TWI392677B - Anti-viral compounds,process for preparation and uses thereof - Google Patents
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本申請案係主張2005年12月21日提出申請之美國臨時申請案號60/752,473之整體內容之權益，且併入本文供參考。The present application claims the benefit of the entire disclosure of U.S. Provisional Application Serial No. 60/752,473, the entire disclosure of which is incorporated herein by reference.
本發明係關於有效抑制C型肝炎病毒("HCV")複製之化合物。本發明亦關於製造此種化合物之方法，包含此種化合物之組合物，用於合成此種化合物之中間物，及方法使用此種化合物/組合物以治療HCV感染或與其有關聯之症狀/病徵。此外，本發明係關於此種化合物供製造藥劑以治療HCV感染之用途。The present invention relates to compounds which are effective in inhibiting replication of hepatitis C virus ("HCV"). The invention also relates to a method of making such a compound, a composition comprising such a compound, an intermediate for the synthesis of such a compound, and a method of using such a compound/composition to treat or have associated symptoms/symptoms of HCV infection . Furthermore, the invention relates to the use of such compounds for the manufacture of a medicament for the treatment of HCV infection.
HCV，一種人類病原，係為歸屬於黃病毒科中肝病毒屬之RNA病毒。正如關於黃病毒科所有其他成員之特徵，HCV具有有包膜之病毒粒子，其含有使所有已知病毒專一蛋白質編碼之正股鏈RNA基因組，在一個單獨不間斷開放譯讀骨架中。該開放譯讀骨架包含大約9500個核苷酸，使約3000個胺基酸之單一大的多蛋白編碼。該多蛋白包含核心蛋白質，被膜蛋白質E1與E2，細胞膜結合之蛋白質p7，及非結構性蛋白質NS2、NS3、NS4A、NS4B、NS5A及NS5B。一種細胞蛋白酶會使病毒蛋白質在NS2－NS3接合處***，允許病毒蛋白酶(NS3蛋白酶)媒介後續***。NS3蛋白質亦顯示核苷三磷酸酶與RNA解螺旋酶活性。NS2與NS4A亦可涉及蛋白分解活性。NS5A為涉及複製之磷蛋白質。NS5B為RNA依賴性RNA聚合酶。2004年12月30日公告之美國專利公報案號2004/0265792指出前文所提及非結構性蛋白質之抑制可抑制HCV複製。HCV, a human pathogen, is an RNA virus belonging to the genus Hepatitis in the Flaviviridae family. As with all other members of the Flaviviridae family, HCV has enveloped virions containing a positive stranded RNA genome encoding all known virus-specific proteins in a single uninterrupted open reading frame. The open reading frame comprises approximately 9500 nucleotides encoding a single large polyprotein of approximately 3000 amino acids. The polyprotein comprises a core protein, a membrane protein E1 and E2, a protein membrane bound to the cell membrane, and a non-structural protein NS2, NS3, NS4A, NS4B, NS5A and NS5B. A cellular protease causes the viral protein to cleave at the NS2-NS3 junction, allowing for subsequent division of the viral protease (NS3 protease) vector. The NS3 protein also showed nucleoside triphosphatase and RNA helicase activity. NS2 and NS4A may also be involved in proteolytic activity. NS5A is a phosphoprotein involved in replication. NS5B is an RNA-dependent RNA polymerase. U.S. Patent Gazette No. 2004/0265792, issued Dec. 30, 2004, teaches that inhibition of the non-structural proteins mentioned above inhibits HCV replication.
HCV感染係與進行性肝臟病理學疾病有關聯，包括肝硬化與肝細胞癌。HCV－有關聯之末期肝病為在成人中關於肝臟移植之最常發生適應徵。慢性C型肝炎可以每週一次注射PEG干擾素－α且併用每日利巴法林(ribavarin)治療。PEG干擾素－α為經連接至聚乙二醇之干擾素－α，以減緩藥物自身體排除。當與干擾素－α每日注射之治療法比較時，這會造成加強之順應性與臨床上優越抗病毒活性。對功效與耐受性之實質限制仍然存在，因許多使用者遭遇到副作用，且病毒自身體排除經常不充分。HCV infection is associated with progressive liver pathology, including cirrhosis and hepatocellular carcinoma. HCV-associated end-stage liver disease is the most common indication for liver transplantation in adults. Chronic hepatitis C can be injected once a week with PEG interferon-α and treated with daily ribavarin. PEG interferon-α is interferon-α linked to polyethylene glycol to slow the elimination of the drug itself. This results in enhanced compliance and clinically superior antiviral activity when compared to the treatment with interferon-alpha daily injection. Substantial limitations on efficacy and tolerability still exist because many users experience side effects and the virus itself is often inadequately excluded.
已進行嘗試以設計會專一性地抑制C型肝炎病毒功能之藥物。Boehringer Ingelheim美國專利6,323,180指出三肽化合物作為HCV絲胺酸蛋白酶抑制劑，建議用於HCV感染之治療。Attempts have been made to design drugs that specifically inhibit the function of hepatitis C virus. U.S. Patent No. 6,323,180 to Boehringer Ingelheim teaches tripeptide compounds as HCV serine protease inhibitors and is recommended for the treatment of HCV infection.
另一種途徑為ISIS－14803(Isis醫藥)，一種對C型肝炎病毒RNA之保守順序互補之反有意義抑制劑。此分子會結合至病毒RNA，且抑制複製所需要蛋白質之表現。Another route is ISIS-14803 (Isis Medicine), an anti-significant inhibitor of the complementary sequence of the hepatitis C virus RNA. This molecule binds to viral RNA and inhibits the performance of the protein required for replication.
HCV轉譯被一種會結合至細胞多肽且防止其與病毒內部核糖體進入位置(IRES)交互作用之酵母RNA之抑制，係描述於Das等人，J.VIROLOGY ,72(7)：5638－5647(1998)中。HCV translation is inhibited by a yeast RNA that binds to a cellular polypeptide and prevents its interaction with the internal ribosome entry site (IRES) of the virus, as described by Das et al., J. VIROLOGY , 72(7): 5638-5647 ( 1998).
稠合雙環雜環族化合物已被提出，針對各式各樣生命科學相關用途。此種雜環族化合物之實例包括啶、吡啶并嘧啶、嘧啶并嘧啶、吡唑并嘧啶及噻唑并/噻吩并嘧啶化合物。Fused bicyclic heterocyclic compounds have been proposed for a wide variety of life science related applications. Examples of such heterocyclic compounds include Pyridine, pyridopyrimidine, pyrimidopyrimidine, pyrazolopyrimidine and thiazolo/thienopyrimidine compounds.
啶型稠合雙環化合物已被研究關於疾病治療用途。例如，1993年7月8日公告之Boots WO 93/13097指出[1,8]啶化合物，譬如4－(4－甲氧基苯胺基)－6－乙氧基－7－甲基－1,8－啶－3－羧酸乙酯鹽酸鹽，建議作為抗風濕劑使用。1995年1月5日公告之Boots WO 95/00511指出經取代環稠合之4－胺基吡啶類，譬如3－乙氧基－5－(2－乙氧基－5－吡啶基胺基)－2－甲基－1,8－啶，建議作為抗風濕劑使用。1998年4月2日公告之Zeneca WO 98/13350指出[1,8]啶化合物，譬如2－乙醯胺基－5－(2－氟基－5－羥基－4－甲基苯胺基)－1,8－啶鹽酸鹽，建議作為抗血管生成劑。2004年7月1日公告之Neurogen WO 2004/055004指出啶化合物，作為辣椒素－受體調制劑，特定化合物為5－(4－三氟甲基－苯基胺基)－2－(3－三氟甲基－吡啶－2－基)－[1,6]啶－7－羧酸與2－甲氧基甲基－4－(4－三氟甲基－苯基胺基)－7－(3－三氟甲基－吡啶－2－基)－[1,8]啶－3－羧酸。 Acridine-type fused bicyclic compounds have been studied for therapeutic use in diseases. For example, Boots WO 93/13097, announced on July 8, 1993, states [1,8] a pyridine compound such as 4-(4-methoxyanilino)-6-ethoxy-7-methyl-1,8- Pyridine-3-carboxylic acid ethyl ester hydrochloride is recommended for use as an anti-rheumatic agent. Boots WO 95/00511, published on January 5, 1995, teaches 4-aminopyridines fused by a substituted ring, such as 3-ethoxy-5-(2-ethoxy-5-pyridylamino) -2-methyl-1,8- Pyridine is recommended for use as an anti-rheumatic agent. Zeneca WO 98/13350, announced on April 2, 1998, states [1,8] a pyridine compound such as 2-acetamido-5-(2-fluoro-5-hydroxy-4-methylanilino)-1,8- Pyridine hydrochloride is recommended as an anti-angiogenic agent. Neugenogen WO 2004/055004, announced on July 1, 2004, states a pyridine compound as a capsaicin-receptor modulator, the specific compound being 5-(4-trifluoromethyl-phenylamino)-2-(3-trifluoromethyl-pyridin-2-yl)-[1 , 6] Pyridin-7-carboxylic acid and 2-methoxymethyl-4-(4-trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-[1 ,8] Pyridine-3-carboxylic acid.
吡啶并嘧啶型稠合雙環化合物已被研究，針對各種疾病治療用途。例如，1998年2月12日公告之Pfizer WO 98/05661指出經取代之吡啶并嘧啶化合物，譬如[8－(1－乙基－丙基)－2－甲基－5,6,7,8－四氫－吡啶并(2,3－d)嘧啶－4基]－(2,4,6－三甲基－苯基)－胺，作為促腎上腺皮質激素釋放因子(激素)CRF(CRH)拮抗劑，建議用於阿耳滋海默氏疾病與肥胖之治療。1998年6月4日公告之Pfizer WO 98/23613指出稠合雙環嘧啶化合物，包括吡啶并嘧啶基－胺基苯基化合物，譬如(3－乙炔基－苯基)－吡啶并[3,4－d]嘧啶－4－基－胺，建議用於過高增生疾病譬如癌症之治療。2001年1月2日頒予之Glaxo Wellcome美國專利6,169,091指出雙環狀雜芳族化合物，譬如4－(4－苄氧基苯胺基)吡啶并[2,3－d]－嘧啶，作為酪胺酸激酶抑制劑，建議用於纖維變性、發炎、神經系統疾病及癌症之治療。2001年5月10日公告之Eli Lilly WO 01/32632指出4－取代之嘧啶化合物，包括2－三氟甲基－4－[2－(2－(2－氯苯基)乙胺基]吡啶并－[2,3－d]嘧啶鹽酸鹽，作為mGluR1拮抗劑，建議用於神經病症與有關聯麩胺酸酯機能障礙之治療，譬如搐搦、偏頭痛、精神病、焦慮及疼痛。2001年8月9日公告之Abbott實驗室WO 01/57040指出6,7－二取代－4－胺基吡啶并[2,3－d]嘧啶化合物，譬如4－胺基－6－(4－甲基苯基)－7－(4－溴苯基)吡啶并[2,3－d]嘧啶，作為腺苷激酶抑制劑，建議用於疼痛與發炎之治療。2004年7月1日公告之Neurogen WO 2004/055004指出吡啶并嘧啶基－胺基苯基化合物，譬如2－甲基－2－{4－[2－甲基－7－(3－甲基－吡啶－2－基)－吡啶并[2,3－d]嘧啶－4－基胺基]－苯基}－丙酸，作為辣椒素－受體調制劑。2002年5月28日頒予之Pfizer美國專利6,395,733指出雜環稠合之嘧啶化合物，譬如3－氯苯基－吡啶并[2,3－d]嘧啶－4－基－胺，建議用於過高增生性疾病譬如癌症之治療。Pyridopyrimidine-type fused bicyclic compounds have been studied for therapeutic use in various diseases. For example, Pfizer WO 98/05661, published on February 12, 1998, teaches substituted pyridopyrimidine compounds such as [8-(1-ethyl-propyl)-2-methyl-5,6,7,8 -tetrahydro-pyrido(2,3-d)pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-amine as a corticotropin releasing factor (hormone) CRF (CRH) Antagonists are recommended for the treatment of Alzheimer's disease and obesity. Pfizer WO 98/23613, published on June 4, 1998, teaches fused bicyclic pyrimidine compounds, including pyridopyrimidinyl-aminophenyl compounds, such as (3-ethynyl-phenyl)-pyrido[3,4- d]pyrimidin-4-yl-amine, recommended for the treatment of hyperproliferative diseases such as cancer. US Patent 6,169,091 to Glaxo Wellcome, issued January 2, 2001, which teaches bicyclic heteroaromatic compounds, such as 4-(4-benzyloxyanilino)pyrido[2,3-d]-pyrimidine, as tyramine Acid kinase inhibitors are recommended for the treatment of fibrosis, inflammation, neurological diseases and cancer. Eli Lilly WO 01/32632, published on May 10, 2001, teaches 4-substituted pyrimidine compounds, including 2-trifluoromethyl-4-[2-(2-(2-chlorophenyl)ethylamino]pyridine And-[2,3-d]pyrimidine hydrochloride, as an mGluR1 antagonist, is recommended for the treatment of neurological disorders associated with glutamate dysfunction, such as convulsions, migraine, psychosis, anxiety and pain. Abbott Laboratories WO 01/57040, published on August 9, states that 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds, such as 4-amino-6-(4-methyl) Phenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine, as an adenosine kinase inhibitor, is recommended for the treatment of pain and inflammation. Neurogen WO announced on July 1, 2004 2004/055004 teaches pyridopyrimidinyl-aminophenyl compounds such as 2-methyl-2-{4-[2-methyl-7-(3-methyl-pyridin-2-yl)-pyridinium [ 2,3-d]pyrimidin-4-ylamino]-phenyl}-propionic acid, as a capsaicin-receptor modulator. Pfizer, U.S. Patent No. 6,395,733, issued May 28, 2002, which is incorporated herein by reference. Pyrimidine compound, such as 3-chloro Yl - pyrido [2,3-d] pyrimidin-4-yl - amine, proposed for treatment of high proliferative diseases such as cancer.
嘧啶并嘧啶型稠合之雙環化合物已被研究，針對害物控制與疾病治療用途。例如，1994年9月27日頒予之Dow Elanco美國專利5,350,749指出4－取代之嘧啶并[2,3－d]嘧啶化合物，建議作為殺真菌劑、殺昆蟲劑及殺蟎劑使用。1995年7月27日公告之Warner－Lambert WO 95/19774指出嘧啶并嘧啶化合物，譬如4－苄胺基－7－甲胺基嘧啶并[4,5－d]嘧啶，作為酪胺酸激酶抑制劑，建議用於癌症、血管再狹窄及牛皮癬之治療。Bis-pyrimidine-pyrimidine-fused bicyclic compounds have been studied for pest control and disease therapeutic use. For example, U.S. Patent No. 5,350,749 to Dow Elanco, issued Sep. 27, 1994, teaches 4-substituted pyrimido[2,3-d]pyrimidine compounds which are suggested for use as fungicides, insecticides and acaricides. Warner-Lambert WO 95/19774, published on July 27, 1995, states that pyrimidopyrimidine compounds, such as 4-benzylamino-7-methylaminopyrimido[4,5-d]pyrimidine, are inhibited as tyrosine kinases. It is recommended for the treatment of cancer, restenosis and psoriasis.
噻吩并嘧啶型稠合之雙環化合物已被研究，針對各種疾病治療用途。例如，1995年7月27日公告之Warner－Lambert WO 95/19774指出稠合之雜環族嘧啶化合物，包括4－(3－溴基苯胺基)噻吩并[2,3－d]嘧啶，作為酪胺酸激酶抑制劑，建議用於癌症、血管再狹窄及牛皮癬之治療。2001年1月2日頒予之Glaxo Wellcome美國專利6,169,091指出雙環狀雜芳族化合物，譬如5－甲基－4－(4－苯氧基苯胺基)噻吩并[2,3－d]嘧啶鹽酸鹽，作為酪胺酸激酶抑制劑，建議用於纖維變性、發炎、神經系統疾病及癌症之治療。2001年5月10日公告之Eli Lilly WO 01/32632指出4－取代之嘧啶化合物，譬如6－甲基－4－[2,6－二氯苄硫基)乙胺基]噻吩并[2,3－d]嘧啶鹽酸鹽，作為mGluR1拮抗劑，建議用於神經病症與有關聯麩胺酸酯機能障礙之治療，譬如搐搦、偏頭痛、精神病、焦慮及疼痛。Thienopyrimidine-type fused bicyclic compounds have been studied for therapeutic use in various diseases. For example, Warner-Lambert WO 95/19774, published on July 27, 1995, teaches fused heterocyclic pyrimidine compounds, including 4-(3-bromoanilino)thieno[2,3-d]pyrimidine, as Tyrosine kinase inhibitors are recommended for the treatment of cancer, restenosis and psoriasis. US Patent 6,169,091 to Glaxo Wellcome, issued January 2, 2001, which teaches bicyclic heteroaromatic compounds such as 5-methyl-4-(4-phenoxyanilino)thieno[2,3-d]pyrimidine. Hydrochloride, as a tyrosine kinase inhibitor, is recommended for the treatment of fibrosis, inflammation, neurological diseases and cancer. Eli Lilly WO 01/32632, published on May 10, 2001, teaches 4-substituted pyrimidine compounds such as 6-methyl-4-[2,6-dichlorobenzylthio)ethylamino]thieno[2, 3-d]pyrimidine hydrochloride, as an mGluR1 antagonist, is recommended for the treatment of neurological disorders associated with glutamate dysfunction such as sputum, migraine, psychosis, anxiety and pain.
2004年2月19日公告之Bristol－Myers Squibb WO 2004/014852指出亞胺基噻唑啶酮，包括2－(4－胺基苯基)－5H－噻唑并[2,3－6]喹唑啉－3－酮之稠合雙環狀衍生物，作為NS5A－蛋白質－抑制劑，經提出以預防HCV複製。Bristol-Myers Squibb WO 2004/014852, published on February 19, 2004, states that iminothiazolidinone, including 2-(4-aminophenyl)-5H-thiazolo[2,3-6]quinazoline A fused dicyclic derivative of 3-ketone, as an NS5A-protein-inhibitor, has been proposed to prevent HCV replication.
2004年2月19日公告之Bristol－Myers Squibb WO 2004/014313指出用於治療病毒疾病之組合療法，包含亞胺基噻唑啶酮NS5A－蛋白質－抑制抗－HCV化合物，且併用其他能夠干擾HCV功能之藥劑。Bristol-Myers Squibb WO 2004/014313, published February 19, 2004, states that combination therapies for the treatment of viral diseases, including iminothiazolidinone NS5A-protein-inhibiting anti-HCV compounds, and other interfering with HCV function Pharmacy.
本發明之特徵為具有式I、II、III、IV、V、VI、VII或VIII之化合物，此等化合物之互變異構物，及此等化合物或互變異構物之藥學上可接受鹽。此等化合物、互變異構物或鹽可無論是個別或併用其他藥物或藥劑，用以抑制HCV或其他病毒之複製。此等化合物、互變異構物或鹽亦可無論是個別或併用其他藥物或藥劑，用以瓦解HCV或其他病毒之功能。The invention features a compound of formula I, II, III, IV, V, VI, VII or VIII, tautomers of such compounds, and pharmaceutically acceptable salts of such compounds or tautomers. Such compounds, tautomers or salts can be used to inhibit the replication of HCV or other viruses, either alone or in combination with other drugs or agents. Such compounds, tautomers or salts may also be used to disintegrate the function of HCV or other viruses, either individually or in combination with other drugs or agents.
本發明之特徵亦為包含本發明之化合物、互變異構物或鹽之組合物。本發明之組合物可包含一或多種本發明之化合物、互變異構物或鹽。本發明之組合物亦可包含一或多種其他抗病毒或治療劑。A feature of the invention is also a composition comprising a compound, tautomer or salt of the invention. The compositions of the present invention may comprise one or more compounds, tautomers or salts of the invention. Compositions of the invention may also comprise one or more other antiviral or therapeutic agents.
此外，本發明之特徵為使用本發明之化合物、互變異構物或鹽，或包含彼等之組合物，以抑制HCV或其他病毒複製之方法。此等方法包括使HCV或另一種病毒或被HCV或該另一種病毒感染之細胞，與有效量之本發明化合物、互變異構物或鹽接觸，藉以抑制HCV或該另一種病毒之複製。Furthermore, the invention features a method of inhibiting HCV or other viral replication using a compound, tautomer or salt of the invention, or a composition comprising the same. Such methods comprise contacting HCV or another virus or a cell infected with HCV or the other virus with an effective amount of a compound, tautomer or salt of the invention to inhibit replication of HCV or the other virus.
本發明之進一步特徵為使用本發明化合物、互變異構物或鹽或包含彼等之組合物以抑制HCV或其他病毒增生或傳遞之方法。此等方法包括使HCV或另一種病毒，或使已被HCV或另一種病毒感染之細胞，與有效量之本發明化合物、互變異構物或鹽接觸，藉以抑制HCV或該另一種病毒之增生或傳遞。A further feature of the invention is the use of a compound, tautomer or salt of the invention or a composition comprising the same to inhibit the proliferation or transmission of HCV or other viruses. Such methods include contacting HCV or another virus, or contacting a cell that has been infected with HCV or another virus, with an effective amount of a compound, tautomer or salt of the invention to inhibit the proliferation of HCV or the other virus. Or pass.
再者，本發明之特徵為使用本發明之化合物、互變異構物或鹽或包含彼等之組合物以治療HCV或其他病毒感染之方法。此等方法包括對需要此種治療之病患投予有效量之本發明化合物、互變異構物或鹽，藉以降低HCV或其他病毒在病患中之血液或組織含量。Furthermore, the invention features a method of treating a HCV or other viral infection using a compound, tautomer or salt of the invention or a composition comprising the same. Such methods include administering to a patient in need of such treatment an effective amount of a compound, tautomer or salt of the invention to reduce the blood or tissue content of the HCV or other virus in the patient.
本發明之特徵亦為本發明之化合物、互變異構物或鹽於藥劑製造上之用途，該藥劑係用於治療HCV或其他病毒感染。A feature of the invention is also the use of a compound, tautomer or salt of the invention in the manufacture of a medicament for the treatment of HCV or other viral infections.
又再者，本發明之特徵為製造本發明化合物、互變異構物或鹽之方法，及被採用於此等方法之中間物。Still further, the invention features a method of making a compound, tautomer or salt of the invention, and an intermediate employed in such methods.
本發明之其他特徵、目的及優點係在下文詳細說明中顯而易見。但應明瞭的是，詳細說明雖然指示本發明之較佳具體實施例，但僅以說明方式給予，並非限制。在本發明範圍內之各種改變與修正，將為熟諳此藝者自詳細說明而明瞭。Other features, objects, and advantages of the invention will be apparent from the description. It is to be understood that the detailed description of the preferred embodiments of the invention Various changes and modifications within the scope of the invention will be apparent to those skilled in the art.
下文說明係為舉例性質，並非意欲限制本發明之揭示內容、應用或用途。The following description is for illustrative purposes and is not intended to limit the disclosure, application, or use of the invention.
