CN118221682A - Amide compound, pharmaceutical composition containing same, preparation method and application thereof - Google Patents
Amide compound, pharmaceutical composition containing same, preparation method and application thereof Download PDFInfo
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- CN118221682A CN118221682A CN202410312284.1A CN202410312284A CN118221682A CN 118221682 A CN118221682 A CN 118221682A CN 202410312284 A CN202410312284 A CN 202410312284A CN 118221682 A CN118221682 A CN 118221682A
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- Prior art keywords
- alkyl
- compound
- cycloalkyl
- independently selected
- int
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- -1 Amide compound Chemical class 0.000 title claims abstract description 194
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 230000000694 effects Effects 0.000 claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims description 430
- 125000000217 alkyl group Chemical group 0.000 claims description 142
- 125000000623 heterocyclic group Chemical group 0.000 claims description 140
- 125000003545 alkoxy group Chemical group 0.000 claims description 81
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 77
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 72
- 229910052799 carbon Inorganic materials 0.000 claims description 69
- 229910052736 halogen Inorganic materials 0.000 claims description 63
- 125000003118 aryl group Chemical group 0.000 claims description 61
- 150000002367 halogens Chemical class 0.000 claims description 60
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 58
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 58
- 125000001072 heteroaryl group Chemical group 0.000 claims description 54
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 53
- 229910052739 hydrogen Inorganic materials 0.000 claims description 47
- 150000003839 salts Chemical class 0.000 claims description 44
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 43
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 38
- 125000005843 halogen group Chemical group 0.000 claims description 33
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 32
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 32
- 125000004076 pyridyl group Chemical group 0.000 claims description 32
- 101710084427 Protein arginine N-methyltransferase 5 Proteins 0.000 claims description 30
- 102100034607 Protein arginine N-methyltransferase 5 Human genes 0.000 claims description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 28
- 125000004429 atom Chemical group 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 25
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 25
- 239000001301 oxygen Substances 0.000 claims description 25
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 21
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 20
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 20
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 19
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 19
- 201000010099 disease Diseases 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 10
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 9
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 208000005017 glioblastoma Diseases 0.000 claims description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 230000005764 inhibitory process Effects 0.000 abstract description 27
- 210000004881 tumor cell Anatomy 0.000 abstract description 5
- 238000006243 chemical reaction Methods 0.000 description 178
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 132
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 121
- 238000003786 synthesis reaction Methods 0.000 description 112
- 230000015572 biosynthetic process Effects 0.000 description 107
- 239000012043 crude product Substances 0.000 description 81
- 239000000203 mixture Substances 0.000 description 81
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 77
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 76
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 64
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 63
- 239000012071 phase Substances 0.000 description 61
- 230000002829 reductive effect Effects 0.000 description 57
- VKBIRDVCOCJGBV-UHFFFAOYSA-N imidazo[1,5-a]quinoxaline-8-carboxamide Chemical compound C1=NC=C2N1C1=CC(=CC=C1N=C2)C(=O)N VKBIRDVCOCJGBV-UHFFFAOYSA-N 0.000 description 48
- 239000000243 solution Substances 0.000 description 48
- 238000003756 stirring Methods 0.000 description 45
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 42
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 34
- 229910052757 nitrogen Inorganic materials 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 28
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 25
- 238000004440 column chromatography Methods 0.000 description 25
- 238000000605 extraction Methods 0.000 description 25
- 238000010898 silica gel chromatography Methods 0.000 description 25
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 25
- 238000000034 method Methods 0.000 description 24
- 125000001424 substituent group Chemical group 0.000 description 23
- 238000012360 testing method Methods 0.000 description 23
- 239000007821 HATU Substances 0.000 description 22
- 239000000706 filtrate Substances 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 239000012267 brine Substances 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 21
- 229910052717 sulfur Inorganic materials 0.000 description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 19
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 18
- 239000005457 ice water Substances 0.000 description 18
- 239000011593 sulfur Substances 0.000 description 18
- 238000001035 drying Methods 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- 238000004007 reversed phase HPLC Methods 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- 238000006467 substitution reaction Methods 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 239000012065 filter cake Substances 0.000 description 13
- 125000005842 heteroatom Chemical group 0.000 description 13
- 102100034187 S-methyl-5'-thioadenosine phosphorylase Human genes 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 101710136206 S-methyl-5'-thioadenosine phosphorylase Proteins 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 11
- 229910002091 carbon monoxide Inorganic materials 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 238000010790 dilution Methods 0.000 description 11
- 239000012895 dilution Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 208000035475 disorder Diseases 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical group [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 230000002378 acidificating effect Effects 0.000 description 8
- 125000004122 cyclic group Chemical group 0.000 description 8
- JCWIWBWXCVGEAN-UHFFFAOYSA-L cyclopentyl(diphenyl)phosphane;dichloropalladium;iron Chemical compound [Fe].Cl[Pd]Cl.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1 JCWIWBWXCVGEAN-UHFFFAOYSA-L 0.000 description 8
- 229910052731 fluorine Inorganic materials 0.000 description 8
- 210000001853 liver microsome Anatomy 0.000 description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 125000006413 ring segment Chemical group 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- BDYWBOBBXXDXHU-UHFFFAOYSA-N 3,4-dihydro-1h-isochromen-4-amine Chemical compound C1=CC=C2C(N)COCC2=C1 BDYWBOBBXXDXHU-UHFFFAOYSA-N 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 239000000651 prodrug Substances 0.000 description 7
- 229940002612 prodrug Drugs 0.000 description 7
- WUUGFSXJNOTRMR-IOSLPCCCSA-N 5'-S-methyl-5'-thioadenosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CSC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 WUUGFSXJNOTRMR-IOSLPCCCSA-N 0.000 description 6
- 150000001204 N-oxides Chemical class 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 238000002875 fluorescence polarization Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 230000035699 permeability Effects 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
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- 229940126254 MRTX1719 Drugs 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 5
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- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 description 4
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 4
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
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- 125000004043 oxo group Chemical group O=* 0.000 description 4
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an amide compound, a pharmaceutical composition containing the same, a preparation method and application thereof. In particular, the invention relates to an amide compound of formula I, which has good inhibition effect on MTAP-deleted tumor cells and good pharmacokinetic properties.
Description
Technical Field
The present invention relates to amide compounds, pharmaceutical compositions comprising the same, methods of preparing the same, and their use for preventing or treating diseases or conditions associated with PRMT5 activity.
Background
Arginine N-terminal methyltransferase 5 (PRMT 5) belongs to the PRMT family, is an important component of posttranslational histone modification (arginine methylation) in eukaryotic cells, and belongs to an epigenetic target. PRMT5 is widely found in the nucleus and cytoplasm of human cells, including tissues such as heart, muscle and testis. PRMT5 catalyzes the transfer of methyl groups on SAM to arginine guanidino in histones or nonhistones, producing monomethylated arginine (MMA) and symmetrical dimethylarginine (sDMA) products, affecting multiple target genes and multiple signaling pathways. PRMT5 can also bind to methyl small protein 50 (MEP 50) to form a heterooctamer PRMT50/MEP50 complex, enhancing PRMT5 methyltransferase activity (Stephen Antonysamy et al.,Crystal structure of the human PRMT5:MEP50 complex,PNAS,2012,vol.109,no.44,17960–17965.).PRMT5 involved in regulating gene expression (activation/inhibition), RNA metabolism, cell cycle and protein function.
PRMT5 can methylate a variety of substrates to alter their biological activity or affect transcriptional regulation of associated pathway genes. In breast cancer, PRMT5 is involved in FOXP1 transcription, upregulates FOXP1 expression, and promotes breast cancer stem cell self-renewal and tumorigenicity. In pancreatic cancer, PRMT5 can bind to the promoter region of E3 ubiquitin ligase FBW7, inhibit FBW7 expression, enhance MYC stability, and promote tumor malignancy progression. In lung cancer cells, PRMT5 inhibits miR-99 family transcription, increases FGFR3 expression, activates Erk1/2 and Ak pathways, and results in cell growth and metastasis.
MTAP is a coding gene of the methylthioadenosine phosphorylase and is located on chromosome 9p21 and is close to the position of the cancer suppressor gene CDKN2A (homozygously deleted frequently), so that MTAP is always deleted with MTN 2A in about 15% of solid tumors in which a co-deletion phenomenon (Marjon K,Kalev P,Marks K.,Cancer Dependencies:PRMT5 and MAT2A in MTAP/p16-Deleted Cancers,Annual Review of Cancer Biology,2021,5(1):371-390.), occurs in tumors.
PRMT5 has 2 cofactors (cofactor), an active cofactor (SAM) and an inhibitory cofactor (MTA; 5' -methylthioadenosine), respectively. In normal cells, MTAP is responsible for converting MTA to Met (methionine) and PRMT5 is responsible for converting SAM to SAH (S-adenosyl-L-homocysteine). MTA is an endogenous competitive inhibitor of PRMT5-SAM, and in tumor cells, the deletion of MTAP causes MTA to accumulate and partially inhibit PRMT5 activity, so that the tumor cells are more dependent on PRMT5. In the above cases, inhibition of PRMT5 may further block the methylation function of PRMT5, resulting in tumor cell death.
Taken together, inhibition of PRMT5 showed synthetic lethality in the case of MTAP deletion. At present, no PRMT5 target inhibitor exists on the market. Thus, there is a need to develop new, highly potent, low toxic PRMT5 inhibitors to meet clinical needs.
Disclosure of Invention
The invention provides an amide compound which has good inhibition effect on MTAP-deleted tumor cells and good pharmacokinetic properties.
One aspect of the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof:
Wherein:
Ring a is selected from a C 6-10 aromatic ring and a 5-10 membered heteroaromatic ring;
R is selected from:
Each R 1 is independently selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl;
Each X 1、X2、X3 is independently selected from CR 9 and N;
R 2 is L-R 2';
l is selected from a direct bond and- (CR 5R6)p -;
R 2' is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 2-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 3-8 cycloalkoxy, C 6-10 aryl, and 5-10 membered heteroaryl, said alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halo, -OH, -CN, -NR 7R8、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkoxy, 3-6 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl;
R 3 is selected from H and C 1-4 alkyl;
R 4 is independently at each occurrence selected from H, -OH, halogen, -CN, -NR 7R8、-NHCOCH3、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-6 heteroalkyl, C 1-4 haloalkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, said heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halogen, -CN, -NR 5R6、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkoxy, 3-6 membered heterocyclyl; or R 3、R4 forms, with the atom to which it is attached, a 3-8 membered heterocyclyl, a 5-8 membered cycloalkyl, a C 6-10 aromatic ring, and a 5-10 membered heteroaromatic ring;
R 5 and R 6 are each independently selected from H, C 1-4 alkyl and C 3-8 cycloalkyl;
R 7 and R 8 are each independently selected from H and C 1-4 alkyl;
Each R 9 is independently selected from H, halogen, C 1-4 alkyl, and C 1-4 haloalkyl;
m is 0, 1 or 2;
n is 0,1, 2 or 3;
p is 1 or 2.
Another aspect of the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, and one or more pharmaceutically acceptable carriers.
Another aspect of the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with PRMT5 activity.
Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, or a pharmaceutical composition of the invention, for use in the prevention or treatment of a disease or condition associated with PRMT5 activity.
Another aspect of the invention provides a method of preventing or treating a disease or condition associated with PRMT5 activity, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, or a pharmaceutical composition of the invention.
In another aspect of the invention, there is provided a process for preparing the compounds of formula I of the invention.
Definition of the definition
Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive (inclusive) or open-ended and do not exclude other unrecited elements or method steps, although other unrecited elements or method steps do not necessarily exist (i.e., the terms also encompass the terms "consisting essentially of … …" and "consisting of … …").
As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example 1 to 6 carbon atoms. For example, as used herein, the terms "C 1-6 alkyl" and "C 1-4 alkyl" refer to a linear or branched group having 1-6 carbon atoms and 1-4 carbon atoms, respectively (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogen (this group is referred to herein as "haloalkyl") (e.g., CH2F、CHF2、CF3、CCl3、C2F5、C2Cl5、CH2CF3、CH2Cl or-CH 2CH2CF3, etc.). The term "C 1-4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).
As used herein, the term "heteroalkyl" refers to a backbone chain atom having one or more atoms independently selected from the group consisting of atoms other than carbon in the backbone carbon atom of the alkyl group, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A range of values (e.g., C 1-6 heteroalkyl) may be given to refer to the number of carbons in the chain, including 1-6 carbon atoms in this example. For example, the-CH 2OCH2CH3 group is referred to as C 3 heteroalkyl and the-CH 2OCH2CH2NHCH3 group is referred to as C 4 heteroalkyl. The attachment to the remainder of the molecule may be through a heteroatom or carbon atom in the heteroalkyl chain.
As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) same or different halogen atoms, and the terms "C 1-8 haloalkyl", "C 1-6 haloalkyl" and "C 1-4 haloalkyl" refer to haloalkyl groups having 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1-4 carbon atoms, respectively, such as -CF3、-C2F5、-CHF2、-CH2F、-CH2CF3、-CH2Cl or-CH 2CH2CF3, and the like.
As used herein, the term "hydroxyalkyl" refers to a group formed by substitution of a hydrogen atom in an alkyl group with one or more hydroxyl groups, such as C 1-4 hydroxyalkyl or C 1-3 hydroxyalkyl, examples of which include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH (OH) CH 3, and the like.
As used herein, the term "alkoxy" means an-O-alkyl group, wherein alkyl groups as described above, alkoxy groups herein may contain 1 to 12 carbon atoms, preferably C 1-8 alkoxy, C 1-6 alkoxy, C 1-4 alkoxy or C 1-3 alkoxy. Representative examples of C 1-6 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like, optionally substituted with one or more (such as 1 to 3) identical or different substituents. The term "haloalkoxy" as used herein means that the hydrogen atoms of the alkoxy groups are replaced with one or more (such as 1 to 3) identical or different halogen atoms.
As used herein, the term "fused ring" or "fused ring" refers to a ring system formed by two or more cyclic structures sharing two adjacent atoms with each other.
As used herein, the term "spiro" refers to a ring system formed by two or more cyclic structures sharing one ring atom with each other.
As used herein, the term "bridged ring" refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.
As used herein, the term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon cyclic group including, but not limited to, monocyclic alkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and the like) and bicyclic alkyl groups including spiro, fused (fused) or bridged ring systems (i.e., spiro alkyl, fused (fused) alkyl, and bridged cycloalkyl groups such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, and the like). In the present invention, cycloalkyl groups are optionally substituted with one or more (such as 1 to 3) identical or different substituents. The carbon atom on the cycloalkyl group is optionally substituted with an oxo (oxo) group (i.e., forming c=o). The term "C 3-8 cycloalkyl" refers to cycloalkyl having 3 to 8 ring-forming carbon atoms, such as C 3-6 cycloalkyl, which may be monocycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, and also bicycloalkyl, such as C 5-8 spirocycloalkyl, C 5-8 bridged cycloalkyl, C 5-8 fused-ring alkyl, C 5-6 spirocycloalkyl, C 5-6 bridged cycloalkyl or C 5-6 fused-ring alkyl.
As used herein, the term "cycloalkoxy" means-O-cycloalkyl, wherein cycloalkyl is as defined above. Representative examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like.
As used herein, the term "heterocyclyl" or "heterocycle" refers to an aliphatic mono-or polycyclic (e.g., a parallel, spiro, or bridged) group having 2 or more (e.g., 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms, and one or more (e.g., 1,2,3, or 4) heteroatoms, including but not limited to oxygen, nitrogen, and sulfur atoms, the carbon atoms and heteroatoms on the heterocyclyl being optionally substituted with oxo groups (e.g., to form c= O, S (=o) or S (=o) 2), or optionally with one or more substituents (such as 1 to 3) independently selected from halogen and C 1-3 alkyl. For example, a C 3-8 heterocyclyl refers to a heterocyclyl having 3 to 8 carbon atoms, such as a C 3-6 heterocyclyl.
The term "3-11 membered heterocyclic group" means a heterocyclic group containing 3-11 ring atoms, including but not limited to 4-10 membered heterocyclic group, 4-9 membered heterocyclic group, 4-8 membered heterocyclic group, 4-7 membered heterocyclic group, 5-6 membered heterocyclic group, 3-10 membered heterocyclic group, 3-8 membered heterocyclic group, 3-7 membered heterocyclic group, 4-7 membered nitrogen-containing heterocyclic group, 4-7 membered oxygen-containing heterocyclic group, 4-7 membered sulfur-containing heterocyclic group, 5-6 membered nitrogen-containing heterocyclic group, 5-6 membered oxygen-containing heterocyclic group, 5-6 membered sulfur-containing heterocyclic group, etc., each of the "nitrogen-containing heterocyclic group", "oxygen-containing heterocyclic group" and "sulfur-containing heterocyclic group" optionally further contains one or more other hetero atoms independently selected from oxygen, nitrogen and sulfur. Examples of 4-11 membered heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinonyl (e.g) Imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl (dithianyl), thiomorpholinyl, piperazinyl, trithianyl (trithianyl).
In the present invention, the heterocyclic group may further include a fused ring structure formed with a heterocyclic group or a cycloalkyl group, and the point of attachment of the fused ring structure to other groups may be on any heterocyclic group or cycloalkyl group, and thus, the heterocyclic group of the present invention further includes, but is not limited to, a heterocyclo-heterocyclic group, a heterocyclo-cycloalkyl group, a mono-heterocyclo-mono-heterocyclic group, a mono-heterocyclo-monocycloalkyl group, for example, a 3-7-membered (mono) heterocyclo-3-7-membered (mono) heterocyclic group, a 3-7-membered (mono) heterocyclo-cycloalkyl group, a 3-7-membered (mono) heterocyclo-C 4-6 (mono) cycloalkyl group, examples of which include, but are not limited to, pyrrolidino-cyclopropyl, cyclopento-aziridinyl, pyrrolidino-pyrrolidino, pyrrolidino-piperidinyl, pyrrolidino-piperazinyl, piperidinyl-morpholinyl,
In the present invention, the heterocyclic group also includes bridged heterocyclic groups and spiro heterocyclic groups.
As used herein, the term "bridged heterocyclic ring" refers to a cyclic structure containing one or more (e.g., 1,2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, and/or sulfur atoms) formed by two saturated rings sharing two ring atoms that are not directly connected, including, but not limited to, 7-10 membered bridged heterocyclic rings, 8-10 membered bridged heterocyclic rings, 7-10 membered nitrogen-containing bridged heterocyclic rings, 7-10 membered oxygen-containing bridged heterocyclic rings, 7-10 membered sulfur-containing bridged heterocyclic rings, and the like, e.g.
Etc. The "nitrogen-containing bridged heterocycle", "oxygen-containing bridged heterocycle", "sulfur-containing bridged heterocycle" optionally also contains one or more additional heteroatoms independently selected from oxygen, nitrogen and sulfur.
As used herein, the term "spiroheterocycle" refers to a cyclic structure containing one or more (e.g., 1,2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, sulfur) formed by two or more saturated rings sharing one ring atom, including but not limited to 5-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, 6-10 membered sulfur-containing spiroheterocycles, and the like, e.g.
The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle", "sulfur-containing spiroheterocycle" optionally further contains one or more additional heteroatoms independently selected from oxygen, nitrogen, sulfur. The term "6-10 membered nitrogen-containing spiroheterocyclyl" refers to a spiroheterocyclyl containing a total of 6-10 ring atoms, at least one of which is a nitrogen atom.
Examples of groups resulting from the condensation of a heterocyclyl group with an aryl group include, but are not limited to:
As used herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused-polycyclic aromatic group having a conjugated pi-electron system. As used herein, the term "C 6-12 aryl (aromatic ring)" means an aryl (aromatic ring) containing 6 to 12 carbon atoms, preferably a C 6-10 aryl (aromatic ring), preferably a phenyl (benzene ring) or naphthyl (naphthalene ring). Aryl is optionally substituted with one or more (such as 1 to 3) identical or different substituents (e.g., halogen, OH, CN, NO 2、C1-C6 alkyl, etc.).
As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or polycyclic aromatic group containing one or more heteroatoms, the same or different, including monocyclic heteroaryl groups and bicyclic or polycyclic ring systems containing at least one heteroaromatic ring (an aromatic ring system containing at least one heteroatom), which may have 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, for example 5, 6, 7, 8, 9, or 10 ring atoms. The heteroatom may be oxygen, nitrogen or sulfur. The carbon atoms and heteroatoms on the heteroaryl group are optionally substituted with oxo groups (e.g., to form c= O, S (=o) or S (=o) 2).
