CN112876419A - Allylamine derivatives, process for producing the same and use thereof - Google Patents
Allylamine derivatives, process for producing the same and use thereof Download PDFInfo
- Publication number
- CN112876419A CN112876419A CN202011305876.9A CN202011305876A CN112876419A CN 112876419 A CN112876419 A CN 112876419A CN 202011305876 A CN202011305876 A CN 202011305876A CN 112876419 A CN112876419 A CN 112876419A
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- Prior art keywords
- compound
- alkyl
- membered
- halogen
- cycloalkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title abstract description 32
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical class NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 title abstract description 5
- 230000008569 process Effects 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 196
- 102100027159 Membrane primary amine oxidase Human genes 0.000 claims abstract description 93
- 238000002360 preparation method Methods 0.000 claims abstract description 83
- 101710132836 Membrane primary amine oxidase Proteins 0.000 claims abstract description 81
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 239000012453 solvate Substances 0.000 claims abstract description 28
- 150000002148 esters Chemical class 0.000 claims abstract description 27
- 239000002207 metabolite Substances 0.000 claims abstract description 27
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 26
- 239000000651 prodrug Substances 0.000 claims abstract description 26
- 229940002612 prodrug Drugs 0.000 claims abstract description 26
- 108010028700 Amine Oxidase (Copper-Containing) Proteins 0.000 claims abstract description 16
- -1 Cyclohexyl Chemical group 0.000 claims description 65
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 40
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 22
- 201000010099 disease Diseases 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 16
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 125000004429 atom Chemical group 0.000 claims description 13
- 208000027866 inflammatory disease Diseases 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 206010037211 Psychomotor hyperactivity Diseases 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 208000035475 disorder Diseases 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 10
- 125000002723 alicyclic group Chemical group 0.000 claims description 8
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- 125000005843 halogen group Chemical group 0.000 claims description 8
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
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- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 2
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- 230000002440 hepatic effect Effects 0.000 claims 1
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- 102000010909 Monoamine Oxidase Human genes 0.000 abstract description 21
- 108010062431 Monoamine oxidase Proteins 0.000 abstract description 21
- 102000016893 Amine Oxidase (Copper-Containing) Human genes 0.000 abstract description 4
- 238000001727 in vivo Methods 0.000 abstract description 4
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 65
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- 239000012074 organic phase Substances 0.000 description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
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- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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Abstract
It relates to allylamine derivatives, and methods of preparation and use thereof, in particular to compounds of formula I, or stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, prodrugs or esters thereof, or pharmaceutically acceptable salts thereof. Said compound has high inhibition activity against vascular adhesion protein 1/semicarbazide-sensitive amine oxidase, good selectivity for monoamine oxidase and diamine oxidase, and in some embodiments, said combination has high in vivo bioavailability and safety,
Description
Technical Field
The invention relates to the field of medicines, in particular to an allylamine derivative which has vascular adhesion protein 1 (VAP-1)/semicarbazide-sensitive amine oxidase (SSAO) inhibitory activity, and a preparation method and application thereof.
Background
Vascular adhesion protein 1 (VAP-1) belongs to the copper-containing Amine Oxidases (AOCs) or semicarbazide-sensitive amine oxidases (SSAO) family members, and two forms exist in humans: membrane bound form and soluble form. The membrane-bound form is mainly expressed in endothelial cells, smooth muscle cells and adipocytes; while the soluble form is present in the circulating plasma, mainly originating from VAP-1 released from vascular endothelial cells.
It was found that vascular adhesion protein 1/semicarbazide-sensitive amine oxidase induced expression significantly during fat differentiation (Fontana, e., et. al., biochem.j.,2001,356,769; Moldes, m., et. al., j.biol.chem.,1999,274,9515). The vascular adhesion protein 1/semicarbazide sensitive amine oxidase plays an important role in aspects such as leucocyte exudation, adhesion cascade reaction, glycometabolism regulation, vascular injury and the like; the expression and the function of the vascular adhesion protein 1/semicarbazide sensitive amine oxidase play a key role in a plurality of clinical diseases such as inflammatory diseases, tissue injury fibrosis, diseases related to carbohydrate metabolism, tumors, cerebral apoplexy, skin diseases and the like; therefore, the VAP-1/SSAO has good application prospect in treating diseases such as diabetes, pneumonia, hepatitis, pulmonary fibrosis, hepatic fibrosis, fatty liver, cancer, psoriasis and the like as a biological target.
Disclosure of Invention
The present invention provides an effective compound having a vascular adhesion protein 1/semicarbazide-sensitive amine oxidase inhibitory activity, which is useful for preventing or treating diseases associated with an overactivity of vascular adhesion protein 1/semicarbazide-sensitive amine oxidase. In more detail, the present invention provides allylamine derivatives of formula (I) having high inhibitory activity against vascular adhesion protein 1/semicarbazide-sensitive amine oxidase, good selectivity against monoamine oxidase and diamine oxidase, and in some embodiments, high bioavailability and safety in vivo.
In one aspect, the present invention provides a compound of formula I, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, prodrug, or ester thereof, or a pharmaceutically acceptable salt thereof:
wherein the content of the first and second substances,
v is selected from-N ═ CR5-and-CR5R6-;
R5Selected from H, C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C6-10Aryl and 5-10 membered heteroaryl;
R6is selected from C1-6An alkyl group; alternatively, the first and second electrodes may be,
R5and R6Together with the atoms to which they are attached form C4-8Alicyclic or 4-8 membered alicyclic heterocyclic ring;
w is selected from-CR7=、-CR7R8-、-C(O)-、-C(S)-、-N=、-NR7-, -O-, -S-, -S (O) -and-SO2-;
R7Selected from H, halogen, C1-6Alkyl and C3-8A cycloalkyl group;
R8selected from H and halogen;
provided that when V is-CR5R6-,R5Selected from H, C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C6-10Aryl and 5-10 membered heteroaryl, R6Is selected from C1-6When alkyl, W is not-CH2-;
R1Selected from H, C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered lipoheterocyclyl, C6-10Aryl and 5-10 membered heteroarylWherein said C is1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered lipoheterocyclyl, C6-10Aryl and 5-10 membered heteroaryl optionally substituted with one or more substituents selected from halogen, -OH, -O, -OC1-6Alkyl, -CN, -S (O)2-C1-6Alkyl, 3-6 membered lipoheterocyclyl, phenyl and 5-6 membered heteroaryl, wherein said phenyl or 5-6 membered heteroaryl is optionally further substituted with one or more halogen or C1-6Alkyl substitution;
R2optionally at each occurrence independently selected from H, halo, -OH, -OC1-6Alkyl, -CN, C1-6Alkyl and C3-8A cycloalkyl group;
R3and R4Each independently selected from H, Cl and F;
n is 0, 1,2 or 3.
The invention also provides the use of the compounds, or stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, prodrugs or esters thereof, or pharmaceutically acceptable salts thereof, for the preparation of VAP-1/SSAO inhibitors.
The invention also provides the use of the compounds, or stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, prodrugs or esters thereof, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of a disease or disorder associated with overactivity of VAP-1/SSAO.
The present invention also provides a method of treating a disease or disorder associated with overactivity of VAP-1/SSAO, comprising administering to a subject in need thereof a therapeutically effective amount of said compound, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, prodrug or ester thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention.
The present application also provides a method of inhibiting VAP-1/SSAO in a cell comprising the step of contacting the cell with an effective amount of the compound, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, prodrug or ester thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.
The present application also provides the compounds, or stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, prodrugs or esters thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for treating diseases or disorders associated with overactivity of VAP-1/SSAO.
The present application also provides the compounds, or stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, prodrugs or esters thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in inhibiting VAP-1/SSAO (vascular adhesion protein 1/semicarbazide sensitive amine oxidase).
In the present invention, the disease or disorder associated with overactivity of VAP-1/SSAO is selected from the group consisting of inflammatory diseases (such as liver-associated inflammatory diseases, e.g. hepatitis, hepatomegaly, liver fibrosis, cirrhosis or liver ascites; such as respiratory-associated inflammatory diseases, e.g. tracheitis, pneumonia, pulmonary fibrosis, asthma, acute lung injury, acute respiratory distress syndrome, bronchitis or chronic obstructive pulmonary disease; such as eye-associated inflammatory diseases, e.g. uveitis; such as other inflammations, e.g. synovitis or peritonitis), organ and/or tissue transplant rejection, autoimmune diseases (e.g. rheumatoid arthritis or multiple sclerosis (e.g. chronic multiple sclerosis)), skin diseases (e.g. eczema or psoriasis), diabetes (e.g. type I or type II diabetes) and stroke.
Detailed Description
[ Compound ] to obtain a compound
In one aspect, the present application provides a compound of formula I, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, prodrug, or ester thereof, or a pharmaceutically acceptable salt thereof:
wherein the content of the first and second substances,
v is selected from-N ═ CR5-and-CR5R6-;
R5Selected from H, C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C6-10Aryl and 5-10 membered heteroaryl;
R6is selected from C1-6An alkyl group; alternatively, the first and second electrodes may be,
R5and R6Together with the atoms to which they are attached form C4-8Alicyclic or 4-8 membered alicyclic heterocyclic ring;
w is selected from ═ CR7-、-CR7R8-、-C(O)-、-C(S)-、=N-、-NR7-, -O-, -S-, -S (O) -and-SO2-;
R7Selected from H, halogen, C1-6Alkyl and C3-8A cycloalkyl group;
R8selected from H and halogen;
provided that when V is-CR5R6-,R5Selected from H, C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C6-10Aryl and 5-10 membered heteroaryl, R6Is selected from C1-6When alkyl, W is not-CH2-;
R1Selected from H, C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered lipoheterocyclyl, C6-10Aryl and 5-10 membered heteroaryl, wherein said C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered lipoheterocyclyl, C6-10Aryl and 5-10 membered heteroaryl optionally substituted with one or more substituents selected from halogen, -OH, -O, -OC1-6Alkyl, -CN, -S (O)2-C1-6Of alkyl, 3-6-membered lipoheterocyclyl, phenyl and 5-6-membered heteroaryl groupsWherein said phenyl or 5-6 membered heteroaryl is optionally further substituted by one or more halogen or C1-6Alkyl substitution;
R2optionally at each occurrence independently selected from H, halo, -OH, -OC1-6Alkyl, -CN, C1-6Alkyl and C3-8A cycloalkyl group;
R3and R4Each independently selected from H, Cl and F;
n is 0, 1,2 or 3.
In some embodiments, V is-CR5R6-; wherein R is5Is selected from C1-6Alkyl radical, R6Is selected from C1-6An alkyl group; or, R5And R6Together with the atoms to which they are attached form C4-6Alicyclic or 4-6 membered aliphatic heterocyclic ring.
In some embodiments, V is-CR5R6-; wherein R is5Is selected from C1-4Alkyl radical, R6Is selected from C1-4An alkyl group; or, R5And R6Together with the atoms to which they are attached form C4-6Alicyclic or 4-6 membered aliphatic heterocyclic ring.
In some embodiments, W is selected from-CR7R8-、-C(O)-、-C(S)-、-NR7-, -O-, -S-, -S (O) -and-SO2-, wherein R7Selected from H, halogen, C1-3Alkyl and C3-6Cycloalkyl radical, R8Selected from H and halogen.
In some embodiments, W is selected from-CR7R8-、-NR7-, -C (O) -, -O-, -S-, -S (O) -, and-SO2-, wherein R7Selected from H, C1-3Alkyl and halogen, R8Selected from H and halogen.
In some embodiments, W is selected from-CH2-, -NH-, -C (O) -and-O-.
In some embodiments, W is selected from the group consisting of-C (O) -and-O-.
In some embodiments, V is-CR5R6-; wherein R is5Is selected from C1-6Alkyl radical, R6Is selected from C1-6An alkyl group; or, R5And R6Together with the atoms to which they are attached form C4-6Alicyclic or 4-6 membered alicyclic heterocyclic ring;
w is selected from-CR7R8-、-C(O)-、-C(S)-、-NR7-, -O-, -S-, -S (O) -and-SO2-, wherein R7Selected from H, halogen, C1-3Alkyl and C3-6Cycloalkyl radical, R8Selected from H and halogen.
In some embodiments, V is-CR5R6-; wherein R is5Is selected from C1-4Alkyl radical, R6Is selected from C1-4An alkyl group; or, R5And R6Together with the atoms to which they are attached form C4-6Alicyclic or 4-6 membered alicyclic heterocyclic ring;
w is selected from-CR7R8-、-NR7-, -C (O) -, -O-, -S-, -S (O) -, and-SO2-, wherein R7Selected from H, C1-3Alkyl and halogen, R8Selected from H and halogen.
