CN104341437A - SYK inhibitor containing bicyclo-radical - Google Patents
SYK inhibitor containing bicyclo-radical Download PDFInfo
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- CN104341437A CN104341437A CN201410353667.XA CN201410353667A CN104341437A CN 104341437 A CN104341437 A CN 104341437A CN 201410353667 A CN201410353667 A CN 201410353667A CN 104341437 A CN104341437 A CN 104341437A
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- 0 CCC(CC(C)(C)*)CNC1CC1 Chemical compound CCC(CC(C)(C)*)CNC1CC1 0.000 description 6
- OXXXNXISRXFPBK-UHFFFAOYSA-N C(COC1)C11CCNCC1 Chemical compound C(COC1)C11CCNCC1 OXXXNXISRXFPBK-UHFFFAOYSA-N 0.000 description 1
- MMBRNIZJPIEFLR-ONEGZZNKSA-N C=CNC(/C=C/N)=O Chemical compound C=CNC(/C=C/N)=O MMBRNIZJPIEFLR-ONEGZZNKSA-N 0.000 description 1
- SPTQOBUBEOBBCK-UNTBIKODSA-N CC(C)[C@@H](C=C)/N=C(\NCNc1cc(N2N=CCC2)ccc1)/S(C)=[U] Chemical compound CC(C)[C@@H](C=C)/N=C(\NCNc1cc(N2N=CCC2)ccc1)/S(C)=[U] SPTQOBUBEOBBCK-UNTBIKODSA-N 0.000 description 1
- BJPKBQNQQCWFLB-DATFTTISSA-N CC(C1)[C@]1(C(NC1=C(C[U])[C@@H]11)N=C1N[IH](CCC=C)=C)O Chemical compound CC(C1)[C@]1(C(NC1=C(C[U])[C@@H]11)N=C1N[IH](CCC=C)=C)O BJPKBQNQQCWFLB-DATFTTISSA-N 0.000 description 1
- RAAJXQVEQBUNMH-UHFFFAOYSA-N CC(N/C=N/CSC)=C Chemical compound CC(N/C=N/CSC)=C RAAJXQVEQBUNMH-UHFFFAOYSA-N 0.000 description 1
- ZTNPDCNEVKWJBK-UHFFFAOYSA-N CC(N=CNc1cc(NC(C(C(NC=C2)=O)=C2N)=NCS(C)O)ccc1)=C Chemical compound CC(N=CNc1cc(NC(C(C(NC=C2)=O)=C2N)=NCS(C)O)ccc1)=C ZTNPDCNEVKWJBK-UHFFFAOYSA-N 0.000 description 1
- RWGBSECIMRIREK-GFCCVEGCSA-N CCN(CCCC[C@@H](C)NC)C(OC(C)(C)C)=O Chemical compound CCN(CCCC[C@@H](C)NC)C(OC(C)(C)C)=O RWGBSECIMRIREK-GFCCVEGCSA-N 0.000 description 1
- CIEMGRSHPFEHRO-UHFFFAOYSA-O CC[NH+](C=NC)C(C=C)=CC(C)Nc1nc(N2CCC3(COCC3)CC2)nc(C=CN2)c1C2=O Chemical compound CC[NH+](C=NC)C(C=C)=CC(C)Nc1nc(N2CCC3(COCC3)CC2)nc(C=CN2)c1C2=O CIEMGRSHPFEHRO-UHFFFAOYSA-O 0.000 description 1
- FGQKPCSUBFZPEL-SECBINFHSA-N C[C@@H](CCNCCC=N)C=C Chemical compound C[C@@H](CCNCCC=N)C=C FGQKPCSUBFZPEL-SECBINFHSA-N 0.000 description 1
- UCXBVKIOSJSEOI-UHFFFAOYSA-N Cc1c(C(N)=C)c(Nc(cc2)ccc2NCCNC)nc(SC)n1 Chemical compound Cc1c(C(N)=C)c(Nc(cc2)ccc2NCCNC)nc(SC)n1 UCXBVKIOSJSEOI-UHFFFAOYSA-N 0.000 description 1
- OKOULUNHMXTZAU-UHFFFAOYSA-N [U]=C1NC=Cc2c1c(Nc1cccc(-[n]3nccn3)c1)nc(NC(C1)CC11CNCC1)n2 Chemical compound [U]=C1NC=Cc2c1c(Nc1cccc(-[n]3nccn3)c1)nc(NC(C1)CC11CNCC1)n2 OKOULUNHMXTZAU-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to an SYK inhibitor containing bicycle-radical as shown in a general formula (I), as well as pharmaceutically acceptable salt, stereoisomer or solvate thereof. In the general formula, X, Y, R1, R2, R3 and R4 are specified as shown in the specification. The invention further relates to a preparation method of these compounds, medicine preparations containing the compounds and application of theses compounds in preparation of medicines for treating and/or preventing syk mediated signal path related diseases.
Description
Technical field
The invention belongs to medical art, be specifically related to the SYK inhibitor containing bicyclic radicals, its pharmacy acceptable salt, its steric isomer or its solvated compounds, the preparation method of these compounds and the pharmaceutical preparation containing these compounds, and these compounds, its pharmacy acceptable salt, its steric isomer or its solvated compounds treat and/or prevent the application in the medicine of the relevant disease of the signal path that mediated by syk in preparation.
Background technology
Protein tyrosine kinase (protein tyrosine kinases, PTKs) be the proteolytic enzyme of one group of energy catalytic substrate protein-tyrosine residue phosphorylation, participate in many signal transduction pathways, and play an important role in control cytodifferentiation, proliferation and spreading.According to the difference of the cell topology of PTKs family member, receptor type and non-receptor type can be divided into.Part is combined with the after birth outskirt of PTKs acceptor, activates tyrosine kinase domain in its born of the same parents, triggers specific signal transduction pathway.In born of the same parents, the PTKs of non-receptor type is as signal transduction member, lack at ligand structure the transmembrane receptor of endogenous PTKs structure etc. many in play an important role.
Syk is a kind of non-receptor tyrosine kinase of solubility.Cloned out from pig spleen cDNA in 1991 by Taniguchi.Mankind Syk encoding gene is Syk gene, is positioned at human chromosomal 9q
22, protein molecular weight is 72KD, is made up of 629 amino acid, in the maturation and reactivation process of B cell, play key effect.
Syk is one of material impact factor of B cell antigen receptor (BCR) signal transduction pathway.After BCR activates, rely on the expression of the signal transduction pathway adjustment B cell clone of Syk, differentiation or apoptosis.Syk is most important kinases in B cell activation signal transductive process, this enzyme contains 2 Src homology functional zone SH2 (N) and SH2 (C), thus the first choice that Immuno-Tyrosine receptor activation motif (immunoreceptor tyrosine-based activation motif, ITAM) phosphorylation is recruited is become.The Syk be recruited becomes the 2nd target of Src effect immediately, and then starts 3 main paties (phosphatidylinositols approach, map kinase relational approach and phosphoinositide 3-kinase approach) of B cell activation signal transduction.Phospholipase C (PLC)-γ 2, phosphatidyl-inositol 3-kinase (PI3K) is the key substrate of Syk tyrosine phosphorylation.In B cell, Syk phosphorylation PLC-γ 2 causes the kinase whose cascade of ERK and JNK to activate, and PI3-K is mediated Akt activation after Syk phosphorylation.The a subunit of Syk preferential phosphorylation tubulin, the support that this subunit is considered to regulate cytoskeletal microtubule albumen to make it as assembling signal transduction complex body.Final activation transcription factor translocation separately enters nucleus, and various cis-acting elements or DNA capsule are combined in gene promoter region, makes corresponding gene generation transcriptional activation and Product Expression.
The signal event of ITAM mediation is the key factor that the activation signal making in immunocyte GPVI in traditional immunization acceptor such as φt cell receptor, B-cell receptor, Fc acceptor and thrombocyte etc. be initiated is passed to molecule such as syk in downstream cellular.The effect of Syk in the conduction of ITAM dependent signals and its expression in many cell types show, suppress the compound of Syk activity to can be used for treating the disease relating to immunity system and inflammation.Such as rhinallergosis, atopic asthma, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematous, multiple sclerosis, psoriasis, hemolytic anemia, immunologic thrombocytopenic purpura, the thrombocytopenia that heparin causes and atherosclerosis, chronic obstructive pulmonary disease, malignant hematologic disease (such as acute myelogenous leukemia, B cell lymphocytic leukemia), B cell lymphoma, t cell lymphoma and epithelial cancer (such as lung cancer, carcinoma of the pancreas and colorectal carcinoma).
Summary of the invention
Technical scheme of the present invention is as follows:
Logical compound shown in formula I, its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein, X is selected from 6-10 unit's aryl or 9-11 unit heterocyclic radical;
R
1be selected from hydrogen atom, halogen atom, amino, hydroxyl, C
1-8alkyl, C
1-8alkoxyl group, C
1-3alcoxyl C
1-8alkoxyl group, C
1-8alkyl amine group, two (C
1-8alkyl) amido, amino C
1-8alkyl, C
1-8alkyl-carbonyl-amino, formamyl, C
1-8alkyl amine group formyl radical, two (C
1-8alkyl) amido formacyl, amino-sulfonyl, C
1-8alkyl formyl radical, halo C
1-8alkyl, halo C
1-8alkoxyl group, hydroxyl C
1-8alkyl, 6-10 unit aryl, C
3-8cycloalkyl or 4-6 unit heterocyclic radical,
R
1can be replaced by an optional 1-3 substituting group further, described substituting group is independently selected from C
1-8alkyl, C
2-8thiazolinyl, C
2-8alkynyl, amino, hydroxyl, C
1-8alkoxyl group, oxo, halogen atom, C
1-8alkyl amine group, two (C
1-8alkyl) amido, C
1-8alkyl-carbonyl, formamyl, C
1-8alkyl-carbonyl-amino, C
1-8alkyl amine group formyl radical, amino C
1-8alkyl, hydroxyl C
1-8alkyl, cyano group, halo C
1-8alkyl, amino-sulfonyl, 6-10 unit aryl, C
3-8cycloalkyl or 4-6 unit heterocyclic radical;
R
2be selected from hydrogen atom or C
1-8alkyl;
R
3, R
4independently selected from hydrogen atom, cyano group, C
1-8alkyl, hydroxyl C
1-8alkyl, amino C
1-8alkyl or C
3-8cycloalkyl;
Y is selected from 6-11 unit's bicyclic radicals or 6-11 unit bicyclic radicals C
1-3alkyl,
Or Y and R
2connect and form 8-11 unit bicyclic radicals together with nitrogen-atoms,
Y or Y and R
2connect the group formed together with nitrogen-atoms can be replaced by 1-3 substituting group further, described substituting group is independently selected from amino, hydroxyl, C
1-8alkyl, C
1-8alkyl amine group, two (C
1-8alkyl) amido, amino C
1-8alkyl, carboxyl, C
1-8alkyl amine group C
1-8alkyl, C
1-8alkoxy C
1-8alkyl, hydroxyl C
1-8alkyl, carboxyl C
1-8alkyl, formamyl, C
3-8cycloalkyl C
1-8alkyl, hydroxyl C
1-8alkoxyl group or C
1-8alkyl-carbonyl.