As used herein, the term "5-10 membered heteroaryl" or "5-10 membered heteroaryl ring" means a heteroaryl group (heteroaryl ring) containing 5 to 10 (e.g., 5 to 6) ring atoms, including 5-10 membered nitrogen-containing heteroaryl, 5-10 membered oxygen-containing heteroaryl, 5-10 membered sulfur-containing heteroaryl, 5-6 membered nitrogen-containing heteroaryl, 5-6 membered oxygen-containing heteroaryl, 5-6 membered sulfur-containing heteroaryl, and the like. The "nitrogen-containing heteroaryl", "oxygen-containing heteroaryl", and "sulfur-containing heteroaryl" each optionally contain one or more additional heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, and the like, or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and 5-10 membered fused ring groups containing these groups.
As used herein, the term "C 3-10 heteroaryl" refers to heteroaryl groups containing 3 to 10 carbon atoms, such as C 5-10 heteroaryl, C 5-6 heteroaryl, or C 3-5 heteroaryl.
In the present invention, heteroaryl (e.g., mono-heteroaryl) may share two adjacent atoms with aryl (e.g., monocyclic aryl, e.g., phenyl), heterocyclyl (e.g., mono-heterocyclyl), cycloalkyl (e.g., mono-alkyl), or another heteroaryl (e.g., another mono-heteroaryl) to form a fused ring structure, the point of attachment of which may be on any heteroaryl ring or on other rings, including, but not limited to, (mono) heteroaryl-mono-heteroaryl, (mono) heteroaryl-mono-heterocyclyl, and (mono) heteroaryl-mono-cycloalkyl, such as a 5-6 membered (mono) heteroarylo 5-6 membered (mono) heteroaryl, 5-6 membered (mono) heteroarylo phenyl, 5-6 membered (mono) heteroarylo 5-6 membered (mono) heterocyclyl or 5-6 membered (mono) heteroarylo C 4-6 (mono) cycloalkyl (e.g., 5-6 membered heteroarylo cyclobutyl, 5-6 membered heteroarylo cyclopentyl or 5-6 membered heteroarylo cyclohexyl), examples of which include but are not limited to indolyl, isoindolyl, indazolyl, benzimidazole, quinolinyl, isoquinolinyl, Etc.
As used herein, the term "halo" or "halogen" group is defined to include F, cl, br or I.
The term "substitution" means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. The compounds of the present application may also be substituted in the appropriate position with suitable substituents, such as those described herein above and those employed by those skilled in the art.
If a substituent is described as "optionally substituted with one or more … …," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent any hydrogens are present) may be replaced with an independently selected optional substituent, alone and/or together. If the nitrogen of a substituent is described as optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogens are present) may each be replaced with an independently selected optional substituent.
If substituents are described as "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.
The term "one or more" as used herein means 1 or more than 1, such as 2, 3, 4,5 or 10, under reasonable conditions.
As used herein, unless indicated, the point of attachment of a substituent may be from any suitable position of the substituent.
When the bond of a substituent is shown as a bond through the ring connecting two atoms, then such substituent may be bonded to any ring-forming atom in the substitutable ring.
The invention also includes all pharmaceutically acceptable isotopically-labelled compounds which are identical to those of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevailing in nature. Examples of isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (2 H), tritium (3 H)); Isotopes of carbon (e.g., 11C、13 C and 14 C); isotopes of chlorine (e.g., 36 Cl); isotopes of fluorine (e.g., 18 F); Isotopes of iodine (e.g., 123 I and 125 I); isotopes of nitrogen (e.g., 13 N and 15 N); Isotopes of oxygen (e.g., 15O、17 O and 18 O); isotopes of phosphorus (e.g., 32 P); and isotopes of sulfur (e.g., 35 S). Certain isotopically-labeled compounds of the present invention (e.g., those into which a radioisotope is incorporated) are useful in pharmaceutical and/or substrate tissue distribution studies (e.g., assays). The radioisotope tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose because of their ease of incorporation and ease of detection. Substitution with positron emitting isotopes (such as 11C、18F、15 O and 13 N) can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopically-labeled compounds of the present invention can be prepared by processes analogous to those described in the accompanying schemes and/or in the examples and preparations by substituting an appropriate isotopically-labeled reagent for the non-labeled reagent previously employed. Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, for example, D 2 O, acetone-D 6 or DMSO-D 6.
The term "stereoisomer" refers to an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, they can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as a mixture of two or more structurally distinct forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. For example, nitroso-oximes may exist in solution in equilibrium in the following tautomeric forms:
It is to be understood that the scope of the present application encompasses all such isomers in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.
Solid lines may be used hereinReal wedge/>Or virtual wedge/>Depicting the chemical bond of the compounds of the present invention. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom (e.g., particular enantiomers, racemic mixtures, etc.) are included. The use of a solid or virtual wedge to depict a bond to an asymmetric carbon atom is intended to indicate the presence of the stereoisomers shown. When present in a racemic mixture, real and imaginary wedges are used to define the relative stereochemistry, not the absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers (which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of any ratio of more than one polymorphs.
Eutectic refers to pharmaceutically active molecules bound in the same lattice with other physiologically acceptable acids, bases, salts, nonionic compounds by hydrogen bonding, pi-pi stacking, van der Waals forces, and other noncovalent bonds.
It will also be appreciated that certain compounds of the invention may exist in free form for use in therapy or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs which, upon administration to a patient in need thereof, are capable of providing the compounds of the invention or metabolites or residues thereof, either directly or indirectly. Thus, when reference is made herein to "a compound of the invention" it is also intended to encompass the various derivative forms of the compounds described above.
Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Such as hexafluorophosphate, meglumine salt, and the like. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts:properties, selection, and Use" (Wiley-VCH, 2002).
As used herein, the term "ester" means an ester derived from each of the compounds of the general formula in the present application, including physiologically hydrolyzable esters (compounds of the present application that can be hydrolyzed under physiological conditions to release the free acid or alcohol form). The compounds of the application may themselves be esters.
The compounds of the invention may be present in the form of solvates (preferably hydrates) wherein the compounds of the invention comprise a polar solvent as a structural element of the compound lattice, in particular for example water, methanol or ethanol. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.
Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides because nitrogen requires available lone pairs to oxidize to oxides. Those skilled in the art will recognize nitrogen-containing heterocycles capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include, but are not limited to, oxidizing heterocycles and tertiary amines with peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydrogen peroxide such as t-butyl hydroperoxide, sodium perborate, and dioxiranes (dioxirane) such as dimethyl dioxirane. These methods for preparing N-oxides have been widely described and reviewed in the literature, see for example: T.L. Gilchrist, comprehensive Organic Synthesis, vol.7, pp 748-750; katritzky and a.j. Boulton, eds., ACADEMIC PRESS; and g.w.h.cheeseman and e.s.g.werstiuk, ADVANCES IN Heterocyclic Chemistry, vol.22, pp390-392, a.r.katritzky and a.j.boulton, eds., ACADEMIC PRESS.
Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances that form in vivo upon administration of the compounds of the invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the compound being administered. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by a process of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.
The invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity, which, when administered into or onto the body, may be converted into the compounds of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Additional information regarding the use of prodrugs can be found in "Pro-drugs as Novel DELIVERY SYSTEMS", vol.14, ACS Symposium Series (T.Higuchi and V.stilla). Prodrugs of the invention may be prepared, for example, by replacing the appropriate functional groups present in the compounds of the invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., "Design of Prodrugs", described in H. Bundgaard (Elsevier, 1985) ".
The invention also encompasses compounds of the invention containing a protecting group. During any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules of interest, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example those described in T.W.Greene & P.G.M.Wuts, protective Groups in Organic Synthesis, john Wiley & Sons,1991, which references are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.
The term "about" means within + -10%, preferably within + -5%, more preferably within + -2% of the stated value. It should be noted that if there is a difference between the described structure and the name of the structure, the described structure will be given a greater weight.
Compounds of formula (I)
In some embodiments, the invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof:
Wherein:
Ring a is selected from a C 6-10 aromatic ring and a 5-10 membered heteroaromatic ring;
R is selected from:
Each R 1 is independently selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl;
Each X 1、X2、X3 is independently selected from CR 9 and N;
R 2 is L-R 2';
l is selected from a direct bond and- (CR 5R6)p -;
R 2' is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 2-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 3-8 cycloalkoxy, C 6-10 aryl, and 5-10 membered heteroaryl, said alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halo, -OH, -CN, -NR 7R8、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkoxy, 3-6 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl;
R 3 is selected from H and C 1-4 alkyl;
R 4 is independently at each occurrence selected from H, -OH, halogen, -CN, -NR 7R8、-NHCOCH3、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-6 heteroalkyl, C 1-4 haloalkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, said heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halogen, CN, -NR 5R6、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkoxy, 3-6 membered heterocyclyl; or R 3、R4 forms, with the atom to which it is attached, a 3-8 membered heterocyclyl, a 5-8 membered cycloalkyl, a C 6-10 aromatic ring, and a 5-10 membered heteroaromatic ring;
R 5 and R 6 are each independently selected from H, C 1-4 alkyl and C 3-8 cycloalkyl;
R 7 and R 8 are each independently selected from H and C 1-4 alkyl;
Each R 9 is independently selected from H, halogen, C 1-4 alkyl, and C 1-4 haloalkyl;
m is 0, 1 or 2;
n is 0,1, 2 or 3;
p is 1 or 2.
In certain embodiments, the present invention provides compounds of formula I wherein ring a is selected from phenyl and pyridyl.
In certain embodiments, the present invention provides compounds of formula I wherein each R 1 is independently selected from H and C 1-4 alkyl.
In certain embodiments, the present invention provides compounds of formula I wherein each R 1 is independently selected from H and methyl.
In certain embodiments, the invention provides compounds of formula I wherein L is selected from a direct bond or- (CR 5R6)p -and p is 1.
In certain embodiments, the present invention provides compounds of formula I wherein R 5 and R 6 are each independently selected from H and C 1-4 alkyl.
In certain embodiments, the present invention provides compounds of formula I wherein R 5 and R 6 are each independently selected from H and methyl.
In certain embodiments, the invention provides compounds of formula I wherein L is selected from the group consisting of a direct bond, -CH 2 -, and-CH (CH 3) -.
In certain embodiments, the present invention provides compounds of formula I wherein R 2' is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 2-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, and 5-10 membered heteroaryl, optionally substituted with one or more halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl.
In certain embodiments, the present invention provides compounds of formula I wherein R 2' is independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 2-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, and 5-10 membered heteroaryl, said alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl optionally substituted with one or more halo, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl.
In certain embodiments, the present invention provides compounds of formula I wherein R 2' is independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 2-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, and 5-6 membered heteroaryl, said alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl optionally substituted with one or more halo, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl.
In certain embodiments, the present invention provides compounds of formula I wherein R 2' is independently selected from the group consisting of C 1-4 alkyl, C 2-6 heteroalkyl, C 3-6 cycloalkyl, and 5-6 membered heteroaryl, optionally substituted with one or more halo, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl.
In certain embodiments, the present invention provides compounds of formula I wherein R 2' is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 2-6 heteroalkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, and C 5-10 heteroaryl, said alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl optionally substituted with one or more halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 5-10 heteroaryl.
In certain embodiments, the present invention provides compounds of formula I wherein R 2' is independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 2-6 heteroalkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, and C 5-10 heteroaryl, said alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl optionally substituted with one or more halo, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 heterocyclyl.
In certain embodiments, the present invention provides compounds of formula I wherein R 2' is independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 2-6 heteroalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, and C 5-6 heteroaryl, said alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl optionally substituted with one or more halo, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 heterocyclyl.
In certain embodiments, the present invention provides compounds of formula I wherein R 2' is independently selected from the group consisting of C 1-4 alkyl, C 2-6 heteroalkyl, C 3-6 cycloalkyl, and C 5-6 heteroaryl, said alkyl, heteroalkyl, cycloalkyl, heteroaryl optionally substituted with one or more halo, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 heterocyclyl.
In certain embodiments, R 2' is independently selected from methyl, pyrimidinyl, pyridinyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like,Pyrazolyl and-C 1-4 alkyl-O-C 1-4 alkyl, said methyl, pyrimidinyl, pyridinyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl optionally substituted by C 1-4 alkyl, halogen.
In certain embodiments, the present invention provides compounds of formula I wherein R 2' is independently selected from the group consisting of methyl, pyrimidinyl, pyridinyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl,Pyrazolyl and-CH 2-O-CH3, said methyl, pyrimidinyl, pyridinyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl optionally being substituted by methyl, ethyl, propyl, F, cl, br and I.
In certain embodiments, R 2' is independently selected from methyl, pyrimidinyl, pyridinyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like,Pyrazolyl and-CH 2-O-CH3, said methyl, pyrimidinyl, pyridinyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl optionally being substituted by methyl, F.
In certain embodiments, the present invention provides compounds of formula I wherein R 2' is independently selected from methyl, pyrimidinyl, isopropyl, cyclopropyl,Pyrazolyl and-CH 2-O-CH3, said methyl, cyclopropyl, pyrazolyl optionally being substituted with methyl.
In certain embodiments, the present invention provides compounds of formula I wherein R 3 is selected from H and C 1-4 alkyl.
In certain embodiments, the present invention provides compounds of formula I wherein R 3 is selected from H, methyl, ethyl, propyl, and butyl.
In certain embodiments, the present invention provides compounds of formula I wherein R 3 is selected from H and methyl.
In certain embodiments, the invention provides compounds of formula I wherein R 3 is H.
In certain embodiments, the invention provides compounds of formula I wherein R 4 is independently at each occurrence selected from the group consisting of H, halogen, CN, -NR 7R8、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-6 heteroalkyl, C 1-4 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, said heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, heteroaryl optionally substituted with one or more halogen, CN, -NR 5R6、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkoxy, 3-6 membered heterocyclyl.
In certain embodiments, the present invention provides compounds of formula I wherein each R 4 at each occurrence is independently selected from H, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, 5-6 membered heteroaryl, optionally substituted with one or more halogen, C 1-4 alkyl, C 1-4 haloalkyl.
In certain embodiments, the present invention provides compounds of formula I wherein each R 4 at each occurrence is independently selected from H, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, 5-6 membered heteroaryl optionally substituted with one or more halogen, C 1-4 alkyl, C 1-4 haloalkyl.
In certain embodiments, the present invention provides compounds of formula I wherein each occurrence of R 4 is independently selected from the group consisting of C 1-4 haloalkyl, C 1-4 haloalkoxy, and 5-6 membered heteroaryl (e.g., pyrazolyl) optionally substituted with one or more halo, C 1-4 alkyl, C 1-4 haloalkyl.
In certain embodiments, the present invention provides compounds of formula I wherein each occurrence of R 4 is independently selected from the group consisting of C 1-4 haloalkyl, C 1-4 haloalkoxy, and
In certain embodiments, the invention provides compounds of formula I wherein R 4 is independently at each occurrence selected from the group consisting of H, halogen, CN, -NR 7R8、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-6 heteroalkyl, C 1-4 haloalkoxy, C 3-8 cycloalkyl, C 3-C8 heterocyclyl, C 5-10 heteroaryl, said heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, heteroaryl optionally substituted with one or more halogen, CN, -NR 5R6、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkoxy, C 3-6 heterocyclyl.
In certain embodiments, the present invention provides compounds of formula I wherein each occurrence of R 4 is independently selected from H, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 5-10 heteroaryl optionally substituted with one or more halogen, C 1-4 alkyl, C 1-4 haloalkyl.
In certain embodiments, the present invention provides compounds of formula I wherein each occurrence of R 4 is independently selected from the group consisting of C 1-4 haloalkyl and C 1-4 haloalkoxy.
In certain embodiments, the present invention provides compounds of formula I wherein each occurrence of R 4 is independently selected from C 1-4 haloalkyl.
In certain embodiments, the present invention provides compounds of formula I wherein each occurrence of R 4 is independently trifluoromethyl, trifluoromethoxy, and
In certain embodiments, the present invention provides compounds of formula I wherein each occurrence of R 4 is independently trifluoromethyl or trifluoromethoxy.
In certain embodiments, the present invention provides compounds of formula I wherein each occurrence of R 4 is independently trifluoromethyl.
In certain embodiments, the present invention provides compounds of formula I wherein R 3 and R 4 together with the atoms to which they are attached form a 5-6 membered heterocyclyl, e.g., a 5-membered oxygen-containing heterocycle, a 6-membered oxygen-containing heterocycle.
In certain embodiments, the present invention provides compounds of formula I wherein R 3 and R 4 together with the atoms to which they are attached form a 5-6 membered heterocyclyl, e.g., a 5-membered oxygen-containing heterocycle.
In certain embodiments, the present invention provides compounds of formula I wherein R 3 and R 4 together with the atoms to which they are attached form the following group:
In certain embodiments, the present invention provides compounds of formula I wherein R 7 and R 8 are each independently selected from H and C 1-4 alkyl.
In certain embodiments, the present invention provides compounds of formula I wherein R 7 and R 8 are each independently selected from H, methyl, ethyl, propyl and butyl.
In certain embodiments, the present invention provides compounds of formula I wherein each X 1、X2 is independently selected from CR 9 and N.
In certain embodiments, the present invention provides compounds of formula I wherein X 1 and X 2 are each independently selected from CR 9.
In certain embodiments, the present invention provides compounds of formula I wherein R 9 is selected from the group consisting of H, halogen, C 1-3 alkyl, and C 1-3 haloalkyl.
In certain embodiments, the present invention provides compounds of formula I wherein R 9 is selected from H, F, cl, methyl and trifluoromethyl.
In certain embodiments, the present invention provides compounds of formula I wherein X 1 is CH, CF, CCl, C (CH 3)、C(CF3) and N.
In certain embodiments, the present invention provides compounds of formula I wherein X 1 is CH.
In certain embodiments, the present invention provides compounds of formula I wherein X 2 is selected from CH and N.
In certain embodiments, the present invention provides compounds of formula I wherein X 2 is selected from CH.
In certain embodiments, the present invention provides compounds of formula I wherein X 3 is selected from N.
In certain embodiments, the present invention provides compounds of formula I wherein m is 0 or 1.
In certain embodiments, the present invention provides compounds of formula I wherein m is 0.
In certain embodiments, the present invention provides compounds of formula I wherein n is 0, 1 or 2, e.g., n is 1 or 2.
In certain embodiments, the present invention provides compounds of formula I wherein p is 1.
In certain embodiments, the invention provides compounds of formula I further having formula I-1 or I-2,
Wherein ring A, R, R 2、R4 is as defined above, q is 0, 1 or 2, for example 1 or 2.
In some embodiments, the present invention provides a compound of formula I-a, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof:
Wherein, the rings A, R 1、R2、R3、R4、X1、X2, m, n are as defined above.
In some embodiments, formula I is further formula I-A-1 or I-A-2:
Wherein, the rings A, R 1、R2、R4、X1、X2, m are as defined above, q is 0, 1 or 2, for example 1 or 2.
In some embodiments, formula I is further formula I-A-1a, I-A-1b, I-A-2a, or I-A-2b:
Wherein, the rings A, R 1、R2、R4、X1、X2, m are as defined above, q is 0, 1 or 2, for example 1 or 2.
In some embodiments, the present invention provides a compound of formula I-B, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof:
Wherein, the rings A, R 1、R2、R3、R4、X1、X2, m, n are as defined above.
In certain embodiments, the present invention provides compounds of formula I-A or I-B, wherein,
Ring a is selected from phenyl and pyridinyl;
each R 1 is independently selected from H and C 1-4 alkyl;
R 2 is L-R 2';
L is selected from a direct bond or- (CR 5R6)p -;
R 5 and R 6 are each independently selected from H and C 1-4 alkyl;
R 2' is independently selected from C 1-4 alkyl, C 2-6 heteroalkyl, C 3-6 cycloalkyl, and 5-to 10-membered heteroaryl (e.g., 5-to 6-membered heteroaryl), said alkyl, heteroalkyl, cycloalkyl, heteroaryl optionally substituted with one or more halo, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3-to 6-membered heterocyclyl;
R 3 is selected from H and C 1-4 alkyl;
R 4 at each occurrence is independently selected from H, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, 5-10 membered heteroaryl optionally substituted with one or more halogen, C 1-4 alkyl, C 1-4 haloalkyl; or R 3 and R 4 together with the atoms to which they are attached form a 3-8 membered heterocyclic ring;
X 1 and X 2 are each independently selected from CR 9 and N, preferably X 1 and X 2 are each independently selected from CR 9;
R 9 is selected from H, halogen, C 1-3 alkyl, and C 1-3 haloalkyl;
m is 0 or 1;
n is 1 or 2;
p is 1.