本發明之特徵為具有式I之化合物，其互變異構物，及該化合物或互變異構物之藥學上可接受鹽，
於一項具體實施例中，本發明之特徵為具有式I之化合物，其互變異構物，及該化合物或互變異構物之藥學上可接受鹽，其中：A與B各獨立選自C4 －C11 碳環基或M4 －M11 雜環基，且各獨立視情況被一或多個R18 取代，其中R18 在每一存在處係獨立選自包括鹵素、酮基、硫酮基、羥基、巰基、硝基、氰基、胺基、羧基、甲醯基、磷酸鹽、疊氮基、C1 －C6 烷基、C2 －C6 烯基、C2 －C6 炔基、C3 －C6 碳環基、M3 －M6 雜環基、－LS －O－RS 、－LS －S－RS 、－LS －C(O)RS 、－LS －OC(O)RS 、－LS －C(O)ORS 、－LS －N(RS RS’ )、－LS －C(＝NRS )RS’ 、－LS －S(O)RS 、－LS －SO2 RS 、－LS －C(O)N(RS RS’ )、－LS －N(RS )C(O)RS’ 、－LS －C(＝NRS )N(RS’ RS” )、－LS －N(RS’ )C(＝NRS )RS” 、－LS －N(RS )C(O)N(RS’ RS” )、－LS －N(RS )SO2 RS’ 、－LS －SO2 N(RS RS’ )及－LS －N(RS )SO2 N(RS’ RS” )；W1 與W2 各獨立選自N或C(R33 )；Z為一個鍵結、－CR41 R41’ －或－NR41 －，其中R41 與R41’ 各獨立選自包括氫、、C1 －C6 烷基、C2 －C6 烯基及C2 －C6 炔基；R10 與R33 在每一存在處係各獨立選自包括氫、鹵素、酮基、硫酮基、羥基、巰基、硝基、氰基、胺基、羧基、甲醯基、磷酸根、疊氮基、烷基、烯基、炔基、碳環基、雜環基、－LS －O－RS 、－LS －S－RS 、－LS －C(O)RS 、－LS －OC(O)RS 、－LS －C(O)ORS 、－LS －N(RS RS’ )、－LS －C(＝NRS )RS’ 、－LS －S(O)RS 、－LS －SO2 RS 、－LS －C(O)N(RS RS’ )、－LS －N(RS )C(O)RS’ 、－LS－C(＝NRS )N(RS’ RS” )、－LS －N(RS’ )C(＝NRS )RS” 、－LS －N(RS )C(O)N(RS’ RS” )、－LS －N(RS )SO2 RS’ 、－LS －SO2 N(RS RS’ )、－LS －N(RS )SO2 N(RS’ RS” )、－LE －Q－LE’ －(C3 －C18 碳環基)及－LE －Q－LE’ －(M3 －M18 雜環基)；X係選自包括一個鍵結、－LS －O－、－LS －S－、－LS －C(O)－、－LS －N(RS )－、－LS－N(RS )C(O)－、－LS －C(O)N(RS )－、－LS －N(RS )C(O)O－、－LS －OC(O)N(RS )－、－LS －N(RS )C(O)N(RS’ )－、－LS －C(＝NRS )N(RS’ )－、－LS －N(RS’ )C(＝NRS )－、－LS －S(O)－、－LS －SO2 －、－LS －C(O)O－及－LS －OC(O)－；R22 為C4 －C11 碳環基或M4 －M11 雜環基，且視情況被一或多個R26 取代，其中R26 在每一存在處係獨立選自包括鹵素、酮基、硫酮基、羥基、巰基、硝基、氰基、胺基、羧基、甲醯基、磷酸根、疊氮基、C1 －C6 烷基、C2 －C6 烯基、C2 －C6 炔基、－LS －O－RS 、－LS －S－RS 、－LS －C(O)RS 、－LS －OC(O)RS 、－LS －C(O)ORS 、－LS －N(RS RS’ )、－LS －C(＝NRS )RS’ 、－LS －S(O)RS 、－LS－SO2 RS 、－LS －C(O)N(RS RS’ )、－LS －N(RS )C(O)RS’ 、－LS －C(＝NRS )N(RS’ RS” )、－LS－N(RS’ )C(＝NRS )RS” 、－LS －N＝C(NRS RS’ )(NRS RS’ )、－LS －N(RS )C(O)N(RS’ RS” )、－LS －N(RS )SO2 RS’ 、－LS －SO2 N(RS RS’ )、－LS －N(RS )SO2 N(RS’ RS” )、－LE －Q－LE’ －(C3 －C18 碳環基)及－LE －Q－LE’ －(M3 －M18 雜環基)；或R22 為C1 －C6 烷基、C1 －C6 烯基或C1 －C6 炔基，且視情況被一或多個R26 取代；或R22 為氫；Y係選自包括一個鍵結、－LS －O－、－LS －C(O)－、－LS －S(O)2 －、－LS －S(O)－、－LS －OS(O)2 －、－LS －OS(O)－、－LS －C(O)O－、－LS －OC(O)－、－LS －OC(O)O－、－LS －C(O)N(R15 )－、－LS －N(R15 )C(O)－、－LS －C(O)N(R15 )O－、－LS －N(R15 )C(O)O－、－LS －C(O)N(R15 )N(R15’ )－、－LS －S－、－LS －C(S)－、－LS －C(S)O－、－LS －OC(S)－、－LS －N(R15 )－、－LS －C(S)N(R15 )－、－LS －N(R15 )C(S)－、－LS －N(R15 )S(O)－、－LS －N(R15 )S(O)2 －、－LS －S(O)2 N(R15 )－、－LS －S(O)N(R15 )－、－LS －C(S)N(R15 )O－及－LS －C(S)N(R15 )N(R15’ )－，其中R15 與R15’ 在每一存在處係各獨立選自包括氫、C1 －C6 烷基、C2 －C6 烯基及C2 －C6 炔基；R50 為－L1 －A1 ，其中A1 係選自包括C4 －C11 碳環基、M4 －M11 雜環基、C1 －C6 烷基、C2 －C6 烯基及C2 －C6 炔基，且L1 係選自包括一個鍵結、C1 －C6 次烷基、C2 －C6 次烯基及C2 －C6 次炔基，其中A1 係視情況被一或多個R30 取代，且R30 在每一存在處係獨立選自包括鹵素、酮基、硫酮基、羥基、巰基、硝基、氰基、胺基、羧基、甲醯基、磷酸根、疊氮基、C1 －C6 烷基、C2 －C6 烯基、C2 －C6 炔基、－LS －O－RS 、－LS －S－RS 、－LS －C(O)RS 、－LS －OC(O)RS 、－LS －C(O)ORS 、－LS －N(RS RS’ )、－LS －C(＝NRS )RS’ 、－LS －S(O)RS 、－LS －SO2 RS 、－LS －C(O)N(RS RS’ )、－LS －N(RS )C(O)RS’ 、－LS －C(＝NRS )N(RS’ RS” )、－LS－N(RS’ )C(＝NRS )RS” 、－LS －N(RS )C(O)N(RS’ RS” )、－LS －N(RS )SO2 RS’ 、－LS－SO2 N(RS RS’ )、－LS －N(RS )SO2 N(RS’ RS” )、－LE －Q－LE’ －(C3 －C18 碳環基)及－LE －Q－LE’ －(M3 －M18 雜環基)，且其中L1 係視情況被一或多個R38 取代，而R38 在每一存在處係獨立選自包括鹵素、酮基、硫酮基、羥基、巰基、硝基、氰基、胺基、羧基、甲醯基、磷酸根、疊氮基、C1 －C6 烷氧基、C1 －C6 硫代烷氧基、C1 －C6 烷羰基、C1 －C6 烷氧羰基、C1 －C6 烷羰基氧基、C1 －C6 烷胺基、C1 －C6 烷氧羰基胺基、－LS －O－RS 、－LS －S－RS 、－LS －C(O)RS 、－LS －OC(O)RS 、－LS －C(O)ORS 、－LS －N(RS RS’ )、－LS －C(＝NRS )RS’ 、－LS －S(O)RS 、－LS －SO2 RS 、－LS －C(O)N(RS RS’ )、－LS －N(RS )C(O)RS’ 、－LS －C(＝NRS )N(RS’ RS” )、－LS－N(RS’ )C(＝NRS )RS” 、－LS －N(RS )C(O)N(RS’ RS” )、－LS －N(RS )SO2 RS’ 、－LS－SO2 N(RS RS’ )、－LS －N(RS )SO2 N(RS’ RS” )、碳環基、雜環基、碳環基C1 －C6 烷基、雜環基C1 －C6 烷基、－LE －Q－LE’ －(C3 －C18 碳環基)及－LE －Q－LE’ －(M3 －M18 雜環基)；LS 在每一存在處係獨立選自包括一個鍵結、C1 －C6 次烷基、C2 －C6 次烯基及C2 －C6 次炔基；RS ,RS’ 及RS” 在每一存在處係各獨立選自包括氫、C1 －C6 烷基、C2 －C6 烯基、C2 －C6 炔基、C1 －C6 烷氧基、C1 －C6 硫代烷氧基、C1 －C6 烷氧基C1 －C6 烷基、C1 －C6 烷氧基C1 －C6 烷氧基C1 －C6 烷基、C1 －C6 硫代烷氧基C1 －C6 烷基、C1 －C6 烷羰基、C1 －C6 烷羰基C1 －C6 烷基、C1 －C6 烷氧羰基、C1 －C6 烷氧羰基C1 －C6 烷基、C1 －C6 烷羰基氧基、C1 －C6 烷羰基氧基C1 －C6 烷基、C1 －C6 烷胺基、C1 －C6 烷胺基C1 －C6 烷基、C1 －C6 烷氧羰基胺基及C1 －C6 烷氧羰基胺基C1 －C6 烷基；LE 與LE’ 在每一存在處係各獨立選自包括一個鍵結、C1 －C6 次烷基、C2 －C6 次烯基及C2 －C6 次炔基；Q在每一存在處係獨立選自包括一個鍵結、C1 －C6 次烷基、C2 －C6 次烯基、C2 －C6 次炔基、－S－、－O－、－C(O)－、－N(RS )－、－N(RS )C(O)－、－C(O)N(RS )－、－N(RS )C(O)O－、－OC(O)N(RS )－、－N(RS )C(O)N(RS’ )－、－C(＝NRS )N(RS’ )－、－N(RS’ )C(＝NRS )－、－S(O)－、－SO2 －、－O－SO2 －、－SO2 －O－、－O－S(O)－、－S(O)－O－、－C(O)O－及－OC(O)－；R10 ,R15 ,R15’ ,R18 ,R26 ,R30 ,R33 ,R38 ,R41 及R41’ 在每一存在處係各獨立視情況被至少一個取代基取代，取代基選自包括鹵素、酮基、硫酮基、羥基、巰基、硝基、氰基、胺基、羧基、甲醯基、磷酸根及疊氮基；且在－LE －Q－LE’ －(C3 －C18 碳環基)與－LE －Q－LE’ －(M3 －M18 雜環基)中之各C3 －C18 碳環基與M3 －M18 雜環基部份基團，在每一存在處係獨立視情況被至少一個取代基取代，取代基選自包括鹵素、酮基、硫酮基、羥基、巰基、硝基、氰基、胺基、羧基、甲醯基、磷酸根、疊氮基、C1 －C6 烷基、C2 －C6 烯基、C2 －C6 炔基、C1 －C6 烷氧基、C1 －C6 硫代烷氧基、C1 －C6 烷氧基C1 －C6 烷基、C1 －C6 硫代烷氧基C1 －C6 烷基、C1 －C6 烷羰基、C1 －C6 烷羰基C1 －C6 烷基、C1 －C6 烷氧羰基、C1 －C6 烷氧羰基C1 －C6 烷基、C1 －C6 烷羰基氧基、C1 －C6 烷羰基氧基C1 －C6 烷基、C1 －C6 烷胺基、C1 －C6 烷胺基C1 －C6 烷基、C1 －C6 烷氧羰基胺基及C1 －C6 烷氧羰基胺基C1 －C6 烷基。In a particular embodiment, the invention features a compound of formula I, a tautomer thereof, and a pharmaceutically acceptable salt of the compound or tautomer, wherein: A and B are each independently selected from C. a 4- C 11 carbocyclic group or an M 4 -M 11 heterocyclic group, and each of which is optionally substituted by one or more R 18 , wherein R 18 is independently selected from the group consisting of halogen, keto, sulfur Keto group, hydroxyl group, mercapto group, nitro group, cyano group, amine group, carboxyl group, formamidine group, phosphate group, azide group, C 1 -C 6 alkyl group, C 2 -C 6 alkenyl group, C 2 -C 6 Alkynyl, C 3 -C 6 carbocyclyl, M 3 -M 6 heterocyclyl, -L S -O-R S , -L S -S-R S , -L S -C(O)R S , -L S -OC(O)R S , -L S -C(O)OR S , -L S -N(R S R S' ), -L S -C(=NR S )R S' ,- L S -S(O)R S , -L S -SO 2 R S , -L S -C(O)N(R S R S' ), -L S -N(R S )C(O)R S' , -L S -C(=NR S )N(R S' R S" ), -L S -N(R S' )C(=NR S )R S" , -L S -N(R S ) C(O)N(R S' R S" ), -L S -N(R S )SO 2 R S' , -L S -SO 2 N(R S R S' ), and -L S - N(R S )SO 2 N(R S' R S" ); W 1 and W 2 are each independently selected from N or C(R 33 ); Z is a bond, -CR 41 R 41 ' -or-NR 41 - wherein R 41 and R 41 ' are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl; R 10 and R 33 are each The respective units are independently selected from the group consisting of hydrogen, halogen, keto, thioketo, hydroxy, decyl, nitro, cyano, amine, carboxyl, formazan, phosphate, azide, alkyl, alkenyl , alkynyl, carbocyclyl, heterocyclic, -L S -O-R S , -L S -S-R S , -L S -C(O)R S , -L S -OC(O)R S , -L S -C(O)OR S , -L S -N(R S R S' ), -L S -C(=NR S )R S' , -L S -S(O)R S , -L S -SO 2 R S , -L S -C(O)N(R S R S' ), -L S -N(R S )C(O)R S' , -LS-C(= NR S )N(R S' R S" ), -L S -N(R S' )C(=NR S )R S" , -L S -N(R S )C(O)N(R S ' R S ' ), -L S -N(R S )SO 2 R S' , -L S -SO 2 N(R S R S' ), -L S -N(R S )SO 2 N(R S' R S" ), -L E -Q-L E' -(C 3 -C 18 carbocyclic group) and -L E -Q-L E '- (M 3 -M 18 heterocyclyl group); X-is selected from a bond include, -L S -O -, - L S -S -, - L S -C (O) -, - L S - N(R S )-, -LS-N(R S )C(O)-, -L S -C(O)N(R S )-, -L S -N(R S )C(O)O -, -L S -OC(O)N(R S )-, -L S -N(R S )C(O)N(R S' )-, -L S -C(=NR S )N( R S' )-, -L S -N(R S' )C(=NR S )-, -L S -S(O)-, -L S -SO 2 -, -L S -C(O) O- and -L S -OC(O)-; R 22 is C 4 -C 11 carbocyclyl or M 4 -M 11 heterocyclyl, and optionally substituted by one or more R 26 , wherein R 26 is Each of the existing units is independently selected from the group consisting of halogen, keto, thioketo, hydroxy, decyl, nitro, cyano, amine, carboxyl, formazan, phosphate, azide, C 1 -C 6 alkane , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -L S -O-R S , -L S -S-R S , -L S -C(O)R S , -L S -OC(O)R S , -L S -C(O)OR S , -L S -N(R S R S' ), -L S -C(=NR S )R S' , -L S - S(O)R S , -LS-SO 2 R S , -L S -C(O)N(R S R S' ), -L S -N(R S C(O)R S' , -L S -C(=NR S )N(R S' R S" ), -LS-N(R S' )C(=NR S )R S" , -L S -N=C(NR S R S' )(NR S R S' ), -L S -N(R S )C(O)N(R S' R S" ), -L S -N(R S )SO 2 R S' , -L S -SO 2 N(R S R S' ), -L S -N(R S )SO 2 N(R S' R S" ), -L E -Q- L E' -(C 3 -C 18 carbocyclic group) and -L E -Q-L E' -(M 3 -M 18 heterocyclic group); or R 22 is C 1 -C 6 alkyl group, C 1 -C 6 alkenyl or C 1 -C 6 alkynyl, and optionally substituted by one or more R 26 ; or R 22 is hydrogen; Y is selected from the group consisting of a bond, -L S -O-, -L S -C(O)-, -L S -S(O) 2 -, -L S -S(O)-, -L S -OS(O) 2 -, -L S -OS(O)-, -L S -C(O)O-, -L S -OC(O)-, -L S -OC(O)O-, -L S -C(O)N(R 15 )-, -L S -N(R 15 )C(O)-, -L S -C(O)N(R 15 )O-, -L S -N(R 15 )C(O)O-, -L S -C( O)N(R 15 )N(R 15' )-, -L S -S-, -L S -C(S)-, -L S -C(S)O-, -L S -OC(S )-, -L S -N(R 15 )-, -L S -C(S)N(R 15 )-, -L S -N (R 15 )C(S)-, -L S -N(R 15 )S(O)-, -L S -N(R 15 )S(O) 2 -, -L S -S(O) 2 N(R 15 )-, -L S -S(O)N(R 15 )-, -L S -C(S)N(R 15 )O- and -L S -C(S)N(R 15 N(R 15 ' )-, wherein R 15 and R 15 ' are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 Alkynyl; R 50 is -L 1 -A 1 , wherein A 1 is selected from the group consisting of C 4 -C 11 carbocyclic, M 4 -M 11 heterocyclyl, C 1 -C 6 alkyl, C 2 -C a 6 alkenyl group and a C 2 -C 6 alkynyl group, and the L 1 group is selected from the group consisting of a bond, a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, and a C 2 -C 6 alkynyl group. Wherein A 1 is optionally substituted by one or more R 30 , and R 30 is independently selected from the group consisting of halogen, keto, thioketo, hydroxy, thiol, nitro, cyano, amine, Carboxyl, carbenyl, phosphate, azide, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -L S -O-R S , -L S - S-R S , -L S -C(O)R S , -L S -OC(O)R S , -L S -C(O)OR S , -L S -N(R S R S' ) , -L S -C(=NR S ) R S' , -L S -S(O)R S , -L S -SO 2 R S , -L S -C(O)N(R S R S' ), -L S -N(R S C(O)R S' , -L S -C(=NR S )N(R S' R S" ), -LS-N(R S' )C(=NR S )R S" , -L S -N(R S )C(O)N(R S' R S" ), -L S -N(R S )SO 2 R S' , -LS-SO 2 N(R S R S' ), -L S -N(R S )SO 2 N(R S' R S" ), -L E -Q-L E' -(C 3 -C 18 carbocyclic group) and -L E -Q-L E ' -(M 3 -M 18 heterocyclyl), and wherein L 1 is optionally substituted by one or more R 38 , and R 38 is independently selected from each of the group consisting of halogen, keto, thiol , hydroxy, decyl, nitro, cyano, amine, carboxyl, methionyl, phosphate, azide, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 - C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylcarbonyloxy, C 1 -C 6 alkylamino, C 1 -C 6 alkoxycarbonylamino, -L S -O- R S , -L S -S-R S , -L S -C(O)R S , -L S -OC(O)R S , -L S -C(O)OR S , -L S -N (R S R S' ), -L S -C(=NR S )R S' , -L S -S(O)R S , -L S -SO 2 R S , -L S -C(O)N(R S R S' ), -L S -N(R S )C(O)R S' , -L S -C(=NR S N(R S' R S" ), -LS-N(R S' )C(=NR S )R S" , -L S -N(R S )C(O)N(R S' R S " ), -L S -N(R S )SO 2 R S' , -LS-SO 2 N(R S R S' ), -L S -N(R S )SO 2 N(R S' R S " ), carbocyclyl, heterocyclyl, carbocyclyl C 1 -C 6 alkyl, heterocyclyl C 1 -C 6 alkyl, -L E -Q-L E' -(C 3 -C 18 carbon a cyclic group) and -L E -Q-L E' -(M 3 -M 18 heterocyclic group); L S is independently selected from each of the substituents including a bond, a C 1 -C 6 alkyl group, C 2 -C 6 -alkenyl and C 2 -C 6 -alkynyl; R S , R S′ and R S ′′ are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C. 2- C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 alkoxy C 1 -C 6 alkyl , C 1 -C 6 alkoxy C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 1 -C 6 thioalkoxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl , C 1 -C 6 alkylcarbonyl C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl group, C 1 -C 6 alkylcarbonyl group, C 1 -C 6 alkylcarbonyl group, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 Alkylamino C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonylamino and C 1 -C 6 alkoxycarbonylamino C 1 -C 6 alkyl; L E and L E ' in each presence Each of the lines is independently selected from the group consisting of a bond, a C 1 -C 6 alkyl group, a C 2 -C 6 alkyl group, and a C 2 -C 6 alkynyl group; Q is independently selected from each of the sites including one Bonded, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -S-, -O-, -C(O)-, -N(R S )-, -N(R S )C(O)-, -C(O)N(R S )-, -N(R S )C(O)O-, -OC(O)N(R S ) -, -N(R S )C(O)N(R S' )-, -C(=NR S )N(R S' )-, -N(R S' )C(=NR S )-, -S(O)-, -SO 2 -, -O-SO 2 -, -SO 2 -O-, -O-S(O)-, -S(O)-O-, -C(O)O - and -OC(O)-; R 10 , R 15 , R 15' , R 18 , R 26 , R 30 , R 33 , R 38 , R 41 and R 41 ' in each case, independent Substituted by at least one substituent selected from the group consisting of halogen, ketone, a thioketo group, a hydroxyl group, a decyl group, a nitro group, a cyano group, an amine group, a carboxyl group, a decyl group, a phosphate group, and an azide group; and in the -L E -Q-L E' -(C 3 -C 18 carbocyclic ring And each of the C 3 -C 18 carbocyclic group and the M 3 -M 18 heterocyclic group in the -L E -Q-L E' -(M 3 -M 18 heterocyclic group) Where present, the substituent is independently substituted with at least one substituent selected from the group consisting of halogen, keto, thioketo, hydroxy, decyl, nitro, cyano, amine, carboxyl, formazan, phosphate, Azido group, C 1 -C 6 alkyl group, C 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group, C 1 -C 6 alkoxy group, C 1 -C 6 thioalkoxy group, C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 1 -C 6 thioalkoxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarbonyl C 1 - C 6 alkyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkoxycarbonyl C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyloxy, C 1 -C 6 alkylcarbonyloxy C 1- C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylamino C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonylamino and C 1 -C 6 alkoxy carbonyl C 1 -C 6 alkyl group
在此項具體實施例之一項實例中，Y為－LS －O－、－LS －S－或－LS －N(R15 )－，而R50 為－L1 －A1 ，其中L1 為一個鍵結、C1 －C6 次烷基、C2 －C6 次烯基或C2 －C6 次炔基，且視情況被一或多個R38 取代，而A1 為C4 －C11 碳環基或M4 －M11 雜環基，且視情況被一或多個R30 取代。In one example of this embodiment, Y is -L S -O -, - L S -S- or -L S -N (R 15) - , and R 50 is -L 1 -A 1, Wherein L 1 is a bond, a C 1 -C 6 alkyl group, a C 2 -C 6 alkylene group or a C 2 -C 6 alkynyl group, and optionally substituted by one or more R 38 , and A 1 Is a C 4 -C 11 carbocyclic group or an M 4 -M 11 heterocyclic group, and is optionally substituted by one or more R 30 .
在此項具體實施例之另一項實例中，Y為一個鍵結，而R50 為－L1 －A1 ，其中L1 為一個鍵結、C1 －C6 次烷基、C2 －C6 次烯基或C2 －C6 次炔基，且視情況被一或多個R38 取代，而A1 為C4 －C11 碳環基或M4 －M11 雜環基，且視情況被一或多個R30 取代。In another embodiment of this embodiment, Y is a bond and R 50 is -L 1 -A 1 , wherein L 1 is a bond, C 1 -C 6 alkyl, C 2 - C 6 -alkenyl or C 2 -C 6 -alkynyl, and optionally substituted by one or more R 38 , and A 1 is C 4 -C 11 carbocyclyl or M 4 -M 11 heterocyclyl, Replaced by one or more R 30 as appropriate.
於此項具體實施例之又另一項實例中，Y為一個鍵結，而R50 為－L1 －A1 ，其中L1 係選自包括一個鍵結、C1 －C6 次烷基、C2 －C6 次烯基及C2 －C6 次炔基，且視情況被一或多個R38 取代，而A1 為氫或R18 。In yet another embodiment of this specific embodiment, Y is a bond and R 50 is -L 1 -A 1 , wherein L 1 is selected from the group consisting of a bond, a C 1 -C 6 alkyl group C 2 -C 6 -alkenyl and C 2 -C 6 -alkynyl, and optionally substituted by one or more R 38 , and A 1 is hydrogen or R 18 .
於此項具體實施例之又另一項實例中，Y係選自包括－LS －S(O)2 N(R15 )－、－LS －OS(O)2 －、－LS －OC(O)－、－LS －C(O)O－、－LS －C(O)－及－N(R15 )C(O)O－。In yet another embodiment of this specific embodiment, Y is selected from the group consisting of -L S -S(O) 2 N(R 15 )-, -L S -OS(O) 2 -, -L S - OC(O)-, -L S -C(O)O-, -L S -C(O)-, and -N(R 15 )C(O)O-.
於此項具體實施例之又再另一項實例中，A與B各獨立選自C5 －C6 碳環基或M5 －M6 雜環基，且各獨立視情況被一或多個R18 取代。In still another example of this embodiment, A and B are each independently selected from a C 5 -C 6 carbocyclic group or an M 5 -M 6 heterocyclic group, and each independently is one or more R 18 is substituted.
於此項具體實施例之又另一項實例中，W1 與W2 為N，且Z為－NR41 －。In yet another embodiment of this specific embodiment, W 1 and W 2 are N and Z is -NR 41 -.
於此項具體實施例之又另一項實例中，X為－O－或－S－，而R22 為C5 －C6 碳環基或M5 －M6 雜環基，且視情況被一或多個R26 取代。In yet another embodiment of this embodiment, X is -O- or -S-, and R 22 is C 5 -C 6 carbocyclyl or M 5 -M 6 heterocyclyl, and is optionally One or more R 26 substitutions.
於此項具體實施例之又另一項實例中，部份基團為，其中：W1 ,W2 ,W3 及W4 各獨立選自N或C(R33 )；且R10 ,R17 ,R33 及R35 在每一存在處係各獨立選自包括氫、鹵素、酮基、硫酮基、羥基、巰基、硝基、氰基、胺基、羧基、甲醯基、磷酸根、疊氮基、C1 －C6 烷基、C2 －C6 烯基、C2 －C6 炔基、C3 －C6 碳環基、M3 －M6 雜環基、－LS －O－RS 、－LS －S－RS 、－LS －C(O)RS 、－LS －OC(O)RS 、－LS －C(O)ORS 、－LS －N(RS RS’ )、－LS －C(＝NRS )RS’ 、－LS －S(O)RS 、－LS －SO2 RS 、－LS －C(O)N(RS RS’ )、－LS －N(RS )C(O)RS’ 、－LS －C(＝NRS )N(RS’ RS” )、－LS －N(RS’ )C(＝NRS )RS” 、－LS －N(RS )C(O)N(RS’ RS” )、－LS －N(RS )SO2 RS’ 、－LS －SO2 N(RS RS’ )、－LS －N(RS )SO2 N(RS’ RS” )、－LE －Q－LE’ －(C3 －C18 碳環基)及－LE －Q－LE’ －(M3 －M18 雜環基)。In yet another example of this embodiment, a portion of the group for Wherein: W 1 , W 2 , W 3 and W 4 are each independently selected from N or C(R 33 ); and R 10 , R 17 , R 33 and R 35 are each independently selected from the group consisting of hydrogen in each presence. , halogen, keto, thioketo, hydroxy, decyl, nitro, cyano, amine, carboxyl, methionyl, phosphate, azide, C 1 -C 6 alkyl, C 2 -C 6 olefin , C 2 -C 6 alkynyl, C 3 -C 6 carbocyclyl, M 3 -M 6 heterocyclyl, -L S -O-R S , -L S -S-R S , -L S - C(O)R S , -L S -OC(O)R S , -L S -C(O)OR S , -L S -N(R S R S' ), -L S -C(=NR S ) R S′ , -L S -S(O)R S , -L S -SO 2 R S , -L S -C(O)N(R S R S' ), -L S -N(R S )C(O)R S' , -L S -C(=NR S )N(R S' R S" ), -L S -N(R S' )C(=NR S )R S" , -L S -N(R S )C(O)N(R S' R S" ), -L S -N(R S )SO 2 R S' , -L S -SO 2 N(R S R S ' ), -L S -N(R S )SO 2 N(R S' R S" ), -L E -Q-L E' -(C 3 -C 18 carbocyclic group) and -L E -Q -L E' -(M 3 -M 18 heterocyclic group).
於此項具體實施例之又另一項實例中，部份基團係選自包括、、及，其中：Q為N或C(R33 )；且R10 ,R17 ,R33 及R35 在每一存在處係各獨立選自包括氫、鹵素、酮基、硫酮基、羥基、巰基、硝基、氰基、胺基、羧基、甲醯基、磷酸根、疊氮基、C1 －C6 烷基、C2 －C6 烯基、C2 －C6 炔基、C3 －C6 碳環基、M3 －M6 雜環基、－LS －O－RS 、－LS －S－RS 、－LS －C(O)RS 、－LS －OC(O)RS 、－LS －C(O)ORS 、－LS －N(RS RS’ )、－LS －C(＝NRS )RS’ 、－LS －S(O)RS 、－LS －SO2 RS 、－LS －C(O)N(RS RS’ )、－LS －N(RS )C(O)RS’ 、－LS －C(＝NRS )N(RS’ RS” )、－LS －N(RS’ )C(＝NRS )RS” 、－LS －N(RS )C(O)N(RS’ RS” )、－LS －N(RS )SO2 RS’ 、－LS －SO2 N(RS RS’ )、－LS －N(RS )SO2 N(RS’ RS” )、－LE －Q－LE’ －(C3 －C18 碳環基)及－LE －Q－LE’ －(M3 －M18 雜環基)。In yet another example of this embodiment, a portion of the group Selected from , , and Wherein: Q is N or C(R 33 ); and R 10 , R 17 , R 33 and R 35 are each independently selected from the group consisting of hydrogen, halogen, keto, thioketo, hydroxy, decyl , nitro, cyano, amine, carboxyl, methionyl, phosphate, azide, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - C 6 carbocyclic group, M 3 -M 6 heterocyclic group, -L S -O-R S , -L S -S-R S , -L S -C(O)R S , -L S -OC( O) R S , -L S -C(O)OR S , -L S -N(R S R S' ), -L S -C(=NR S )R S' , -L S -S(O R S , -L S -SO 2 R S , -L S -C(O)N(R S R S' ), -L S -N(R S )C(O)R S' , -L S -C(=NR S )N(R S' R S" ), -L S -N(R S' )C(=NR S )R S" , -L S -N(R S )C(O) N(R S' R S" ), -L S -N(R S )SO 2 R S' , -L S -SO 2 N(R S R S' ), -L S -N(R S )SO 2 N(R S' R S" ), -L E -Q-L E' -(C 3 -C 18 carbocyclic group) and -L E -Q-L E' -(M 3 -M 18 heterocyclic ring base).
於此項具體實施例之進一步實例中，A與B各獨立選自C5 －C6 碳環基或M5 －M6 雜環基，且各獨立視情況被一或多個R18 取代，其中：W1 與W2 為N；Z為－NR41 －；X為－O－或－S－；R22 為C5 －C6 碳環基或M5 －M6 雜環基，且視情況被一或多個R26 取代；Y為一個鍵結、－LS －O－、－LS －S－或－LS －N(R15 )－；且A1 為C5 －C10 碳環基或M5 －M10 雜環基，且視情況被一或多個R30 取代。In a further example of this particular embodiment, A and B are each independently selected from a C 5 -C 6 carbocyclic group or an M 5 -M 6 heterocyclic group, and each is independently substituted with one or more R 18 , as appropriate. Wherein: W 1 and W 2 are N; Z is -NR 41 -; X is -O- or -S-; R 22 is a C 5 -C 6 carbocyclic group or an M 5 -M 6 heterocyclic group, and The situation is replaced by one or more R 26 ; Y is a bond, -L S -O-, -L S -S- or -L S -N(R 15 )-; and A 1 is C 5 -C 10 Carbocyclyl or M 5 -M 10 heterocyclyl, and optionally substituted by one or more R 30 .
在此項具體實施例之另一項實例中，A與B各獨立選自C5 －C6 碳環基或M5 －M6 雜環基，且各獨立視情況被一或多個R18 取代，其中：W1 與W2 為N；Z為－NR41 －；X為－O－或－S－；R22 為、或，其中R48 為羥基、胺基、C1 －C6 烷胺基、C1 －C6 烷氧基、C1 －C6 烷氧羰基胺基或C1 －C6 烷羰基氧基，且R22 (例如R48 或在R22 中之苯環)係視情況被一或多個R26 取代；Y為一個鍵結、－LS －O－、－LS －S－或－LS －N(R15 )－；且A1 為C5 －C10 碳環基或M5 －M10 雜環基，且視情況被一或多個R30 取代。In another embodiment of this particular embodiment, A and B are each independently selected from a C 5 -C 6 carbocyclic group or an M 5 -M 6 heterocyclic group, and each independently is one or more R 18 as appropriate. Substituted, wherein: W 1 and W 2 are N; Z is -NR 41 -; X is -O- or -S-; R 22 is , or Wherein R 48 is hydroxy, amino, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonylamino or C 1 -C 6 alkylcarbonyloxy, and R 22 (for example R 48 or a benzene ring in R 22 ) is optionally substituted by one or more R 26 ; Y is a bond, -L S -O-, -L S -S- or -L S -N(R 15 )-; and A 1 is a C 5 -C 10 carbocyclic group or an M 5 -M 10 heterocyclic group, and is optionally substituted by one or more R 30 .
於此項具體實施例之又另一項實例中，部份基團係選自包括、、及，其中：Q為N或C(R33 )；R10 ,R17 ,R33 及R35 在每一存在處係各獨立選自包括氫、鹵素、酮基、硫酮基、羥基、巰基、硝基、氰基、胺基、羧基、甲醯基、磷酸根、疊氮基、C1 －C6 烷基、C2 －C6 烯基、C2 －C6 炔基、C3 －C6 碳環基、M3 －M6 雜環基、－LS －O－RS 、－LS －S－RS 、－LS －C(O)RS 、－LS －OC(O)RS 、－LS －C(O)ORS 、－LS －N(RS RS’ )、－LS －C(＝NRS )RS’ 、－LS －S(O)RS 、－LS －SO2 RS 、－LS －C(O)N(RS RS’ )、－LS －N(RS )C(O)RS’ 、－LS －C(＝NRS )N(RS’ RS” )、－LS －N(RS’ )C(＝NRS )RS ”、－LS －N(RS )C(O)N(RS’ RS” )、－LS －N(RS )SO2 RS’ 、－LS －SO2 N(RS RS’ )、－LS －N(RS )SO2 N(RS’ RS” )、－LE －Q－LE’ －(C3 －C18 碳環基)及－LE －Q－LE’ －(M3 －M18 雜環基)；A為C5 －C6 碳環基或M5 －M6 雜環基，且視情況被一或多個R18 取代，Z為－NR41 －；X為－O－或－S－；R22 為、或，其中R48 為羥基、胺基、C1 －C6 烷胺基、C1 －C6 烷氧基、C1 －C6 烷氧羰基胺基或C1 －C6 烷羰基氧基，且R22 (例如R48 或在R22 中之苯環)係視情況被一或多個R26 取代；Y為一個鍵結、－LS －O－、－LS －S－或－LS －N(R15 )－；且A1 為C5 －C10 碳環基或M5 －M10 雜環基，且視情況被一或多個R30 取代。In yet another example of this embodiment, a portion of the group Selected from , , and Wherein: Q is N or C(R 33 ); R 10 , R 17 , R 33 and R 35 are each independently selected from the group consisting of hydrogen, halogen, keto, thioketo, hydroxy, thiol, Nitro, cyano, amine, carboxyl, methionyl, phosphate, azide, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 carbocyclic group, M 3 -M 6 heterocyclic group, -L S -O-R S , -L S -S-R S , -L S -C(O)R S , -L S -OC(O R S , -L S -C(O)OR S , -L S -N(R S R S' ), -L S -C(=NR S )R S' , -L S -S(O) R S , -L S -SO 2 R S , -L S -C(O)N(R S R S' ), -L S -N(R S )C(O)R S' , -L S - C(=NR S )N(R S' R S" ), -L S -N(R S' )C(=NR S )R S ", -L S -N(R S )C(O)N (R S' R S" ), -L S -N(R S )SO 2 R S' , -L S -SO 2 N(R S R S' ), -L S -N(R S )SO 2 N(R S' R S" ), -L E -Q-L E' -(C 3 -C 18 carbocyclic group) and -L E -Q-L E' -(M 3 -M 18 heterocyclic group A; a C 5 -C 6 carbocyclic group or an M 5 -M 6 heterocyclic group, and optionally substituted by one or more R 18 , Z is -NR 41 - ; X is -O- or -S-; R 22 is , or Wherein R 48 is hydroxy, amino, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonylamino or C 1 -C 6 alkylcarbonyloxy, and R 22 (for example R 48 or a benzene ring in R 22 ) is optionally substituted by one or more R 26 ; Y is a bond, -L S -O-, -L S -S- or -L S -N(R 15 )-; and A 1 is a C 5 -C 10 carbocyclic group or an M 5 -M 10 heterocyclic group, and is optionally substituted by one or more R 30 .
於另一項具體實施例中，本發明之特徵為吡啶并嘧啶基－胺基苯基醚化合物之族群，該化合物之互變異構物，或該化合物或互變異構物之藥學上可接受鹽，其中此族群之化合物係在結構上相應於式II：
其中：R6 係選自包括氫與氰基；R8 係選自包括氫與芳烷基；R25 係選自包括氫與烷基；R37 係選自包括氫、烷基、羥烷基及環烷基；R42 係選自包括芳基硫基、雜芳基硫基及芳氧基；其中R42 係視情況被一或多個獨立選自R46 之取代基取代；R46 為一或多個取代基，選自包括氫、羥基、胺基、鹵素、二烷胺基及烷氧羰基胺基；R70 係選自包括芳基與雜環基；其中R70 係視情況被R75 取代；R75 為一或多個取代基，獨立選自包括氫、鹵素、烷氧基、氰基、烷基、鹵烷基及芳基。Wherein: R 6 is selected from the group consisting of hydrogen and cyano; R 8 is selected from the group consisting of hydrogen and aralkyl; R 25 is selected from the group consisting of hydrogen and alkyl; and R 37 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl. and cycloalkyl; R 42 is selected from group comprising aryl, heteroaryl, aryloxy and arylthio group; wherein R 42 optionally lines with one or more substituents independently selected from R of 46; R 46 is One or more substituents selected from the group consisting of hydrogen, hydroxyl, amine, halogen, dialkylamino and alkoxycarbonylamino; R 70 is selected from the group consisting of aryl and heterocyclic; wherein R 70 is optionally R 75 is substituted; R 75 is one or more substituents independently selected from the group consisting of hydrogen, halogen, alkoxy, cyano, alkyl, haloalkyl and aryl.
在式II內之此項具體實施例之一個子集族群中，R6 係選自包括氫與氰基；R8 係選自包括氫與苯基甲基；R25 係選自包括氫與甲基；R37 係選自包括氫、甲基、乙基、第三－丁基、異丙基、羥甲基乙基及環己基；R42 係選自包括苯基硫基、苯氧基及嘧啶基硫基；R46 係選自包括氫、羥基、胺基、N,N－二甲胺基及第三－丁氧羰基胺基；R70 係選自包括苯基、噻唑基、吡啶基、四氫呋喃基、萘基、喹啉基及噻吩基；R75 為一或多個取代基，選自包括氫、甲基、丁基、羥基、甲氧基、溴基、氯基、氟基、氰基、三氟甲基及苯基。In a subset of the specific embodiment of Formula II, R 6 is selected from the group consisting of hydrogen and cyano; R 8 is selected from the group consisting of hydrogen and phenylmethyl; and R 25 is selected from the group consisting of hydrogen and R 37 is selected from the group consisting of hydrogen, methyl, ethyl, tert-butyl, isopropyl, hydroxymethylethyl and cyclohexyl; and R 42 is selected from the group consisting of phenylthio, phenoxy and a pyrimidinylthio group; R 46 is selected from the group consisting of hydrogen, a hydroxyl group, an amine group, an N,N-dimethylamino group and a third-butoxycarbonylamino group; and the R 70 is selected from the group consisting of a phenyl group, a thiazolyl group, and a pyridyl group. , tetrahydrofuranyl, naphthyl, quinolyl and thienyl; R 75 is one or more substituents selected from the group consisting of hydrogen, methyl, butyl, hydroxy, methoxy, bromo, chloro, fluoro, Cyano, trifluoromethyl and phenyl.
於又再另一項具體實施例中，本發明之特徵為吡啶并嘧啶基－胺基苯基烷基醚化合物之族群，該化合物之互變異構物，或該化合物或互變異構物之藥學上可接受鹽，其中此族群之化合物係在結構上相應於式III：
其中R80 係選自包括氫、烷羰基及鹵芳基。Wherein R 80 is selected from the group consisting of hydrogen, alkylcarbonyl and haloaryl.
在式III內之此項具體實施例之一個子集族群中，R80 係選自包括氫、甲基羰基及溴苯基。In a subset of this particular embodiment of Formula III, R 80 is selected from the group consisting of hydrogen, methylcarbonyl, and bromophenyl.