The preferred version of logical compound shown in formula I, its pharmacy acceptable salt, its steric isomer or its solvated compounds is:
Wherein, X is selected from 6-10 unit's aryl or 9-11 unit heterocyclic radical;
R
1be selected from hydrogen atom, halogen atom, C
1-6alkyl, C
1-6alkoxyl group, C
1-3alcoxyl C
1-6alkoxyl group, C
1-6alkyl-carbonyl-amino, amino, C
1-6alkyl amine group, two (C
1-6alkyl) amido, amino-sulfonyl, halo C
1-6alkyl, halo C
1-6alkoxyl group, 6-10 unit aryl, C
3-8cycloalkyl or 4-6 unit heterocyclic radical;
R
1can be replaced by an optional 1-3 substituting group further, described substituting group is independently selected from C
1-6alkyl, hydroxyl, C
1-6alkoxyl group, oxo, halogen atom, C
1-6alkyl-carbonyl, formamyl, C
1-6alkyl-carbonyl-amino, C
1-6alkyl amine group formyl radical, amino C
1-6alkyl, cyano group, halo C
1-6alkyl or amino-sulfonyl;
R
2be selected from hydrogen atom or C
1-6alkyl;
R
3, R
4independently selected from hydrogen atom, C
1-6alkyl, hydroxyl C
1-6alkyl, amino C
1-6alkyl or C
3-8cycloalkyl;
Y is selected from the assorted bicyclic radicals of 6-11 unit or the assorted bicyclic radicals C of 6-11 unit
1-3alkyl,
Or Y and R
2connect and form the assorted bicyclic radicals of 8-11 unit together with nitrogen-atoms,
Y or Y and R
2connect the group formed together with nitrogen-atoms can be replaced by 1-3 substituting group further, described substituting group is independently selected from amino, hydroxyl, C
1-6alkyl, C
1-6alkyl amine group, two (C
1-6alkyl) amido, amino C
1-6alkyl, carboxyl, C
1-6alkyl amine group C
1-6alkyl, C
1-6alkoxy C
1-6alkyl, hydroxyl C
1-6alkyl, carboxyl C
1-6alkyl or C
1-6alkyl-carbonyl.
The preferred version of logical compound shown in formula I, its pharmacy acceptable salt, its steric isomer or its solvated compounds is:
Wherein, X is selected from 6-10 unit's aryl or 9-10 unit heterocyclic radical;
R
1be selected from hydrogen atom, halogen atom, C
1-6alkyl, amino, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkoxyl group, C
1-3alcoxyl C
1-6alkoxyl group, phenyl, C
3-6cycloalkyl or 4-6 unit heterocyclic radical;
R
2, R
3, R
4independently selected from hydrogen atom or C
1-6alkyl;
Y is selected from the assorted bicyclic radicals of 6-10 unit or the assorted bicyclic radicals C of 6-10 unit
1-3alkyl,
Or Y and R
2connect and form the assorted bicyclic radicals of 9-10 unit together with nitrogen-atoms,
Y or Y and R
2connect the group formed together with nitrogen-atoms can be replaced by 1-2 substituting group further, described substituting group is independently selected from amino, C
1-6alkyl amine group, two (C
1-6alkyl) amido, hydroxyl, carboxyl, C
1-6alkyl, hydroxyl C
1-6alkyl, carboxyl C
1-6alkyl or C
1-6alkyl-carbonyl.
The preferred version of logical compound shown in formula I, its pharmacy acceptable salt, its steric isomer or its solvated compounds is:
Wherein, X is selected from phenyl, quinolyl, indazolyl, benzothiazolyl or Isosorbide-5-Nitrae-benzdioxan base;
R
1be selected from hydrogen atom, fluorine atom, methyl, amino, methyl amido, two (methyl) amido, methoxyl group, oxyethyl group, methoxyethoxy, imidazolyl, pyrazolyl, pyridyl, 1,2,3-triazol radical or 1,3,4-triazol radical;
R
2, R
3, R
4independently selected from hydrogen atom or methyl;
Y is selected from
n is the integer of 0 or 1,
Or Y and R
2connect and formed together with nitrogen-atoms
The preferred version of logical compound shown in formula I, its pharmacy acceptable salt, its steric isomer or its solvated compounds is:
Wherein, X is selected from phenyl, indazolyl, benzothiazolyl, quinolyl or Isosorbide-5-Nitrae-benzdioxan base;
R
1be selected from hydrogen atom, methoxyl group, methoxyethoxy, imidazolyl, pyrazolyl, pyridyl or 1,2,3-triazol radical;
R
2, R
3, R
4independently selected from hydrogen atom;
Y is selected from
Or Y and R
2connect and formed together with nitrogen-atoms
Further preferred compound is as follows:
In the present invention, term " halogen atom " refers to fluorine atom, chlorine atom, bromine atoms or atomic iodine.
In the present invention, term " C
1-8alkyl " refer to the alkyl of the straight or branched containing 1-8 carbon atom, comprising such as " C
1-6alkyl ", " C
1-4alkyl ", " C
1-3alkyl ", " C
2-4alkyl ", " C
2-5alkyl " etc., the example includes but not limited to such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, 2-methyl-propyl, 1-methyl-propyl, 1, 1-dimethyl ethyl, n-pentyl, 3-methyl butyl, 2-methyl butyl, 1-methyl butyl, 1-ethyl propyl, n-hexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3, 3-dimethylbutyl, 2, 2-dimethylbutyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 2-ethyl-butyl, 1, 2-dimethyl propyl, heptyl, octyl group etc.
In the present invention, term " C
2-8thiazolinyl " refer to containing double bond carbonatoms and be the thiazolinyl of the straight or branched of 2-8, comprising such as " C
2-6thiazolinyl ", " C
2-4thiazolinyl ", " C
2-5thiazolinyl ", " C
2-3thiazolinyl " etc., the example includes but not limited to such as vinyl, 1-propenyl, 2-propenyl, 1-methyl ethylene, 1-butylene base, crotyl, 3-butenyl, 1-methyl-1-propylene base, 2-methyl-1-propylene base, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl isophthalic acid-butenyl, 2-methyl-1-butene thiazolinyl, 3-methyl-1-butene base, 1-methyl-2-butene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentene thiazolinyl, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, 4-methyl-1-pentene base, 1-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-crotyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butylene base, 1,2-dimethyl-crotyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butylene base, 1,3-dimethyl-crotyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butylene base, 2,3-dimethyl-crotyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butylene base, 3,3-dimethyl-crotyl, 1-ethyl-1-butylene base, 1-ethyl-crotyl, 1-ethyl-3-butenyl, 2-ethyl-1-butylene base, 2-ethyl-crotyl, 2-ethyl-3-butenyl, 1,1,2-trimethylammonium-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-Ethyl-2-Methyl-1-propenyl, 1-Ethyl-2-Methyl-2-propenyl, 1,3-butadiene, 1,3-pentadiene, Isosorbide-5-Nitrae-pentadiene, Isosorbide-5-Nitrae-hexadiene etc.
In the present invention, term " C
2-8alkynyl " refer to containing triple bond carbonatoms and be the alkynyl of the straight or branched of 2-8, comprising such as " C
2-6alkynyl ", " C
2-5alkynyl ", " C
2-4alkynyl ", " C
2-3alkynyl " etc., the example includes but not limited to such as ethynyl, 2-propynyl, 2-butyne base, 3-butynyl, 1-methyl-2-propynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-methyl-2-butyne base, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base, 1-methyl-valerylene base, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-valerylene base, 1, 1-dimethyl-2-butyne base, 1, 1-dimethyl-3-butynyl, 1, 2-dimethyl-3-butynyl, 2, 2-dimethyl-3-butynyl, 1-ethyl-2-butyne base, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl etc.
In the present invention, term " C
1-8alkoxyl group " refer to " C
1-8alkyl-O-" group that connects of mode, " C
1-8alkyl " definition as mentioned before; Comprising such as " C
1-6alkoxyl group ", " C
1-4alkoxyl group ", " C
1-3alkoxyl group ", " C
2-4alkoxyl group ", " C
2-5alkoxyl group " etc.
In the present invention, term " oxo " refers to that Sauerstoffatom is connected to double bond form on the atom that is substituted.
In the present invention, term " C
3-8cycloalkyl " refer to containing 3-8 carbon atom cycloalkyl, comprising such as " C
3-6cycloalkyl ", " C
4-6cycloalkyl ", " C
5-6cycloalkyl " etc., the example includes but not limited to such as cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, suberane base, cyclooctane base etc.
In the present invention, term " halo C
1-8alkyl ", " halo C
1-8alkoxyl group " refer to that one or more " halogen atom " replaces " C defined above
1-8alkyl ", " C
1-8alkoxyl group " the group that derives, be preferably chloro or fluoro.
In the present invention, term " 6-10 unit aryl " refers to that annular atoms is all the 6-10 unit cyclic aromatic groups of carbon atom, and comprise monocyclic aryl, also comprise fused ring aryl, and fused ring aryl can be undersaturated, also can be fractional saturation.Such as phenyl, naphthyl, benzo C
3-6cycloalkyl, benzo C
4-6cycloalkenyl group, specific examples is as 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, Isosorbide-5-Nitrae-dihydro naphthyl etc.
In the present invention, term " 4-6 unit heterocyclic radical ", refer to the cyclic group containing 4-6 annular atoms (wherein at least containing a heteroatoms), described heteroatoms has nitrogen, oxygen and sulphur etc., and carbon atom, nitrogen-atoms and sulphur atom can by oxos simultaneously.The example includes but not limited to such as tetramethylene base, pentamethylene base, cyclohexyl, tetrahydrofuran base, 2,5-dihydro-thiophene base, tetrahydro-thienyl, Pyrrolidine base, 1,3-dioxolane base, imidazolidyl, 4,5-pyrazoline base, pyrazolidyl, 4,5-dihydro-oxazole base, 4,5-dihydro-isoxazole base, THP trtrahydropyranyl, 3,4-dihydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 1,3-dioxane base, Isosorbide-5-Nitrae-dioxane base, furyl, thienyl, pyrryl, thiazolyl, isothiazolyl, thiadiazolyl group, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazoles base, 1,2,4-triazolyl, tetrazyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridone, 4-pyridone, pyrimidyl, Isosorbide-5-Nitrae-Dioxin base, 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, 1,2,4-triazinyl, 1,3,5-triazines base, 1,3,4-triazinyl or 1,2,4,5-tetrazine base.
In the present invention, term " 9-11 unit heterocyclic radical ", refer to the bicyclic radicals containing 9-11 annular atoms (wherein at least containing a heteroatoms), comprising such as " 9-10 unit heterocyclic radical ", the example includes but not limited to such as quinolyl, isoquinolyl, 2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxa cyclic group, benzothiazolyl, indazolyl, indyl, pseudoindoyl, benzofuryl, benzothienyl, benzoxazolyl, benzimidazolyl-etc.
In the present invention, term " 6-11 unit bicyclic radicals ", refer to that the group of two ring compositions containing 6-11 annular atoms (comprises and ring, volution or condensed ring), comprising such as " 6-10 unit bicyclic radicals ", " 8-11 unit bicyclic radicals ", " 9-10 unit bicyclic radicals " etc., the example includes but not limited to such as 2, 7-diaza spiro [4.5] decane-7-base, 1, 7-diaza spiro [4.4] nonane-7-base, 1, 8-diaza spiro [4.5] decane-8-base, 3-azabicyclo [3.1.0] hexane-6-base, octahydro pentamethylene is [b] tetramethyleneimine-5-base also, octahydro pentamethylene is [c] tetramethyleneimine-5-base also, 7-azaspiro [3.5] nonane-1-base, 7-azaspiro [3.5] nonane-2-base, 6-azaspiro [3.4] octane-2-base, 3-azabicyclo [3.1.1] heptane-2-base, 2-oxa--8-azaspiro [4.5] decane-8-base.