In certain embodiments, the present invention provides compounds of formula I-A or I-B, wherein,
Ring a is selected from phenyl and pyridinyl;
Each R 1 is independently selected from H and methyl;
L is selected from the group consisting of a direct bond, -CH 2 -, and-CH (CH 3) -;
r 2' is independently selected from methyl, pyrimidinyl, pyridinyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and, Pyrazolyl and-CH 2-O-CH3, said methyl, pyrimidinyl, pyridinyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl optionally substituted with methyl, F;
R 3 is selected from H and C 1-4 alkyl;
r 4 at each occurrence is independently selected from H, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, 5-6 membered heteroaryl optionally substituted with one or more halogen, C 1-4 alkyl, C 1-4 haloalkyl; or R 3 and R 4 together with the atoms to which they are attached form a 3-8 membered heterocyclic ring;
X 1 and X 2 are each independently selected from CR 9 and N;
r 9 is selected from H, F, cl, C 1-3 alkyl (e.g., methyl) and C 1-3 haloalkyl (e.g., trifluoromethyl);
m is 0 or 1; n is 1 or 2.
In certain embodiments, the present invention provides compounds of formula I-A or I-B, wherein,
Ring a is selected from phenyl and pyridinyl;
each R 1 is independently selected from H and C 1-4 alkyl;
L is selected from a direct bond or- (CR 5R6)p -;
R 5 and R 6 are each independently selected from H and C 1-4 alkyl;
R 2' is independently selected from C 1-4 alkyl, C 2-6 heteroalkyl, C 3-6 cycloalkyl, and C 5-6 heteroaryl, the alkyl, heteroalkyl, cycloalkyl, heteroaryl optionally substituted with one or more halo, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 heterocyclyl;
R 3 is selected from H and C 1-4 alkyl;
Each occurrence of R 4 is independently selected from H, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 5-10 heteroaryl optionally substituted with one or more halogen, C 1-4 alkyl, C 1-4 haloalkyl; or R 3 and R 4 together form a 3-8 membered heterocyclic ring;
X 1 and X 2 are each independently selected from CR 9;
R 9 is selected from H, halogen, C 1-3 alkyl, and C 1-3 haloalkyl;
m is 0 or 1;
n is 1 or 2;
p is 1.
In certain embodiments, the present invention provides compounds of formula I-A or I-B, wherein,
Ring a is selected from phenyl and pyridinyl;
Each R 1 is independently selected from H and methyl;
L is selected from the group consisting of a direct bond, -CH 2 -, and-CH (CH 3) -;
r 2' is independently selected from methyl, pyrimidinyl, pyridinyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and, Pyrazolyl and-CH 2-O-CH3, said methyl, pyrimidinyl, pyridinyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl optionally substituted with methyl, ethyl, propyl, F, cl, br and I;
R 3 is selected from H and C 1-4 alkyl;
R 4 is independently at each occurrence selected from the group consisting of C 1-4 haloalkyl, C 1-4 haloalkoxy, and Or R 3 and R 4 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring;
X 1 and X 2 are each independently selected from CR 9;
r 9 is selected from H, F, cl, C 1-3 alkyl (e.g., methyl) and C 1-3 haloalkyl (e.g., trifluoromethyl);
m is 0 or 1;
n is 1 or 2.
In certain embodiments, the present invention provides compounds of formula I-A or I-B, wherein,
Ring a is selected from phenyl and pyridinyl;
Each R 1 is independently selected from H and methyl;
L is selected from the group consisting of a direct bond, -CH 2 -, and-CH (CH 3) -;
r 2' is independently selected from methyl, pyrimidinyl, pyridinyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and, Pyrazolyl and-CH 2-O-CH3, said methyl, pyrimidinyl, pyridinyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl optionally substituted with methyl, F;
R 3 is selected from H and C 1-4 alkyl;
R 4 is independently at each occurrence selected from C 1-4 haloalkyl and C 1-4 haloalkoxy; or R 3 and R 4 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring;
X 1 and X 2 are each independently selected from CR 9;
r 9 is selected from H, F, cl, C 1-3 alkyl (e.g., methyl) and C 1-3 haloalkyl (e.g., trifluoromethyl);
m is 0 or 1;
n is 1 or 2.
In certain embodiments, the present invention provides compounds of formula I-A or I-B, wherein,
Ring a is selected from phenyl and pyridinyl;
Each R 1 is independently selected from H and methyl;
L is selected from the group consisting of a direct bond, -CH 2 -, and-CH (CH 3) -;
r 2' is independently selected from methyl, pyrimidinyl, isopropyl, cyclopropyl, Pyrazolyl and-CH 2-O-CH3, said methyl, cyclopropyl, pyrazolyl optionally substituted with methyl; /(I)
R 3 is selected from H and C 1-4 alkyl;
R 4 is independently at each occurrence selected from C 1-4 haloalkyl; or R 3 and R 4 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring;
X 1 and X 2 are each independently selected from CR 9;
r 9 is H;
m is 0 or 1; n is 1 or 2.
In some embodiments, in the compounds of formula I, I-1, I-2, I-A, I-B, I-A-1, I-A-2, I-A-1a, I-A-1b, I-A-2a or I-A-2b of the invention, one or more of the following are satisfied:
(1) Ring a is selected from phenyl and pyridinyl; preferably selected from phenyl;
(2) Each R 1 is independently H;
(3) X 1 and X 2 are each independently selected from CR 9 and N; preferably selected from CR 9;
(4) R 2' is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 2-6 heteroalkyl, Non-cyclopropyl C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 3-8 cycloalkoxy, C 6-10 aryl and non-pyrazolyl 5-10 membered heteroaryl, preferably selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 2-6 heteroalkyl, 3-to 8-membered heterocyclyl, C 3-8 cycloalkoxy, c 6-10 aryl, or preferably a 5-to 10-membered heteroaryl group selected from C 1-4 alkyl, C 2-6 heteroalkyl, non-cyclopropyl C 3-6 cycloalkyl and non-pyrazolyl, Preferably selected from the group consisting of C 1-4 alkyl, C 2-6 heteroalkyl, cyclobutyl, cyclopentyl, Pyrimidinyl, pyridinyl, preferably selected from C 1-4 alkyl, C 2-6 heteroalkyl, said alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halo, -OH, -CN, -NR 7R8、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-8 cycloalkoxy, 3-6 membered heterocyclyl, C 6-10 aryl;
(5) R 4 is independently at each occurrence selected from H, -OH, halogen, -CN, -NR 7R8、-NHCOCH3、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-6 heteroalkyl, C 1-4 haloalkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-to 8-membered heterocyclyl, C 6-10 aryl and non-pyrazolyl 5-10 membered heteroaryl, preferably selected from H, -OH, halogen, -CN, -NR 7R8、-NHCOCH3、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-6 heteroalkyl, C 1-4 haloalkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-to 8-membered heterocyclyl, C 6-10 aryl, preferably selected from H, halogen, CN, -NR 7R8、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-6 heteroalkyl, C 1-4 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, preferably selected from H, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, non-pyrazolyl 5-10 membered heteroaryl, preferably selected from C 1-4 haloalkyl and C 1-4 haloalkoxy, preferably selected from C 1-4 haloalkyl, The heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halogen, -CN, -NR 5R6、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkoxy, 3-6 membered heterocyclyl;
(6) R 5 and R 6 are each independently selected from H, C 1-4 alkyl;
(7) Each R 9 is independently selected from halogen, C 1-4 alkyl and C 1-4 haloalkyl, preferably from halogen, preferably from F;
(8) m is 0 or 1, preferably 0;
(9) n is 0, 1 or 2, preferably 1 or 2;
(10) p is 1;
(11) q is 0, 1 or 2, preferably 1 or 2.
In some embodiments, the present invention provides compounds of formula I-A-1, wherein,
Ring a is selected from phenyl and pyridinyl;
Each R 1 is independently H;
X 1 and X 2 are each independently selected from CR 9 and N, preferably from CR 9;
R 2 is L-R 2';
L is selected from a direct bond or- (CR 5R6)p -;
R 2' is independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 2-6 heteroalkyl, non-cyclopropyl C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 3-8 cycloalkoxy, C 6-10 aryl, and non-pyrazolyl 5-10 membered heteroaryl, said alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halo, -OH, -CN, -NR 7R8、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-8 cycloalkoxy, 3-6 membered heterocyclyl, C 6-10 aryl;
R 4 at each occurrence is independently selected from H, -OH, halogen, -CN, -NR 7R8、-NHCOCH3、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-6 heteroalkyl, C 1-4 haloalkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl other than pyrazolyl, said heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halogen, -CN, -NR 5R6、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkoxy, 3-6 membered heterocyclyl;
R 5 and R 6 are each independently selected from H and C 1-4 alkyl;
R 7 and R 8 are each independently selected from H and C 1-4 alkyl;
each R 9 is independently selected from halogen, C 1-4 alkyl, and C 1-4 haloalkyl;
m is 0 or 1;
q is 1 or 2;
And p is 1.
In some embodiments, the present invention provides compounds of formula I-A-1, wherein,
Ring a is selected from phenyl and pyridinyl;
Each R 1 is independently H;
X 1 and X 2 are each independently selected from CR 9 and N, preferably from CR 9;
R 2 is L-R 2';
L is selected from a direct bond or- (CR 5R6)p -;
R 2' is independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 2-6 heteroalkyl, 3-8 membered heterocyclyl, C 3-8 cycloalkoxy, C 6-10 aryl, said alkyl, alkoxy, hydroxyalkyl, heteroalkyl, heterocyclyl, cycloalkoxy, aryl optionally substituted with one or more halo, -OH, -CN, -NR 7R8、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-8 cycloalkoxy, 3-6 membered heterocyclyl, C 6-10 aryl;
R 4 is independently at each occurrence selected from H, -OH, halogen, -CN, -NR 7R8、-NHCOCH3、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-6 heteroalkyl, C 1-4 haloalkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, C 6-10 aryl, said heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl optionally substituted with one or more halogen, -CN, -NR 5R6、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkoxy, 3-6 membered heterocyclyl;
R 5 and R 6 are each independently selected from H and C 1-4 alkyl;
R 7 and R 8 are each independently selected from H and C 1-4 alkyl;
each R 9 is independently selected from halogen, C 1-4 alkyl, and C 1-4 haloalkyl;
m is 0 or 1;
q is 1 or 2;
And p is 1.
In some embodiments, the present invention provides compounds of formula I, I-1, I-2, I-A, I-B, I-A-1, I-A-2, I-A-1a, I-A-1b, I-A-2a, or I-A-2b that satisfy one or more of the following:
(1) X 1 and X 2 are each independently selected from CR 9;
(2) R 2' is independently selected from C 1-4 alkyl, C 2-6 heteroalkyl, optionally substituted with C 1-4 alkyl or halo;
(3) R 4 is independently at each occurrence selected from C 1-4 haloalkyl and C 1-4 haloalkoxy;
(4) R 9 are each independently selected from halogen.
The invention encompasses any combination of the above embodiments.
In some embodiments, compounds of the invention include, but are not limited to:
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In some embodiments, the compounds of the invention are not the following:
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preparation method
In certain embodiments, the present invention provides a process for preparing a compound of formula I-a comprising the steps of:
Route A
The first step: the compound I-A-1 and the compound I-A-2 are subjected to condensation reaction to generate a compound I-A-3;
and a second step of: heating and deprotecting the compound I-A-3 under acidic conditions to produce a compound I-A;
Wherein:
Each group is as defined above;
The reaction conditions of each step are as follows:
The first step: the compounds I-A-1 and I-A-2 undergo condensation reactions (such as HATU and DIPEA; POCl 3 and pyridine, etc.) to form the compound I-A-3;
and a second step of: the compound I-A-3 is heated and deprotected under acidic conditions (trifluoroacetic acid and the like are used as acids) to generate a compound I-A;
The synthesis of the compounds of formula I-B is similar to that described above.
Pharmaceutical compositions, formulations and methods of treatment
In some embodiments, the invention provides pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, and one or more pharmaceutically acceptable carriers.
In some embodiments, the present invention provides a pharmaceutical formulation selected from the group consisting of a solid formulation, a semi-solid formulation, a liquid formulation, and a gaseous formulation.
In some embodiments, the pharmaceutical composition or pharmaceutical formulation may further comprise one or more other therapeutic agents.
In some embodiments, the pharmaceutical composition or pharmaceutical formulation is administered by oral, intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or transdermal route.
In some embodiments, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, or a pharmaceutical composition of the invention, or a pharmaceutical formulation of the invention, in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with PRMT5 activity.
In some embodiments, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, or a pharmaceutical composition of the invention, or a pharmaceutical formulation of the invention, in the manufacture of a medicament for modulating (e.g., reducing or inhibiting) PRMT5 activity.
In some embodiments, the invention provides a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, or a pharmaceutical composition of the invention, or a pharmaceutical formulation of the invention, for use in preventing or treating a disease or condition associated with PRMT5 activity.
In some embodiments, the invention provides a method of preventing or treating a disease or condition associated with PRMT5 activity, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, or a pharmaceutical composition of the invention, or a pharmaceutical formulation of the invention.
In some embodiments, the disease or condition associated with PRMT5 activity is an MTAP-deleted cancer or tumor.
In some embodiments, the cancer or tumor is selected from the group consisting of esophageal cancer, lung cancer, pancreatic cancer, glioblastoma, cholangiocarcinoma, bladder cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, prostate cancer, melanoma, gastric cancer, colon cancer, leukemia (B-CLL), and lymphoma.
By "pharmaceutically acceptable carrier" is meant a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting the tissues of humans and/or other animals within the scope of sound medical judgment without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
The pharmaceutical compositions of the present invention may act systematically and/or locally. For this purpose, they may be administered by a suitable route.
For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms.
The term "effective amount" as used herein refers to the amount of a compound that, upon administration, will alleviate to some extent one or more symptoms of the disorder being treated.
The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the doses may be proportionally reduced or increased as indicated by the urgent need for a therapeutic situation. It is noted that the dosage value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions.
The amount of the compound of the invention administered will depend on the severity of the individual, disorder or condition being treated, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. Generally, an effective dose is about 0.0001 to about 50mg per kg body weight per day. In some cases, dosage levels not higher than the lower limit of the aforementioned range may be sufficient, while in other cases larger doses may still be employed without causing any adverse side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.
The compounds of the present invention may be present in the pharmaceutical composition or pharmaceutical formulation in an amount or amount of about 0.01mg to about 1000mg.
As used herein, unless otherwise indicated, the term "preventing" refers to the prior administration of a drug to avoid or prevent the appearance of one or more symptoms of a disease or disorder. Those of ordinary skill in the medical arts recognize that the term "preventing" is not an absolute term. In the medical field, it is understood that prophylactic administration of a drug to substantially reduce the likelihood or severity of a disorder or symptoms of a disorder is intended in the meaning of the present disclosure. Physician's desk reference (Physician' S DESK REFERENCE), standard text in the field, uses the term "prevent" hundreds of times. As used herein, the term "preventing" with respect to a disorder or disease refers to avoiding the cause, effect, symptom, or progression of the disease or disorder before the disease or disorder is fully manifested.
The term "treating" means reversing, alleviating, inhibiting the progression of a disorder or condition to which such term applies or one or more symptoms of such disorder or condition.
As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from a disease (e.g., a disease described herein). "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
In some embodiments, the pharmaceutical compositions or pharmaceutical formulations of the present invention may further comprise one or more additional therapeutic or prophylactic agents (e.g., other agents useful in the treatment of cancer or neoplastic disease). In some embodiments, the methods of treatment of the present invention may further comprise administering one or more additional therapeutic or prophylactic agents (e.g., other agents useful in treating cancer or neoplastic disease).
Detailed Description
Examples
The invention is further described below in connection with examples, which are not intended to limit the scope of the invention. Abbreviations used herein have the following meanings:
The compounds of the invention are isolated and purified by preparative TLC, silica gel column chromatography, prep-HPLC and/or Flash column chromatography (Flash column chromatography), the structure of which is confirmed by 1 H NMR and/or MS. Reaction monitoring was performed by TLC or LC-MS.
1 H NMR spectroscopy used a Bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD MHz).
LC/MS employed Aglient 1260 Infinity/Aglient 6120 Quadrupole.
TLC uses silica gel GF 254 as the stationary phase.
Column chromatography generally uses 200-300 mesh silica gel (Qingdao ocean) as the stationary phase.
Flash column chromatography using a Biotage flash column chromatograph.
Prep-HPLC employed Agilent type 1260 and Waters 2489.
The microwave reaction was performed using a BiotageInitiator microwave reactor.
In the examples below, the temperature of the reaction was room temperature (15-30 ℃ C.) unless otherwise specified.
The reagents used in the present application are available from Acros Organics, ALDRICH CHEMICAL Company, or Tebert chemistry, among others.
Synthetic examples:
intermediate Int-A:4- ((2, 4-dimethylbenzyl) amino) imidazo [1,5-a ] quinoxaline-8-carboxylic acid
The first step: synthesis of intermediate N- (4-bromo-2-fluorophenyl) -1H-imidazole-5-carboxamide (Compound Int A-3)
Int A-1 (15 g,133.83 mmol) was dissolved in anhydrous DMF (50 mL) in an ice-water bath, DIPEA (34.59 g,267.65 mmol) was slowly added dropwise, after stirring well, HATU (76.33 g,200.74 mmol) in anhydrous DMF was added dropwise, stirring continued for 1h, finally Int A-2 (27.97 g,147.21 mmol) in anhydrous DMF was added dropwise, and the mixture was allowed to react naturally to 25℃for 16 h. After the reaction, water was added thereto, and the mixture was stirred, extracted and concentrated with ethyl acetate to obtain a crude product, which was purified by silica gel column chromatography (mobile phase PE: ea=40:60) to obtain intermediate Int a-3 (16.00 g). MS (ESI, m/z): 284.0[ M+H ] +.
And a second step of: synthesis of intermediate 8-bromoimidazo [1,5-a ] quinoxalin-4 (5H) -one (Compound Int A-4)
Int A-3 (2.27 g,7.98 mmol) was dissolved in anhydrous DMAc (20 mL), naH (479.01 mg,11.98 mmol) was added in portions under ice bath, and after stirring for 10min, the reaction was performed at 140℃for 48hr under nitrogen. After the reaction is finished, the majority of DMAc is dried by decompression and rotation, cooled to room temperature, added with water and stirred, and filtered by suction, and a filter cake is leached twice by water to obtain an intermediate Int A-4 (2.0 g), and the intermediate Int A-4 is dried and used. MS (ESI, m/z): 264.0[ M+H ] +.
And a third step of: synthesis of intermediate methyl 4-oxo-4, 5-dihydroimidazo [1,5-a ] quinoxaline-8-carboxylate (Compound Int A-5)
To the autoclave were added Int A-4 (2.0 g,7.57 mmol), TEA (2.30 g,22.72 mmol), pd (dppf) 2Cl2 (613.90 mg, 757.35. Mu. Mol) and dissolved with methanol (30 mL), and after CO substitution, the mixture was pressurized to 1.2atm and reacted at 120℃for 16hr. After the reaction is finished, the temperature is reduced to room temperature, suction filtration is carried out, a filter cake is intermediate Int A-5 (700 mg), and the filter cake is used after drying. MS (ESI, m/z): 244.1[ M+H ] +.
Fourth step: synthesis of intermediate 4- ((2, 4-dimethoxybenzyl) amino) imidazo [1,5-a ] quinoxaline-8-carboxylic acid methyl ester (Compound Int A-7)
To anhydrous DMF (20 mL) was added Int A-5 (700 mg,2.88 mmol) and PyBOP (2.25 g,4.32 mmol) under ice bath, DIPEA (1.12 g,8.63 mmol) was added dropwise and stirred for 10min, and finally Int A-6 (962.46 mg,5.76 mmol) was added and reacted at 60℃for 16hr. After the reaction, water was added and stirred, EA was extracted and concentrated to give crude product, which was purified by silica gel column chromatography (mobile phase DCM: meoh=95:5) to give intermediate Int a-7 (904 mg). MS (ESI, m/z): 393.2[ M+H ] +.
Fifth step: synthesis of intermediate 4- ((2, 4-dimethoxybenzyl) amino) imidazo [1,5-a ] quinoxaline-8-carboxylic acid (Compound Int A)
Int A-7 (284 mg,2.30 mmol) was dissolved in 30mL of methanol under ice bath, and an aqueous solution (15 mL) of NaOH (552.90 mg,13.82 mmol) was added dropwise thereto, and the mixture was allowed to react at 25℃for 16hr. After the reaction, the methanol was dried by spin drying, dilute hydrochloric acid was added dropwise to the remaining portion under ice bath until the solution became acidic, suction filtration was performed, and the filter cake was washed with water 2 times to obtain intermediate Int a (840 mg). MS (ESI, m/z): 379.2[ M+H ] +.
