CN102970868A - Treatment of cancers having K-RAS mutations - Google Patents

Treatment of cancers having K-RAS mutations Download PDF

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CN102970868A
CN102970868A CN2011800290564A CN201180029056A CN102970868A CN 102970868 A CN102970868 A CN 102970868A CN 2011800290564 A CN2011800290564 A CN 2011800290564A CN 201180029056 A CN201180029056 A CN 201180029056A CN 102970868 A CN102970868 A CN 102970868A
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鲁迪·宝
赖正荣
钱长庚
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Curis Inc
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
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    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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Abstract

The present invention provides a method of treating a cancer associated with a K- ras mutation in a subject in need thereof. The method comprises the steps of (1) identifying a subject with a cancer associated with a K-ras mutation; and (2) adminsiterign to the subject (i) an inhibitor of PI3 kinase and (ii) an HDAC inhibitor, wherein the PI3 kinase inhibitor and the HDAC inhibitor are administered in amounts which together are therapeutically effective.

Description

Treatment with cancer of K-RAS sudden change
Related application
The application requires the right of No. the 61/324th, 912, the U.S. Provisional Patent Application submitted on April 16th, 2010.Whole being taught in here of above-mentioned application all incorporated this paper into by quoting as proof.
Background technology
The member of ras gene family can the encoded film conjugated protein, and this protein is approximately 21KD, therefore is named as " p21-ras ".These protein are believed to take over acceptor from activation to the kinase whose growth signals of intracellular protein and differentiation signal.The ras gene family comprises K-ras, H-ras and N-ras.The ras gene is proto-oncogene; In polytype cancer, can find the ras gene that suddenlys change.These mutant strains show single base pair substitution usually, show in codon 12,13,146 or 161 that usually this can be created in the p21-ras product that corresponding amino acid position has the expression of point mutation.In wild type K-ras, codon 12 coding glycine, but in this codon, the most common sudden change is aspartic acid, valine, arginine or cysteine (Mu et al., World J.Gastroenterol.2004,10:471-475).Wild type p21-ras only can be by the receptor activation of activation, and after the downstream signal inactivation, however, the p21-ras mutant strain is to consist of activation, and therefore can be in the situation that does not have signal continuous stimulating growth and differentiation (Bos, J.L., Cancer Res. (cancer research) 1989,49:4682-4689).
In polytype cancer, find the ras family gene of sudden change.Especially K-ras sudden change ubiquity in cancer of pancreas, colorectal cancer, thyroid cancer, neck cancer and carcinoma of endometrium.In some precancerous situation, also can identify the K-ras sudden change, for example, in myelodysplastic syndrome and thyroid adenoma and colonic adenoma.
The occurrence rate of supposing cancer is relevant with the K-ras of sudden change, then there are needs in this new methods for the treatment of that is particularly suitable for such cancer.
Summary of the invention
The invention provides be used for the treatment of cancer and pre-cancer situation method and composition, described cancer and pre-cancer situation characteristics be that its proliferative cell has K-ras sudden change.
In one embodiment, the invention provides a kind of method that suppresses cell proliferation, described cell has K-ras sudden change, for example precancer cell or cancer cell.The method may further comprise the steps: (1) identification has the cell of K-ras sudden change; (2) the PI3 kinase signal approach in the inhibition cell; (3) suppress HDAC activity in the cell.In one embodiment, active by cell and a kind of the first compound and a kind of the second Compound Phase being contacted to suppress PI3 kinase signal approach and HDAC, described the first compound can suppress the PI3 kinase activity, and the second compound can suppress the HDAC activity.In second embodiment, active by cell and a kind of Compound Phase being contacted to suppress PI3 kinase signal approach and HDAC, described compound can either suppress the PI3 kinase activity can suppress the HDAC activity again.
In another embodiment, the invention provides a kind of treat cancer in the host who needs or pre-cancer situation method, described cancer or pre-cancer situation suddenly change relevant with K-ras.The method may further comprise the steps: (1) identification suffer from the cancer relevant with K-ras sudden change or pre-cancer situation the host; (2) to a certain amount of PI3 inhibitors of kinases of host's administration (i) and (ii) a certain amount of hdac inhibitor, wherein, the amount that can suppress the amount of the kinase whose compound of PI3 and can suppress the compound of HDAC be treatment effectively.The simultaneously administration of described PI3 inhibitors of kinases and hdac inhibitor or order administration can be made respectively composition and also be may reside in the single composition.
In another embodiment still, the invention provides a kind of treat cancer in the host who needs or pre-cancer situation method, described cancer or pre-cancer situation relevant with the K-ras of sudden change.This method may further comprise the steps: (1) identification suffer from the cancer relevant with K-ras sudden change or pre-cancer situation the host; (2) to the compound of host's effective dosage, described compound is a kind of PI3 inhibitors of kinases and hdac inhibitor.
The present invention also is included in compound and the composition that uses in the method disclosed herein.
Embodiment
Phosphoric acid inosinic acid (PI) is the derivative of diphosphoinositide, and phosphoric acid inosinic acid (PI) is necessary for eukaryotic, can regulate nuclear process, cytoskeleton power, signal generation and film transportation.In the involved enzyme of phosphoric acid inosinic acid (PI) metabolism, PI3-kinases (PI3K) receives special concern owing to its carcinogenic character with as the effectiveness of drug target.The PI3-kinases on the 3-position of inositol ring with phosphatidylinositols or phosphoric acid inosinic acid (PI) phosphorylation.(Lindmo et.al.Journal of Cell Science 119,605-614,2006). pleckstrin homology (PH) zone that the phosphatide by the active 3-phosphorylation that produces of PI3K can bindin kinase B (PKB or AKT), cause protein kinase B to the cell membrane displacement and the phosphorylation of protein kinase B occurs subsequently.The protein kinase B of phosphorylation can suppress apoptosis-induced protein, and therefore is considered to play the part of important role in the cancer process, and described apoptosis-induced protein is FKHR, Bad and caspases for example.PI3K is divided into the I-III class, and the I class is further divided into Ia and Ib subclass.Between these isotypes, the Ia fermentoid is considered to the most important effect of performance (Hayakawa et.al., Bioorganic﹠amp in the response cell proliferation that growth factor-the tyrosine kinase pathway activation causes; Medicinal Chemistry (biological organic matter and pharmaceutical chemistry) 14 6847-6858,2006). in cancer, three kinds of common sudden changes structurally activate PI3K α, and, when at cells, they are by the chronic activation that some molecules cause carcinogenic conversion and downstream signal to occur, and described molecule is protein kinase B, S6K and 4E bp1 for example, and these molecules are found in cancer cell usually.(Stephens et.al., Current Opinion in Pharmacology (the existing viewpoint of pharmaceutics), 5 (4) 357-365,2005). same, the PI3-kinases is the very attractive target spot for the treatment of proliferative diseases.
Known several PI3-inhibitors of kinases comprises wortmannin and LY294002.Although wortmannin is a kind of effective PI3K inhibitor, and has lower nanomole IC50 value, its antitumor activity in vivo is lower.(Hayakawa et al, Bioorg Med Chem 14 (20), 6847-6858 (2006)). recently, the quinazoline, Pyridopyrimidine and the Thienopyrimidine compound that have the report morpholine to replace can establishment PI3 kinases p110 α. (Hayakawa, 6847-6858).The oral dose of the Thienopyrimidine compound (GDC-0941) that morpholine replaces shows inhibitory action to the glioblastoma xenograft in vivo.(Folkes et.al., Journal of Medicinal Chemistry (pharmaceutical chemistry magazine), 51,5522-5532,2008). following publication discloses a series of Thienopyrimidine base PI3-inhibitors of kinases, Pyridopyrimidine base PI3-inhibitors of kinases and quinazolyl PI3-inhibitors of kinases: WO 2008/073785; WO 2008/070740; WO 2007/127183; U.S. Patent Publication No. 20080242665.
Acetylation of histone is a kind of reversibly modified, can carry out deacetylation by a kind of enzymatic that is called histon deacetylase (HDAC) (HDAC).Histon deacetylase (HDAC) (HDAC ' s) by 18 gene representations, and is divided into four kinds of different kinds (referring to J Mol Biol " molecular biology magazine ",, 338:1,17-31 in 2004) in human body.In mammal; the I histone deacetylases (HDAC ' s) (HDAC 1-3; with HDAC8) relevant with yeast RPD3 histon deacetylase (HDAC) (HDAC); 2 histone deacetylases (HDAC ' s) (HDAC4-7; HDAC9 and HDAC10) relevant with yeast HDAl; 4 classes (HDAC11) and 3 classes (a kind of anti-ageing enzyme (sirtuins) that comprises is in interior distinct kind, and Sir2 is relevant with yeast).
The article that Csordas delivered in Biochem.J. (" journal of biological chemistry ") 286:23-38 in nineteen ninety has instructed the epsilon-amino to the terminal lysine residue of N of histone to carry out rear translation acetylization, and this is the reaction by histone acetyltransferase (HAT1) catalysis.Acetylization can in and the positive charge on the lysine side-chain, and be considered to can be to affecting the chromatin Structure thing.In fact; can improve the amount that transcription factor enters the chromatin template by the excessive acetylization of histone, and its enrichment in not deacetylated histone H 4 is found (article of delivering in Science " science " 272:408-411 in 1996 referring to people such as Tanuton) in genomic transcribed spacer.To tumor suppressor gene, because the translation that histone modification causes stops to cause carcinogenic rotten and cancer.
The clinical investigation person estimates a few class histone deacetylases (HDAC) inhibitor.Example comprises hydroxamic acid derivative, suberoyl base aniline hydroxamic acid (SAHA), PXD101 and LAQ824, and these histone deacetylase inhibitors are current to be among the clinical research.In the benzamides histone deacetylase inhibitors, MS-275, MGCD0103 and CI-99 have passed through clinical testing.The people such as Mourne (summary #4725, AACR 2005) have proved that the benzamide that sulfur phenenyl is modified has strengthened the histone deacetylase inhibitors activity of resisting HDAC1 significantly.
Although relevant for PI3 inhibitors of kinases and hdac inhibitor record (Denlinger, C.E.et al., the J.Thorac.Cardiovasc.Surg.2005:1422-1429 in conjunction with the application for the treatment of cancer; WO 2009/058895; WO 2009/155659), but do not recognize that this treatment is especially effective to the cancer relevant with the K-ras mutant strain before.
The invention provides be used for the treatment of with the relevant cancer of K-ras of sudden change and pre-cancer situation method.The present invention relates to a discovery, that is, this cancer is responsive especially in conjunction with inhibitory action to PI3 kinases and HDAC's.
In one embodiment, the invention provides a kind of method for the treatment of cancer, described cancer comprises the cancer cell with K-ras sudden change, and the method is included in and suppresses simultaneously PI3 kinase activity and HDAC activity in the described cancer cell.
As described here, if cell interior K-ras gene is undergone mutation with respect to corresponding wild type gene and can produce from wild type K-ras protein and compare the gene outcome with different amino acid sequences through this sudden change mode, cancer cell or be considered to have the K-ras gene of sudden change with the relevant cell of situation pre-cancer so.Preferably, described mutator gene has one or more than one nucleotide at one or above codon and replaces the site, and coding has the albumen of one or one above point mutation with respect to wild-type protein.Preferred, described sudden change is positioned on single password of K-ras gene, for example on the codon 12,13 or 16.Most preferred, described sudden change is positioned on codon 12 or 13.
As described here, if there is the K-ras gene of sudden change in the cell that obtains from the host, the host who then suffers from cancer or precancerous condition is relevant with the K-ras of sudden change.Those of ordinary skills can identify the K-ras sudden change fully.And, in one embodiment, this identification be by, for example method disclosed herein or other methods well known in the prior art are finished.In another embodiment, if the host is diagnosed as a kind of cancer, and this cancer has higher K-ras mutation probability, comprise that cancer of pancreas (for example, pancreas adenocarcinoma) or adenocarcinoma of colon or adenocarcinoma of lung, then this host is identified as suffering from the cancer relevant with the K-ras of sudden change.
Can use technology identification K-ras sudden change known in the art.For example, the existence that analyzed check suddenlys change from the cell of tumour slicer (for example, surgical biopsy or pin aspirate).Described cell can also obtain from body fluid, for example obtains from blood or urine, perhaps obtains from the stool sample.The method of check K-ras sudden change is known in the art, includes but are not limited in Publication about Document disclosed: Poehlmann, A.et al., Pathol.Res.Pract.2007,203:489-497; Van Heek, N.T.et al., J.Clin.Pathol.2005,58,1315-1320; Taback, B.et al., Int.J.Cancer 2004,111:409-414; Lleonart, M.E.et al., Nucleic Acids Res.2006,34:e12; Bjornheim J.et al.Mutat.Res.1998,403:103-112; Chen, C.Y.et al., Clin.Chem.2004,50:481-489; Maekawa, M.et al., Clin.Chem.2004,50:1322-1327; Bos, J.L.et al., Nucleic Acids Res.1984,12:9155-9163; Corominas, M.et al., Environ.Health Perspect.1991,93:19-25; Su, Y.-H.et al., Ann.NY Acad.Sci.2008,1137:197-206.
The cancer relevant with the K-ras of sudden change comprises cancer of pancreas, such as the malignant adenoma (comprising duct adenocarcinoma) of pancreas; Lung cancer, such as non-small cell lung cancer and lung malignant adenoma; Colorectal cancer, for example malignant adenoma of colon; Thyroid cancer, such as ovarian follicle cancer, undifferentiated carcinoma, and papillary carcinoma; Two ball shape cancers are such as seminoma; Leukemia is such as acute myeloid leukaemia, chronic myelogenous leukemia, Huppert's disease and acute lymphatic leukemia; Huppert's disease, liver cancer, breast cancer, prostate cancer, oophoroma and carcinoma of endometrium.
Comprise adenoma with the relevant non-cancer situation of K-ras of sudden change, for example colonic adenoma and thyroid adenoma, and myelodysplastic syndrome.
In one embodiment, suffer from a kind of cancer if the host is diagnosed as, the occurrence rate of K-ras sudden change is greater than about 50% in this cancer, and then this host just is determined and suffers from the cancer relevant with the K-ras sudden change.Such cancer comprises cancer of pancreas, duct adenocarcinoma for example, and this is the highest cancer of K-ras sudden change occurrence rate.Therefore, the obvious cancer that has nothing to do than the K-ras with sudden change of this cancer more likely, and, be diagnosed as cancer of pancreas, for example on the basis of duct adenocarcinoma, the doctor can determine to use PI3 inhibitors of kinases of the present invention and hdac inhibitor combined treatment, and the additional testing that does not need to carry out other confirms the existence that K-ras suddenlys change.
Term as used herein " PI3 inhibitors of kinases " is a kind of compound, and this compound can suppress intracellular signal and pass the PI3K/AKT signal pathway.The PI3 inhibitors of kinases can be, for example, the inhibitor that relates to a kind of or more than one protein of sort signal approach, these protein comprise the PI3 kinases, for example, PI3K α, PI3K β, PI3K γ and PI3k δ, other protein in the mammal target spot of protein kinase B (AKT), rapamycin (" mTOR ") and/or this approach.The method that suppresses the ability of this protein for assessing compound here is described, and these methods are known in this area.In one embodiment, the PI3 inhibitors of kinases is selected from LY294002 (Eli Lily company), wortmannin, the wortmannin analog, the wortmannin of Pegylation, 17-hydroxyl-the wortmannin of Pegylation, PX-866, SF1124 (Semafore pharmaceutical companies), SF1126 (Semafore pharmaceutical companies), BEZ235 (Novartis Co.,Ltd), BGT226 (Novartis Co.,Ltd), BKM120 (Novartis Co.,Ltd), XL-765 (Exelexis drugmaker), XL-147 (Exelexis drugmaker), GDC-0941 (Genentech drugmaker), AS-252424, ONC-201 (Oncalis drugmaker), CAL-101 (Calistoga drugmaker), CAL-263 (calistoga drugmaker), Atu-027, PF-4691502, PBI-05204 (Phoenix bioprocess technology company), GSK-2126458, PIK-90, PIK-75, PI-103, ZSTK-474, TGX115, TGX-221 and TGX126.
In one embodiment, described PI3 inhibitors of kinases is selected from compound as described below:
Figure BPA00001656443900081
Figure BPA00001656443900101
2-morpholinyl-4-base-8-phenyl benzopyrane-4-ketone; Acetic acid (1S, 4E, 10R, 11R, 13S, 14R)-[4-diallyl aminomethylene-6-hydroxyl-1-methoxy methyl isophthalic acid 0,13-dimethyl-3,7,17-, three oxygen-1,3,4,7,10,11,12,13,14,15,16,17-, ten dihydros-2-oxa--cyclopenta [a] phenanthrene-11-base ester; 9-(3-pyridylmethyl) oxygen-2-morpholinyl-4H-pyrido [1,2-a] pyrimidin-4-one (TGX-140); 7-methyl-9-phenylamino methyl-2-morpholinyl-4H-pyrido [1,2-a] pyrimidin-4-one (TGX-183); 8-(4-methylphenol) 2-) 4-morpholinyl)-4 (1H)-quinoline (TGX-113); 8-(4-fluorinated phenoxy)-2-(4-morpholinyl)-4 (1H)-quinoline (TGX-121); 2-morpholinyl-8-(phenyl methyl)-4H-1-benzopyran-4-one (TGX-90); 2-(4-morpholinyl)-8-(4-fluoro-2-aminomethyl phenyl) oxygen-4H-1-benzopyran-4-one (TGX-184); The 9-[[(2-chlorophenyl)-and methyl] ammonia-7-methyl-2-(4-morpholinyl)-4H-pyrido [1,2-a] pyrimidin-4-one (TGX-167); The 9-[[(2-methoxyphenyl)-and methyl] ammonia]-7-methyl-2-(4-morpholinyl)-4H-pyrido [1,2-a] pyrimidin-4-one (TGX-137); 7-methyl-2-(4-morpholinyl)-9-[(phenyl methyl) ammonia]-4H-pyrido [1,2-a] pyrimidin-4-one (TGX-126); 9-[[(4-fluoro-2-aminomethyl phenyl) ammonia]-7-methyl-2-(4-morpholinyl)-4H-pyrido [1-, 2-a] pyrimidin-4-one (TGX-170); 7-methyl-2-(4-morpholinyl)-9-[[(1R)-1-phenylethyl] ammonia]-4H-pyrido [1,2-a] pyrimidin-4-one (TGX-123); 7-methyl-2-(4-morpholinyl)-9-[(2-pyridylmethyl) ammonia]-4H-pyrido [1,2-a] pyrimidin-4-one (TGX-161); The 9-[[(4-chlorophenyl) methyl] ammonia]-7-methyl-2-(4-morpholinyl)-4H-pyrido [1,2-a] pyrimidin-4-one (TGX-108); 2-(4-morpholinyl)-9-(phenyl methyl)-4H-pyrido [1,2-a] pyrimidin-4-one (TGX-040); 7-methyl-9-(N-M ethyl-N-phenyl) aminomethyl-2-(4-morpholinyl)-4H-pyrido [1,2-a] pyrimidin-4-one (TGX-195); 2-(4-morpholinyl)-8-(phenyl methyl) oxygen-4H-1-benzopyran-4-one (TGX-102); 2-(4-morpholinyl)-8-(phenyl methyl) ammonia-4H-1-benzopyran-4-one (TGX-204); 2-(4-morpholinyl)-8-phenylamino-4H-1-benzopyran-4-one (TGX-324); 8-(3-chlorophenyl) oxygen-2-(4-morpholinyl)-4H-1-benzopyran-4-one (TGX-259); 8-(3-aminomethyl phenyl)-2-(4-morpholinyl)-4 (1H)-quinoline (TGX-127); 8-(2-difluorophenyl)-2-(4-morpholinyl)-4 (1H)-quinoline (TGX-143); (+/-)-7-methyl-2-morpholinyl-4-base-9-[1-(3-pyridine radicals ammonia) ethyl]-pyrido [1,2--a] pyrimidin-4-one (KN-304); (+/-)-7-methyl-9-{[methyl (phenyl) ammonia] methyl }-2-morpholinyl-4-base-pyrido [1 ,-2-a] pyrimidine 4-ketone (TGX-195); (+/-)-7-methyl-2-morpholinyl-4-base-9-(1-phenylamino ethyl)-pyrido [1,2-a] pyrimidin-4-one (TGX-221); (+/-)-7-methyl-2-morpholinyl-4-base-9-[1-(4-difluorophenyl ammonia) ethyl]-pyrido [1,2-a] pyrimidin-4-one (TGX-224); (+/-)-9-[1-(3,4-difluoro-benzene base ammonia) ethyl]-7-methyl-2-morpholinyl-4-base-pyrido [1,2-a] pyrimidine 4-ketone (TGX-237); (+/-)-9-[1-(2,5-difluoro-benzene base ammonia) ethyl]-7-methyl-2-morpholinyl-4-base-pyrido [1,2-a] pyrimidin-4-one (TGX-238); (+/-)-9-[1-(3,5-difluoro-benzene base ammonia) ethyl]-7-methyl-2-morpholinyl-4-base-pyrido [1,2-a] pyrimidin-4-one (TGX-239); (+/-)-9-[1-(4-fluoro-2-aminomethyl phenyl ammonia) ethyl]-7-methyl-2-morpholinyl-4-base-pyrido [1,2-a] pyrimidin-4-one (TGX-240); (+/-)-9-[1-(4-chlorophenyl ammonia) ethyl]-7-methyl-2-morpholinyl-4-base-pyrido [1,2-a] pyrimidin-4-one (TGX-243); (+/-)-9-[1-(3,4-dichloro-phenyl ammonia) ethyl]-7-methyl-2-morpholinyl-4-base-pyrido [1,2-a] pyrimidine 4-ketone (TGX-244); (+/-)-9-[1-(3 difluorophenyl ammonia) ethyl]-7-methyl-2-morpholinyl-4-base-pyrido [1,2-a] pyrimidin-4-one (TGX-247); (+/-)-9-[1-(3-chlorophenyl ammonia) ethyl]-7-methyl-2-morpholinyl-4-base-pyrido [1,2-a] pyrimidin-4-one (TGX-248); (+/-)-7-methyl-2-morpholinyl-4-base-9-[1-(2-thiazolyl ammonia) ethyl]-pyrido [1,2-a] pyrimidin-4-one (TGX-261);
(+/-)-7-methyl-9-[1-(3-aminomethyl phenyl ammonia) ethyl]-2-morpholinyl-4-base-pyrido [1,2-a] pyrimidin-4-one (TGX-262); (+/-)-7-methyl-2-morpholinyl-4-base-9-[1-(3-three fluoro aminomethyl phenyl ammonia) ethyl]--pyrido [1,2-a] pyrimidin-4-one (TGX-264); (+/-)-7-methyl-2-morpholinyl-4-base-9-[1-(2-pyridine radicals ammonia) ethyl]-pyrido [1,2-a] pyrimidin-4-one (TGX-295); (+/-)-2-({ 1-[7-methyl-2-(morpholinyl 4-yl)-4-oxygen-pyrido [1,2-a] pyrimidine-9-base-] ethyl } ammonia) benzoic acid (KN-309);
(+/-) methyl 2-(1-[7-methyl-2-(morpholinyl-4-yl)-4-oxygen-pyrido [1,2-a] pyrimidine-9-yl] and ethyl-1} ammonia) benzoate (KN-321); (+/-)-2-({ 1-[7-methyl-2-(morpholine-4-yl)-4-oxygen-pyrido [1,2-a] pyrimidine-9-base-] ethyl } ammonia) benzonitrile (KN-320); (+/-)-7-methyl-2-(morpholinyl-4-yl)-9-(1-{[2-(2H-tetrazolium-5-yl) phenyl] ammonia-} ethyl)-pyrido [1,2-a] pyrimidin-4-one (KN-325); (+/-)-2-(4-morpholinyl)-8[1-(phenylamino) ethyl]-4H-1-benzopyran-4-one (TGX-280); (3-(4-(4-morpholinyl) pyrido [3 ', ': 4,5] fluorine [3,2-d] pyrimidine-2-base) phenol); 2-methyl-2-(4-(3-methyl-2-oxygen-8-(quinoline-3-yl)-2,3-dihydro-1H-imidazoles [4,5-c] quinoline-1-yl) phenyl) propionitrile (BEZ-235); 5-[[5-(4-fluoro-2-hydroxyphenyl)-2-furyl] methylene]-2,4-thiazolidinedione (AS252424); 3-(4-(4-morpholinyl) pyrido [3 ', 2 ': 4,5] furans [3,2-d] pyrimidine-2-base) phenol (PI-103); 2-(2-two fluoro tolimidazole quinoline-1-yls)-4,6-dimorpholine base-1,3,5-triazines (ZSTK474).
Other PI3 inhibitors of kinases that here use comprise 42-(3-hydroxyl-2-(hydroxymethyl)-rapamycin 2 Methylpropionic acid ester (CCI-779, Wyeth company); 42-O-(2-hydroxyethyl)-rapamycin (Novartis Co.,Ltd) and 42-(dimethyl phopsinoyl)-rapamycin (Ariad company),
Other PI3 inhibitors of kinases that can be used in the method for the present invention comprise those of setting forth in the following patent application: United States Patent (USP) the 7th, 598, No. 377; United States Patent (USP) the 7th, 662, No. 977; United States Patent (USP) the 7th, 544, No. 677; United States Patent (USP) the 7th, 524, No. 850; United States Patent (USP) the 7th, 511, No. 041; Openly apply for No. 2009/0098135 with the U.S.; The U.S. openly applies for No. 2009/0029997; The U.S. openly applies for No. 2009/0029998 and the U.S. openly applies for WO2006/065601, WO2008/144463 No. 2010/0061982, WO2009/071888, WO2009/032651, WO2009/032652, WO2009/032653, WO2009/017822, WO2009/053716; WO2009/143317; WO2008/152387, WO2010/005558, WO2010/001126, WO/2009/143313, WO2009/021083, WO2008/127226, WO2009/155052 and WO2009/155121, these patents and patent application are all incorporated this paper into by quoting as proof.
The PI3 inhibitors of kinases that uses in the method for the invention further comprises PI3 inhibitors of kinases pharmaceutically acceptable salt as described herein, ester and pro-drug.
It is a kind ofly can suppress compounds a kind of or more than one histone deacetylase isotype enzymic activitys that term as used herein " hdac inhibitor " is worth.Can come with the method known in the art ability of assessing compound inhibition HDAC activity, the method that these methods include, but are not limited to describe here.
Suitable hdac inhibitor includes but are not limited to, hydroxamic acid, cyclic peptide, benzamide and aliphatic acid.In one embodiment, described hdac inhibitor is selected from by Vorinostat (SAHA), butyric acid, valproic acid and romidepsin.In other embodiment, described hdac inhibitor is belinostat, mocetinostat, LAQ824, LBH589, CI994, BML-210, M344, MS275, JNJ-26481585 or MGCD0103.In other embodiment, described hdac inhibitor is selected from:
Figure BPA00001656443900151
((E)-N-hydroxyl-3-[4-[[2-hydroxyethyl-[2-(1H-indyl-3-yl) ethyl] ammonia] methyl] phenyl] third-2-alkene acid amides;
4-(acetyl group ammonia)-N-(2-aminophenyl) benzamide;
Pyridine radicals-3-ylmethyl 4-(2-aminophenyl carbamyl) benzyl carbamate;
N-(2-aminophenyl)-N '-phenyl suberamide;
4-(dimethylamino)-N-[7-(hydroxyl ammonia)-7-oxygen heptyl] benzamide;
(2E)-3-[3-(aniline sulfonyl) phenyl]-the N-hydroxyl acetamide;
N-(2-aminophenyl)-4-[[(4-pyridin-3-yl pyrimidine-2-base) ammonia] methyl] benzamide; With
2-(6-{[(6-fluoro quinoline-2-yl) methyl] ammonia dicyclo [3.1.0] oneself-the 3-yl)-N-hydroxy pyrimidine-5-acid amides.
In another embodiment, hdac inhibitor is EVP-0334, MGCD-290, CHR-3996 or DAC-0060.
Other hdac inhibitors that can be used in the method for the present invention comprise those of setting forth in the following patent application: WO2008/019025, WO2006/094068, WO2007/054719, WO2005/007091, WO2010/028193, WO2008/082646, WO2007/045962, WO2005/087724, WO2005/065681, WO2004/113366, WO2004/054999, WO2003/011851, WO2009/026446, WO2009/006403, WO2009/150129, WO2007/113644, WO2009/045440, WO2008/087514 and WO2008/068176, above-mentioned each all incorporate this paper at this by reference.
The hdac inhibitor that uses in the method for the invention further comprises hdac inhibitor pharmaceutically acceptable salt as described herein, ester and pro-drug.
In one embodiment, PI3 inhibitors of kinases and hdac inhibitor are independent compounds.In another embodiment, the PI3 inhibitors of kinases is identical compound with hdac inhibitor, that is to say, is the compound of same bi-functional, and this bi-functional compound namely can also can be used as hdac inhibitor as the PI3 inhibitors of kinases.In one embodiment, described bi-functional molecule comprises and can suppress the kinase whose group of PI3 and group that can inhibition of histone deacetylate enzyme.Suitable bi-functional molecule comprises the molecule with general formula A-B-C, and wherein, A a kind ofly can suppress the kinase whose group of PI3, and C is a kind of group that can suppress HDAC, and B is a kind of connector.
In a kind of preferred embodiment, described bi-functional molecule is selected from the compound of record in No. the 13/078th, 769, U.S. Patent Publication No. the 2010/0222343rd and the U.S. Patent application, and these patents are all incorporated this paper into by being cited in this.
In one embodiment, the bi-functional compound has following general structure formula (I):
Structural formula I
Figure BPA00001656443900171
Or the geometry isomer of above-claimed cpd, enantiomter, diastereoisomer, racemic mixture, the acceptable salt of pharmacology or pro-drug,
Wherein
Figure BPA00001656443900172
Represent a singly-bound or two key;
Q, r and s independently are 0 or 1 separately, q wherein, and at least one is 1 among r and the s; Preferably, q, have among r and the s one be 1 and remaining be 0;
N is 0,1,2,3 or 4;
P is 0,1 or 2, preferably 0 or 1;
T is 0 or 1; Preferably, when s was 1, t was 0;
X and Y independently are CR separately 1, N (R 8), S or O; Wherein in X and Y is CR 1The time, another one is N (R 8), S or O; Preferred X is that S and Y are CR 1
G 1CR 1, S, O, NR 10Perhaps NS (O) 2R 10
G 2Substituted or unsubstituted aryl, substituted or unsubstituted iso-aryl or, substituted or unsubstituted heterocycle;
G 3Substituted or unsubstituted C 1-C 8Alkyl, substituted or unsubstituted C 2-C 8Thiazolinyl or substituted or unsubstituted C 2-C 8Alkynyl;
Each R 8Independently be hydrogen separately, acetyl group, aliphatic or substituted aliphatic;
R 1And R 2In each be dead key or independently be selected from separately hydrogen, hydroxyl, amino, halogen, alkoxyl, alkyl amino, dialkyl amido, CF 3, CN, NO 2, sulfonyl, acyl group, aliphatic, substituted aliphatic, aryl, substituted aryl, iso-aryl, substituted iso-aryl, heterocycle, and substituted heterocycle;
R aBe optional substituted alkyl, optional substituted aryl or optional substituted iso-aryl;
R bBe hydrogen, optional substituted alkyl, optional substituted aryl or optional substituted iso-aryl;
Perhaps R aWith R bTogether formed an optional substituted heterocyclic group with the described nitrogen-atoms that is connected them;
R 10Be selected from hydrogen, hydroxyl, amino, alkoxyl, alkyl amino, dialkyl amido, sulfonyl, acyl group, aliphatic, substituted aliphatic, aryl, substituted aryl, iso-aryl, substituted iso-aryl, heterocycle, and substituted heterocycle; Preferred R 10Hydrogen, acetyl group, aliphatic or substituted aliphatic;
B is an attachment; And
C is selected from
(a)
Figure BPA00001656443900191
Wherein W is O or S; J is O, NH or NCH 3And R 31Hydrogen or low alkyl group;
(b)
Figure BPA00001656443900192
Wherein W is O or S; Y 2Dead key, N, perhaps CH; Z is N or CH; R 32And R 34Independently be hydrogen separately, hydroxyl, if aliphatic group is R 32And R 34All be dead key, R 32Perhaps R 34If in one be necessary for hydroxyl and Y 2Dead key, R 34Be necessary for hydroxyl; And R 33Hydrogen or aliphatic group;
(c)
Figure BPA00001656443900193
Wherein W is O or S; Y 1And Z 1Independently be N separately, C or CH; And
(d) Z wherein, Y 2, and W is defined previously; R 11And R 12Independently be selected from separately hydrogen or aliphatic; R 21, R 22And R 23Independently be selected from separately hydrogen, hydroxyl, amino, halogen, alkoxyl, alkyl amino, dialkyl amido, CF 3, CN, NO 2, sulfonyl, acyl group, aliphatic, substituted aliphatic, aryl, substituted aryl, iso-aryl, substituted iso-aryl, heterocycle, and substituted heterocycle;
In another embodiment, R 1And R 2In each independently be dead key separately, hydrogen, hydroxyl, amino, halogen, alkoxyl, alkyl amino, dialkyl amido, CF 3, CN, NO 2, sulfonyl, acyl group, aliphatic, substituted aliphatic, aryl, substituted aryl, iso-aryl, substituted iso-aryl, heterocycle, and substituted heterocycle; Aryl alkyl, substituted aryl alkyl, iso-aryl alkyl, substituted iso-aryl alkyl, Heterocyclylalkyl or substituted Heterocyclylalkyl.
In one embodiment, bi-functional compound described in the present invention is by structural formula (II) or the represented compound of structural formula (III), or the geometry isomer of above-claimed cpd, enantiomter, diastereoisomer, racemic mixture, pharmacology acceptable salt, perhaps pro-drug:
Figure BPA00001656443900201
Wherein
Figure BPA00001656443900202
Representing a singly-bound or two key and G 1, G 2, G 3, R 1, R 2, X, Y, n, p, q, r, s, B and C be middle the definition as mentioned.Preferably, in structural formula (III), q be 1 and r be 0.
In another embodiment, bi-functional compound described in the present invention be by as hereinafter described in structural formula (IV) or the represented compound of structural formula (V), or the geometry isomer of above-claimed cpd, enantiomter, diastereoisomer, racemic mixture, the acceptable salt of pharmacology, and pro-drug:
Figure BPA00001656443900203
Structural formula IV structural formula V,
Wherein Representing a singly-bound or two key; G 1, G 2, R 1, R 2, R 8, n, p, q, r, s, B and C be middle the definition as mentioned; And G 4NR 8, S or O, preferably S.Preferred G 1O.
In another embodiment, bi-functional compound described in the present invention be by as hereinafter described in structural formula (VI) or the represented compound of structural formula (VII), or the geometry isomer of above-claimed cpd, enantiomter, diastereoisomer, racemic mixture, the acceptable salt of pharmacology, and pro-drug:
Structural formula VI structural formula VII,
Figure BPA00001656443900212
Wherein
Figure BPA00001656443900213
Representing a singly-bound or two key; G 1, G 4, R 1, R 2, R 3, R 8, n, m, p, q, r, s, B and C be middle the definition as mentioned; And o is 1,2,3 or 4.
In the preferred embodiment that the compound shown in the structural formula I to V has, q and r be 0 and s be 1.Another preferred embodiment in, q is that 1 simultaneously r and s are 0.Another preferred embodiment in, q and s be 0 and r be 1.
In the preferred embodiment that the compound shown in the structural formula II I has, r be 0 and q be 1.
In the preferred embodiment that the compound shown in structural formula VI and the VII has, q be 1 and s be 0.
A kind of preferred embodiment in, B is C 1-C 8Alkyl, one or more CH 2Optional by O, S, SO 2, NR 8Perhaps-and CONH-replaces, and C is-C (O) N (H) OH, and G 1Be-O.Another preferred embodiment in, B is C 1-C 8Alkyl, one or more CH 2Optional by O, S, SO 2, NR 8Perhaps-and CONH-replaces, and C is-C (O) N (H) OH, and G 1-NS (O) 2CH 3Another preferred embodiment in, B is aryl, iso-aryl, C 1-C 10Alkylaryl, C 1-C 10Alkyl iso-aryl group, C 1-C 10The alkyl heterocycle aryl, C 1-C 10The alkyl heterocycle iso-aryl, C 1-C 10Alkyl heterocycle aryl-C 1-C 10Alkyl, perhaps C 1-C 10Alkyl heterocycle iso-aryl-C 1-C 10Alkyl group, one or more CH 2Optional by O, S, SO 2, NR 8Perhaps-CONH-replaces, and G 1Be-O or-NS (O) 2CH 3
In another embodiment, bi-functional compound described in the present invention be by as hereinafter described in structural formula (VIII) or the represented compound of structural formula (IX), or the geometry isomer of above-claimed cpd, enantiomter, diastereoisomer, racemic mixture, the acceptable salt of pharmacology or pro-drug:
Structural formula VIII structural formula IX,
Figure BPA00001656443900221
Wherein Representing a singly-bound or two key; G 1, G 2, G 4, R a, R b, R 1, R 2, n, p, q, s, B and C be middle the definition as mentioned; And o is 1,2,3 or 4.In preferred embodiment, G 2Optional substituted phenyl, pyridine radicals, pyrimidine radicals, indyl, indazolyl, pyrido pyrrole radicals, pyrrole radicals, imidazole radicals, pyrazolyl or benzimidazolyl.
In the preferred embodiment that the described compound shown in structural formula VIII and the IX has, q be 0 and s be 1.Another preferred embodiment in, q be 1 and s be 0.A kind of preferred embodiment in, B is C 1-C 8Alkyl, one or more CH 2Optional by O, S, SO 2, NR 8Perhaps-and CONH-replaces, and C is-C (O) N (H) OH, and G 1Be-O.Another preferred embodiment in, B is C 1-C 8Alkyl, one or more CH 2Optional by O, S, SO 2, NR 8Perhaps-and CONH-replaces, and C is-C (O) N (H) OH, and G 1-NS (O) 2CH 3
In another embodiment, bi-functional compound described in the present invention be by as hereinafter described in structural formula X and the represented compound of structural formula XI, or the geometry isomer of above-claimed cpd, enantiomter, diastereoisomer, racemic mixture, the acceptable salt of pharmacology or pro-drug:
Structural formula X structural formula XI,
Figure BPA00001656443900231
G wherein 1, G 2, n, p, B, C, R 1And R 2Define as mentioned.In preferred embodiment, G 2Optional substituted phenyl, pyridine radicals, pyrimidine radicals, indyl, indazolyl, pyrido pyrrole radicals, pyrrole radicals, imidazole radicals, pyrazolyl or benzimidazolyl.
In the preferred embodiment that the described compound shown in the structural formula X-XI has, wherein B is C 1-C 8Alkyl, one or more CH 2Optional by O, S, SO 2, NR 8,-CONH-, aryl, substituted aryl, iso-aryl, substituted iso-aryl, heterocycle or substituted heterocyclic group replace, and C is-C (O) N (H) OH, and G 1Be-O.Another preferred embodiment in, B is C 1-C 8Alkyl, one or more CH 2Optional by O, S, SO 2, NR 8,-CONH-, aryl, substituted aryl, iso-aryl, substituted iso-aryl, heterocycle or substituted heterocyclic group replace,, C is-C (O) N (H) OH, and G 1-NS (O) 2CH 3
In another embodiment, bi-functional compound described in the present invention be by as hereinafter described in the represented compound of structural formula XII, or the geometry isomer of above-claimed cpd, enantiomter, diastereoisomer, racemic mixture, pharmacology acceptable salt, perhaps pro-drug:
Figure BPA00001656443900241
N wherein, p, B, C, R 1, R 2Define as mentioned.
In another embodiment, bi-functional compound described in the present invention be by as hereinafter described in the represented compound of structural formula XIII, or the geometry isomer of above-claimed cpd, enantiomter, diastereoisomer, racemic mixture, pharmacology acceptable salt, perhaps pro-drug:
Figure BPA00001656443900251
Structural formula XIII,
N wherein, p, Y 2, W, Z, G 1, G 4, G 2, R 1, R 2, R 3, R 32, R 33And R 34Define as mentioned; M 1Dead key, O, S, NR 8, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, aryl, iso-aryl, heterocycle, SO, SO 2Perhaps C=O; M 2Dead key, C 1-C 6Alkyl, O, NR 8, heterocycle, aryl, iso-aryl, perhaps C=O; M 3Dead key, O, NR 8, S, SO, SO 2, CO, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, aryl, iso-aryl, or heterocycle; M 4Dead key, O, NR 8, iso-aryl, heterocycle or aryl; And M 5Dead key, C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, iso-aryl, heterocycle or aryl.In preferred embodiment, G 2Optional substituted phenyl, pyridine radicals, pyrimidine radicals, indyl, indazolyl, pyrido pyrrole radicals, pyrrole radicals, imidazole radicals, pyrazolyl or benzimidazolyl.In more preferred embodiment, G 2Optional substituted phenyl, pyridine radicals, pyrimidine radicals, indyl, indazolyl, pyrrole radicals or benzimidazolyl.
In another embodiment, bi-functional compound described in the present invention be by as hereinafter described in the represented compound of structural formula (XIV), or the geometry isomer of above-claimed cpd, enantiomter, diastereoisomer, racemic mixture, pharmacology acceptable salt, perhaps pro-drug:
Figure BPA00001656443900261
Structural formula XIV,
G wherein 1, G 2, G 4, n, p, R 1, R 2And R 3Define as mentioned; T, v and w independently are 0,1,2 or 3 separately; U is 0,1,2,3,4,5,6,7 or 8; G 5Dead key, C 1-C 8Alkyl or a C who is blocked 1-C 8Alkyl, wherein said alkyl are to utilize in the following radicals one or more to block: O, S, S (O), N (R 8), perhaps C (O); Preferred G 5Be-N (R 8)-C 1-C 4Alkyl, t be 1 and u be 0.
G 6Be selected from CR 1Perhaps NR 8, R wherein 1And R 8Define as mentioned;
G 7Be selected from-CR 1,-NR 8, S or O be R wherein 1And R 8Define as mentioned; Perhaps
G 7Be selected from-C (R 1) 2, and-N; R 5And R 6Independently be selected from separately dead key, hydrogen, hydroxyl, amino, halogen, alkoxyl, alkyl amino, dialkyl amido, CF 3, CN, NO 2, sulfonyl, acyl group, aliphatic, substituted aliphatic, aryl, substituted aryl, iso-aryl, substituted iso-aryl, heterocycle, and substituted heterocycle.In preferred embodiment, G 2Optional substituted phenyl, pyridine radicals, pyrimidine radicals, indyl, indazolyl, pyrido pyrrole radicals, pyrrole radicals, imidazole radicals, pyrazolyl or benzimidazolyl.In more preferred embodiment, G 2Optional substituted phenyl, pyridine radicals, pyrimidine radicals, indyl, indazolyl, pyrrole radicals or benzimidazolyl.Preferably, work as G 7CR 1Perhaps during N, described pyrimidine ring directly and G 7Carried out combination.
In another embodiment, bi-functional compound described in the present invention be by as hereinafter described in the represented compound of structural formula XV, or the geometry isomer of above-claimed cpd, enantiomter, diastereoisomer, racemic mixture, pharmacology acceptable salt, perhaps pro-drug:
Structural formula XV,
Figure BPA00001656443900271
G wherein 1, G 2, G 4, G 5, n, p, w, y, R 1, R 2, and R 6Define as mentioned.In preferred embodiment, G 2Optional substituted phenyl, pyridine radicals, pyrimidine radicals, indyl, indazolyl, pyrido pyrrole radicals, pyrrole radicals, imidazole radicals, pyrazolyl or benzimidazolyl.In more preferred embodiment, G 1O, G 2Optional substituted phenyl, pyridine radicals, pyrimidine radicals, indyl, indazolyl, pyrrole radicals or benzimidazolyl.G 5Be-N (R 8)-C 1-C 4Alkyl and u are 0.
Had by the compound shown in the said structure formula more preferred embodiment in, G 2Be phenyl, the pyridine radicals that selectivity replaces, pyrimidine radicals or pyrrole radicals are selected from the following group:
Preferably in these groups, m is 1 and R 3Hydroxyl, hydroxymethyl, amino, acyl amino, for example acetyl-amino, perhaps methylamino.Another preferred embodiment in, G 2Be indyl or the benzene imidazole radicals that selectivity replaces, be selected from as in the group as shown in hereinafter:
R wherein 3, R 8And m defines in as mentioned.
Had by the compound shown in the said structure formula some preferred embodiment in, G 2Optional substituted single aryl or single iso-aryl group.In more preferred embodiment, G 2Phenyl, pyridine radicals, pyrimidine radicals or pyrrole radicals, above-mentioned group has one or more substituting group, and described substituting group is including, but not limited to hydroxyl, hydroxymethyl, amino and substituted amino; G 1O, G 5Be-N (R 8)-C 1-C 4Alkyl and u are 0.For example, G 2Can be phenyl, pyridine radicals, pyrimidine radicals or pyrrole radicals, above-mentioned group is replaced by hydroxyl, hydroxymethyl, acetyl-amino, amino or methylamino group.Such compound has significant inhibitory activity for mammal rapamycin targeting proteins (mTOR) and phosphoinositide 3 (PI3) kinases and histone deacetylase (HDAC).
Highly preferred embodiment is for C:
Figure BPA00001656443900291
R wherein 33Be selected from hydrogen and low alkyl group.
A kind of preferred embodiment in, the B of described divalence be a direct key or straight chain or side chain, substituted or unsubstituted alkyl, substituted or unsubstituted thiazolinyl, substituted or unsubstituted alkynyl, aryl alkyl, aryl alkenyl, aromatic yl polysulfide yl, iso-aryl alkyl, iso-aryl thiazolinyl, the iso-aryl alkynyl, Heterocyclylalkyl, heterocycloalkenyl, the heterocycle alkynyl, aryl, iso-aryl, heterocycle, cycloalkyl, cycloalkenyl group, the alkylaryl alkyl, alkylaryl thiazolinyl, alkylaryl alkynyl, the alkenyl aryl alkyl, alkenyl aryl thiazolinyl, alkenyl aryl alkynyl, the alkynyl aryl alkyl, the alkynyl aryl alkenyl, alkynyl aromatic yl polysulfide yl, alkyl iso-aryl alkyl, alkyl iso-aryl thiazolinyl, alkyl iso-aryl alkynyl, thiazolinyl iso-aryl alkyl, thiazolinyl iso-aryl thiazolinyl, thiazolinyl iso-aryl alkynyl, alkynyl iso-aryl alkyl, alkynyl iso-aryl thiazolinyl, alkynyl iso-aryl alkynyl, the alkyl heterocycle alkyl, the alkyl heterocycle thiazolinyl, alkyl heterocycle alkynyl, thiazolinyl Heterocyclylalkyl, the thiazolinyl heterocycloalkenyl, thiazolinyl heterocycle alkynyl, alkynyl Heterocyclylalkyl, alkynyl heterocycloalkenyl, alkynyl heterocycle alkynyl, alkylaryl, alkenyl aryl, alkynyl aryl, the alkyl iso-aryl, the thiazolinyl iso-aryl, perhaps alkynyl iso-aryl, one or more methylene can be blocked or stop by following radicals, described group is: O, S, S (O), SO 2, N (R 8), C (O), substituted or unsubstituted aryl, substituted or unsubstituted iso-aryl, substituted or unsubstituted heterocycle; The B attachment of such divalence is including, but not limited to alkyl, thiazolinyl, alkynyl, alkylaryl, alkenyl aryl, alkynyl aryl, the alkyl heterocycle aryl, alkyl heterocycle aryl alkyl, alkyl heterocycle iso-aryl, alkyl heterocycle iso-aryl alkyl, alkoxy aryl, alkyl amino aryl, alkoxyalkyl, alkyl amino alkyl, alkyl heterocycle alkyl, alkyl iso-aryl alkyl, alkyl amino, N (R 8) thiazolinyl, N (R 8) alkynyl, N (R 8) alkoxyalkyl, N (R 8) the alkyl amino alkyl, N (R 8) alkyl amino-carbonyl, N (R 8) alkylaryl, N (R 8) alkenyl aryl, N (R 8) the alkynyl aryl, N (R 8) alkoxy aryl, N (R 8) the alkyl amino aryl, N (R 8) cycloalkyl, N (R 8) aryl, N (R 8) iso-aryl, N (R 8) Heterocyclylalkyl, N (R 8) the alkyl heterocycle alkyl, alkoxyl, O-thiazolinyl, the O-alkynyl, O-alkoxyalkyl, O-alkyl amino alkyl, the O-alkyl amino-carbonyl, O-alkylaryl, O-alkenyl aryl, O-alkynyl aryl, O-alkoxy aryl, O-alkyl amino aryl, the O-cycloalkyl, O-aryl, O-iso-aryl, the O-Heterocyclylalkyl, O-alkyl heterocycle alkyl, C (O) alkyl, C (O)-thiazolinyl, C (O) alkynyl, C (O) alkylaryl, C (O) alkenyl aryl, C (O) alkynyl aryl, C (O) alkoxyalkyl, C (O) alkyl amino alkyl, C (O) alkyl amino-carbonyl, C (O) cycloalkyl, C (O) aryl, C (O) iso-aryl, C (O) Heterocyclylalkyl, CON (R 8), CON (R 8) alkyl, CON (R 8) thiazolinyl, CON (R 8) alkynyl, CON (R 8) alkylaryl, CON (R 8) alkenyl aryl, CON (R 8) the alkynyl aryl, CON (R 8) alkoxyalkyl, CON (R 8) the alkyl amino alkyl, CON (R 8) alkyl amino-carbonyl, CON (R 8) alkoxy aryl, CON (R 8) the alkyl amino aryl, CON (R 8) cycloalkyl, CON (R 8) aryl, CON (R 8) iso-aryl, CON (R 8) Heterocyclylalkyl, CON (R 8) the alkyl heterocycle alkyl, N (R 8) C (O) alkyl, N (R 8) C (O) thiazolinyl, N (R 8) C (O)-alkynyl, N (R 8) C (O) alkylaryl, N (R 8) C (O) alkenyl aryl, N (R 8) C (O) alkynyl aryl, N (R 8) C (O) alkoxyalkyl, N (R 8) C (O) alkyl amino alkyl, N (R 8) C (O) alkyl amino-carbonyl, N (R 8) C (O) alkoxy aryl, N (R 8) C (O) alkyl amino aryl, N (R 8) C (O) cycloalkyl, N (R 8) C (O) aryl, N (R 8) C (O) iso-aryl, N (R 8) C (O) Heterocyclylalkyl, N (R 8) C (O) alkyl heterocycle alkyl, NHC (O) NH, NHC (O) NH-alkyl, NHC (O) NH-thiazolinyl, NHC (O) NH-alkynyl, NHC (O) NH-alkylaryl, NHC (O) NH-alkenyl aryl, NHC (O) NH-alkynyl aryl, NHC (O) NH-alkoxy aryl, NHC (O) NH-alkyl amino aryl, NHC (O) NH-cycloalkyl, NHC (O) NH-aryl, NHC (O) NH-iso-aryl, NHC (O) NH-Heterocyclylalkyl, NHC (O) NH-alkyl heterocycle alkyl, S-alkyl, the S-thiazolinyl, the S-alkynyl, S-alkoxyalkyl, S-alkyl amino alkyl, the S-alkylaryl, the S-alkyl amino-carbonyl, S-alkylaryl, S-alkynyl aryl, the S-alkoxy aryl, S-alkyl amino aryl, S-cycloalkyl, S-aryl, the S-iso-aryl, the S-Heterocyclylalkyl, S-alkyl heterocycle alkyl, S (O) alkyl, S (O) thiazolinyl, S (O) alkynyl, S (O) alkoxyalkyl, S (O) alkyl amino alkyl, S (O) alkyl amino-carbonyl, S (O) alkylaryl, S (O) alkenyl aryl, S (O) alkynyl aryl, S (O) alkoxy aryl, S (O) alkyl amino aryl, S (O) cycloalkyl, S (O) aryl, S (O) iso-aryl, S (O) Heterocyclylalkyl, S (O) alkyl heterocycle alkyl, S (O) 2Alkyl, S (O) 2Thiazolinyl, S (O) 2Alkynyl, S (O) 2Alkoxyalkyl, S (O) 2The alkyl amino alkyl, S (O) 2Alkyl amino-carbonyl, S (O) 2Alkylaryl, S (O) 2Alkenyl aryl, S (O) 2The alkynyl aryl, S (O) 2Alkoxy aryl, S (O) 2The alkyl amino aryl, S (O) 2Cycloalkyl, S (O) 2Aryl, S (O) 2Iso-aryl, S (O) 2Heterocyclylalkyl, S (O) 2The alkyl heterocycle alkyl, S (O) 2Heterocyclylalkyl, S (O) 2Heterocycloalkenyl, S (O) 2The heterocycle alkynyl, SO 2NH, SO 2The NH-alkyl, SO 2The NH-thiazolinyl, SO 2The NH-alkynyl, SO 2The NH-alkylaryl, SO 2The NH-alkenyl aryl, SO 2NH-alkynyl aryl, SO 2The NH-cycloalkyl, SO 2The NH-aryl, SO 2The NH-iso-aryl, SO 2The NH-Heterocyclylalkyl, SO 2NH-alkyl heterocycle alkyl, alkyl-aryloxy alkoxyl, alkyl-aryloxy alkyl amino, the alkyl aryl amino alkoxyl, the alkyl aryl amino alkyl amino, alkylaryl alkyl amino alkoxyl, alkylaryl alkyl amino alkoxyl, thiazolinyl aryloxy group alcoxyl base, the thiazolinyl aryloxy alkyl amino, the alkenyl aryl aminoalkoxy, the alkenyl aryl aminoalkyl is amino, alkenyl aryl alkyl amino alkoxyl, alkenyl aryl alkyl amino alkyl amino.
A kind of more preferred embodiment in, B is the alkyl of a straight chain, thiazolinyl, alkynyl, aryl alkyl, aryl alkenyl, aromatic yl polysulfide yl, iso-aryl alkyl, iso-aryl thiazolinyl, the iso-aryl alkynyl, Heterocyclylalkyl, heterocycloalkenyl, the heterocycle alkynyl, aryl, iso-aryl, heterocycle, cycloalkyl, cycloalkenyl group, the alkylaryl alkyl, alkylaryl thiazolinyl, alkylaryl alkynyl, the alkenyl aryl alkyl, alkenyl aryl thiazolinyl, alkenyl aryl alkynyl, the alkynyl aryl alkyl, alkynyl aryl alkenyl, alkynyl aromatic yl polysulfide yl, alkyl iso-aryl alkyl, alkyl iso-aryl thiazolinyl, alkyl iso-aryl alkynyl, thiazolinyl iso-aryl alkyl, thiazolinyl iso-aryl thiazolinyl, thiazolinyl iso-aryl alkynyl, alkynyl iso-aryl alkyl, alkynyl iso-aryl thiazolinyl, alkynyl iso-aryl alkynyl, alkyl heterocycle alkyl, the alkyl heterocycle thiazolinyl, the alkyl heterocycle alkynyl, thiazolinyl Heterocyclylalkyl, thiazolinyl heterocycloalkenyl, thiazolinyl heterocycle alkynyl, the alkynyl Heterocyclylalkyl, alkynyl heterocycloalkenyl, alkynyl heterocycle alkynyl, alkylaryl, alkenyl aryl, alkynyl aryl, alkyl iso-aryl, thiazolinyl iso-aryl, perhaps alkynyl iso-aryl.One or more methylene can be blocked or stop by following radicals, and described group is :-O-,-N (R 8)-,-C (O)-,-C (O) N (R 8)-, perhaps-C (O) O-.Preferably, described C group is connected with B via fat half family, and wherein said fat half family is present among the described B.
In one embodiment, described attachment B has 1-24 atom, preferably has 4-24 atom, preferably has 4-18 atom, more preferably has 4-12 atom, and highly preferredly has about 4-10 atom.
A kind of preferred embodiment in, B is selected from the C of straight chain 1-C 10Alkyl, C 1-C 10Thiazolinyl, C 1-C 10Alkynyl, C 1-C 10Alkoxyl, alkoxy C 1-C 10Alkoxyl, C 1-C 10Alkyl amino, alkoxy C 1-C 10Alkyl amino, C 1-C 10Alkyl-carbonyl-amino, C 1-C 10Alkyl amino-carbonyl, aryloxy group C 1-C 10Alkoxyl, aryloxy group C 1-C 10Alkyl amino, aryloxy group C 1-C 10Alkyl amino-carbonyl, C 1-C 10-alkyl amino alkyl amino-carbonyl, C 1-C 10Alkyl (N-alkyl) aminoalkyl-amino carbonyl, the alkyl amino alkyl amino, the alkyl-carbonyl-amino alkyl amino, alkyl (N-alkyl) aminoalkyl is amino, (N-alkyl) alkyl-carbonyl-amino alkyl amino, the alkyl amino alkyl, alkyl amino alkyl amino alkyl, alkylpiperazinyl alkyl, piperazinyl alkyl, alkylpiperazinyl, thiazolinyl aryloxy group C 1-C 10Alkoxyl, the amino C of alkenyl aryl 1-C 10Alkoxyl, alkenyl aryl alkyl amino C 1-C 10Alkoxyl, thiazolinyl aryloxy group C 1-C 10Alkyl amino, thiazolinyl aryloxy group C 1-C 10Alkyl amino-carbonyl, piperazinyl alkyl aryl, iso-aryl C 1-C 10Alkyl, iso-aryl C 2-C 10Thiazolinyl, iso-aryl C 2-C 10Alkynyl, iso-aryl C 1-C 10Alkyl amino, iso-aryl C 1-C 10Alkoxyl, different aryloxy group C 1-C 10Alkyl, different aryloxy group C 2-C 10Thiazolinyl, different aryloxy group C 2-C 10Alkynyl, different aryloxy group C 1-C 10Alkyl amino, different aryloxy group C 1-C 10Alkoxyl.In described highly preferred embodiment, described C group is connected with B via a fat half family's carbochain, an aromatic yl group or an iso-aryl group, and wherein said fat half family's carbochain, aromatic yl group or iso-aryl group are present among the B.
In a kind of particularly preferred embodiment, B is an aryl, iso-aryl, C 1-C 10-alkylaryl, C 1-C 10-alkyl iso-aryl group, C 1-C 10-alkyl heterocycle aryl, C 1-C 10-alkyl heterocycle iso-aryl, C 1-C 10-alkyl heterocycle aryl-C 1-C 10-alkyl, perhaps C 1-C 10-alkyl heterocycle iso-aryl-C 1-C 10-alkyl group.
Should be understood that, alkyl, thiazolinyl, alkynyl, aryl, iso-aryl, cycloalkyl, heterocycle and similar group can be carried out further replacement.
In some embodiment that is had by the described compound shown in the structural formula I-XIX, B is selected from the following group:
Figure BPA00001656443900331
Figure BPA00001656443900341
In another embodiment, B is
Figure BPA00001656443900342
In aforesaid structural formula, d and e independently are 0,1,2,3,4,5,6,7 or 8 separately; And R 100Be hydrogen or be selected from the group that is formed by following radicals: C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, and C 3-C 8Cycloalkyl.Preferred alkyl group is-CH 3,-CH 2CH 3,-CH 2CH 2CH 3,-CH (CH 3) CH 3,-C (CH 3) 2CH 3,-C (CH 3) 3Preferably, R 100Hydrogen or methyl.
According to the present invention, representational bi-functional compound is that those are selected from the compound among hereinafter the form A, or the geometry isomer of these compounds, enantiomter, diastereoisomer, racemic mixture, the acceptable salt of pharmacology, and pro-drug.Should be understood that in the arbitrary structures in form A, nitrogen-atoms is represented as has open chemical valence, described chemical valence is taken by a hydrogen atom.
Form A
Figure BPA00001656443900351
Figure BPA00001656443900361
Figure BPA00001656443900371
Figure BPA00001656443900391
Figure BPA00001656443900401
Figure BPA00001656443900411
Figure BPA00001656443900431
Figure BPA00001656443900441
Figure BPA00001656443900461
Figure BPA00001656443900471
Figure BPA00001656443900481
Figure BPA00001656443900491
Figure BPA00001656443900501
Figure BPA00001656443900511
Figure BPA00001656443900521
Figure BPA00001656443900531
Figure BPA00001656443900551
Figure BPA00001656443900561
Figure BPA00001656443900581
Figure BPA00001656443900591
Figure BPA00001656443900601
Figure BPA00001656443900611
Figure BPA00001656443900621
Figure BPA00001656443900631
Figure BPA00001656443900641
Figure BPA00001656443900651
Figure BPA00001656443900661
Figure BPA00001656443900671
Figure BPA00001656443900681
Figure BPA00001656443900711
Figure BPA00001656443900721
Figure BPA00001656443900731
Figure BPA00001656443900751
Figure BPA00001656443900761
Figure BPA00001656443900771
Figure BPA00001656443900791
Figure BPA00001656443900801
Figure BPA00001656443900821
Figure BPA00001656443900841
Figure BPA00001656443900851
Figure BPA00001656443900861
Figure BPA00001656443900871
Figure BPA00001656443900881
Figure BPA00001656443900891
Figure BPA00001656443900901
Figure BPA00001656443900911
Figure BPA00001656443900931
Figure BPA00001656443900941
Figure BPA00001656443900951
Figure BPA00001656443900971
Figure BPA00001656443900981
Figure BPA00001656443900991
Figure BPA00001656443901001
Figure BPA00001656443901011
In one embodiment, PI3 inhibitors of kinases and hdac inhibitor, perhaps described bi-functional compound is used as a kind of pharmaceutical composition, and described pharmaceutical composition comprises reactive compound and a kind of pharmaceutically acceptable carrier or excipient.Suitable pharmaceutical composition comprises any solid form or the liquid form of described reactive compound.For example, described compound can be in crystal form, amorphous form, and has any grain diameter.Described particle can be by micronized or agglomerating discrete particles, powder, finish, oils suspension or other any solid or liquid form.Suitable pharmaceutical composition generally comprises reactive compound and a kind of pharmaceutically acceptable carrier for the treatment of effective dose.
Compound described in the present invention can be used in any suitable manner, and described mode includes, but are not limited to, parenteral, intravenous is in the muscle, subcutaneous, perfusion, oral, sublingual gland, oral cavity, nasal cavity, lung, transdermal, part, vagina, rectum, and mucous membrane is used or similar method of application thoroughly.Local application can comprise the use of transdermal administration equally, and wherein said transdermal administration is for example transdermal patch or Iontophoretic device.Pharmaceutical preparation comprises and contains the compound described in the present invention as the solid pharmaceutical preparation of active component, semisolid preparation or liquid preparation (tablet, globule, tablet, capsule, suppository, creme, ointment, aerosol, powder, liquid, emulsion, suspension, syrup, injection etc.), described preparation can be fit to selection that mode of administration is carried out.In one embodiment, described pharmaceutical composition is by Orally administered, and therefore it is mixed with a kind of Orally administered form that is fit to, and, becomes a kind of solid pharmaceutical preparation or a kind of liquid preparation that is.Suitable solid orally ingestible comprises tablet, capsule, pill, granule, globule, sachet and effervescent agent, powder, and similar preparation.Suitable liquid oral medicine comprises solution, suspension, dispersion liquid, emulsion, oil and similar preparation.In one embodiment of the invention, described composition is formulated into and is capsule.According to this embodiment, except comprising described reactive compound and described inert carrier or thinner, also comprise a kind of hard gel capsule in the composition of the present invention.
The excipient of any inertia of usually using as carrier or thinner can be used in the preparation of the present invention, and described inert excipient is colloid for example, starch, sugar, fibrous matter, acrylates, or the mixture of above-mentioned substance.A kind of preferred thinner is microcrystalline cellulose.Can further comprise a kind of decomposition agent (for example, Ac-Di-Sol) and a kind of lubricant (for example dolomol) in the described composition, and can be other comprise that one or more are selected from the additive in the following substances: adhesive, buffer, protease inhibitors, surfactant, solubilizer, plasticizer, emulsifier, stabilizing agent, viscosity-increasing agent, sweetener, film forming agent, or any combination of above-mentioned substance.Further, the composition described in the present invention can be with the form of described controlled release preparation or the dosage form that discharges immediately exists.
For liquid preparation, the carrier of pharmacology acceptability can be aqueous solution or non-aqueous solution, suspension, emulsion or oil.The example of non-aqueous solvent is propane diols, polyethylene glycol, and injection-type organic ester ethyl oleate for example.Aqueous carrier comprises water, ethanol/water solution, and emulsion or suspension comprise physiological saline and buffer medium.The example of oil is that those derive from oil, animal, and plant, the perhaps oil in artificial source, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and cod-liver oil.Can comprise following component equally in solution or the suspension: sterile diluent is water for injection for example, normal saline solution, fixed oil, polyethylene glycol, glycerine, propane diols or other synthetic property solvent; Antibacterium reagent is phenmethylol or hexacosoic acid methyl esters for example; Antioxidant is ascorbic acid or sodium hydrogensulfite for example; Chelating agent is ethylenediamine tetra-acetic acid (EDTA) for example; Buffer is acetate for example, citrate or phosphate, and be used for reagent that described tensity (tonicity) is adjusted for example sodium chloride or glucose.Can use acid or alkali that described pH is adjusted, wherein said acid or alkali are for example hydrochloric acid or sodium hydroxide.
In addition, can comprise further in the described composition that adhesive (for example, gum Arabic, corn starch, gel, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvidone), decomposition agent (for example, corn starch, potato starch, alginic acid, silica, Ac-Di-Sol, PVPP, guar gum, sodium starch glycollate, sodium carboxymethyl starch), (for example have the buffer of various pH and ion strength, tris hydrochloric acid, acetate, phosphate), can prevent from being absorbed into surperficial additive for example albumin or gel, abstergent (for example, polysorbas20, Tween 80, Pluronic (polypropylene glycol and ethylene oxide copolymer) F68, bile salt), protease inhibitors, surfactant (for example, lauryl sodium sulfate), penetration enhancer, solubilizer (for example, glycerine, polyethylene glycol), glidant (for example, cataloid), antioxidant (for example, ascorbic acid, sodium metabisulfite, butylated hydroxyanisol), stabilizing agent (for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose), viscosity-increasing agent (for example, carbomer, cataloid, ethyl cellulose, guar gum), sweetener (for example, sucrose, Aspartame, citric acid), flavouring agent (for example, peppermint oil, methyl salicylate, perhaps orange flavor essence), preservative (for example, thimerosal, phenmethylol, p-hydroxybenzoate), lubricant (for example, stearic acid, dolomol, polyethylene glycol, lauryl sodium sulfate), flow promortor is (for example, cataloid), plasticizer (for example, ethyl phthalate, triethyl citrate), emulsifier (for example, carbomer, hydroxypropyl cellulose, lauryl sodium sulfate), polymer coating (for example, the husky amine of poloxamer or pool Lip river), become coating and film forming agent (for example, ethyl cellulose, acrylates, polymethacrylates) and/or adjuvant.
In one embodiment, described reactive compound and carrier together are prepared, wherein said carrier can avoid described compound to eliminate rapidly from described body, makes for example a kind of controlled release preparation, comprises and implanting and the microcapsules delivery system.Can use the polymer of biodegradability, biological compatibility, wherein said polymer is ethylene vinyl acetate for example, poly-acid anhydrides, polyglycolic acid, collagen, poe, and PLA.Method for the preparation of such preparation will be apparent to those skilled in the art.Described raw material can be bought acquisition from Alza company and Nova (Novartis) drugmaker equally.Can utilize equally liposome suspension (comprising that with the liposome of infected cell as target, wherein said infected cell is with the monoclone antibody for viral antigen) to use as the acceptable carrier of medicine.Such liposome suspension can prepare according to method known to those skilled in the art, and described known method for example is, according to the method described in the U.S. Patent No. 4522811.
For the ease of using and the homogeneous of preservation dose, be particularly advantageous with the form preparation Orally administered composition of dosage device.Employed dosage unit form refers to physically discontinuous unit from the form of integral dose to the host who receives treatment that provide with is provided in the present invention; The reactive compound that contains predetermined amount in each unit, described amount are the amounts that can together generate with the pharmaceutical carrier of described needs desired result for the treatment of through calculating.The concrete specification of dosage unit form of the present invention determines and directly depends on following factors by following factor: the peculiar property that described reactive compound has and the described specific result for the treatment of that will reach, and will a kind of like this reactive compound for the composition restriction intrinsic to the treatment of described individuality itself.
Described pharmaceutical composition can be accommodated in container with using specification, parcel is perhaps in the distributor.
The preparation that contains the pharmaceutical composition of reactive compound is known in the described field, and for example, by mixing, granulation perhaps forms the process of tablet.Described active treatment composition usually with the pharmacology acceptability and mix with excipient that described active component has a compatibility.Orally administered in order to carry out, described active agent is used for realizing that with usual the additive of this purpose mixes, wherein said additive is solvent for example, stabilizing agent, perhaps inert diluent, and utilize usual method to convert it into the form that is fit to use, tablet for example, coated tablet, hard gel capsule or soft gel capsule, the aqueous solution, alcoholic solution or oil solution and the similar type of describing in detail hereinbefore.
Be lower than the dosage that can in described patient body, cause toxicity for the dosage of the described compound that described patient uses.In some embodiments, being lower than for the dosage of the described compound that described patient uses can be so that the concentration of the described compound in described patient's blood plasma equals or is higher than the dosage of the toxic level of described compound.The concentration that preferably, will be present in the described compound in described patient's the blood plasma maintains about 10 and receives and rub.The concentration that in one embodiment, will be present in the described compound in described patient's the blood plasma maintains about 25 and receives and rub.The concentration that in one embodiment, will be present in the described compound in described patient's the blood plasma maintains about 50 and receives and rub.The concentration that in one embodiment, will be present in the described compound in described patient's the blood plasma maintains about 100 and receives and rub.The concentration that in one embodiment, will be present in the described compound in described patient's the blood plasma maintains about 500 and receives and rub.The concentration that in one embodiment, will be present in the described compound in described patient's the blood plasma maintains about 1000 and receives and rub.The concentration that in one embodiment, will be present in the described compound in described patient's the blood plasma maintains about 2500 and receives and rub.The concentration that in one embodiment, will be present in the described compound in described patient's the blood plasma maintains about 5000 and receives and rub.In practice of the present invention, will depend on the type of the cancer that employed specific compound and needs are treated for the optimal dose of the described compound that described patient uses.
Definition
What hereinafter list is to be used to describe the definition that various different terms of the present invention have.Unless in concrete situation, carry out other restriction, these definition will be applied in whole specification and claim in employed these terms, no matter described term be separately with or use as the part in the larger phrase.
" aliphatic group " or " aliphatic " is a kind of nonaromatic half family, it can be saturated (for example, singly-bound) or contain one or more unsaturated unit, for example, two keys and/or triple bond.An aliphatic group can be straight chain, side chain or ring-type, contain carbon, hydrogen or optional contains one or more hetero atom and it can be substituted or unsubstituted.When being used as a kind of attachment, aliphatic group preferably have about 1 to about 24 atoms, what be more preferably has about 4 what be more preferably has about 4-12 atom to about 24 atoms, more typically has about 4 about 8 atoms extremely.When being used as a kind of substituting group, aliphatic group preferably have about 1 to about 24 atoms, what be more preferably has about 1 what be more preferably has about 1-8 atom to about 10 atoms, more typically has about 1 about 6 atom extremely.Except aliphatic hydrocarbon groups, aliphatic group comprises, for example, poly-alkoxyalkyl, polyalkylene glycols for example, polyamine class, and poly-imines class, for example.Such aliphatic group can be further substituted.Should be understood that aliphatic group can be included in alkyl described in the present invention, substituted alkyl, thiazolinyl, substituted thiazolinyl, alkynyl, substituted alkynyl group.
Described term " substituted carbonyl " comprises such compound and half family, contains a carbon in described compound and half family, and described carbon is connected with an oxygen atom by two keys, and the tautomeric form of above-mentioned half family.The example that contains half family of a substituted carbonyl comprises aldehydes, ketone, and carboxylic acid, amide-type, the ester class, the acid anhydride class, etc.Described term " carbonyl half family " for example refers to the such group of " alkyl-carbonyl " group, one of them alkyl group is combined on the carbonyl group in the mode of covalency, " alkenyl carbonyl " group, one of them alkenyl group is combined on the carbonyl group in the mode of covalency, " alkynyl carbonyl " group, one of them alkynyl group is combined on the carbonyl group in the mode of covalency, " aryl carbonyl " group, one of them aromatic yl group is combined on the described carbonyl group in the mode of covalency.Further, described term refers to such group equally, and one or more hetero atom is combined in described carbonyl half family in the mode of covalency.For example, described term comprises half such family, for example, amino carbonyl half family (one of them nitrogen-atoms is combined on the carbon that described carbonyl group has, for example, and a kind of acid amides).
Described term " acyl group " refers to the carbonyl group that is replaced by following radicals: hydrogen, alkyl, saturated cycloalkyl fractional saturation or complete, saturated heterocycle fractional saturation or complete, aryl, and iso-aryl.For example, acyl group comprises routine group described as follows: (C 1-C 6) silane alcohol base (for example, formoxyl, acetyl group, propiono, bytyry, valeryl, caproyl, tert-butyl group acetyl group, etc.), (C 3-C 6) naphthene base carbonyl (for example, cyclopropyl carbonyl, cyclobutyl carbonyl; cyclopentylcarbonyl, cyclohexyl-carbonyl, etc.); heterocycle carbonyl (for example, pyrrolidinyl carbonyl, 2-Pyrrolidone-5-carbonyl; piperidino carbonyl; piperazinyl carbonyl, the tetrahydrofuran base carbonyl, etc.); aroyl (for example; benzoyl) and different aroyl (for example, sulfenyl phenyl-2-carbonyl, sulfenyl phenyl-3-carbonyl; furyl-2-carbonyl; furyl-3-carbonyl, 1H-pyrrole radicals-2-carbonyl, 1H-pyrrole radicals-3-carbonyl; benzo [b] sulfenyl phenyl-2-carbonyl, etc.).In addition, the alkyl in the described carboxyl groups, cycloalkyl, heterocycle, aryl and iso-aryl part can be at each of above-mentioned group any group described in self-defined.When being represented as " optional substituted "; described carboxyl groups can be unsubstituted or optional (typical by one or more substituting group; one to three substituting group) replaces; wherein said substituting group independently is selected from substituting group group listed in the following definition for " substituted " separately; the perhaps alkyl in the described carboxyl groups; cycloalkyl; heterocycle; aryl and iso-aryl part can be substituted, and wherein said replacement is according to above respectively at substituent preference lists and more preferably described in the tabulation.
Described term " alkyl " has comprised and had Linear-free base or a side chain free radical to about 20 carbon atoms, and is perhaps preferred, has one to Linear-free base or the side chain free radical of about 12 carbon atoms.The alkyl diradical that is more preferably is that " " free radical, described free radical have one to about ten carbon atom to low alkyl group.Most preferably has one to the low alkyl group free radical of about eight carbon atoms.The example of such free radical comprises methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, isopentyl, hexyl and similar free radical.
Described term " thiazolinyl " has comprised two Linear-free base or side chain free radicals to about 20 carbon atoms with at least one carbon-to-carbon double bond, perhaps preferred, have two to Linear-free base or the side chain free radical of about 12 carbon atoms.The alkenyl radical that is more preferably is " low-grade alkenyl " free radical, described free radical have two to about ten carbon atoms and having of being more preferably about two to about eight carbon atoms.The example of alkenyl radical comprises vinyl, pi-allyl, acrylic, cyclobutenyl and 4-methyl butene base.Described term " thiazolinyl " and " low-grade alkenyl " comprise the free radical with " cis " and " trans " direction or " E " and " Z " direction.
Described term " alkynyl " has comprised two Linear-free base or side chain free radicals to about 20 carbon atoms with at least one carbon-to-carbon triple bond, perhaps preferred, have two to Linear-free base or the side chain free radical of about 12 carbon atoms.The alkynyl free radical that is more preferably is " low-grade alkynyl " free radical, described free radical have two to about ten carbon atoms and having of being more preferably about two to about eight carbon atoms.The example of alkynyl free radical comprises propargyl, 1-propinyl, 2-propynyl, 1-butine, 2-butynyl and 1-pentynyl.
Described term " cycloalkyl " has comprised and has had three saturated isocyclic free radicals to about 12 carbon atoms.Described term " cycloalkyl " has comprised and has had three saturated isocyclic free radicals to about 12 carbon atoms.The cyclic alkyl radical that is more preferably is " low-grade cycloalkyl " free radical, and described free radical has three to about eight carbon atoms.The example of such free radical comprises cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.
Described term " cycloalkenyl group " has comprised and has had three undersaturated isocyclic free radicals of the part to 12 carbon atoms.Contain the undersaturated isocyclic free radical of part of two two keys (can be or be not conjugation), such cycloalkenyl group free radical can be called " ring alkylidene ".The cycloalkenyl group free radical that is more preferably is " lower alkenyl ring " free radical, and described free radical has four to about eight carbon atoms.The example of such free radical comprises the cyclobutane base, cyclopentenyl and cyclohexenyl group.
Described term " alkoxyl " has comprised and has had one to the linearity of about 20 carbon atoms or the free radical that contains aerobic of side chain, wherein each contains in the free radical of aerobic and contains moieties, perhaps preferred, it has one to about 12 carbon atoms.The alkoxy radical that is more preferably is " lower alkoxy " free radical, described free radical have one to about ten carbon atom and be more preferably have one to about eight carbon atoms.The example of such free radical comprises methoxyl group, ethyoxyl, propoxyl group, butoxy and tert-butoxy.
Described term " alkoxyalkyl " has comprised the alkyl diradical with one or more alkoxy radical, wherein said alkoxy radical has occured to be connected with described alkyl diradical, so, monoalkoxy alkyl diradical and dialkoxy alkyl diradical have been formed.
The described term " aryl " that is used singly or in combination refers to and contains one, the aromatic ring carbon system of two or three rings, wherein said ring can link together in a kind of uncertain mode, perhaps can be thick and.Described term " aryl " has comprised the aromatic series free radical, for example phenyl, naphthyl, tetralyl, indanyl and diphenyl.
Described term " heterocyclic radical (heterocyclyl) ", " heterocycle (heterocycle) " " heterocycle (heterocyclic) " or " heterocycle is (heterocyclo) also " comprised contain heteroatomic saturated, part is undersaturated and undersaturated annular free radical, it also can be called " Heterocyclylalkyl " accordingly, " heterocycloalkenyl " and " iso-aryl ", wherein said hetero atom can be selected from nitrogen, sulphur and oxygen.The example of saturated Heterocyclylalkyl free radical comprises heteromonocyclic group group saturated, that contain 3 to 6 members, contain in the described heteromonocyclic group group 1 to 4 nitrogen-atoms (for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.); 1 to 2 oxygen atom and 1 to 3 nitrogen-atoms (for example, morpholinyl, etc.) are contained in heteromonocyclic group group saturated, that contain 3 to 6 members in the described heteromonocyclic group group; 1 to 2 sulphur atom and 1 to 3 nitrogen-atoms (for example, thiazolyl, etc.) are contained in heteromonocyclic group group saturated, that contain 3 to 6 members in the described heteromonocyclic group group.The example of the undersaturated Heterocyclylalkyl free radical of part comprises dihydro-thiophene, dihydropyran, dihydrofuran and thiazoline.The Heterocyclylalkyl free radical can comprise the nitrogen of a pentavalent, for example in tetrazolium and pyridine radical.Described term " heterocycle " comprise equally those and aryl free radical or cyclic alkyl radical occur thick and the Heterocyclylalkyl free radical.Like this thick and the example of dicyclo free radical comprise benzofuran, benzothiophene, and similar free radical.
Described term " iso-aryl " has comprised undersaturated heterocycle free radical.1 to 4 nitrogen-atoms is contained in the described heteromonocyclic group group in the heteromonocyclic group group that the example of iso-aryl free radical comprises is undersaturated, contain 3 to 6 members, for example, and pyrrole radicals, pyrrolinyl, imidazole radicals, pyrazolyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, triazolyl (for example, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazole radical is (for example, the 1H-TETRAZOLE base, the 2H-tetrazole radical, etc.), etc.; Undersaturated, thick and heterocycloalkyl, contain 1 to 5 nitrogen-atoms in the described heterocycloalkyl, for example, indyl, isoindolyl, indoline base, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, the BTA base, the tetrazole radical pyridazinyl is (for example, tetrazole radical [1,5-b] pyridazinyl, etc.), etc.; Undersaturated, as to contain 3 to 6 members heteromonocyclic group group, described heteromonocyclic group contains 1 oxygen atom in rolling into a ball, for example, and pyranose, furyl, etc.; Undersaturated, as to contain 3 to 6 members heteromonocyclic group group, described heteromonocyclic group contains 1 sulphur atom in rolling into a ball, for example, thienyl, etc.; Undersaturated, as to contain 3 to 6 members heteromonocyclic group group, described heteromonocyclic group contains 1 to 2 oxygen atom and 1 to 3 nitrogen-atoms in rolling into a ball, for example, oxazolyl, isoxazolyl, the oxadiazole base is (for example, 1,2,4-oxadiazole base, 1,3,4-oxadiazole base, 1,2,5-oxadiazole base, etc.) etc.; Undersaturated, thick and heterocycloalkyl, contain in the described heterocycloalkyl 1 to 2 oxygen atom and 1 to 3 nitrogen-atoms (for example, benzoxazolyl, benzo oxadiazole base, etc.); Undersaturated, as to contain 3 to 6 members heterocycloalkyl contains 1 to 2 sulphur atom and 1 to 3 nitrogen-atoms in the described heterocycloalkyl, for example, thiazolyl, thiadiazolyl group are (for example, 1,2,4-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, 1,2,5-thiadiazolyl group, etc.) etc.; Undersaturated, thick and heterocycloalkyl, contain in the described heterocycloalkyl 1 to 2 sulphur atom and 1 to 3 nitrogen-atoms (for example, benzothiazolyl, the diazosulfide base, etc.) and similar group.
Described term " Heterocyclylalkyl " has comprised the alkyl diradical with heterocyclic substituted.The Heterocyclylalkyl free radical that is more preferably is " rudimentary Heterocyclylalkyl " free radical, wherein has one to six carbon atom in described heterocycle free radical.
Described term " alkyl sulfenyl " has comprised and has had one to free radical about ten carbon atoms, that contain the alkyl diradical of a linearity or side chain, and wherein said alkyl diradical is connected with the sulphur atom of a divalence.Contained alkyl diradical has one to about 20 carbon atoms in the preferred alkyl sulfenyl free radical, and is perhaps preferred, and it has one to about 12 carbon atoms.The alkyl sulfenyl free radical that contains alkyl diradical that is more preferably is " low alkyl group sulfenyl " free radical, and described free radical has one to about ten carbon atom.Most preferred alkyl sulfenyl free radical is to have one to the alkyl sulfenyl free radical of the low alkyl group free radical of about eight carbon atoms.The example of such low alkyl group sulfenyl free radical is the methyl sulfenyl, ethyl sulfenyl, propyl group sulfenyl, butyl sulfenyl and hexyl sulfenyl.
Described term " aralkyl " or " aryl alkyl " have comprised the alkyl diradical with aryl substituent, benzyl for example, diphenyl methyl, trityl group, phenylethyl, and diphenyl-ethyl.
Described term " aryloxy group " has comprised by the aryl free radical that oxygen atom is connected with other free radical.
Described term " aralkoxy " or " alkoxy aryl " have comprised by the arylalkyl radical that oxygen atom is connected with other free radical.
Described term " aminoalkyl " has comprised the alkyl diradical with amino radical replacement.In the preferred aminoalkyl free radical contained alkyl diradical have about one to about 20 carbon atoms, perhaps preferred, have one to about 12 carbon atoms.The aminoalkyl free radical that is more preferably is " rudimentary aminoalkyl ", and the contained alkyl diradical of described free radical has one to about ten carbon atom.The aminoalkyl free radical that most preferably contains the low alkyl group free radical, wherein said low alkyl group free radical have one to eight carbon atom.The example of such free radical comprises amino methyl, amino-ethyl, and similar free radical.
What described term " alkyl amino " represented is to have the amino group that one or two alkyl diradicals replace.In the preferred alkylamino radical contained alkyl diradical have about one to about 20 carbon atoms, perhaps preferred, have one to about 12 carbon atoms.The alkylamino radical that is more preferably is " low-grade alkyl amino ", and contained alkyl diradical has one to about ten carbon atom in the described free radical.The alkylamino radical that most preferably contains the low alkyl group free radical, wherein said low alkyl group free radical have one to about eight carbon atoms.Suitable low-grade alkyl amino can be mono-substituted N-alkyl amino to occur or dibasic N occurs, N-alkyl amino, N-methylamino for example, N-ethylamino, N, N-dimethylamino, N, N-diethylamino or similar free radical.
Described term " attachment (linker) " refers to two-part organic half family that connects a compound.Attachment generally comprises a direct key or atom for example oxygen atom or sulphur atom, and unit is NR for example 8, C (O), C (O) NH, SO, SO 2, SO 2NH or a series of atom, substituted or unsubstituted alkyl for example, substituted or unsubstituted thiazolinyl, substituted or unsubstituted alkynyl, aryl alkyl, aryl alkenyl, aromatic yl polysulfide yl, iso-aryl alkyl, iso-aryl thiazolinyl, the iso-aryl alkynyl, Heterocyclylalkyl, heterocycloalkenyl, the heterocycle alkynyl, aryl, iso-aryl, heterocycle, cycloalkyl, cycloalkenyl group, the alkylaryl alkyl, alkylaryl thiazolinyl, alkylaryl alkynyl, the alkenyl aryl alkyl, the alkenyl aryl thiazolinyl, alkenyl aryl alkynyl, alkynyl aryl alkyl, the alkynyl aryl alkenyl, the alkynyl aromatic yl polysulfide yl, alkyl iso-aryl alkyl, alkyl iso-aryl thiazolinyl, alkyl iso-aryl alkynyl, thiazolinyl iso-aryl alkyl, thiazolinyl iso-aryl thiazolinyl, thiazolinyl iso-aryl alkynyl, alkynyl iso-aryl alkyl, alkynyl iso-aryl thiazolinyl, alkynyl iso-aryl alkynyl, alkyl heterocycle alkyl, the alkyl heterocycle thiazolinyl, the alkyl heterocycle alkynyl, thiazolinyl Heterocyclylalkyl, thiazolinyl heterocycloalkenyl, thiazolinyl heterocycle alkynyl, the alkynyl Heterocyclylalkyl, alkynyl heterocycloalkenyl, alkynyl heterocycle alkynyl, alkylaryl, alkenyl aryl, alkynyl aryl, alkyl iso-aryl, the thiazolinyl iso-aryl, the alkynyl iso-aryl, one or more methylene can be blocked or stop by following radicals: O, S, S (O), SO 2, N (R 8), C (O), substituted or unsubstituted aryl, substituted or unsubstituted iso-aryl, substituted or unsubstituted heterocycle; R wherein 8Hydrogen, acyl group, aliphatic or substituted aliphatic.In one embodiment, described attachment B has 1-24 atom, preferably has 4-24 atom, preferably has 4-18 atom, and what be more preferably has a 4-12 atom, and highly preferredly has about 4-10 atom.In some embodiments, described attachment is C (O) NH (alkyl) chain or oxyalkyl chain.Should be understood that, a kind of asymmetric attachment, for example a kind of alkylaryl can connect distinct half family on two structures with the form in its two kinds of orientation that may have.
Described term " substituted " refers to one of the substituting group radical pair that uses appointment and substitutes to one or more hydroperoxyl radical in the fixed structure, and the substituting group free radical of wherein said appointment includes, but are not limited to: halogen, alkyl; thiazolinyl, alkynyl, aryl, heterocycle; sulfenyl, alkyl sulfenyl, artyl sulfo, alkyl sulfenyl alkyl; the artyl sulfo aryl, alkyl sulphonyl, alkyl sulphonyl alkyl, aryl sulfonyl alkyl; alkoxyl, aryloxy group, alkoxy aryl, amino carbonyl; alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkoxy carbonyl, aryloxycarbonyl; the halogen alkyl, amino, trifluoromethyl, cyano group; nitro, alkyl amino, arylamino; the alkyl amino alkyl, the arylamino alkyl, aminoalkyl is amino; hydroxyl, alkoxyalkyl, carboxyalkyl; alkoxy carbonyl alkyl, amino carbonyl alkyl, acyl group; aryl-alkoxy carbonyl, carboxylic acid, sulfonic acid; sulfonyl, phosphonic acids, aryl; iso-aryl, heterocycle, and aliphatic.Can be understood that further replacement can occur described substituting group.
For easy purpose, chemistry that be defined and indication half family can be chemistry half family (for example, alkyl, the aryl of unit price in suitable structure situation, etc.) or half family of multivalence, wherein said suitable structure situation is that those skilled in the art understand.For example, " alkyl " half family can refer to free radical (for example, the CH of a unit price 3-CH 2-), perhaps in other situation, " alkyl " can be connection half family of a divalence, in this case those skilled in the art can understand the free radical that described alkyl is a kind of divalence (for example ,-CH 2-CH 2-), it is equivalent to described term " thiazolinyl ".Similarly, divalence half family need to appear and described divalence half family is called as " alkoxyl ", " alkyl amino " at some, " aryloxy group ", " alkyl sulfenyl ", " aryl ", " iso-aryl ", " heterocycle ", " alkyl ", " thiazolinyl ", " alkynyl ", " aliphatic ", perhaps in the situation of " cycloalkyl ", those skilled in the art can understand described term " alkoxyl ", " alkyl amino ", " aryloxy group ", " alkyl sulfenyl ", " aryl ", " iso-aryl ", " heterocycle ", " alkyl ", " thiazolinyl ", " alkynyl ", " aliphatic ", perhaps " cycloalkyl " refers to corresponding described divalence half family.
When being carried out use in the present invention, described term " halogen " refers to and is selected from fluorine, chlorine, the atom of bromine and iodine.
When being carried out use in the present invention, described term " abnormality proliferation " refers to unusual Growth of Cells.
Described term " attached treatment " has comprised the treatment of using reagent that the host is carried out, wherein said reagent can alleviate or avoid the side effect relevant with the combined therapy described in the present invention, described reagent comprises, but be not limited to, for example those can alleviate the reagent of the toxic action that described anticancer medicine has, for example, bone resorption inhibitor, Cardioprotective reagent; Can prevent or alleviate the reagent of the incidence of feeling sick and vomitting relevant with chemotherapy, radiation treatment or operation; Perhaps can alleviate the reagent with the incidence of using relevant infection of bone marrow suppression anticancer medicine.
When being carried out use in the present invention; described term " Apoptosis " refers to the death of program cell; wherein said death is that the cell nucleus by the human cell with normal function and zooblast sends signal, and sending of described signal is that health and illness situation by age of cell or cell is specified." apoptosis-inducing reagent " can trigger the death process of described program cell.
When being carried out use in the present invention, described term " cancer " expression be one type disease or obstacle, the ability that it is characterized in that the out of control of Cell Differentiation and these its hetero-organizations of cell invasion, described invasion and attack refer to these cells and directly grow in contiguous tissue by the invasion and attack effect, and perhaps these cells are implanted in the site of far-end by transferance.
Described term " compound " is defined as comprising the acceptable salt of pharmacology of the compound with structural formula listed among the present invention, solvate, hydrate in the present invention, polymorph, enantiomter, diastereoisomer, racemic mixture and similar form.
Described term " device " refers to the arbitrarily utensil that is designed to finish a kind of specific function, and described utensil is normally mechanical or electric.
When being carried out in the present invention when using, described term " dysplasia " refers to unusual Growth of Cells, and generally refers to the premalignant lesion of the earliest form that the pathologist can identify in tissue biopsy.
When being carried out use in the present invention, described term " effective dose of described motif compound " is when being used to described theme methods for the treatment of, refer to such dosage that described motif compound has: when it is sent as the part in the dosage of expectation, it can bring change for the differentiation state of for example described cell proliferation speed and/or cell and/or the survival speed of cell, makes it reach the standard of clinical acceptability.This dosage may further be alleviated one or more symptoms in the described neoplasia obstacle to a certain extent, and described alleviation includes, but are not limited to: the quantity that 1) reduces described cancer cell; 2) reduce the size of tumour; 3) suppress the infiltration of (that is, slow down to a certain extent, preferably stop) cancer cell in the peripheral organ; 4) transfer of inhibition (that is, slow down to a certain extent, preferably stop) tumour; 5) suppress to a certain extent the growth of tumour; 6) alleviate to a certain extent or alleviate one or more symptoms relevant with described obstacle; And/or 7) alleviate or alleviate the side effect relevant with using of described anticancer reagent.
When being carried out use in the present invention, described term " hyper-proliferative " refers to excessive Cell Differentiation or growth.
Described term " immunization therapy reagent " refers to by the inoculation effect immunity of immune donor is transferred to the employed reagent of host, and wherein said immune donor for example is, another one people or animal.Described term has comprised the use of following substances: contain serum or the gamma Globulin of carrying out antibody, wherein said execution antibody is individual or zoogenic by another one; Non-specific systematicness stimulates; Adjuvant; Active specific active immunotherapy; And passive (adoptive) immunization therapy.Passive immunization therapy refers to the treatment of disease being carried out by methods for the treatment of or reagent, described treatment comprise sensitized lymphocyte, transfer factor, immune ribonucleic acid or be present in serum or gamma Globulin in the host inoculation of antibody.
In the situation of the growth of the growth of neoplasia, tumour or tumour cell, can by following aspect to described term " inhibition " estimate: except other situations, the delay of the appearance of primary tumor or inferior natural disposition tumour, slowing down of the formation of primary tumor or inferior natural disposition tumour, the reduction of the incidence of disease of primary tumor or inferior natural disposition tumour, the slowing down or alleviate of the seriousness of the secondary effect of disease, the stopping and the decline of tumour of tumor growth.In extreme situation, suppress fully, refer in the present invention prevention or chemoproection.
When being carried out use in the present invention, described term " transfer " refers to the migration that described cancer cell occurs via blood and lymphatic ducts from described original tumor sites, thereby forms cancer in other tissue.Shift and also be used to describe time natural disposition cancer in the growth of a far-end site.
When being carried out use in the present invention, described term " excrescence " refers to the abnormal mass of the tissue that is produced by excessive Cell Differentiation.Excrescence can be optimum (not belonging to carcinous) or pernicious (carcinous) and can be called tumour.Described term " neoplasia " is to cause swollen neoplastic pathological process.
When being carried out use in the present invention, described term " before the cancer " refers to so a kind of situation: described situation is not pernicious, if but it is not treated, it has becomes pernicious possibility.
Described term " propagation " refers to the mitotic cell of experience.
Described term " disease or the obstacle relevant with phosphoinositide 3 (PI3) kinases " refers to disease or obstacle take the kinase whose activity of inappropriate phosphoinositide-3-as feature or disease or obstacle take the kinase whose overactivity of phosphoinositide-3-(perhaps excessive activation) as feature.Inappropriate activity refers to any in the following situation: (i) do not express under normal circumstances the kinase whose expression of phosphoinositide 3 (PI3) has occured in the kinase whose cell of phosphoinositide 3 (PI3); (ii) the kinase whose expression of phosphoinositide 3 (PI3) that increases, described expression have caused the cell proliferation do not expected, differentiation and/or growth; Perhaps (iii) kinase whose expression of phosphoinositide 3 (PI3) of reducing, described expression have caused the cell proliferation do not expected, the minimizing of differentiation and/or growth aspect.The kinase whose overactivity of phosphoinositide 3 (PI3) refers to the amplification of the kinase whose gene of coding a kind of specific phosphoinositide 3 (PI3), perhaps to a certain degree the generation of phosphoinositide 3 (PI3) kinase activity, the kinase whose activity of wherein said phosphoinositide 3 (PI3) may with a kind of cell proliferation, there are association in differentiation and/or growth disorder (namely, when the kinase whose degree of described phosphoinositide 3 (PI3) increased, the order of severity of one or more symptoms of described cell obstacle increased).
Described term " radiation treatment reagent " refers to employed electromagnetic radiation thing or corpuscular radiation thing in neoplastic treatment.
When being carried out use in the present invention, described term " recurrence " refers to described cancer in the reduction after rehabilitation after a while.This may be owing to not removing the cell that comes from the described initial cancer fully, and the possibility of result as transfer (near initial cancer, may be present in described lymph node or the tissue) and/or the far-end generation in local (site identical with initial cancer), zone.
Described term " treatment " refers to any process, effect, use, treatment, perhaps similarly behavior, wherein make the mammal relief that is medically treated in the behavior of even number, its purpose is directly or indirectly to improve described mammiferous illness, and wherein said mammal comprises the mankind.
Described term " vaccine " comprises that the immune system that can induce described patient produces the reagent for the immune response of described tumour, and wherein said reagent is by the cell of expressing tumor related antigen (through the electro photoluminescence of skin acupuncture point) is attacked to realize inducing.
When being carried out use in the present invention, described term " the acceptable salt of pharmacology " refers to such salt, they are present within the scope of rational medical judgment, unsuitable toxicity is used and can not produced to suitable the contact with described human tissue and zootic tissue, excitant, hypersensitivity is replied and similar phenomenon, and has the interests that match/risk ratio.The acceptable salt of pharmacology is well known in the art.For example, the people (in 1977) such as S.M.Berge is described in detail the acceptable salt of pharmacology in the article that J.Pharmaceutical Sciences " pharmaceutical science magazine " 66:1-19 delivers.Prepare in position described salt in the process of the final separation of described compound and purifying in the present invention, perhaps by described free radical functional group is reacted to prepare described salt with a kind of suitable organic acid or inorganic acid separately.The example of the non-toxic acid addition salts of pharmacology acceptability includes, but are not limited to, the salt that is formed by amino group and inorganic acid or the salt that forms with organic acid or the salt that forms by employed additive method in this area, the method of ion exchange for example, wherein said inorganic acid are hydrochloric acid for example, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, described organic acid are acetic acid for example, maleic acid, tartaric acid, citric acid, succinic acid, lactobionic acid or malonic acid.The acceptable salt of other pharmacology includes, but are not limited to adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, disulfate, borate, butyrate, camphorate, camsilate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethane sulfonate, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2-hydroxyl-ethane sulfonate, Lactobionate, lactate, laruate, sulfated lauryl alcohol, malate, maleate, malonate, methane sulfonates, 2-naphthyl sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, embonate, pectate, persulfate, 3-phenylpropionic acid salt, phosphate, picrate, pivalate, propionate, stearate, succinate, sulphate, tartrate, rhodanate, tosilate, undecylate, valerate, and similar salt.Representational alkali metal salt or alkali salt comprise sodium salt, lithium salts, sylvite, calcium salt, magnesium salts, and similar salt.Further the acceptable salt of medicine comprises, when in place, and nontoxic ammonium salt, quaternary ammonium salt, and the amine cationic salts that uses counter ion counterionsl gegenions to form, halide for example, hydroxide, carboxylate, sulphate, phosphate, citrate, alkyl, sulfonate and arylsulphonate with 1 to 6 carbon atom.
When being carried out use in the present invention, described term " pharmacology acceptable ester " refers to the ester that is hydrolyzed in vivo, thereby and comprises that those can be easy to be decomposed leave the ester of described maternal compound or its salt in described human body.The ester group that is fit to comprises that for example, those come from the ester of the fatty acid carboxylate of pharmacology acceptability, particularly alkanoic acid, alkenoic acid, and loop chain alkanoic acid and alkanedioic acid, wherein each favourable having of alkyl half family or thiazolinyl half family is no more than 6 carbon atoms.The example of concrete ester includes, but are not limited to, formic acid esters, acetate, propionic ester, butyrate, acrylate and ethyl succinate.
When being carried out use in the present invention, described term " pro-drug of pharmacology acceptability " refers to the pro-drug that the compound described in the present invention has, described pro-drug is present within the scope of rational medical judgment, unsuitable toxicity is used and can not produced to suitable the contact with described human tissue and zootic tissue, excitant, hypersensitivity is replied and similar phenomenon, has rational interests/risk ratio, and can effectively be used for their set purposes, under possible situation, described pro-drug comprises the zwitterionic form of compound described in the present invention equally.When being carried out use in the present invention, " pro-drug " refers to a kind of like this compound, and described compound can be converted into the compound described in the present invention in vivo by the mode (for example, passing through hydrolysis) of metabolism.The various form that pro-drug has is known in the art, for example, discusses in following article: the Design of Prodrugs of Bundgaard (in 1985) (editor) " pro-drug design ", Elsevier; The people's such as Widder (in 1985) (editor) Methods in Enzymology " Enzymology method " the 4th volume, Academic Press (academic press); The people's such as Krogsgaard-Larsen (in 1991) (editor) " Design and Application of Prodrugs " design of pro-drug and application " ", Textbook of Drug Design and Development " drug design and research and development handbook the 5th chapter, 113-191; The article that the people such as Bundgaard (in 1992) deliver in Journal of Drug Deliver Reviews " drug delivery review " 8:1-38; Bundgaard (in 1988) is at J.of Pharmaceutical Sciences " pharmaceutical science magazine " 77:285 and the article delivered in (et seq) thereafter; The Prodrugs as Novel Drug Delivery Systems " as the pro-drug of new drug delivery system " of Higuchi and Stella (in 1975) (editor), American Chemical Society (American Chemical Society); And Bernard Testa﹠amp; " the Hydrolysis In Drug And Prodrug Metabolism:Chemistry; Biochemistry And Enzymology " chemistry; the drug hydrolysis on biochemistry and the zymetology and the metabolism of pro-drug " " that Joachim Mayer (in 2002) delivers, John Wiley and Sons, Ltd.
When being carried out use in the present invention, " the acceptable carrier of pharmacology " is intended to comprise arbitrarily and whole solvents, dispersion medium, coating, antibacterium reagent and antifungal agents, equipressure and absorption delay reagent, and similarly and medicine use the carrier with compatibility, for example aseptic water that does not contain pyrogen.In " the Lei Mingdun pharmaceutical science " of latest edition (Remington ' s Pharmaceutical Sciences), the carrier that is fit to is described, " Lei Mingdun pharmaceutical science " is the canonical reference handbook in affiliated field, and above-mentioned handbook is introduced into as a reference in the present invention.The preferred example of such carrier or thinner includes, but are not limited to, water, and physiological saline, Luo Geshi solution (Ringer ' s solution), dextrose solution, and 5% human serum albumin.Liposome and non-aqueous solvent for example fixed oil are operable equally.Such medium and the reagent purposes in the pharmacologic activity material is well known in the art.Except with the scope of the inconsistent medium of described reactive compound or reagent, the medium of any routine or the reagent purposes in described composition all can be expected.Attached reactive compound can be directed among the described composition equally.
When being carried out in the present invention when using, described term " before the cancer " refers to so a kind of situation: described situation is not pernicious, if but it is not treated, it has and becomes pernicious possibility.
When being carried out use in the present invention, described term " host " refers to a kind of animal.Preferably, described animal is a kind of mammal.Be more preferably, described mammal is human.The host refers to equally, for example, and dog, cat, horse, cow, pig, cavy, fish, bird and similar host.
Can modify the compound described in the present invention by the mode of adding suitable functional group, thereby the selectivity organism that strengthens described compound is learned character.Such modification is known in the art and may comprises that those to a given biology system (for example can increase, blood, lymphatic system, central nervous system) biology permeability, increase oral availability, increase and allow to allow to inject the dissolubility of using, the modification that changes metabolism and change discharge rate.
The described compound that is synthesized can be separated from a kind of reactant mixture and by column chromatography for example, the method for high performance liquid chromatography or recrystallization is carried out further purifying to it.As those skilled in the art can be cognitive, will be apparent for those of ordinary skills for the synthesis of the further method of the compound with structural formula described in the present invention.In addition, can finish described various synthesis step with a kind of order that replaces or order, thereby obtain desired compound.For the synthesis of the synthetic chemistry conversion of described compound and the method (protect and go and protect) of blocking group are known in the art and comprise in the present invention, for example, the Comprehensive Organic Transformations " widely organo-functional group conversion " that described in following article those: R.Larock (in 1989) delivers, VCH publishing house; The Protective Groups in Organic Synthesis " the protectiveness group in the organic synthesis " that T.W.Greene and P.G.M.Wuts (in 1991) deliver, second edition, John Wiley and Sons; Fieser and Fieser ' the s Reagents for Organic Synthesis that L.Fieser and M.Fieser (in 1994) deliver " expense million and the organic synthesis reagent that takes million ", John Wiley and Sons; And L.Paquette (in nineteen ninety-five) editor's Encyclopedia of Reagents for Organic Synthesis " organic synthesis reagent encyclopedia ", John Wiley and Sons, and version subsequently.
Described compound contains one or more symmetrical centre and enantiomter therefore occurred in the present invention, diastereoisomer, and other stereoisomeric forms in any ratio, above-mentioned form can be defined as according to the absolute stereo chemistry (R)-or (S)-, perhaps be defined as (D)-amino acid or (L)-amino acid.The invention is intended to comprise all so possible isomer, and their racemic mixtures of having and optional purified form.Can from their optical activity precursors separately, prepare optical isomer by described step above or the decomposition by described racemic mixture.Can carry out described decomposition in the situation of decomposing agents existing, wherein said decomposition is to make up to carry out by chromatographic technique or by recrystallization or by certain of these technology, and these technology are well known by persons skilled in the art.About the Enantiomers that the further details of decomposition can be delivered people such as Jacques, Racemates, and Resolutions " enantiomter, racemic modification and decomposition " (John Wiley﹠amp; Sons, 1981) in find.In the described compound of describing in the present invention, contain olefinic double bonds, other unsaturated bond, perhaps during other geometry symmetrical centre, and except as otherwise noted, it is intended to show that described compound comprises E geometric isomer and Z geometric isomer and/or cis-isomer and transisomer simultaneously.Same, all tautomeric forms are intended to be included equally.Selection for the configuration of any carbon-to-carbon double bond that occurs among the present invention only is for convenient, and and be not intended to and specify a kind of specific configuration, unless be like this statement in the literary composition; Therefore be described as trans carbon-to-carbon double bond or the two keys of carbon-hetero atom may be cis by random in the present invention, trans, or the mixture of the arbitrary proportion of above-mentioned two kinds of forms.
Pharmaceutical composition
Pharmaceutical composition described in the present invention comprises the compound described in the present invention who treats effective dose, and one or more pharmacology acceptable carrier or the excipient formulated together with described compound.
When being carried out use in the present invention, described term " the acceptable carrier of pharmacology or excipient " refers to the nontoxic of a kind of any type, the solid of inertia, semisolid or liquid filling agent, thinner, capsule material or formulation aid.Some example that can be used as the material of the acceptable carrier of pharmacology is for example lactose of sugar, glucose and sucrose; Cyclodextrin is the α cyclodextrin for example, beta cyclodextrin and γ cyclodextrin; Starch is corn starch and potato starch for example; Cellulose and derivative thereof be sodium carboxymethylcellulose for example, ethyl cellulose and cellulose acetate; Powdered tragacanth; Fructus Hordei Germinatus; Gel; Talcum; Excipient is cocoa butter and suppository wax for example; Oil is peanut oil for example, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; Glycols (glycols) is propane diols for example; The ester class is ethyl oleate and ethyl laurate for example; Agar; Buffer reagent is magnesium hydroxide and aluminium hydroxide for example; Alginic acid; The water that does not contain pyrogen; Isobaric physiological saline; Luo Geshi solution; Alcohol, and phosphate buffer, and the lubricant of other nontoxic tolerability for example sldium lauryl sulfate and dolomol, and colouring agent, releasing agent, coating agent, sweetener, flavouring agent and flavouring agent, preservative and antioxidant can be present in the described composition too, and this can be according to the judgement of described formulator.
Pharmaceutical composition described in the present invention can be used by following manner: oral, parenteral is by sucking spraying, the part is in the rectum, in the nose, in the oral cavity, use in the vagina or via the mode of implantable pump, preferably by Orally administered or use by injection.Nontoxic pharmacology acceptable carrier, adjuvant or the solvent that can contain any routine in the pharmaceutical composition described in the present invention.In some cases, can use the acceptable acid of pharmacology, alkali or buffer are adjusted the pH of described preparation, thereby strengthen the stability of described preparation compound or its delivery form.When being carried out use in the present invention, described term parenteral comprises subcutaneous, intracutaneous, and intravenous, in the muscle, in the joint, in the artery, in the synovial membrane, in the breastbone, in the sheath, focus is interior and skull is interior injection technique or integration technology.
Be used for carrying out emulsion, microemulsion, solution, suspension, syrup and the elixir that Orally administered liquid dosages form comprises the pharmacology acceptability.Except described reactive compound, described liquid dosages form can contain the inert diluent that generally uses in described field, for example, water or other solvents, solubilizer and emulsifier be alcohol for example, isopropyl alcohol, ethyl carbonate, ethyl acetic acid, phenmethylol, the phenylamino benzoic acid methyl esters, propane diols, 1, the 3-butanediol, dimethyl formamide, oil is (concrete, cotton seed oil, arachis oil, corn oil, embryo oil, olive oil, castor oil, and sesame oil), glycerine, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitol fatty acid ester, and the mixture of above-mentioned substance.Except inert diluent, can also comprise for example wetting agent of adjuvant in the described Orally administered composition, emulsifier and suspending agent, sweetener, flavouring agent, and flavouring agent.
The injection-type preparation, for example, the aseptic injection type aqueous solution or oleagenous suspension can be prepared according to the suitable dispersant of known method utilization or wetting agent and suspending agent.Described aseptic injection type preparation can also be a kind of aseptic injection-type solution, suspension or emulsion, wherein said solution, suspension or emulsion are present among a kind of thinner or solvent of nontoxic parenteral acceptability, for example, as a kind of solution of 1,3-BDO.Among the solvent and solvent of described acceptability, operable is water, Luo Geshi solution, U.S.P. and isobaric sodium chloride solution.In addition, aseptic fixed oil is carried out use as a kind of solvent or suspension media usually.In order to reach this purpose, can use the fixed oil of any gentleness, comprise synthetic monoglyceride or diglyceride.In addition, in described injection-type preparation, use for example oleic acid of fatty acid.
Described injection-type preparation can be sterilized, for example, by the filtration via bacterium Rejection filter, perhaps by importing the mode of sterilization reagent, wherein said sterilization reagent is that the form with aseptic solid composite exists, can be before using with its dissolving or be dispersed in the sterile water or in other the aseptic injection type medium.
The effect that has in order to prolong described medicine, the absorption of the medicine that usually expecting slows down comes from hypodermic injection or intramuscular injection.The making of the liquid suspension that this can be by crystal or the liquid suspension of amorphous materials realizes that the liquid suspension of wherein said crystal or the liquid suspension of amorphous materials have poor water-soluble.So, the absorption rate of described medicine depends on its rate of dissolution, and this may depend on the size of crystal and the type of crystallization then.Perhaps alternative, by with described medicine dissolving or the delay that is dispersed in the medicament forms of realizing parenteral administration in a kind of oily solvent absorb.The injection-type file layout is to prepare by the microcapsules matrix that generates described medicine in the biodegradability polymer, and wherein said biodegradability polymer is PLA-poly-Glycolic acid for example.Can control the rate of release of described medicine, wherein said rate of release depends on the ratio of medicine and polymer and the character of employed described concrete polymer.The example of other biodegradability polymer comprises poe and poly-acid anhydrides.Storage injection-type preparation can also prepare by the mode that described medicine is embedded in liposome or the microemulsion, and wherein said liposome or microemulsion and body tissue have compatibility.
Be used for carrying out using in the rectum or vagina in the composition used suppository preferably, described suppository can be by preparing the compound described in the present invention with the mode that suitable non-irritating excipient or carrier mix, wherein said excipient or carrier are cocoa butter for example, polyethylene glycol or suppository wax, they are solid at ambient temperature but are liquid under organism temperatures, and therefore described reactive compound occurs to melt and discharge in described rectal cavity or vaginal canal.
Be used for carrying out Orally administered solid dosage form and comprise capsule, tablet, pill, powder, and particle.In such solid dosage form, described reactive compound and at least a inertia, the acceptable excipient of pharmacology or carrier for example sodium citrate or Dicalcium Phosphate and/or following substances mix: a) filler or swelling agent starch for example, lactose, sucrose, glucose, mannitol, and silicic acid, b) adhesive is for example, carboxymethyl cellulose, alginates, gel, polyvinylpyrrolidone, sucrose, and gum Arabic, c) wetting agent glycerine for example, d) decomposition agent agar for example, calcium carbonate, potato starch or tapioca, alginic acid, some silicate, and sodium carbonate, e) solution retarding agent paraffin for example, f) sorbefacient quaternary ammonium compound for example, g) wetting agent for example, hexadecanol and glycerin monostearate, h) for example kaolin and bentonite of absorbent, and i) lubricant talcum for example, calcium stearate, dolomol, solid polyethylene glycol, sldium lauryl sulfate, and the mixture of above-mentioned substance.At capsule, in the situation of tablet and pill, can also comprise buffer reagent in the described dosage form.
The solid composite of similar type can also be used to wherein use such excipient in soft filling and the hard gel capsule of filling as filler: the polyethylene glycol of lactose and HMW and similar reagent.
Described tablet, dragee, capsule, pill, and the such solid dosage form of granule can be prepared with coating and shell, wherein said coating and shell are other coatings of for example knowing in casing coating and the described medicine formulation art.They can be chosen wantonly contains opacifier and it also may be so a kind of composition, described composition only or in preferential certain part in described enteron aisle discharges described active component, choose wantonly, carry out described release in a kind of mode of delay.The example of operable embedding composition comprises polymeric material and wax.
The dosage form that has for compound described in the present invention who carries out local application or transdermal administration comprises ointment, patch, creme, emulsion, gel, powder, solution, spraying, inhalant or paster agent (patch).Under aseptic condition, the acceptable carrier of described active component and pharmacology and any essential preservative or the buffer that may need are mixed.Can be contemplated that ophthalmic preparation equally, the ear dropping liquid, spongaion, powder and solution also are comprised within the scope of the present invention.
Except the reactive compound described in the present invention, described ointment, patch, can contain excipient for example animal tallow and plant fat in creme and the gel, oil, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicones, bentonite, silicic acid, talcum and zinc oxide, or the mixture of above-mentioned substance.
Except the compound described in the present invention, can contain for example lactose of excipient in powder and the spray, talcum, silicic acid, aluminium hydroxide, calcium silicates and polyamide powder, or the mixture of these materials.Can also additionally contain for example chlorine fluorohydrocarbon of conventional propellant in the spray.
Transdermal patch has extra advantage: the mode with controlled delivery provides compound to described body.Such dosage form can prepare by described compound is dissolved in or is scattered in the suitable medium.Can also increase the flux that described compound passes through described skin with sorbefacient.Mode that can be by a kind of rate controlling membranes is provided or the mode that described compound is scattered in a kind of polymer substrate or the gel controlled described speed.
In order to carry out pulmonary delivery, therapeutic composition described in the present invention is prepared and by the mode directly used the composition of solid or liquid particle form is applied to described patient, and the described mode of directly using is for example to be sucked in the described respiratory system.For solid or the liquid particle form of putting into practice the described reactive compound that the present invention prepares comprises the particulate with the size that can suck: namely, the size of particulate is enough little, can pass mouth and throat and enter into described bronchi and alveolar via the suction effect.Sending of the therapeutic agent of aerosol, particularly the antibiotic of aerosol sent, be known in the art (referring to, U.S. Patent No. 5767068 such as people such as VanDevanter, the people's such as Smith U.S. Patent No. 5508269 and the WO 98/43650 of Montgomery, above-mentioned document all is introduced into as a reference in the present invention).Discussion for antibiotic pulmonary delivery can be found in U.S. Patent No. 6014969 equally, and above-mentioned document is introduced into as a reference in the present invention.
Preferably, the treatment effective dose of the combination of compound or compound refers to a kind of like this dosage of described compound: described dosage can provide a kind of therapeutic efficiency for the described host who receives treatment, with rational interests/risk than being applied among any therapeutic treatment.
Described therapeutic efficiency can be objectively (that is, being measured by certain test or mark) or subjective (that is, providing indication or sensation for effect by the host).Above the effective dose that has of described described compound can be in about 0.1 mg/kg to the scope of about 500 mg/kg, preferably about 1 to the scope of about 50 mg/kg.Effective dose equally will be according to route of administration, and with the possibility of the common use of other reagent and change.Yet, should be understood that total usage amount will be determined by described attending doctor the every day that the compound described in the present invention and composition have in the scope of rational medical judgment.For concrete patient arbitrarily, described concrete treatment effective dose level will depend on various factor, comprise the described obstacle of receiving treatment and the order of severity of described obstacle; The activity that employed particular compound has; Employed concrete composition; Described patient's age, body weight, general health, sex and diet; The time of application of employed particular compound, route of administration, and discharge rate; The described treatment duration; Be used in combination with employed particular compound or medicine that the same time uses; And the similar factor of in described medical domain, knowing.