The preparation method of application claims protection formula I compound, formula I compound can adopt the method that describes in following flow process and/or other technology known to persons of ordinary skill in the art to synthesize, but is not limited only to following methods.
Reaction equation:
Wherein, raw material 2:NH
2xR
1, raw material 3:YNHR
2.
Reactions steps:
Step 1: raw material 1 and raw material 2, alkali (such as triethylamine, DIEA, salt of wormwood, sodium carbonate, sodium acetate etc.) is dissolved in polar solvent, and reacting by heating terminates.Residuum after solvent evaporate to dryness is dissolved in organic solvent, washes with water, concentrate after dry and be separated to obtain intermediate 1 through silicagel column.
Step 2: be dissolved in polar solvent and water mixed solution by intermediate 1 and alkali (such as NaOH, LiOH, KOH etc.), reacts under room temperature to raw material and disappears.After concentrated, add water, acidifying, filters, and obtains intermediate 2 after solid drying.
Step 3: be dissolved in organic solvent by intermediate 2, slowly drip oxalyl chloride, reacts to raw material disappearance, by solvent evaporate to dryness under room temperature.Residuum being dissolved in organic solvent again, slowly dripping ammoniacal liquor, reacting to terminating under room temperature.Or intermediate 2 is dissolved in organic solvent, add HATU and triethylamine.Stirred at ambient temperature reacts, and adding ammoniacal liquor, reacting to terminating under room temperature.Add water, with organic solvent extraction, dry, concentrated, solid is separated to obtain intermediate 3 through silicagel column.
Step 4: be dissolved in DMF by intermediate 3, drip LiHMDS, be heated to back flow reaction to terminating, or be dissolved in DMF-DMA and DMF solution by intermediate 3, reacting by heating is to terminating, and by solvent evaporate to dryness, then be dissolved in acetic acid, reacting by heating is to terminating.Residuum is added water, extraction, dry, obtain intermediate 4 after concentrated.
Step 5: be dissolved in organic solvent by intermediate 4, add m-CPBA, reacts under room temperature to raw material and disappears.Reaction solution saturated sodium bicarbonate cancellation, extraction, dry, obtain intermediate 5 after concentrated.
Step 6: by intermediate 5, organic bases (such as triethylamine, DIEA etc.) is dissolved in organic solvent, and ice-water bath drips raw material 3, reacting to terminating, adding water under room temperature, extraction, is separated to obtain formula I compound after drying is concentrated through silicagel column.
X, Y, R in above reaction equation
1, R
2, R
3, R
4as defined hereinabove.If desired, can protect needing the functional group of protection, after this sloughing blocking group by ordinary method; If desired, according to the character of compound, suitable replacement can be carried out to reaction solvent; If desired, according to the character of compound, some compound can be saved or increase the preparation of some compound.
The above-mentioned arbitrary compound " pharmacy acceptable salt " of the present invention comprises the salt of the active compound adopting the acid of relative nontoxic or alkali to prepare according to the specified substituent that described compound herein exists.When the compounds of this invention is containing relatively acid functional group, the alkali by this compound with enough needs that make neutral form is independent or contact in suitable inert solvent and obtain base addition salt.The example of the salt derived by pharmaceutically acceptable mineral alkali comprises aluminium, ammonium, calcium, copper, ferric iron, ferrous iron, lithium, magnesium, manganese, bivalent manganese, potassium, sodium, zinc etc.The salt derived by pharmaceutically acceptable organic bases comprises primary, the salt of the second month in a season and tertiary amine, they comprise the amine of replacement, cyclammonium, natural amine etc., such as arginine, trimethyl-glycine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2-DEAE diethylaminoethanol, DMAE, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, glycosamine, methylglucosamine, Histidine, Methionin, Isopropylamine, morpholine, piperazine, piperidines, versamid 900, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, Trometamol etc.When the compounds of this invention contains the functional group of alkalescence relatively, the acid by this compound with enough needs that make neutral form is independent or contact in suitable inert solvent and obtain acid salt.The example of pharmaceutically acceptable acid salt comprises by the salt of inorganic acids, such as hydrochloride, hydrobromate, nitrate, carbonate, supercarbonate, phosphoric acid salt, hydrophosphate, dihydrogen phosphate, vitriol, hydrosulfate, hydriodate or phosphite etc.; The salt derivative by the organic acid of relative nontoxic, described organic acid is such as acetic acid, propionic acid, isopropylformic acid, propanedioic acid, oxysuccinic acid, succsinic acid, suberic acid, fumaric acid, amygdalic acid, phthalic acid, Phenylsulfonic acid, tosic acid, citric acid, tartrate, methylsulfonic acid etc.Also comprise the salt of amino acid such as arginine etc. and organic acids as the salt of glucuronic acid or galactosonic acid etc.Some compound of the present invention contains alkalescence or acidic functionality, makes compound can be converted into alkali or acid salt.
The present invention also comprises the steric isomer of formula I compound or its pharmacy acceptable salt.Owing to there is chiral molecules in formula I compound of the present invention or its pharmacy acceptable salt, can exist with a kind of optical isomeric form, therefore, the present invention also comprises these optically active isomers and composition thereof.If when formula I compound of the present invention or its pharmacy acceptable salt are containing double bond or duvet structure, due to double bond in molecule or ring interatomic key rotate freely interrupted, there is different spatial disposition modes and produce steric isomer, also known as cis-trans-isomer, the present invention also comprises these cis-trans-isomers and composition thereof.The present invention also comprises the rotation due to singly-bound, makes to be connected to atom on carbon or atomic group and to change in the arrangement position in space the steric isomer produced thereupon, also known as conformational isomerism, also comprise its mixture.
Of the present invention containing the compound shown in above-mentioned formula (I), its pharmacy acceptable salt, its steric isomer or its solvated compounds administering mode as the pharmaceutical composition of effective constituent, the oral administration by tablet, capsule, granule, powder, syrup etc. can be exemplified, or pass through the non-oral administration of intravenous injection, intramuscular dose, injectable sterile powder, concentrated solution for injection, suppository, inhalation, transdermic absorbent, eye drops, nasal drop etc.In addition, when preparing the pharmaceutical preparation of above-mentioned various formulation, can be used alone this effective constituent, or with other pharmaceutically acceptable carrier, namely vehicle, binding agent, extender, disintegrating agent, tensio-active agent, lubricant, dispersion agent, buffer reagent, correctives, spices, coating agent, thinner etc. are appropriately combined, adopt ordinary method to make pharmaceutical preparation.
Present invention also offers the compound shown in logical formula I, its pharmacy acceptable salt, its steric isomer or its solvated compounds and treat and/or prevent application in the medicine of the relevant disease of the signal path that mediated by syk in preparation, further for the preparation for the treatment of and/or preventing with the application in undesirable inflammatory immune response medicine that is feature or the inflammatory diseases relevant with undesirable inflammatory immune response or cell proliferation disorders.
" treatment " of the present invention, refers to and alleviates, improves, eliminates or reduce the sign relevant to disease or illness and symptom.
" prevention " of the present invention, refers to the generation or development that prevent or postpone disease or illness or prevents or postpone disease therewith or the relevant sign of illness or symptom.
Described inflammatory diseases is selected from disease such as non Hodgkin lymphom, anti-phospholipid syndrome, lupus erythematosus, psoriatic, multiple sclerosis and the end-stage renal disease etc. of allergy, asthma, rheumatoid arthritis, anaphylaxis conjunctivitis, anaphylactic keratitis, xerophthalmia, B cell mediation.
Described cell proliferation disorders is selected from leukemia, lymphoma, myelosis disease, leukemia and Chronic Spontaneous myelofibrosis etc.
External pharmacologically active below by way of part the compounds of this invention sets forth the beneficial effect of the compounds of this invention further, other compound of the present invention has identical beneficial effect with part the compounds of this invention cited in test, but this should be interpreted as the compounds of this invention only has following beneficial effect.
The external pharmacologically active of experimental example 1 the compounds of this invention
Trial-product: the compounds of this invention: self-control, its chemical name, structural formula and preparation method are shown in the preparation embodiment of each compound;
Experimental technique: zymetology experiment (enzyme assay)
HTRF SYK Assay：
This experiment adopts HTRFR KinEASE
tM– TK test kit (Cisbio, 62TK0PEB).Accurately take trial-product, add DMSO and dissolve, fully mix, be made into 10mM.50 times of final concentrations are diluted to DMSO.Shift in 30 μ l compound to 96 orifice plates, carry out 3 times of serial dilutions, totally 10 concentration.Get 2 μ l to be more respectively transferred to containing in 38 μ l Kinase buffer, obtain the working fluid that final concentration is 25 μMs to the maximum.This compound is added to respectively in 384 orifice plates, every hole 4 μ l.Add the SYK kinases 2 μ l that concentration is 0.04ng/ μ l again, after hatching 10min, add ATP and Substrate cocktail 4 μ l.25 DEG C hatch 30min after, add 10 μ l Streptavidin-XL665 and TK Antibody-Cryptate mixed solution.25 DEG C hatch 1h after, detect the fluorescent value of sample at 615nm and 665nm place respectively by microplate reader.Data processing is as follows:
Ratio=(665nm fluorescent value/615nm fluorescent value) × 10
4
Adopt GraphPad 5.0 software to carry out curve fitting, fit equation is Y=Bottom+ (Top-Bottom)/(1+10^ ((LogIC
50-X) * HillSlope)), draw IC
50value.
Table 1 the compounds of this invention is to the IC of SYK
50value
Conclusion: from table 1, the compounds of this invention has good inhibit activities to SYK.
The cell in vitro inhibit activities of experimental example 2 the compounds of this invention
Trial-product:
The compounds of this invention: self-control, its chemical name, structural formula and preparation method are shown in the preparation embodiment of each compound.
1. laboratory apparatus
Envision2104 reads plate instrument, PerkinElmer, (U.S.)
CO
2incubator, SANYO. (Japan)
Inverted microscope, XDS-1B, Chongqing broadcasting and TV (Chongqing, China)
PH meter, Mettler Toledo Five easy (China)
MACS separator (Miltenyi, the U.S.)
FACSCalibur (BD, the U.S.)
2. cell
At 37 DEG C, 5%CO
2in incubator, use the foetal calf serum of the ultralow immunoglobulin (Ig) containing 10%, penicillin/streptomycin, 5mM HEPES, the RPMI1640 culture medium culturing Balb/c mouse primary splenic B cells of 50 μMs of beta-mercaptoethanols.Substratum purchased from American GIBCO.
3. mouse
Male, the Balb/c mouse in 6-8 week.
4. reagent and compound are prepared
1) CellTiter-Glo (CTG) (article No.: G7572, Promega), is stored in-20 DEG C by CTG damping fluid and CTG substrate, recommends to prepare CTG reagent with following method:
Melt CTG damping fluid before using and balance to room temperature, conveniently, it is good and in room temperature preservation by more than 48 hours that CTG damping fluid can melt before use.The CTG substrate of freeze-drying is equilibrated to room temperature, and the damping fluid getting 100ml, in the amber bottle that substrate is housed, just obtains CTG reagent.Mixing is until obtain homogeneous solution gently, and substrate should melt completely in 1 minute, and packing also preserves CTG reagent for a long time in-20 DEG C of refrigerators.