於又另一項具體實施例中，本發明之特徵為噻唑并嘧啶基－胺基苯基與噻吩并嘧啶基－胺基苯基化合物之族群，該化合物之互變異構物，或該化合物或互變異構物之藥學上可接受鹽，其中此族群之化合物係在結構上相應於式IV：
其中：Q係選自包括N與CH；R1 係選自包括烷硫基、氰基烷基硫基及烷基；R19 係選自包括烷基與鹵芳基烷氧基；R56 係選自包括氫、羥基、烷基及烷羰基胺基。Wherein: Q is selected from the group consisting of N and CH; R 1 is selected from the group consisting of alkylthio, cyanoalkylthio and alkyl; R 19 is selected from alkyl and haloalkoxy; R 56 It is selected from the group consisting of hydrogen, hydroxyl, alkyl and alkylcarbonyl amine groups.
在式IV內之此項具體實施例之一個子集族群中，R1 係選自包括甲硫基、氰基甲硫基、丙基及丁基；R19 係選自包括甲基與溴苯基甲氧基；R56 係選自包括氫、羥基、甲基及甲基羰基胺基。In a subset of the specific embodiment of Formula IV, R 1 is selected from the group consisting of methylthio, cyanomethylthio, propyl and butyl; and R 19 is selected from the group consisting of methyl and bromobenzene. Methoxy; R 56 is selected from the group consisting of hydrogen, hydroxy, methyl and methylcarbonylamino.
於進一步具體實施例中，本發明之特徵為嘧啶并嘧啶基－胺基苯基化合物之族群，該化合物之互變異構物，或該化合物或互變異構物之藥學上可接受鹽，其中此族群之化合物係在結構上相應於式V：
其中：R5 係選自包括氫與烷硫基；R29 係選自包括烷基、芳基烷氧基、鹵素及鹵芳基烷氧基；R47 係選自包括烷基、鹵烷基、烷硫基、芳烷基硫基及雜環基；R64 係選自包括氫、烷氧基及烷基；R66 係選自包括氫、羥基、芳氧基、烷基磺醯氧基、烷羰基胺基芳基碸基基氧基、鹵芳基磺醯氧基、氰基、芳基烷氧基、烷羰基胺基、鹵素及烷基；R81 係選自包括氫、烷氧基及羰基。Wherein R 5 is selected from the group consisting of hydrogen and alkylthio; R 29 is selected from the group consisting of alkyl, arylalkoxy, halogen and haloarylalkoxy; and R 47 is selected from alkyl, haloalkyl. , alkylthio, aralkylthio and heterocyclic; R 64 is selected from the group consisting of hydrogen, alkoxy and alkyl; R 66 is selected from the group consisting of hydrogen, hydroxy, aryloxy, alkylsulfonyloxy An alkylcarbonylaminoarylalkyloxy group, a halogenarylsulfonyloxy group, a cyano group, an arylalkoxy group, an alkylcarbonylamino group, a halogen and an alkyl group; and the R 81 group is selected from the group consisting of hydrogen and alkoxy Base and carbonyl.
在式V內之此項具體實施例之一個子集族群中，R5 係選自包括氫與甲硫基；R29 係選自包括甲基、乙基、氟基、苯基甲氧基及溴苯基甲氧基；R47 係選自包括氫、丙基、異丙基、乙基硫基、六氫吡啶基、嗎福啉基、七氟丙基及苯基甲硫基；R64 係選自包括氫、甲氧基、羥基及甲氧基；R66 係選自包括氫、甲基、羥基、甲氧基、苯氧基、苯基甲氧基、苯基硫基氧基、異丙基磺醯氧基、甲基羰基胺基苯基磺醯氧基、溴苯基硫基氧基、氰基、甲基羰基胺基及氟基；R81 係選自包括氫、第三－丁氧基及羰基。In a subset of the specific embodiment of Formula V, R 5 is selected from the group consisting of hydrogen and methylthio; and R 29 is selected from the group consisting of methyl, ethyl, fluoro, phenylmethoxy, and Bromophenylmethoxy; R 47 is selected from the group consisting of hydrogen, propyl, isopropyl, ethylthio, hexahydropyridyl, morpholinyl, heptafluoropropyl and phenylmethylthio; R 64 Is selected from the group consisting of hydrogen, methoxy, hydroxy and methoxy; R 66 is selected from the group consisting of hydrogen, methyl, hydroxy, methoxy, phenoxy, phenylmethoxy, phenylthiooxy, Isopropyl sulfonyloxy, methylcarbonylaminophenylsulfonyloxy, bromophenylthiooxy, cyano, methylcarbonylamino and fluoro; R 81 is selected from the group consisting of hydrogen, third - Butoxy and carbonyl.
於另一項具體實施例中，本發明之特徵為吡唑并嘧啶基－胺基苯基化合物之族群，該化合物之互變異構物，或該化合物或互變異構物之藥學上可接受鹽，其中此族群之化合物係在結構上相應於式VI：
其中：R73 為烷基；R76 係選自包括羥基、烷胺基羰基及烷羰基胺基。Wherein: R 73 is an alkyl group; and R 76 is selected from the group consisting of a hydroxyl group, an alkylaminocarbonyl group, and an alkylcarbonylamino group.
在式VI內之此項具體實施例之一個子集族群中，R73 係選自包括甲基與丁基；R76 係選自包括羥基、甲胺基羰基及甲基羰基胺基。In a subset of this particular embodiment of Formula VI, R 73 is selected from the group consisting of methyl and butyl; and R 76 is selected from the group consisting of hydroxy, methylaminocarbonyl and methylcarbonylamino.
於又再更另一項具體實施例中，本發明之特徵為吡啶并嘧啶基－胺基苯基化合物之族群，該化合物之互變異構物，或該化合物或互變異構物之藥學上可接受鹽，其中此族群之化合物係在結構上相應於式VII：
其中：A係選自包括O與S；R21 係選自包括氫與羥基；或R21 與R39 一起採用，形成5－12員雜環，含有至少兩個選自包括O、N及S之雜原子；其中該雜環為視情況經取代之芳基或鹵素；或R39 係選自包括氫、烷基、芳烯基、二烷胺基、雜芳基、鹵雜芳基、鹵芳基胺基磺醯基、芳基磺醯氧基、烷羰基氧基、環烷胺基羰基、芳基烷氧羰基胺基、鹵雜芳基、烷氧羰基及NH－R99 ；R99 係選自包括氫、芳烷基、環烷基烷基、芳基、雜芳基、鹵芳基烷胺基、芳烷基胺基及烷基雜芳基；R67 係選自包括氫、烷基、環烷基及烷基環烷基；R96 係選自包括氫、羥基、胺基、烷氧基、芳基磺醯氧基、烷羰基胺基、烷氧基、鹵素、烷氧羰基氧基、鹵烷氧基羰基胺基及芳基烷氧基。Wherein: A is selected from the group consisting of O and S; R 21 is selected from the group consisting of hydrogen and hydroxyl; or R 21 is used together with R 39 to form a 5-12 membered heterocyclic ring containing at least two selected from the group consisting of O, N and S. a hetero atom; wherein the heterocyclic ring is an optionally substituted aryl or halogen; or R 39 is selected from the group consisting of hydrogen, alkyl, aralkenyl, dialkylamino, heteroaryl, haloaryl, halo Arylaminosulfonyl, arylsulfonyloxy, alkylcarbonyloxy, cycloalkylaminocarbonyl, arylalkyloxycarbonylamino, haloaryl, alkoxycarbonyl and NH-R 99 ; R 99 Is selected from the group consisting of hydrogen, aralkyl, cycloalkylalkyl, aryl, heteroaryl, haloarylalkylamino, aralkylamino and alkylheteroaryl; R 67 is selected from the group consisting of hydrogen, An alkyl group, a cycloalkyl group and an alkylcycloalkyl group; R 96 is selected from the group consisting of hydrogen, hydroxyl, amine, alkoxy, arylsulfonyloxy, alkylcarbonylamino, alkoxy, halogen, alkoxy Carbonyloxy, haloalkoxycarbonylamino and arylalkoxy.
在式VII內之此項具體實施例之一個子集族群中，R21 係選自包括氫與羥基，或當與R39 一起採用時，形成視情況被苯基或溴基取代之苯并唑基；或R39 係選自包括氫、甲基、苯基乙烯基、N,N－二丙基胺基、吡咯基、溴苯基胺基磺醯基、苯磺醯基氧基、第三－丁基羰基氧基、N－環己胺基羰基、N－環戊基胺基羰基、苯基甲氧羰基胺基、甲氧羰基胺基、甲氧羰基及溴基苯并咪唑基；R67 係選自包括氫、甲基、乙基、異丙基、第三－丁基、第二－丁基、環丙基、環丁基及甲基環丙基；R96 係選自包括氫、羥基、胺基、苯磺醯基氧基、甲基羰基胺基、甲氧基、氟基、第三－丁氧羰基胺基、三氯乙氧基羰基胺基及苯基甲氧基；R99 係選自包括氫、苯基甲基、苯基乙基、環戊基甲基、呋喃基、噻吩基、萘基、溴苯基甲胺基、苯基甲胺基及甲基吡啶并[2,3－d]嘧啶基。In a subset of this particular embodiment of Formula VII, R 21 is selected from the group consisting of hydrogen and hydroxy, or, when employed together with R 39 , forms benzo which is optionally substituted with a phenyl or bromo group. Thiazolyl; or R 39 is selected from consisting of hydrogen, methyl, phenyl, vinyl, N, N- dipropyl group, a pyrrolyl group, a sulfo group bromophenyl acyl, acyl group benzenesulfonamide, a first Tri-butylcarbonyloxy, N-cyclohexylaminocarbonyl, N-cyclopentylaminocarbonyl, phenylmethoxycarbonylamino, methoxycarbonylamino, methoxycarbonyl and bromobenzimidazolyl; R 67 is selected from consisting of hydrogen, methyl, ethyl, isopropyl, tertiary - butyl, sec - butyl, cyclopropyl, cyclobutyl and cyclopropyl methyl; R 96 is selected from comprising Hydrogen, hydroxyl, amine, benzenesulfonyloxy, methylcarbonylamino, methoxy, fluoro, tert-butoxycarbonylamino, trichloroethoxycarbonylamino and phenylmethoxy R 99 is selected from the group consisting of hydrogen, phenylmethyl, phenylethyl, cyclopentylmethyl, furyl, thienyl, naphthyl, bromophenylmethylamino, phenylmethylamino and methylpyridine And [2,3-d]pyrimidinyl.
於又另一項具體實施例中，本發明之特徵為吡啶并嘧啶基－胺基苯基化合物之族群，該化合物之互變異構物，或該化合物或互變異構物之藥學上可接受鹽，其中此族群之化合物係在結構上相應於式VIII：
其中：R23 係選自包括氫、烷氧基芳基、烷氧基芳基硫基、羥芳基硫基、鹵芳基烷氧基、氰基芳基烷氧基及芳基烷氧基；R31 係選自包括氫與鹵素；R49 係選自包括氫、芳基烷氧基、鹵芳基羰基胺基、烷氧基芳基羰基胺基、芳烯基、芳烷基、鹵素、氰基、鹵芳基氧基烷基、烷基、烷氧基芳基硫基、鹵雜芳基及烷氧羰基；R52 係選自包括氫、鹵素、烷基、羥芳基氧基、芳氧基、羥烷基芳氧基、烷氧基芳烷基、烷氧基芳氧基、烷基芳基烷氧基芳胺基、芳烷基、雜芳基及胺基芳氧基；R77 係選自包括氫、烷基及環烷基。Wherein R 23 is selected from the group consisting of hydrogen, alkoxyaryl, alkoxyarylthio, hydroxyarylthio, haloarylalkoxy, cyanoarylalkoxy and arylalkoxy R 31 is selected from the group consisting of hydrogen and halogen; R 49 is selected from the group consisting of hydrogen, arylalkoxy, haloarylcarbonylamino, alkoxyarylcarbonylamino, aralkenyl, aralkyl, halogen , cyano, haloaryloxyalkyl, alkyl, alkoxyarylthio, haloaryl and alkoxycarbonyl; R 52 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxyaryloxy , aryloxy, hydroxyalkylaryloxy, alkoxyarylalkyl, alkoxyaryloxy, alkylarylalkoxyarylamine, aralkyl, heteroaryl and aminaryloxy R 77 is selected from the group consisting of hydrogen, alkyl and cycloalkyl.
在式VIII內之此項具體實施例之一個子集族群中，R23 係選自包括氫、甲氧苯基、甲氧苯基硫基、羥苯基硫基、氟苯基甲氧基、二氟苯基甲氧基、氰基苯基甲氧基、苯基甲氧基、溴苯基甲氧基及甲氧苯基甲氧基；R31 係選自包括氫、氯基及氟基；R49 係選自包括氫、甲基、苯基甲氧基、溴苯基羰基胺基、氯苯基羰基胺基、甲氧苯基羰基胺基、氟苯基羰基胺基、苯基乙烯基、苯基乙基、氯基、氟基、溴基、氰基、溴基苯氧基甲基及羥苯基硫基。In a subset of a particular embodiment of Formula VIII, R 23 is selected from the group consisting of hydrogen, methoxyphenyl, methoxyphenylthio, hydroxyphenylthio, fluorophenylmethoxy, Difluorophenylmethoxy, cyanophenylmethoxy, phenylmethoxy, bromophenylmethoxy and methoxyphenylmethoxy; R 31 is selected from the group consisting of hydrogen, chloro and fluoro ; R 49 is selected from the group consisting of hydrogen, methyl, phenylmethoxy, bromophenylcarbonylamino, chlorophenylcarbonylamino, methoxyphenylcarbonylamino, fluorophenylcarbonylamino, phenylethylene Base, phenylethyl, chloro, fluoro, bromo, cyano, bromophenoxymethyl and hydroxyphenylthio.
R52 係選自包括氫、氟基、溴基、甲基、苯氧基、羥基苯氧基、羥乙基苯氧基、甲氧苯基乙基、甲氧基苯氧基、N－甲基－N－4－苯基甲氧基苯胺基、苯基甲基及噻唑基苯并咪唑基；R77 係選自包括氫、甲基及異丙基。R 52 is selected from the group consisting of hydrogen, fluoro, bromo, methyl, phenoxy, hydroxyphenoxy, hydroxyethylphenoxy, methoxyphenylethyl, methoxyphenoxy, N-methyl a base-N-4-phenylmethoxyanilino group, a phenylmethyl group and a thiazolyl benzimidazolyl group; and R 77 is selected from the group consisting of hydrogen, methyl and isopropyl.
本發明化合物或其互變異構物可以鹽形式使用。依特定化合物而定，化合物之鹽可為有利的，此係由於鹽之一或多個物理性質所致，譬如在不同溫度與濕度中之經加強醫藥安定性，或在水或油中之所期望溶解度。於一些情況中，化合物之鹽亦可作為助劑使用於化合物之單離、純化及/或解析。The compounds of the invention or their tautomers can be used in the form of a salt. Depending on the particular compound, the salt of the compound may be advantageous due to one or more physical properties of the salt, such as enhanced medical stability at different temperatures and humidities, or in water or oil. The solubility is expected. In some cases, the salt of the compound can also be used as an adjuvant for the isolation, purification and/or resolution of the compound.
在意欲將鹽投予病患之情況下，此鹽較佳為藥學上可接受的。藥學上可接受之鹽係包括但不限於常用以形成自由態酸或自由態鹼之鹼金屬鹽及/或形成加成鹽之鹽類。一般而言，此等鹽典型上可藉習用方式，使用本發明化合物製成，例如經由使適當酸或鹼與該化合物反應。Where the salt is intended to be administered to a patient, the salt is preferably pharmaceutically acceptable. Pharmaceutically acceptable salts include, but are not limited to, alkali metal salts which are commonly used to form free acid or free bases and/or salts which form addition salts. In general, such salts are typically prepared by conventional methods using the compounds of the invention, for example, by reacting the appropriate acid or base with the compound.
本發明化合物之藥學上可接受酸加成鹽類可製自無機或有機酸。適當無機酸類之實例包括鹽酸、氫溴酸、氫離子性酸、硝酸、碳酸、硫酸及磷酸。適當有機酸類通常包括例如有機酸類之脂族、環脂族、芳族、芳脂族、雜環基、羧酸及磺酸種類。適當有機酸類之特殊實例包括醋酸鹽、三氟醋酸鹽、甲酸鹽、丙酸鹽、琥珀酸鹽、乙醇醛鹽、葡萄糖酸鹽、二葡萄糖酸鹽、乳酸鹽、蘋果酸鹽、酒石酸、檸檬酸鹽、抗壞血酸鹽、醛糖酸鹽、順丁烯二酸鹽、反丁烯二酸鹽、丙酮酸鹽、天冬胺酸鹽、麩胺酸鹽、苯甲酸鹽、鄰胺基苯甲酸、甲烷磺酸鹽、硬脂酸鹽、柳酸鹽、對－羥基苯甲酸鹽、苯基醋酸鹽、苯乙醇酸鹽、雙羥基萘酸鹽(雙羥萘酸鹽)、甲烷磺酸鹽、乙烷磺酸鹽、苯磺酸鹽、泛酸鹽、甲苯磺酸鹽、2－羥基乙烷磺酸鹽、磺胺酸鹽、環己胺基磺酸鹽、海藻酸、b－羥丁酸、半乳糖二酸鹽、半乳糖醛酸鹽、己二酸鹽、海藻酸鹽、酸性硫酸鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、環戊烷丙酸鹽、十二基硫酸鹽、糖庚酸鹽、甘油磷酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、菸鹼酸鹽、2－萘磺酸鹽、草酸鹽、棕櫚酸鹽、果膠酯酸鹽、過硫酸鹽、3－苯基丙酸鹽、苦味酸鹽、三甲基醋酸鹽、硫氰酸鹽、甲苯磺酸鹽及十一烷酸鹽。The pharmaceutically acceptable acid addition salts of the compounds of the invention may be prepared from inorganic or organic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydrogen ionic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids typically include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid species of the organic acid. Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolaldehyde, gluconate, digluconate, lactate, malate, tartaric acid, lemon Acid salt, ascorbate, aldonic acid salt, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, ortho-aminobenzoic acid , methanesulfonate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, benzate, bishydroxynaphthalate (hydroxyl naphate), methanesulfonate , ethanesulfonate, besylate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sulfonate, cyclohexylamine sulfonate, alginic acid, b-hydroxybutyric acid , galactosedioate, galacturonate, adipate, alginate, acid sulfate, butyrate, camphorate, camphorsulfonate, cyclopentane propionate, dodecyl sulfate Salt, sugar heptanoate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, nicotinic acid salt, 2-naphthalene sulfonate, oxalate, palm Salts, pectinate, persulfate, 3-phenylpropionate, picrate, trimethylacetic acid, thiocyanate, tosylate, and undecanoate.
本發明化合物之藥學上可接受鹼加成鹽係包括例如金屬鹽與有機鹽。較佳金屬鹽包括但不限於鹼金屬(第Ia族)鹽、鹼土金屬(第IIa族)鹽及其他生理學上可接受之金屬鹽。此種鹽可製自鋁、鈣、鋰、鎂、鉀、鈉及鋅。較佳有機鹽之非限制性實例可製自三級胺類與四級胺鹽，譬如丁三醇胺、二乙胺、N,N'－二苄基乙二胺、氯普魯卡因、膽鹼、二乙醇胺、乙二胺、甲基葡胺(N－甲基葡萄糖胺)及普魯卡因。鹼性含氮基團可以作用劑四級化，譬如低碳烷基(C1 －C6 )鹵化物(例如甲基、乙基、丙基及丁基氯化物、溴化物及碘化物)、二烷基硫酸鹽(例如二甲基、二乙基、二丁基及二戊基硫酸鹽)、長鏈鹵化物(例如癸基、月桂基、肉豆蔻基及硬脂基氯化物、溴化物及碘化物)、芳烷基鹵化物(例如苄基與苯乙基溴化物)及其他。The pharmaceutically acceptable base addition salts of the compounds of the invention include, for example, metal salts and organic salts. Preferred metal salts include, but are not limited to, alkali metal (Group Ia) salts, alkaline earth metal (Group IIa) salts, and other physiologically acceptable metal salts. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Non-limiting examples of preferred organic salts can be prepared from tertiary amines and quaternary amine salts such as tributylamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, Choline, diethanolamine, ethylenediamine, methylglucamine (N-methylglucamine) and procaine. The basic nitrogen-containing group can be tetracyclized, such as a lower alkyl (C 1 -C 6 ) halide (eg, methyl, ethyl, propyl, and butyl chloride, bromide, and iodide), Dialkyl sulfates (eg dimethyl, diethyl, dibutyl and dipentyl sulfate), long chain halides (eg sulfhydryl, lauryl, myristyl and stearyl chloride, bromide) And iodide), aralkyl halides (such as benzyl and phenethyl bromide) and others.
本發明化合物、其互變異構物及其鹽亦可以溶劑合物之形式存在，具有水，例如水合物，或具有有機溶劑，譬如甲醇、乙醇或乙腈，以個別形成甲醇化物、乙醇化物或乙腈化物。本發明化合物可以各溶劑合物之形式或其混合物存在。The compounds of the present invention, their tautomers and salts thereof may also exist in the form of solvates, having water, such as hydrates, or having an organic solvent, such as methanol, ethanol or acetonitrile, to form methanolates, ethanolates or acetonitrile individually. Compound. The compounds of the invention may exist in the form of individual solvates or mixtures thereof.
於一方面，本發明之化合物、互變異構物或鹽可呈前體藥物形式。一些係為衍生自本發明化合物上之酸性基團之脂族或芳族酯類。其他係為本發明化合物上之羥基或胺基之脂族或芳族酯類。本發明之特徵亦為本發明化合物上羥基之磷酸酯前體藥物。In one aspect, the compounds, tautomers or salts of the invention may be in the form of a prodrug. Some are aliphatic or aromatic esters derived from acidic groups on the compounds of the invention. Others are aliphatic or aromatic esters of a hydroxyl or amine group on the compounds of the invention. A feature of the invention is also a phosphate prodrug of a hydroxyl group on the compound of the invention.
本發明化合物可包含經不對稱取代之碳原子，稱為對掌中心。此等對掌中心係被稱為"R"或"S"，依環繞該對掌性碳原子之取代基組態而定。於本文中使用之"R"與"S"術語，係如在有機化學命名法段落E中所定義之組態：立體化學,建議1974,PURE APPL.CHEM. ,45：11－30(1976)。本發明化合物可在非限制下以單一立體異構物(例如單一對掌異構物或單一非對映異構物)、立體異構物之混合物(例如對掌異構物或非對映異構物之任何混合物)或外消旋混合物存在。所有此種單一立體異構物、混合物及外消旋物，均被涵蓋在本發明之範圍內。於本文中經確認為單一立體異構物之化合物，係意欲描述以實質上不含其他立體異構物(例如其他對掌異構物或非對映異構物)之形式存在之化合物。所謂"實質上不含"係意指在組合物中之至少80%化合物係為所要之立體異構物；較佳為在組合物中之至少90%化合物係為所要之立體異構物；而更佳為在組合物中之至少95%、96%、97%、98%或99%化合物係為所要之立體異構物。在存在於化學結構中之對掌性碳之立體化學未被指定之情況下，該化學結構係意欲涵蓋含有存在於該化學結構中之各對掌中心之任一種立體異構物之化合物。The compounds of the invention may comprise asymmetrically substituted carbon atoms, referred to as the center of the palm. These pairs of palm centers are referred to as "R" or "S" depending on the configuration of the substituents surrounding the pair of palmar carbon atoms. The terms "R" and "S" as used herein are as defined in paragraph E of the Organic Chemistry Nomenclature: Stereochemistry, Recommendation 1974, PURE APPL.CHEM. , 45:11-30 (1976) . The compounds of the present invention may, without limitation, be a single stereoisomer (e.g., a single pair of palmomers or a single diastereomer), a mixture of stereoisomers (e.g., palmomere or diastereoisomers). Any mixture of constructs) or a racemic mixture is present. All such single stereoisomers, mixtures and racemates are intended to be encompassed within the scope of the invention. Compounds identified herein as single stereoisomers are intended to describe compounds which are substantially free of other stereoisomers (e.g., other palmier isomers or diastereomers). By "substantially free" is meant that at least 80% of the compound in the composition is the desired stereoisomer; preferably at least 90% of the compound in the composition is the desired stereoisomer; More preferably, at least 95%, 96%, 97%, 98% or 99% of the compound in the composition is the desired stereoisomer. Where the stereochemistry of the palmitic carbon present in the chemical structure is not specified, the chemical structure is intended to encompass compounds containing any of the stereoisomers present in the center of each pair of palms present in the chemical structure.
本發明化合物之個別立體異構物可使用此項技藝中已知之許多方法製備。此等方法包括但不限於立體特異性合成、非對映異構物之層析分離、對掌異構物之層析解析，在對掌異構混合物中之對掌異構物之轉化成非對映異構物，接著為非對映異構物之層析方式分離，及個別對掌異構物之再生，以及酵素解析。Individual stereoisomers of the compounds of the invention can be prepared using a number of methods known in the art. Such methods include, but are not limited to, stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of palmomerisomers, conversion of palmomeromers in the palm-to-isomeric mixture to non- The enantiomers are then separated by chromatographic separation of the diastereomers, as well as the regeneration of individual palmomers, and enzyme resolution.
立體特異性合成典型上係涉及利用適當光學上純(對掌異構上純)或實質光學上純物質，及不會造成對掌中心處之立體化學之消旋作用或逆轉之合成反應。由於合成反應所造成化合物之立體異構物混合物，包括外消旋混合物，可例如藉由層析技術分離，如一般熟諳此項技藝者所明瞭。對掌異構物之層析解析可在對掌性層析樹脂上達成，其中許多係為市購可得。在一項非限制性實例中，係將外消旋物置於溶液中，並裝填至含有對掌固定相之管柱上。然後，可藉HPLC分離對掌異構物。Stereospecific synthesis typically involves the use of a suitable optically pure (p-isomeric pure) or substantially optically pure material, and does not cause a racemic effect on the stereochemistry or reversal of the stereochemistry at the center of the palm. Mixtures of stereoisomers of the compounds, including racemic mixtures, which result from the synthesis reaction, can be separated, for example, by chromatographic techniques, as will be apparent to those skilled in the art. Chromatographic resolution of palmomeromers can be achieved on palm chromatography resins, many of which are commercially available. In one non-limiting example, the racemate is placed in solution and loaded onto a column containing the palm stationary phase. The palmomer isomer can then be separated by HPLC.
對掌異構物之解析亦可以下述方式達成，使混合物中之對掌異構物經由與對掌性輔助劑反應，而被轉化成非對映異構物。所形成之非對映異構物可藉管柱層析或結晶化作用/再結晶作用分離。當欲被分離之化合物含有將與對掌性輔助劑形成鹽或共價鍵之羧基、胺基或羥基時，此項技術可以使用。適當對掌性輔助劑之非限制性實例包括對掌上純胺基酸類、有機羧酸類或有機磺酸類。一旦非對映異構物被層析分離，即可使個別對掌異構物再生。對掌性輔助劑經常可被回收且再一次使用。The resolution of the palmomer isomer can also be achieved by converting the palmomerate in the mixture to a diastereomer by reaction with a palmitic adjuvant. The diastereomers formed can be separated by column chromatography or crystallization/recrystallization. This technique can be used when the compound to be separated contains a carboxyl group, an amine group or a hydroxyl group which will form a salt or a covalent bond with the palmitic adjuvant. Non-limiting examples of suitable palmitic adjuvants include palm pure amino acids, organic carboxylic acids or organic sulfonic acids. Once the diastereomers are separated by chromatography, the individual palmomers can be regenerated. The palmitic adjuvant can often be recycled and used again.
酵素，譬如酯酶、磷酸酶或脂肪酶，可用於對掌異構混合物中之對掌異構物衍生物之解析。例如，在欲被分離化合物中之羧基之酯衍生物，可以會選擇性地僅使混合物中之一種對掌異構物水解之酵素處理。所形成之對掌異構上純酸可接著自未經水解之酯分離。Enzymes, such as esterases, phosphatases or lipases, can be used to resolve the palmier isomer derivatives in the palm-isomeric mixture. For example, an ester derivative of a carboxyl group in the compound to be separated may selectively treat only one of the mixture to the enzyme which hydrolyzes the palmoisomer. The resulting palmitic isomeric pure acid can then be separated from the unhydrolyzed ester.
或者，在混合物中之對掌異構物之鹽，可使用此項技藝中已知之任何方法製備，包括該羧酸以適當光學上純鹼處理，譬如植物鹼或苯乙胺，接著為對掌異構上純鹽之沉澱作用或結晶化作用/再結晶作用。適用於解析/分離立體異構物之混合物包括外消旋混合物之方法，可參閱對掌異構物、外消旋物及解析 (Jacques等人,1981,John Wiley & Sons,New York,NY)。Alternatively, the salt of the palmoisomer in the mixture can be prepared by any method known in the art, including treatment of the carboxylic acid with an appropriate optically soda ash, such as a plant base or phenethylamine, followed by a palm Precipitation or crystallization/recrystallization of pure salt. Suitable methods for the resolution/isolation of mixtures of stereoisomers, including racemic mixtures, can be found in Palmomers, racemates and resolution (Jacques et al., 1981, John Wiley & Sons, New York, NY). .
本發明化合物可具有一或多個不飽和碳－碳雙鍵。所有雙鍵異構物，譬如順式(Z)與反式(E)異構物及其混合物，係意欲被涵蓋在所敘述化合物之範圍內，除非另有指明。此外，在化合物以各種互變異構形式存在之情況下，所敘述之化合物並不限於任一種特定互變異構物，而是意欲涵蓋所有互變異構形式。The compounds of the invention may have one or more unsaturated carbon-carbon double bonds. All double bond isomers, such as cis (Z) and trans (E) isomers, and mixtures thereof, are intended to be encompassed within the scope of the recited compounds unless otherwise indicated. Moreover, where a compound exists in various tautomeric forms, the recited compounds are not limited to any particular tautomer, but are intended to encompass all tautomeric forms.
本發明之某些化合物可以可分離之不同安定構形形式存在。歸因於環繞不對稱單鍵之受限制旋轉所致之扭轉不對稱性，例如由於立體阻礙或環應變，可允許不同構形異構物之分離。本發明化合物包括此等化合物之各構形異構物及其混合物。Certain compounds of the invention may exist in different stable conformational forms that are separable. The torsional asymmetry due to the restricted rotation around the asymmetric single bond, for example due to steric hindrance or ring strain, allows for the separation of different conformational isomers. The compounds of the invention include the various configurational isomers of such compounds and mixtures thereof.
本發明之某些化合物亦可以兩性離子性形式存在，且本發明係包括此等化合物之各兩性離子性形式及其混合物。Certain compounds of the invention may also exist in zwitterionic form, and the invention includes the various zwitterionic forms of such compounds and mixtures thereof.
本發明化合物係一般性地使用標準命名法描述於本文中。關於具有不對稱中心之所敘述化合物，應明瞭的是，化合物之所有立體異構物及其混合物，係被涵蓋在本發明中，除非另有指明。立體異構物之非限制性實例包括對掌異構物、非對映異構物及順式－反式異構物。在所敘述之化合物以各種互變異構形式存在之情況下，該化合物係意欲涵蓋所有互變異構形式。某些化合物係使用包含變數(例如R10 、W1 、A、L1 、X或Y)之通式被描述本文中。除非另有指明，否則在此種化學式內之各變數係被定義，而與任何其他變數無關，且在式中出現超過一次之任何變數係在每一存在處獨立地被定義。若取代基係被描述為"獨立地選自"一種基團，則各取代基係與他者獨立地經選擇。因此，各取代基可相同於或不同於其他取代基。The compounds of the invention are generally described herein using standard nomenclature. With respect to the recited compounds having asymmetric centers, it is to be understood that all stereoisomers of the compounds and mixtures thereof are encompassed by the present invention unless otherwise indicated. Non-limiting examples of stereoisomers include palmo isomers, diastereomers, and cis-trans isomers. Where the recited compounds exist in various tautomeric forms, the compounds are intended to cover all tautomeric forms. Certain compounds are described herein using a formula containing a variable (eg, R 10 , W 1 , A, L 1 , X, or Y). Unless otherwise indicated, each variable within such formula is defined, and any variable that is independent of any other variable, and that occurs more than once in the formula, is independently defined at each occurrence. If a substituent is described as being "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same or different from the other substituents.