Every TDD that compound was had described in the present invention who uses to human or other animals with single dosage form or the dosage form that separates can be, for example, the amount of from 0.01 to 50 mg/kg body weight, the perhaps amount of from 0.1 to 25 mg/kg body weight more normally.Can contain such dosage or the approximate number of this dosage in the composition of single dose form, thereby form described every daily dose.Generally speaking, according to therapeutic scheme of the present invention comprise the patient who carries out this treatment with single dosage form or multiple dosage form to needs every day use about 10 milligrams to the compound described in about 1000 milligrams of the present invention.
Described compound with structural formula described in the present invention is passable, for example, is carried out by following form and uses: injection, and intravenous, in the artery, under the corium, in the peritonaeum, in the muscle, perhaps subcutaneous; Perhaps oral, in the oral cavity, in the nose, saturating mucous membrane, the part is with the form of ophthalmic preparation, perhaps use by suction, the dosage of using be per 4 to 120 hours about 0.1 to the scope of about 500 mg/kg body weight, perhaps dosage at 1 milligram between the 1000 milligrams/dosage, perhaps according to the selective dose that requires of described concrete medicine.Described method can be contemplated that the compound of using effective dose or the composition of compound in the present invention, can obtain effect desired or that claim.Generally, the pharmaceutical composition described in the present invention will be used to about 6 times frequency for about 1 time with every day, perhaps can select, in a kind of mode of SE.Such method of application can be used as chronic treatment or acute treatment.Can will change according to the host who receives treatment and described concrete administration form with the dosage that described pharmacology excipient or carrier make up to prepare a kind of described active component of single dosage form.To contain about 5% to about 95% reactive compound (w/w) in a kind of typical preparation.Perhaps alternative, can contain about 20% to about 80% reactive compound in such preparation.
May need than the lower or higher dosage of those dosage of above setting forth.For the patient of any specific, concrete dosage and therapeutic scheme will depend on various factor, comprise the activity that employed described particular compound has, age, body weight, general health situation, sex, diet, time of application, discharge rate, the combination of medicine, the order of severity of described disease, illness or symptom and process, described patient is for the processing of described disease, illness or symptom, and described treatment doctor's judgement.
For the illness to the patient is improved, if necessary, can use compound, composition or the combination described in the present invention of maintenance dose.Subsequently, when described symptom has been alleviated the level that arrives a kind of expectation, can be with described application dosage or frequency of administration, perhaps both as a kind of function of symptom, are reduced on the level of the state that can keep described process improvement simultaneously.Yet when the recurrence of any degree appearred in described disease symptoms, the patient may accept the treatment of discontinuity within a segment length period.
Synthetic method
In conjunction with following synthetic schemes, can better understand the compound described in the present invention and method, described synthetic schemes has been described the method that can be used for preparing the compound described in the present invention, described method only is intended to be described, and does not consist of the restriction of the scope that the present invention is had.
Scheme 1
Figure BPA00001656443901321
Scheme 2
Figure BPA00001656443901331
Scheme 3
Figure BPA00001656443901341
Scheme 4
Figure BPA00001656443901351
Scheme 5
Figure BPA00001656443901361
Scheme 6
Figure BPA00001656443901362
Scheme 7
Figure BPA00001656443901371
Scheme 8
Figure BPA00001656443901381
Scheme 9
Figure BPA00001656443901382
Scheme 10
Figure BPA00001656443901391
Scheme 11
Scheme 12
Figure BPA00001656443901411
Scheme 13
Figure BPA00001656443901421
Scheme 14
Figure BPA00001656443901431
Scheme 15
Figure BPA00001656443901441
Scheme 16
Embodiment
In conjunction with following embodiment, can better understand the compound described in the present invention and method, wherein said embodiment only is intended to be described, and does not consist of the restriction of the scope that the present invention is had.Various changes and the modification carried out for above-mentioned disclosed embodiment will be apparent to those skilled in the art, and this change and modification comprise, but be not limited to, can not deviate under spirit of the present invention and the prerequisite by accompanying claim limited range, those relate to the present invention and plant described chemical constitution, substituting group, derivative, change and the modification of prescription and/or method.
Embodiment 1:N-hydroxyl-5-(4-(6-((4-methyl sulphonyl) piperazine-1-yl) Methyl)-4-morpholine bithiophene a pair of horses going side by side [3,2-d] pyrimidine-2-base)-1H-indazole-1-yl) valeryl Amine (compound 3)
Step 1a:1-(methyl sulfo-peroxy) piperazine trifluoroacetate (compound 0103)
Under reflux state, to compound 0101 (10.0 grams, 54 millis rub), methylsufonyl chloride (6.5 grams, 57 millis rub) and the formed mixture of dichloromethane solution (50 milliliters) of triethylamine stir and spend the night.Described reaction mixture is cooled to room temperature and it is filtered.Thereby described filtrate is concentrated acquisition compound 0102, and described compound need not to carry out further purifying can be carried out use in next step.
At room temperature, the formed mixed liquor of dichloromethane solution (100 milliliters) of compound 0102 and trifluoroacetic acid (15 milliliters) carried out 3 hours stirring.Described reaction mixture is filtered and described filtrate is concentrated, thereby obtain a kind of described title compound 0103 (9.7 gram, 66%) of white solid form.LCMS:165[M+1] + 1HNMR (400 megahertzes, deuterochloroform): δ 2.99 (s, 3H), 3.21 (m, 4H), 3.33 (m, 4H), 8.95 (brs, 2H).
Step 1b:4-bromo-1H-indazole (compound 0106-3)
In the chloroformic solution (5 milliliters) of 3-bromo-2-aminotoluene (0104) (0.50 gram, 2.69 millis rub), add potassium acetate (0.28 gram, 2.82 millis rub).Utilize ice-water bath that described mixed liquor is cooled off and after this to wherein adding acetic anhydride (0.50 milliliter, 5.37 milli rub).Remove after this ice-water bath and at room temperature mixed liquor obtained above is carried out 10 minutes stirring, through having formed a kind of tremelloid solid of white after 10 minutes the stirrings.Add after this 18-hat-6 (0.14 gram, 0.54 milli rubs), after this add isoamyl nitrite (0.80 milliliter, 5.90 millis rub).After this under refluxad described mixed liquor is carried out 18 hours heating.Allow described reaction mixture to cool off, and utilize chloroform (3x10 milliliter) and saturated sodium bicarbonate aqueous solution (10 milliliters) that it is separated.Utilize salt solution (10 milliliters) that the organic extract of described merging is washed, carry out drying by sodium sulphate, filter and evaporation, thereby obtain a kind of crude product, (be present in the ethyl acetate in the benzinum by column chromatography, 10% volume/volume) described crude product is carried out purifying, thereby obtain a kind of 1-(4-bromo-indazole-1-yl) of orange solids form-ethyl ketone (0105) (0.31 gram, 49%), and a kind of 4-bromo-1H-indazole (0106-3) of dark orange solids form (0.21 gram, 40%).Compound 0105:LCMS:239[M+1] + 1HNMR (400 megahertzes, deuterochloroform) δ 2.80 (s, 3H), 7.41 (t, J=6.8Hz, 1H), 7.50 (d, J=6.0Hz, 1H), 8.15 (s, 1H), 8.40 (d, J=6.8Hz, 1H).Compound 0106:LCMS:197[M+1] + 1HNMR (400 megahertzes, deuterochloroform) δ 7.25 (t, J=6.0Hz, 1H), 7.34 (d, J=6.4Hz, 1H), 7.46 (d, J=6.8Hz, 1H), 8.12 (s, 1H).
The middle aqueous hydrochloric acid solution (3.0 milliliters) that adds 6N of methanol solution (5.0 milliliters) to compound 0105 (0.30 gram, 1.29 rub in the least).At room temperature described mixed liquor is carried out 7 hours stirring.Evaporation methyl alcohol and utilize ethyl acetate (2x50 milliliter) and water (5.0 milliliters) separates described mixed liquor.Utilize salt solution (5.0 milliliters) that the organic layer of described merging is washed, carry out drying by sodium sulphate, filter and evaporation, thereby obtain 4-bromo-1H-indazole (0106-3) (0.24 gram, 94%).
Step 1c:4-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl)-1H-indazole (compound 0107-3)
To (500 milligrams of compounds 0106,2.54 milli rubs) and join (968 milligrams of boric acid pinacol esters, 3.81 milli rubs) the agitating solution (20 milliliters) of dimethyl sulfoxide (DMSO) (DMSO) in add (747 milligrams of potassium acetates, 7.61 milli rubs) and (3 % by mole of two (Diphenyl phosphino ferrocene) palladium chlorides, 62 milligrams, 0.076 milli rubs).Utilize argon gas to carry out degassed to described mixed liquor and under 80 ℃, it is carried out 40 hours heating.Allow described reaction mixture to cool off and utilize water (50 milliliters) and ether (3x50 milliliter) separates it.Organic layer to described merging separates, utilize salt solution (50 milliliters) that it is washed, carry out drying by magnesium sulfate, filter and evaporation, thereby obtain thick material, by column chromatography (being present in the ethyl acetate in the benzinum, 20% volume/volume) described thick material is carried out purifying, thereby obtain the compound 0107-3 (370 milligrams, 60%) of pale solid form: LCMS:245[M+1] + 1HNMR (400 megahertzes, deuterochloroform) δ 1.41 (s, 12H), 7.40 (dd, J=6.8Hz, 8.4Hz, 1H), 7.62 (d, J=8.8Hz, 1H), 7.90 (d, J=6.8Hz, 1H), 8.50 (s, 1H).
Step 1d: thiophene a pair of horses going side by side [3,2-d] pyrimidine-2,4-(1H, 3H)-diketone (compound 0109)
Under 190 ℃, 3-amino-2-Thiophene Carboxylic Acid methyl esters (0108) (13.48 grams, 85.85 millis rub) and the mixture of urea (29.75 gram, 0.43 rubs) are carried out 2 hours heating.Be poured onto the reaction mixture of described heat among the sodium hydroxide solution and by removing by filter the insolubility material.Utilize after this hydrochloric acid solution of 2N that described mixed liquor is carried out acidifying.Collect solid obtained above by filtering, thereby it is carried out the title compound 0109 (9.62 grams, 67%) that drying obtains a kind of white solid form.LCMS:169[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 6.92 (d, J=4.0Hz, 1H), 8.04 (d, J=4.0Hz, 1H), 11.19 (d, J=14.0Hz, 1H), 11.60 (s, 1H).
Step 1e:2,4-dichloro-thiophene a pair of horses going side by side [3,2-d] pyrimidine (compound 0110)
Under refluxad, compound 0109 (9.49 grams, 56.49 millis rub) and the mixed liquor of phosphorus oxychloride (150 milliliters) are carried out 10 hours heating.Remove after this described solvent and described residue is poured on ice/water, the stirring that simultaneous is violent, thus obtain a kind of title compound 0110 (8.62 grams, 74%) of white solid form: LCMS:205[M+1] + 1HNMR (400 megahertzes, deuterochloroform): δ 7.48 (d, J=5.6Hz, 1H), 8.05 (d, J=5.6Hz, 1H).
Step 1f:4-(2-chlorothiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) morpholine (compound 0111)
At room temperature, the methyl alcohol mixed liquor (150 milliliters) of compound 0110 (8.68 grams, 42.34 millis rub) and morpholine (8.11 milliliters, 93.15 millis rub) carried out 1 hour stirring.After this described reaction mixture is filtered, utilize water (50 milliliters of x3) and methyl alcohol (50 milliliters of x1) that it is washed, thereby obtain a kind of described title compound 0111 (11.04 grams, 100%) of white solid form: LCMS:256[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 3.76 (t, J=4.8Hz, 4H), 3.91 (t, J=4.8Hz, 4H), 7.41 (d, J=5.6Hz, 1H), 8.31 (d, J=5.6Hz, 1H).
Step 1g:2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-aldehyde (compound 0112)
Under-78 ℃, to compound 0111 (1.75 grams, 6.85 milli rubs) anhydrous tetrahydro furan suspension (40 milliliters) in add the oxolane (THF) of the lithium diisopropyl amido (LDA) of 2.0M/hexane solution (20.55 milliliters, 41.1 millis rub).After 1 hour stirring, to wherein adding DMF (3.2 milliliters, 41.1 millis rub).Under-78 ℃, described reaction mixture is carried out 1 hour stirring and slowly is warming up to after this room temperature.At room temperature passed through after 10 hours the further stirring, described reaction mixture has been poured onto on the saturated solution of ammonium chloride, utilized ethyl acetate (100 milliliters of x3) to extract, carried out drying and filtration by sodium sulphate.Thereby described filtrate concentrating stayed residue, utilize ethyl acetate (10 milliliters of x2) that described residue is washed, thereby obtain a kind of described title compound 0112 (0.66 gram, 35%) of yellow solid form: LCMS:284[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 3.76 (t, J=4.8Hz, 4H), 4.10 (t, J=4.8Hz, 4H), 8.29 (s, 1H), 10.21 (s, 1H).
Step 1h:4-(2-chloro-6-((4-methylthiophene peroxy) piperazine-1-yl) methyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) morpholine (compound 0113)
Under refluxad, to compound 0112 (1.10 grams, 3.89 milli rubs), 0103 (2.20 grams, 7.78 milli rubs), triethylamine (471 milligrams, 4.7 millis rub) and too sour four isopropyl esters (1.30 grams, 4.67 millis rub) formed chloroform mixed liquor (30 milliliters) stir and spend the night.Remove after this described solvent, and to wherein adding 1,2-dichloroethane (40 milliliters) and sodium cyanoborohydride (368 milligrams, 5.84 millis rub).At room temperature described reaction mixture is carried out after this 12 hours stirring.Concentrate and utilize ethanol that solid obtained above is recrystallized to described reaction mixture, thereby obtain a kind of described title compound 0113 (800 milligrams, 48%) of yellow solid form: LCMS:432[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 2.57 (t, J=4.4Hz, 4H), 2.89 (s, 3H), 3.13 (t, J=4.4Hz, 4H), 3.74 (t, J=5.2Hz, 4H), 3.88 (t, J=5.2Hz, 4H), 3.91 (s, 2H), 7.31 (s, 1H).
Step 1i:4-(2-chloro-6-((4-methylthiophene peroxy) piperazine-1-yl) methyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) morpholine (compound 0114)
Utilize nitrogen to (800 milligrams of compounds 0113,1.86 milli rubs), (500 milligrams of 0107-3,2.04 milli rubs), (470 milligrams of sodium bicarbonates, 5.58 milli rubs) and the mixed liquor that forms in toluene (20 milliliters), ethanol (12 milliliters) and water (5.6 milliliters) of two (Diphenyl phosphino ferrocene) palladium chloride (0) (80 milligrams, 0.093 milli rub) washes and in the heating of it being carried out 1 hour under the microwave condition under 120 ℃.Utilize carrene and water that described reaction mixture is separated.Described organic layer is separated and utilizes salt solution that it is washed, carry out drying by magnesium sulfate, filter and evaporation.By column chromatography (silica gel, carrene, 2%, volume/volume) residue obtained above is carried out purifying, thereby obtain a kind of title compound 0114 (350 milligrams, 37%) of white solid form.Fusing point 148-149 ℃.LCMS:514[M+1] + 1HNMR (400 megahertzes, deuterochloroform): δ 2.70 (t, J=4.4Hz, 4H), 2.81 (s, 3H), 3.13 (t, J=4.4Hz, 4H), 3.92 (m, 6H), 4.09 (t, J=5.6Hz, 4H), 7.41 (s, 1H), 7.50 (m, 1H), 7.59 (d, J=8.4Hz, 1H), 8.28 (d, J=6.8Hz, 1H), (9.00 s, 1H), 10.32 (brs, 1H).
Step 1j:5-(4-(6-((4-(methyl sulphonyl) piperazine-1-yl) methyl)-4-morpholine thiophene a pair of horses going side by side [3; 2-d] pyrimidine-2-base)-2H-indazole-2-yl) ethyl valerate (compound 0116-3) and 5-(4-(6-((4-(methyl sulphonyl) piperazine-1-yl) methyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-2-base)-1H-indazole-1-yl) ethyl valerate (compound 0115-3)
To compound 0114 (370 milligrams, 0.72 milli rubs), the acetonitrile mixed liquor (50 milliliters) of 5-bromine ethyl valerate (181 milligrams, 0.87 milli rubs) and potash (199 milligrams, 1.44 millis rub) carries out 58 hours backflow.Remove solvent and utilize carrene and water separates described residue.Described organic layer is separated and utilizes salt solution that it is washed, carry out drying by magnesium sulfate, filter and evaporation, thereby obtain a kind of crude product, (HPLC) carries out purifying to described crude product by preparative high performance liquid chromatography, thereby described title compound 0115-3 (80 milligrams, 17%) and 0116-3 (60 milligrams, 13%) have been obtained.
Compound 0115-3: a kind of white solid: LCMS:642[M+1] + 1HNMR (400 megahertzes, deuterochloroform): δ 1.15 (t, J=7.2Hz, 3H), (1.61 m, 2H), 1.94 (m, 2H), (2.26 t, J=7.2Hz, 2H), 2.62 (t, J=4.4Hz, 4H), 2.74 (s, 3H), (3.23 t, J=4.4Hz, 4H), (3.84 m, 6H), 4.01 (m, 6H), 4.38 (t, J=6.8Hz, 2H), 7.33 (s, 1H), (7.42 m, 2H), 8.17 (m, 1H), 8.81 (s, 1H). 13CNMR (100MHz, CDCl 3): δ 172.2,161.6, and 159.5,157.1,147.8,139.3,133.7,131.2,125.0,123.0,121.4,120.8,112.1,109.7,65.8 (2C), 59.3,56.3,51.4,47.5 (2C), 45.6 (2C), 44.8 (2C), 33.5,32.8,28.6,21.2,13.2.
Compound 0116-3: a kind of white solid: LCMS:642[M+1] + 1HNMR (400 megahertzes, deuterochloroform): δ 1.15 (t, J=7.2Hz, 3H), (1.60 m, 2H), 2.06 (m, 2H), (2.29 t, J=7.2Hz, 2H), 2.63 (s, 4H), 2.74 (s, 3H), 3.24 (s, 4H), 3.84 (m, 6H), (4.04 m, 6H), 4.43 (t, J=6.8Hz, 2H), 7.33 (m, 2H), 7.74 (d, J=8.4Hz, 1H), 8.19 (d, J=6.8Hz, 1H), 8.82 (s, 1H). 13CNMR (100MHz, CDCl 3): δ 172.1,161.5, and 159.5,156.9,148.8,147.4,130.0,124.6,123.1,122.2,119.0,118.8,112.0,65.8 (2C), 59.4,56.3,52.4,51.4 (2C), 45.5 (2C), 44.8 (2C), 33.5,32.7,28.6,21.1,13.1.
Step 1k:N-hydroxyl-5-(4-(6-((4-(methyl sulphonyl) piperazine-1-yl) methyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-2-base)-1H-indazole-1-yl) pentanamide (compound 3)
Under 0 ℃, (24 milliliters) add the methanol solution (14 milliliters) of sodium hydroxide (5.61 grams, 100 millis rub) in the agitating solution of methyl alcohol of hydroxylamine hydrochloride (4.67 grams, 67 millis rub).Through after adding, under 0 ℃, described mixed liquor carried out 30 minutes stirring.Sediment obtained above removed by filter and described filtrate preparation is become free hydroxylamine solution.
The hydroxylamine solution (4.00 milliliters) of above-mentioned fresh preparation is placed in 10 milliliters the flask.Add compound 0115-3 (80 milligrams, 0.12 milli rubs) in this solution and under 0-10 ℃, it is carried out 15 minutes stirring.(TLC) monitors described course of reaction by thin layer chromatography.After described reaction is finished, described reaction mixture is filtered.Utilize water and methyl alcohol that the above-mentioned solid of collecting is washed, drying, thus obtain a kind of compound 3 (45 milligrams, 58%) of white solid form: fusing point 139-143 ℃.LCMS:629[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 1.47 (m, 2H), 1.83 (m, 2H), 1.98 (t, J=7.4Hz, 2H), 2.62 (s, 4H), 2.91 (s, 3H), 3.17 (s, 4H), 3.84 (s, 4H), 3.86 (s, 2H), 4.01 (m, 4H), 4.47 (t, J=6.6Hz, 2H), 7.52 (m, 2H), (7.82 d, J=8.4Hz, 1H), 8.24 (d, J=6.8Hz, 1H), (8.67 s, 1H), 8.86 (s, 1H), 10.36 (s, 1H).
Embodiment 2:N-hydroxyl-3-(4-(6-((4-(methyl sulphonyl) piperazine-1- Base) methyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-2-base)-1H-indazole-1-yl) third The preparation of acid amides (compound 4)
Step 2a:6-(4-(6-((4-(methyl sulphonyl) piperazine-1-yl) methyl)-4-morpholine thiophene a pair of horses going side by side [3; 2-d] pyrimidine-2-base)-2H-indazole-2-yl) ethyl hexanoate (compound 0116-4) and 3-(4-(6-((4-(methyl sulphonyl) piperazine-1-yl) methyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-2-base)-1H-indazole-1-yl) ethyl propionate (compound 0115-4)
To compound 0114 (160 milligrams, 0.37 milli rubs), the backflow that the acetonitrile mixed liquor (50 milliliters) of 6-bromocaproic acid ethyl ester (83 milligrams, 0.37 milli rubs) and potash (85 milligrams, 0.62 milli rubs) spends the night.Remove solvent and utilize carrene and water separates described residue.Described organic layer is separated and utilizes salt solution that it is washed, carry out drying by magnesium sulfate, filter and under vacuum condition, evaporate.(HPLC) carries out purifying to residue obtained above by preparative high performance liquid chromatography, thereby obtained described title compound 0116-4 (40 milligrams, 20%) and 0115-4 (70 milligrams, 34%).
Compound 0116-4: a kind of oil; LCMS:657[M+1] + 1HNMR (400 megahertzes, deuterochloroform): δ 1.14 (t, J=7.2Hz, 3H), (1.34 m, 2H), 1.60 (m, 2H), (2.02 m, 2H), 2.22 (t, J=7.2Hz, 2H), 2.62 (s, 4H), 2.73 (s, 3H), 3.23 (m, 4H), 3.82 (s, 2H), 3.84 (m, 4H), 4.00 (m, 6H), 4.40 (t, J=7.2Hz, 2H), (7.33 m, 2H), 7.74 (d, J=8.4Hz, 1H), 8.19 (d, J=6.8Hz, 1H), 8.82 (s, 1H). 13CNMR (100 megahertzes, deuterochloroform): δ 172.4,161.7, and 159.6,156.7,148.6,147.5,130.1,124.6,123.1,122.1,119.2,118.8,112.0,65.8,59.4,56.4,52.6,51.2,45.3,44.8,33.3,32.9,29.3,25.1,23.4,13.4.
Compound 0115-4: a kind of oil; LCMS:657[M+1] + 1HNMR (400 megahertzes, deuterochloroform): δ 1.14 (t, J=7.2Hz, 3H), (1.27 m, 2H), 1.59 (m, 2H), (1.90 m, 2H), 2.19 (t, J=7.2Hz, 2H), 2.61 (m, 4H), 2.72 (s, 3H), 3.22 (m, 4H), (3.83 m, 6H), 4.00 (m, 6H), 4.35 (t, J=7.2Hz, 2H), 7.31 (s, 1H), (7.41 m, 2H), 8.16 (m, 1H), 8.81 (s, 1H). 13CNMR (100 megahertzes, deuterochloroform): δ 172.6,161.7, and 159.8,157.1,147.7,139.2,133.5,131.2,124.9,123.2,121.4,120.7,112.1,109.7,65.8 (2C), 59.2,56.3,51.4,47.7,45.6,44.8,33.5,33.0,28.6,23.5,19.8,13.2.
Step 2b:N-hydroxyl-3--(4-(6-((4-(methyl sulphonyl) piperazine-1-yl) methyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-2-base)-1H-indazole-1-yl) propionamide (compound 4)
Described title compound 4 is (45 milligrams of solids by using a kind of yellow that the similar step of a kind of and step (embodiment 1) that be used for to describe compound 3 prepares, 22%), the methanol solution (5.0 milliliters) that is the azanol by 0115-4 (210 milligrams, 0.32 milli rub) and fresh preparation prepares: fusing point 186-187 ℃.LCMS:643[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.22 (m, 2H), 1.52 (m, 2H), (1.84-1.93 m, 4H), 2.61 (m, 4H), (2.91 s, 3H), 3.17 (m, 4H), (3.82-3.85 m, 4H), 3.95 (s, 2H), (3.99-4.01 m, 4H), 4.44 (t, J=6.8Hz, 2H), 7.51 (m, 2H), (7.80 d, J=8.8Hz, 1H), (8.23 d, J=8.8Hz, 1H), (8.63 s, 1H), 8.85 (s, 1H), 10.30 (s, 1H).
Embodiment 3:N-hydroxyl-7-(4-(6-((4-(methyl sulphonyl) piperazine-1- Base) methyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-2-base)-1H-indazole-1-yl) heptan The preparation of acid amides (compound 5)
Step 3a:7-(4-(6-((4-(methyl sulphonyl) piperazine-1-yl) methyl)-4-morpholine thiophene a pair of horses going side by side [3; 2-d] pyrimidine-2-base)-2H-indazole-2-yl) cognac oil (compound 0116-5) and 7-(4-(6-((4-(methyl sulphonyl) piperazine-1-yl) methyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-2-base)-1H-indazole-1-yl) cognac oil (compound 0115-5)
(110 milligrams of described title compound 0115-5,27%) and (60 milligrams of 0116-5,16%) be by using the similar step of a kind of and step (embodiment 1) that be used for to describe compound 0115-3 and compound 0116-3, by 0114 (280 milligrams, 0.55 milli rubs), the acetonitrile solution (25 milliliters) of 7-bromine cognac oil (133 milligrams, 0.65 milli rubs) and potash (152 milligrams, 1.10 millis rub) prepares:
Compound 0115-3: a kind of white solid; LCMS:670[M+1] + 1HNMR (400 megahertzes, deuterochloroform): δ 1.15 (t, J=7.2Hz, 3H), (1.29 m, 4H), 1.46 (m, 2H), (1.84 m, 2H), 2.23 (t, J=7.2Hz, 2H), 2.61 (s, 4H), 2.91 (s, 3H), 3.16 (s, 4H), 3.83 (m, 4H), 3.95 (s, 2H), 4.00 (m, 6H), 4.45 (t, J=6.6Hz, 2H), (7.51 m, 2H), 7.79 (d, J=8.8Hz, 1H), 8.23 (d, J=6.8Hz1H), 8.86 (s, 1H).
Compound 0116-3: a kind of white solid; LCMS:670[M+1] + 1HNMR (400 megahertzes, deuterochloroform): δ 1.14 (t, J=7.2Hz, 3H), (1.31 m, 4H), 1.53 (m, 2H), (1.97 m, 2H), 2.25 (t, J=7.6Hz, 2H), 2.61 (s, 4H), 2.91 (s, 3H), 3.17 (s, 4H), 3.83 (m, 4H), 3.95 (s, 2H), 4.00 (m, 6H), 4.50 (t, J=7.0Hz, 2H), (7.37 t, J=7.8Hz, 1H), 7.52 (s, 1H), 7.46 (d, J=8.8Hz, 1H), (8.17 d, J=6.8Hz1H), 9.02 (s, 1H).
Step 3b:N-hydroxyl-7-(4-(6-((4-(methyl sulphonyl) piperazine-1-yl) methyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-2-base)-1H-indazole-1-yl) heptamide (compound 5)
Described title compound 5 is (70 milligrams of solids by using a kind of white that the similar step of a kind of and step (embodiment 1) that be used for to describe compound 3 prepares, 71%), the methanol solution (4.0 milliliters) that is the azanol by 0115-5 (100 milligrams, 0.15 milli rub) and fresh preparation prepares: fusing point 127-130 ℃.LCMS:657[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 1.26 (s, 4H), 1.44 (m, 2H), (1.84 m, 2H), 1.91 (t, J=7.2Hz, 2H), 2.61 (s, 4H), 2.91 (s, 3H), 3.16 (s, 4H), 3.83 (m, 4H), 3.95 (s, 2H), 4.00 (m, 4H), 4.45 (t, J=6.8Hz, 2H), (7.5 m, 2H), 7.80 (d, J=8.4Hz, 1H), 8.23 (d, J=7.6Hz, 1H), (8.65 s, 1H), 8.86 (s, 1H), 10.32 (s, 1H).
The preparation of embodiment 4:N-hydroxyl-5-(4-(6-((4-(methyl sulphonyl) piperazine-1-yl) methyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-2-base)-2H-indazole-2-yl) pentanamide (compound 7)
Described title compound 7 is (35 milligrams of solids by using a kind of white that the similar step of a kind of and step (embodiment 1) that be used for to describe compound 3 prepares, 47%), the methanol solution (4.0 milliliters) that is the azanol by 0116-3 (60 milligrams, 0.12 milli rub) and fresh preparation prepares: fusing point 146-169 ℃.LCMS:629[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 1.57 (m, 2H), 2.00 (m, 2H), 2.07 (t, J=7.2Hz, 2H), 2.67 (s, 4H), 2.97 (s, 3H), 3.23 (s, 4H), 3.89 (s, 4H), 4.01 (s, 2H), 4.04 (m, 4H), 4.57 (t, J=7.0Hz, 2H), 7.43 (t, J=7.8Hz, 1H), 7.58 (s, 1H), 7.81 (d, J=8.4Hz, 1H), (8.28 d, J=6.8Hz, 1H), 9.08 (s, 1H).
The preparation of embodiment 5:N-hydroxyl-6-(4-(6-((4-(methyl sulphonyl) piperazine-1-yl) methyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-2-base)-2H-indazole-2-yl) caproamide (compound 8)
Described title compound 8 is (15 milligrams of solids by using a kind of yellow that the similar step of a kind of and step (embodiment 1) that be used for to describe compound 3 prepares, 11%), the methanol solution (5.0 milliliters) that is the azanol by 0116-4 (140 milligrams, 0.21 milli rub) and fresh preparation prepares: fusing point 124-125 ℃.LCMS:643[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 1.23 (m, 2H), 1.55 (m, 2H), (1.92-1.97 m, 4H), 2.61 (m, 4H), (2.91 s, 3H), 3.17 (m, 4H), (3.82-3.85 m, 4H), 3.95 (s, 2H), (3.99-4.01 m, 4H), 4.50 (t, J=6.8Hz, 2H), 7.37 (m, 1H), 7.53 (s, 2H), 7.74 (d, J=8.4Hz, 1H), (8.21 d, J=6.8Hz, 1H), (8.64 s, 1H), 9.02 (s, 1H), 10.31 (s, 1H).
Embodiment 6:N-hydroxyl-7-(4-(6-((4-(methyl sulphonyl) piperazine-1- Base) methyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-2-base)-2H-indazole-2-yl) heptan The preparation of acid amides (compound 9)
Described title compound 9 is (45 milligrams of solids by using a kind of white that the similar step of a kind of and step (embodiment 1) that be used for to describe compound 3 prepares, 76%), the methanol solution (4.0 milliliters) that is the azanol by 0116-5 (60 milligrams, 0.09 milli rub) and fresh preparation prepares: fusing point 123-126 ℃.LCMS:657[M+1] + 1H NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 1.29 (s, 4H), 1.48 (m, 2H), (1.93 m, 4H), 2.61 (s, 4H), (2.91 s, 3H), 3.16 (s, 4H), (3.83 m, 4H), 3.95 (s, 2H), (3.98 m, 4H), 4.50 (t, J=7.0Hz, 2H), 7.37 (t, J=7.8Hz, 1H), (7.52 s, 1H), 7.75 (d, J=8.8Hz, 1H), 8.22 (d, J=6.8Hz, 1H), (8.65 s, 1H), 9.03 (s, 1H), 10.32 (s, 1H).
Embodiment 7:5-(4-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3, 2-d] pyrimidine-6-yl) methyl) piperazine-1-yl)-N-hydroxyl pentanamide (compound 11) Preparation
Step 7a:4-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester (compound 0201)
In the chloroform mixed liquor (50 milliliters) of 0112 (4.0 grams, 14.10 millis rub) and piperazine-1-carboxylic acid tert-butyl ester (3.94 grams, 21.15 millis rub), add tetraisopropyl titanate (4.81 grams, 16.92 millis rub).At room temperature described mixed liquor is carried out stirred overnight.Under reduced pressure, remove described solvent.Described residue is dissolved among the carrene (60 milliliters) and in described mixed liquor adds sodium cyanoborohydride (1.33 grams, 21.15 millis rub).At room temperature described mixed liquor is carried out 4 hours stirring and utilizes sodium bicarbonate solution that it is diluted.Utilize after this ethyl acetate that described mixed liquor is extracted.Described organic facies is separated, dry and concentrated, thereby obtained described product 0201 (5.2 grams, 81%): LCMS:454[M+1] + 1HNMR (400 megahertzes, deuterochloroform) δ 1.46 (s, 9H), 2.49 (s, 4H), 3.47 (t, J=4.4Hz, 4H), 3.80 (s, 2H), 3.84 (t, J=5.2Hz, 4H), 3.99 (t, J=4.8Hz, 4H), 7.17 (s, 1H).
Step 7b:4-(2-chloro-6-(piperazine-1-ylmethyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) morpholine (compound 0202)
Under condition of nitrogen gas, add hydrochloric acid/dioxane (30 milliliters) of 4N to 0201 in the dioxane mixed liquor of (5.2 grams, 11.45 millis rub).At room temperature described reaction mixture is carried out 5 hours stirring.Described mixed liquor is poured in the water (30 milliliters), utilize saturated sodium bicarbonate solution that pH is adjusted to 7, utilize ethyl acetate that it is extracted, dry and concentrated, thereby obtain described product 0202 (3.0 grams, 74%): LCMS:354[M+1] + 1HNMR (400 megahertzes, deuterochloroform) δ 2.52 (s, 4H), 2.93 (t, J=4.8Hz, 4H), 3.78 (s, 2H), 3.84 (t, J=4.8Hz, 4H), 3.99 (t, J=4.4Hz, 4H), 7.16 (s, 1H).
Step 7c:5-(4-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) piperazine-1-yl) ethyl valerate (compound 0203-11)
In dimethyl formamide (DMF) mixed liquor (3 milliliters) of 0202 (0.3 gram, 0.85 milli rubs), add cesium carbonate (0.61 gram, 1.87 millis rub) and 5-bromine ethyl valerate (0.2 gram, 0.93 milli rubs).At room temperature described reaction mixture is stirred and spend the night and after this it is poured on the water (10 milliliters).Utilize ethyl acetate that described mixed liquor is extracted.Described organic facies is separated and utilized water (10 milliliters of x5) and salt solution that it is washed, carry out drying by sodium sulphate, filter and concentrated, thereby obtained a kind of described product 0203-11 (0.36 gram, 80%) of gray solid form: LCMS:482[M+1] + 1HNMR (400 megahertzes, deuterochloroform) δ 1.25 (t, J=7.2Hz, 3H), (1.52-1.69 m, 6H), 2.30-2.37 (s, 2H), (2.55 m, 6H), 3.79 (s, 2H), (3.84 t, J=5.2Hz, 4H), 3.98 (t, J=4.4Hz, 4H), 4.13 (q, J=6.8Hz, 2H), 7.16 (s, 1H).
Step 7d:5-(4-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) piperazine-1-yl) ethyl valerate (compound 0204-11)
Utilize nitrogen to (250 milligrams of compound 0203-11,0.52 milli rubs), (140 milligrams of 0107-3,0.57 milli rubs), (131 milligrams of sodium bicarbonates, 1.56 milli rubs) and the mixed liquor that forms in toluene (4.8 milliliters), ethanol (2.5 milliliters) and water (1.3 milliliters) of two (Diphenyl phosphino ferrocene) palladium chloride (18 milligrams, 0.026 milli rub) washes and in the heating of it being carried out 2 hours under the microwave condition under 130 ℃.In described mixed liquor, add water (10 milliliters) and utilize ethyl acetate that it is extracted.Described organic layer is separated and utilizes salt solution that it is washed, carry out drying by sodium sulphate, thereby filter and concentrate and obtain described crude product, by the silicagel column (dichloromethane solution of methyl alcohol, 5% volume/volume) crude product obtained above is carried out purifying, thereby obtain a kind of described title compound 0204-11 (62 milligrams, 21%) of white solid form: LCMS:565[M+2] + 1HNMR (400 megahertzes, deuterochloroform) δ 1.23 (m, 3H), 1.27 (m, 2H), (1.55 m, 2H), 1.65 (m, 2H), 2.32 (t, J=7.6Hz, 2H), 2.40 (m, 2H), 2.54 (m, 2H), 2.64 (m, 4H), 3.86 (s, 2H), (3.92 t, J=4.8Hz, 4H), 4.09 (t, J=5.2Hz, 4H), 4.13 (q, J=7.2Hz, 2H), 7.38 (s, 1H), 7.50 (t, J=7.2Hz, 1H), 7.59 (d, J=8.0Hz, 1H), 8.28 (dd, J=7.2Hz, 0.8Hz, 1H), 9.01 (d, J=1.2Hz, 1H).
Step 7e:5-(4-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) piperazine-1-yl)-N-hydroxyl pentanamide (compound 11)
Described title compound 11 is (21 milligrams of solids by using a kind of white that the similar step of a kind of and step (embodiment 1) that be used for to describe compound 3 prepares, 17%), by (129 milligrams of 0204-11,0.23 milli rubs) and (1.0 milliliters of the methanol solutions of the azanol of fresh preparation, 1.77 rub in the least/liter) prepare: fusing point 125-127 ℃, LCMS:552[M+2] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.23 (s, 2H), 1.39 (m, 2H), (1.48 m, 2H), 1.94 (t, J=7.6Hz, 2H), 2.09 (s, 2H), 2.26 (t, J=6.8Hz,, 2H), 2.50 (m, 4H), 2.64 (m, 4H), 3.86 (m, 6H), 4.00 (m, 4H), 7.47 (t, J=6.8Hz, 1H), 7.67 (d, J=8.4Hz, 1H), 8.22 (d, J=6.8Hz, 1H), (8.88 s, 1H), 10.27 (s, 1H), 13.20 (s, 1H).
Embodiment 8:6-(4-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3, 2-d] pyrimidine-6-yl) methyl) piperazine-1-yl)-N-hydroxyl hexanamide (compound 12) Preparation
Step 8a:6-(4-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) piperazine-1-yl) ethyl hexanoate (compound 0203-12)
Described title compound 0203-12 is by the solid that uses a kind of a kind of grey with preparing for the similar step of the step (embodiment 7) of describing compound 0203-11 (0.57 gram, 82%), by 0202 (0.5 gram, 1.41 milli rubs), cesium carbonate (0.92 gram, 2.82 milli rubs) and 6-bromocaproic acid ethyl ester (0.35 gram, 1.55 millis rub/liter) prepare: LCMS:496[M+1] + 1HNMR (megahertz, deuterochloroform) δ 1.25 (m, 4H), 1.34 (m, 2H), (1.64 m, 2H), 2.30 (t, J=7.6Hz, 2H), (2.38 m, 2H), 2.60 (m, 8H), 3.80 (s, 2H), 3.84 (t, J=4.4Hz, 4H), (3.40 t, J=4.8Hz, 4H), 4.11 (q, J=7.2Hz, 2H), 7.16 (s, 1H).
Step 8b:6-(4-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) piperazine-1-yl) ethyl hexanoate (compound 0204-12)
Described title compound 0204-12 is (56 milligrams of solids by using a kind of white that the similar step of a kind of and step (embodiment 7) that be used for to describe compound 0204-11 prepares, 16%), by (295 milligrams of 0203-12,0.61 milli rubs), (164 milligrams of 0107-3,0.67 milli rubs), (150 milligrams of sodium bicarbonates, 1.79 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (23 milligrams, 0.031 milli rub) at toluene (5.6 milliliters), ethanol (3 milliliters) and water (1.5 milliliters) solution prepare: LCMS:579[M+2] + 1HNMR (400 megahertzes, deuterochloroform) δ 1.25 (t, J=7.6Hz, 3H), (1.41 m, 2H), 1.67 (m, 2H), (1.81 m, 2H), 2.32 (t, J=7.2Hz, 2H), 3.02 (m, 8H), 3.61 (m, 2H), 3.96 (m, 5H), 4.13 (q, J=14.4Hz, 2H), 4.19 (m, 2H), (7.39 t, J=7.2Hz, 1H), 7.55 (s, 1H), 7.60 (d, J=8.8Hz, 1H), 7.97 (d, J=6.8Hz, 1H), 8.50 (s, 1H).
Step 8c:6-(4-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) piperazine-1-yl)-N-hydroxyl hexanamide (compound 12)
Described title compound 12 is (15 milligrams of solids by using a kind of white that the similar step of a kind of and step (embodiment 1) that be used for to describe compound 3 prepares, 13%), by (120 milligrams of 0204-12,0.21 milli rubs) and the methanol solution of the azanol of fresh preparation (1.0 milliliters, 1.77 millis rub/liter) prepare: fusing point 123-124 ℃.LCMS:565[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.23 (m, 2H), 1.26 (m, 2H), 1.36 (m, 2H), (1.93 t, J=7.2Hz, 2H), 2.25 (t, J=6.8Hz, 2H), (2.39 m, 4H), 3.30 (m, 4H), 3.85 (m, 6H), (4.00 t, J=5.2Hz, 4H), 7.47 (d, J=15.2Hz, 2H), (7.66 d, J=8.4Hz, 1H), 8.22 (d, J=6.8Hz, 1H), 8.65 (s, 1H), 8.88 (s, 1H).
Embodiment 9:7-(4-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3, 2-d] pyrimidine-6-yl) methyl) piperazine-1-yl)-N-hydroxyl heptamide (compound 13) Preparation
Step 9a:7-(4-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) piperazine-1-yl) cognac oil (compound 0203-13)
Described title compound 0203-132 is by the solid that uses a kind of a kind of grey with preparing for the similar step of the step (embodiment 7) of describing compound 0203-11 (0.55 gram, 76%), by 0202 (0.5 gram, 1.41 milli rubs), cesium carbonate (0.92 gram, 2.82 milli rubs) and 6-bromocaproic acid ethyl ester (0.35 gram, 1.55 millis rub/liter) prepare: 512[M+2] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.17 (t, J=6.8Hz, 3H), 1.28 (m, 4H), (1.52 m, 2H), 1.61 (m, 2H), 2.28 (t, J=7.2Hz, 2H), 2.49 (m, 4H), 3.05 (m, 6H), 3.75 (t, J=4.4Hz, 4H), 3.88 (t, J=4.8Hz, 2H), 3.97 (m, 2H), 4.04 (q, J=14Hz, 2H), 7.34 (s, 1H).
Step 9b:7-(4-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) piperazine-1-yl) cognac oil (compound 0204-13)
Described title compound 0204-13 is (56 milligrams of solids by using a kind of white that the similar step of a kind of and step (embodiment 7) that be used for to describe compound 0204-11 prepares, 16%), by (300 milligrams of 0203-12,0.60 milli rubs), (162 milligrams of 0107-3,0.67 milli rubs), (151 milligrams of sodium bicarbonates, 1.80 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (21 milligrams, 0.03 milli rub) at toluene (5.5 milliliters), ethanol (3 milliliters) and water (1.5 milliliters) solution prepare: LCMS:592[M+1] + 1H NMR (400 megahertzes, deuterochloroform) δ 1.25 (m, 3H), 1.33 (m, 4H), (1.51 m, 2H), 1.63 (m, 2H), 2.29 (t, J=7.6Hz, 2H), 2.37 (m, 2H), 2.52 (m, 4H), 2.64 (m,, 4H), 3.86 (s, 2H), 3.92 (t, J=4.4Hz, 4H), 4.09 (t, J=6.0Hz, 4H), 4.12 (q, J=14.4Hz, 2H), 7.38 (s, 1H), 7.50 (t, J=8.4Hz, 1H), 7.59 (d, J=8.4Hz, 1H), 8.28 (dd, J=7.6Hz, 0.8Hz, 1H), 9.02 (d, J=0.8Hz, 1H).
Step 9c:7-(4-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) piperazine-1-yl)-N-hydroxyl heptamide (compound 13)
Described title compound 13 is (25 milligrams of solids by using a kind of white that the similar step of a kind of and step (embodiment 1) that be used for to describe compound 3 prepares, 37%), by (68 milligrams of 0204-13,0.11 milli rubs) and the methanol solution of the azanol of fresh preparation (0.5 milliliter, 1.77 millis rub/liter) prepare: fusing point 119-122 ℃.LCMS:580[M+2] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.27 (m, 4H), 1.50 (m, 2H), (1.62 m, 2H), 1.94 (t, J=6.8Hz, 2H), 2.47 (m, 4H), 3.06 (m, 6H), 3.85 (t, J=4.0Hz, 4H), (4.02 m, 6H), 4.00 (t, J=5.2Hz, 4H), 7.49 (t, J=8.4Hz, 1H), (7.56 s, 1H), 7.69 (d, J=8.0Hz, 1H), 8.21 (d, J=7.2Hz, 1H), (8.87 s, 1H), 9.39 (s, 1H), 10.35 (s, 1H).
Embodiment 10:2-(4-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3, 2-d] pyrimidine-6-yl) methyl) piperazine-1-yl)-N-hydroxypyrimidine-5-carboxamides (chemical combination Thing 14) preparation
Step 10a:(Z)-2-(ethoxyl methyl)-3-methoxy acrylic acid ethyl ester (compound 0302)
At room temperature in the mixed liquor of benzene (200 milliliters) and ethanol (27 gram) formation, add sodium (13.8 gram).Under 0 ℃, in above-mentioned mixed liquor, add the mixed liquor that is formed by Ethyl formate (45.0 grams, 0.61 rubs) and 3-ethoxyl ethyl propionate (44.0 grams, 0.30 rubs) slowly.Reaction mixture obtained above is carried out 2 hours stirring and after this to wherein adding dimethyl suflfate (76.0 gram, 0.61 rubs) and carry out 3 hours stirring under 50 ℃.Described mixed liquor is filtered, and utilize water that described filtrate is washed.Described organic layer is separated and to wherein adding triethylamine chlorine (40.0 gram, 0.29 rubs) and sodium hydroxide (7.00 grams, 0.175 rubs).Mixed liquor obtained above is carried out 4 hours stirring and filters after this.Utilize water that described filtrate is washed, carry out drying by sodium sulphate, filter and evaporation, thereby obtain a kind of residue, under vacuum condition, described residue is distilled, thereby compound 0302 (18.8 grams, 33%) is provided, and described compound need not to carry out further purifying and can directly be used in following step: 1HNMR (400 megahertzes, deuterochloroform): δ 1.26 (m, 6H), 3.48 (m, 3H), 3.63 (m, 3H), 4.20 (m, 2H).
Step 10b:2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid, ethyl ester (compound 0303)
Under reflux state, compound 0302 (21.4 grams, 0.11 rubs), urea (5.70 grams, 0.095 rubs) and the alcohol mixeding liquid (300 milliliters) of concentrated hydrochloric acid (36%-38%, 5 milliliters) are carried out heated overnight.After pervaporation, from ethanol, described residue is recrystallized, thereby obtains a kind of compound 0303 (7.80 gram, 65%) of colourless prismatic form: LCMS:171[M+1] +, 1HNMR (400 megahertzes, deuterochloroform): δ 1.27 (t, J=7.2Hz, 3H), 4.19 (m, 4H), 5.28 (s, 1H), 7.21 (d, J=5.6Hz, 1H), 7.40 (s, 1H).
Step 10c:2-oxo-1,2-dihydro-pyrimidin-5-carboxylic acid, ethyl ester (compound 0304)
Under reflux state, the acetic acid solution (55 milliliters) of compound 0303 (2.50 grams, 14.7 millis rub) and bromine (2.40 grams, 15 millis rub) carried out 1.5 hours heating.Thereby remove described solvent and obtain crude compound 0304 (3.60 grams, 99%), described compound need not to carry out further purifying and can directly be used in following step: LCMS:169[M+1] +, 1HNMR (400 megahertzes, deuterochloroform): δ 1.27 (t, J=7.2Hz, 3H), 4.28 (q, J=7.2Hz, 2H), 8.85 (s, 2H), 12.19 (ds, 2H).
Step 10d:2-chlorine pyrimidine-5-carboxylic acid ethyl ester (compound 0305)
Under reflux state, to compound 0304 (3.60 grams, 21 millis rub), phosphorus oxychloride (25 milliliters), and the mixed liquor of DMA (2.5 milliliters) carries out 1.5 hours heating.Through after the removal of described solvent, in described residue, add frozen water (10 milliliters).Described mixed liquor is joined among the sodium hydroxide (90 milliliters) of 2N, and utilize ethyl acetate that it is extracted.Described organic layer is evaporated and carries out purifying by column chromatography (being present in the ethyl acetate in the benzinum, 5% volume/volume), thereby obtain compound 0305 (1.20 grams, 30%): LCMS:187[M+1] +, 1HNMR (300 megahertzes, deuterochloroform): δ 1.42 (t, J=7.5Hz, 3H), 4.48 (q, J=7.5Hz, 2H), 9.15 (s, 2H); 1HNMR (400MHz, DMSO-d 6): δ 1.33 (t, J=6.8Hz, 3H); (4.37 q, J=6.8Hz, 2H), 9.18 (s, 2H).
Step 10e:2-(piperazine-1-yl) pyrimidine-5-carboxylic acid's ethyl ester (compound 0306)
At room temperature, dimethyl formamide (DMF) (50 milliliters) mixed liquor of compound 0305 (1.10 grams, 5.9 millis rub) and piperazine (1.02 grams, 11.8 millis rub) carried out 1.5 hours stirring.Utilize water that described mixed liquor is diluted and utilize ethyl acetate that it is extracted.Utilize water that described organic layer is washed and drying, concentrated, thereby obtain compound 0306 (1.20 grams, 86%): LCMS:237[M+1] +, 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.29 (t, J=7.2Hz, 3H), 2.73 (t, J=5.2Hz, 4H), 3.77 (t, J=5.2Hz, 4H), 4.25 (q, J=7.2Hz, 2H), 8.76 (s, 2H).
Step 10f:2-(4-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) piperazine-1-yl) pyrimidine-5-carboxylic acid's ethyl ester (compound 0307)
Among the chloroform mixed liquor (40 milliliters) of compound 0112 (500 milligrams, 1.77 millis rub) and compound 0306 (376 milligrams, 1.59 millis rub), add tetraisopropyl titanate (754 milligrams, 2.66 millis rub).Under reflux state, described mixed liquor is carried out stirred overnight.Evaporating solvent and after this to wherein adding 1,2-dichloroethane (50 milliliters) and sodium cyanoborohydride (168 milligrams, 2.66 milli rub).At room temperature mixed liquor obtained above is carried out 12 hours stirring.Be poured onto described mixed liquor among the saturated sodium bicarbonate and utilize ethyl acetate (2x50 milliliter) that it is extracted.Described organic layer is separated and evaporates, thereby obtain a kind of mixture, (be present in the ethyl acetate in the benzinum by silica gel column chromatography, 10% volume/volume) described mixture is carried out purifying, thereby obtain a kind of compound 0307 (270 milligrams, 34%) of yellow solid form: LCMS:504[M+1] + 1HNMR (400 megahertzes, deuterochloroform) δ 1.35 (t, J=6.8Hz, 3H), 2.62 (s, 4H), (3.85 m, 6H), 4.00 (m, 8H), 4.33 (q, J=6.8Hz, 2H), 7.26 (s, 1H), 8.84 (s, 2H).
Step 10g:2-(4-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) piperazine-1-yl) pyrimidine-5-carboxylic acid's ethyl ester (compound 0308)
Described title compound 0308 is (60 milligrams of solids by using a kind of yellow that the similar step of a kind of and step (embodiment 7) that be used for to describe compound 0204-11 prepares, 23%), by 0307 (220 milligrams, 0.44 milli rubs), (161 milligrams of 0107-3,0.66 milli rubs), (111 milligrams of sodium bicarbonates, 1.32 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (19 milligrams, 0.022 milli rub) at toluene (4.7 milliliters), ethanol (2.8 milliliters) and water (1.2 milliliters) solution prepare: LCMS:586[M+1] + 1HNMR (400 megahertzes, deuterochloroform): δ 1.35 (t, J=6.8Hz, 3H), 2.66 (s, 4H), 3.93 (m, 6H), 4.01 (m, 4H), (4.11 m, 4H), 4.33 (q, J=6.8Hz, 2H), (7.41 s, 1H), 7.51 (m, 1H), 7.69 (d, J=8.4Hz, 1H), 8.28 (d, J=6.8Hz, 1H), (8.84 s, 2H), 9.01 (s, 1H).
Step 10h:2-(4-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) piperazine-1-yl)-N-hydroxypyrimidine-5-carboxamides (compound 14)
Described title compound 14 is (30 milligrams of solids by using a kind of yellow that the similar step of a kind of and step (embodiment 1) that be used for to describe compound 3 prepares, 52%), by 0308 (60 milligrams, 0.10 milli rubs) and the methanol solution of the azanol of fresh preparation (3.0 milliliters, 1.77 millis rub/liter) prepare: fusing point 209-221 ℃.LCMS:573[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 2.59 (s, 4H), 3.85 (m, 8H), 3.95 (s, 2H), 4.01 (m, 4H), 7.47 (m, 1H), (7.52 m, 1H), 7.67 (d, J=8.4Hz, 1H), (8.23 d, J=6.8Hz, 1H), 8.68 (s, 2H), (8.89 s, 1H), 9.00 (s, 1H), (11.07 s, 1H), 13.19 (s, 1H).
Embodiment 11:2-(4-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3, 2-d] pyrimidine-6-yl) methylamino) methyl) piperidin-1-yl)-N-hydroxy pyrimidine-5-first The preparation of acid amides (compound 15)
Step 11a:2 (4-(amino methyl) piperidin-1-yl) pyrimidine-5-carboxylic acid's ethyl ester (compound 0401)
At room temperature, to 0405 (1.10 grams, 5.9 millis rub), the mixed liquor (50 milliliters) of 2-(dimethylamino) acetamide of piperidin-4-yl methylamine (1.35 grams, 11.8 millis rub) carries out 1.5 hours stirring.Through after the removal of described solvent, column chromatography by carrying out at silica gel (is present in the methyl alcohol among the carrene, 6% volume/volume) described residue is carried out purifying, thereby obtained target product 0401 (1.27 grams, 81%): LCMS:265[M+1] +, 1HNMR (400 megahertzes, deuterochloroform): δ 1.16 (m, 2H), 1.22 (m, 5H), (1.36 m, 1H), 1.64 (m, 1H), 1.85 (d, J=12Hz, 2H), 2.62 (d, J=6.42Hz, 2H), 2.94 (ds, J=12.8Hz, J=2.4Hz, 2H), 4.91 (d, J=11.2Hz, 2H), (7.26 s, 1H), 8.82 (s, 2H).
Step 11b:2-(4-(((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) methyl) piperidin-1-yl) pyrimidine-5-carboxylic acid's ethyl ester (compound 0402-15)
Among the chloroform mixed liquor (50 milliliters) of compound 0112 (589 milligrams, 2.08 millis rub) and compound 0401 (500 milligrams, 1.89 millis rub), add tetraisopropyl titanate (644 milligrams, 2.26 millis rub).Under reflux state, described mixed liquor is carried out stirred overnight.Evaporating solvent and after this to wherein adding 1,2-dichloroethane (30 milliliters) and sodium cyanoborohydride (179 milligrams, 2.84 milli rub).At room temperature mixed liquor obtained above is carried out 12 hours stirring.Be poured onto described mixed liquor among the saturated sodium bicarbonate and utilize ethyl acetate (2x50 milliliter) that it is extracted.Described organic layer is separated and evaporates.By silicagel column (being present in the ethyl acetate in the benzinum, 10% volume/volume) described residue is carried out purifying, thereby obtain compound 0402 (630 milligrams, 57%): LCMS:533[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.05-1.14 (m, 2H), 1.29 (t, J=7.2Hz, 3H), 1.78-1.85 (m, 3H), 2.46 (d, J=6.0Hz, 2H), 2.68 (brs, 1H), (2.98 t, J=11Hz, 2H), 3.75 (t, J=4.8Hz, 4H), (3.88 t, J=4.8Hz, 4H), 4.02 (s, 2H), (4.26 t, J=7.2Hz, 2H), 4.74 (d, J=13Hz, 2H), 7.23 (s, 1H), 8.74 (s, 2H).
Step 11c:2-(4-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) methyl) piperidin-1-yl) pyrimidine-5-carboxylic acid's ethyl ester (compound 0403-15)
Described title compound 0403 is (120 milligrams of solids by using a kind of white that the similar step of a kind of and step (embodiment 7) that be used for to describe compound 0204-11 prepares, 17%), by 0402 (630 milligrams, 1.18 milli rubs), (580 milligrams of 0107-3,2.37 milli rubs), (297 milligrams of sodium bicarbonates, 3.54 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (25 milligrams, 0.036 milli rub) at toluene (11 milliliters), ethanol (6.6 milliliters) and water (3.1 milliliters) solution prepare: LCMS:614[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.09-1.14 (m, 2H), 1.28 (t, J=7.2Hz, 3H), 1.82-1.87 (m, 3H), 3.00 (t, J=12Hz, 2H), 3.83 (t, J=4.6Hz, 4H), 4.01 (t, J=4.6Hz, 4H), (4.07 s, 2H), 4.26 (t, J=7.2Hz, 2H), 4.75 (d, J=13Hz, 2H), (7.47 t, J=7.6Hz, 2H), 7.66 (d, J=8.0Hz, 1H), 8.22 (d, J=7.2Hz, 1H), 8.75 (s, 2H), 8.89 (s, 1H), 13.18 (s, 1H).
Step 11d:2-(4-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) methyl) piperidin-1-yl)-N-hydroxypyrimidine-5-carboxamides (compound 15)
Described title compound 15 is (30 milligrams of solids by using a kind of yellow that the similar step of a kind of and step (embodiment 1) that be used for to describe compound 3 prepares, 52%), by 0403 (50 milligrams, 0.08 milli rubs) and the methanol solution of the azanol of fresh preparation (3.0 milliliters, 1.77 millis rub/liter) prepare: fusing point 170-172 ℃.LCMS:601[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.05-1.13 (m, 2H), 1.23 (m, 1H), (1.82-1.85 m, 3H), 2.95 (t, J=12Hz, 2H), 3.84 (s, 4H), 4.01 (s, 4H), 4.07 (s, 2H), 4.71 (d, J=13Hz, 2H), 7.47 (t, J=7.6Hz, 2H), 7.66 (d, J=8.0Hz, 1H), (8.22 d, J=7.2Hz, 1H), 8.65 (s, 2H), 8.88 (s, 1H), (8.98 s, 1H), 11.03 (s, 1H), 13.18 (s, 1H).
Embodiment 12:2-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 54) preparation
Step 12a:(2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl alcohol (compound 0501)
In the methyl alcohol mixed liquor (10 milliliters) of compound 0112 (500 milligrams, 1.77 millis rub), add sodium borohydride (200 milligrams, 5.3 millis rub).At room temperature described mixed liquor is carried out 1 hour stirring.Utilize water that described reaction is quenched and utilize ethyl acetate that it is extracted, carry out drying and concentrated by sodium sulphate, thereby obtain a kind of crude compound 0501 (500 milligrams, 99%) of yellow solid form: LCMS:286[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) .. δ 3.74 (t, J=4.4Hz, 4H), 3.88 (t, J=4.4Hz, 4H), 4.80 (d, J=5.6Hz, 2H), 5.93 (t, J=5.6Hz, 1H), 7.21 (s, 1H).
Step 12b:4-(6-(bromomethyl)-2-chlorothiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) morpholine (compound 0502)
In the dichloromethane solution (100 milliliters) of compound 0501 (1.6 grams, 5.6 millis rub), add N-bromine succinimide (1.2 grams, 6.7 millis rub) and triphenylphosphine (1.75 grams, 6.7 millis rub).Under 25 ℃, described mixed liquor carried out 3 hours stirring.Remove described solvent and (be present in the ethyl acetate in the benzinum by column chromatography, 20% volume/volume) described residue is carried out purifying, thereby obtain a kind of described title compound 0502 (1.16 milligrams, 60%) of yellow solid form: LCMS:348[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) .. δ 3.74 (t, J=4.8Hz, 4H), 3.88 (t, J=4.4Hz, 4H), 4.79 (s, 2H), 7.21 (s, 1H).
Step 12c:(2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl)-N-methyl methylamine (compound 0503-54)
Mixed liquor to the alcoholic solution (50 milliliters) of compound 0502 (190 milligrams) and methylamine under reflux temperature carries out 1 hour stirring.Under reduced pressure, remove described solvent and (be present in the methyl alcohol among the carrene by column chromatography, 12% volume/volume) described residue is carried out purifying, thereby obtain a kind of title compound 0503-54 (190 milligrams, 54%) of yellow solid form: LCMS:299[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 2.06 (s, 3H), 2.93 (s, 1H), 3.45 (t, J=4.4Hz, 4H), 3.57 (t, J=4.4Hz, 4H), 3.73 (s, 2H), 7.02 (s, 1H).
Step 12d:2-(((2-chloro-4-thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0504-54)
At room temperature, to compound 0503-54 (215 milligrams, 0.72 milli rubs), the stirring that the acetonitrile mixed liquor (30 milliliters) of compound 0305 (336 milligrams, 1.8 millis rub) and DIPEA (20 milliliters) spends the night.Under reduced pressure, remove described solvent and utilize ethyl acetate that precipitation obtained above is washed and it is carried out drying, thereby obtain a kind of described title compound 0504-54 (210 milligrams, 65%) of yellow solid form: LCMS:531[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.4 (t, J=6.8Hz, 3H), 3.35 (s, 3H), 3.81 (t, J=4Hz, 4H), 3.93 (t, J=4Hz, 4H), 4.38 (q, J=7.2Hz, 2H), (5.31 s, 2H), 7.05 (s, 1H), 8.97 (s, 2H).
Step 12e:2-(((2-(1H-indazole-4-yl)-4-thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0505)
Utilize nitrogen to (210 milligrams of compounds 0504,0.47 milli rubs), (171 milligrams of 0107-3,0.7 milli rubs), (118 milligrams of sodium bicarbonates, 1.4 milli rubs) and the mixed liquor that forms in toluene (5 milliliters), ethanol (3 milliliters) and water (1.3 milliliters) of two (Diphenyl phosphino ferrocene) palladium chloride (α) (16 milligrams, 0.02 milli rub) washes and in the heating of it being carried out 1 hour under the microwave condition under 120 ℃.In described reaction mixture, add entry and utilize ethyl acetate that it is extracted.Collect described ethyl acetate layer and utilize salt solution that it is washed, carry out drying by magnesium sulfate, filter and evaporation, thereby obtain a kind of residue, utilize carrene that described residue is washed, thereby obtain a kind of described title compound 0505-54 (130 milligrams, 52%) of white solid form: LCMS:449[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.37 (t, J=6.8Hz, 3H), 3.36 (s, 3H), 3.86 (t, J=4.8Hz, 4H), 4.02 (t, J=4.8Hz, 4H), 4.35 (q, J=6.8Hz, 2H), 5.33 (s, 2H), 7.53 (m, 1H), 7.66 (s, 1H), 7.73 (d, J=8Hz, 1H), 8.28 (d, J=7.2Hz, 1H), 8.95 (dd, J1=8Hz, J2=7.6Hz, 1H), 13.28 (s, 1H).
Step 12f:2-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 54)
Described title compound 54 is (17 milligrams of solids by using a kind of white that the similar step of a kind of and step (embodiment 1) that be used for to describe compound 3 prepares, 15%), by (120 milligrams of 0505-54,0.22 milli rubs) and the methanol solution of the azanol of fresh preparation (4.0 milliliters, 1.77 millis rub/liter) prepare: fusing point 197-200 ℃.LCMS:518[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6):. δ 3.26 (s, 3H), 3.86 (t, J=4.0Hz, 4H), 3.96 (t, J=4.0Hz, 4H), 5.23 (s, 2H), 7.47 (t, J=7.6Hz, 1H), 7.58 (s, 1H), 7.67 (d, J=8Hz, 1H), 8.22 (d, J=7.2Hz, 1H), (8.76 s, 2H), 8.87 (s, 1H), 9.09 (s, 1H), 11.16 (s, 1H), 13.22 (s, 1H).
Embodiment 13:2-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 53) Preparation
Step 13a:(2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamine (compound 0503-53)
In the methanol solution (20 milliliters) of compound 0502 (1.5 grams, 4.3 millis rub), add ammoniacal liquor (20 milliliters).The stirring of under 65 ℃, described mixed liquor being spent the night.Under reduced pressure, remove described solvent and (be present in the ethyl acetate among the benzinum by column chromatography, 50% volume/volume) residue obtained above is carried out purifying, thereby obtain a kind of title compound 0503-53 (270 milligrams, 22%) of yellow solid form: LCMS:285[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 3.75 (t, J=4.8Hz, 4H), 3.89 (t, J=4.4Hz, 4H), 4.06 (s, 2H), 7.22 (s, 1H).
Step 13b:2-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0504-53)
At room temperature, to compound 0503-53 (270 milligrams, 0.95 milli rubs), the stirring that the acetonitrile mixed liquor (10 milliliters) of compound 0305 (353 milligrams, 1.9 millis rub) and DIPEA (2 milliliters) spends the night.Under reduced pressure, remove described solvent and utilize carrene that described sediment is washed, drying, thus obtain a kind of described title compound 0504-53 (160 milligrams, 39%) of white solid form: LCMS:435[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.29 (t, J=7.2Hz, 3H), 3.72 (t, J=5.2Hz, 4H), 3.84 (t, J=4.8Hz, 4H), 4.27 (dd, J 1=14.0Hz, J 2=6.8Hz, 2H), 4.88 (d, J=6Hz, 2H), 7.30 (s, 1H), 8.79 (s, 2H), 8.85 (t, J=6Hz, 1H).
Step 13c:2-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0503-53)
Utilize nitrogen to (160 milligrams of compound 0504-53,0.37 milli rubs), (135 milligrams of 0107-3,0.55 milli rubs), (93 milligrams of sodium bicarbonates, 1.11 milli rubs) and the mixed liquor that forms in toluene (5 milliliters), ethanol (3 milliliters) and water (1.3 milliliters) of two (Diphenyl phosphino ferrocene) palladium chloride (α) (13 milligrams, 0.02 milli rub) washes and in the heating of it being carried out 1 hour under the microwave condition under 120 ℃.In described reaction mixture, add entry and utilize ethyl acetate that it is extracted.Collect described organic layer and utilize salt solution that it is washed, carry out drying by magnesium sulfate, filter and evaporation, thereby obtain a kind of residue, utilize carrene that described residue is washed, thereby obtain a kind of described title compound 0505-53 (80 milligrams, 42%) of white solid form: LCMS:517[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.29 (t, J=6.8Hz, 3H), 3.81 (t, J=4.8Hz, 4H), 3.97 (t, J=4.0Hz, 4H), 4.27 (dd, J 1=14.0Hz, J 2=6.8Hz, 2H), 4.93 (d, J=6.0Hz, 2H), 7.45-7.50 (m, 2H), (7.66 d, J=8.0Hz, 1H), 8.22 (d, J=7.6Hz, 1H), 8.81 (d, J=6.4Hz, 2H), 8.88 (s, 2H), 13.2 (s, 1H).
Step 13d:2-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 53)
Described title compound 53 is by using (19 milligrams of a kind of a kind of flaxen solids with preparing for the similar step of the step (embodiment 1) of describing compound 3,24%), by (80 milligrams of 0505-53,0.15 milli rubs) and the methanol solution of the azanol of fresh preparation (5.0 milliliters, 1.77 millis rub/liter) prepare: fusing point 234-237 ℃.LCMS:504[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6):. δ 2.09 (s, 2H), 3.81 (t, J=4.8Hz, 4H), 3.97 (t, J=4.4Hz, 4H), 4.90 (d, J=6.0Hz, 2H), 7.47 (t, J=9.2Hz, 2H), 7.66 (d, J=8.4Hz, 1H), 8.22 (d, J=6.8Hz, 1H), 8.56 (t, J=6.0Hz, 1H), (8.68 s, 2H), 8.88 (s, 1H), 9.04 (s, 1H), 11.09 (s, 1H), 13.21 (s, 1H).
Embodiment 14:2-(4-((((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3, 2-d] pyrimidine-6-yl) methyl) (methyl) amino) methyl) piperidin-1-yl)-the N-hydroxyl The preparation of pyrimidine-5-formamide (compound 16)
Step 14a:2-(4-((((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) methyl) piperidin-1-yl) pyrimidine-5-carboxylic acid's ethyl ester (compound 0402-16)
With (510 milligrams of compound 0402-15,0.96 milli rubs) and (58 milligrams of paraformaldehydes, 1.92 milli rubs) be dissolved among the methyl alcohol (20 milliliters), after this to wherein adding (121 milligrams of sodium cyanoborohydrides, 1.92 milli rubs), the stirring of at room temperature described mixed liquor being spent the night.Remove methyl alcohol and in described residue, add ethyl acetate and water.Utilize water and salt solution that described organic layer is washed, utilize anhydrous sodium sulfate that it is carried out drying.Filter, concentrated and by post (being present in the ethyl acetate among the benzinum, 40% volume/volume) described residue is carried out purifying, thus obtain a kind of compound 0402-16 (265 milligrams, 51%) of yellow solid form.LCMS:546[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.04 (m, 2H), 1.28 (t, J=7.2,3H), 1.84-1.88 (m, 3H), 2.24 (s, 3H), 2.28 (d, J=6.8Hz, 2H), 3.01 (t, J=11.6Hz, 2H), 3.75 (m, 4H), 3.83 (m, 2H), 3.88 (m, 4H), (4.25 q, J=7.2Hz, 2H), 4.74 (d, J=13.2Hz, 2H), 7.27 (s, 1H), 8.75 (s, 2H).
Step 14b:2-(4-((((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) methyl) piperidin-1-yl) pyrimidine-5-carboxylic acid's ethyl ester (compound 0403-16)
Utilize nitrogen to (246 milligrams of compound 0402-16,0.45 milli rubs), (221 milligrams of 0107-3,0.90 milli rubs), (12.6 milligrams of sodium bicarbonates, 1.5 milli rubs) and the mixed liquor that forms in toluene (5 milliliters), ethanol (2.9 milliliters) and water (1.3 milliliters) of two (Diphenyl phosphino ferrocene) palladium chloride (II) (19 milligrams, 0.023 milli rub) washes and in the heating of it being carried out 1 hour under the microwave condition under 120 ℃.Utilize carrene and water that described reaction mixture is separated, utilize salt solution that organic layer is washed, carry out drying by magnesium sulfate, filter and vacuum evaporation.Use column chromatography that residue obtained above is carried out purifying, the methyl alcohol (2% volume/volume) that is present in the carrene is carried out wash-out, thereby obtain a kind of title compound 0403-16 (200 milligrams, 71%) of yellow solid form.LCMS:628[M+1] + 1HNMR (400 megahertzes, deuterochloroform): δ 1.18 (m, 2H), 1.35 (t, J=7.2Hz, 3H), 1.94-1.97 (m, 3H), 2.34-2.36 (m, 5H), (2.97 t, J=12.8Hz, 2H), 3.84 (m, 2H), 3.94 (m, 4H), 4.10 (m, 4H), 4.32 (q, J=7.2Hz, 2H), (4.90 d, J=13.2Hz, 2H), 7.36 (s, 1H), 7.49 (t, J=8.0Hz, 1H), (7.57 d, J=8.0Hz, 1H), 8.27 (d, J=7.2Hz, 1H), 8.82 (s, 2H), (9.01 s, 1H), 10.42 (s, 1H).
Step 14c:2-(4-((((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) methyl) piperidin-1-yl)-N-hydroxypyrimidine-5-carboxamides (compound 16)
Under 0 ℃, add the methanol solution (14 milliliters) of potassium hydroxide (5.61 grams, 100 millis rub) among the agitating solution (24 milliliters) of methyl alcohol of hydroxylamine hydrochloride (4.67 grams, 67 millis rub).Through after adding, under 0 ℃, described mixed liquor carried out 30 minutes stirring, and allow it to leave standstill at low temperatures.Sediment obtained above is separated, and described solution preparation is become free azanol.
The hydroxylamine solution (10.00 milliliters) of above-mentioned fresh preparation is positioned in 100 milliliters the flask.Add compound 111-47-2 (200 milligrams, 0.32 milli rubs) in this solution and under 0 ℃, carry out 15 minutes degassed.(TLC) monitors described course of reaction by thin layer chromatography.Utilize dry ice that described mixed liquor is neutralized, filter and utilize water, methyl alcohol and carrene (DCM) that it is washed, thereby obtain a kind of described title compound 111-47 (130 milligrams, 66%) of yellow solid form: fusing point 174-175 ℃.LCMS:616[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 1.03 (m, 2H), 1.85-1.94 (m, 3H), (2.27-2.31 m, 5H), 2.97 (t, J=12.0Hz, 2H), 3.84 (m, 6H), 4.00 (m, 4H), 4.71 (d, J=12.8Hz, 2H), (7.45-7.49 m, 2H), 7.66 (d, J=8.4Hz, 1H), 8.22 (d, J=7.2Hz, 1H), 8.65 (s, 2H), 8.89 (s, 1H), (9.00 s, 1H), 11.06 (s, 1H), 13.22 (s, 1H).
Embodiment 15:4-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methylamino)-preparation of N-maloyl group amine (compound 41)
Step 15a:4-(tert-butoxycarbonyl ((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) ethyl butyrate (compound 0404-41)
15a-1:4-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) ethyl butyrate
With hydrochloric acid 4-Aminobutanoicacid ethyl ester (1.97 grams, 11.77 milli rubs) be dissolved among the chloroform (30 milliliters) and utilize triethylamine that the pH of described mixed liquor is adjusted to 8-9, after this to wherein adding compound 0112 (1.66 grams, 5.88 milli rubs) and tetraisopropyl titanate (2.01 grams, 7.06 millis rub) and the stirring of under reflux state, described mixed liquor being spent the night.Remove described solvent, after this to wherein adding 1,2-dichloroethane (50 milliliters) and sodium cyanoborohydride (1.48 grams, 23.53 millis rub) and at room temperature carrying out after this 12 hours stirring.Be poured onto described mixed liquor among the saturated sodium bicarbonate solution and utilize ethyl acetate (3x50 milliliter) that it is extracted and (be present in the ethyl acetate among the benzinum by post, 50% volume/volume) carries out purifying, thereby obtain 4-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3 of a kind of yellow solid form, 2-d] pyrimidine-6-yl) methylamino) ethyl butyrate (1.38 grams, 59%).LCMS:399[M+1] + 1HNMR (400 megahertzes, deuterochloroform) δ 1.15 (t, J=7.2Hz, 3H), 1.68 (m, 2H), 2.35 (t, J=7.2Hz, 2H), (2.55 t, J=7.2Hz, 2H), 3.74 (t, J=4.8Hz, 4H), 3.89 (t, J=4.8Hz, 4H), 4.00 (s, 2H), 4.03 (q, J=7.2Hz, 2H), 7.25 (s, 1H).
15a-2:4-(tert-butoxycarbonyl ((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) ethyl butyrate (0404-41)
To 4-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) (400 milligrams of ethyl butyrates, 1.0 milli rubs) oxolane (THF) solution (10 milliliters) in add di-tert-butyl dicarbonate (218 milligrams, 1.0 millis rub).The stirring of at room temperature described mixed liquor being spent the night after this.Utilize ethyl acetate to extract and utilize water, salt solution that it is washed to described reaction mixture, and carry out drying by sodium sulphate.Use column chromatography (being present in the ethyl acetate among the benzinum, 75% volume/volume) that described crude product is carried out purifying, thereby obtain a kind of title compound 0404-41 (330 milligrams, 66%) of colourless liquid form.LCMS:499[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.16 (t, J=7.2Hz, 3H), 1.42 (s, 9H), (1.74 m, 2H), 2.26 (t, J=7.2Hz, 2H), (3.23 t, J=7.2Hz, 2H), 3.74 (t, J=4.4Hz, 4H), 3.87 (t, J=4.4Hz, 4H), 4.03 (q, J=7.2Hz, 2H), (4.64 s, 2H), 7.30 (s, 1H).
Step 15b.4-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (tert-butoxycarbonyl) amino) ethyl butyrate (compound 0405-41)
Utilize nitrogen to (386 milligrams of compound 0404-41,0.78 milli rubs), (378 milligrams of 0107-3,1.55 milli rubs), (196 milligrams of sodium bicarbonates, 2.33 milli rubs) and the mixed liquor that forms in toluene (8 milliliters), ethanol (5 milliliters) and water (2 milliliters) of two (Diphenyl phosphino ferrocene) palladium chloride (α) (27 milligrams, 0.05 milli rub) washes and in the heating of it being carried out 1 hour under the microwave condition under 120 ℃.Utilize carrene and water that described reaction mixture is separated, utilize salt solution that organic layer is washed, carry out drying by sodium sulphate, filter and vacuum evaporation.Use column chromatography that residue obtained above is carried out purifying, the methyl alcohol (2-5% volume/volume) that is present in the carrene is carried out wash-out, thereby obtain a kind of title compound 0405-41 (396 milligrams, 79%) of white solid form.LCMS:581[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.16 (t, J=7.2Hz, 3H), 1.44 (s, 9H), 1.78 (m, 2H), 2.28 (t, J=7.2Hz, 2H), 3.28 (t, J=6.8Hz, 2H), 3.83 (m, 4H), 4.03 (m, 6H), 4.70 (s, 2H), 7.47 (t, J=8.0Hz, 1H), 7.51 (s, 1H), (7.67 d, J=8.0Hz, 1H), 8.22 (d, J=8.0Hz, 1H), 8.88 (s, 1H), 13.22 (s, 1H).
Step 15c:4-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino)-N-maloyl group amine (compound 41)
Under 0 ℃, add the methanol solution (14 milliliters) of potassium hydroxide (5.64 grams, 100 millis rub) among the agitating solution (24 milliliters) of methyl alcohol of hydroxylamine hydrochloride (4.67 grams, 67 millis rub).Through after adding, under 0 ℃, described mixed liquor carried out 30 minutes stirring, and allow it to leave standstill at low temperatures.Sediment obtained above is separated, and described solution preparation is become free azanol.
The hydroxylamine solution (6.00 milliliters) of above-mentioned fresh preparation is positioned in 50 milliliters the flask.Add compound 0405-41 (300 milligrams, 0.51 milli rubs) in this solution and at room temperature described mixed liquor is carried out 30 minutes degassed.(TLC) monitors described course of reaction by thin layer chromatography.Utilize dry ice that described mixed liquor is neutralized, filter, and utilize methyl alcohol and water that described sediment is washed, thereby obtain a kind of (2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3 of white solid form, 2-d] pyrimidine-6-yl) methyl (4-(hydroxyl amino)-4-oxo butyl) t-butyl carbamate (267 milligrams, 91%).LCMS:568[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 1.45 (s, 9H), 1.74 (m, 2H), 1.96 (t, J=7.2Hz, 2H), 3.23 (m, 2H), 3.83 (m, 4H), 4.00 (m, 4H), 7.47 (t, J=8.0Hz, 1H), 7.50 (s, 1H), 7.67 (d, J=8.0Hz, 1H), 8.22 (d, J=8.0Hz, 1H), 8.70 (s, 1H), 8.88 (s, 1H), 10.39 (s, 1H), 13.22 (s, 1H).
After this compound of above-mentioned preparation is added among the solution (7.00 milliliters) of the hydrochloric acid isopropyl alcohol of fresh preparation.At room temperature described reaction mixture is carried out 2 hours stirring.Described mixed liquor is evaporated and it is dissolved in the water.Under 0 ℃, utilize after this ammonia that described mixed liquor is neutralized, filter and utilize methyl alcohol and water that described sediment is washed, thereby obtain described crude product, utilize preparative high performance liquid chromatography (HPLC) that described crude product is carried out purifying.Form with a kind of orange solids has obtained compound 41 (50 milligrams, 24%): fusing point 149-152 ℃.
LCMS:468[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 1.55 (m, 2H), 1.87 (t, J=7.2Hz, 2H), (2.45 t, J=7.2Hz, 2H), 3.68 (m, 4H), (3.86 m, 6H), 3.96 (s, 2H), 7.32 (m, 2H), 7.51 (d, J=8.0Hz, 1H), 7.98 (s, 1H), 8.07 (d, J=8.0Hz, 1H), 8.56 (s, 1H), 8.73 (s, 1H), 13.06 (s, 1H).
Embodiment 16:5-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methylamino)-preparation of N-hydroxyl pentanamide (compound 42)
Step 16a:5-(tert-butoxycarbonyl ((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) ethyl valerate (compound 0404-42)
Described title compound 0404-42 (0.75 gram, 33.3%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 15) of describing compound 0404-41, by 0112 (1.2 grams, 4.24 milli rubs), hydrochloric acid 5-aminovaleric acid salt (1.416 grams, 8.48 milli rubs) prepare, described preparation need not to carry out further purifying: LCMS:399[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.39-1.47 (m, 2H), 1.52-1.60 (m, 2H), (2.30 t, J=7.2Hz, 2H), 2.53 (t, J=6.8Hz, 2H), 3.58 (s, 3H), (3.74 t, J=4.8Hz, 4H), 3.88 (t, J=4.8Hz, 4H), 3.99 (s, 2H), 7.23 (s, 1H). compound 0404-42:LCMS:499[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.23 (s, 9H), 1.47-1.49 (m, 4H), (2.30 t, J=6.8Hz, 2H), 3.20 (s, 2H), 3.56 (s, 3H), 3.74 (t, J=4.8Hz, 4H), 3.88 (t, J=4.8Hz, 4H), 4.64 (s, 2H), 7.31 (s, 1H).
Step 16b.5-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (tert-butoxycarbonyl) amino) methyl valerate (compound 0405-42)
(260 milligrams of described title compound 0405-42,55.8%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 15) of describing compound 0404-42, by (400 milligrams of compound 0404-42,0.803 milli rubs), (216 milligrams of 0107-3,0.884 milli rubs), (202.4 milligrams of sodium bicarbonates, 2.41 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (α) (30 milligrams, 0.0402 milli rub) at toluene (8 milliliters), the mixed liquor that forms in ethanol (5 milliliters) and the water (2 milliliters) is prepared from: LCMS:581[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.44 (s, 9H), 1.50-1.52 (m, 4H), 3.25 (s, 2H), 3.56 (s, 3H), 3.83 (d, J=5.2Hz, 4H), 4.00-4.10 (m, 6H), 4.69 (s, 2H), (7.47-7.51 m, 2H), 7.67 (d, J=8.4Hz, 1H), 8.23 (d, J=6.8Hz, 1H), (8.88 s, 1H), 13.20 (s, 1H).
Step 16c:5-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino)-N-hydroxyl pentanamide (compound 42)
Described title compound 42 is (23 milligrams of solids by using a kind of white that the similar step of a kind of and step (embodiment 15) that be used for to describe compound 41 prepares, 13.9%), the methanol solution (8.0 milliliters) that is the azanol by 0405-42 (260 milligrams, 0.45 milli rub) and fresh preparation prepares: fusing point 145-147 ℃.LCMS:482[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.54-1.63 (m, 4H), 1.99 (t, J=7.2Hz, 2H), 3.02 (s, 2H), 3.87 (m, 4H), 4.05 (m, 4H), 4.58 (t, J=4.4Hz, 2H), 7.49 (t, J=8.4Hz, 1H), 7.70 (d, J=8Hz, 1H), 7.78 (s, 1H), 8.24 (d, J=10.4Hz, 1H), 8.87 (s, 1H), 9.11 (s, 2H), 10.42 (s, 1H), 13.28 (s, 1H).
Embodiment 17:6-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methylamino)-preparation of N-hydroxyl hexanamide (compound 43)
Step 17a:6-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) ethyl hexanoate (compound 0404-43)
(343 milligrams of described title compound 0404-43,38%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 15) of describing compound 0404-41, by 0112 (0.6 gram, 2.12 milli rubs) and hydrochloric acid 6-aminocaprolc acid ethyl ester (0.83 gram, 4.24 millis rub) prepare: LCMS:427[M+1] + 1HNMR (400 megahertzes, deuterochloroform) δ 1.17 (t, J=6.4Hz, 3H), 1.24-1.33 (m, 2H), 1.40-1.45 (m, 2H), 1.48-1.55 (m, 2H), (2.09 s, 1H), 2.27 (t, J=7.2Hz, 2H), (2.53 t, J=6.8Hz2H), 3.74 (t, J=5.2Hz, 4H), (3.88 t, J=4.8Hz, 4H), 3.99 (s, 2H), (4.03 q, J=6.4Hz, 2H), 7.23 (s, 1H).
Step 17b.6-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) ethyl hexanoate (compound 0405-43)
Utilize nitrogen to (343 milligrams of compound 0404-43,0.80 milli rubs), (294 milligrams of 0107-3,1.2 milli rubs), (294 milligrams of sodium bicarbonates, 2.4 milli rubs) and the mixed liquor that forms in toluene (8 milliliters), ethanol (5 milliliters) and water (2 milliliters) of two (Diphenyl phosphino ferrocene) palladium chloride (α) (29 milligrams, 0.05 milli rub) washes and in the heating of it being carried out 1 hour under the microwave condition under 120 ℃.Utilize carrene and water that described reaction mixture is separated, utilize salt solution that organic layer is washed, carry out drying by magnesium sulfate, filter and vacuum evaporation.Use column chromatography that residue obtained above is carried out purifying, the methyl alcohol (2-5%, volume/volume) that is present in the carrene is carried out wash-out, thereby obtain a kind of title compound 0405-43 (120 milligrams, 29%) of yellow solid form.LCMS:509[M+1] + 1HNMR (400 megahertzes, deuterochloroform): δ 1.17 (t, J=7.2Hz, 3H), (1.28-1.35 m, 2H), 1.42-1.57 (m, 4H), (2.28 t, J=7.2Hz, 2H), 2.57 (t, J=6.8Hz, 2H), 3.83 (t, J=4.0Hz, 4H), 3.97-4.06 (m, 6H), (7.45 s, 1H), 7.47 (d, J=7.6Hz, 1H), 7.66 (d, J=8.0Hz, 1H), 8.22 (d, J=7.2Hz, 1H), 8.88 (s, 1H), 13.21 (s, 1H).
Step 17c:6-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino)-N-hydroxyl hexanamide (compound 43)
(17 milligrams of described title compounds 43,15%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (4.0 milliliters) that is the azanol by 0405-43 (120 milligrams, 0.24 milli rub) and fresh preparation prepares: fusing point 128-130 ℃.LCMS:496[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 1.23-1.32 (m, 2H), 1.42-1.53 (m, 4H), (1.95 t, J=6.8Hz, 2H), 2.57 (t, J=7.2Hz, 2H), 3.84 (t, J=4.0Hz, 4H), 4.01 (t, J=4.0Hz, 4H), (4.06 s, 2H), 7.45 (s, 1H), (7.48 d, J=7.6Hz, 1H), 7.66 (d, J=8Hz, 1H), 8.22 (d, J=7.2Hz, 1H), 8.66 (s, 1H), (8.88 s, 1H), 10.34 (s, 1H), 13.21 (s, 1H).
Embodiment 18:7-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methylamino)-preparation of N-hydroxyl heptamide (compound 44)
Step 18a:7-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) cognac oil (compound 0404-44)
(700 milligrams of described title compound 0404-44,45%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 15) of describing compound 0404-41, by 0112 (1 gram, 3.5 milli rubs) and hydrochloric acid ethyl 7-aminoheptanoate (1.5 grams, 7.0 millis rub) prepare: LCMS:442[M+1] + 1HNMR (400 megahertzes, deuterochloroform) δ 1.16 (t, J=7.2Hz, 3H), 1.21-1.27 (m, 4H), 1.45 (m, 2H), 1.50 (m, 2H), (2.21-2.28 m, 2H), 2.52 (t, J=7.2Hz, 2H), (2.66 s, 1H), 3.74 (t, J=5.2Hz, 4H), 3.88 (t, J=4.8Hz, 4H), (4.00-4.06 m, 4H), 7.23 (s, 1H).
Step 18b.7-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) cognac oil (compound 0405-44)
(260 milligrams of described title compound 0405-44,63%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 17) of describing compound 0405-43, by (350 milligrams of 0404-44,0.79 milli rubs) and 0107-03 (290 milligrams, 1.19 milli rub) prepare: LCMS:523[M+1] + 1HNMR (400 megahertzes, deuterochloroform): δ 1.16 (t, J=6Hz, 3H), (1.26-1.31 m, 4H), 1.44 (m, 2H), (1.52 m, 2H), 2.21-2.28 (m, 2H), 2.56 (t,, J=7.2Hz, 2H), 3.83 (t,, J=4.8Hz, 4H), (4.01 t, J=4.8Hz, 4H), 4.04 (s, 2H), 7.46 (m, 2H), 7.66 (d, J=8.4Hz, 1H), 8.22 (d, J=7.2Hz, 1H), 8.88 (s, 1H), 13.20 (s, 1H).
Step 18c:7-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino)-N-hydroxyl heptamide (compound 44)
(37 milligrams of described title compounds 44,24%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (3.0 milliliters) that is the azanol by 0405-44 (160 milligrams, 0.31 milli rub) and fresh preparation prepares: fusing point 188-190 ℃.LCMS:510[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 1.19-1.33 (m, 4H), 1.41-1.52 (m, 4H), (1.93 t, J=7.2Hz, 2H), 2.56 (t, J=6.8Hz, 2H), 3.83 (t, J=4.4Hz, 4H), 4.01 (t, J=4.4Hz, 4H), (4.05 s, 2H), 7.44 (s, 1H), (7.48 d, J=7.6Hz, 1H), 7.66 (d, J=8Hz, 1H), 8.22 (d, J=6.8Hz, 2H), 8.68 (s, 1H), (8.88 s, 1H), 10.34 (s, 1H), 13.21 (s, 1H).
Embodiment 19:4-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methyl) (methyl) amino)-N-maloyl group amine (compound 101) Preparation
Step 19a:4-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) ethyl butyrate (compound 0404-101)
In the methanol solution (5 milliliters) of 4-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) ethyl butyrate (100 milligrams, 0.25 milli rubs), add polyformaldehyde (15 milligrams, 0.50 milli rubs).Through at room temperature having carried out after 30 minutes the stirring, to wherein adding slowly sodium cyanoborohydride (32 milligrams, 0.50 milli rubs), and described mixed liquor is carried out 30 minutes stirring again.By 0 ℃ of lower mode of adding water (5 milliliters) described reaction being stopped and stirring.Sediment obtained above is filtered and utilizes water to wash, thereby obtain a kind of 0404-101 (85 milligrams, 83%) of yellow solid form.LCMS:413[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.14 (t, J=7.2Hz, 3H), 1.72 (m, 2H), (2.22 s, 3H), 2.32 (t, J=7.2Hz, 2H), (2.41 t, J=7.2Hz, 2H), 3.75 (t, J=4.4Hz, 4H), 3.82 (s, 2H), (3.88 t, J=4.4Hz, 4H), 4.02 (q, J=7.2Hz, 2H), 7.27 (s, 1H).
Step 19b:4-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) ethyl butyrate (compound 111-48-3)
(200 milligrams of described title compound 0405-101,56%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 17) of describing compound 0405-43, by (300 milligrams of 0404-101,0.73 milli rubs) and 0107-03 (356 milligrams, 1.46 milli rub) prepare: LCMS:495[M+1] + 1HNMR (400 megahertzes, deuterochloroform): δ 1.15 (t, J=7.2Hz, 3H), 1.75 (m, 2H), 2.25 (s, 3H), 2.35 (t, J=7.2Hz, 2H), 2.44 (t, J=7.2Hz, 2H), 3.83 (m, 6H), 4.02 (m, 6H), 7.47 (m, 2H), (7.67 d, J=8.0Hz, 1H), 8.22 (d, J=8.0Hz, 1H), 8.89 (s, 1H), 13.21 (s, 1H).
Step 19c:4-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-maloyl group amine (compound 101)
(160 milligrams of described title compounds 101,88%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (6.0 milliliters) that is the azanol by 0405-101 (187 milligrams, 0.38 milli rub) and fresh preparation prepares: fusing point 115-118 ℃.LCMS:482[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 1.72 (m, 2H), 2.02 (t, J=6.0Hz, 2H), (2.25 s, 3H), 2.42 (t, J=6.0Hz, 2H), (3.85 m, 6H), 4.01 (m, 4H), (7.47 m, 2H), 7.67 (d, J=7.6Hz, 1H), 8.22 (d, J=6.8Hz, 1H), (8.89 s, 1H), 13.26 (s, 1H).
Embodiment 20:5-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxyl pentanamide (compound 102) Preparation
Step 20a:5-(((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) methyl valerate (compound 0404-102)
Described title compound 0404-102 (0.62 gram, 86%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 19) of describing compound 0404-101, by 5-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) (700 milligrams of methyl valerates, 1.76 milli rubs), (106 milligrams of paraformaldehydes, 3.52 milli rubs) methanol solution (30 milliliters) and sodium cyanoborohydride (221 milligrams, 3.52 milli rub) be prepared from: LCMS:413[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.45-1.59 (m, 4H), 2.21 (s, 3H), (2.32 t, J=6.8Hz, 2H), 2.40 (t, J=7.2Hz, 2H), 3.58 (s, 3H), (3.75 t, J=5.2Hz, 4H), 3.81 (s, 2H), 3.88 (t, J=4.8Hz, 4H), 7.26 (s, 1H).
Step 20b:5-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) methyl valerate (compound 0405-102)
(305 milligrams of described title compound 0405-102,61.7%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 17) of describing compound 0405-43, by (350 milligrams of 0404-102,0.85 milli rubs) and 0107-03 (311 milligrams, 1.27 milli rub) prepare: LCMS:495[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.48-1.57 (m, 4H), 2.24 (s, 3H), 2.34 (t, J=6.8Hz, 2H), 2.44 (t, J=6.8Hz, 2H), (3.58 s, 3H), 3.84 (d, J=8.4Hz, 6H), (3.97-4.04 m, 4H), 7.49 (m, 2H), 7.67 (d, J=8.4Hz, 1H), 8.22 (d, J=7.2Hz, 1H), (8.88 s, 1H), 13.20 (s, 1H).
Step 20c:5-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxyl pentanamide (compound 102)
(60 milligrams of described title compounds 102,25%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (8.0 milliliters) that is the azanol by 0405-102 (240 milligrams, 0.48 milli rub) and fresh preparation prepares: fusing point 120-122 ℃.LCMS:496[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 1.48-1.54 (m, 4H), 1.98 (t, J=6.8Hz, 2H), (2.24 s, 3H), 2.44 (t, J=7.2Hz, 2H), (3.85 d, J=6.8Hz, 4H), 4.01 (s, 4H), (7.46 s, 2H), 7.66 (d, J=7.2Hz, 1H), (8.22 d, J=7.6Hz, 1H), 8.88 (s, 1H), (10.31 s, 1H), 13.18 (s, 1H).
Embodiment 21:6-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxyl hexanamide (compound 103) Preparation
Step 21a:6-(((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) ethyl hexanoate (compound 0404-103)
Described title compound 0404-103 (0.62 gram, 86%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 19) of describing compound 0404-101, by 0404-43 (0.67 gram, 1.57 milli rubs), (94 milligrams of paraformaldehydes, 3.14 milli rubs) and sodium cyanoborohydride (197 milligrams, 3.14 milli rub) be prepared from: LCMS:441[M+1] +1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.16 (t, J=7.2Hz, 3H), 1.24-1.32 (m, 2H), (1.43-1.55 m, 4H), 2.21 (s, 3H), 2.27 (t, J=7.2Hz, 2H), 2.39 (t, J=7.6Hz, 2H), (3.75 t, J=4.8Hz, 4H), 3.81 (s, 2H), (3.88 t, J=4.4Hz, 4H), 4.03 (q, J=7.2Hz, 2H), 7.26 (s, 1H).
Step 21b:6-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) ethyl hexanoate (compound 0405-103)
(190 milligrams of described title compound 0405-103,54%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 17) of describing compound 0405-43, by (300 milligrams of 0404-103,0.68 milli rubs) and 0107-03 (199 milligrams, 0.82 milli rub) prepare: LCMS:523[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.16 (t, J=7.2Hz, 3H), 1.28-1.35 (m, 2H), (1.47-1.57 m, 4H), 2.27 (m, 5H), 2.41 (t, J=6.4Hz, 2H), 3.84 (m, 6H), 4.04 (m, 6H), 7.47 (m, 2H), 7.67 (d, J=8Hz, 1H), 8.23 (d, J=6.8Hz, 1H), (8.89 s, 1H), 13.21 (s, 1H).
Step 21c:6-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxyl hexanamide (compound 103)
(75 milligrams of described title compounds 103,41%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (4.0 milliliters) that is the azanol by 0405-103 (190 milligrams, 0.22 milli rub) and fresh preparation prepares: fusing point 115-118 ℃.LCMS:510[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 1.23-1.27 (m, 2H), 1.45-1.55 (m, 4H), 1.95 (t, J=7.2Hz, 2H), 2.24 (s, 3H), 2.42 (t, J=7.2Hz, 2H), (3.84 m, 6H), 4.00 (m, 4H), 7.47 (m, 2H), 7.66 (d, J=8.4Hz, 1H), 8.22 (d, J=7.6Hz, 1H), 8.68 (s, 1H), 8.89 (s, 1H), 10.35 (s, 1H), 13.21 (s, 1H).
Embodiment 22:7-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxyl heptamide (compound 104) Preparation
Step 22a:7-(((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) cognac oil (compound 0404-104)
(670 milligrams of described title compound 0404-104,95%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 19) of describing compound 0404-101, by 0404-44 (0.67 gram, 1.52 milli rubs), (91 milligrams of paraformaldehydes, 3.04 milli rubs) and sodium cyanoborohydride (191 milligrams, 3.04 milli rub) be prepared from: LCMS:455[M+1]+; 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d6): δ 1.16 (t, J=7.2Hz, 3H), 1.23-1.32 (m, 4H), 1.42-1.54 (m, 4H), 2.21 (s, 3H), (2.25 t, J=7.6Hz, 2H), 2.39 (t, J=7.2Hz, 2H), 3.74 (t, J=4Hz, 4H), 3.80 (s, 2H), 3.88 (t, J=4.8Hz, 4H), 4.03 (q, J=7.2Hz, 2H), 7.25 (s, 1H).
Step 22b:7-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) cognac oil (compound 0405-104)
(260 milligrams of described title compound 0405-104,67%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 17) of describing compound 0405-43, by (330 milligrams of 0404-104,0.73 milli rubs) and 0107-03 (176 milligrams, 0.73 milli rub) prepare: LCMS:537[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.14 (t, J=7.2Hz, 3H), 1.28-1.41 (m, 4H), (1.49-1.55 m, 4H), 2.25 (m, 5H), 2.41 (t, J=6.8Hz, 2H), 3.83 (m, 6H), 4.01 (m, 6H), 7.46 (m, 2H), 7.65 (d, J=7.6Hz, 1H), 8.21 (d, J=6.8Hz, 1H), (8.87 s, 1H), 13.17 (s, 1H).
Step 22c:7-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxyl heptamide (compound 104)
(65 milligrams of described title compounds 104,55%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (4.0 milliliters) that is the azanol by 0405-104 (120 milligrams, 0.22 milli rub) and fresh preparation prepares: fusing point 131-133 ℃.LCMS:524[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 1.21-1.27 (m, 4H), 1.34-1.43 (m, 4H), 1.94 (t, J=7.6Hz, 2H), 2.24 (s, 3H), 2.43 (t, J=7.6Hz, 2H), (3.84 m, 6H), 4.00 (m, 4H), 7.47 (m, 2H), 7.67 (d, J=8Hz, 1H), 8.22 (d, J=7.2Hz, 1H), 8.68 (s, 1H), 8.89 (s, 1H), 10.34 (s, 1H), 13.21 (s, 1H).
Embodiment 23:2-(((2-(6-fluoro-1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3, 2-d] pyrimidine-6-yl) methyl) (methyl) amino)-(change of N-hydroxypyrimidine-5-carboxamides Compound 69) preparation
Step 23a:3-bromo-5-fluoro-2-methylbenzene amine (compound 0104-69)
To 4-fluorine-2-nitro methylbenzene (10.0 grams, 64.4 milli rubs) trifluoroacetic acid solution (40 milliliters) in add the concentrated sulfuric acid (12.5 milliliters) and add subsequently N-bromosuccinimide (NBS) (17.2 grams, 96.6 milli rubs), and at room temperature described reaction mixture is carried out 16 hours stirring.After this described reaction mixture is poured onto in ice and the water and carries out 15 minutes stirring.Utilize ethyl acetate that it is extracted and utilize salt solution that described organic layer is washed, drying, concentrated, thus obtain a kind of compound 1-bromo-5-fluoro-2-methyl-3-nitro benzene (15.0 grams, 100%) of yellow oil form. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 2.41 (s, 3H), 7.96 (dd, J=8.0,2.4Hz, 1H), 8.02 (dd, J=8.0,2.4Hz, 1H).Under reflux state, to the compound (15.0 grams, 64.4 millis rub) by above-mentioned preparation, iron (18.0 grams, 0.32 rub), mixed liquor (150 milliliters) and the water (30 milliliters) of the methyl alcohol that concentrated hydrochloric acid (2 milliliters) forms carry out 4 hours stirring.Utilize after this sodium hydrate aqueous solution that the pH of described mixed liquor is adjusted to 12 and filter.Remove described solvent and utilize water that it is diluted.Utilize ethyl acetate to extract, drying, concentrated.By column chromatography (being present in the ethyl acetate among the benzinum, 7%) described residue is carried out purifying, thereby obtain the compound 0104-69 (5.8 grams, 44%) of yellow oil form.LCMS:204[M+1] +, 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 2.12 (s, 3H), 5.57 (s, 2H), 6.45 (dd, J=11.2,2.4Hz, 1H), 6.60 (dd, J=8.0,2.4Hz, 1H).
Step 23b:4-bromo-6-fluoro-1H-indazole (compound 0106-69)
Described title compound 0106-69 (3.7 grams, 61%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 0106-3, by 0104-69 (5.8 grams, 28.4 milli rubs), potassium acetate (2.93 grams, 29.8 milli rubs), acetic anhydride (5.8 grams, 56.8 milli rubs) and isoamyl nitrite (7.32 grams, 62.5 milli rubs) and subsequently hydrolysis prepare, wherein said hydrolysis is to realize by aqueous hydrochloric acid solution (6N, 35 milliliters): LCMS:215[M+1] +, 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 7.37-7.44 (m, 2H), 8.07 (s, 1H), 13.54 (s, 1H).
Step 23c:6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl)-1H-indazole (compound 107-69)
(700 milligrams of described title compound 0107-69,57%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 0107-3, by 0106-69 (1.0 grams, 4.65 milli rubs), connection boric acid pinacol ester (1.77 grams, 6.98 milli rubs), (380 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.47 milli rubs) and the dioxane solution (40 milliliters) of anhydrous acetic acid potassium (1.37 grams, 14.0 millis rub) prepare: LCMS:263[M+1] +.
Step 23d:2-(((2-(6-fluoro-1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0505-69)
Utilize nitrogen to (200 milligrams of compound 0504-54,0.45 milli rubs), (135 milligrams of 0107-69,0.5 milli rubs), (115 milligrams of sodium bicarbonates, 1.3 milli rubs) and the mixed liquor that forms in toluene (8 milliliters), ethanol (5 milliliters) and water (2 milliliters) of two (Diphenyl phosphino ferrocene) palladium chloride (II) (15 milligrams, 0.02 milli rub) washes and in the heating of it being carried out 5 hours under the microwave condition under 120 ℃.Utilize ethyl acetate and water that described reaction mixture is separated, utilize salt solution that described organic layer is washed, carry out drying by sodium sulphate, filter, concentrated and utilize ethyl acetate that it is washed, thereby obtain a kind of described title compound 0505-69 (100 milligrams, 41%) of yellow solid form.LCMS:549[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.30 (t, J=7.2Hz, 3H), 3.29 (s, 3H), (3.79 t, J=4.4Hz, 4H), 3.96 (t, J=4.4Hz, 4H), 4.29 (q, J=7.2Hz, 2H), 5.27 (s, 2H), 7.46 (d, J=7.2Hz, 1H), 7.62 (s, 1H), 7.98 (dd, J=10.4Hz, 2.4Hz, 1H), (8.94 m, 3H), 13.27 (s, 1H).
Step 23e:2-(((2-(6-fluoro-1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 69)
(24 milligrams of described title compounds 69,25%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (10.0 milliliters) that is the azanol by 0505-69 (100 milligrams, 0.18 milli rub) and fresh preparation prepares: fusing point 215-217 ℃.LCMS:536[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 3.26 (s, 3H), 3.79 (m, 4H), 3.96 (m, 4H), 5.24 (s, 2H), 7.46 (d, J=7.6Hz, 1H), 7.59 (s, 1H), 7.98 (dd, J=10.8,2.0Hz, 1H), 8.76 (s, 2H), (8.89 s, 1H), 9.08 (s, 1H), (11.14 s, 1H), 13.28 (s, 1H).
Embodiment 24:2-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methyl) (neopentyl) amino)-N-hydroxypyrimidine-5-carboxamides (chemical combination Thing 83) preparation
Step 24a:N-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl)-2,2-dimethyl propylene-1-amine (compound 0503-83)
Under 35 ℃, to compound 0503-53 (600 milligrams, 2.1 millis rub), (912 milligrams of trimethyl-acetaldehydes, 10.6 milli rubs) and chloroform/methyl alcohol (8 milliliters/4 milliliters) solution of tetraethyl titanate (958 milligrams, 4.2 milli rub) carry out 20 hours stirring.After this to wherein adding sodium cyanoborohydride (530 milligrams, 8.4 millis rub) and under 45 ℃, carrying out 3 hours stirring.Utilize water that this mixed liquor is diluted, utilize carrene that it is extracted, by sodium sulphate it is carried out drying, and concentrate, thereby obtain a kind of 0503-83 (631 milligrams, 85%) of yellow solid form.LCMS:355[M+1] +. 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 0.95 (s, 9H), 2.29 (s, 2H), 3.74 (m, 4H), 3.88 (m, 4H), 4.02 (s, 2H), 7.23 (s, 1H).
Step 24b:2-(((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (neopentyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0504-83)
Under 70 ℃, to (400 milligrams of compound 0503-83,1.13 milli rubs), 0305 (846 milligrams, 4.52 milli rubs) and diisopropylethylamine (DIPEA) (1.5 grams, 11.3 the milli rub) acetonitrile mixed liquor (8 milliliters) carry out 24 hours stirring, concentrated, (be present in the ethyl acetate among the benzinum by column chromatography, 10% volume/volume) it is carried out purifying, thereby obtain a kind of compound 0504-83 (530 milligrams, 93%) of yellow solid form.LCMS:505[M+1] +, 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 0.97 (s, 9H), 1.29 (m, 3H), 3.67 (s, 2H), 3.72 (m, 4H), 3.87 (m, 4H), 4.27 (m, 2H), 5.19 (s, 2H), 7.35 (s, 1H), 8.84 (s, 2H).
Step 24c:2-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (neopentyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0505-83)
Utilize nitrogen to (300 milligrams of compound 0504-83,0.6 milli rubs), (176 milligrams of 0107-3,0.72 milli rubs), (152 milligrams of sodium bicarbonates, 1.8 milli rubs) and the mixed liquor that forms in toluene (4 milliliters), ethanol (2 milliliters) and water (1 milliliter) of two (Diphenyl phosphino ferrocene) palladium chloride (II) (22 milligrams, 0.03 milli rub) washes and in the heating of it being carried out 1 hour under the microwave condition under 120 ℃.Utilize carrene and water that described reaction mixture is separated, utilize salt solution that described organic layer is washed, carry out drying by sodium sulphate, filter and vacuum evaporation.Use column chromatography (being present in the methyl alcohol among the carrene, the 2-5% volume/volume) that residue obtained above is carried out purifying, thereby obtain a kind of described title compound 0505-83 (300 milligrams, 85%) of white solid form.LCMS:587[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 0.99 (s, 9H), 1.29 (t, J=7.2Hz, 3H), 3.70 (s, 2H), 3.79 (m, 4H), 3.95 (m, 4H), 4.27 (q, J=7.6Hz, 2H), 5.24 (s, 2H), 7.46 (t, J=7.6Hz, 1H), 7.55 (s, 1H), 7.67 (d, J=8.4Hz, 1H), 8.21 (d, J=7.2Hz, 1H), 8.85 (s, 2H), 8.89 (s, 1H), 13.21 (s, 1H).
Step 24d:2-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (neopentyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 83)
(191 milligrams of described title compounds 83,65%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (20.0 milliliters) that is the azanol by 0505-83 (300 milligrams, 0.51 milli rub) and fresh preparation prepares: fusing point 240-242 ℃.LCMS:574[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 0.99 (s, 9H), 3.67 (s, 2H), 3.80 (m, 4H), (3.95 m, 4H), 5.22 (s, 2H), 7.46 (t, J=8.0Hz, 1H), 7.54 (s, 1H), 7.67 (d, J=8.0Hz, 1H), 8.21 (d, J=7.2Hz, 1H), (8.73 s, 2H), 8.89 (s, 1H), 9.07 (s, 1H), 11.12 (s, 1H), 13.20 (s, 1H).
Embodiment 25:2-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methyl) (propyl group) amino)-N-hydroxypyrimidine-5-carboxamides (compound 84) preparation
Step 25a:N-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) third-1-amine (compound 0503-84)
Be dissolved in compound 0502 (500 milligrams, 1.43 milli rub) among the methyl alcohol (30 milliliters) and after this to wherein adding third-1-amine (5 milliliters).Under 65 ℃, described mixed liquor is stirred and by thin layer chromatography (TLC) described course of reaction is monitored.Under reduced pressure, remove after this described solvent and utilize carrene and water separates described sediment, utilize salt solution that organic layer is washed and by anhydrous sodium sulfate it is carried out drying, filter, vacuum evaporation and (be present in the methyl alcohol among the carrene by column chromatography after this, 1.7% volume/volume) it is carried out purifying, thereby obtain a kind of title compound 0503-84 (412 milligrams, 88%) of faint yellow solid form.LCMS:327[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 0.86 (t, J=7.4Hz, 3H), 1.39-1.48 (m, 2H), 2.49 (t, J=2.0Hz, 2H), 2.82 (s, 1H), 3.73 (t, J=4.8Hz, 4H), 3.87 (t, J=4.8Hz, 4H), 4.00 (s, 2H), 7.23 (s, 1H).
Step 25b:2-(((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (propyl group) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0504-84)
(477 milligrams of described title compound 0504-84,79%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 24) of describing compound 0504-83, by (412 milligrams of 0503-84,1.26 milli rubs) and 0305 (353 milligrams, 1.89 the milli rub) acetonitrile solution (30 milliliters), and DIPEA (3 milliliters) prepares: LCMS:477[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 0.86 (t, J=7.6Hz, 3H), 1.30 (t, J=7.2Hz, 3H), 1.57-1.66 (m, 2H), 3.65 (t, J=7.6Hz, 2H), 3.71 (t, J=4.8Hz, 4H), (3.83 t, J=4.6Hz, 4H), 4.28 (q, J=7.2Hz, 2H), 5.17 (s, 2H), (7.42 s, 1H), 8.86 (s, 2H).
Step 25c:2-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (propyl group) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0505-84)
(240 milligrams of described title compound 0505-84,82%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 24) of describing compound 0505-83, by (250 milligrams of 0504-84,0.52 milli rubs), (154 milligrams of 0107-3,0.63 milli rubs), (132 milligrams of sodium bicarbonates, 1.57 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (II) (18.5 milligrams, 0.026 milli rub) at toluene (8 milliliters), the solution that forms in ethanol (5 milliliters) and the water (2 milliliters) prepares: LCMS:559[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 0.88 (t, J=7.2Hz, 3H), 1.30 (t, J=7.0Hz, 3H), 1.61-1.71 (m, 2H), (3.70 t, J=7.4Hz, 2H), 3.80 (t, J=4.6Hz, 4H), 3.96 (t, J=4.6Hz, 4H), 4.29 (q, J=7.2Hz, 2H), (5.23 s, 2H), 7.47 (t, J=7.8Hz, 1H), 7.61 (s, 1H), 7.67 (d, J=8.4Hz, 1H), 8.22 (d, J=6.8Hz, 1H), 8.88 (s, 3H), 13.20 (s, 1H).
Step 25d:2-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (propyl group) amino)-N-hydroxypyrimidine-5-carboxamides (compound 84)
(189 milligrams of described title compounds 84,81%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (16.0 milliliters) that is the azanol by 0505-84 (240 milligrams, 0.43 milli rub) and fresh preparation prepares: fusing point 224-226 ℃.LCMS:546[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 0.88 (t, J=7.4Hz, 3H), 1.60-1.69 (m, 2H), 3.67 (t, J=7.6Hz, 2H), (3.80 t, J=4.4Hz, 4H), 3.96 (t, J=4.8Hz, 4H), 5.20 (s, 2H), (7.47 t, J=7.8Hz, 1H), 7.59 (s, 1H), 7.67 (d, J=8.0Hz, 1H), (8.22 d, J=6.8Hz, 1H), 8.75 (s, 2H), 8.88 (s, 1H), (9.07 s, 1H), 11.12 (s, 1H), 13.20 (s, 1H).
Embodiment 26:2-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methyl) (butyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 85) preparation
Step 26a:N-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) fourth-1-amine (compound 0503-85)
(430 milligrams of described title compound 0503-85,88%) be by using a kind of a kind of flaxen solid with preparing for the similar step of the step (embodiment 25) of describing compound 0503-84, the methanol solution (30 milliliters) that is (500 milligrams, 1.43 millis rub) and fourth-1-amine (5 milliliters) by 0502 prepares: LCMS:341[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 0.93 (t, J=7.4Hz, 3H), 1.33-1.42 (m, 2H), 1.45-1.52 (m, 2H), 2.61 (t, J=7.0Hz, 2H), 2.90 (s, 1H), 3.81-3.82 (m, 4H), (3.94-3.95 d, 4H), 4.07 (s, 2H), 7.30 (s, 1H).
Step 26b:2-(butyl ((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0504-85)
(519 milligrams of described title compound 0504-85,84%) be by using a kind of a kind of flaxen solid with preparing for the similar step of the step (embodiment 24) of describing compound 0504-83, by (430 milligrams of 0503-85,1.26 milli rubs) and 0305 (353 milligrams, 1.89 the milli rub) acetonitrile solution (30 milliliters), and DIPEA (3 milliliters) prepares: LCMS:491[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 0.88 (t, J=7.4Hz, 3H), 1.26-1.34 (m, 5H), 1.55-1.62 (m, 2H), 3.67-3.72 (m, 6H), 3.83 (t, J=4.8Hz, 4H), (4.28 q, J=7.1Hz, 2H), (5.17 s, 2H), 7.41 (s, 1H), 8.86 (s, 2H).
Step 26c:2-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (butyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0505-85)
(255 milligrams of described title compound 0505-85,87%) be by using a kind of solid of a kind of faint yellow look with preparing for the similar step of the step (embodiment 24) of describing compound 0505-83, by (250 milligrams of 0504-85,0.51 milli rubs), (149 milligrams of 0107-3,0.61 milli rubs), (128 milligrams of sodium bicarbonates, 1.53 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (α) (17.8 milligrams, 0.025 milli rub) at toluene (8 milliliters), the solution that forms in ethanol (5 milliliters) and the water (2 milliliters) prepares: LCMS:573[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.04 (t, J=7.4Hz, 3H), 1.43-1.48 (m, 5H), 1.73-1.81 (m, 2H), 3.88 (t, J=7.6Hz, 2H), 3.94 (t, J=4.6Hz, 4H), 4.10 (t, J=4.6Hz, 4H), (4.43 q, J=7.1Hz, 2H), 5.37 (s, 2H), 7.61 (t, J=7.8Hz, 1H), (7.75 s, 1H), 7.81 (d, J=8.0Hz, 1H), 8.36 (d, J=6.8Hz, 1H), 9.02 (s, 3H), 13.34 (s, 1H).
Step 26d:2-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (butyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 85)
(131 milligrams of described title compounds 85,53%) be by using a kind of a kind of linen solid with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (16.0 milliliters) that is the azanol by 0505-85 (255 milligrams, 0.45 milli rub) and fresh preparation prepares: fusing point 234-236 ℃.LCMS:560[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 0.96 (t, J=7.4Hz, 3H), 1.32-1.42 (m, 2H), 1.64-1.72 (m, 2H), 3.77 (t, J=7.2Hz, 2H), 3.86 (t, J=4.2Hz, 4H), 4.02 (t, J=4.4Hz, 4H), (5.26 s, 2H), 7.53 (t, J=7.8Hz, 1H), 7.66 (s, 1H), 7.73 (d, J=8.4Hz, 1H), 8.28 (d, J=7.2Hz, 1H), 8.81 (s, 2H), 8.94 (s, 1H), 9.14 (s, 1H), 11.18 (s, 1H), 13.27 (s, 1H).
Embodiment 27:2-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methyl) (2-hydroxyethyl) amino)-(change of N-hydroxypyrimidine-5-carboxamides Compound 86) preparation
Step 27a:2-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) ethanol (compound 0503-86)
(230 milligrams of described title compound 0503-86,41%) be by using a kind of a kind of flaxen solid with preparing for the similar step of the step (embodiment 25) of describing compound 0503-84, the methanol solution (60 milliliters) that is (600 milligrams, 1.72 millis rub) and 2-ethylaminoethanol (6 milliliters) by 0502 prepares: LCMS:329[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 2.62 (t, J=5.8Hz, 2H), 2.74 (s, 1H), 3.47 (dd, J 1=11.2Hz, J 2=6.0Hz, 2H), 3.73 (t, J=4.8Hz, 4H), 3.88 (t, J=5.0Hz, 4H), 4.04 (s, 2H), 4.53 (t, J=5.2Hz, 1H), 7.24 (s, 1H).
Step 27b:2-(((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (2-hydroxyethyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0504-86)
(170 milligrams of described title compound 0504-86,51%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 24) of describing compound 0504-83, by (230 milligrams of 0503-86,0.7 milli rubs) and 0305 (157 milligrams, 0.84 the milli rub) acetonitrile solution (20 milliliters), and DIPEA (4 milliliters) prepares: LCMS:479[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.29 (t, J=7.2Hz, 3H), 3.62 (dd, J 1=11.2Hz, J 2=6.0Hz, 2H), 3.70 (t, J=4.6Hz, 4H), 3.76 (t, J=6.0Hz, 2H), 3.82 (t, J=4.6Hz, 4H), 4.27 (dd, J 1=13.6Hz, J 2=6.8Hz, 2H), 4.86 (t, J=5.2Hz, 1H), 5.23 (s, 2H), 7.39 (s, 1H), 8.85 (s, 2H).
Step 27c:2-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (2-hydroxyethyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0505-86)
(120 milligrams of described title compound 0505-86,60%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 24) of describing compound 0505-83, by (170 milligrams of 0504-86,0.35 milli rubs), (104 milligrams of 0107-3,0.43 milli rubs), (89 milligrams of sodium bicarbonates, 1.06 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (α) (13 milligrams, 0.02 milli rub) at toluene (4 milliliters), the solution that forms in ethanol (2.5 milliliters) and the water (1 milliliter) prepares: LCMS:561[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.29 (t, J=6.8Hz, 3H), 3.66 (dd, J 1=10.8Hz, J 2=5.6Hz, 2H), 3.78-3.83 (m, 6H), 3.95 (t, J=4.6Hz, 4H), 4.28 (dd, J 1=14.4Hz, J 2=7.2Hz, 2H), 4.88 (t, J=5.4Hz, 1H), 5.29 (s, 2H), 7.46 (t, J=7.8Hz, 1H), 7.59 (s, 1H), 7.66 (d, J=8.4Hz, 1H), (8.21 d, J=7.2Hz, 1H), 8.87 (s, 3H), 13.2 (s, 1H).
Step 27d:2-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (2-hydroxyethyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 86)
(42 milligrams of described title compounds 86,36%) be by using a kind of a kind of linen solid with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (8.0 milliliters) that is the azanol by 0505-86 (120 milligrams, 0.21 milli rub) and fresh preparation prepares: fusing point 190-194 ℃.LCMS:548[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 3.64 (dd, J 1=10.8Hz, J 2=5.6Hz, 2H), 3.79 (dd, J 1=8.4Hz, J 2=4.4Hz, H), 3.95 (t, J=4.4Hz, 4H), 4.85 (t, J=5.2Hz, 1H), 5.25 (s, 2H), 7.46 (t, J=7.8Hz, 1H), 7.57 (s, 1H), 7.66 (d, J=8.4Hz, 1H), 8.21 (d, J=6.8Hz, 1H), (8.74 s, 2H), 8.87 (s, 1H), 9.07 (s, 1H), 11.13 (s, 1H), 13.20 (s, 1H).
Embodiment 28:2-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methyl) (2-methoxy ethyl) amino)-the N-hydroxypyrimidine-5-carboxamides The preparation of (compound 90)
Step 28a:N-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl)-2-methoxyethyl amine (compound 0503-90)
(230 milligrams of described title compound 0503-90,41%) be by using a kind of a kind of oil with preparing for the similar step of the step (embodiment 25) of describing compound 0503-84, by 0502 (520 milligrams, 1.5 milli rubs) and the methanol solution (20 milliliters) of 2-methoxyethyl amine (1.1 grams, 10.0 millis rub) prepare: LCMS:343[M+1] + 1HNMR (400 megahertzes, deuterochloroform) δ 2.858 (t, J=7.2Hz, 3H), (3.37 s, 3H), 3.53 (t, J=5.2Hz, 2H), 3.53 (t, J=5.2Hz, 2H), (3.83 t, J=5.2Hz, 4H), 3.99 (t, J=4.8Hz, 4H), 4.12 (s, 2H), 7.16 (s, 1H).
Step 28b:2-(((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (2-methoxy ethyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0504-90)
(400 milligrams of described title compound 0504-90,81%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 24) of describing compound 0504-83, by (342 milligrams of 0503-90,1.0 milli rubs) and 0305 (205 milligrams, 1.1 the milli rub) acetonitrile solution (20 milliliters), and DIPEA (400 milligrams, 3.3 milli rub) prepares: LCMS:493[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.29 (t, J=6.8Hz, 3H), 3.22 (s, 3H), 3.56 (t, J=5.2Hz, 2H), (3.70 brs, 4H), 3.82 (brs, 4H), (3.88 t, J=5.2Hz, 2H), 4.27 (q, J=6.8Hz, 2H), 5.19 (s, 2H), (7.39 s, 1H), 8.86 (s, 1H).
Step 28c:2-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (2-methoxy ethyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0505-90)
(260 milligrams of described title compound 0505-90,90%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 24) of describing compound 0505-83, by (246 milligrams of 0504-90,0.5 milli rubs), (146 milligrams of 0107-3,0.6 milli rubs), (126 milligrams of sodium bicarbonates, 1.5 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (α) (18 milligrams, 0.025 milli rub) at toluene (8.0 milliliters), the solution that forms in ethanol (5 milliliters) and the water (3 milliliters) prepares: LCMS:575[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO) 6) δ 1.38 (t, J=7.2Hz, 3H), 3.44 (s, 3H), 3.69 (t, J=5.6Hz, 2H), 3.87 (m, 4H), 4.02 (m, 6H), (4.27 q, J=7.2Hz, 2H), 5.34 (s, 2H), (7.55 t, J=7.6Hz, 1H), 7.67 (s, 1H), (7.75 d, J=8.0Hz, 1H), 8.30 (d, J=6.8Hz, 1H), 8.97 (s, 2H), 13.29 (s, 1H).
Step 28d:2-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (2-methoxy ethyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 90)
(180 milligrams of described title compounds 90,71%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (15.0 milliliters) that is the azanol by 0505-90 (260 milligrams, 0.45 milli rub) and fresh preparation prepares: fusing point 219-222 ℃.LCMS:482[M+1] +. 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.26 (s, 3H), 3.59 (t, J=5.6Hz, 2H), 3.79 (m, 4H), 3.90 (t, J=5.6Hz, 2H), 3.95 (m, 4H), (5.22 s, 2H), 7.46 (t, J=7.2Hz, 1H), 7.56 (s, 1H), 7.65 (d, J=8.4Hz, 1H), 8.21 (d, J=7.2Hz, 1H), 8.74 (s, 2H), 8.87 (s, 1H), 9.07 (brs, 1H), 11.12 (s, 1H), 13.19 (s, 1H).
Embodiment 29:2-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methyl) (isobutyl group) amino)-N-hydroxypyrimidine-5-carboxamides (chemical combination Thing 93) preparation
Step 29a:N-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl)-2-methyl-prop-1-amine (compound 0503-93)
Described title compound 0503-93 (0.6 gram, 88%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 25) of describing compound 0503-84, by 0502 (694 milligrams, 2.0 milli rubs), 2-methyl-prop-1-amine (1.5 grams, 20 millis rub) and the methanol solution (20 milliliters) of diisopropylethylamine (DIPEA) (2.6 grams, 20 millis rub) prepare: LCMS:341[M+1] +. 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 0.87 (d, J=6.8Hz, 6H), 1.69 (m, 1H), 2.35 (d, J=6.8Hz, 2H), 2.60 (s, 1H), 3.74 (m, 4H), 3.88 (m, 4H), 4.00 (s, 2H), 7.23 (s, 1H).
Step 29b:2-(((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (isobutyl group) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0504-93)
(500 milligrams of described title compound 0504-93,57%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 24) of describing compound 0504-83, by (613 milligrams of 0503-93,1.8 milli rubs) and 0305 (675 milligrams, 3.6 the milli rub) acetonitrile solution (8 milliliters), and DIPEA (1.2 grams, 9 millis rub) prepares: LCMS:491[M+1] +, 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO) d 6) δ 0.87 (d, J=6.8Hz, 6H), 1.29 (t, J=7.2Hz, 3H), 2.17 (m, 1H), (3.58 d, J=7.6Hz, 2H), 3.71 (m, 4H), 3.83 (m, 4H), 4.28 (q, J=7.2Hz, 2H), 5.17 (s, 2H), (7.41 s, 1H), 8.85 (s, 2H).
Step 29c:2-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (isobutyl group) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0505-93)
(257 milligrams of described title compound 0505-93,91%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 24) of describing compound 0505-83, by (245 milligrams of 0504-93,0.5 milli rubs), (147 milligrams of 0107-3,0.6 milli rubs), (126 milligrams of sodium bicarbonates, 1.5 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (α) (18 milligrams, 0.025 milli rub) at toluene (4.0 milliliters), the solution that forms in ethanol (2 milliliters) and the water (1 milliliter) prepares: LCMS:573[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 0.89 (d, J=6.8Hz, 6H), 1.29 (m, 3H), 2.20 (m, 1H), 3.60 (d, J=7.6Hz, 2H), 3.79 (m, 4H), (3.95 m, 4H), 4.27 (m, 2H), 5.21 (s, 2H), (7.47 t, J=8.0Hz, 1H), 7.60 (s, 1H), 7.68 (d, J=8.4Hz, 1H), 8.22 (d, J=8.0Hz, 1H), 8.86 (s, 2H), 8.90 (s, 1H), 13.22 (s, 1H).
Step 29d:2-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (isobutyl group) amino)-N-hydroxypyrimidine-5-carboxamides (compound 93)
(90 milligrams of described title compounds 93,26%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (20.0 milliliters) that is the azanol by 0505-93 (357 milligrams, 0.6 milli rub) and fresh preparation prepares: fusing point 196-198 ℃.LCMS:560[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 0.89 (d, J=6.4Hz, 6H), 2.20 (m, 1H), 3.59 (d, J=7.6Hz, 2H), 3.80 (m, 4H), 3.96 (m, 4H), (5.20 s, 2H), 7.47 (t, J=8.0Hz, 1H), 7.59 (s, 1H), 7.68 (d, J=8.0Hz, 1H), 8.22 (d, J=7.2Hz, 1H), 8.75 (s, 2H), 8.90 (s, 1H), 9.12 (s, 1H), 11.14 (s, 1H), 13.23 (s, 1H).
Embodiment 30:6-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methylamino)-preparation of N-hydroxy nicotinoyl amine (compound 76)
Step 30a:6-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) isopropyl nicotinate (compound 0309-76)
To 0112 (3.4 grams, 12 millis rub) and (912 milligrams of 6-amino-nicotinic acid ethyl esters, 6 millis rub) toluene suspension (50 milliliters) in the stirring adding tetraisopropyl titanate (2 grams, 7.2 millis rub) and under 120 ℃, described mixed liquor is spent the night.In described reaction mixture, add triacetic acid sodium borohydride (1.9 grams, 9 millis rub), after this described mixed liquor is cooled to room temperature and proceeds 4 hours stirring, utilize carrene (10 milliliters of x2) that it is extracted.Utilize saturated sodium bicarbonate (aqueous solution, 20 milliliters), salt solution (20 milliliters of x2) washs the organic layer of above-mentioned merging, and is dry and concentrated.Described residue is carried out purifying by column chromatography in that silica gel (being present in the ethyl acetate among the benzinum, 20% volume/volume) is upper, thereby obtain a kind of 0309-76 (1.5 grams, 28%) of white solid form.LCMS:448[M+1] + 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.29 (d, J=6Hz, 6H) 3.73 (m, 4H), (3.85 m, 4H), 4.89 (d, J=5.6Hz, 2H), 5.09 (m, 1H), 6.64 (d, J=8.8Hz, 1H), 6.81 (s, 1H), (7.31 s, 1H), 7.86 (d, J=2Hz, 1H), 8.58 (s, 1H).
Step 30b:6-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) methyl nicotinate (compound 0310-76)
Described 6-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) (200 milligrams of isopropyl nicotinates, 82%) is a kind of solid of yellow, by using a kind of and preparing for the similar step of the step (embodiment 24) of describing compound 0505-83, by (200 milligrams of 0309-76,0.462 milli rubs), (124 milligrams of 0107-3,0.51 milli rubs), (120 milligrams of sodium bicarbonates, 1.4 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (II) (16 milligrams, 0.0231 milli rub) at toluene (8 milliliters), the solution that forms in ethanol (5 milliliters) and the water (2 milliliters) prepares: LCMS:530[M+1] + 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.28 (d, J=6Hz, 6H) 3.81 (m, 4H), 3.98 (m, 4H), (4.94 d, J=5.6Hz, 2H), 5.08 (m, 1H), 6.67 (d, J=8.8Hz, 1H), 7.47 (t, J=8.4Hz, 1H), 7.51 (s, 1H), 7.677 (d, J=8.4Hz, 1H), 7.90 (d, J=2.4Hz, 1H), 8.21 (d, J=7.6Hz, 2H), 8.60 (s, 1H), 8.87 (s, 1H), 13.20 (s, 1H).
Dropwise the interpolation concentrated sulfuric acid (2 milliliters) in the methyl alcohol mixed liquor (8 milliliters) of above-claimed cpd (200 milligrams, 0.378 milli rub).The backflow that described mixed liquor is spent the night.Thereby evaporation obtains described thick methyl esters, and 0310-76 (140 milligrams, 75%), described thick methyl esters need not to carry out further purifying and can directly be used in the following step.LCMS:502[M+1] + 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.77 (s, 3H), 3.81 (m, 4H), 3.98 (m, 4H), (4.94 d, J=5.6Hz, 2H), 6.67 (d, J=8.8Hz, 1H), (7.47 t, J=8.4Hz, 1H), 7.51 (s, 1H), (7.677 d, J=8.4Hz, 1H), 7.91 (d, J=2.4Hz, 1H), 8.21 (d, J=7.6Hz, 2H), 8.62 (s, 1H), 8.87 (s, 1H), 13.21 (s, 1H).
Step 30c:6-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino)-N-hydroxy nicotinoyl amine (compound 76)
(23 milligrams of described title compounds 76,16%) be by using a kind of solid of a kind of brown with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (10.0 milliliters) that is the azanol by 0310-76-2 (140 milligrams, 0.28 milli rub) and fresh preparation prepares: fusing point 218-220 ℃.LCMS:503[M+1] +. 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 3.81 (m, 4H), 3.98 (m, 4H), 4.90 (d, J=4.8Hz, 2H), 6.62 (d, J=6.8Hz, 1H), 7.46 (t, J=8Hz, 1H), 7.50 (s, 1H), 7.62 (d, J=8Hz, 1H), (7.78 d, J=4Hz, 1H), 7.89 (t, J=4.8Hz, 1H), (8.21 d, J=6.4Hz, 1H), 8.43 (s, 1H), 8.85 (s, 1H), 10.95 (s, 1H), 13.19 (s, 1H).
Embodiment 31:4-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methylamino)-preparation of N-hydroxybenzamide (compound 78)
Step 31a:4-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) ethyl benzoate (compound 0309-78)
(580 milligrams of described title compound 0309-78,95%) be by using a kind of a kind of orange solid with preparing for the similar step of the step (embodiment 30) of describing compound 0309-76, by (256 milligrams of PABA ethyl esters, 1.55 milli rubs), 0112 (400 milligrams, 1.41 milli rubs) and tetraisopropyl titanate (480 milligrams, 1.69 milli rub) prepare.LCMS:433[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.26 (t, J=7.2Hz, 3H), 3.71 (t, J=4.8Hz, 4H), 3.83 (t, J=4.6Hz, 4H), 4.20 (q, J=5.3Hz, 2H), 4.71 (d, J=6.0Hz, 2H), 6.68 (d, J=9.2Hz, 2H), (7.35 t, J=6.4Hz, 1H), 7.36 (s, 1H), 7.69 (d, J=8.4Hz, 2H).
Step 31b:4-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) ethyl benzoate (compound 0310-78)
(85 milligrams of described title compound 0310-78,33%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 30) of describing compound 0310-76, by (216 milligrams of 0309-78,0.5 milli rubs), (256 milligrams of 0107-3,0.53 milli rubs), (126 milligrams of sodium bicarbonates, 1.5 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (II) (18 milligrams, 0.025 milli rub) at toluene (4.0 milliliters), the solution that forms in ethanol (2.5 milliliters) and the water (1.5 milliliters) prepares: LCMS:515[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.25 (t, J=7.2Hz, 3H), 3.80 (t, J=4.6Hz, 4H), 3.97 (t, J=4.6Hz, 4H), 4.20 (q, J=5.3Hz, 2H), (4.75 d, J=6.0Hz, 2H), 6.73 (d, J=8.8Hz, 2H), 7.39 (t, J=6.0Hz, 1H), 7.47 (t, J=8.0Hz, 1H), (7.56 s, 1H), 7.67 (d, J=8.4Hz, 1H), 7.71 (d, J=8.8Hz, 2H), 8.22 (d, J=7.2Hz, 1H), 8.88 (s, 1H).
Step 31c:4-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino)-N-hydroxybenzamide (compound 78)
(41 milligrams of described title compounds 78,28%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (10.0 milliliters) that is the azanol by 0310-78 (150 milligrams, 0.29 milli rub) and fresh preparation prepares: fusing point 180-183 ℃.LCMS:502[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.80 (brs, 4H), 3.96 (t, 4H), 4.72 (d, J=5.6Hz, 2H), 6.68 (d, J=8.8Hz, 2H), 7.09 (t, J=6.0Hz, 1H), 7.47 (t, J=8.0Hz, 1H), 7.54 (d, J=8.4Hz, 2H), 7.57 (s, 1H), 7.67 (d, J=8.0Hz, 1H), (8.22 d, J=7.2Hz, 1H), 8.72 (s, 1H), 8.87 (s, 1H), 10.81 (s, 1H), 13.22 (s, 1H).
Embodiment 32:(E)-3-(4-((2-(1H-indazole-4-yl)-4-morpholine thiophene A pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) phenyl)-N-hydroxyacrylamide (chemical combination Thing 80) preparation
Step 32a:(E)-3-(4-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) phenyl) ethyl acrylate (compound 0309-80)
(968 milligrams of described title compound 0309-80,71%) be by using a kind of a kind of flaxen solid with preparing for the similar step of the step (embodiment 30) of describing compound 0309-76, by (623 milligrams of (E)-3-(4-aminophenyl) ethyl acrylates, 3.26 milli rubs), 0112 (840 milligrams, 2.96 milli rubs) and tetraisopropyl titanate (1 gram, 3.55 millis rub) prepare.LCMS:459[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.22 (t, J=7.2Hz, 3H), 3.71 (t, J=4.6Hz, 4H), (3.83 t, J=4.6Hz, 4H), 4.13 (q, J=7.2Hz, 2H), (4.69 d, J=6.0Hz, 2H), 6.27 (d, J=16.0Hz, 1H), 6.65 (d, J=8.8Hz, 2H), 7.17 (t, J=6.0Hz, 1H), 7.36 (s, 1H), 7.44 (d, J=8.8Hz, 2H), 7.48 (d, J=16.0Hz, 1H).
Step 32b:(E)-3-(4-((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) phenyl) ethyl acrylate (compound 0310-80)
(490 milligrams of described title compound 0310-80,69%) be by using a kind of a kind of flaxen solid with preparing for the similar step of the step (embodiment 30) of describing compound 0310-76, by (600 milligrams of 0309-80,1.31 milli rubs), (383 milligrams of 0107-3,1.57 milli rubs), (329 milligrams of sodium bicarbonates, 3.92 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (II) (46 milligrams, 0.065 milli rub) at toluene (16.0 milliliters), the solution that forms in ethanol (10 milliliters) and the water (4 milliliters) prepares: LCMS:541[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.22 (t, J=7.2Hz, 3H), 3.82 (t, J=4.0Hz, 4H), 3.97 (t, J=4.4Hz, 4H), 4.12 (q, J=7.2Hz, 2H), (4.74 d, J=5.2Hz, 2H), 6.27 (d, J=15.6Hz, 1H), 6.70 (d, J=8.8Hz, 2H), 7.21 (t, J=5.8Hz, 1H), (7.45-7.50 m, 4H), 7.57 (s, 1H), (7.67 d, J=8.0Hz, 1H), 8.22 (d, J=6.8Hz, 1H), 8.87 (s, 1H), 13.21 (s, 1H).
Step 32c:(E)-3-(4-((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino)-N-hydroxybenzamide (compound 80)
(71 milligrams of described title compounds 80,15%) be by using a kind of a kind of flaxen solid with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (20.0 milliliters) that is the azanol by 0310-80 (490 milligrams, 0.91 milli rub) and fresh preparation prepares: fusing point is greater than 300 ℃.LCMS:528[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 3.87 (t, J=4.6Hz, 4H), 4.03 (t, J=4.6Hz, 4H), 4.78 (d, J=5.6Hz, 2H), 6.21 (d, J=15.6Hz, 1H), (6.76 d, J=8.8Hz, 2H), 7.11 (t, J=5.8Hz, 1H), 7.34-7.39 (m, 3H), (7.53 t, J=7.8Hz, 1H), 7.63 (s, 1H), 7.73 (d, J=8.0Hz, 1H), (8.29 d, J=7.6Hz, 1H), 8.93 (d, J=4.8Hz, 2H), 10.60 (s, 1H), 13.27 (s, 1H).
Embodiment 33:(E)-3-(4-(((2-(1H-indazole-4-yl)-4-morpholine thiophene A pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) phenyl)-N-hydroxyl propylene The preparation of acid amides (compound 81)
Step 33a:(E)-3-(4-(((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) phenyl) ethyl acrylate (compound 0309-81)
At room temperature, to compound 0309-80 (1.0 grams, 2.2 millis rub), iodomethane (6.2 grams, 44 millis rub), and anhydrous acetonitrile/dimethyl formamide (DMF) solution (5 milliliters/milliliter) of cesium carbonate (1.44 grams, 4.4 millis rub) carries out 3 days stirring.Under vacuum condition, remove iodomethane and acetonitrile and utilize water that described residue is diluted, utilize ethyl acetate that it is extracted, carry out drying by sodium sulphate, and (be present in the ethyl acetate among the benzinum by column chromatography on the silica gel, 20% volume/volume) described crude product is carried out purifying, thereby obtain a kind of 0309-81 (0.3 gram, 30%) of yellow solid form.LCMS:473[M+1] +. 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.23 (t, J=7.2Hz, 3H), 3.12 (s, 3H), 3.70 (m, 4H), 3.82 (m, 4H), 4.14 (q, J=7.2Hz, 2H), (4.97 s, 2H), 6.33 (d, J=16.4Hz, 1H), 6.82 (d, J=8.8Hz, 2H), (7.31 s, 1H), 7.53 (m, 3H).
Step 33b:(E)-3-(4-(((2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) phenyl) ethyl acrylate (compound 0310-81)