W is selected from-CH2-, -NH-, -C (O) -and-O-; preferably, W is selected from the group consisting of-C (O) -and-O-.
W is selected from-CH2-, -NH-, -C (O) -and-O-; preferably, W is selected from the group consisting of-C (O) -and-O-.
In some embodiments, V is selected from-N ═ and-CR5Wherein R is5Selected from H, C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C6-10Aryl and 5-10 membered heteroaryl.
In some embodiments, V is selected from-N ═ and-CR5Wherein R is5Selected from H, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocycloalkyl, and phenyl.
In some embodiments, V is-N ═ N.
In some embodiments, V is-CR5Wherein R is5Selected from H, -CH3、-C(CH3)3Cyclohexyl, phenyl and tetrahydropyranyl.
In some embodiments, W is selected from ═ CR7-and ═ N-, wherein R7Selected from H, halogen, C1-2Alkyl and C3-6A cycloalkyl group.
In some embodiments, W is selected from ═ CR7-and ═ N-, wherein R7Selected from H, halogen and C1-2An alkyl group.
In some embodiments, W is ═ CR7-, wherein R7Selected from H, halogen and C1-2An alkyl group.
In some embodiments, W is ═ CH-.
In some embodiments, V is selected from-N ═ and-CR5Wherein R is5Selected from H, C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C6-10Aryl and 5-10 membered heteroaryl;
w is selected from ═ CR7-and ═ N-, wherein R7Selected from H, halogen, C1-2Alkyl and C3-6A cycloalkyl group.
In some embodiments, V is selected from-N ═ and-CR5Wherein R is5Selected from H, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocycloalkyl, and phenyl; w is selected from ═ CR7-and ═ N-, wherein R7Selected from H, halogen and C1-2An alkyl group.
In some embodiments, V is-N ═ N; w is ═ CR7-, wherein R7Selected from H, halogen and C1-2An alkyl group; preferably, W is ═ CH-.
In some embodiments, V is-CR5Wherein R is5Selected from H, -CH3、-C(CH3)3Cyclohexyl, phenyl and tetrahydropyranyl; w is ═ CR7-, wherein R7Selected from H, halogen and C1-2An alkyl group; preferably, W is ═ CH-.
In some embodiments, R1Selected from H, C1-4Alkyl radical, C3-6Cycloalkyl and 3-6 membered lipoheterocyclyl, wherein said C is1-4Alkyl is optionally substituted by one or more groups selected from-OH, -SO2-C1-3Alkyl, phenyl and 5-6 membered heteroaryl, wherein said phenyl and 5-6 membered heteroaryl are optionally further substituted with one or more-CH3And (4) substitution.
In some embodiments, R1Selected from H, C1-4Alkyl and 3-6 membered lipoheterocyclyl, wherein said C1-4Alkyl is optionally substituted by one or more groups selected from-OH, -SO2-CH3Phenyl and 5-6 membered heteroaryl, wherein said phenyl and 5-6 membered heteroaryl are optionally further substituted with one or more-CH3And (4) substitution.
In some embodiments, R1Selected from H and C1-3An alkyl group.
In some embodiments, R1Is selected from H and-CH3。
In some embodiments, R2Each occurrence independently selected from F, Cl, C1-4Alkyl and C3-6A cycloalkyl group; n is 0, 1,2 or 3.
In some embodiments, R2Each independently at each occurrence is optionally selected from F, Cl and-CH3(ii) a n is 0 or 1.
In some embodiments, n is 0.
In some embodiments, R3Is H, R4Is F; or, R3Is F, R4Is H.
In some embodiments, R3Is H, R4Is F.
In some embodiments, V is selected from-N ═ and-CR5Wherein R is5Is H;
w is selected from ═ CR7-and ═ N-, wherein R7Is H;
R1selected from H, C1-4Alkyl and 3-6 membered lipoheterocyclyl, wherein, said C1-4Alkyl is optionally substituted by one or more groups selected from-OH, -SO2-C1-3Alkyl, phenyl and 5-6 membered heteroaryl, wherein said phenyl and 5-6 membered heteroaryl are optionally further substituted with one or more-CH3Substitution; preferably, R1Selected from H, C1-4Alkyl and 3-6 membered lipoheterocyclyl, wherein, said C1-4Alkyl is optionally substituted by one or more groups selected from-OH, -SO2-C1-3Alkyl and 5-6 membered heteroaryl;
R2optionally at each occurrence independently selected from H, halo, -OH, -OC1-6Alkyl, -CN, C1-6Alkyl and C3-8A cycloalkyl group; preferably, R2Is H;
R3selected from H, Cl and F; preferably, R3Is H;
R4selected from H, Cl and F; preferably, R4Is F;
n is 0, 1,2 or 3.
In some embodiments, V is-CR5Wherein R is5Is selected from C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C6-10Aryl radicalsAnd 5-10 membered heteroaryl; preferably, R5Is selected from C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocycloalkyl and C6-10An aryl group;
w is ═ CR7-, wherein R7Is H;
R1is H;
R2optionally at each occurrence independently selected from H, halo, -OH, -OC1-6Alkyl, -CN, C1-6Alkyl and C3-8A cycloalkyl group;
R3selected from H, Cl and F; preferably, R3Is H;
R4selected from H, Cl and F; preferably, R4Is F;
n is 0, 1,2 or 3.
In some embodiments, V is-CR5R6-, wherein R5And R6Together with the atoms to which they are attached form C4-8Alicyclic or 4-8 membered alicyclic heterocyclic ring;
w is selected from-CR7R8-, -C (O) -, -C (S) -, -NH-, -O-, -S-, -S (O) -, and-SO2-, in which R7Selected from H, halogen, C1-3Alkyl and C3-6Cycloalkyl radical, R8Selected from H and halogen; preferably, W is selected from-CR7R8-and-O-, wherein R7Is H, R8Is H;
R1is H;
R2optionally at each occurrence independently selected from H, halo, -OH, -OC1-6Alkyl, -CN, C1-6Alkyl and C3-8A cycloalkyl group;
R3selected from H, Cl and F; preferably, R3Is H;
R4selected from H, Cl and F; preferably, R4Is F;
n is 0, 1,2 or 3.
In some embodiments, V is-CR5R6-, in which R5And R6Each independently selected from C1-6Alkyl (e.g., methyl);
w is selected from-CR7R8-, -C (O) -, -C (S) -, -NH-, -O-, -S-, -S (O) -, and-SO2-, in which R7And R8Each independently selected from halogen (e.g., F);
R1is H or C1-6An alkyl group;
R2optionally at each occurrence independently selected from H, halo, -OH, -OC1-6Alkyl, -CN, C1-6Alkyl and C3-8A cycloalkyl group;
R3selected from H, Cl and F; preferably, R3Is H;
R4selected from H, Cl and F; preferably, R4Is F;
n is 0, 1,2 or 3.
In some embodiments, the compound has the structure of formula VIII:
wherein W and R1As hereinbefore defined.
It will be understood by those skilled in the art that the present invention encompasses compounds resulting from any combination of technical features in the various embodiments. Embodiments resulting from the combination of features from one embodiment or preferred features with features from another embodiment or preferred features are also included within the scope of the present invention.
In a preferred embodiment, the compound is selected from:
in a preferred embodiment, the pharmaceutically acceptable salt described herein is the trifluoroacetate or hydrochloride salt of the compound.
In some preferred embodiments, the pharmaceutically acceptable salt of the compound is selected from:
in a second aspect, the present invention provides a pharmaceutical composition comprising a compound according to the first aspect of the present invention, or a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically labeled compound, a metabolite, a prodrug or ester thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical excipients.
The pharmaceutical excipients as referred to herein refer to excipients and additives used in the manufacture of pharmaceutical products and in the formulation of pharmaceutical formulations, and refer to substances which have been reasonably evaluated in terms of safety and which are included in pharmaceutical preparations, in addition to the active ingredient. The pharmaceutic adjuvant can be used for excipient and serving as a carrier, improves the stability, has important functions of solubilization, dissolution assistance, sustained and controlled release and the like, and is an important component which can possibly influence the quality, safety and effectiveness of the medicine. They can be classified into natural, semi-synthetic and total synthetic ones according to their origin. According to their action and use, they can be divided into: solvents, propellants, solubilizers, solubilizing agents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adherents, antioxidants, chelating agents, permeation promoters, pH regulators, buffers, plasticizers, surfactants, foaming agents, antifoaming agents, thickeners, encapsulating agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, release retardants, and the like; according to the administration route, the medicine can be divided into oral administration, injection, mucous membrane, percutaneous or local administration, nasal or oral inhalation administration, ocular administration and the like.
The pharmaceutical composition may be administered in any form as long as it achieves prevention, alleviation, prevention or cure of symptoms in a human or animal patient. For example, various suitable dosage forms can be prepared according to the administration route.
When administered orally, the pharmaceutical composition may be formulated into any orally acceptable dosage form including, but not limited to, tablets, capsules, granules, pills, syrups, oral solutions, oral suspensions, oral emulsions, and the like.
When administered transdermally or topically, the pharmaceutical compositions may be formulated in the form of suitable ointments, lotions or liniments in which the active ingredient is suspended or dissolved in one or more carriers.
The pharmaceutical composition can also be used in the form of injection, including injection, sterile powder for injection and concentrated solution for injection. Among the carriers and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, the sterilized fixed oil may also be employed as a solvent or suspending medium, such as a monoglyceride or diglyceride.
The composition or compound of the present invention is generally administered twice a day to 1 time every 3 days, preferably 1 time a day, and the total amount is 0.01 to 1000 mg/time. Generally, the dosage of treatment will vary depending on considerations such as, for example: the age, sex and general health of the patient to be treated; the frequency of treatment and the nature of the desired effect; the degree of tissue damage; duration of symptoms; and other variables that can be adjusted by the individual physician. The desired dose may be administered in one or more administrations to achieve the desired result. The pharmaceutical compositions according to the invention may also be provided in unit dosage form.
The present invention also provides a process for the preparation of a compound according to the first aspect, selected from the following schemes:
the first scheme is as follows:
carrying out nucleophilic substitution reaction on the compound SM-1 and the compound IM-1 to generate a compound IM-2; deprotecting the compound IM-2 to obtain a target product;
scheme II:
carrying out Mitsnobu reaction on the compound SM-1 and the compound IM-3 to generate a compound IM-2; deprotecting the compound IM-2 to obtain a target product;
the third scheme is as follows:
carrying out nucleophilic substitution reaction on the compound SM-2 and the compound IM-1 to generate a compound IM-4; compounds IM-4 and R1-Lg undergoes a substitution reaction to obtain a compound IM-2; deprotecting the compound IM-2 to obtain a target product;
and the scheme is as follows:
carrying out Mitsnobu reaction on the compound SM-2 and the compound IM-3 to generate a compound IM-4; compounds IM-4 and R1-Lg undergoes a substitution reaction to obtain a compound IM-2; deprotecting the compound IM-2 to obtain a target product;
in the preparation methods of scheme one, scheme two, scheme three and scheme four, Lg represents a leaving group, such as halogen, -OTs, etc.; pg represents an amino protecting group such as Boc, Cbz, Fmoc, benzyl, etc.; the remaining atoms and groups are as defined above.
In some preferred embodiments, Lg is halogen; in a more preferred embodiment, Lg is selected from Br and Cl.
In some preferred embodiments, Pg is selected from Boc and Cbz; in a more preferred embodiment, Pg is Boc.
The substitution reaction described herein may be carried out in the presence of a base. In some preferred embodiments, the base is selected from potassium carbonate, cesium carbonate, sodium hydride, triethylamine, DIPEA, and DBU; in a more preferred embodiment, the base is potassium carbonate.
The mitsunobu reaction described herein may be carried out in the presence of an organophosphine and an azo compound. In some preferred embodiments, the organic phosphine is selected from triphenylphosphine and tri-n-butylphosphine. In another preferred embodiment, the azo compound is selected from the group consisting of diethyl azodicarboxylate, diisopropyl azodicarboxylate, and azodicarbonamide.
The deprotection reactions described herein may be carried out under acidic or catalytic hydrogenolysis conditions. In some preferred embodiments, the acid is selected from the group consisting of trifluoroacetic acid and hydrochloric acid. In another preferred embodiment, the metal catalyst is palladium on carbon.
The starting materials for the preparation process of the present invention may be obtained from commercial sources or may be prepared according to known methods; the intermediates IM-1 and IM-3 are commercially available or can be obtained by the methods described in the specific examples of the present invention.