Intermediate Int-B:5- (bis (4-methoxybenzyl) amino) imidazo [1,5-c ] quinazoline-9-carboxylic acid
The first step: synthesis of 6-bromo-4-methylquinazolin-2-amine (Compound Int B-2)
To the reaction flask, int B-1 (1 g,4.67 mmol) and a 4M HCl solution in 1, 4-dioxane (10 mL) were added, and the mixture was stirred at room temperature for 20min, concentrated to dryness under reduced pressure, and then an aqueous cyanamide solution (5.00 mL) was added to the reaction flask, followed by reaction at 50℃for 16hr under nitrogen. And after the reaction is finished, cooling the reaction liquid to room temperature, adding water for dilution, adding saturated Na 2CO3 solution for regulating the pH value to 8-9, filtering, washing a filter cake with clear water, and drying to obtain the compound Int B-2.MS (ESI, m/z): 238.0[ M+H ] +.
And a second step of: synthesis of 9-bromoimidazo [1,5-c ] quinazolin-5-amine (Compound Int B-3)
To the flask were added Int B-2 (1.1 g,4.62 mmol), glycine (694 mg,9.24 mmol), TBAI (3411 mg, 924.05. Mu. Mol), DMSO (10 mL), acOH (832 mg,13.86 mmol), TBHP (6M, 3.08 mL), and the mixture was reacted at 95℃for 16hr under nitrogen. After the reaction is finished, the reaction solution is cooled to room temperature, water is added for dilution, saturated Na 2CO3 solution is added for regulating the pH value to 8-9, filtration is carried out, filter cakes are washed by clear water, and the compound Int B-3 (1 g) is obtained after drying. MS (ESI, m/z): 263.0[ M+H ] +.
And a third step of: synthesis of 9-bromo-N, N-bis (4-methoxybenzyl) imidazo [1,5-c ] quinazolin-5-amine (Compound Int B-4)
Int B-3 (200 mg, 760.19. Mu. Mol) and DMF (10 mL) are added into a reaction bottle, dissolved and placed in an ice water bath for cooling, naH (122 mg,3.04 mmol) is added, the ice water bath is kept for reaction for 30min, and pair PMBCl (356 mg,2.28 mmol) is added for reaction at0 ℃ for 20min, and then the temperature is slowly raised to room temperature for reaction for 16hr. The reaction solution was then diluted with water, extracted with ethyl acetate (30 ml x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (mobile phase EA: pe=35:65), and was collected and dried to give compound Int B-4 (130 mg). MS (ESI, m/z): 503.1[ M+H ] +.
Fourth step: synthesis of methyl 5- (bis (4-methoxybenzyl) amino) imidazo [1,5-c ] quinazoline-9-carboxylate (Compound Int B-5)
To the autoclave were added Int B-4 (130 mg, 258.25. Mu. Mol), pd (dppf) Cl 2. DCM (19 mg, 25.82. Mu. Mol), meOH (10 mL), TEA (78 mg, 774.75. Mu. Mol). CO is replaced twice, and then the mixture is filled to 10 to 12 atmospheres, and the temperature is raised to 120 ℃ for reaction for 5 hours. After completion of the reaction, water was added for dilution, extraction with ethyl acetate (30 ml×3), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (mobile phase EA: pe=35:65) to give compound Int B-5 (90 mg). MS (ESI, m/z): 483.2[ M+H ] +.
Fifth step: synthesis of 5- (bis (4-methoxybenzyl) amino) imidazo [1,5-c ] quinazoline-9-carboxylic acid (Compound Int B)
212E (90 mg, 186.52. Mu. Mol) and THF (3 mL) were added to the flask, dissolved, and then a solution of LiOH H 2 O (20 mg, 466.29. Mu. Mol) in H 2 O (0.5 mL) was added thereto, and the mixture was reacted at 50℃for 8 hours under nitrogen atmosphere. After the reaction is finished, the pH of the reaction solution is regulated to 6-7 by using 2M hydrochloric acid, and the solvent is directly concentrated to dryness under reduced pressure to obtain a compound Int B. MS (ESI, m/z): 469.2[ M+H ] +.
Intermediate Int C (R) -1- (pyrimidin-2-yl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) ethan-1-amine (Int C)
First step (R) -2-methyl-N- (1- (pyrimidin-2-yl) ethylene) propane-2-sulfinamide (compound Int C-3) Synthesis
Int C-1 (1 g,8.19 mmol) and Int C-2 (1.78 g,9.83 mmol) were dissolved in anhydrous THF (20 mL), ti (iPrO) 4 (4.65 g,16.38mmol,4.85 mL) was slowly added, and the temperature was raised to 75℃after the addition to react for 12hr. After the reaction was completed, the reaction was cooled to room temperature to give Compound Int C-3 (1.8 g), which was directly added to the next step. MS (ESI, m/z): 226.1[ M+H ] +.
And a second step of: synthesis of (R) -2-methyl-N- ((R) -1- (pyrimidin-2-yl) ethyl) propane-2-sulfinamide (compound Int C-4)
NaBH 4 (604.49 mg,15.98 mmol) was added to a reaction flask of one step Int C-3 (1.8 g,7.99 mmol) at 25deg.C, the reaction was continued at 25deg.C for 2hr, after completion of the reaction, an appropriate amount of water was added to quench the reaction, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (mobile phase DCM: meOH=93:7) to give Compound Int C-4 (1.5 g). MS (ESI, m/z): 228.1[ M+H ] +.
And a third step of: synthesis of (R) -1- (pyrimidin-2-yl) ethane-1-amine (compound Int C-5)
Int C-4 (1.5 g,6.60 mmol) was dissolved in MeOH (15 mL), then 4N HCl 1, 4-dioxane solution (5 mL) was slowly added, the reaction system was reacted at 25℃for 1hr, after completion of the reaction, the reaction was concentrated under reduced pressure, then a proper amount of methanol was added for dissolution, and several drops of triethylamine were added for pH adjustment to 7-8, and then concentrated under reduced pressure to give Compound Int C-5 (800 mg). MS (ESI, m/z): 124.1[ M+H ] +.
Fourth step: synthesis of (R) -1- (pyrimidin-2-yl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) ethan-1-amine (Int C)
Int C-5 (600 mg,1.46 mmol) and Int C-6 (255.93 mg,1.46 mmol) were dissolved in anhydrous DCM (20 mL) and AcOH (175.53 mg,2.92 mmol) was added and the resulting mixture stirred at 25℃for 30min. NaBH (OAc) 3 (464.65 mg,2.19 mmol) was then added and after the addition was complete the reaction was continued at 25℃for 1.5hr. After completion of the reaction, the reaction was quenched with methanol, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (mobile phase DCM: meoh=92:8) to give compound Int C (230 mg). MS (ESI, m/z): 283.1[ M+H ] +.
Intermediate Int D4- ((2, 4-dimethylbenzyl) amino) -3-methylimidazo [1,5-a ] quinoxaline-8-carboxylic acid (Int D)
The first step: synthesis of N- (4-bromo-2-fluorophenyl) -4-methyl-1H-imidazole-5-carboxamide (Compound Int D-2)
Int D-1 (5 g,39.65 mmol) was dissolved in anhydrous DMF (60 mL) in an ice-water bath, DIPEA (10.25 g,79.29 mmol) was slowly added dropwise, after stirring well, HATU (22.61 g,59.47 mmol) in anhydrous DMF was added dropwise, stirring continued for 1h, finally Int A-2 (8.29 g,43.61 mmol) in anhydrous DMF was added dropwise, and the mixture was allowed to react naturally to 25℃for 16 h. After the reaction, water was added thereto, followed by stirring, extraction with ethyl acetate and concentration to obtain a crude product, which was purified by silica gel column chromatography (mobile phase PE: ea=40:60) to obtain compound Int D-2 (5.40 g). MS (ESI, m/z): 298.0[ M+H ] +.
And a second step of: synthesis of 8-bromo-3-methylimidazo [1,5-a ] quinoxalin-4 (5H) -one (Compound Int D-3)
Int D-2 (5.40 g,18.11 mmol) was dissolved in anhydrous DMAc (50 mL), 60% pure sodium hydride (1.09 g,27.17 mmol) was added in portions under ice, and after stirring for 10min, the mixture was reacted at 140℃for 48hr. After the completion of the reaction, the mixture was cooled to room temperature, stirred with water, and concentrated by extraction with ethyl acetate to give Compound Int D-3 (3.50 g). MS (ESI, m/z): 278.0[ M+H ] +.
And a third step of: synthesis of 8-bromo-N- (2, 4-dimethoxybenzyl) -3-methylimidazo [1,5-a ] quinoxalin-4-amine (Compound Int D-4)
To anhydrous DMF (20 mL) was added Int D-3 (2.00 g,7.19 mmol) and PyBOP (7.48 g,14.38 mmol) under ice bath, DIPEA (2.79 g,21.57 mmol) was added dropwise and stirred for 10min, and finally Int A-6 (2.40 g,14.38 mmol) was added and reacted at 60℃for 16hr. After the reaction, water was added thereto, followed by stirring, extraction with ethyl acetate and concentration to obtain a crude product, which was purified by reverse phase HPLC column chromatography (mobile phase H 2O[0.05% NH4HCO3: ACN=20:80) to obtain Compound Int D-4 (1.20 g). MS (ESI, m/z): 427.1[ M+H ] +.
Fourth step: synthesis of methyl 4- ((2, 4-dimethoxybenzyl) amino) -3-methylimidazo [1,5-a ] quinoxaline-8-carboxylate (Compound Int D-5)
To the autoclave were added Int D-4 (1.20 g,2.81 mmol), TEA (852.54 mg,8.43 mmol), pd (dppf) 2Cl2 (227.64 mg, 280.84. Mu. Mol), and dissolved in methanol (30 mL), and after carbon monoxide substitution, the mixture was pressurized to 1.2atm and reacted at 120℃for 16hr. After the reaction, the temperature is reduced to room temperature, the mixture is filtered by suction, and the filter cake is compound Int D-5 (614 mg). MS (ESI, m/z): 407.2[ M+H ] +.
Fifth step: synthesis of 4- ((2, 4-dimethoxybenzyl) amino) -3-methylimidazo [1,5-a ] quinoxaline-8-carboxylic acid (Compound Int D)
Int D-5 (614 mg,1.51 mmol) was dissolved in methanol (10 mL) under ice bath, and an aqueous solution (2 mL) of sodium hydroxide (181.28 mg,4.53 mmol) was added dropwise thereto and reacted at 55℃for 3hr. After the reaction, the methanol is dried by spinning, dilute hydrochloric acid is added dropwise to the rest part of the solution until the solution is acidic in ice bath, suction filtration is carried out, and a filter cake is washed with water for 2 times, thus obtaining a compound Int D (446 mg). MS (ESI, m/z): 393.1[ M+H ] +.
Intermediate Int E (S) -N-methyl-6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-amine (Int E)
The first step: synthesis of tert-butyl (S) - (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) carbamate (Int E-2)
Int E-1 (200 mg, 984.44. Mu. Mol), TEA (109.58 mg,1.08 mmol) were dissolved in DCM (15 mL) under an ice-water bath, and (Boc) 2 O (214.85 mg, 984.44. Mu. Mol) was slowly added and the mixture was allowed to react at 25℃for 16hr. After the reaction, the mixture was concentrated and purified by silica gel column chromatography (mobile phase DCM: meoh=98:2) to give compound Int E-2 (295.45 mg).
And a second step of: synthesis of tert-butyl (S) -methyl (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) carbamate (Int E-3)
Int E-2 (100 mg, 329.73. Mu. Mol) was dissolved in anhydrous THF (10 mL), 60% pure sodium hydride (19.78 mg, 494.60. Mu. Mol) was added in portions under ice bath, stirred for 15min, methyl iodide (51.48 mg, 362.71. Mu. Mol) was added dropwise thereto, and the mixture was reacted at 0℃for 16hr. After the reaction, the mixture was concentrated and purified by silica gel column chromatography (mobile phase DCM: meoh=100:0) to give compound Int E-3 (100.00 mg).
And a third step of: synthesis of (S) -N-methyl-6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-amine (Int E) hydrochloride
Int E-3 (100 mg, 315.16. Mu. Mol) was dissolved in methylene chloride (9 mL), and 4M dioxane hydrochloride solution (1.5 mL) was added dropwise thereto at 0℃and the temperature was raised naturally to 25℃for 6hr. After the reaction, the mixture was concentrated to give the hydrochloride salt of Int E (68.8 mg). MS (ESI, m/z): 218.2[ M+H ] +.
Intermediate Int F4- ((2, 4-dimethoxybenzyl) amino) -7-methylimidazo [1,5-a ] quinoxaline-8-carboxylic acid (Int F)
The first step: synthesis of N- (4-bromo-2-fluoro-5-methylphenyl) -1H-imidazole-5-carboxamide (Int F-2)
Int A-1 (3 g,26.77 mmol) was dissolved in anhydrous DMF (50 mL) in an ice-water bath, DIPEA (6.92 g,53.53 mmol) was slowly added dropwise, after stirring well, HATU (15.27 g,40.15 mmol) in anhydrous DMF was added dropwise, stirring continued for 1h, finally Int F-1 (6.01 g,29.44 mmol) in anhydrous DMF was added dropwise, and the mixture was allowed to react naturally to 25℃for 16 h. After the reaction, water was added thereto, and the mixture was stirred, extracted and concentrated with ethyl acetate to obtain a crude product, which was purified by silica gel column chromatography (mobile phase PE: ea=15:85) to obtain compound Int F-2 (5.65 g). MS (ESI, m/z): 298.0[ M+H ] +.
And a second step of: synthesis of 8-bromo-7-methylimidazo [1,5-a ] quinoxalin-4 (5H) -one (Int F-3)
Int F-2 (5.65 g,18.95 mmol) was dissolved in anhydrous DMAc (35 mL), naH (1.14 g,28.43 mmol) was added in portions under ice, and after stirring for 10min, the reaction was carried out at 140℃for 48hr. After the reaction is completed, cooling to room temperature, naturally precipitating, and carrying out suction filtration to obtain a compound Int F-3 (1.70 g), and drying the crude product for use. MS (ESI, m/z): 278.0[ M+H ] +.
And a third step of: synthesis of 8-bromo-N- (2, 4-dimethoxybenzyl) -7-methylimidazo [1,5-a ] quinoxalin-4-amine (Int F-4)
To anhydrous DMF (20 mL) was added Int F-3 (700 mg,2.52 mmol) and PyBOP (1.96 g,3.78 mmol) under ice bath, DIPEA (975.91 mg,7.55 mmol) was added dropwise and stirred for 10min, and finally Int A-6 (841.72 mg,5.03 mmol) was added and reacted at 60℃for 16hr. After the reaction, water was added thereto, followed by stirring, extraction with ethyl acetate and concentration to obtain a crude product, which was purified by reverse phase HPLC column chromatography (mobile phase H 2 O: acn=20:80) to give compound Int F-4 (900 mg). MS (ESI, m/z): 427.0[ M+H ] +.
Fourth step: synthesis of methyl 4- ((2, 4-dimethoxybenzyl) amino) -7-methylimidazo [1,5-a ] quinoxaline-8-carboxylate (Int F-5)
To the autoclave were added Int F-4 (800 mg,1.87 mmol), TEA (568.36 mg,5.62 mmol), pd (dppf) 2Cl2 (151.76 mg, 187.22. Mu. Mol), and dissolved in 30mL of methanol, and after carbon monoxide substitution, the mixture was pressurized to 1.2atm and reacted at 120℃for 16hr. After the reaction, the temperature is reduced to room temperature, the crude product is concentrated to obtain a crude product, and the crude product is purified by silica gel column chromatography (mobile phase DCM: meOH=96:4) to obtain a compound Int F-5 (332 mg), and the compound Int F-5 is dried and used. MS (ESI, m/z): 407.1[ M+H ] +.
Fifth step: synthesis of 4- ((2, 4-dimethoxybenzyl) amino) -7-methylimidazo [1,5-a ] quinoxaline-8-carboxylic acid (Int F)
Int F-5 (336 mg, 816.86. Mu. Mol) was dissolved in methanol (10 mL) in an ice bath, and an aqueous solution (2 mL) of NaOH (98.02 mg,2.45 mmol) was added dropwise thereto and reacted at 55℃for 3hr. After the reaction is finished, the methanol is dried by spinning, dilute hydrochloric acid is added dropwise to the rest part of the solution until the solution is acidic in an ice bath, suction filtration is carried out, a filter cake is washed with water for 2 times, and the compound Int F (236.80 mg) is obtained, and is used after drying without purification. MS (ESI, m/z): 393.1[ M+H ] +.
Intermediate Int G4- ((2, 4-dimethoxybenzyl) amino) -7-trifluoromethylimidazo [1,5-a ] quinoxaline-8-carboxylic acid (Int G)
The first step: synthesis of N- (4-bromo-2-fluoro-5- (trifluoromethyl) phenyl) -1H-imidazole-5-carboxamide (Int G-2)
Int A-1 (2.17G, 19.38 mmol) was dissolved in anhydrous DMF (50 mL) in an ice-water bath, DIPEA (3.76G, 29.07 mmol) was slowly added dropwise, HATU (8.84G, 23.25 mmol) was added after stirring well, stirring was continued for 1h, and finally Int G-1 (5G, 19.38 mmol) was added and the reaction was allowed to proceed naturally to 25℃for 16hr. After the reaction, water was added thereto, and the mixture was stirred, extracted and concentrated with EA to obtain a crude product, which was purified by silica gel column chromatography (mobile phase PE: ea=47:53) to obtain compound Int G-2 (1.55G). MS (ESI, m/z): 351.9[ M+H ] +.
And a second step of: synthesis of 8-bromo-7- (trifluoromethyl) imidazo [1,5-a ] quinoxalin-4 (5H) -one (Int G-3)
Int G-2 (1.55G, 4.40 mmol) was dissolved in anhydrous DMAc (50 mL), and sodium hydride (264.14 mg,6.60 mmol) was added in portions under ice, followed by stirring for 10min and then reaction at 100℃for 12hr. After the completion of the reaction, the mixture was cooled to room temperature, stirred with water, and concentrated by extraction with ethyl acetate to give Compound Int G-3 (1.40G). MS (ESI, m/z): 332.0[ M+H ] +.
And a third step of: synthesis of 8-bromo-N- (2, 4-dimethoxybenzyl) -7- (trifluoromethyl) imidazo [1,5-a ] quinoxalin-4-amine (Int G-4)
To anhydrous DMF (5 mL) was added Int G-3 (0.40G, 1.20 mmol) and PyBOP (940.25 mg,1.81 mmol) in ice bath, DIPEA (467.03 mg,3.61 mmol) was added dropwise and then stirred for 10min, and finally Int A-6 (302.11 mg ) was added and reacted at 60℃for 16hr. After the reaction, water was added thereto, followed by stirring, extraction with ethyl acetate and concentration to obtain a crude product, which was purified by reverse phase HPLC column chromatography (mobile phase H 2 O: acn=36:64) to obtain compound Int G-4 (0.25G). MS (ESI, m/z): 481.1[ M+H ] +.
Fourth step: synthesis of methyl 4- ((2, 4-dimethoxybenzyl) amino) -7- (trifluoromethyl) imidazo [1,5-a ] quinoxaline-8-carboxylate (Int G-5)
To the autoclave were added Int G-4 (0.25G, 519.46. Mu. Mol), TEA (157.69 mg,1.56 mmol), pd (dppf) 2Cl2 (42.11 mg, 51.95. Mu. Mol), and dissolved in methanol (10 mL), and after carbon monoxide substitution, the mixture was pressurized to 1.2atm and reacted at 120℃for 12 hours. Cooling to room temperature after the reaction, filtering, concentrating under reduced pressure, and separating and purifying by Prep-TLC (PE: EA=8:2) to obtain a compound Int G-5 (70 mg). MS (ESI, m/z): 461.1[ M+H ] +.
Fifth step: synthesis of 4- ((2, 4-dimethoxybenzyl) amino) -7- (trifluoromethyl) imidazo [1,5-a ] quinoxaline-8-carboxylic acid (Int G)
Int G-5 (70 mg, 152.04. Mu. Mol) was dissolved in ethanol (10 mL) and H 2 O (2 mL), naOH (12.16 mg, 304.08. Mu. Mol) was added, and the mixture was reacted at 55℃for 3hr. After completion of the reaction, the solvent was removed by concentration under reduced pressure to give Compound Int G (65 mg). MS (ESI, m/z): 447.1[ M+H ] +.
Intermediate Int H N-methyl-6- (trifluoromethyl) isochroman-4-amine (Int H)
The first step: synthesis of 1- ((allyloxy) methyl) -2-bromo-4- (trifluoromethyl) benzene (Compound Int H-2)
To the reaction flask were added Int H-1 (10.50 g,41.17 mmol), allyl bromide (14.94 g,123.51 mmol), tert-butyl ammonium bisulfate (2.10 g,6.18 mmol), KOH (4.39 g,78.23 mmol), and the mixture was reacted at 25℃for 16hr under nitrogen protection without solvent. After the reaction was completed, the reaction mixture was diluted with water, extracted with ethyl acetate (150 ml×3), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (mobile phase EA: pe=5:95) and dried by spin to give compound Int H-2 (11.87 g).