(200 milligrams of described title compound 0310-81,71%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 30) of describing compound 0310-76, by (240 milligrams of 0309-81,0.5 milli rubs), (135 milligrams of 0107-3,0.55 milli rubs), (126 milligrams of sodium bicarbonates, 1.5 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (II) (18 milligrams, 0.025 milli rub) at toluene (4 milliliters), the solution that forms in ethanol (2 milliliters) and the water (1 milliliter) prepares: LCMS:555[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.23 (m, 3H), 3.17 (s, 3H), 3.80 (m, 4H), (3.95 m, 4H), 4.15 (m, 2H), 5.01 (s, 2H), (6.33 d, J=15.6Hz, 1H), 6.86 (d, J=8.8Hz, 2H), 7.46 (m, 1H), 7.54 (m, 4H), (7.66 d, J=8.0Hz, 1H), 8.21 (d, J=7.2Hz, 1H), 8.87 (s, 1H), 13.21 (s, 1H).
Step 33c:(E)-3-(4-(((2-(1H-indazole-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxyacrylamide (compound 81)
(24 milligrams of described title compounds 81,10%) be by using a kind of a kind of flaxen solid with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (20.0 milliliters) that is the azanol by 0310-81 (250 milligrams, 0.45 milli rub) and fresh preparation prepares: fusing point 188-190 ℃.LCMS:542[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 3.14 (s, 3H), 3.80 (m, 4H), (3.95 m, 4H), 4.98 (s, 2H), (6.21 d, J=15.2Hz, 1H), 6.86 (d, J=8.8Hz, 2H), 7.32 (d, J=15.2Hz, 1H), 7.40 (d, J=8.4Hz, 2H), (7.46 t, J=7.6Hz, 1H), 7.50 (s, 1H), 7.66 (d, J=8.0Hz, 1H), (8.21 d, J=7.2Hz, 1H), 8.34 (s, 1H), 8.87 (s, 1H), 10.58 (s, 1H), 13.23 (s, 1H).
Embodiment 34:(2-(((2-(3-acetamido phenyl)-4-morpholine thiophene a pair of horses going side by side [3, 2-d] pyrimidine-6-yl) methyl) (methyl) amino) phenyl)-N-hydroxy pyrimidine-5 formyl The preparation of amine (compound 107)
Step 34a:N-(3-bromophenyl) acetamide (compound 0601-107)
Under 0 ℃, among the dichloromethane solution (50 milliliters) of 3-bromaniline (6.3 grams, 63.7 millis rub), add acetyl group chlorine (3.75 grams, 47.7 millis rub) and triethylamine (7.4 grams, 73.4 millis rub), carry out 2 hours stirring.Utilize water, salt solution washs described mixed liquor, carries out drying by sodium sulphate, filters, and concentrated under reduced pressure, thereby obtains a kind of described title compound 0601-107 (7.8 grams, 99.3%) of brown solid.LCMS:215[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 2.05 (s, 3H), 7.22 (m, 2H), 7.46 (d, J=7.6Hz, 1H), 7.95 (s, 1H), 10.11 (s, 1H).
Step 34b:N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) phenyl) acetamide (compound 0602-107)
To compound 0601-107 (2.5 grams, 11.6 milli rubs) and connection boric acid pinacol ester (4.4 grams, 17.5 milli rubs) the solution (100 milliliters) of dioxane in add potassium acetate (3.4 grams, 35 millis rub) and two (Diphenyl phosphino ferrocene) palladium chloride (0.95 gram, 1.1 millis rub).Utilize nitrogen to carry out degassed to described mixed liquor and under 85 ℃ to its heating of spending the night.Thereby under reduced pressure, described reaction mixture concentrated and obtain described crude product, (be present in the ethyl acetate among the benzinum by column chromatography, 15% volume/volume) described crude product is carried out purifying, thereby obtain a kind of described compound 0602-107 (1.55 grams, 51%) of pink solid form.LCMS:262[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.29 (s, 12H), 2.03 (s, 3H), 7.30 (s, 1H), 7.31 (d, J=2.0Hz1H), 7.73 (d, J=2.0Hz, 1H), 7.89 (d, J=1.6Hz, 1H), 9.93 (s, 1H).
Step 34c:2-(((2-(3-acetamido phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-107)
(160 milligrams of described title compound 0603-107,99%) be by using a kind of solid of a kind of grey with preparing for the similar step of the step (embodiment 30) of describing compound 0310-76, by (130 milligrams of 0504-54,0.30 milli rubs), (84 milligrams of 0602-107,0.7 milli rubs), (74 milligrams of sodium bicarbonates, 0.88 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (II) (12 milligrams, 0.014 milli rub) at toluene (2.5 milliliters), the solution that forms in ethanol (1.6 milliliters) and the water (0.7 milliliter) prepares.LCMS:548[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.31 (t, J=6.8Hz, 3H), 2.07 (s, 3H), 3.27 (s, 1H), 3.77 (t, J=5.2Hz, 4H), 3.94 (t, J=5.2Hz, 4H), 4.29 (q, J=7.2Hz, 2H), 5.24 (s, 2H), (7.39 t, J=8.4Hz, 1H), 7.49 (s, 1H), 7.82 (d, J=8.0Hz, 1H), 8.05 (d, J=8.8Hz, 1H), 8.52 (s, 1H), 8.89 (s, 2H), 10.08 (s, 1H).
Step 34d:(2-(((2-(3-acetamido phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) phenyl)-N-hydroxy pyrimidine-5 formamide (compound 107)
(64 milligrams of described title compounds 107,50%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (4.0 milliliters) that is the azanol by 0603-107 (130 milligrams, 0.23 milli rub) and fresh preparation prepares: fusing point 183-185 ℃.LCMS:535[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 2.07 (s, 3H), 3.24 (s, 3H), 3.77 (t, J=4.0Hz, 4H), 3.94 (t, J=4.0Hz, 4H), 5.21 (s, 2H), (7.39 t, J=8Hz, 1H), 7.46 (s, 1H), 7.82 (d, J=7.6Hz, 1H), 8.05 (d, J=8Hz, 1H), (8.51 s, 1H), 8.75 (s, 2H), 9.07 (s, 1H), 10.08 (s, 1H), 11.13 (s, 1H).
Embodiment 35:(2-(((2-(3-dimethylamino) phenyl)-4-morpholine thiophene A pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) phenyl)-the N-hydroxy pyrimidine The preparation of-5 formamides (compound 108)
Step 35a:6-(2-chloro-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-base is amino) ethyl hexanoate (compound 0602-108)
(600 milligrams of described title compound 0602-108,80%) be by using a kind of a kind of oil with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by 3-bromo-N, (600 milligrams of accelerines, 3.0 milli rubs), connection boric acid pinacol ester (1.14 grams, 4.5 milli rubs), (882 milligrams of potassium acetates, 9.0 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (245 milligrams, 0.3 milli rub) prepare: LCMS:248[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.34 (s, 12H), 2.97 (s, 6H), 7.19 (m, 2H), 7.26 (m2H).
Step 35b:2-(((2-(3-dimethylamino) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-108)
(245 milligrams of described title compound 0603-108,91%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (224 milligrams of 0504-54,0.5 milli rubs), (490 milligrams of 0602-108,2.0 milli rubs), (126 milligrams of sodium bicarbonates, 1.5 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (II) (18 milligrams, 0.025 milli rub) at toluene (4 milliliters), the solution that forms in ethanol (2 milliliters) and the water (1 milliliter) prepares.LCMS:534[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.30 (t, J=6.8Hz, 3H), 2.97 (s, 3H), (3.27 s, 2H), 3.76 (m, 4H), 3.92 (m, 4H), 4.28 (q, J=6.8Hz, 2H), 5.23 (s, 2H), 6.85 (m, 1H), 7.28 (t, J=8.0Hz, 1H), 7.49 (s, 1H), 7.71 (d, J=7.2Hz, 1H), 7.79 (brs, 1H), 8.79 (s, 1H).
Step 35c:(2-(((2-(3-dimethylamino) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) phenyl)-N-hydroxy pyrimidine-5 formamide (compound 108)
(35 milligrams of described title compounds 108,15%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (20 milliliters) that is the azanol by 0603-108 (130 milligrams, 0.23 milli rub) and fresh preparation prepares: fusing point 172-175 ℃.LCMS:521[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 2.96 (s, 3H), 3.23 (s, 2H), 3.75 (m, 4H), 3.91 (m, 4H), 5.19 (s, 2H), (6.84 m, 1H), 7.27 (t, J=8.0Hz, 1H), (7.46 s, 1H), 7.70 (d, J=7.2Hz, 1H), (7.75 brs, 1H), 8.74 (s, 1H), (9.11 brs, 1H), 11.16 (brs, 1H).
Embodiment 36:N-hydroxyl-2-(methyl ((4-morpholinyl-2-(pyridin-3-yl) thiophene Fen a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (compound 109) Preparation
Step 36a:2-(methyl ((4-morpholinyl-2-(pyridin-3-yl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-109)
(140 milligrams of described title compound 0603-109,94%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (135 milligrams of 0504-54,0.30 milli rubs), (41 milligrams of 3-pyridine boric acid, 0.60 milli rubs), (76 milligrams of sodium bicarbonates, 0.90 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (11 milligrams, 0.015 milli rub) at toluene (2.5 milliliters), the solution that forms in ethanol (1.6 milliliters) and the water (0.7 milliliter) prepares.LCMS:492[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (t, J=7.2Hz, 3H), 3.28 (s, 3H), 3.76 (m, 4H), 3.95 (m, 4H), 5.25 (s, 2H), 7.53 (m, 2H), 8.66 (m, 2H), 8.88 (s, 2H), 9.51 (s, 1H).
Step 36b:N-hydroxyl-2-(methyl ((4-morpholinyl-2-(pyridin-3-yl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (compound 109)
(30 milligrams of described title compounds 109,44%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (10 milliliters) that is the azanol by 0603-109 (70 milligrams, 0.14 milli rub) and fresh preparation prepares: fusing point 160-164 ℃.LCMS:479[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.24 (s, 3H), 3.77 (s, 4H), 3.94 (s, 4H), 5.21 (s, 2H), 7.52 (m, 2H), 8.67 (m, 2H), 8.76 (s, 2H), (9.09 s, 1H), 9.52 (s, 1H), 11.15 (s, H).
Embodiment 37:(2-(((2-(6-aminopyridine-3-yl)-4-morpholine thiophene a pair of horses going side by side [3, 2-d] pyrimidine-6-yl) methyl) (methyl) amino) phenyl)-N-hydroxy pyrimidine-5 formyl The preparation of amine (compound 110)
Step 37a:5-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) pyridine-2-amine (compound 0602-110)
(500 milligrams of described title compound 0602-110,23%) be by using a kind of a kind of oil with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by 2-amino-5-bromopyridine (1.73 grams, 10 millis rub), connection boric acid pinacol ester (3.81 grams, 15 millis rub), potassium acetate (3 grams, 30 millis rub) and two (Diphenyl phosphino ferrocene) palladium chloride (480 milligrams, 5 milli rub) prepare: LCMS:221[M+1] +.1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.25 (s, 12H), 6.30 (s, 2H), 6.39 (d, J=8.0Hz, 1H), 7.54 (d, J=10.0Hz, 1H), 8.16 (s, 1H).
Step 37b:2-(((2-(6-aminopyridine-3-yl)-4-thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-110)
(200 milligrams of described title compound 0603-110,59%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (300 milligrams of 0602-110,0.67 milli rubs), (176 milligrams of 0504-54,0.8 milli rubs), (172 milligrams of sodium bicarbonates, 2 millis rub) and two (Diphenyl phosphino ferrocene) palladium chloride (II) (23 milligrams, 0.0335 milli rub) at toluene (8 milliliters), the solution that forms in ethanol (5 milliliters) and the water (2 milliliters) prepares.LCMS:507[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.29 (t, J=6.8Hz, 3H), 3.29 (s, 3H), 3.81 (m, 4H), 3.95 (m, 4H), 4.28 (m, 2H), (5.24 s, 2H), 6.42 (s, 2H), 6.56 (d, J=8.8Hz, 1H), 7.44 (s, 1H), 8.327 (d, J=8.8Hz, 1H), 8.81 (s, 2H), 8.99 (s, 1H), 9.13 (s, 1H), 11.69 (s, 1H).
Step 37c:(2-(((2-(6-aminopyridine-3-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) phenyl)-N-hydroxy pyrimidine-5 formamide (compound 110)
(25 milligrams of described title compounds 110,13%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (20 milliliters) that is the azanol by 0603-110 (200 milligrams, 0.4 milli rub) and fresh preparation prepares: fusing point 175-181 ℃.LCMS:494[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.29 (s, 3H), 3.81 (m, 4H), 3.95 (m, 4H), 5.24 (s, 2H), 6.42 (s, 2H), (6.56 d, J=8.8Hz, 1H), 7.44 (s, 1H), 8.327 (d, J=8.8Hz, 1H), (8.81 s, 2H), 8.99 (s, 1H), (9.13 s, 1H), 11.195 (s, 1H).
Embodiment 38:(2-(((2-(2-aminopyrimidine-5-yl)-4-morpholine thiophene a pair of horses going side by side [3, 2-d] pyrimidine-6-yl) methyl) (methyl) amino)-(change of N-hydroxy pyrimidine-5 formamide Compound 115) preparation
Step 38a:5-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) pyrimidine-2-amine (compound 0602-115)
(120 milligrams of described title compound 0602-115,11%) be by using a kind of a kind of oil with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by (865 milligrams of 2-amino-5-bromo pyrimi piperidine, 5.0 milli rubs) and connection boric acid pinacol ester (2.54 grams, 10 millis rub), potassium acetate (1.47 grams, 15 millis rub) and two (Diphenyl phosphino ferrocene) palladium chloride (204 milligrams, 0.25 milli rub) prepare: LCMS:222[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.26 (s, 12H), 7.04 (s, 2H), 8.37 (s, 2H).
Step 38b:2-(((2-(2-aminopyrimidine-5-yl)-4-thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-115)
(110 milligrams of described title compound 0603-115,51%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (120 milligrams of 0602-115,0.54 milli rubs), (200 milligrams of 0504-54,0.45 milli rubs), (114 milligrams of sodium bicarbonates, 1.35 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (II) (16 milligrams, 0.0225 milli rub) at toluene (8 milliliters), the solution that forms in ethanol (5 milliliters) and the water (2 milliliters) prepares.LCMS:508[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.39 (t, J=6.8Hz, 3H), 3.32 (s, 3H), 3.89 (m, 4H), 4.02 (m, 4H), 4.36 (q, J=6.8Hz, 2H), (5.20 s, 2H), 5.43 (s, 2H), (7.44 s, 1H), 8.94 (s, 2H), 9.31 (s, 2H).
Step 38c:(2-(((2-(2-aminopyrimidine-5-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxy pyrimidine-5 formamide (compound 115)
(25 milligrams of described title compounds 115,23%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (20 milliliters) that is the azanol by 0603-115 (110 milligrams, 0.2 milli rub) and fresh preparation prepares: fusing point 175-181 ℃.LCMS:495[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.21 (s, 3H), 3.75 (m, 4H), 3.91 (m, 4H), 5.19 (s, 2H), 7.13 (s, 2H), 7.41 (s, 1H), 8.74 (s, 2H), (9.02 brs, 1H), 9.10 (s, 2H), 11.13 (brs, 1H).
Embodiment 39:N-hydroxyl 2-(methyl ((2-(methylamino) pyrimidine-5-yl) -4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5 formamide (is changed Compound 116) preparation
Step 39a:5-bromine N-methylpyrimidine-2-amine (compound 0601-116) and 5-bromo-N, N-dimethyl pyrimidine-2-amine (compound 0601-117)
5-bromo pyrimi piperidine-2-amine (3.48 grams, 20 millis rub) and the mixed liquor of dimethyl formamide (DMF) (20 milliliters) are cooled to 0 ℃.In described mixed liquor, add sodium hydride (60%, 1.44 gram, 36 millis rub).After 15 minutes, to wherein adding iodomethane and carrying out 0.5 hour stirring under 0 ℃ and in the time at 4 hours described mixed liquor is being warming up to room temperature.To wherein adding entry (30 milliliters) and utilizing ethyl acetate (3x30 milliliter) that it is extracted.Utilize salt solution that the organic layer of described merging is washed, carry out drying by sodium sulphate, concentrated and (be present in the ethyl acetate among the benzinum by column chromatography on the silica gel, 10% volume/volume) it is carried out purifying, thereby obtain two kinds of compounds: compound 0601-116 (0.76 gram, 20%) is a kind of solid of white, LCMS:190[M+2] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 2.75 (d, J=4.8Hz, 3H), 7.35 (d, J=4.0Hz, 1H), 8.34 (s, 2H); Compound 0601-117 (1.96 grams, 49%) is a kind of solid of yellow, LCMS:202[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.12 (s, 6H), 8.43 (s, 2H).
Step 39b:N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) pyrimidine-2-amine (compound 0602-116)
(350 milligrams of described title compound 0602-116,50%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by 5-bromo-N-methylpyrimidine-2-amine (0.56 gram, 3 millis rub), connection boric acid pinacol ester (1.14 grams, 4.5 milli rubs), potassium acetate (0.88 gram, 9 millis rub) and two (Diphenyl phosphino ferrocene) palladium chloride (490 milligrams, 0.6 milli rub) prepare: LCMS:236[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.27 (s, 12H), 2.82 (d, J=4.8Hz, 3H), 7.47 (m, 1H), 8.38 (m, 1H), 8.45 (m, 1H).
Step 39c:2-(methyl ((2-(2-methylamino) pyrimidine-5-yl)-4-thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-116)
(100 milligrams of described title compound 0603-116,64%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (135 milligrams of 0504-54,0.30 milli rubs), (106 milligrams of 0602-116,0.45 milli rubs), (76 milligrams of sodium bicarbonates, 0.90 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (11 milligrams, 0.015 milli rub) at toluene (2.5 milliliters), the solution that forms in ethanol (1.6 milliliters) and the water (0.7 milliliter) prepares.LCMS:522[M+1] + 1HNMR (400 megahertzes, deuterochloroform) δ 1.39 (t, J=7.2Hz, 3H), 3.09 (d, J=5.2Hz, 3H), 3.31 (s, 3H), 3.85 (t, J=4.8Hz, 4H), 3.98 (t, J=4.8Hz, 4H), (4.36 q, J=7.2Hz, 2H), 5.19 (s, 2H), (5.47 d, J=4.8Hz, 1H), 7.34 (s, 1H), (8.93 s, 2H), 9.26 (s, 2H).
Step 39d:(2-(methyl ((2-(2-(methylamino) pyrimidine-5-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino)-N-hydroxy pyrimidine-5 formamide (compound 116)
(50 milligrams of described title compounds 116,54%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (5 milliliters) that is the azanol by 0603-116 (96 milligrams, 0.13 milli rub) and fresh preparation prepares: fusing point 183-187 ℃.LCMS:509[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 2.88 (d, J=4.4Hz, 3H), 3.23 (s, 3H), 3.74 (s, 4H), 3.90 (s, 4H), 5.19 (s, 2H), 7.40 (s, 1H), 7.55 (d, J=4.4Hz, 1H), (8.75 s, 2H), 9.07 (s, 1H), (9.13 m, 2H), 11.13 (s, 1H).
Embodiment 40:2-(((2-(dimethylamino) pyrimidine-5-yl)-4-morpholine thiophene A pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxy pyrimidine-5 formyl The preparation of amine (compound 117)
Step 40a:N, N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) pyrimidine-2-amine (compound 0602-117)
(194 milligrams of described title compound 0602-117,26%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by 5-bromo-N, N-dimethyl pyrimidine-2-amine (0.61 gram, 3 millis rub), connection boric acid pinacol ester (1.14 grams, 4.5 milli rubs), potassium acetate (0.88 gram, 9 millis rub) and two (Diphenyl phosphino ferrocene) palladium chloride (490 milligrams, 0.6 milli rub) prepare: LCMS:168[M-81] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.27 (s, 12H), 3.14 (s, 6H), 8.47 (s, 2H).
Step 40b:2-(((2-(2-(dimethylamino) pyrimidine-5-yl)-4-thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-117)
(100 milligrams of described title compound 0603-117,64%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (135 milligrams of 0504-54,0.30 milli rubs), (112 milligrams of 0602-117,0.45 milli rubs), (76 milligrams of sodium bicarbonates, 0.90 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (11 milligrams, 0.015 milli rub) at toluene (2.5 milliliters), the solution that forms in ethanol (1.6 milliliters) and the water (0.7 milliliter) prepares.LCMS:536[M+1] + 1HNMR (400 megahertzes, deuterochloroform) δ 1.38 (t, J=7.2Hz, 3H), 2.37 (s, 6H), 3.30 (s, 3H), 3.83 (t, J=4.8Hz, 4H), 3.97 (t, J=4.8Hz, 4H), 4.36 (q, J=7.2Hz, 2H), (5.18 s, 2H), 7.35 (s, 1H), (8.93 s, 2H), 9.30 (s, 2H).
Step 40c:(2-(((2-(2-(dimethylamino) pyrimidine-5-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxy pyrimidine-5 formamide (compound 117)
(60 milligrams of described title compounds 117,66%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (5 milliliters) that is the azanol by 0603-117 (93 milligrams, 0.173 milli rub) and fresh preparation prepares: fusing point 200-206 ℃.LCMS:523[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.18 (d, J=8.8Hz, 6H), 3.23 (s, 3H), 3.74 (d, J=4.8Hz, 4H), 3.90 (d, J=4.4Hz, 4H), 5.17 (s, 2H), 7.39 (s, 1H), 8.75 (s, 2H), 9.19 (s, 2H).
Embodiment 41:N-hydroxyl-2-(methyl ((4-morpholinyl-2-(pyrimidine-5-yl) thiophene Fen a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5 formamide (compound 119) Preparation
Step 41a:2-(methyl ((4-morpholinyl-2-(pyrimidine-5-yl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-119)
(160 milligrams of described title compound 0603-119,46%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (314 milligrams of 0504-54,0.7 milli rubs), (175 milligrams of pyrimidine-2-base boric acid, 1.4 milli rubs), (176 milligrams of sodium bicarbonates, 2.1 milli rubs) and two (Diphenyl phosphino ferrocene) palladium chloride (II) (24 milligrams, 0.03 milli rub) at toluene (8 milliliters), the solution that forms in ethanol (5 milliliters) and the water (3 milliliters) prepares.LCMS:493[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.35 (t, J=7.2Hz, 3H), 3.31 (d, J=8.4Hz, 3H), 3.76 (m, 4H), 3.92 (m, 4H), (4.33 q, J=6.8Hz, 2H), 5.28 (d, J=12.0Hz, 2H), 7.47 (s, 0.5H), 7.59 (s, 0.5H), (8.53 s, 0.5H), 8.92 (d, J=6.0Hz, 2H), (9.34 s, 0.5H), 9.67 (s, 1H).
Step 41b:N-hydroxyl-2-(methyl ((4-morpholinyl-2-(pyrimidine-5-yl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5 formamide (compound 119)
(60 milligrams of described title compounds 119,40%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (5 milliliters) that is the azanol by 0603-119 (150 milligrams, 0.3 milli rub) and fresh preparation prepares: fusing point 159-160 ℃.LCMS:480[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.40 (s, 3H), 3.92 (m, 4H), 4.13 (m, 4H), 5.19 (s, 2H), 6.84 (m, 1H), (7.27 t, J=8.0Hz, 1H), 7.46 (s, 1H), 7.70 (d, J=7.2Hz, 1H), (7.75 brs, 1H), 8.74 (s, 1H), (9.11 brs, 1H), 11.16 (brs, 1H).
Embodiment 42:N-hydroxyl-2-(methyl ((2-(2-methylpyrimidine-5-yl)-4- Quinoline thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5 formamide (chemical combination Thing 120) preparation
Step 42a:5-bromo-2-methylpyrimidine (compound 0601-120)
Careful sodium (356 milligrams, 15.5 millis rub) is joined ethanol (5.9 milliliters) thus among the ethanolic solution of preparation sodium ethoxide.The ethanolic solution (3.5 milliliters) of the sodium ethoxide of above-mentioned fresh preparation is joined in the stirred suspension of ethenylamidine hydrochloride (0.91 gram, 9.69 millis rub).Described mixed liquor is warming up to 50 ℃, remove after this described heating bath and with a kind of speed that can keep a kind of stationary temperature to wherein dropwise adding mucobromic acid (1 gram, 3.87 milli rubs) ethanolic solution, after this further add the ethanolic solution (2 milliliters) of sodium ethoxide.After supercooling, described mixed liquor is filtered and is evaporated to a kind of residue of acquisition, utilize hydrochloric acid (2M x2.4 milliliter) that described residue is carried out violent vibration.The sediment of described brown is filtered and utilizes cold water that it is washed, carry out after this freeze drying, thereby obtain a kind of 5 Bromo 2 methyl pyridine of brown solid-4-carboxylic acid (350 milligrams, 42%).LCMS:218[M+1] +, 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 2.62 (s, 3H), 9.03 (s, 1H).
The dimethylbenzene mixed liquor (5 milliliters) of compound 5 Bromo 2 methyl pyridine-4-carboxylic acid (350 milligrams, 1.6 millis rub) is carried out 2 hours backflow.After supercooling, described mixed liquor is directly used on silica column, utilize benzinum that it is carried out wash-out, utilize after this ethyl acetate (5% volume/volume) be present among the benzinum that it is carried out wash-out, thereby the compound 0601-120 (170 milligrams, 61%) of acquisition-kind of white solid form.LCMS:173[M+1] +, 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 2.59 (s, 3H), 8.87 (s, 2H).
Step 42b:2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) pyrimidine (compound 0602-120)
(100 milligrams of described title compound 0602-120,52%) be by using a kind of oil of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by (150 milligrams of 0601-120,0.87 milli rubs), (331 milligrams of connection boric acid pinacol esters, 1.3 milli rubs), (21 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.026 milli rubs) and anhydrous acetic acid potassium (256 milligrams, 2.62 milli rub) prepare.LCMS:221[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.32 (s, 12H), 2.64 (s, 3H), 8.81 (s, 2H).
Step 42c:2-(methyl ((2-(2-methylpyrimidine-5-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-120)
(210 milligrams of described title compound 0603-120,74%) be by using a kind of a kind of linen solid with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (250 milligrams of 0504-54,0.56 milli rubs), (880 milligrams of 0602-120,4 millis rub), (168 milligrams of sodium bicarbonates, 2 millis rub) and two (Diphenyl phosphino ferrocene) palladium chloride (II) (23 milligrams, 0.03 milli rub) at toluene (8 milliliters), the solution that forms in ethanol (5 milliliters) and the water (2 milliliters) prepares.LCMS:507[M+1] + 1HNMR (400 megahertzes, deuterochloroform): δ 1.31 (t, J=7.2Hz, 3H), 2.74 (s, 3H), 3.25 (s, 3H), 3.79 (t, J=4.4Hz, 4H), 3.94 (t, J=4.4Hz, 4H), 4.29 (q, J=7.2Hz, 2H), (5.14 s, 2H), 7.32 (s, 1H), (8.86 s, 2H), 9.48 (s, 2H).
Step 42d:N-hydroxyl-2-(methyl ((2-(2-methylpyrimidine-5-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5 formamide (compound 120)
(150 milligrams of described title compounds 120,73%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (5 milliliters) that is the azanol by 0603-120 (210 milligrams, 0.41 milli rub) and fresh preparation prepares: fusing point 184-186 ℃.LCMS:494[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 2.69 (s, 3H), 3.24 (s, 3H), (3.76 t, J=4.4Hz, 4H), 3.94 (t, J=4.4Hz, 4H), 5.21 (s, 2H), (7.49 s, 1H), 8.76 (s, 2H), (9.06 s, 1H), 9.9.48 (s, 2H), 11.14 (s, 1H).
Embodiment 43:2-(((2-(2-ethyl-pyrimidine-5-yl)-4-morpholine thiophene a pair of horses going side by side [3, 2-d] pyrimidine-6-yl) methyl) (methyl) amino) (the change of N-hydroxy pyrimidine-5 formamide Compound 121) preparation
Step 43a:5-bromo-2-ethyl-pyrimidine (0601-121)
After being dissolved in propionitrile (38 grams, 0.69 milli rubs) in the absolute ethyl alcohol (100 milliliters), under 0 ℃, passed into hydrogen chloride gas 4 hours.The stirring of at room temperature described mixed liquor being spent the night and under vacuum condition, remove excessive hydrogen chloride gas and ethanol.To wherein adding ether (100 milliliters) and described solid matter being filtered and utilizes ether (100 milliliters) that it is washed.To described solid carry out drying and after this it is dissolved among the ethanol (100 milliliters) and under 0 ℃ to wherein passing into ammonia gas 1 hour, described solution is filtered and described filtrate is concentrated into 1/2nd of described initial volume, described solid filtering is removed.Thus obtained described solid is carried out filtration again and described filtrate concentrated, thereby obtain a kind of hydrochloric acid the third amidine (34 grams, 45%) of white solid form.GCMS:71[M-1] +, 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.17 (t, J=7.6Hz, 3H), 2.40 (q, J=7.6Hz, 2H), 8.79 (s, 2H), 9.09 (s, 2H).
Careful sodium (356 milligrams, 15.5 millis rub) is joined ethanol (5.9 milliliters) thus among the ethanolic solution of preparation sodium ethoxide.The ethanolic solution (3.5 milliliters) of the sodium ethoxide of above-mentioned fresh preparation is joined in the stirred suspension of hydrochloric acid the third amidine (1.05 grams, 9.69 millis rub).Described mixed liquor is warming up to 55 ℃, remove after this described heating bath and with a kind of speed that can keep a kind of stationary temperature to wherein dropwise adding mucobromic acid (1 gram, 3.87 milli rubs) ethanolic solution, after this further add the ethanolic solution (2 milliliters) of sodium ethoxide.After supercooling, described mixed liquor is filtered and is evaporated to a kind of residue of acquisition, utilize hydrochloric acid (2M x2.4 milliliter) that described residue is carried out violent vibration.The sediment of described brown is filtered and utilizes cold water that it is washed, carry out after this freeze drying, thereby obtain a kind of 5-bromo-2-ethyl-pyrimidine of yellow solid form-4-carboxylic acid (330 milligrams, 37%).LCMS:231[M+1] +, 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.25 (t, J=7.6Hz, 3H), 2.88 (q, J=7.6Hz, 2H), 9.05 (s, 1H).
The dimethylbenzene mixed liquor (50 milliliters) of compound 5-bromo-2-ethyl-pyrimidine-4-carboxylic acid (5.6 grams, 24.3 millis rub) is carried out 2 hours backflow.After supercooling, described mixed liquor is directly used on silica column, utilize benzinum that it is carried out wash-out, utilize after this ethyl acetate (5%) be present among the benzinum that it is carried out wash-out, thereby obtain a kind of compound 0601-121 (1.7 grams, 38%) of yellow liquid form. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): 1.26 (t, J=7.6Hz, 3H), 2.87 (q, J=7.6Hz, 2H), 8.90 (s, 2H).
Step 43b:2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) pyrimidine (compound 0602-121)
Described title compound 0602-121 (crude product, 3.7 be by using a kind of oil of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107 gram), by 0601-121 (1.7 grams, 9.1 milli rubs), connection boric acid pinacol ester (3.5 grams, 13.6 milli rubs), (222 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.27 milli rubs) and potassium acetate (2.7 grams, 27 millis rub) prepare.LCMS:235[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.27 (t, J=7.6Hz, 3H), 1.32 (s, 12H), 2.91 (q, J=7.6Hz, 2H), 8.84 (s, 2H).
Step 43c:2-(((2-(2-ethyl-pyrimidine-5-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-121)
(120 milligrams of described title compound 0603-121,41%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (250 milligrams of 0504-54,0.56 milli rubs), 0602-121 (3.7 grams, crude product), (168 milligrams of sodium bicarbonates, 2 millis rub) and two (Diphenyl phosphino ferrocene) palladium chloride (II) (23 milligrams, 0.03 milli rub) at toluene (8 milliliters), the solution that forms in ethanol (5 milliliters) and the water (2 milliliters) prepares.LCMS:521[M+1] + 1HNMR (400 megahertzes, deuterochloroform): δ 1.29-1.36 (m, 6H), 3.00 (q, J=8Hz, 2H), 3.25 (s, 3H), 3.79 (t, J=4.4Hz, 4H), 3.94 (t, J=4.4Hz, 4H), 4.29 (q, J=7.2Hz, 2H), (5.14 s, 2H), 7.32 (s, 1H), (8.86 s, 2H), 9.51 (s, 2H).
Step 43d:2-(((2-(2-ethyl-pyrimidine-5-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) N-hydroxy pyrimidine-5 formamide (compound 121)
(66 milligrams of described title compounds 121,56%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (8 milliliters) that is the azanol by 0603-121 (120 milligrams, 0.23 milli rub) and fresh preparation prepares: fusing point 153-156 ℃.LCMS:508[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.32 (t, J=7.2Hz, 3H), 2.97 (q, J=7.2Hz, 2H), 3.24 (s, 3H), 3.76 (t, J=4.4Hz, 4H), 3.95 (t, J=4.4Hz, 4H), (5.21 s, 2H), 7.49 (s, 1H), (8.75 s, 2H), 9.06 (s, 1H), (9.52 s, 2H), 11.13 (s, 1H).
Embodiment 44:2-(((2-(2-amino-4 methylpyrimidines-5-yl)-4-morpholine thiophene A pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) N-hydroxy pyrimidine-5 formyl The preparation of amine (compound 125)
Step 44a:5-bromo-4-methylpyrimidine-2-amine (compound 0601-125)
At room temperature to 2-amino-4-methylpyrimidine (4.0 grams, 36.7 milli rubs), the chloroform mixed liquor (100 milliliters) of N-bromosuccinimide (NBS) (7.18 grams, 40.3 millis rub) carries out 2 hours stirring, removes after this described solvent under vacuum condition.To wherein adding entry (100 milliliters) and at room temperature carrying out 30 minutes stirring, filter.Utilize water that described solid is washed and drying, thereby obtain a kind of compound 0601-125 (6.3 grams, 91%) of white solid form.LCMS:188[M+1] +, 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 2.32 (s, 3H), 6.79 (s, 2H), 8.21 (s, 1H).
Step 44b:4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) pyrimidine-2-amine (compound 0602-125)
(430 milligrams of described title compound 0602-125,69%) be by using a kind of solid of a kind of grey with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by (500 milligrams of 0601-125,2.66 milli rubs), connection boric acid pinacol ester (1.01 grams, 4.0 milli rubs), (217.2 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.27 milli rubs), potassium acetate (783 milligrams, 7.98 millis rub) prepares.LCMS:236[M+1] +, 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.27 (s, 12H), 2.37 (s, 3H), 6.89 (s, 2H), 8.30 (s, 1H).
Step 44c:2-(((2-(2-amino-4-methylpyrimidine-5-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-125)
(160 milligrams of described title compound 0603-125,55%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (376 milligrams of 0504-54,0.84 milli rubs), (130 milligrams of 0602-125,0.56 milli rubs), (256 milligrams of cesium fluorides, 1.68 milli rubs) and (59 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides (II), 0.084 milli rubs) solution of formation in Isosorbide-5-Nitrae-dioxane (5 milliliters) and the water (1 milliliter) prepares.LCMS:522[M+1] + 1HNMR (400 megahertzes, deuterochloroform): δ 1.38 (d, J=7.2Hz, 3H), 2.73 (s, 3H), 3.31 (s, 3H), 3.84 (m, 4H), 3.96 (m, 4H), 4.37 (q, J=7.2Hz, 2H), 5.20 (s, 2H), (5.23 s, 2H), 7.35 (s, 1H), (8.89 s, 1H), 8.93 (s, 2H).
Step 44d:2-(((2-(2-amino-4-methylpyrimidine-5-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) N-hydroxy pyrimidine-5 formamide (compound 125)
(92 milligrams of described title compounds 125,62%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (20 milliliters) that is the azanol by 0603-125 (150 milligrams, 0.29 milli rub) and fresh preparation prepares: fusing point 195-198 ℃.LCMS:509[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 2.62 (s, 3H), 3.23 (s, 3H), (3.74 m, 4H), 3.86 (m, 4H), (5.20 s, 2H), 6.86 (s, 2H), (7.42 s, 1H), 8.77 (s, 2H), (8.81 s, 1H), 9.10 (s, 1H), 11.21 (s, 1H).
Embodiment 45:N-hydroxyl-2-(((2-(3-methoxyphenyl))-4-morpholine thiophene A pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5 formamide (chemical combination Thing 130) preparation
Step 45a:2-(3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane (compound 0602-130)
(800 milligrams of described title compound 0602-130,68%) be by using a kind of a kind of oil with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by (930 milligrams of 1-bromo-methoxybenzenes, 5.0 milli rubs), connection boric acid pinacol ester (2.54 grams, 10 millis rub), potassium acetate (1.47 grams, 15 millis rub), and two (Diphenyl phosphino ferrocene) palladium chloride (204 milligrams, 0.25 milli rub) prepares.LCMS:235[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.34 (s, 12H), 3.83 (s, 3H), 7.0 (d, J=6.4Hz, 2H), 7.29 (m, 2H), 7.41 (d, J=5.6Hz, 1H).
Step 45b:2-(((2-(3-methoxyphenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-130)
(120 milligrams of described title compound 0603-130,51%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (126 milligrams of 0602-130,0.54 milli rubs), (200 milligrams of 0504-54,0.45 milli rubs), (114 milligrams of sodium bicarbonates, 1.35 milli rubs) and (16 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides (II), 0.0225 milli rubs) at toluene (8 milliliters), the solution that forms in ethanol (5 milliliters) and the water (2 milliliters) prepares.LCMS:521[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.30 (t, J=6.8Hz, 3H), 3.27 (s, 3H), 3.76 (m, 4H), 3.83 (s, 3H), 3.92 (m, 4H), 3.94 (s, 2H), 4.29 (q, J=6.8Hz, 2H), 5.23 (s, 2H), 7.06 (d, J=7.2Hz1H), 7.39 (t, J=10.4Hz, 1H), 7.49 (s, 1H), 7.92 (s, 1H), (7.99 d, J=8Hz, 1H), 8.82 (s, 1H).
Step 45c:N-hydroxyl-2-(((2-(3-methoxyphenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) N-hydroxy pyrimidine-5 formamide (compound 130)
(15 milligrams of described title compounds 130,15%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (20 milliliters) that is the azanol by 0603-130 (110 milligrams, 0.2 milli rub) and fresh preparation prepares: fusing point 179-181 ℃.LCMS:508[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.23 (s, 3H), 3.77 (m, 4H), 3.83 (s, 3H), 3.93 (m, 4H), 5.21 (s, 2H), (7.07 d, J=9.2Hz, 1H), 7.39 (t, J=10.4Hz, 1H), 7.42 (s, 1H), 7.91 (s, 1H), (8.0 d, J=16.4Hz, 1H), 8.75 (s, 2H), (9.02 brs, 1H), 11.14 (brs, 1H).
Embodiment 46:N-hydroxyl-2-(((2-(3-hydroxy phenyl))-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5 formamide (compound 132) preparation
Step 46a:3-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) phenol (compound 0602-132)
(600 milligrams of described title compound 0602-132,68%) be by using a kind of a kind of oil with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by (700 milligrams of 3-bromophenols, 4.0 milli rubs), connection boric acid pinacol ester (1.5 grams, 6 millis rub), potassium acetate (1.2 grams, 12 millis rub), and two (Diphenyl phosphino ferrocene) palladium chloride (163 milligrams, 0.2 milli rub) prepares.LCMS:221[M+1] +.1HNMR (400 megahertzes, deuterochloroform) δ 1.34 (s, 12H), 5.37 (s, 1H), 6.96 (d, J=4.0Hz, 1H), 7.26 (m, 2H), 7.36 (d, J=7.2Hz, 1H).
Step 46b:2-(((2-(3-hydroxy phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-132)
(160 milligrams of described title compound 0603-132,47%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (300 milligrams of 0602-132,0.67 milli rubs), (176 milligrams of 0504-54,0.8 milli rubs), (172 milligrams of sodium bicarbonates, 2 millis rub) and (23 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides (II), 0.0335 milli rubs) at toluene (8 milliliters), the solution that forms in ethanol (5 milliliters) and the water (2 milliliters) prepares.LCMS:507[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.30 (t, J=6.8Hz, 3H), 3.27 (s, 3H), (3.76 m, 4H), 3.92 (m, 4H), 4.29 (q, J=6.8Hz, 2H), 5.24 (s, 2H), 6.84 (d, J=16.8Hz, 2H), 7.24 (t, J=8Hz, 1H), (7.48 s, 1H), 7.83 (m, 2H), (8.88 s, 2H), 9.49 (s, 1H).
Step 46c:N-hydroxyl-2-(((2-(3-hydroxy phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) N-hydroxy pyrimidine-5 formamide (compound 132)
(53 milligrams of described title compounds 132,34%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (20 milliliters) that is the azanol by 0603-132 (160 milligrams, 0.32 milli rub) and fresh preparation prepares: fusing point 175-181 ℃.LCMS:494[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.23 (s, 3H), 3.76 (m, 4H), (3.92 m, 4H), 5.19 (s, 2H), (6.85 d, J=10.4Hz, 1H), 7.24 (t, J=6.8Hz, 1H), 7.44 (s, 1H), (7.82 m, 2H), 8.74 (s, 2H), 9.51 (brs, 1H).
Embodiment 47:2-(((2-(3-aminophenyl))-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 134) preparation
Step 47a:2-(((2-(3-aminophenyl))-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-134)
Under 50 ℃, add aqueous hydrochloric acid solution (6M, 10 milliliters) in oxolane (THF) solution (10 milliliters) of 0603-107 (170 milligrams, 0.31 milli rub) and under this temperature, described mixed liquor carried out 2 hours stirring.Utilize saturated sodium bicarbonate aqueous solution that described mixed liquor is neutralized and utilize ethyl acetate that it is extracted.Utilize water, salt solution washs isolated described organic layer, carries out drying by sodium sulphate, filter, and under reduced pressure, concentrate, thereby obtain a kind of described title compound 0603-134 (130 milligrams, 83%) of white solid form.LCMS:506[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (t, J=7.6Hz, 3H), 3.27 (s, 3H), 3.40 (s, 2H), 3.76 (t, J=5.2Hz, 4H), 3.93 (t, J=4.8Hz, 4H), 7.89 (q, J=7.6Hz, 2H), 5.24 (s, 1H), (6.79 d, J=7.6Hz, 1H), 7.19 (t, J=8.0Hz, 1H), 7.47 (s, 1H), 7.69 (d, J=8.0Hz, 1H), 7.77 (s, 1H), 8.88 (s, 1H).
Step 47b:2-(((2-(3-aminophenyl))-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 134)
(35 milligrams of described title compounds 134,28%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (4 milliliters) that is the azanol by 0603-134 (130 milligrams, 0.25 milli rub) and fresh preparation prepares: fusing point 179-182 ℃.LCMS:493[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 3.24 (s, 3H), 3.77 (t, J=4.0Hz, 4H), (3.96 t, J=4.0Hz, 4H), 5.22 (s, 2H), (6.98 d, J=7.6Hz, 1H), 7.32 (t, J=7.6Hz, 1H), 7.47 (s, 1H), 7.86 (d, J=7.6Hz, 1H), 7.91 (s, 1H), 8.76 (s, 2H), (9.07 s, 1H), 11.15 (s, 1H).
Embodiment 48:2-(((2-(4-amino methyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3, 2-d] pyrimidine-6-yl) methyl) (methyl) amino)-(change of N-hydroxypyrimidine-5-carboxamides Compound 135) preparation
Step 48a:N-(4-Brombenzyl) acetamide (compound 0601-135)
Under 0 ℃; to hydrochloric acid 4-bromobenzene methylamine (1.2 grams; 5.4 milli rubs) and the dichloromethane solution (10 milliliters) of triethylamine (5.5 grams, 54 millis rub) in add acetyl group chlorine (555 milligrams, 7.02 millis rub) and under 30 ℃, carry out 2 hours stirring.After this described mixed liquor is concentrated and described residue is dissolved among the carrene (30 milliliters), utilize water that it is washed, carry out drying and concentrated by sodium sulphate, thereby obtain a kind of 0601-135 (1.3 grams, 100%) of yellow solid form.LCMS:228[M+1] +, 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 2.00 (s, 3H), 4.33 (d, J=6.4Hz, 2H), 6.26 (s, 1H), 7.13 (d, J=8.4Hz, 2H), 7.43 (d, J=8.4Hz, 2H).
Step 48b:N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) benzyl) acetamide (compound 0602-135)
(825 milligrams of described title compound 0602-135,60%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by 0601-135 (1.2 grams, 5 millis rub), connection boric acid pinacol ester (1.9 grams, 7.5 milli rubs), potassium acetate (1.47 grams, 15 millis rub), and two (Diphenyl phosphino ferrocene) palladium chloride (410 milligrams, 0.5 milli rub) prepares.LCMS:276[M+1] +, 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.27 (s, 12H), 1.87 (s, 3H), 4.26 (d, J=6.0Hz, 2H), 7.25 (d, J=8.0Hz, 2H), 7.62 (d, J=8.0Hz, 2H), 8.36 (t, J=5.6Hz, 1H).
Step 48c:2-(((2-(4-amino methyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's methyl esters (compound 0603-135)
Utilize nitrogen to (200 milligrams of compound 0602-135,0.73 milli rubs), (261 milligrams of 0504-54,0.58 milli rubs), (184 milligrams of sodium bicarbonates, 2.2 milli rubs) and the mixed liquor that forms in toluene (4 milliliters), ethanol (2 milliliters) and water (0.5 milliliter) of two (Diphenyl phosphino ferrocene) palladium chloride (II) (52 milligrams, 0.073 milli rub) washes and in the heating of it being carried out 2 hours under the microwave condition under 130 ℃.Utilize carrene and water that described reaction mixture is separated, utilize salt solution that organic layer is washed, carry out drying by sodium sulphate, filter and under vacuum condition, evaporate.(be present in the methyl alcohol among the carrene by column chromatography; the 2-5% volume/volume) residue obtained above is carried out purifying; thereby obtain 2-(((2-(4-acetyl group methyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3 of a kind of white solid form; 2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's methyl esters (300 milligrams, 92%).LCMS:562[M+1] + 1H NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.36 (m, 3H), 1.96 (s, 3H), 3.33 (s, 3H), 3.83 (m, 4H), 3.94 (m, 4H), (4.36 m, 4H), 5.29 (s, 2H), (7.41 d, J=7.6Hz, 2H), 7.54 (s, 1H), 8.39 (d, J=8.0Hz, 2H), (8.47 m, 1H), 8.94 (s, 2H).
Ethyl ester obtained above (250 milligrams, 0.45 milli rub) is dissolved among the oxolane (THF) (8 milliliters), after this to the aqueous solution that wherein adds hydrochloric acid (6M, 12 milliliters) and under 85 ℃, carry out 12 hours stirring.Under 0 ℃, utilize after this sodium hydroxide that the pH of described mixed liquor is adjusted to 4, filter and utilize carrene that it is washed, thereby obtain 2-(((2-(4-amino methyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3 of a kind of white solid form, 2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's (200 milligrams, 91%).Described solid need not to carry out further purifying can directly be carried out use in following step.LC-MS：492[M+1] +.
Acid obtained above (230 milligrams, 0.47 milli rubs) is dissolved among the methyl alcohol (10 milliliters).Under 0 ℃, in mentioned solution, add thionyl chloride (5 milliliters) and under reflux state, carry out 1.5 hours stirring.After this described mixed liquor is concentrated, add entry, utilize saturated sodium bicarbonate aqueous solution that pH is adjusted to 8, utilize carrene that it is extracted and under vacuum condition, evaporate, thereby obtain a kind of compound 0603-135 (210 milligrams, 88%) of yellow solid form.LC-MS:506[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.28 (s, 3H), 3.83 (m, 9H), 3.97 (m, 4H), 5.20 (m, 2H), 7.38 (m, 3H), 8.34 (m, 2H), 8.86 (m, 2H).
Step 48d:2-(((2-(4-amino methyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 135)
(60 milligrams of described title compounds 135,30%) be by using a kind of a kind of flaxen solid with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (20 milliliters) that is the azanol by 0603-135 (200 milligrams, 0.40 milli rub) and fresh preparation prepares: fusing point 184-186 ℃.LCMS:507[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 3.23 (s, 3H), 3.76 (m, 4H), 3.93 (m, 6H), 5.20 (s, 2H), 7.45 (s, 1H), 7.49 (d, J=8.4Hz, 2H), 8.36 (d, J=8.0Hz, 2H), 8.75 (s, 2H).
Embodiment 49:2-(((2-(3-(amino methyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-the N-hydroxypyrimidine-5-carboxamides The preparation of (compound 137)
Step 49a:N-(3-Brombenzyl) acetamide (compound 0601-137)
Under 0 ℃; to hydrochloric acid 3-bromobenzene methylamine (1.2 grams; 5.4 milli rubs) and the dichloromethane solution (10 milliliters) of triethylamine (5.5 grams, 54 millis rub) in add acetyl group chlorine (555 milligrams, 7.02 millis rub) and under 30 ℃, carry out 2 hours stirring.After this described mixed liquor is concentrated and described residue is dissolved among the carrene, utilize water that it is washed, carry out drying and concentrated by sodium sulphate, thereby obtain a kind of 0601-137 (1.2 grams, 98%) of yellow solid form.LCMS:228[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.88 (s, 3H), 4.25 (d, J=6.0Hz, 2H), 7.28 (m, 2H), 7.43 (m, 2H), 8.39 (s, 1H).
Step 49b:N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) benzyl) acetamide (compound 0602-137)
Described title compound 0602-137 (1.0 grams, 72%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by 0601-137 (1.2 grams, 5 millis rub), connection boric acid pinacol ester (1.9 grams, 7.5 milli rubs), potassium acetate (1.47 grams, 15 millis rub), and two (Diphenyl phosphino ferrocene) palladium chloride (410 milligrams, 0.5 milli rub) prepares.LCMS:276[M+1] +, 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.28 (s, 12H), 1.85 (s, 3H), 4.23 (d, J=6.0Hz, 2H), 7.33 (m, 2H), 7.54 (d, J=7.2Hz, 1H), 7.57 (s, 1H), 8.35 (t, J=5.6Hz, 1H).
Step 49c:2-(((2-(3-(amino methyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's methyl esters (compound 0603-137)
Utilize nitrogen to (400 milligrams of compound 0602-137,1.46 milli rubs), (522 milligrams of 0504-54,1.16 milli rubs), (368 milligrams of sodium bicarbonates, 4.4 milli rubs) and the mixed liquor that forms in toluene (4 milliliters), ethanol (2 milliliters) and water (0.5 milliliter) of two (Diphenyl phosphino ferrocene) palladium chloride (II) (104 milligrams, 0.146 milli rub) washes and in the heating of it being carried out 2 hours under the microwave condition under 130 ℃.Utilize carrene and water that described reaction mixture is separated, utilize salt solution that organic layer is washed, carry out drying by sodium sulphate, filter and under vacuum condition, evaporate.(be present in the methyl alcohol among the carrene by column chromatography; the 2-5% volume/volume) residue obtained above is carried out purifying; thereby obtain a kind of 2-(((2-(3-(acetyl group methyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3 of white solid form; 2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's methyl esters (580 milligrams, 89%).LCMS:562[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.28 (m, 3H), 1.88 (s, 3H), (3.27 s, 3H), 3.76 (m, 4H), (3.92 m, 4H), 4.27 (m, 4H), (5.23 s, 2H), 7.38 (m, 2H), (7.49 m, 1H), 8.30 (m, 2H), (8.43 m, 1H), 8.87 (s, 2H).
Ethyl ester obtained above (300 milligrams, 0.53 milli rub) is dissolved among the oxolane (THF) (8 milliliters), after this to the aqueous solution that wherein adds hydrochloric acid (6M, 12 milliliters) and under 85 ℃, carry out 12 hours stirring.Under 0 ℃, utilize after this sodium hydroxide that the pH of described mixed liquor is adjusted to 4, filter and utilize carrene that it is washed, thereby obtain a kind of 2-(((2-(3-(amino methyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3 of white solid form, 2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's (245 milligrams, 93%).LC-MS：492[M+1] +.
Acid obtained above (300 milligrams, 0.61 milli rubs) is dissolved among the methyl alcohol (10 milliliters).Under 0 ℃, in mentioned solution, add thionyl chloride (5 milliliters) and under reflux state, carry out 1.5 hours stirring.After this described mixed liquor is concentrated, add entry, utilize sodium bicarbonate that pH is adjusted to 8, utilize carrene that it is extracted and under vacuum condition, evaporate, thereby obtain a kind of compound 0603-137 (260 milligrams, 84%) of yellow solid form.LC-MS:506[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.27 (s, 3H), 3.76 (m, 4H), 3.82 (s, 3H), 3.95 (m, 6H), 5.24 (s, 2H), 7.45 (m, 3H), 8.31 (m, 1H), 8.41 (s, 1H), 8.88 (m, 2H).
Step 49d:2-(((2-(3-(amino methyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 137)
(46 milligrams of described title compounds 137,18%) be by using a kind of a kind of flaxen solid with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (20 milliliters) that is the azanol by 0603-137 (250 milligrams, 0.5 milli rub) and fresh preparation prepares: fusing point 173-176 ℃.LCMS:507[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 3.23 (s, 3H), 3.76 (m, 4H), (3.94 m, 4H), 3.99 (s, 2H), (5.20 s, 2H), 7.45 (s, 1H), (7.50 m, 2H), 8.32 (m, 1H), (8.38 s, 2H), 8.43 (s, 1H), 8.75 (s, 2H).
Embodiment 50:N-hydroxyl-2-(((2-(3-(hydroxymethyl) phenyl)-4-morpholine Thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-formamide The preparation of (compound 138)
Step 50a:(3-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) phenyl) methyl alcohol (compound 0602-138)
(300 milligrams of described title compound 0602-138,43%) be by using a kind of oil of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by a bromobenzene methyl alcohol (0.56 gram, 3 millis rub), connection boric acid pinacol ester (1.14 grams, 4.5 milli rubs), potassium acetate (1.32 grams, 9 millis rub), and two (Diphenyl phosphino ferrocene) palladium chloride (490 milligrams, 0.6 milli rub) prepares.LCMS:252[M+18] + 1HNMR (400 megahertzes, deuterochloroform) δ 1.35 (s, 12H), 1.66 (s, 1H), 4.70 (s, 2H), 7.38 (t, J=7.2Hz, 1H), 7.49 (d, J=7.6Hz, 1H), 7.74 (d, J=7.2Hz, 1H), 7.80 (s, 1H).
Step 50b:2-(((2-(3-hydroxymethyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-138)
(140 milligrams of described title compound 0603-138,90%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (135 milligrams of 0504-54,0.30 milli rubs), (105 milligrams of 0602-138,0.45 milli rubs), (76 milligrams of sodium bicarbonates, 0.90 milli rubs) and (11 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides (II), 0.015 milli rubs) at toluene (2.5 milliliters), the solution that forms in ethanol (1.6 milliliters) and the water (0.7 milliliter) prepares.LCMS:521[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (t, J=7.2Hz, 3H), 3.27 (s, 3H), (3.77 m, 4H), 3.93 (q, J=7.2Hz, 2H), (4.59 d, J=6.0Hz, 2H), 5.24 (s, 2H), (5.29 t, J=5.6Hz, 1H), 7.43 (m, 2H), (7.50 s, 1H), 8.26 (m, 1H), (8.37 s, 1H), 8.88 (s, 2H).
Step 50c:N-hydroxyl-2-(((2-(3-(hydroxymethyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-formamide (compound 138)
(30 milligrams of described title compounds 138,44%) be by using a kind of a kind of flaxen solid with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (10 milliliters) that is the azanol by 0603-138 (70 milligrams, 0.13 milli rub) and fresh preparation prepares: fusing point 160-164 ℃.LCMS:508[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.24 (s, 3H), 3.77 (s, 4H), (3.94 s, 2H), 4.59 (d, J=5.6Hz, 2H), 5.21 (s, 2H), 5.28 (t, J=5.6Hz, 1H), 7.44 (m, 3H), (8.27 m, 1H), 8.37 (s, 1H), (8.75 s, 2H), 9.07 (s, 1H).
Embodiment 51:N-hydroxyl-2-(((2-(3-(methoxy) phenyl)-4- Morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-first The preparation of acid amides (compound 139)
Step 51a:1-bromo-3-(methoxy) benzene (compound 0601-139)
Under 0 ℃, in oxolane (THF) solution (10 milliliters) of a bromobenzene methyl alcohol (1.0 grams, 5.3 millis rub), add sodium hydride (0.26 gram, 10.6 milli rubs), carry out 10 minutes stirring, carry out after this interpolation of iodomethane (1.1 grams, 7.9 millis rub).Reaction mixture obtained above carried out 1 hour stirring.Add ethyl acetate (30 milliliters) in described mixed liquor, utilize water, salt solution washs it, carry out drying by sodium sulphate, filter, and under reduced pressure, concentrate, thereby obtain a kind of described title compound 0601-139 (1.0 grams, 93%) of oil form. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 3.30 (s, 3H), 4.41 (s, 2H), 7.29 (t, J=8.0Hz, 1H), 7.40 (t, J=7.6Hz, 1H), 7.47 (d, J=8.0Hz, 1H), 7.64 (d, J=8.0Hz, 1H).
Step 51b:2-(3-(methoxy) phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane (compound 0602-139)
Described title compound 0602-139 (1.2 grams, 97%) be by using a kind of a kind of oil with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by 0601-139 (1.1 grams, 5.4 milli rubs), connection boric acid pinacol ester (2.1 grams, 8.1 millis rub), potassium acetate (1.6 grams, 16.3 milli rubs), and two (Diphenyl phosphino ferrocene) palladium chloride (45 milligrams, 0.05 milli rub) prepares. 1H NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.28 (s, 12H), 3.28 (s, 3H), 4.40 (s, 2H), 7.35 (t, J=7.2Hz, 1H), 7.42 (d, J=7.2Hz, 1H), 7.58 (d, J=7.2Hz, 1H), 7.63 (s, 1H).
Step 51c:2-(((2-(3-methoxy) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-139)
(180 milligrams of described title compound 0603-139,71%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (210 milligrams of 0504-54,0.46 milli rubs), (174 milligrams of 0602-139,0.7 milli rubs), (118 milligrams of sodium bicarbonates, 1.4 milli rubs) and (16 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides (II), 0.02 milli rubs) at toluene (8 milliliters), the solution that forms in ethanol (2 milliliters) and the water (1 milliliter) prepares.LCMS:535[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.30 (t, J=7.2Hz, 3H), 3.27 (s, 3H), (3.33 s, 3H), 3.76 (m, 4H), 3.93 (m, 4H), 4.28 (q, J=7.2Hz, 2H), 4.50 (s, 2H), 5.23 (s, 2H), 7.45 (q, J=7.2Hz, 1H), 7.49 (s, 1H), 8.31 (d, J=7.6Hz, 1H), 8.34 (s, 1H), 8.87 (m, 2H).
Step 51d:N-hydroxyl-2-(((2-(3-(methoxy) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-formamide (compound 139)
(56 milligrams of described title compounds 139,47%) be by using a kind of a kind of orange solid with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (8 milliliters) that is the azanol by 0603-139 (120 milligrams, 0.22 milli rub) and fresh preparation prepares: fusing point 178-181 ℃.LCMS:522[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 3.24 (s, 3H), 3.33 (s, 3H), 3.77 (m, 4H), 3.93 (m, 4H), 4.51 (s, 2H), (5.21 s, 2H), 7.43 (q, J=7.6Hz, 2H), (7.47 s, 1H), 8.31 (d, J=7.2Hz, 1H), (8.34 s, 1H), 8.75 (s, 2H), (9.05 s, 1H), 11.12 (s, 1H).
Embodiment 52:N-hydroxyl-2-(((2-(4-(methoxy) phenyl)-4- Morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-first The preparation of acid amides (compound 140)
Step 52a:(4-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) phenyl) methyl alcohol (compound 0602-140)
(670 milligrams of described title compound 0602-140,94%) be by using a kind of a kind of oil with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by (4-bromophenyl) methyl alcohol (0.56 gram, 3 millis rub), connection boric acid pinacol ester (1.14 grams, 4.5 milli rubs), potassium acetate (1.32 grams, 9 millis rub), and two (Diphenyl phosphino ferrocene) palladium chloride (490 milligrams, 0.6 milli rub) prepares.LCMS:217[M-OH] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.28 (s, 12H), 4.51 (d,, J=5.6Hz2H), 5.23 (t, J=6.0Hz, 1H), 7.32 (d, J=8.0Hz, 2H), 7.62 (d, J=7.6Hz, 2H).
Step 52b:2-(((2-(4-methoxy) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-140)
(120 milligrams of described title compound 0603-140,77%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (135 milligrams of 0504-54,0.30 milli rubs), (105 milligrams of 0602-140,0.45 milli rubs), (76 milligrams of sodium bicarbonates, 0.90 milli rubs) and (11 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides (II), 0.015 milli rubs) at toluene (2.5 milliliters), the solution that forms in ethanol (1.6 milliliters) and the water (0.7 milliliter) prepares.LCMS:521[M+1] + 1HNMR (400 megahertzes, the δ 1.28 (t, J=7.2Hz, 3H) of dimethyl sulfoxide (DMSO)-d6), (3.25 s, 3H), 3.74 (t, J=4.4Hz, 4H), 3.90 (t, J=7.2Hz, 4H), (4.26 q, J=7.2Hz, 2H), (4.56 d, J=6.4Hz, 2H), (5.21 s, 2H), 5.26 (t, J=5.6Hz, 1H), 7.41 (d, J=8.0Hz, 2H), 7.46 (s, 1H), 8.34 (d, J=8.8Hz, 2H), 8.85 (s, 2H).
Step 52c:N-hydroxyl-2-(((2-(4-(hydroxymethyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-formamide (compound 140)
(61 milligrams of described title compounds 140,63%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (10 milliliters) that is the azanol by 0603-140 (100 milligrams, 0.19 milli rub) and fresh preparation prepares: fusing point 218-223 ℃.LCMS:508[M+1] + 1HNMR (400 megahertzes, the δ 3.23 (s, 3H) of dimethyl sulfoxide (DMSO)-d6), 3.76 (d, J=4.4Hz, 4H), 3.91 (d, J=4.0Hz, 4H), 4.56 (d, J=4.8Hz, 2H), 5.19 (s, 2H), 5.27 (t, J=5.6Hz, 1H), 7.42 (t, J=8.8Hz, 3H), (8.34 d, J=8.0Hz, 2H), 8.74 (s, 2H), (9.08 s, 1H), 11.13 (s, 1H).
Embodiment 53:N-hydroxyl-2-(((2-(2-(hydroxymethyl) phenyl)-4-morpholine Thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-formamide The preparation of (compound 141)
Step 53a:2-bromoacetic acid benzene methyl (compound 0601-141)
Under 0 ℃; in the dichloromethane solution (20 milliliters) of adjacent bromobenzene methyl alcohol (2.0 grams, 10.7 millis rub), add acetyl group chlorine (1.1 grams, 13.9 millis rub) and triethylamine (TEA) (2.16 grams; 21.4 milli rubs), carry out after this 2 hours stirring.Utilize water, salt solution washs described reaction mixture, carries out drying by sodium sulphate, filters, and concentrated under reduced pressure, thereby obtains a kind of described title compound 0601-141 (2.4 grams, 97%) of yellow solid form. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 2.09 (s, 3H), 5.10 (s, 2H), 7.29 (t, J=8.0Hz, 1H), 7.40 (t, J=7.6Hz, 1H), 7.47 (d, J=8.0Hz, 1H), 7.64 (d, J=8.0Hz, 1H).
Step 53b:(2-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) phenylmethyl acetate (compound 0602-141)
Described title compound 0602-141 (2.3 grams, 80%) be by using a kind of a kind of oil with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by 0601-141 (2.4 grams, 10.5 milli rubs), connection boric acid pinacol ester (4.1 grams, 16.3 millis rub), potassium acetate (3.2 grams, 32.7 milli rubs), and two (Diphenyl phosphino ferrocene) palladium chloride (89 milligrams, 0.11 milli rub) prepares.LCMS:277[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.28 (s, 12H), 2.03 (s, 3H), 5.23 (s, 2H), 7.34 (t, J=7.2Hz, 1H), 7.37 (d, J=7.2Hz, 1H), 7.89 (t, J=7.6Hz, 1H), 7.70 (d, J=7.2Hz, 1H).
Step 53c:2-(((2-(2-(hydroxymethyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-141)
(80 milligrams of described title compound 0603-141,17%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (420 milligrams of 0504-54,0.92 milli rubs), (386 milligrams of 0602-141,1.4 milli rubs), (236 milligrams of sodium bicarbonates, 2.8 milli rubs) and (32 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides (II), 0.04 milli rubs) at toluene (8 milliliters), the solution that forms in ethanol (4 milliliters) and the water (2 milliliters) prepares.LCMS:521[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.29 (t, J=7.2Hz, 3H), 3.26 (s, 3H), 3.74 (m, 4H), 3.88 (m, 4H), 4.28 (q, J=6.8Hz, 2H), (4.75 d, J=6.0Hz, 2H), 5.24 (s, 2H), 5.44 (t, J=6.0Hz, 1H), 7.35 (t, J=7.2Hz, 1H), 7.44 (t, J=7.6Hz, 1H), 7.45 (s, 1H), 7.62 (m, 1H), (7.92 d, J=6.8Hz, 1H), 8.87 (s, 1H).
Step 53d:N-hydroxyl-2-(((2-(2-(hydroxymethyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-formamide (compound 141)
(58 milligrams of described title compounds 141,37%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (4 milliliters) that is the azanol by 0603-141 (160 milligrams, 0.3 milli rub) and fresh preparation prepares: fusing point 173-176 ℃.LCMS:508[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 3.23 (s, 3H), 3.73 (m, 4H), 3.88 (m, 4H), (4.75 d, J=6.0Hz, 2H), 5.20 (s, 2H), 5.45 (t, J=6.0Hz, 1H), 7.35 (t, J=6.8Hz, 1H), 7.42 (d, J=7.6Hz, 1H), 7.46 (s, 1H), 7.61 (d, J=7.6Hz, 1H), 7.92 (d, J=7.6Hz, 1H), 8.74 (s, 2H), 9.05 (s, 1H), 11.12 (s, 1H).
Embodiment 54:2-(((2-(3-carbamoyl phenyl)-4-morpholine thiophene a pair of horses going side by side [3, 2-d] pyrimidine-6-yl) methyl) (methyl) amino)-(change of N-hydroxypyrimidine-5-carboxamides Compound 142) preparation
Step 54a:3-brombenzamide (compound 0601-142)
Under 0 ℃, in dimethyl sulfoxide (DMSO) (DMSO) solution (6 milliliters) of a bromobenzylcyanide (2 grams, 10 millis rub), add 30% hydrogen peroxide (5 grams, 13 millis rub) and potash, and at room temperature carry out 30 minutes stirring.Be poured onto described mixed liquor in the water and filter, utilize water that described solid is washed, drying, thus obtain a kind of described compound 0601-142 (1.8 grams, 82%) of white solid form.LCMS:200[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 7.41 (t, J=8.0Hz, 1H), 7.50 (s, 1H), 7.70 (dd, J1,2=8.0,0.8Hz, 1H), 7.85 (d, J=8.0Hz, 1H), 8.03 (t, J=1.6Hz, 1H), 8.06 (s, 1H).
Step 54b:3-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) benzamide (compound 0602-142)
(450 milligrams of described title compound 0602-142,73%) be by using a kind of a kind of solid with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by (500 milligrams of 0601-142,2.5 milli rubs), (952 milligrams of connection boric acid pinacol esters, 3.75 milli rubs), (735 milligrams of potassium acetates, 7.5 milli rubs), and two (Diphenyl phosphino ferrocene) palladium chloride (61 milligrams, 0.075 milli rub) prepares.LCMS:248[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 1.31 (s, 12H), 7.34 (s, 1H), 7.46 (t, J=7.2Hz, 1H), 7.79 (d, J=7.2Hz, 1H), 7.98 (m, 1H), 8.04 (s, 1H), 8.19 (s, 1H).
Step 54c:2-(((2-(3-carbamoyl phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-142)
(180 milligrams of described title compound 0603-142,50%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (305 milligrams of 0504-54,0.68 milli rubs), (200 milligrams of 0602-142,0.81 milli rubs), (21 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.03 milli rubs) and (171 milligrams of sodium bicarbonates, 2.04 milli rubs) at toluene (5 milliliters), the solution that forms in ethanol (3 milliliters) and the water (1.3 milliliters) prepares.LCMS:534[M+1] +. 1HNMR (400 megahertzes, deuterochloroform) δ 1.38 (t, J=7.6Hz, 3H), (3.32 s, 3H), 3.87 (t, J=4.6Hz, 4H), 4.03 (t, J=4.8Hz, 4H), (4.37 q, J=7.6Hz, 2H), 5.20 (s, 2H), 5.77 (br, 1H), 6.37 (br, 1H), 7.39 (s, 1H), 7.55 (t, J=7.8Hz, 1H), 7.96 (d, J=7.6Hz, 4H), 8.59 (d, J=7.6Hz, 1H), 8.84 (s, 1H), 8.93 (s, 2H).
Step 54d:2-(((2-(3-carbamoyl phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-formamide (compound 142)
(65 milligrams of described title compounds 142,44%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (8 milliliters) that is the azanol by 0603-142 (150 milligrams, 0.28 milli rub) and fresh preparation prepares.LCMS:521[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.25 (s, 3H), 2.77-3.79 (m, 4H), 3.95-3.97 (m, 4H), (5.22 s, 2H), 7.44 (s, 1H), 7.50 (s, 1H), 7.56 (t, J=7.6Hz, 1H), 7.97 (d, J=8.0Hz, 1H), 8.13 (s, 1H), 8.52 (d, J=7.6Hz, 1H), 8.76 (s, 2H), 8.96 (s, 1H), 9.03 (br, 1H), 10.93 (br, 1H).
Embodiment 55:N-hydroxyl-2-(methyl ((2-(3-methylamino formoxyl) benzene Base)-and 4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formyl The preparation of amine (compound 144)
Step 55a:3-bromo-N-methyl-benzamide (compound 0601-144)
With the anhydrous methylene chloride suspension (50 milliliters) of methylamine hydrochloride (1.85 grams, 27 millis rub) and triethylamine (4.6 grams, 45 millis rub) be cooled to 0 ℃ and utilize between benzoyl bromide chlorine (2 grams, 9 millis rub) it is processed.Described mixed liquor is warming up to room temperature and carries out 4 hours stirring.In described reaction mixture, add ethyl acetate, utilize water, salt solution that it is washed, and carry out drying by sodium sulphate, concentrated, thus obtain a kind of compound 0601-144 (1.9 grams, 97%) of white solid form.LCMS:214[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 2.78 (d, J=4.4Hz, 3H), 7.43 (t, J=7.6Hz, 1H), 7.72 (d, J=8.8Hz, 1H), 7.83 (d, J=7.6Hz, 1H), 8.00 (s, 1H), 8.57 (s, 1H).
Step 55b:N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) benzamide (compound 0602-144)
(480 milligrams of described title compound 0602-144,82%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by (500 milligrams of 0601-144,2.3 milli rubs), (890 milligrams of connection boric acid pinacol esters, 3.5 milli rubs), (687 milligrams of potassium acetates, 7 millis rub), and two (Diphenyl phosphino ferrocene) palladium chloride (57.2 milligrams, 0.07 milli rub) prepares.LCMS:262[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 1.21 (s, 12H), 2.77 (d, J=4.8Hz, 3H), 7.47 (t, J=7.6Hz, 1H), 7.79 (d, J=7.6Hz, 1H), 7.94 (d, J=8.0Hz, 1H), 8.14 (s, 1H), 8.51 (m, 1H).
Step 55c:2-(methyl ((2-(3-(methylamino formoxyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-144)
(250 milligrams of described title compound 0603-144,68%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (300 milligrams of 0504-54,0.67 milli rubs), (349 milligrams of compound 0602-144,1.34 milli rubs), (168 milligrams of sodium bicarbonates, 2.0 milli rubs), (23 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.03 milli rubs) at toluene (5 milliliters), the solution that forms in ethanol (3 milliliters) and the water (1.3 milliliters) prepares.LCMS:548[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (t, J=6.8Hz, 3H), 2.82 (d, J=4.8Hz, 3H), (3.28 s, 3H), 3.77 (m, 4H), 3.95 (m, 4H), (4.28 q, J=6.8Hz, 2H), 5.24 (s, 2H), 7.52 (s, 1H), 7.56 (t, J=8.0Hz, 1H), 7.91 (d, J=8.0Hz, 1H), 8.51 (d, J=8.0Hz, 1H), 8.56 (m, 1H), 8.82 (s, 1H), 8.88 (s, 1H).
Step 55d:N-hydroxyl-2-(methyl ((2-(3-(methylamino formoxyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (compound 144)
(116 milligrams of described title compounds 144,48%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (8 milliliters) that is the azanol by 0603-144 (250 milligrams, 0.45 milli rub) and fresh preparation prepares.Fusing point: 215-217 ℃.LCMS:535[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 2.81 (d, J=4.4Hz, 3H), 3.25 (s, 3H), (3.78 m, 4H), 3.95 (m, 4H), 5.22 (s, 2H), 7.50 (s, 1H), 7.56 (t, J=7.6Hz, 1H), 7.91 (d, J=7.6Hz, 1H), 8.51 (d, J=7.6Hz, 1H), 8.56 (m, 1H), (8.76 s, 2H), 8.82 (s, 1H).
Embodiment 56:2-(((2-(4-aminophenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 150) preparation
Step 56a:N-(4-bromophenyl) acetamide (compound 0601-150)
Under 0 ℃; in the dichloromethane solution (50 milliliters) of 4-bromaniline (6.3 grams, 63.7 millis rub), add acetyl group chlorine (3.75 grams, 47.7 millis rub) and triethylamine (TEA) (7.4 grams; 73,4 millis rub), carry out 2 hours stirring.Utilize water, salt solution that described reaction mixture is washed, carry out drying by sodium sulphate, filter, and under reduced pressure, concentrate, thereby obtain a kind of described title compound 0601-150 (3.6 grams, 46%) of brown solid.LCMS:214[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) .. δ 2.05 (s, 3H), 7.46 (d, J=8.8Hz, 2H), 7.57 (d, J=8.8Hz, 2H), 10.12 (s, 1H).
Step 56b:N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) phenyl) acetamide (compound 0602-150)
Described title compound 0602-150 (2.3 grams, 94%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by 0601-150 (2.0 grams, 9.3 milli rubs), connection boric acid pinacol ester (4.4 grams, 17.5 milli rubs), potassium acetate (3.5 grams, 14 millis rub), and two (Diphenyl phosphino ferrocene) palladium chloride (76 milligrams, 0.088 milli rub) prepares.LCMS:262[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.27 (d, J=6.8Hz, 12H), 2.04 (s, 3H), 7.58 (s, 4H), 10.03 (s, 1H).
Step 56c:2-(((2-(4-aminophenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-150)
Utilize nitrogen to (210 milligrams of compound 0504-54,0.46 milli rubs), (159 milligrams of 0602-150,0.60 milli rubs), (118 milligrams of sodium bicarbonates, 1.4 milli rubs) and the mixed liquor that forms in toluene (4 milliliters), ethanol (2 milliliters) and water (1 milliliter) of two (Diphenyl phosphino ferrocene) palladium chloride (II) (17 milligrams, 0.02 milli rub) washes and in the heating of it being carried out 2 hours under the microwave condition under 120 ℃.Utilize ethyl acetate and water that described reaction mixture is separated, utilize salt solution that organic layer is washed, carry out drying by magnesium sulfate, filter and under vacuum condition, evaporate.Utilize carrene that described residue is washed; thereby obtain a kind of 2-(((2-(4-acetylphenyl)-4-morpholine thiophene a pair of horses going side by side [3 of white solid form; 2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (136 milligrams, 53%).LCMS:548[M+1] +, 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.29 (t, J=7.2Hz, 3H), 2.06 (s, 6H), (3.26 s, 3H), 3.75 (m, 4H), 3.91 (m, 4H), 4.28 (q, J=7.2Hz, 2H), 5.22 (s, 2H), 7.45 (s, 1H), 7.67 (d, J=8.8Hz, 1H), 8.31 (d, J=8.8Hz, 1H), (8.87 s, 1H), 10.10 (s, 1H).
Under 40 ℃, to (280 milligrams of above-mentioned ethyl esters, 0.51 milli rubs) oxolane (THF) solution (10 milliliters) in add the aqueous solution (6M of hydrochloric acid, 15 milliliters), carry out 2 hours stirring, utilize sodium bicarbonate that described reaction mixture is neutralized and utilize carrene that it is extracted, utilize water, salt solution washs described organic layer, carry out drying by sodium sulphate, filter, and concentrated, (be present in the methyl alcohol among the carrene by column chromatography, 2% volume/volume) it is carried out purifying, thereby obtain a kind of title compound 0603-150 (180 milligrams, 48%) of white solid form.LCMS:506[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.29 (t, J=7.6Hz, 3H), 3.24 (s, 3H), 3.73 (m, 4H), 3.86 (m, 4H), 4.27 (q, J=6.8Hz, 2H), (5.20 s, 2H), 6.59 (d, J=8.8Hz, 2H), 7.36 (s, 1H), 8.07 (d, J=8.0Hz, 2H), 8.86 (s, 1H).
Step 56d:2-(((2-(4-aminophenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 150)
(43 milligrams of described title compounds 150,26%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (4 milliliters) that is the azanol by 0603-150 (170 milligrams, 0.3 milli rub) and fresh preparation prepares.Fusing point: 183-186 ℃.LCMS:493[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 3.22 (s, 3H), 3.74 (m, 4H), (3.87 m, 4H), 4.27 (q, J=6.8Hz, 2H), 5.20 (s, 2H), 5.50 (s, 2H), 6.59 (d, J=8.8Hz, 2H), (7.36 s, 1H), 8.07 (d, J=8.0Hz, 2H), 8.86 (s, 2H).
Embodiment 57:2-(((2-(4-acetylphenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 157) preparation
Step 57a:2-(((2-(4-acetylphenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 157)
(104 milligrams of described title compounds 157; 61%) be by using a kind of solid of a kind of grey with preparing for the similar step of the step (embodiment 1) of describing compound 3; by 2-(((2-(4-acetylphenyl)-4-morpholine thiophene a pair of horses going side by side [3; 2-d] pyrimidine-6-yl) methyl) (methyl) amino) methanol solution (10 milliliters) of azanol of pyrimidine-5-carboxylic acid's ethyl ester (170 milligrams, 0.3 milli rub) and fresh preparation prepares.Fusing point: 228-230 ℃.LCMS:535[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 2.07 (s, 3H), 3.24 (s, 3H), 3.77 (m, 4H), 3.91 (m, 4H), 5.19 (s, 2H), (7.44 s, 1H), 7.68 (d, J=8.8Hz, 2H), 8.31 (d, J=8.8Hz, 2H), (8.75 s, 2H), 9.06 (s, 1H), (10.12 s, 1H), 11.13 (s, 1H).
Embodiment 58:2-(((2-(1H-indazole-4-yl)-4-(phenyl amino) thiophene A pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxy pyrimidine-5-formyl The preparation of amine (chemical combination 164)
Step 58a:2-chloro-N-phenyl thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-amine (compound 0701-164)
At room temperature, in the acetonitrile suspension (100 milliliters) of compound 0110 (4.00 grams, 19.608 millis rub), add triethylamine (4.00 grams, 39.216 millis rub) and aniline (2.00 grams, 21.581 millis rub).The stirring of under 50 ℃, described mixed liquor being spent the night, evaporation.Described residue is carried out purifying by column chromatography (being present in the ethyl acetate among the benzinum, the 20%-30% volume/volume) on the silica gel, thereby obtain a kind of compound 0701-164 (2.00 grams, 39%) of lark solid form.LCMS:262[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 7.20 (t, J=7.6Hz, 1H), 7.42 (m, 3H), 7.69 (d, J=7.6Hz, 1H), 8.27 (d, J=5.2Hz, 1H), 10.16 (s, 1H).
Step 58b:2-chlorothiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl (phenyl) t-butyl carbamate (compound 0702-164)
At room temperature, to compound 0701-164 (5.60 grams, 21.456 milli rubs) and di-tert-butyl dicarbonate (5.60 grams, 25.747 milli rubs) oxolane (THF) solution (100 milliliters) in add dimethylamino naphthyridine (DMAP) (130 milligrams, 1.073 millis rub) and carry out 3 hours stirring.Remove solvent and by column chromatography (being present in the ethyl acetate among the benzinum, the 15%-30% volume/volume) described residue is carried out purifying, thereby obtain a kind of compound 0702-164 (6.20 restrain 80%) of white solid form.LCMS:362[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.44 (s, 9H), 7.31 (d, J=7.6Hz, 2H), 7.39 (m, 1H), 7.43 (m, 2H), 7.56 (d, J=5.6Hz, 1H), 8.48 (d, J=5.2Hz, 1H).
Step 58c:2-chloro-6-formyl thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl (phenyl) t-butyl carbamate (compound 0703-164)
Compound 0702-164 (2.90 grams, 8.033 millis rub) is suspended among the oxolane (THF) (80 milliliters) and is cooled to-50 ℃.Dropwise adding lithium diisopropyl amido (LDA) solution (2M in the described mixed liquor, 12 milliliters, 24.099 milli rubs) temperature is remained on be lower than-30 ℃ and carry out 1 hour stirring simultaneously, after this under-50 ℃ to wherein adding dimethyl formamide (DMF) (2 milliliters).Described mixed liquor proceeded 30 minutes stirring.Dropwise the saturated aqueous ammonium chloride solution (20 milliliters) of adding under-50 to-60 ℃.In described mixed liquor, add ethyl acetate (300 milliliters), utilize saturated aqueous ammonium chloride solution (2x100 milliliter), water (2x100 milliliter), salt solution (200 milliliters) that it is washed, by anhydrous sodium sulfate it is carried out drying, concentrated and on silica gel, (be present in the ethene in the benzinum by column chromatography, the 20%-50% volume/volume) described residue is carried out purifying, thereby obtain a kind of compound 0703-164 (900 milligrams, 29%) of little yellow solid form.LCMS:390[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.46 (s, 9H), 7.30 (d, J=6.8Hz, 1H), 7.36 (m, 2H), 7.43 (m, 2H), 8.43 (s, 1H), 10.21 (s, 1H).
Step 58d:2-chloro-6-(hydroxymethyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl (phenyl) t-butyl carbamate (compound 0704-164)
At room temperature in the methyl alcohol/tetrahydrofuran solution (10/5 milliliter) of 0703-164 (900 milligrams, 2.314 millis rub), add slowly sodium borohydride (176 milligrams, 4.627 millis rub) and carry out 30 minutes stirring.Through after the removal of solvent, utilize water that described residue is washed and filters, thereby obtain a kind of 0704-164 (800 milligrams, 88%) of white solid form.LCMS:392[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.44 (s, 9H), 4.80 (d, J=5.6Hz, 2H), 6.02 (t, J=5.6Hz, 1H), 7.28 (d, J=4.8Hz, 2H), 7.37 (m, 2H), 7.45 (m, 2H).
Step 58e:(4-(tert-butoxycarbonyl (phenyl) amino)-2-chlorothiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylmethane sulfonic acid (compound 0705-164)
Under the ice bath temperature, in oxolane (THF) solution (20 milliliters) of 0704-164 (500 milligrams, 1.279 millis rub) and triethylamine (2 milliliters), add methane sulfonyl chlorine (175 milligrams, 1.534 millis rub).At room temperature to the described stirring of carrying out 30 minutes with the mixed liquor of white solid.Through after the removal of solvent, utilize water that described residue is washed and filters, thereby obtain a kind of 0705-164 (600 milligrams, 83%) of white solid form.LCMS：470[M+1] +.
Step 58f:2-chloro-6-((methylamino) methyl)-N-phenyl thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-amine (compound 0706-164)
Compound 0705-164 (600 milligrams, 1.279 milli rub) is dissolved in the methanol solution (5 milliliters) of 32% methylamine.At room temperature this mixed liquor is carried out 1 hour stirring.Under reduced pressure, remove described solvent and utilize water that described residue is washed, filter, thereby obtain a kind of 0706-164 (300 milligrams, 77%) of white solid form.LCMS：305[M+1] +.
Step 58g:2-(((2-chloro-4-(phenyl amino) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0707-164)
At room temperature, to compound 0706-164 (260 milligrams, 0.855 milli rubs) and acetonitrile solution (5 milliliters) the middle interpolation triethylamine (0.5 milliliter) of compound 0305 (159 milligrams, 0.855 milli rubs) and the stirring of spending the night.Through after concentrated, utilize water that described residue is washed, filter, thereby obtain a kind of compound 0707-164 (200 milligrams, 52%) of white solid form.LCMS:455[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.31 (t, J=4.2Hz, 3H), 3.25 (s, 3H), 4.29 (m, 2H), 5.23 (s, 2H), 7.15 (t, J=6.0Hz.1H), 7.37 (t, J=6.4Hz, 2H), 7.42 (s, 1H), (7.64 d, J=6.4Hz, 2H), 8.88 (s, 2H), 9.98 (s, 1H).
Step 58h:2-(((2-(1H-indazole-4-yl)-4-(phenyl amino) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0708-164)
(210 milligrams of described title compound 0708-164,89%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (200 milligrams of 0706-164,0.440 milli rubs), (118 milligrams of compound 0107-3,0.484 milli rubs), (110 milligrams of sodium bicarbonates, 1.320 milli rubs), and (15 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides (II), 0.022 milli rubs) at toluene (5.6 milliliters), the solution that forms in ethanol (3.5 milliliters) and the water (1.4 milliliters) prepares.LCMS:537[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.33 (t, J=7.2Hz, 3H), 3.31 (s, 3H), 4.31 (m, 2H), 5.31 (s, 2H), 7.16 (t, J=7.2Hz, 1H), (7.41 t, J=4.4Hz, 2H), 7.47 (t, J=8.0Hz, 1H), 7.62 (s, 1H), (7.65 d, J=8.4Hz, 1H), 7.79 (d, J=7.6Hz, 2H), 8.21 (d, J=7.2Hz, 1H), 8.63 (s, 1H), (8.92 s, 2H), 9.66 (s, 1H), 13.16 (s, 1H).
Step 58i:2-(((2-(1H-indazole-4-yl)-4-(phenyl amino) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 164)
(100 milligrams of described title compounds 164,49%) be by using a kind of a kind of linen solid with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (8 milliliters) that is the azanol by 0708-164 (210 milligrams, 0.392 milli rub) and fresh preparation prepares.Fusing point: 232-235 ℃; LCMS:524[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 3.27 (s, 3H), 5.27 (s, 2H), (7.16 t, J=7.2Hz, 1H), 7.41 (t, J=4.4Hz, 2H), 7.47 (t, J=8.0Hz, 1H), 7.59 (s, 1H), 7.65 (d, J=8.4Hz, 1H), 7.78 (d, J=7.6Hz, 2H), 8.21 (d, J=7.2Hz, 1H), (8.78 s, 2H), 8.81 (s, 1H), 9.07 (s, 1H), (9.64 s, 1H), 11.15 (s, 1H), 13.14 (s, 1H).
Embodiment 59:2-(((2-(1H-indazole-4-yl)-4-(pyridine-2-base is amino) Thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxy pyrimidine-5- The preparation of formamide (compound 168)
Step 59a:2-chloro-N-(pyridine-2-yl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-amine (compound 0701-168)
At room temperature, to compound 0110 (5.00 grams, 24.510 milli rubs) oxolane (THF) suspension (200 milliliters) in add tert-butoxy potassium (4.19 grams, 36.765 millis rub) and pyridine-2-amine (2.30 grams, 24.510 millis rub).Under 50 ℃, described mixed liquor stirred and spend the night, on silica gel, described mixed liquor is carried out purifying by column chromatography after this, utilization is present in the ethyl acetate (20% to 40% among the benzinum, volume/volume) it is carried out wash-out, thereby obtain a kind of compound 0701-168 (3.00 grams, 47%) of lark solid form.LCMS:263[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 7.18 (m, 1H), 7.43 (d, J=5.2Hz, 1H), 7.87 (m, 2H), 8.33 (d, J=5.6Hz, 1H), 8.40 (d, J=4.8Hz, 1H), 10.94 (s, 1H).
Step 59b:2-chlorothiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl (pyridine-2-yl) t-butyl carbamate (compound 0702-168)
Described title compound 0702-168 (2.80 grams, 100%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 58) of describing compound 0702-164, by 0701-168 (2.40 grams, 9.160 milli rubs), di-tert-butyl dicarbonate (3.00 grams, 13.740 milli rubs), and dimethylamino naphthyridine (DMAP) (56 milligrams, 0.458 milli rub) prepares.LCMS:363[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.44 (s, 9H), 7.36 (m, 1H), 7.64 (m, 2H), 7.97 (t, J=7.6Hz, 1H), 8.34 (m, 1H), 8.54 (d, J=5.6Hz, 1H).
Step 59c:2-chloro-6-formyl thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl (pyridine-2-yl) t-butyl carbamate (compound 0703-168)
Described title compound 0703-168 (1.90 grams, 48%) be by using a kind of a kind of flaxen solid with preparing for the similar step of the step (embodiment 58) of describing compound 0703-164, by 0702-168 (3.69 grams, 10.199 milli rubs), lithium diisopropyl amido (LDA) solution (2M, 15.3 milliliter, 30.597 millis rub), and dimethyl formamide (DMF) (4 milliliters) prepares.LCMS:391[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.46 (s, 9H), 7.41 (m, 1H), 77.66 (d, J=8.0Hz, 1H), 8.00 (m, 1H), 8.40 (m, 1H), 8.49 (s, 1H), 10.12 (s, 1H).
Step 59d:2-chloro-6-(hydroxymethyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl (pyridine-2-yl) t-butyl carbamate (compound 0704-168)
Described title compound 0704-168 (1.9 grams, 100%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 58) of describing compound 0704-164, by 0703-168 (1.9 grams, 4.870 milli rubs) and sodium borohydride (227 milligrams, 7.31 milli rub) prepare.LCMS：393[M+1] +； 1HNMR(400MHz，DMSO-d 6)：δ1.44(s，9H)，4.84(d，J＝5.4Hz，2H)，6.05(t，J＝6.0Hz，1H)，7.34(m，1H)，7.43(s，1H)，7.65(d，J＝8.0Hz，1H)，7.96(t，J＝7.6Hz，1H)，8.33(m，1H).
Step 59e:(4-tert-butoxycarbonyl (pyridine-2-yl) amino)-and 2-chlorothiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylmethane sulfonic acid (compound 0705-168)
Described title compound 0705-168 (2.10 grams; 92%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 58) of describing compound 0705-164; by 0704-168 (1.90 grams; 4.847 milli rubs); triethylamine (2 milliliters); and methane sulfonyl chlorine (1.10 grams, 9.694 millis rub) prepares.LCMS:471[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.44 (s, 9H), 3.31 (s, 3H), 5.68 (s, 2H), 7.37 (m, 1H), 7.65 (d, J=8.0Hz, 1H), 7.74 (s, 1H), 7.99 (t, J=7.6Hz, 1H), 8.36 (m, 1H).
Step 59f:2-chloro-6-((methylamino) methyl)-N-(pyridine-2-yl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-amine (compound 0706-168)
Described title compound 0706-168 (1.80 grams, 100%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 58) of describing compound 0706-164, that methanol solution (5 milliliters) by 0705-168 (2.00 grams, 4.255 millis rub) and 32% methylamine prepares.LCMS:306[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 2.32 (s, 3H), 3.97 (s, 2H), 7.15 (m, 1H), 7.26 (s, 1H), 7.83 (m, 2H), 8.38 (m, 1H), 9.71 (s, 1H).
Step 59g:2-(((2-chloro-4-(pyridine-2-base is amino) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0707-168)
(410 milligrams of described title compound 0707-168,69%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 58) of describing compound 0707-164, by (400 milligrams of 0706-168,1.311 milli rubs) and compound 0305 (244 milligrams, 1.311 milli rub) prepare.LCMS:456[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.31 (t, J=7.2Hz, 3H), 3.25 (s, 3H), 4.29 (m, 2H), (5.21 s, 2H), 7.13 (m, 1H), 7.40 (s, 1H), 7.84 (m, 2H), 8.30 (m, 1H), 8.88 (s, 2H), 10.84 (s, 1H).
Step 59h:2-(((2-(1H-indazole-4-yl)-4-(pyridine-2-base is amino) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0708-168)
(200 milligrams of described title compound 0708-168,85%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (200 milligrams of 0707-168,0.440 milli rubs), (118 milligrams of compound 0107-3,0.484 milli rubs), (110 milligrams of sodium bicarbonates, 1.320 milli rubs), and (15 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides (II), 0.022 milli rubs) at toluene (8 milliliters), the solution that forms in ethanol (5 milliliters) and the water (2 milliliters) prepares.LCMS:538[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.33 (t, J=7.2Hz, 3H), 3.29 (s, 3H), (4.30 m, 2H), 5.26 (s, 2H), 7.12 (m, 1H), 7.7.57 (s, 1H), 7.84 (m, 1H), 8.23 (d, J=7.2Hz, 1H), (8.33 m, 1H), 8.89 (s, 2H), (10.39 s, 1H), 13.19 (s, 1H).
Step 59i:2-(((2-(1H-indazole-4-yl)-4-(pyridine-2-base is amino) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 168)
(80 milligrams of described title compounds 168,82%) be by using a kind of a kind of linen solid with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (8 milliliters) that is the azanol by 0708-168 (100 milligrams, 0.186 milli rub) and fresh preparation prepares.Fusing point: 232-235 ℃; LCMS:525[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 3.34 (s, 3H), 5.30 (s, 2H), (7.19 t, J=6.0Hz, 1H), 7.55 (t, J=8.0Hz, 1H), 7.62 (s, 1H), (7.47 d, J=8.0Hz, 1H), 7.91 (t, J=8.8Hz, 1H), 8.00 (d, J=8.4Hz, 1H), 8.30 (d, J=7.6Hz, 1H), (8.41 s, 1H), 8.84 (s, 2H), (9.04 s, 1H), 9.14 (s, 1H), (10.46 s, 1H), 11.01 (s, 1H), 13.25 (s, 1H).
Embodiment 60:5-(4-(2-(1H-indazole-4-yl)-6-((4-(methyl sulphonyl) piperazine-1-yl) methyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) piperazine-1-yl) N-hydroxyl pentanamide (compound 30)
Step 60a:4-(2-chlorothiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (compound 0801-30)
At room temperature, to compound 0110 (20 grams, 98 millis rub), the 1-piperazine carboxylic acid tert-butyl ester (21.9 grams, 118 millis rub), and the methyl alcohol mixed liquor (400 milliliters) of triethylamine (14.8 grams, 147 millis rub) carries out 4 hours stirring.Thereby described reaction mixture filtered obtain a kind of solid, as first crude product.Described mother liquor is concentrated and utilizes water (500 milliliters) that it is diluted and described solid is collected, in order to the crude product as second batch.Product to above-mentioned merging carries out drying, thereby obtains a kind of compound 0801-30 (22 grams, 63%) of yellow solid form.LCMS:355[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.43 (s, 9H), 3.53 (m, 4H), 3.95 (m, 4H), 7.41 (d, J=5.6Hz, 1H), 8.32 (d, J=5.6Hz, 1H).
Step 60b:4-(2-chloro-6-formyl thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (compound 0802-30)
With compound 0801-30 (10 grams, 28.2 milli rubs) be suspended among the oxolane (THF) (200 milliliters) and be cooled to-70 ℃, after this to wherein dropwise interpolation lithium diisopropyl amido (LDA) solution (2M, 71 milliliters) and described reaction temperature remained on below-65 ℃.After this described mixed liquor is carried out 1 hour stirring.Dropwise adding dimethyl formamide (DMF) (15 milliliters) in the described mixed liquor remains on described reaction temperature below-65 ℃ simultaneously.Mixed liquor obtained above is carried out 30 minutes stirring, and by under-50 to-60 ℃, utilizing saturated aqueous ammonium chloride solution to quench.Utilize ethyl acetate (500 milliliters) that described mixed liquor is diluted, utilize saturated ammonium bicarbonate aqueous solution (2x300 milliliter), water (2x500 milliliter), salt solution (200 milliliters) that it is washed, carry out drying by sodium sulphate, concentrated and (be present in the methyl alcohol among the carrene by column chromatography on the silica gel, 2% volume/volume) described residue is carried out purifying, thereby obtain a kind of compound 0802-30 (4.9 grams, 45%) of faint yellow solid form.LCMS:383[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.43 (s, 9H), 3.55 (m, 4H), 3.99 (m, 4H), 8.29 (s, 1H), 10.21 (s, 1H).
Step 60c:4-(2-chloro-6-(hydroxymethyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (compound 0803-30)
Under 0 ℃, within 10 minutes time, in the methanol suspension (20 milliliters) of compound 0802-30 (3.73 grams, 9.764 millis rub), add slowly sodium borohydride (1.11 grams, 29.293 millis rub).Solution to the clarification of above-mentioned formation carries out 10 minutes stirring, evaporation.Utilize water that described residue is washed and filters, thereby obtain a kind of compound 0803-30 (3.10 grams, 83%) of white solid form.LCMS:385[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.43 (s, 9H), 3.52 (brs, 4H), 3.92 (brs, 4H), 4.81 (d, J=4.8Hz, 2H), 5.96 (t, J=5.2Hz, 1H), 7.22 (s, 1H).
Step 60d:4-(6-(bromomethyl)-2-chlorothiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (compound 0804-30)
At room temperature, to compound 0803-30 (3.10 grams, 8.073 milli rubs) and the carrene suspension (30 milliliters) of triphenylphosphine (2.54 grams, 9.687 millis rub) in add N-bromosuccinimide (NBS) (1.72 grams, 9.687 millis rub).At room temperature described mixed liquor is carried out 2 hours stirring and concentrate.Described residue is carried out purifying by column chromatography (being present in the carrene among the benzinum, 10% to 50% volume/volume) on the silica gel, thereby obtain a kind of compound 0804-30 (2.60 grams, 72%) of white solid form.LCMS:447[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.42 (s, 9H), 3.52 (brs, 4H), 3.90 (brs, 4H), 5.10 (s, 2H), 7.49 (s, 1H).
Step 60e:4-(2-chloro-6-((4-(methyl sulphonyl) piperazine-1-yl) methyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) piperazine-1-carboxylic acid tert-butyl ester (compound 0805-30)
At room temperature, to compound 0804-30 (3.5 grams, crude product), compound 0103 (1.14 grams, 4.1 milli rubs), and the mixed liquor of potash (1.58 grams, 11.4 millis rub) in acetonitrile (35 milliliters) and dimethyl formamide (17 milliliters) stirring of spending the night.Utilize water (200 milliliters) that described reaction mixture is diluted and utilize carrene (200 milliliters) that it is extracted.Utilize water (5x200 milliliter), salt solution that described organic layer is washed, carry out drying by sodium sulphate, concentrated, thereby acquisition crude product, compound 0805-30 (3.9 grams, contain some triphenylphosphine oxides), described compound is a kind of solid of yellow, it does not need to carry out further purifying and can be used in the following step.LCMS:531[M+1] +. 1HNMR (megahertz, dimethyl sulfoxide (DMSO)-d 6) δ 1.42 (s, 9H), 2.59 (m, 4H), 2.90 (s, 3H), 3.15 (m, 4H), 3.52 (m, 4H), 3.91 (m, 6H), 7.31 (s, 1H).
Step 60f:2-chloro-6-((4-(methyl sulphonyl) piperazine-1-yl) methyl)-4-(piperazine-1-yl) thiophene a pair of horses going side by side [3,2-d] pyrimidine (compound 0806-30)
To oxolane (THF) solution (50 milliliters) the middle interpolation concentrated hydrochloric acid (10 milliliters) of compound 0805-30 (5 gram) and at room temperature to its stirring of spending the night.Utilize water (200 milliliters) that described reaction mixture is diluted and utilize carrene (100 milliliters) that it is extracted.Utilize after the aqueous hydrochloric acid solution (100 milliliters) of 0.1M washs, described organic layer is abandoned.Utilize solid sodium bicarbonate that the pH of described water layer is adjusted to 7, utilize carrene (200 milliliters) that it is extracted.In the process of extracting, add low dose of methyl alcohol until described the color of the solution by orange change into colourless.Make described extract carry out drying and concentrated by sodium sulphate, thereby obtain a kind of compound 0806-30 (1.9 grams, in two steps not 76%) of yellow solid form.LCMS:431[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 2.57 (t, J=4.4Hz, 4H), 2.83 (t, J=5.2Hz, 4H), 2.90 (s, 3H), 3.14 (t, J=4.4Hz, 4H), 3.82 (t, J=4.4Hz, 4H), 3.90 (s, 2H), 7.28 (s, 1H).
Step 60g:5-(4-(2-chloro-6-((4-methyl sulphonyl) piperazine-1-yl) methyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) piperazine-1-yl) ethyl valerate (compound 0807-30)
Under 80 ℃, to compound 0806-30 (450 milligrams, 1.04 millis rub), (327 milligrams of 5-bromine ethyl valerates, 1.6 milli rubs), and the mixed liquor (8 milliliter) of triethylamine (211 milligrams, 2.1 millis rub) in dimethyl formamide (DMF) carries out 2 hours stirring.Described mixed liquor is poured onto water (100 milliliters) upward and is accompanied by stirring.By filtering described solid is collected and (is present in the methyl alcohol among the carrene by column chromatography at silica gel, 2% volume/volume) upward it is carried out purifying, thereby obtain a kind of compound 0807-30 (500 milligrams, 86%) of faint yellow solid form.LCMS:560[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.18 (t, J=7.2Hz, 3H), 1.46 (m, 2H), 1.56 (m, 2H), 2.32 (m, 4H), 2.46 (m, 4H), 2.57 (m, 4H), 2.90 (s, 3H), 3.14 (m, 4H), 3.88 (m, 6H), 4.05 (q, J=7.6Hz, 2H), 7.29 (s, 1H).
Step 60h:5-(4-(2-(1H-indazole-4-yl)-6-((4-(methyl sulphonyl) piperazine-1-yl) methyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) piperazine-1-yl) ethyl valerate (compound 0808-30)
(250 milligrams of described title compound 0808-30,73%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (300 milligrams of 0807-30,0.54 milli rubs), (157 milligrams of compound 0107-3,0.64 milli rubs), (135 milligrams of sodium bicarbonates, 1.61 milli rubs), and (19 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.03 milli rubs) at toluene (5 milliliters), the solution that forms in ethanol (3 milliliters) and the water (1.3 milliliters) prepares.LCMS:641[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.19 (t, J=7.2Hz, 3H), 1.51 (m, 2H), (1.56 m, 2H), 2.33 (m, 4H), 2.58 (m, 8H), 2.91 (s, 3H), 3.17 (m, 4H), (3.94 m, 2H), 4.06 (m, 6H), 7.47 (m, 2H), 7.66 (d, J=8.4Hz, 1H) .8.21 (d, J=7.2Hz, 1H), 8.88 (s, 1H), 13.20 (s, 1H).
Step 60i:5-(4-(2-(1H-indazole-4-yl)-6-((4-(methyl sulphonyl) piperazine-1-yl) methyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) piperazine-1-yl)-N-hydroxyl pentanamide (compound 30)
(95 milligrams of described title compounds 30,39%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (6 milliliters) that is the azanol by 0808-30 (250 milligrams, 0.39 milli rub) and fresh preparation prepares.Fusing point: 142-145 ℃.LCMS:628[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.53 (m, 4H), 1.99 (t, J=6.8Hz, 2H) 2.35 (t, J=6.8Hz, 2H), 2.59 (m, 8H), 2.91 (s, 3H), 3.17 (m, 4H), 3.94 (s, 2H), 4.02 (m, 4H), 7.47 (m, 2H), 7.66 (d, J=8.0Hz, 1H), 8.16 (s, 1H), 8.22 (d, J=6.8Hz, 1H), 8.88 (s, 1H), 10.36 (s, 1H), 13.20 (s, 1H).
The preparation of embodiment 61:6-(4-(2-(1H-indazole-4-yl)-6-((4-(methyl sulphonyl) piperazine-1-yl) methyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) piperazine-1-yl)-N-hydroxyl hexanamide (compound 31)
Step 61a:6-(4-(2-chloro-6-((4-(methyl sulphonyl) piperazine-1-yl) methyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) piperazine-1-yl) ethyl hexanoate (compound 0807-31)
(290 milligrams of described title compound 0807-31,44%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 60) of describing compound 0807-30, by 0806 (400 milligrams, 0.928 milli rubs), (310 milligrams of 6-bromocaproic acid ethyl esters, 1.39 milli rubs), and triethylamine (187 milligrams, 1.86 milli rub) prepares.LCMS:573[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.18 (t, J=7.2Hz, 3H), 1.29 (m, 2H), (1.45 m, 2H), 1.54 (m, 2H), 2.29 (m, 4H), 2.50 (m, 4H), 2.57 (m, 4H), 2.90 (s, 3H), 3.14 (m, 4H), 3.88 (m, 6H), 4.05 (q, J=7.2Hz, 2H), 7.29 (s, 1H).
Step 61b:6-(4-(2-(1H-indazole-4-yl)-6-((4-(methyl sulphonyl) piperazine-1-yl) methyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) piperazine-1-yl) ethyl hexanoate (compound 0808-31)
(300 milligrams of described title compound 0808-31,91%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (290 milligrams of 0807-31,0.506 milli rubs), (185 milligrams of compound 0107-3,0.607 milli rubs), (128 milligrams of sodium bicarbonates, 1.52 milli rubs), and (18 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.025 milli rubs) at toluene (5 milliliters), the solution that forms in ethanol (3 milliliters) and the water (1.3 milliliters) prepares.LCMS:655[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.17 (t, J=6.8Hz, 3H), 1.20 (m, 2H), 1.52 (m, 4H), 2.32 (m, 4H), 2.58 (m, 8H), 2.91 (s, 3H), 3.17 (m, 4H), 3.95 (m, 2H), 4.01 (m, 4H), 4.05 (q, J=6.8Hz, 2H), 7.48 (m, 2H), 7.66 (d, J=8.0Hz, 1H) .8.21 (d, J=6.8Hz, 1H), 8.88 (s, 1H), 13.20 (s, 1H).
Step 61c:6-(4-(2-(1H-indazole-4-yl)-6-((4-(methyl sulphonyl) piperazine-1-yl) methyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) piperazine-1-yl)-N-hydroxyl hexanamide (compound 31)
(41 milligrams of described title compounds 31,14%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (5 milliliters) that is the azanol by 0808-31 (300 milligrams, 0.46 milli rub) and fresh preparation prepares.Fusing point: 140-145 ℃.LCMS:642[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.28 (m, 2H), 1.51 (m, 4H), 1.96 (t, J=7.2Hz, 2H) 2.33 (t, J=7.2Hz, 2H), 2.60 (m, 8H), 2.91 (s, 3H), 3.17 (m, 4H), 3.94 (s, 2H), 4.01 (m, 4H), 7.47 (m, 2H), 7.66 (d, J=8.0Hz, 1H) .8.21 (d, J=7.2Hz, 1H), 8.68 (s, 1H), 8.88 (s, 1H), 10.35 (s, 1H), 13.20 (s, 1H).
Embodiment 62:7-(4-(2-(1H-indazole-4-yl)-6-((4-(sulfonyloxy methyl Base) piperazine-1-yl) methyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) piperazine-1-yl)-N- The preparation of hydroxyl heptamide (compound 32)
Step 62a:7-(4-(2-chloro-6-((4-(methyl sulphonyl) piperazine-1-yl) methyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) piperazine-1-yl) cognac oil (compound 0807-32)
(550 milligrams of described title compound 0807-32,81%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 60) of describing compound 0807-30, by 0806 (500 milligrams, 1.16 milli rubs), (412 milligrams of 7-bromine cognac oil, 1.74 milli rubs), triethylamine (235 milligrams, 2.3 millis rub) prepares.LCMS:587[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.18 (t, J=7.2Hz, 3H), 1.28 (m, 4H), (1.45 m, 2H), 1.52 (m, 2H), 2.29 (m, 4H), 2.46 (m, 4H), 2.57 (m, 4H), 2.90 (s, 3H), 3.14 (m, 4H), 3.89 (m, 6H), 4.05 (q, J=7.2Hz, 2H), 7.29 (s, 1H).
Step 62b:7-(4-(2-(1H-indazole-4-yl)-6-((4-(methyl sulphonyl) piperazine-1-yl) methyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) piperazine-1-yl) cognac oil (compound 0808-32)
(220 milligrams of described title compound 0808-32,63%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 30) of describing compound 0603-107, by (300 milligrams of 0807-32,0.51 milli rubs), (150 milligrams of compound 0107-3,0.61 milli rubs), (129 milligrams of sodium bicarbonates, 1.53 milli rubs), (18 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.026 milli rubs) at toluene (5 milliliters), the solution that forms in ethanol (3 milliliters) and the water (1.3 milliliters) prepares.LCMS:669[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.18 (t, J=7.2Hz, 3H), 1.30 (m, 4H), 1.52 (m, 2H), 1.55 (m, 2H), 2.30 (m, 4H), 2.57 (m, 8H), 2.91 (s, 3H), 3.17 (m, 4H), (3.94 m, 2H), 4.06 (m, 6H), 7.47 (m, 2H), 7.66 (d, J=8.4Hz, 1H) .8.21 (d, J=7.2Hz, 1H), 8.88 (s, 1H), 13.19 (s, 1H).
Step 62c:7-(4-(2-(1H-indazole-4-yl)-6-((4-(methyl sulphonyl) piperazine-1-yl) methyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-4-yl) piperazine-1-yl)-N-hydroxyl heptamide (compound 32)
(80 milligrams of described title compounds 32,37%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (6 milliliters) that is the azanol by 0808-32 (20 milligrams, 0.33 milli rub) and fresh preparation prepares.Fusing point: 131-134 ℃.LCMS:656[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.29 (m, 4H), 1.49 (m, 4H), 1.95 (t, J=6.8Hz, 2H), 2.35 (t, J=6.4Hz, 2H), 2.60 (m, 8H), (2.91 s, 3H), 3.17 (m, 4H), 3.95 (m, 6H), (7.47 m, 2H), 7.66 (d, J=8.0Hz, 1H), 8.16 (s, 1H), 8.22 (d, J=7.2Hz, 1H), 8.88 (s, 1H), 10.35 (s, 1H), 13.20 (s, 1H).
Embodiment 63:2-(((2-(6-acetylpyridine-3-yl)-4-morpholine thiophene a pair of horses going side by side [3, 2-d] pyrimidine-6-yl) methyl) (methyl) amino)-(change of N-hydroxypyrimidine-5-carboxamides Compound 112) preparation
Step 63a:N-(5-bromopyridine-2-yl) acetamide (compound 0601-112)
At room temperature, to 2-amino-5-bromopyridine (0.50 gram, 2.9 milli rubs) oxolane (THF) solution (10 milliliters) in the stirring adding pyridine (343 milligrams, 4.3 millis rub) and acetic anhydride (295 milligrams, 2.9 millis rub) and spend the night.In described mixed liquor, add water (30 milliliters), utilize ethyl acetate (3x30 milliliter) that it is extracted.Utilize saturated sodium bicarbonate aqueous solution and salt solution that the organic layer of described merging is washed, carry out drying by sodium sulphate, concentrate, thereby obtain a kind of described title compound (0.58 gram, 92%) of white solid form.LCMS:215[M+2] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 2.09 (s, 3H), 7.97 (dd, J=8.8,2.4Hz, 1H), 8.06 (d, J=8.8Hz, 1H), 8.41 (d, J=1.2Hz, 1H), 10.64 (s, 1H).
Step 63b:N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) pyridine-2-yl) acetamide (compound 0602-112)
(400 milligrams of described title compound 0602-112,57%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by 0601-112 (0.57 gram, 2.7 milli rubs), connection boric acid pinacol ester (1.00 grams, 4.0 milli rubs), potassium acetate (0.78 gram, 8.0 milli rubs), and two (Diphenyl phosphino ferrocene) palladium chloride (217 milligrams, 0.3 milli rub) prepares.LCMS:263[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (s, 12H), 2.10 (s, 3H), 7.96 (dd, J=8.4,1.6Hz, 1H), 8.09 (d, J=8.4Hz, 1H), 8.51 (d, J=0.4Hz, 1H), 10.65 (s, 1H).
Step 63c:2-(((2-(6-acetylpyridine-3-yl) 4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-112)
(120 milligrams of described title compound 0603-112,73%) be by using a kind of a kind of linen solid with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (135 milligrams of 0504-54,0.30 milli rubs), (157 milligrams of 0602-112,0.60 milli rubs), (76 milligrams of sodium bicarbonates, 0.90 milli rubs), (11 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.015 milli rubs) at toluene (2.5 milliliters), the solution that forms in ethanol (1.6 milliliters) and the water (0.7 milliliter) prepares.LCMS:549[M+1] + 1HNMR (400 megahertzes, deuterochloroform) δ 1.38 (t, J=7.2Hz, 3H), 2.25 (s, 3H), 3.31 (s, 3H), 3.87 (t, J=4.4Hz, 4H), 4.01 (t, J=4.4Hz, 4H), 4.36 (q, J=7.2Hz, 2H), 5.20 (s, 2H), 7.38 (s, 1H), 8.28 (m, 2H), 8.70 (dd, J=8.8,2.0Hz, 1H), 9.28 (d, J=2.0Hz, 1H).
Step 63d:2-(((2-(6-acetylpyridine-3-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 112)
(20 milligrams of described title compounds 112,19%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (10 milliliters) that is the azanol by 0603-112 (108 milligrams, 0.20 milli rub) and fresh preparation prepares.Fusing point: 192-201 ℃.LCMS:536[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 2.13 (s, 3H), 3.24 (s, 3H), 3.76 (t, J=4.4Hz, 4H), 3.93 (t, J=4.4Hz, 4H), (5.21 s, 2H), 7.46 (s, 1H), 8.18 (d, J=8.8Hz, 1H), 8.64 (d, J=1.2Hz, 1H), 8.75 (s, 2H), 9.24 (d, J=2.0Hz, 1H), 10.72 (s, 1H).
Embodiment 64:2-(((2-(6-(dimethylamino) pyridin-3-yl)-4-morpholine Thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxy pyrimidine-5- The preparation of formamide (compound 114)
Step 64a:5-bromo-N, N-lutidines-2-amine (compound 0601-114)
Under 0 ℃, to 5-bromopyridine-2-amine (1.0 grams, 5.8 milli rubs) oxolane (THF) solution (25 milliliters) in add sodium hydride (0.92 gram, 23.1 milli rubs) and carry out 10 minutes stirring, add after this iodomethane (1 milliliter, 16 millis rub) and carry out 1 hour stirring.To wherein adding water (30 milliliters) and utilizing ethyl acetate (3x30 milliliter) that it is extracted.Utilize salt solution that the organic layer of above-mentioned merging is washed, by sodium sulphate it is carried out drying, concentrated and (be present in the ethyl acetate among the benzinum by column chromatography on the silica gel, 10% volume/volume) it is carried out purifying, thereby obtain a kind of described title compound (1.1 grams, 94%) of white solid form.LCMS:203[M+2] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 2.99 (s, 6H), 6.61 (d, J=9.6Hz, 1H), 7.62 (dd, J=9.2,2.8Hz, 1H), 8.12 (d, J=2.4Hz, 1H).
Step 64b:N, N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) pyridine-2-amine (compound 0602-114)
Described title compound 0602-114 (0.81 gram, 67%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by 0601-114 (1.0 grams, 5.0 milli rubs), connection boric acid pinacol ester (1.90 grams, 7.5 milli rubs), potassium acetate (1.46 grams, 14.9 milli rubs), and two (Diphenyl phosphino ferrocene) palladium chloride (1.90 grams, 7.5 millis rub) prepares.LCMS:167[M-81] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.27 (s, 12H), 3.05 (s, 6H), 6.58 (d, J=8.8Hz, 1H), 7.67 (dd, J=8.4,1.6Hz, 1H), 8.32 (d, J=1.2Hz, 1H).
Step 64c:2-(((2-(6-(dimethylamino) pyridin-3-yl) 4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-114)
(98 milligrams of described title compound 0603-114,61%) be by using a kind of a kind of linen solid with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (135 milligrams of 0504-54,0.30 milli rubs), (149 milligrams of 0602-114,0.60 milli rubs), (76 milligrams of sodium bicarbonates, 0.90 milli rubs), (11 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.015 milli rubs) at toluene (2.5 milliliters), the solution that forms in ethanol (1.6 milliliters) and the water (0.7 milliliter) prepares.LCMS:535[M+1] + 1HNMR (400 megahertzes, deuterochloroform) δ 1.38 (t, J=7.2Hz, 3H), 3.18 (s, 6H), (3.30 s, 3H), 3.84 (t, J=4.8Hz, 4H), 3.99 (t, J=4.8Hz, 4H), 4.36 (q, J=7.2Hz, 2H), (5.18 s, 2H), 6.58 (d, J=9.2,1H), (7.37 s, 1H), 8.49 (d, J=7.6Hz, 1H), (8.93 s, 2H), 9.25 (d, J=2.0Hz, 1H).
Step 64d:2-(((2-(6-(dimethylamino) pyridin-3-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 114)
(75 milligrams of described title compounds 114,82%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (5 milliliters) that is the azanol by 0603-114 (93 milligrams, 0.17 milli rub) and fresh preparation prepares.Fusing point: 190-195 ℃.LCMS:522[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.10 (s, 6H), 3.23 (s, 3H), 3.74 (s, 4H), 3.89 (s, 4H), 5.19 (s, 2H), 6.89 (d, J=7.6Hz, 1H), (7.40 s, 1H), 8.37 (d, J=7.2Hz, 1H), 8.75 (s, 2H), 9.09 (s, 2H), 11.14 (d, J=1.2Hz, 1H).
Embodiment 65:2-(((2-(2-(amino methyl) pyrimidine-5-yl)-4-morpholine thiophene Fen a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxy pyrimidine-5-first The preparation of acid amides (compound 124)
Step 65a:(5-bromo pyrimi piperidine-2-yl) the methyl carbamic acid tert-butyl ester (compound 0601-124)
To (100 milligrams of 5 Bromo 2 methyl pyridines, 0.58 milli rubs), N-bromosuccinimide (103 milligrams, 0.58 milli rubs), the tetrachloromethane mixed liquor (10 milliliters) of Di benzoyl peroxide paste (10 milligrams, 0.04 milli rubs) carries out 36 hours backflow.Under vacuum condition, remove described solvent and (be present in the ethyl acetate among the benzinum by column chromatography on the silica gel, 1% volume/volume) described residue is carried out purifying, thereby obtain a kind of 5-bromo-2-(bromomethyl) pyrimidine (70 milligrams, 48%) of white solid form. 1HNMR (400 megahertzes, deuterochloroform) δ 4.49 (s, 2H), 8.72 (s, 2H).
Add to the methanol solution (5 milliliters) of 5-bromo-2-(bromomethyl) pyrimidine (350 milligrams, 1.4 milli rub) among the ammonia spirit (25-28%, 10 milliliters) and at room temperature carry out 2 hours stirring.Remove described solvent and after this carrying out the interpolation of ethanol (20 milliliters).Described solvent is evaporated and add carrene (10 milliliters) in described residue, (379 milligrams of triethylamines, 3.72 milli rubs), (603 milligrams of di-tert-butyl dicarbonates, 2.79 milli rubs), dimethylamino naphthyridine (DMAP) (22 milligrams, 0.19 milli rubs).At room temperature mixed liquor obtained above is carried out 2 hours stirring.Described solvent is removed and on silica gel it carried out purifying by column chromatography, thereby obtain a kind of 0601-124 (380 milligrams, 82%) of white solid form.LCMS:232[M-56] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.38 (s, 9H), 4.28 (d, J=5.6Hz, 2H), 7.30 (t, J=6.4Hz, 1H), 8.95 (s, 2H).
Step 65b:(5-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) pyrimidine-2-base) the methyl carbamic acid tert-butyl ester (compound 0602-124)
(410 milligrams of described title compound 0602-124,93%) be by using a kind of oil of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by (380 milligrams of 0601-124,4.0 milli rubs), connection boric acid pinacol ester (0.50 gram, 2.0 milli rubs), (388 milligrams of potassium acetates, 4.0 milli rubs), and two (Diphenyl phosphino ferrocene) palladium chloride (108 milligrams, 0.1 milli rub) prepares.LCMS:198[M-137] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.32 (s, 12H), 1.39 (s, 9H), 4.33 (d, J=6.0Hz, 2H), 7.30 (t, J=6.0Hz, 1H), 8.87 (s, 1H).
Step 65c:2-(((2-(2-(amino methyl) pyrimidine-5-yl) 4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-124)
Described compound 2-(((2-(2-(amino methyl) pyrimidine-5-yl) 4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) (248 milligrams of pyrimidine-5-carboxylic acid's ethyl esters, 66%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (270 milligrams of 0504-54,0.6 milli rubs), (395 milligrams of 0602-124,1.2 milli rubs), (152 milligrams of sodium bicarbonates, 1.8 milli rubs), (21 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.03 milli rubs) at toluene (5 milliliters), the solution that forms in ethanol (3.2 milliliters) and the water (1.4 milliliters) prepares.LCMS:622[M+1] + 1HNMR (400 megahertzes, deuterochloroform) δ 1.39 (t, J=7.2Hz, 3H), 1.49 (s, 9H), 3.33 (s, 3H), 3.87 (t, J=4.4Hz, 4H), 4.01 (t, J=4.4Hz, 4H), 4.37 (q, J=7.2Hz, 2H), 4.68 (d, J=4.4Hz, 2H), (5.21 s, 2H), 5.79 (s, 1H), 7.40 (s, 1H), 8.94 (s, 2H), 9.62 (s, 2H).
In the dichloromethane solution (3 milliliters) of above-claimed cpd (247 milligrams, 0.4 milli rubs), add trifluoroacetic acid (TFA) (1.5 milliliters) and at room temperature carry out 4 hours stirring.To wherein adding entry (50 milliliters) and utilizing carrene (200 milliliters) that it is extracted.Utilize saturated sodium bicarbonate aqueous solution, salt solution that described organic layer is washed, dry and concentrated.By ethyl acetate and benzinum (50% volume/volume) described residue is recrystallized, thereby obtains a kind of 0603-124 (300 milligrams, 100%) of pale solid form.LCMS:522[M+1] + 1HNMR (400 megahertzes, deuterochloroform) δ 1.28 (t, J=6.8Hz, 3H), (3.26 s, 3H), 3.75 (d, J=4.4Hz, 4H), 3.94 (d, J=4.4Hz, 6H), (4.26 q, J=7.2Hz, 2H), 5.23 (s, 2H), 7.51 (s, 1H), 8.86 (s, 2H), 9.54 (s, 2H).
Step 65d:2-(((2-(amino methyl) pyrimidine-5-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 124)
(110 milligrams of described title compounds 124,54%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (16 milliliters) that is the azanol by 0603-124 (300 milligrams, 0.6 milli rub) and fresh preparation prepares.Fusing point: greater than 300 ℃.LCMS:509[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.17 (s, 6H), 3.17 (s, 3H), 3.74 (s, 4H), 3.92 (s, 4H), 3.95 (s, 2H), 5.19 (s, 2H), 7.48 (s, 1H), 8.73 (s, 2H), 9.53 (s, 2H).
Embodiment 66:N-hydroxyl-2-(methyl ((4-morpholinyl-2-phenyl thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methyl) amino) preparation of pyrimidine-5-formamide (compound 129)
Step 66a:2-(methyl ((4-morpholinyl-2-phenyl thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-129)
(110 milligrams of described title compounds 124,54%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (358 milligrams of 0504-54,0.80 milli rubs), (195 milligrams of phenylboric acids, 1.60 milli rubs), (520 milligrams of cesium carbonates, 1.60 milli rubs) and (65 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.08 milli rubs) solution of formation in Isosorbide-5-Nitrae-dioxane (6 milliliters) and the water (0.2 milliliter) prepares.LCMS:491[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (t, J=7.2Hz, 3H), 3.28 (s, 3H), 3.76 (t, J=4.8Hz, 4H), (3.94 t, J=4.8Hz, 4H), 4.29 (q, J=7.2Hz, 2H), 5.24 (s, 2H), (7.47-7.50 m, 4H), 8.38-8.41 (m, 2H), 8.89 (s, 2H).
Step 66b:N-hydroxyl-2-(methyl ((4-morpholinyl-2-phenyl thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-formamide (compound 129)
(140 milligrams of described title compounds 129,72%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (15 milliliters) that is the azanol by 0603-129 (200 milligrams, 0.41 milli rub) and fresh preparation prepares.Fusing point: 199-200 ℃.LCMS:478[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.23 (s, 3H), 3.76 (s, 4H), 3.93 (s, 4H), 5.20 (s, 2H), 7.47 (m, 4H), 8.39 (m, 2H), 8.75 (s, 2H).
Embodiment 67:N-hydroxyl-2-(((2-(4-methoxyphenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-formamide (chemical combination Thing 131) preparation
Step 67a:2-(((2-(4-methoxyphenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-131)
(230 milligrams of described title compound 0603-131,66%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (300 milligrams of 0504-54,0.67 milli rubs), (204 milligrams of 4-methoxybenzene ylboronic acids, 1.34 milli rubs), (24 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.03 milli rubs), (202 milligrams of sodium bicarbonates, 2.01 milli rubs) at toluene (5 milliliters), the solution that forms in ethanol (3 milliliters) and the water (1.3 milliliters) prepares.LCMS:521[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (t, J=7.2Hz, 3H), 3.27 (s, 1H), (3.75 t, J=4.4Hz, 4H), 3.82 (s, 3H), (3.91 t, J=4.6Hz, 4H), 4.29 (dd, J=7.2,7.2Hz, 2H), 5.22 (s, 2H), 7.02 (d, J=9.2Hz, 2H), 7.45 (s, 1H), 8.33 (d, J=8.8Hz, 2H), 8.88 (s, 2H).
Step 67b:N-hydroxyl-2-(((2 (4-methoxyphenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-formamide (compound 131)
(60 milligrams of described title compounds 131,23%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (8 milliliters) that is the azanol by 0603-131 (230 milligrams, 0.44 milli rub) and fresh preparation prepares.Fusing point: 247 ℃ (having decomposed).LCMS:509[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.24 (s, 3H), 3.75-3.77 (m, 4H), (3.82 s, 3H), 3.90-3.92 (m, 4H), (5.20 s, 2H), 7.02 (d, J=8.4Hz, 2H), 7.43 (s, 1H), 8.34 (d, J=8.4Hz, 2H), 8.75 (s, 2H), (9.08 br, 1H), 11.12 (br, 1H).
Embodiment 68:N-hydroxyl-2-(((2-(4-hydroxy phenyl)-4-morpholine thiophene a pair of horses going side by side [3, 2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-formamide (compound 133) Preparation
Step 68a:2-(((2-(4-hydroxy phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-133)
(170 milligrams of described title compound 0603-133,50%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (300 milligrams of 0504-54,0.67 milli rubs), (111 milligrams of 4-hydroxy phenyl boric acid, 0.802 milli rubs), (168 milligrams of sodium bicarbonates, 2.00 milli rubs), (23 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.0334 milli rubs) at ethanol (2.3 milliliters), the solution that forms in toluene (4 milliliters) and the water (1 milliliter) prepares.LCMS:507[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (t, J=6.8Hz, 3H), 3.27 (s, 3H), (3.75 m, 4H), 3.90 (m, 4H), 4.29 (q, J=7.2Hz, 2H), 5.22 (s, 2H), (6.84 d, J=8.8Hz, 2H), 7.43 (s, 1H), 8.23 (d, J=8.4Hz, 2H), (8.88 s, 2H), 9.81 (s, 1H).
Step 68b:N-hydroxyl-2-(((2 (4-hydroxy phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-formamide (compound 133)
(69 milligrams of described title compounds 133,42%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (10 milliliters) that is the azanol by 0603-133 (170 milligrams, 0.336 milli rub) and fresh preparation prepares.Fusing point: 185-195 ℃.LCMS:494[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.23 (s, 3H), 3.75 (m, 4H), 3.90 (m, 4H), 5.19 (s, 2H), 6.84 (d, J=8.4Hz, 2H), 7.40 (s, 1H), 8.23 (d, J=8.4Hz, 2H), 8.78 (s, 2H), 9.90 (s, 2H).
Embodiment 69:2-(((2-(4-(acetyl group methyl) phenyl)-4-morpholine thiophene A pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxy pyrimidine-5-formyl The preparation of amine (compound 136)
Step 69a:2-(((2-(4-(acetyl group methyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 136)
(75 milligrams of described title compounds 136; 31%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3; by 2-(((2-(4-(acetyl group methyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3; 2-d] pyrimidine-6-yl) methyl) (methyl) amino) (250 milligrams of pyrimidine-5-carboxylic acid's ethyl esters; 0.45 milli rubs, embodiment 48) and the methanol solution (20 milliliters) of the azanol of fresh preparation prepare.Fusing point: 178-180 ℃.LCMS:549[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 1.89 (s, 3H), 3.23 (s, 3H), 3.76 (m, 4H), 3.91 (m, 4H), 4.31 (d, J=5.6Hz, 2H), 5.20 (s, 2H), 7.34 (d, J=8.0Hz, 2H), 7.45 (s, 1H), (8.33 d, J=8.4Hz, 2H), 8.41 (t, J=5.6Hz, 1H), 8.75 (s, 2H).
Embodiment 70:2-(((2-(4-carbamoyl phenyl)-4-morpholine thiophene a pair of horses going side by side [3, 2-d] pyrimidine-6-yl) methyl) (methyl) amino)-(change of N-hydroxypyrimidine-5-carboxamides Compound 143) preparation
Step 70a:4-brombenzamide (compound 0601-143)
Under 0 ℃, to 4-bromobenzylcyanide (2 grams, 10 millis rub) dimethyl sulfoxide (DMSO) (DMSO) solution (6 milliliters) among add 30% hydrogen peroxide (5 grams, 13 millis rub) and potash and at room temperature described mixed liquor carried out 30 minutes stirring.Described reaction mixture is poured onto in the water and to it filters.Utilize water that the described solid of collecting is washed and drying, thereby obtain a kind of described compound 0601-143 (2.1 grams, 96%) of white solid form.LCMS:200[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 7.48 (s, 1H), 7.67 (d, J=8.4Hz, 2H), 7.81 (d, J=8.4Hz, 2H), 8.06 (s, 1H).
Step 70b:4-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) benzamide (compound 0602-143)
(570 milligrams of described title compound 0602-143,92%) be by using a kind of and preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by (500 milligrams of 0601-143,2.5 milli rubs), connection boric acid pinacol ester (952 milligrams, 3.75 millis rub), (735 milligrams of potassium acetates, 7.5 milli rubs), and two (Diphenyl phosphino ferrocene) palladium chloride (61 milligrams, 0.075 milli rub) prepares.LCMS:248[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 1.31 (s, 12H), 7.43 (s, 1H), 7.73 (d, J=8.4Hz, 2H), 7.87 (d, J=7.6Hz, 2H), 8.03 (s, 1H).
Step 70c:2-(((2-(4-carbamoyl phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-143)
(300 milligrams of described title compound 0603-143,84%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (300 milligrams of 0504-54,0.67 milli rubs), (330 milligrams of 0602-143,1.34 milli rubs), (168 milligrams of sodium bicarbonates, 2.00 milli rubs), (23 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.03 milli rubs) at toluene (5 milliliters), the solution that forms in ethanol (3 milliliters) and the water (1.3 milliliters) prepares.LCMS:534[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (t, J=6.8Hz, 3H), 3.28 (s, 3H), (3.77 m, 4H), 3.93 (m, 4H), 4.28 (q, J=7.2Hz, 2H), 5.24 (s, 2H), 7.45 (s, 1H), 7.51 (s, 1H), 7.97 (d, J=8.4Hz, 2H), 8.07 (s, 1H), 8.43 (d, J=8.4Hz, 2H), 8.88 (s, 2H).
Step 70d:2-(((2 (4-carbamoyl phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 143)
(183 milligrams of described title compounds 143,63%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (8 milliliters) that is the azanol by 0603-143 (300 milligrams, 0.47 milli rub) and fresh preparation prepares.Fusing point: 200-202 ℃.LCMS:521[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.25 (s, 3H), 3.77 (m, 4H), (3.94 m, 4H), 5.21 (s, 2H), (7.46 s, 1H), 7.49 (s, 1H), (7.97 d, J=8.4Hz, 2H), 8.08 (s, 1H), 8.44 (d, J=8.4Hz, 2H), 8.76 (s, 1H).
Embodiment 71:2-(((2-(4-cyano-phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 146) preparation
Step 71a:2-(((2-(4-cyano-phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-146)
(400 milligrams of described title compound 0603-146,70%) be by using a kind of a kind of linen solid with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (500 milligrams of 0504-54,1.1 milli rubs), (245 milligrams of 4-cyano-phenyl boric acid, 1.67 milli rubs), (280 milligrams of sodium bicarbonates, 3.34 milli rubs), (39 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.05 milli rubs) at toluene (5 milliliters), the solution that forms in ethanol (3 milliliters) and the water (1.3 milliliters) prepares.LCMS:516[M+1] +. 1HNMR (400 megahertzes, deuterochloroform) δ 1.39 (t, J=7.6Hz, 3H), 3.32 (s, 3H), 3.87 (m, 4H), 4.02 (m, 4H), 4.36 (q, J=7.2Hz, 2H), (5.21 s, 2H), 7.39 (s, 1H), (7.74 d, J=8.0Hz, 2H), 8.53 (d, J=8.8Hz, 2H), 8.93 (s, 2H).
Step 71b:2-(((2 (4-cyano-phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 146)
(40 milligrams of described title compounds 146,10%) be by using a kind of a kind of linen solid with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (12 milliliters) that is the azanol by 0603-146 (400 milligrams, 0.77 milli rub) and fresh preparation prepares.Fusing point: 214-216 ℃.LCMS:503[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.24 (s, 3H), 3.77 (m, 4H), (3.95 m, 4H), 5.22 (s, 2H), (7.51 s, 1H), 7.95 (d, J=8.4Hz, 2H), 8.54 (d, J=8.2Hz, 2H), (8.75 s, 2H), 9.13 (s, 1H), 11.11 (s, 1H).
(((2-(4-chlorphenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] is phonetic for embodiment 72:2- Pyridine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 147) preparation
Step 72a:2-(((2-(4-chlorphenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-147)
(250 milligrams of described title compound 0603-147,73%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (300 milligrams of 0504-54,0.67 milli rubs), (209 milligrams of 4-chlorophenylboronic acids, 1.34 milli rubs), (24 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.03 milli rubs), (202 milligrams of sodium bicarbonates, 2.01 milli rubs) at toluene (5 milliliters), the solution that forms in ethanol (3 milliliters) and the water (1.3 milliliters) prepares.LCMS:525[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (t, J=7.0Hz, 3H), 3.27 (s, 3H), (3.76 t, J=4.8Hz, 4H), 3.92 (t, J=4.8Hz, 4H), 4.29 (dd, J=6.8,7.2Hz, 2H), (5.24 s, 2H), 7.50 (s, 1H), (7.54 d, J=8.8Hz, 2H), 8.40 (d, J=8.4Hz, 2H), 8.88 (s, 2H).