在烴基取代基中之碳原子數可藉由字首"Cx －Cy "指示，其中x為在取代基中之最低，而y為最高碳原子數。因此，例如"C1 －C6 烷基"係指含有1至6個碳原子之烷基取代基。進一步說明，C3 －C6 環烷基係意謂含有3至6個碳環原子之飽和烴基環。經連接至多成份取代基之字首，僅應用於緊接跟隨在該字首後之第一種成份。茲說明之，"烷基芳基"一詞係含有兩種成份：烷基與芳基。因此，例如C1 －C6 烷基芳基係指C1 －C6 烷基，經過芳基附加至母分子部份基團。同樣地，烷基C6 －C10 芳基係指烷基，經過C6 －C10 芳基附加至母分子部份基團。類似地，在鹵烷氧基烷基上之字首"鹵基"表示烷氧基成份係被一或多個鹵素基團取代，而在烷氧基鹵烷基上之字首"鹵基"表示烷基成份係被一或多個鹵素基團取代。The number of carbon atoms in the hydrocarbyl substituent can be indicated by the prefix "C x -C y " where x is the lowest of the substituents and y is the highest number of carbon atoms. Thus, for example, "C 1 -C 6 alkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms. Further, the C 3 -C 6 cycloalkyl group means a saturated hydrocarbon group ring having 3 to 6 carbon ring atoms. The prefix connected to the multi-component substituent is applied only to the first component immediately following the prefix. It is to be noted that the term "alkylaryl" contains two components: alkyl and aryl. Thus, for example, a C 1 -C 6 alkylaryl group refers to a C 1 -C 6 alkyl group which is attached to a parent molecular moiety via an aryl group. Similarly, an alkyl C 6 -C 10 aryl group refers to an alkyl group which is attached to a parent molecular moiety via a C 6 -C 10 aryl group. Similarly, the prefix "halo" on a haloalkoxyalkyl group means that the alkoxy group is substituted by one or more halo groups, and the radical "halo" on the alkoxyhaloalkyl group. Indicates that the alkyl component is substituted with one or more halo groups.
當使用字詞以描述所描繪化學結構之兩種其他構件間之連結構件時，該連結構件之最左邊所描述成份係為被結合至所描繪結構中之左邊構件之成份。茲說明之，若化學結構為X－L－Y，且L係被描述為甲基芳基乙基，則此化學係為X－甲基－芳基－乙基－Y。When a word is used to describe a joining member between two other members of the depicted chemical structure, the leftmost component of the joining member is the component of the left member that is bonded to the depicted structure. It is noted that if the chemical structure is X-L-Y and the L system is described as a methylarylethyl group, the chemical system is X-methyl-aryl-ethyl-Y.
若在所描繪結構中之連結構件為一個鍵結，則在所描繪結構中之左邊構件係直接結合至所描繪結構中之右邊構件。例如，若化學結構係被描繪為X－L－Y，且L係經選擇為一個鍵結，則該化學結構係為X－Y。關於另一項實例，若化學部份基團係被描繪為－L－X，且L係經選擇為一個鍵結，則化學部份基團係為－X。關於又再另一項實例，若化學結構係被描繪為X－L1 －L2 －Y、X－L1 －L2 －L3 －Y或X－L1 －L2 －… －LN －Y，且L1 、L2 、L3 ...LN 係經選擇為一個鍵結，則化學結構係為X－Y。If the joining member in the depicted structure is a bond, the left member in the depicted structure is directly bonded to the right member of the depicted structure. For example, if the chemical structure is depicted as X-L-Y and the L system is selected as a bond, the chemical structure is X-Y. For another example, if the chemical moiety is depicted as -L-X and the L is selected as a linkage, the chemical moiety is -X. In yet another example, if the chemical structure is depicted as X-L 1 -L 2 -Y, X-L 1 -L 2 -L 3 -Y or X-L 1 -L 2 - ... -L N -Y, and L 1 , L 2 , L 3 ... L N are selected as one bond, and the chemical structure is X-Y.
當使用化學式以描述取代基時，於該化學式之右(或左)側上之虛線係指示具有自由價鍵之取代基部份。When a chemical formula is used to describe a substituent, the dotted line on the right (or left) side of the formula indicates a substituent moiety having a free valence bond.
若取代基被描述為"經取代"，則一個非氫基團係在取代基之碳、氮或氧上之一或多個氫基團之位置上。因此，例如，經取代之烷基取代基係為烷基取代基，其中至少一個非氫基團係在烷基取代基上之氫基之位置。茲說明之，單氟烷基為被一個氟基取代之烷基，而二氟烷基為被兩個氟基取代之烷基。應明瞭的是，若在取代基上有兩個或多個取代，則各非氫基團可為相同或不同，除非另有述及。If a substituent is described as "substituted," a non-hydrogen group is attached to one or more hydrogen groups on the carbon, nitrogen or oxygen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent wherein at least one non-hydrogen group is at the position of the hydrogen group on the alkyl substituent. It is to be noted that the monofluoroalkyl group is an alkyl group substituted by one fluorine group, and the difluoroalkyl group is an alkyl group substituted by two fluorine groups. It should be understood that if there are two or more substitutions on a substituent, the respective non-hydrogen groups may be the same or different unless otherwise stated.
若取代基包含至少一個結合至一或多個氫原子之碳、氮或氧原子，則該取代基係為"可取代"。A substituent is "substitutable" if it contains at least one carbon, nitrogen or oxygen atom bonded to one or more hydrogen atoms.
若取代基被描述為"視情況經取代"，則取代基可為無論是經取代或未經取代。若取代基被描述為視情況被至高特定數目之非氫基團取代，則該取代基可為無論是未經取代，或被至高該特定數目之非氫基團，或被至高達該取代基上可取代位置之最高數目取代，看那一個較少。因此，例如，若取代基被描述為雜芳基，視情況被至高三個非氫基團取代，則具有低於三個可取代位置之任何雜芳基，係視情況被至高只有與該雜芳基所具有可取代位置一樣多之非氫基團取代。茲說明之，四唑基(其僅具有一個可取代位置)係視情況被至高一個非氫基團取代。茲進一步說明之，若胺基氮被描述為視情況被至高兩個非氫基團取代，則一級胺基氮係視情況被至高兩個非氫基團取代，然而二級胺基氮係視情況被至高只有一個非氫基團取代。If a substituent is described as "optionally substituted", the substituent may be either substituted or unsubstituted. If a substituent is described as being substituted with a particular number of non-hydrogen groups as appropriate, the substituent may be either unsubstituted or up to the particular number of non-hydrogen groups, or up to the substituent Replace the highest number of positions that can be replaced, and see which one is less. Thus, for example, if a substituent is described as a heteroaryl group, optionally substituted with up to three non-hydrogen groups, then any heteroaryl group having less than three substitutable positions is as high as the The aryl group has as many non-hydrogen group substitutions as the replaceable position. It is noted that the tetrazolyl group, which has only one substitutable position, is optionally substituted with one non-hydrogen group. Further, if the amine nitrogen is described as being substituted by up to two non-hydrogen groups, the primary amine nitrogen is optionally replaced by two non-hydrogen groups, whereas the secondary amine nitrogen is The situation is replaced by only one non-hydrogen group.
"烯基"一詞(單獨或併用另外之術語)係意謂直鏈或分枝鏈烴基取代基，含有一或多個雙鍵，且典型上為2至20個碳原子，更典型上為2至8個碳原子，而又更典型上為2至6個碳原子。各碳－碳雙鍵可具有無論是順式或反式幾何形狀在烯基部份基團內，相對於雙鍵碳上所取代之基團。此種取代基之非限制性實例包括乙烯基、2－丙烯基、3－丙烯基、1,4－戊二烯基、1,4－丁二烯基、1－丁烯基、2－丁烯基及3－丁烯基。The term "alkenyl" (alone or in combination with another term) means a straight or branched chain hydrocarbyl substituent containing one or more double bonds, and typically 2 to 20 carbon atoms, more typically 2 to 8 carbon atoms, and more typically 2 to 6 carbon atoms. Each carbon-carbon double bond can have a group that is substituted in the alkenyl moiety relative to the double bond carbon, whether in cis or trans geometry. Non-limiting examples of such substituents include ethenyl, 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butyl Alkenyl and 3-butenyl.
"次烯基"一詞(單獨或併用另外之術語)係指二價不飽和烴基，其可為線性或分枝狀，且其具有至少一個碳－碳雙鍵。次烯基典型上含有2至20個碳原子，更典型上為2至8個碳原子，而又更典型上為2至6個碳原子。次烯基之非限制性實例包括－C(H)＝C(H)－、－C(H)＝C(H)－CH2 －、－C(H)＝C(H)－CH2 －CH2 －、－CH2 －C(H)＝C(H)－CH2 －、－C(H)＝C(H)－CH(CH3 )－及－CH2 －C(H)＝C(H)－CH(CH2 CH3 )－。The term "subalkenyl" (alone or in combination with another term) refers to a divalent unsaturated hydrocarbon group which may be linear or branched and which has at least one carbon-carbon double bond. The alkenyl group typically has from 2 to 20 carbon atoms, more typically from 2 to 8 carbon atoms, and more typically from 2 to 6 carbon atoms. Non-limiting examples of the alkenyl group include -C(H)=C(H)-, -C(H)=C(H)-CH 2 -, -C(H)=C(H)-CH 2 - CH 2 -, -CH 2 -C(H)=C(H)-CH 2 -, -C(H)=C(H)-CH(CH 3 )- and -CH 2 -C(H)=C (H)-CH(CH 2 CH 3 )-.
"烷氧基"一詞(單獨或併用另外之術語)係指烷基，經過氧基部份基團附加至母分子部份基團(意即－O－烷基)。此種取代基之非限制性實例包括甲氧基(－O－CH3 )、乙氧基、正－丙氧基、異丙氧基、正－丁氧基、異丁氧基、第二－丁氧基及第三－丁氧基。The term "alkoxy" (alone or in combination with another term) refers to an alkyl group appended to the parent molecular moiety (ie, -O-alkyl) via an oxy moiety. Non-limiting examples of such substituents include methoxy (-O-CH 3 ), ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second - Butoxy and tert-butoxy.
"烷氧烷基"一詞(單獨或併用另外之術語)係指烷氧基，經過次烷基附加至母分子部份基團。烷氧烷基之非限制性實例包括第三－丁氧基甲基、2－乙氧基乙基、2－甲氧基乙基及甲氧基甲基。The term "alkoxyalkyl" (alone or in combination with another term) refers to an alkoxy group appended to the parent molecular moiety through a subalkyl group. Non-limiting examples of alkoxyalkyl groups include tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
"烷氧羰基"一詞(單獨或併用另外之術語)係指烷氧基，經過羰基附加至母分子部份基團(意即－C(O)－O－烷基)。烷氧羰基之代表性實例包括但不限於甲氧羰基、乙氧羰基()及第三－丁氧羰基。The term "alkoxycarbonyl" (alone or in combination with another term) refers to an alkoxy group appended to the parent molecular moiety (ie, -C(O)-O-alkyl) via a carbonyl group. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl ( And a third-butoxycarbonyl group.
"烷氧羰基胺基"一詞(單獨或併用另外之術語)係指N(RA RB )－，其中RA 為烷基－O－C(O)－，且RB 為烷基－O－C(O)－或氫。RA 與RB 可為相同或不同。The term "alkoxycarbonylamino" (alone or in combination with another term) refers to N(R A R B )-, wherein R A is alkyl-O-C(O)- and R B is alkyl- O-C(O)- or hydrogen. R A and R B may be the same or different.
"烷氧羰基胺基烷基"一詞(單獨或併用另外之術語)係指N(RA RB )－次烷基－，其中RA 為烷基－O－C(O)－，且RB 為烷基－O－C(O)－或氫。RA 與RB 可為相同或不同。The term "alkoxycarbonylaminoalkyl" (alone or in combination with another term) refers to N(R A R B )-alkylidene-, wherein R A is alkyl-O-C(O)-, and R B is alkyl-O-C(O)- or hydrogen. R A and R B may be the same or different.
"烷氧羰基烷基"一詞(單獨或併用另外之術語)係指烷氧羰基，經過次烷基附加至母分子部份基團。烷氧羰基烷基之代表性實例包括但不限於2－甲氧基－2－酮基乙基、2－乙氧基－2－酮基乙基、3－甲氧基－3－酮基丙基、3－乙氧基－3－酮基丙基、4－乙氧基－2－(乙氧羰基)－4－酮基丁基、5－甲氧基－5－酮基戊基及6－甲氧基－6－氧己基。The term "alkoxycarbonylalkyl" (alone or in combination with another term) refers to an alkoxycarbonyl group appended to a parent molecular moiety through a subalkyl group. Representative examples of alkoxycarbonylalkyl include, but are not limited to, 2-methoxy-2-ketoethyl, 2-ethoxy-2-ketoethyl, 3-methoxy-3-ketopropyl , 3-ethoxy-3-ketopropyl, 4-ethoxy-2-(ethoxycarbonyl)-4-ketobutyl, 5-methoxy-5-ketopentyl and 6 -Methoxy-6-oxohexyl.
"烷基"一詞(單獨或併用另外之術語)係意謂直鏈或分枝鏈飽和烴基取代基，典型上含有1至20個碳原子，更典型上為1至8個碳原子，而又更典型上為1至6個碳原子。此種取代基之非限制性實例包括甲基、乙基、正－丙基、異丙基、正－丁基、異丁基、第二－丁基、第三－丁基、戊基、異戊基、己基及辛基。The term "alkyl" (alone or in combination with another term) means a straight or branched chain saturated hydrocarbyl substituent, typically having from 1 to 20 carbon atoms, more typically from 1 to 8 carbon atoms. More typically, it is from 1 to 6 carbon atoms. Non-limiting examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second-butyl, tert-butyl, pentyl, iso Pentyl, hexyl and octyl.
"烷胺基"一詞(單獨或併用另外之術語)係指－NRA RB ，其中RA 為烷基且RB 為氫或烷基。RA 與RB 可為相同或不同。例如，C1 －C6 烷胺基係指－NRA RB ，其中RA 為C1 －C6 烷基，且RB 為氫或C1 －C6 烷基。The term "alkylamino" (alone or in combination with another term) refers to -NR A R B wherein R A is alkyl and R B is hydrogen or alkyl. R A and R B may be the same or different. For example, C 1 -C 6 alkylamino refers to -NR A R B , wherein R A is C 1 -C 6 alkyl, and R B is hydrogen or C 1 -C 6 alkyl.
"烷胺基烷基"一詞(單獨或併用另外之術語)係指N(RA RB )－次烷基－，其中RA 為烷基，且RB 為氫或烷基。RA 與RB 可為相同或不同。因此C1 －C6 烷胺基C1 －C6 烷基係指N(RA RB )－C1 －C6 次烷基－，其中RA 為C1 －C6 烷基，且RB 為氫或C1 －C6 烷基。The term "alkylaminoalkyl" (alone or in combination with another term) refers to N(R A R B )-alkylidene-, wherein R A is alkyl and R B is hydrogen or alkyl. R A and R B may be the same or different. Thus C 1 -C 6 alkylamino C 1 -C 6 alkyl means N(R A R B )-C 1 -C 6 alkyl-, wherein R A is C 1 -C 6 alkyl, and R B is hydrogen or a C 1 -C 6 alkyl group.
"烷羰基"一詞(單獨或併用另外之術語)係指烷基，經過羰基附加至母分子部份基團(意即－C(O)－烷基)。烷羰基之代表性實例包括但不限於乙醯基、乙基羰基()、1－酮基丙基、2,2－二甲基－1－酮基丙基、1－酮基丁基及1－酮基戊基。The term "alkylcarbonyl" (alone or in combination with another term) refers to an alkyl group appended to the parent molecular moiety (ie, -C(O)-alkyl) via a carbonyl group. Representative examples of alkylcarbonyl include, but are not limited to, ethyl hydrazine, ethyl carbonyl ( ), 1-ketopropyl, 2,2-dimethyl-1-ketopropyl, 1-ketobutyl and 1-ketopentyl.
"烷羰基烷基"一詞(單獨或併用另外之術語)係指烷羰基，經過次烷基附加至母分子部份基團。烷羰基烷基之代表性實例包括但不限於2－酮基丙基、3,3－二甲基－2－酮基丙基、3－酮基丁基及3－酮基戊基。The term "alkylcarbonylalkyl" (alone or in combination with another term) refers to an alkylcarbonyl group appended to the parent molecular moiety through a subalkyl group. Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-ketopropyl, 3,3-dimethyl-2-ketopropyl, 3-ketobutyl, and 3-ketopentyl.
"烷羰基氧基"一詞(單獨或併用另外之術語)係指烷羰基，經過氧基部份基團附加至母分子部份基團。烷羰基氧基之代表性實例包括但不限於乙醯氧基、乙基羰基氧基及第三－丁基羰基氧基。The term "alkylcarbonyloxy" (alone or in combination with another term) refers to an alkylcarbonyl group appended to the parent molecular moiety through an oxy moiety. Representative examples of alkylcarbonyloxy include, but are not limited to, ethoxycarbonyl, ethylcarbonyloxy, and tert-butylcarbonyloxy.
"烷羰基氧基烷基"一詞(單獨或併用另外之術語)係指烷羰基氧基，經過次烷基部份基團附加至母分子部份基團。烷羰基氧基烷基之代表性實例包括但不限於2－(乙醯氧基)乙基、3－(乙醯氧基)丙基及3－(丙醯氧基)丙基。The term "alkylcarbonyloxyalkyl" (alone or in combination with another term) refers to an alkylcarbonyloxy group appended to a parent molecular moiety through a subalkyl moiety. Representative examples of alkylcarbonyloxyalkyl include, but are not limited to, 2-(ethyloxy)ethyl, 3-(ethyloxy)propyl, and 3-(propyloxy)propyl.
"次烷基"或"伸烷基"術語(單獨或併用另外之術語)表示衍生自直鏈或分枝狀飽和烴基鏈之二價基團，典型上含有1至20個碳原子，更典型上為1至8個碳原子，而又更典型上為1至6個碳原子。次烷基之代表性實例包括但不限於－CH2 －、－CH2 CH2 －、－CH2 CH2 CH2 －、－CH2 CH2 CH2 CH2 －及－CH2 CH(CH3 )CH2 －。The term "alkylidene" or "alkylene" (alone or in combination with another term) denotes a divalent radical derived from a straight or branched saturated hydrocarbyl chain, typically having from 1 to 20 carbon atoms, more typically It is from 1 to 8 carbon atoms, and more typically from 1 to 6 carbon atoms. Representative examples of the alkylidene group include but are not limited to -CH 2 -, - CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, - CH 2 CH 2 CH 2 CH 2 - and -CH 2 CH (CH 3 ) CH 2 -.
"炔基"一詞(單獨或併用另外之術語)係意謂直鏈或分枝鏈烴基取代基，含有一或多個參鍵，且典型上為2至20個碳原子，更典型上為2至8個碳原子，而又更典型上為2至6個碳原子。此種取代基之非限制性實例包括乙炔基、1－丙炔基、2－丙炔基、3－丙炔基、癸炔基、1－丁炔基、2－丁炔基及3－丁炔基。The term "alkynyl" (alone or in combination with another term) means a straight or branched chain hydrocarbyl substituent containing one or more reference bonds, and typically 2 to 20 carbon atoms, more typically 2 to 8 carbon atoms, and more typically 2 to 6 carbon atoms. Non-limiting examples of such substituents include ethynyl, 1-propynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl and 3-butyl Alkynyl.
"次炔基"術語(單獨或併用另外之術語)係指二價不飽和烴基，其可為線性或分枝狀，且其具有至少一個碳－碳參鍵。代表性次炔基，舉例言之，係包括－C≡C－、－C≡C－CH2 －、－C≡C－CH2 －CH2 －、－CH2 －C≡C－CH2 －、－C≡C－CH(CH3 )－及－CH2 －C≡C－CH(CH2 CH3 )－。The term "cisynyl" (alone or in combination with another term) refers to a divalent unsaturated hydrocarbon group which may be linear or branched and which has at least one carbon-carbon reference. Representative alkynyl groups, by way of example, include -C≡C-, -C≡C-CH 2 -, -C≡C-CH 2 -CH 2 -, -CH 2 -C≡C-CH 2 - , -C≡C-CH(CH 3 )- and -CH 2 -C≡C-CH(CH 2 CH 3 )-.
"胺基"一詞(單獨或併用另外之術語)係意謂－NH2 。"單取代胺基"一詞(單獨或併用另外之術語)係意謂胺基取代基，其中氫基團之一係被非氫取代基置換。"二取代胺基"一詞(單獨或併用另外之術語)係意謂胺基取代基，其中兩個氫原子係被可為相同或不同之非氫取代基置換。The term "amino" (alone or in combination with another of the term) based means -NH 2. The term "monosubstituted amine" (alone or in combination with another term) is intended to mean an amine substituent wherein one of the hydrogen groups is replaced by a non-hydrogen substituent. The term "disubstituted amine group" (alone or in combination with another term) means an amine substituent wherein two hydrogen atoms are replaced by a non-hydrogen substituent which may be the same or different.
"胺基羰基"一詞(單獨或併用另外之術語)係意謂－C(O)－NH2
，其亦可被描繪為：
"胺基烷基"一詞(單獨或併用另外之術語)係意謂－次烷基－NH2 。The term "alkyl amino" (alone or in combination with another term of) -based mean - alkylidene -NH 2.
"胺基烷羰基"一詞(單獨或併用另外之術語)係意謂－C(O)－次烷基－NH2
。例如，"胺基甲基羰基"可被描繪為：
"胺基磺醯基"一詞(單獨或併用另外之術語)係意謂－S(O)2
－NH2
，其亦可被描繪為：
"芳基"一詞(單獨或併用另外之術語)係指含有6至14個碳環原子之芳族碳環基。芳基之非限制性實例包括苯基、萘基、蒽基及茚基。芳基可經過基團之任何可取代碳原子連接至母分子部份基團。The term "aryl" (alone or in combination with another term) refers to an aromatic carbocyclic group containing from 6 to 14 carbon ring atoms. Non-limiting examples of aryl groups include phenyl, naphthyl, anthryl and anthracenyl. The aryl group can be attached to the parent molecular moiety through any substitutable carbon atom of the group.
"芳烷基"一詞(單獨或併用另外之術語)係指芳基，經過次烷基附加至母分子部份基團。經取代/未經取代芳烷基之代表性實例包括但不限於苄基、4－(苄氧基)苄基、4－甲氧基苄基、4－羥苄基、3－(1,3－苯并二氧伍圜烯－5－基)－2－甲基丙基、3－(苯氧基)苄基、3－(1,3－苯并二氧伍圜烯－5－基)丙基、2－苯基乙基、3－苯基丙基、2－萘基甲基、3,5－二－第三－丁基－2－羥苄基、3－甲氧基苄基、3,4－二甲氧基苄基、4－(二甲胺基)苄基、4－[3－(二甲胺基)丙氧基]苄基、(6－甲氧基－2－萘基)甲基及2－萘－2－基乙基。The term "aralkyl" (alone or in combination with another term) refers to an aryl group appended to the parent molecular moiety through a subalkyl group. Representative examples of substituted/unsubstituted aralkyl include, but are not limited to, benzyl, 4-(benzyloxy)benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, 3-(1,3 -benzodioxanthene-5-yl)-2-methylpropyl, 3-(phenoxy)benzyl, 3-(1,3-benzodioxanthene-5-yl) Propyl, 2-phenylethyl, 3-phenylpropyl, 2-naphthylmethyl, 3,5-di-tert-butyl-2-hydroxybenzyl, 3-methoxybenzyl, 3,4-Dimethoxybenzyl, 4-(dimethylamino)benzyl, 4-[3-(dimethylamino)propoxy]benzyl, (6-methoxy-2-naphthalene) Methyl and 2-naphthalen-2-ylethyl.
"芳烷基羰基"一詞(單獨或併用另外之術語)係指芳烷基，經過羰基附加至母分子部份基團(意即芳烷基－C(O)－)。芳烷基羰基之代表性實例包括但不限於2－萘基乙醯基與苯乙醯基。The term "aralkylcarbonyl" (alone or in combination with another term) refers to an aralkyl group appended to the parent molecular moiety (ie, aralkyl-C(O)-) via a carbonyl group. Representative examples of aralkylcarbonyl include, but are not limited to, 2-naphthylethyl and phenethyl.
"芳基烷氧基"一詞(單獨或併用另外之術語)係指芳烷基，經過氧基部份基團附加至母分子部份基團(意即芳烷基－O－)。芳基烷氧基之代表性實例包括但不限於2－苯基乙氧基、3－萘－2－基丙氧基及5－苯基戊氧基。The term "arylalkoxy" (alone or in combination with another term) refers to an aralkyl group appended to the parent molecular moiety (ie, aralkyl-O-) via an oxy moiety. Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3-naphthalen-2-ylpropoxy, and 5-phenylpentyloxy.
"芳基烷氧烷基"一詞(單獨或併用另外之術語)係指芳基烷氧基，經過次烷基附加至母分子部份基團。芳基烷氧烷基之代表性實例包括但不限於苄氧基甲基、2－(苄氧基)乙基及(2－苯基乙氧基)甲基。The term "arylalkoxyalkyl" (alone or in combination with another term) refers to an arylalkoxy group appended to the parent molecular moiety through a subalkyl group. Representative examples of arylalkoxyalkyl include, but are not limited to, benzyloxymethyl, 2-(benzyloxy)ethyl, and (2-phenylethoxy)methyl.
"芳基烷氧羰基"一詞(單獨或併用另外之術語)係指芳基烷氧基，經過羰基附加至母分子部份基團。芳基烷氧羰基之代表性實例包括但不限於苄氧羰基與萘－2－基甲氧羰基。The term "arylalkoxycarbonyl" (alone or in combination with another term) refers to an arylalkoxy group appended to the parent molecular moiety through a carbonyl group. Representative examples of arylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl and naphthalen-2-ylmethoxycarbonyl.
"芳基羰基"一詞(單獨或併用另外之術語)係指芳基，經過羰基附加至母分子部份基團。芳基羰基之代表性實例包括但不限於苯甲醯基與萘甲醯基。The term "arylcarbonyl" (alone or in combination with another term) refers to an aryl group attached to a parent molecular moiety through a carbonyl group. Representative examples of arylcarbonyl include, but are not limited to, benzamidine and naphthylmethyl.
"芳氧基"一詞(單獨或併用另外之術語)係指芳基，經過氧基部份基團附加至母分子部份基團。經取代/未經取代芳氧基之代表性實例包括但不限於苯氧基、萘氧基、3－溴基苯氧基、4－氯苯氧基、4－甲基苯氧基及3,5－二甲氧基苯氧基。The term "aryloxy" (alone or in combination with another term) refers to an aryl group appended to the parent molecular moiety through an oxy moiety. Representative examples of substituted/unsubstituted aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy, and 3. 5-Dimethoxyphenoxy.
"芳氧基烷基"一詞(單獨或併用另外之術語)係指芳氧基，經過次烷基附加至母分子部份基團。芳氧基烷基之代表性實例包括但不限於2－苯氧基乙基、3－萘－2－基氧基丙基及苯氧基甲基。The term "aryloxyalkyl" (alone or in combination with another term) refers to an aryloxy group appended to the parent molecular moiety through a subalkyl group. Representative examples of aryloxyalkyl include, but are not limited to, 2-phenoxyethyl, 3-naphthalen-2-yloxypropyl, and phenoxymethyl.
"芳氧基羰基"一詞(單獨或併用另外之術語)係指芳氧基，經過羰基附加至母分子部份基團。The term "aryloxycarbonyl" (alone or in combination with another term) refers to an aryloxy group appended to the parent molecular moiety through a carbonyl group.
"芳基硫基"一詞(單獨或併用另外之術語)係指芳基，經過硫原子附加至母分子部份基團(意即芳基－S－)。芳基硫基之代表性實例包括但不限於苯硫基、萘－1－基硫基及萘－2－基硫基。The term "arylthio" (alone or in combination with another term) refers to an aryl group attached to a parent molecular moiety (ie, aryl-S-) via a sulfur atom. Representative examples of arylthio groups include, but are not limited to, phenylthio, naphthalen-1-ylthio, and naphthalen-2-ylthio.
"芳基硫基烷基"一詞(單獨或併用另外之術語)係指芳基－S－次烷基－。芳基硫基烷基之代表性實例包括但不限於(苯硫基)甲基、2－(苯硫基)乙基及3－(苯硫基)丙基。The term "arylthioalkyl" (alone or in combination with another term) refers to aryl-S-alkylene-. Representative examples of arylthioalkyl include, but are not limited to, (phenylthio)methyl, 2-(phenylthio)ethyl, and 3-(phenylthio)propyl.
"芳基硫代烷氧基"一詞(單獨或併用另外之術語)係指芳基硫基烷基，經過氧基附加至母分子部份基團。The term "arylthioalkoxy" (alone or in combination with another term) refers to an arylthioalkyl group appended to the parent molecular moiety through an oxy group.
"芳基硫代烷氧基烷基"一詞(單獨或併用另外之術語)係指芳基硫代烷氧基，經過次烷基附加至母分子部份基團。The term "arylthioalkoxyalkyl" (alone or in combination with another term) refers to an arylthioalkoxy group appended to the parent molecular moiety through a subalkyl group.
"碳環"或"碳環族"或"碳環基"術語(單獨或併用另外之術語)係指飽和(例如"環烷基")、部份飽和(例如"環烯基"或"環炔基")或完全不飽和(例如"芳基")環系統，含有零個雜原子環原子，且典型上為3至18個碳環原子。"環原子"或"環員"係為經結合在一起以形成環狀取代基之一或多個環之原子。碳環基可為但不限於單環，或兩個或多個稠合環，或經橋接或螺環。碳環基可含有3至14個環員(意即C3 －C14 碳環基，譬如C3 －C14 環烷基)，3至10個環員(意即C3 －C10 碳環基，譬如C3 －C10 環烷基)，3至8個環員(意即C3 －C8 碳環基，譬如C3 －C8 環烷基)，3至6個環員(意即C3 －C6 碳環基，譬如C3 －C6 環烷基)，4至10個環員(意即C4 －C10 碳環基，譬如C4 －C10 環烷基與C4 －C10 環烯基)，4至8個環員(意即C4 －C8 碳環基，譬如C4 －C8 環烷基與C4 －C8 環烯基)，或5至7個環員(意即C5 －C7 碳環基，譬如C5 －C7 環烷基、C5 －C7 環烯基及苯基)。經取代之碳環基可具有無論是順式或反式幾何形狀。碳環基之代表性實例包括但不限於環丙基、環丁基、環戊基、環己基、環庚基、環辛基、環戊烯基、環戊二烯基、環己二烯基、金鋼烷基、十氫－萘基、八氫－茚基、環己烯基、苯基、萘基、茀基、氫茚基、1,2,3,4－四氫－萘基、茚基、異茚基、雙環癸基、蒽基、菲、苯并環烷基(亦稱為"萉基")、十氫萘基及正苹基。碳環基可經過基團之任何可取代碳原子連接至母分子部份基團。The term "carbocyclic" or "carbocyclic" or "carbocyclyl" (alone or in combination with another term) refers to saturated (eg, "cycloalkyl"), partially saturated (eg, "cycloalkenyl" or "cyclic" An alkynyl") or fully unsaturated (eg, "aryl") ring system containing zero heteroatom ring atoms, and typically from 3 to 18 carbon ring atoms. A "ring atom" or "ring member" is an atom that is bonded together to form one or more rings of a cyclic substituent. A carbocyclic group can be, but is not limited to, a single ring, or two or more fused rings, or bridged or spiro rings. Carbocyclyl may contain from 3 to 14 ring members (ie, C 3 -C 14 carbocyclic groups, such as C 3 -C 14 cycloalkyl groups), from 3 to 10 ring members (ie, C 3 -C 10 carbocyclic rings) a group, such as a C 3 -C 10 cycloalkyl group, 3 to 8 ring members (ie, a C 3 -C 8 carbocyclic group, such as a C 3 -C 8 cycloalkyl group), 3 to 6 ring members (meaning That is, a C 3 -C 6 carbocyclic group, such as a C 3 -C 6 cycloalkyl group, of 4 to 10 ring members (ie, a C 4 -C 10 carbocyclic group, such as a C 4 -C 10 cycloalkyl group and C 4 -C 10 cycloalkenyl), 4-8 membered ring (which means C 4 -C 8 carbocyclic group, such as C 4 -C 8 cycloalkyl and C 4 -C 8 cycloalkenyl), or 5 to 7 ring members (ie, C 5 -C 7 carbocyclic groups such as C 5 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl and phenyl). The substituted carbocyclic group can have either a cis or trans geometry. Representative examples of carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl, cyclohexadienyl , gold steel alkyl, decahydro-naphthyl, octahydro-indenyl, cyclohexenyl, phenyl, naphthyl, anthryl, hydroquinone, 1,2,3,4-tetrahydro-naphthyl, Indenyl, isodecyl, bicycloindenyl, fluorenyl, phenanthrene, benzocycloalkyl (also known as "fluorenyl"), decahydronaphthyl and n-butyl. A carbocyclic group can be attached to a parent molecular moiety through any substitutable carbon atom of the group.