And a second step of: synthesis of 4-methylene-6- (trifluoromethyl) isochroman (Compound Int H-3)
To the flask was added Int H-2(11.87g,40.22mmol)、DMF(100mL)、PPh3(3.17g,12.07mmol)、Cs2CO3(15.73g,48.27mmol),, followed by stirring, pd (OAc) 2 (903 mg,4.02 mmol), nitrogen blanket, and reaction at 90℃for 16hr. After the reaction was completed, the reaction mixture was diluted with water, extracted with ethyl acetate (80 ml×3), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (mobile phase EA: pe=5:95) and dried by spin to give compound Int H-3 (6.5 g).
And a third step of: synthesis of 6- (trifluoromethyl) isochroman-4-one (Compound Int H-4)
To the reaction flask were added Int H-3 (6 g,28.01 mmol), 1, 4-dioxane (75 mL), H 2 O (75 mL), and after stirring well, the mixture was cooled in an ice-water bath, naIO 4 (17.98 g,84.04 mmol) was added, and after stirring for 5min, K 2OsO4·2H2 O (516 mg,1.40 mmol) was added, and the mixture was reacted at 0℃for 3hr. After the reaction was completed, the reaction mixture was diluted with water, extracted with ethyl acetate (80 ml×3), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (mobile phase EA: pe=15:85) and dried by spin to give compound Int H-4 (4.65 g).
Fourth step: synthesis of 6- (trifluoromethyl) isochroman-4-ol (Compound Int H-5)
Int H-4 (4.65 g,21.51 mmol) and MeOH (80 mL) were added to the flask, dissolved, cooled in an ice-water bath, and then NaBH 4 (1.06 g,27.97 mmol) was added thereto for reaction at 0℃for 1hr under nitrogen protection. After the reaction was completed, the reaction mixture was quenched with water, the solvent was concentrated to dryness under reduced pressure, diluted with water, extracted with ethyl acetate (60 ml×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the compound Int H-5 (4.5 g). MS (ESI, m/z): 201.1[ M+H-18] +.
Fifth step: synthesis of 6- (trifluoromethyl) isochroman-4-yl 4-methylbenzenesulfonate (Compound Int H-6)
The reaction flask was charged with compound Int H-5 (4.7 g,21.54 mmol), tsCl (4.52 g,23.70 mmol), DCM (100 mL), DMAP (131 mg,1.08 mmol), TEA (5.45 g,53.86 mmol), under nitrogen, and reacted at 25℃for 30min. After the reaction was completed, the reaction mixture was diluted with water, extracted with DCM (80 ml×3), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound Int H-6 (8.3 g). MS (ESI, m/z): 390.2[ M+18] +.
Sixth step: synthesis of 1- (6- (trifluoromethyl) isochroman-4-yl) triazane (Compound Int H-7)
To the flask were added Int H-6 (8.3 g,22.29 mmol), naN 3 (2.17 g,33.44 mmol), acetone (150 mL), and the mixture was reacted at 40℃for 16hr under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate (60 ml×3), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (mobile phase EA: pe=10:90) and dried by spin to give compound Int H-7 (5.2 g).
Seventh step: synthesis of 6- (trifluoromethyl) isochroman-4-amine (Compound Int H-8)
To the flask was added Int H-7 (5.4 g,22.21 mmol), pd/C (2.70 g,22.21 mmol), meOH (100 mL), hydrogen balloon displacement, and reaction at 25℃for 3hr. After the reaction was completed, the reaction mixture was directly filtered through celite, and the cake was washed with MeOH, and the filtrate was collected and concentrated under reduced pressure to give the compound Int H-8 (4.6 g). MS (ESI, m/z): 218.1[ M+H ] +.
Eighth step: synthesis of tert-butyl (6- (trifluoromethyl) isochroman-4-yl) carbamate (Compound Int H-9)
Int H-8 (4.6 g,21.18 mmol), TEA (2.57 g,25.42 mmol), di-tert-butyl dicarbonate (4.62 g,21.18 mmol) was added to DCM (200 mL) and stirred overnight at room temperature. After the reaction was completed, the reaction mixture was diluted with water, extracted with DCM (80 ml×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (mobile phase EA: pe=10:90) and dried by spin to give compound Int H-9 (4.65 g). MS (ESI, m/z): 262.1[ M+H-56] +.
Ninth step: synthesis of tert-butyl (6- (trifluoromethyl) isochroman-4-yl) carbamate (Compound Int H-10)
Int H-9 (4.65 g,14.65 mmol) and THF (120 mL) were added to the flask, the temperature was lowered in an ice-water bath under nitrogen protection, naH (879.29 mg,21.98 mmol) was added thereto, and after 30min reaction at 0deg.C, CH 3 I (2.39 g,16.85mmol,1.05 mL) was added thereto, and the reaction was carried out at room temperature for 16hr while naturally warming. After the completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate (70 ml×3), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Compound Int H-10 (4.5 g). MS (ESI, m/z): 276.1[ M-56] +.
Tenth step: synthesis of N-methyl-6- (trifluoromethyl) isochroman-4-amine (Compound Int H)
To the flask was added Int H-10 (4.5 g,13.58 mmol), 4M HCl in 1, 4-dioxane (25 mL), DCM (50 mL), and the mixture was reacted at 25℃for 2hr under nitrogen. After the reaction is finished, the crude product is obtained by directly concentrating under reduced pressure. Saturated sodium bicarbonate solution was added to dilute, extraction was performed with ethyl acetate (60 ml x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound Int H (3 g,12.98 mmol). MS (ESI, m/z): 232.1[ M+H ] +.
Eleventh step: synthesis of (R) -N-methyl-6- (trifluoromethyl) isochroman-4-amine (Compound Int H-Peak 1) and (S) -N-methyl-6- (trifluoromethyl) isochroman-4-amine (Compound Int H-Peak 2)
Int H was resolved by SFC (column: DAICEL CHIRALPAK IG (250 mm. 30mm,10 μm); mobile phase: A phase: N-hexane; B phase: ethanol (0.1% isopropylamine), elution gradient: A%: B% = 100%:0%, isocratic elution (isocratic elution mode)) to give (R) -N-methyl-6- (trifluoromethyl) isochroman-4-amine (compound Int H-peak 1) (retention time 1.889min,93.8% ee) and (S) -N-methyl-6- (trifluoromethyl) isochroman-4-amine (compound Int H-peak 2) (retention time 2.226min,98.9% ee).
Compound Int H-peak 1:1H NMR(400MHz,CD3OD)δ7.48-7.58(m,2H),7.40(s,1H),4.90(s,1H),4.70-4.78(m,1H),4.17(dd,J=12.0,2.4Hz,1H),3.82(dd,J=12.0,2.8Hz,1H),3.61(s,1H),2.43(s,3H).
Compound Int H-peak 2:1H NMR(400MHz,CD3OD)δ7.48-7.58(m,2H),7.40(s,1H),4.90(s,1H),4.70-4.77(m,1H),4.17(dd,J=12.0,2.4Hz,1H),3.82(dd,J=12.0,2.8Hz,1H),3.61(s,1H),2.43(s,3H).
Intermediate Int I7-chloro-4- ((2, 4-dimethoxybenzyl) amino) imidazo [1,5-a ] quinoxaline-8-carboxylic acid (Int I)
First step, synthesis of N- (4-bromo-5-chloro-2-fluorophenyl) -1H-imidazole-5-carboxamide (Compound Int I-2)
Int A-1 (2.50 g,22.28 mmol) was dissolved in anhydrous DMF (50 mL) in an ice-water bath, DIPEA (8.64 g,66.83 mmol) was slowly added dropwise, after stirring well, HATU (16.94 g,44.55 mmol) in anhydrous DMF was added dropwise, stirring continued for 1h, finally Int I-1 (5.0 g,22.28 mmol) in anhydrous DMF was added dropwise and the reaction was carried out by naturally rising to 80℃for 16h. After the reaction, water was added thereto, followed by stirring, extraction with ethyl acetate and concentration to obtain a crude product, which was purified by silica gel column chromatography (mobile phase PE: ea=24:76) to obtain compound Int I-2 (3.94 g). MS (ESI, m/z): 317.9[ M+H ] +.
And a second step of: synthesis of 8-bromo-7-chloroimidazo [1,5-a ] quinoxalin-4 (5H) -one (Compound Int I-3)
Int I-2 (3.94 g,12.37 mmol) was dissolved in anhydrous DMAc (40 mL), sodium hydride (742.16 mg,18.55 mmol) was added in portions under ice, and after stirring for 10min, the reaction was carried out at 140℃for 48hr. After the completion of the reaction, the mixture was cooled to room temperature, stirred with water, and concentrated by extraction with ethyl acetate to give Compound Int I-3 (2.59 g). MS (ESI, m/z): 298.0[ M+H ] +.
And a third step of: synthesis of 8-bromo-7-chloro-N- (2, 4-dimethoxybenzyl) imidazo [1,5-a ] quinoxalin-4-amine (Compound Int I-4)
To anhydrous DMF (20 mL) was added Int I-3 (2.59 g,8.68 mmol) and PyBOP (9.03 g,17.35 mmol) under ice bath, DIPEA (3.36 g,26.03 mmol) was added dropwise and stirred for 10min, and finally Int A-6 (4.35 g,26.03 mmol) was added and reacted at 60℃for 16hr. After the reaction, water was added thereto, followed by stirring, extraction with ethyl acetate and concentration to obtain a crude product, which was purified by reverse phase HPLC column chromatography (mobile phase H 2 O: acn=20:80) to give compound Int I-4 (1.00 g). MS (ESI, m/z): 447.1[ M+H ] +.
Fourth step: synthesis of methyl 7-chloro-4- ((2, 4-dimethoxybenzyl) amino) imidazo [1,5-a ] quinoxaline-8-carboxylate (Compound Int I-5)
To the autoclave were added Int I-4 (1.00 g,2.23 mmol), TEA (678.05 mg,6.70 mmol), pd (dppf) 2Cl2 (163.43 mg, 223.36. Mu. Mol), and dissolved in methanol (30 mL), and after carbon monoxide substitution, the mixture was pressurized to 1.2atm and reacted at 120℃for 16hr. After the reaction, the temperature is reduced to room temperature, and the compound Int I-5 (950 mg) is obtained by direct concentration. MS (ESI, m/z): 427.2[ M+H ] +.
Fifth step: synthesis of 7-chloro-4- ((2, 4-dimethoxybenzyl) amino) imidazo [1,5-a ] quinoxaline-8-carboxylic acid (Compound Int I)
Int I-5 (950 mg,2.23 mmol) was dissolved in methanol (30 mL) under ice-bath, and an aqueous solution (4 mL) of sodium hydroxide (267.07 mg,6.68 mmol) was added dropwise thereto and reacted at 55℃for 3hr. After the reaction, dilute hydrochloric acid is added dropwise under ice water bath until the solution is acidic, the solution is concentrated to obtain a crude product, and the crude product is purified by reversed-phase HPLC column chromatography (mobile phase H 2 O: ACN=44:56) to obtain a compound Int I (200 mg). MS (ESI, m/z): 413.0[ M+H ] +.
Intermediate Int J7-fluoro-4- ((2, 4-dimethoxybenzyl) amino) imidazo [1,5-a ] quinoxaline-8-carboxylic acid (Int J)
The first step: synthesis of N- (4-bromo-2, 5-difluorophenyl) -1H-imidazole-5-carboxamide (Compound Int J-2)
Int A-1 (2.69 g, 24.04) was dissolved in anhydrous DMF (150 mL) in an ice-water bath, DIPEA (4.66 g,36.06 mmol) was slowly added dropwise, after stirring well HATU (10.97 g,28.85 mmol) was added, stirring was continued for 1h, and finally Int J-1 (5 g, 24.04) was added and the reaction was continued for 48hr at 60 ℃. After the reaction, water was added thereto, and the mixture was stirred, extracted and concentrated with ethyl acetate to obtain a crude product, which was purified by silica gel column chromatography (mobile phase PE: ea=63:37) to obtain compound Int J-2 (6.0 g). MS (ESI, m/z): 302.0[ M+H ] +.
And a second step of: synthesis of 8-bromo-7-fluoroimidazo [1,5-a ] quinoxalin-4 (5H) -one (Compound Int J-3)
Int J-2 (6.0 g,19.86 mmol) was dissolved in anhydrous DMAc (100 mL), and sodium hydride (1.19 g,29.79 mmol) was added in portions while stirring for 10min and then heated to 140℃for reaction for 72hr. After the reaction was completed, the mixture was cooled to room temperature, stirred with water, extracted with ethyl acetate, concentrated, and then purified by reverse phase column chromatography (H 2 O [0.05% ammonium bicarbonate ]: meCN=72:28) to give Compound Int J-3 (0.5 g). MS (ESI, m/z): 282.0[ M+H ] +.
And a third step of: synthesis of 8-bromo-N- (2, 4-dimethoxybenzyl) -7-fluoroimidazo [1,5-a ] quinoxalin-4-amine (Compound Int J-4)
To anhydrous DMF (30 mL) was added Int J-3 (380 mg,1.35 mmol) and PyBOP (1.05 g,2.02 mmol) under ice bath, DIPEA (522.33 mg,4.04 mmol) was added dropwise thereto and then stirred for 10min, and finally Int A-6 (337.88 mg,2.02 mmol) was added thereto and reacted at 60℃for 16hr. After the reaction, water was added thereto, followed by stirring, extraction with ethyl acetate and concentration to obtain a crude product, which was purified by reverse phase column chromatography (mobile phase H 2 O: acn=36:64) to give compound Int J-4 (0.50 g). MS (ESI, m/z): 431.1[ M+H ] +.
Fourth step: synthesis of methyl 4- ((2, 4-dimethoxybenzyl) amino) -7-fluoroimidazo [1,5-a ] quinoxaline-8-carboxylate (Compound Int J-5)
To the autoclave were added Int J-4 (0.50 g,1.16 mmol), TEA (351.96 mg,3.48 mmol), pd (dppf) 2Cl2 (93.98 mg, 115.94. Mu. Mol), and dissolved in methanol (20 mL), and after carbon monoxide substitution, the mixture was pressurized to 1.2MPa and reacted at 120℃for 6hr. After the reaction, the temperature is reduced to room temperature, suction filtration and decompression concentration are carried out to obtain the compound Int J-5 (70 mg). MS (ESI, m/z): 411.1[ M+H ] +.
Fifth step: synthesis of 4- ((2, 4-dimethoxybenzyl) amino) -7-fluoroimidazo [1,5-a ] quinoxaline-8-carboxylic acid (Compound Int J)
Int J-5 (400 mg, 974.66. Mu. Mol) was dissolved in ethanol (10 mL) and H 2 O (2 mL), sodium hydroxide (77.97 mg,1.95 mmol) was added thereto, and the mixture was heated to 90℃and reacted for 2hr. After the completion of the reaction, the solvent was removed by concentration under reduced pressure, and purified by reverse phase column chromatography (mobile phase H 2 O [0.05% formic acid ]: ACN=65:35) to give compound Int J (320 mg). MS (ESI, m/z): 397.1[ M+H ] +.
Intermediate Int K4-Aminoimidazo [1,5-a ] pyrido [3,4-e ] pyrazine-8-carboxylic acid (Int K)
First step, synthesis of N- (4, 6-dichloropyridin-3-yl) -1H-imidazole-5-carboxamide (Compound Int K-3)
Compound Int K-1 (8 g,49.08 mmol) was dissolved in anhydrous THF (100 mL), naHDMS (2M, 49.08mL,98.16 mmol) was added at-10deg.C, stirring was completed for 1hr at-10deg.C, then Int K-2 (5.77 g,24.54 mmol) in THF (100 mL) was added, the reaction was continued for 2hr at 25deg.C, after completion of the reaction, an appropriate amount of acetic acid was added for quenching, concentrating under reduced pressure, then saturated aqueous sodium bicarbonate was added, filtering, collecting the solid product, washing with water and hexane, and drying to obtain Compound Int K-3 (10 g). MS (ESI, m/z): 257.0[ M+H ] +.
And a second step of: synthesis of 8-chloroimidazo [1,5-a ] pyrido [3,4-e ] pyrazin-4 (5H) -one (Compound Int K-4)
Compound Int K-3 (10 g,38.90 mmol) was dissolved in anhydrous DMF (100 mL), DBU (17.77 g,116.70 mmol) was added and the reaction was carried out at 160℃for 1hr. After the reaction is completed, cooling to room temperature, concentrating under reduced pressure, adding water, dissolving saturated ammonium chloride aqueous solution, filtering, washing with water, collecting filter cakes, drying and concentrating to obtain a compound Int K-4 (8 g). MS (ESI, m/z): 221.0[ M+H ] +.
And a third step of: synthesis of 8-chloro-N- (2, 4-dimethoxybenzyl) imidazo [1,5-a ] pyrido [3,4-e ] pyrazin-4-amine (Compound Int K-5)
Compound Int K-4 (5 g,22.66 mmol), DIPEA (4.39 g,34.00 mmol) and Int A-6 (5.68 g,34.00 mmol) were dissolved in anhydrous DMF (300 mL), pyBOP (12.97 g,24.93 mmol) was added in portions with stirring and the addition was warmed to 60℃for 5hr. After the reaction, water was added for dilution, EA extraction and concentration gave a crude product, which was purified by reverse phase column chromatography (mobile phase H 2 O (0.05% hydrogen carbonate amine): ACN=36:64) to give compound Int K-5 (4.5 g). MS (ESI, m/z): 370.1[ M+H ] +.
Fourth step: synthesis of methyl 4- ((2, 4-dimethoxybenzyl) amino) imidazo [1,5-a ] pyrido [3,4-e ] pyrazine-8-carboxylate (Compound Int K-6)
To the autoclave was added compound Int K-5 (4.50 g,12.17 mmol), TEA (3.69 g,36.51 mmol), pd (dppf) Cl 2. DCM (986.37 mg,1.22 mmol) and dissolved with methanol (20 mL), pressurized to 1.2MPa after carbon monoxide substitution, and then warmed to 120℃for reaction for 12hr. After the reaction, the temperature is reduced to room temperature, suction filtration and decompression concentration are carried out to obtain the compound Int K-6 (4.7 g). MS (ESI, m/z): 394.1[ M+H ] +.
Fifth step: synthesis of 4- ((2, 4-dimethoxybenzyl) amino) imidazo [1,5-a ] pyrido [3,4-e ] pyrazine-8-carboxylic acid (Compound Int K-7)
Compound Int K-6 (4.7 g,11.95 mmol) was dissolved in methanol (150 mL) and H 2 O (30 mL), sodium hydroxide (955.78 mg,23.89 mmol) was added, and the temperature was raised to 60℃after the addition to react for 3hr. After the reaction, the mixture is concentrated under reduced pressure to remove methanol, a small amount of water is added for dilution, 1N hydrochloric acid is added for adjusting the pH to about 6, solid is separated out, filtered, washed with water, and a filter cake is dried to obtain a compound Int K-7 (4.3 g). MS (ESI, m/z): 380.2[ M+H ] +.
Sixth step: synthesis of 4-aminoimidazo [1,5-a ] pyrido [3,4-e ] pyrazine-8-carboxylic acid (Compound Int K)
Compound Int K-7 (4.3 g,3.78 mmol) was dissolved in TFA (80 mL) and reacted at 90℃for 2hr. After the completion of the reaction, the solvent was removed by concentration under reduced pressure to give Compound Int K (3.8 g). MS (ESI, m/z): 230.0[ M+H ] +.
Intermediate Int L6-Aminoimidazo [1,5-a ] pyrido [3,2-e ] pyrazine-2-carboxylic acid (Int L)
The first step: synthesis of N- (2, 6-dichloropyridin-3-yl) -1H-imidazole-5-carboxamide (Compound Int L-2)
Int L-1 (5.1 g,31.29 mmol) was dissolved in anhydrous THF (100 mL), naHDMS (2.0M, 31.29mL,62.57 mmol) was added at-10℃and stirred for 1hr at-10℃after the addition, then Int K-2 (2.94 g,15.64 mmol) in THF (50 mL) was added and the reaction was continued for 2hr at 25℃after the addition was completed, quenched by addition of an appropriate amount of acetic acid, concentrated under reduced pressure, then saturated aqueous sodium bicarbonate was added, filtered, the solid product was collected, washed with water and hexane and dried to give Compound Int L-2 (4.7 g). MS (ESI, m/z): 257.0[ M+H ] +.
And a second step of: synthesis of 2-chloroimidazo [1,5-a ] pyrido [3,2-e ] pyrazin-6 (5H) -one (Compound Int L-3)
Compound Int L-2 (14.7 g,18.28 mmol) was dissolved in anhydrous DMAc (100 mL), K 2CO3 (7.58 g,54.85 mmol) was added, and the temperature was raised to 130℃after the addition to react for 6hr. After the reaction was completed, cooling to room temperature, concentrating under reduced pressure, adding water, dissolving in saturated ammonium chloride aqueous solution, filtering, washing with water, collecting a cake, drying, and concentrating to obtain Compound Int L-3 (3.4 g). MS (ESI, m/z): 221.0[ M+H ] +.