Step 72b:2-(((2 (4-chlorphenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 147)
(69 milligrams of described title compounds 147,29%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (8 milliliters) that is the azanol by 0603-147 (250 milligrams, 0.48 milli rub) and fresh preparation prepares.Fusing point: 153-153 ℃.LCMS:512[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.24 (s, 3H), 3.75-3.77 (m, 4H), (3.91-3.93 m, 4H), 5.21 (s, 2H), (7.47 s, 1H), 7.54 (d, J=7.6Hz, 2H), 8.39 (d, J=8.0Hz, 2H), (8.76 s, 2H), 9.07 (br, 1H), 11.14 (br, 1H).
Embodiment 73:N-hydroxyl 2-(((2-(4-isopropyl phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-formamide (chemical combination Thing 148) preparation
Step 73a:2-(((2-(4-isopropyl phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-148)
(250 milligrams of described title compound 0603-148,73%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (300 milligrams of 0504-54,0.67 milli rubs), (220 milligrams of 4-cumene ylboronic acids, 1.34 milli rubs), (24 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.03 milli rubs), (202 milligrams of sodium bicarbonates, 2.01 milli rubs) at toluene (5 milliliters), the solution that forms in ethanol (3 milliliters) and the water (1.3 milliliters) prepares.LCMS:533[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.24 (d, J=7.2Hz, 6H), 1.30 (t, J=7.2Hz, 3H), (2.90-2.98 m, 1H), 3.27 (s, 3H), 3.76 (t, J=4.6Hz, 4H), 3.92 (t, J=4.4Hz, 4H), 4.29 (dd, J=7.2,7.2Hz, 2H), 5.23 (s, 2H), (7.34 d, J=8.0Hz, 2H), 7.48 (s, 1H), (8.30 d, J=8.4Hz, 2H), 8.88 (s, 2H).
Step 73b:N-hydroxyl-2-(((2 (4-isopropyl phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-formamide (compound 148)
(58 milligrams of described title compounds 148,27%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (8 milliliters) that is the azanol by 0603-148 (250 milligrams, 0.47 milli rub) and fresh preparation prepares.Fusing point: 155 ℃ (having decomposed).LCMS:520[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.24 (d, J=6.4Hz, 6H), 2.92-2.98 (m, 1H), (3.24 s, 3H), 3.75-3.77 (m, 4H), 3.91-3.93 (m, 4H), 5.20 (s, 2H), 7.34 (d, J=8.0Hz, 2H), 7.46 (s, 1H), 8.30 (d, J=8.0Hz, 2H), 8.76 (s, 2H), (9.08 br, 1H), 11.10 (br, 1H).
Embodiment 74:N-hydroxyl 2-(methyl ((2-(4-(methyl sulphonyl) phenyl) -4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (is changed Compound 149) preparation
Step 74a:2-(methyl ((2-(4-(methyl sulphonyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-149)
(250 milligrams of described title compound 0603-149; 77%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107; by (300 milligrams of 0504-54; 0.67 milli rubs); (268 milligrams of 4-(methyl sulphonyl) phenylboric acids; 1.34 milli rubs); (24 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides; 0.03 milli rubs); (202 milligrams of sodium bicarbonates; 2.01 milli rubs) at toluene (5 milliliters), the solution that forms in ethanol (3 milliliters) and the water (1.3 milliliters) prepares.LCMS:569[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (t, J=7.2Hz, 3H), 3.27 (s, 3H), (3.28 s, 3H), 3.76-3.78 (m, 4H), 3.95-3.97 (m, 4H), 4.29 (q, J=7.2Hz, 2H), (5.25 s, 2H), 7.54 (s, 1H), (8.03 d, J=8.4Hz, 2H), 8.61 (d, J=8.8Hz, 2H), 8.88 (s, 2H).
Step 74b:N-hydroxyl-2-(methyl ((2 (4-(methyl sulphonyl) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (compound 149)
(160 milligrams of described title compounds 149,65%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (8 milliliters) that is the azanol by 0603-149 (250 milligrams, 0.44 milli rub) and fresh preparation prepares.Fusing point: 206-208 ℃.LCMS:556[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.24 (s, 3H), 3.26 (s, 3H), 3.77 (t, J=4.4Hz, 4H), 3.96 (t, J=4.4Hz, 4H), (5.22 s, 2H), 7.52 (s, 1H), (8.03 d, J=8.4Hz, 2H), 8.61 (d, J=8.8Hz, 2H), 8.75 (s, 2H), (9.06 br, 1H), 11.13 (br, 1H).
(((2-(4-fluorophenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] is phonetic for embodiment 75:2- Pyridine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 200) preparation
Step 75a:2-(((2-(4-fluorophenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-200)
(300 milligrams of described title compound 0603-200,76%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (350 milligrams of 0504-54,0.78 milli rubs), (164 milligrams of 4-fluorophenyl boric acid, 1.17 milli rubs), (27 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.039 milli rubs), (196 milligrams of sodium bicarbonates, 2.34 milli rubs) at toluene (8 milliliters), the solution that forms in ethanol (5 milliliters) and the water (2 milliliters) prepares.LCMS:509[M+1] + 1HNMR (400 megahertzes, deuterochloroform): δ 1.31 (t, J=7.2Hz, 3H), (3.24 s, 3H) 3.80 (t, J=4.8Hz, 4H), (3.94 t, J=4.6Hz, 4H), 4.30 (q, J=7.1Hz, 2H), 5.13 (s, 2H), (7.04-7.08 m, 2H), 7.30 (s, 1H), (8.34-8.37 m, 2H), 8.86 (s, 2H).
Step 75b:2-(((2 (4-fluorophenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 200)
(240 milligrams of described title compounds 200,82%) be by using a kind of a kind of linen solid with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (16 milliliters) that is the azanol by 0603-200 (300 milligrams, 0.59 milli rub) and fresh preparation prepares.Fusing point: 168-170 ℃.LCMS:496[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 3.23 (s, 3H), 3.76 (t, J=4.6Hz, 4H), 3.92 (t, J=4.4Hz, 4H), (5.20 s, 2H), 7.28-7.32 (m, 2H), (7.46 s, 1H), 8.41-8.45 (m, 2H), (8.74 s, 2H), 9.05 (s, 1H), 11.12 (s, 1H).
Embodiment 76:N-hydroxyl-2-(methyl ((p-tolyl thiophene a pair of horses going side by side of 4-morpholinyl-2- [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (compound 201) Preparation
Step 76a:2-(methyl ((the p-tolyl thiophene a pair of horses going side by side of 4-morpholinyl-2-[3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-201)
(306 milligrams of described title compound 0603-201,78%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (350 milligrams of 0504-54,0.78 milli rubs), (212 milligrams of 4-aminomethyl phenyl boric acid, 1.56 milli rubs), (27 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.039 milli rubs), (196 milligrams of sodium bicarbonates, 2.34 milli rubs) at toluene (8 milliliters), the solution that forms in ethanol (5 milliliters) and the water (2 milliliters) prepares.LCMS:505[M+1] + 1HNMR (400 megahertzes, deuterochloroform): δ 1.31 (t, J=7.0Hz, 3H), 2.34 (s, 3H), 3.23 (s, 3H), 3.79 (t, J=4.8Hz, 4H), 3.93 (t, J=4.8Hz, 4H), 4.29 (q, J=7.2Hz, 2H), 5.12 (s, 2H), 7.19 (d, J=8.0Hz, 2H), 7.31 (s, 1H), 8.24 (d, J=8.0Hz, 2H), 8.86 (s, 2H).
Step 76b:N-hydroxyl-2-(methyl ((the p-tolyl thiophene a pair of horses going side by side of 4-morpholinyl-2-[3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (compound 201)
(27 milligrams of described title compounds 201,9%) be by using a kind of a kind of linen solid with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (16 milliliters) that is the azanol by 0603-201 (306 milligrams, 0.61 milli rub) and fresh preparation prepares.Fusing point: 170-172 ℃.LCMS:492[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 2.35 (s, 3H), 3.22 (s, 3H), 3.75 (m, 4H), 3.90 (m, 4H), 5.19 (s, 2H), 7.27 (d, J=7.6Hz, 2H), 7.43 (s, 1H), 8.27 (d, J=8.4Hz, 2H), 8.73 (s, 2H).
Embodiment 77:N-hydroxyl-2-(methyl ((4-morpholinyl-2-(4-(trifluoromethyl) Phenyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (is changed Compound 202) preparation
Step 77a:2-(methyl ((4-morpholinyl-2-(4-(trifluoromethyl) phenyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-202)
(527 milligrams of described title compound 0603-202, crude product) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (350 milligrams of 0504-54,0.78 milli rubs), (296 milligrams of 4-trifluoromethyl phenyl boronic acids, 1.56 milli rubs), (27 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.039 milli rubs), (196 milligrams of sodium bicarbonates, 2.34 milli rubs) at toluene (8 milliliters), the solution that forms in ethanol (5 milliliters) and the water (2 milliliters) prepares.LCMS:559[M+1] + 1HNMR (400 megahertzes, deuterochloroform): δ 1.32 (t, J=7.0Hz, 3H), 3.24 (s, 3H), 3.81 (t, J=4.8Hz, 4H), 3.96 (t, J=4.6Hz, 4H), 4.30 (q, J=7.1Hz, 2H), (5.12 s, 2H), 7.34 (s, 1H), (7.63 d, J=8.4Hz, 2H), 8.45 (d, J=8.0Hz, 2H), 8.86 (s, 2H).
Step 77b:N-hydroxyl-2-(methyl ((4-morpholinyl-2-(4-(trifluoromethyl) phenyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (compound 202)
(162 milligrams of described title compounds 202,38%) be by using a kind of a kind of linen solid with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (16 milliliters) that is the azanol by 0603-202 (527 milligrams, crude product) and fresh preparation prepares.Fusing point: 222-223 ℃.LCMS：546[M+1] +； 1HNMR(400MHz，DMSO-d 6)：.δ3.23(s，3H)，3.76(t，J＝4.4Hz，4H)，3.94(t，J＝4.2Hz，4H)，5.21(s，2H)，7.50(s，1H)，7.84(d，J＝8.8Hz，2H)，8.57(d，J＝8.4Hz，2H)，8.74(s，2H)，9.06(s，1H)，11.13(s，1H).
Embodiment 78:N-hydroxyl-2-(methyl ((2-(4-(methylamino) phenyl) -4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (is changed Compound 151) preparation
Step 78a:4-bromo-methylphenylamine (compound 0601-151) and 4-bromo-DMA (compound 0601-152)
At room temperature, to 4-bromaniline (3 grams, 17.4 milli rubs) and the middle interpolation of oxolane (THF) solution (30 milliliters) iodomethane (2.2 milliliters, 34.8 millis rub) of potash (3.62 grams, 26.2 millis rub) and the stirring of spending the night.In described reaction mixture, add water (6 milliliters) and utilize ethyl acetate (50 milliliters of x3) that described mixed liquor is extracted.Described organic layer is carried out drying, concentrated and (be present in the ethyl acetate among the benzinum by column chromatography on the silica gel, 10% volume/volume) it is carried out purifying, thereby obtain a kind of 0601-151 (840 milligrams, 26%) of white solid form.LCMS:187[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 2.63 (s, 3H), 5.85 (br, 1H), 6.48 (d, J=9.2Hz, 2H), the 0601-152 of 7.20 (d, J=8.4Hz, 2H) and a kind of white solid form (680 milligrams, 20%).LCMS:201[M+1] +. 1HNMR (400 megahertzes, and price markup sulfoxide-d 6) δ 2.87 (s, 6H), 6.65 (d, J=9.2Hz, 2H), 7.29 (d, J=8.8Hz, 2H).
Step 78b:N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) aniline (compound 0602-151)
(301 milligrams of described title compound 0602-151,60%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by (400 milligrams of 0601-151,2.15 milli rubs), (819 milligrams of connection boric acid pinacol esters, 3.23 milli rubs), (632 milligrams of potassium acetates, 6.4 milli rubs), and two (Diphenyl phosphino ferrocene) palladium chloride (351 milligrams, 0.43 milli rub) prepares.LCMS:234[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.24 (s, 12H), 2.67 (d, J=5.2Hz, 3H), 6.04 (br, 1H), 6.48 (d, J=8.4Hz, 2H), 7.39 (d, J=8.4Hz, 2H).
Step 78c:2-(methyl ((2-(4-(methylamino) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-151)
(100 milligrams of described title compound 0603-151,64%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (135 milligrams of 0504-54,0.3 milli rubs), (100 milligrams of 0602-151,0.42 milli rubs), (10.5 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.015 milli rubs), (76 milligrams of sodium bicarbonates, 0.9 milli rubs) at toluene (2.5 milliliters), the solution that forms in ethanol (1.6 milliliters) and the water (0.7 milliliter) prepares.LCMS:520[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (t, J=7.2Hz, 3H), 2.73 (d, J=4.8Hz, 3H), 3.26 (s, 3H), 3.75 (m, 4H), (3.88 m, 4H), 4.29 (q, J=7.2Hz, 2H), (5.21 s, 2H), 6.10 (m, 1H), 6.58 (d, J=8.8Hz, 2H), 7.39 (s, 1H), 8.15 (d, J=8.4Hz, 2H), 8.88 (d, J=4.8Hz, 2H).
Step 78d:N-hydroxyl-2-(methyl ((2-(4-(methylamino) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (compound 151)
(40 milligrams of described title compounds 151,42%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (6 milliliters) that is the azanol by 0603-151 (100 milligrams, 0.19 milli rub) and fresh preparation prepares.Fusing point: 218-220 ℃.LCMS:507[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 2.73 (d, J=4.4Hz, 3H), 3.75 (d, J=4.0Hz, 4H), 3.87 (d, J=4.0Hz, 4H), 5.18 (s, 2H), 6.11 (d, J=4.8Hz, 1H), 6.58 (d, J=8.0Hz, 2H), 7.37 (s, 1H), 8.15 (d, J=8.4Hz, 2H), 8.75 (s, 2H), (9.06 s, 1H), 11.13 (br, 1H).
Embodiment 79:2-(((2-(4-(dimethylamino) phenyl)-4-morpholine thiophene A pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxy pyrimidine-5-formyl Amine (compound 152)
Step 79a:N, N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) aniline (compound 0602-152)
(360 milligrams of described title compound 0602-152,61%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by (480 milligrams of 0601-152,2.4 milli rubs), (914 milligrams of connection boric acid pinacol esters, 3.6 milli rubs), (706 milligrams of potassium acetates, 7.2 milli rubs), and two (Diphenyl phosphino ferrocene) palladium chloride (390 milligrams, 0.48 milli rub) prepares.LCMS:248[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.25 (s, 12H), 2.93 (s, 6H), 6.66 (d, J=8.8Hz, 2H), 7.48 (d, J=8.8Hz, 2H).
Step 79b:2-(((2-(4-(dimethylamino) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-152)
(100 milligrams of described title compound 0603-152,53%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (161 milligrams of 0504-54,0.36 milli rubs), (150 milligrams of 0602-152,0.61 milli rubs), (13 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.018 milli rubs), (91 milligrams of sodium bicarbonates, 1.08 milli rubs) at toluene (2.5 milliliters), the solution that forms in ethanol (1.6 milliliters) and the water (0.7 milliliter) prepares.LCMS:534[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.22 (m, 3H), 2.97 (s, 6H), (3.22 s, 3H), 3.74 (m, 4H), (3.87 m, 4H), 4.14 (m, 2H), (5.17 s, 2H), 6.75 (d, J=8.8Hz, 2H), 7.37 (s, 1H), 8.20 (d, J=9.2Hz, 2H), 8.73 (s, 2H).
Step 79c:2-(((2-(4-(dimethylamino) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 152)
(30 milligrams of described title compounds 152,30%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (6 milliliters) that is the azanol by 0603-152 (100 milligrams, 0.19 milli rub) and fresh preparation prepares.Fusing point: 208-210 ℃.LCMS:521[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 2.98 (s, 6H), 3.23 (s, 3H), (3.76 d, J=4.0Hz, 4H), 3.89 (s, 4H), 5.18 (s, 2H), 6.76 (d, J=8.8Hz, 2H), 7.39 (s, 1H), (8.22 d, J=8.4Hz, 2H), 8.75 (s, 2H), 9.07 (br, 1H).
Embodiment 80:2-(((2-(4-(ethylamino) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-the N-hydroxypyrimidine-5-carboxamides The preparation of (compound 153)
Step 80a:4-bromo-N-ethylaniline (compound 0601-153)
In the acetonitrile solution (50 milliliters) of 4-bromaniline (2.00 grams, 11.67 millis rub) and iodoethane (5.50 grams, 35.28 millis rub), add potash (6.48 grams, 47.04 millis rub).The stirring of under 60 ℃, described mixed liquor being spent the night.Under vacuum condition, described reaction mixture concentrated and (be present in the ethyl acetate among the benzinum by column chromatography on the silica gel, the 0%-10% volume/volume) described residue is carried out purifying, thereby obtain a kind of compound 0601-153 (800 milligrams, 38%) of flaxen oil form.LCMS:200[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.13 (t, J=6.8Hz, 3H), 2.97 (m, 2H), 5.73 (brs, 1H), 6.48 (d, J=8.8Hz, 2H), 7.17 (d, J=8.8Hz, 2H).
Step 80b:N-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) aniline (compound 0602-153)
(640 milligrams of described title compound 0602-153,72%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by (884 milligrams of 0601-153,4.420 milli rubs), connection boric acid pinacol ester (1.68 grams, 6.630 milli rubs), potassium acetate (1.30 grams, 13.3 milli rubs), and two (Diphenyl phosphino ferrocene) palladium chloride (362 milligrams, 0.44 milli rub) prepares.LCMS:248[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.13 (m, 15H), 3.03 (m, 2H), 5.94 (brs, 1H), 6.49 (d, J=8.4Hz, 2H), 7.37 (d, J=8.8Hz, 2H).
Step 80c:2-(((2-(4-(ethylamino) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-153)
(200 milligrams of described title compound 0603-153,71%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (240 milligrams of 0504-54,0.53 milli rubs), (172 milligrams of 0602-153,0.69 milli rubs), (37 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.053 milli rubs), (134 milligrams of sodium bicarbonates, 1.6 milli rubs) at toluene (8 milliliters), the solution that forms in ethanol (5 milliliters) and the water (2 milliliters) prepares.LCMS:534[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.17 (t, J=7.2Hz, 3H), 2.29 (t, J=7.6Hz, 3H), (3.09 m, 2H), 3.25 (s, 3H), 3.73 (brs, 4H), 3.87 (brs, 4H), 4.27 (m, 2H), (5.20 s, 2H), 6.02 (t, J=4.8Hz, 1H), (6.58 d, J=8.8Hz, 2H), 7.37 (s, 1H), (8.12 d, J=8.8Hz, 2H), 8.87 (s, 2H) .P49
Step 80d:2-(((2-(4-(ethylamino) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 153)
(110 milligrams of described title compounds 153,56%) be by using a kind of a kind of linen solid with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (8 milliliters) that is the azanol by 0603-153 (200 milligrams, 0.38 milli rub) and fresh preparation prepares.Fusing point: 185-187 ℃; LCMS:521[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.18 (t, J=6.8Hz, 3H), 3.09 (m, 2H), (3.23 s, 3H), 3.75 (brs, 4H), 3.87 (brs, 4H), 5.18 (s, 2H), 6.02 (t, J=4.8Hz, 1H), 6.59 (d, J=8.8Hz, 2H), 7.36 (s, 1H), 8.13 (d, J=8.4Hz, 2H), 8.74 (s, 2H), 9.06 (s, 1H), 11.13 (s, 1H).
Embodiment 81:2-(((2-(4-(diethylamino) phenyl)-4-morpholine thiophene A pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxy pyrimidine-5-formyl The preparation of amine (compound 154)
Step 81a:4-bromo-N, N-diethylaniline (compound 0601-154)
Described title compound 0601-154 (1.10 grams, 40%) synthesizes according to the employed described synthesis step of preparation compound 0601-153, to use 4-bromaniline (2.00 grams, 11.67 milli rubs) and iodoethane (5.50 grams, 35.28 millis rub) as initial substance.LCMS:228[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.05 (t, J=7.2Hz, 6H), 3.30 (m, 4H), 6.58 (d, J=8.8Hz, 2H), 7.22 (d, J=8.8Hz, 2H).
Step 81b:N-N-diethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) aniline (compound 0602-154)
(860 milligrams of described title compound 0602-154,63%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by 0601-154 (1.21 grams, 5.33 milli rubs), connection boric acid pinacol ester (2.03 grams, 8.00 milli rubs), potassium acetate and two (Diphenyl phosphino ferrocene) palladium chloride prepare.LCMS:276[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.06 (t, J=6.8Hz, 6H), 1.24 (s, 12H), 3.34 (m, 4H), 6.60 (d, J=8.4Hz, 2H), 7.44 (d, J=8.8Hz, 2H).
Step 81c:2-(((2-(4-(diethylamino) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-154)
(260 milligrams of described title compound 0603-154,85%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (240 milligrams of 0504-54,0.53 milli rubs), (220 milligrams of 0602-154,0.8 milli rubs), two (Diphenyl phosphino ferrocene) palladium chloride, sodium bicarbonate is at toluene (8 milliliters), and the solution that forms in ethanol (5 milliliters) and the water (2 milliliters) prepares.LCMS:562[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.12 (t, J=7.2Hz, 6H), 1.29 (t, J=6.8Hz, 3H), 3.25 (s, 3H), 3.40 (m, 4H), (3.74 brs, 4H), 3.87 (brs, 4H), 4.27 (m, 2H), 5.20 (s, 2H), 6.69 (d, J=8.8Hz, 2H), 7.39 (s, 1H), 8.18 (d, J=8.8Hz, 2H), 8.87 (s, 2H).
Step 81d:2-(((2-(4-(diethylamino) phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 154)
(180 milligrams of described title compounds 154,71%) be by using a kind of a kind of linen solid with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (8 milliliters) that is the azanol by 0603-154 (260 milligrams, 0.463 milli rub) and fresh preparation prepares.Fusing point: 192-196 ℃; LCMS:549[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.12 (t, J=7.2Hz, 6H), 3.23 (s, 3H), (3.41 m, 4H), 3.75 (brs, 4H), 3.87 (brs, 4H), 5.18 (s, 2H), 6.70 (d, J=8.8Hz, 2H), 7.37 (s, 1H), 8.19 (d, J=8.8Hz, 2H), 8.74 (s, 2H), (9.06 s, 1H), 11.11 (s, 1H).
Embodiment 82:N-hydroxyl-2-(methyl ((4-morpholinyl-2-(4-(pyrroles-1-yl) Phenyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (is changed Compound 155) preparation
Step 82a:1-(4-bromophenyl) pyrroles (compound 0601-155)
Under 60 ℃, to 4-bromaniline (1 gram, 5.81 millis rub), cesium carbonate (5.68 grams, 17.44 millis rub), 1, the stirring that the mixed liquor (20 milliliter) of 4-dibromobutane (1.88 grams, 8.72 millis rub) in dimethyl formamide (DMF) spends the night.Through being cooled to after the room temperature, utilizing water (200 milliliters) that described mixed liquor is diluted and utilize ethyl acetate (2x100 milliliter) that it is extracted.Utilize water (3x100 milliliter) and salt solution (100 milliliters) that described organic layer is washed, carry out drying by sodium sulphate, concentrated and by column chromatography (benzinum) on silica gel it is carried out purifying, thereby obtain a kind of compound 0601-155 (720 milligrams, 46%) of form of colourless oil.LCMS:226[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.94 (t, J=6.4Hz, 4H), 3.18 (t, J=6.4Hz, 4H), 6.47 (d, J=9.2Hz, 1H), 7.27 (d, J=9.2Hz, 1H).
Step 82b:1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) phenyl) pyrroles (compound 0602-155)
(500 milligrams of described title compound 0602-155,57%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by (720 milligrams of 0601-155,3.18 milli rubs), connection boric acid pinacol ester (1.21 grams, 4.78 milli rubs), (938 milligrams of potassium acetates, 9.56 milli rubs), two (Diphenyl phosphino ferrocene) palladium chloride (78 milligrams, 0.0956 milli rubs) prepares.LCMS:274[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.25 (s, 12H), 1.95 (t, J=6.8Hz, 4H), 3.23 (t, J=6.4Hz, 4H), 6.49 (d, J=8.8Hz, 1H), 7.46 (d, J=8.4Hz, 1H).
Step 82c:2-(methyl ((4-morpholinyl-2-(4-(pyrroles-1-yl) phenyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-155)
(320 milligrams of described title compound 0603-155,86%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (300 milligrams of 0504-54,0.668 milli rubs), (219 milligrams of 0602-155,0.80 milli rubs), (168 milligrams of sodium bicarbonates, 2.00 milli rubs), (23 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.033 milli rubs) at ethanol (2.3 milliliters), the solution that forms in toluene (4 milliliters) and the water (1 milliliter) prepares.LCMS:560[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (t, J=7.6Hz, 3H), 1.98 (m, 4H), (3.26 s, 3H), 3.30 (m, 4H), 3.75 (m, 4H), 3.90 (m, 4H), 4.29 (q, J=6.8Hz, 2H), 5.22 (s, 2H), 6.59 (d, J=8.8Hz, 2H), 7.40 (s, 1H), 8.21 (d, J=8.8Hz, 2H), 8.88 (s, 2H).
Step 82d:N-hydroxyl-2-(methyl ((2-(4-morpholinyl-2-(4-(pyrroles-1-yl) phenyl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (compound 155)
(55 milligrams of described title compounds 155,28%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (10 milliliters) that is the azanol by 0603-155 (200 milligrams, 0.49 milli rub) and fresh preparation prepares.Fusing point: 187-192 ℃.LCMS:547[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.97 (m, 4H), 3.23 (s, 3H), 3.30 (m, 4H), 3.76 (m, 4H), 3.88 (m, 4H), (5.18 s, 2H), 6.59 (d, J=8.8Hz, 2H), 7.37 (s, 1H), 8.21 (d, J=8.4Hz, 2H), 8.75 (s, 2H), (9.06 s, 1H), 11.12 (s, 1H).
Embodiment 83:2-(((2-(3,4-diamino-phenyl)-4-morpholine thiophene a pair of horses going side by side [3, 2-d] pyrimidine-6-yl) methyl) (methyl) amino)-(change of N-hydroxypyrimidine-5-carboxamides Compound 156) preparation
Step 83a:4-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) benzene-1,2-diamines (compound 0602-156)
Described title compound 0602-156 (1.0 grams, 43%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by 4-bromobenzene-1,2-diamines (1.87 grams, 10 millis rub), connection boric acid pinacol ester (3.9 grams, 15 millis rub) (817 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 1 milli rubs) and potassium acetate (2.9 grams, 30 millis rub) prepare.LCMS:235[M+1] +, 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.23 (s, 12H), 4.38 (s, 2H), 4.82 (s, 2H), 6.46 (d, J=7.6Hz, 1H), 6.77 (dd, J=7.6,0.8Hz, 1H), 6.88 (d, J=0.8Hz, 1H).
Step 83b:2-(((2-(3,4-diamino-phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-156)
(300 milligrams of described title compound 0603-156,86%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (300 milligrams of 0504-54,0.67 milli rubs), (190 milligrams of 0602-156,0.80 milli rubs), (169 milligrams of sodium bicarbonates, 2.0 milli rubs), (203 milligrams of cesium fluorides, 1.34 milli rubs), (47 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.067 milli rubs) at toluene (4 milliliters), the solution that forms in ethanol (2 milliliters) and the water (0.5 milliliter) prepares.LCMS:521[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.30 (t, J=7.2Hz, 3H), 3.26 (s, 3H), 3.75 (m, 4H), 3.87 (m, 4H), 4.29 (q, J=7.2Hz, 2H), (4.55 s, 2H), 4.89 (s, 2H), 5.21 (s, 2H), 6.54 (d, J=8.4Hz, 1H), 7.36 (s, 1H), 7.52 (dd, J=8.4,2.0Hz, 1H), (7.63 d, J=2.0Hz, 1H), 8.88 (s, 2H).
Step 83d:2-(((2-(3,4-diamino-phenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 156)
(128 milligrams of described title compounds 156,44%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (20 milliliters) that is the azanol by 0603-156 (300 milligrams, 0.58 milli rub) and fresh preparation prepares.Fusing point: 222-225 ℃.LCMS:508[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 3.21 (s, 3H), 3.75 (m, 4H), (3.87 m, 4H), 4.54 (s, 2H), (4.88 s, 2H), 5.14 (s, 2H), (6.53 d, J=8.4Hz, 1H), 7.33 (s, 1H), 7.52 (d, J=7.6Hz, 1H), (7.62 s, 1H), 8.73 (s, 2H).
Embodiment 84:2-(((2-(1H-indoles-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] Pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 176) preparation
Step 84a:4-bromo-1H-indoles-1-carboxylic acid tert-butyl ester (compound 0601-176)
At room temperature, to (394 milligrams of 4-bromo indoles, 2.00 milli rubs), (523 milligrams of di-tert-butyl dicarbonates, 2.40 milli rubs), dimethylamino naphthyridine (DMAP) (293 milligrams, 2.4 millis rub) and the solution (6 milliliter) of triethylamine (0.4 milliliter) in acetonitrile carry out 2 hours stirring.Remove described solvent and described residue is dissolved among the ethyl acetate (40 milliliters), utilize water (3x20 milliliter) and salt solution (1x20 milliliter) that it is washed, described organic layer is concentrated and by column chromatography (benzinum) on silica gel it carried out purifying, thereby obtain a kind of compound 0601-176 (508 milligrams, 85%) of form of colourless oil. 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.64 (s, 9H), 6.67 (d, J=3.2Hz, 1H), 7.28 (t, J=8.0Hz, 1H), 7.48 (m, 1H), 7.80 (d, J=3.2Hz, 1H), 8.08 (m, 1H).
Step 84b:4-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl)-1H-indoles-1-carboxylic acid tert-butyl ester (compound 0602-176)
(448 milligrams of described title compound 0602-176,77%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by (503 milligrams of 0601-176,1.69 milli rubs), (644 milligrams of connection boric acid pinacol esters, 2.54 milli rubs) (138 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.17 milli rubs) and potassium acetate (497 milligrams, 5.07 milli rub) prepare. 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.34 (s, 12H), 1.64 (s, 9H), 6.98 (d, J=2.8Hz, 1H), 7.33 (t, J=8.0Hz, 1H), 7.58 (m, 1H), 7.72 (d, J=2.8Hz, 1H), 8.20 (m, 1H).
Step 84c:2-(((2-(1H-indoles-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-176)
Described title compound 4-(6-(((5-(ethoxy carbonyl) pyrimidine-2-base) (methyl) amino) methyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-2-base)-(368 milligrams of 1H-indoles-1--carboxylic acid tert-butyl ester, 59%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (448 milligrams of 0504-54,1.00 milli rubs), (343 milligrams of 0602-176,1.00 milli rubs), (652 milligrams of cesium carbonates, 2.00 milli rubs), (203 milligrams of cesium fluorides, 1.34 milli rubs) and (82 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.10 milli rubs) solution of formation in Isosorbide-5-Nitrae-dioxane (6 milliliters) and the water (0.2 milliliter) prepares.LCMS:630[M+1] +. 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (t, J=7.2Hz, 3H), 1.65 (s, 9H), (3.28 s, 3H), 3.78 (m, 4H), 3.93 (m, 4H), 4.29 (q, J=7.2Hz, 2H), 5.25 (s, 2H), 7.44 (m, 1H), 7.55 (s, 1H), (7.72 m, 1H), 7.77 (m, 1H), (8.25 m, 2H), 8.88 (s, 2H).
At room temperature, the mixed liquor (4 milliliter) of above-mentioned solid (368 milligrams, 0.59 milli rubs) in trifluoroacetic acid carried out 1 hour stirring.Utilize 10% sodium hydrate aqueous solution that pH is adjusted to 7, and utilize carrene (60 milliliters) that it is extracted.Utilize salt solution (1x30 milliliter) that described organic layer is washed, dry and concentrate, thus obtain a kind of compound 0603-176 (312 milligrams, 100%) of yellow solid form.LCMS:530[M+1] +. 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.31 (t, J=6.8Hz, 3H), 3.29 (s, 3H), (3.79 m, 4H), 3.94 (m, 4H), 4.30 (q, J=7.2Hz, 2H), 5.26 (s, 2H), 7.19 (t, J=8.0Hz, 1H), 7.43 (m, 2H), (7.53 s, 1H), 8.11 (m, 1H), (8.89 s, 2H), 11.23 (s, 1H).
Step 84d:2-(((2-(1H-indoles-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 176)
(78 milligrams of described title compounds 176,25%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (10 milliliters) that is the azanol by 0603-176 (318 milligrams, 0.60 milli rub) and fresh preparation prepares.Fusing point: 200-212 ℃.LCMS:517[M+1] +. 1H-NMR (400 megahertzes, the δ 3.26 (s, 3H) of dimethyl sulfoxide (DMSO)-d6), 3.79 (m, 4H), (3.94 m, 4H), 5.22 (s, 2H), 7.19 (t, J=8.0Hz, 1H), 7.43 (m, 2H), 7.52 (m, 2H), 8.12 (d, J=8.0Hz, 1H), (8.77 s, 2H), 9.07 (s, 1H), (11.14 s, 1H), 11.24 (s, 1H).
Embodiment 85:N-hydroxyl-2-(((2-(indoline-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-formamide (chemical combination Thing 177) preparation
Step 85a:4-bromo indole quinoline-1-carboxylic acid tert-butyl ester (compound 0601-177)
At room temperature, the stirring that the mixed liquor that oxolane (THF) solution (2M, 40 milliliters) by 4-bromo indole ketone (2.77 grams, 0.01 rubs) and boron hydride is formed spends the night.Described mixed liquor is cooled to 0 ℃ and utilize 30 milliliters methyl alcohol that it is diluted, adds after this hydrochloric acid (7.5 milliliters) of 12N.At room temperature mixed liquor obtained above is carried out 1 hour stirring, utilize 10% sodium hydrate aqueous solution that pH is adjusted to 8-9.In described mixed liquor, add water and utilize ethyl acetate (3x100 milliliter) that it is extracted.Described organic layer is carried out drying and concentrated, thereby obtain described crude product, described crude product is washed through a silicagel column (be present in benzinum among ethyl acetate (10%)).Described crude product is dissolved among 10% the hydrochloric acid (3x10 milliliter).Utilize sodium bicarbonate with the p of described water layer, H is adjusted to 7, utilizes ethyl acetate (3x20 milliliter) that it is extracted.Described organic layer is carried out drying and concentrated, thereby obtain a kind of 4-bromo indole ketone (1.16 grams, 45%) of oil form.LCMS:200[M+1] +. 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 2.90 (t, J=8.8Hz, 2H), 3.46 (t, J=8.8Hz, 2H), 5.86 (s, 1H), 6.43 (m, 1H), 6.64 (m, 1H), 6.83 (t, J=8.0Hz, 1H).
The stirring of at room temperature, the formonitrile HCN mixed liquor (8 milliliters) of the 4-bromo indole ketone of above-mentioned acquisition (759 milligrams, 3.81 millis rub) and di-tert-butyl dicarbonate (976 milligrams, 4.48 millis rub) being spent the night.After pervaporation, described residue is dissolved among the ethyl acetate (40 milliliters), utilize water (3x20 milliliter) and salt solution (1x20 milliliter) that it is washed.Described organic layer is concentrated and by column chromatography (benzinum) on silica gel it carried out purifying, thereby obtain a kind of 0601-177 (840 milligrams, 74%) of white solid form. 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.50 (s, 9H), 3.02 (t, J=8.8Hz, 2H), 3.94 (t, J=8.8Hz, 2H), 7.12 (m, 2H), 7.56 (m, 1H).
Step 85b:4-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) indoline-1-carboxylic acid tert-butyl ester (compound 0602-177)
(814 milligrams of described title compound 0602-177,84%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by (840 milligrams of 0601-177,2.81 milli rubs), connection boric acid pinacol ester (1.07 grams, 4.21 milli rubs), (229 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.28 milli rubs) and potassium acetate (826 milligrams, 8.43 milli rub) prepare.LCMS:290[M-55] + 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.35 (s, 12H), 1.57 (s, 9H), 3.24 (t, J=8.4Hz, 2H), 3.94 (t, J=8.4Hz, 2H), 7.20 (m, 1H), 7.28 (m, 1H), 7.88 (m, 1H).
Step 85c:2-(((2-(indoline-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-177)
Described compound 4-(6-(((5-(ethoxy carbonyl) pyrimidine-2-base) (methyl) amino) methyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-2-base) (463 milligrams of indolines-1-carboxylic acid tert-butyl ester, 73%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (448 milligrams of 0504-54,1.00 milli rubs), (345 milligrams of 0602-177,1.00 milli rubs), (652 milligrams of cesium carbonates, 2.00 milli rubs) and (82 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.10 milli rubs) solution of formation in Isosorbide-5-Nitrae-dioxane (6 milliliters) and the water (0.2 milliliter) prepares.LCMS:632[M+1] +. 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (t, J=7.2Hz, 3H), 1.52 (s, 9H), (3.27 s, 3H), 3.55 (m, 2H), 3.87 (m, 4H), 3.94 (m, 6H), 4.29 (q, J=7.2Hz, 2H), 5.23 (s, 2H), 7.26 (m, 1H), (7.46 s, 1H), 7.81 (m, 1H), (7.89 m, 1H), 8.87 (s, 2H).
At room temperature, above-mentioned product (463 milligrams, 0.73 milli rubs) and the mixed liquor of trifluoroacetic acid (4 milliliters) are carried out 1 hour stirring.Utilize 10% sodium hydrate aqueous solution that the pH of described mixed liquor is adjusted to 7, utilize carrene (60 milliliters) that it is extracted.Utilize salt solution (1x30 milliliter) that described organic layer is washed, dry and concentrated, thus obtain a kind of 0603-177 (283 milligrams, 73%) of pale solid form.LCMS:532[M+1] +. 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (t, J=6.8Hz, 3H), 3.27 (s, 3H), (3.41 m, 4H), 3.75 (m, 4H), 3.86 (m, 4H), 4.29 (q, J=6.8Hz, 2H), 5.23 (s, 2H), 5.58 (s, 1H), 6.58 (m, 1H), 7.01 (t, J=8.0Hz, 1H), (7.47 m, 2H), 8.88 (s, 2H).
Step 85d:N-hydroxyl-2-(((2-(indoline-4-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-formamide (compound 177)
(130 milligrams of described title compounds 177,49%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (8 milliliters) that is the azanol by 0603-177 (273 milligrams, 0.51 milli rub) and fresh preparation prepares.Fusing point: 146-156 ℃.LCMS:519[M+1] +. 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.24 (s, 3H), 3.42 (m, 4H), 3.75 (m, 4H), 3.87 (m, 4H), 5.20 (s, 2H), (5.57 s, 1H), 6.58 (m, 1H), 7.01 (t, J=8.0Hz, 1H), 7.43 (s, 1H), (7.48 m, 1H), 8.76 (s, 2H), (9.07 s, 1H), 11.13 (s, 1H).
Embodiment 86:2-(((2-(3,4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae] oxygen piperazine-6-that mixes Base)-and 4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N- The preparation of hydroxypyrimidine-5-carboxamides (compound 182)
Step 86a:6-bromo-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] oxygen piperazine-4-carboxylic acid tert-butyl ester (compound 0601-182) of mixing
Under 70 ℃, to compound 4-bromo-2-nitrophenol (1 the gram, 4.59 the milli rub) and stannous chloride (5.2 the gram, 22.9 the milli rub) alcohol mixeding liquid (10 milliliters) carry out 2 hours stirring.After cooling down, utilize water (100 milliliters) that described mixed liquor is diluted, utilize saturated sodium bicarbonate aqueous solution that pH is adjusted to 7 and utilize ethyl acetate (100 milliliters) that it is extracted.Utilize salt solution (50 milliliters) that described organic layer is washed, carry out drying by sodium sulphate, concentrate, thereby obtain a kind of 2-amino-4-bromophenol (770 milligrams, 89%) of gray solid form.LCMS:188[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 4.79 (s, 2H), 6.48 (dd, J1=2.4Hz, J2=8.4Hz, 1H), 6.55 (d, J=8.4Hz, 1H), 6.71 (d, J=2.4Hz, 1H), 9.26 (s, 1H).
At room temperature, to (500 milligrams of described product 2-amino-4-bromophenols, 2.66 milli rubs), 1,2-ethylene dibromide (2.5 grams, 13.3 the milli rub) and potash (1.84 the gram, 13.3 the milli rub) dimethyl formamide (DMF) mixed liquor (10 milliliters) carry out 4 hours stirring.Utilize water (100 milliliters) that described mixed liquor is diluted and utilize ethyl acetate (100 milliliters) that it is extracted.Utilize water (3x50 milliliter) and salt solution (50 milliliters) that described organic layer is washed, concentrated and (be present in the ethyl acetate among the oil by column chromatography on the silica gel, 10% volume/volume) it is carried out purifying, thereby obtain a kind of 5-bromo-2-(2-bromine oxethyl) aniline (250 milligrams, 37%) of yellow solid form.LCMS:294[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.79 (t, J=6.0Hz, 2H), 4.25 (t, J=5.6Hz, 2H), 5.06 (s, 2H), 6.63 (dd, J1=2.4Hz, J2=8.0Hz, 1H), 6.77 (d, J=8.4Hz, 1H), 6.82 (d, J=2.4Hz, 1H).
Under 60 ℃, to (250 milligrams of described product 5-bromo-2-(2-bromine oxethyl) aniline, 0.848 milli rubs) and dimethyl formamide (DMF) mixed liquor (5 milliliters) of potash (234 milligrams, 1.695 milli rub) carry out 4 hours stirring.Utilize water (100 milliliters) that described mixed liquor is diluted and utilize ethyl acetate (100 milliliters) that it is extracted.Utilize water (3x50 milliliter) and salt solution (50 milliliters) that described organic layer is washed, concentrated, thus obtain a kind of 6-bromo-3 of form of oil of yellow, 4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae] oxygen piperazine (170 milligrams, 94%) of mixing.LCMS:214[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.26 (m, 2H), 4.08 (t, J=4.8Hz, 2H), 6.06 (s, 1H), 6.56 (m, 2H), 6.69 (d, J=1.6Hz, 1H).
At room temperature, to described product 6-bromo-3,4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae] mix the oxygen piperazine (1.37 the gram, 6.4 the milli rub), di-tert-butyl dicarbonate (1.676 grams, 7.68 milli rubs), triethylamine (970 milligrams, 9.6 millis rub), the stirring that oxolane (THF) mixed liquor (27 milliliters) of dimethylamino naphthyridine (DMAP) (78 milligrams, 0.64 milli rubs) spends the night.Utilize water (200 milliliters) that described reaction mixture is diluted and utilize ethyl acetate (100 milliliters) that it is extracted.Utilize water (50 milliliters) and salt solution that described organic layer is washed, by sodium sulphate it is carried out drying and concentrated, thereby obtain a kind of compound 0601-182 (1.3 grams, 65%) of oil form of yellow.LCMS:258[M-55] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.49 (s, 9H), 3.78 (t, J=4.8Hz, 2H), 4.21 (t, J=4.4Hz, 2H), 6.83 (d, J=4.4Hz, 1H), 7.12 (dd, J1=2.0Hz, J2=8.4Hz, 2H), 8.01 (s, 1H).
Step 86b:6-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] oxygen piperazine-4-carboxylic acid tert-butyl ester (compound 0602-182) of mixing
Described title compound 0602-182 (1.4 grams, 98%) be by using a kind of a kind of oil with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by 0601-182 (1.16 grams, 3.69 milli rubs), connection boric acid pinacol ester (1.41 grams, 5.54 milli rubs), (90 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.111 milli rubs) and potassium acetate (1.09 grams, 11.07 millis rub) prepare.LCMS:306[M-55] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.27 (s, 12H), 1.49 (s, 9H), 3.79 (t, J=4.4Hz, 2H), 4.23 (t, J=4.0Hz, 2H), 6.88 (d, J=8.0Hz, 1H), 7.25 (d, J=9.6Hz, 2H), 8.13 (s, 1H).
Step 86c:2-(((2-(3,4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae] mix oxygen piperazine-6-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-182)
Described compound 6-(6-(((5-(ethoxy carbonyl) pyrimidine-2-base) (methyl) amino) methyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-2-base)-2,3-dihydrobenzo [b] [1,4] assorted oxygen piperazine-4-carboxylic acid tert-butyl ester is (250 milligrams, 58%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (300 milligrams of 0504-54,0.668 milli rubs), (290 milligrams of 0602-182,0.802 milli rubs), (168 milligrams of sodium bicarbonates, 2.00 milli rubs), (23 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.0334 milli rubs) at ethanol (2.3 milliliters), the solution that forms in toluene (4 milliliters) and the water (1 milliliter) prepares.LCMS:648[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (t, J=6.8Hz, 3H), 1.52 (s, 9H), (3.26 s, 3H), 3.75 (m, 4H), 3.83 (m, 2H), 3.92 (m, 4H), 4.28 (m, 4H), (5.23 s, 2H), 6.93 (d, J=8.4Hz, 1H), (7.45 s, 1H), 8.02 (d, J=8.8Hz, 1H), (8.80 s, 1H), 8.88 (s, 2H).
Add trifluoroacetic acid (2.5 milliliters) in the dichloromethane solution (25 milliliters) of the compound of above-mentioned preparation (250 milligrams, 0.386 milli rubs) and at room temperature to its stirring of spending the night.Utilize ethyl acetate (100 milliliters) that described mixed liquor is diluted and utilize saturated sodium bicarbonate aqueous solution (50 milliliters), water (100 milliliters) and salt solution (50 milliliters) that it is washed, carry out drying by sodium sulphate, concentrated, thereby obtain a kind of 0603-182 (200 milligrams, 95%) of yellow solid form.LCMS:548[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (t, J=7.2Hz, 3H), 3.26 (s, 3H), 3.30 (m, 2H), 3.75 (m, 4H), 3.89 (m, 4H), 4.17 (m, 2H), 4.28 (q, J=7.2Hz, 2H), 5.22 (s, 2H), 5.92 (s, 1H), 6.70 (d, J=8.4Hz, 1H), 7.42 (s, 1H), 7.56 (d, J=10.0Hz, 1H), 7.68 (s, 1H), 8.88 (s, 2H).
Step 86d:2-(((2-(3,4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae] mix oxygen piperazine-6-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 182)
(72 milligrams of described title compounds 182,37%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (10 milliliters) that is the azanol by 0603-182 (200 milligrams, 0.365 milli rub) and fresh preparation prepares.Fusing point: 170-183 ℃.LCMS:535[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.23 (s, 3H), 3.30 (m, 2H), 3.75 (m, 4H), 3.89 (m, 4H), 4.17 (m, 2H), (5.19 s, 2H), 5.91 (s, 1H), 6.70 (d, J=8.0Hz, 1H), 7.40 (s, 1H), 7.57 (d, J=8.0Hz, 1H), 7.68 (s, 1H), 8.75 (s, 2H), 9.07 (s, 1H), 11.01 (s, 1H).
Embodiment 87:2-(((2-(1H-benzo [d] imidazoles-5-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-the N-hydroxypyrimidine-5-carboxamides The preparation of (compound 187)
Step 87a:5-bromo-1H-benzo [d] imidazoles-1-carboxylic acid tert-butyl ester (compound 0601-187)
To 4-bromobenzene-1, add trimethyl orthoformate (44 milliliters) and concentrated hydrochloric acid (1.5 milliliters) in dimethyl formamide (DMF) solution (22 milliliters) of 2-diamines (3 grams, 16 millis rub) and at room temperature described mixed liquor is carried out 1 hour stirring.Utilize water (200 milliliters) that described mixed liquor is diluted and utilize saturated sodium bicarbonate aqueous solution that pH is adjusted to 7, utilize ethyl acetate (200 milliliters) that it is extracted.Described organic layer is carried out drying by sodium sulphate, concentrated, thus obtain a kind of 5-bromo-1H-benzo [d] imidazoles (3.25 grams, 100%) of pale solid form.LCMS:197[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 7.33 (t, J=8.8Hz, 1H), 7.55 (dd, J1=7.6Hz, J=40Hz, 1H), 7.79 (d, J=47.2Hz, 1H), 8.26 (s, 1H), 12.61 (d, J=25.6Hz, 1H).
5-bromo-1H-benzo [d] imidazoles (3.25 grams to above-mentioned preparation, 22.1 milli rubs) oxolane (THF) solution (65 milliliters) in add di-tert-butyl dicarbonate (5.79 grams, 26.5 milli rubs), triethylamine (3.35 grams, 33.15 milli rubs) and dimethylamino naphthyridine (DMAP) (270 milligrams, 2.21 millis rub).At room temperature described mixed liquor is carried out 4 hours stirring, utilize water (200 milliliters) that it is diluted, utilize ethyl acetate (200 milliliters) to extract.Utilize water (2x100 milliliter) and salt solution (100 milliliters) that described organic layer is washed, carry out drying by sodium sulphate, concentrate, thereby obtain a kind of 0601-187 (4.8 grams, 98%) of oil form.LCMS:241[M-55] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.65 (s, 9H), 7.57 (dd, J 1=8.4Hz, J 2=20Hz, 1H), 7.73 (d, J=8.4Hz, 1H), 7.88 (d, J=9.2Hz, 1H), 8.03 (d, J=35.6Hz, 1H), 8.70 (d, J=8.0Hz, 1H).
Step 87b:5-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl)-1H-benzo [d] imidazoles-1-carboxylic acid tert-butyl ester (compound 0602-187)
Described title compound 0602-187 (0.94 gram, 81%) be by using a kind of a kind of colourless oil with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by 0601-187 (1 gram, 3.37 milli rubs), connection boric acid pinacol ester (1.28 grams, 5.05 milli rubs), (82 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.101 milli rubs) and potassium acetate (991 milligrams, 10.1 milli rub) prepare.LCMS:289[M-55] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.32 (s, 12H), 1.65 (s, 9H), 7.65 (d, J=7.2Hz, 0.5H), 7.74 (t, J=8.4Hz, 1H), 7.97 (d, J=8.4Hz, 1H), 8.37 (s, 0.5H), 8.69 (d, J=18.8Hz, 1H).
Step 87c:2-(((2-(1H-benzo [d] imidazoles-5-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-187)
(260 milligrams of described compound 0603-187,62%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (300 milligrams of 0504-54,0.668 milli rubs), (276 milligrams of 0602-187,0.8 milli rubs), (168 milligrams of sodium bicarbonates, 2.00 milli rubs), (23 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.0334 milli rubs) at ethanol (2.3 milliliters), the solution that forms in toluene (4 milliliters) and the water (1 milliliter) prepares.LCMS:531[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (t, J=7.2Hz, 3H), 3.28 (s, 3H), (3.78 m, 4H), 3.95 (m, 4H), 4.29 (q, J=6.8Hz, 2H), 5.24 (s, 2H), 7.50 (s, 1H), 7.65 (d, J=8.0Hz, 1H), (8.32 m, 2H), 8.64 (s, 1H), (8.88 s, 2H), 12.59 (s, 1H).
Step 87d:2-(((2-(1H-benzo [d] imidazoles-5-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) (methyl) amino)-N-hydroxypyrimidine-5-carboxamides (compound 187)
(34 milligrams of described title compounds 187,13%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (10 milliliters) that is the azanol by 0603-187 (260 milligrams, 0.49 milli rub) and fresh preparation prepares.Fusing point: 231-239 ℃.LCMS:518[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.25 (s, 3H), 3.79 (m, 4H), 3.95 (m, 4H), 5.21 (s, 2H), 7.48 (s, 1H), 7.65 (dd, J 1=8.4Hz, J 2=47.2Hz, 1H), 8.31 (m, 2H), 8.64 (d, J=44.8Hz, 1H), 8.76 (s, 2H), 9.09 (s, 1H), 11.03 (s, 1H), 12.59 (s, 1H).
Embodiment 88:N-hydroxyl-2-(methyl ((2-(2-methyl-3H-benzo [d] imidazoles -5-yl)-and 4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5- The preparation of formamide (compound 199)
Step 88a:N, N '-(4-bromo-1,2-phenyl) diacetayl amide (compound 0601-199)
Under 0 ℃; to 4-bromobenzene-1,2-diamines (1.87 grams, 10 millis rub) and triethylamine (10.1 grams; 100 millis rub) dichloromethane solution (20 milliliters) among add acetyl group chlorine (1.73 grams, 22 millis rub) and under 30 ℃, it carried out 2 hours stirring.Described mixed liquor is concentrated and described residue is dissolved among the carrene, utilize water to wash, carry out drying by sodium sulphate, concentrated, thus obtain a kind of 0601-199 (1.4 grams, 52%) of yellow solid form.LCMS:271[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 2.08 (d, J=3.2Hz, 6H), 7.28 (m, 1H), 7.50 (d, J=8.8Hz, 1H), 7.83 (s, 1H), 9.38 (d, J=3.2Hz, 2H).
Step 88b:N, N '-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl)-1,2-phenyl) diacetayl amide (compound 0602-199)
Described title compound 0602-199 (1.0 grams, 63%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by 0601-199 (1.4 grams, 5.2 milli rubs), connection boric acid pinacol ester (2.0 grams, 7.8 milli rubs), (425 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.52 milli rubs) and potassium acetate (1.53 grams, 15.6 millis rub) prepare.LCMS:319[M+1] +, 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.28 (s, 12H), 2.07 (d, J=6.0Hz, 6H), 7.41 (d, J=8.0Hz, 1H), 7.70 (d, J=8.4Hz, 1H), 7.79 (s, 1H), 9.36 (d, J=9.6Hz, 2H).
Step 88c:2-(methyl ((2-(2-methyl-3H-benzo [d] imidazoles-5-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-199)
(((2-(3 for described compound 2-; 4-diacetyl phenyl)-4-morpholine thiophene a pair of horses going side by side [3; 2-d] pyrimidine-6-yl) methyl) (methyl) amino) (260 milligrams of pyrimidine-5-carboxylic acid's ethyl esters; 75%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107; by (261 milligrams of 0504-54; 0.58 milli rubs); (240 milligrams of 0602-199; 0.75 milli rubs); (147 milligrams of sodium bicarbonates; 1.8 milli rubs); (41 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides (II); 0.058 milli rubs) at toluene (4 milliliters), the solution that forms in ethanol (2 milliliters) and the water (0.5 milliliter) prepares.LCMS:605[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.30 (m, 3H), 2.11 (s, 6H), 3.27 (s, 3H), 3.76 (m, 4H), 3.92 (m, 4H), (4.30 m, 2H), 5.24 (s, 2H), (7.48 m, 1H), 7.76 (m, 1H), (8.15 m, 1H), 8.50 (m, 1H), (8.88 m, 2H), 8.45 (m, 2H).
Add the hydrochloric acid (12 milliliters) of 6M in oxolane (THF) solution (8 milliliters) of the compound of above-mentioned preparation (360 milligrams, 0.6 milli rubs) and under 40 ℃, it is carried out 10 hours stirring.Under 0 ℃, utilize saturated aqueous sodium carbonate that the pH of described mixed liquor is adjusted to 8, utilize ethyl acetate that it is extracted.Described organic layer is carried out drying, concentrated and (be present in the methyl alcohol among the carrene by column chromatography on the silica gel, the 2-5 volume/volume) it is carried out purifying, thereby obtain a kind of title compound 0603-199 (160 milligrams, 50%) of white solid form.LC-MS:545[M+1] +. 1H NMR (400 megahertzes, deuterochloroform). δ 1.38 (t, J=6.8Hz, 3H), 2.60 (s, 3H), 3.30 (s, 3H), 3.85 (m, 4H), (4.01 m, 4H), 4.36 (q, J=7.2Hz, 2H), (5.18 s, 2H), 7.38 (s, 1H), 7.60 (d, J=8.0Hz, 1H), 8.36 (d, J=8.4Hz, 1H), (8.67 s, 1H), 8.92 (s, 2H).
Step 88d:N-hydroxyl-2-(methyl ((2-(2-methyl-3H-benzo [d] imidazoles-5-yl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (compound 199)
(38 milligrams of described title compounds 199,24%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (20 milliliters) that is the azanol by 0603-199 (160 milligrams, 0.30 milli rub) and fresh preparation prepares.Fusing point: 230-233 ℃.LCMS:532[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 2.51 (s, 3H), 3.24 (s, 3H), 3.78 (m, 4H), 3.93 (m, 4H), 5.21 (s, 2H), (7.47 s, 1H), 7.50 (dd, J=42.8,8.4Hz, 1H), 8.25 (t, J=8.8Hz, 1H), 8.48 (d, J=42.8Hz, 1H), 8.76 (s, 2H), 9.09 (s, 1H), 11.00 (s, 1H), 12.33 (s, 1H).
Embodiment 89:N-hydroxyl-2-(methyl ((4-morpholinyl-2-(2-oxo-2,3- Dihydro-1H-benzo [d] imidazoles-5-yl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) ammonia Base) preparation of pyrimidine-5-formamide (compound 186)
Step 89a:5-bromo-1H-benzo [d] imidazoles-2 (3H)-ketone (compound 0601-186)
Under 40 ℃, to 4-bromobenzene-1,2-diamines (3.74 grams, 20 millis rub), N, the Isosorbide-5-Nitrae of N-carbonyl dimidazoles (CDI) (3.9 grams, 24 millis rub)-dioxane mixed liquor (20 milliliters) carries out 1 hour stirring.Filter and utilize benzinum and carrene that it is washed to described mixed liquor, thereby obtain a kind of compound 0601-186 (3.0 grams, 70%) of white solid form.LCMS:213[M+1] +, 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 6.86 (d, J=8.0Hz, 1H), 7.06 (m, 1H), 7.08 (m, 1H), 10.77 (s, 2H).
Step 89b:5-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl)-1H-benzo [d] imidazoles-2 (3H)-ketone (compound 0602-186)
(340 milligrams of described title compound 0602-186,21%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by 0601-186 (1.3 grams, 6 millis rub), connection boric acid pinacol ester (2.3 grams, 9 millis rub), (490 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.6 milli rubs) and potassium acetate (1.8 grams, 18 millis rub) prepare.LCMS:261[M+1] +, 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.27 (s, 12H), 6.91 (d, J=7.6Hz, 1H), 7.17 (s, 1H), 7.28 (d, J=7.6Hz, 1H), 10.65 (s, 1H), 10.77 (s, 1H).
Step 89c:2-(methyl ((4-morpholinyl-2-(2-oxo-2,3-dihydro-1H-benzo [d] imidazoles-5-yl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-186)
(214 milligrams of described compound 0603-186,68%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (261 milligrams of 0504-54,0.58 milli rubs), (197 milligrams of 0602-186,0.75 milli rubs), (147 milligrams of sodium bicarbonates, 1.8 milli rubs) and (41 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides (II), 0.058 milli rubs) at toluene (4 milliliters), the solution that forms in ethanol (2 milliliters) and the water (0.5 milliliter) prepares.LCMS:547[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6): δ 1.30 (t, J=6.8Hz, 3H), 3.27 (s, 3H), (3.77 m, 4H), 3.91 (m, 4H), 4.28 (q, J=6.8Hz, 2H), 5.23 (s, 2H), 6.99 (d, J=8.0Hz, 1H), 7.46 (s, 1H), 7.97 (s, 1H), 8.08 (d, J=9.2Hz, 1H), 8.88 (s, 2H), 10.71 (s, 1H), 10.80 (s, 1H).
Step 89d:N-hydroxyl-2-(methyl ((4-(morpholinyl-2-(2-oxo-2,3-dihydro-1H-benzo [d] imidazoles-5-yl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (compound 186)
(75 milligrams of described title compounds 186,36%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (20 milliliters) that is the azanol by 0603-186 (214 milligrams, 0.40 milli rub) and fresh preparation prepares.Fusing point: 272-275 ℃.LCMS:534[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 3.23 (s, 3H), 3.77 (m, 4H), (3.91 m, 4H), 5.20 (s, 2H), (7.00 d, J=8.0Hz, 1H), 7.44 (s, 1H), 7.98 (s, 1H), 8.09 (d, J=8.4Hz, 1H), 8.75 (s, 2H), (10.71 s, 1H), 10.82 (s, 1H).
Embodiment 90:N-hydroxyl-2-(methyl ((4-morpholinyl-2-(2-oxindole quinoline -5-yl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (is changed Compound 194) preparation
Step 90a:5-bromo indole quinoline-2-ketone (compound 0601-194)
To 5-bromo indole-2,3-diketone (2.25 grams, 10 millis rub) adds potassium hydroxide (1.68 grams, 30 millis rub) in the mixed liquor of ethylene glycol (45 milliliters) and hydrazine hydrate (1.06 grams, 21.10 millis rub).Under 80 ℃, described reaction mixture carried out 4 hours stirring.Described mixed liquor is cooled to room temperature and is poured onto it among frozen water and the hydrochloric acid that utilizes 12N is adjusted to 1-2 with the pH of described mixed liquor, and at room temperature described mixed liquor is carried out 12 hours stirring.Described mixed liquor is filtered and utilizes water (5 milliliters) that described solid is washed and carry out drying, thereby obtain described crude product, (be present in the methyl alcohol among the carrene by column chromatography on the silica gel, 0.5% volume/volume) described crude product is carried out purifying, thereby obtain a kind of 0601-194 (785 milligrams, 37%) of yellow solid form.LCMS:214[M+1] +. 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.51 (s, 2H), 6.76 (d, J=8.0Hz, 1H), 7.34 (dd, J=8.0,2.0Hz, 1H), 7.38 (m, 1H), 10.49 (s, 1H).
Step 90b:5-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl) indole-2-ketone (compound 0602-194)
(323 milligrams of described title compound 0602-194,83%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by (317 milligrams of 0601-194,1.5 milli rubs), (572 milligrams of connection boric acid pinacol esters, 2.25 milli rubs), (126 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.15 milli rubs) and potassium acetate (441 milligrams, 4.5 milli rub) prepare.LCMS:260[M+1] +. 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.27 (s, 12H), 3.46 (s, 2H), 6.81 (d, J=8.0Hz, 1H), 7.50 (m, 2H), 10.54 (s, 1H).
Step 90c:2-(methyl ((4-morpholinyl-2-(2-oxindole quinoline-5-yl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-194)
(350 milligrams of described title compounds 194,80%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (358 milligrams of 0504-54,0.80 milli rubs), (207 milligrams of 0602-194,0.80 milli rubs), (522 milligrams of cesium carbonates, 1.60 milli rubs) and (65 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.08 milli rubs) solution of formation in Isosorbide-5-Nitrae-dioxane (6 milliliters) and the water (0.2 milliliter) prepares.LCMS:546[M+1] +. 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (t, J=7.2Hz, 3H), 3.27 (s, 3H), (3.57 m, 2H), 3.76 (m, 4H), 3.91 (m, 4H), 4.29 (q, J=7.2Hz, 2H), 5.23 (s, 2H), 6.90 (d, J=8.4Hz, 1H), (7.44 s, 1H), 8.28 (m, 2H), (8.88 s, 2H), 10.59 (s, 1H).
Step 90d:N-hydroxyl-2-(methyl ((4-(morpholinyl-2-(2-oxindole quinoline-5-yl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (compound 194)
(85 milligrams of described title compounds 194,25%) be by using a kind of solid of a kind of white with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (7.5 milliliters) that is the azanol by 0603-194 (350 milligrams, 0.64 milli rub) and fresh preparation prepares.Fusing point: 270 ℃.LCMS:533[M+1] +. 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.24 (s, 3H), 3.57 (s, 2H), 3.77 (m, 4H), 3.91 (m, 4H), 5.20 (s, 2H), 6.90 (m, 1H), 7.42 (m, 1H), (8.26 m, 2H), 8.76 (s, 2H), 10.52 (s, 1H).
Embodiment 91:N-hydroxyl-2-(methyl ((4-morpholinyl-2-(1H-pyrazoles-4-yl) Thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (compound 196) preparation
Step 91a:4-(4,4,5,5-tetramethyl-1,3,2-dioxa pentaborane-2-yl)-1H-pyrazoles (compound 0602-196)
(400 milligrams of described title compound 0602-196,30%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0602-107, by 4-bromine pyrazoles (1 gram, 6.8 milli rubs), connection boric acid pinacol ester (2.6 grams, 10.2 milli rubs), (166 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.2 milli rubs) and potassium acetate (gram, 20.4 milli rub) prepare.LCMS:195[M+1] + 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6). δ 1.25 (s, 12H), 7.93 (s, 2H), 13.09 (s, 1H).
Step 91b:2-(methyl ((4-morpholinyl-2-(2-(1H-pyrazoles-4-yl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-196)
(150 milligrams of described compound 0603-196,47%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (300 milligrams of 0504-54,0.67 milli rubs), (259 milligrams of 0602-196,1.33 milli rubs), (168 milligrams of sodium bicarbonates, 2.0 milli rubs), (23 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides (II), 0.03 milli rubs) at toluene (5 milliliters), the solution that forms in ethanol (3 milliliters) and the water (1.3 milliliters) prepares.LCMS:481[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.30 (t, J=6.8Hz, 3H), 3.26 (s, 3H), 3.73 (m, 4H), 3.88 (m, 4H), 4.28 (q, J=7.6Hz, 2H), (5.21 s, 2H), 7.38 (s, 1H), (8.04 s, 1H), 8.30 (s, 1H), (8.88 s, 2H), 13.07 (s, 1H).
Step 91c:N-hydroxyl-2-(methyl ((4-(morpholinyl-2-(1H-indazole-4-yl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (compound 196)
(59 milligrams of described title compounds 196,41%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (8 milliliters) that is the azanol by 0603-196 (150 milligrams, 0.31 milli rub) and fresh preparation prepares.Fusing point: 214-217 ℃.LCMS:468[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.23 (s, 3H), 3.73 (m, 4H), (3.87 m, 4H), 5.18 (s, 2H), (7.35 s, 1H), 8.05 (s, 1H), (8.30 s, 1H), 8.74 (s, 2H), (9.07 s, 1H), 11.11 (s, 1H), 13.07 (s, 1H).
Embodiment 92:N-hydroxyl-2-(methyl ((4-morpholinyl-2-(1H-pyrroles-3-yl) Thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (compound 197) preparation
Step 92a:3-bromo-1-(triisopropyl silicyl)-1H-pyrroles (compound 0601-197)
Under nitrogen environment, under-78 ℃ to oxolane (THF) solution (2.5M of n-BuLi, 19.6 milliliter, 49 millis rub) in add the agitating solution be present in the pyrroles's (3 grams, 44.7 millis rub) among the anhydrous tetrahydro furan (THF) (20 milliliters).After this described mixed liquor is warming up to room temperature and under this temperature, it is carried out 10 minutes stirring.Described mixed liquor is cooled to-78 ℃ again, and stirs to dropwise adding tri isopropyl silane chlorine (10.5 grams, 44.7 millis rub) simultaneous wherein.After this described mixed liquor is warming up to room temperature and carries out again 30 minutes stirring, utilize water (200 milliliters) that it is diluted, utilize ether (200 milliliters) that it is extracted.Utilize water (2x100 milliliter) and salt solution (100 milliliters) that described organic layer is washed, carry out drying by sodium sulphate, concentrated, thus a kind of thick 1-(triisopropyl silicyl) of oil form-1H-pyrroles's (11 grams, 100%) obtained.LCMS:224[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 0.98 (m, 18H), 1.40 (m3H), 6.20 (m, 2H), 6.80 (m, 2H).
Under-78 ℃, to the above-mentioned 1-for preparing (triisopropyl silicyl)-1H-pyrroles (5.85 grams, 26.2 milli rubs) oxolane (THF) solution (50 milliliters) among add N-bromosuccinimide (NBS) (4.66 grams, 26.2 millis rub) and under-78 ℃, mixed liquor obtained above carried out 2 hours stirring.Described mixed liquor is warming up to room temperature and again it is carried out 1 hour stirring.Described mixed liquor is concentrated and by column chromatography (oil) on silica gel it carried out purifying, thereby obtain a kind of compound 0601-197 (6.8 grams, 63%) of colourless oil form.LCMS:302[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 0.98 (m, 18H), 1.47 (m3H), 6.26 (d, J=6.0Hz, 1H), 6.82 (m, 1H), 6.89 (m, 1H).
Step 92b:1-(triisopropyl silicyl)-1H-pyrroles-3-ylboronic acid (compound 0602-197)
Under nitrogen environment, under-78 ℃ to oxolane (THF) solution (2.5M of n-BuLi, 1.58 milliliter, 3.96 millis rub) in add the agitating solution be present in the 0601-197 (1 gram, 3.31 millis rub) among the anhydrous tetrahydro furan (THF) (20 milliliters).Under this temperature, mixed liquor obtained above carried out 30 minutes stirring.Dropwise adding trimethyl boric acid (687 milligrams, 6.6 millis rub) in the described mixed liquor.After this described mixed liquor is warming up to room temperature and again it is carried out 1 hour stirring.Utilize water (200 milliliters) that described mixed liquor is diluted, utilize ethyl acetate (200 milliliters) that it is extracted.Utilize water (2x100 milliliter) and salt solution (100 milliliters) that described organic layer is washed, carry out drying by sodium sulphate, concentrated, thereby obtain a kind of (280 milligrams of crude compound 0602-197 of oil form, 32%), described oil need not to carry out further purifying and can be used directly in the following step.LCMS：268[M+1] +.
Step 92c:2-(methyl ((4-morpholinyl-2-(2-(1H-pyrroles-3-yl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-197)
(260 milligrams of described compound 0603-197,81%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (300 milligrams of 0504-54,0.67 milli rubs), 0602-197 (0.8 gram), (168 milligrams of sodium bicarbonates, 2.0 milli rubs), (23 milligrams of two (Diphenyl phosphino ferrocene) palladium chlorides, 0.03 milli rubs) at toluene (5 milliliters), the solution that forms in ethanol (3 milliliters) and the water (1 milliliter) prepares.LCMS:480[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.28 (t, J=7.2Hz, 3H), 3.24 (s, 3H), (3.71 m, 4H), 3.84 (m, 4H), 4.27 (q, J=7.2Hz, 2H), 5.18 (s, 2H), (6.65 s, 1H), 6.77 (s, 1H), (7.33 s, 1H), 7.47 (s, 1H), (8.86 s, 2H), 11.07 (s, 1H).
Step 92d:N-hydroxyl-2-(methyl ((4-(morpholinyl-2-(1H-pyrroles-3-yl) thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methyl) amino) pyrimidine-5-formamide (compound 197)
(63 milligrams of described title compounds 197,25%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (10 milliliters) that is the azanol by 0603-197 (260 milligrams, 0.54 milli rub) and fresh preparation prepares.Fusing point: 175-189 ℃.LCMS:467[M+1] +. 1HNMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.21 (s, 3H), 3.72 (m, 4H), (3.83 m, 4H), 5.15 (s, 2H), (6.65 s, 1H), 6.75 (s, 1H), (7.30 s, 1H), 7.46 (s, 1H), (8.73 m, 2H), 9.05 (s, 1H), (11.05 s, 1H), 11.11 (s, 1H).
Embodiment 93:2-((2-(4-aminophenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine -6-yl) methylamino)-preparation of N-hydroxypyrimidine-5-carboxamides (compound 211)
Step 93a:2-((2-(4-(aminophenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino) pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-211)
(65 milligrams of described title compound 0603-211,22%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 34) of describing compound 0603-107, by (256 milligrams of 0504-53,0.59 milli rubs), 4-(4,4,5,5-tetramethyl-1,3,2 dioxas pentaborane-2-yl) aniline is (155 milligrams, 0.71 milli rubs), (48 milligrams of cesium carbonate (577 milligrams, 1.77 millis rub) and two (Diphenyl phosphino ferrocene) palladium chlorides, 0.06 milli rubs) solution of formation in Isosorbide-5-Nitrae-dioxane (6 milliliters) and the water (0.2 milliliter) prepares.LCMS:492[M+1] +. 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 1.29 (t, J=7.2Hz, 3H), 3.75 (m, 4H), 3.89 (m, 4H), 4.27 (q, J=7.2Hz, 2H), 4.87 (d, J=6.0Hz, 2H), 5.53 (s, 2H), 6.60 (m, 2H), 7.28 (s, 1H), 8.09 (m, 2H), 8.83 (m, 3H).
Step 93d:2-((2-(4-aminophenyl)-4-morpholine thiophene a pair of horses going side by side [3,2-d] pyrimidine-6-yl) methylamino)-N-hydroxypyrimidine-5-carboxamides (compound 211)
(28 milligrams of described title compounds 211,45%) be by using a kind of solid of a kind of yellow with preparing for the similar step of the step (embodiment 1) of describing compound 3, the methanol solution (6 milliliters) that is the azanol by 0603-211 (65 milligrams, 0.13 milli rub) and fresh preparation prepares.Fusing point: 217-223 ℃.LCMS:479[M+1] +. 1H-NMR (400 megahertzes, dimethyl sulfoxide (DMSO)-d 6) δ 3.76 (m, 4H), 3.89 (m, 4H), (4.84 d, J=5.6Hz, 2H), 5.53 (s, 2H), 6.60 (m, 2H), 7.27 (s, 1H), 8.90 (m, 2H), 8.51 (t, J=5.6Hz, 1H), 8.66 (s, 2H), (9.05 s, 1H), 11.09 (s, 1H).
Embodiment 94:(E)-3-(4-(N-(2-(2-Aminometradine-5-yl)-4-morpholine Base thiophene [3,2-d] pyrimidine-6-yl) sulfonamide) phenyl)-(change of N-hydroxyacrylamide Compound 217)
Step 94a:7-bromo thiophene [3,2-d] pyrimidine-2,4 (1H, 3H)-diketone (compound 1001)
At ambient temperature, in the solution of compound 0109 (10 grams, 0.059 mole) in acetic acid (166 milliliters), add bromine (9.1 milliliters, 178 mMs).After the adding, reaction is heated to 70 ℃ and stir and to spend the night.Reactant mixture is cooled to room temperature, and injects ice-water (1L).Filtration gained mixture also washes with water.With Solid Suspension at saturated Na 2S 2O 3Stirred 30 minutes in the solution and after filtering.Water and saturated NaHCO3 solution washing solid, dry in a vacuum, 1001 (14.6 restrain 87%) that produce the yellow solid shape.LCMS:247.0[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 8.22 (s, 1H), 11.40 (s, 1H), 11.51 (s, 1H).
Step 94b:7-bromo-2,4-dichloro-thiophene [3,2-d] pyrimidine (compound 1002)
With compound 1001 (12.8 gram, 51 mMs) at POCl 3Mixture in (150 milliliters) added hot reflux 12 hours.Remove in a vacuum excessive POCl 3, residue is injected the ice of crushing, filter the title compound 1002 that produces the yellow solid shape.(11.8g, 80.2%) .LCMS:284.8[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 8.86 (s, 1H).
Step 94c:4-(7-bromo-2 chloro thiophene [3,2-d] pyrimidine-4-yl) morpholinyl (compound 1003)
At ambient temperature, compound 1002 (11.8 grams, 41.5 mMs) is suspended in the methyl alcohol (150 milliliters).Add morpholine (11.2 milliliters, 124.5 mMs).Stirred at ambient temperature the gained mixture 2 hours, subsequent filtration.Water, methanol wash solid, and dry under vacuum condition, the compound 1003 of generation yellow solid shape.(11.5g, 82.7%) .LCMS:336.0[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.77 (t, J=5.2Hz, 4H), 3.92 (t, J=5.2Hz, 4H), 8.52 (s, 1H).
Step 94d:4-(7-bromo-2 chloros-6-nitrothiophene [3,2-d] pyrimidine-4-yl)-morpholinyl (compound 1004)
Under 0 ℃, to concentrated H 2SO 4Portions adds compound 1003 (11.5 grams, 34.3 mMs) in (35 milliliters).Then under 0 ℃, within 15-30 minute time, dropwise add the HNO of aerosolization in the mentioned solution 3(9 milliliters, 206 mMs).Under 0 ℃ of condition, stir the gained mixture 2 hours, inject subsequently the ice of crushing.Filter the gained mixture, wash with water and dry in a vacuum, produce 1004 (12.0 grams, 90.0%) of yellow solid shape.LCMS:371.0[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.78 (t, J=5.2Hz, 4H), 3.94 (t, J=5.2Hz, 4H).
Step 94e:2-chloro-4-morpholinyl thiophene [3,2-d] pyrimidine-6-amine (compound 1005)
(12.0 grams of agitate compounds 1004 under 50 ℃ of conditions, 31.5 mM), glass putty (11.0 gram, 94.7 mMs) and the mixture of HCl (31.6 milliliters) in methyl alcohol (350 milliliters) that concentrate 1 hour are until they become limpid solution.In solution, add more glass putty (7.6 grams, 65.4 mMs) and concentrated hydrochloric acid (25 milliliters), then under 50 ℃ of conditions, stir the gained mixture whole night.Reactant mixture is cooled to room temperature and filters generation light yellow solid (4.0 grams, 47%).LCMS:271.0[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.69 (s, 8H), 5.94 (s, 1H), 7.15 (s, 2H).
Step 94f:(E)-M ethyl 3-(4-(N-(2-chloro-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) sulfonamide) phenyl) acrylate (compound 1007-217)
In 1006-217 (300 milligrams, 1.11 mMs) and 1005 (400 milligrams, 1.56 mMs) mixture in oxolane (30 milliliters), add NaH (300 milligrams, 12.5 mMs).Stirred reaction mixture is 3 hours at ambient temperature.Concentrated reaction mixture.Add entry in the described mixture and stirred 30 minutes.With also filtering with the gained mixture among the HOAc.The dissolution of solid collected in methyl alcohol (20 milliliters), is added H2SO4 (5).With reaction mixture refluxed 3 hours and concentrated.Water (20 milliliters) is processed residue and is filtered.The gained solid is produced title compound 1007-217 (250 milligrams, 46%) by water washing and dry.The gained compound does not just need to be further purified and can use in the reaction of next step.
Step 94g:(E)-M ethyl 3-(4-(N-(2-(2-Aminometradine-5-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) sulfonamide) phenyl) acrylate (compound 1008-217)
At 130 ℃, stir 1007-217 (250 milligrams, 0.516 mole), 5-(4 under the condition of nitrogen gas, 4,5,5-tetramethyl-1,3,2-, two assorted pentaborane-2-yls) pyrimidine-2-amine (0602-217) (200 milligrams, 1.43 mMs), saturated NaHCO 3(2 milliliters) and Pd (PPh 3) 4(50 milligrams) mixture in dimethyl sulfoxide (DMSO) (15 milliliters).In reactant mixture, add entry, and neutralize with acetic acid.Filter the collecting precipitation thing.Use column chromatography to purify semifinished product, produce the title compound 1008-217 (160 milligrams, 57.3%) of yellow solid shape. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.73 (s, 3H), 3.76 (s, 4H), 3.95 (s, 4H), 6.71 (d, J=16.0Hz, 1H), 7.4 (br, 2H), 7.66 (d, J=16.0Hz, 1H), 7.82 (br, 4H), 8.99 (s, 2H).
Step 94h:(E)-3-(4-(N-(2-(2-Aminometradine-5-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) sulfonamide) phenyl)-N-hydroxyacrylamide (compound 217)
The solution of mixture in CH2Cl2 (5 milliliters) of the NH2OH that under 0 ℃ of condition, stirs 1008-217 (150 milligrams) and just prepared (8 milliliters, concentration is 1.79M in methyl alcohol) 2 hours.The pH value of the water-based HCl conditioned reaction mixture of use 1.2M is to 6-7, and filtration.Use preparative high performance liquid chromatography to purify filter cake, produce the title compound 94 (70 milligrams, 57.3%) of yellow solid shape.M.p.＞300 ℃ .LCMS:555[M+1]+. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.75 (s, 3H), 3.92 (s, 4H), 6.30 (br, 1H), 6.51 (d, J=16.0Hz, 1H), 7.30 (br, 1H), 7.45 (d, J=16.0Hz, 2H), (7.66 d, J=7.6Hz, 2H), 7.81 (d, J=8.0Hz, 2H), 8.99 (s, 2H), (9.08 s, 1H), 10.82 (s, 1H).
Embodiment 95:(E)-3-(3-(N-(2-(2-Aminometradine-5-yl)-4-morpholine Base thiophene [3,2-d] pyrimidine-6-yl) sulfonamide) phenyl)-(change of N-hydroxyacrylamide Compound 218)
Step 95a:(E)-M ethyl 3-(3-(chloro sulphonyl) phenyl) acrylate (1006-218)
To 3-nitro-benzaldehyde (15 grams, 0.1 mole), add NaOMe (10.7 grams, 0.198 mole) in the solution of (dimethoxy-phosphoryl) methyl acetate (27 grams, 0.148 mole) in dimethyl formamide (100 milliliters).With thin-layer chromatography monitoring reaction.After reaction is finished, use the HCl aqueous solution that pH is adjusted to 1, and evaporation.Wash the gained solid with water, produce (E)-methyl 3-(3-nitrobenzene) acrylate (20.14 grams, 98%) of yellow solid shape.
(E)-methyl 3-(3-nitrobenzophenone) acrylate (20.14 grams, 0.097 mole), Fe (32.5 grams, 0.58 mole), the concentrated solution of HCl (3.5 milliliters) in 50% ethyl acetate were refluxed 2 hours.After finishing, wash by diatomite filtration solution and with ethanol.Collect filtrate and extract with carrene.Organic facies with the dried over mgso combination is also concentrated, produces (E)-methyl 3-(3-aminophenyl) acrylate (9.73 grams, 57%) of yellow solid shape.
In the solution of (E)-methyl 3-(3-aminophenyl) acrylate (11.55 grams, 0.065 mole) in acetic acid (13 milliliters), add concentrated hydrochloric acid (45 milliliters).By ethanol/dry ice ice bath the gained mixture is cooled to-10 ℃.Dropwise add NaNO2 solution (in 7.2 ml waters, have 5 gram), add speed for not making internal temperature surpass-5 ℃, thus formation diazo-reaction solution.Under HOAc (65 milliliters) liquid level, introduce SO2 (gram) until obviously saturated.Add CuCl (1.7 gram) in the gained solution and continue to pass into SO2 until the yellow green suspension becomes blue-green, then be cooled to 0 ℃.In reactant mixture, add the diazotising solution that portions prepares above adding, and sustained response 30 minutes.Extract with reactant mixture injection ice and with carrene.Use column chromatography to purify semifinished product, produce the 1006-218 of yellow solid shape. 1HNMR(400MHz，CDCl 3)：δ3.84(s，3H)，6.57(d，J＝16Hz，1H)，7.66(t，J＝8.0Hz，1H)，7.72(d，J＝16Hz，1H)，7.85(d，J＝7.6Hz，1H)，8.04(d，J＝8.0Hz，1H)，8.16(s，1H).
Step 95b:(E)-M ethyl 3-(3-(N-(2-chloro-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) sulfonamide) phenyl) acrylate (compound 1007-218)
In 1006-218 (300 milligrams, 1.11 mMs) and 1005 (400 milligrams, 1.56 mMs) mixture in oxolane (30 milliliters), add NaH (300 milligrams, 12.5 mMs).Stirred reaction mixture is 3 hours at ambient temperature.Concentrated reaction mixture.Add entry in the described mixture and stirred 30 minutes.With also filtering with the gained mixture among the HOAc.The dissolution of solid collected in methyl alcohol (20 milliliters), is added H2SO4 (5).With reaction mixture refluxed 3 hours and concentrated.Water (20 milliliters) is processed residue and is filtered.The gained solid is produced the title compound 1007-218 (320 milligrams, 58%) of yellow solid shape by water washing and dry.
1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.70-3.79 (m, 11H), 6.67 (s, 1H), (6.72 d, 16.0Hz, 1H), 7.66 (t, J=6.0Hz, 1H), 7.74 (d, J=16.0Hz, 1H), 7.88 (d, J=8.4Hz, 1H), 8.04 (d, J=8.0Hz, 1H), 8.17 (s, 1H).
Step 95c:(E)-M ethyl 3-(3-(N-(2-(2-Aminometradine-5-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) sulfonamide) phenyl) acrylate (compound 1008-218)
The similar process (embodiment 94) that uses when using with description compound 1008-217, from (300 milligrams of 1007-218,0.6 mole), 5-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) pyrimidine-2-amine (0602-217) (300 milligrams, 2.16 mMs), saturated NaHCO 3(2 milliliters) and Pd (PPh 3) 4The title compound 1008-218 of preparation yellow solid shape in (50 milligrams) solution in dimethyl sulfoxide (DMSO) (10 milliliters): 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.79-3.83 (m, 7H), 4.01 (s, 4H), (6.40 br, 1H), 6.72 (d, J=16.0Hz, 1H), 7.42 (br, 2H), 7.62 (t, J=7.6Hz, 1H), 7.78 (d, J=16.0Hz, 1H), 7.88-7.98 (m, 3H), 8.13 (s, 1H), 9.03 (s, 2H).
Step 95d:(E)-3-(3-(N-(2-(2-Aminometradine-5-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) sulfonamide) phenyl)-N-hydroxyacrylamide (compound 218)
The similar method (embodiment 94) of using during according to description compound 217, the title compound 218 (83 milligrams) of preparation faint yellow solid shape from the hydroxylamine methanol solution (10 milliliters) of 1008-218 (150 milligrams) and fresh preparation: M.p.:＞300 ℃ of .LCMS:555[M+1] +. 1HNMR:(400MHz, dimethyl sulfoxide (DMSO)-d 6): δ .3.75 (s, 4H), 3.95 (s, 4H), 6.13 (br, 1H), 6.55 (d, J=16.0Hz, 1H), 7.47-7.55 (m, 3H), 7.70-7.79 (m, 2H), 7.98 (s, 1H), 9.00 (s, 2H), 9.15 (s, 1H), 10.15 (br, 1H), 10.81 (s, 1H), 13,4 (br, 1H).
Embodiment 96:(E)-N-hydroxyl-3-(3-(N-(2-(6-methoxypyridine-3- Base)-and 4-morpholine thiophene [3,2-d] pyrimidine-6-yl) sulfonamide) phenyl) acrylamide (change Compound 221)
Step 96a:(E)-M ethyl 3-(3-(N-(2-(6-methoxypyridine-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) sulfonamide) phenyl) acrylate (compound 1008-221)
Add Pd (PPh in 1007-218 (300 milligrams, 0.61 mM) after stir and the mixture of 0602-221 (287 milligrams, 1.22 mMs) in dimethyl sulfoxide (DMSO) (20 milliliters) 3) 4(36.7 milligrams, 0.032 mM) and saturated NaHCO 3The aqueous solution (2 milliliters).The gained mixture is heated to 120 ℃ and kept 4 hours.The pH value that adds entry in the reactant mixture and use acetic acid conditioned reaction mixture is to 6-7.Filter the collecting precipitation thing.Use column chromatography to purify semifinished product, produce the title compound 1008-221 (250 milligrams, productive rate 72%) of yellow solid shape.
1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.71 (s, 3H), 3.76 (t, J=4.4Hz, 4H), (3.92-3.98 m, 7H), 6.68 (d, J=16.0Hz, 1H), (6.97 d, J=8.8Hz, 1H), 7.52-7.60 (m, 2H), (7.73 d, J=16.0Hz, 1H), 7.85 (d, J=8.0Hz, 1H), 7.94 (d, J=5.4Hz, 1H), 8.10 (s, 1H), 8.43-8.46 (m, 1H), 9.02 (s, 1H).
Step 96b:(E)-N-hydroxyl-3-(3-(N-(2-(6-methoxypyridine-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) sulfonamide) phenyl) acrylamide (compound 221)
The similar method (embodiment 94) of using during according to description compound 217, from (150 milligrams of 1008-221,0.264 mM) and (10 milliliters of the hydroxylamine methanol solutions of fresh preparation, concentration is 1.79M in methyl alcohol) the middle title compound (70 milligrams, productive rate 46%) for preparing white look solid shape: M.p.:＞300 ℃ of .LCMS:569.2[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.77 (s, 4H), 3.94 (s, 7H), 6.55 (d, J=16.0Hz, 1H), 6.97 (d, J=8.4Hz, 1H), 7.47-7.57 (m, 2H), 7.72-7.80 (m, 2H), 7.99 (s, 1H), 8.45 (d, J=8.0Hz, 1H), 9.02 (s, 1H), (9.06 br, 1H), 10.78 (s, 1H).
Embodiment 97:N-hydroxyl-3-{4-[2-(6-methoxyl group-pyridin-3-yl)-4-morpholinyl-4- Base-thiophene [3,2-d] pyrimidine-6-base sulfonamide]-phenyl }-acrylamide (compound 222)
Step 97a:3-{4-[2-(6-methoxyl group-pyridin-3-yl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-base sulfonamide]-phenyl }-methyl acetate (compound 1008-222)
The similar process (embodiment 96) that uses when using with description compound 1008-221, from (300 milligrams of 1007-217,0.61 mole), 0602-221 is (287 milligrams, 1.22 mM), Pd (PPh3) 4 (36.7 milligrams, 0.032 mM) and saturated NaHCO3 (2 milliliters) and the solution in dimethyl sulfoxide (DMSO) (20 milliliters) in the title compound 1008-222 (200 milligrams, 58%) of preparation yellow solid shape: LCMS:568.2[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.72 (s, 3H), 3.76 (t, J=4.4Hz, 4H), 3.93 (s, 7H), 5.75 (s, 1H), 6.71 (d, J=16Hz, 1H), (6.96 br, 1H), 7.67 (d, J=16Hz, 1H), 7.81-7.85 (m, 4H), 8.45 (br, 1H), 9.02 (s, 1H).
Step 97b:N-hydroxyl-3-{4-[2-(6-methoxyl group-pyridin-3-yl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-base sulfonamide]-phenyl }-acrylamide (compound 222)
The similar method (embodiment 94) of using during according to description compound 217, from (150 milligrams of 1008-222,0.264 mM) and (5 milliliters of the hydroxylamine methanol solutions of fresh preparation, 1.79M) the middle title compound 222 (32 milligrams, 21.%) for preparing white solid: M.p.:＞300 ℃ of .LCMS:569.2[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.72 (s, 4H), 3.75 (s, 4H), 3.87 (s, 3H), 6.04 (s, 1H), 6.44 (d, J=16Hz, 1H), 6.83 (d, J=8.8Hz, 1H), 7.40 (d, J=16Hz, 1H), 7.56 (d, J=8Hz, 2H), (7.73 d, J=7.6Hz, 2H), 8.47 (d, J=8.4Hz, 1H), 9.03 (m, 2H), 10.79 (s, 1H).
(2-(2-Aminometradine-5-yl)-4-morpholinyl thiophene [3,2-d] is phonetic for embodiment 98:4- Pyridine-6-base ammonia)-N-maloyl group amine (compound 225)
Step 98a: tert-butyl group 2-chloro-4-morpholinyl thiophene [3,2-d] pyrimidine-6-aminocarbamic acid salt (compound 1101)
With compound 1005 (2.0 gram, 7.4 mMs) and (Boc) 2O (1.95 grams, 8.9 mMs) pours in the dimethyl formamide (10 milliliters), adds subsequently NaH (0.90 gram, 22.2 mMs).Under 0 ℃ of condition, stirred the gained mixture 3 hours.With thin-layer chromatography monitoring reaction.After reaction is finished, the mixture portions is put into carrene and water.With salt water washing gained organic layer, produce semifinished product with dried over sodium sulfate and evaporation, use column chromatography hexane/ethyl acetate elution purification of crude goods, obtain the title compound (1.3 grams, 47.5%) of faint yellow solid shape.LCMS:371.0[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.51 (s, 9H), 3.75 (t, J=4.8Hz, 4H), 3.84 (t, J=4.8Hz, 4H), 6.64 (s, 1H), 11.26 (s, 1H).
Step 98b:4-((2-(2-Aminometradine-5-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) (tert butoxy carbonyl) ammonia) ethyl butyrate (compound 1103-225)
1101 (300 milligrams, 0.81 mM), (236 milligrams of 4-bromo ethyl butyrates, 1.22 mM) and the mixture of Cs2CO3 (528 milligrams, 1.62 mMs) be placed in the dimethyl formamide (10 milliliters), and under 100 ℃ of conditions the heating 2 hours.In reactant mixture, add entry and use ethyl acetate extraction.Concentrated ethyl acetate extract produces crude product 1102-225, does not need just to be further purified and can use in next step.
Be filled with (280 milligrams of compound 1102-225 with nitrogen, 0.58 mM), 5-(4,4,5,5-tetramethyl-1,3, the assorted pentaborane of 2-two-2-yls) pyrimidine-2-amine (0602-217) is (640 milligrams, 2.9 mM), (150 milligrams of NaHCO3,1.5 mM), with (100 milligrams of two (triphenyl phosphatization hydrogen) palladium (II) chlorides, 0.14 mM) mixture at toluene (23 milliliters), solution in the mixed solvent of ethanol (14 milliliters) and water (6 milliliters), and under 130 ℃ of conditions, heated 3.5 hours.Collect reactant mixture and the residue portions is put into ethyl acetate and water.With salt water washing organic layer, with dried over sodium sulfate and the evaporation.Use column chromatography purification of crude goods, use the DCM/EtOAc elution, produce the title compound 1103-225 (160 milligrams, 51%) of white solid.
HNMR：(400MHz，CDCl 3)：δ1.28(t，J＝7.2Hz，3H)，1.60(s，9H)，2.08-2.11(m，2H)，2.40-2.44(m，2H)，3.87(t，J＝4.4Hz，4H)，3.98-4.02(m，6H)，4.17(q，J＝7.2Hz，2H)，5.26(s，2H)，6.85(s，1H)，9.27(s，2H).
Step 98c:4-(2-(2-aminopyrimidine-5-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-base ammonia)-N-maloyl group amine (compound 225)
The solution of agitate compounds 1103-225 (160 milligrams, 0.3 mM) in trifluoroacetic acid (2 milliliters) is 5 hours at ambient temperature.Then, extract with the saturated sodium bicarbonate neutralise mixt and with carrene.After concentrated, obtain the crude product 1104-225 of white solid, and just can be for the reaction of next step without being further purified.
With crude product 1104-225 (160 milligrams, 0.36 mM) pour into the NH2OH methanol solution (5 milliliters, 1.79M) and among the DCM (2 milliliters), and stirred overnight at ambient temperature.Use the pH value of acetic acid adjusting gained mixture to 6-7, and collect solid.Use preparative high performance liquid chromatography to purify semifinished product, produce the title compound 225 (40 milligrams) of pale solid shape.M.p.:220-230 ℃ of .LCMS:431.0[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.81-1.83 (m, 2H), 2.05-2.07 (m, 2H), (3.15-3.17 m, 2H), 3.75-3.76 (m, 8H), (6.02 s, 1H), 6.99 (s, 2H), (7.49 t, J=5.2Hz, 1H), (8.72 s, 1H), 9.05 (s, 2H), 10.40 (s, 1H).
Embodiment 99:4-(2-(2-aminopyrimidine-5-yl)-4-morpholinyl thiophene [3,2-d] Pyrimidine-6-base ammonia)-N-maloyl group amine (compound 226)
Step 99a:5-[tert butoxy carbonyl-(2-chloro-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-yl)-ammonia]-ethyl valerate (compound 1102-226)
Agitate compounds 1101 under 100 ℃ of conditions (300 milligrams, 0.81 mM), ethyl 5-bromo valerate (314 milligrams, 1.62 mMs) and Cs 2CO 3(0.53 gram, 1.62 mMs) mixture in dimethyl formamide (23 milliliters) 2 hours.Described reactant mixture is cooled to room temperature, and portions is put into ethyl acetate (25 milliliters) and water (25 milliliters).With salt water washing organic layer, use dried over sodium sulfate, filter and evaporation.Obtain the thick product 1102-226 of yellow solid shape after concentrated, just then do not need to be further purified and to be used for next step. 1H?NMR(400MHz，CDCl 3)：δ1.25(J＝7.2Hz，t，3H)，1.59(s，9H)，1.60-1.80(m，4H)，2.34(t，J＝7.2Hz，2H)，3.86(t，J＝4.4Hz，4H)，3.88(t，J＝7.6Hz，2H)，3.95(t，J＝4.4Hz，4H)，4.14(t，J＝7.2Hz，q，2H)，6.65(s，1H).
Step 99b:5-{[2-(2-amino-pyrimidine-5-yl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-yl]-tert butoxy carbonyl-ammonia }-ethyl valerate (compound 1103-226)
To 1102-226 (280 milligrams, 0.56 mM), 5-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) pyrimidine-2-amine (0602-217) (620 milligrams, 2.8 mMs), NaHCO 3(150 milligrams, 1.8 mM) and (100 milligrams of two (triphenyl phosphatization hydrogen) palladium (II) chlorides, 0.14 mM) the solution of mixture in toluene (23 milliliters), ethanol (14 milliliters) and water (6 milliliters) mixed solvent in pour nitrogen, and under 130 ℃ of conditions the heating 3.5 hours.Concentrated reaction mixture is also put into ethyl acetate and water with the residue portions.With salt water washing organic layer, use dried over sodium sulfate, and evaporation.Purify semifinished product with column chromatography, use the dichloromethane/ethyl acetate elution, thereby produce the 1103-226 (160 milligrams, 51%) of white solid.LCMS：558[M+1] +. 1H?NMR(400MHz，CDCl 3)：δ1.25(t，J＝7.2Hz，3H)，1.59(s，9H)，1.76-1.90(m，4H)，2.36(t，J＝7.2Hz，2H)，3.86(t，J＝4.4Hz，4H)，3.92(t，J＝7.2Hz，2H)，4.00(t，J＝4.4Hz，4H)，4.14(q，J＝7.2Hz，2H)，5.30(s，2H)，6.76(s，1H)，9.26(s，2H).
Step 99c:4-(2-(2-aminopyrimidine-5-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-base ammonia)-N-maloyl group amine (compound 226)
From (160 milligrams of 1103-226,0.28 mM) and the middle title compound 226 for preparing the pale solid shape of trifluoroacetic acid (2 milliliters), similar method when using subsequently with description compound 1103-225 (embodiment 98), with the hydroxylamine methanol solution of recently preparation (5 milliliters 1.79M) are processed: m.p:175-180 ℃ of .LCMS:445.0[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.57 (br, 4H), 1.99 (t, J=6.4Hz, 2H), 3.17 (s, 2H), 3.75 (s, 4H), 3.77 (s, 4H), 6.01 (s, 1H), 6.99 (br, 2H), 7.50 (br, 1H), 8.67 (s, 1H), 9.04 (s, 2H), 10.35 (s, 1H).
Embodiment 100:N-hydroxyl-5-(2-(2-(methyl ammonia) pyrimidine-5-yl)-4- Quinoline thiophene [3,2-d] pyrimidine-6-base ammonia) pentanamide (compound 227)
Step 100a:5-(tert butoxy carbonyl (2-(2-(methyl ammonia) pyrimidine-5-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) ammonia) ethyl valerate (compound 1103-227)
Under 90 ℃ of conditions, in nitrogen environment, stir (300 milligrams of 1102-226,0.6 mM), N-methyl-5-(4,4,5,5-tetramethyl-1, the assorted pentaborane of 3,2-two-2-yls) solution of mixture in toluene (6 milliliters), ethanol (4 milliliters) and water (1 milliliter) mixed solvent 3 hours of pyrimidine-2-amine (0602-227) (645 milligrams, 4.22 mMs) and Pd (PPh3) 2Cl2 (12.7 milligrams).After reaction is finished (by the thin-layer chromatography monitoring), concentrated gained reactant mixture uses column chromatography to purify residue, is used in the methyl alcohol elution in the carrene, produces the title product (150 milligrams, 43%) of colorless oil. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.16 (t, J=7.2Hz, 3H), 1.53 (s, 9H), (1.60-1.80 m, 4H), 2.36 (t, J=6.4Hz, 2H), (2.87 d, J=4.8Hz, 3H), 3.78 (t, J=4.4Hz, 4H), 3.90-3.96 (m, 6H), 4.04 (q, J=7.2Hz, 2H), 6.99 (s, 1H), 7.52 (d, J=4.8Hz, 1H), 9.14 (br, 2H).
Step 100b: ethyl 5-(2-(2-(methyl ammonia) pyrimidine-5-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-base ammonia) valerate (compound 1104-227)
Stir at ambient temperature the mixture 1.5 hours of 1103-227 (150 milligrams, 0.26 mM) and trifluoroacetic acid (7 milliliters).In reaction is finished, under 10 ℃, in mixture, add entry.Then use 30% NaOH to regulate the pH value=10-12 of mixture, and extract with carrene.Purify semifinished product with column chromatography (methylene chloride/methanol), thereby produce the described title compound (75 milligrams, 61%) of faint yellow solid shape. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.16 (t, J=7.2Hz, 3H), 1.60-1.65 (m, 4H), 2.34 (m, 2H), 2.87 (d, J=4.8Hz, 3H), 3.18-3.20 (m, 2H), (3.75-3.76 m, 8H), 4.06 (q, J=7.2Hz, 2H), 6.02 (s, 1H), 7.41-7.47 (m, 1H), 9.09 (br, 2H).
Step 100c:N-hydroxyl-5-(2-(2-(methyl ammonia) pyrimidine-5-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-base ammonia) pentanamide (compound 227)
The similar method of introducing when using to description compound 217 (embodiment 94), from (75 milligrams of 1104-227,0.16 mM) and recently the preparation hydroxylamine methanol solution (1.79M, 20 milliliters) middle title compound 227 compounds 227 (45 milligrams, 60%) that prepare white solid: m.p.:206-210 ℃ of .LCMS:459.0[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.57-1.59 (m, 4H), 1.00 (t, J=6.4Hz, 2H), 2.86 (d, J=4.8Hz, 3H), (3.14-3.18 m, 2H), 3.75-3.76 (m, 8H), (6.01 s, 1H), 7.41-7.47 (m, 1H), (8.68 s, 1H), 9.09 (br, 2H), 10.36 (s, 1H).
Embodiment 101:N-hydroxyl-5-(2-(6-(methyl ammonia) pyridin-3-yl)-4- Quinoline base-thiophene [3,2-d] pyrimidine-6-base ammonia) pentanamide (compound 228)
Step 101a: ethyl 5-(tert butoxy carbonyl (2-(6-(methyl ammonia) pyridin-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) ammonia) valerate (compound 1103-228)
Use nitrogen to 1102-226 (500 milligrams, 1.11 mMs), methyl-[5-(4,4,5,5-tetramethyl-[1,3,2], two assorted pentaborane-2-yls)-pyridine-2-yl]-amine (0602-228) (920 milligrams, 6.01 mMs), NaHCO 3(253 milligrams, 3.01 mMs) and Pd (PPh 3) 2Cl 2The mixture of (35 milligrams) is at toluene/EtOH/H 2Solution among the O (16 milliliters/10 milliliters/4 milliliters) carries out degassed, and heats whole night under 110 ℃ of conditions.Thin layer chromatography shows to react to be finished.Concentrated reaction mixture.Thereby use column chromatography to purify the 1103-228 (370 milligrams, 65%) that residue produces the pale solid shape.LCMS：[M+1] +＝571.
Step 101b: ethyl 5-(2-(6-(methyl ammonia) pyridin-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-base ammonia) valerate (compound 1104-228)
Described similar method when using to description compound 1104-227 (embodiment 100), from (370 milligrams of 1103-228,0.65 mM) and the middle title compound 1104-228 (300 milligrams, 98%) for preparing the yellow solid shape of trifluoroacetic acid (4 milliliters): LCMS:[M+1] +=471
Step 101c:N-hydroxyl-5-(2-(6-(methyl ammonia) pyridin-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-base ammonia) pentanamide (compound 228)
The similar method of introducing when using to description compound 217 (embodiment 94), from (160 milligrams of 1104-228,0.34 mM) and recently the preparation hydroxylamine methanol solution (1.79M, 10 milliliters) the middle title compound 228 (80 milligrams, 51%) for preparing the faint yellow solid shape: M.p.:199-201 ℃ of .LCMS:438[M+1] +. 1HNMR:(400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.58 (s, 4H), 2.00 (s, 2H), 2.82 (d, J=4.4Hz, 2H), 3.16 (d, J=4.0Hz, 2H), 3.75 (s, 8H), 5.99 (s, 1H), 6.47 (d, J=8.8Hz, 1H), 6.83 (d, J=4.0Hz, 1H), 7.43 (s, 1H), 8.23 (d, J=8.4Hz, 1H), 8.72 (s, 1H), 8.96 (s, 1H), 10.39 (s, 1H).
Embodiment 102:N-hydroxyl-5-(2-(2-methylpyrimidine-5-yl)-4-morpholinyl thiophene Fen [3,2-d] pyrimidine-6-base ammonia) pentanamide (compound 229)
Step 102a: ethyl 5-(tert butoxy carbonyl (2-(2-methylpyrimidine-5-yl)-4-morpholinyl o-thiophene [3,2-d] pyrimidine-6-yl) ammonia) valerate (compound 1103-229)
In nitrogen, stir (300 milligrams of 1102-226 under 120 ℃ of conditions, 0.619 mM), the 2-methyl-[5-(4,4,5,5-tetramethyl-1,3, the assorted pentaborane of 2-two-2-yls) solution of mixture in toluene/EtOH/H2O (5.0 milliliters/3.2 milliliters/1.4 milliliters) 5 hours of pyrimidine (0602-229) (681 milligrams, 3.10 mMs), NaHCO3 (155 milligrams, 1.854 mMs) and Pd (PPh3) 2Cl2 (50 milligrams).Concentrated reaction mixture.Thereby use column chromatography to purify the described title compound (300 milligrams, productive rate 89.8%) that residue produces the pale solid shape.
Step 102b: ethyl 5-(2-(2-methylpyrimidine-5-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-base ammonia) valerate (compound 1104-229)
Described similar method when using to description compound 1104-227 (embodiment 100), the title compound 1104-229 (130 milligrams) of preparation white solid from 1103-229 (300 milliliters) and trifluoroacetic acid (3 milliliters).
Step 102c:N-hydroxyl-5-(2-(2-methylpyrimidine-5-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-base ammonia) pentanamide (compound 229)
The similar method of introducing when using to description compound 217 (embodiment 94), the title compound 229 (55 milligrams) of the white look solid shape of preparation from the hydroxylamine methanol solution (1.79M, 10 milliliters) of 1104-229 (130 milligrams) and recently preparation: M.p.:248-252 ℃ of .LCMS:444.0[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.58 (s, 4H), 2.00-2.01 (m, 2H), 2.69 (s, 3H), 3.18 (d, J=5.2Hz, 2H), 3.76 (d, J=4.4Hz, 4H), 3.80 (d, J=4.4Hz, 4H), 6.09 (s, 1H), 7.60 (t, J=5.2Hz, 1H), 8.71 (s, 1H), (9.44 s, 2H), 10.28 (s, 1H).
Embodiment 103:6-[2-(2-amino-pyrimidine-5-yl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-base ammonia]-caproic acid hydroxylamine (compound 232)
Step 103a:6-[tert butoxy carbonyl-(2-chloro-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-yl)-ammonia]-ethyl hexanoate (compound 1102-232)
Described similar method (embodiment 99) when using to description compound 1102-226, from 1101 (300 milligrams, 0.81 mM), (360 milligrams of 6-bromonexanoic acid ethyl esters, 1.62 mM) and Cs2CO3 (0.53 gram, 1.62 mM) the compound 1102-232 (480 milligrams, productive rate 100%) of preparation yellow solid shape in dimethyl formamide (23 milliliters): 1HNMR (400MHz, CDCl 3): δ 1.16 (t, J=7.2Hz, 3H), 1.30-1.37 (m, 2H), (1.52 s, 9H), 1.55-1.65 (m, 4H), 2.24-2.30 (m, 2H), 3.26 (t, 2H), 3.74 (t, J=4.8Hz, 4H), 3.84 (t, J=4.4Hz, 4H), (3.90 t, J=7.2Hz, 2H), 4.04 (q, J=7.2Hz, 2H), 6.90 (s, 1H).
Step 103b:6-{[2-(2-amino-pyrimidine-5-yl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-yl]-tert butoxy carbonyl-ammonia }-ethyl hexanoate (compound 1103-232)
Described similar method (embodiment 99) when using to description compound 1103-226, from (400 milligrams of 1102-232,0.78 mM), 5-(4,4,5,5-tetramethyl-1,3, the assorted pentaborane of 2-two-2-yls) pyrimidine-2-amine (0602-217) is (730 milligrams, 3.3 mM), (200 milligrams of NaHCO3,2.4 mM) and (140 milligrams of two (triphenyl phosphatization hydrogen) palladium (II) chlorides, 0.39 mM) at toluene (32 milliliters), the title compound 1103-232 (300 milligrams, 67%) of preparation white solid: LCMS:572.2[M+1 in ethanol (20 milliliters) and the water (8 milliliters)] +. 1H NMR (400MHz, CDCl 3): δ 1.25 (t, J=7.2Hz, 3H), 1.39-1.45 (m, 2H), 1.59 (s, 9H), δ 1.67-1.80 (m, 4H), 2.32 (t, J=7.2Hz, 2H), (3.85-3.91 m, 6H), 4.00 (t, J=5.2Hz, 4H), 4.14 (q, J=7.2Hz, 2H), (6.75 s, 1H), 9.27 (s, 2H).
Step 103c:6-[2-(2-amino-pyrimidine-5-yl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-base ammonia]-ethyl hexanoate (compound 1104-232)
Described similar method when using to description compound 1104-227 (embodiment 100), the title compound 1104-232 (200 milligrams) of preparation white solid from 1103-232 (300 milliliters, 0.5 mM) and trifluoroacetic acid (3 milliliters).LCMS：472.2[M+1] +. 1H?NMR(400MHz，CDCl 3)：δ1.17(t，J＝7.2Hz，3H)，1.35-1.40(m，2H)，1.55-1.61(m，4H)，2.29(t，J＝7.2Hz，2H)，3.13-3.18(m，2H)，3.70-3.75(m，8H)，δ4.04(q，J＝7.2Hz，2H)，5.99(s，1H)，δ6.91(s，2H)，δ7.39(t，J＝5.6Hz，1H)，9.04(s，2H).
Step 103d:6-[2-(2-amino-pyrimidine-5-yl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-base ammonia]-caproic acid hydroxylamine (compound 232)
The similar method of introducing when using to description compound 217 (embodiment 94), from (100 milligrams of 1104-232,0.21 mM) and the middle title compound 232 (20 milligrams) for preparing canescence look solid shape of the hydroxylamine methanol solution (1.79M, 5 milliliters) that recently prepares: m.p:220-225 ℃ of .LCMS:459.0[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.30-1.37 (m, 2H), 1.49-1.62 (m, 4H), (1.96 t, J=7.2Hz, 2H), 3.15-3.17 (m, 2H), 3.76-3.91 (m, 8H), 6.11 (s, 1H), 7.2 (br, 2H), 8.6 (br, 1H), 9.09 (s, 2H), 10.39 (s, 1H), 11.8 (br, 1H).
Embodiment 104:6-[2-(6-methoxyl group-pyridin-3-yl)-4-morpholinyl-4-base-thiophene Fen [3,2-d] pyrimidine-6-base ammonia]-caproic acid hydroxylamine (compound 233)
Step 104a:6-{ tert butoxy carbonyl-[2-(6-methoxyl group-pyridin-3-yl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-yl]-ammonia }-ethyl hexanoate (compound 1103-233)
Use nitrogen to pour (200 milligrams of compound 1102-232,0.39 mM), (183 milligrams of 0602-221,0.78 mM), (98 milligrams of NaHCO3,1.17 mM) and (14 milligrams of two (triphenyl phosphatization hydrogen) palladium (II) chlorides, 0.039 mM) mixture in toluene (14 milliliters), ethanol (8.8 milliliters) and water (3.5 milliliters), and heating is whole night under 120 ℃ of conditions.Concentrated reaction mixture is also put into ethyl acetate and water with the residue portions.With salt water washing organic layer, use dried over sodium sulfate.Purify semifinished product with column chromatography, use the dichloromethane/ethyl acetate elution, thereby produce the title compound 1103-233 (200 milligrams, 88%) of white solid.LCMS：586.2[M+1] +.
Step 104b: ethyl 6-(2-(6-methoxypyridine-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-base ammonia) caproate (compound 1104-233)
Described similar method when using to description compound 1104-227 (embodiment 100), from (200 milliliters of 1103-233,0.34 mM) and the middle title compound 1104-233 (160 milligrams, 96%) for preparing white solid of trifluoroacetic acid (3 milliliters): LCMS:486.5[M+1] +. 1H NMR (400MHz, CDCl 3): δ 1.26 (t, J=7.2Hz, 3H), 1.30-1.45 (m, 2H), (1.46-1.80 m, 4H), 2.30-2.34 (m, 2H), 3.30-3.40 (m, 2H), 3.84-3.90 (m, 8H), 4.00 (s, 3H), (4.14 m, 2H), 4.62 (br, 1H), 6.22 (s, 1H), 6.79 (d, J=8.8Hz, 1H), 8.55 (dd, J=8.8Hz, 2.4Hz, 1H), 9.10 (s, 1H).
Step 104c:6-[2-(6-methoxyl group-pyridin-3-yl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-base ammonia]-caproic acid hydroxylamine (compound 233)
The similar method of introducing when using to description compound 217 (embodiment 94), from (160 milligrams of 1104-233,0.33 mM) and the middle title compound 233 (50 milligrams) for preparing the pale solid shape of the hydroxylamine methanol solution (1.79M, 10 milliliters) that recently prepares: m.p:125-130 ℃ of .LCMS:473[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.32-1.34 (m, 2H), 1.51-1.60 (m, 4H), 1.94-1.98 (m, 2H), 3.14-3.16 (m, 2H), 3.74-3.79 (m, 8H), (3.91 s, 3H), 6.03 (s, 1H), 6.88 (d, J=8.8Hz, 1H), 7.48 (t, J=5.2Hz, 1H), (8.51 dd, J=8.4Hz, 2.4Hz, 1H), 8.67 (s, 1H), 9.08 (s, 1H), 10.34 (s, 1H).
Embodiment 105:7-[2-(2-amino-pyrimidine-5-yl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-base ammonia]-enanthic acid hydroxy amide (compound 234)
Step 105a:7-[tert butoxy carbonyl-(2-chloro-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-yl)-ammonia]-cognac oil (compound 1102-234)
Described similar method (embodiment 99) when using to description compound 1102-226, from 1101 (300 milligrams, 0.81 mM), (383 milligrams of 7-bromide ethyl caproates, 1.62 mM) and Cs2CO3 (0.53 gram, 1.62 mM) the compound 1102-234 (480 milligrams, productive rate 100%) of preparation yellow solid shape: LCMS:527.2[M+1 in dimethyl formamide (23 milliliters)] +.
Step 105b:7-{[2-(2-amino-pyrimidine-5-yl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-yl]-tert butoxy carbonyl-ammonia }-cognac oil (compound 1103-234)
Described similar method (embodiment 99) when using to description compound 1103-226, from (400 milligrams of 1102-234,0.76 mM), 5-(4,4,5,5-tetramethyl-1,3, the assorted pentaborane of 2-two-2-yls) pyrimidine-2-amine (0602-217) is (840 milligrams, 3.8 mM), (200 milligrams of NaHCO3,2.4 mM) and (140 milligrams of two (triphenyl phosphatization hydrogen) palladium (II) chlorides, 0.39 mM) at toluene (32 milliliters), the title compound 1103-234 (220 milligrams, 49%) of preparation white solid: LCMS:586[M+1 in ethanol (20 milliliters) and the water (8 milliliters)] +. 1H NMR (400MHz, CDCl 3): δ 1.25 (t, J=7.2Hz, 3H), 1.40-1.41 (m, 2H), (1.59 s, 9H), 1.63-1.76 (m, 2H), 2.30 (t, J=7.6Hz, 2H), 3.85-3.90 (m, 6H), (4.00 t, J=4.4Hz, 4H), 4.13 (q, J=7.2Hz, 2H), 5.38 (s, 2H), (6.76 s, 1H), 9.26 (s, 2H).
Step 105c:7-[2-(2-amino-pyrimidine-5-yl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-base ammonia]-cognac oil (compound 1104-234)
Described similar method when using to description compound 1104-227 (embodiment 100), the title compound 1104-234 (200 milligrams) of preparation white solid: LCMS:486.3[M+1 from 1103-234 (220 milliliters, 0.38 mM) and trifluoroacetic acid (3 milliliters)] +.
Step 105d:7-[2-(2-amino-pyrimidine-5-yl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-base ammonia]-enanthic acid hydroxy amide (compound 234)
The similar method of introducing when using to description compound 217 (embodiment 94), from (100 milligrams of 1104-234,0.21 mM) and the middle title compound 234 (100 milligrams) for preparing canescence look solid shape of the hydroxylamine methanol solution (1.79M, 5 milliliters) that recently prepares: m.p:235-240 ℃ of .LCMS:473.0[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d6): δ 1.23-1.35 (m, 4H), 1.48-1.59 (m, 4H), (1.95 t, J=7.6Hz, 2H), 3.12-3.19 (m, 2H), 3.74-3.75 (m, 8H), 5.99 (s, 1H), 6.97 (s, 2H), 7.43 (t, J=5.2Hz, 1H), 8.64 (s, 1H), (9.04 s, 2H), 10.32 (s, 1H)
Embodiment 106:N-hydroxyl-2-(methyl ((2-(6-(methyl ammonia) pyridine-3- Base)-and 4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) ammonia) pyrimidine-5-phosphoamide (compound 111)
Step 106a:(2-chloro-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-ylmethyl)-methyl-amine (compound 0503)
Under condition of nitrogen gas, in 0112 (20.0 grams, 70.4 mMs) solution in methyl alcohol (125 milliliters), add the solution (27% volume/volume, 75 milliliter, 563.2 mM) of methyl amine in methyl alcohol.At room temperature stirred reaction mixture whole night, then in a vacuum desolventizing produces the crude product solid product, under condition of nitrogen gas, described crude product solid product is dissolved in methyl alcohol (550 milliliters) and the oxolane (220 milliliters).Sodium borohydride (8 gram, 211.2 mMs) portions adds in the reactant mixture, and stirred overnight at room temperature.Evaporation reaction mixture and add entry (300 milliliters) in a vacuum.Extract aqueous mixture with METHYLENE CHLORIDE, and use the extract of dried over sodium sulfate combination, and concentrated.Residue is dissolved among the HCl (230 milliliters) of 6M and stirred 30 minutes.With the METHYLENE CHLORIDE wash water solution several times, and with NaOH (4N) regulate pH=9-10. by filtering collecting precipitation solid and dry (60 ℃, 6 hours) thus produce flaxen solid (18 grams, 85%).
LCMS:299[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 2.32 (s, 3H), 3.74 (t, J=5.2Hz, 4H), 3.88 (t, J=5.2Hz, 4H), 3.96 (s, 2H), 7.24 (s, 1H).
Step 106b:2-[(2-chloro-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-ylmethyl)-methyl-ammonia]-pyrimidine-5-carboxylic acid's ethyl ester (compound 0504)
At room temperature stir the mixture of 0503 (10 grams, 33.6 mMs), CH3CN (400 milliliters) and 0305 (6.8 grams, 36.4 mMs).Then add diisopropylethylamine (DIPEA) (220 milliliters, 1.26 moles), and with gained solution stirred overnight and evaporation.Afterwards, wash organic facies with water in adding METHYLENE CHLORIDE (300 milliliters), with dried over sodium sulfate and concentrated under vacuum condition, stay residue.In residue, add ethyl acetate, then in ice-water bath, stirred the mixture 50 minutes.Collect the title product 0504 (10.6 grams, 70%) of white solid.LCMS:449[M+1] + 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.30 (t, J=7.2Hz, 3H), 3.25 (s, 3H), 3.71 (t, J=5.2Hz, 4H), 3.83 (t, J=4.8Hz, 4H), 4.29 (m, 2H), (5.21 s, 2H), 7.39 (s, 1H), 8.87 (s, 2H).
Step 106c: ethyl 2-(methyl ((2-(6-(methyl ammonia) pyridin-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-111)
With N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) pyridine-2-amine (0602-227) (351 milligrams, 1.5 mMs), 0504 (314 milligrams, 0.7 mM), NaHCO 3(176 milligrams, 2.1 mMs) and Pd (PPh 3) 2Cl 2The mixture of (24.6 milligrams, 0.035 mM) is dissolved in toluene/EtOH/H 2Among the O (2.5 milliliters/1.6 milliliters/0.7 milliliter).Stirring reaction and under 120 ℃ of conditions microwave 2 hours.In mixture, add entry (8 milliliters) and use ethyl acetate (15 milliliters of x3) to extract.Organic facies is carried out drying, concentrates, also used column chromatography purifying (methyl alcohol in carrene, 5% volume/volume), thereby obtain the title compound 0603-111 (150 milligrams, 41%) of white solid.LCMS:521[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.28 (t, J=7.2Hz, 3H), 2.81 (d, J=4.4Hz, 3H), (3.24 s, 3H), 3.73 (d, J=4.4Hz, 4H), 3.86 (d, J=4.4Hz, 4H), 4.27 (q, J=7.2Hz, 2H), 5.20 (s, 2H), 6.48 (d, J=8.4Hz, 1H), 6.91 (d, J=4.4Hz, 1H), 7.39 (s, 1H), 8.25 (d, J=8.4Hz, 1H), 8.86 (s, 2H), 8.90 (s, 1H).
Step 106d:N-hydroxyl-2-(methyl ((2-(6-(methyl ammonia) pyridin-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) ammonia) pyrimidine-5-phosphoamide (compound 111)
The similar method of introducing when using to description compound 217 (embodiment 94), from (150 milligrams of 0603-236,0.29 mM) and the middle title compound 111 (21 milligrams, 14%) for preparing the brown solid shape of the hydroxylamine methanol solution (6 milliliters) that recently prepares: mp:193-195 ℃ of .LCMS:508[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 2.83 (d, J=4.8Hz, 3H), 3.23 (s, 3H), (3.74 m, 4H), 3.89 (m, 4H), 5.20 (s, 2H), 6.50 (d, J=8.8Hz, 1H), 6.92 (d, J=5.2Hz, 1H), 7.39 (s, 1H), 8.27 (dd, J=8.8,2.0Hz, 1H), 8.75 (s, 2H), (9.01 d, J=2.0Hz, 1H), 9.07 (br, 1H).
Embodiment 107:N-hydroxyl-2-(methyl (1-(2-(6-(methyl ammonia) pyridine-3- Base)-and 4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) ethyl) ammonia) pyrimidine-5-phosphoamide (compound 237)
Step 107a:1-(2-chloro-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) ethyl ketone (compound 1201)
Under-78 ℃ of conditions, in the solution of compound 0111 (5 grams, 20 mMs) in oxolane (100 milliliters), dropwise add nBuLi/ oxolane (2.5M, 11 milliliters) solution.At room temperature stirred described reactant mixture about 30 minutes.Add DMA (7 grams, 80 mMs) and then make reactant mixture slowly be warming up to room temperature, and stirred 2 hours.Reactant mixture is injected the freezing HCl aqueous solution.Semifinished product is precipitated out from solution, collects by filtering, and produces the title compound (5 grams, 86%) of yellow solid shape.
Step 107b:1-(2-chloro-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl)-N-methyl ethyl-amine (compound 1202)
In 1201 (2.36 grams, 7.9 mMs) suspension in methyl alcohol (120 milliliters), add MeNH2/MeOH (7.3 grams, 27%).Under 45 ℃ of conditions, stir described reactant mixture whole night.Concentrated reaction mixture also is dissolved in residue in methyl alcohol/oxolane (58 milliliters/23 milliliters).Add magnesium sulfate (2.4 grams, 0.02 mole), NaBH4 (897 milligrams, 23.7 mMs) and stirred overnight at ambient temperature in the gained solution.In reactant mixture, add entry.Use hydrochloric acid to regulate the pH value=5-6 of mixture, and use washed with dichloromethane.Use the NaOH aqueous solution that the pH value of water layer is adjusted to 8-9, and extract with carrene.The organic facies of dry combination is also concentrated under the pressure that reduces, and produces the thick product (1.5 grams, 60%) of yellow solid shape.Need just can not be used for next step through purifying.
Step 107c: ethyl 2-((1-(2-chloro-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) ethyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 1203)
In 1202 (1.29 grams, 4.12 mMs) solution in dioxane (40 milliliters), add 0305 (962 milligrams, 5.15 mMs) and DIPEA (1.28 grams, 9.9 mMs).With reaction mixture refluxed whole night.Concentrated reaction mixture also uses column chromatography purifying residue, produces the title compound (1.9 grams, 99%) of white solid.
1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.31 (t, J=7.2Hz, 3H), 1.71 (d, J=7.2Hz, 3H), 3.01 (s, 3H), (3.70 t, J=4.4Hz, 4H), 3.82 (t, J=4.0Hz, 4H), 4.29 (q, J=7.2Hz, 2H), 6.50 (q, J=7.2Hz, 1H), (7.38 s, 1H), 8.88 (s, 2H).
Step 107d: ethyl 2-(methyl (1-(2-(6-(methyl ammonia) pyridin-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) ethyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 1204-237)
To compound 1203 (350 milligrams, 0.76 mM) and compound 0602-237 (533 milligrams, 2.3 mMs) at toluene/EtOH/H 2Add Pd (PPh in the mixture after stirring among the O (20 milliliters/10 milliliters/2 milliliters) 3) 2Cl 2(28.7 milligrams, 0.038 mM) and NaHCO 3(191.52 milligrams, 2.28 mMs).The gained mixture is heated to 120 ℃ and stirred 5 hours.Thereby concentrated gained mixture is removed most of solvent.Use column chromatography purifying residue, thereby obtain the title compound 111-327-1 (260 milligrams, 64%) of yellow solid shape, 1H NMR (400MHz, CDCl 3): δ 1.39 (t, J=7.2Hz, 3H), 1.74 (s, 3H), 2.99 (d, J=5.2Hz, 3H), (3.05 s, 3H), 3.84 (t, J=4.8Hz, 4H), 3.97 (t, J=4.4Hz, 4H), (4.36 q, J=7.2Hz, 2H), 4.89 (d, J=4.0Hz, 1H), 6.45 (d, J=8.8Hz, 1H), 6.62 (q, J=6.4Hz, 1H), (7.33 s, 1H), 8.46 (dd, J=8.4Hz, 2.0Hz, 1H), 8.93 (s, 2H), 9.17 (s, 1H).
Step 107e:N-hydroxyl-2-(methyl (1-(2-(6-(methyl ammonia) pyridin-3-yl)-4-morpholinyl-thiophene [3,2-d] pyrimidine-6-yl) ethyl) ammonia) pyrimidine-5-phosphoamide (compound 111-327)
At room temperature stir 1204-237 (150 milligrams, 0.28 mM) and a kind of recently mixture 0.5 hour of the solution (10 milliliter, in methyl alcohol concentration be 1.79M) of NH2OH in methyl alcohol of preparation.Use the 2M HCl aqueous solution to regulate mixture pH value=5-6 and concentrated.Use preparation type-high-efficient liquid phase chromatogram purification residue, thereby obtain (60 milligrams of the title compound 111-237 of white solid.40％)。M.p.:270-275 ℃ of .LCMS:522[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.71 (s, 3H), 2.84 (d, J=4.0Hz, 3H), (2.98 s, 3H), 3.74 (s, 4H), 3.88 (s 4H), (6.45-6.25 m, 2H), 6.90 (s, 1H), 7.39 (s, 1H), 8.27 (d, J=8.4Hz, 1H), (8.76 s, 2H), 9.02 (s, 1H), (9.06 s, 1H), 11.13 (s, 1H).
Embodiment 108:N-hydroxyl-2-(2-(2-(6-(methyl ammonia) pyridin-3-yl) -4-morpholine thiophene [3,2-d] pyrimidine-6-yl) third-2-base ammonia) pyrimidine-5-phosphoamide (chemical combination Thing 240)
Step 108a:2-(2-chloro-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) propan-2-ol (compound 1205)
Under-70 ℃ of conditions, in 0111 (5.10 grams, 20.00 mMs) suspension in oxolane (120 milliliters), dropwise add n-BuLi/ hexane solution (2.5M, 22 milliliters, 55 mMs).Under-20 ℃ of conditions, stirred suspension 45 minutes.Again cool off gained red solution and dry, then under-70 ℃ of conditions, add dry acetone (5.8 grams, 100 mMs), then under-20 ℃ of conditions, stirred 5 hours.With frozen water (125 milliliters) the described reactant mixture that quenches, and use ethyl acetate extraction.Use the organic layer of dried over mgso combination, and under vacuum condition, concentrate the generation semifinished product, use column chromatography (ethyl acetate in hexane) purification of crude goods to produce the title compound 1205 (3.79 grams, 60%) of white solid.LC-MS:314.1[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.56 (s, 6H), 3.74 (m, 4H), 3.89 (m, 4H), 5.94 (s, 1H), 7.22 (s, 1H).
Step 108b:N-(2-(2-chloro-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) third-2-yl) formamide (compound 1206)
At room temperature in the suspension among the TMSCN (6 grams, 60 mMs), add slowly the concentrated sulfuric acid (13 grams, 132 mMs) to 1205 (3.79 grams, 12 mMs).At room temperature stirred described reactant mixture 5 hours.With the described reactant mixture of ice water quenching, and with the NH3H2O alkalization, extract with carrene.
With column chromatography (ethyl acetate/hexane) purifying crude product, produce the title compound 1206 (3.56 grams, 87%) of pale solid shape.LC-MS:341.1[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.69 (s, 6H), 3.74 (m, 4H), 3.86 (m, 4H), 7.23 (s, 1H), 7.98 (s, 1H), 8.71 (s, 1H).
Step 108c:2-(2-chloro-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) third-2-amine (compound 1207)
At room temperature stir 1206 (3.55 grams, 10.40 mMs) solution in methyl alcohol (18 milliliters), H2O (12 milliliters) and dense HCl (47 milliliters) whole night.Concentrated reaction mixture also is dissolved in the water, with the saturated sodium bicarbonate neutralization, extracts with carrene.Use the organic layer of dried over mgso combination, and under vacuum condition, concentrate the generation semifinished product, use column chromatography (ethyl acetate/hexane) purification of crude goods to produce the title compound 1207 (2.93 grams, 90%) of white solid.
LC-MS:313[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.49 (s, 6H), 2.40 (s, 2H), 3.74 (m, 4H), 3.89 (m, 4H), 7.23 (s, 1H).
Step 108d: ethyl 2-(2-(2-chloro-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) third-2-base-ammonia) pyrimidine-5-carboxylic acid's salt (compound 1208)
Under 120 ℃ of conditions, heated 1207 (1.50 restrain 5 mMs), 0305 (1.85 grams, 10 mMs) and the mixture of DIPEA (1.92 grams, 15 mMs) in dioxane (30 milliliters) 48 hours.Then water (125 milliliters) the described reaction of quenching, and use ethyl acetate extraction.Use the organic layer of dried over mgso combination, and under vacuum condition, concentrate the generation semifinished product, use column chromatography (ethyl acetate/hexane) purification of crude goods to produce the title compound 1208 (976 milligrams, 42%) of pale solid shape.LC-MS:463.3[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.25 (t, J=6.8Hz, 3H), 1.82 (s, 6H), 3.70 (m, 4H), 3.81 (m, 4H), 4.23 (q, J=6.8Hz, 2H), 7.20 (s, 1H), 8.71 (m, 3H).
Step 108e: ethyl 2-(2-(2-(6-(methyl ammonia) pyridin-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) third-2-base ammonia) pyrimidine-5-carboxylic acid's salt (compound 1210-240)
1208 (185 milligrams, 0.40 mM), 0602-237 (187 milligrams, 0.80 mM), NaHCO3 (101 milligrams, 1.20 mMs) and PdCl 2(PPh 3) 2(28 milligrams, 0.04 mM) at toluene (8 milliliters), the mixture in ethanol (5 milliliters) and the water (2 milliliters).The described suspension of heating whole night under 120 ℃ of conditions.Concentrated reaction mixture is also using column chromatography (ethyl acetate/hexane) purifying residue, thereby produces the title compound 1210-240 (71 milligrams, 33%) of white solid.LC-MS:535[M+1] +. 1H NMR:(400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.25 (t, J=7.2Hz, 3H), 1.85 (s, 6H), (2.83 d, J=0.8Hz), 3.74 (m, 4H), 3.87 (m, 4H), 4.22 (q, J=7.2Hz, 2H), 6.50 (d, J=8.8Hz, 1H), 6.88 (d, J=4.8Hz, 1H), (7.24 s, 1H), 8.27 (dd, J=2.0 and 8.8Hz, 1H), (8.69 m, 3H), 9.01 (d, J=2.4Hz, 1H).
Step 108f:N-hydroxyl-2-(2-(2-(6-(methyl ammonia) pyridin-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) third-2-base ammonia) pyrimidine-5-phosphoamide (compound 240)
(25 milliliters, 1.79M) mixture in CH2Cl2 (4 milliliters) is 1 hour at room temperature to stir 1210-240 (100 milligrams, 0.19 mM) and a kind of NH2OH/ methanol solution that recently prepares.Filter described solution and use second acid for adjusting pH value=7.In described mixture, add entry (30 milliliters), collect compound 240 (96 milligrams) by filtering.M.p.200-205 ℃ of .LC-MS:522[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.83 (s, 6H), 2.83 (d, J=4.8Hz, 3H), 3.74 (m, 4H), 3.86 (m, 4H), 6.49 (d, J=8.8Hz, 1H), 6.88 (s, 1H), 7.23 (s, 1H), (8.27 dd, J=8.8Hz, 2.4Hz, 1H), 8.34 (s, 1H), 8.53 (br, 2H), 8.97 (s, 1H), (9.01 d, J=2.4Hz, 1H), 10.95 (s, 1H).
Embodiment 109:N-hydroxyl-2-(methyl ((2-(1-methyl isophthalic acid H-pyrazoles-4-yl) -4-morpholine thiophene [3,2-d] pyrimidine-6-yl) methyl) ammonia) pyrimidine-5-phosphoamide (chemical combination Thing 246)
Step 109a: ethyl 2-(methyl ((2-(1-methyl isophthalic acid H-pyrazoles-4-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-246)
Use described similar method (embodiment 99) when describing compound 11-3-226, from 0504 (500 milligrams, 1.11 mM), 1-methyl-4-(4,4,5,5-tetramethyl-1,3, the assorted pentaborane of 2-two-2-yls)-(579 milligrams of 1H-pyrazoles, 2.78 mM) and (23 milligrams of Pd (PPh3) 2Cl2,0.033 mM) the title compound 0603-246 (196 milligrams, 35%) of preparation yellow solid shape in the solution of toluene (11.2 milliliters), ethanol (7 milliliters) and water (2.3 milliliters).
Step 109b:N-hydroxyl-2-(methyl ((2-(1-methyl isophthalic acid H-pyrazoles-4-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) ammonia) pyrimidine-5-phosphoamide (compound 246)
The similar method of introducing when using to description compound 217 (embodiment 94), from (190 milligrams of 0603-246,0.38 mM) and recently the preparation the hydroxylamine methanol solution (concentration is 1.79M in methyl alcohol, 20 milliliters) title compound 246 (80 milligrams, 45%) of preparation white solid in the solution in carrene (2 milliliters).M.p.:164-169 ℃ of .LCMS:482[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.22 (s, 3H), 3.73 (d, J=4.4Hz, 4H), 3.86-3.90 (m, 7H), 5.18 (s, 2H), 7.35 (s, 1H), 7.97 (s, 1H), 8.31 (s, 1H), (8.75 s, 2H), 9.09 (s, 1H), 11.15 (s, 1H).
Embodiment 110:N-hydroxyl-2-((1-(2-(6-methoxypyridine-3-yl)-4- Morpholinyl-thiophene [3,2-d] pyrimidine-6-yl) ethyl) (methyl) ammonia) pyrimidine-5-phosphinylidyne Amine (compound 247)
Step 110a: ethyl 2-((1-(2-(6-methoxypyridine-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) ethyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 1210-247)
Described similar method (embodiment 107) when using to description compound 1204-237, from 1208 (200 milligrams, 0.43 mM), 2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) pyridine is (153 milligrams, 0.65 mM), (109 milligrams of NaHCO3,1.29 mM) and two (triphenyl phosphatization hydrogen) palladium (II) chloride (15 milligrams, 0.02 mM) at toluene (8 milliliters), the title compound 1210-247 (240 milligrams, 95%) of preparation yellow solid shape: LCMS:536.0[M+1 in ethanol (5 milliliters) and the water (1 milliliter)] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.31 (t, J=7.2Hz, 3H), 1.74 (d, J=7.2Hz, 3H), (3.03 s, 3H), 3.75 (t, J=4.4Hz, 4H), 3.91～3.93 (m, 7H), 4.30 (q, J=7.2Hz, 2H), 6.50 (q, J=7.2Hz, 1H), 6.92 (d, J=8.4Hz, 1H), 7.48 (s, 1H), 7.57 (dd, J=8.4Hz, 2.4Hz, 1H), (8.89 s, 2H), 9.15 (d, J=2.4Hz, 1H).
Step 110b:N-hydroxyl-2-((1-(2-(6-methoxypyridine-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) ethyl) (methyl) ammonia) pyrimidine-5-phosphoamide (compound 247)
The similar method of introducing when using to description compound 237 (embodiment 107), from (220 milligrams of 1210-247,0.41 mM) and recently the preparation hydroxylamine methanol solution (1.79M, 30 milliliters) the middle title compound 247 (120 milligrams, 56%) for preparing a bright pink solid shape: LCMS:523.0[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.70 (d, J=6.8Hz, 3H), 2.97 (s, 3H), (3.32 m, 1H), 3.73～3.75 (m, 4H), 3.91～3.93 (m, 7H), 6.46 (d, J=6.8Hz, 1H), 6.91 (d, J=8.8Hz, 1H), 7.45 (s, 1H), 8.57 (dd, J=8.8Hz, 2.0Hz, 1H), 8.76 (s, 2H), 9.15 (d, J=2.4Hz, 1H).
Embodiment 111:N-hydroxyl-2-(2-(2-(6-methoxypyridine-3-yl)-4- Quinoline base o-thiophene [3,2-d] pyrimidine-6-yl) third-2-base ammonia) pyrimidine-5-phosphoamide (is changed Compound 250)
Step 111a: ethyl 2-(2-(2-(6-methoxypyridine-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) third-2-base ammonia) pyrimidine-5-carboxylic acid's salt (compound 1210-250)
Use described similar method (embodiment 107) when describing compound 1204-237, from 1208 (185 milligrams, 0.40 mM), 0602-222 (188 milligrams, 0.80 mM), NaHCO3 (101 milligrams, 1.20 mMs) and PdCl 2(PPh 3) 2 (28 milligrams, 0.04 mM) prepare the title compound 1210-250 (160 milligrams, 75%) of white solid: LC-MS:536.3[M+1 in toluene (8 milliliters), ethanol (5 milliliters) and water (2 milliliters)] +. 1H NMR:(400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.30 (t, J=6.8Hz, 3H), 1.91 (s, 6H), (3.81 m, 4H), 3.96 (m, 4H), 3.99 (s, 3H), 4.28 (q, J=6.8Hz, 2H), 6.97 (d, J=8.8Hz, 1H), 7.36 (s, 1H), 8.62 (dd, J=8.4Hz, 2.4Hz, 1H), 8.74 (m, 3H), 9.20 (d, J=2.0Hz, 1H).
Step 111b:N-hydroxyl-2-(2-(2-(6-methoxypyridine-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) third-2-base ammonia) pyrimidine-5-phosphoamide (compound 250)
