)+.1H NMR(500MHz,d6-DMSO)11.99(s,1H),8.80(s,1H),8.10–8.07(m,1H),7.98(d,J＝10.0Hz,1H),7.69–7.62(m,1H),7.46–7.39(m,2H),6.92(s,1H),6.78–6.70(m,1H),3.77(s,3H),3.30–3.22(m,1H),2.89–2.82(m,1H),2.00–1.91(m,2H),1.90–1.76(m,2H),1.60–1.46(m,3H),1.44–1.31(m,5H).
Compound 28(6.69mg) was obtained as a second eluting isomer in 9% yield as a white solid. (ESI): M/z404.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.02(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.67(t,J＝8.5Hz,1H),7.58(s,1H),7.39(d,J＝8.5Hz,1H),7.08(s,1H),6.74(t,J＝10.0Hz,1H),3.76(s,3H),3.46–3.36(m,2H),2.15–2.07(m,1H),2.06–1.98(m,1H),1.92–1.83(m,2H),1.82–1.69(m,2H),1.67–1.59(m,1H),1.58–1.51(m,1H),1.33(d,J＝6.5Hz,3H),1.22–1.14(m,1H).
Example 7: compound 35 and compound 36
Compound 35 (trans, racemic) and compound 36 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (50mg) and 4-bromo-1, 2-phenylenediamine.
To give Compound 35(12.85mg), the first eluting isomerBody, white solid, yield 17%. (ESI): M/z452.3(M + H)+.1H NMR(500MHz,d6-DMSO)12.39(d,J＝22.9Hz,1H),8.80(s,1H),8.10–8.04(m,1H),7.98(d,J＝11.0Hz,1H),7.74(s,1H),7.65(t,J＝8.5Hz,1H),7.46–7.38(m,2H),7.26(t,J＝9.0Hz,1H),3.31–3.24(m,1H),2.95–2.87(m,1H),1.99–1.90(m,2H),1.89–1.79(m,2H),1.61–1.46(m,3H),1.46–1.30(m,5H).
Compound 36(15.29mg) was obtained as a second eluting isomer in 20% yield as a white solid. (ESI): M/z452.3(M + H)+.1H NMR(500MHz,d6-DMSO)12.42(s,1H),8.86(s,1H),8.12–8.07(m,1H),7.98(d,J＝11.0Hz,1H),7.73(s,1H),7.69–7.63(m,1H),7.60–7.56(m,1H),7.49(d,J＝9.0Hz,1H),7.28–7.22(m,1H),3.45–3.38(m,2H),2.15–2.08(m,1H),2.07–1.99(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.59(m,1H),1.58–1.52(m,1H),1.34(d,J＝6.0Hz,3H),1.18–1.11(m,1H).
Example 8: compound 37 and compound 38
Compound 37 (trans, racemic) and compound 38 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (40mg) and 6-chloro-2, 3-diaminopyridine.
Compound 37(4.03mg) was obtained as the first eluting isomer in 7% yield as a white solid. MS (ESI) M/z409.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.79(s,1H),8.80(s,1H),8.11–8.04(m,1H),8.02–7.87(m,2H),7.66(t,J＝8.0Hz,1H),7.44(s,1H),7.24(d,J＝8.0Hz,1H),3.30–3.23(m,1H),2.98–2.89(m,1H),2.00–1.91(m,2H),1.90–1.80(m,2H),1.61–1.47(m,3H),1.45–1.35(m,5H).
Compound 38(7.12mg), the second eluting isomer, was obtained as a white solid in 12% yield. MS (ESI) M/z409.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.81(s,1H),8.87(d,J＝4.5Hz,1H),8.10(dd,J＝9.5,6.0Hz,1H),8.03–7.90(m,2H),7.67(td,J＝9.0,3.0Hz,1H),7.59(d,J＝4.5Hz,1H),7.23(d,J＝8.5Hz,1H),3.47–3.39(m,2H),2.18–2.12(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.71(m,2H),1.69–1.61(m,1H),1.59–1.53(m,1H),1.35(d,J＝7.0Hz,3H),1.17–1.11(m,1H).
Example 9: compound 39 and compound 40
Compound 39 (trans, racemic) and compound 40 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (40mg) and 5-chloro-2, 3-diaminopyridine.