2)
b cell separating kit (number of ordering: 130-090-862, Miltenyi)
3) PE anti-biotin antibody (article No.: 409003, Biolegend)
4) PE/cy7anti-mouse CD45R/B220antibody (article No.: 103221, Biolegend)
5) Cell strainer (article No.: 352340, BD Falcon)
6) AffiniPure F (ab')
2fragment goat anti mouse IgM, μ chain specific (article No.: 115-006-020, Jackson)
7) test compounds is prepared
Preparation test compounds liquid storage: compound powder is dissolved in DMSO, obtains 10mM concentration liquid storage.
Preparation test compounds gradient dilution solution: first, gets test compounds liquid storage DMSO 3 times of continuous gradient dilutions of 10mM, totally 10 concentration.The test compounds solution getting the different concns of the DMSO dilution of 10 μ L is more respectively added in 90 μ L Compound Dilution Buffer, the compound containing 10%DMSO dilution getting 10 μ L is more respectively added in 90 μ L Compound Dilution Buffer, compound maximum concentration is 1mM, DMSO concentration is 1%, totally 10 concentration gradients.
5. experimental technique
1) Balb/c mouse B cell is separated:
Get Balb/c mouse spleen, smash to pieces in MACS damping fluid, obtain single cell suspension with the Nylon cell screen filtration of 40 μm.
4 DEG C, by the cell suspension that obtains at 400g centrifugal five minutes, remove supernatant liquor, add the erythrocyte cracked liquid of 1ml under room temperature and resuspended cell mass lightly.After two minutes, add the MACS damping fluid of precooling.With the cell screen filtration cell suspensions of 40 μm in a new centrifuge tube.4 DEG C, 400g carrys out collecting cell in centrifugal 5 minutes.
Before adding magnetic bead, with MACS damping fluid, cell density is adjusted to 10
7individual cell/40 μ l.Every 10
7the biotinylated mixtures of antibodies of 10 μ l is added in individual cell.20 minutes are hatched on ice, every 10 after mixing
7add the magnetic bead of the MACS damping fluid of 30 μ l and the antibiotin of 20 μ l in individual cell and hatch 20 minutes on ice.The MACS damping fluid re-suspended cell of centrifugal rear use 500 μ l.The MACS sorting post of precooling is placed in MACS sorter, cell suspension is added in MACS sorting post.Collect the cell of the non-binding antibody flowed down.
By the cell of flow cytometry before PE anti-biotin antibody and CD45R (B220) antibody test grouping system and after sorting.
2) cytotoxicity experiment and IC
50measure
With the mouse B cell of blood counting chamber counting fresh separated, expect that blue staining detection Cell viability should more than 98% by a word used in place name.
With substratum, cell density is adjusted to every milliliter 3.89 × 10
5individual cell.Get 90 μ l cell suspensions in 96 orifice plates with multichannel pipettor, obtaining final cell density is every hole 3.5 × 10
4individual cell.
Form storage liquid with DMSO dissolved dilution test compound and positive compound, add a series of compound solutions of 10 μ l preparations to (each concentration of each compound does 3 repetitions) in 96 orifice plates.At 37 DEG C, 5%CO
2hatch 30 minutes in incubator, and then add 50 μ l B cell stimulation mixed solutions, the final concentration stimulating anti-Igm in mixed solution is 10 μ g/ml.
By cell plate at 37 DEG C, 5%CO
2detect by the method for CTG after continuing to hatch 72 hours in incubator.
Melt CTG reagent and balance to room temperature, being transferred in 96 orifice plates with multichannel pipettor, 50 μ l CTG reagent/holes, the quick oscillator of microwell plate shaking after 2 minutes and place 10 minutes in the dark, detecting luminescence with Envision and read value.
6. data analysis
The data obtained can be analyzed with Excel2007 and GraphPad Prism5.0 software, in order to calculate IC
50, return fitting data by utilizing non-linear S curve and draw a dose-effect curve, GraphPad Prism5.0 software can provide IC automatically
50value.
The following formula of cell survival rate calculates: V
sample/ V2
solvent control× 100%, V
samplebe compound treatment hole read value, V2
solvent controlthe mean value that value is read in solvent control hole (V2).
7. experimental result:
Table 2 compound is to Balb/c mouse B cell cell in vitro inhibit activities
Experiment conclusion: from table 2, the compounds of this invention has good restraining effect to Balb/c mouse B cell propagation.
Embodiment
The embodiment of form by the following examples, is described in further detail foregoing of the present invention.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following examples.
embodiment 1 2-(2,7-diaza spiro [4.5] decane-7-base)-4-(3,4,5-trimethoxy-benzene amido) preparation of pyrido [4,3-d] pyrimidine-5 (6H)-one trifluoroacetate (compound 1 trifluoroacetate)
(1) 4-methyl-2-(first sulfydryl)-6-(3,4,5-trimethoxy-benzene amido) pyrimidine-5-carboxylic acid's methyl esters
By chloro-for 4-6-methyl-2-(first sulfydryl) pyrimidine-5-carboxylic acid's methyl esters (3.5g, 15mmol), 3,4,5-trimethoxy-aniline (4.0g, 22.7mmol), sodium acetate trihydrate (10g, 75mmol) be dissolved in 100mL ethanol, heat 75 DEG C of reactions to spend the night, residuum after solvent evaporate to dryness is dissolved in ethyl acetate, washes with water, 5.0g product is concentrated to obtain, productive rate 88% after dry.
(2) 4-methyl-2-(first sulfydryl)-6-(3,4,5-trimethoxy-benzene amido) pyrimidine-5-carboxylic acid
By 4-methyl-2-(first sulfydryl)-6-(3,4,5-trimethoxy-benzene amido) pyrimidine-5-carboxylic acid's methyl esters (5.0g, 13mmol), NaOH (2.6g, 65mmol), be dissolved in 80mL ethanol, 20mL THF and 20mL water, under room temperature, react 12h, after concentrated, add water, acidifying, is extracted with ethyl acetate.Concentrate to obtain crude product 4g after dry, this product does not need to purify further and is directly used in next step reaction.
(3) 4-methyl-2-(first sulfydryl)-6-(3,4,5-trimethoxy-benzene amido) pyrimidine-5-methane amide
By 4-methyl-2-(first sulfydryl)-6-(3,4,5-trimethoxy-benzene amido) pyrimidine-5-carboxylic acid (4.0g, 11mmol) is dissolved in 30mLDMF, slowly adds HATU (5.4g, 14.2mmol), TEA (3.3g, 33mmol), stirred at ambient temperature 10min, then ammoniacal liquor (12.8g, 110mmol) is added.12h is reacted under room temperature.Add water, with dichloromethane extraction, dry, concentrate to obtain product 2.2g, this product is directly used in next step reaction without purification.
(4) 2-(first sulfydryl)-4-(3,4,5-trimethoxy-benzene amido) pyrido [4,3-d] pyrimidine-5 (6H)-one
By 4-methyl-2-(first sulfydryl)-6-(3,4,5-trimethoxy-benzene amido) pyrimidine-5-methane amide (2.2g, 6mmol) be dissolved in 20mLDMF, add DMF-DMA (2.1g, 18mmol), after 85 DEG C of reaction 2h, by solvent evaporate to dryness.Residuum is dissolved in 50mL acetic acid, 105 DEG C of reaction 18h.By solvent evaporate to dryness, solids with methanol washs to obtain product 1.2g, productive rate 54%.
(5) 2-(methylsulfinyl)-4-(3,4,5-trimethoxy-benzene amido) pyrido [4,3-d] pyrimidine-5 (6H)-one
By 2-(first sulfydryl)-4-(3,4,5-trimethoxy-benzene amido) pyrido [4,3-d] pyrimidine-5 (6H)-one (500mg, 1.3mmol) be dissolved in 20mL DMF, add m-CPBA (440mg, 2.6mmol), under room temperature, reaction is spent the night.Reaction solution saturated sodium bicarbonate cancellation, is extracted with ethyl acetate, dry, obtains product 510mg, productive rate 100% after concentrated.
(6) preparation of 2-(2-Boc-2,7-diaza spiro [4.5] decane-7-base)-4-(3,4,5-trimethoxy-benzene amido) pyrido [4,3-d] pyrimidine-5 (6H)-one
By 2-(methylsulfinyl)-4-(3; 4; 5-trimethoxy-benzene amido) pyrido [4; 3-d] pyrimidine-5 (6H)-one (510mg; 1.3mmol) with triethylamine (520mg; 5.2mmol) be dissolved in 20mL DMF, under ice-water bath, add 2,7-diaza spiro [4.5] decane-2-carboxylic acid tert-butyl ester (380mg; 1.6mmol); react 18h under room temperature, add water, with dichloromethane extraction; dry; concentrated, be separated (water and acetonitrile) through preparative chromatography and obtain product 300mg, productive rate 40%.
(7) preparation of 2-(2,7-diaza spiro [4.5] decane-7-base)-4-(3,4,5-trimethoxy-benzene amido) pyrido [4,3-d] pyrimidine-5 (6H)-one trifluoroacetate
By 2-(2-Boc-2,7-diaza spiro [4.5] decane-7-base)-4-(3,4,5-trimethoxy-benzene amido) pyrido [4,3-d] pyrimidine-5 (6H)-one (300mg, 0.53mmol) be dissolved in 10mL DCM, add 2mL trifluoroacetic acid, after reacting 2h under room temperature, by solvent evaporate to dryness, solid washed with ether obtains product 180mg, productive rate 59%.
Mass spectrum (m/e): 467.2 (M+1)
1H-NMR(400MHz,DMSO-d
6,δ
ppm):1.68(m,6H),2.98(t,2H),3.25(t,2H),3.68(m,5H),3.82(s,6H),4.02(m,2H),6.20(d,1H),7.06(s,2H),7.47(d,1H),8.90(s,2H),11.41(s,1H),11.96(s,1H)._
embodiment 2 4-[3-(2H-1,2,3-triazole-2-base) anilino] preparation of-2-(six hydrogen pentamethylene are [b] tetramethyleneimine-5-base amido also) pyrido [4,3-d] pyrimidine-5 (6H)-one (compound 2)
(1) preparation of 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(1-Boc-six hydrogen pentamethylene is [b] tetramethyleneimine-5-base amido also) pyrido [4,3-d] pyrimidine-5 (6H)-one
Operation is with embodiment 1 (6); throw 4-[3-(2H-1; 2; 3-triazole-2-base) anilino]-2-(methylsulfinyl) pyrido [4,3-d] pyrimidine-5 (6H)-one (500mg, 1.36mmol); 1-Boc-six hydrogen pentamethylene is [b] tetramethyleneimine-5-base amino (307mg also; 1.36mmol), obtain product 260mg, productive rate 36%.
(2) preparation of 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(six hydrogen pentamethylene are [b] tetramethyleneimine-5-base amido also) pyrido [4,3-d] pyrimidine-5 (6H)-one
By 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(1-Boc-six hydrogen pentamethylene is [b] tetramethyleneimine-5-base amido also) pyrido [4,3-d] pyrimidine-5 (6H)-one (260mg, 0.49mmol) be dissolved in 1mL trifluoroacetic acid, stirred at ambient temperature 1h.Then by trifluoroacetic acid evaporate to dryness, add methylene dichloride, adjust pH=7 with sodium bicarbonate, washing, dry, obtain product 100mg after concentrated, productive rate 47.5%.