It will be appreciated by those skilled in the art that one or more of the steps in the above routes may be omitted depending on the desired resulting product structure. The order of the reaction steps may also be appropriately adjusted and the protection/deprotection reaction steps may be added or omitted as necessary by those skilled in the art.
The compounds of the present invention can be synthesized by similar methods with reference to the above embodiments.
The invention also provides the use of the compounds, or stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, prodrugs or esters thereof, or pharmaceutically acceptable salts thereof, for the preparation of VAP-1/SSAO inhibitors. In some preferred embodiments, the inhibitor is used to inhibit the expression of VAP-1/SSAO or to block a biological function of VAP-1/SSAO in a cell.
The invention also provides the use of the compounds, or stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, prodrugs or esters thereof, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of a disease or disorder associated with overactivity of VAP-1/SSAO.
The present invention also provides a method of treating a disease or disorder associated with overactivity of VAP-1/SSAO, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined above, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, prodrug or ester thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention.
An "effective amount" as referred to herein is an amount sufficient to obtain, or at least partially obtain, the desired effect. For example, a "prophylactically effective amount" refers to an amount sufficient to prevent, or delay the onset of a disease; by "therapeutically effective amount" is meant an amount sufficient to cure or at least partially arrest the disease and its complications in a patient already suffering from the disease. It is well within the ability of those skilled in the art to determine such effective amounts. For example, an amount effective for therapeutic use will depend on the severity of the disease to be treated, the general state of the patient's own immune system, the general condition of the patient, e.g., age, weight and sex, the mode of administration of the drug, and other treatments administered concurrently, and the like.
In the present invention, the disease or disorder associated with overactivity of VAP-1/SSAO is selected from the group consisting of inflammatory diseases (such as liver-associated inflammatory diseases, e.g. hepatitis, hepatomegaly, liver fibrosis, cirrhosis or liver ascites; such as respiratory-associated inflammatory diseases, e.g. tracheitis, pneumonia, pulmonary fibrosis, asthma, acute lung injury, acute respiratory distress syndrome, bronchitis or chronic obstructive pulmonary disease; such as eye-associated inflammatory diseases, e.g. uveitis; such as other inflammations, e.g. synovitis or peritonitis), organ and/or tissue transplant rejection, autoimmune diseases (e.g. rheumatoid arthritis or multiple sclerosis (e.g. chronic multiple sclerosis)), skin diseases (e.g. eczema or psoriasis), diabetes (e.g. type I or I I diabetes) and stroke.
In the present invention, the subject is selected from any animal, preferably a mammal, such as bovine, equine, ovine, porcine, canine, feline, rodent, primate. Among these, particularly preferred subjects are humans.
The present invention also provides a method of inhibiting VAP-1/SSAO in a cell (e.g., inhibiting expression of VAP-1/SSAO in a cell or blocking a biological function of VAP-1/SSAO) comprising the step of contacting the cell with an effective amount of a compound as defined above, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, prodrug or ester thereof, or a pharmaceutically acceptable salt thereof.
In some embodiments of the invention, the methods are used in vivo, e.g., the cells are in a subject (e.g., a mammal; e.g., a bovine, an equine, an ovine, a porcine, a canine, a feline, a rodent, a primate; e.g., a human); alternatively, the method is used in vitro, e.g., the cell is an in vitro cell (e.g., a cell line or a cell from a subject).
The invention also provides the compounds, or stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, prodrugs or esters thereof, or pharmaceutically acceptable salts thereof, for use in inhibiting VAP-1/SSAO (e.g., inhibiting expression of VAP-1/SSAO in a cell or blocking a biological function of VAP-1/SSAO in a cell).
The invention also provides the compounds, or stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, prodrugs or esters thereof, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition of the invention for use in treating a disease or disorder associated with overactivity of VAP-1/SSAO.
The present invention also provides a kit for reducing or inhibiting VAP-1/SSAO activity in a cell, said kit comprising a compound of the invention, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, prodrug or ester thereof, or a pharmaceutically acceptable salt thereof, and optionally further comprising instructions for use.
In the present invention, unless otherwise specified, scientific and technical terms used herein have the meanings that are commonly understood by those skilled in the art. For a better understanding of the present invention, the following provides definitions and explanations of relevant terms.
In the present invention, "hydrogen" and hydrogen in each group include protium (H), deuterium (D), tritium (T).
In the present invention, "halogen" includes fluorine, chlorine, bromine and iodine.
In the present invention, "C1-6Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms, e.g. C1-4Alkyl radical, C1-3Alkyl radical, C1-2Alkyl radical, C1Alkyl radical, C2Alkyl radical, C3Alkyl radical, C4Alkyl radical, C5Alkyl or C6An alkyl group. Specific examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.
In the present invention, "C3-8Cycloalkyl "means a saturated or partially saturated monocyclic hydrocarbon group containing 3 to 8 carbon atoms, for example a 3 to 6 membered cycloalkyl group. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.
In the present invention, "3-8 membered heterocycloalkyl" means a saturated cyclic group having no aromaticity, which contains 3 to 8 ring members, and at least one ring member is a heteroatom selected from N, O and S, preferably, the number of the heteroatoms is 1,2,3 or 4. For example, a 3-6 membered heterocycloalkyl group, a 3-8 membered nitrogen-containing heterocycloalkyl group, a 3-8 membered oxygen-containing heterocycloalkyl group, a 3-8 membered sulfur-containing heterocycloalkyl group, a 3-6 membered nitrogen-containing heterocycloalkyl group, a 3-6 membered oxygen-containing heterocycloalkyl group, a 3-6 membered sulfur-containing heterocycloalkyl group. Specific examples include, but are not limited to, oxiranyl, oxocyclobutylalkyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, homopiperazinyl, and the like.
In the present invention, "C6-10Aryl "means a monocyclic or polycyclic hydrocarbon group having aromatic character containing 6 to 10 ring members, and specific examples include, but are not limited to, phenyl, naphthyl and the like.
In the present invention, "5-to 10-membered heteroaryl" means a monocyclic group having aromaticity, which contains 5 to 10 ring members, and at least one ring member is a heteroatom selected from N, O and S, preferably, the number of the heteroatoms is 1,2,3 or 4, for example, 5-to 6-membered heteroaryl, 5-to 10-membered oxyheteroaryl, 5-to 10-membered sulfurous heteroaryl, 5-to 10-membered nitrogenous heteroaryl, 5-to 6-membered oxyheteroaryl, 5-to 6-membered sulfurous heteroaryl, 5-to 6-membered nitrogenous heteroaryl. Specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, azepinotrienyl, 1, 3-diazacycloheptotrienyl and the like.
In the present invention, "C4-8Alicyclic "refers to a saturated or partially saturated carbocyclic ring having no aromatic character containing 4 to 8 ring members. For example comprising C5-6Alicyclic ring, C4Alicyclic ring, C5Alicyclic ring, C6Alicyclic ring, C7Alicyclic rings and C8Alicyclic rings, and the like. Specific examples include, but are not limited to, but are contained within the group consisting of butanes, pentanes, hexanes, hexenes, hexadienes, heptanes, heptatrienes, octanes, and the like.
In the present invention, "4-8 membered lipoheterocyclic ring" or "3-8 membered lipoheterocyclic group" means an aliphatic saturated or partially saturated ring having no aromatic character, which contains 4 to 8 or 3 to 8 ring members, and at least one ring member is a heteroatom selected from N, O and S, preferably, the number of the heteroatoms is 1,2,3 or 4. For example, a 4-to 8-membered nitrogen-containing aliphatic heterocycle, a 4-to 8-membered oxygen-containing aliphatic heterocycle, a 4-to 8-membered sulfur-containing aliphatic heterocycle, a 4-to 6-membered nitrogen-containing aliphatic heterocycle, a 4-to 6-membered sulfur-containing aliphatic heterocycle, a 5-to 6-membered nitrogen-containing aliphatic heterocycle, a 5-to 6-membered oxygen-containing aliphatic heterocycle, a 5-to 6-membered sulfur-containing aliphatic heterocycle, a 4-to 6-membered aliphatic heterocycle, a 4-membered aliphatic heterocycle, a 5-membered aliphatic heterocycle, a 6-membered aliphatic heterocycle, a 7-membered aliphatic heterocycle, an 8-membered aliphatic heterocycle and the like. Specific examples include, but are not limited to, oxobutyl ring, pyrrole ring, tetrahydrofuran ring, piperidine ring, piperazine ring, morpholine ring, tetrahydropyran ring, homopiperazine ring, and the like.
In the present invention, "metabolite" refers to a compound produced in a subject after administration of a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, isotopically labeled compound or any crystal form or racemate thereof to a subject in need thereof.
In the present invention, "pharmaceutically acceptable salts" refer to those salts that retain the biological effectiveness and properties of the parent compound, for example, by being prepared: protonating a proton accepting moiety and/or deprotonating a proton donating moiety of the compound. It should be noted that protonation of the proton accepting moiety results in the formation of cationic species, where the charge is balanced by the presence of physiological anions, while deprotonation of the proton donating moiety results in the formation of anionic species, where the charge is balanced by the presence of physiological cations. Specific examples include, but are not limited to, hydrochloride or trifluoroacetate salts.
Each atom in the compounds of the present invention may be isotopically labeled, and if not otherwise specified, the atom encompasses all isotopes thereof. For example, H or hydrogen includes1H、2H and3H。
in the present invention, "formulation" or "dosage form" shall include both solid and liquid formulations of the compounds of the present invention, and it will be understood by those skilled in the art that the compounds of the present invention may be present in different formulations depending on the desired dosage and pharmacokinetic parameters.
In an embodiment of the invention, the compound or salt thereof may be present in the form of a solvate selected from organic solvents (e.g. ethanol, acetone).
In an embodiment of the present invention, the compound or a salt thereof may exist in the form of a hydrate.
In embodiments of the invention, if a chiral carbon is present in the compound, the invention includes isomers formed based on any stereoconfiguration of the chiral carbon, including, for example, racemates or any mirror image isomers. Moreover, the present invention includes all other stereoisomers that may be present. That is, the compounds of the present invention include all enantiomers, diastereomers, cis-trans isomers, racemates, and the like.
Advantageous effects of the invention
Through intensive research, the invention unexpectedly discovers that the compounds shown in the formula I have VAP-1/SSAO inhibitory activity, can be used for treating diseases related to VAP-1/SSAO excessive activity, have higher inhibitory activity on vascular adhesion protein 1/semicarbazide sensitive amine oxidase, have better selectivity on monoamine oxidase and diamine oxidase, and improve bioavailability, in vivo metabolic stability or toxicological safety.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Recording at ambient temperature with a Bruker instrument (400MHz)1H NMR spectrum using TMS as internal standard. Chemical shifts (δ) are given in ppm and coupling constants (J) are given in hertz (Hz).1The split weight of H NMR peaks is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad). The solvent was determined to be deuterated methanol (CD)3OD), deuterated chloroform (CDCl)3) Or hexadeuterated dimethyl sulfoxide (DMSO-d 6).
LC-MS adopts an Aglient 1200 liquid chromatograph combined with an Aglient 6120Quadrupole type mass spectrometer to detect at 214nm and 254 nm.
Preparative liquid chromatography using a SHIMADZU CBM-20A and active 1260 model preparative liquid chromatography, C18 OBD 19 × 150mm 5 μ M preparative column, detection wavelength 214nm, mobile phase a water, mobile phase B acetonitrile (0.5 ‰ formic acid added), linear gradient elution was performed according to the following table:
time (min) | A% | B% |
0 | 90 | 10 |
15 | 40 | 60 |
30 | 10 | 90 |
MS was determined using an Agilent (ESI) mass spectrometer, manufacturer: Agilent.
Preparation of high performance liquid chromatography (YMC, ODS, 250X 20mml column) was prepared using Shimadzu LC-8A.
Thin layer chromatography silica gel plate (TLC) an aluminum plate (20X 20cm) from Merck was used, and the silica gel specification for separation and purification by thin layer chromatography was GF 254 (0.4-0.5 nm) from cigarette bench.
The reaction was monitored by Thin Layer Chromatography (TLC) or LCMS using the following developer systems: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, and volume ratio of solvent is regulated according to different polarity of compound, and triethylamine can also be added for regulation.
Unless otherwise indicated, the reaction solvents were all commercial anhydrous or HPLC grade solvents without further purification.
The microwave reaction used a BiotageInitiator + (400W, RT-300 ℃ C.) microwave reactor.
In the examples, the reaction temperature is room temperature (20 ℃ C. -30 ℃ C.)
The reagents used in the present invention were purchased from Acros Organics, Aldrich Chemical Company, Texas Chemical, and the like.
Unless otherwise specified, each abbreviation used in the conventional synthetic methods and examples and intermediate synthetic examples has the following meanings.