Compound 39(5.08mg) was obtained as the first eluting isomer in 9% yield as a white solid. MS (ESI) M/z409.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.80(s,1H),8.81(s,1H),8.12–8.05(m,1H),8.04–7.88(m,2H),7.65(t,J＝8.0Hz,1H),7.43(s,1H),7.26(d,J＝8.0Hz,1H),3.31–3.23(m,1H),2.99–2.88(m,1H),2.02–1.90(m,2H),1.93–1.81(m,2H),1.60–1.46(m,3H),1.46–1.34(m,5H).
Compound 40(8.37mg), the second eluting isomer, was obtained as a white solid in 15% yield. MS (ESI) M/z409.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.81(s,1H),8.81(s,1H),8.12–8.04(m,1H),8.03–7.87(m,2H),7.64(t,J＝8.0Hz,1H),7.45(s,1H),7.26(d,J＝8.0Hz,1H),3.46–3.37(m,2H),2.15–2.07(m,1H),2.05–1.98(m,1H),1.93–1.85(m,2H),1.84–1.68(m,2H),1.67–1.60(m,1H),1.57–1.50(m,1H),1.36(d,J＝6.5Hz,3H),1.25–1.14(m,1H).
Example 10: compound 41 and Compound 42
Compound 41 (trans, racemic) and compound 42 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (40mg) and 6-chloro-3, 4-diaminopyridine.
Compound 41(2.98mg) was obtained as the first eluting isomer in 5% yield as a white solid. MS (ESI) M/z409.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.89(s,1H),8.87(s,1H),8.63(s,1H),8.14–8.08(m,1H),7.98(d,J＝11.0Hz,1H),7.70–7.55(m,3H),3.48–3.40(m,1H),3.01–2.92(m,1H),2.05–1.94(m,2H),1.96–1.85(m,2H),1.65–1.49(m,3H),1.48–1.38(m,5H).
Compound 42(3.17mg), the second eluting isomer, was obtained as a white solid in 6% yield. MS (ESI) M/z409.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.90(s,1H),8.87(s,1H),8.63(s,1H),8.14–8.07(m,1H),7.99(d,J＝11.0Hz,1H),7.71–7.56(m,3H),3.49–3.40(m,2H),2.18–2.11(m,1H),2.07–2.01(m,1H),1.93–1.83(m,2H),1.82–1.72(m,2H),1.69–1.61(m,1H),1.60–1.53(m,1H),1.36(d,J＝6.0Hz,3H),1.17–1.10(m,1H).
Example 11: compound 29 and compound 30
Compound 29 (trans, racemic) and compound 30 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (40mg) and 4-chloro-5-fluoro-1, 2-phenylenediamine.
Compound 29(3.45mg) was obtained as the first eluting isomer in 5% yield as a white solid. MS (ESI) M/z426.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.49(s,1H),8.79(d,J＝4.5Hz,1H),8.10–8.04(m,1H),7.97(d,J＝11.0Hz,1H),7.68–7.57(m,2H),7.48(d,J＝9.5Hz,1H),7.44-7.41(m,1H),3.29-3.23(m,1H),2.94-2.88(m,1H),1.99-1.90(m,2H),1.88-1.79(m,2H),1.61–1.46(m,3H),1.44-1.34(m,5H).
Compound 30(4.15mg), the second eluting isomer, was obtained as a white solid in 6% yield. MS (ESI) M/z426.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.54(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.18–1.11(m,1H).
Example 12: compound 45 and compound 46
Compound 45 (trans, racemic) and compound 46 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (40mg) and 2-amino-4-chlorophenol.
Compound 45(6.36mg) was obtained as the first eluting isomer in 12% yield as a white solid. MS (ESI) M/z409.4(M + H)+.1H NMR(500MHz,d6-DMSO)8.87(d,J＝4.5Hz,1H),8.11(dd,J＝9.0,6.0Hz,1H),8.00(dd,J＝11.0,3.0Hz,1H),7.93(d,J＝2.0Hz,1H),7.74(d,J＝8.5Hz,1H),7.69(td,J＝8.5,3.0Hz,1H),7.65(d,J＝4.5Hz,1H),7.42(dd,J＝8.5,2.0Hz,1H),3.65–3.56(m,1H),3.48–3.44(m,1H),2.17–2.11(m,1H),2.05–1.98(m,1H),1.92–1.71(m,5H),1.67–1.61(m,1H),1.39(d,J＝7.0Hz,3H),1.30–1.25(m,1H).