Mass spectrum (m/e): 430.2 (M+1)
1H-NMR(400MHz,DMSO-d
6,δ
ppm):12.31(s,1H),11.40(br s,1H),8.09(s,1H),8.09-8.19(m,3H),7.71-7.73(m,1H),7.48-7.52(m,1H),7.37-7.40(m,1H),7.19-7.22(m,1H),6.07-6.09(m,1H),2.60-3.30(m,4H),1.60-1.90(m,7H).
embodiment 3 4-[3-(2H-1,2,3-triazole-2-base) anilino] preparation of-2-(six hydrogen pentamethylene are [c] tetramethyleneimine-5-base amido also) pyrido [4,3-d] pyrimidine-5 (6H)-one formate (compound 3 formate)
(1) preparation of 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(2-Cbz-six hydrogen pentamethylene is [c] tetramethyleneimine-5-base amido also) pyrido [4,3-d] pyrimidine-5 (6H)-one
Operation is with embodiment 1 (6); throw 4-[3-(2H-1; 2; 3-triazole-2-base) anilino]-2-(methylsulfinyl) pyrido [4,3-d] pyrimidine-5 (6H)-one (500mg, 1.36mmol); 2-Cbz-six hydrogen pentamethylene is [c] tetramethyleneimine-5-base amino (0.425g also; 1.63mmol), obtain product 0.2g, productive rate 26%.
(2) preparation of 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(six hydrogen pentamethylene are [c] tetramethyleneimine-5-base amido also) pyrido [4,3-d] pyrimidine-5 (6H)-one
By 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(2-Cbz-six hydrogen pentamethylene is [c] tetramethyleneimine-5-base amido also) pyrido [4,3-d] pyrimidine-5 (6H)-one (200mg, 0.38mmol) is dissolved in 10mL methylene dichloride, 10mL methyl alcohol, in 10mL tetrahydrofuran (THF) and 2mL formic acid, palladium hydrogenated carbon, after reaction terminates, by solvent evaporate to dryness, residuum acetonitrile wash obtains product formic acid salt.Productive rate 26%.
Mass spectrum (m/e): 430.2 (M+1)
1H-NMR(400MHz,DMSO-d
6,δ
ppm):1.42(m,2H),2.48(t,2H),2.84(t,2H),2.95(d,2H),3.30(d,2H),4.45(s,1H),6.06(d,1H),7.28(d,1H),7.36(d,1H),7.51(t,1H)7.73(d,2H),8.15(s,2H),8.27(m,3H),9.2(s,1H),11.4(br s,1H),12.27(s,1H).
embodiment 4 4-[3-(2H-1,2,3-triazole-2-base) anilino] preparation of-2-[(six hydrogen pentamethylene are [c] tetramethyleneimine-5-base also) methylamino] pyrido [4,3-d] pyrimidine-5 (6H)-one trifluoroacetate (compound 4 trifluoroacetate)
(1) 4-[3-(2H-1,2,3-triazole-2-base) anilino] preparation of-2-[(2-Boc-six hydrogen pentamethylene is [c] tetramethyleneimine-5-base also) methylamino] pyrido [4,3-d] pyrimidine-5 (6H)-one
Operation is with embodiment 1 (6); throw 4-[3-(2H-1; 2; 3-triazole-2-base) anilino]-2-(methylsulfinyl) pyrido [4,3-d] pyrimidine-5 (6H)-one (500mg, 1.36mmol); 2-Boc-six hydrogen pentamethylene is [c] tetramethyleneimine-5-base also) methylamino-(0.68g; 2.84mmol), obtain product 0.13g, productive rate 18%.
(2) preparation of 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(six hydrogen pentamethylene are [c] tetramethyleneimine-5-base amido also) pyrido [4,3-d] pyrimidine-5 (6H)-one trifluoroacetate
By 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-[(2-boc-six hydrogen pentamethylene is [c] tetramethyleneimine-5-base also) methylamino] pyrido [4,3-d] pyrimidine-5 (6H)-one (130mg, 0.24mmol) be dissolved in 3mL methylene dichloride and 5mL trifluoroacetic acid, stirred at ambient temperature 1h.Then by trifluoroacetic acid evaporate to dryness, residuum washed with dichloromethane obtains product trifluoroacetate 51mg, productive rate 38%.
Mass spectrum (m/e): 444.3 (M+1)
1H-NMR(400MHz,DMSO-d
6,δ
ppm):1.51(m,1H),1.63(m,1H),2.07(m,2H),2.20(m,1H),2.35(m,2H),3.12(m,4H),3.53(t,2H),6.32(d,1H),7.45(t,1H),7.58(d,1H),7.81(m,2H),8.14(s,2H),8.70-9.13(m,3H),9.45(s,1H),12.47(d,1H),12.62(s,1H).
embodiment 5 4-[3-(2H-1,2,3-triazole-2-base) anilino] preparation of-2-(7-azaspiro [3.5] nonane-1-base amido) pyrido [4,3-d] pyrimidine-5 (6H)-one trifluoroacetate (compound 5 trifluoroacetate)
(1) 1-[4-[3-(2H-1,2,3-triazole-2-base) anilino]-5-oxo-5,6-dihydro pyrido [4,3-d] pyrimidine-2-base amido]-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
Operation is with embodiment 1 (6); throw 4-[3-(2H-1; 2; 3-triazole-2-base) anilino]-2-(methylsulfinyl) pyrido [4,3-d] pyrimidine-5 (6H)-one (700mg, 1.91mmol); 7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester hydrochloride (582mg; 2.1mmol), obtain product 215mg, productive rate 21%.
(2) 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(7-azaspiro [3.5] nonane-1-base amido) pyrido [4,3-d] pyrimidine-5 (6H)-one trifluoroacetate
Operation is with embodiment 1 (7), throw 1-[4-[3-(2H-1,2,3-triazole-2-base) anilino]-5-oxo-5,6-dihydro pyrido [4,3-d] pyrimidine-2-base amido]-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (215mg, 0.4mmol), obtain product 93mg, productive rate 53%.
Mass spectrum (m/e): 444.2 (M+1)
1H-NMR(400MHz,MD
3OD,δ
ppm):1.60～1.67(m,2H),1.72～1.74(m,2H),1.78～1.79(m,2H),2.03～2.06(m,1H),2.92～2.95(m,1H),3.13～3.14(m,2H),3.30～3.31(m,1H),3.31～3.36(m,1H),3.48～3.50(m,1H),6.48～6.50(m,1H),7.44～7.46(m,1H),7.59～7.61(m,1H),7.63(m,1H),7.74～7.76(m,1H),7.97～7.99(m,1H),8.02(m,2H),9.05(m,1H).
embodiment 6 4-[3-(2H-1,2,3-triazole-2-base) anilino] preparation of-2-(7-azaspiro [3.5] nonane-2-base amido) pyrido [4,3-d] pyrimidine-5 (6H)-one formate (compound 6 formate)
(1) preparation of 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(7-Cbz-7-azaspiro [3.5] nonane-2-base amido) pyrido [4,3-d] pyrimidine-5 (6H)-one
Operation is with embodiment 1 (6); throw 4-[3-(2H-1; 2; 3-triazole-2-base) anilino]-2-(methylsulfinyl) pyrido [4,3-d] pyrimidine-5 (6H)-one (406mg, 1.1mmol); 7-Cbz-7-azaspiro [3.5] nonane-2-base amino (0.3g; 1.1mmol), obtain product 0.26g, productive rate 41%.
(2) preparation of 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(7-azaspiro [3.5] nonane-2-base amido) pyrido [4,3-d] pyrimidine-5 (6H)-one formate
Operation is with embodiment 3 (2), by 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(7-Cbz-7-azaspiro [3.5] nonane-2-base amido) pyrido [4,3-d] pyrimidine-5 (6H)-one 0.26g drops into reaction, obtain product 20mg, productive rate 10%.
Mass spectrum (m/e): 444.2 (M+1)
1H-NMR(400MHz,DMSO-d
6,δ
ppm):1.63(m,4H),1.80(m,2H),2.25(m,2H),2.97(m,4H),4.51(m,1H),6.06(d,1H),7.36(d,2H),7.54(t,1H),7.71(t,2H)7.91(d,1H),8.13(s,2H),8.28(m,2H),8.91(s,1H),11.52(s,1H),12.23(s,1H).
embodiment 7 4-[3-(2H-1,2,3-triazole-2-base) anilino] preparation of-2-(6-azaspiro [3.4] octane-2-base amido) pyrido [4,3-d] pyrimidine-5 (6H)-one formate (compound 7 formate)
(1) preparation of 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(6-Cbz-6-azaspiro [3.4] octane-2-base amido) pyrido [4,3-d] pyrimidine-5 (6H)-one
Operation is with embodiment 1 (6); throw 4-[3-(2H-1; 2; 3-triazole-2-base) anilino]-2-(methylsulfinyl) pyrido [4,3-d] pyrimidine-5 (6H)-one (1.1mg, 3mmol); 6-Cbz-6-azaspiro [3.4] octane-2-base amino (1.5g; 5.7mmol), obtain product 300mg, productive rate 17.7%.
(2) preparation of 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(6-azaspiro [3.4] octane-2-base amido) pyrido [4,3-d] pyrimidine-5 (6H)-one formate
Operation is with embodiment 3 (2), by 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(6-Cbz-6-azaspiro [3.4] octane-2-base amido) pyrido [4,3-d] pyrimidine-5 (6H)-one 300mg drops into reaction, obtain product 80mg, productive rate 35.2%.
Mass spectrum (m/e): 430.2 (M+1)
1H-NMR(400MHz,DMSO-d
6,δ
ppm):12.26(m,1H),8.99(s,1H),7.89-8.32(m,6H),7.72(m,1H),7.50(m,1H),7.40(m,2H),6.00(d,1H),4.55(m,2H),3.57(s,1H),3.05(m,2H),1.83～2.48(m,6H).
embodiment 8 4-[3-(2H-1,2,3-triazole-2-base) anilino] preparation of-2-(3-azabicyclo [3.1.1] heptane-6-base amido) pyrido [4,3-d] pyrimidine-5 (6H)-one (compound 8)
(1) preparation of 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(3-benzyl-3-azabicyclo [3.1.1] heptane-2-base amido) pyrido [4,3-d] pyrimidine-5 (6H)-one
Operation is with embodiment 1 (6); throw 4-[3-(2H-1; 2; 3-triazole-2-base) anilino]-2-(methylsulfinyl) pyrido [4,3-d] pyrimidine-5 (6H)-one (451mg, 1.23mmol); 3-benzyl-3-azabicyclo [3.1.1] heptane-2-base amino (372mg; 1.85mmol), obtain product 179mg, productive rate 28%.
(2) preparation of 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(3-azabicyclo [3.1.1] heptane-2-base-5-base amido) pyrido [4,3-d] pyrimidine-5 (6H)-one
Operation is with embodiment 3 (2), throw 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(3-benzyl-3-azabicyclo [3.1.1] heptane-2-base amido) pyrido [4,3-d] pyrimidine-5 (6H)-one 179mg, obtain product 7mg, productive rate 4.7%.
Mass spectrum (m/e): 416.2 (M+1)
1H-NMR(400MHz,DMSO-d
6,δ
ppm):1.42～1.45(m,1H),1.83-1.89(m,1H),2.65～2.68(m,1H),2.80～2.94(m,3H),3.05(m,1H),3.73～3.79(m,1H),4.33(m,1H),4.64(m,1H),6.12～6.19(m,1H),7.26～7.28(m,1H),7.35～7.38(m,1H),7.50～7.54(m,1H),7.68(m,1H),8.12～8.13(m,2H),8.13(m,1H),9.15～9.27(m,1H),11.10～11.74(m,1H),12.21(m,1H).
embodiment 9 4-[3-(2H-1,2,3-triazole-2-base) anilino] preparation of-2-(2-oxa--8-azaspiro [4.5] decane-8-base) pyrido [4,3-d] pyrimidine-5 (6H)-one (compound 9)
Operation is with embodiment 1 (6); throw 4-[3-(2H-1; 2; 3-triazole-2-base) anilino]-2-(methylsulfinyl) pyrido [4,3-d] pyrimidine-5 (6H)-one (420mg, 1.14mmol); 2-oxa--8-azaspiro [4.5] decane (194mg; 1.37mmol), obtain product 68mg, productive rate 13%.