DMF: n, N-dimethylformamide;
DMA: n, N-dimethylacetamide;
DMSO, DMSO: dimethyl sulfoxide;
NMP: n-methyl pyrrolidone;
DIBAL-H: diisobutylaluminum hydride;
DIPEA: n, N-diisopropylethylamine;
DBU: 1, 8-diazacyclo [5,4,0] undec-7-ene;
THF: tetrahydrofuran;
boc: a tert-butoxycarbonyl group;
NBS: n-bromosuccinimide;
cbz: a benzyloxycarbonyl group;
fmoc: fluorenylmethyloxycarbonyl;
Cbz-Cl: benzyl chloroformate;
m-CPBA: m-chloroperoxybenzoic acid;
TFA: trifluoroacetic acid;
Et2o: diethyl ether;
EtOH: ethanol;
a Dioxane: 1, 4-dioxane;
TLC: thin layer chromatography;
HATU: o- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate;
me: a methyl group;
DCM: dichloromethane;
EA: ethyl acetate;
DDQ: 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone;
XPhos: 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl;
PE: petroleum ether;
MTBE: methyl tert-butyl ether;
ACN: acetonitrile;
room temperature: 22-38 ℃.
Example A: preparation of tert-butyl (2- (bromomethyl) -3-fluoroallyl) carbamate (Int-1)
The first step is as follows: preparation of hydroxymethyl-triphenylphosphonium tetrafluoroborate (1)
Paraformaldehyde (30g,1.00mol) and triphenylphosphine (250g,0.95mol) were placed in a reaction flask and diethyl ether (2L) was added. To the stirred reactor was slowly added an aqueous solution of fluoroboric acid (525g,2.38 mol). The reaction was carried out at room temperature for 5 days. The ether in the reaction solution was concentrated and filtered to obtain a solid. The solid was washed with diethyl ether (500mL), water (500mL) and diethyl ether (500mL) in that order. The solid was oven dried (50 ℃ C.) overnight to give the product hydroxymethyl triphenyl phosphonium tetrafluoroborate (240g, 67%).
The second step is that: preparation of fluoromethyltriphenylphosphonium tetrafluoroborate (2)
Compound 1(150g,0.396mol) was dissolved in dichloromethane (1.5L) and cooled to 0 ℃. DAST (191g,1.187mol) was slowly added dropwise to the reaction system. After the addition, the temperature was raised to room temperature for reaction overnight. The reaction solution was quenched by adding ice water. Extraction with dichloromethane and combination of the organic phases. The organic phase was washed once with water (500mL) and brine (500mL), and dried over anhydrous sodium sulfate and concentrated. The crude product was dissolved in dichloromethane (350mL) under heating and slowly added dropwise to stirred petroleum ether. The process is accompanied by solids precipitation. The solid was filtered and oven dried (50 ℃ C.) overnight to give the product fluoromethyltriphenylphosphonium tetrafluoroborate (110g, 73%).
The third step: preparation of tert-butyl (2, 3-dihydroxypropyl) carbamate (3)
3-amino-1, 2-propanediol (10.0g,110mmol) was added to dry methanol (200mL), and triethylamine (23mL,170mL) and (Boc) were added with stirring2O (26.4g,120mmol), and stirred at room temperature overnight. The reaction mixture was concentrated, extracted 2 times with water and ethyl acetate, and the organic phase was concentrated by drying to obtain a yellow oily liquid (12.7g, 4%).
The fourth step: preparation of tert-butyl (3- ((tert-butyldimethylsilyl) oxy) -2-hydroxypropyl) carbamate (4)
Compound 3(12.7g,66.5mmol) was dissolved in dichloromethane (100mL), triethylamine (11.6mL,113.0mmol) and imidazole (410mg,6.0mmol) were added, TBSCl (11g,72.0mmol) was added with stirring in an ice bath, and the reaction was allowed to warm slowly to room temperature overnight. Extracting with dichloromethane and saturated saline for 2 times, concentrating organic phase to obtain yellowish oily liquid, and purifying by column chromatography to obtain compound 4(15g, 75%).
The fifth step: preparation of tert-butyl (3- ((tert-butyldimethylsilyl) oxy) -2-oxopropyl) carbamate (5)
Compound 4(120g,400mmol) was dissolved in dichloromethane (1L) and Des-Martin oxidant (250g,600mmol), NaHCO added under ice bath3(100g,1190mmol), warmed to room temperature and reacted overnight. Filtering the reaction solution, adding saturated Na into the mother liquor2SO3Extraction with dichloromethane was carried out 4 times to obtain an organic phase, which was dried, concentrated and separated by column chromatography to obtain a colorless oily liquid (50g, 42%).
And a sixth step: preparation of tert-butyl (2- ((tert-butyldimethylsilyl) oxy) methyl) -3-fluoroallyl) carbamate (6)
Compound 2(158g,0.416mol) was dissolved in THF (200mL) and cooled to-20 ℃. NaHMDS (208mL,0.417mol,2N in THF) was slowly added dropwise to the reaction over 30min under nitrogen. After 30 minutes of reaction at-20 ℃ Compound 5(42g,0.139mol) was dissolved in THF (100mL) and slowly added dropwise to the reaction. The cooling bath was removed and allowed to naturally warm to room temperature for 2 hours. After the reaction was complete, the reaction solution was quenched by adding ice water. Concentrating at low temperature to remove organic solvent, extracting with ethyl acetate, and mixing organic phases. The organic phase was washed successively with water, saturated brine and dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography to give the title compound (18g, 41%).
The seventh step: preparation of tert-butyl (3-fluoro-2- (hydroxymethyl) allyl) carbamate (7)
Compound 6(18.0g,56.4mmol) was dissolved in THF (200mL), TBAF (21.4g,67.7mmol) was added, and the reaction was allowed to proceed at room temperature for 3 hours. After the reaction is completed, water is added for quenching, ethyl acetate is used for extraction, and organic phases are combined. The organic phase was washed once with saturated brine, dried over magnesium sulfate and concentrated. The crude product was used directly in the next reaction.
Eighth step: preparation of tert-butyl (2- (bromomethyl) -3-fluoroallyl) carbamate (Int-1)
Compound 7(56.4mmol) and triethylamine (19.3g,169.3mmol) were dissolved in acetone (200 mL). The temperature is reduced to 0 ℃, methane sulfonyl chloride (7.7g,67.7mmol) is slowly dropped (a large amount of solid is separated out), and reaction is carried out for 2 hours at room temperature after dropping. After completion of the reaction, it was filtered, and lithium bromide (24.5g,282.0mmol) was added to the filtrate. The reaction was allowed to proceed overnight at room temperature, and after completion of the reaction, the solid was filtered. Concentrating the filtrate, adding water and ethyl acetate, separating layers, extracting water phase, and mixing organic phases. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography to give the desired product (6.0g, 40%).
Example B: preparation of 6-methoxyphthalazin-1 (2H) -one (Int-2)
The first step is as follows: preparation of 2-formyl-4-methoxybenzoic acid (9)
Compound 8(5.77g,24.97mmol) was dissolved in anhydrous THF, nBuLi (52.44mmol,21mL) was added slowly at-78 deg.C, reacted at this temperature for 30min, DMF (19.89g, 272.09mmol) was added and the reaction continued at this temperature for 2 h. The reaction was quenched by addition of an appropriate amount of saturated aqueous ammonium chloride solution, extracted three times with ethyl acetate (100mL each) and the organic phase concentrated to a white solid (2.50g, 55%).
The second step is that: preparation of 6-methoxyphthalazin-1 (2H) -one (Int-2)
Compound 9(2.00g, 11.1mmol) was added to ethanol (20mL), hydrazine hydrate (1.67g, 33.3mmol) was added, reaction was carried out at 85 ℃ for 1 hour, a saturated aqueous sodium carbonate solution was added to make the system alkaline, the organic phase was concentrated, solid was precipitated by cooling, filtration was carried out, the cake was washed with water, and drying was carried out to obtain the title compound (1.00g, 55%).
EXAMPLE 1 preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2- (2- (methylsulfonyl) ethyl) phthalazin-1 (2H) -one trifluoroacetate (TM1)
The first step is as follows: preparation of 6-methoxy-2- (2- (methylsulfonyl) ethyl) phthalazin-1 (2H) -one (1-1)
Compound Int-2(0.2g, 1.14mmol) was added to acetone (6mL), potassium carbonate (470mg, 3.41mmol) was added, 2-bromoethylmethylsulfone was added, the reaction was allowed to react overnight at 60 degrees, the solid was filtered off, and the organic phase was concentrated to give a white solid (300mg, 93%).
The second step is that: preparation of 6-hydroxy-2- (2- (methylsulfonyl) ethyl) phthalazin-1 (2H) -one (1-2)
Compound 1-1(300mg, 1.06mmol) was added to toluene (10mL), aluminum trichloride (708mg, 5.31mmol) was added to react at 110 ℃ for 30 minutes, the solvent was concentrated, water was slowly added under an ice-water bath to precipitate a solid, and a white solid (160mg, 56%) was filtered.
The third step: preparation of tert-butyl (3-fluoro-2- ((2- (2- (methylsulfonyl) ethyl) -1-oxo-1, 2-dihydrophthalazin-6-oxy) methyl) allyl) carbamate (1-3)
Compound 1-2(160mg, 0.59mmol) was added to DMF (3mL), Int-1(239mg, 0.89mmol) was added, potassium carbonate (247mg, 1.79mmol) was added, the reaction was allowed to react at room temperature for 2 hours, water was added, dichloromethane was extracted three times, and the organic phase was concentrated to give a yellow liquid (200mg, 73%).
The fourth step: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2- (2- (methylsulfonyl) ethyl) phthalazin-1 (2H) -one trifluoroacetate (TM1)
Compound 1-3(200mg, 0.43mmol) was added to dichloromethane (2mL), TFA (1mL) was added, the reaction was carried out at room temperature for 1 hour, the organic phase was concentrated, separated by reverse phase preparative HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid), and lyophilized to give the title compound (100mg, 50%).
MS m/z(ESI):356.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.21(d,J=9.5Hz,1H),8.17(s,3H),7.53–7.48(m,2H),7.40(d,J=65.9Hz,1H),4.77(d,J=2.6Hz,2H),4.54(t,J=6.9Hz,2H),3.68(s,2H),3.62(t,J=6.9Hz,2H),3.07(s,3H).
Example 2: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2- (pyrimidin-2-ylmethyl) phthalazin-1 (2H) -one trifluoroacetate (TM2)
The title compound was prepared in a similar manner to that described in example 1, except that 2- (chloromethyl) pyrimidine was used in the first step of this example instead of 2-bromoethylmethylsulfone in the first step of example 1, and aqueous hydrobromic acid was used in the second step instead of aluminum trichloride and toluene in the second step of example 1, in an overall yield of 20%.
MS m/z(ESI):342.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.74(d,J=4.9Hz,2H),8.39(s,1H),8.19(d,J=8.6Hz,1H),8.12(s,3H),7.55–7.50(m,2H),7.40(d,J=63.4Hz,1H),7.42(t,J=4.9Hz,1H),5.51(s,2H),4.79(d,J=2.7Hz,2H),3.69(s,2H).
Example 3: (E) preparation of (E) -7- ((2- (aminomethyl) -3-fluoroallyl) oxy) -3- (pyrimidin-2-ylmethyl) quinazolin-4 (3H) -one trifluoroacetate (TM3)
The title compound was prepared in 22% overall yield in analogy to the procedure described in example 2, except for substituting 7-methoxy-4 (1H) -quinazolinone for Int-2 of the first step of example 2 in the first step of this example.
MS m/z(ESI):342.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.76(d,J=4.9Hz,2H),8.49(s,1H),8.06(s,3H),8.04(s,1H),7.40(d,J=81.8Hz,1H),7.44(t,J=4.9Hz,1H),7.25(d,J=2.5Hz,1H),7.19(dd,J=8.8,2.5Hz,1H),5.40(s,2H),4.78(d,J=3.1Hz,2H),3.67(d,J=4.9Hz,2H).
Example 4: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2- (2-hydroxyethyl) phthalazin-1 (2H) -one trifluoroacetate (TM4)
The first step is as follows: preparation of 6-hydroxyphthalizin-1 (2H) -one (4-1)
Compound Int-2(0.70g, 3.97mmol) was added to toluene (20mL), aluminum trichloride (1.59g, 11.92mmol) was added, the reaction was carried out at 105 ℃ for 40 minutes, most of toluene was removed by spinning, water was slowly added to precipitate a solid, and a white solid was obtained by filtration (530mg, 82%).