"碳環基烷基"一詞(單獨或併用另外之術語)係指碳環基，經過次烷基附加至母分子部份基團。例如，C3 －C10 碳環基C1 －C6 烷基係指C3 －C10 碳環基，經過C1 －C6 次烷基附加至母分子部份基團。同樣地，C5 －C7 碳環基C1 －C6 烷基係指C5 －C7 碳環基，經過C1 －C6 次烷基附加至母分子部份基團。The term "carbocyclylalkyl" (alone or in combination with another term) refers to a carbocyclic group that is attached to a parent molecular moiety through a subalkyl group. For example, a C 3 -C 10 carbocyclic C 1 -C 6 alkyl group refers to a C 3 -C 10 carbocyclic group which is attached to a parent molecular moiety via a C 1 -C 6 alkyl group. Similarly, a C 5 -C 7 carbocyclic C 1 -C 6 alkyl group refers to a C 5 -C 7 carbocyclic group which is attached to a parent molecular moiety through a C 1 -C 6 alkyl group.
"碳環基烷氧基"一詞(單獨或併用另外之術語)係指碳環基烷基，經過氧基附加至母分子部份基團(意即碳環基－次烷基－O－)。例如C3 －C10 碳環基C1 －C6 烷氧基係指C3 －C10 碳環基C1 －C6 烷基，經過氧基附加至母分子部份基團。同樣地，C5 －C7 碳環基C1 －C6 烷氧基係指C5 －C7 碳環基C1 －C6 烷基，經過氧基附加至母分子部份基團。The term "carbocyclylalkoxy" (alone or in combination with another term) refers to a carbocyclylalkyl group appended to the parent molecular moiety through an oxy group (ie, carbocyclyl-alkylene-O-). ). For example, a C 3 -C 10 carbocyclic C 1 -C 6 alkoxy group means a C 3 -C 10 carbocyclic C 1 -C 6 alkyl group which is attached to the parent molecular moiety via an oxy group. Similarly, a C 5 -C 7 carbocyclic C 1 -C 6 alkoxy group means a C 5 -C 7 carbocyclic C 1 -C 6 alkyl group which is attached to the parent molecular moiety via an oxy group.
"碳環基烷氧烷基"一詞(單獨或併用另外之術語)係指碳環基烷氧基，經過次烷基附加至母分子部份基團(意即碳環基－次烷基－O－次烷基－)。例如，C3 －C10 碳環基C1 －C6 烷氧基C1 －C6 烷基係指C3 －C10 碳環基C1 －C6 烷氧基，經過C1 －C6 次烷基附加至母分子部份基團。The term "carbocyclylalkoxyalkyl" (alone or in combination with another term) refers to a carbocyclic alkoxy group appended to the parent molecular moiety through a subalkyl group (ie, carbocyclyl-alkylene) -O-alkylene-). For example, a C 3 -C 10 carbocyclic C 1 -C 6 alkoxy C 1 -C 6 alkyl group means a C 3 -C 10 carbocyclic C 1 -C 6 alkoxy group, passing through a C 1 -C 6 A secondary alkyl group is attached to a parent molecular moiety.
"碳環基烷氧羰基"一詞(單獨或併用另外之術語)係指碳環基烷氧基，經過羰基附加至母分子部份基團(意即－C(O)－O－次烷基－碳環基)。例如，C3
－C10
碳環基C1
－C6
烷氧羰基係指C3
－C10
碳環基C1
－C6
烷氧基，經過羰基附加至母分子部份基團。作為非限制性實例，"苯基乙氧羰基"可被描繪為：
"碳環基烷羰基"一詞(單獨或併用另外之術語)係指碳環基烷基，經過羰基附加至母分子部份基團(意即－C(O)－次烷基－碳環基)。例如，"苯基乙基羰基"可被描繪為：
"碳環基羰基"一詞(單獨或併用另外之術語)係指碳環基，經過羰基附加至母分子部份基團(意即碳環基－C(O)－)。例如，"苯基羰基"可被描繪為：
"碳環基氧基"一詞(單獨或併用另外之術語)係指碳環基，經過氧基部份基團附加至母分子部份基團(意即碳環基－O－)。The term "carbocyclyloxy" (alone or in combination with another term) refers to a carbocyclic group appended to the parent molecular moiety (ie, carbocyclyl-O-) via an oxy moiety.
"碳環基氧基烷基"一詞(單獨或併用另外之術語)係指碳環基氧基，經過次烷基附加至母分子部份基團(意即碳環基－O－次烷基－)。The term "carbocyclyloxyalkyl" (alone or in combination with another term) refers to a carbocyclyloxy group appended to the parent molecular moiety through a subalkyl group (ie, carbocyclyl-O-decane) base-).
"碳環基氧基羰基"一詞(單獨或併用另外之術語)係指碳環基氧基，經過羰基附加至母分子部份基團(意即－C(O)－O－碳環基)。例如，"苯基氧基羰基"可被描繪為：
"碳環基硫基"一詞(單獨或併用另外之術語)係指碳環基，經過硫原子附加至母分子部份基團(意即碳環基－S－)。The term "carbocyclylthio" (alone or in combination with another term) refers to a carbocyclic group which is attached to a parent molecular moiety (i.e., carbocyclyl-S-) via a sulfur atom.
"碳環基硫代烷氧基"一詞(單獨或併用另外之術語)係指碳環基－次烷基－S－。The term "carbocyclylthioalkoxy" (alone or in combination with another term) refers to carbocyclyl-alkylene-S-.
"碳環基硫代烷氧基烷基"一詞(單獨或併用另外之術語)係指碳環基－次烷基－S－次烷基－。The term "carbocyclylthioalkoxyalkyl" (alone or in combination with another term) refers to carbocyclyl-alkylene-S-alkylene-.
"碳環基硫基烷基"一詞(單獨或併用另外之術語)係指碳環基硫基，經過次烷基附加至母分子部份基團(意即碳環基－S－次烷基－)。The term "carbocyclylthioalkyl" (alone or in combination with another term) refers to a carbocyclylthio group appended to the parent molecular moiety through a subalkyl group (ie, carbocyclyl-S-decane) base-).
"碳環基碳環基"一詞(單獨或併用另外之術語)係指碳環基，經過另一個碳環基附加至母分子部份基團(意即碳環基－碳環基－)。例如，C3 －C10 碳環基C5 －C7 碳環基係指C3 －C10 碳環基，經過C5 －C7 碳環基附加至母分子部份基團(意即C3 －C10 碳環基－C5 －C7 碳環基－)。The term "carbocyclyl carbocyclyl" (alone or in combination with another term) refers to a carbocyclyl group appended to a parent molecular moiety through another carbocyclic group (ie carbocyclyl-carbocyclyl-) . For example, a C 3 -C 10 carbocyclic C 5 -C 7 carbocyclic group refers to a C 3 -C 10 carbocyclic group appended to a parent molecular moiety through a C 5 -C 7 carbocyclic group (ie, C 3 -C 10 carbocyclyl -C 5 -C 7 carbocyclic yl -).
"碳環基碳環基烷基"一詞(單獨或併用另外之術語)係指碳環基碳環基，經過次烷基附加至母分子部份基團。The term "carbocyclyl carbocyclylalkyl" (alone or in combination with another term) refers to a carbocyclic carbocyclyl group appended to a parent molecular moiety through a subalkyl group.
"碳環基烷氧基碳環基烷基"一詞(單獨或併用另外之術語)係指碳環基－次烷基－O－碳環基－次烷基－。例如，C3 －C10 碳環基C1 －C6 烷氧基C5 －C7 碳環基C3 －C4 烷基係指C3 －C10 碳環基－C1 －C6 次烷基－O－C5 －C7 碳環基－C3 －C4 次烷基－。The term "carbocyclylalkoxy carbocycloalkyl" (alone or in combination with another term) refers to carbocyclyl-alkylene-O-carbocyclyl-alkylene-. For example, C 3 -C 10 carbocyclyl C 1 -C 6 alkoxy C 5 -C 7 carbocyclic C 3 -C 4 alkyl means C 3 -C 10 carbocyclyl-C 1 -C 6 times Alkyl-O-C 5 -C 7 carbocyclyl-C 3 -C 4 -alkyl-.
"(碳環基烷基)碳環基烷基"一詞(單獨或併用另外之術語)係指碳環基－次烷基－碳環基－次烷基－。例如，C3 －C10 碳環基C1 －C6 烷基C5 －C7 碳環基C3 －C4 烷基係指C3 －C10 碳環基－C1 －C6 次烷基－C5 －C7 碳環基－C3 －C4 次烷基－。The term "(carbocyclylalkyl)carbocyclylalkyl" (alone or in combination with another term) refers to carbocyclyl-alkylene-carbocyclyl-alkylene-. For example, a C 3 -C 10 carbocyclic C 1 -C 6 alkyl C 5 -C 7 carbocyclic C 3 -C 4 alkyl group means a C 3 -C 10 carbocyclyl-C 1 -C 6 alkane Base-C 5 -C 7 carbocyclic-C 3 -C 4 -alkyl-.
"碳環基烷氧基雜環烷基"一詞(單獨或併用另外之術語)係指碳環基－次烷基－O－雜環基－次烷基－。The term "carbocyclylalkoxyheterocycloalkyl" (alone or in combination with another term) refers to carbocyclyl-alkylene-O-heterocyclyl-alkylene-.
"碳環基羰基雜環烷基"一詞(單獨或併用另外之術語)係指碳環基－C(O)－雜環基－次烷基－。The term "carbocyclylcarbonylheterocycloalkyl" (alone or in combination with another term) refers to carbocyclyl-C(O)-heterocyclyl-alkylene-.
"碳環基雜環烷基"一詞(單獨或併用另外之術語)係指碳環基－雜環基－次烷基－。The term "carbocyclylheterocycloalkyl" (alone or in combination with another term) refers to carbocyclyl-heterocyclyl-alkylene-.
"碳環基羰基碳環基烷基"一詞(單獨或併用另外之術語)係指碳環基－C(O)－碳環基－次烷基－。例如，C3 －C10 碳環基羰基C4 －C8 碳環基C1 －C6 烷基係指C3 －C10 碳環基－C(O)－C4 －C8 碳環基－C1 －C6 次烷基－。The term "carbocyclylcarbonyl carbocyclylalkyl" (alone or in combination with another term) refers to carbocyclyl-C(O)-carbocyclyl-alkylene-. For example, a C 3 -C 10 carbocyclic carbonyl C 4 -C 8 carbocyclic C 1 -C 6 alkyl group means a C 3 -C 10 carbocyclic-C(O)-C 4 -C 8 carbocyclic group. -C 1 -C 6 -alkyl-.
"(碳環基烷基)雜環烷基"一詞(單獨或併用另外之術語)係指碳環基－次烷基－雜環基－次烷基。The term "(carbocyclylalkyl)heterocycloalkyl" (alone or in combination with another term) refers to carbocyclyl-alkylene-heterocyclyl-alkylene.
"羰基"一詞(單獨或併用另外之術語)係指－C(O)－，其亦可被描繪為：
"羧基"一詞(單獨或併用另外之術語)係意謂－C(O)－OH，其亦可被描繪為：
"羧基烷基"一詞(單獨或併用另外之術語)係指羧基，經過次烷基附加至母分子部份基團。羧基烷基之代表性實例包括但不限於羧甲基、2－羧乙基及3－羧基丙基。The term "carboxyalkyl" (alone or in combination with another term) refers to a carboxy group appended to the parent molecular moiety through a subalkyl group. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl, and 3-carboxypropyl.
"環狀胺基"一詞(單獨或併用另外之術語)係意謂雜環基部份基團，包含至少一個氮環原子，其中其餘環原子為碳，且視情況為氮或硫。此種部份基團之非限制性實例包括六氫吡啶基、六氫吡基及噻基團。The term "cyclic amine group" (alone or in combination with another term) means a heterocyclyl moiety comprising at least one nitrogen ring atom wherein the remaining ring atoms are carbon and, if appropriate, nitrogen or sulfur. Non-limiting examples of such partial groups include hexahydropyridyl, hexahydropyridyl Base and thiophene Group.
"環烯基"一詞(單獨或併用另外之術語)係指非芳族部份不飽和碳環基取代基，具有零個雜原子環員，且典型上為4至18個碳環成員。環烯基基團之代表性實例包括但不限於環丁烯基、環戊烯基、環己烯基及八氫萘基。The term "cycloalkenyl" (alone or in combination with another term) refers to a non-aromatic partially unsaturated carbocyclic substituent having zero heteroatom ring members and is typically from 4 to 18 carbon ring members. Representative examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, and octahydronaphthyl.
"環烷基"一詞(單獨或併用另外之術語)係指飽和碳環基，含有零個雜原子環員，且典型上為3至18個碳環成員。環烷基之非限制性實例包括環丙基、環丁基、環戊基、環己基、環庚基、環辛基、十氫萘基及正苹基。The term "cycloalkyl" (alone or in combination with another term) refers to a saturated carbocyclic group containing zero heteroatom ring members, and typically from 3 to 18 carbon ring members. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthyl and n-butyl.
"環烷基羰基"一詞(單獨或併用另外之術語)係指環烷基，經過羰基附加至母分子部份基團。The term "cycloalkylcarbonyl" (alone or in combination with another term) refers to a cycloalkyl group attached to a parent molecular moiety through a carbonyl group.
"氰基"一詞(單獨或併用另外之術語)係意謂－CN，其亦可被描繪為。The term "cyano" (alone or in combination with another term) means -CN, which can also be described as .
"二烷胺基"一詞(單獨或併用另外之術語)係指－NRA RB ，其中RA 與RB 係獨立選自烷基。The term "dialkylamino" (alone or in combination with another term) refers to -NR A R B wherein R A and R B are independently selected from alkyl.
"二烷胺基羰基"一詞(單獨或併用另外之術語)係指二烷胺基，經過羰基附加至母分子部份基團(意即N(RA RB )－C(O)－，其中RA 與RB 係獨立選自烷基)。The term "dialkylaminocarbonyl" (alone or in combination with another term) refers to a dialkylamino group attached to the parent molecular moiety through a carbonyl group (ie, N(R A R B )-C(O)- Wherein R A and R B are independently selected from alkyl).
"甲醯基"一詞(單獨或併用另外之術語)係指－C(O)H基團。The term "methyl thiol" (alone or in combination with another term) refers to a -C(O)H group.
"鹵素"或"鹵基"術語(單獨或併用另外之術語)係意謂氟基團(其可被描述為－F)、氯基團(其可被描述為－Cl)、溴基團(其可被描述為－Br)或碘基團(其可被描述為－I)。The term "halogen" or "halo" (alone or in combination with another term) means a fluoro group (which may be described as -F), a chloro group (which may be described as -Cl), a bromine group ( It can be described as -Br) or an iodine group (which can be described as -I).
"鹵基"字首係表示字首所連接之取代基係被一或多個獨立選擇之鹵素基團取代。例如，"鹵烷基"(單獨或併用另外之術語)係意謂烷基取代基，其中至少一個氫基係被鹵素基團置換。鹵烷基之非限制性實例包括氯基甲基、1－溴基乙基、氟基甲基、二氟甲基、三氟甲基及1,1,1－三氟乙基。進一步說明，"鹵烷氧基"(單獨或併用另外之術語)係意謂烷氧基取代基，其中至少一個氫基係被鹵素基團置換。鹵烷氧基取代基之非限制性實例包括氯基甲氧基、1－溴基乙氧基、氟基甲氧基、二氟甲氧基、三氟甲氧基(亦稱為"全氟甲氧基")及1,1,1,－三氟乙氧基。應明瞭的是，若取代基被一個以上之鹵素基團取代，則此等鹵素基團可為相同或不同(除非另有述及)。The "halo" prefix indicates that the substituent attached to the prefix is replaced by one or more independently selected halo groups. For example, "haloalkyl" (alone or in combination with another term) means an alkyl substituent wherein at least one hydrogen group is replaced by a halo group. Non-limiting examples of haloalkyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl. Further, "haloalkoxy" (alone or in combination with another term) means an alkoxy substituent wherein at least one of the hydrogen groups is replaced by a halo group. Non-limiting examples of haloalkoxy substituents include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoro" Methoxy") and 1,1,1,-trifluoroethoxy. It should be understood that if a substituent is substituted with more than one halo group, the halo groups may be the same or different (unless otherwise stated).
字首"全鹵"係表示該字首所連接取代基上之每個氫基係被獨立經選擇之鹵素基團置換，意即取代基上之各氫基係被鹵素基團置換。若所有鹵素基團均為相同，則字首典型上將確認該鹵素基團。因此，例如，"全氟"一詞係意謂字首所連接取代基上之每個氫基係被氟基團取代。茲說明之，"全氟烷基"一詞係意謂烷基取代基，其中氟基團係在各氫基之位置上。全氟烷基取代基之非限制性實例包括三氟甲基(－CF3 )、全氟異丙基、全氟丁基、全氟癸基及全氟十二基。茲進一步說明之，"全氟烷氧基"一詞係意謂烷氧基取代基，其中各氫基係被氟基團置換。全氟烷氧基取代基之非限制性實例包括三氟甲氧基(－O－CF3 )、全氟異丙氧基、全氟丁氧基、全氟癸氧基及全氟十二氧基。The prefix "perhalogen" means that each hydrogen radical on the substituent attached to the prefix is replaced by an independently selected halo group, meaning that each hydrogen radical on the substituent is replaced by a halo group. If all of the halo groups are the same, the halo group will typically be confirmed by the prefix. Thus, for example, the term "perfluoro" means that each hydrogen radical on the substituent attached to the prefix is substituted with a fluoro group. As used herein, the term "perfluoroalkyl" means an alkyl substituent wherein the fluoro group is attached to each hydrogen group. Non-limiting examples of perfluoroalkyl substituents include trifluoromethyl (-CF 3), perfluoroisopropyl, perfluorobutyl, perfluorodecyl, and perfluorododecyl group. Further, the term "perfluoroalkoxy" means an alkoxy substituent wherein each hydrogen group is replaced by a fluoro group. Non-limiting examples of perfluoroalkoxy substituents include trifluoromethoxy (-O-CF 3 ), perfluoroisopropoxy, perfluorobutoxy, perfluorodecyloxy, and perfluorododeoxy base.
"雜環"或"雜環并"或"雜環基"術語(單獨或併用另外之術語)係指飽和(例如"雜環烷基")、部份不飽和(例如"雜環烯基"或"雜環炔基")或完全不飽和(例如"雜芳基")環系統，典型上含有3至18個環原子，其中至少一個環原子為雜原子(意即氮、氧或硫)，其中其餘環原子係獨立選自包括碳、氮、氧及硫。雜環基可經由此基團中之任何可取代碳或氮原子，被連結至母分子部份基團，其條件是會造成安定分子。The terms "heterocyclic" or "heterocyclic" or "heterocyclyl" (alone or in conjunction with another term) mean saturated (eg "heterocycloalkyl"), partially unsaturated (eg "heterocycloalkenyl"). Or a "heterocyclic alkynyl" or fully unsaturated (eg "heteroaryl") ring system, typically containing from 3 to 18 ring atoms, wherein at least one ring atom is a hetero atom (ie nitrogen, oxygen or sulfur) Wherein the remaining ring atoms are independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur. A heterocyclyl group can be attached to a parent molecular moiety via any substitutable carbon or nitrogen atom in the group, provided that a stable molecule is formed.
雜環基可為但不限於單環，其典型上含有3至14個環原子(意即M3 －M14 雜環基)，3至8個環原子(意即M3 －M8 雜環基)，3至6個環原子(意即M3 －M6 雜環基)，或5至6個環原子(意即M5 －M6 雜環基)。單環雜環基之非限制性實例包括呋喃基、二氫呋喃基、四氫呋喃基、吡咯基、異吡咯基、二氫吡咯基、四氫吡咯基、咪唑基、異咪唑基、二氫咪唑基、四氫咪唑基、吡唑基、二氫吡唑基、四氫吡唑基、***基、四唑基、二硫伍圜基、氧硫伍圜基、唑基、異唑基、噻唑基、異噻唑基、噻唑啉基、異噻唑啉基、噻唑啶基、異噻唑啶基、硫二唑基、噻唑基、二唑基(包括1,2,3－二唑基、1,2,4－二唑基(亦稱為"偶氮肟基")、1,2,5－二唑基(亦稱為"呋呫基")及1,3,4－二唑基)、***基(包括1,2,3,4－***基與1,2,3,5－***基)、二唑基(包括1,2,3－二唑基、1,2,4－二唑基、1,3,2－二唑基及1,3,4－二唑基)、氧硫伍圜基、哌喃基(包括1,2－哌喃基與1,4－哌喃基)、二氫哌喃基、吡啶基、六氫吡啶基、二基(包括嗒基(亦稱為"1,2－二基")、嘧啶基(亦稱為"1,3－二基")及吡基(亦稱為"1,4－二基"))、六氫吡基、三基(包括對稱－三基(亦稱為"1,3,5－三基")、不對稱－三基(亦稱為1,2,4－三基)及毗－三基(亦稱為"1,2,3－三基)、基(包括1,2,3－基、1,3,2－基、1,3,6－基(亦稱為"戊唑基")、1,2,6－基及1,4－基)、異基(包括鄰－異基與對－異基)、四氫唑基、異四氫唑基、噻基(包括1,2,5－噻基或1,2,6－噻基)、二基(包括1,4,2－二基與1,3,5,2－二基)、嗎福啉基、一氮七圜烯基、氧七圜烯基、硫七圜烯基及二氮七圜烯基。The heterocyclic group may be, but not limited to, a monocyclic ring, which typically has 3 to 14 ring atoms (ie, M 3 -M 14 heterocyclic group), and 3 to 8 ring atoms (ie, M 3 -M 8 heterocyclic ring). a group of 3 to 6 ring atoms (ie, M 3 -M 6 heterocyclic group), or 5 to 6 ring atoms (ie, M 5 -M 6 heterocyclic group). Non-limiting examples of monocyclic heterocyclic groups include furyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, isopyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, imidazolyl, isoimidazolyl, dihydroimidazolyl , tetrahydroimidazolyl, pyrazolyl, dihydropyrazolyl, tetrahydropyrazolyl, triazolyl, tetrazolyl, dithiol, oxathiol, Azolyl, different Azyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiadiazolyl, Thiazolyl, Diazolyl (including 1,2,3- Diazolyl, 1,2,4- Diazolyl (also known as "azoindolyl"), 1,2,5- Diazolyl (also known as "furazan") and 1,3,4- Diazolyl), Triazolyl (including 1,2,3,4- Triazolyl and 1,2,3,5- Triazolyl), two Azolyl (including 1,2,3-di Azolyl, 1,2,4-di Azolyl, 1,3,2-di Azolyl and 1,3,4-di Azolyl), oxysulfuryl, piperidyl (including 1,2-piperidyl and 1,4-piperidyl), dihydropentanyl, pyridyl, hexahydropyridyl, Base (including 嗒 Base (also known as "1,2-two Base"), pyrimidinyl (also known as "1,3-two Base") and pyridyl Base (also known as "1,4-two Base ")), hexahydropyridyl Base, three Base (including symmetry - three Base (also known as "1,3,5-three Base"), asymmetry - three Base (also known as 1,2,4-three Base) and adjacent-three Base (also known as "1, 2, 3-three base), Base (including 1, 2, 3- Base, 1,3,2- Base, 1,3,6- Base (also known as "e" Azolyl "), 1, 2, 6- Base and 1,4- Base) Base (including neighbor-different Base and right Base) Azolyl, isotetrahydro Azolyl, Thio Base (including 1, 2, 5- Thio Base or 1,2,6- Thio base), two Base (including 1,4,2- two Base with 1,3,5,2- two a group, a phenanthroline group, a heptyl heptaenyl group, an oxygen heptaenyl group, a sulfur heptaenyl group, and a diaza heptaenyl group.
雜環基亦可包括但不限於兩個或多個環稠合在一起，例如啶基(包括[1,8]啶基與[1,6]啶基)、噻唑嘧啶基、噻吩并嘧啶基、嘧啶并嘧啶基、吡啶并嘧啶基、吡唑并嘧啶基、吲基、吡啉啶基、哌喃并吡咯基、4H－喹基、嘌呤基、吡啶并吡啶基(包括吡啶并[3,4－b]－吡啶基、吡啶并[3,2－b]－吡啶基及吡啶并[4,3－b]－吡啶基)、吡啶并嘧啶及喋啶基。稠合環雜環基之其他非限制性實例包括苯并稠合雜環基，譬如吲哚基、異吲哚基、吲哚烯基(亦稱為"假吲哚基")、異吲唑基(亦稱為"苯并吡唑基")、苯并基(包括喹啉基(亦稱為"1－苯并基")與異喹啉基(亦稱為"2－苯并基"))、呔基、喹喏啉基、苯并二基(包括啈啉基(亦稱為"1,2－苯并二基")與喹唑啉基(亦稱為"1,3－苯并二基"))、苯并哌喃基(包括"烯基"與"異烯基")、苯并硫代哌喃基(亦稱為"硫烯基")、苯并唑基、吲哚基(亦稱為"苯并異唑基")、苯甲醯亞胺基、苯并二氧伍圜烯基、苯并二氧陸圜基、苯并二唑基、苯并呋喃基(亦稱為"香豆酮基")、異苯并呋喃基、苯并噻吩基(亦稱為"苯并硫苯基"、"硫環烷基"及"苯并硫代呋喃基")、異苯并噻吩基(亦稱為"異苯并苯硫基"、"異硫萘基"及"異苯并硫代呋喃基")、苯并噻唑基、苯并噻二唑基、苯并咪唑基、苯并***基、苯并基(包括1,3,2－苯并基、1,4,2－苯并基、2,3,1－苯并基及3,1,4－苯并基)、苯并異基(包括1,2－苯并異基與1,4－苯并異基)、四氫異喹啉基、咔唑基、基及吖啶基。Heterocyclyl groups can also include, but are not limited to, two or more rings fused together, for example Pyridyl (including [1,8] Pyridyl and [1,6] Pyridyl), thiazolidinyl, thienopyrimidinyl, pyrimidopyrimidinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, anthracene Base, pyridinyl, piperacinopyryl, 4H-quin Base, fluorenyl, pyridopyridyl (including pyrido[3,4-b]-pyridyl, pyrido[3,2-b]-pyridyl and pyrido[4,3-b]-pyridyl) , pyridopyrimidine and acridinyl. Other non-limiting examples of fused ring heterocyclic groups include benzofused heterocyclic groups such as fluorenyl, isodecyl, decene. Base (also known as "pseudo-fluorenyl"), isoxazolyl (also known as "benzopyrazolyl"), benzo Base (including quinolyl (also known as "1-benzo" ") and isoquinolyl (also known as "2-benzo" Base ")), 呔 Base, quinoxaline, benzoic acid Basis (including porphyrinyl (also known as "1,2-benzo" Base") with quinazolinyl (also known as "1,3-benzoic acid" Base ")), benzopyranyl (including " Alkenyl Alkenyl "), benzothiopiperidyl (also known as "sulfur Alkenyl "), benzo Azolyl, anthracene Benzoin Azyl"), benzamidine, benzodioxanyl, benzodioxan, benzo Diazolyl, benzofuranyl (also known as "coumarone"), isobenzofuranyl, benzothienyl (also known as "benzothiophenyl", "thiocycloalkyl"and"Benzothiofuranyl"), isobenzothiophenyl (also known as "isobenzophenylthio", "isothionaphthyl" and "isobenzothiofuranyl"), benzothiazolyl, Benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzo Base (including 1,3,2-benzo Base, 1,4,2-benzo Base, 2,3,1-benzo And 3,1,4-benzophenone Base) Base (including 1,2-benziso Base with 1,4-benzene Base, tetrahydroisoquinolinyl, carbazolyl, Base and acridinyl.
"兩個稠合環"雜環基一詞(單獨或併用另外之術語)係意謂含有兩個稠合環之飽和、部份飽和或芳族雜環基。兩個稠合環雜環基之非限制性實例包括啶基(包括[1,8]啶基與[1,6]啶基)、噻唑嘧啶基、噻吩并嘧啶基、嘧啶并嘧啶基、吡啶并嘧啶基、吡唑并嘧啶基、吲基、吡啉啶基、哌喃并吡咯基、4H－喹基、嘌呤基、吡啶并吡啶基、喋啶基、吲哚基、異吲哚基、吲哚烯基、異吲唑基、苯并基、呔基、喹喏啉基、喹唑啉基、苯并二基、苯并哌喃基、苯并硫代哌喃基、苯并唑基、吲哚基、苯甲醯亞胺、苯并二氧伍圜烯基、苯并二氧陸圜基、苯并二唑、苯并呋喃基、異苯并呋喃基、苯并噻吩基、異苯并噻吩基、苯并噻唑基、苯并噻二唑基、苯并咪唑基、苯并***基、苯并基、苯并異基及四氫異喹啉基。The term "two fused ring" heterocyclic groups (alone or in combination with another term) means a saturated, partially saturated or aromatic heterocyclic group containing two fused rings. Non-limiting examples of two fused ring heterocyclic groups include Pyridyl (including [1,8] Pyridyl and [1,6] Pyridyl), thiazolidinyl, thienopyrimidinyl, pyrimidopyrimidinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, anthracene Base, pyridinyl, piperacinopyryl, 4H-quin Base, fluorenyl, pyridopyridyl, acridinyl, fluorenyl, isodecyl, decene Base, isoxazolyl, benzo Base Base, quinoxalinyl, quinazolinyl, benzodiazepine Base, benzopipetanyl, benzothiopiperidyl, benzo Azolyl, anthracene Base, benzamidine, benzodioxanyl, benzodioxan, benzo Diazole, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothiophenyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzo Base and benzene And tetrahydroisoquinolyl.
雜環基可包含一或多個硫原子作為環員；而在一些情況中，硫原子係被氧化成SO或SO2 。在雜環基中之氮雜原子可以或可以不被四級化，且可以或可以不被氧化成N－氧化物。此外，氮雜原子可以或可以不經N－保護。The heterocyclic group may contain one or more sulfur atoms as a ring member; and in some cases, the sulfur atom is oxidized to SO or SO 2 . The nitrogen heteroatom in the heterocyclic group may or may not be quaternized and may or may not be oxidized to an N-oxide. Furthermore, the nitrogen heteroatoms may or may not be N-protected.
當於本文中使用時，在雜環基部份基團中之環原子數，可藉由字首"Mx －My "確認，其中x為在雜環基部份基團中環原子之最低值，而y為最高數目。As used herein, the number of ring atoms in a heterocyclyl moiety can be confirmed by the prefix "M x -M y " where x is the lowest of the ring atoms in the heterocyclic moiety. Value, and y is the highest number.
"雜環烷氧基"一詞(單獨或併用另外之術語)係指雜環烷基，經過氧基附加至母分子部份基團。The term "heterocycloalkoxy" (alone or in combination with another term) refers to a heterocycloalkyl group appended to the parent molecular moiety through an oxy group.
"雜環烷氧基烷基"一詞(單獨或併用另外之術語)係指雜環烷氧基，經過次烷基附加至母分子部份基團(意即雜環基－次烷基－O－次烷基－)。The term "heterocycloalkoxyalkyl" (alone or in combination with another term) refers to a heterocycloalkoxy group appended to the parent molecular moiety through a subalkyl group (ie, a heterocyclyl-alkylene group). O-alkylene-).
"雜環烷氧基羰基"一詞(單獨或併用另外之術語)係指雜環烷氧基，經過羰基附加至母分子部份基團(意即雜環基－次烷基－O－C(O)－)。The term "heterocycloalkoxycarbonyl" (alone or in combination with another term) refers to a heterocycloalkoxy group appended to the parent molecular moiety through a carbonyl group (ie, heterocyclyl-alkylene-O-C) (O)-).
"雜環烷基"一詞(單獨或併用另外之術語)係指雜環基，經過次烷基附加至母分子部份基團(例如雜環基C1 －C6 烷基)。The term "heterocycloalkyl" (alone or in combination with another term) refers to a heterocyclyl group appended to a parent molecular moiety (eg, heterocyclyl C 1 -C 6 alkyl) via a subalkyl group.