Mass spectrum (m/e): 445.2 (M+1)
1H-NMR(400MHz,d
6-DMSO,δ
ppm):1.58-1.72(m,4H),1.86(m,2H),3.66(s,2H),3.94(m,4H),4.07(m,2H),6.3(t,1H),7.21(m,1H),7.43(t,2H),7.8(m,3H),9.12(s,1H),9.4(d,1H),11.7(s,1H).
embodiment 10 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(2,7-diaza spiro [4.5] decane-7-base) preparation of pyrido [4,3-d] pyrimidine-5 (6H)-one trifluoroacetate (compound 10 trifluoroacetate)
(1) 7-[4-[3-(2H-1,2,3-triazole-2-base) anilino]-5-oxo-5,6-dihydro pyrido [4,3-d] pyrimidine-2-base]-2,7-diaza spiros [4.5] decane-2-carboxylic acid tert-butyl ester
Operation, with embodiment 1 (6), is thrown 2,7-diaza spiro [4.5] decane-2-carboxylic acid tert-butyl ester (576mg, 2.4mmol), is obtained product 200mg, productive rate 15%.
(2) 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(2,7-diaza spiro [4.5] decane-7-base) pyrido [4,3-d] pyrimidine-5 (6H)-one trifluoroacetate
Operation is with embodiment 1 (7), throw 7-[4-[3-(2H-1,2,3-triazole-2-base) anilino]-5-oxo-5,6-dihydro pyrido [4,3-d] pyrimidine-2-base]-2,7-diaza spiros [4.5] decane-2-carboxylic acid tert-butyl ester 200mg, obtain product 140mg, productive rate 85%.
Mass spectrum (m/e): 444.3 (M+1)
1H-NMR(400MHz,d
6-DMSO,δ
ppm):1.52～2.00(m,6H),2.82～3.15(m,2H),3.15～3.35(m,2H),3.50～4.25(m,4H),6.20～6.30(s,1H),7.30～7.40(s,1H),7.40～7.60(m,2H),7.70～7.80(m,1H),8.11～8.20(s,2H),8.50～9.20(m,3H),11.55～11.80(m,1H),12.20～12.50(m,1H).
embodiment 11 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(1,7-diaza spiro [4.4] nonane-7-base amido) preparation of pyrido [4,3-d] pyrimidine-5 (6H)-one trifluoroacetate (compound 11 trifluoroacetate)
(1) 7-[4-[3-(2H-1,2,3-triazole-2-base) anilino]-5-oxo-5,6-dihydro pyrido [4,3-d] pyrimidine-2-base]-1,7-diazaspiracyclic [4.4] nonane-1-carboxylic acid tert-butyl ester
Operation is with embodiment 1 (6); throw 4-[3-(2H-1; 2,3-triazole-2-base) anilino]-2-(methylsulfinyl) pyrido [4,3-d] pyrimidine-5 (6H)-one (420mg; 1.14mmol); 1,7-diazaspiracyclic [4.4] nonane-1-carboxylic acid tert-butyl ester (310mg, 1.37 mmol); obtain product 78mg, productive rate 13%.
(2) 4-[3-(2H-1,2,3-triazole-2-base) anilino]-2-(1,7-diaza spiro [4.4] nonane-7-base amido) pyrido [4,3-d] pyrimidine-5 (6H)-one trifluoroacetate
Operation is with embodiment 4 (2), throw 7-[4-[3-(2H-1,2,3-triazole-2-base) anilino]-5-oxo-5,6-dihydro pyrido [4,3-d] pyrimidine-2-base]-1,7-diazaspiracyclic [4.4] nonane-1-carboxylic acid tert-butyl ester (78mg, 0.15mmol), obtain product 45mg, productive rate 71%.
Mass spectrum (m/e): 430.2 (M+1)
1H-NMR(400MHz,d6-DMSO,δ
ppm):2.02-2.17(m,4H),2.32-2.54(m,2H),3.3(m,1H),3.84(m,2H),3.97(m,1H),4.05-4.2(m,2H),6.30(t,1H),7.39(m,1H),7.53(m,3H),7.76(m,1H),8.12(d,2H),8.96-9.24(m,2H),11.7(d,1H),12.3(s,1H).
embodiment 12 4-(2,3-dihydrobenzo [b] [1,4] dioxane-6-base amido)-2-(2,7-diaza spiro [4.5] decane-7-base) preparation of pyrido [4,3-d] pyrimidine-5 (6H)-one trifluoroacetate (compound 12 trifluoroacetate)
(1) 4-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxane-6-amido)-6-methyl-2-(first sulfydryl) pyrimidine-5-carboxylic acid's methyl esters
Operation, with embodiment 1 (1), throws 4-chloro-6-methyl-2-first mercapto-pyrimidine-5-carboxylate methyl ester (3.5g, 15mmol), 2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxane-6-amino (3.4g, 22.7mmol), obtain product 4.5g, productive rate 86%.
(2) 4-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxane-6-amido)-6-methyl-2-(first sulfydryl) pyrimidine-5-carboxylic acid
Operation, with embodiment 1 (2), throws 4-(2,3-dihydrobenzo [b] [1,4] dioxane-6-amido)-6-methyl-2-(first sulfydryl) pyrimidine-5-carboxylic acid's methyl esters (4.5g, 13mmol), obtain product 3.8g, productive rate 88%.
(3) 4-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxane-6-amido)-6-methyl-2-(first sulfydryl) pyrimidine-5-methane amide
Operation, with embodiment 1 (3), throws 4-(2,3-dihydrobenzo [b] [1,4] dioxane-6-amido)-6-methyl-2-(first sulfydryl) pyrimidine-5-carboxylic acid (3.8g, 11mmol), obtain product 1g, productive rate 27%.
(4) 4-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxane-6-amido)-2-(first sulfydryl) pyrido [4,3-d] pyrimidine-5 (6H)-one
Operation, with embodiment 1 (4), throws 4-(2,3-dihydrobenzo [b] [1,4] dioxane-6-amido)-6-methyl-2-(first sulfydryl) pyrimidine-5-methane amide (1g, 3mmol), obtain product 0.8g, productive rate 78%.
(5) 4-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxane-6-amido)-2-(methylsulfinyl) pyrido [4,3-d] pyrimidine-5 (6H)-one
Operation is with embodiment 1 (5), throw 4-(2,3-dihydrobenzo [b] [1,4] dioxane-6-amido)-2-(first sulfydryl) pyrido [4,3-d] pyrimidine-5 (6H)-one (0.5g, 1.46mmol) react, this product is not purified is directly used in next step reaction.
(6) 4-(2,3-dihydrobenzo [b] [1,4] dioxane-6-base amido) preparation of-2-(2-Boc-2,7-diaza spiro [4.5] decane-7-base) pyrido [4,3-d] pyrimidine-5 (6H)-one
Operation is with embodiment 1 (6), and in above-mentioned reaction solution, add 2-Boc-2,7-diaza spiro [4.5] decane (384mg, 1.6mmol), obtains product 260mg, productive rate 33%.
(7) 4-(2,3-dihydrobenzo [b] [1,4] dioxane-6-base amido) preparation of-2-(2,7-diaza spiro [4.5] decane-7-base) pyrido [4,3-d] pyrimidine-5 (6H)-one trifluoroacetate
Operation is with embodiment 1 (7), throw 4-(2,3-dihydrobenzo [b] [1,4] dioxane-6-base amido)-2-(2-Boc-2,7-diaza spiro [4.5] decane-7-base) pyrido [4,3-d] pyrimidine-5 (6H)-one (260mg, 0.49mmol), obtain product 140mg, productive rate 52%.
Mass spectrum (m/e): 435.2 (M+1)
1H-NMR(400MHz,DMSO-d
6,δ
ppm):1.59-1.87(m,6H),2.97(t,2H),3.25(t,2H),3.57-3.99(m,4H),4.25(t,4H),6.10(d,1H),6.87(m,2H),7.35(t,2H),8.94(s,2H),11.37(d,1H),11.89(s,1H).
embodiment 13 4-[4-(2-methoxyethoxy) anilino]-2-(2,7-diaza spiro [4.5] decane-7-base) pyrido [4,3-d] pyrimidine-
the preparation of 5 (6H)-one (compound 13)
(1) 4-[4-(2-methoxyethoxy) anilino]-6-methyl-2-(first sulfydryl) pyrimidine-5-carboxylic acid's methyl esters
Operate and throw the chloro-6-methyl of 4--2-first mercapto-pyrimidine-5-carboxylate methyl ester (4g with embodiment 1 (1), 17.3mmol), 4-(2-methoxyethoxy) phenylamino (4.35g, 26mmol), obtain product 5.4g, productive rate 86%.
(2) 4-[4-(2-methoxyethoxy) anilino]-6-methyl-2-(first sulfydryl) pyrimidine-5-carboxylic acid
Operation, with embodiment 1 (2), is thrown 4-[4-(2-methoxyethoxy) anilino]-6-methyl-2-(first sulfydryl) pyrimidine-5-carboxylic acid's methyl esters (5.4g, 14.8mmol), is obtained product 2g, productive rate 38%.
(3) 4-[4-(2-methoxyethoxy) anilino]-6-methyl-2-(first sulfydryl) pyrimidine-5-methane amide
Operation, with embodiment 1 (3), is thrown 4-[4-(2-methoxyethoxy) anilino]-6-methyl-2-(first sulfydryl) pyrimidine-5-carboxylic acid (2g, 5.8mmol), is obtained product 1.5g, productive rate 75%.
(4) 4-[4-(2-methoxyethoxy) anilino]-2-(first sulfydryl) pyrido [4,3-d] pyrimidine-5 (6H)-one
Operation, with embodiment 1 (4), is thrown 4-[4-(2-methoxyethoxy) anilino]-6-methyl-2-(first sulfydryl) pyrimidine-5-methane amide (1.5g, 4.3mmol), is obtained product 1g, productive rate 65%.
(5) 4-[4-(2-methoxyethoxy) anilino]-2-(methylsulfinyl) pyrido [4,3-d] pyrimidine-5 (6H)-one
Operation is with embodiment 1 (5), throw 4-[4-(2-methoxyethoxy) anilino]-2-(first sulfydryl) pyrido [4,3-d] pyrimidine-5 (6H)-ketone (0.6g, 1.68mmol) react, this product is not purified is directly used in next step reaction.
(6) preparation of 4-[4-(2-methoxyethoxy) anilino]-2-(2-Boc-2,7-diaza spiro [4.5] decane-7-base) pyrido [4,3-d] pyrimidine-5 (6H)-one
Operation is with embodiment 1 (6); throw 4-[4-(2-methoxyethoxy) anilino]-2-(methylsulfinyl) pyrido [4; 3-d] pyrimidine-5 (6H)-one (626mg; 1.68mmol); obtain product 420mg, productive rate 46%.