Compound 46(9.27mg), the second eluting isomer, was obtained as a white solid in 17% yield. MS (ESI) M/z409.4(M + H)+.1H NMR(500MHz,d6-DMSO)8.86(d,J＝4.5Hz,1H),8.10(dd,J＝9.0,6.0Hz,1H),8.01(dd,J＝11.0,3.0Hz,1H),7.92(d,J＝2.0Hz,1H),7.72(d,J＝8.5Hz,1H),7.68(td,J＝8.5,3.0Hz,1H),7.63(d,J＝4.5Hz,1H),7.41(dd,J＝8.5,2.0Hz,1H),3.64–3.50(m,2H),2.17–2.11(m,1H),2.05–1.98(m,1H),1.92–1.71(m,5H),1.67–1.61(m,1H),1.39(d,J＝7.0Hz,3H),1.30–1.25(m,1H).
Example 13: compound 43 and compound 44
Compound 43 (trans, racemic) and compound 44 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (40mg) and 2-amino-5-chlorophenol.
Compound 43(8.42mg) was obtained as the first eluting isomer in 16% yield as a white solid. MS (ESI) M/z409.4(M + H)+.1H NMR(500MHz,d6-DMSO)8.86(d,J＝4.5Hz,1H),8.10(dd,J＝9.0,6.0Hz,1H),8.01(dd,J＝11.0,3.0Hz,1H),7.92(d,J＝2.0Hz,1H),7.72(d,J＝8.5Hz,1H),7.68(td,J＝8.5,3.0Hz,1H),7.63(d,J＝4.5Hz,1H),7.41(dd,J＝8.5,2.0Hz,1H),3.64–3.56(m,1H),3.48–3.43(m,1H),2.17–2.11(m,1H),2.05–1.98(m,1H),1.92–1.71(m,5H),1.67–1.61(m,1H),1.39(d,J＝7.0Hz,3H),1.30–1.25(m,1H).
Compound 44(10.05mg), the second eluting isomer, was obtained as a white solid in 19% yield. MS (ESI) M/z409.4(M + H)+.1H NMR(500MHz,d6-DMSO)8.86(d,J＝4.5Hz,1H),8.10(dd,J＝9.0,6.0Hz,1H),8.01(dd,J＝11.0,3.0Hz,1H),7.92(d,J＝2.0Hz,1H),7.72(d,J＝8.5Hz,1H),7.68(td,J＝8.5,3.0Hz,1H),7.63(d,J＝4.5Hz,1H),7.41(dd,J＝8.5,2.0Hz,1H),3.64–3.50(m,2H),2.17–2.11(m,1H),2.05–1.98(m,1H),1.92–1.71(m,5H),1.67–1.61(m,1H),1.39(d,J＝7.0Hz,3H),1.30–1.25(m,1H).
Example 14: compound 48
Compound 48 was prepared via general scheme four starting from intermediate H "(40 mg) and 4-methyl-1, 2-phenylenediamine. Compound 48(28.67mg) was obtained as a white solid in 56% yield. (ESI): M/z386.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.32(s,1H),8.82(s,1H),8.11–8.04(m,1H),8.00(d,J＝11.0Hz,1H),7.66(t,J＝8.5Hz,1H),7.39(s,1H),7.37–7.29(m,1H),7.29–7.19(m,1H),6.91(d,J＝8.0Hz,1H),3.42–3.37(m,1H),2.37(s,3H),2.28–2.20(m,1H),2.08–2.02(m,1H),1.95–1.86(m,3H),1.59–1.46(m,2H),1.46–1.41(m,1H),1.23(d,J＝13.5Hz,1H),1.15–1.03(m,2H).