"雜環烷基羰基"一詞(單獨或併用另外之術語)係指雜環烷基，經過羰基附加至母分子部份基團(意即－C(O)－次烷基－雜環基)。The term "heterocycloalkylcarbonyl" (alone or in combination with another term) refers to a heterocycloalkyl group appended to the parent molecular moiety through a carbonyl group (ie, -C(O)-alkylene-heterocyclyl) ).
"雜環羰基"一詞(單獨或併用另外之術語)係指雜環基，經過羰基附加至母分子部份基團(意即－C(O)－雜環基)。The term "heterocyclic carbonyl" (alone or in combination with another term) refers to a heterocyclyl group appended to the parent molecular moiety (ie, -C(O)-heterocyclyl) via a carbonyl group.
"雜環基氧基"或"(雜環基)氧基"術語(單獨或併用另外之術語)係指雜環基，經過氧基部份基團附加至母分子部份基團。The term "heterocyclyloxy" or "(heterocyclyl)oxy" (alone or in combination with another term) refers to a heterocyclyl group appended to a parent molecular moiety through an oxy moiety.
"(雜環基)氧基烷基"一詞(單獨或併用另外之術語)係指雜環基氧基，經過次烷基附加至母分子部份基團(意即雜環基－O－次烷基－)。The term "(heterocyclyl)oxyalkyl" (alone or in combination with another term) refers to a heterocyclyloxy group appended to the parent molecular moiety through a subalkyl group (ie, heterocyclyl-O- Alkylene-).
"(雜環基)氧基羰基"一詞(單獨或併用另外之術語)係指(雜環基)氧基，經過羰基附加至母分子部份基團(意即雜環基－O－C(O)－)。The term "(heterocyclyl)oxycarbonyl" (alone or in combination with another) refers to a (heterocyclyl)oxy group appended to the parent molecular moiety through a carbonyl group (ie, heterocyclyl-O-C). (O)-).
"雜環硫基"一詞(單獨或併用另外之術語)係指雜環基，經過－S－附加至母分子部份基團。The term "heterocyclicthio" (alone or in combination with another term) refers to a heterocyclyl group appended to the parent molecular moiety through -S-.
"雜環基硫代烷氧基"一詞(單獨或併用另外之術語)係指雜環基－次烷基－S－。The term "heterocyclylthioalkoxy" (alone or in combination with another term) refers to heterocyclyl-alkylene-S-.
"雜環基硫代烷氧基烷基"一詞(單獨或併用另外之術語)係指雜環基－次烷基－S－次烷基－。The term "heterocyclylthioalkoxyalkyl" (alone or in combination with another term) refers to heterocyclyl-alkylene-S-alkylene-.
"雜環基硫基烷基"一詞(單獨或併用另外之術語)係指雜環硫基，經過次烷基附加至母分子部份基團(意即雜環基－S－次烷基－)。The term "heterocyclylthioalkyl" (alone or in combination with another term) refers to a heterocyclic thio group appended to the parent molecular moiety through a subalkyl group (ie, a heterocyclyl-S-alkylene group). -).
"雜環基碳環基"一詞(單獨或併用另外之術語)係指雜環基，經過碳環基附加至母分子部份基團(意即雜環基－碳環基－)。The term "heterocyclylcarbocyclyl" (alone or in combination with another term) refers to a heterocyclyl group appended to the parent molecular moiety (ie, heterocyclyl-carbocyclyl-) via a carbocyclic group.
"雜環基碳環基烷基"一詞(單獨或併用另外之術語)係指雜環基碳環基，經過次烷基附加至母分子部份基團(意即雜環基－碳環基－次烷基－)。The term "heterocyclylcarbocyclyl" (alone or in combination with another term) refers to a heterocyclyl carbocyclyl group appended to a parent molecular moiety through a subalkyl group (ie, a heterocyclyl-carbocycle). Alkyl-alkyl-).
"(雜環基)烷氧基碳環基烷基"一詞(單獨或併用另外之術語)係指雜環基－次烷基－O－碳環基－次烷基－。The term "(heterocyclyl)alkoxycarbocycloalkyl" (alone or in combination with another term) refers to heterocyclyl-alkylene-O-carbocyclyl-alkylene-.
"(雜環基)羰基碳環基烷基"一詞(單獨或併用另外之術語)係指雜環基－C(O)－碳環基－次烷基－。The term "(heterocyclyl)carbonyl carbocyclylalkyl" (alone or in combination with another term) refers to heterocyclyl-C(O)-carbocyclyl-alkylene-.
"(雜環基)雜環烷基"一詞(單獨或併用另外之術語)係指雜環基－雜環基－次烷基－。The term "(heterocyclyl)heterocycloalkyl" (alone or in combination with another term) refers to heterocyclyl-heterocyclyl-alkylene-.
"(雜環基)烷氧基雜環烷基"一詞(單獨或併用另外之術語)係指雜環基－次烷基－O－雜環基－次烷基－。The term "(heterocyclyl)alkoxyheterocycloalkyl" (alone or in combination with another term) refers to heterocyclyl-alkylene-O-heterocyclyl-alkylene-.
"(雜環基)羰基雜環烷基"一詞(單獨或併用另外之術語)係指雜環基－C(O)－雜環基－次烷基－。The term "(heterocyclyl)carbonylheterocycloalkyl" (alone or in combination with another term) refers to heterocyclyl-C(O)-heterocyclyl-alkylene-.
"(雜環烷基)碳環基烷基"一詞(單獨或併用另外之術語)係指雜環基－次烷基－碳環基－次烷基－。The term "(heterocycloalkyl)carbocyclylalkyl" (alone or in combination with another term) refers to heterocyclyl-alkylene-carbocyclyl-alkylene-.
"(雜環烷基)雜環烷基"一詞(單獨或併用另外之術語)係指雜環基－次烷基－雜環基－次烷基－。因此，例如，(M3 －M10 雜環基C1 －C6 烷基)M5 －M6 雜環基C1 －C3 烷基係意謂M3 －M10 雜環基－C1 －C6 次烷基－M5 －M6 雜環基－C1 －C3 次烷基－。The term "(heterocycloalkyl)heterocycloalkyl" (alone or in combination with another term) refers to heterocyclyl-alkylene-heterocyclyl-alkylene-. Thus, for example, (M 3 -M 10 heterocyclyl C 1 -C 6 alkyl) M 5 -M 6 heterocyclyl C 1 -C 3 alkyl means M 3 -M 10 heterocyclyl-C 1 -C 6 -alkyl-M 5 -M 6 -heterocyclyl-C 1 -C 3 -alkyl-.
"雜芳基"一詞(單獨或併用另外之術語)係意謂芳族雜環基，典型上含有5至18個環原子。雜芳基可為單環或兩個或多個稠合環。五員雜芳基之非限制性實例包括咪唑基；呋喃基；硫苯基(或噻吩基或硫代呋喃基)；吡唑基；唑基；異唑基；噻唑基；1,2,3－,1,2,4－,1,2,5－及1,3,4－二唑基；及異噻唑基。六員雜芳基之非限制性實例包括吡啶基；吡基；嘧啶基；嗒基；及1,3,5－,1,2,4－及1,2,3－三基。6/5－員稠合環雜芳基之非限制性實例包括苯并硫代呋喃基、異苯并硫代呋喃基、苯并異唑基、苯并唑基、嘌呤基及苯甲醯亞胺。6/6－員稠合環雜芳基之非限制性實例包括喹啉基；異喹啉基；及苯并基(包括啈啉基與喹唑啉基)。The term "heteroaryl" (alone or in combination with another term) means an aromatic heterocyclic group, typically containing from 5 to 18 ring atoms. The heteroaryl group can be a single ring or two or more fused rings. Non-limiting examples of the five-membered heteroaryl group include imidazolyl; furanyl; thiophenyl (or thienyl or thiofuranyl); pyrazolyl; Azolyl Azolyl; thiazolyl; 1,2,3-,1,2,4-,1,2,5- and 1,3,4- Diazolyl; and isothiazolyl. Non-limiting examples of six-membered heteroaryl groups include pyridyl; pyridyl Pyrimidine group Base; and 1,3,5-,1,2,4- and 1,2,3-three base. Non-limiting examples of 6/5-membered fused ring heteroaryls include benzothiofuranyl, isobenzothiofuranyl, benzopyrene Azolyl, benzo Azolyl, fluorenyl and benzamidine. Non-limiting examples of 6/6-membered fused ring heteroaryls include quinolinyl; isoquinolinyl; and benzo Base (including porphyrin group and quinazolinyl group).
"雜芳基烷氧基"一詞(單獨或併用另外之術語)係指雜芳烷基，經過氧基附加至母分子部份基團(意即雜芳基－次烷基－O－)。雜芳基烷氧基之代表性實例包括但不限於2－吡啶－3－基乙氧基、1,3－噻唑－5－基甲氧基、3－喹啉－3－基丙氧基及5－吡啶－4－基戊氧基。The term "heteroarylalkoxy" (alone or in combination with another term) refers to a heteroarylalkyl group appended to the parent molecular moiety through an oxy group (ie, heteroaryl-alkylidene-O-). . Representative examples of heteroarylalkoxy include, but are not limited to, 2-pyridin-3-ylethoxy, 1,3-thiazol-5-ylmethoxy, 3-quinolin-3-ylpropoxy, and 5-pyridin-4-ylpentyloxy.
"雜芳基烷氧烷基"一詞(單獨或併用另外之術語)係指雜芳基烷氧基，經過次烷基附加至母分子部份基團(意即雜芳基－次烷基－O－次烷基－)。雜芳基烷氧烷基之代表性實例包括但不限於(2－吡啶－3－基乙氧基)甲基、(3－喹啉－3－基丙氧基)甲基、(1,3－噻唑－5－基甲氧基)甲基及2－(5－吡啶－4－基戊氧基)乙基。The term "heteroarylalkoxyalkyl" (alone or in combination with another term) refers to a heteroarylalkoxy group appended to the parent molecular moiety through a subalkyl group (ie, a heteroaryl-alkylene group). -O-alkylene-). Representative examples of heteroarylalkoxyalkyl include, but are not limited to, (2-pyridin-3-ylethoxy)methyl, (3-quinolin-3-ylpropoxy)methyl, (1,3) -thiazol-5-ylmethoxy)methyl and 2-(5-pyridin-4-ylpentyloxy)ethyl.
"雜芳基烷氧羰基"一詞(單獨或併用另外之術語)係指雜芳基烷氧基，經過羰基附加至母分子部份基團(意即雜芳基－次烷基－O－C(O)－)。雜芳基烷氧羰基之代表性實例包括但不限於(2－吡啶－3－基乙氧基)羰基、(3－喹啉－3－基丙氧基)羰基、2－(1,3－噻唑－5－基甲氧基)羰基及(5－吡啶－4－基戊氧基)羰基。The term "heteroarylalkoxycarbonyl" (alone or in combination with another term) refers to a heteroarylalkoxy group appended to the parent molecular moiety through a carbonyl group (ie, a heteroaryl-alkylene-O- group). C(O)-). Representative examples of heteroarylalkoxycarbonyl include, but are not limited to, (2-pyridin-3-ylethoxy)carbonyl, (3-quinolin-3-ylpropoxy)carbonyl, 2-(1,3- Thiazol-5-ylmethoxy)carbonyl and (5-pyridin-4-ylpentyloxy)carbonyl.
"雜芳烷基"一詞(單獨或併用另外之術語)係指雜芳基，經過次烷基附加至母分子部份基團。雜芳烷基之代表性實例包括但不限於3－喹啉基甲基、3－吡啶基甲基、4－吡啶基甲基、1H－咪唑－4－基甲基、1H－吡咯－2－基甲基、吡啶－3－基甲基及2－嘧啶－2－基丙基。The term "heteroaralkyl" (alone or in combination with another term) refers to a heteroaryl group appended to a parent molecular moiety through a subalkyl group. Representative examples of heteroarylalkyl include, but are not limited to, 3-quinolinylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 1H-imidazol-4-ylmethyl, 1H-pyrrole-2- Methyl, pyridin-3-ylmethyl and 2-pyrimidin-2-ylpropyl.
"雜芳烷基羰基"一詞(單獨或併用另外之術語)係指雜芳烷基，經過羰基附加至母分子部份基團(意即雜芳基－次烷基－C(O)－)。The term "heteroaralkylcarbonyl" (alone or in combination with another term) refers to a heteroarylalkyl group appended to the parent molecular moiety through a carbonyl group (ie, heteroaryl-alkylene-C(O)- ).
"雜芳基羰基"一詞(單獨或併用另外之術語)係指雜芳基，經過羰基附加至母分子部份基團。雜芳基羰基之代表性實例包括但不限於吡啶－3－基羰基、(1,3－噻唑－5－基)羰基及喹啉－3－基羰基。The term "heteroarylcarbonyl" (alone or in combination with another term) refers to a heteroaryl group attached to a parent molecular moiety through a carbonyl group. Representative examples of heteroarylcarbonyl include, but are not limited to, pyridin-3-ylcarbonyl, (1,3-thiazol-5-yl)carbonyl, and quinolin-3-ylcarbonyl.
"雜芳基氧基"一詞(單獨或併用另外之術語)係指雜芳基，經過氧基部份基團附加至母分子部份基團。雜芳基氧基之代表性實例包括但不限於吡啶－3－基氧基與喹啉－3－基氧基。The term "heteroaryloxy" (alone or in combination with another term) refers to a heteroaryl group appended to the parent molecular moiety through an oxy moiety. Representative examples of heteroaryloxy include, but are not limited to, pyridin-3-yloxy and quinolin-3-yloxy.
"雜芳基氧基烷基"一詞(單獨或併用另外之術語)係指雜芳基氧基，經過次烷基附加至母分子部份基團(意即雜芳基－O－次烷基－)。The term "heteroaryloxyalkyl" (alone or in combination with another term) refers to a heteroaryloxy group appended to the parent molecular moiety through a subalkyl group (ie, a heteroaryl-O-decane). base-).
"雜芳基氧基羰基"一詞(單獨或併用另外之術語)係指雜芳基氧基，經過羰基附加至母分子部份基團(意即雜芳基－O－C(O)－)。The term "heteroaryloxycarbonyl" (alone or in combination with another term) refers to a heteroaryloxy group appended to the parent molecular moiety through a carbonyl group (ie, heteroaryl-O-C(O)- ).
"雜芳基硫基"一詞(單獨或併用另外之術語)係指雜芳基，經過－S－附加至母分子部份基團。The term "heteroarylthio" (alone or in combination with another term) refers to a heteroaryl group appended to the parent molecular moiety through -S-.
"雜芳基硫代烷氧基"一詞(單獨或併用另外之術語)係指雜芳基－次烷基－S－。The term "heteroarylthioalkoxy" (alone or in combination with another term) refers to heteroaryl-alkylene-S-.
"雜芳基硫代烷氧基烷基"一詞(單獨或併用另外之術語)係指雜芳基－次烷基－S－次烷基－。The term "heteroarylthioalkoxyalkyl" (alone or in combination with another term) refers to a heteroaryl-alkylidene-S-alkylene-.
"雜芳基硫基烷基"一詞(單獨或併用另外之術語)係指雜芳基硫基，經過次烷基附加至母分子部份基團(意即雜芳基－S－次烷基－)。The term "heteroarylthioalkyl" (alone or in combination with another term) refers to a heteroarylthio group appended to the parent molecular moiety through a subalkyl group (ie, a heteroaryl-S-decane). base-).
"氫"一詞(單獨或併用另外之術語)係指氫基，且可被描述為－H。The term "hydrogen" (alone or in combination with another term) refers to a hydrogen radical and may be described as -H.
"羥基"一詞(單獨或併用另外之術語)係指－OH。The term "hydroxy" (alone or in combination with another term) refers to -OH.
"羥烷基"一詞(單獨或併用另外之術語)係指烷基取代基，其中一或多個氫基團係被－OH置換。羥烷基之代表性實例包括但不限於羥甲基、2－羥乙基、3－羥丙基及2－乙基－4－羥庚基。The term "hydroxyalkyl" (alone or in combination with another term) refers to an alkyl substituent wherein one or more hydrogen groups are replaced by -OH. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and 2-ethyl-4-hydroxyheptyl.
"酮基"一詞(單獨或併用另外之術語)係意謂酮基，且可被描述為＝O。The term "keto" (alone or in combination with another term) means a keto group and may be described as =0.
"亞胺基烷基"一詞(單獨或併用另外之術語)係指式之基團，其中H可視情況被烷基或羥基取代，於此種情況中，取代基係個別為烷基亞胺基烷基或羥亞胺基烷基。The term "iminoalkyl" (alone or in combination with another term) refers to A group wherein H may be optionally substituted by an alkyl group or a hydroxyl group, in which case the substituents are each an alkyliminoalkyl group or a hydroxyiminoalkyl group.
"硝基"一詞(單獨或併用另外之術語)係意謂－NO2 。The term "nitro" (alone or in combination with another term) means -NO 2 .
"酮基"一詞(單獨或併用另外之術語)係指＝O部份基團(意即)。The term "keto" (alone or in combination with another term) means a group of =O groups (ie ).
"氧基"一詞(單獨或併用另外之術語)係意謂－O－。The term "oxy" (alone or in combination with another term) means -O-.
"炔丙基"一詞(單獨或併用另外之術語)係意謂單價基團，被描述為：－CH2 －CH≡CH。The term "propargyl" (alone or in combination with another term) means a monovalent group and is described as: -CH 2 -CH≡CH.
"磺醯基"一詞(單獨或併用另外之術語)係意謂－S(O)2
－，其亦可被描述為：
"亞磺醯基"一詞(單獨或併用另外之術語)係意謂－S(O)－，其亦可被描述為：
"硫基"或"噻"術語(單獨或併用另外之術語)係意謂－S－。The term "thio" or "thio" (alone or in combination with another term) means -S-.
"硫醇"、"巰基"或"氫硫基"術語(單獨或併用另外之術語)係意謂氫硫基取代基(意即－SH)。因此，例如，硫醇烷基係意謂烷基取代基，其中一或多個氫基團係被－SH置換，而烷硫基係意謂烷基－S－。The terms "thiol", "thiol" or "hydrogenthio" (alone or in combination with another term) mean a thiol substituent (ie, -SH). Thus, for example, a thioalkylalkyl group means an alkyl substituent wherein one or more hydrogen groups are replaced by -SH and the alkylthio group is alkyl-S-.
"硫代烷氧基"一詞(單獨或併用另外之術語)係指烷基，經過－S－附加至母分子部份基團。硫代烷氧基之代表性實例包括但不限於甲硫基、乙硫基及丁基硫基。The term "thioalkoxy" (alone or in combination with another term) refers to an alkyl group which is appended to the parent molecular moiety through -S-. Representative examples of thioalkoxy include, but are not limited to, methylthio, ethylthio, and butylthio.
"硫代烷氧基烷基"一詞(單獨或併用另外之術語)係指硫代烷氧基，經過次烷基附加至母分子部份基團(意即烷基－S－次烷基－)。The term "thioalkoxyalkyl" (alone or in combination with another term) refers to a thioalkoxy group appended to the parent molecular moiety through a subalkyl group (ie, an alkyl-S-alkylene group). -).
"硫代羰基"一詞(單獨或併用另外之術語)係意謂羰基，其中氧原子已被硫置換。此種取代基可被描述為－C(S)－，且亦可被描繪為：
"藥學上可接受"一詞係以形容詞方式使用，意謂被修飾之名詞適合作為醫藥產物或作為醫藥產物之一部份使用。The term "pharmaceutically acceptable" is used in the form of an adjective, meaning that the modified noun is suitable for use as a pharmaceutical product or as part of a pharmaceutical product.
"治療上有效量"一詞，係指各活性物質之總量，其足以顯示有意義之病患利益，例如降低病毒負載。The term "therapeutically effective amount" refers to the total amount of each active substance that is sufficient to show a meaningful patient benefit, such as reducing viral load.
"前體藥物"一詞係指本發明化合物之衍生物，其具有化學上或代謝上可***之基團，且藉由溶劑分解或在生理學條件下變成本發明化合物，其在活體內係為醫藥活性。化合物之前體藥物可經由化合物官能基(譬如胺基、羥基或羧基)之反應，以習用方式形成。前體藥物衍生物形式經常在哺乳動物生物體中提供溶解度、組織相容性或延遲釋出之利益(參閱Bungard,H.,前體藥物之設計 ,第7－9,21－24頁,Elsevier,Amsterdam 1985)。前體藥物包括此項技藝之執行者所習知之酸衍生物，例如經由母體酸性化合物與適當醇之反應所製成之酯類，或經由母體酸化合物與適當胺之反應所製成之醯胺類。前體藥物之實例包括但不限於本發明化合物內之醇或胺官能基之醋酸酯、甲酸酯、苯甲酸酯或其他醯基化衍生物。The term "prodrug" refers to a derivative of a compound of the invention having a chemically or metabolically cleavable group and which is converted into a compound of the invention by solvolysis or under physiological conditions, which is in vivo. For pharmaceutical activity. The prodrug of the compound can be formed in a conventional manner by reaction of a compound functional group such as an amine group, a hydroxyl group or a carboxyl group. Prodrug derivative forms often provide solubility, tissue compatibility, or delayed release benefits in mammalian organisms (see Bungard, H., Design of Prodrugs, pages 7-9, 21-24, Elsevier , Amsterdam 1985). Prodrugs include acid derivatives known to those skilled in the art, such as esters prepared by reaction of a parent acidic compound with a suitable alcohol, or by a reaction of a parent acid compound with a suitable amine. class. Examples of prodrugs include, but are not limited to, acetate, formate, benzoate or other thiolated derivatives of alcohol or amine functional groups within the compounds of the invention.
"溶劑合物"一詞係指本發明化合物與一或多個無論是有機或無機之溶劑分子之物理締合作用。此物理締合作用經常包括氫鍵。在某些情況中，溶劑合物係能夠隔離，例如當一或多個溶劑分子被併入結晶性固體之晶格中時。"溶劑合物"涵蓋溶液相與可單離溶劑合物兩者。舉例之溶劑合物包括但不限於水合物、乙醇化物及甲醇化物。The term "solvate" refers to the physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. This physical association often includes hydrogen bonding. In some cases, the solvate is capable of isolation, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" encompasses both the solution phase and the solvate. Exemplary solvates include, but are not limited to, hydrates, ethanolates, and methanolates.
"對掌性"一詞係指未具有對稱平面，且因此不可重疊在其鏡像上之分子。對掌性分子可以兩種形式存在，一種右手式與一種左手式。The term "for palmity" refers to a molecule that does not have a plane of symmetry and therefore cannot be superimposed on its mirror image. The palm of the hand can exist in two forms, a right hand and a left hand.
"立體異構物"一詞係指具有其原子以相同順序連接，但具有不同三次元排列之異構物。立體異構物一詞包括例如對掌異構物與非對映異構物。The term "stereoisomer" refers to an isomer having its atoms joined in the same order but having a different three-dimensional arrangement. The term stereoisomers includes, for example, palmo isomers and diastereomers.
"順－反異構物"一詞係指在其環繞雙鍵或環之立體化學上有差異之立體異構物。順－反異構物亦被稱為幾何異構物。The term "cis-trans isomer" refers to a stereoisomer that differs in its stereochemistry around a double bond or ring. Cis-trans isomers are also known as geometric isomers.
"對掌異構物"一詞係指具有鏡像關係之對掌性物質之立體異構物。The term "pair of palmomers" refers to a stereoisomer of a palm-like substance having a mirror image relationship.
"非對映異構物"一詞係指不為對掌異構物或彼此之鏡像之立體異構物。The term "diastereomer" refers to a stereoisomer that is not mirrored to the palmomer or to each other.
"外消旋混合物"一詞係指包含對掌性物質之相等部份(＋)與(－)對掌異構物之混合物。即使個別分子係為對掌性，外消旋混合物係為光學上不活性。The term "racemic mixture" means a mixture of equal parts (+) and (-) of palmar isomers. The racemic mixture is optically inactive even if the individual molecules are palmar.
"互變異構物"一詞係指可相互轉化之異構物。例如，烯醇類與酮類係為互變異構物，因其係經由以無論是酸或鹼處理而相互轉化。The term "tautomer" refers to an isomer that is interconvertible. For example, enols and ketones are tautomers which are converted to each other via treatment with either an acid or a base.
"位置異構物"一詞係指在特定取代基或基團之位置上有差異之兩種或多種構造異構物之任一種。官能基可被連接在碳骨架上之結構上不相等位置處。例如，被描繪為之[1,3]咪唑，與被描繪為之[1,4]咪唑，係為位置異構物。The term "positional isomer" refers to any of two or more structural isomers that differ in the position of a particular substituent or group. The functional groups can be attached to structurally unequal positions on the carbon skeleton. For example, is depicted as [1,3]imidazole, and is depicted as The [1,4]imidazole is a positional isomer.
"N－保護基"或"經N－保護"術語係指能夠保護胺基以防止不期望反應之基團。常用N－保護基係被描述於Greene與Wuts,化學合成上之保護基 (第3版,John Wiley & Sons,NY(1999))，其係以其全文併入本文供參考。N－保護基之非限制性實例包括醯基，譬如甲醯基、乙醯基、丙醯基、三甲基乙醯基、第三－丁基乙醯基、2－氯基乙醯基、2－溴基乙醯基、三氟乙醯基、三氯乙醯基、鄰苯二甲醯基、鄰－硝基苯氧基乙醯基、苯甲醯基、4－氯基苯甲醯基、4－溴基苯甲醯基或4－硝基苯甲醯基；磺醯基，譬如苯磺醯基或對－甲苯磺醯基；硫基，譬如苯基硫基(苯基－S－)或三苯甲基硫基(三苯甲基－S－)；亞磺醯基，譬如對－甲基苯亞磺醯基(對－甲基苯基－S(O)－)或第三－丁基亞磺醯基(t－Bu－S(O)－)；可形成胺基甲酸酯之基團，譬如苄氧羰基、對－氯苄基氧基羰基、對－甲氧基苄氧羰基、對－硝基苄氧羰基、2－硝基苄基氧基羰基、對－溴基苄氧羰基、3,4－二甲氧基苄氧羰基、3,5－二甲氧基苄氧羰基、2,4－二甲氧基苄氧羰基、4－甲氧基苄氧羰基、2－硝基－4,5－二甲氧基苄氧羰基、3,4,5－三甲氧基苄氧羰基、1－(對－聯苯基)－1－甲基乙氧羰基、二甲基－3,5－二甲氧基苄氧羰基、二苯甲基氧基羰基、第三－丁氧羰基、二異丙基甲氧羰基、異丙氧羰基、乙氧羰基、甲氧羰基、烯丙氧基羰基、2,2,2－三氯－乙氧基羰基、苯氧基羰基、4－硝基－苯氧基羰基、茀基－9－甲氧羰基、環戊氧基羰基、金鋼烷基氧基羰基、環己基氧基羰基或苯基硫代羰基；烷基，譬如苄基、對－甲氧基苄基、三苯甲基或苄氧基甲基；對－甲氧苯基；及矽烷基，譬如三甲基矽烷基。較佳N－保護基包括甲醯基、乙醯基、苯甲醯基、三甲基乙醯基、第三－丁基乙醯基、苯磺醯基、苄基、第三－丁氧羰基(Boc)及苄氧羰基(Cbz)。The term "N-protecting group" or "N-protected" refers to a group capable of protecting an amine group from undesired reactions. Commonly used N-protecting systems are described in Greene and Wuts, Protective Groups on Chemical Synthesis (3rd Edition, John Wiley & Sons, NY (1999)), which is incorporated herein by reference in its entirety. Non-limiting examples of N-protecting groups include sulfhydryl groups such as methyl ketone, ethyl hydrazino, propyl fluorenyl, trimethyl ethinyl, tri-butyl acetyl, 2-chloroethyl fluorenyl, 2-Bromoethenyl, trifluoroethenyl, trichloroacetamido, phthalic acid, o-nitrophenoxyethyl fluorenyl, benzamidine, 4-chlorobenzamide , 4-bromobenzylidene or 4-nitrobenzylidene; sulfonyl, such as phenylsulfonyl or p-toluenesulfonyl; thio, phenylthio (phenyl-S) -) or tritylthio (trityl-S-); sulfinyl, such as p-methylphenylsulfinyl (p-methylphenyl-S(O)-) or Tri-butylsulfinyl (t-Bu-S(O)-); a group capable of forming a carbamate such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxy Benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxy Benzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyl Carbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenyl)-1-methylethoxycarbonyl, dimethyl-3,5-dimethoxybenzyloxycarbonyl, Benzyloxycarbonyl, tert-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloro- Ethoxycarbonyl, phenoxycarbonyl, 4-nitro-phenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, gold steel alkyloxycarbonyl, cyclohexyloxycarbonyl or benzene Alkylthiocarbonyl; alkyl, such as benzyl, p-methoxybenzyl, trityl or benzyloxymethyl; p-methoxyphenyl; and nonylalkyl, such as trimethyldecyl. Preferred N-protecting groups include indolyl, ethenyl, benzhydryl, trimethylethenyl, tert-butylethenyl, phenylsulfonyl, benzyl, and tert-butoxycarbonyl. (Boc) and benzyloxycarbonyl (Cbz).
下列縮寫係被使用於下文所述之一般合成方法與實例中：AcOH＝醋酸atm＝大氣Boc＝N－第三－丁氧羰基(保護基)CDI＝1,1'－羰基二咪唑CH2 Cl2 ＝二氯甲烷CuI＝碘化亞銅[碘化銅(I)]DCE＝1,2－二氯乙烷DEAD＝偶氮二羧酸二乙酯DMA＝N－N－二甲基乙醯胺DMAP＝4－二甲胺基吡啶DMF＝N,N－二甲基甲醯胺DMSO＝二甲亞碸EDCI＝(N－乙基－N'－(3－二甲胺基丙基)碳化二亞胺鹽酸鹽EMME＝2－乙氧基亞甲基－丙二酸二乙酯Et3 N＝三乙胺醚＝***EtI＝碘化乙烷EtOAc＝醋酸乙酯EtOH＝乙醇Fe＝鐵Fe(AcAc)3 ＝乙醯基丙酮酸鐵(III)Fmoc氯化物＝氯甲酸9－茀基甲酯HOBt＝N－羥基苯并***Hunig氏鹼＝N,N－二異丙基乙胺IPA＝異丙醇K2 CO3 ＝碳酸鉀KOH＝氫氧化鉀LDA＝鋰二異丙基胺MeOH＝甲醇MsCl＝氯化甲烷磺醯NaH＝氫化鈉NH2 OH．HCl＝羥胺鹽酸鹽NMP＝1－甲基－2－四氫吡咯酮Mg2 SO4 ＝硫酸鎂Na2 SO4 ＝硫酸鈉NH3 ＝氨NH4 Cl＝氯化銨NH4 OH＝氫氧化銨PG＝保護基，譬如Boc－或Troc－POCl3 ＝氯化磷醯R－MgCl＝Grignard試劑R－I＝烷基碘化物或經取代之烷基碘化物SnCl2 ＝氯化亞錫(氯化錫(II))TFA＝三氟醋酸THF＝四氫呋喃TLC＝薄層層析法三氟甲烷磺酐＝三氟甲烷磺酸酐Troc＝2,2,2－三氯乙氧基羰基－(保護基)The following abbreviations are used in the general synthetic methods and examples described below: AcOH = acetic acid atm = atmospheric Boc = N - tert-butoxycarbonyl (protecting group) CDI = 1,1 '-carbonyl diimidazole CH 2 Cl 2 = dichloromethane CuI = cuprous iodide [copper iodide (I)] DCE = 1,2-dichloroethane DEAD = diethyl azodicarboxylate DMA = N-N-dimethylacetamidine Amine DMAP = 4-dimethylaminopyridine DMF = N, N-dimethylformamide DMSO = dimethyl hydrazine EDCI = (N-ethyl-N'-(3-dimethylaminopropyl) carbonization Diimine hydrochloride EMME = 2-ethoxymethylene-malonic acid diethyl ester Et 3 N = triethylamine ether = diethyl ether EtI = iodine iodide EtOAc = ethyl acetate EtOH = ethanol Fe = iron Fe(AcAc) 3 = iron (III) acetyl phthalate Fmoc chloride = 9-fluorenyl methyl chloroformate HOBt = N-hydroxybenzotriazole Hunig's base = N, N-diisopropylethylamine IPA = isopropanol K 2 CO 3 = potassium carbonate KOH = potassium hydroxide LDA = lithium diisopropylamine MeOH = methanol MsCl = chlorinated methane sulfonium NaH = sodium hydride NH 2 OH. HCl = hydroxylamine hydrochloride NMP =1-methyl-2-tetrahydropyrrolidone Mg 2 SO 4 = magnesium sulfate Na 2 SO 4 = sodium sulfate NH 3 = ammonia NH 4 Cl = ammonium chloride NH 4 OH = ammonium hydroxide PG = protecting group, such as Boc- or Troc-POCl 3 = phosphonium chloride R-MgCl = Grignard reagent R-I = alkyl iodide or Substituted alkyl iodide SnCl 2 = stannous chloride (tin (II) chloride) TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography trifluoromethanesulfonic anhydride = trifluoromethanesulfonic anhydride Troc = 2,2,2-trichloroethoxycarbonyl-(protecting group)
下述合成方法與圖式係說明可藉其製備本發明化合物之一般方法。起始物質可得自商業來源或使用一般熟諳此項技藝者所習知之方法製備。舉例言之，可使用類似下文所示之合成途徑，以及合成有機化學技藝中已知之合成方法，或如熟諳此藝者所明瞭之其變型。The following synthetic methods and schemes illustrate the general methods by which the compounds of the invention can be prepared. The starting materials can be obtained from commercial sources or prepared by methods well known to those skilled in the art. For example, synthetic routes similar to those shown below, as well as synthetic methods known in the art of synthetic organic chemistry can be used, or variations thereof as would be apparent to those skilled in the art.