The second step is that: preparation of tert-butyl (3-fluoro-2- ((1-oxo-1, 2-dihydrophthalazin-6-yl) oxy) methyl) allyl) carbamate (4-2)
Compound 4-1(318mg, 1.96mmol) was added to DMF (8mL), Int-1(473mg, 1.77mmol) and potassium carbonate (324mg, 2.35mmol) were added, the reaction was carried out at 25 ℃ for 1 hour, water was added, dichloromethane was extracted three times, the combined organic phases were concentrated, and silica gel column chromatography (dichloromethane: methanol 10:1) gave a white solid (479mg, 77%).
The third step: preparation of tert-butyl (3-fluoro-2- ((2- (2-hydroxyethyl) -1-oxo-1, 2-dihydrophthalazin-6-oxy) methyl) allyl) carbamate (4-3)
Compound 4-2(50mg, 0.14mmol) was added to acetone (2mL), 2-bromoethane (36mg, 0.28mmol) and potassium carbonate (49mg, 0.36mmol) were added, the reaction was heated at 55 ℃ overnight, the insolubles were filtered off, and the solvent was concentrated and used directly in the next step (30mg, 53%).
The fourth step: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2- (2-hydroxyethyl) phthalazin-1 (2H) -one trifluoroacetate (TM4)
Compound 4-3 was added to dichloromethane (1mL), trifluoroacetic acid (1mL) was added, the reaction was allowed to proceed at room temperature for 1 hour, the organic phase was concentrated, separated by reverse phase preparative HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid), and lyophilized to give the title compound (10mg, 31%).
MS m/z(ESI):294.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.36(s,1H),8.21(d,J=9.5Hz,1H),8.02(s,3H),7.42(d,J=81.6Hz,1H),7.49–7.44(m,2H),4.80(s,1H),4.76(d,J=3.0Hz,2H),4.17(t,J=6.1Hz,2H),3.73(t,J=5.9Hz,2H),3.68(d,J=4.8Hz,2H).
Example 5: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2- (tetrahydro-2H-pyran-4-yl) phthalazin-1 (2H) -one trifluoroacetate (TM5)
The title compound was prepared in 14% overall yield by a method similar to that described in example 4, except that 4-bromotetrahydropyran was used in the third step of this example instead of 2-bromoethanol, which is the third step in example 4.
MS m/z(ESI):334.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.43(s,1H),8.22(d,J=9.6Hz,1H),8.06(s,3H),7.41(d,J=81.7Hz,1H),7.50–7.45(m,2H),5.16–5.05(m,1H),4.76(d,J=3.0Hz,2H),3.99(dd,J=11.2,4.1Hz,2H),3.67(s,2H),3.51(t,J=11.2Hz,2H),2.06–1.92(m,2H),1.71(dd,J=12.4,2.3Hz,2H).
Example 6: (E) preparation of (E) -7- ((2- (aminomethyl) -3-fluoroallyl) oxy) -3- (pyrazin-2-ylmethyl) quinazolin-4 (3H) -one trifluoroacetate (TM6)
The title compound was prepared in 18% overall yield in analogy to the procedure described for example 3, except that in the first step of this example 2- (chloromethyl) pyrazine was used instead of 2- (chloromethyl) pyrimidine in the first step of example 3.
MS m/z(ESI):342.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.87(d,J=1.4Hz,1H),8.72–8.69(m,1H),8.66(d,J=2.5Hz,1H),8.38(s,1H),8.12–8.08(m,1H),8.03(s,3H),7.31(d,J=81.8Hz,1H),7.30–7.26(m,2H),5.45(s,2H),4.64(d,J=2.5Hz,2H),3.51(d,J=4.4Hz,2H).
Example 7: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2- (2- (pyridin-2-yl) ethyl) phthalazin-1 (2H) -one trifluoroacetate (TM7)
The title compound was prepared in 17% overall yield in a similar manner to that described in example 4, except that 2- (2-chloroethyl) pyridine was used in the third step of this example instead of 2-bromoethanol in the third step of example 4.
MS m/z(ESI):355.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.58(d,J=4.7Hz,1H),8.31(s,1H),8.18(d,J=9.2Hz,1H),8.11(s,3H),7.92(t,J=7.5Hz,1H),7.41(d,J=81.6Hz,1H),7.49–7.40(m,4H),4.76(d,J=2.7Hz,2H),4.50(t,J=7.1Hz,2H),3.67(d,J=4.5Hz,2H),3.29(t,J=7.1Hz,2H).
Example 8: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2- (thien-2-ylmethyl) phthalazin-1 (2H) -one trifluoroacetate (TM8)
The title compound was prepared in 15% overall yield by a method similar to that described in example 4, except that 2- (chloromethyl) thiophene was used in the third step of this example instead of 2-bromoethanol in the third step of example 4.
MS m/z(ESI):346.0[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),8.23(d,J=9.5Hz,1H),8.03(s,3H),7.53–7.49(m,1H),7.40(d,J=71.0Hz,1H),7.48(s,1H),7.44(dd,J=5.1,1.2Hz,1H),7.15(d,J=2.5Hz,1H),6.98(dd,J=5.1,3.5Hz,1H),5.45(s,2H),4.76(d,J=3.0Hz,2H),3.67(d,J=4.5Hz,2H).
Example 9: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -3-methylisoquinolin-1 (2H) -one trifluoroacetate (TM9)
The first step is as follows: preparation of 6-methoxy-3-methyl-1H-isochroman-1-one (9-1)
2-bromo-4-methoxy-benzoic acid (1g, 4.33mmol) was added to DMF (10mL), acetylacetone (520mg, 5.19mmol) was added, copper iodide (82mg, 0.43mmol) and potassium phosphate (1.84g, 8.66mmol) were added, reaction was carried out overnight at 98 deg.C, appropriate amount of water was added, ethyl acetate was extracted three times, and the solvent was concentrated by column chromatography on silica gel (petroleum ether: ethyl acetate 5:1) to give a yellow solid (550mg, 66%).
The second step is that: preparation of 6-methoxy-3-methylisoquinolin-1 (2H) -one (9-2)
Compound 9-1(550mg, 2.89mmol) was added to a solution of ammonia in methanol (10mL, 7M) and reacted in a closed pot at 130 ℃ for 4 hours, and the solvent was concentrated to give a pale yellow solid (530mg, 96%).
The third step to the fifth step: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -3-methylisoquinolin-1 (2H) -one trifluoroacetate (TM9)
The title compound TM9 was prepared in a similar manner to that described in the second to fourth steps in example 1, except that 9-2 was used in the third step in this example instead of 1-1 in the second step in example 1 (three-step yield 30%).
MS m/z(ESI):263.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),8.05(d,J=9.0Hz,1H),8.02(s,3H),7.38(d,J=82.2Hz,1H),7.06–6.99(m,2H),6.25(s,1H),4.68(d,J=2.9Hz,2H),3.65(s,2H),2.19(s,3H).
Example 10: (E) preparation of (2- (aminomethyl) -3-fluoroallyl) oxy) -2',4' -dihydro-1 ' H spiro [ cyclopentane-1, 3' -isoquinolin-1 ' -one trifluoroacetate (TM10)
The first step is as follows: preparation of ethyl 1- (3-methoxybenzyl) cyclopentanoate (10-1)
Ethyl cyclopentylcarboxylate (1.36g,9.58mmol) was added to THF (50mL), LDA (12.45mmol, 6.3mL) was added slowly at-78 deg.C, then slowly warmed to room temperature, reacted overnight, water was added, the solvent was concentrated, extracted three times with ethyl acetate, and the organic phase was concentrated to give a yellow liquid (2.40g, 95%).
The second step is that: synthesis of 1- (3-methoxybenzyl) cyclopentanecarboxylic acid (10-2)
Compound 10-1(2.40g, 9.15mmol) was added to ethanol (50mL), an aqueous solution of sodium hydroxide (2.56g, 64.04mmol, 2M) was added, heated at 85 ℃ for 5 hours, the ethanol was concentrated, water was added, dichloromethane was extracted three times, and the organic phase was concentrated to give a yellow liquid (1.20g, 55%).
The third step: preparation of 6 '-methoxy-2', 4 '-dihydro-1' H-spiro [ cyclopentane-1, 3 '-isoquinolin-1' -one (10-3)
Compound 10-2(0.5g, 2.13mmol) was added to toluene (10mL), triethylamine (259mg, 2.56mmol) was added, diphenyl phosphorazidate (646mg, 2.35mmol) was added, reaction was carried out at room temperature for 1 hour, heating was carried out at 90 ℃ for 1 hour, cooling was carried out at room temperature, the solvent was concentrated, methylene chloride (10mL) was added, aluminum trichloride (845mg, 6.36mmol) was added, reaction was carried out at room temperature for 2 hours, the solvent was removed by concentration, water was slowly added, the solid was precipitated by stirring, and a white solid was obtained by filtration (350mg, 71%).
Fourth to sixth steps: (E) preparation of (2- (aminomethyl) -3-fluoroallyl) oxy) -2',4' -dihydro-1 ' H spiro [ cyclopentane-1, 3' -isoquinolin-1 ' -one trifluoroacetate (TM10)
The title compound TM10 was prepared in a similar manner to that described in the second to fourth steps in example 1 except that 10-3 was used in the fourth step of this example instead of 1-1 of the second step in example 1 (three-step yield 30%).
MS m/z(ESI):305.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.03(s,3H),7.93(s,1H),7.78(d,J=8.5Hz,1H),7.35(d,J=81.9Hz,1H),6.93(dd,J=8.5,2.4Hz,1H),6.89(d,J=2.2Hz,1H),4.63(d,J=3.0Hz,2H),3.64(d,J=4.9Hz,2H),2.90(s,2H),1.78–1.67(m,2H),1.67–1.50(m,6H).
Example 11: (E) preparation of (E) -6'- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2',4 '-dihydro-1' H-spiro [ cyclobutane-1, 3 '-isoquinolin-1' -one trifluoroacetate (TM11)
The title compound was prepared in 12% overall yield using a procedure similar to that described in example 10, except that ethyl cyclobutanecarboxylate was used in the first step of this example instead of ethyl cyclopentylcarboxylate in the first step of example 10.
MS m/z(ESI):291.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.20(s,1H),7.95(s,3H),7.76(d,J=8.3Hz,1H),7.31(d,J=82.2Hz,1H),6.98–6.91(m,2H),4.67(d,J=2.9Hz,2H),3.58(s,2H),3.04(s,2H),2.17–2.05(m,2H),1.99–1.86(m,2H),1.82–1.57(m,2H).
Example 12: (E) preparation of (E) -6'- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2',4 '-dihydro-1' H-spiro [ cyclohexane-1, 3 '-isoquinolin-1' -one trifluoroacetate (TM12)
The title compound was prepared in 13% overall yield by a procedure similar to that described in example 10, except that ethyl cyclohexanecarboxylate was used in the first step of this example instead of ethyl cyclopentylcarboxylate in the first step of example 10.
MS m/z(ESI):319.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.05(s,3H),8.03(s,1H),7.38(d,J=81.85Hz,1H),7.09(d,J=2.1Hz,1H),7.03(dd,J=8.8,2.3Hz,1H),6.27(s,1H),4.69(d,J=2.6Hz,2H),3.65(d,J=4.7Hz,2H),1.89(d,J=12.1Hz,2H),1.79(d,J=12.4Hz,2H),1.69(d,J=12.6Hz,1H),1.50–1.17(m,6H).
Example 13: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2,2', 3', 4,5', 6' -hexahydro-1H-spiro [ isoquinoline-3, 4' -pyran ] -1-one trifluoroacetate (TM13)
The title compound was prepared in 12% overall yield by a method similar to that described in example 10, except that tetrahydropyran-4-carboxylic acid ethyl ester was used in the first step of this example instead of cyclopentylcarboxylic acid ethyl ester in the first step of example 10.
MS m/z(ESI):321.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.01(s,3H),7.97(s,1H),7.79(d,J=8.4Hz,1H),7.36(d,J=81.9Hz,1H),6.98–6.89(m,2H),4.63(d,J=3.1Hz,2H),3.77–3.68(m,2H),3.67–3.59(m,2H),3.59–3.49(m,2H),3.00(s,2H),1.64–1.51(m,4H).
Example 14: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2-methylphthalazin-1 (2H) -one trifluoroacetate (TM14)
The title compound was prepared in a similar manner to that described in example 1, except that methyl iodide was used in the first step of this example instead of 2-bromoethylmethylsulfone in the first step of example 1, and aqueous hydrobromic acid was used in the second step instead of aluminum trichloride and toluene in the second step of example 1, in a total yield of 13%.