(7) preparation of 4-[4-(2-methoxyethoxy) anilino]-2-(2,7-diaza spiro [4.5] decane-7-base) pyrido [4,3-d] pyrimidine-5 (6H)-one
Operation is with embodiment 1 (7), throw 4-[4-(2-methoxyethoxy) anilino]-2-(2-Boc-2,7-diaza spiro [4.5] decane-7-base) pyrido [4,3-d] pyrimidine-5 (6H)-one (150mg, 0.27mmol), obtain product 62mg, productive rate 51%.
Mass spectrum (m/e): 451.3 (M+1)
1H-NMR(400MHz,DMSO-d
6,δ
ppm):1.21(m,1H),1.53～1.59(m,5H),2.70(m,1H),2.88(m,2H),3.30(s,3H),3.40(m,2H),3.63(m,4H),3.81(m,2H),4.07(m,2H),6.08(d,1H),6.94(d,2H),7.33(d,1H),7.59(d,2H),11.67(s,1H).
Be separated by the chiral chromatography of the racemic compound to compound 13 and obtain (+)-compound 13.
Ee value is 100.0%, optical value [α]
d 24=+44.0 (c=0.5, CH
3oH)
The actual conditions that chiral chromatography splits is (ChiralPak AD, 50mm × 250mm, 10um; Ethanol: Virahol: Tri N-Propyl Amine=70:30:0.1; Column temperature: 35 DEG C; Flow velocity: 70mL/min; Sample size: 8mL; Sample introduction concentration: 1mg/mL; 254nm)
Be separated by the chiral chromatography of the racemic compound to compound 13 and obtain (-)-compound 13.
Ee value is 97.7%, optical value [α]
d 24=-33.6 (c=0.5, CH
3oH)
The actual conditions that chiral chromatography splits is (ChiralPak AD, 50mm × 250mm, 10um; Ethanol: Virahol: Tri N-Propyl Amine=70:30:0.1; Column temperature: 35 DEG C; Flow velocity: 70mL/min; Sample size: 8mL; Sample introduction concentration: 1mg/mL; 254nm)
embodiment 14 4-[3-(2H-1,2,3-triazole-2-base) anilino] preparation of-2-(1,8-diaza spiro [4.5] decane-8-base) pyrido [4,3-d] pyrimidine-5 (6H)-one (compound 14)
Operation is with embodiment 1 (6); throw 4-[3-(2H-1; 2,3-triazole-2-base) anilino]-2-(methylsulfinyl) pyrido [4,3-d] pyrimidine-5 (6H)-one (500mg; 1.36mmol); 1,8-diaza spiro [4.5] decane (445mg, 1.75mmol); obtain product 140mg, productive rate 23%.
Mass spectrum (m/e): 444.2 (M+1)
1H-NMR(400MHz,DMSO-d
6,δ
ppm):12.16(s,1H),9.11(s,1H),8.12(s,2H),7.68～7.75(m,1H),7.50～7.55(m,1H),7.33～7.40(m,2H),6.15(d,1H),3.85～4.00(m,4H),2.85～2.95(m,2H),1.71～1.80(m,2H),1.48～1.60(m,6H).
embodiment 15 4-[2,3-dihydrobenzo [b] [1.4] dioxane-6-base amido]-2-(2-oxa--8-azaspiro [4.5] decane-8-base
) preparation of pyrido [4,3-d] pyrimidine-5 (6H)-one (compound 15)
Operation is with embodiment 1 (6); throw 4-[2; 3-dihydrobenzo [b] [1.4] dioxane-6-base amido]-2-(methylsulfinyl) pyrido [4; 3-d] pyrimidine-5 (6H)-one (300mg; 0.84mmol), 2-oxa--8-azaspiro [4.5] decane hydrochloride (177mg, 1mmol); obtain product 130mg, productive rate 36%.
Mass spectrum (m/e): 436.2 (M+1)
1H-NMR(400MHz,d
6-DMSO,δ
ppm):11.3(s,1H),10.69(m,1H),7.45(s,1H),7.21(t,1H),7.18(m,1H),6.84(d,1H),6.26(d,1H),4.26(s,4H),3.98(m,6H),3.80(m,2H),1.84(t,2H)1.68(m,4H).
the preparation of embodiment 16 2-(2-oxa--8-azaspiro [4.5] decane-8-base)-4-(3,4,5-trimethoxy-aniline) pyrido [4,3-d] pyrimidine-5 (6H)-one (compound 16)
Operation is with embodiment 1 (6); throw 2-(methylsulfinyl)-4-(3; 4; 5-trimethoxy-benzene amido) pyrido [4,3-d] pyrimidine-5 (6H)-one (500mg, 1.28mmol); 2-oxa--8-azaspiro [4.5] decane hydrochloride (271mg; 1.53mmol), obtain product 270mg, productive rate 45%.
Mass spectrum (m/e): 468.2 (M+1)
1H-NMR(400MHz,d
6-DMSO,δ
ppm):11.86(s,1H),11.32(m,1H),7.36(t,1H),7.07(s,2H),6.13(d,1H),3.96(m,2H),3.79(m,11H),3.64(s,2H),3.49(s,2H),1.86(t,2H),1.58(m,4H).
the preparation of embodiment 17 4-[4-(2-methoxyethoxy) aniline]-2-(2-oxa--8-azaspiro [4.5] decane-8-base)-pyrido [4,3-d] pyrimidine-5 (6H)-one (compound 17)
Operation is with embodiment 1 (6); throw 2-(methylsulfinyl)-4-(2-methoxyethoxy anilino) pyrido [4; 3-d] pyrimidine-5 (6H)-one (374mg; 1.0mmol); 2-oxa--8-azaspiro [4.5] decane hydrochloride (213mg; 1.2mmol), obtain product 120mg, productive rate 27%.
Mass spectrum (m/e): 452.2 (M+1)
1H-NMR(400MHz,d
6-DMSO,δ
ppm):1.50～1.53(m,4H),1.73～1.77(m,2H),3.29～3.33(m,2H),3.37～3.38(m,3H),3.62～3.69(m,6H),3.71～3.75(m,2H),4.05～4.08(m,2H),6.09～6.11(m,1H),6.92～6.95(m,2H),7.31～7.35(m,1H),7.56～7.59(m,2H),11.28～11.30(m,1H),11.67(m,1H).
the preparation of embodiment 18 4-(1H-indazole-5-base amido)-2-(2-oxa--8-azaspiro [4.5] decane-8-base)-pyrido [4,3-d] pyrimidine-5 (6H)-one (compound 18)
Operation is with embodiment 1 (6); throw 2-(methylsulfinyl)-4-(1H-indazole-5-base amido) pyrido [4; 3-d] pyrimidine-5 (6H)-one (510mg; 1.5mmol); 2-oxa--8-azaspiro [4.5] decane hydrochloride (263mg; 1.5mmol), obtain product 75mg, productive rate 12%.
Mass spectrum (m/e): 418.2 (M+1)
1H-NMR(400MHz,d
6-DMSO,δ
ppm):13.2(br s,1H)12.32(s,1H)12.01(s,1H)；8.28(s,1H)；8.02(s,1H)；7.83(d,1H)；7.62(t,1H)；7.10(d,1H)；6.40(d,1H)；3.93(m,2H)；3.78(t,4H)；3.59(s,2H)；1.79(t,2H)；1.64(m,4H).
the preparation of embodiment 19 4-(benzo [d] thiazole-6-base amido)-2-(2-oxa--8-azaspiro [4.5] decane-8-base)-pyrido [4,3-d] pyrimidine-5 (6H)-one (compound 19)
Operation, with embodiment 1 (6), is thrown 2-oxa--8-azaspiro [4.5] decane hydrochloride (258mg, 1.46mmol), is obtained product 150mg, productive rate 24%.
Mass spectrum (m/e): 435.2 (M+1)
1H-NMR(400MHz,d
6-DMSO,δ
ppm):.12.08(s,1H),13.39(d,1H),9.27(s,1H),8.60(d,1H),8.04(d,1H),7.74(m,1H),7.37(t,1H),6.14(d,1H),3.92(m,2H),3.75(m,4H),3.49(s,2H),1.76(t,2H),1.55(s,4H).
the preparation of embodiment 20 4-(quinoline-6-base amido)-2-(2-oxa--8-azaspiro [4.5] decane-8-base)-pyrido [4,3-d] pyrimidine-5 (6H)-one (compound 20)
Operation is with embodiment 1 (6); throw 2-(methylsulfinyl)-4-(quinoline-6-base amido) pyrido [4; 3-d] pyrimidine-5 (6H)-one (527mg; 1.5mmol); 2-oxa--8-azaspiro [4.5] decane hydrochloride (263mg; 1.5mmol), obtain product 22mg, productive rate 3.4%.
Mass spectrum (m/e): 429.2 (M+1)
1H-NMR(400MHz,d
6-DMSO,δ
ppm):12.3(s,1H)11.7(s,1H)；8.86(d,1H)；8.54(d,1H)；8.38(d,1H)；8.04(m,1H)；7.97(m,1H)；7.60(m,1H)；7.48(m,1H)；6.25(d,1H)；3.96(m,2H)；3.78(m,4H)；3.51(m,2H)；1.79(t,2H)；1.62(m,4H).
the preparation of embodiment 21 4-[3-(pyridine-2-base) anilino]-2-(2-oxa--8-azaspiro [4.5] decane-8-base)-pyrido [4,3-d] pyrimidine-5 (6H)-one (compound 21)
Operation is with embodiment 1 (6); throw 2-(methylsulfinyl)-4-[3-(pyridine-2-base) anilino] pyrido [4; 3-d] pyrimidine-5 (6H)-one (415mg; 1.1mmol); 2-oxa--8-azaspiro [4.5] decane hydrochloride (235g; 1.32mmol), obtain product 156mg, productive rate 32%.
Mass spectrum (m/e): 455.2 (M+1)
1H-NMR(400MHz,d
6-DMSO,δ
ppm):12.04(m,1H),11.38(m,1H),8.84(m,1H),8.64～8.66(m,1H),7.95～7.97(m,1H),7.88(m,1H),7.75(d,1H),7.55～7.57(m,1H),7.44～7.48(m,1H),7.35～7.38(m,2H),6.13～6.15(d,1H),3.98(m,2H),3.75～3.79(m,4H),3.50(m,2H),1.76～1.79(m,2H),1.56(m,4H).
the preparation of embodiment 22 4-[3-(1H-pyrazol-1-yl) anilino]-2-(2-oxa--8-azaspiro [4.5] decane-8-base)-pyrido [4,3-d] pyrimidine-5 (6H)-one (compound 22)
Operation is with embodiment 1 (6); throw 2-(methylsulfinyl)-4-[(1H-pyrazol-1-yl) anilino] pyrido [4; 3-d] pyrimidine-5 (6H)-one (575mg; 1.57mmol); 2-oxa--8-azaspiro [4.5] decane hydrochloride (400g; 2.25mmol), obtain product 180mg, productive rate 26%.
Mass spectrum (m/e): 444.2 (M+1)
1H-NMR(400MHz,d
6-DMSO,δ
ppm):12.07(s,1H),11.37～11.40(m,1H),8.69～8.71(s,1H),8.47～8.48(s,1H),7.72(s,1H),7.49～7.52(m,1H),7.42～7.47(t,1H),7.35～7.39(m,2H),6.53(s,1H),6.14～6.16(d,1H),3.95～4.00(m,2H),3.75～3.80(m,4H),3.50(s,2H),1.75～1.80(t,2H),1.56(m,4H).
the preparation of embodiment 23 4-[3-(1H-imidazoles-1-base) anilino]-2-(2-oxa--8-azaspiro [4.5] decane-8-base)-pyrido [4,3-d] pyrimidine-5 (6H)-one (compound 23)
Operation is with embodiment 1 (6); throw 2-(methylsulfinyl)-4-[(1H-imidazoles-1-base) anilino] pyrido [4; 3-d] pyrimidine-5 (6H)-one (470mg; 1.28mmol); 2-oxa--8-azaspiro [4.5] decane hydrochloride (400g; 2.25mmol), obtain product 56mg, productive rate 10%.