本發明係意欲涵蓋藉由無論是合成方法或代謝過程所製成之化合物。代謝過程包括發生在人類或動物身體(活體內)中者，或發生在活體外者。The present invention is intended to encompass compounds made by either synthetic methods or metabolic processes. Metabolic processes include those that occur in the human or animal body (in vivo) or in the living body.
若本文中所述之取代基與本發明之合成方法不能相容，則取代基可以適當保護基保護，其對使用於此等方法中之反應條件為安定的。保護基可在反應順序中之適當時點被移除，以提供所要之中間物或標的化合物。適當保護基與保護或去除保護取代基之方法，係為此項技藝中所習知，其實例可參閱Greene與Wuts，同前文出處。If the substituents described herein are incompatible with the synthetic methods of the present invention, the substituents may be suitably protected by a protecting group which is stable to the reaction conditions employed in such methods. The protecting group can be removed at the appropriate point in the reaction sequence to provide the desired intermediate or target compound. Suitable protecting groups and methods for protecting or removing protecting substituents are well known in the art, examples of which can be found in Greene and Wuts, supra.
式I－VIII化合物之製備 式I化合物可經由使與反應合成而得，其中W1 ,W2 ,A,B,X,Y,R10 ,R22 及R50 ，均具有如上文具體實施例或實例中所提出之意義，且K為Cl或另一種鹵素。同樣地，式II－VIII化合物可經由使,,,,,或與, ,,,或個別反應而製成。 Preparation of compounds of formula I-VIII The compounds of formula I can be versus The reaction is synthesized, wherein W 1 , W 2 , A, B, X, Y, R 10 , R 22 and R 50 have the meanings as set forth in the above specific examples or examples, and K is Cl or another A halogen. Likewise, a compound of formula II-VIII can be , , , , , or versus , , , , or Made by individual reactions.
式I－VIII化合物之合成係舉例於圖式1－8中。The synthesis of the compounds of formula I-VIII is illustrated in Schemes 1-8.
式I之代表性化合物，其中為，R10 、R17 及R35 均如上文定義，且Z為NR41 ，可使用如圖式1中所概述之程序製成。a representative compound of formula I, wherein for R 10 , R 17 and R 35 are all as defined above, and Z is NR 41 and can be prepared using the procedure outlined in Scheme 1.
式(2)胺類，其中R41 為氫，可以式(1)之N,N－二甲基甲脒化合物，於酸存在下，譬如但不限於醋酸，在高溫(例如約80℃至約150℃)下處理，於是產生式(3)化合物。醋酸可充作溶劑。其他適當溶劑亦可被使用於反應中。An amine of formula (2) wherein R 41 is hydrogen, which may be a N,N-dimethylformamidine compound of formula (1), in the presence of an acid, such as, but not limited to, acetic acid, at elevated temperatures (eg, from about 80 ° C to about Treatment at 150 ° C) yields the compound of formula (3). Acetic acid can be used as a solvent. Other suitable solvents can also be used in the reaction.
式(2)化合物，其中R41 為氫，其N烷基化作用係提供式(2)與(3)，其中R41 為烷基。此程序可藉助於式R41 X1 之烷基化試劑，其中X1 為鹵素、甲苯磺酸鹽、三氟甲烷磺酸鹽或甲烷磺酸鹽，於鹼存在下，譬如但不限於有機鹼，譬如三乙胺或二異丙基胺，或無機鹼，譬如碳酸鈉、銫或鉀，在適當溶劑中，及在溫度範圍從約室溫至約100℃下。A compound of formula (2) wherein R 41 is hydrogen and the N alkylation thereof provides formulas (2) and (3) wherein R 41 is alkyl. This procedure can be carried out by means of an alkylating agent of the formula R 41 X 1 wherein X 1 is halogen, tosylate, trifluoromethanesulfonate or methanesulfonate in the presence of a base such as, but not limited to, an organic base For example, triethylamine or diisopropylamine, or an inorganic base such as sodium carbonate, cesium or potassium, in a suitable solvent, and at a temperature ranging from about room temperature to about 100 °C.
式(1)之N,N－二甲基甲脒化合物之製備，可按圖式2中所述達成。式(4)酮類與式(5)酯類，於鹼存在下，譬如但不限於氫化鈉或鉀(或鈉金屬)，在約0℃下，於適當溶劑中，譬如但不限於***，係提供式(6)鹽，其中M為鉀或鈉。式(6)以2－氰基乙醯胺之處理，於六氫吡啶醋酸鹽存在下，在約回流下，係獲得式(7a)與(7b)之腈類。區域異構物(7a)與(7b)可於此時或稍後，在合成途徑中，使用熟諳此藝者已知之純化技術分離。式(7a)化合物可無論是經由以氯化磷醯處理，而被轉化成式(8)化合物，其中X2 為Cl，或經由以四丁基溴化銨與五氧化二磷，在適當溶劑中，於回流下處理，而被轉化成式(8)化合物，其中X2 為Br。將式(8)化合物之溶液，其中X2 為Cl或Br，與液態氨，在密封高壓容器中，於高溫例如在約130℃下反應，以提供式(9)化合物。式(9)化合物與N,N－二甲基甲醯胺二甲基縮醛，在溶劑中，譬如但不限於甲苯，於回流下，產生式(1)之N,N－二甲基甲脒化合物。The preparation of the N,N-dimethylformamidine compound of the formula (1) can be achieved as described in Scheme 2. a ketone of the formula (4) and an ester of the formula (5) in the presence of a base such as, but not limited to, sodium or potassium hydride (or sodium metal) at about 0 ° C in a suitable solvent such as, but not limited to, diethyl ether. A salt of formula (6) wherein M is potassium or sodium is provided. The nitrile of the formula (7a) and (7b) is obtained by the treatment of 2-cyanoacetamide in the presence of hexahydropyridine acetate at about reflux. The regioisomers (7a) and (7b) can be isolated at this or later, in the synthetic route, using purification techniques known to those skilled in the art. The compound of formula (7a) can be converted to a compound of formula (8), wherein X 2 is Cl, or via tetrabutylammonium bromide and phosphorus pentoxide in a suitable solvent, either by treatment with phosphonium chloride. The product is converted to the compound of formula (8) wherein X 2 is Br. A solution of a compound of formula (8) wherein X 2 is Cl or Br, with liquid ammonia, is reacted in a sealed high pressure vessel at elevated temperature, for example at about 130 ° C, to provide a compound of formula (9). a compound of formula (9) and N,N-dimethylformamide dimethyl acetal, in a solvent such as, but not limited to, toluene, under reflux to yield N,N-dimethyl form of formula (1)脒 compound.
式(2)化合物，其中R41 為氫，且X為O或S，可根據圖式3製自式化合物(10)，其中R101 為脫離基，譬如但不限於鹵素、三氟甲烷磺酸鹽或甲烷磺酸鹽(後述兩種可製自其相應之醇，使用熟諳此藝者所已知之操作法)，經由兩步驟合成，意即硝基之還原，接著為R101 之置換，或R101 之置換，接著為硝基之還原。A compound of formula (2) wherein R 41 is hydrogen and X is O or S can be prepared according to Scheme 3 from formula (10) wherein R 101 is a leaving group such as, but not limited to, halogen, trifluoromethanesulfonic acid Salt or methane sulfonate (the latter two can be prepared from their corresponding alcohols, using methods known to those skilled in the art), synthesized via two steps, meaning reduction of the nitro group followed by substitution of R 101 , or Substitution of R 101 followed by reduction of the nitro group.
R101 以R22 XH之置換，其中X為O或S，可於適當鹼存在下，譬如但不限於碳酸或重碳酸之鉀、銫或鈉鹽，或氫化鈉或鉀，且視情況於18－冠－6醚存在下，於高溫下被促進。反應可一般性地在溶劑中，譬如但不限於N,N－二甲基甲醯胺或二甲亞碸，於溫度約室溫至約180℃下進行。反應亦可在微波爐中進行。應明瞭式(11)化合物亦可由式(10)，其中R101 為－X－H，與式R22 X3 化合物，其中X3 為脫離基，譬如但不限於鹵素、三氟甲烷磺酸鹽或甲烷磺酸鹽，使用前文所提及之反應條件進行反應而獲得。此置換反應亦可於金屬觸媒存在下，譬如但不限於銅金屬、CuI或醋酸鈀，視情況於配位體存在下，譬如但不限於2,2'－雙(二苯基膦基)－1,1'－聯萘或三－第三－丁基膦，及視情況於鹼譬如但不限於吡啶、三乙胺、第三－丁醇鈉、碳酸銫或氫化鈉存在下達成。反應通常係在溫度從約室溫至約180℃，在溶劑譬如但不限於甲苯或N,N－二甲基甲醯胺中進行。R 101 is substituted with R 22 XH, wherein X is O or S, in the presence of a suitable base such as, but not limited to, carbonic acid or potassium bicarbonate, hydrazine or sodium salt, or sodium or potassium hydride, and optionally 18 - In the presence of crown-6 ether, it is promoted at high temperatures. The reaction can be carried out generally in a solvent such as, but not limited to, N,N-dimethylformamide or dimethylhydrazine at a temperature of from about room temperature to about 180 °C. The reaction can also be carried out in a microwave oven. It is to be understood that the compound of formula (11) may also be of formula (10) wherein R 101 is -X-H, and a compound of formula R 22 X 3 wherein X 3 is a leaving group such as, but not limited to, halogen, trifluoromethanesulfonate Or a methanesulfonate obtained by carrying out the reaction under the reaction conditions mentioned above. The displacement reaction may also be in the presence of a metal catalyst such as, but not limited to, copper metal, CuI or palladium acetate, optionally in the presence of a ligand such as, but not limited to, 2,2'-bis(diphenylphosphino) -1,1'-binaphthyl or tri-tert-butylphosphine, and optionally in the presence of a base such as, but not limited to, pyridine, triethylamine, sodium tributoxide, cesium carbonate or sodium hydride. The reaction is usually carried out at a temperature of from about room temperature to about 180 ° C in a solvent such as, but not limited to, toluene or N,N-dimethylformamide.
硝基之還原可經由以還原劑，譬如但不限於鐵粉/氯化銨或氯化錫(II)，在適當溶劑中，處理硝基化合物而達成。Reduction of the nitro group can be achieved by treating the nitro compound with a reducing agent such as, but not limited to, iron powder/ammonium chloride or tin (II) chloride in a suitable solvent.
亦明瞭的是，式(10)化合物亦可被轉化成式(2)化合物，其方式是首先使硝基官能基還原，接著為置換反應，使用如上文所述之反應條件。It is also apparent that the compound of formula (10) can also be converted to the compound of formula (2) by first reducing the nitro function followed by a displacement reaction using the reaction conditions as described above.
胺基苯基偶合劑(10、11及12)之製備 極多種胺基苯基偶合劑均可行。在圖式4中之作用劑係為此種類之舉例。 Preparation of Amino Phenyl Coupling Agents (10, 11 and 12) A wide variety of aminophenyl coupling agents are acceptable. The agent in Scheme 4 is an example of this type.
在一種典型製備法中，係於約50℃下，將二甲基甲醯胺(DMF)中之經取代2－氯－硝基苯化合物以硫酚鈉處理約2小時，使其冷卻，並以二氯甲烷稀釋，以水洗滌，以硫酸鈉脫水乾燥，過濾，及在真空下濃縮，獲得經取代之2－苯基硫基－硝基苯化合物。然後，使此硝基苯化合物以氯化亞錫(SnCl2 )或鐵(Fe)在乙醇中還原。將反應混合物以1N氫氯化鈉調整至pH 12，以醋酸乙酯萃取，以硫酸鈉脫水乾燥，過濾，及在真空下濃縮，獲得經取代之2－苯基硫基－胺基苯化合物10 。In a typical preparation, the substituted 2-chloro-nitrobenzene compound in dimethylformamide (DMF) is treated with sodium thiophenol at about 50 ° C for about 2 hours to cool it. Diluted with dichloromethane, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give the subt. 2-phenylthio-nitrobenzene compound. Then, the nitrobenzene compound is reduced with stannous chloride (SnCl 2 ) or iron (Fe) in ethanol. The reaction mixture was adjusted to pH 12 with 1N sodium hydrogen chloride, extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo to give the substituted 2-phenylthio-aminobenzene compound 10 .
同樣地，使其相應之經取代2－羥基－硝基苯化合物溶於二甲基甲醯胺中，與苯氧化鈉溶液反應，攪拌，及加熱至100℃，歷經約5天。使反應混合物冷卻，並以二氯甲烷稀釋，以水洗滌，以硫酸鈉脫水乾燥，過濾，及在真空下濃縮，獲得經取代之2－苯氧基－硝基苯化合物。然後，使此硝基苯化合物以氯化亞錫(SnCl2 )與鐵(Fe)在乙醇中還原。將反應混合物以1N氫氧化鈉調整至pH 12，以醋酸乙酯萃取，以硫酸鈉脫水乾燥，過濾，及在真空下濃縮，獲得經取代之2－苯氧基－胺基苯化合物12 。Similarly, the corresponding substituted 2-hydroxy-nitrobenzene compound is dissolved in dimethylformamide, reacted with a sodium phenoxide solution, stirred, and heated to 100 ° C for about 5 days. The reaction mixture was cooled and diluted with dichloromethane, washed with water, dried over sodium sulfate, filtered, and concentrated under vacuum to give the substituted 2-phenoxy-nitrobenzene compound. Then, the nitrobenzene compound is reduced with stannous chloride (SnCl 2 ) and iron (Fe) in ethanol. The reaction mixture was adjusted the pH to 12 with 1N sodium hydroxide solution, extracted with ethyl acetate, dehydrated over sodium sulfate, filtered, and concentrated in vacuo to give the substituted 2-phenoxy - aminobenzene compound 12.
同樣地，任一種化合物10 ，其中R9 為羥基－或經保護之羥基－，可進一步使用經取代之溴化苄，經由使羥基－烷基化而被改質，獲得其相應之5－取代－苯氧基－2－取代－苯基硫基－胺基苯化合物11 。Similarly, any compound 10 wherein R 9 is hydroxy- or protected hydroxy- may be further modified with a substituted benzyl bromide via a hydroxy-alkylation to give the corresponding 5-substituted -Phenoxy-2-substituted-phenylthio-aminobenzene compound 11 .
7－取代－4－胺基苯基－取代－吡啶并[2,3－d]嘧啶化合物之製備 7－取代－4－胺基苯基－取代－吡啶并[2,3－d]嘧啶化合物(圖式6)之典型製備法，係涉及經取代胺基苯基偶合劑(描述於圖式4中)與6－取代－2－甲脒基－3－氰基吡啶化合物9 (圖式5)之偶合反應。 Preparation of 7-substituted-4-aminophenyl-substituted-pyrido[2,3-d]pyrimidine compounds 7-substituted-4-aminophenyl-substituted-pyrido[2,3-d]pyrimidine compounds A typical preparation of (Formula 6) involves a substituted aminophenyl coupling agent (described in Scheme 4) and a 6-substituted-2-methylindolyl-3-cyanopyridine compound 9 (Figure 5). The coupling reaction.
如圖式4中所述，極多種胺基苯基偶合劑均可行。As described in Scheme 4, a wide variety of aminophenyl coupling agents are acceptable.
7－取代－4－胺基苯基－取代－吡啶并[2,3－d]嘧啶類之製備，可經由使N,N－二甲基亞胺甲基胺基化合物9以多種偶合劑偶合而達成，一些偶合劑係描述於圖式4中。Preparation of 7-substituted-4-aminophenyl-substituted-pyrido[2,3-d]pyrimidines by coupling N,N-dimethyliminemethylamino compound 9 with various coupling agents To achieve this, some coupling agents are described in Scheme 4.
N,N－二甲基甲脒化合物9之製備可按圖式5中所述達成。於約0℃下，將經取代之烷基甲基酮與甲酸乙酯添加至氫化鈉(或鈉金屬)之***溶液中，歷經約2小時。於添加後，將反應物在室溫下攪拌過夜。添加另外之***，並藉真空過濾快速地單離沉澱物，在真空乾燥器中乾燥。使此物質與2－氰基乙醯胺一起溶於水中。添加六氫吡啶醋酸鹽溶液，並將所形成之溶液於回流下加熱約2小時。使混合物冷卻至室溫，並以冰醋酸調整至pH 4。藉真空過濾單離所形成之固體，以水沖洗，並乾燥，且經確認為6－取代－2－酮基－1,2－二氫吡啶－3－甲腈24 。化合物24 可無論是以氯化磷醯轉化成2－氯－吡啶(如圖式5中所示)或2－溴基吡啶。2－溴基吡啶係以下述方式製成，採用化合物24 之甲苯溶液，並與四丁基溴化銨及五氧化二磷在回流下反應約5小時。使反應混合物冷卻，添加水，並將混合物在室溫下攪拌約2小時。將反應混合物以甲苯稀釋，分離有機層，以鹽水洗滌，並以硫酸鎂脫水乾燥，過濾，及在真空下濃縮，獲得2－溴基吡啶。將無論是2－氯基吡啶或2－溴基吡啶之乙醇溶液與液態氨，在密封高壓容器中，於約130℃下反應約20小時。使反應混合物在真空下濃縮，並以水洗滌殘留物，及乾燥，獲得6－取代－2－胺基－菸鹼腈25 。使化合物25 與N,N－二甲基甲醯胺二甲基縮醛溶於甲苯中，並加熱至回流，歷經約3小時。使所形成之溶液冷卻至室溫，並於真空下濃縮，獲得6－取代－3－氰基－吡啶－2－基－N,N－二甲基甲脒9 。The preparation of N,N-dimethylformamidine compound 9 can be achieved as described in Scheme 5. The substituted alkyl methyl ketone and ethyl formate were added to a solution of sodium hydride (or sodium metal) in diethyl ether at about 0 ° C for about 2 hours. After the addition, the reaction was stirred at room temperature overnight. Additional diethyl ether was added and the precipitate was quickly separated by vacuum filtration and dried in a vacuum desiccator. This material was dissolved in water together with 2-cyanoacetamide. A solution of the hexahydropyridine acetate was added and the resulting solution was heated under reflux for about 2 hours. The mixture was allowed to cool to room temperature and was adjusted to pH 4 with glacial acetic acid. Formed by vacuum filtration of the resulting solid isolated, rinsed with water, and dried, and was identified as 6-substituted-2-one-1,2-dihydropyridine-3-carbonitrile 24. Compound 24 can be converted to 2-chloro-pyridine (as shown in Formula 5) or 2-bromopyridine, either as phosphonium chloride. The 2-bromopyridine was prepared in the following manner using a toluene solution of Compound 24 and reacting with tetrabutylammonium bromide and phosphorus pentoxide under reflux for about 5 hours. The reaction mixture was allowed to cool, water was added, and the mixture was stirred at room temperature for about 2 hours. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. A solution of either 2-chloropyridine or 2-bromopyridine in ethanol and liquid ammonia is reacted in a sealed high pressure vessel at about 130 ° C for about 20 hours. The reaction mixture was concentrated in vacuo, and the residue was washed with water, and dried to give 6-substituted-2-amino - nicotine nitrile 25. Compound 25 was dissolved in toluene with N,N-dimethylformamide dimethyl acetal and heated to reflux for about 3 hours. The formed it was cooled to room temperature and concentrated in vacuo to give 6-substituted-3-cyano - pyridin-2-yl -N, N- dimethyl-formamidine 9.
如上文所述，7－取代－4－胺基苯基－取代－吡啶并[2,3－d]嘧啶類之製備可經由使如圖式5中所示之經取代6－取代－3－氰基－吡啶－2－基－N,N－二甲基甲脒9 與多種偶合劑偶合而達成，一些偶合劑係描述於圖式4中。此偶合反應係描述於圖式6中。As described above, the preparation of the 7-substituted-4-aminophenyl-substituted-pyrido[2,3-d]pyrimidines can be carried out via the substituted 6-substituted-3- as shown in the formula 5 Cyano-pyridin-2-yl-N,N-dimethylformamidine 9 is achieved by coupling with various coupling agents, and some coupling agents are described in Scheme 4. This coupling reaction is depicted in Scheme 6.
在一種典型製備法中，係使化合物9 與類似圖式4中所述之胺基苯基偶合劑溶於醋酸中，並在約130℃下攪拌約15分鐘。使混合物冷卻至室溫，在真空下移除醋酸，並將所形成之殘留物藉逆相層析純化。此時，任何官能性保護基，譬如Boc、Troc或其他基團，可藉由已知方法移除，獲得最後產物。In a typical preparation, compound 9 is dissolved in acetic acid with an aminophenyl coupling agent similar to that described in Scheme 4 and stirred at about 130 ° C for about 15 minutes. The mixture was allowed to cool to room temperature, the acetic acid was removed in vacuo and the residue formed was purified by reverse phase chromatography. At this point, any functional protecting group, such as Boc, Troc or other groups, can be removed by known methods to obtain the final product.
式I之代表性化合物，其中之環B為五員環雜環，且W1 為CH，R10 、R17 及R35 均如上文定義，而Z為NR41 ，可使用如圖式7中所概述之程序，且包括使烷胺基取代之雜環譬如13 ，與Meldrum氏酸及原甲酸三乙酯反應，並加熱至約100℃而製成。使反應混合物濃縮，並藉層析純化，獲得胺基亞甲基丙二酸酯14 。然後，使化合物14 溶於二苯基醚中，並將所形成之溶液加熱至250℃，歷經約30分鐘，獲得15 。將化合物15 之混合物與氯化磷醯(POCl3 )混合，並加熱至約50℃，及攪拌6小時，冷卻，藉由傾倒至冰上使反應淬滅。接著，使其冷卻，以濃氫氧化銨調整至pH 10，並以二氯甲烷萃取，以無水硫酸鈉脫水乾燥，過濾，及在真空下濃縮，獲得16 。在一種典型製備法中，係使化合物16 與類似圖式4中所述之胺基苯基偶合劑，與2,8,9－三異丁基－2,5,8,9－四氮－1－磷雙環并[3.3.3]十一烷參(二苯亞甲基丙酮)－二鈀及第三－丁醇鈉，在溶劑中，典型上在甲苯及其類似物中偶合，以提供21 。a representative compound of formula I, wherein Ring B is a five-membered ring heterocyclic ring, and W 1 is CH, R 10 , R 17 and R 35 are as defined above, and Z is NR 41 , and the procedure outlined in Figure 7 can be used, and includes An alkylamino substituted heterocyclic ring such as 13 , is reacted with Meldrum's acid and triethyl orthoformate, and heated to about 100 ° C to produce. The reaction mixture was concentrated and purified by chromatography to give the amine 14 methylene malonate. Compound 14 was then dissolved in diphenyl ether and the resulting solution was heated to 250 ° C for about 30 minutes to give 15 . The acyl compound mixture with phosphorus trichloride (POCl 3) 15 of the mixing, and heated to about 50 ℃, and stirred for 6 hours, cooled, poured onto ice by the reaction was quenched. Then, it was cooled, adjusted to pH 10 with concentrated aqueous ammonium hydroxide, and extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 16 . In a typical preparation, compound 16 is similar to the aminophenyl coupling agent described in Scheme 4, and 2,8,9-triisobutyl-2,5,8,9-tetrazine- 1-Phosodicyclo[3.3.3]undecane (diphenylmethyleneacetone)-dipalladium and sodium tributoxide, coupled in a solvent, typically in toluene and its analogs, to provide 21 .
式I之代表性化合物，其中之環B為五員環雜環，且W1 為N，R10 、R17 及R35 均如上文定義，而Z為NR41 ，可使用如圖式8中所概述之程序，且包括使烷胺基取代之雜環譬如17 ，與甲醯胺，於回流下反應而製成。然後，使嘧啶產物18 與氯化磷醯(POCl3 )反應，獲得偶合配對物19 。在一種典型製備法中，係使化合物19 與類似圖式4中所述之胺基苯基偶合劑溶於乙醇中，並加熱至回流，歷經12小時，以提供20 。a representative compound of formula I, wherein Ring B is a five-membered ring heterocyclic ring, and W 1 is N, R 10 , R 17 and R 35 are as defined above, and Z is NR 41 , and the procedure outlined in Figure 8 can be used, and includes An alkylamino substituted heterocyclic ring such as 17 is prepared by reacting with formamide under reflux. Then, the pyrimidine product 18 is reacted with phosphonium chloride (POCl 3 ) to obtain a coupling partner 19 . In a typical preparation, compound 19 is dissolved in ethanol with an aminophenyl coupling agent similar to that described in Scheme 4 and heated to reflux for 12 hours to provide 20 .
式I之代表性化合物，其中之環B為五員環雜環，且W1 為N或CH，R10 、R17 及R35 均如上文定義，而Z為NR41 ，係可被製成。a representative compound of formula I, wherein Ring B is a five-membered ring heterocyclic ring, and W 1 is N or CH, and R 10 , R 17 and R 35 are all as defined above, and Z is NR 41 , which can be prepared.
關於各個別步驟之最適宜反應條件與反應時間，可依所採用之特定反應物與存在於所使用反應物中之取代基而改變。除非另有指明，否則溶劑、溫度及其他反應條件可容易地由一般熟諳此藝者選擇。反應物可以習用方式處理，例如藉由從殘留物脫除溶劑，及根據此項技藝中一般已知之方法進一步純化，譬如但不限於結晶化作用、蒸餾、萃取、研製及層析。The most suitable reaction conditions and reaction times for the individual steps may vary depending on the particular reactant employed and the substituents present in the reactants employed. Unless otherwise indicated, solvents, temperatures, and other reaction conditions can be readily selected by those skilled in the art. The reactants can be treated conventionally, for example, by solvent removal from the residue, and further purified according to methods generally known in the art, such as, but not limited to, crystallization, distillation, extraction, trituration, and chromatography.
應明瞭的是，上述具體實施例與圖式及下述實例係藉由說明方式給予，並非限制。於本發明範圍內之各種改變與修正，將為熟諳此藝者自本說明文而明瞭。It is to be understood that the foregoing specific embodiments and the drawings and the following examples are given by way of illustration and not limitation. Various changes and modifications within the scope of the invention will be apparent to those skilled in the art.
4－胺基－N－[2－(4－羥基－苯基硫基)－5－甲基－苯基]－2－(2－甲氧基－乙胺基)－嘧啶－5－羧甲脒將2－甲氧基－乙胺(1毫升)中之得自實例156之產物(42毫克，0.1毫莫耳)，於180℃下，在微波反應器中加熱2小時。蒸發溶劑，並使殘留物藉HPLC以TFA方法純化，而得標題化合物，為三氟醋酸鹽(15毫克，28%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：2.31(s,3H)3.28(s,3H)3.49(m,4H)6.86(m,3H)7.28(m,4H)8.17(s,br,3H)8.73(s,br,1H)9.75(s,br,2H)11.33(s,br,1H)；MS(ESI＋)m/z 425(M＋H)＋.4-amino-N-[2-(4-hydroxy-phenylsulfanyl)-5-methyl-phenyl]-2-(2-methoxy-ethylamino)-pyrimidine-5-carboxyl The product from Example 156 (42 mg, 0.1 mmol) was obtained from 2-methoxy-ethylamine (1 mL) and heated in a microwave reactor for 2 hours at 180 °C. The solvent was evaporated, EtOAc EtOAcqqqqqq 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 2.31 (s, 3H) 3.28 (s, 3H) 3.49 (m, 4H) 6.86 (m, 3H) 7.28 (m, 4H) 8.17 (s, br ,3H)8.73(s,br,1H)9.75(s,br,2H)11.33(s,br,1H);MS(ESI+)m/z 425(M+H)+.
4－胺基－2－丁基胺基－N－[2－(4－羥基－苯基硫基)－5－甲基－苯基]－嘧啶－5－羧甲脒將丁胺(1毫升)中之得自實例156之產物(42毫克，0.1毫莫耳)，於180℃下，在微波反應器中加熱2小時。蒸發溶劑，並使殘留物藉HPLC以TFA方法純化，而得標題化合物，為三氟醋酸鹽(13毫克，24%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：0.90(t,J＝7.35 Hz,3H)1.29(m,2H)1.51(m,2H)2.30(s,3H)3.32(m,2H)6.85(m,3H)7.27(m,4H)8.15(s,br,3H)8.71(s,br,1H)9.55(s,br,1H)9.92(s,br,1H)11.23(s,br,1H)；MS(ESI＋)m/z 423(M＋H)＋.4-Amino-2-butylamino-N-[2-(4-hydroxy-phenylsulfanyl)-5-methyl-phenyl]-pyrimidine-5-carboxamidine butylamine (1 ml The product from Example 156 (42 mg, 0.1 mmol) was heated in a microwave reactor at 180 °C for 2 hours. The solvent was evaporated and the residue was crystallijjjjjjjjj 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 0.90 (t, J = 7.35 Hz, 3H) 1.29 (m, 2H) 1.51 (m, 2H) 2.30 (s, 3H) 3.32 (m, 2H) 6.85(m,3H)7.27(m,4H)8.15(s,br,3H)8.71(s,br,1H)9.55(s,br,1H)9.92(s,br,1H)11.23(s,br, 1H); MS (ESI+) m/z 423 (M+H)+.
N－{4－[4－甲基－2－(6－丙基－噻吩并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－苯基}－乙醯胺N-{4-[4-Methyl-2-(6-propyl-thieno[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenyl}-acetamide
實例3a 2－胺基－5－丙基噻吩－3－羧酸乙酯於環境溫度下，將等莫耳量之氰基醋酸乙酯與硫磺在二甲基甲醯胺中之溶液，以三乙胺(0.5當量)處理，然後於溫熱至50℃時，逐滴添加戊醛(1當量)。3小時後，以水使反應淬滅，並以醋酸乙酯萃取。濃縮有機層，提供標題化合物。Example 3a 2-Amino-5-propylthiophene-3-carboxylic acid ethyl ester A solution of a molar amount of ethyl cyanoacetate and sulfur in dimethylformamide at ambient temperature Treatment with ethylamine (0.5 eq.) then pentaldehyde (1 eq.) was added dropwise while warming to 50 °C. After 3 hours, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was concentrated to give the title compound.
實例3b 6－丙基噻吩并[2,3－d]嘧啶－4－醇使實例3a之產物與過量甲醯胺於回流下反應3小時。以水使反應混合物淬滅，並藉過濾收集所形成之沉澱物，且以水洗滌，及於真空下乾燥，提供標題化合物。Example 3b 6-propylthieno[2,3-d]pyrimidin-4-ol The product of Example 3a was reacted with excess formamide over reflux for 3 hours. The reaction mixture was quenched with water and EtOAc EtOAc m.
實例3c 4－氯基－6－丙基噻吩并[2,3－d]嘧啶使實例3b之產物與過量POCl3 於回流下反應3小時，然後在室溫下16小時。將反應物傾倒於冰上，並於水與醋酸乙酯之間作分液處理。濃縮有機層，提供標題化合物。Example 3c 4- chloro-6-propyl-thieno [2,3-d] pyrimidine The product of Example 3b so that the reaction with an excess of POCl 3 at reflux for 3 hours, then 16 hours at room temperature. The reaction was poured onto ice and partitioned between water and ethyl acetate. The organic layer was concentrated to give the title compound.
實例3d N－{4－[4－甲基－2－(6－丙基－噻吩并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－苯基}－乙醯胺使實例3c之產物與實例7b之產物在乙醇中，於回流下反應16小時。濃縮反應物，以產生標題化合物。Example 3d N-{4-[4-Methyl-2-(6-propyl-thieno[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenyl}-B The product of Example 3c was reacted with the product of Example 7b in ethanol under reflux for 16 hours. The reaction was concentrated to give the title compound.