MS m/z(ESI):264.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.36(s,1H),8.24–8.20(m,1H),8.06(s,3H),7.48(dd,J=5.7,2.4Hz,2H),7.43(d,J=81.74Hz,1H),4.77(d,J=2.9Hz,2H),3.71(s,3H),3.69(s,2H).
Example 15: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2- (pyridin-2-ylmethyl) phthalazin-1 (2H) -one trifluoroacetate (TM15)
The title compound was prepared in a similar manner to that described in example 1, except that 2-chloromethylpyridine was used in the first step of this example in place of 2-bromoethylmethylsulfone in the first step of example 1, and aqueous hydrobromic acid was used in the second step in place of aluminum trichloride and toluene in the second step of example 1, in an overall yield of 15%.
MS m/z(ESI):341.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.49(d,J=4.5Hz,1H),8.40(s,1H),8.22(d,J=9.0Hz,1H),8.05(s,3H),7.78(t,J=7.5Hz,1H),7.54–7.50(m,2H),7.41(d,J=66.7Hz,1H),7.32–7.28(m,1H),7.25(d,J=8.0Hz,1H),5.43(s,2H),4.78(s,2H),3.68(d,J=4.7Hz,2H).
Example 16: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2- (pyrazin-2-ylmethyl) phthalazin-1 (2H) -one trifluoroacetate (TM16)
The title compound was prepared in a similar manner to that described in example 1, except that 2-chloromethylpyrazine was used in the first step of this example instead of 2-bromoethylmethylsulfone in the first step of example 1, and aqueous hydrobromic acid was used in the second step instead of aluminum trichloride and toluene in the second step of example 1, in an overall yield of 16%.
MS m/z(ESI):342.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.57–8.54(m,2H),8.40(s,1H),8.20(d,J=8.5Hz,1H),8.13(s,3H),7.52(d,J=5.5Hz,2H),7.40(d,J=65.45Hz,1H),5.50(s,2H),4.78(d,J=2.8Hz,2H),3.68(s,2H).
Example 17: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2- ((1-methyl-1H-pyrazol-5-yl) methyl) phthalazin-1 (2H) -one trifluoroacetate (TM17)
The title compound was prepared in a similar manner to that described in example 1, except that 5- (chloromethyl) -1-methyl-1H-pyrazole was used in the first step of this example in place of 2-bromoethylmethylsulfone in the first step of example 1, and an aqueous hydrobromic acid solution was used in the second step in place of aluminum trichloride and toluene in the second step of example 1, in a total yield of 16%.
MS m/z(ESI):344.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),8.22(d,J=9.6Hz,1H),8.08(s,3H),7.53–7.47(m,2.5H),7.33–7.30(m,1.5H),6.16(d,J=1.8Hz,1H),5.38(s,2H),4.76(d,J=3.0Hz,2H),3.95–3.82(s,3H),3.67(s,2H).
Example 18: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2- (thiazol-2-ylmethyl) phthalazin-1 (2H) -one trifluoroacetate (TM18)
The title compound was prepared in 15% overall yield by a method similar to that described in example 4, except that 2-chloromethylthiazole was used in the third step of this example instead of 2-bromoethanol in the third step of example 4.
MS m/z(ESI):347.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.44(s,1H),8.24(d,J=9.6Hz,1H),8.05(s,3H),7.75(d,J=3.3Hz,1H),7.69(d,J=3.3Hz,1H),7.53–7.51(m,2H),7.41(d,J=71.97Hz,1H),5.61(s,2H),4.77(d,J=3.0Hz,2H),3.68(s,2H).
Example 19: (E) preparation of (E) -7- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2, 2-dimethyl-2H-benzo [ e ] [1,3] oxazin-4 (3H) -one trifluoroacetate (TM19)
The first step is as follows: preparation of 7-hydroxy-2, 2-dimethyl-2H-benzo [ e ] [1,3] oxazin-4 (3H) -one (19-1)
2, 4-Dihydroxybenzamide (1g, 6.53mmol) was added to acetone (10mL), 2-dimethoxypropane (10mL) was added, p-toluenesulfonic acid monohydrate (124mg, 0.65mmol) was added, and reaction was carried out at room temperature for 2 hours to give a large amount of solid, which was filtered, washed with water, and dried to give a white solid (730mg, 58%).
The second step is that: preparation of tert-butyl (2- ((2, 2-dimethyl-4-oxo-3, 4-dihydro-2H-benzo [ e ] [1,3] oxazin-7-yl) oxy) methyl) -3-fluoroallyl) carbamate (19-2)
Compound (19-1) (0.1g, 0.51mmol) was added to DMF (2mL), followed by the addition of intermediate Int-1(146mg, 0.54mmol), followed by the addition of potassium carbonate (143mg, 1.04mmol), reaction at room temperature for 1 hour, extraction with water, dichloromethane three times, and concentration of the organic phase to give the crude product, which was used directly in the next step.
The third step: (E) preparation of (E) -7- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2, 2-dimethyl-2H-benzo [ e ] [1,3] oxazin-4 (3H) -one trifluoroacetate (TM19)
The crude product (19-2) from the previous step was added to methylene chloride (1.5mL) in its entirety, trifluoroacetic acid (1mL) was added, the reaction was carried out at room temperature for 1 hour, the organic phase was concentrated, separated by reverse phase preparative HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid solution), and lyophilized to give the title compound (80mg, two-step yield 40%)
MS m/z(ESI):281.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.49(s,1H),8.00(s,3H),7.69(d,J=8.6Hz,1H),7.34(d,J=81.9Hz,1H),6.70(dd,J=8.6,2.3Hz,1H),6.59(d,J=2.3Hz,1H),4.62(d,J=3.1Hz,2H),3.63(d,J=3.6Hz,2H),1.52(s,6H).
Example 20: (E) preparation of (E) -7- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2', 3', 5', 6' -tetrahydrospiro [ benzo [ e ] [1,3] oxazine-2, 4' -pyran-4 (3H) -one trifluoroacetate (TM20)
The title compound was prepared in 28% overall yield in a similar manner to the procedure described in example 19, except that in the first step of this example tetrahydropyran-4-one, toluene and a 120 degree reaction temperature were used instead of 2, 2-dimethoxypropane, acetone and a room temperature reaction, respectively, of the first step of example 19.
MS m/z(ESI):323.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.03(s,3H),7.69(d,J=8.6Hz,1H),7.34(d,J=81.8Hz,1H),6.72(dd,J=8.6,2.3Hz,1H),6.69(d,J=2.3Hz,1H),4.63(d,J=3.1Hz,2H),3.79–3.71(m,2H),3.70–3.58(m,4H),2.00–1.78(m,4H).
Example 21: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -3- (tert-butyl) isoquinolin-1 (2H) -one trifluoroacetate (TM21)
The first step is as follows: preparation of 3- (tert-butyl) -6-methoxyisoquinolin-1 (2H) -one (21-1)
Diethylamine (182mg, 2.5mmol) was dissolved in THF (5mL), added slowly to n-butyllithium in THF (20.1mmol, 8mL) at-78 degrees followed by stirring at 0 degrees for 30 minutes and then cooling to-78 degrees, a THF solution (5mL) of 4-methoxy-2-methyl-benzoic acid (0.94g, 5.66mmol) was added slowly to the reaction solution, cooled to-78 degrees after reaction at 0 degrees for 30 minutes, a THF solution (5mL) of trimethylacetonitrile (470mg, 5.66mmol) was added slowly to the system followed by slowly raising the temperature to room temperature, reacted at room temperature for 3 hours, quenched with water, concentrated the organic phase, precipitated a solid, filtered to give a pale yellow solid (940mg, 72%).
The second step to the fourth step: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -3- (tert-butyl) isoquinolin-1 (2H) -one trifluoroacetate (TM21)
The title compound TM21 was prepared in a similar manner to that described in the second to fourth steps in example 1, except that 21-1 was used in the second step of this example instead of 1-1 in the second step of example 1 (three-step yield 32%).
MS m/z(ESI):305.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),8.06(d,J=8.8Hz,1H),8.02(s,3H),7.38(d,J=81.8Hz,1H),7.15(d,J=2.4Hz,1H),7.05(dd,J=8.8,2.5Hz,1H),6.33(d,J=1.6Hz,1H),4.70(d,J=3.1Hz,2H),3.65(d,J=3.9Hz,2H),1.30(s,9H).
Example 22: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -3-phenylisoquinolin-1 (2H) -one trifluoroacetate (TM22)
The title compound was prepared in 10% overall yield in a similar manner to that described in example 21, except that benzonitrile was used in the first step of this example instead of trimethylacetonitrile in the first step of example 21.
MS m/z(ESI):325.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),8.14(d,J=8.8Hz,1H),8.05(s,3H),7.79–7.76(m,2H),7.54–7.48(m,3H),7.39(s,J=66.03Hz,1H),7.24(d,J=2.4Hz,1H),7.13(dd,J=8.8,2.4Hz,1H),6.86(s,1H),4.73(d,J=2.7Hz,2H),3.67(s,2H).
Example 23: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -3-cyclohexylisoquinolin-1 (2H) -one trifluoroacetate (TM23)
The title compound was prepared in 12% overall yield by a procedure similar to that described in example 21, except that cyclohexanecarbonitrile was used in the first step of this example instead of trimethylacetonitrile in the first step of example 21.
MS m/z(ESI):331.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.05(s,3H),8.03(s,1H),7.38(d,J=81.85Hz,1H),7.09(d,J=2.1Hz,1H),7.03(dd,J=8.8,2.3Hz,1H),6.27(s,1H),4.69(d,J=2.6Hz,2H),3.65(d,J=4.7Hz,2H),1.89(d,J=12.1Hz,2H),1.79(d,J=12.4Hz,2H),1.69(d,J=12.6Hz,1H),1.56–1.09(m,6H).
Example 24: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -3- (tetrahydro-2H-pyran-4-yl) isoquinolin-1 (2H) -one trifluoroacetate (TM24)
The title compound was prepared in 15% overall yield by a method similar to that described in example 21, except that in the first step of this example tetrahydro-pyran-4-carbonitrile was used instead of trimethylacetonitrile in the first step of example 21.
MS m/z(ESI):333.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.05(d,J=8.8Hz,1H),8.02(s,3H),7.38(d,J=81.8Hz,1H),7.12(d,J=2.4Hz,1H),7.05(dd,J=8.8,2.5Hz,1H),6.30(s,1H),4.69(d,J=3.2Hz,2H),3.96(dd,J=11.0,3.4Hz,2H),3.65(d,J=4.3Hz,2H),3.38(t,J=10.8Hz,2H),2.72–2.64(m,1H),1.86–1.80(m,2H),1.71–1.60(m,2H).
Example 25: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2-isopropylphthalazin-1 (2H) -one trifluoroacetate (TM25)
The title compound was prepared in 16% overall yield by a method similar to that described in example 4, except that 2-bromopropane was used in place of 2-bromoethanol in the third step of this example in the third step of example 4.
MS m/z(ESI):292.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),8.21(d,J=9.8Hz,1H),8.04(s,3H),7.50–7.44(m,2H),7.41(d,J=81.76Hz,1H),5.29–5.21(m,1H),4.76(d,J=2.9Hz,2H),3.67(s,2H),1.32(s,3H),1.30(s,3H).
Example 26: (E) preparation of (26) -7- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2, 2-dimethyl-2, 3-dihydroquinazolin-4 (1H) -one
The first step is as follows: preparation of 2-amino-4-methoxybenzamide (26-2)
Compound (26-1) (1.77 g, 10mmol) was added to DMSO (40 mL), hydrogen peroxide (2.27 g, 20.00mmol, content 30%) was added, ammonia water (4.20 g, 30.00 mmol, content 25%) was added, followed by reaction at 25 ℃ for 12 hours, water 40mL was added, ethyl acetate was extracted three times, the organic solvent was concentrated, and light yellow solid (0.63g, 38%) was isolated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1).
The second step is that: preparation of 7-methoxy-2, 2-dimethyl-2, 3-dihydroquinazolin-4 (1H) -one (26-3)
Compound (26-2) (0.63g, 3.79 mmol) was added to acetone (15 mL), p-toluenesulfonic acid monohydrate (72mg, 379 umol) was added, the reaction was carried out at 50 ℃ for 2 hours, the organic phase was concentrated, and a yellow solid (0.4g, 51%) was isolated by silica gel column chromatography (petroleum ether: ethyl acetate 1:1-1: 2).
The third step: preparation of 7-hydroxy-2, 2-dimethyl-2, 3-dihydroquinazolin-4 (1H) -one (26-4)
The compound (26-3) was added to dichloromethane (5mL), boron tribromide (577mg, 2.3mmol) was added under an ice-water bath, followed by reaction at room temperature for 5 hours, quenching with methanol, and concentration of the organic phase to give a pale yellow crude product which was used directly in the next step.