Mass spectrum (m/e): 444.2 (M+1)
1H-NMR(400MHz,d
6-DMSO,δ
ppm):12.05(s,1H),11.41(d,1H),8.20(d,2H),7.70(s,1H),7.48-7.53(m,2H),7.32-7.38(m,2H),7.11(s,1H),6.14(d,1H),3.89(m,2H),3.76(m,4H),3.48(s,2H),1.75(t,2H),1.53(m,4H)。
Claims (11)
1. logical compound shown in formula I, its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein, X is selected from 6-10 unit's aryl or 9-11 unit heterocyclic radical;
R
1be selected from hydrogen atom, halogen atom, amino, hydroxyl, C
1-8alkyl, C
1-8alkoxyl group, C
1-3alcoxyl C
1-8alkoxyl group, C
1-8alkyl amine group, two (C
1-8alkyl) amido, amino C
1-8alkyl, C
1-8alkyl-carbonyl-amino, formamyl, C
1-8alkyl amine group formyl radical, two (C
1-8alkyl) amido formacyl, amino-sulfonyl, C
1-8alkyl formyl radical, halo C
1-8alkyl, halo C
1-8alkoxyl group, hydroxyl C
1-8alkyl, 6-10 unit aryl, C
3-8cycloalkyl or 4-6 unit heterocyclic radical,
R
1can be replaced by an optional 1-3 substituting group further, described substituting group is independently selected from C
1-8alkyl, C
2-8thiazolinyl, C
2-8alkynyl, amino, hydroxyl, C
1-8alkoxyl group, oxo, halogen atom, C
1-8alkyl amine group, two (C
1-8alkyl) amido, C
1-8alkyl-carbonyl, formamyl, C
1-8alkyl-carbonyl-amino, C
1-8alkyl amine group formyl radical, amino C
1-8alkyl, hydroxyl C
1-8alkyl, cyano group, halo C
1-8alkyl, amino-sulfonyl, 6-10 unit aryl, C
3-8cycloalkyl or 4-6 unit heterocyclic radical;
R
2be selected from hydrogen atom or C
1-8alkyl;
R
3, R
4independently selected from hydrogen atom, cyano group, C
1-8alkyl, hydroxyl C
1-8alkyl, amino C
1-8alkyl or C
3-8cycloalkyl;
Y is selected from 6-11 unit's bicyclic radicals or 6-11 unit bicyclic radicals C
1-3alkyl,
Or Y and R
2connect and form 8-11 unit bicyclic radicals together with nitrogen-atoms,
Y or Y and R
2connect the group formed together with nitrogen-atoms can be replaced by 1-3 substituting group further, described substituting group is independently selected from amino, hydroxyl, C
1-8alkyl, C
1-8alkyl amine group, two (C
1-8alkyl) amido, amino C
1-8alkyl, carboxyl, C
1-8alkyl amine group C
1-8alkyl, C
1-8alkoxy C
1-8alkyl, hydroxyl C
1-8alkyl, carboxyl C
1-8alkyl, formamyl, C
3-8cycloalkyl C
1-8alkyl, hydroxyl C
1-8alkoxyl group or C
1-8alkyl-carbonyl.
2. compound, its pharmacy acceptable salt, its steric isomer or its solvated compounds as claimed in claim 1:
Wherein, X is selected from 6-10 unit's aryl or 9-11 unit heterocyclic radical;
R
1be selected from hydrogen atom, halogen atom, C
1-6alkyl, C
1-6alkoxyl group, C
1-3alcoxyl C
1-6alkoxyl group, C
1-6alkyl-carbonyl-amino, amino, C
1-6alkyl amine group, two (C
1-6alkyl) amido, amino-sulfonyl, halo C
1-6alkyl, halo C
1-6alkoxyl group, 6-10 unit aryl, C
3-8cycloalkyl or 4-6 unit heterocyclic radical;
R
1can be replaced by an optional 1-3 substituting group further, described substituting group is independently selected from C
1-6alkyl, hydroxyl, C
1-6alkoxyl group, oxo, halogen atom, C
1-6alkyl-carbonyl, formamyl, C
1-6alkyl-carbonyl-amino, C
1-6alkyl amine group formyl radical, amino C
1-6alkyl, cyano group, halo C
1-6alkyl or amino-sulfonyl;
R
2be selected from hydrogen atom or C
1-6alkyl;
R
3, R
4independently selected from hydrogen atom, C
1-6alkyl, hydroxyl C
1-6alkyl, amino C
1-6alkyl or C
3-8cycloalkyl;
Y is selected from the assorted bicyclic radicals of 6-11 unit or the assorted bicyclic radicals C of 6-11 unit
1-3alkyl,
Or Y and R
2connect and form the assorted bicyclic radicals of 8-11 unit together with nitrogen-atoms,
Y or Y and R
2connect the group formed together with nitrogen-atoms can be replaced by 1-3 substituting group further, described substituting group is independently selected from amino, hydroxyl, C
1-6alkyl, C
1-6alkyl amine group, two (C
1-6alkyl) amido, amino C
1-6alkyl, carboxyl, C
1-6alkyl amine group C
1-6alkyl, C
1-6alkoxy C
1-6alkyl, hydroxyl C
1-6alkyl, carboxyl C
1-6alkyl or C
1-6alkyl-carbonyl.
3. compound, its pharmacy acceptable salt, its steric isomer or its solvated compounds as claimed in claim 2:
Wherein, X is selected from 6-10 unit's aryl or 9-10 unit heterocyclic radical;
R
1be selected from hydrogen atom, halogen atom, C
1-6alkyl, amino, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkoxyl group, C
1-3alcoxyl C
1-6alkoxyl group, phenyl, C
3-6cycloalkyl or 4-6 unit heterocyclic radical;
R
2, R
3, R
4independently selected from hydrogen atom or C
1-6alkyl;
Y is selected from the assorted bicyclic radicals of 6-10 unit or the assorted bicyclic radicals C of 6-10 unit
1-3alkyl,
Or Y and R
2connect and form the assorted bicyclic radicals of 9-10 unit together with nitrogen-atoms,
Y or Y and R
2connect the group formed together with nitrogen-atoms can be replaced by 1-2 substituting group further, described substituting group is independently selected from amino, C
1-6alkyl amine group, two (C
1-6alkyl) amido, hydroxyl, carboxyl, C
1-6alkyl, hydroxyl C
1-6alkyl, carboxyl C
1-6alkyl or C
1-6alkyl-carbonyl.
4. compound, its pharmacy acceptable salt, its steric isomer or its solvated compounds as claimed in claim 3:
Wherein, X is selected from phenyl, quinolyl, indazolyl, benzothiazolyl or Isosorbide-5-Nitrae-benzdioxan base;
R
1be selected from hydrogen atom, fluorine atom, methyl, amino, methyl amido, two (methyl) amido, methoxyl group, oxyethyl group, methoxyethoxy, imidazolyl, pyrazolyl, pyridyl, 1,2,3-triazol radical or 1,3,4-triazol radical;
R
2, R
3, R
4independently selected from hydrogen atom or methyl;
Y is selected from
n is the integer of 0 or 1,
Or Y and R
2connect and formed together with nitrogen-atoms
5. compound, its pharmacy acceptable salt, its steric isomer or its solvated compounds as claimed in claim 4:
Wherein, X is selected from phenyl, indazolyl, benzothiazolyl, quinolyl or Isosorbide-5-Nitrae-benzdioxan base;
R
1be selected from hydrogen atom, methoxyl group, methoxyethoxy, imidazolyl, pyrazolyl, pyridyl or 1,2,3-triazol radical;
R
2, R
3, R
4independently selected from hydrogen atom;
Y is selected from
Or Y and R
2connect and formed together with nitrogen-atoms
6. compound, its pharmacy acceptable salt, its steric isomer or its solvated compounds as claimed in claim 5, compound is selected from:
7. the compound as described in any one of claim 1-6, its pharmacy acceptable salt, its steric isomer or its solvated compounds, its described pharmacy acceptable salt is benzoate, benzene sulfonate, tosilate, Citrate trianion, maleate, fumarate, tartrate, hydrobromate, hydrogen chlorate, vitriol, nitrate, phosphoric acid salt, arginic acid salt, meglumine salt, glucosamine salt or ammonium salt, lithium salts, sodium salt, sylvite, calcium salt, magnesium salts, zinc salt, barium salt.
8. the pharmaceutical composition of the compound as described in any one of claim 1-6, its pharmacy acceptable salt, its steric isomer or its solvated compounds and one or more pharmaceutical carriers and/or thinner is pharmaceutically acceptable arbitrary formulation.
9. the compound as described in any one of claim 1-6, its pharmacy acceptable salt, its steric isomer or its solvated compounds are for the preparation of the application treated and/or prevented in the medicine of the relevant disease of the signal path that mediated by syk.
10. as claimed in claim 9 compound, its pharmacy acceptable salt, its steric isomer or its solvated compounds are for the preparation of the application in the medicine that to treat and/or prevent with undesirable inflammatory immune response be feature or the inflammatory diseases relevant with undesirable inflammatory immune response or cell proliferation disorders.
11. apply as claimed in claim 10, and wherein inflammatory diseases is selected from asthma, allergy, rheumatoid arthritis, anaphylaxis conjunctivitis, anaphylactic keratitis or xerophthalmia, and cell proliferation disorders is selected from leukemia, lymphoma and myelosis disease.
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| WO2022192431A1 (en) * | 2021-03-10 | 2022-09-15 | Blueprint Medicines Corporation | Egfr inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010019637A1 (en) * | 2008-08-12 | 2010-02-18 | Smithkline Beecham Corporation | Chemical compounds |
| CN102695416A (en) * | 2009-10-29 | 2012-09-26 | 金纳斯克公司 | Kinase inhibitors |
| CN102811619A (en) * | 2009-11-13 | 2012-12-05 | 金纳斯克公司 | Kinase inhibitors |
| CN102838601A (en) * | 2011-06-24 | 2012-12-26 | 山东亨利医药科技有限责任公司 | Selective phosphatidylinositol-3 kinase delta inhibitor |
| CN102838600A (en) * | 2011-06-24 | 2012-12-26 | 山东亨利医药科技有限责任公司 | Phenylquinazoline PI3Kdelta inhibitors |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010019637A1 (en) * | 2008-08-12 | 2010-02-18 | Smithkline Beecham Corporation | Chemical compounds |
| CN102695416A (en) * | 2009-10-29 | 2012-09-26 | 金纳斯克公司 | Kinase inhibitors |
| CN102811619A (en) * | 2009-11-13 | 2012-12-05 | 金纳斯克公司 | Kinase inhibitors |
| CN102838601A (en) * | 2011-06-24 | 2012-12-26 | 山东亨利医药科技有限责任公司 | Selective phosphatidylinositol-3 kinase delta inhibitor |
| CN102838600A (en) * | 2011-06-24 | 2012-12-26 | 山东亨利医药科技有限责任公司 | Phenylquinazoline PI3Kdelta inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2022192431A1 (en) * | 2021-03-10 | 2022-09-15 | Blueprint Medicines Corporation | Egfr inhibitors |
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