The similar method of introducing when using to description compound 237 (embodiment 107), from (160 milligrams of 1210-250,0.30 mM) and the hydroxylamine methanol solution (1.79M, 30 milliliters) of recently preparation in CH2Cl2 (4 milliliters), prepare the title compound 247 (140 milligrams) of white solid: LC-MS:523[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.90 (s, 6H), 3.81 (m, 4H), (3.96 m, 4H), 3.99 (s, 3H), (6.97 d, J=8.4Hz, 1H), 7.36 (s, 1H), 8.43 (s, 1H), 8.60 (m, 3H), 9.04 (s, 1H), 9.20 (d, J=2.0Hz, 1H), 11.10 (s, 1H).
Embodiment 112:N-hydroxyl-2-((2-(2-(6-methoxypyridine-3-yl)-4- Morpholine thiophene [3,2-d] pyrimidine-6-yl) third-2-yl) (methyl) ammonia) pyrimidine-5-phosphinylidyne Amine (compound 251)
Step 112a: ethyl 2-((2-(2-chloro-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) third-2-yl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 1209)
Under-70 ℃ of conditions, in the solution of compound 1208 (278 milligrams, 0.60 mM) in the oxolane (25 milliliters) of drying, add NaHDMS (in oxolane, being 2.0M, 1.5 milliliters), add subsequently MeOTf (0.34 milliliter, 3 mMs).Under-70 ℃ of conditions, stirred the gained mixture 0.5 hour.Then use the described reaction of water-quenching, and use ethyl acetate extraction.Organic layer with the dried over sodium sulfate combination.Purify semifinished product with column chromatography (hexane/ethyl acetate), thereby produce the described title compound 1209 (52 milligrams, 18%) of white solid.LCMS:477.3[M+1] +. 1H NMR:(400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.24 (t, J=7.2Hz, 3H), 1.89 (s, 6H), 3.48 (s, 3H), 3.69-3.71 (m, 4H), 3.78-3.80 (m, 4H), 4.21 (q, J=7.2Hz, 2H), 7.16 (s, 1H), 8.65 (s, 2H).
Step 112b: ethyl 2-((2-(2-(6-methoxypyridine-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) third-2-yl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 1211-251)
Under 120 ℃ of conditions, heat 1209 (52 milligrams, 0.11 mM), 6-methoxypyridine-3-ylboronic acid (68 milligrams, 0.44 mM), NaHCO 3(27 milligrams, 0.32 mM) and PdCl 2(PPh 3) 2(7.8 milligrams, 0.011 mM) at toluene (2.6 milliliters), the mixture in ethanol (1.6 milliliters) and the water (0.6 milliliter) whole night.Concentrated reaction mixture also uses column chromatography (hexane/ethyl acetate) purifying residue, thereby produces the title compound 1211-251 (53 milligrams, 88%) of white solid.LCMS:550.4[M+1] +. 1H NMR:(400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.23 (t, J=6.8Hz, 3H), 1.93 (s, 6H), (3.50 s, 3H), 3.74-3.76 (m, 4H), 3.88-3.90 (m, 4H), 3.92 (s, 3H), 4.20 (q, J=7.2Hz, 2H), 6.90 (d, J=8.4Hz, 1H), 7.25 (s, 1H), 8.55 (dd, J=2.0Hz, 8.8Hz, 1H), (8.65 s, 2H), 9.12 (d, J=2.0Hz, 1H).
Step 112c:N-hydroxyl-2-((2-(2-(6-methoxypyridine-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) third-2-yl) (methyl) ammonia) pyrimidine-5-phosphoamide (compound 251)
The similar method of introducing when using to description compound 237 (embodiment 107), from (95 milligrams of 1210-250,0.17 mM) and recently the preparation hydroxylamine methanol solution (1.79M, 30 milliliters) title compound 251 (32 milligrams, 35%) of preparation white solid in CH2Cl2 (4 milliliters): m.p.175-178 ℃ of .LCMS:537.4[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.91 (s, 6H), 3.46 (s, 3H), (3.73-3.74 m, 4H), 3.86-3.90 (m, 4H), (3.92 s, 3H), 6.90 (d, J=8.8Hz, 1H), 7.24 (s, 1H), 8.53-8.57 (m, 3H), 8.91 (br, 1H), 9.12 (d, J=2.0Hz, 1H), 10.91 (br, 1H).
Embodiment 113:2-[2-(6-methoxyl group-pyridin-3-yl)-4-morpholinyl-4-base-thiophene Fen [3,2-d] pyrimidine-6-sulphonyl ammonia]-pyrimidine-5-carboxylic acid's hydroxy amide (compound 252)
Step 113a:2-chloro-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-sulfonic acid chloride (compound 1301)
Under-78 ℃ of conditions, in the nitrogen environment, in 0111 (10 grams, 39.2 mMs) suspension in oxolane (220 milliliters), add slowly the solution (2.5M, 47.06 mM) of n-BuLi in hexane.The temperature recovery of gained slurries to-40 ℃, can be observed a kind of brown solution of clarification.Gained solution is cooled to-50 ℃, and adds slowly SO 2Cl 2(6.3 milliliters, 78.43 mMs).Under-40 ℃ of conditions, stirred gained solution 2 hours.Concentrated reaction mixture and use the column chromatography purifying is used the hexane/ethyl acetate elution, obtains the compound 1301 (3.7 grams, 26.8%) of yellow solid shape.LCMS:353.8[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.75 (t, J=4.4Hz, 4H), 3.89 (t, J=4.4Hz, 4H), 7.27 (s, 1H).
Step 113b:2-chloro-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-sulfonic acid amides (compound 1302)
(2 grams, 5.67 mMs) are poured in the solution of NH3 in methyl alcohol with 1301, and stirred overnight at room temperature.Concentrated reaction mixture and in column chromatography purifying, use the solution of 2% methyl alcohol in carrene, thereby produce compound 1302 (0.97 gram, 51%).LCMS:335.0[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.77 (t, J=4.4Hz, 4H), 3.92 (t, J=4.4Hz, 4H), 7.75 (s, 1H), 8.15 (s, 2H).
Step 113c:2-(2-chloro-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-sulphonyl ammonia)-pyrimidine-5-carboxylic acid's ethyl ester (compound 1303)
With 1302 (400 milligrams, 1.2 mMs), 0305 (335 milligrams, 1.8 mMs) and the mixture stirring and refluxing of TEA in carrene 3 days.By the carrene diluted reaction mixture and wash with water.Use column chromatography purification of crude goods, produce compound 1303 (210 milligrams, 36%).
LCMS:485.0[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.27 (t, J=7.2Hz, 3H), 3.79 (s, 4H), 3.94 (s, 4H), 4.27 (q, J=7.2Hz, 2H), 7.64 (s, 1H), 8.71 (s, 2H).
Step 113d:2-[2-(6-methoxyl group-pyridin-3-yl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-sulphonyl ammonia]-pyrimidine-5-carboxylic acid's ethyl ester (compound 1304-252)
Use described similar method when describing compound 1211-251 (embodiment 112), from 1303 (260 milligrams, 0.54 mM), (246 milligrams of 6-methoxypyridines-3-ylboronic acid, 1.61 mM) and the solution of Pd (PPh3) 4 (10 milligrams) in dioxane (9 milliliters) and saturated NaHCO3 (3 milliliters) in the title compound 1304-252 (100 milligrams, 38%) of preparation gray solid shape: 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.28 (t, J=7.2Hz, 3H), 3.80 (t, J=4.4Hz, 4H), 3.92 (s, 3H), 4.00 (t, J=4.4Hz, 4H), 4.29 (q, J=7.2Hz, 2H), 6.93 (d, J=8.4Hz, 2H), 8.02 (s, 1H), (8.58 dd, J=8.8Hz, 2.4Hz, 1H), (8.99 s, 2H), 9.16 (s, 1H).
Step 113e:2-[2-(6-methoxyl group-pyridin-3-yl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-sulphonyl ammonia]-pyrimidine-5-carboxylic acid's hydroxy amide (compound 252)
The similar method of introducing when using to description compound 237 (embodiment 107), from 1304-252 (100 milligrams) and recently the preparation hydroxylamine methanol solution (1.79M, 16 milliliters) the middle title compound 252 (21 milligrams, 23%) for preparing white solid: m.p.:259-265 ℃.
LCMS:545.3[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.81 (s, 4H), 3.96 (s, 3H), (4.00 s, 4H), 6.93 (d, J=8.4Hz, 2H), 7.99 (s, 1H), 8.58 (d, J=8.0Hz, 1H), 8.84 (s, 2H), (9.16 s, 1H), 9.18 (s, 1H), 11.23 (s, 1H).
Embodiment 114:2-(((2-(6-ethoxy pyridine-3-yl)-4-morpholinyl thiophene [3, 2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-(change of N-hydroxy pyrimidine-5-phosphoamide Compound 255)
Step 114a:5-bromo-2-ethoxy pyridine (compound 0601-255)
Use 2,5-, two bromos-pyridine to process the recently solution of caustic alcohol in ethanol of preparation, and added hot reflux 28 hours.Enriched mixture and portions are put into carrene and water, use salt water washing organic layer, and use dried over mgso, filtration also evaporated under vacuum condition, obtain compound 0601-255 (3 grams, 70%).LCMS：202.0[M+1] +
Step 114b:2-ethyoxyl-5-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) pyridine (compound 0602-255)
With compound 0601-255 (3.0 grams, 15.0 mM), connection boric acid pinacol ester (5.7 grams, 22.0 mM), [1,1 '-two (diphenylphosphine) ferrocene] (327 milligrams of palladium chlorides (PdCl2 (dppf)), 0.45 mM) and the slurries of potassium acetate (4.4 gram, 45.0 mMs) in anhydrous Isosorbide-5-Nitrae-dioxane (30 milliliters) under 110 ℃ of conditions, heat whole night.Filter reactant mixture and concentrated.Thereby produce the title compound (2.7 grams, 73%) of white solid by column chromatography purification of crude goods. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.29 (s, 12H), 1.29 (t, J=7.2Hz, 3H), 4.34 (q, J=7.2Hz, 2H), 6.76 (d, J=8.4Hz, 1H), 7.85 (dd, J=8.4Hz, 1.6Hz, 1H), 8.38 (d, J=1.6Hz, 1H).
Step 114c: ethyl 2-(((2-(6-ethoxy pyridine-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-255)
Described similar method (embodiment 99) when using to description compound 0603-226, from 0504 (300 milligrams, 0.67 mM), (333 milligrams of 0602-255,1.34 mM), (168 milligrams of NaHCO3,2 mMs) and (23 milligrams of two (triphenyl phosphatization hydrogen) palladium (II) chlorides, 0.03 mM) the title compound 0603-255 (335 milligrams, 94%) of preparation white solid in toluene (8 milliliters), ethanol (5 milliliters) and water (1 milliliter): 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.31-1.37 (m, 6H), 3.76 (t, J=4.4Hz, 4H), 3.87 (3,3H), 3.92 (t, J=4.4Hz, 4H), 4.30 (q, J=7.2Hz, 2H), 4.40 (q, J=7.2Hz, 2H), (5.24 s, 2H), 6.87 (d, J=8.8Hz, 1H), (7.46 s, 1H), 8.56 (dd, J=8.4Hz, 1.2Hz, 1H), 8.88 (s, 2H)., 9.13 (s, 1H).
Step 114d:2-(((2-(6-ethoxy pyridine-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-N-hydroxy pyrimidine-5-phosphoamide (compound 255)
The similar method of introducing when using to description compound 237 (embodiment 107), from (200 milligrams of 0603-255,0.37 mM) and recently the preparation hydroxylamine methanol solution (1.79M, 50 milliliters) the middle title compound 255 (90 milligrams, 46%) for preparing white solid: m.p.:162-165 ℃ of .LCMS:523.0[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.34 (t, J=7.2Hz, 3H), 3.24 (s, 3H), 3.75 (t, J=4.0Hz, 4H), 3.92 (t, J=4.0Hz, 4H), 4.37 (q, J=7.2Hz, 2H), 5.20 (s, 2H), 6.88 (d, J=8.4Hz, 1H), 7.44 (s, 1H), 8.56 (dd, J=8.4Hz, 1.2Hz, 1H), 8.75 (s, 2H)., 9.04 (s, 1H), 9.12 (s, 1H), 11.12 (s, 1H).
Embodiment 115:N-hydroxyl-2-(((2-(6-(2-hydroxyl-oxethyl) pyridine-3- Base)-and 4-morpholine thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carbon Acid amides (compound 256)
Step 115a:2-(5-pyridine bromide-2-base oxygen) ethanol (compound 0601-256)
Under 0 ℃, portions adds NaH (17 restrain 0.425 mole) in the solution after stirring among NMP (100 milliliters) to 2,5-, two bromo pyridines (20 gram, 85 mMs).Under 0 ℃ of condition, stirred the gained mixture 1 hour.Add ethylene glycol.Heating gained mixtures are 4 hours under 110 ℃.Reactant mixture is cooled to room temperature and portions is put into ethyl acetate and water.Wash organic layer with water, use dried over sodium sulfate, and concentrated.With column chromatography purifying residue, use the hexane/ethyl acetate elution, produce the title compound 0601-256 (7.2 grams, productive rate 39%) of pale solid shape.
LCMS：218.0[M+1] +. 1H?NMR(400MHz，CDCl 3)：δ3.45-3.48(t，1H，J＝5.6Hz)，3.92-3.95(m，2H)，4.39-4.42(m，2H)，6.70(d，J＝8.8Hz，1H)，7.66(dd，J＝8.8Hz，2.4Hz，1H)，8.16(d，J＝2.4Hz，1H).
Step 115b:2-(5-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) pyridine-2-base oxygen) ethanol (compound 0602-256)
With the degassed 0601-256 of nitrogen (5 grams, 0.023 mole), connection boric acid pinacol ester (7 grams, 0.028 mole), KOAc (6.8 grams, 0.069 mole) and [1,1 '-two (diphenylphosphine) ferrocene] (336.7 milligrams of palladium chlorides (Pd (dppf) Cl2), 0.46 mM) mixture in the dioxane (50 milliliters) of drying, and heating 4 hours under 90 ℃ of conditions.Concentrated reaction mixture.Residue is suspended among the CH2Cl2, and stirred 30 minutes, and filter.Concentrated filtrate, and use the column chromatography purifying, use the hexane/ethyl acetate elution, produce the title compound 0602-256 (9 grams comprise connection boric acid pinacol ester) of yellow oily.LCMS：266.0[M+1] +. 1H?NMR(400MHz，CDCl 3)：δ1.334(s，12H)，3.87(m，1H)，3.94(m，2H)，4.48-4.51(m，2H)，6.77(d，J＝8.4Hz，1H)，7.95(dd，J＝8.4Hz，2.0Hz，1H)，8.50(d，1H，J＝1.2Hz，1H).
Step 115c: ethyl 2-(((2-(6-(2-hydroxyl-oxethyl) pyridin-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-256)
Use described similar method when describing compound 1103-226 (embodiment 99), from (708 milligrams of 0602-256,2.67 mM), 0504 (400 milligrams, 0.89 mM), (224 milligrams of NaHCO3,2.67 mM) and (31 milligrams of Pd (PPh3) 2Cl2,0.05 mM) the title compound 0603-256 (150 milligrams, 30%) of preparation pale solid shape: LCMS:552[M+1 in toluene/ethanol/water (16 milliliters/10 milliliters/4 milliliters)] +.
Step 115d:N-hydroxyl-2-(((2-(6-(2-hydroxyl-oxethyl) pyridin-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-phosphoamide (compound 256)
The similar method of introducing when using to description compound 237 (embodiment 107), from (150 milligrams of 0603-256,0.27 mM) and recently the preparation hydroxylamine methanol solution (1.79M, 20 milliliters) the middle title compound 256 (55 milligrams, 36%) for preparing yellowish solid shape: m.p.:143-145 ℃ of .LCMS:539.0[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.24 (s, 3H), 3.75 (s, 6H), 3.92 (s, 4H), 4.35 (s, 2H), 4.84～4.87 (br, 1H), (5.20 s, 2H), 6.90 (d, J=6.8Hz, 1H), (7.44 s, 1H), 8.57 (d, J=6.4Hz, 1H), (8.76 s, 2H), 9.06 (s, 1H), (9.12 s, 1H), 11.26 (s, 1H).
Embodiment 116:2-(((2-(6-(2-(dimethylamino) ethyoxyl) pyridine-3- Base)-and 4-morpholine thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-the N-hydroxyl Pyrimidine-5-phosphoamide (compound 257)
Step 116a:2-(2-bromo ethyoxyl)-5-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) pyridine (compound 0601-257)
0602-256 (2.9 grams, 0.01 mole) and the mixture of PBr3 (3 milliliters) in toluene (30 milliliters) were heated 3 hours under 80 ℃ of conditions.Described reactant mixture is cooled to 0 ℃ also adds slowly entry, until the pH value equals 7-8, and use ethyl acetate extraction.With the organic matter of salt water washing combination, use dried over mgso, with concentrated, produce the crude product 0601-257 (2 grams, 61.2%) of pink solid shape.LCMS：328.1[M+1] +. 1H?NMR(400MHz，CDCl 3)：δ1.24(s，12H)，3.65(t，J＝6.4Hz，2H)，4.25(t，J＝6.4Hz，2H)，6.56(d，J＝8.8Hz，1H)，7.60(dd，J＝8.8Hz，1.6Hz，1H)，7.70(d，J＝1.6Hz，1H).
Step 116b: ethyl 2-(((2-(6-(2-(dimethylamino) ethyoxyl) pyridin-3-yl)-4-morpholine thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-257)
0601-257 (600 milligrams, 1.83 mMs) is poured among the Me2NH (being 20 milliliters in CH3OH), and at room temperature stirred 3 hours.Thereby concentrated reaction mixture produces the crude product 0602-257 (650 milligrams) of yellow solid shape, does not just need to be further purified to be used for next step.
To 0602-257 (600 milligrams), 0504 (350 milligrams, 0.78 mM), NaHCO3 (196 milligrams, 2.33 mMs) and Pd (PPh 3) 2Cl 2It is degassed that (27 milligrams) mixture in toluene/ethanol/water (16 milliliters/10 milliliters/4 milliliters) carries out nitrogen, and heated 3 hours under 110 ℃ of conditions.Concentrated reaction mixture.Residue is suspended in CH 2Cl 2Also filter in (50 milliliters).Concentrated filtrate.Use the column chromatography purifying crude product, obtain the 0603-257 (200 milligrams, 44%) of white solid.
Step 116c:2-(((2-(6-(2-(dimethylamino) ethyoxyl) pyridin-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-N-hydroxy pyrimidine-5-phosphoamide (compound 257)
Use the similar method of introducing when describing compound 237 (embodiment 107), from 0603-257 (100 milligrams, 0.28 mM) and the hydroxylamine methanol solution (1.79M, 10 milliliters) that recently prepares at CH 2Cl 2The title compound 257 (30 milligrams, 30%) of the yellowish solid shape of preparation in (2 milliliters).M.p.:140-143 ℃ of .LCMS:566[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 2.21 (s, 6H), 2.56 (t, J=5.2Hz, 2H), 3.23 (s, 3H), 3.75 (s, 4H), 3.90 (s, 4H), 4.12 (s, 2H), 5.16 (s, 2H), 6.46 (dd, J=8.8Hz, 1.2Hz, 1H), 7.40 (s, 1H), 8.17 (s, 1H), 8.30 (dd, J=8.4Hz, 4.4Hz, 1H), 8.63 (d, J=12Hz, 1H), 8.80 (s, 2H), 11.11 (br, 1H).
Embodiment 117:N-hydroxyl-2-(methyl ((2-(6-(2-(methyl ammonia) ethoxy Base) pyridin-3-yl)-and 4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) ammonia) phonetic Pyridine-5-phosphoamide (compound 258)
Step 117a:N-M ethyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls)-pyridine-2-base oxygen) ethamine (compound 0602-258)
At room temperature stir the mixture 3 hours of 0601-257 (300 milligrams, 0.917 mM) and MeNH2 (20 milliliters, in alcohol).Concentrated reaction mixture produces crude product 0602-258, does not need to purify just to use in the next step again.LCMS：279.1[M+1] +. 1H?NMR(400MHz，CDCl 3)：δ1.24(s，12H)，3.13(s，3H)，4.06-4.08(m，2H)，4.60-4.64(m，2H)，6.84(d，J＝9.2Hz，1H)，7.92(s，1H)，8.04(d，J＝8.8Hz，1H).
Step 117b: ethyl 2-(methyl ((2-(6-(2-(methyl ammonia) ethyoxyl) pyridin-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-258)
Use described similar method when describing compound 1103-226 (embodiment 99), from 0602-258 (above prepare), 0504 (400 milligrams, 0.89 mM), (230 milligrams of NaHCO3,2.75 mM) and Pd (PPh3) 2Cl2 (10 milligrams) in toluene/ethanol/water (16 milliliters/10 milliliters/4 milliliters), prepare the title compound 0603-258 (120 milligrams, 24%) of gray solid shape: LCMS:565[M+1] +. 1H NMR (400MHz, CDCl 3): δ 1.38 (t, J=7.2Hz, 3H), 3.19 (s, 3H), 3.32 (s, 3H), 3.87 (t, J=5.2Hz, 4H), 3.99 (t, J=5.2Hz, 4H), 4.15 (t, J=6.4Hz, 2H), (4.37 q, 2H, J=7.2Hz), 4.76 (t, J=5.6Hz, 2H), 5.20 (s, 2H), (6.93 d, J=8.8Hz, 1H), 7.32 (s, 1H), 8.71 (d, J=2.4Hz, 1H), 8.78 (dd, J=9.2Hz, 1.6Hz, 1H), 8.93 (s, 2H).
Step 117c:N-hydroxyl-2-(methyl ((2-(6-(2-(methyl ammonia) ethyoxyl) pyridin-3-yl)-4-morpholine thiophene [3,2-d] pyrimidine-6-yl) methyl) ammonia) pyrimidine-5-phosphoamide (compound 258)
The similar method of introducing when using to description compound 237 (embodiment 107), from (120 milligrams of 0603-258,0.21 mM) and recently the preparation hydroxylamine methanol solution (1.79M, 10 milliliters) title compound 258 (55 milligrams, 47%) of the yellowish solid shape of preparation in CH2Cl2 (2 milliliters).M.p.:170-175 ℃ of .LCMS:552.3[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 2.98 (s, 3H), 3.23 (s, 3H), (3.71-3.77 m, 6H), 3.90-3.92 (m, 4H), (4.32 br, 2H), 5.19 (s, 2H), (6.94 d, 1H, J=9.6Hz), 7.39 (s, 1H), 8.42-8.45 (d, 2H), 8.68 (s, 1H), 8.71 (s, 2H).
Embodiment 118:2-(((2-(6-(2-amino ethoxy) pyridin-3-yl)-4- Morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-the N-hydroxy pyrimidine -5-phosphoamide (compound 259)
Step 118a:2-(2-azepine ethyoxyl)-5-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) pyridine (compound 0602-259)
At 60 ℃ of lower heating 0601-257 (260 milligrams, 0.8 mM) and NaN 3(103.4 milligrams, 1.59 mMs) mixture in dimethyl formamide 2 hours.The reactant mixture portions is put into CH 2Cl 2In water.With salt water washing organic layer, use dried over sodium sulfate.Semifinished product is dissolved in the toluene, and is directly used in the next step.
LCMS：291.1[M+1] +.
Step 118b: ethyl 2-(((2-(6-(2-ammonia ethyoxyl) pyridin-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-259)
It is degassed that 0602-259,0504 (350 milligrams, 0.78 mM), NaHCO3 (200 milligrams, 2.4 mMs) and the mixture of Pd (PPh3) 2Cl2 (10 milligrams) in toluene/ethanol/water (16 milliliters/10 milliliters/4 milliliters) are carried out nitrogen, and heating 3 hours under 110 ℃ of conditions.Concentrated reaction mixture.Use the chromatography purification residue, with the elution of CH2Cl2/ methyl alcohol, produce title compound, ethyl 2-(((2-(6-(2-azido ethyoxyl) pyridin-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt. compound is dissolved in the methyl alcohol, and is directly used in the next step.LCMS：577.3[M+1] +
At room temperature, stir ethyl 2-(((2-(6-(2-azepine ethyoxyl) pyridin-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (preparing above) and the mixture overnight of Pd/C (100 milligrams) in MeOH (10 milliliters) in hydrogen (1 atmospheric pressure) environment.With carrene (10 milliliters) diluted reaction mixture and use diatomite filtration.Concentrated filtrate produces the title compound 0603-259 (130 milligrams, 15.3%, 2 step) of faint yellow solid shape.LCMS：551[M+1] +. 1H?NMR(400MHz，CDCl 3)：δ1.38(t，J＝7.2Hz，3H)，3.15(q，J＝5.6Hz，2H)，3.31(s，3H)，3.84-3.87(m，4H)，3.94-3.97(m，4H)，4.12(t，J＝6Hz，2H)，4.36(q，2H，J＝7.2Hz)，5.18(s，2H)，6.63(d，J＝9.2Hz，1H)，7.27(s，1H)，8.37(dd，J＝9.6Hz，2.4Hz，1H)，8.51(d，J＝2.4Hz，1H)，8.93(s，2H).
Step 118c:2-(((2-(6-(2-amino ethoxy) pyridin-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-N-hydroxy pyrimidine-5-phosphoamide (compound 259)
The similar method of introducing when using to description compound 237 (embodiment 107), from (130 milligrams of 0603-259,0.24 mM) and recently the preparation hydroxylamine methanol solution (1.79M, 10 milliliters) title compound 259 (40 milligrams, 31%) of the yellowish solid shape of preparation in CH2Cl2 (2 milliliters).M.p.:110-115 ℃ of .LCMS:538.3[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 2.89 (q, J=6Hz, 2H), 3.23 (s, 3H), (3.75 t, J=4.8Hz, 4H), 3.90 (t, J=4.4Hz, 4H), 4.01 (t, J=6Hz, 2H), 5.19 (s, 2H), 6.47 (d, J=9.2Hz, 1H), 7.37 (s, 1H), 8.32 (dd, J=9.6Hz, 2.4Hz, 1H), (8.63 d, J=2.4Hz, 1H), 8.75 (s, 2H).
Embodiment 119:N-hydroxyl-2-(((2-(2-methoxy pyrimidine-5-yl)-4-morpholine Thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-formamide (is changed Compound 261)
Step 119a:5-bromo-2-methoxy pyrimidine (compound 0601-261)
Pour in the methyl alcohol (50 milliliters) also 5-bromo-2-Chloropyrimide (10 gram, 52 mMs) and sodium methoxide (8.42 grams, 156 mMs) at room temperature stirred overnight.Concentrated reaction mixture also adds entry subsequently.With ethyl acetate extraction gained mixture and use dried over mgso.Obtain title compound (8.07 grams, 82.5%) after concentrated.
Step 119b:2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) pyrimidine (compound 0602-261)
In high-pressure bottle, with 0601-261 (0.5 gram, 2.65 mMs), 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-two (1,3,2-, two assorted pentaboranes) (1.35 grams, 5.3 mM), (100 milligrams of KOAc (780 milligrams, 7.95 mMs), [1,1 '-two (diphenylphosphine) ferrocene] palladium chloride, 0.133 mM) pour in Isosorbide-5-Nitrae-dioxane (10 milliliters), heating is 5 hours under 100 ℃ of conditions.Filter reactant mixture by the tripoli pad, and with carrene elution (50 milliliters).Obtain the title compound (0.5 gram, 90%) of white solid after concentrated.
Step 119c: ethyl 2-(((2-(2-methoxy pyrimidine-5-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-261)
Described similar method (embodiment 99) when using to description compound 0603-226, with 0504 (450 milligrams, 1.0 mM), (472 milligrams of 0602-261,2.0 mM), (252 milligrams of NaHCO3,3 mMs) and (120 milligrams of two (triphenyl phosphatization hydrogen) palladium (II) chlorides, 0.15 mM) pour in ethanol (10 milliliters), water (6 milliliters) and the toluene (8 milliliters), the title compound 0603-261 (120 milligrams, 24%) of preparation gray solid shape.
Step 119d:N-hydroxyl-2-(((2-(2-methoxy pyrimidine-5-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-phosphoamide (compound 261)
The similar method of introducing when using to description compound 237 (embodiment 107), from (160 milligrams of 0603-261,0.31 mM) and recently the preparation hydroxylamine methanol solution (1.79M, 20 milliliters) the middle title compound 261 (30 milligrams, 19.4%) for preparing white solid: m.p.:215-220 ℃ of .LCMS:510.0[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.24 (s, 3H), 3.74-3.76 (m, 4H), 3.92-3.95 (m, 4H), 4.00 (s, 3H), 5.20 (s, 2H), 7.46 (s, 1H), 8.75 (s, 2H), (9.04 s, 1H), 9.42 (s, 2H), 11.12 (s, 1H).
Embodiment 120:N-hydroxyl-2-((1-(2-(2-methoxy pyrimidine-5-yl)-4- Morpholine thiophene [3,2-d] pyrimidine-6-yl) ethyl) (methyl) ammonia) pyrimidine-5-phosphoamide (compound 262)
Step 120a: ethyl 2-((1-(2-(2-methoxy pyrimidine-5-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) ethyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 1204-262)
Described similar method (embodiment 107) when using to description compound 1204-237, from 1203 (180 milligrams, 0.388 mM), 602 (183 milligrams, 0.777 mM), (98 milligrams of NaHCO3,1.17 mM) and (50 milligrams of two (triphenyl phosphatization hydrogen) palladium (II) chlorides, 0.02 mM), ethanol (5 milliliters), in water (2 milliliters) and the toluene (8 milliliters), the title compound 1204-262 (150 milligrams, 72%) of preparation gray solid shape: LCMS:537.2[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d6): δ 1.31 (t, J=7.2Hz, 3H), 1.74 (d, J=6.8Hz, 3H), 3.03 (s, 3H), 3.74 (s, 4H), 3.94 (s, 4H), 4.00 (s, 3H), 4.30 (q, J=7.2Hz, 2H), (6.52 s, 1H), 7.51 (s, 1H), (8.89 s, 2H), 9.42 (s, 2H).
Step 120b:N-hydroxyl-2-((1-(2-(2-methoxy pyrimidine-5-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) ethyl) (methyl) ammonia) pyrimidine-5-phosphoamide (compound 262)
The similar method of introducing when using to description compound 237 (embodiment 107), from (150 milligrams of 1204-262,0.28 mM) and recently the preparation hydroxylamine methanol solution (1.79M, 20 milliliters) the middle title compound 262 (80 milligrams, 55%) for preparing white solid: m.p.:210-215 ℃ of .LCMS:524.1[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.72 (d, J=6.8Hz, 3H), 2.98 (s, 3H), 3.74 (s, 4H), (3.92 s, 4H), 4.00 (s, 3H), 6.48 (q, J=5.2Hz, 1H), (7.48 s, 1H), 8.76 (s, 2H), 9.41 (s, 2H).
Embodiment 121:N-hydroxyl-2-(2-(2-(2-methoxy pyrimidine-5-yl)-4-morpholine Penthienate [3,2-d] pyrimidine-6-yl) third-2-base ammonia) pyrimidine-5-formamide (compound 263)
Step 121a: ethyl 2-(2-(2-(2-methoxy pyrimidine-5-yl)-4-morpholine penthienate [3,2-d] pyrimidine-6-yl) third-2-base ammonia) pyrimidine-5-carboxylic acid's salt (compound 1210-263)
The similar process (embodiment 107) that uses when using with description compound 1204-237, from 1208 (185 milligrams, 0.40 mole), borate is (189 milligrams, 0.80 mM), (101 milligrams of NaHCO3,1.20 mM) and Pd (PPh3) 4 (28 milligrams, 0.04 mM) the title compound 1210-263 (167 milligrams, 78%) of preparation white solid: LC-MS:537.3[M+1 in the solution in toluene (8 milliliters), ethanol (5 milliliters) and water (2 milliliters)] +.
Step 121b:N-hydroxyl-2-(2-(2-(2-methoxy pyrimidine-5-yl)-4-morpholine penthienate [3,2-d] pyrimidine-6-yl) third-2-base ammonia) pyrimidine-5-formamide (compound 263)
The similar method (embodiment 107) of using during according to description compound 237, from (167 milligrams of 1210-263,0.31 mM) and (20 milliliters of the hydroxylamine methanol solutions of fresh preparation, 1.79M) in, the title compound 263 (30 milligrams) of preparation white solid in CH2Cl2 (4 milliliters).M.p.202-207 ℃ of .LC-MS:524.3[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.84 (s, 6H), 3.74 (m, 4H), (3.92 m, 4H), 4.00 (s, 3H), (7.31 s, 1H), 8.38 (s, 1H), (8.43 s, 1H), 8.52 (br, 2H), (8.98 s, 1H), 9.41 (s, 2H), 10.95 (s, 1H).
Embodiment 122:2-(2-(2-(4-aminophenyl)-4-morpholine penthienate [3,2-d] Pyrimidine-6-yl) third-2-base ammonia)-N-hydroxypyrimidine-5-carboxamides (compound 269)
Step 122a: ethyl 2-(2-(2-(4-aminophenyl)-4-morpholine penthienate [3,2-d] pyrimidine-6-yl) third-2-base ammonia) pyrimidine-5-carboxylic acid's salt (compound 1210-269)
The similar process (embodiment 107) that uses when using with description compound 1204-237, from 1208 (185 milligrams, 0.40 mole), borate (0602-217) is (175 milligrams, 0.80 mM), (101 milligrams of NaHCO3,1.20 mM) and Pd (PPh3) 4 (28 milligrams, 0.04 mM) the title compound 1210-269 (100 milligrams, 48%) of preparation white solid: LC-MS:520.4[M+1 in the solution in toluene (8 milliliters), ethanol (5 milliliters) and water (2 milliliters)] +.
Step 122b:2-(2-(2-(4-aminophenyl)-4-morpholine penthienate [3,2-d] pyrimidine-6-yl) third-2-base ammonia)-N-hydroxypyrimidine-5-carboxamides (compound 269)
The similar method (embodiment 107) of using during according to description compound 237, from (100 milligrams of 1210-269,0.19 mM) and (20 milliliters of the hydroxylamine methanol solutions of fresh preparation, 1.79M) in, the title compound 269 (77 milligrams, 75%) of preparation white solid in CH2Cl2 (4 milliliters).LC-MS:507.3[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.82 (s, 6H), 3.28 (s, 1H), 3.74 (m, 4H), 3.85 (m, 4H), 5.48 (s, 2H), (6.60 d, J=8.8Hz, 2H), 7.19 (s, 1H), 8.07 (d, J=8.8Hz, 2H), (8.33 s, 1H), 8.53 (br, 2H), (8.96 s, 1H), 10.94 (s, 1H).
Embodiment 123:2-[2-(4-amino-phenyl)-4-morpholinyl-4-base-thiophene [3, 2-d] pyrimidine-6-sulphonyl ammonia]-pyrimidine-5-carboxylic acid's hydroxy amide (compound 271)
Step 123a:2-[2-(4-amino-phenyl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-sulphonyl ammonia]-pyrimidine-5-carboxylic acid's ethyl ester (compound 1304-271)
At 110 ℃, stir 1103 (270 milligrams, 0.56 mM), 4-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) aniline (368 milligrams, 1.67 mMs) and Pd (PPh under the condition of nitrogen gas 3) 4(200 milligrams, 0.3 mM) are at dioxane (9 milliliters) and saturated NaHCO 3Mixture in (3 milliliters) 3 hours.After finishing, concentration response also uses the column chromatography purifying, produces compound 1304-271 (170 milligrams, 56%).LCMS:542.3[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.28 (t, J=7.2Hz, 3H), 3.79 (t, J=4.4Hz, 4H), 3.96 (t, J=4.4Hz, 4H), 4.27 (q, J=7.2Hz, 2H), (6.62 d, J=8.4Hz, 2H), 7.85 (s, 1H), 8.08 (d, J=8.4Hz, 2H), 8.89 (s, 2H).
Step 123b:2-[2-(4-amino-phenyl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-sulphonyl ammonia]-pyrimidine-5-carboxylic acid's hydroxyl acid amides (compound 271)
The similar method (embodiment 107) of using during according to description compound 237, from (20 milliliters of the hydroxylamine methanol solutions of 1304-271 (160 milligrams) and fresh preparation, 1.79M) the middle title compound 271 (26 milligrams, 17%) for preparing white solid.M.p.:197-205 ℃ of .LCMS:529.2[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.79 (s, 4H), 3.94 (s, 4H), 6.60 (d, J=8.4Hz, 2H), 7.83 (s, 1H), 8.08 (d, J=8.4Hz, 2H), 8.76 (s, 2H), 9.16 (s, 1H), 11.18 (s, 1H).
Embodiment 124:2-(((2-(4-amino-3-chlorophenyl)-4-morpholine penthienate [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-(change of N-hydroxypyrimidine-5-carboxamides Compound 275)
Step 124a: ethyl 2-(((2-(4-ammonia-3-chlorophenyl)-4-morpholine penthienate [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-275)
In high-pressure bottle, with (516 milligrams of 4-bromos-2-chloro aminobenzen, 2.5 mM), the connection boric acid pinacol ester (952 milligrams, 3.75 mMs), [1,1 '-two (diphenylphosphine) ferrocene] (102 milligrams of palladium chlorides, 0.125 mM) and the mixture of KOAc (735 milligrams, 7.5 mMs) in anhydrous dioxane (10 milliliters) under 100 ℃ of conditions, heated 3 hours.Filter gained solution and wash solid with carrene (20 milliliters).Concentrated filtrate in a vacuum.Obtain auburn mixture, with (505 milligrams in auburn mixture and 0504,1.125 mM), (280 milligrams of NaHCO3,3.375 mM) and PdCl2 (PPh3) 2 (39 milligrams, 0.056 mM) in toluene (11 milliliters), ethanol (7 milliliters) and water (2.8 milliliters), mix.In high-pressure bottle, gained suspension is heated whole night under 130 ℃ of conditions.Be cooled to afterwards room temperature, add CH2Cl2 (10 milliliters) and water (10 milliliters) and filtering mixt.Separate organic layer, use salt water washing organic layer, also evaporate with dried over mgso.Use the dry crude product compound of column chromatography (hexane/ethyl acetate), produce the title compound of faint yellow solid shape.(478 milligrams, 78%) .LC-MS:540.3[M+1] +. 1H NMR:(400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.31 (t, J=6.8Hz, 3H), 3.24 (s, 3H), 3.74 (t, J=4.4Hz, 4H), 3.89 (t, J=4.0Hz, 4H), (4.29 q, J=6.8Hz, 2H), 5.22 (s, 2H), (5.75 s, 2H), 6.85 (d, 1H), 7.40 (s, 1H), 8.07 (dd, J=8.4Hz, 1.6Hz, 1H), (8.18 d, J=2.0Hz, 1H), 8.87 (s, 3H).
Step 124b:2-(((2-(4-amino-3-chlorophenyl)-4-morpholine penthienate [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-N-hydroxypyrimidine-5-carboxamides (compound 275)
The similar method (embodiment 107) of using during according to description compound 237, from (100 milligrams of 0603-275,0.185 mM) and (2.1 milliliters of the hydroxylamine methanol solutions of fresh preparation, 1.79M) in, the title compound 275 (20 milligrams, 21%) of the yellowish solid shape of preparation in CH2Cl2 (4 milliliters).M.p.241-246 ℃ of .LC-MS:527.4[M+1] +. 1H NMR (300MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.21 (s, 3H), 3.74 (s, 4H), 3.87 (s, 4H), 5.16 (s, 2H), 5.74 (s, 2H), 6.85 (m, 1H), 7.36 (s, 1H), (8.07 m, 1H), 8.17 (s, 1H), 8.72 (s, 2H).
Embodiment 125:2-(((2-(4-amino-3-difluorophenyl)-4-morpholine penthienate [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-(change of N-hydroxypyrimidine-5-carboxamides Compound 276)
Step 125a: ethyl 2-(((2-(4-ammonia-3-difluorophenyl)-4-morpholine penthienate [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-276)
The similar process (embodiment 124) that uses when using with description compound 0603-275, from (475 milligrams of 4-bromos-2-Fluoroaniline, 2.5 mM), (952 milligrams of connection boric acid pinacol esters, 3.75 mM), [1,1 '-two (diphenylphosphine) ferrocene] (102 milligrams of palladium chlorides, 0.125 mM) and (735 milligrams of KOAc, 7.5 mM) at the mixture of anhydrous dioxane (10 milliliters), add subsequently 0504 (505 milligrams, 1.125 mMs), NaHCO 3(280 milligrams, 3.375 mMs) and PdCl 2(PPh 3) 2(39 milligrams, 0.056 mM) solution in toluene (11 milliliters), ethanol (7 milliliters) and water (2.8 milliliters), thereby the title compound 0603-276 (503 milligrams, 85%) for preparing yellowish solid shape: LC-MS:524.3[M+1] +. 1H NMR:(400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.31 (t, J=7.2Hz, 3H), 3.27 (s, 3H), (3.75 t, J=4.8Hz, 4H), 3.89 (t, J=4.8Hz, 4H), 4.30 (q, J=7.2Hz, 2H), (5.22 s, 2H), 5.55 (s, 2H), (6.84-6.79 m, 1H), 7.40 (s, 1H), (7.97-7.91 m, 2H), 8.88 (s, 2H).
Step 125b:2-(((2-(4-amino-3-difluorophenyl)-4-morpholine penthienate [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-N-hydroxypyrimidine-5-carboxamides (compound 276)
The similar method (embodiment 107) of using when describing compound 237, from the hydroxylamine methanol solution (3.3 milliliters, concentration is 1.79M in methyl alcohol) of 0603-276 (150 milligrams, 0.286 mM) and fresh preparation at CH 2Cl 2The title compound 276 (55 milligrams, 38%) of the yellowish solid shape of preparation in (4 milliliters).M.p.203-206 ℃ of .LC-MS:511[M+1] +. 1H NMR (300MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.23 (s, 3H), 3.82 (m, 4H), (3.88 m, 4H), 5.18 (s, 2H), (5.53 s, 2H), 6.79-6.83 (m, 1H), (7.37 s, 1H), 7.91-7.96 (m, 2H), (8.74 s, 2H), 9.02 (br, 1H), 11.08 (br, 1H).
Embodiment 126:2-(((2-(4-amino-3-nitrobenzophenone)-4-morpholine penthienate [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-(change of N-hydroxypyrimidine-5-carboxamides Compound 278)
Step 126a: ethyl 2-(((2-(4-ammonia-3-nitrobenzophenone)-4-morpholine penthienate [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-278)
The similar process (embodiment 124) that uses when using with description compound 0603-275, from (543 milligrams of 4-bromos-2-nitroaniline, 2.5 mM), (952 milligrams of connection boric acid pinacol esters, 3.75 mM), [1,1 '-two (diphenylphosphine) ferrocene] (102 milligrams of palladium chlorides, 0.125 mM) and (735 milligrams of KOAc, 7.5 mM) at the mixture of anhydrous dioxane (10 milliliters), add subsequently 0504 (505 milligrams, 1.125 mM), (280 milligrams of NaHCO3,3.375 mM) and PdCl2 (PPh3) 2 (39 milligrams, 0.056 mM) at toluene (11 milliliters), solution in ethanol (7 milliliters) and the water (2.8 milliliters), thereby the title compound 0603-278 (538 milligrams, 86%) for preparing yellowish solid shape.
Step 126b:2-(((2-(4-amino-3-nitrobenzophenone)-4-morpholine penthienate [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-N-hydroxypyrimidine-5-carboxamides (compound 278)
The similar method (embodiment 107) of using during according to description compound 237, from (150 milligrams of 111-243-2,0.272 mM) and (3.3 milliliters of the hydroxylamine methanol solutions of fresh preparation, concentration is 1.79M in methyl alcohol) title compound 278 (35 milligrams, 23%) of the bright pink solid shape of preparation in CH2Cl2 (3 milliliters).M.p.202-206 ℃ of .LCMS:538.5[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.24 (s, 3H), 3.77 (m, 4H), (3.91 m, 4H), 5.19 (s, 2H), (7.10 d, J=6.6Hz, 1H), 7.44 (s, 1H), 7.69 (s, 2H), 8.37 (dd, J=6.6,1.5Hz, 1H), 8.74 (s, 2H), 9.00 (d, J=1.5Hz, 2H).
Embodiment 127:2-(((2-(4-amino-3-hydroxy base)-4-morpholine penthienate [3, 2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-N-hydroxypyrimidine-5-carboxamides (chemical combination Thing 279)
Step 127a: ethyl 2-(((2-(4-ammonia-3-hydroxy phenyl)-4-morpholine penthienate [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-279)
The similar process (embodiment 124) that uses when using with description compound 0603-275, from 2-ammonia-5-bromophenol (1 gram, 5.3 mM), 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-two (1,3,2-two assorted pentaboranes) (2.7 grams, 10.6 mM), in KOAc (1.5 gram, 15.9 mMs) and [1,1 '-two (diphenylphosphine) ferrocene] palladium chloride (200 milligrams) solution in dimethyl sulfoxide (DMSO) (15 milliliters), add 0504 (500 milligrams, 2.12 mM), 2-ammonia-5-(4,4,5,5-tetramethyl-1,3,2-, two assorted pentaborane-2-yls) phenol (dimethyl sulphoxide solution that in abovementioned steps, prepares, saturated sodium bicarbonate (2 milliliters) and Pd (PPh3) 4 (100 milligrams) be at dimethyl sulfoxide (DMSO) (50 milliliters), thereby prepare the title compound 0603-279 (200 milligrams) of yellowish solid shape.
Step 127b:2-(((2-(4-amino-3-hydroxy base)-4-morpholine penthienate [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-N-hydroxypyrimidine-5-carboxamides (compound 279)
The similar method (embodiment 107) of using during according to description compound 237, from (8 milliliters of the hydroxylamine methanol solutions of 111-247-3 (200 milligrams) and fresh preparation, concentration is 1.79M in methyl alcohol) title compound 279 (50 milligrams, 25%) of the yellowish solid shape of preparation in CH2Cl2 (3 milliliters).M.p.:214-218 ℃ of .LCMS:509[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.20 (s, 3H), 3.76 (t, J=4.4Hz, 4H), 3.88 (t, J=4.0Hz, 4H), 5.17 (s, 2H), 6.49 (s, 2H), 6.58-6.64 (m, 2H), (7.44 s, 1H), 7.73 (s, 1H), 8.69 (s, 2H).
Embodiment 128:2-(((2-(4-Amino 3 cyano phenyl)-4-morpholine penthienate [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-(change of N-hydroxypyrimidine-5-carboxamides Compound 280)
Step 128a:2-amino-5-bromobenzene formonitrile HCN (compound 0601-280)
2-anthranilo nitrile (5.0 grams, 42.3 mMs) is poured in the carrene (60 milliliters).Add NBS (7.54 grams, 42.3 mMs) and under 0 ℃ of condition, stirred 3 hours.With the carrene diluted reaction mixture and with salt water washing gained mixture, produce semifinished product with dried over mgso, use column chromatography (hexane/ethyl acetate=10/1) purification of crude goods, obtain title compound (7.20 grams, 87%). 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 6.22 (s, 2H), 6.75 (d, J=9.2Hz, 1H), 7.42 (dd, J=8.8Hz, 2.4Hz, 1H), 7.58 (s, 1H).
Step 128b: ethyl 2-(((2-(4-ammonia-3-cyano-phenyl)-4-morpholine penthienate [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-280)
At 90 ℃ of lower heating 0601-280 (500 milligrams, 2.54 mMs), 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-two (1,3,2-, two assorted pentaboranes) (775 milligrams, 3.04 mMs), KOAc are (742 milligrams, 7.62 mM) and [1,1 '-two (diphenylphosphine) ferrocene] palladium chloride (66 milligrams) mixture in anhydrous dioxane (20 milliliters) 12 hours.Filter reactant mixture and concentrated, produce the crude product 0602-280 (550 milligrams) of brown solid shape, do not need just to be further purified and in next step, to use.
In 140 ℃, stir (500 milligrams of 0602-280, the above prepares), 0504 (500 milligrams, 1.11 mM), NaHCO3 (269 milligrams, 3.2 mMs), PdCl2 (Ph3P) 2 (60 milligrams) mixture in toluene/ethanol/water (17.1 milliliters/10.5 milliliters/4.5 milliliters) whole night.Filter reactant mixture and concentrated in a vacuum.Use column chromatography to purify semifinished product, produce the 0603-280 (140 milligrams, 24%) of white solid.LCMS:531.4[M+1] +. 1HNMR, (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.31 (t, J=7.2Hz, 3H), 3.27 (s, 3H), (3.75 s, 4H), 3.91 (s, 4H), (4.29 q, J=7.2Hz, 2H), 5.22 (s, 2H), 6.44 (s, 2H), 6.87 (d, J=8.8Hz, 1H), 7.41 (s, 1H), (8.29-8.34 m, 2H), 8.88 (s, 1H).
Step 128c:2-(((2-(4-Amino 3 cyano phenyl)-4-morpholine penthienate [3,2-d] pyrimidine-6-y1) methyl) (methyl) ammonia)-N-hydroxypyrimidine-5-carboxamides (compound 280)
The similar method (embodiment 107) of using during according to description compound 237, from (150 milligrams of 0603-280,0.28 mM) and (6 milliliters of the hydroxylamine methanol solutions of fresh preparation, concentration is 1.79M in methyl alcohol) title compound 280 (20 milligrams, 14%) of preparation yellow solid shape in CH2Cl2 (2 milliliters).M.p.:237-240 ℃ of .LCMS:518.0[M+1] +. 1HNMR, (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.23 (s, 3H), 3.75 (s, 4H), 3.89 (s, 4H), 5.18 (s, 2H), 6.86 (s, 2H), 6.87 (d, J=8.4Hz, 1H), (7.38 s, 1H), 8.29-8.33 (m, 2H), 8.74 (s, 1H).
Embodiment 129:2-{[2-(3-acetyl-4-ammonia-phenyl)-4-morpholinyl-4-base-thiophene [3,2-d] Pyrimidine-6-ylmethyl]-methyl-ammonia }-pyrimidine-5-carboxylic acid's hydroxyl acid amides (compound 281)
Step 129a:1-(2-amino-5-bromo-phenyl)-ethyl ketone (compound 0601-281)
In the mixture of 1-(2-aminophenyl) ethyl ketone (5.0 grams, 0.037 mole) in carrene (60 milliliters), add NBS (7.3 grams, 0.04 mole).The gained mixture is cooled to 0 ℃, then adds H 2SO 4(0.05 milliliter).Reactant is got warm again after a cold spell to room temperature, and stirred overnight.In reactant mixture, add entry, extract, produce semifinished product with dried over mgso with carrene, use column chromatography purification of crude goods and use the ethyl acetate/hexane elution, obtain the title compound (4.6 grams, 58%) of yellow solid shape.m.p?87-89℃. 1H?NMR(400MHz，CDCl 3)：δ2.56(s，3H)，6.31(s，2H)，7.56(d，J＝8.8Hz，1H)，7.33(dd，J＝2.4Hz，1H)，7.80(d，J＝2.4Hz，1H).
Step 129b:1-[2-amino-5-(4,4,5,5-tetramethyl-[1,3,2], two assorted pentaborane-2-yls)-phenyl]-ethyl ketone (compound 0602-281)
In high-pressure bottle, with 0601-281 (1 gram, 4.7 mM), connection boric acid pinacol ester (1.66 grams, 6.5 mMs), [1,1 '-two (diphenylphosphine) ferrocene] (230 milligrams of palladium chlorides (PdCl2 (dppf)), 0.28 mM) and the mixture of KOAc (1.48 gram, 15 mMs) in anhydrous dioxane (30 milliliters) under 100 ℃ of conditions, heated 4 hours.Filter reactant mixture and use the washed with dichloromethane solid.In a vacuum concentrated filtrate, and use cylindricality chromatography purifying (3% ethyl acetate/hexane), the 0602-281 of generation pale solid shape (1 gram, 83%).m.p?45-48℃. 1H?NMR(400MHz，CDCl 3)：δ1.33(s，12H)，2.62(s，3H)，6.49(s，2H)，6.60(d，J＝8.4Hz，1H)，7.66(d，J＝8.0Hz，1H)，8.18(s，1H).
Step 129c:2-{[2-(3-acetyl-4-ammonia-phenyl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-ylmethyl]-methyl-ammonia }-pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-281)
The similar process (embodiment 99) that uses when using with description compound 1103-226 is from 0602-281 (720 milligrams, 2.7 mMs), 0504 (412 milligrams, 0.9 mM), NaHCO 3(232 milligrams, 2.7 mMs) and PdCl 2(PPh 3) 2The title compound 0603-281 (450 milligrams, 92%) of the yellowish solid shape of preparation: LCMS:548.4[M+1 in (107 milligrams) solution in toluene (7.5 milliliters), ethanol (4.8 milliliters) and water (2.1 milliliters)] +.
Step 129d:2-{[2-(3-acetyl-4-ammonia-phenyl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-ylmethyl]-methyl-ammonia }-pyrimidine-5-carboxylic acid's hydroxyl acid amides (compound 281)
The similar method (embodiment 107) of using when describing compound 237, from the hydroxylamine methanol solution (12 milliliters, concentration is 1.79M in methyl alcohol) of 0603-281 (500 milligrams) and fresh preparation at CH 2Cl 2The title compound 281 (40 milligrams) of the pale yellow solid shape of preparation in (4 milliliters).M.p.:156-158 ℃ of .LC-MS:535[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 2.61 (s, 3H), 3.23 (s, 3H), 3.76 (s, 4H), 3.90 (s, 4H), 5.19 (s, 2H), 6.84 (m, 1H), 7.40 (s, 1H), 7.53 (s, 2H), 8.27 (m, 1H), 8.78 (d, J=23.2Hz, 3H), (9.02 s, 1H), 11.09 (s, 1H).
Embodiment 130:2-(((2-(4-amino-3,5-difluoro-benzene base)-4-morpholine ring Thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-N-hydroxy pyrimidine-5-formyl Amine (compound 282)
Step 130a:2,6-two fluoro-4-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) aniline (compound 0602-282)
Use the similar method described in the compound 0602-281 (embodiment 129) of describing, from 4-bromo-2,6-difluoro-benzene amine (2.08 grams, 10 mMs), 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-two (1,3,2-, two assorted pentaboranes) (3.79 grams, 15 mMs), KOAc (3 grams, 30 mMs) and the title compound 0602-282 (3 gram) of [1,1 '-two (diphenylphosphine) ferrocene] palladium chloride (400 milligrams, 0.5 mM) preparation pale solid shape in dioxy six alkane (50 milliliters). 1H?NMR(400MHz，CDCl 3)：δ1.31(s，12H)，3.91(br，2H)，7.22-7.25(m，2H).
Step 130b: ethyl 2-(((2-(4-ammonia-3,5-difluoro-benzene base)-4-morpholine penthienate [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-282)
The similar process (embodiment 99) that uses when using with description compound 1103-226, from (500 milligrams of 0602-282,2 mMs), 0504 (300 milligrams, 0.669 mM), (168 milligrams of NaHCO3,2 mMs) and Pd (PPh3) 2Cl2 (50 milliliters) in toluene/ethanol/water (5 milliliters/3.2 milliliters/1.4 milliliters), prepare the title compound 0603-282 (200 milligrams, 55%) of yellow solid shape: 1HNMR:(400MHz, CDCl 3): δ 1.31 (t, J=7.2Hz, 3H), 3.28 (s, 3H), 3.76-3.77 (m, 4H), 3.89-3.91 (m, 4H), 4.30 (q, J=7.2Hz, 2H), (5.23 s, 2H), 5.59 (s, 2H), (7.42 s, 1H), 7.86 (d, J=9.6Hz, 2H), 8.88 (s, 2H).
Step 130c:2-(((2-(4-amino-3,5-difluoro-benzene base)-4-morpholine penthienate [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-N-hydroxypyrimidine-5-carboxamides (compound 282)
The similar method (embodiment 107) of using during according to description compound 237, from (150 milligrams of 0603-282,0.277 mM) and (4 milliliters of the hydroxylamine methanol solutions of fresh preparation, concentration is 1.79M in methyl alcohol) title compound 282 (95 milligrams, 63%) of preparation white solid in CH2Cl2 (2 milliliters).m.p.：190-193℃.LCMS：529[M+1] +. 1HNMR：(400MHz，CDCl 3)：δ3.23(s，3H)，3.75(br，4H)，3.89(br，4H)，5.18(s，2H)，5.62(s，2H)，7.39(s，1H)，7.85(d，J＝8.4Hz，2H)，8.74(s，2H)，9.02(br，1H)，11.08(s，1H).
Embodiment 131:2-{[2-(4-amino-2-fluoro-phenyl)-4-morpholinyl-4-base- Thiophene [3,2-d] pyrimidine-6-ylmethyl]-methyl-ammonia }-(change of pyrimidine-5-carboxylic acid's hydroxy amide Compound 283)
Step 131a:4-bromo-3-fluoro-phenyl amine (compound 0601-283)
3-Fluoroaniline (4.44 grams, 40 mMs), NBS (7.11 grams, 40 mMs) are introduced in the carrene (30 milliliters).Add two concentrated sulfuric acids.Under 0 ℃ of condition, stirred the gained mixture 4 hours.Then the described reactant mixture of dilute with water, and use ethyl acetate extraction.With the extract of sodium bicarbonate aqueous solution washing combination, use dried over sodium sulfate.With column chromatography (hexane/ethyl acetate=10/1) purifying crude product, produce the title compound (5.00 grams, 66%) of faint yellow solid shape.LCMS：190[M+1] +.
1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 5.53 (s, 2H), 6.34 (dd, J=8.8Hz, 3.2Hz, 1H), 6.45 (dd, J=11.6Hz, 2.4Hz, 1H), 7.18 (t, 1H).
Step 131b:2-{[2-(4-amino-2-fluoro-phenyl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-ylmethyl]-methyl-ammonia }-pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-283)
Use the similar method described in the compound 0603-275 (embodiment 124) of describing, to (500 milligrams of 0601-283,3.44 mM), 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-two (1,3,2-two assorted pentaboranes) (1.74 grams, 6.87 mMs), KOAc (842 milligrams, 8.60 mMs), [1,1 '-two (diphenylphosphine) ferrocene] palladium chloride (50 milligrams) is anhydrous 1, add 3-fluoro-4-(4,4,5 in 4-dioxy six alkane (5 milliliters), 5-tetramethyl-[1,3,2] two assorted pentaborane-2-yls)-phenyl amine, 0504 (772 milligrams, 1.72 mM), NaHCO3 (433 milligrams, 5.16 mMs), the solution of PdCl2 (Ph3P) 2 (75 milligrams) in toluene/ethanol/water (8 milliliters/4 milliliters/2 milliliters), thereby the title compound 0602-283 (250 milligrams, 28%) of preparation faint yellow solid shape.LCMS:524[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.31 (t, J=6.8Hz, 3H), 3.25 (s, 3H), (3.72 m, 4H), 3.85 (m, 4H), 3.88 (m, 2H), 4.28 (q, J=7.2Hz, 2H), 5.20 (s, 2H), 6.34 (d, J=12.8Hz, 1H), 6.43 (d, J=8.4Hz, 1H), 7.38 (s, 1H), (7.83-7.90 m, 1H), 8.86 (s, 2H).
Step 131c:2-{[2-(4-amino-2-fluoro-phenyl)-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-ylmethyl]-methyl-ammonia }-pyrimidine-5-carboxylic acid's hydroxy amide (compound 283)
The similar method of introducing when using to description compound 237 (embodiment 107), from (250 milligrams of 0603-283,0.48 mM) and recently the preparation the hydroxylamine methanol solution (concentration is 1.79M in methyl alcohol, 8 milliliters) title compound 283 (50 milligrams, 20%) of preparation white solid in CH2Cl2 (2 milliliters).M.p:195～197 ℃ .LCMS:511[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.22 (s, 3H), 3.71-3.74 (m, 4H), 3.84-3.87 (m, 4Hm), 5.18 (s, 2H), 5.74 (s, 2H), (6.34 dd, J=13.6Hz, 1.6Hz, 1H), 6.43 (dd, J=8.4Hz, 1.6Hz, 1H), 7.36 (s, 1H), (7.85 t, J=8.4Hz, 1H), 8.74 (2H, s), (9.02 br, 1H), 11.01 (br, 1H).
Embodiment 132:2-(((2-(4-amino-2-chlorophenyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-(change of N-hydroxy pyrimidine-5-phosphoamide Compound 284)
Step 132a:3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) aniline (compound 0602-284)
The similar process (embodiment 129) that uses when using with description compound 0602-281, from 4-bromo-3-chlorophenol (1.23 grams, 5.9 mM), 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-two (1,3,2-, two assorted pentaboranes) (2.2 grams, 8.9 mMs), KOAc (1.7 grams, 17.7 mM) and [1,1 '-two (diphenylphosphine) ferrocene] the title compound 0602-284 of the yellowish solid shape of preparation in the solution of palladium chloride (200 milligrams, 0.24 mM) in dimethyl sulfoxide (DMSO) (1 gram, 66.7%). 1HNMR(400MHz，CDCl 3)：δ3.84(br，2H)，1.33(s，12H)，6.49(d，J＝8.0Hz，1H)，6.44(s，1H)，7.51(d，J＝8.0Hz，1H).
Step 132b: ethyl 2-(((2-(4-ammonia-2-chlorophenyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-284)
Use described similar method when describing compound 1103-226 (embodiment 99), from 0602-284 (220 milligrams, 0.869 mM), 0504 (300 milligrams, 0.66 mM), NaHCO 3(166 milligrams, 2 mMs) and Pd (PPh 3) 2Cl 2(50 milligrams) prepare the title compound 0603-284 (200 milligrams, 55%) of yellow solid shape in toluene/ethanol/water (5 milliliters/3.2 milliliters/1.4 milliliters): 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.31 (t, J=7.2Hz, 2H), 3.72 (t, J=4.0Hz, 4H), 3.87 (t, J=4.0Hz, 4H), 4.29 (q, J=7.2Hz, 2H), 5.23 (s, 2H), 5.61 (br, 2H), 6.57 (d, J=8.4Hz, 1H), 6.67 (s, 1H), 7.41 (s, 1H), 7.60 (d, J=8.0Hz, 2H), 8.88 (s, 2H).
Step 132c:2-(((2-(4-amino-2-chlorophenyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-N-hydroxy pyrimidine-5-phosphoamide (compound 284)
The similar method of introducing when using to description compound 237 (embodiment 107), from (200 milligrams of 0603-284,0.37 mM) and recently the preparation the hydroxylamine methanol solution (concentration is 1.79M in methyl alcohol, 4 milliliters) title compound 284 (31 milligrams, 15%) of the light brown solid shape of preparation in CH2Cl2 (2 milliliters).M.p.:179-183 ℃ of .LCMS:527.0[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.22 (s, 3H), 3.72 (t, J=4.8Hz, 4H), (3.87 t, J=4.0Hz, 4H), 5.19 (s, 2H), 5.61 (s, 2H), 6.57 (dd, J=8.4Hz, 2Hz, 1H), 6.67 (s, 1H), 7.39 (s, 1H), 7.60 (d, J=8.4Hz, 2H), 8.73 (s, 2H).
Embodiment 133:2-(((2-(4-amino-3-(hydroxymethyl) phenyl)-4- Quinoline base thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-N-hydroxy pyrimidine-5- Phosphoamide (compound 285)
Step 133a:(2-amino-5-bromo phenyl) methyl alcohol (compound 0601-285)
Under 0 ℃, in the nitrogen environment, in the solution of 2-amino-5-bromo-benzoic acid (5.0 grams, 23.15 mMs) in anhydrous tetrahydro furan, dropwise add LiAlH 4(2.2 grams, 58 mMs) mixture in oxolane.The gained mixture is got warm again after a cold spell to room temperature, and stirred 2 hours.Under 0 ℃, by in reactant mixture, adding Na 2SO 410H 2The O reaction of quenching.Filter the gained mixture, filtrate is concentrated, the title compound 0601-285 of generation pale solid shape (2.05 grams, 43%), m.p.103-106 ℃.Thick product does not need just to be further purified and can use in next step. 1H?NMR(400MHz，CDCl 3)：δ4.61(s，2H)；6.56(d，J＝8.0Hz，2H，)；7.19-7.26(m，2H).
Step 133b:(2-amino-5-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) phenyl) methyl alcohol (compound 0602-285)
Use described similar method when describing compound 0602-281 (embodiment 129), from (950 milligrams of 0601-285,4.7 mM), connection boric acid pinacol ester (1.8 grams, 7.08 mM), AcOK (1.38 the gram, 14 mMs), [1,1 '-two (diphenylphosphine) ferrocene] (390 milligrams of palladium chlorides (PdCl2 (dppf)), 0.478 mM) the title compound 0602-285 (900 milligrams, 77%) of preparation yellow solid shape in anhydrous dioxane.LCMS：250.3[M+1] +.
1HNMR(400MHz，CDCl 3)：δ1.31(s，12H)；4.40(br，2H)；4.66(s，2H)；6.66(d，J＝8.0Hz，1H)；7.51(s，1H)；7.58(dd，J＝8.0Hz，1.2Hz，1H).
Step 133c: ethyl 2-(((2-(4-ammonia-3-(hydroxymethyl) phenyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-285)
Use described similar method when describing compound 1103-226 (embodiment 99), from 0602-285 (450 milligrams, 1.8 mMs), 0504 (360 milligrams, 0.8 mM), NaHCO 3(202 milligrams, 2.4 mMs), Pd (PPh 3) 2Cl 2(60 milligrams, 0.085 mM) (239 milligrams of the title compound 0603-285 of preparation faint yellow solid shape in toluene (12 milliliters), ethanol (7 milliliters) and water (3 milliliters), 55.8%): mp 215-217 ℃ .LCMS, 536.3[M+1] + 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.33, (m, 3H), 3,77 (m, 4H), 3,92 (m, 4H), 3.30 (m, 3H), (4.32 m, 2H), 4.50 (m, 2H), 5.04 (m, 1H), 5.22 (m, 2H), 5.33 (m, 2H), (6.70 m, 1H), 7.40 (m, 1H), 8.07 (m, 1H), 8.19 (m, 1H), 8.92 (s, 2H).
Step 133d:2-(((2-(4-amino-3-(hydroxymethyl) phenyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-N-hydroxy pyrimidine-5-phosphoamide (compound 285)
The similar method of introducing when using to description compound 237 (embodiment 307), from (115 milligrams of 0603-285,0.2147 mM) and the hydroxylamine methanol solution (1.79M, 30 milliliters) of recently preparation in CH2Cl2 (2 milliliters), prepare the title compound 285 (97 milligrams) of yellowish solid shape.M.p.:195-200 ℃ of .LCMS:523.0[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.17 (s, 3H); (3.76 s, 4H); (3.89 s, 4H); (4.46 s, 2H); (5.18 s, 2H); (5.33 s, 2H); (8.67 t, J=3.6Hz, 1H); (7.37 s, 1H); (8.04 d, J=7.2Hz, 1H); (8.16 s, 1H), 8.74 (s, 2H).
Embodiment 134:2-(2-[3-(2-hydroxyl-ethyoxyl)-phenyl]-4-morpholinyl-4- Base-thiophene [3,2-d] pyrimidine-6-ylmethyl }-methyl-ammonia)-pyrimidine-5-carboxylic acid's hydroxy amide (compound 289)
Step 134a:[2-(3-bromo-phenoxy group)-ethyoxyl]-tert-butyl group-dimethyl-silane (compound 0601-289)
Under the ice-water bath temperature; in the solution of 2-(3-bromo-phenoxy group)-ethanol (2.0 grams, 9.2 moles) in carrene (15 milliliters), add (1.25 grams, 1.84 mMs) imidazoles; under nitrogen protection, add subsequently TBSCl (1.67 grams, 11 mMs).In 1 hour, thin layer chromatography shows to react to be finished.Filter reactant mixture.Wash with water and leach thing, use dried over sodium sulfate.With column chromatography purification of crude goods, use the hexane/ethyl acetate elution, obtain the title product (2.65 grams, 87%) of light oily.
Step 134b:2-{3-[2-(tert-butyl group-dimethyl-silanyloxy)-ethyoxyl]-phenyl }-4,4,5,5-tetramethyl-[1,3,2] two assorted pentaboranes (compound 0602-289)
Use described similar method when describing compound 0602-281 (embodiment 129), from 0601-289 (2.65 grams, 8 mMs), connection boric acid pinacol ester, AcOK (2.36 grams, 24 mMs) and [1,1 '-two (diphenylphosphine) ferrocene] palladium chloride (PdCl2 (dppf)) (0.117 gram, 2 mMs) the title compound 0602-289 of preparation pale solid shape (1.94 grams, 64%) in anhydrous dioxane (30 milliliters).
Step 134c:2-(2-[3-(2-hydroxyl-ethyoxyl)-phenyl]-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-ylmethyl }-methyl-ammonia)-pyrimidine-5-carboxylic acid's ethyl ester (compound 0603-289)
With 0602-289 (1.94 grams, 5.1 mM), 0504 (0.5079 the gram, 1.3 mM) and NaHCO3 (0.323 gram, 3.8 mM) mixture pour in 10 milliliters of toluene (10 milliliters), ethanol (6.4 milliliters) and the water (2.8 milliliters), add subsequently Pd (PPh3) 2Cl2 (54 milligrams).Heating gained mixture whole night under 120 ℃ of conditions.Thin layer chromatography shows to react to be finished.Use the diatomite filtration reactant mixture, and use washed with dichloromethane.Use column chromatography purification of crude goods, use the hexane/ethyl acetate elution, thereby the 2-[(2-{3-[2-(tert-butyl group-dimethyl-silanyloxy) of generation pale solid shape-ethyoxyl]-phenyl }-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-ylmethyl)-methyl-ammonia]-pyrimidine-5-carboxylic acid's ethyl ester (0.71 gram, 83%).LC-MS：665[M+1] +.
With 2-[(2-{3-[2-(tert-butyl group-dimethyl-silanyloxy)-ethyoxyl]-phenyl }-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-ylmethyl)-methyl-ammonia]-(680 milligrams of pyrimidine-5-carboxylic acid's ethyl esters, 1.02 mM) pour among the THF (20 milliliters), add subsequently tetrabutyl ammonium fluoride (533 milligrams, 2.04 mMs).At room temperature stirred the gained mixture 30 minutes.Thin layer chromatography shows to react to be finished.Use the ethyl acetate diluted reaction mixture, wash with water, and use dried over mgso.With column chromatography purification of crude goods, use the hexane/ethyl acetate elution, obtain the title compound (540 milligrams, 96%) of pale solid shape.m.p.：216-220℃.LC-MS：551.3[M+1] +. 1H?NMR(400MHz，CDCl 3)：δ1.38(t，J＝6.8Hz，3H)，3.31(s，3H)，3.86(t，J＝5.2Hz，4H)，3.99-4.02(m，6H)，4.20(t，J＝4.4Hz，2H)，4.37(q，J＝7.2Hz，2H)，5.19(s，2H).7.01(dd，J＝8Hz，2Hz，1H)，7.35-7.39(m，2H).8.01-8.05(m，2H)，8.92(s，2H).
Step 134e:2-(2-[3-(2-hydroxyl-ethyoxyl)-phenyl]-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-ylmethyl }-methyl-ammonia)-pyrimidine-5-carboxylic acid's hydroxy amide (compound 289)
The similar method of introducing when using to description compound 237 (embodiment 107), from 0603-289 (100 milligrams) and recently the preparation the hydroxylamine methanol solution (concentration is 1.79M methyl alcohol, 3 milliliters) title compound 289 (70 milligrams, 71.7%) of preparation white solid in CH2Cl2 (1 milliliter).M.p.:148-152 ℃ of .LC-MS:538.0[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.24 (S, 3H), 3.75-3.78 (m, 6H), 3.92 (t, J=4.8Hz, 4H), 4.06 (t, J=5.2Hz, 2H) .4.85 (t, J=4.4Hz, 1H), (5.20 s, 2H), 7.05 (dd, J=8.0Hz, 2Hz, 1H) .7.38 (t, J=8Hz, 1H), 7.46 (s, 1H) .7.92 (s, 1H), 7.97 (d, J=3.6Hz, 1H), 8.75 (s, 2H), 9.02 (s, 1H), 11.09 (s, 1H).
Embodiment 135:N-hydroxyl-2-(((2-(3-(2-hydroxyethyl sulphur) phenyl)-4- Morpholine thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-phosphoamide (compound 290)
Step 135a:2-(3-bromo phenyl sulphur) ethanol (compound 0601-290)
3-bromo phenyl sulphur (1.5 grams, 7.93 mMs), 2-bromo ethanol (1.19 grams, 9.52 mMs) and the mixture of Cs2CO3 (5.16 grams, 15.8 mMs) in dimethyl formamide (10 milliliters) are heated to 50 ℃ whole night.Dilute described reactant mixture with ethyl acetate, and with filtering.Wash with water and leach thing and dry.Thereby produce title compound (1.5 grams, 81%) by column chromatography purification of crude goods. 1HNMR(400MHz，CDCl 3)：δ3.12(t，J＝6.0Hz，2H)，3.77(t，J＝6.4Hz，2H)，7.14(t，J＝8.0Hz，1H)，7.26-7.34(m，2H)，7.51(s，1H).
Step 135b: ethyl 2-(((2-(3-(2-hydroxyethyl sulphur) phenyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-290)
Use described similar method when describing compound 0603-275 (embodiment 124), to (487 milligrams of 0601-290,2.1 mM), connection boric acid pinacol ester (0.8 gram, 3.15 mM), (720 milligrams of AcOK, 7.35 mM) and [1,1 '-two (diphenylphosphine) ferrocene] palladium chloride (PdCl 2(dppf)) add 0504 (600 milligrams, 1.33 mMs), 0602-290, NaHCO3 (400 milligrams, 4.76 mMs), Pd (PPh in (190 milligrams, 0.26 mM) solution in dioxane 3) 2Cl 2(60 milligrams, 0.086 mM) prepare the title compound 0603-290 (525 milligrams, 60%) of faint yellow solid shape in toluene (12 milliliters), ethanol (8 milliliters) and water (6 milliliters).M.p.:144-147 ℃ of .LCMS:567.2[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.30 (t, J=6.8Hz, 3H), 3.10 (t, J=6.8Hz, 2H), 3.59-3.64 (m, 2H), (3.76 br, 4H), 3.93 (br, 4H), (4.29 q, J=6.8Hz, 2H), 4.91 (t, J=4.2Hz, 1H), 5.24 (s, 2H), 7.43-7.45 (br, 2H); (8.19 d, J=7.2Hz, 1H), 8.33 (s, 1H); (8.87 s, 2H).
Step 135c:N-hydroxyl-2-(((2-(3-(2-hydroxyethyl sulphur) phenyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-phosphoamide (compound 290)
The similar method of introducing when using to description compound 237 (embodiment 107), from (260 milligrams of 0603-290,0.46 mM) and the middle title compound 290 (97 milligrams) for preparing white solid of the hydroxylamine methanol solution (concentration is 1.79M in methyl alcohol, 30 milliliters) that recently prepares.M.p.:188-192 ℃ of .LCMS:554.0[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.10 (t, J=6.8Hz, 2H), 3.24 (s, 3H), (3.58-3.63 m, 2H), 3.76 (br, 4H), 3.92 (br, 4H), 4.99 (t, J=5.2Hz, 1H), 5.20 (s, 2H), 7.43-7.49 (br, 3H), 8.18 (d, J=6.8Hz, 1H), 8.32 (s, 1H), 8.75 (s, 2H), (9.08 br, 1H), 11.15 (s, 1H).
Embodiment 136:2-(((2-(2-fluoro-5-hydroxy phenyl)-4-morpholinyl thiophene [3, 2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-(change of N-hydroxy pyrimidine-5-phosphoamide Compound 292)
Step 136a: ethyl 2-(((2-(2-fluoro-5-hydroxy phenyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-292)
Use described similar method when describing compound 0603-275 (embodiment 124), to 3-bromo-4-fluorophenol (1.425 grams, 7.5 mM), connection boric acid pinacol ester (2.86 grams, 11.25 mM), (306 milligrams of PdCl2 (dppf), 0.375 mM), and KOAc (2.205 grams, 22.5 mM) add 0504 (1.5 grams in the solution in anhydrous dioxane (20 milliliters), 3.375 mM), (850 milligrams of NaHCO3,10.13 mM) and PdCl2 (PPh3) 2 (118 milligrams, 0.168 mM) at toluene (11 milliliters), ethanol (7 milliliters) and water (2.8 milliliters), thereby the title compound 0603-292 of preparation gray solid shape (1.32 grams, 74.9%).LCMS:525.2[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.30 (m, 3H), 3.27 (s, 3H), (3.74 m, 4H), 3.88 (m, 4H), (4.29 m, 2H), 5.24 (s, 2H), (6.83 m, 1H), 7.07 (m, 1H), (7.42 m, 2H), 8.88 (s, 2H), 9.48 (s, 1H).
Step 136b:2-(((2-(2-fluoro-5-hydroxy phenyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-N-hydroxy pyrimidine-5-phosphoamide (compound 292)
The similar method of introducing when using to description compound 237 (embodiment 107), from (560 milligrams of 0603-292,1.07 mM) and the middle title compound 292 (380 milligrams) for preparing sepia solid shape of the hydroxylamine methanol solution (concentration is 1.79M in methyl alcohol, 30 milliliters) that recently prepares.M.p.250-255 ℃ of .LCMS:512[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.24 (s, 3H), 3.73 (m, 4H), (3.88 m, 4H), 5.21 (s, 2H), (6.83 m, 1H), 7.06 (m, 1H), (7.42 m, 1H), 7.45 (s, 1H), (8.75 s, 2H), 9.04 (s, 1H), (9.45 s, 1H), 11.11 (s, 1H).
Embodiment 137:N-hydroxyl-2-(((2-(3-hydroxyl-4-nitrobenzophenone)-4-morpholine Base thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-phosphoamide (is changed Compound 293)
Step 137a:2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) phenol (compound 0602-293)
The similar process (embodiment 129) that uses when using with description compound 0602-281, from 5-bromo-2-nitrophenol (3 grams, 13.76 mM), 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-two (1,3,2-, two assorted pentaboranes) (5.25 grams, 20.69 mM), KOAc (3.75 grams, 41.28 mM) and [2,9,2,9 '-two (diphenylphosphine) ferrocene] the title compound 0602-293 of preparation yellow solid shape (2.9 grams, 80%) in the solution of palladium chloride (300 milligrams) in dioxane (100 milliliters).LCMS：266.2[M+1] +. 1HNMR(400MHz，CDCl 3)：δ1.44(s，12H)，6.80(d，J＝8.8Hz，1H)，6.84(s，1H)，8.04(d，J＝8.8Hz，1H).
Step 137b: ethyl 2-(((2-(3-hydroxyl-4-nitrobenzophenone)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-293)
Use described similar method when describing compound 1103-226 (embodiment 99), from (350 milligrams of 0602-293,1.337 mM), 0504 (300 milligrams, 0.668 mM), saturated NaHCO3 (4 milliliters) and Pd (PPh3) 4 (100 milligrams) prepare the title compound 0603-293 (100 milligrams, 27%) of yellow solid shape: LCMS:552.3[M+1 in dioxane (12 milliliters)] +. 1HNMR:(400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.36 (t, J=6.8Hz, 3H), 3.76 (s, 4H), 3.86 (s, 4H), 4.35 (d, J=6.4Hz, 2H), 5.30 (s, 2H), (7.00 d, J=7.6Hz, 1H), 7.33 (s, 1H), 7.52 (s, 1H), 7.85 (d, J=8.8Hz, 1H), 8.94 (s, 2H).
Step 137c:N-hydroxyl-2-(((2-(3-hydroxyl-4-nitrobenzophenone)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-phosphoamide (compound 293)
The similar method of introducing when using to description compound 237 (embodiment 107), from 0603-293 (130 milligrams) and recently the preparation the hydroxylamine methanol solution (concentration is 1.79M methyl alcohol, 3 milliliters) the middle title compound 293 (40 milligrams, 30%) for preparing the yellow solid shape.M.p.:258-261 ℃ of .LCMS:559[M+1] +. 1HNMR:(400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.23 (s, 3H), 3.69 (s, 4H), 3.79 (s, 4H), 5.20 (s, 2H), 6.90 (s, 1H), 7.20 (s, 1H), 7.44 (s, 1H), 7.79 (s, 1H), 8.74 (s, 2H).
Embodiment 138:N-hydroxyl-2-(((2-(3-(1-hydroxyethyl) phenyl)-4- Morpholine thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-phosphoamide (compound 294)
Step 138a: ethyl 2-(((2-(3-(1-hydroxyethyl) phenyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-294)
With 1-(3-bromo phenyl) ethyl ketone (1.00 grams, 5.02 mMs), 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-two (1,3,2-, two assorted pentaboranes) (2.55 grams, 10.05 mM), KOAc (1.23 the gram, 12.55 mM) and [1,1 '-two (diphenylphosphine) ferrocene] palladium chloride (100 milligrams) is poured in anhydrous Isosorbide-5-Nitrae-dioxy six alkane (10 milliliters) and 100 ℃ of lower heating 3 hours.After being cooled to room temperature, reactant mixture is filtered and concentrates.Separate the thick product (1.2 gram) of brown solid shape and use in next step without just being further purified.
Under 130 ℃ of conditions, with 0602-294 (1.2 grams, the above prepares), 0504 (563 milligrams, 1.26 mMs), NaHCO 3(318 milligrams, 3.78 mMs), PdCl 2(Ph 3P) 2(55 milligrams), the mixture stirred overnight in toluene/ethanol/water (4 milliliters/2 milliliters/1 milliliter).The filtration reactant mixture is also concentrating.By the column chromatography purifying crude product; obtain the ethyl 2-(((2-(3-acetylphenyl)-4-morpholinyl thiophene [3 of pale solid shape; 2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (350 milligrams, 52%).LCMS 533.3[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.31 (t, J=7.2Hz, 3H), 2.66 (s, 3H), 3.30 (s, 3H), 3.76-3.80 (m, 4H), 3.92-3.97 (m, 4H), 4.29 (q, J=7.2Hz, 2H), 4.79-4.84 (m, 1H), 5.24 (s, 2H), (7.40-7.49 m, 2H), 7.49 (s, 1H), 8.07 (dd, J=6.4Hz, 1.6Hz, 1H), 8.63 (d, J=7.6Hz, 1H), 8.88 (s, 2H), 8.90 (s, 1H).
Stir at ambient temperature ethyl 2-(((2-(3-acetylphenyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (350 milligrams, 0.66 mM), NaBH 4(124 milligrams, 3.29 mMs) mixture in anhydrous tetrahydro furan 0.5 hour.Extract with the water-quenching reactant mixture and with carrene.The organic facies of the combination that obtains is by the salt water washing, and uses dried over mgso.Can obtain the thick product 0603-294 (200 milligrams, 57%) of white solid after the filtration, this product does not just need to be further purified and can use in next step reaction.LCMS:535.4[M+1 +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.31 (t, J=7.2Hz, 3H), 1.38 (d, J=6.4Hz, 3H), 3.28 (s, 3H), 3.76-3.80 (m, 4H), (3.92-3.97 m, 4H), 4.29 (q, J=7.2Hz, 2H), (4.79-4.84 m, 1H), 5.24 (s, 2H), 7.40-7.49 (m, 2H), 7.49 (s, 1H), 8.23-8.26 (m, 1H), (8.39 s, 1H), 8.88 (s, 2H).
Step 138b:N-hydroxyl-2-(((2-(3-(1-hydroxyethyl) phenyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-phosphoamide (compound 294)
The similar method (embodiment 107) of using during according to description compound 237, from (200 milligrams of 0603-294,0.37 mM) and (8 milliliters of the hydroxylamine methanol solutions of fresh preparation, concentration is 1.79M in methyl alcohol) title compound 294 (70 milligrams, productive rate is 36%) of the yellowish solid shape of preparation in carrene (2 milliliters).M.p.:168～171 ℃ .LCMS:522.0[M+1] +. 1H-NMR, (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ (ppm) 1.37 (d, J=6.0Hz, 3H), 3.24 (s, 3H), (3.77 s, 4H), 3.93 (s, 4H), (4.81 br, 1H), 5.20 (s, 3H), 7.39-7.47 (3H, m), 8.25 (d, J=6.0Hz, 1H), (8.38 s, 1H), 8.75 (s, 2H), (9.02 s, 1H), 11.09 (s, 1H).
Embodiment 139:2-(((2-(2-fluoro-5-(1-hydroxyethyl) phenyl)-4- Quinoline base thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-N-hydroxy pyrimidine-5- Phosphoamide (compound 295)
Step 139a: ethyl 2-(((2-(5-acetyl group-2-difluorophenyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-295)
The similar process (embodiment 124) that uses when using with description compound 0603-275, from (500 milligrams of 1-(3-bromo-4-difluorophenyl) ethyl ketones, 2.3 mM), 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-two (1,3,2-, two assorted pentaboranes) (1.17 grams, 4.6 mM), KOAc (1.35 grams, 6.9 mM) and [1,1 '-two (diphenylphosphine) ferrocene] palladium chloride solution in Isosorbide-5-Nitrae-dioxy six alkane (10 milliliters) in, add 0504 (516 milligrams, 1.15 mMs), NaHCO 3(290 milligrams, 3.45 mM), (40 milligrams of two (triphenylphosphine) palladium chlorides, 0.06 mM) solution in ethanol (5 milliliters), water (10 milliliters), toluene (2.5 milliliters), thereby the title compound 0603-295 (500 milligrams, 79%) of preparation faint yellow solid shape.
Step 139b:2-(((2-(2-fluoro-5-(1-hydroxyethyl) phenyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia)-N-hydroxy pyrimidine-5-phosphoamide (compound 295)
Stir at ambient temperature 0603-295 (180 milligrams, 0.33 mM), NaBH 4The mixture of (110 milligrams, 1.3 mMs) and oxolane (10 milliliters) 2 hours.Add entry in the reactant mixture and extract with carrene.With the organic facies of salt water washing combination and use dried over mgso.Obtain the semifinished product (180 milligrams) of pale solid shape after concentrated and use in next step without just being further purified.
Pour ethoxy intermediate (160 milligrams, 0.29 mM) into NH 2In the OH methanol solution (20 milliliters, concentration is 1.79M in methyl alcohol), and stirred 1 hour.With acetic acid the pH value of reactant mixture is adjusted to 6, concentrated subsequently.With water residue is ground and filters.Use the preparation high performance liquid chromatography (HPLC) to purify semifinished product, produce the title compound 295 (45 milligrams, 29%) of white solid.M.p.:230-235 ℃ of .LCMS:540.0[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.34 (d, J=6.4Hz, 3H), 3.23 (s, 3H), 3.72-3.75 (m, 4H), 3.87-3.90 (m, 4H), 4.78 (q, J=6.4Hz, 1H), (5.21 s, 2H), 7.21 (dd, J=10.8Hz, 8.4Hz, 1H), (7.43 d, J=1.2Hz, 1H), 7.48 (s, 1H), (7.96 dd, J=7.6Hz, 2.4Hz, 1H), 8.74 (s, 2H), 9.15 (br, 1H), 11.13 (s, 1H).
Embodiment 140:(S)-N-hydroxyl-2-(((2-(3-(1-hydroxyethyl) phenyl) -4-morpholine thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-phosphinylidyne Amine (compound 296)
Step 140a:(S)-ethyl 2-(((2-(3-(1-hydroxyethyl) phenyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-296)
The similar process (embodiment 124) that uses when using with description compound 0603-275, from (500 milligrams of 1-(3-bromo phenyl) ethanol, 2.49 mM), 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-two (1,3,2-, two assorted pentaboranes) (1.26 grams, 4.98 mMs), KOAc (6.1 grams, 6.22 mM) and [1,1 '-two (diphenylphosphine) ferrocene] in the solution of palladium chloride (50 milligrams) in dimethyl sulfoxide (DMSO) (10 milliliters), add 0504 (400 milligrams, 0.89 mM), NaHCO 3(150 milligrams, 1.78 mMs), PdCl 2(Ph 3P) 2(40 milligrams) solution in toluene/ethanol/water (12 milliliters/6 milliliters/3 milliliters), thereby the title compound 0603-296 (400 milligrams, 82%) of preparation pale solid shape.LCMS:535.0[M+1] +. 1H-NMR, (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ (ppm) 1.31 (t, J=6.8Hz, 3H), 1.37 (d, J=6.4Hz, 3H), 3.28 (s, 3H), (3.76-3.78 m, 4H), 3.92-3.95 (m, 4H), (4.28 q, J=6.8Hz, 2H), 4.78-4.84 (m, 1H), 5.17 (d, J=4.4Hz, 1H), 5.24 (s, 2H), (5.24 1H, s), 7.39-7.44 (m, 2H), 7.45 (s, 1H), (8.22-8.26 m, 1H), 8.39 (s, 1H), 8.90 (s, 2H).
Step 140b:(S)-N-hydroxyl-2-(((2-(3-(1-hydroxyethyl) phenyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-phosphoamide (compound 296)
The similar method (embodiment 107) of using during according to description compound 237, from (200 milligrams of 0603-296,0.37 mM) and (10 milliliters of the hydroxylamine methanol solutions of fresh preparation, concentration is 1.79M in methyl alcohol) title compound 296 (110 milligrams, 57%) of preparation white solid in carrene (4 milliliters).M.p.:168-172 ℃ of .LCMS:522.0[M+1]. 1H-NMR, (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ (ppm) 1.37 (d, J=6.4Hz, 3H), 3.22 (s, 3H), 3.77 (m, 4H), 3.93 (m, 4H), 4.81 (br, 1H), 5.20 (s, 2H), 5.24 (1H, s), 7.41-7.48 (m, 3H), 8.25 (d, J=6.4Hz, 1H), (8.39 s, 1H), 8.75 (s, 2H).
Embodiment 141:(R)-N-hydroxyl-2-(((2-(3-(1-hydroxyethyl) phenyl) -4-morpholine thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-phosphinylidyne Amine (compound 297)
Step 141a:(R)-ethyl 2-(((2-(3-(1-hydroxyethyl) phenyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-297)
The similar process (embodiment 124) that uses when using with description compound 0603-275, from (500 milligrams of (R) 1-(3-bromo phenyl) ethanol, 2.49 mM), 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-two (1,3,2-, two assorted pentaboranes) (1.26 grams, 4.98 mMs), KOAc (6.10 grams, 6.22 mM) and [1,1 '-two (diphenylphosphine) ferrocene] in the solution of palladium chloride (50 milligrams) in dimethyl sulfoxide (DMSO) (10 milliliters), add 0504 (350 milligrams, 0.89 mM), NaHCO 3(150 milligrams, 1.78 mMs), PdCl 2(Ph 3P) 2(40 milligrams) solution in toluene/ethanol/water (12 milliliters/6 milliliters/3 milliliters), thereby the title compound 0603-297 (350 milligrams, 74%) of preparation pale solid shape.LCMS:535.0[M+1] +. 1H-NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.30 (t, J=7.2Hz, 3H), 1.37 (d, J=6.4Hz, 3H), 3.28 (s, 3H), (3.75-3.78 m, 4H), 3.92-3.95 (m, 4H), (4.28 q, J=7.2Hz, 2H), 4.78-4.84 (m, 1H), 5.17 (d, J=4.4Hz, 1H), 5.24 (s, 2H), (5.24 1H, s), 7.39-7.44 (m, 2H), 7.45 (s, 1H), (8.22-8.26 m, 1H), 8.39 (s, 1H), 8.90 (s, 2H).
Step 141b:(R)-N-hydroxyl-2-(((2-(3-(1-hydroxyethyl) phenyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-phosphoamide (compound 297)
The similar method (embodiment 107) of using during according to description compound 237, from (200 milligrams of 0603-297,0.37 mM) and (10 milliliters of the hydroxylamine methanol solutions of fresh preparation, concentration is 1.79M in methyl alcohol) title compound 297 (130 milligrams, 67%) of preparation white solid in carrene (4 milliliters).M.p.:169-173 ℃ of .LCMS:522.0[M+1]. 1H-NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.37 (d, J=6.4Hz, 3H), 3.25 (s, 3H), (3.77 m, 4H), 3.93 (m, 4H), 4.80-4.84 (m, 1H), 5.21 (s, 2H), 5.22 (1H, s), (7.40-7.48 m, 3H), 8.25 (d, J=6.8Hz, 1H), (8.39 s, 1H), 8.75 (s, 2H), (9.05 br, 1H), 11.14 (br, 1H)
Embodiment 142:2-(4-aminophenyl)-N-((1-(5-(hydroxyl carbamyl) Pyrimidine-2-base) piperidin-4-yl) methyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-phosphinylidyne Amine (compound 307)
Step 142a:2-chloro-4-morpholinyl thiophene [3,2-d] pyrimidine-6-carboxylic acid (compound 1401)
0112 (5 grams, 17.67 mMs) are suspended in the carrene (100 milliliters), add subsequently mCPBA (75%, 4g, 22.97 mMs).Heating gained mixture also refluxed 24 hours.After finishing, mixture is cooled to room temperature and is concentrated to 1/2 volume.Filtering mixt obtains the crude product yellow solid, and this crude product is recrystallized from hexane/ethyl acetate=1/1, produces the title compound (3.2 grams, 61%) of faint yellow solid shape. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.74-3.3.78 (m, 4H), 3.92-3.95 (m, 4H), 7.86 (s, 1H).
Step 142b: ethyl 2-(4-((2-chloro-4-morpholinyl thiophene [3,2-d] pyrimidine-6-formamide) methyl) piperidin-1-yl) pyrimidine-5-carboxylic acid's salt (compound 1402)
Under 0 ℃, to (644 milligrams of 1401 (400 milligrams, 1.34 mMs), 0401 (384 milligrams, 1.47 mMs) and TBTU, 2.07 mM) add DIPEA (518 milligrams, 4.02 mMs) in the suspension in carrene (80 milliliters).Stirred reaction mixture is 1 hour at ambient temperature.With the carrene diluted reaction mixture and wash with water.Grind thick product and filter the title compound (473 milligrams, 65%) of generation white solid with water. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.15-1.43 (m, 7H), 1.78-1.82 (m, 2H), 1.82-1.84 (m, 1H), 2.98-3.15 (m, 2H), 3.77 (br, 4H); (3.93 br, 4H), 4.25-4.28 (m, 2H), 4.75-4.78 (m, 2H), 8.02 (s, 1H), 8.78 (s, 2H), 9.02-9.06 (m, 1H).
Step 142c: ethyl 2-(4-((2-(4-aminophenyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-formamide) methyl) piperidin-1-yl) pyrimidine-5-carboxylic acid's salt. (compound 1403-307)
With 1402 (300 milligrams, 0.55 mM), 4-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) aniline (180 milligrams, 0.82 mM) and Pd (PPh 3) 2Cl 2(12 milligrams) are poured in toluene (6 milliliters), ethanol (3.6 milliliters) and the water (1.2 milliliters), at 120 ℃, stir the mixture under the condition of nitrogen gas 2 hours.After reaction is finished, with ice-water-bath cooling, add subsequently entry (50 milliliters).Stirred afterwards solid collected by filtration, and use column chromatography purifying, the title compound (200 milligrams, 60%) of generation white solid 1 hour. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.10-1.40 (m, 7H), 1.80-2.00 (m, 3H), 2.98-3.10 (m, 2H), 3.21-3.25 (m, 2H), 3.80 (br, 4H); (3.99 br, 4H), 4.26 (t, J=6.8Hz, 2H), 4.75-4.79 (m, 2H), (5.55 s, 2H), 6.62 (d, J=8.4Hz, 2H), 8.06 (s, 1H), (8.10 d, J=8.8Hz, 2H), 8.77 (s, 2H), 8.95 (br, 1H).
Step 142d:2-(4-aminophenyl)-N-((1-(5-(hydroxyl carbamyl) pyrimidine-2-base) piperidin-4-yl) methyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-phosphoamide (compound 307)
Pour 1403-307 (190 milligrams, 0.32 mM) NH of firm preparation into 2In OH methanol solution (20 milliliters, concentration is 1.79M in methyl alcohol) and the carrene (3 milliliters).Sealing gained mixture and stirred reaction mixture 4 hours at ambient temperature.Reaction uses the pH value of aqueous hydrochloric acid solution (1.2M) conditioned reaction solution to be 7-8 after finishing.Add entry, subsequent filtration produces the product (130 milligrams, 70%) of yellow solid shape.M.p:232-238 ℃ of .LCMS:590.0[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.09 (m, 2H), 1.79 (d, J=11.6Hz, 2H), 1.93 (m, 1H), 2.93-2.99 (m, 2H), 3.21-3.31 (m, 2H), 3.80 (br, 4H), 3.96 (br, 4H), 4.72 (d, J=13.2Hz, 2H), 5.55 (s, 2H), 6.62 (d, J=8.4Hz, 2H), 8.07-8.12 (m, 3H), 8.66 (s, 2H), (8.95 d, J=10.0Hz, 2H), 11.03 (s, 1H).
Embodiment 143:N-((1-(5-(hydroxyl carbamyl) pyrimidine-2-base) piperidines -4-yl) methyl)-2-(6-(methyl ammonia) pyridin-3-yl)-4-morpholinyl thiophene [3, 2-d] pyrimidine-6-phosphoamide (compound 308)
Step 143a: ethyl 2-(4-((2-(6-(methyl ammonia) pyridin-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-formamide) methyl) piperidin-1-yl) pyrimidine-5-carboxylic acid's salt (compound 1403-308)
The similar process (embodiment 142) that uses when using with description compound 1403-307, from 1402 (240 milligrams, 0.44 mole), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) pyridine-2-amine (154 milligrams, 0.66 mM), NaHCO 3(111 milligrams, 1.3 mMs) and Pd (PPh 3) 2Cl 2The title compound 0403-308 (110 milligrams, 41%) of preparation yellow solid shape in (9.6 milligrams) solution in toluene (8 milliliters), ethanol (4.8 milliliters) and water (1.6 milliliters). 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.16-1.20 (m, 2H), 1.29 (t, J=7.2Hz, 3H), 1.78-1.82 (m, 2H), 1.95-2.00 (m, 1H), 2.84 (d, J=4.4Hz, 3H), (3.01 t, J=11.6Hz, 2H), 3.21-3.24 (m, 2H), 3.79 (t, J=5.2Hz, 4H), (3.98 t, J=4.8Hz, 4H), 4.26 (q, J=6.8Hz, 2H), 4.76 (d, J=12.6Hz, 2H), 6.52 (d, J=8.8Hz, 2H), (6.91 d, J=4.8Hz, 1H), 8.11 (s, 1H), 8.27 (dd, J=8.8Hz, 2Hz, 1H), 8.76 (s, 2H), 8.91 (t, J=4.2Hz, 1H), 9.04 (s, 1H).
Step 143b:N-((1-(5-(hydroxyl carbamyl) pyrimidine-2-base) piperidin-4-yl) methyl)-2-(6-(methyl ammonia) pyridin-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-phosphoamide (compound 308)
The similar method (embodiment 142) of using during according to description compound 307, from (110 milligrams of 1403-308,0.18 mM) and (20 milliliters of the hydroxylamine methanol solutions of fresh preparation, concentration is 1.79M in methyl alcohol) title compound 308 (55 milligrams, 51%) of preparation white solid in carrene (3 milliliters).m.p：215-218℃.LCMS：605.0[M+1] +.
1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.16-1.23 (m, 2H), 1.78-1.82 (m, 2H), 1.90-1.94 (m, 1H), 2.84 (d, J=4.8Hz, 3H), 2.93 (t, J=4.8Hz, 2H), 3.21-3.24 (m, 2H), 3.80 (t, J=5.2Hz, 4H), 3.98 (t, J=4.8Hz, 4H), (4.72 d, J=13.2Hz, 2H), 6.51 (d, J=8.8Hz, 2H), 6.96 (d, J=4.8Hz, 1H), 8.11 (s, 1H), 8.27 (dd, J=8.8Hz, 2Hz, 1H), 8.66 (s, 2H), 8.96 (d, J=13.2Hz, 2H), (9.04 s, 1H), 11.05 (s, 1H).
Embodiment 144:N-hydroxyl-2-(4-((2-(6-(methyl ammonia) pyridin-3-yl) -4-morpholine thiophene [3,2-d] pyrimidine-6-sulfonamide) methyl) piperidin-1-yl) pyrimidine-5- Phosphoamide (compound 310)
Step 144a: ethyl 2-(4-((2-(6-(methyl ammonia) pyridin-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-sulfonamide) methyl) piperidin-1-yl) pyrimidine-5-carboxylic acid's salt (compound 1405-310)
The similar process (embodiment 142) that uses when using with description compound 1403-307, from 1404 (400 milligrams, 0.704 mole), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) pyridine-2-amine (247 milligrams, 1.06 mMs), NaHCO 3(177 milligrams, 2.11 mMs) and (PPh 3) 4The title compound 0405-310 (350 milligrams, 78%) of preparation yellow solid shape in the solution of Pd (40 milligrams, 0.035 mM) in toluene (8 milliliters), ethanol (16 milliliters) and water (4 milliliters).LCMS:654.0[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.07～1.13 (m, 2H), 1.28 (t, J=7.2Hz, 3H), 1.76～1.79 (m, 3H), 2.78～3.00 (m, 7H), (3.80 t, J=4.4Hz, 4H), 3.97 (t, J=4.4Hz, 4H), 4.25 (q, J=6.8Hz, 2H), 4.72 (d, J=12.4Hz, 2H), (6.52 d, J=8.8Hz, 1H), 6.97 (d, J=4.4Hz, 1H), 7.60 (d, J=6.4Hz, 1H), 7.82 (s, 1H), 8.29 (d, J=4.4Hz, 1H), 8.34 (s, 1H), (8.75 s, 2H), 9.04 (s, 1H).
Step 144b:N-hydroxyl-2-(4-((2-(6-(methyl ammonia) pyridin-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-sulfonamide) methyl) piperidin-1-yl) pyrimidine-5-phosphoamide (compound 310)
The similar method (embodiment 142) of using during according to description compound 307, from (200 milligrams of 1405-310,0.306 mM) and (25 milliliters of the hydroxylamine methanol solutions of fresh preparation, concentration is 1.79M in methyl alcohol) title compound 310 (183 milligrams, 94%) of preparation white solid in carrene (3 milliliters).M.p.：190-197℃.LCMS：641.0[M+1] +.
1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.02～1.11 (m, 2H), 1.74～1.77 (m, 3H), 2.83～2.94 (m, 7H), (3.79 t, J=4.4Hz, 4H), 3.97 (t, J=4.4Hz, 4H), (4.67 d, J=12.8Hz, 2H), 6.52 (d, J=8.8Hz, 1H), 6.99 (d, J=4.8Hz, 1H), 7.82 (s, 1H), 8.28 (dd, J=8.8Hz, 2Hz, 1H), (8.63 s, 2H), 9.03 (d, J=2.4Hz, 1H).
Embodiment 145:N-hydroxyl-2-(methyl ((7-morpholinyl-5-(2-(three fluoro first Base)-and 1H-benzo [d] imidazoles-5-yl) benzo [b] thiophene-2-yl) methyl) ammonia) pyrimidine -5-phosphoamide (compound 318)
Step 145a:5-bromo-2-(three fluoro methyl)-1H-benzo [d] imidazoles (compound 0601-318)
With 4-bromobenzene-1, the mixture of 2-diamines (3.0 grams, 16.0 mMs), trifluoroacetic acid (9.5 milliliters, 128.3 mMs) and the HCl aqueous solution (3M, 32 milliliters) adds hot reflux whole night.Concentrated reaction mixture also uses the column chromatography purifying, produces title compound (2.60 grams, 60%).LCMS:265.0[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 7.52 (dd, J=8.8Hz, 1.2Hz, 1H), 7.69 (d, J=8.4Hz, 1H), 7.95 (s, 1H), 14.20 (br, 1H).
Step 145b: ethyl 2-(methyl ((7-morpholinyl-5-(2-(three fluoro methyl)-1H-benzo [d] imidazoles-5-yl) benzo [b] thiophene-2-yl) methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-318)
With 0601-318 (100 milligrams, 0.38 mM), 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-two (1,3,2-, two assorted pentaboranes) (107 milligrams, 0.42 mM), [1,1 '-two (diphenylphosphine) ferrocene] palladium chloride (PdCl2 (dppf)) (10 milligrams) and the mixture of KOAc (74 milligrams, 0.76 mM) in anhydrous dioxane (2 milliliters) stirred overnight under 100 ℃ of conditions.The filtration reactant mixture is also concentrating.Obtain the semifinished product (150 milligrams) of brown solid shape, this semifinished product does not need just to be further purified and can use in next step.
Above-mentioned crude product borate, 0504 (119 milligrams, 0.27 mM), PdCl 2(Ph 3P) 2(10 milligrams), NaHCO 3(68 milligrams, 0.81 mM) are introduced in toluene/ethanol/water (4 milliliters/2 milliliters/1 milliliter) and stirred 3 hours under 130 ℃ of conditions.The filtration reactant mixture is also concentrating.With column chromatography purifying residue, produce the title compound (129 milligrams, 80%) of pale solid shape. 1HNMR, (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.30 (t, J=6.8Hz, 3H), 3.28 (s, 3H), (3.77-3.81 m, 4H), 3.95-3.97 (m, 4H), 4.28 (q, J=6.4Hz, 2H), 5.24 (s, 2H), 7.50 (s, 1H), 7.75 (br, 1H), 8.48 (br, 1H), 8.48 (d, J=7.6Hz, 1H), (8.73 s, 1H), 8.87 (s, 2H).
Step 145c:N-hydroxyl-2-(methyl ((7-morpholinyl o-5-(2-(tri fluoro methyl)-1H-benzo [d] imidazoles-5-yl) benzo [b] thiophene-2-yl) methyl) ammonia) pyrimidine-5-phosphoamide (compound 318)
The similar method (embodiment 107) of using during according to description compound 307, from (100 milligrams of 0603-318,0.167 mM) and (2 milliliters of the hydroxylamine methanol solutions of fresh preparation, concentration is 1.79M in methyl alcohol) the middle title compound 318 (15 milligrams, 15%) for preparing a pale solid shape.M.p.＞300 ℃ .LCMS:586[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.25 (s, 3H), 3.77-3.80 (m, 4H), (3.95-3.97 m, 4H), 5.22 (s, 2H), (7.50 s, 1H), 7.70 (d, J=8.4Hz, 0.5H), 7.88 (d, J=8.4Hz, 0.5H), (8.44 d, J=8.4Hz, 0.5H), (8.52 d, J=8.4Hz, 0.5H), (8.65 s, 0.5H), 8.81 (s, 0.5H), 8.76 (s, 2H), (9.02 s, 1H), 11.09 (s, 1H), 14.03 (s, 1H).
Embodiment 146:N-hydroxyl-5-(4-(6-((4-(sulfonyloxy methyl) piperazine-1- Base) methyl)-and 4-morpholinyl thiophene [3,2-d] pyrimidine-2-base) phenoxy group) pentanamide (compound 319)
Step 146a:5-(4-bromo-phenoxy group)-ethyl valerate (compound 1502-319)
80 ℃ of lower heating 4-bromo-phenol (12 grams, 68.0 mMs), Cs2CO3 (44.0 grams, 0.136 mM), the mixture of 5-bromo-ethyl valerate (16.9 grams, 82.0 mMs) in dimethyl formamide 4 hours.The dilute with water reactant mixture is also used ethyl acetate extraction.Wash the organic facies of combination with water and use dried over sodium sulfate.Use the preparation column chromatography to purify semifinished product, produce the title compound 1502-319 (16.0 gram) of oily. 1HNMR(400MHz，CDCl 3)：δ1.25(t，J＝7.2Hz，3H)；1.81(m，4H)；2.35-2.39(m，2H)，3.93(t，J＝6.0Hz，2H)，4.13(q，J＝7.2Hz，2H)，6.76(d，J＝8.8Hz，2H)，7.35(d，J＝8.8Hz，2H).
Step 146b: ethyl 5-(4-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) phenoxy group) valerate (compound 1503-319)
In anhydrous dioxane, add hot reflux 1502-319 (5.0 grams, 0.0167 mM), connection boric acid pinacol ester (6.4 grams, 0.025 mole), [1,1 '-two (diphenylphosphine) ferrocene] (610 milligrams of palladium chlorides (PdCl2 (dppf)), 0.835 mM), the mixture of KOAc (5 gram, 0.05 mole) whole night.With the ethyl acetate/hexane diluted reaction mixture and stirred 30 minutes.Solids removed by filtration, the concentrated title compound 1503-319 (3.5 grams, 60%) that produces the brown solid shape. 1HNMR：(400MHz，CDCl 3)：δ1.28(t，J＝7.2Hz，3H)，1.33(s，12H)，1.82(br，4H)，2.37(m，2H)，3.99(m，2H)，4.13(q，J＝7.2Hz，2H)，6.87(d，J＝8.8Hz，2H)，7.73(d，J＝8.4Hz，2H).
Step 146c: ethyl 5-(4-(6-((4-(sulfonyloxy methyl) piperazine-1-yl) methyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-2-base) phenoxy group) valerate (compound 1504-319)
In nitrogen environment, at 108 ℃ of lower heating 1503-319 (350 milligrams, 1 mM), 0113 (300 milligrams, 0.486 mM), NaHCO 3(126 milligrams, 1.5 mMs) and the mixture of two (triphenylphosphine) palladium chloride (40 milligrams, 0.057 mM) in toluene (12 milliliters), ethanol (8.0 milliliters) and water (3.0 milliliters) 4 hours.The reactant mixture portions is put into ethyl acetate also separates with water.With column chromatography purification of crude goods thing, produce the title compound (180 milligrams, 60%) of yellowish solid shape.m.p.：110-114℃.LCMS：618.4[M+1] +. 1H?NMR：(400MHz，CDCl 3)：δ1.26(t，J＝7.2Hz，3H)，1.85(m，4H)，2.39(t，J＝6.8Hz，2H)，2.67(t，J＝4.8Hz，4H)，2.80(s，3H)，3.29(t，J＝4.8Hz，4H)，3.86-3.90(m，6H)，4.03-4.05(m，6H)，4.14(q，J＝6.8Hz，2H)，6.95(d，J＝8.8Hz，2H)，7.31(s，1H)，8.37(d，J＝8.8Hz，2H).
Step 146d:N-hydroxyl-5-(4-(6-((4-(sulfonyloxy methyl) piperazine-1-yl) methyl)-4-morpholine thiophene [3,2-d] pyrimidine-2-base) phenoxy group) pentanamide (compound 319)
The similar method (embodiment 107) of using during according to description compound 307, from (150 milligrams of 1504-319,0.243 mM) and (30 milliliters of the hydroxylamine methanol solutions of fresh preparation, concentration is 1.79M in methyl alcohol) the middle title compound 319 (100 milligrams, 66%) for preparing a white solid.M.p.140-144 ℃ of .LC-MS:605.2[M+1] +. 1H NMR:(400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.66-1.72 (br, 4H), 2.01-2.04 (m, 2H), 2.59 (m, 4H), 2.90 (s, 3H), 3.16 (d, J=3.6Hz, 4H); (3.80 t, J=4.0Hz, 4H), 3.95-4.05 (m, 8H), 7.01 (d, J=8.8Hz, 2H), 7.38 (s, 1H), 8.33 (d, J=8.8Hz, 2H), 10.39 (br, 1H).
Embodiment 147:N-hydroxyl-6-(4-(6-((4-(sulfonyloxy methyl) piperazine-1- Base) methyl)-and 4-morpholinyl thiophene [3,2-d] pyrimidine-2-base) phenoxy group) caproamide (change Compound 320)
Step 147a: ethyl 6-(4-bromo phenoxy group) caproate (compound 1502-320)
The similar method (embodiment 146) of using during according to description compound 1502-319, from 4-bromo-phenol (3.0 grams, 17.34 mM), Cs2CO3 (11.3 the gram, 34.68 mM), ethyl 6-bromonexanoic acid salt (16.9 the gram, 82 mMs) the title compound 1502-320 of preparation oily in dimethyl formamide (4 grams, 74%). 1HNMR(400MHz，CDCl 3)：δ1.25(t，J＝7.2Hz，3H)，1.54(q，J＝8.4Hz，2H)，1.66-1.73(m，2H)；1.74-1.82(m，2H)，2.32(t，J＝7.6Hz，2H)，3.91(t，J＝6.4Hz，2H)，4.13(q，J＝7.2Hz，2H)，6.75(d，J＝9.2Hz，2H)，7.35(d，J＝8.8Hz，2H).
Step 147b: ethyl 6-(4-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) phenoxy group) caproate (compound 1503-320)
The similar method (embodiment 146) of using during according to description compound 1502-319, from 1502-320 (2.0 grams, g, 6.35 mM), connection boric acid pinacol ester (2.42 grams, 9.5 mM), [1,1 '-two (diphenylphosphine) ferrocene] (300 milligrams of palladium chlorides (PdCl2 (dppf)), 0.41 mM), the title compound 1503-320 of KOAc (1.86 gram, 19.0 mMs) brown oily of preparation in anhydrous dioxane. 1HNMR：(400MHz，CDCl 3)：δ1.25(t，J＝7.2Hz，3H)，1.33(s，12H)，1.46-1.54(m，2H)，1.63-1.73(m，2H)，1.77-1.84(m，2H)，2.32(t，J＝7.2Hz，2H)，3.98(t，J＝6.4Hz，2H)；4.13(q，J＝7.2Hz，2H)，6.87(d，J＝8.8Hz，2H)，7.73(d，J＝8.8Hz，2H).
Step 147c: ethyl 6-(4-(6-((4-(sulfonyloxy methyl) piperazine-1-yl) methyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-2-base) phenoxy group) caproate (compound 1504-320)
The similar process (embodiment 146) that uses when using with description compound 1504-319, from (420 milligrams of 1503-320,1.16 mM), 0113 (250 milligrams, 0.58 mM), (150 milligrams of NaHCO3,1.74 mM) and (50 milligrams of two (triphenylphosphine) palladium chlorides, 0.071 mM) the title compound 1504-320 (185 milligrams, 50%) of preparation pale solid shape in the solution in toluene (10 milliliters), ethanol (8 milliliters) and water (3 milliliters).m.p.；125-129℃.LCMS：632.4[M+1] +. 1HNMR：(400MHz，CDCl 3)：δ1.26(t，J＝7.2Hz，3H)，1.50-1.57(br，2H)，1.68-1.74(m，2H)，1.80-1.87(m，2H)，2.34(t，J＝7.2Hz，2H)，2.67(m，4H)，2.80(s，3H)，3.29(m，4H)，3.82-3.90(m，6H)，4.01-4.04(m，6H)，4.14(q，J＝7.2Hz，2H)，6.95(d，J＝8.8Hz，2H)，7.31(s，1H)，8.37(d，J＝8.8Hz，2H).
Step 147d:N-hydroxyl-6-(4-(6-((4-(sulfonyloxy methyl) piperazine-1-yl) methyl)-4-morpholinyl thiophene [3,2-d] pyrimidine-2-base) phenoxy group) caproamide (compound 320)
The similar method (embodiment 142) of using during according to description compound 307, from (200 milligrams of 1504-330,0.316 mM) and (30 milliliters of the hydroxylamine methanol solutions of fresh preparation, concentration is 1.79M in methyl alcohol) the middle title compound 320 (70 milligrams, 36%) for preparing white solid.M.p.140-142 ℃ of .LCMS:619.2[M+1] +. 1HNMR:(400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.42-1.44 (m, 2H), 1.54-1.58 (m, 2H), 1.72-1.754 (m, 2H), (1.98 t, J=7.2Hz, 2H), 2.59 (br, 4H), 2.90 (s, 3H), 3.15 (br, 4H), 3.79 (t, J=4.0Hz, 4H), 3.81-4.04 (m, 8H), 7.01 (d, J=8.8Hz, 2H), 7.37 (s, 1H), 8.32 (d, J=8.8Hz, 2H), 8.67 (s, 1H), 10.35 (s, 1H).
Embodiment 148:N-hydroxyl-7-(4-(6-((4-(sulfonyloxy methyl) piperazine-1-yl) Methyl)-and 4-morpholinyl thiophene [3,2-d] pyrimidine-2-base) phenoxy group) heptamide (change Compound 321)
Step 148a:7-(4-bromo phenoxy group) cognac oil (compound 1502-321)
The similar method (embodiment 146) of using during according to description compound 1502-319, from 4-bromo-phenol (1.1 grams, 6.5 mM), Cs2CO3 (4.0 the gram, 13 mMs), ethyl 7-bromo enanthate (1.7 the gram, 7.2 mM) the title compound 1502-321 of preparation oily in dimethyl formamide (1.6 grams, 80%). 1HNMR：(400MHz，CDCl 3)：δ1.25(t，J＝7.2Hz，3H)，1.35-1.51(m，4H)，1.617-1.69(m，2H)，1.75-1.78(m，2H)，2.30(t，J＝7.2Hz，2H)，3.90(t，J＝6.4Hz，2H)，4.12(q，J＝7.2Hz，2H)，6.76(d，J＝8.8Hz，2H)，7.35(d，J＝8.8Hz，2H).
Step 148b:7-(4-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) phenoxy group) cognac oil (compound 1503-321)
The similar method (embodiment 146) of using during according to description compound 1503-319, from 1502-321 (1.9 grams, 5.8 mM), connection boric acid pinacol ester (2.2 grams, 8.7 mM), [1,1 '-two (diphenylphosphine) ferrocene] (212 milligrams of palladium chlorides (PdCl2 (dppf)), 0.29 mM), KOAc (1.8 the gram, 17.4 mM) the title compound 1503-321 (1.7g, 60%) of preparation oily in anhydrous dioxane. 1HNMR：(400MHz，CDCl 3)：δ1.25(t，J＝7.2Hz，3H)，1，33(s，12H)，1.37-1.43(m，2H)，1.46-1.50(m，2H)，1.62-1.70(m，2H)；1.75-1.80(m，2H)，2.30(d，J＝7.6Hz，2H)，3.97(t，J＝6.8Hz，2H)，4.12(q，J＝7.2Hz，2H)，6.87(d，J＝8.8Hz，2H)，7.73(d，J＝8.8Hz，2H).
Step 148c:N-hydroxyl-7-(4-(6-((4-(sulfonyloxy methyl) piperazine-1-yl) methyl)-4-morpholine thiophene [3,2-d] pyrimidine-2-base) phenoxy group) heptamide (compound 1504-321)
The similar process (embodiment 146) that uses when using with description compound 1504-319, from (600 milligrams of 1503-321,1.60 mM), 0113 (350 milligrams, 0.81 mM), (200 milligrams of NaHCO3,2.4 mM) and (60 milligrams of two (triphenylphosphine) palladium chlorides, 0.085 mM) the title compound 1504-321 (260 milligrams, 50%) of preparation light yellow solid shape in the solution in toluene (12 milliliters), ethanol (9 milliliters) and water (4 milliliters).m.p.：154-157℃.LCMS：646.4[M+1] +. 1H?NMR：(400MHz，CDCl 3)：δ1.25(t，J＝7.2Hz，3H)，1.47-1.54(m，2H)，1.54-1.60(m，2H)，1.66-1.68(m，2H)，1.78-1.85(m，2H)，2.31(d，J＝7.6Hz，2H)，2.67(m，4H)，2.79(s，3H)，3.29(m，4H)，3.85-3.89(m，6H)，4.00-4.03(m，6H)，4.13(q，J＝7.2Hz，2H)，6.96(d，J＝8.8Hz，2H)，7.31(s，1H)，8.37(d，J＝8.8Hz，2H).
Step 148d:N-hydroxyl-7-(4-(6-((4-(sulfonyloxy methyl) piperazine-1-yl) methyl)-4-morpholine thiophene [3,2-d] pyrimidine-2-base) phenoxy group) heptamide (compound 321)
The similar method (embodiment 142) of using during according to description compound 307, from (220 milligrams of 1504-321,0.34 mM) and (30 milliliters of the hydroxylamine methanol solutions of fresh preparation, concentration is 1.79M in methyl alcohol) the middle title compound 321 (130 milligrams, 54.5%) for preparing white solid.M.p.143-145 ℃ of .LC-MS:633.2[M+1] +. 1HNMR:(400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.30-1.56 (m, 6H), 1.73 (t, J=6.4Hz, 2H), (1.96 t, J=7.6Hz, 2H), 2.59 (br, 4H), (2.89 s, 3H), 3.15 (br, 4H), 3.80 (m, 4H), 3.80-4.04 (m, 8H), 7.01 (d, J=8.8Hz, 2H), 7.38 (s, 1H), 8.32 (d, J=8.8Hz, 2H), 8.66 (s, 1H), 10.33 (s, 1H).
Embodiment 149:N-hydroxyl-2-(((2-(6-methoxypyridine-3-yl)-4-morpholine Base thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-phosphoamide (is changed Compound 236)
Step 149a:5-bromo-2-methoxypyridine (compound 0601-236)
With 2-methoxyl group-pyridine (100 gram, 0.92 mole), the solution stirring and refluxing of NBS (180 grams, 1.0 moles) in acetonitrile (1.0 liters) 21 hours.Thin layer chromatography shows to react to be finished.Reaction mixture is to room temperature and concentrated.Collect about 900 milliliters solvent.The gained suspension is filtered and washs (about 400 milliliters) with n-hexane.Thereby concentrated filtrate produces semifinished product again.Under the pressure that reduces, distill semifinished product (30 ℃/0.3 millimetres of mercury) thereby the title compound (146 grams, 84%) of generation clarification oily.LCMS(m/z)：190.0[M+1] +. 1H?NMR(400MHz，CDCl 3)：δ3.90(s，3H)，6.65(d，J＝8.8Hz，1H)，7.62(dd，J＝8.8Hz，2.4Hz，1H)，8.19(s，1H).
Step 149b:6-methoxypyridine-3-ylboronic acid (compound 1601-236):
Under-78 ℃ of conditions, to compound 0601-236 (20 grams, 0.11 mole) dropwise add n-BuLi (59 milliliters, the concentration in oxolane is 2M) in the solution in anhydrous tetrahydro furan (180 milliliters), stirred the gained reactant mixture 1 hour.At-78 ℃ of lower triisopropyl borates (37 milliliters) that add, reactant mixture is got warm again after a cold spell to room temperature, and continue to stir and spend the night.Thin layer chromatography (hexane/ethyl acetate) demonstration reacts completely.Use the HCl (90 milliliters) of 4N to adjust the pH value of mixture to 3-4.Thereby filter the collecting precipitation thing and produce crude product compound 1601-236 (21 grams, 128%).In crude product compound 1601-236 (21 gram) water-soluble (200 milliliters), use concentrated ammonia solution that the pH value is adjusted to 8-9, by filtration collecting precipitation thing, thus the pure title compound 1601-236 of generation white solid (11 grams, 67%).LCMS (m/z): 154.1[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d6): δ 3.86 (s, 3H), 6.76 (d, J=8.4Hz, 1H), 7.99 (dd, J=8.4Hz, 2.0Hz, 1H), 8.05 (br, 2H), 8.52 (d, J=2.0Hz, 1H).
Step 149c:2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-two assorted pentaborane-2-yls) pyridine (compound 0602-236)
Under 108 ℃, heating compound 0601-236 in the nitrogen environment (55 grams, 0.29 mole), 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-two (1,3,2-two assorted pentaboranes) (90 grams, 0.35 mole), potassium acetate (57 grams, 0.58 mole) and the mixture of two (triphenyl phosphatization hydrogen) palladium chloride (2.2 grams, 3 mMs) in anhydrous dioxane (500 milliliters) are whole night.Concentrated reaction mixture and use the column chromatography purifying is used the hexane/ethyl acetate elution, obtains compound 0602-236 (58 grams, 84%). 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.30 (s, 12H), 3.88 (s, 3H), 6.81 (d, J=8.0Hz, 1H), 7.88 (dd, J=8.0Hz, 2.0Hz, 1H), 8.41 (d, J=2.0Hz, 1H).
Step 149d: ethyl-2-(((2-(6-methoxypyridine-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 0603-236)
Method A: (12 grams of heating compound 0504 in 108 ℃ of lower nitrogen environments, 26.7 mM), 1601-236 (4.9 the gram, 32 mMs), NaHCO3 (6.7 the gram, 80.1 mM) and the two mixture of (triphenyl phosphatization hydrogen) palladium chloride (188 milligrams, 0.267 mM) in toluene (80 milliliters), ethanol (50 milliliters) and water (10 milliliters) mixed solvent 4.5 hours.Thin layer chromatography shows to react to be finished.Then reactant mixture is cooled to room temperature, adds entry (20 milliliters).Filter and collect the gained solid, then be suspended in the ethanol (100 milliliters).At room temperature stirred described suspension about 30 minutes, and then filtered.Collect solid and wash the gained solid with ethanol, dry in a vacuum, the title compound 0603-236 of generation white solid (10 grams, 72%).
Method B: (1.5 grams of heating compound 0504 in 108 ℃ of lower nitrogen environments, 3.34 mM), 0602-236 (1.6 the gram, 6.68 mM), NBHCO3 (0.84 the gram, 10.0 mM) and the two mixture of (triphenyl phosphatization hydrogen) palladium chloride (118 milligrams, 0.167 mM) in toluene (24 milliliters), ethanol (15 milliliters) and water (3 milliliters) mixed solvent whole night.The reactant mixture portions is put into carrene and water.Separate organic layer and use the salt water washing, use the organic layer of dried over sodium sulfate combination, filter and evaporation generation residue under vacuum condition, use column chromatography purifying residue, use the hexane/ethyl acetate elution, produce the compound 0603-236 (1.7 grams, 98%) of white solid.
M.p.198-202 ℃ of .LCMS:522.30[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 1.31 (t, J=7.2Hz, 3H), 3.28 (s, 3H), 3.76 (t, J=4.4Hz, 4H), 3.93 (t, J=4.4Hz, 4H), 3.94 (s, 3H), 4.30 (q, J=7.2Hz, 2H), 5.24 (s, 2H), 6.92 (d, J=8.8Hz, 1H), 7.47 (s, 1H), 8.57 (dd, J=8.8Hz, 2.0Hz, 1H), (8.88 s, 2H), 9.15 (d, J=2.0Hz, 1H).
Step 149e:2-[(2-chloro-4-morpholinyl-4-base-thiophene [3,2-d] pyrimidine-6-ylmethyl)-methyl-ammonia]-pyrimidine-5-carboxylic acid's methyl esters (compound 1602-236)
The mixture of agitate compounds 0503 (25 gram, 84 mMs), CH3CN (500 milliliters) and 2-Chloropyrimide-5-carboxylate methyl ester (16 restrain 92 mMs) at room temperature.Add diisopropylethylamine (DIPEA) (500 milliliters, 2.9 moles).Agitating solution whole night and the evaporation.Afterwards, wash organic facies with water in adding METHYLENE CHLORIDE (500 milliliters), with dried over sodium sulfate and concentrated under vacuum condition.In residue, add ethyl acetate (200 milliliters), then in ice-water bath, stirred the mixture 50 minutes.Collect the title product (29.4 grams, 81%) of white solid.LCMS (m/z): 435.2[M+1] +. 1HNMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): 3.25 (s, 3H), 3.71 (t, J=5.2Hz, 4H), 3.82-3.84 (m, 7H), 5.21 (s, 2H), 7.39 (s, 1H), 8.87 (s, 2H).
Step 149f:M ethyl-2-(((2-(6-methoxypyridine-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-carboxylic acid's salt (compound 1603-236)
Heating compound 1602-236 in 108 ℃ of lower nitrogen environments (29.4 grams, 67.7 mMs), 1601-236 (12.4 grams, 81.3 mMs), NaHCO 3(17.1 grams, 203 mMs) and the two mixture of (triphenyl phosphatization hydrogen) palladium chloride (475 milligrams, 0.68 mM) in toluene (480 milliliters), ethanol (300 milliliters) and water (60 milliliters) mixed solvent 6.5 hours.Thin layer chromatography shows to react to be finished.Reactant mixture is cooled to room temperature and removes by filter all insoluble solids, then add entry/ethanol (150 milliliters/150 milliliters).Filter and collect the gained precipitation.Be suspended in the ethanol solids in (200 milliliters) and at room temperature stirred 30 minutes.Filter and with ethanol washing gained solid, dry in a vacuum, produce the title compound 1603-236 (25 grams, 73%) of white solid.LCMS (m/z): 508.30[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.27 (s, 3H), 3.75 (t, J=4.4Hz, 4H), (3.82 s, 3H), 3.93 (t, J=4.4Hz, 4H), (3.90-3.93 m, 7H), 5.23 (s, 2H), 6.90 (d, J=8.8Hz, 1H), 7.47 (s, 1H), 8.57 (dd, J=8.4Hz, 2.0Hz, 1H), 8.88 (s, 2H), 9.15 (d, J=2.0Hz, 1H).
Step 149g:N-hydroxyl-2-(((2-(6-methoxypyridine-3-yl)-4-morpholinyl thiophene [3,2-d] pyrimidine-6-yl) methyl) (methyl) ammonia) pyrimidine-5-phosphoamide (compound 236)
The preparation of azanol methanol solution
At 60-65 ℃ of lower heating NH 2The mixture of OH.HCl (80 grams, 1.12 moles) in methyl alcohol (400 milliliters) 1 hour forms settled solution.Then in ice-water bath, cool off.In cooled mixture, dropwise add the solution of KOH (96 grams, 1.68 moles) in methyl alcohol (240 milliliters), keep simultaneously reaction temperature at 0-10 ℃.Under 0 ℃, stirred the gained mixture 30 minutes, then filter by the constant pressure funnel of filling anhydrous sodium sulfate (700 gram).In ice bath, collect filtrate, then in refrigerator, store in order to using later on.
Prepare compound 236 from compound 0603-236
Compound 0603-236 (10 grams, 19 mMs) is suspended in the azanol methanol solution (1.79M, 350 milliliters) of above-mentioned recently preparation.In this mixture, add carrene (100 milliliters).The sealed reaction flask also stirred the mixture 5 hours at ambient temperature, transferred it to settled solution subsequently.Extra stirring reaction 9 hours.Then filter, remove any insoluble solid.The pH value that adds acetic acid adjusting filtrate is 6-7, forms solid sediment.The methanol wash of solid collected by filtration and water and minimum, vacuum drying is 5 hours in 60 ℃, produces the compound 236 (9.2 grams, 96%) of white solid.M.p.177-180 ℃ of .LCMS:509.3[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.24 (s, 3H), 3.76 (t, J=5Hz, 4H), (3.92 t, J=5Hz, 4H), 3.92 (s, 3H), (5.20 s, 2H), 6.90 (d, J=8.8Hz, 1H), (7.44 s, 1H), 8.57 (dd, J=8.8Hz, 2.4Hz, 1H), 8.75 (s, 2H), 9.01 (s, 1H), (9.14 d, J=2.0Hz, 1H), 11.08 (s, 1H).
Prepare compound 236 from compound 1603-236
Compound 1603-236 (500 milligrams, 0.98 mM) is suspended in the azanol methanol solution (1.79M, 12 milliliters) of above-mentioned recently preparation.Add carrene (5 milliliters).The sealed reaction flask also stirred the mixture 5 hours at ambient temperature, transferred it to settled solution subsequently.Filtering reacting solution is removed all insoluble solids and is added entry (5 milliliters).Add acetic acid the pH value is adjusted to 9, and dropwise add entry (10 milliliters).Filter the gained reactant mixture, and the methanol wash of water and minimum.Collect white solid and 60 ℃ of lower vacuum dryings 5 hours, produce the compound 236 (388 milligrams, 77%) of white solid.LCMS (m/z): 509.4[M+1] +. 1H NMR (400MHz, dimethyl sulfoxide (DMSO)-d 6): δ 3.24 (s, 3H), 3.76 (t, J=5Hz, 4H), (3.92 t, J=5Hz, 4H), 3.93 (s, 3H), (5.20 s, 2H), 6.91 (d, J=8.8Hz, 1H), (7.45 s, 1H), 8.57 (dd, J=8.8Hz, 2.0Hz, 1H), 8.75 (s, 2H), 9.01 (s, 1H), (9.15 d, J=2.0Hz, 1H), 11.09 (s, 1H).
Biological Detection
Following detection is used to IC that the compound described in the present invention is had 50Measure, wherein said compound is identified as belonging to phosphoinositide 3 (PI3) inhibitors of kinases, histon deacetylase (HDAC) (HDAC) enzyme inhibitor and mTOR inhibitors.
(a) vitro detection of determining in order to the ability of inhibition of phosphoinositide 3-kinase α (PI3K α) that test-compound is had
Use is measured the activity that phosphoinositide 3-kinase α (PI3K α) has available from the ADP-Glo detection of Promega company.Phosphoinositide 3-kinase α (PIK3 α), be by the N-end with total length human p85 α (GenBank Accession No.U79143XM_043865) the formed compound of the human p110 α of the total length of histidine-tagged restructuring (GenBank Accession No.U79143) with the restructuring of the terminal histidine mark of N-, above-mentioned human p110 α and human p85 α have carried out coexpression in a kind of expression system of the Sf9 cell through baculovirus infection.Carry out ADP-Glo test process by the amount of ATP hydrolysis generation ADP, described ADP and phosphatidylinositol diphosphate salt (PIP2) are by the phosphorylation coupling of the phosphoinositide 3-kinase α (PI3K α) (p110 α/p85 α) of the restructuring of purifying.(the HEPES that 20 millis rub in reaction buffer, pH7.4, the sodium chloride that 150 millis rub, the magnesium chloride that 5 millis rub, the dithiothreitol (DTT) that 1 milli rubs, 3 little sodium vanadates that rub, 10 little adenosine triphosphates that rub and 0.5% dimethyl sulfoxide (DMSO)), utilize 20 little phosphatidylinositol diphosphate salt (PIP2) substrates that rub that phosphoinositide 3-kinase α (PI3K α) is cultivated, wherein said cultivation is the cultivation of at room temperature carrying out 1 hour.Then, use is available from the ADP of the ADP-Glo detection assay generation of Promega company.Described detection is that fluorescence ADP detects test.The ADP-Glo test is carried out in two steps, and the first, after kinase reaction, think kinase reaction terminal adding ADP-Glo reagent and exhaust remaining ATP.The second, when ADP is converted into ATP, add kinase assay reagent, and use luciferase/luciferin reaction to measure new synthetic ATP.
(b) vitro detection of determining in order to the ability of inhibition of phosphoinositide 3-kinase beta (PI3K β) that test-compound is had
Use is measured the activity that phosphoinositide 3-kinase beta (PI3K β) has available from the ADP-Glo detection of Promega company.Phosphoinositide 3-kinase α (PIK3 α), be by the N-end with total length human p85 α (GenBank Accession No.U79143XM_043865) the formed compound of the human p110 β of the total length of histidine-tagged restructuring (GenBank Accession No.NM_006219) with unlabelled restructuring, above-mentioned human p110 β and human p85 α have carried out coexpression in a kind of expression system of the Sf9 cell through baculovirus infection.Carry out ADP-Glo test process by the amount of ATP hydrolysis generation ADP, described ADP and phosphatidylinositol diphosphate salt (PIP2) are by the phosphorylation coupling of the phosphoinositide 3-kinase α (PI3K α) (p110 α/p85 α) of the restructuring of purifying.(the HEPES that 10 millis rub in reaction buffer, pH7.5, the sodium chloride that 50 millis rub, the magnesium chloride that 5 millis rub, 10 little adenosine triphosphates that rub and 0.5% dimethyl sulfoxide (DMSO)), utilize 20 little phosphatidylinositol diphosphate salt (PIP2) substrates that rub that phosphoinositide 3-kinase α (PI3K α) is cultivated, wherein said cultivation is the cultivation of at room temperature carrying out 90 minutes.Then, use is available from the ADP of the ADP-Glo detection assay generation of Promega company.Described detection is that fluorescence ADP detects test.The ADP-Glo test is carried out in two steps, and the first, after kinase reaction, think kinase reaction terminal adding ADP-Glo reagent and exhaust remaining ATP.The second, when ADP is converted into ATP, add kinase assay reagent, and use luciferase/luciferin reaction to measure new synthetic ATP.
(c) vitro detection of determining in order to the ability of inhibition of phosphoinositide 3-kinase δ (PI3K δ) that test-compound is had
Use is measured the activity that phosphoinositide 3-kinase δ (PI3K δ) has available from the ADP-Glo detection of Promega company.Phosphoinositide 3-kinase δ (PIK3 δ), be by the N-end with total length human p85 α (GenBank Accession No.U79143XM_043865) the formed compound of the human p110 δ of the total length of histidine-tagged restructuring (GenBank Accession No.NM_005026) with unlabelled restructuring, above-mentioned human p110 δ and human p85 α have carried out coexpression in a kind of expression system of the Sf9 cell through baculovirus infection.Carry out ADP-Glo test process by the amount of ATP hydrolysis generation ADP, described ADP and phosphatidylinositol diphosphate salt (PIP2) are by the phosphorylation coupling of the phosphoinositide 3-kinase α (PI3K δ) (p110 δ/p85 δ) of the restructuring of purifying.(the HEPES that 10 millis rub in reaction buffer, pH7.5, the sodium chloride that 50 millis rub, the magnesium chloride that 5 millis rub, 10 little adenosine triphosphates that rub and 0.5% dimethyl sulfoxide (DMSO)), utilize 20 little phosphatidylinositol diphosphate salt (PIP2) substrates that rub that phosphoinositide 3-kinase δ (PI3K δ) is cultivated, wherein said cultivation is the cultivation of at room temperature carrying out 90 minutes.Then, use is available from the ADP of the ADP-Glo detection assay generation of Promega company.Described detection is that fluorescence ADP detects test.The ADP-Glo test is carried out in two steps, and the first, after kinase reaction, think kinase reaction terminal adding ADP-Glo reagent and exhaust remaining ATP.The second, when ADP is converted into ATP, add kinase assay reagent, and use luciferase/luciferin reaction to measure new synthetic ATP.
(d) vitro detection of determining in order to the ability of inhibition of phosphoinositide 3-kinase γ (PI3K γ) that test-compound is had
Use is measured the activity that phosphoinositide 3-kinase γ (PI3K γ) has available from the ADP-Glo detection of Promega company.Phosphoinositide 3-kinase γ (PIK3 γ), be the N-end with the human p120 γ (GenBank Accession No.AF327656) of the total length of histidine-tagged restructuring, in a kind of expression system of the Sf9 cell through baculovirus infection, carried out coexpression.Carry out ADP-Glo test process by the amount of ATP hydrolysis generation ADP, described ADP and phosphatidylinositol diphosphate salt (PIP2) are by the phosphorylation coupling of the phosphoinositide 3-kinase γ (PI3K γ) (p110 δ/p85 δ) of the restructuring of purifying.(the Tris-HCl that 10 millis rub in reaction buffer, pH7.5, the sodium chloride that 50 millis rub, the magnesium chloride that 5 millis rub, 10 little adenosine triphosphates that rub and 0.5% dimethyl sulfoxide (DMSO)), utilize 20 little phosphatidylinositol diphosphate salt (PIP2) substrates that rub that phosphoinositide 3-kinase γ (PI3K γ) is cultivated, wherein said cultivation is the cultivation of at room temperature carrying out 90 minutes.Then, use is available from the ADP of the ADP-Glo detection assay generation of Promega company.Described detection is that fluorescence ADP detects test.The ADP-Glo test is carried out in two steps, and the first, after kinase reaction, think kinase reaction terminal adding ADP-Glo reagent and exhaust remaining ATP.The second, when ADP is converted into ATP, add kinase assay reagent, and use luciferase/luciferin reaction to measure new synthetic ATP.
(e) in order to the vitro detection of the ability of the enzyme activity of determining test-compound inhibition of histone deacetylase (HDAC)
Use Biomol Color de Lys system (histon deacetylase (HDAC) fluorophotometric detection kit) (AK-500; Biomol; Plymouth Meeting, PA) histone deacetylase (HDAC) inhibitory activity is screened.Briefly, test is used as the source of histone deacetylase (HDAC) with epidermis cancer cell (Hela cell) nuclear extract of propagation.Utilize dimethyl sulfoxide (DMSO) (DMSO) that the test-compound of variable concentrations is carried out gradient dilution and under the condition of the artificial substrate that has a kind of colorimetric, tests epidermis cancer cell (Hela cell) nuclear extract of using propagation to wherein adding.In final testing conditions, contain the Tris/Cl that 50 millis rub, pH8.0, the sodium chloride that 137 millis rub, the magnesium chloride that the potassium chloride that 2.7 millis rub and 1 milli rub.At room temperature (25 ℃) carry out 1 hour reaction, add after this developer in order to stop.Utilize WALLAC Victor II 1420 little culture plate readers that described relative activity is measured, wherein utilize fluorescence intensity that described relative activity is represented (excitation wavelength: 350-380 nanometer; Emission wavelength: the 440-460 nanometer).Use GraphPad Prism (edition 4 .0a) to data analysis, and use S shape dose response curve match algorithm that the IC50 value is calculated.
(f) in order to determine that test-compound suppresses the vitro detection of the ability of mammal rapamycin targeting proteins (mTor) serine/threonine protein kitase
The radioisotope detection that use acts on kinase whose standard detects the active ability of inhibition mammal rapamycin targeting proteins (mTOR) that described compound has.Briefly, in the Sf21 cell, use baculovirus expression system that human mammal rapamycin targeting proteins (mTor) (GenBank accession No.NM_004958) is expressed, and use the antibody affinity column that it is carried out purifying, wherein said mammal rapamycin targeting proteins (mTor) is a kind of with the human mammal rapamycin targeting proteins (mTor) of the total length FLAG label, restructuring.Under the condition that has adenosine triphosphate (ATP), utilize the c-terminal fragment of p70S6K that purified enzyme is cultivated, wherein with the c-terminal fragment of described p70S6K as substrate.P33 adenosine triphosphate (ATP) tracer is comprised among the described detection, in order to described enzymic activity is monitored.Final testing conditions is to contain the HEPES that 50 millis rub, its pH is 7.5, the ethylene glycol diethyl ether ethylenediamine tetraacetic acid (EDTA) (EGTA) that 1 milli rubs, 0.01% polysorbas20, the substrate of 2 mg/ml, manganese chloride and 70 little adenosine triphosphates that rub (ATP) that 3 millis rub, and described detection is the time of at room temperature having carried out 40 minutes.By the mode of adding 3% phosphoric acid solution described reaction is stopped after this.The reactant liquor of described 10 microlitres dropped on the P30 filtermat filter and among the phosphoric acid that 75 millis rub it is carried out three washings, described wash time is 5 minutes, and the washing that once utilizes methyl alcohol to carry out, after this it is carried out drying and scinticounting.Add the compound of variable concentrations in the reactant liquor, estimate in order to the kinase whose activity of the human mammal rapamycin targeting proteins (mTor) of inhibition that described compound is had.Use Prism software that IC50 is calculated, wherein said calculating utilizes S shape dose response curve match algorithm to carry out.
Listed the representative compounds described in the present invention and they among the following form B and detected at histone deacetylase (HDAC), the activity that phosphoinositide 3-kinase (PI3K) detects and mammal rapamycin targeting proteins (mTOR) has in detecting.In these detect, use following rank: for IC 50, I＞10 are little rubs, and 10 little rubbing 〉=II 〉=1 is little rubs, and 1 little rubbing 〉=III 〉=0.1 is little rubs, and IV＜0.1 is little rubs.
Form B
Figure BPA00001656443904291
Figure BPA00001656443904301
Figure BPA00001656443904311
Figure BPA00001656443904321
Figure BPA00001656443904331
Figure BPA00001656443904341
Figure BPA00001656443904361
Figure BPA00001656443904371
Cel l proliferation detects:
Cancerous cell line with being placed horizontally in the flat culture plate in 96 holes of every hole 5000 to 10000, is wherein contained the compound of various variable concentrations in described culture plate.Having under the condition of 0.5% hyclone the cultivation that utilizes compound described cell to be carried out 72 hours.Detection by adenosine triphosphate (ATP) content is estimated the inhibitory action of growth, has wherein used Promega CellTiter-Glo kit in described detection.Promega CellTiter-Glo kit is a kind of adenosine triphosphate based on firefly luciferase (ATP) monitoring system.Briefly, mammalian cell solvent soln and the substrate solution of 16 microlitres added in each hole of the medium that contains 84 microlitres, in order to described cell is dissolved and described adenosine triphosphate (ATP) is stablized.Shake mix is also cultivated 30 minutes, and subsequently described photism is measured.
Listed the antiproliferative activity (IC50 (μ M)) that the representative compounds described in the present invention and they have among following form C, D and the E in the detection based on cell.In these detect, use following rank: for IC 50, I＞10 are little rubs, and 10 little rubbing 〉=II 〉=1 is little rubs, and 1 little rubbing 〉=III 〉=0.1 is little rubs, and IV＜0.1 is little rubs.
Table C
Figure BPA00001656443904381
Form D
Figure BPA00001656443904391
Form E
Figure BPA00001656443904392
Described patent documentation and scientific literature mentioned among the present invention have been set up the knowledge that those skilled in the art can obtain.Whole United States Patent (USP) of quoting in the present invention and U.S. Patent application disclosed or that be not disclosed all are introduced into as a reference.Whole foreign patents and the patent application of quoting in the present invention all are introduced into as a reference.Other whole open reference books of quoting in the present invention, document, manuscript and scientific literature all are introduced into as a reference.
Although the present invention preferred embodiment has been carried out special expression and description with reference to it, those skilled in the art can be understood that, under the prerequisite that does not deviate from the scope of the present invention that is contained by accompanying claim, can carry out on the various forms and the change on the details.