Fourth to fifth steps: (E) preparation of (26) -7- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2, 2-dimethyl-2, 3-dihydroquinazolin-4 (1H) -one
The trifluoroacetate salt of title compound 26 was prepared in a similar manner to that described in the third to fourth steps of example 1 except that 26-4 was used in the fourth step of this example in place of 1-2 in the third step of example 1, and subjected to reverse phase preparative HPLC separation (mobile phase a: acetonitrile, mobile phase B: 0.05% aqueous ammonium formate solution) and freeze-dried to give the title compound (yield 10% in the third to fifth steps).
MS m/z(ESI):280.2[M+H]+
1H NMR(400 MHz,DMSO-d6)δ7.79(s,1H),7.52(d,J=8.6 Hz,1H),7.27(d,J=82.3Hz,1H),7.26(s,2H),6.70(s,1H),6.28(dd,J=8.6,2.3 Hz,1H),6.17(d,J=2.2 Hz,1H),4.53(d,J=2.8 Hz,2H),3.57(s,2H),1.36(s,6H).
Example 27: (E) preparation of (E) -7- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2,2, 3-trimethyl-2H-benzo [ e ] [1,3] oxazin-4 (3H) -one trifluoroacetate (TM27)
The first step is as follows: preparation of 2, 4-dihydroxy-N-methylbenzamide (27-2)
Compound (27-1) (2.68g, 16mmol) was added to methanol (20mL), 30% methylamine in methanol (16.5g, 159mmol) was added, the reaction was carried out at room temperature for 50 hours, the organic phase was concentrated, and separation by silica gel column chromatography (petroleum ether: ethyl acetate 1:1) gave a yellow solid (0.8g, 30%).
The second step is that: preparation of 7-hydroxy-2, 2, 3-trimethyl-2H-benzo [ e ] [1,3] oxazin-4 (3H) -one (27-3)
Compound (27-2) (0.2g, 1.2mmol) was added to chloroform (8mL), acetone (2g, 36mmol) and trimethylchlorosilane (3.9g, 36mmol) were added, reacted at 65 ℃ for 24 hours, made basic by addition of aqueous sodium carbonate, extracted three times with dichloromethane, the combined organic phases concentrated to give a yellow solid crude which was used directly in the next step.
The third step to the fourth step: (E) preparation of (E) -7- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2,2, 3-trimethyl-2H-benzo [ e ] [1,3] oxazin-4 (3H) -one trifluoroacetate (TM27)
The title compound TM27 was prepared in a similar manner to that described in the third to fourth steps in example 1, except that 27-3 was used in the third step of this example instead of 1-2 in the third step of example 1 (yield from the second to fourth steps was 15%).
MS m/z(ESI):294.9[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.01(s,3H),7.70(d,J=8.6Hz,1H),7.33(d,J=81.9Hz,1H),6.72(dd,J=8.6,2.3Hz,1H),6.60(d,J=2.3Hz,1H),4.63(d,J=3.1Hz,2H),3.63(s,2H),2.96(s,3H),1.58(s,6H).
Example 28: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -3, 3-dimethyl-2, 3-dihydroisoquinoline-1, 4-dione trifluoroacetate (TM28)
The first step is as follows: preparation of 4, 4-dibromo-6-methoxy-3, 3-dimethyl-3, 4-dihydroisoquinoline-1 (2H) -one (28-2)
Compound (28-1) (280mg, 1.36mmol) was added to carbon tetrachloride (6mL), NBS (728mg, 4mmol) was added, followed by reaction at 70 ℃ for 15 hours, the organic phase was concentrated, and a white solid (480mg, 97%) was isolated by silica gel column chromatography (petroleum ether: ethyl acetate 2: 1).
The second step is that: preparation of 6-methoxy-3, 3-dimethyl-2, 3-dihydroisoquinoline-1, 4-dione (28-3)
Compound (28-2) (480mg, 1.32mmol) was added to tetrahydrofuran/water (5/10mL), sodium carbonate (560mg, 5.2mmol) was added, reaction was carried out at 70 ℃ for 2 hours, diluted hydrochloric acid was added to adjust the system to weak acidity, dichloromethane was added to extract three times, the organic phase was concentrated, and separation by silica gel column chromatography (petroleum ether: ethyl acetate 1:1) gave a yellow solid (240mg, 83%).
The third step to the fifth step: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -3, 3-dimethyl-2, 3-dihydroisoquinoline-1, 4-dione trifluoroacetate (TM28)
The title compound TM28 was prepared in a similar manner to that described in the third to fifth steps in example 26, except that 28-3 was used in the third step of this example instead of 26-3 in example 26 (three-step total yield 20%).
MS m/z(ESI):293.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.07(d,J=8.5Hz,1H),8.01(s,3H),7.53–7.25(m,3H),4.76(d,J=2.9Hz,2H),3.66(s,2H),1.41(s,6H).
Example 29: (E) preparation of (E) -7- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2, 2-dimethyl-2H-benzo [ e ] [1,3] oxazin-4 (3H) -one hydrochloride (HC19)
The first step is as follows: (E) preparation of (E) -7- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2, 2-dimethyl-2H-benzo [ e ] [1,3] oxazin-4 (3H) -one (29-1)
Compound TM19(50mg, 0.12mmol) was made basic with an appropriate amount of aqueous sodium carbonate (1M), the solid was filtered and dried to give a white solid (25mg, 70%).
The second step is that: (E) preparation of (E) -7- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2, 2-dimethyl-2H-benzo [ e ] [1,3] oxazin-4 (3H) -one hydrochloride (HC19)
Compound (29-1) (25mg, 0.09mmol) was added to ethyl acetate (1mL), stirred in an ice-water bath, a solution of hydrogen chloride in ethyl acetate (65uL, 0.13mmol) was slowly added, the solid precipitated, filtered, dissolved in purified water, and lyophilized to give the title compound (26mg, 91%).
MS m/z(ESI):281.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.49(s,1H),8.18(s,3H),7.68(d,J=8.6Hz,1H),7.33(d,J=81.9Hz,1H),6.70(dd,J=8.6,2.3Hz,1H),6.59(d,J=2.2Hz,1H),4.65(d,J=2.6Hz,2H),3.60(s,2H),1.52(s,6H).
Example 30: (E) preparation of (E) -7- ((2- (aminomethyl) -3-fluoroallyl) oxy) -2,2, 3-trimethyl-2H-benzo [ e ] [1,3] oxazin-4 (3H) -one hydrochloride (HC27)
The title compound was prepared in 90% overall yield by a method similar to that described in example 29, except that TM27 was substituted for TM19 of the first step of example 29 in the first step of this example.
MS m/z(ESI):295.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.11(s,3H),7.70(d,J=8.6Hz,1H),7.33(d,J=81.9Hz,1H),6.72(dd,J=8.7,2.4Hz,1H),6.60(d,J=2.3Hz,1H),4.65(d,J=2.8Hz,2H),3.61(d,J=2.8Hz,2H),2.96(s,3H),1.58(s,6H).
Example 31: (E) preparation of (E) -6- ((2- (aminomethyl) -3-fluoroallyl) oxy) -3, 3-dimethyl-2, 3-dihydroisoquinoline-1, 4-dione hydrochloride (HC28)
The title compound was prepared in 92% overall yield by a method similar to that described in example 29, except that TM28 was substituted for TM19 of the first step of example 29 in the first step of this example.
MS m/z(ESI):293.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.07(d,J=8.5Hz,1H),8.03(s,3H),7.53–7.24(m,3H),4.77(s,2H),3.65(s,2H),1.41(s,6H).
Comparative example 1: 6- ((2-aminomethyl-3-fluoroallyl) oxy) -3, 3-dimethyl-3, 4-dihydroisoquinolin-1 (2H) -one trifluoroacetate salt
Comparative example 2: 6- ((2-aminomethyl-3-fluoroallyl) oxy) -2-methyl-3, 4-dihydroisoquinolin-1 (2H) -one trifluoroacetate salt
Test example 1: VAP-1 enzymatic activity inhibition assay
1. The detection kit comprises: MAO-GLO Assay kit, manufacturer: promega, enzyme: VAP-1, manufacturer: and R & D.
Method for detecting inhibition of VAP-1 enzymatic activity
The VAP-1 protein and compounds to be detected with different concentrations are pre-incubated for 10min at room temperature, then substrates are added, after reaction for 1h at room temperature, 10 muL Detection buffer is added to each hole, and reaction is carried out for 20min at room temperature. After the reaction is finished, the reaction product is placed on a BMG LABTECH multifunctional microplate reader, and data are read in a Luminescence mode. The relative activity of each concentration group is calculated by using a solvent group (DMSO) as a negative control and a Buffer group (containing no enzyme) as a blank control, and the median Inhibitory Concentration (IC) of the compound is calculated by analyzing data through a four-parameter equation by using Graphpad Prism 5.0 software50). The calculation equation is as follows:
(Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)))
wherein, X ═ compound test concentration; bottom: a baseline response value; top: a maximum response value; HillSlope: a slope factor; y represents the relative response rate.
3. Test results
The inhibition of VAP-1 activity by the compounds was determined as described above and the results are shown in Table 1.
TABLE 1 results of VAP-1 enzyme activity inhibition test
Example numbering | IC50(nM) |
Example 1 | 10.02±1.09 |
Example 3 | 11.96±1.82 |
Example 4 | 20.29±4.87 |
Example 6 | 16.87±3.11 |
Example 8 | 2.87±0.22 |
Example 9 | 8.47±2.60 |
Example 10 | 5.81±1.39 |
Example 11 | 10.24±1.69 |
Example 12 | 7.79±1.19 |
Example 13 | 36.04±18.69 |
Example 14 | 5.02±0.70 |
Example 16 | 7.72±1.73 |
Example 18 | 4.78±0.75 |
Example 19 | 8.46±1.27 |
Example 20 | 38.8±13.74 |
Example 21 | 17.16±3.20 |
Example 27 | 3.89±0.10 |
Example 28 | 7.41±0.42 |
Test results show that the compound has stronger activity of inhibiting VAP-1.
Test example 2: MAO-A enzymatic Activity inhibition assay
1. The detection kit comprises: MAO-GLO Assay kit, manufacturer: promega, protein: MAO-A, manufacturer: sigma.
MAO-A enzyme activity inhibition detection method
According to the method of the kit specification, the MAO-A protein and the compounds to be detected with different concentrations are pre-incubated for 10min at room temperature, then A substrate is added, after reaction for 1h at room temperature, 10 muL Detection buffer is added to each hole, and the reaction is carried out for 20min at room temperature. After the reaction is finished, the reaction product is placed on a BMG LABTECH multifunctional microplate reader, and data are read in a Luminescence mode. The relative activity of each concentration group was calculated using vehicle group (DMSO) as negative control and Buffer group (without enzyme) as blank control.
Calculating IC according to the following formula50The value of (c):
IC50(relative activity percent)/(1-relative activity percent) X,
where X ═ compound test concentration.
3. Test results
The inhibition of MAO-A activity by the compounds was determined as described above and the results are shown in Table 2.
TABLE 2 MAO-A enzyme activity inhibition test results
Example numbering | IC50(μM) |
Example 1 | >100 |
Example 2 | >100 |
Example 8 | 62.30±7.10 |
Example 10 | >100 |
Example 11 | >100 |
Example 12 | >100 |
Example 19 | >100 |
Example 22 | >100 |
Example 23 | 42.01±1.93 |
Example 27 | 35.54±9.72 |
Example 28 | >100 |
The results show that the compound of the invention has lower inhibition effect on MAO-A.
Test example 3: MAO-B enzymatic Activity inhibition assay
1. The detection kit comprises: MAO-GLO Assay kit, manufacturer: promega; protein: MAO-B, manufacturer: sigma.
MAO-B enzyme activity inhibition detection method
According to the method of the kit specification, the MAO-B protein and the compounds to be detected with different concentrations are pre-incubated for 10min at room temperature, then a substrate is added, after reaction for 1h at room temperature, 10 muL Detection buffer is added to each hole, and reaction is carried out for 20min at room temperature. After the reaction is finished, the reaction product is placed on a BMG LABTECH multifunctional microplate reader, and data are read in a Luminescence mode. The relative activity of each concentration group was calculated using vehicle group (DMSO) as negative control and Buffer group (without enzyme) as blank control.
Calculating IC according to the following formula50The value of (c):
IC50x (percent relative activity)/(1-percent relative activity);
where X ═ compound test concentration.