And a third step of: synthesis of 2-chloro-N- (2, 4-dimethoxybenzyl) imidazo [1,5-a ] pyrido [3,2-e ] pyrazin-6-amine (Compound Int L-4)
Compound Int L-3 (3.4 g,15.41 mmol), DIPEA (2.99 g,23.12 mmol) and Int A-6 (3.87 g,23.12 mmol) were dissolved in anhydrous DMF (200 mL), pyBOP (9.62 g,18.49 mmol) was added in portions with stirring and the addition was warmed to 60℃for 16hr. After the reaction, water was added for dilution, and EA was extracted and concentrated to obtain a crude product, which was purified by reverse phase column chromatography (mobile phase H 2 O (0.05% hydrogen carbonate amine): acn=36:64) to obtain compound Int L-4 (2.4 g). MS (ESI, m/z): 370.1[ M+H ] +.
Fourth step: synthesis of methyl 6- ((2, 4-dimethoxybenzyl) amino) imidazo [1,5-a ] pyrido [3,2-e ] pyrazine-2-carboxylate (Compound Int L-5)
To the autoclave were added Int L-4 (2.4 g,6.49 mmol), pd (dppf) Cl 2. DCM (526.07 mg, 648.99. Mu. Mol), TEA (1.97 g,19.47 mmol) and dissolved with methanol (15 mL), pressurized to 1.2MPa after carbon monoxide substitution, and then warmed to 120℃for reaction for 12hr. Cooling to room temperature after the reaction, filtering, and concentrating under reduced pressure to obtain a compound Int L-5 (2.5 g). MS (ESI, m/z): 394.1[ M+H ] +.
Fifth step: synthesis of 6- ((2, 4-dimethoxybenzyl) amino) imidazo [1,5-a ] pyrido [3,2-e ] pyrazine-2-carboxylic acid (Compound Int L-6)
Compound Int L-5 (2.5 g,6.35 mmol) was dissolved in methanol (100 mL) and H 2 O (20 mL), sodium hydroxide (508.39 mg,12.71 mmol) was added, and the temperature was raised to 60℃after the addition to react for 2hr. After the reaction, the mixture was concentrated under reduced pressure to remove methanol, diluted with a small amount of water, adjusted to pH 6 with 1N hydrochloric acid, precipitated as a solid, filtered, washed with water, and dried to give Compound Int L-6 (2.4 g). MS (ESI, m/z): 380.2[ M+H ] +.
Sixth step: synthesis of 6-aminoimidazo [1,5-a ] pyrido [3,2-e ] pyrazine-2-carboxylic acid (Compound Int L)
Int L-6 (0.1 g, 263.60. Mu. Mol) was dissolved in TFA (2 mL), and the mixture was heated to 90℃for 2hr. After completion of the reaction, the solvent was removed by concentration under reduced pressure to give Compound Int L (90 mg). MS (ESI, m/z): 230.1[ M+H ] +.
Intermediate Int M4- ((2, 4-dimethoxybenzyl) amino) imidazo [1,5-a ] pyrido [2,3-e ] pyrazine-8-carboxylic acid (Int M)
The first step: synthesis of N- (5-bromo-3-chloropyridin-2-yl) -1H-imidazole-5-carboxamide (Compound Int M-3)
Int M-1 (1.75 g,8.43 mmol) was dissolved in anhydrous THF (10 mL) in an ice-water bath, naH (674.16 mg,16.85 mmol) was added slowly in portions, stirred at room temperature for 30min, then Int M-2 (1.10 g,8.43 mmol) was added, and the mixture was allowed to react at room temperature for 8hr. After the reaction was completed, a small amount of water was added to quench the reaction, and the crude product was purified by silica gel column chromatography (mobile phase DCM: meoh=90:10) to give compound Int M-3 (1.00 g). MS (ESI, m/z): 300.9[ M+H ] +.
And a second step of: synthesis of 8-bromoimidazo [1,5-a ] pyrido [2,3-e ] pyrazin-4 (5H) -one (Compound Int M-4)
Int M-3 (1.00 g,3.32 mmol) was dissolved in anhydrous DMF (10 mL), and K 2CO3 (1.38 g,9.95 mmol) was added and reacted at 160℃for 6hr. After the completion of the reaction, the mixture was cooled to room temperature, stirred with water, and concentrated by EA extraction to give Compound Int M-4 (380 mg). MS (ESI, m/z): 265.0[ M+H ] +.
And a third step of: synthesis of 8-bromo-N- (2, 4-dimethoxybenzyl) imidazo [1,5-a ] pyrido [2,3-e ] pyrazin-4-amine (Compound Int M-5)
To anhydrous DMF (10 mL) was added Int M-4 (380 mg,1.43 mmol) and PyBOP (392.88 mg,2.15 mmol) under ice bath, DIPEA (555.84 mg,4.30 mmol) was added dropwise thereto and then stirred for 10min, and finally Int A-6 (479.41 mg,2.87 mmol) was added thereto for 16hr at 80 ℃. After the reaction, water was added thereto under stirring, and the crude product was concentrated by EA extraction and purified by silica gel column chromatography (mobile phase DCM: meoh=95:5) to give compound Int M-5 (340 mg). MS (ESI, m/z): 414.0[ M+H ] +.
Fourth step: synthesis of methyl 4- ((2, 4-dimethoxybenzyl) amino) imidazo [1,5-a ] pyrido [2,3-e ] pyrazine-8-carboxylate (Compound Int M-6)
To the autoclave were added Int M-5 (340 mg, 822.8. Mu. Mol), TEA (249.15 mg,2.46 mmol), pd (dppf) 2Cl2 (60.06 mg, 82.08. Mu. Mol), and dissolved in methanol (30 mL), and after carbon monoxide substitution, the mixture was pressurized to 1.2atm and reacted at 120℃for 16 hours. After the reaction, the temperature is reduced to room temperature, the crude product is concentrated and purified by reversed phase HPLC (mobile phase H 2 O: ACN=30:70) to obtain the compound Int M-6 (250 mg). MS (ESI, m/. Z): 394.2[ M+H ] +.
Fifth step: synthesis of 4- ((2, 4-dimethoxybenzyl) amino) imidazo [1,5-a ] pyrido [2,3-e ] pyrazine-8-carboxylic acid (Compound Int M)
Int M-6 (200 mg, 510.00. Mu. Mol) was dissolved in methanol (10 mL) in an ice bath, and an aqueous solution (2 mL) of sodium hydroxide (81.34 mg,2.04 mmol) was added dropwise thereto and reacted at 60℃for 3hr. After the reaction, the methanol was dried by spin drying, dilute hydrochloric acid was added dropwise to the remaining portion under ice bath until the solution became acidic, and the filter cake was washed with water 2 times to obtain the compound Int M (190.00 mg). MS (ESI, m/z): 380.2[ M+H ] +.
Intermediate Int N4-amino-9-fluoroimidazo [1,5-a ] quinoxaline-8-carboxylic acid (Int N)
The first step: synthesis of N- (4-bromo-2, 3-difluorophenyl) -1H-imidazole-5-carboxamide (Compound Int N-2)
Int N-1 (2 g,9.62 mmol) was dissolved in anhydrous THF (10 mL) in an ice-water bath, naH (1.54 g,38.46 mmol) was added slowly in portions, stirred at room temperature for 15min, int K-2 (2.89 g,11.54 mmol) was added, and the mixture was allowed to react at 60℃for 16hr. After the reaction, water was added thereto and stirred, and the mixture was concentrated by EA extraction to give Compound Int N-2 (1.50 g). MS (ESI, m/z): 302.0[ M+H ] +.
And a second step of: synthesis of 8-bromo-9-fluoroimidazo [1,5-a ] quinoxalin-4 (5H) -one (Compound Int N-3)
Int N-2 (1.50 g,4.97 mmol) was dissolved in anhydrous DMF (10 mL), and K 2CO3 (2.06 g,14.90 mmol) was added and reacted at 160℃for 4hr. After the completion of the reaction, the mixture was cooled to room temperature, water was added thereto, and a solid was precipitated by stirring, followed by suction filtration to obtain Compound Int N-3 (1.00 g). MS (ESI, m/z): 282.0[ M+H ] +.
And a third step of: synthesis of 8-bromo-N- (2, 4-dimethoxybenzyl) -9-fluoroimidazo [1,5-a ] quinoxalin-4-amine (Compound Int N-4)
To anhydrous DMF (10 mL) was added Int N-3 (400 mg,1.42 mmol) and PyBOP (1.11 g,2.13 mmol) under ice bath, DIPEA (549.82 mg,4.25 mmol) was added dropwise thereto and then stirred for 10min, and finally Int A-6 (474.21 mg,2.84 mmol) was added thereto and reacted at 60℃for 16hr. After the reaction, water was added and stirred, EA was extracted and concentrated to give a crude product, which was purified by silica gel column chromatography (mobile phase DCM: meoh=97:3) to give compound Int N-4 (294 mg). MS (ESI, m/z): 431.0[ M+H ] +.
Fourth step: synthesis of methyl 4- ((2, 4-dimethoxybenzyl) amino) -9-fluoroimidazo [1,5-a ] quinoxaline-8-carboxylate (Compound Int N-5)
To the autoclave were added Int N-4 (254 mg, 681.73. Mu. Mol), TEA (206.95 mg,2.05 mmol), pd (dppf) 2Cl2 (55.26 mg, 68.17. Mu. Mol), and dissolved in methanol (25 mL), and after carbon monoxide substitution, the mixture was pressurized to 1.2atm and reacted at 120℃for 5 hours. After the reaction, the temperature is reduced to room temperature, the crude product is concentrated and purified by reversed phase HPLC (mobile phase: H 2 O: ACN=30:70) to obtain the compound Int N-5 (212 mg). MS (ESI, m/. Z): 411.2[ M+H ] +.
Fifth step: synthesis of 4- ((2, 4-dimethoxybenzyl) amino) -9-fluoroimidazo [1,5-a ] quinoxaline-8-carboxylic acid (Compound Int N-6)
Compound Int N-5 (212 mg, 516.57. Mu. Mol) was dissolved in methanol (10 mL) in an ice bath, and an aqueous solution (2 mL) of sodium hydroxide (82.65 mg,2.07 mmol) was added dropwise thereto and reacted at 55℃for 3hr. After the reaction, the methanol was dried by spin drying, dilute hydrochloric acid was added dropwise to the remaining portion under ice bath until the solution became acidic, and the filter cake was washed with water 2 times to obtain the compound Int N-6 (200.00 mg). MS (ESI, m/z): 397.1[ M+H ] +.
Sixth step: synthesis of 4-amino-9-fluoroimidazo [1,5-a ] quinoxaline-8-carboxylic acid (Compound Int N)
Int N-6 (200 mg, 504.58. Mu. Mol) was added to TFA (10 mL) in an ice bath, and reacted at 80℃for 2hr. After completion of the reaction, TFA was spin-dried to give compound Int N (120 mg). MS (ESI, m/z): 247.2[ M+H ] +.
Example 1: (R) -5-amino-N- (1- (pyrimidin-2-yl) ethyl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,5-c ] quinazoline-9-carboxamide
The first step: synthesis of (R) -5- (bis (4-methoxybenzyl) amino) -N- (1- (pyrimidin-2-yl) ethyl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,5-c ] quinazoline-9-carboxamide (Compound 1-1)
To the flask were added Int B (30 mg, 51.23. Mu. Mol), int C (15 mg, 51.23. Mu. Mol), HATU (24 mg, 61.47. Mu. Mol) and DMF (2 mL), and after stirring to dissolve, DIPEA (10 mg, 76.84. Mu. Mol) was added and the mixture was reacted at 25℃for 2hr under nitrogen. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate (30 ml×3), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by chromatography on a silica gel plate (developer DCM: meoh=10:1) to give compound 1-1 (13 mg).
And a second step of: synthesis of (R) -5-amino-N- (1- (pyrimidin-2-yl) ethyl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,5-c ] quinazoline-9-carboxamide (Compound 1)
The reaction flask was charged with Compound 1-1 (13 mg, 17.74. Mu. Mol), TFA (3 mL), nitrogen-protected, and reacted at 90℃for 5hr. After the reaction was completed, the reaction solution was dried by spin-drying, diluted with saturated NaHCO 3 solution, extracted with ethyl acetate (30 ml×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by Pre-HPLC to give compound 1.MS (ESI, m/z): 493.2[ M+H ] +.
1H NMR(400MHz,DMSO-d6)δ8.86–8.78(m,3H),8.64(s,1H),8.22–8.08(m,2H),7.94–7.74(m,3H),7.58(d,J=8.0Hz,2H),7.46–7.37(m,2H),5.52–5.35(m,1H),4.92(d,J=17.2Hz,1H),4.57(d,J=16.8Hz,1H),1.62(d,J=7.2Hz,3H).
Example 2: 5-amino-N-isobutyl-N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,5-c ] quinazoline-9-carboxamide
The first step: synthesis of 5- (bis (4-methoxybenzyl) amino) -N-isobutyl-N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,5-c ] quinazoline-9-carboxamide (Compound 2-2)
To the flask were added Int B (30 mg, 51.23. Mu. Mol), 2-1 (12 mg, 51.23. Mu. Mol), HATU (24 mg, 61.47. Mu. Mol) and DMF (2 mL), and after stirring and dissolution, DIPEA (10 mg, 76.84. Mu. Mol) was added thereto, and the mixture was reacted at 25℃for 2hr under nitrogen. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate (30 ml×3), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (mobile phase DCM: meoh=97:3) to give compound 2-2 (20 mg). MS (ESI, m/z): 683.3[ M+H ] +.
And a second step of: synthesis of 5-amino-N-isobutyl-N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,5-c ] quinazoline-9-carboxamide (Compound 2)
2-2 (20 Mg, 29.29. Mu. Mol), TFA (3 mL), nitrogen blanket, and reaction at 90℃for 5hr were added to the flask. After the reaction was completed, the reaction solution was dried by spin-drying, diluted with saturated NaHCO 3 solution, extracted with ethyl acetate (30 ml×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by Pre-HPLC to give compound 2.MS (ESI, m/z): 443.2[ M+H ] +.
1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.62(d,J=8.4Hz,1H),8.19(d,J=25.2Hz,1H),8.03(d,J=25.2Hz,1H),7.85–7.63(m,3H),7.49–7.24(m,3H),4.89–4.73(m,2H),3.27(d,J=7.2Hz,2H),2.08(br,1H),0.94(s,3H),0.70(s,3H).
Example 3: (R) -4-amino-N- (1- (pyrimidin-2-yl) ethyl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,5-a ] quinoxaline-8-carboxamide
The first step: synthesis of (R) -4- ((2, 4-dimethoxybenzyl) amino) -N- (1- (pyrimidin-2-yl) ethyl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,5-a ] quinoxaline-8-carboxamide (compound 3-1)
Int A (50 mg, 132.14. Mu. Mol) and Int C (31.08 mg, 110.12. Mu. Mol) were dissolved in anhydrous DMF (2 mL) in an ice-water bath, HATU (62.81 mg, 165.18. Mu. Mol) was added with stirring, DIPEA (42.70 mg, 330.36. Mu. Mol) was added dropwise thereto, and the reaction was continued at 25℃for 5hr. After the reaction, water was added and stirred, ethyl acetate was extracted and concentrated to give a crude product, which was purified by silica gel column chromatography (mobile phase DCM: meoh=92:8) to give compound 3-1 (43.00 mg). MS (ESI, m/z): 643.3[ M+H ] +.
And a second step of: synthesis of (R) -4-amino-N- (1- (pyrimidin-2-yl) ethyl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,5-a ] quinoxaline-8-carboxamide (Compound 3)
Compound 3-1 (43 mg, 66.91. Mu. Mol) was dissolved in a mixed solvent of TFA (5 mL) and methanol (1 mL), and reacted at 100℃for 2hr. After the reaction was completed, the saturated sodium bicarbonate solution was washed to neutrality, extracted with ethyl acetate, and concentrated, and the crude product was purified by reverse phase HPLC to give compound 3 (4.0 mg). MS (ESI, m/z): 493.3[ M+H ] +.
1H NMR(400MHz,DMSO-d6)δ9.16(s,1H),8.85(s,1H),8.79(d,J=4.9Hz,2H),8.39(s,1H),8.11(d,J=7.9Hz,1H),7.92(s,1H),7.63–7.53(m,2H),7.45(dt,J=9.7,6.6Hz,4H),5.45(t,J=12.3Hz,1H),4.93(d,J=17.0Hz,1H),4.57(d,J=16.8Hz,1H),1.64(d,J=6.5Hz,3H).
The following compounds were prepared by the methods and general procedures described in reference example 3, and the desired additional starting materials were obtained commercially or synthetically by conventional reactions from commercially available reagents by those of skill in the art of organic synthesis.
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Example 32: (S) -4-amino-N-methyl-N- (7- (trifluoromethyl) isochroman-4-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide
The first step: synthesis of (S) -4- ((2, 4-dimethoxybenzyl) amino) -N-methyl-N- (7- (trifluoromethyl) isochroman-4-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide (Compound 31-1)
Int A (45 mg, 118.93. Mu. Mol) and Int H-peak 2 compound (27.50 mg, 118.93. Mu. Mol) were dissolved in anhydrous DMF (2 mL) in an ice-water bath, HATU (54.26 mg, 142.71. Mu. Mol) was added with stirring, and DIPEA (23.06 mg, 178.39. Mu. Mol) was added dropwise thereto for reaction at 60℃for 5hr. After the reaction, water was added thereto, and the mixture was stirred, extracted and concentrated with ethyl acetate to obtain a crude product, which was purified by silica gel column chromatography (mobile phase DCM: meoh=97:3) to obtain compound 31-1 (40.0 mg). MS (ESI, m/z): 592.2[ M+H ] +.
And a second step of: synthesis of (S) -4-amino-N-methyl-N- (7- (trifluoromethyl) isochroman-4-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide (Compound 31)
Compound 31-1 (40 mg, 67.62. Mu. Mol) was dissolved in TFA (2 mL) and reacted at 80℃for 2hr. After completion of the reaction, the saturated sodium bicarbonate solution was washed to neutrality, extracted with ethyl acetate, and concentrated to give compound 31 (12.51 mg) as a crude product by reverse phase HPLC. MS (ESI, m/z): 442.0[ M+H ] +.
1H NMR(400MHz,DMSO-d6)δ9.26–9.16(m,1H),8.41–8.34(m,1H),7.92(s,1H),7.72–7.42(m,7H),5.81–4.62(m,3H),4.22–4.07(m,2H),2.76(s,3H).
Example 33: (R) -4-amino-N-methyl-N- (7- (trifluoromethyl) isochroman-4-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide
The first step: synthesis of (R) -4- ((2, 4-dimethoxybenzyl) amino) -N-methyl-N- (7- (trifluoromethyl) isochroman-4-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide (Compound 32-1)
Int A (45 mg, 118.93. Mu. Mol) and Int H-peak 1 compound (27.50 mg, 118.93. Mu. Mol) were dissolved in anhydrous DMF (2 mL) under ice-water bath, HATU (54.26 mg, 142.71. Mu. Mol) was added with stirring, and DIPEA (23.06 mg, 178.39. Mu. Mol) was added dropwise thereto for reaction at 60℃for 5hr. After the reaction, water was added thereto, and the mixture was stirred, extracted and concentrated with ethyl acetate to obtain a crude product, which was purified by silica gel column chromatography (mobile phase DCM: meoh=97:3) to obtain compound 32-1 (30.0 mg). MS (ESI, m/z): 592.2[ M+H ] +.
And a second step of: synthesis of (R) -4-amino-N-methyl-N- (7- (trifluoromethyl) isochroman-4-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide (Compound 32)
Compound 32-1 (25 mg, 41.77. Mu. Mol) was dissolved in TFA (2 mL) and reacted at 80℃for 2hr. After completion of the reaction, the saturated sodium bicarbonate solution was washed to neutrality, extracted with ethyl acetate, and concentrated to give compound 32 (7.71 mg) as a crude product by reverse phase HPLC. MS (ESI, m/z): 442.0[ M+H ] +.
1H NMR(400MHz,DMSO)δ9.25–9.16(m,1H),8.41–8.34(m,1H),7.91(s,1H),7.71–7.39(m,7H),5.81–4.62(m,3H),4.22–4.07(m,2H),2.76(s,3H).