Claims (42)

1. an inhibition has the method for the cell proliferation of K-ras sudden change, and the method may further comprise the steps: (1) identification has the cell of K-ras sudden change; (2) the PI3 kinase signal approach in the inhibition cell; (3) suppress HDAC activity in the cell, thereby suppress cell proliferation.
2. method according to claim 1, wherein, described cell be cancer cell or pre-cancer cell.
3. method according to claim 1, wherein, step (b) comprises cell is contacted with a kind of the first Compound Phase, described the first compound is a kind of PI3 inhibitors of kinases, and, step (c) comprises cell is contacted with a kind of the second Compound Phase that described the second compound is a kind of hdac inhibitor.
4. method according to claim 1, wherein, step (b) comprises together with step (c) cell is contacted with a kind of Compound Phase that described compound can either suppress PI3 kinases/AKT signal transduction path and can suppress the HDAC activity.
One kind treat cancer in the host who needs or pre-cancer situation method, described cancer or pre-cancer situation relevant with K-ras sudden change, the method may further comprise the steps: (1) identification suffer from the cancer relevant with the K-ras sudden change or pre-cancer situation the host; (2) to the PI3 inhibitors of kinases of host's administration (i) effective dose and (ii) hdac inhibitor of effective dose.
6. method according to claim 5, wherein, described PI3 inhibitors of kinases and hdac inhibitor are independent compounds.
7. method according to claim 5, wherein, the first and second compounds are by while administration or order administration.
8. method according to claim 6, wherein, the PI3 inhibitors of kinases is selected from LY294002, wortmannin, the wortmannin analog, the wortmannin of Pegylation, 17-hydroxyl-the wortmannin of Pegylation, PX-866, SF1124, SF1126, BEZ235, BGT226, BKM120, XL-765, XL-147, GDC-0941, AS-252424, ONC-201, CAL-101, CAL-263, Atu-027, PF-4691502, PBI-05204, GSK-2126458, PIK-90, PIK-75, PI-103, ZSTK-474, TGX115, in the group that TGX-221 and TGX126 form, or its pharmaceutically acceptable salt, ester and pro-drug.
9. method according to claim 6, wherein, hdac inhibitor is selected from the group that is comprised of Vorinostat (SAHA), butyric acid, valproic acid, romidepsin, LAQ824, LBH589, CI994, MS275, MGCD0103, or its pharmaceutically acceptable salt, ester and pro-drug.
10. method according to claim 6, wherein said patient suffers from the cancer relevant with the K-ras of sudden change, and wherein, described cancer is selected from cancer of pancreas, colon cancer, lung cancer, cervix cancer and carcinoma of endometrium.
11. method according to claim 10, wherein, described cancer of pancreas is duct adenocarcinoma.
12. method according to claim 6, wherein the host is that suffer from is selected from myelodysplasia syndrome and adenoma with relevant situation pre-cancer of K-ras sudden change.
13. one kind treat cancer in the host who needs or pre-cancer situation method, described cancer or pre-cancer situation relevant with the K-ras of sudden change, said method comprising the steps of: (1) identification suffer from the cancer relevant with K-ras sudden change or pre-cancer situation the host; (2) to the compound of host's effective dosage, described compound has suppressed PI3 kinases and HDAC.
14. method according to claim 13, wherein said compound have as shown in the formula the structure shown in (I);
Structural formula I
Figure FPA00001656443800031
Or the geometry isomer of above-claimed cpd, enantiomter, diastereoisomer, racemic mixture, the acceptable salt of pharmacology or pro-drug,
Wherein
Figure FPA00001656443800032
Represent a singly-bound or two key;
Q, r and s independently are 0 or 1 separately, q wherein, and at least one is 1 among r and the s;
T is 0 or 1;
N is 0,1,2,3 or 4;
P is 0,1 or 2,
X and Y independently are CR separately 1, N (R 8), S or O; Wherein in X and Y is CR 1The time, another one is N (R 8), S or O;
G 1CR 1, S, O, NR 10Perhaps NS (O) 2R 10
G 2Substituted or unsubstituted aryl, substituted or unsubstituted iso-aryl or, substituted or unsubstituted heterocycle;
G 3Substituted or unsubstituted C 1-C 8Alkyl, substituted or unsubstituted C 2-C 8Thiazolinyl or substituted or unsubstituted C 2-C 8Alkynyl;
Each R 8Independently be hydrogen separately, acetyl group, aliphatic or substituted aliphatic;
R 1And R 2In each be dead key or independently be selected from separately hydrogen, hydroxyl, amino, halogen, alkoxyl, alkyl amino, dialkyl amido, CF 3, CN, NO 2, sulfonyl, acyl group, aliphatic, substituted aliphatic, aryl, substituted aryl, iso-aryl, substituted iso-aryl, heterocycle, and substituted heterocycle;
R aBe optional substituted alkyl, optional substituted aryl or optional substituted iso-aryl;
R bBe hydrogen, optional substituted alkyl, optional substituted aryl or optional substituted iso-aryl;
Perhaps R aWith R bTogether formed an optional substituted heterocyclic group with the described nitrogen-atoms that is connected them;
R 10Be selected from hydrogen, hydroxyl, amino, alkoxyl, alkyl amino, dialkyl amido, sulfonyl, acyl group, aliphatic, substituted aliphatic, aryl, substituted aryl, iso-aryl, substituted iso-aryl, heterocycle, and substituted heterocycle;
B is an attachment; And
C is selected from
(a)
Figure FPA00001656443800041
Wherein W is O or S; J is O, NH or NCH 3And R 31Hydrogen or low alkyl group;
(b)
Figure FPA00001656443800042
Wherein W is O or S; Y 2Dead key, N, perhaps CH; Z is N or CH; R 32And R 34Independently be hydrogen separately, hydroxyl, if aliphatic group is R 32And R 34All be dead key, R 32Perhaps R 34In one be necessary for hydroxyl, and if Y 2Dead key, R 34Be necessary for hydroxyl; And R 33Hydrogen or aliphatic group;
(c)
Figure FPA00001656443800051
Wherein W is O or S; Y 1And Z 1Independently be N separately, C or CH; And
(d)
Figure FPA00001656443800052
Z wherein, Y 2, and W is defined previously; R 11And R 12Independently be selected from separately hydrogen or aliphatic; R 21, R 22And R 23Independently be selected from separately hydrogen, hydroxyl, amino, halogen, alkoxyl, alkyl amino, dialkyl amido, CF 3, CN, NO 2, sulfonyl, acyl group, aliphatic, substituted aliphatic, aryl, substituted aryl, iso-aryl, substituted iso-aryl, heterocycle, and substituted heterocycle.
15. method according to claim 14, wherein, B is selected from the C of straight chain 1-C 10Alkyl, C 1-C 10Thiazolinyl, C 1-C 10Alkynyl, C 1-C 10Alkoxyl, alkoxy C 1-C 10Alkoxyl, C 1-C 10Alkyl amino, alkoxy C 1-C 10Alkyl amino, C 1-C 10Alkyl-carbonyl-amino, C 1-C 10Alkyl amino-carbonyl, aryloxy group C 1-C 10Alkoxyl, aryloxy group C 1-C 10Alkyl amino, aryloxy group C 1-C 10Alkyl amino-carbonyl, C 1-C 10-alkyl amino alkyl amino-carbonyl, C 1-C 10Alkyl (N-alkyl) aminoalkyl-amino carbonyl, the alkyl amino alkyl amino, the alkyl-carbonyl-amino alkyl amino, alkyl (N-alkyl) aminoalkyl is amino, (N-alkyl) alkyl-carbonyl-amino alkyl amino, the alkyl amino alkyl, alkyl amino alkyl amino alkyl, alkylpiperazinyl alkyl, piperazinyl alkyl, alkylpiperazinyl, thiazolinyl aryloxy group C 1-C 10Alkoxyl, the amino C of alkenyl aryl 1-C 10Alkoxyl, alkenyl aryl alkyl amino C 1-C 10Alkoxyl, thiazolinyl aryloxy group C 1-C 10Alkyl amino, thiazolinyl aryloxy group C 1-C 10Alkyl amino-carbonyl, piperazinyl alkyl aryl, iso-aryl C 1-C 10Alkyl, iso-aryl C 2-C 10Thiazolinyl, iso-aryl C 2-C 10Alkynyl, iso-aryl C 1-C 10Alkyl amino, iso-aryl C 1-C 10Alkoxyl, different aryloxy group C 1-C 10Alkyl, different aryloxy group C 2-C 10Thiazolinyl, different aryloxy group C 2-C 10Alkynyl, different aryloxy group C 1-C 10Alkyl amino, different aryloxy group C 1-C 10Alkoxyl.
16. method according to claim 14, wherein, described compound is represented by structural formula (II):
Figure FPA00001656443800061
Structural formula II
Wherein, X, Y, G 1, G 2, R 1, R 2, R 8, n, p, q, r, s, the definition in B and C such as the claim 14.
17. method according to claim 14, wherein, G 2Optional substituted phenyl, pyridine radicals, pyrimidine radicals, indyl, indazolyl, pyrrole radicals or benzimidazolyl.
18. method according to claim 17, wherein, G 2Optional substituted phenyl, pyridine radicals, pyrimidine radicals, indyl, pyrrole radicals or benzimidazolyl, wherein, described group is replaced by hydroxyl, methylol, amino, amide groups, acetylamino or methylamino group.
19. method according to claim 14, wherein, described compound is by structural formula (IV) or the represented compound of structural formula (V),
Figure FPA00001656443800062
Structural formula IV structural formula V
Or its geometry isomer, enantiomter, diastereoisomer, racemic mixture, the acceptable salt of pharmacology, and pro-drug,
Wherein
Figure FPA00001656443800071
Representing a singly-bound or two key; G 1, G 2, R 1, R 2, R 8, n, p, q, r, s, B and C are as defined in claim 14; And G 4NR 8, S or O,
20. method according to claim 19, wherein, G 2Be selected from following group:
Figure FPA00001656443800072
Wherein, R 3, R 8Has as described in claim 19 definition with m.
21. method according to claim 20, wherein, m is 1 and R 3Be selected from by hydroxyl, hydroxymethyl, amino, acyl amino, acetyl-amino is in the group that perhaps methylamino forms.
22. method according to claim 14, wherein, described compound is by structural formula (VII) or the represented compound of structural formula (VIII):
Figure FPA00001656443800073
Structural formula VII structural formula VIII
Or the geometry isomer of above-claimed cpd, enantiomter, diastereoisomer, racemic mixture, the acceptable salt of pharmacology, and pro-drug
Wherein
Figure FPA00001656443800081
Representing a singly-bound or two key; G 1, G 2, R 1, R 2, R 8, n, p, q, r, s, the definition in B and C such as the above-mentioned claim 14;
G 4NR 8, S or O, and
O is 1,2,3,4,5,6,7 or 8.
23. method according to claim 22, wherein, G 2Be selected from following groups:
Figure FPA00001656443800082
Wherein,
M is 0,1,2 or 3;
R 3Be selected from disappearance, hydrogen, hydroxyl, amino, halogen, alkoxyl, alkyl ammonia, dialkyl amino, CF 3, CN, NO 2, sulphonyl, the different cyclic group of the iso-aryl of the aryl of the aliphatic of acyl group, aliphatic, replacement, aryl, replacement, iso-aryl, replacement, different cyclic group, replacement; With
R 8Definition as claimed in claim 22.
24. method according to claim 22, wherein, m is 1 and R 3Be selected from by hydroxyl, hydroxymethyl, amino, acyl amino, acetyl-amino is in the group that perhaps methylamino forms.
25. method according to claim 14, wherein, described compound is by following structural formula (IX) or (X) represented:
Structural formula IX structural formula X
Figure FPA00001656443800091
G wherein 1, G 2, n, p, B, C, R 1, R 2And R 8Such as the definition in the claim 14.
26. method according to claim 25, wherein, G 2Be selected from following groups:
Wherein,
M is 0,1,2 or 3;
R 3Be selected from disappearance, hydrogen, hydroxyl, amino, halogen, alkoxyl, alkyl ammonia, dialkyl amino, CF 3, CN, NO 2, sulphonyl, the different cyclic group of the iso-aryl of the aryl of the aliphatic of acyl group, aliphatic, replacement, aryl, replacement, iso-aryl, replacement, different cyclic group, replacement; With
R 8Definition as claimed in claim 25.
27. method according to claim 26, wherein, m is 1 and R 3Be selected from by hydroxyl, hydroxymethyl, amino, acyl amino, acetyl-amino is in the group that perhaps methylamino forms.
28. method according to claim 14, wherein, described compound is represented by following structural formula XI;
Structural formula XI
Figure FPA00001656443800101
G wherein 2, n, p, B, C, R 1, R 2, and R 8Such as the definition in the claim 14.
29. method according to claim 28, wherein, G 2Be selected from following groups:
Figure FPA00001656443800102
Wherein,
M is 0,1,2 or 3;
R 3Be selected from disappearance, hydrogen, hydroxyl, amino, halogen, alkoxyl, alkyl ammonia, dialkyl amino, CF 3, CN, NO 2, sulphonyl, the different cyclic group of the iso-aryl of the aryl of the aliphatic of acyl group, aliphatic, replacement, aryl, replacement, iso-aryl, replacement, different cyclic group, replacement; With
R 8Definition as claimed in claim 28.
30. method according to claim 29, wherein, m is 1 and R 3Be selected from by hydroxyl, hydroxymethyl, amino, acyl amino, acetyl-amino is in the group that perhaps methylamino forms.
31. according to claim 14, described method 4,16,19,22,25 or 28 of any one among 16,19,22,25 or 28, wherein, B is selected from:
Figure FPA00001656443800111
Figure FPA00001656443800121
Wherein, d and e independently are 0,1,2,3,4,5,6,7 or 8 separately; And R 100Be hydrogen or be selected from the group that is formed by following radicals: C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, and C 3-C 8Cycloalkyl.
32. method according to claim 28, wherein, C is-C (O) N (H) OH.
33. method according to claim 14, wherein, compound is represented by following structural formula XX or XXI:
Structural formula XII
N wherein, m, p, Y 2, W, Z, G 1, G 2, G 4, R 1, R 2, R 8, R 32, R 33And R 34Such as the definition in the claim 14,
G 4NR 8, S or O;
M 1Dead key, O, S, NR 8, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, aryl, iso-aryl, heterocycle, SO, SO 2Perhaps C=O; M 2Dead key, C 1-C 6Alkyl, O, NR 8, heterocycle, aryl, iso-aryl, perhaps C=O; M 3Dead key, O, NR 8, S, SO, SO 2, CO, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, aryl, iso-aryl, or heterocycle; M 4Dead key, O, NR 8, iso-aryl, heterocycle or aryl; And M 5Dead key, C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, iso-aryl, heterocycle or aryl.
34. method according to claim 33, wherein, G 2Be selected from following groups:
Figure FPA00001656443800132
Wherein,
M is 0,1,2 or 3;
R 3Be selected from disappearance, hydrogen, hydroxyl, amino, halogen, alkoxyl, alkyl ammonia, dialkyl amino, CF 3, CN, NO 2, sulphonyl, the different cyclic group of the iso-aryl of the aryl of the aliphatic of acyl group, aliphatic, replacement, aryl, replacement, iso-aryl, replacement, different cyclic group, replacement; With
R 8Definition as claimed in claim 33.
35. method according to claim 34, wherein, m is 1 and R 3Be selected from by hydroxyl, hydroxymethyl, amino, acyl amino, acetyl-amino is in the group that perhaps methylamino forms.
36. method according to claim 14, wherein, described compound is represented by structural formula XIII:
Structural formula XIII
Figure FPA00001656443800141
Wherein, G 1, G 2, n, p, R 1, R 2, and R 8Such as the definition in the claim 14;
T, v and w independently are 0,1,2 or 3 separately; U is 0,1,2,3,4,5,6,7 or 8;
M is 0,1,2 or 3;
G 4NR 8, S or O;
G 5Dead key, C 1-C 8Alkyl or a C who is blocked 1-C 8Alkyl, wherein said alkyl are to utilize in the following radicals one or more to block: O, S, S (O), N (R 8), perhaps C (O); G 6Be selected from CR 1Perhaps NR 8
G 7Be selected from-CR 1,-NR 8, S or O; And
R 5And R 6Independently be selected from separately dead key, hydrogen, hydroxyl, amino, halogen, alkoxyl, alkyl amino, dialkyl amido, CF 3, CN, NO 2, sulfonyl, acyl group, aliphatic, substituted aliphatic, aryl, substituted aryl, iso-aryl, substituted iso-aryl, heterocycle, and substituted heterocycle.
37. method according to claim 36, wherein, G 2Be selected from following groups:
Wherein,
M is 0,1,2 or 3;
R 3Be selected from disappearance, hydrogen, hydroxyl, amino, halogen, alkoxyl, alkyl ammonia, dialkyl amino, CF 3, CN, NO 2, sulphonyl, the different cyclic group of the iso-aryl of the aryl of the aliphatic of acyl group, aliphatic, replacement, aryl, replacement, iso-aryl, replacement, different cyclic group, replacement; With
R 8Definition as claimed in claim 36.
38. described method according to claim 37, wherein, m is 1 and R 3Be selected from by hydroxyl, hydroxymethyl, amino, acyl amino, acetyl-amino is in the group that perhaps methylamino forms.
39. method according to claim 14, wherein compound is represented by following structural formula XIV:
Structural formula XIV
Figure FPA00001656443800161
Wherein, G 1, G 2, n, p, R 1, R 2And R 8Such as the definition in the claim 14;
W and m independently are 0,1,2 or 3 separately;
U is 0,1,2,3,4,5,6,7 or 8;
G 4NR 8, S or O;
G 5Dead key, C 1-C 8Alkyl or a C who is blocked 1-C 8Alkyl, wherein said alkyl are to utilize in the following radicals one or more to block: O, S, S (O), N (R 8), perhaps C (O); R 6Be selected from dead key, hydrogen, hydroxyl, amino, halogen, alkoxyl, alkyl amino, dialkyl amido, CF 3, CN, NO 2, sulfonyl, acyl group, aliphatic, substituted aliphatic, aryl, substituted aryl, iso-aryl, substituted iso-aryl, heterocycle, and substituted heterocycle.
40. described method according to claim 39, wherein, G 2Be selected from following groups:
Figure FPA00001656443800171
Wherein,
M is 0,1,2 or 3;
R 3Be selected from disappearance, hydrogen, hydroxyl, amino, halogen, alkoxyl, alkyl ammonia, dialkyl amino, CF 3, CN, NO 2, sulphonyl, the different cyclic group of the iso-aryl of the aryl of the aliphatic of acyl group, aliphatic, replacement, aryl, replacement, iso-aryl, replacement, different cyclic group, replacement; With
R 8Definition as claimed in claim 39.
41. described method according to claim 40, wherein, m is 1 and R 3Be selected from by hydroxyl, hydroxymethyl, amino, acyl amino, acetyl-amino is in the group that perhaps methylamino forms.
42. method according to claim 13, wherein, described compound is selected from the compound among the form A, or the geometry isomer of these compounds, enantiomter, diastereoisomer, racemic mixture, the acceptable salt of pharmacology, and pro-drug:
Table A
Figure FPA00001656443800181
Figure FPA00001656443800191
Figure FPA00001656443800201
Figure FPA00001656443800211
Figure FPA00001656443800221
Figure FPA00001656443800231
Figure FPA00001656443800251
Figure FPA00001656443800261
Figure FPA00001656443800271
Figure FPA00001656443800281
Figure FPA00001656443800291
Figure FPA00001656443800301
Figure FPA00001656443800311
Figure FPA00001656443800331
Figure FPA00001656443800341
Figure FPA00001656443800351
Figure FPA00001656443800361
Figure FPA00001656443800371
Figure FPA00001656443800381
Figure FPA00001656443800391
Figure FPA00001656443800401
Figure FPA00001656443800411
Figure FPA00001656443800421
Figure FPA00001656443800431
Figure FPA00001656443800441
Figure FPA00001656443800461
Figure FPA00001656443800471
Figure FPA00001656443800491
Figure FPA00001656443800501
Figure FPA00001656443800521
Figure FPA00001656443800551
Figure FPA00001656443800561
Figure FPA00001656443800571
Figure FPA00001656443800581
Figure FPA00001656443800601
Figure FPA00001656443800611
Figure FPA00001656443800621
Figure FPA00001656443800631
Figure FPA00001656443800651
Figure FPA00001656443800661
Figure FPA00001656443800671
Figure FPA00001656443800681
Figure FPA00001656443800691
Figure FPA00001656443800701
Figure FPA00001656443800711
Figure FPA00001656443800721
Figure FPA00001656443800731
Figure FPA00001656443800741
Figure FPA00001656443800751
Figure FPA00001656443800761
Figure FPA00001656443800771
Figure FPA00001656443800781
Figure FPA00001656443800791
Figure FPA00001656443800801
Figure FPA00001656443800811
Figure FPA00001656443800831
Figure FPA00001656443800841
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103601745A (en) * 2013-11-26 2014-02-26 大连联化化学有限公司 Preparation method of commonly used acetamidopyridine boronic acid pinacol ester
WO2016169417A1 (en) * 2015-04-21 2016-10-27 成都金瑞长青生物科技有限公司 Purinyl-n-hydroxyl pyrimidine formamide derivatives, preparation method therefor and use thereof
CN106456643A (en) * 2014-03-31 2017-02-22 斯克里普斯研究学院 Pharmacophore for trail induction
CN110669047A (en) * 2013-11-15 2020-01-10 昂克希尔迪克斯有限公司 Compounds for treating cancer, compositions and methods of use thereof
CN113735830A (en) * 2021-10-11 2021-12-03 成都自豪药业有限公司 Hydroximic acid derivatives and application thereof
WO2024041519A1 (en) * 2022-08-24 2024-02-29 上海璎黎药业有限公司 Morpholinyl quinazoline compound, and pharmaceutical composition and use thereof