Example 15: compound 49
Compound 49 was prepared via general scheme five starting from intermediate I' "(40 mg) and 4-chloro-1, 2-phenylenediamine. Compound 49(15.23mg) was obtained as a white solid in 28% yield. (ESI): M/z420.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.32(s,1H),8.82(s,1H),8.11–8.04(m,1H),8.00(d,J＝11.0Hz,1H),7.66(t,J＝8.5Hz,1H),7.39(s,1H),7.37–7.29(m,1H),7.29–7.19(m,1H),6.91(d,J＝8.0Hz,1H),2.45(s,3H),3.42–3.37(m,1H),2.28–2.20(m,1H),2.08–2.02(m,1H),1.95–1.86(m,3H),1.59–1.46(m,2H),1.46–1.41(m,1H),1.15–1.03(m,2H).
Example 16: compound 19 and compound 20
Compound 19 and compound 20 were obtained from compound 18 of example 2 by chiral column resolution. Wherein, the compound 19 corresponds to the former in chiral resolution, and the compound 20 corresponds to the latter in chiral resolution.
Compound 19: MS (ESI) M/z392.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.33(s,1H),8.86(s,1H),8.13–8.07(m,1H),7.98(d,J＝10.5Hz,1H),7.67(t,J＝8.5Hz,1H),7.58(s,1H),7.44–7.39(m,1H),7.24(d,J＝8.5Hz,1H),7.01–6.92(m,1H),3.45–3.35(m,2H),2.15–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.53(m,1H),1.33(d,J＝6.0Hz,3H),1.21–1.14(m,1H).
Compound 20: MS (ESI) M/z392.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.34(s,1H),8.87(s,1H),8.13–8.07(m,1H),7.98(d,J＝10.5Hz,1H),7.67(t,J＝8.5Hz,1H),7.58(s,1H),7.44–7.39(m,1H),7.24(d,J＝8.5Hz,1H),7.01–6.92(m,1H),3.45–3.35(m,2H),2.15–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.53(m,1H),1.34(d,J＝6.5Hz,3H),1.21–1.14(m,1H).
Example 17: compound 23 and compound 24
Compound 23 and compound 24 were obtained from compound 22 in example 3 by chiral column resolution. Wherein, the compound 23 corresponds to the former in chiral resolution, and the compound 24 corresponds to the latter in chiral resolution.
Compound 23: MS (ESI) M/z388.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.03(s,1H),8.86(s,1H),8.13–8.06(m,1H),7.97(d,J＝10.5Hz,1H),7.66(t,J＝9.0Hz,1H),7.58(s,1H),7.41–7.18(m,2H),6.93(s,1H),3.46–3.34(m,2H),2.38(s,3H),2.16–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.70(m,2H),1.66–1.58(m,1H),1.57–1.50(m,1H),1.33(d,J＝6.5Hz,3H),1.21–1.14(m,1H).
Compound 24: MS (ESI) M/z388.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.07(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.97(d,J＝10.5Hz,1H),7.66(t,J＝9.0Hz,1H),7.58(s,1H),7.41–7.18(m,2H),6.93(s,1H),3.46–3.34(m,2H),2.38(s,3H),2.16–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.70(m,2H),1.66–1.58(m,1H),1.57–1.50(m,1H),1.33(d,J＝6.5Hz,3H),1.21–1.14(m,1H).
Example 18: compound 15 and compound 16
Compound 15 and compound 16 were obtained from compound 14 in example 4 by chiral column resolution. Wherein compound 15 corresponds to the former in chiral resolution and compound 16 corresponds to the latter in chiral resolution.
Compound 15: MS (ESI) M/z408.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.41(s,1H),8.87(s,1H),8.12–8.06(m,1H),7.98(d,J＝10.5Hz,1H),7.67(t,J＝8.5Hz,1H),7.61–7.56(m,2H),7.46(d,J＝8.5Hz,1H),7.17–7.11(m,1H),3.45–3.37(m,2H),2.16–2.09(m,1H),2.07–2.00(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.35(d,J＝6.5Hz,3H),1.19–1.12(m,1H).
Compound 16: MS (ESI) M/z408.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.46(s,1H),8.87(s,1H),8.12–8.06(m,1H),7.98(d,J＝10.5Hz,1H),7.67(t,J＝8.5Hz,1H),7.62–7.40(m,3H),7.14(d,J＝8.5Hz,1H),3.45–3.37(m,2H),2.16–2.09(m,1H),2.07–2.00(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.35(d,J＝6.5Hz,3H),1.19–1.12(m,1H).