Example 34: (S) -4-amino-7-fluoro-N-methyl-N- (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide
The first step: synthesis of 4-amino-7-fluoroimidazo [1,5-a ] quinoxaline-8-carboxylic acid (Compound 33-1)
Int J (1.5 g,3.78 mmol) was dissolved in TFA (20 mL), and the reaction was warmed to 90℃for 2hr. After completion of the reaction, the solvent was removed by concentration under reduced pressure to give Compound 33-1 (1.35 g). MS (ESI, m/z): 247.0[ M+H ] +.
And a second step of: synthesis of (S) -4-amino-7-fluoro-N-methyl-N- (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide (Compound 33)
33-1 (1.35 G,3.75 mmol) and Int E (950.60 mg,3.75 mmol) were dissolved in anhydrous NMP (20 mL), DIPEA (2.42 g,18.74 mmol) and HATU (1.71 g,4.50 mmol) were added and the reaction was allowed to react at 25℃for 2 hrs. After the reaction, water was added to dilute the mixture, ethyl acetate was used for extraction, saturated brine was used for washing, anhydrous sodium sulfate was used for drying, filtration was used for separation and purification by silica gel column chromatography (DCM: meoh=93:7), and then reversed phase column chromatography (mobile phase H 2 O (0.05% ammonium bicarbonate): acn=58:42) was used for separation and purification to obtain compound 33 (1.2 g). MS (ESI, m/z): 446.0[ M+H ] +.
1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.49–8.25(m,1H),8.00–7.88(m,1H),7.74–7.17(m,6H),6.58–5.59(m,1H),4.93–4.62(m,2H),2.73–2.59(m,3H).
Example 35: (S) -4-amino-7-chloro-N-methyl-N- (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide
The first step: synthesis of (S) -7-chloro-4- ((2, 4-dimethoxybenzyl) amino) -N-methyl-N- (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide (Compound 34-1)
To the flask were added Int E (25 mg, 96.89. Mu. Mol), int I (40 mg, 96.89. Mu. Mol), HATU (44 mg, 116.27. Mu. Mol) and NMP (2 mL), and after stirring and dissolution, DIPEA (19 mg, 145.34. Mu. Mol) was added thereto, and the mixture was reacted at 60℃for 5 hours under nitrogen. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (mobile phase DCM: meoh=97:3) to give compound 34-1 (36 mg). MS (ESI, m/z): 612.2[ M+H ] +.
And a second step of: synthesis of (S) -4-amino-7-chloro-N-methyl-N- (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide (Compound 34)
DDQ (67 mg, 294.12. Mu. Mol) was added to a solution of compound 34-1 (36 mg, 58.82. Mu. Mol) in DCM (5 mL), and reacted at 25℃for 2hr under nitrogen. The reaction solution was concentrated under reduced pressure to give a crude product, which was dried by spinning, diluted with saturated NaHCO 3 solution, extracted with EA (30 ml x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by Pre-HPLC to give compound 34 (14 mg). MS (ESI, m/z): 462.0[ M+H ] +.
1H NMR(400MHz,DMSO-d6)δ9.22–9.06(m,1H),8.60–8.29(m,1H),7.96–7.90(m,1H),7.70–7.46(m,4H),7.38–7.23(m,2H),6.64–5.46(m,1H),4.93–4.58(m,2H),2.74–2.52(m,3H).
Example 36: (S) -4-amino-7-chloro-N-methyl-N- (7- (trifluoromethyl) isochroman-4-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide
The first step: synthesis of (S) -7-chloro-4- ((2, 4-dimethoxybenzyl) amino) -N-methyl-N- (7- (trifluoromethyl) isochroman-4-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide (Compound 36-1)
To the flask were added Int H-peak 2 (22 mg, 96.89. Mu. Mol), int I (40 mg, 96.89. Mu. Mol), HATU (44 mg, 116.27. Mu. Mol) and NMP (2 mL), and after stirring and dissolution, DIPEA (19 mg, 145.34. Mu. Mol) was added thereto, and the mixture was reacted at 60℃for 5 hours under nitrogen. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (mobile phase DCM: meoh=97:3) to give compound 36-1 (40 mg). MS (ESI, m/z): 626.2[ M+H ] +.
And a second step of: synthesis of (S) -4-amino-7-chloro-N-methyl-N- (7- (trifluoromethyl) isochroman-4-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide (Compound 36)
TFA (2 mL) and 36-1 (40 mg, 53.06. Mu. Mol) were added to the flask, and the mixture was reacted at 80℃for 2hr under nitrogen. The reaction was dried by spinning, diluted with saturated NaHCO 3 solution, extracted with EA (30 ml x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give the crude product. The crude product was purified by Pre-HPLC to give compound 36 (14 mg). MS (ESI, m/z): 476.1[ M+H ] +.
1H NMR(400MHz,DMSO-d6)δ9.21–9.09(m,1H),8.62–8.27(m,1H),7.95–7.91(m,1H),7.80–7.47(m,6H),5.89–4.59(m,3H),4.22–3.99(m,2H),2.82–2.58(m,3H).
Example 37: (S) -4-amino-N-methyl-7- (trifluoromethyl) -N- (7- (trifluoromethyl) isochroman-4-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide
The first step: synthesis of (S) -4- ((2, 4-dimethoxybenzyl) amino) -N-methyl-7- (trifluoromethyl) -N- (7- (trifluoromethyl) isochroman-4-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide (Compound 38-1)
To the flask were added Int H-peak 2 (21 mg, 89.61. Mu. Mol), int G (40 mg, 89.61. Mu. Mol), HATU (41 mg, 107.5. Mu. Mol) and NMP (2 mL), and after stirring and dissolution, DIPEA (17 mg, 132.34. Mu. Mol) was added thereto, followed by reaction at 60℃for 1hr under nitrogen. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (mobile phase DCM: meoh=97:3) to give compound 38-1 (20 mg). MS (ESI, m/z): 660.2[ M+H ] +.
And a second step of: synthesis of (S) -4-amino-N-methyl-7- (trifluoromethyl) -N- (7- (trifluoromethyl) isochroman-4-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide (Compound 38)
TFA (2 mL) and 38-1 (35 mg, 53.06. Mu. Mol) were added to the flask, and the mixture was reacted at 80℃for 2hr under nitrogen. The reaction was dried by spinning, diluted with saturated NaHCO 3 solution, extracted with EA (30 ml x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give the crude product. The crude product was purified by Pre-HPLC to give compound 38 (16 mg). MS (ESI, m/z): 510.2[ M+H ] +.
1H NMR(400MHz,DMSO-d6)δ9.32–9.20(m,1H),8.63–8.36(m,1H),8.03–7.94(m,1H),7.81–7.30(m,6H),5.83(s,1H),4.99–4.59(m,2H),4.37–3.84(m,2H),2.80–2.52(m,3H).
Example 38: (S) -6-amino-N-methyl-N- (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) imidazo [1,5-a ] pyrido [3,2-e ] pyrazine-2-carboxamide
Int L (80 mg, 233.09. Mu. Mol), int E (50.62 mg, 199.58. Mu. Mol) were dissolved in anhydrous NMP (3 mL), DIPEA (150.62 mg,1.17 mmol) was added, HATU (106.29 mg, 279.71. Mu. Mol) and the reaction system was reacted at 25℃for 2hr. After the completion of the reaction, water was added for dilution, extraction with ethyl acetate, saturated brine, drying over anhydrous sodium sulfate, filtration, and separation and purification of the crude product by Prep-HPLC to give compound 48 (70 mg). MS (ESI, m/z): 429.2[ M+H ] +.
1H NMR(400MHz,DMSO-d6)δ9.09–8.88(m,1H),8.06–7.59(m,6H),7.41–7.30(m,1H),7.29–7.19(m,1H),6.51–6.11(m,1H),4.95–4.66(m,2H),2.94–2.61(m,3H).
Example 39: (S) -4-amino-9-fluoro-N-methyl-N- (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide (Compound 49)
Int N (50 mg, 203.09. Mu. Mol), int E (51.51 mg, 203.09. Mu. Mol), HATU (115.83 mg, 304.63. Mu. Mol) were added to NMP (8 mL), and DIPEA (78.74 mg, 609.27. Mu. Mol) was finally added dropwise thereto for reaction at 60℃for 2hr. After the reaction, water was added thereto and stirred, and the crude product was concentrated by EA extraction, and purified by reverse phase HPLC to give Compound 49 (10 mg). MS (ESI, m/z): 446.2[ M+H ] +.
1H NMR(400MHz,DMSO-d6)δ9.09–8.60(m,1H),8.14–7.87(m,1H),7.73–7.49(m,3H),7.47–7.10(m,4H),6.57–5.57(m,1H),5.07–4.35(m,2H),2.76–2.54(m,3H).
Example 40: (S) -4-amino-N-methyl-N- (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) imidazo [1,5-a ] pyrido [2,3-e ] pyrazine-8-carboxamide (Compound 50)
The first step: synthesis of (S) -4- ((2, 4-dimethoxybenzyl) amino) -N-methyl-N- (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) imidazo [1,5-a ] pyrido [2,3-e ] pyrazine-8-carboxamide (Compound 50-1)
Int M(100mg,263.60μmol)、Int E(66.86mg,263.60μmol)、HATU(200.57mg,527.20μmol)、DIPEA(102.20mg,790.79μmol) Was added to NMP (10 mL) in an ice bath and reacted at 60℃for 2hr. After the reaction, water was added thereto under stirring, and the crude product was concentrated by EA extraction and purified by silica gel column chromatography (mobile phase DCM: meoh=95:5) to give compound 50-1 (60 mg). MS (ESI, m/z): 579.2[ M+H ] +.
And a second step of: synthesis of (S) -4-amino-N-methyl-N- (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) imidazo [1,5-a ] pyrido [2,3-e ] pyrazine-8-carboxamide (Compound 50)
50-1 (60 Mg, 103.71. Mu. Mol), DDQ (47.08 mg, 207.42. Mu. Mol) was added to DCM (10 mL) and reacted at 25℃for 3hr. After the reaction, saturated sodium bicarbonate solution was added for washing, EA extraction and concentration gave a crude product, which was purified by reverse phase HPLC to give Compound 50 (10 mg). MS (ESI, m/z): 429.2[ M+H ] +.
1H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.82–8.65(m,1H),8.66–8.53(m,1H),8.11–7.79(m,3H),7.75–7.60(m,1H),7.48–7.09(m,2H),6.59–6.15(m,1H),5.03–4.41(m,2H),2.72(s,3H).
Example 41: (S) -4-amino-N-methyl-N- (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) imidazo [1,5-a ] pyrido [3,4-e ] pyrazine-8-carboxamide
Int K (3.5 g,10.20 mmol), int E (2.59 g,10.20 mmol)) were dissolved in anhydrous NMP (100 mL), DIEA (6.59 g,50.99 mmol) was added, HATU (4.65 g,12.24 mmol) and the reaction system was reacted at 25℃for 3hr. After the reaction was completed, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was purified by silica gel column chromatography (DCM: meoh=92:8), followed by reversed-phase column chromatography (mobile phase H 2 O (0.05% ammonium bicarbonate): acn=58:42) to give compound 47 (3.45 g). MS (ESI, m/z): 429.2[ M+H ] +.
1H NMR(400MHz,DMSO-d6)δ9.36–9.28(m,1H),8.72–8.63(m,1H),8.59–8.50(m,1H),8.02–7.96(m,1H),7.81–7.56(m,3H),7.40–7.23(m,2H),6.49–6.00(m,1H),4.91–4.67(m,2H),2.80–2.66(m,3H).
Example 42: 4-amino-N-isobutyl-N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,5-a ] quinoxaline-8-carboxamide
The first step: synthesis of 4- ((2, 4-dimethoxybenzyl) amino) -N-isobutyl-N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,5-a ] quinoxaline-8-carboxamide (Compound 4-1)
Int A (50 mg, 132.14. Mu. Mol) was added to anhydrous THF (10 mL), pyridine (41.81 mg, 528.57. Mu. Mol) and phosphorus oxychloride (30.39 mg, 198.21. Mu. Mol) were sequentially added dropwise under ice bath, and after stirring for 10min, 2-1 (30.69 mg, 132.14. Mu. Mol) was added and the mixture was allowed to react at room temperature for 3hr. After the reaction was completed, water was added thereto, extraction was performed with ethyl acetate, and the crude product was purified by silica gel column chromatography (mobile phase DCM: meoh=95:5) to give compound 4-1 (10 mg). MS (ESI, m/z): 593.2[ M+H ] +.
And a second step of: synthesis of 4-amino-N-isobutyl-N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,5-a ] quinoxaline-8-carboxamide (Compound 4)
Compound 4-1 (10 mg, 16.87. Mu. Mol) was added to TFA (8 mL) and reacted at 60℃for 4hr. After the reaction, the mixture was concentrated under reduced pressure, washed with saturated sodium bicarbonate solution to be alkaline, extracted with ethyl acetate, and concentrated to give a crude product, which was purified by reverse phase HPLC to give Compound 4 (3.99 mg). MS (ESI, m/z): 443.2[ M+H ] +.
1H NMR(400MHz,DMSO-d6)δ9.28–9.05(m,1H),8.98(s,1H),8.54–7.63(m,4H),7.53–7.27(m,4H),4.99–4.69(m,2H),3.29(d,J=7.4Hz,2H),2.14–1.85(m,1H),0.95(s,3H),0.71(s,3H).
The following compounds were prepared by the methods and general procedures described in reference example 42, and the desired additional starting materials were obtained commercially or synthetically by conventional reactions from commercially available reagents by those of skill in the art of organic synthesis.
Example 44: (R) -4-amino-3-methyl-N- (1- (pyrimidin-2-yl) ethyl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,5-a ] quinoxaline-8-carboxamide
The first step: synthesis of (R) -4- ((2, 4-dimethylbenzyl) amino) -3-methyl-N- (1- (pyrimidin-2-yl) ethyl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,5-a ] quinoxaline-8-carboxamide (compound 10-1)
Int D (60 mg, 137.61. Mu. Mol) was added to anhydrous THF (10 mL), pyridine (65.31 mg, 825.67. Mu. Mol) and phosphorus oxychloride (63.30 mg, 412.84. Mu. Mol) were sequentially added dropwise under ice bath, and after stirring for 10min, int C (38.84 mg, 137.61. Mu. Mol) was added and reacted at 60℃for 3hr. After the reaction, water was added thereto for quenching, and the mixture was extracted with ethyl acetate and concentrated to give Compound 10-1 (50 mg). MS (ESI, m/z): 657.2[ M+H ] +.
And a second step of: synthesis of (R) -4-amino-3-methyl-N- (1- (pyrimidin-2-yl) ethyl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,5-a ] quinoxaline-8-carboxamide (compound 10)
10-1 (50 Mg, 76.14. Mu. Mol) was added to TFA (12 mL) and reacted at 100℃for 2hr. After the reaction, the mixture was concentrated under reduced pressure, washed with saturated sodium bicarbonate solution to be alkaline, extracted with ethyl acetate, and concentrated to give a crude product, which was purified by reverse phase HPLC to give Compound 10 (24.01 mg). MS (ESI, m/z): 507.2[ M+H ] +.
1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.86(s,1H),8.80(d,J=4.8Hz,2H),8.33(s,1H),8.12(d,J=7.6Hz,1H),7.71–7.15(m,4H),6.92(s,2H),5.61–5.26(m,1H),5.12–4.38(m,2H),2.65(s,3H),1.64(d,J=6.4Hz,3H).
Example 45: 4-amino-N-isobutyl-3-methyl-N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,5-a ] quinoxaline-8-carboxamide
The first step: synthesis of 4- ((2, 4-dimethylbenzyl) amino) -N-isobutyl-3-methyl-N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,5-a ] quinoxaline-8-carboxamide (Compound 11-1)
Int D (7 mg, 17.84. Mu. Mol), DIPEA (4.61 mg, 35.68. Mu. Mol) and HATU (10.17 mg, 26.76. Mu. Mol) were added to anhydrous DMF (5 mL) in an ice bath, stirred for 10min, then added with 2-1 (4.14 mg, 17.84. Mu. Mol) and reacted at 25℃for 3hr. After the reaction, water was added thereto for quenching, and the mixture was extracted with ethyl acetate and concentrated to give Compound 11-1 (6 mg). MS (ESI, m/z): 607.3[ M+H ] +.
And a second step of: synthesis of 4-amino-N-isobutyl-3-methyl-N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,5-a ] quinoxaline-8-carboxamide (Compound 11)
11-1 (6 Mg, 9.89. Mu. Mol) was added to TFA (10 mL) and reacted at 100℃for 2hr. After the reaction was completed, the mixture was concentrated under reduced pressure, washed with saturated sodium bicarbonate solution to be alkaline, extracted and concentrated with ethyl acetate to obtain a crude product, and the crude product was purified by reverse phase HPLC to obtain Compound 11 (1.62 mg). MS (ESI, m/z): 457.2[ M+H ] +.
1H NMR(400MHz,DMSO-d6)δ9.24–8.86(m,2H),8.43–8.08(m,2H),7.93–7.22(m,3H),6.92(d,J=8.4Hz,2H),5.39–4.18(m,2H),3.34(d,J=7.2Hz,3H),2.68(s,2H),2.22–1.84(m,1H),1.01(s,3H),0.76(s,3H).
Example 46: (S) -4-amino-N-methyl-N- (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide
The first step: synthesis of (S) -4- ((2, 4-dimethylbenzyl) amino) -N-methyl-N- (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide (Compound 13-1)
Int A (84 mg, 222.00. Mu. Mol) was added to anhydrous THF (10 mL), pyridine (105.36 mg,1.33 mmol) and phosphorus oxychloride (136.16 mg, 887.99. Mu. Mol) were sequentially added dropwise under ice bath, and after stirring for 10min, int E hydrochloride (56.31 mg, 222.00. Mu. Mol) was added and the mixture was allowed to react at room temperature for 16hr. After the reaction was completed, water was added thereto, extraction was performed with ethyl acetate, and the crude product was purified by silica gel column chromatography (mobile phase DCM: meoh=90:10), compound 13-1 (36 mg). MS (ESI, m/z): 578.1[ M+H ] +.
And a second step of: synthesis of (S) -4-amino-N-methyl-N- (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) imidazo [1,5-a ] quinoxaline-8-carboxamide (Compound 13)
13-1 (10 Mg, 17.31. Mu. Mol) was dissolved in methylene chloride (10 mL), DDQ (58.96 mg, 259.72. Mu. Mol) was added thereto under an ice bath, and the mixture was allowed to react at 25℃for 24hr. After completion of the reaction, the solution was dried by spin-drying, and purified by reverse phase HPLC to give Compound 13 (1.20 mg). MS (ESI, m/z): 428.1[ M+H ] +.
1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.34(s,1H),7.92(s,1H),7.64(d,J=7.6Hz,1H),7.57–7.40(m,4H),7.34(d,J=7.6Hz,1H),7.26(s,1H),6.50–6.28(m,1H),5.00–4.41(m,2H),2.68(s,3H).
The following compounds were prepared by the methods and general procedures described in reference example 46, and the desired additional starting materials were obtained commercially or synthetically by conventional reactions from commercially available reagents by those of skill in the art of organic synthesis.
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Example 51: (S) -4-amino-N-methyl-N- (7- (trifluoromethyl) isochroman-4-yl) imidazo [1,5-a ] pyrido [3,4-e ] pyrazine-8-carboxamide
The first step: synthesis of (S) -4- ((2, 4-dimethoxybenzyl) amino) -N-methyl-N- (7- (trifluoromethyl) isochroman-4-yl) imidazo [1,5-a ] pyrido [3,4-e ] pyrazine-8-carboxamide (Compound 51-1)
Int H-Peak 2 (30.50 mg, 131.92. Mu. Mol), int K-7 (50 mg, 101.43. Mu. Mol)) were dissolved in anhydrous NMP (3 mL), DIPEA (65.49 mg, 506.70. Mu. Mol) was added, HATU (66.43 mg, 121.61. Mu. Mol) and the reaction system was reacted at 20℃for 2hr. After the reaction was completed, water was added thereto for dilution, extraction with ethyl acetate, saturated brine, drying over anhydrous sodium sulfate, filtration, and separation and purification of the crude product by silica gel column chromatography (DCM: meoh=93:7) gave compound 51-1 (40 mg). MS (ESI, m/z): 593.3[ M+H ] +.
And a second step of: synthesis of (S) -4-amino-N-methyl-N- (7- (trifluoromethyl) isochroman-4-yl) imidazo [1,5-a ] pyrido [3,4-e ] pyrazine-8-carboxamide (Compound 51)
51-1 (40 Mg, 67.50. Mu. Mol) was dissolved in TFA (3 mL), the reaction was warmed to 90℃for 2hr, after completion of the reaction, concentrated under reduced pressure, EA was dissolved, washed with saturated aqueous sodium bicarbonate, and the organic layer was dried and concentrated, and purified by reverse phase column chromatography (mobile phase H 2 O (0.05% formic acid): ACN=60:40) to give compound 51 (18 mg). MS (ESI, m/z): 443.2[ M+H ] +.