3. Test results
The inhibition of MAO-B activity by the compounds was determined as described above and the results are shown in Table 3.
TABLE 3 MAO-B enzyme activity inhibition test results
Example numbering | IC50(μM) |
Example 2 | >10 |
Example 11 | >10 |
Example 12 | >10 |
Example 19 | >10 |
Example 27 | 9.46±3.48 |
Example 28 | 88.85±22.57 |
The results show that the compound of the invention has lower inhibition effect on MAO-B.
Test example 4: DAO enzymatic Activity inhibition assay
1. The detection kit comprises:red Monoamine oxide Assay, manufacturer: life; protein: DAO, manufacturer: r&D。
DAO enzyme activity inhibition detection method
The reaction was initiated by preincubation of the DAO protein with different concentrations of compound for 10min at room temperature and addition of substrate, HRP and resolufin. The reaction plate was placed in a microplate reader and the fluorescence signal was measured in the kinetic mode at Ex/Em-540/590 nm. The relative activity of each concentration group was calculated by using the ratio of fluorescence signal-reaction time (slope) in the linear range as the reaction rate, the vehicle group (DMSO) as a negative control, and the Buffer group (containing no enzyme) as a blank control.
Calculating IC according to the following formula50The value of (c):
IC50x (percent relative activity)/(1-percent relative activity);
where X ═ compound test concentration.
3. Test results
The inhibition of DAO activity by the compounds was determined as described above and the results are shown in table 4.
TABLE 4 DAO enzyme activity inhibition test results
The results show that the compound of the invention has lower inhibition effect on DAO, and has lower inhibition effect compared with the compound of comparative example 1 and comparative example 2, and has obvious advantages.
In conclusion, DAO activity inhibition tests of VAP-1 and MAO-A, MAO-B show that compared with VAP-1, the compound of the invention has low DAO inhibition effect on MAO-A, MAO-B, and shows that the compound of the invention has good selective inhibition effect on VAP-1.
Test example 5: hERG inhibition assay
Reagent: PredictorTMhERG Fluorescence Polarization Assay Kit, manufacturer: thermo.
Test method
The potential of compounds to induce prolongation of cardiac QT interval was assessed using the kit described above. Adding a test compound, a positive control (E4031) and a negative control (experiment buffer) into a microplate containing an hERG cell membrane, adding a Tracer Tracer with high hERG affinity, incubating the microplate at 25 ℃ for 2 hours, detecting the change of a fluorescence polarization value (mP) by using a BMG PHARESTar multifunctional microplate reader, and finally calculating the percent inhibition (%) at different concentrations to judge the half maximum Inhibition Concentration (IC) of the compound50) The range of (1).
Percent inhibition ═ 100% (1- (mP of mP-30 μ M E4031 for test compound)/(mP of mP-30 μ M E4031 for experimental buffer));
calculating IC according to the following formula50The value of (c):
IC50(1-percent inhibition)/percent inhibition X;
wherein X is the test concentration of the compound
Test results
Inhibition of hERG by compounds was determined using the methods described above and the results are shown in table 5.
TABLE 5 hERG inhibition assay results
Test results show that the hERG of the compounds is more than 10 mu M, and the compounds have good safety.
Test example 6: CYP enzyme inhibition assay
The test system comprises:
P450-GloTMYP 1A2 Screening System, manufacturer: promega;
P450-GloTMYP 2D6 Screening System, manufacturer: promega;
P450-GloTMYP 3A4 Screening System, manufacturer: promega.
Test parameters are as follows:
BMG PHERAstar FS Luminescent。
the test steps are as follows:
inhibition of CYP1a 2: the compounds of the present invention with different concentrations were added to 384-well microwell plates, and the substrates luciferin-ME (100. mu.M), Potasssium Phosphate Buffer (100mM), CYP1A2 or Membrane (0.01 pmol/. mu.L) were added for pre-incubation at room temperature for 10min, followed by addition of a2 XNADPH regeneration system, reaction at room temperature for 30min, and finally, an equal volume of detection Buffer was added for incubation at room temperature for 20min before chemiluminescence detection.
Inhibition of CYP2D 6: adding the compounds of the invention with different concentrations into a 384-well microplate, adding substrates luciferin-ME EGE (30 mu M), Potasssium Phosphatate Buffer (100mM), CYP2D6 or Membrane (5nM) for pre-incubation at room temperature for 10min, then adding a2 XNADPH regeneration system, reacting at 37 ℃ for 30min, finally adding an equal volume of detection Buffer, incubating at room temperature for 20min, and performing chemiluminescence detection.
Inhibition of CYP3a 4: adding the compounds of the invention with different concentrations into 384-well micro-porous plates, adding substrates Luciferin-IPA (3 muM), Potasssium Phosphatate Buffer (100mM), CYP3A4 or Membrane (2nM) for pre-incubation at room temperature for 10min, then adding a2 XNADPH regeneration system, reacting at room temperature for 30min, finally adding an equal volume of detection Buffer, incubating at room temperature for 20min, and performing chemiluminescence detection.
Data processing:
the inhibition was calculated using vehicle group (DMSO) as negative control and Membrance (inactive enzyme) as blank control.
Percent inhibition ═ 100% (1- (each compound concentration group signal-blank signal)/(negative control signal-blank signal))/.
Half maximal Inhibitory Concentration (IC) of compounds was estimated based on their inhibition of P450 enzyme at different concentrations50) Or a range.
IC50X (1-percent inhibition)/percent inhibition;
wherein, X is the test concentration of the compound.
And (3) test results:
the inhibition of three CYPs by the compounds was determined as described above and the results are shown in table 6.
TABLE 6 CYPs inhibition test results
Test results show that the compound has no obvious inhibition effect on CYP2D6 and CYP3A4 subtype, has weak inhibition effect on CYP1A2 subtype, and shows that the potential drug interaction possibility is relatively low and the compound has good drug property.
While specific embodiments of the invention have been described in detail, it will be appreciated by those skilled in the art that various modifications and alternatives to those details could be developed in light of the overall teachings of the disclosure, and that such modifications are intended to be included within the scope of the disclosure. The full scope of the invention is given by the appended claims and any equivalents thereof.
Claims (11)
1. A compound of formula I, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, prodrug, or ester thereof, or a pharmaceutically acceptable salt thereof:
wherein the content of the first and second substances,
v is selected from-N ═ CR5-and-CR5R6-;
R5Selected from H, C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C6-10Aryl and 5-10 membered heteroaryl;
R6is selected from C1-6An alkyl group; alternatively, the first and second electrodes may be,
R5and R6Together with the atoms to which they are attached form C4-8Alicyclic or 4-8 membered alicyclic heterocyclic ring;
w is selected from ═ CR7-、-CR7R8-、-C(O)-、-C(S)-、=N-、-NR7-, -O-, -S-, -S (O) -and-SO2-;
R7Selected from H, halogen, C1-6Alkyl and C3-8A cycloalkyl group;
R8selected from H and halogen;
provided that when V is-CR5R6-,R5Selected from H, C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C6-10Aryl and 5-10 membered heteroaryl, R6Is selected from C1-6When alkyl, W is not-CH2-;
R1Selected from H, C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered lipoheterocyclyl, C6-10Aryl and 5-10 membered heteroaryl, wherein said C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered lipoheterocyclyl, C6-10Aryl and 5-10 membered heteroaryl optionally substituted with one or more substituents selected from halogen, -OH, -O, -OC1-6Alkyl, -CN, -S (O)2-C1-6Alkyl, 3-6 membered aliphatic heterocyclic group, benzeneAnd a 5-6 membered heteroaryl, wherein said phenyl or 5-6 membered heteroaryl is optionally further substituted with one or more halogens or C1-6Alkyl substitution;
R2optionally at each occurrence independently selected from H, halo, -OH, -OC1-6Alkyl, -CN, C1-6Alkyl and C3-8A cycloalkyl group;
R3and R4Each independently selected from H, Cl and F;
n is 0, 1,2 or 3.
2. The compound of claim 1, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, prodrug or ester thereof, or a pharmaceutically acceptable salt thereof, wherein,
v is-CR5R6-; wherein R is5Is selected from C1-6Alkyl radical, R6Is selected from C1-6An alkyl group; or, R5And R6Together with the atoms to which they are attached form C4-6Alicyclic or 4-6 membered alicyclic heterocyclic ring;
w is selected from-CR7R8-、-C(O)-、-C(S)-、-NR7-, -O-, -S-, -S (O) -and-SO2-, in which R7Selected from H, halogen, C1-3Alkyl and C3-6Cycloalkyl radical, R8Selected from H and halogen;
preferably, V is-CR5R6-; wherein R is5Is selected from C1-4Alkyl radical, R6Is selected from C1-4An alkyl group; or, R5And R6Together with the atoms to which they are attached form C4-6Alicyclic or 4-6 membered alicyclic heterocyclic ring;
w is selected from-CR7R8-、-NR7-, -C (O) -, -O-, -S-, -S (O) -, and-SO2-, in which R7Selected from H, C1-3Alkyl and halogen, R8Selected from H and halogen;
W is selected from-CH2-, -NH-, -C (O) -and-O-.
3. The compound of claim 1, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, prodrug or ester thereof, or a pharmaceutically acceptable salt thereof, wherein,
v is selected from-N ═ and-CR5Wherein R is5Selected from H, C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C6-10Aryl and 5-10 membered heteroaryl;
w is selected from ═ CR7-and ═ N-, wherein R7Selected from H, halogen, C1-2Alkyl and C3-6A cycloalkyl group;
preferably, V is selected from-N ═ and-CR5Wherein R is5Selected from H, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocycloalkyl, and phenyl;
w is selected from ═ CR7-and ═ N-, wherein R7Selected from H, halogen and C1-2An alkyl group;
preferably, V is-N ═ N;
w is ═ CR7-, wherein R7Selected from H, halogen and C1-2An alkyl group; preferably, W is ═ CH —;
alternatively, the first and second electrodes may be,
v is-CR5Wherein R is5Selected from H, -CH3、-C(CH3)3Cyclohexyl, phenyl and tetrahydropyranyl;
w is ═ CR7-, wherein R7Selected from H, halogen and C1-2An alkyl group; preferably, W is ═ CH-.
4. The compound of any one of claims 1 to 3, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, prodrug or ester thereof, or a pharmaceutically acceptable salt thereof, wherein,
R1selected from H, C1-4Alkyl radical, C3-6Cycloalkyl and 3-6 membered lipoheterocyclyl, wherein, said C1-4Alkyl is optionally substituted by one or more groups selected from-OH, -SO2-C1-3Alkyl, phenyl and 5-6 membered heteroaryl, wherein said phenyl and 5-6 membered heteroaryl are optionally further substituted with one or more-CH3Substitution;
preferably, R1Selected from H and C1-3An alkyl group;
preferably, R1Is selected from H and-CH3。
5. The compound of any one of claims 1 to 4, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, prodrug or ester thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula VIII:
wherein W and R1As defined in any one of claims 1 to 4.
7. A pharmaceutically acceptable salt of the compound of any one of claims 1 to 6 which is the trifluoroacetate or hydrochloride salt of the compound.
8. A pharmaceutical composition comprising a compound of any one of claims 1 to 7, or a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically labeled compound, a metabolite, a prodrug or ester thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical excipients.
9. Use of a compound according to any one of claims 1 to 7, or a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically labeled compound, a metabolite, a prodrug or an ester thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8 for the preparation of a VAP-1/SSAO (vascular adhesion protein 1/semicarbazide sensitive amine oxidase) inhibitor.
10. Use of a compound according to any one of claims 1 to 7, or a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically labeled compound, a metabolite, a prodrug or an ester thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8 in the manufacture of a medicament for the treatment of a disease or disorder associated with an overactivity of VAP-1/SSAO.
11. The use according to claim 10, wherein, the disease or disorder associated with overactivity of VAP-1/SSAO is selected from the group consisting of inflammatory diseases (such as liver-associated inflammatory diseases, e.g. hepatitis, hepatomegaly, liver fibrosis, cirrhosis or hepatic ascites; such as respiratory-associated inflammatory diseases, e.g. tracheitis, pneumonia, pulmonary fibrosis, asthma, acute lung injury, acute respiratory distress syndrome, bronchitis or chronic obstructive pulmonary disease; such as eye-associated inflammatory diseases, e.g. uveitis; such as other inflammations, e.g. synovitis or peritonitis), organ and/or tissue transplant rejection, autoimmune diseases (e.g. rheumatoid arthritis or multiple sclerosis (e.g. chronic multiple sclerosis)), skin diseases (e.g. eczema or psoriasis), diabetes (e.g. type I or type II diabetes) and stroke.
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