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2366489T3 (en) * 2006-09-15 2011-10-20 Pfizer Products Inc. PIRID COMPOUND (2,3-D) PIRIDINONE AND ITS USE AS PI3 INHIBITORS.
ME02230B (en) 2009-01-08 2016-02-20 Curis Inc Phosphoinositide 3 - kinase inhibitors with a zinc binding moiety
EP2694075B1 (en) 2011-04-01 2016-04-27 Curis, Inc. Phosphoinositide 3-kinase inhibitor with a zinc binding moiety
ES2575143T3 (en) * 2011-11-23 2016-06-24 Cancer Research Technology Limited Atypical protein kinase C thienopyridine inhibitors
US8940742B2 (en) * 2012-04-10 2015-01-27 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
WO2015043398A1 (en) * 2013-09-30 2015-04-02 上海璎黎药业有限公司 Fused pyrimidine compound, intermediate, preparation method therefor, and composition and application thereof
US9403779B2 (en) * 2013-10-08 2016-08-02 Acetylon Pharmaceuticals, Inc. Combinations of histone deacetylase inhibitors and either Her2 inhibitors or PI3K inhibitors
CN104131034B (en) * 2014-06-19 2017-04-05 中山大学 A kind of chimeric vector and its preparation method and application
EA038960B1 (en) * 2015-01-30 2021-11-15 Басф Се Herbicidal phenylpyrimidines
CN105037345B (en) * 2015-06-09 2019-01-25 天津渤海职业技术学院 Antitumoral compounds, preparation method and use
US9630968B1 (en) 2015-12-23 2017-04-25 Arqule, Inc. Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof
JP2019530650A (en) 2016-08-24 2019-10-24 アークル インコーポレイテッド Amino-pyrrolopyrimidinone compounds and methods of use thereof
JPWO2018062382A1 (en) * 2016-09-29 2019-07-11 第一三共株式会社 [2- (1-Methyl-1H-pyrazol-4-yl) -6- (morpholin-4-yl) -9H-purin-8-yl] [4- (morpholin-4-yl) piperidin-1-yl Crystals of Methanone and its pharmaceutically acceptable salts
CN111315735B (en) * 2017-09-04 2024-03-08 C4医药公司 Dihydrobenzimidazolone
EP3694511A1 (en) * 2017-10-13 2020-08-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Combination treatment of pancreatic cancer
KR20210009331A (en) * 2018-05-10 2021-01-26 유니버시티 오브 루이빌 리서치 파운데이션, 인코포레이티드 Inhibitor of RAS oncoprotein, preparation method and method of use thereof
MX2021002742A (en) 2018-09-11 2021-08-11 Curis Inc Combination therapy with a phosphoinositide 3-kinase inhibitor with a zinc binding moiety.
EP3898609A1 (en) 2018-12-19 2021-10-27 Shy Therapeutics LLC Compounds that interact with the ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
EP3935050A4 (en) 2019-03-06 2023-01-04 C4 Therapeutics, Inc. Heterocyclic compounds for medical treatment
BR112022022669A2 (en) 2020-05-08 2023-01-17 Halia Therapeutics Inc NEK7 KINASE INHIBITORS
BR112022024300A2 (en) * 2020-06-04 2023-01-24 Pillai Universal Llc SMALL MOLECULES FOR TARGETED DEGRADATION OF UNTARGETED KRAS IN CANCER THERAPY