1HNMR(400MHz,DMSO-d6)δ9.34–9.28(m,1H),8.69–8.63(m,1H),8.61–8.52(m,1H),8.01–7.96(m,1H),7.78–7.51(m,5H),5.85–5.34(m,1H),4.95–4.65(m,2H),4.17–4.07(m,2H),2.82–2.74(m,3H).
Separation method
The Prep-HPLC purification of the compounds in the examples was carried out by using Aglient type 1260 or Waters 2489 type HPLC, the separation column type was Waters SunFire Prep C18 OBD(19mm×150mm×5.0μm)、Waters Xbridge Prep C18 OBD(19mm×150mm×5.0μm) or YMC Actus Triart C 18 (20 mm. Times.150 mm. Times.5.0 μm), the column temperature was 25 ℃, the detection wavelength was 214nm, 254nm or 280nm, the mobile phase A was acetonitrile, the mobile phase B was 0.05% formic acid aqueous solution or 0.05% ammonium bicarbonate aqueous solution or 0.05% TFA aqueous solution, and the volume ratio of the mobile phase was adjusted according to the polarity of the compounds; the mobile phase flow rate was 28mL/min.
Reference example 1:
The preparation process is referred to WO2022169948A1.
Reference example 2:
The preparation process is referred to WO2022169948A1.
Reference example 3:
The preparation process is referred to WO2022169948A1.
Reference example 4:
The preparation process is referred to WO2022169948A1.
Reference example 5:
The preparation process is referred to WO2022169948A1.
Reference example 6:
The preparation process is referred to WO2022169948A1.
Biological evaluation
Experimental example 1: test for inhibition of PRMT5-MTA methyltransferase Activity by Compounds
Pre-incubating the prepared protein solution (PRMT 5/MEP50 (Reaction) and MTA (MCE) mixed solution) with the compound to be tested (500 nM initial, 5-fold dilution, 7 points; or 100nM initial, 5-fold dilution, 7 points) of the invention at 25 ℃ for 30min, adding the prepared substrate solution (biotinylated histone H4 peptide (Biotinylated histone H peptide, sangon)) and incubating at 25 ℃ for 90min; after the reaction, a prepared detection reagent mixture (Protein A-Eu (Cisbio), an Anti-histone H4 antibody (Anti-Histone H Anti, abcam) and strepavidin-D2 (Cisbio)) was added, and incubated at 25℃for 60 minutes, and the Ratio of fluorescence signals (Ratio) was detected by using a BMG microplate reader.
The percent inhibition of compounds at different concentrations was calculated as follows using the solvent set (DMSO) as negative control and the reaction buffer set (without prmt5. Mtase) as blank:
Percentage inhibition = (negative control Ratio-test compound Ratio)/(negative control Ratio-blank Ratio) ×100%.
The detected signal values were fitted using the "log (inhibitor) vs. response-Variable slope" four parameter equation y=bottom+ (Top-Bottom)/(1+10 ((LogIC 50 -X) × Hillslope)) in GRAPHPAD PRISM 8 to calculate IC 50 values. Wherein Y is the relative inhibition activity percentage, top and Bottom are the maximum and minimum of the fitted curve, respectively, X is the logarithmic concentration of the compound, hillslope is the slope of the curve. The inhibition of PRMT5-MTA methyltransferase by the compounds was determined as described above and the results are shown in Table 1.
TABLE 1 inhibitory Activity of the compounds of the invention on PRMT5-MTA
Numbering of compounds | PRMT5-MTA(IC50,nM) |
1 | 0.73 |
2 | 1.04 |
3 | 0.78 |
4 | 1.16 |
Experimental results show that the compound has a strong inhibition effect on PRMT5-MTA enzyme.
Experimental example 2: compound inhibition test of MTAP deletion (Deleted)/Parental (Parentil) HCT116 cell proliferation
MTAP deleted/parental HCT116 cells (purchased from HORIZON) were grown in vitro in monolayers under 10% FBS+1% P/S RPMI6140 medium (source culture), 37℃and 5% CO 2. Cells in logarithmic growth phase were digested and concentration was adjusted, 250 cells per well were inoculated in 96-well plates for overnight incubation, pre-diluted test compounds (5000 nM start, 4-fold dilution, 9 spots) were added, DMSO was added to the negative control, culture medium was added to the blank control, and after incubation in a 5% CO 2 incubator at 37℃for 8 days, 50 μ L CELLTITER-Glo (Promega) was added per well for 10 minutes at room temperature in a dark place, the test solution was transferred to 96-well opaque white plates, and then the relative chemiluminescent unit values were read in the chemiluminescent detection mode of the microplate reader.
The percent inhibition of compounds at different concentrations was calculated according to the following formula:
percentage inhibition = (1- (chemiluminescent signal value of test compound-chemiluminescent signal value of control)/(chemiluminescent signal value of negative control-chemiluminescent signal value of control)) ×100%.
The percent inhibition of compounds at different concentrations was plotted against compound concentration, and IC 50 values were calculated by fitting a curve according to a four parameter model by the following formula:
y=min+ (Max-Min)/(1+ (x/IC 50)/(Hillslope)), wherein: y is the percent inhibition; max and Min are the maximum value and the minimum value of the fitting curve respectively; x is the logarithmic concentration of the compound; and Hillslope is the slope of the curve.
The proliferation inhibitory activity of the compounds against MTAP deficiency/parent HCT116 cells was measured as described above and the results are shown in Table 2.
TABLE 2 proliferation inhibitory Activity of the inventive Compounds against MTAP deletion/parental HCT116 cells
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Experimental results show that the compound has a strong inhibition effect on MTAP-deleted HCT116 cells, and has a certain selectivity relative to MTAP parent HCT116 cells.
Experimental example 3: liver microsome stability test
Human liver microsome solutions were used to examine the stability of the compounds of the present invention and the compounds of reference examples in microsomes. The compound of the invention and the compound of the reference example are respectively added into the liver microsome solution and are uniformly blown and mixed, 50 μl of the liver microsome solution is mixed with 25 μl of PBS, after 5min of pre-incubation (37 ℃), NADPH (25 μl) is added, so that the final concentration of the compound to be detected is 1 μM, the final concentration of the human liver microsome protein is 0.5mg/ml, and the incubation time is 0 and 15 min. After the corresponding reaction time, 300 μl of glacial acetonitrile containing the internal standard is added to terminate the reaction, vortex and temporarily store at-80deg.C for testing. Detecting the original shape of the compound to be detected in the sample by adopting an LC-MS/MS method, and calculating the original shape residual rate after incubation for 15 minutes. The results of the liver microsome stability test are shown in Table 3 below.
TABLE 3 original shape residual Rate after incubation of the inventive and reference Compounds in human liver microsomes for 15min
Numbering of compounds | 15 Minutes original form residual rate (%) |
28 | 99.5 |
31 | 87.1 |
33 | 92.8 |
Reference example 6 | 82.2 |
Reference example 2 | 83.7 |
Reference example 4 | 80.6 |
Experimental results show that the compound is relatively stable in human liver microsomes.
Experimental example 4: in vitro permeability test
In vitro permeability was tested using MDCK cells. The permeation experiments were performed in duplicate in a transwell system at a single concentration (2 μm) and incubated for 120 min. The apical to basolateral (A to B ) and basolateral to apical (B to A ) transport of the corresponding compounds was measured and the permeation rate (apparent permeability) of the test compound (P appx 10-6 cm/s) was calculated. The in vitro permeability test results are shown in Table 4 below.
TABLE 4 in vitro permeability data for the compounds of the invention and reference example compounds
Remarks: permeability grade :Low:Papp≤0.5(×10-6cm/s);Moderate:0.5<Papp<2.5(×10-6cm/s);High:Papp≥2.5(×10-6cm/s).
The test results show that the compound of the invention permeates well on MDCK cells.
Experimental example 5 Biochemical hERG inhibition assay
1. Test system:
The kit comprises: predictor TM hERG Fluorescence Polarization Assay, (thermo fisher),
The kit comprises:
positive control compound hERG potassium channel blocker E4031;
hERG cell membrane;
affinity Tracer tracker;
hERG buffer.
2. Test parameters:
hERG concentration: 1X
Tracer concentration: 1nM
Incubation time: 2h
BMG PHERAstar FS FP
3. The test method comprises the following steps:
The test was performed according to the kit instructions, the steps were as follows:
Test group: the compounds to be tested were added at different concentrations to microwells containing hERG cell membranes, and a Tracer with high hERG affinity was added to each well, and after incubating the microwells for 2 hours at room temperature, the change in fluorescence polarization (extraction: 540nm; emission:590 nm) was detected using a multifunctional microplate reader.
Positive control group: the test compound was replaced with 30. Mu.M positive control compound E4031, and the experimental procedure was the same as that of the test group.
Blank control group: the test compounds were replaced with hERG buffer and hERG cell membranes were not added, and the experimental procedure was the same as for the test group.
4. And (3) data processing:
the percent inhibition of hERG by the compounds of the invention at various concentrations was calculated according to the following formula.
Percentage inhibition = (1- (fluorescence polarization value of test compound-fluorescence polarization value of positive control)/(fluorescence polarization value of blank control-fluorescence polarization value of positive control)) = (100%)
When the percent inhibition is between 30-80%, half inhibition concentration (IC 50) or range of the compound to hERG is estimated according to the following formula:
IC 50 = X (1-percent inhibition (%))/percent inhibition (%), wherein: x is the test concentration of the compound at an inhibition rate of 30-80%.
5. Experimental results:
inhibition of hERG by compounds was determined using the methods described above and the results are shown in table 5 below.
Table 5 herg inhibition assay results
Numbering of compounds | IC50(μM) |
11 | >10 |
22 | >10 |
34 | >10 |
13 | 3.77 |
31 | >10 |
33 | >10 |
47 | >10 |
Reference example 5 | 1.96 |
Reference example 1 | 0.38 |
Reference example 2 | 4.82 |
Reference example 4 | 8.77 |
The test results show that the compounds of the invention have no obvious hERG inhibitory activity.
Experimental example 6: pharmacokinetic testing of Compounds in balb/c mice
The compound of the present invention and the compound of the reference example were administered intravenously (1 mg/kg) and intragastrically (10 mg/kg). IV solvent is: 5% DMSO+5% Solutol+90% Saline, PO vehicle: 10% solutol+90% h 2 O. Blood was taken from the orbit 40-50. Mu.l, placed in K2-EDTA anticoagulation tube, centrifuged at 4000rpm for 10min (4 ℃) and plasma was isolated at-80℃for testing at 0h before and 0.083, 0.25, 0.5, 1,2, 6, 10, 24 and 48h after administration (i.e., intravenous) and 0.25, 0.5, 1,2, 4, 6, 8, 10, 24 and 48h after administration (lavage). 10. Mu.l of plasma sample was added with 90. Mu.l of acetonitrile containing an internal standard, and after shaking and mixing, the mixture was centrifuged at 4000rpm at 4℃for 10min, and the supernatant was subjected to LC-MS/MS analysis. Pharmacokinetic parameters were calculated using the non-compartmental model using WinNonlin 6.3 software, and the results are shown in table 6.
Table 6: pharmacokinetic parameters of Compounds in mice
Conclusion:
The experimental results show that the compound has low in-vivo clearance rate, high blood concentration and in-vivo exposure in mice and good oral absorption effect.
Various modifications of the application, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this disclosure (including all patents, patent applications, journal articles, books, and any other publications) is hereby incorporated by reference in its entirety.
Claims (23)
1. A compound of formula I-a or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically labeled compound:
Wherein:
Ring a is selected from a C 6-10 aromatic ring and a 5-10 membered heteroaromatic ring;
Each R 1 is independently selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl;
Each X 1、X2 is independently selected from CR 9 and N;
R 2 is L-R 2';
l is selected from a direct bond and- (CR 5R6)p -;
R 2' is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 2-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 3-8 cycloalkoxy, C 6-10 aryl, and 5-10 membered heteroaryl, said alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halo, -OH, -CN, -NR 7R8、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkoxy, 3-6 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl;
R 3 is selected from H and C 1-4 alkyl;
R 4 is independently at each occurrence selected from H, -OH, halogen, -CN, -NR 7R8、-NHCOCH3、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-6 heteroalkyl, C 1-4 haloalkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, said heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halogen, -CN, -NR 5R6、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkoxy, 3-6 membered heterocyclyl; or R 3、R4 forms, with the atom to which it is attached, a 3-8 membered heterocyclyl, a 5-8 membered cycloalkyl, a C 6-10 aromatic ring, and a 5-10 membered heteroaromatic ring;
R 5 and R 6 are each independently selected from H, C 1-4 alkyl and C 3-8 cycloalkyl;
R 7 and R 8 are each independently selected from H and C 1-4 alkyl;
Each R 9 is independently selected from H, halogen, C 1-4 alkyl, and C 1-4 haloalkyl;
m is 0, 1 or 2;
n is 0,1, 2 or 3;
p is 1 or 2.
2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, ring a being selected from phenyl and pyridinyl.
3. The compound according to any one of claims 1-2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, R 1 each independently being selected from H and C 1-4 alkyl.
4. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically labeled compound thereof, R 2' is selected from C 1-6 alkyl, C 1-6 alkoxy, C 2-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, and 5-10 membered heteroaryl, optionally substituted with one or more halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl.
5. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically labeled compound thereof, R 2' is independently selected from C 1-4 alkyl, C 2-6 heteroalkyl, C 3-6 cycloalkyl, and 5-6 membered heteroaryl, optionally substituted with one or more halo, C 1-4 alkyl, C 1-4 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl.
6. The compound according to any one of claims 1-2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, R 2' is independently selected from methyl, pyrimidinyl, pyridinyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and,Pyrazolyl and-CH 2-O-CH3, said methyl, pyrimidinyl, pyridinyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl optionally being substituted by methyl, F.
7. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically labeled compound thereof, R 4 at each occurrence is independently selected from H, halogen, CN, -NR 7R8、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-6 heteroalkyl, C 1-4 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, the heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, heteroaryl optionally substituted with one or more halogen, CN, -NR 5R6、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkoxy, 3-6 membered heterocyclyl.
8. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically labeled compound, R 4 at each occurrence is independently selected from C 1-4 haloalkyl, C 1-4 haloalkoxy, and 5-6 membered heteroaryl, optionally substituted with one or more halo, C 1-4 alkyl, C 1-4 haloalkyl.
9. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, R 7 and R 8 are each independently selected from H and C 1-4 alkyl.
10. The compound according to any one of claim 1-2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof,
Ring a is selected from phenyl and pyridinyl;
each R 1 is independently selected from H and C 1-4 alkyl;
R 2 is L-R 2';
L is selected from a direct bond or- (CR 5R6)p -;
R 5 and R 6 are each independently selected from H and C 1-4 alkyl;
R 2' is independently selected from the group consisting of C 1-4 alkyl, C 2-6 heteroalkyl, C 3-6 cycloalkyl, and 5-10 membered heteroaryl, said alkyl, heteroalkyl, cycloalkyl, heteroaryl optionally substituted with one or more halo, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 heterocyclyl;
R 3 is selected from H and C 1-4 alkyl;
R 4 at each occurrence is independently selected from H, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, 5-10 membered heteroaryl optionally substituted with one or more halogen, C 1-4 alkyl, C 1-4 haloalkyl; or R 3 and R 4 together with the atoms to which they are attached form a 3-8 membered heterocyclic ring;
X 1 and X 2 are each independently selected from CR 9 and N;
R 9 is selected from H, halogen, C 1-3 alkyl, and C 1-3 haloalkyl;
m is 0 or 1;
n is 1 or 2; and p is 1.
11. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, wherein R 3 and R 4 together with the atoms to which they are attached form a 5-6 membered heterocyclyl.
12. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, wherein R 3 and R 4 together with the atoms to which they are attached form a 5-membered oxygen-containing heterocycle or a 6-membered oxygen-containing heterocycle.
13. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, wherein R 3 and R 4 together with the atoms to which they are attached form the group:
14. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, wherein formula I-a is further formula I-a-1 or formula I-a-2:
Wherein q is 0, 1 or 2.
15. The compound of claim 14, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, having the structure of formula I-A-1,
Wherein ring a is selected from phenyl and pyridinyl;
Each R 1 is independently H;
X 1 and X 2 are each independently selected from CR 9 and N;
R 2 is L-R 2';
L is selected from a direct bond or- (CR 5R6)p -;
R 2' is independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 2-6 heteroalkyl, non-cyclopropyl C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 3-8 cycloalkoxy, C 6-10 aryl, and non-pyrazolyl 5-10 membered heteroaryl, said alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halo, -OH, -CN, -NR 7R8、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-8 cycloalkoxy, 3-6 membered heterocyclyl, C 6-10 aryl;
R 4 at each occurrence is independently selected from H, -OH, halogen, -CN, -NR 7R8、-NHCOCH3、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-6 heteroalkyl, C 1-4 haloalkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl other than pyrazolyl, said heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halogen, -CN, -NR 5R6、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkoxy, 3-6 membered heterocyclyl;
R 5 and R 6 are each independently selected from H and C 1-4 alkyl;
R 7 and R 8 are each independently selected from H and C 1-4 alkyl;
each R 9 is independently selected from halogen, C 1-4 alkyl, and C 1-4 haloalkyl;
m is 0 or 1;
q is 1 or 2;
And p is 1.
16. The compound of claim 15, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, which satisfies one or more of the following:
(1) X 1 and X 2 are each independently selected from CR 9;
(2) R 2' is independently selected from C 1-4 alkyl, C 2-6 heteroalkyl, cyclobutyl, cyclopentyl, Pyrimidinyl, pyridinyl, said alkyl, heteroalkyl, pyrimidinyl, pyridinyl, cyclobutyl, cyclopentyl optionally substituted with C 1-4 alkyl or halogen;
(3) R 4 is independently at each occurrence selected from C 1-4 haloalkyl and C 1-4 haloalkoxy;
(4) R 9 are each independently selected from halogen.
17. The compound of claim 14, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, having the structure of formula I-A-1,
Wherein ring a is selected from phenyl and pyridinyl;
Each R 1 is independently H;
X 1 and X 2 are each independently selected from CR 9 and N;
R 2 is L-R 2';
L is selected from a direct bond or- (CR 5R6)p -;
R 2' is independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 2-6 heteroalkyl, 3-8 membered heterocyclyl, C 3-8 cycloalkoxy, C 6-10 aryl, said alkyl, alkoxy, hydroxyalkyl, heteroalkyl, heterocyclyl, cycloalkoxy, aryl optionally substituted with one or more halo, -OH, -CN, -NR 7R8、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-8 cycloalkoxy, 3-6 membered heterocyclyl, C 6-10 aryl;
R 4 is independently at each occurrence selected from H, -OH, halogen, -CN, -NR 7R8、-NHCOCH3、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-6 heteroalkyl, C 1-4 haloalkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, C 6-10 aryl, said heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl optionally substituted with one or more halogen, -CN, -NR 5R6、C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkoxy, 3-6 membered heterocyclyl;
R 5 and R 6 are each independently selected from H and C 1-4 alkyl;
R 7 and R 8 are each independently selected from H and C 1-4 alkyl;
each R 9 is independently selected from halogen, C 1-4 alkyl, and C 1-4 haloalkyl;
m is 0 or 1;
q is 1 or 2;
And p is 1.
18. The compound of claim 17, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, which satisfies one or more of the following:
(1) X 1 and X 2 are each independently selected from CR 9;
(2) R 2' is independently selected from C 1-4 alkyl, C 2-6 heteroalkyl, optionally substituted with C 1-4 alkyl or halo;
(3) R 4 is independently at each occurrence selected from C 1-4 haloalkyl and C 1-4 haloalkoxy;
(4) R 9 are each independently selected from halogen.
19. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, wherein the compound is:
20. a pharmaceutical composition comprising a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, and one or more pharmaceutically acceptable carriers.
21. Use of a compound according to any one of claims 1-19, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound, or a pharmaceutical composition according to claim 20, in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with PRMT5 activity.
22. The use according to claim 21, wherein the disease or condition associated with PRMT5 activity is MTAP-deleted cancer or tumor.
23. The use of claim 22, wherein the cancer or tumor is selected from the group consisting of esophageal cancer, lung cancer, pancreatic cancer, glioblastoma, cholangiocarcinoma, bladder cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, prostate cancer, melanoma, gastric cancer, colon cancer, leukemia, and lymphoma.
Applications Claiming Priority (6)
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CN2023105596937 | 2023-05-17 | ||
CN202310559693 | 2023-05-17 | ||
CN202310855795 | 2023-07-12 | ||
CN2023108557953 | 2023-07-12 | ||
CN2024100154696 | 2024-01-04 | ||
CN202410015469 | 2024-01-04 |
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