Example 19: compound 31 and compound 32
Compound 31 and compound 32 were obtained from compound 30 of example 11 by chiral column resolution. Wherein, the compound 31 corresponds to the former in chiral resolution, and the compound 32 corresponds to the latter in chiral resolution.
Compound 31: MS (ESI) M/z426.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.55(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.18–1.11(m,1H).
Compound 32: MS (ESI) M/z426.4(M + H)+.1H NMR(500MHz,d6-DMSO)12.54(s,1H),8.86(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.18–1.11(m,1H).
Example 20: compound 51 and Compound 52
Compound 51 (trans, racemic) and compound 52 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (40mg) and 4, 5-difluoro-1, 2-phenylenediamine.
Compound 51(3.45mg) was obtained as the first eluting isomer in 5% yield as a white solid. MS (ESI) M/z410.2(M + H)+.1H NMR(500MHz,d6-DMSO)12.49(s,1H),8.79(d,J＝4.5Hz,1H),8.10–8.04(m,1H),7.97(d,J＝11.0Hz,1H),7.68–7.57(m,2H),7.48(d,J＝9.5Hz,1H),7.44-7.41(m,1H),3.29-3.23(m,1H),2.94-2.88(m,1H),1.99-1.90(m,2H),1.88-1.79(m,2H),1.61–1.46(m,3H),1.44-1.34(m,5H).
Compound 52(4.15mg), the second eluting isomer, was obtained as a white solid in 6% yield. MS (ESI) M/z410.2(M + H)+.1H NMR(500MHz,d6-DMSO)12.54(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.18–1.11(m,1H).
Example 21: compound 53 and compound 54
Compound 53 and compound 54 were obtained by chiral column resolution of compound 52 in example 21. Wherein, the compound 53 corresponds to the former in chiral resolution, and the compound 54 corresponds to the latter in chiral resolution.
Compound 53: MS (ESI) M/z410.2(M + H)+.1H NMR(500MHz,d6-DMSO)12.54(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.18–1.11(m,1H).
Compound 54: MS (ESI) M/z410.2(M + H)+.1H NMR(500MHz,d6-DMSO)12.54(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.18–1.11(m,1H).
Claims (2)
1. A process for the preparation of a compound of formula a, characterized by the steps of:
the first step is as follows: dissolving triethyl phosphonoacetate in ultra-dry tetrahydrofuran, and adding sodium tert-butoxide at 0 ℃ in an ice bath; adding the tetrahydrofuran solution of the intermediate E' into the reaction solution; after 2 hours of reaction, quench with water; extracting the aqueous solution with 20mL ethyl acetate for three times, combining organic phases, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, concentrating, and separating the residue with a rapid column chromatography to obtain an intermediate F ";
the second step is that: NaH was added to 15mL of dimethyl sulfoxide, trimethyl sulfoxide iodide was added to the suspension, the mixture was stirred at room temperature for 1.5 hours, and then a dimethyl sulfoxide solution of intermediate F' was added to the reaction solution. The reaction is stirred overnight at room temperature, then quenched with water, extracted with ethyl acetate and separated by a fast column chromatography to obtain an intermediate G ";
the third step: dissolving the intermediate G 'in 10mL of ethanol, adding 4mL of 2mol/L sodium hydroxide solution, heating the reaction solution to 50 ℃, reacting for 2 hours, cooling the reaction solution to room temperature, neutralizing the reaction solution with 4mol/L hydrochloric acid solution until the pH value is 1, extracting the water phase with ethyl acetate, combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating, and separating the residue by preparative thin-layer chromatography to obtain an intermediate H';
the fourth step: dissolving the intermediate H' in N, N-dimethylformamide, adding HATU and diisopropylethylamine, adding the substituted 1, 2-diamine to the reaction solution, stirring the reaction mixture at 30 ℃ overnight, adding water and ethyl acetate to the reaction solution, washing the organic phase with saturated saline, drying over anhydrous sodium sulfate, filtering, and concentrating. The crude intermediate obtained was dissolved in acetic acid, the mixture was stirred at 100 ℃ for reaction for 19 hours, then the reaction solution was concentrated, and the residue was purified by reverse phase high performance liquid chromatography to give the final compound.
2. The method of claim 1 wherein the substituted o-amino aniline is selected from the group consisting of 4-methyl-1, 2-phenylenediamine.
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