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101626758A (en) * 2007-02-15 2010-01-13 诺瓦提斯公司 Combinations of therapeutic agents for treating cancer
CN101675053A (en) * 2006-12-07 2010-03-17 健泰科生物技术公司 Phosphoinositide 3-kinase inhibitor compounds and methods of use
CN102341108A (en) * 2009-01-08 2012-02-01 柯瑞斯公司 Phosphoinositide 3-kinase inhibitors with zinc binding moiety

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1362675B (en) * 2005-03-15 2009-06-25 Menarini Internat Operations Luxembourg Sa N-HYDROXYAMIDES - SUBSTITUTED WITH TRICYCLIC GROUPS AS INHIBITORS OF THE ISLANDS DEACELITASIS, THEIR PREPARATION AND USE IN PHARMACEUTICAL FORMULATIONS
AU2007334343A1 (en) * 2006-12-15 2008-06-26 Ordway Research Institute, Inc. Treatments of therapy-resistant diseases comprising drug combinations
CA2721218C (en) * 2008-04-15 2015-03-24 Pharmacyclics, Inc. Selective inhibitors of histone deacetylase
WO2009155659A1 (en) * 2008-06-27 2009-12-30 The University Of Queensland Combination therapy

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101675053A (en) * 2006-12-07 2010-03-17 健泰科生物技术公司 Phosphoinositide 3-kinase inhibitor compounds and methods of use
CN101626758A (en) * 2007-02-15 2010-01-13 诺瓦提斯公司 Combinations of therapeutic agents for treating cancer
CN102341108A (en) * 2009-01-08 2012-02-01 柯瑞斯公司 Phosphoinositide 3-kinase inhibitors with zinc binding moiety

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DENNIS WEGENER ET AL: "Identification of novel small-molecule histone deacetylase inhibitors by medium-throughput screening using a fluorigenic assay", 《BIOCHEM.J.》, vol. 413, 31 December 2008 (2008-12-31) *
JEFFREY A.ENGELMAN: "targeting PI3K signalling in cancer：opportunities，challenges and limitations", 《NATURE REVIEWS CANCER》, vol. 9, 31 August 2009 (2009-08-31), XP002693047, DOI: doi:10.1038/NRC.2664 *
SHIN-ICHI YAGUCHI ET AL: "Antitumor activity of ZSTK474,a new phosphatidylinositol 3-kinase inhibitor", 《JOURNAL OF THE NATIONAL CANCER INSTITUTE》, vol. 98, no. 8, 19 April 2006 (2006-04-19), XP008149295, DOI: doi:10.1093/jnci/djj133 *
无: "curis presents preclinical data for CU-903 at keystone symposia event "PI3 kinase signaling in disease"", 《HTTP://WWW.DRUGS.COM/CLINICAL_TRIALS/CURIS-PESENTS-PRECLINICAL-DATA-CU-903-KEYSTONE-SYMPOSIA-EVENT-8220-PI3-KINASE-SIGNALING-8221-7094.HTML#0_UNDEFINED,0_》, 30 April 2009 (2009-04-30) *

Cited By (16)

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US10633385B2 (en) 2014-03-31 2020-04-28 The Scripps Research Institute Pharmacophore for trail induction
US11891392B2 (en) 2014-03-31 2024-02-06 The Scripps Research Institute Pharmacophore for trail induction
US10239877B2 (en) 2014-03-31 2019-03-26 The Scripps Research Institute Pharmacophore for trail induction
CN111499636A (en) * 2014-03-31 2020-08-07 斯克里普斯研究学院 Pharmacophores for TRAI L induction
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EA033106B1 (en) * 2015-04-21 2019-08-30 Гуйчжоу Бэйлинг Груп Фармасьютикал Ко., Лтд. Purinyl-n-hydroxyl pyrimidine formamide derivatives, preparation methods therefor and uses thereof
AU2016250972B2 (en) * 2015-04-21 2019-01-17 Chengdu Zenitar Biomedical Technology Co., Ltd. Purinyl-n-hydroxyl pyrimidine formamide derivative, preparation methods and uses thereof
WO2016169417A1 (en) * 2015-04-21 2016-10-27 成都金瑞长青生物科技有限公司 Purinyl-n-hydroxyl pyrimidine formamide derivatives, preparation method therefor and use thereof
US10227347B2 (en) 2015-04-21 2019-03-12 Guizhou Bailing Group Pharmaceutical Co., Ltd. Purinyl-N-hydroxyl pyrimidine formamide derivative, preparation methods and uses thereof
CN113735830A (en) * 2021-10-11 2021-12-03 成都自豪药业有限公司 Hydroximic acid derivatives and application thereof
WO2023061368A1 (en) * 2021-10-11 2023-04-20 成都自豪药业有限公司 Hydroximic acid derivative and use thereof
WO2024041519A1 (en) * 2022-08-24 2024-02-29 上海璎黎药业有限公司 Morpholinyl quinazoline compound, and pharmaceutical composition and use thereof

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