(6－丁基－噻吩并[2,3－d]嘧啶－4－基)－(5－甲基－2－苯基硫基－苯基)－胺標題化合物係根據實例3之程序，以己醛取代實例3a中之戊醛製成。(6-Butyl-thieno[2,3-d]pyrimidin-4-yl)-(5-methyl-2-phenylthio-phenyl)-amine The title compound was obtained according to the procedure of Example 3 Hexanal was prepared by substituting valeraldehyde in Example 3a.
(5－甲基－2－苯基硫基－苯基)－(2－丙基－噻唑并[5,4－b]吡啶－7－基)－胺(5-Methyl-2-phenylthio-phenyl)-(2-propyl-thiazolo[5,4-b]pyridin-7-yl)-amine
實例5A丁醯基胺基－醋酸甲酯將甘胺酸鹽酸鹽(1.00克，7.964毫莫耳)在二氯甲烷(40毫升)中之已冷卻至0°之懸浮液，於氮大氣下以三乙胺(4.44毫升，31.86毫莫耳)與氯化丁醯(0.93毫升，8.76毫莫耳)處理，並將混合物在室溫下攪拌2.5小時。以飽和碳酸氫鈉水溶液(50毫升)、水(50毫升)及鹽水洗滌反應物。使有機相以無水硫酸鈉脫水乾燥，過濾，及在真空下濃縮，獲得標題化合物。藉矽膠急驟式層析之純化，使用25%醋酸乙酯/二氯甲烷，獲得標題化合物，為無色油(0.776克，4.88毫莫耳，61%)。Example 5A Butanylamino-Methyl Acetate A suspension of glycine hydrochloride (1.00 g, 7.964 mmol) in dichloromethane (40 mL) cooled to 0 ° under a nitrogen atmosphere Ethylamine (4.44 mL, 31.86 mmol) was treated with butyl chloride (0.93 mL, 8.76 mmol) and the mixture was stirred at room temperature for 2.5 hours. The reaction was washed with aq. aq. sodium hydrogen sulfate (50 mL) The organic phase was dried over anhydrous sodium sulfate, filtered The title compound was obtained as a colorless oil (yield: 0.776 g, 4.88 mmol, 61%).
實例5B硫基丁醯基胺基－醋酸甲酯將實例5A之產物(0.774克，4.862毫莫耳)在無水THF(50毫升)中之溶液，以Lawesson試劑(1.338克，3.209毫莫耳)處理，然後於回流及氮大氣下加熱30分鐘。使反應物冷卻至0°，並慢慢逐滴添加飽和碳酸氫鈉水溶液(40毫升)。將混合物於室溫下攪拌15分鐘，接著以醋酸乙酯(100毫升)萃取，並以飽和碳酸氫鈉水溶液(50毫升)、水(2 x 25毫升)及鹽水洗滌有機萃液。使有機相以無水硫酸鈉脫水乾燥，過濾，及在真空下濃縮，獲得標題化合物。藉矽膠急驟式層析之純化，使用1%醋酸乙酯/二氯甲烷，獲得標題化合物，為無色油(0.790克，4.508毫莫耳，93%)。Example 5B thiobutyrylamido-methyl acetate A solution of the product from Example 5A (0.774 g, 4.462 <RTI ID=0.0></RTI> </RTI> <RTIgt; It was then heated under reflux for 30 minutes under a nitrogen atmosphere. The reaction was cooled to 0 ° and a saturated aqueous solution of sodium bicarbonate (40 mL). The mixture was stirred at room temperature for 15 min then EtOAc (EtOAc)EtOAc. The organic phase was dried over anhydrous sodium sulfate, filtered The title compound was obtained as a colorless oil (yield: 0.790 g, 4.508 mmol, 93%).
實例5C 2－硫基丁醯基胺基－乙醯胺使實例5B之產物(0.788克，4.496毫莫耳)在甲醇(30毫升)中之溶液以氨氣飽和，並將反應物在室溫下，於加有塞子之燒瓶中攪拌17小時。在真空下濃縮溶劑，獲得標題化合物，並使固體藉矽膠急驟式層析純化，使用10%甲醇/二氯甲烷，而得標題化合物，為白色固體(500毫克，3.12毫莫耳，69%)。Example 5C 2-thiosuccinylamino-acetamide A solution of the product of Example 5B (0.788 g, 4.466 m.) in methanol (30 mL) was sat. Stir for 17 hours in a stoppered flask. The solvent was concentrated under EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH .
實例5D 2－丙基－噻唑－5－基胺於氮大氣下，將實例5C之產物(395毫克，2.465毫莫耳)在無水醋酸乙酯(12毫升)中之溶液，以三溴化磷(0.189毫升，1.972毫莫耳)處理，並於室溫下攪拌20分鐘。添加另外之三溴化磷(0.050毫升)，並將其攪拌5分鐘。以醋酸乙酯(50毫升)稀釋反應混合物，並以飽和碳酸氫鈉水溶液(25毫升)洗滌。以醋酸乙酯(2 x 50毫升)萃取含水洗液，並合併有機萃液，且以鹽水洗滌，以無水硫酸鈉脫水乾燥，過濾，及在真空下濃縮，獲得標題化合物。藉矽膠急驟式層析之純化，使用3%甲醇/二氯甲烷，獲得標題產物(175毫克，1.23毫莫耳，50%)。EXAMPLE 5D 2-Propyl-thiazol-5-ylamine A solution of the product from Example 5C (395 mg, 2.465 mmol) in anhydrous ethyl acetate (12 mL). (0.189 ml, 1.972 mmol) was added and stirred at room temperature for 20 min. Additional phosphorus tribromide (0.050 mL) was added and stirred for 5 minutes. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The aqueous broth was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The title product (175 mg, 1.23 mmol, 50%) was obtained.
實例5E 2,2－二甲基－5－[(2－丙基－噻唑－5－基胺基)－亞甲基]－[1,3]二氧陸圜－4,6－二酮將實例5D之產物(212.7毫克，1.496毫莫耳)在無水乙醇(5毫升)中之溶液，以Meldrum氏酸(237毫克，1.645毫莫耳)與原甲酸三乙酯(0.25毫升，1.496毫莫耳)在室溫下處理，並將反應物於經預熱之100°油浴中加熱。15分鐘後，使反應物冷卻至室溫，並藉迴轉式蒸發在真空下移除溶劑。藉矽膠急驟式層析之純化，使用10%至20%醋酸乙酯/二氯甲烷之梯度液，獲得標題化合物，為灰白色固體(240毫克，0.8099毫莫耳，54%)。Example 5E 2,2-Dimethyl-5-[(2-propyl-thiazol-5-ylamino)-methylene]-[1,3]dioxanthene-4,6-dione A solution of the product of Example 5D (212.7 mg, 1.496 mmol) in dry ethanol (5 mL) eluted with Meldrum acid (237 mg, 1.645 mM) and triethyl orthoformate (0.25 ml, 1.496 mM) The ear was treated at room temperature and the reaction was heated in a preheated 100 ° oil bath. After 15 minutes, the reaction was cooled to room temperature and the solvent was removed in vacuo by rotary evaporation. The title compound was obtained as a white solid (240 mg, <RTI ID=0.0></RTI> </RTI> <RTIgt;
實例5F 2－丙基－4H－噻唑并[5,4－b]吡啶－7－酮於氮大氣下，將實例5E之產物(230毫克，0.7781毫莫耳)添加至回流之二苯基醚(5毫升)中。於回流5分鐘後，使溶液在冰浴中冷卻，並以己烷(50毫升)稀釋。藉真空過濾收集所形成之金色固體，並以己烷充分洗滌，而得標題化合物(125毫克，0.644毫莫耳，83%)。Example 5F 2-propyl-4H-thiazolo[5,4-b]pyridin-7-one The product of Example 5E (230 mg, 0.7781 mmol) was added to reflux diphenyl ether under nitrogen atmosphere. (5 ml). After refluxing for 5 minutes, the solution was cooled in an ice-bath and diluted with hexane (50 mL). The resulting golden solid was collected by EtOAc (EtOAc EtOAc)
實例5G 7－氯基－2－丙基－噻唑并[5,4－b]吡啶使實例5F之產物(123毫克，0.6332毫莫耳)與氯化磷醯(2毫升)在氮大氣下回流1小時。使溶液在冰浴中冷卻，以冰處理，並以6N氫氧化鈉水溶液調整pH至7。以二氯甲烷(3 x 50毫升)萃取，並使合併之有機萃液以無水硫酸鈉脫水乾燥，過濾，及在真空下濃縮，獲得標題化合物，為褐色油(120毫克，0.564毫莫耳，89%)。Example 5G 7-Chloro-2-propyl-thiazolo[5,4-b]pyridine The product of Example 5F (123 mg, 0.6332 mmol) and EtOAc (2 mL) 1 hour. The solution was cooled in an ice bath, treated with ice and the pH was adjusted to 7 with 6N aqueous sodium hydroxide. Extracted with dichloromethane (3 x 50 mL), EtOAc m. 89%).
實例5H 4－甲基－2－硝基－1－苯基硫基－苯於50℃下，將硫酚鈉(3.96克，30毫莫耳)在60毫升DMF中之溶液，與4－氯基－3－硝基甲苯(2.65毫升，20毫莫耳)一起加熱，並攪拌2天。冷卻至室溫，並以CH2 Cl2 稀釋。以水洗滌，並使有機層以Na2 SO4 脫水乾燥。過濾，及在真空下濃縮，獲得標題化合物(4.29克，87%)。1 H NMR(300 MHz,CDCl3 )δ ppm：2.36(s,3H)6.76(d,J＝8.09 Hz,1H)7.16(d,J＝8.46 Hz,1H)7.45(m,3H)7.58(m,2H)8.03(s,1H).Example 5H 4-Methyl-2-nitro-1-phenylthio-benzene at 50 ° C, a solution of sodium thiophenol (3.96 g, 30 mmol) in 60 mL of DMF with 4-chloro The base-3-nitrotoluene (2.65 ml, 20 mmol) was heated together and stirred for 2 days. Cooled to room temperature and diluted with CH 2 Cl 2. It was washed with water and the organic layer was dried over Na 2 SO 4 . Filtration and EtOAc (EtOAc) 1 H NMR (300 MHz, CDCl 3 ) δ ppm: 2.36 (s, 3H) 6.76 (d, J = 8.09 Hz, 1H) 7.16 (d, J = 8.46 Hz, 1H) 7.45 (m, 3H) 7.58 (m) , 2H) 8.03 (s, 1H).
實例5I 5－甲基－2－苯基硫基－苯胺將得自實例5H之產物(1.17克，7.0毫莫耳)在25毫升無水EtOH與SnCl2 (3.58克，29.8毫莫耳)中之溶液，於室溫下攪拌16小時。以1N NaOH調整至pH 12，並以EtOAc萃取。以Na2 SO4 脫水乾燥，過濾，及在真空下濃縮，獲得標題化合物(835毫克，82%)。1 H NMR(300 MHz,CDCl3 )δ ppm；2.30(2,3H)6.62(d,J＝8.83 Hz,1H)6.69(s,1H)7.10(m,3H)7.21(m,2H)7.54(d,J＝7.72 Hz,2H).Examples 5I 5- methyl-2-phenyl thio - aniline from Example 5H The product (1.17 g, 7.0 mmol) in 25 ml of absolute EtOH and SnCl 2 (3.58 g, 29.8 mmol) in the The solution was stirred at room temperature for 16 hours. Adjust to pH 12 with 1N NaOH and extract with EtOAc. In Na 2 SO 4 dried, filtered, and concentrated in vacuo to give the title compound (835 mg, 82%). 1 H NMR (300 MHz, CDCl 3 ) δ ppm; 2.30 (2, 3H) 6.62 (d, J = 8.83 Hz, 1H) 6.69 (s, 1H) 7.10 (m, 3H) 7.21 (m, 2H) 7.54 ( d, J = 7.72 Hz, 2H).
實例5J(5－甲基－2－苯基硫基－苯基)－(2－丙基－噻唑并[5,4－b]吡啶－7－基)－胺於乾燥之經氮滌氣之燒瓶中，添加2,8,9－三異丁基－2,5,8,9－四氮－1－磷雙環并[3.3.3]十一烷(38毫克，0.111毫莫耳)、參(二苯亞甲基丙酮)－二鈀(25.4毫克，0.0277毫莫耳)及第三－丁醇鈉(82.4毫克，0.8322毫莫耳)。經由注射器添加實例5G之產物(118毫克，0.5548毫莫耳)在無水甲苯(2毫升)中之溶液，與得自實例5I之產物(107.5毫克，0.4993毫莫耳)在甲苯(3毫升)中之溶液。將反應物於回流下，在經預熱之120°油浴中加熱18小時，冷卻至室溫，以另外之參(二苯亞甲基丙酮)二鈀(25.4毫克)處理，並於回流下再加熱2.5小時。使反應物冷卻至室溫，並藉迴轉式蒸發在真空中移除溶劑。藉矽膠急驟式層析之純化，使用1%至3%醋酸乙酯/二氯甲烷之梯度液，獲得標題化合物(29毫克，0.074毫莫耳，15%)。1 H NMR(300 MHz,DMSO－D6)^D6)δ ppm：1.00(t,J＝7.35 Hz,3H)1.71－1.90(m,2H)2.38(s,3H)3.05(t,J＝7.35 Hz,2H)6.87(d,J＝5.52 Hz,1H)7.07(dd,J＝7.91,1.29 Hz,1H)7.12－7.31(m,5H)7.37－7.46(m,2H)8.15(d,J＝5.52 Hz,1H)8.52(s,1H)；MS(DCI/NH3 )m/z 392(M＋H)＋ .Example 5J (5-methyl-2-phenylthio-phenyl)-(2-propyl-thiazolo[5,4-b]pyridin-7-yl)-amine in dry nitrogen-purified gas In the flask, 2,8,9-triisobutyl-2,5,8,9-tetrazo-1-phosphabicyclo[3.3.3]undecane (38 mg, 0.111 mmol) was added. (Diphenylmethyleneacetone)-dipalladium (25.4 mg, 0.0277 mmol) and sodium tributoxide (82.4 mg, 0.8322 mmol). A solution of the product from Example 5G (118 mg, 0.5548 mmol) eluted elute elute elut elut elut elut elut Solution. The reaction was heated under reflux in a preheated 120° oil bath for 18 hours, cooled to room temperature and treated with additional bis(diphenylmethyleneacetone)dipalladium (25.4 mg) and refluxed. Heat for another 2.5 hours. The reaction was allowed to cool to room temperature and the solvent was removed in vacuo by rotary evaporation. The title compound (29 mg, 0.074 mmol, 15%) eluted elute 1 H NMR (300 MHz, DMSO-D6)^D6) δ ppm: 1.00 (t, J = 7.35 Hz, 3H) 1.71-1.90 (m, 2H) 2.38 (s, 3H) 3.05 (t, J = 7.35 Hz , 2H) 6.87 (d, J = 5.52 Hz, 1H) 7.07 (dd, J = 7.91, 1.29 Hz, 1H) 7.12 - 7.31 (m, 5H) 7.37 - 7.46 (m, 2H) 8.15 (d, J = 5.52) Hz, 1H) 8.52 (s, 1H); MS (DCI/NH 3 ) m/z 392 (M+H) + .
4－[4－甲基－2－(2－丙基－噻唑并[5,4－b]吡啶－7－基胺基)－苯基硫基]－酚4-[4-methyl-2-(2-propyl-thiazolo[5,4-b]pyridin-7-ylamino)-phenylthio]-phenol
實例6a三氟－甲烷磺酸4－甲基－2－硝基－苯酯於N2 大氣及0℃下，將4－甲基－2－硝基酚(6.0克，39.1毫莫耳)與Et3 N(16.38毫升，117.5毫莫耳)在100毫升CH2 Cl2 中之溶液，以三氟甲烷磺酸酐(7.25毫升，43.1毫莫耳)處理30分鐘。藉由添加MeOH使反應淬滅。以10%檸檬酸、0.5M KOH及水相繼洗滌。以MgSO4 脫水乾燥，過濾，及在真空下濃縮，獲得標題化合物，使其藉矽膠管柱層析純化，以CH2 Cl2 溶離，獲得琥珀色油(11.22克，100%)。Example 6a Trimethyl-methanesulfonic acid 4-methyl-2-nitro-phenyl ester 4-methyl-2-nitrophenol (6.0 g, 39.1 mmol) with N 2 atmosphere and 0 ° C et 3 N (16.38 mL, 117.5 mmol) in 100 ml CH 2 Cl 2 in the solution to trifluoromethanesulfonic anhydride (7.25 ml, 43.1 mmol) for 30 minutes. The reaction was quenched by the addition of MeOH. Wash with 10% citric acid, 0.5 M KOH and water. In MgSO 4 dried, filtered, and concentrated in vacuo to give the title compound, which was purified by silica gel column to eluting CH 2 Cl 2 to give an amber oil (11.22 g, 100%).
實例6b 4－(4－甲基－2－硝基－苯基硫基)－酚將100毫升EtOH中之得自實例6a之產物(11.22克，39.3毫莫耳)與4－巰基酚(4.96克，39.3毫莫耳)以Na2 CO3 處理，並於回流下加熱過夜。冷卻至室溫，並以水使反應淬滅。以EtOAc萃取。以MgSO4 脫水乾燥，過濾，及在真空下濃縮，獲得標題化合物，使其藉矽膠管柱層析純化，以25% EtOAc/己烷溶離，獲得紅色油(8.65克，85%)。Example 6b 4-(4-Methyl-2-nitro-phenylsulfanyl)-phenol The product from Example 6a (11.22 g, 39.3 mmol) and 4-nonylphenol (4.96) from 100 mL of EtOH. g, 39.3 mmol) Na 2 CO 3 to the processing, and heated at reflux overnight. Cool to room temperature and quench the reaction with water. Extract with EtOAc. In MgSO 4 dried, filtered, and concentrated in vacuo to give the title compound, it was purified by silica gel column chromatography, in 25% EtOAc / hexanes eluting to give a red oil (8.65 g, 85%).
實例6c 4－(2－胺基－4－甲基－苯基硫基)－酚按照得自實例5I之程序，使得自實例6b之產物(8.65克，31.3毫莫耳)以SnCl2 還原，獲得標題化合物，為白色固體(8.51克，100%)。Example 6c 4- (2- amino-4-methyl - phenylsulfanyl) - phenol according to the procedure from Example 5I, the product from Example 6b of such (8.65 g, 31.3 mmol) SnCl 2 reduction in, The title compound was obtained as a white solid (8.51 g, 100%).
實例6d 4－(4－甲基－2－(2－丙基噻唑并[5,4－b]吡啶－7－基胺基)苯硫基)酚於乾燥之經氮滌氣之燒瓶中，添加2,8,9－三異丁基－2,5,8,9－四氮－1－磷雙環并[3.3.3]十一烷(40.4毫克，0.118毫莫耳)、參(二苯亞甲基丙酮)－二鈀(27毫克，0.0295毫莫耳)及第三－丁醇鈉(87.7毫克，0.885毫莫耳)。經由注射器添加實例5G之產物(125.5毫克，0.590毫莫耳)在無水甲苯(5毫升)中之溶液，接著為得自實例6c之產物(136毫克，0.590毫莫耳)。將反應物於回流下，在經預熱之110°油浴中加熱14小時，冷卻至室溫，以另外之2,8,9－三異丁基－2,5,8,9－四氮－1－磷雙環并[3.3.3]十一烷(40.4毫克)與參(二苯亞甲基丙酮)二鈀(27毫克)處理，並於回流下再加熱7小時。使反應物冷卻至室溫，並藉迴轉式蒸發在真空中移除溶劑。藉矽膠急驟式層析之純化，使用15%至30%醋酸乙酯/二氯甲烷之梯度液，獲得不純物質。藉矽膠急驟式層析之純化，使用1%至2%甲醇/二氯甲烷之梯度液，獲得所要之標題化合物，為淡黃色固體(20毫克，0.049毫莫耳，8%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.03(t,J＝7.35 Hz,3H)1.76－1.94(m,2H)2.31(s,3H)3.10(t,J＝7.35 Hz,2H)5.76(s,1H)6.67－6.73(m,2H)6.96－7.04(m,1H)7.08－7.14(m,1H)7.20(d,J＝8.46 Hz,2H)7.29(s,1H)8.14(d,J＝5.52 Hz,1H)8.55(s,1H)9.73(s,1H)；MS(DCI/NH3 )m/z 408(M＋H)＋ .Example 6d 4-(4-Methyl-2-(2-propylthiazolo[5,4-b]pyridin-7-ylamino)phenylthio)phenol in a dry nitrogen purged flask, Add 2,8,9-triisobutyl-2,5,8,9-tetrazo-1-phosphinobicyclo[3.3.3]undecane (40.4 mg, 0.118 mmol), ginseng (diphenyl) Methylene acetonide)-dipalladium (27 mg, 0.0295 mmol) and sodium tributoxide (87.7 mg, 0.885 mmol). A solution of the product of Example 5G (125.5 mg, 0.590 mmol) eluted elute The reaction was heated under reflux in a preheated 110° oil bath for 14 hours, cooled to room temperature, and further 2,8,9-triisobutyl-2,5,8,9-tetrazine 1-Phosphate bicyclo[3.3.3]undecane (40.4 mg) was treated with bis(dibenzylideneacetone)dipalladium (27 mg) and heated under reflux for a further 7 hours. The reaction was allowed to cool to room temperature and the solvent was removed in vacuo by rotary evaporation. Purification by flash chromatography, using a gradient of 15% to 30% ethyl acetate in dichloromethane to give an impurity. The title compound was obtained as a pale yellow solid (20 mg, EtOAc, EtOAc). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.03 (t, J = 7.35 Hz, 3H) 1.76-1.94 (m, 2H) 2.31 (s, 3H) 3.10 (t, J = 7.35 Hz, 2H) 5.76(s,1H)6.67-6.73(m,2H)6.96-7.04(m,1H)7.08-7.14(m,1H)7.20(d,J=8.46 Hz,2H)7.29(s,1H)8.14(d , J = 5.52 Hz, 1H) 8.55 (s, 1H) 9.73 (s, 1H); MS (DCI / NH 3 ) m / z 408 (M + H) + .
N－{4－[4－甲基－2－(2－丙基－噻唑并[5,4－b]吡啶－7－基胺基)－苯基硫基]－苯基}－乙醯胺N-{4-[4-Methyl-2-(2-propyl-thiazolo[5,4-b]pyridin-7-ylamino)-phenylthio]-phenyl}-acetamide
實例7a N－[4－(4－甲基－2－硝基－苯基硫基)－苯基]－乙醯胺按照得自實例6b之程序，使得自實例6a之產物(1克，3.51毫莫耳)與N－(4－巰基－苯基)－乙醯胺(0.65克，351毫莫耳)反應18小時，獲得標題化合物(1.04克，98%)。Example 7a N-[4-(4-Methyl-2-nitro-phenylsulfanyl)-phenyl]-acetamide The product from Example 6a was obtained according to the procedure from Example 6b (1 g, 3.51 Reaction with N-(4-mercapto-phenyl)-acetamide (0.65 g, 351 mmol) for 18 hr.
實例7b N－[4－(2－胺基－4－甲基－苯基硫基)－苯基]－乙醯胺按實例5I中所述，使得自實例7a之產物(0.30克，1毫莫耳)與SnCl2 反應，而得標題化合物(0.27克，100%)，為琥珀色油，使用之而無需進一步純化。Example 7b N-[4-(2-Amino-4-methyl-phenylsulfanyl)-phenyl]-acetamide The product from Example 7a (0.30 g, 1 m. mole) the reaction with SnCl 2, to give the title compound (0.27 g, 100%) as an amber oil used without further purification of the.
實例7c N－(4－(4－甲基－2－(2－丙基噻唑并[5,4－b]吡啶－7－基胺基)苯硫基)苯基)乙醯胺於乾燥之經氮滌氣之燒瓶中，添加2,8,9－三異丁基－2,5,8,9－四氮－1－磷雙環并[3.3.3]十一烷(38.6毫克，0.1128毫莫耳)、參(二苯亞甲基丙酮)－二鈀(25.8毫克，0.0282毫莫耳)及第三－丁醇鈉(83.8毫克，0.8463毫莫耳)。經由注射器添加實例5G之產物(120毫克，0.5642毫莫耳)在無水甲苯(5毫升)中之溶液，接著為得自實例7b之產物(130毫克，0.4773毫莫耳)。將反應物在經預熱之100℃油浴中加熱2.5小時，冷卻至室溫，以另外之2,8,9－三異丁基－2,5,8,9－四氮－1－磷雙環并[3.3.3]十一烷(38.6毫克)、參(二苯亞甲基丙酮)二鈀(25.8毫克)及起始苯胺(130毫克)處理，並於100℃下再加熱18小時。使反應物冷卻至室溫，並藉迴轉式蒸發在真空中移除溶劑。藉矽膠急驟式層析之純化，使用40%至60%醋酸乙酯/二氯甲烷之梯度液，獲得所要之標題化合物，為黃褐色泡沫物(26毫克，10%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：1.01(t,J＝7.35 Hz,3H)1.73－1.91(m,2H)2.01(s,3H)2.34(s,3H)3.07(t,J＝7.54 Hz,2H)6.78(d,J＝5.52 Hz,1H)6.97－7.09(m,1H)7.16－7.30(m,3H)7.36(s,1H)7.51(d,J＝8.82 Hz,2H)8.15(d,J＝5.52 Hz,1H)8.53(s,1H)9.99(s,1H)；MS(DCI/NH3 )m/z 449(M＋H)＋ .Example 7c N-(4-(4-methyl-2-(2-propylthiazolo[5,4-b]pyridin-7-ylamino)phenylthio)phenyl)acetamide in dry In a nitrogen purged flask, 2,8,9-triisobutyl-2,5,8,9-tetrazo-1-phosphabicyclo[3.3.3]undecane (38.6 mg, 0.1128 m) was added. Mohr), ginseng (dibenzylideneacetone)-dipalladium (25.8 mg, 0.0282 mmol) and sodium tributoxide (83.8 mg, 0.8463 mmol). A solution of the product from Example 5G (120 mg, 0.5642 mmol) eluted elute The reaction was heated in a preheated 100 ° C oil bath for 2.5 hours, cooled to room temperature, and further 2,8,9-triisobutyl-2,5,8,9-tetrazo-1-phosphate Bicyclo[3.3.3]undecane (38.6 mg), bis(diphenylmethyleneacetone)dipalladium (25.8 mg) and starting aniline (130 mg) were treated and heated at 100 ° C for an additional 18 hours. The reaction was allowed to cool to room temperature and the solvent was removed in vacuo by rotary evaporation. Purification by flash chromatography eluting with EtOAc EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 1.01 (t, J = 7.35 Hz, 3H) 1.73-1.91 (m, 2H) 2.01 (s, 3H) 2.34 (s, 3H) 3.07 (t, J=7.54 Hz, 2H) 6.78 (d, J=5.52 Hz, 1H) 6.97-7.09 (m, 1H) 7.16-7.30 (m, 3H) 7.36 (s, 1H) 7.51 (d, J = 8.82 Hz, 2H 8.15 (d, J = 5.52 Hz, 1H) 8.53 (s, 1H) 9.99 (s, 1H); MS (DCI / NH 3 ) m / z 449 (M + H) + .
N－{4－[4－甲基－2－(2－甲基－2H－吡唑并[3,4－b]吡啶－4－基胺基)－苯基硫基]－苯基}－乙醯胺N-{4-[4-Methyl-2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-4-ylamino)-phenylthio]-phenyl}- Acetamine
實例8a 2,2－二甲基－5－[(1－甲基－1H－吡唑－3－基胺基)－亞甲基]－[1,3]二氧陸圜－4,6－二酮將1－甲基－1H－吡唑－3－基胺(1.05克，10.8毫莫耳)、2,2－二甲基－[1,3]二氧陸圜－4,6－二酮(1.71克，11.9毫莫耳)及原甲酸三乙酯(1.60克，10.8毫莫耳)在25毫升圓底燒瓶中之混合物，於100℃油浴中加熱15分鐘。使混合物冷卻至室溫，並添加EtOH(10毫升)。將反應混合物加熱，以溶解所有固體，然後冷卻回復至室溫。藉過濾單離所形成之固體，以乙醇沖洗，並乾燥，提供標題化合物(1.81克，66%產率)。Example 8a 2,2-Dimethyl-5-[(1-methyl-1H-pyrazol-3-ylamino)-methylene]-[1,3]dioxane-4,6- Diketone will be 1-methyl-1H-pyrazol-3-ylamine (1.05 g, 10.8 mmol), 2,2-dimethyl-[1,3]dioxane-4,6-di A mixture of ketone (1.71 g, 11.9 mmol) and triethyl orthoformate (1.60 g, 10.8 mmol) in a 25 mL round bottom flask was heated in a 100 ° C oil bath for 15 min. The mixture was cooled to room temperature and EtOH (10 mL) was added. The reaction mixture was heated to dissolve all solids and then cooled to room temperature. The resulting solid was isolated by EtOAc (EtOAc) elute
實例8b 2－甲基－2,7－二氫－吡唑并[3,4－b]吡啶－4－酮將實例8a之產物(1.50克，5.97毫莫耳)與二苯基醚(25毫升)之混合物於回流下加熱1小時，並藉蒸餾移除所形成之丙酮。然後將溶劑傾析，並使殘留之固體殘留物溶於二氯甲烷(5毫升)中，且於矽膠上藉層析純化，以0－10% MeOH/CH2 Cl2 梯度液溶離，提供標題化合物(0.360克，40%產率)。Example 8b 2-Methyl-2,7-dihydro-pyrazolo[3,4-b]pyridin-4-one The product of Example 8a (1.50 g, 5.97 mmol) and diphenyl ether (25) The mixture of ml) was heated under reflux for 1 hour and the acetone formed was removed by distillation. The solvent was then decanted and the solid residue and the residue was dissolved in dichloromethane (5 mL) and purified by chromatography on silica to 0-10% MeOH / CH 2 Cl 2 eluting with a gradient, to provide the title Compound (0.360 g, 40% yield).
實例8c 4－氯基－2－甲基－2H－吡唑并[3,4－b]吡啶將實例8b之產物(0.177克，1.19毫莫耳)與氯化磷醯(3毫升)之混合物於回流下加熱30分鐘，然後冷卻至室溫。將反應混合物傾倒於冰上，藉由添加1N氫氧化鈉水溶液，帶至pH 8，並以二氯甲烷(3 x 30毫升)萃取。使合併之有機相以無水硫酸鎂脫水乾燥，過濾，及在減壓下蒸發，提供標題化合物(0.170克，88%產率)。Example 8c 4-Chloro-2-methyl-2H-pyrazolo[3,4-b]pyridine A mixture of the product of Example 8b (0.177 g, 1.19 mmol) and EtOAc (3 mL) Heat under reflux for 30 minutes and then cool to room temperature. The reaction mixture was poured onto ice and taken to aq. The combined organic phases were dried with EtOAc EtOAcjjjjjjj
實例8d N－{4－[4－甲基－2－(2－甲基－2H－吡唑并[3,4－b]吡啶－4－基胺基)－苯基硫基]－苯基}－乙醯胺將實例8c之產物(47.3毫克，0.282毫莫耳)、實例7b之產物(84.6毫克，0.310毫莫耳)、Pd2 (dba)3 (12.9毫克，0.0141毫莫耳)、第三－丁醇鈉(67.8毫克，0.706毫莫耳)及2,8,9－三異丁基－2,5,8,9－四氮－1－磷雙環并[3,3,3]十一烷(19.3毫克，0.0564毫莫耳)在甲苯(4毫升)中之混合物脫氣，留置於氮正壓力下，並在回流下加熱2小時。添加另外量之Pd2 (dba)3 (4.0毫克，0.0044毫莫耳)與PN3(4.5毫克，0.013毫莫耳)，將反應混合物於回流下再加熱2小時。然後使混合物冷卻至室溫，並於醋酸乙酯(30毫升)與水(30毫升)之間作分液處理。以醋酸乙酯萃取水相，並使合併之有機相以無水硫酸鎂脫水乾燥，過濾，及在減壓下蒸發。使殘留物於矽膠上藉層析純化，以5% MeOH/CH2 Cl2 溶離，提供標題化合物(0.0195克，17%產率)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：2.03(s,3H),2.29(s,3H),4.11(s,3H),5.97(d,J＝5.15 Hz,1H),6.94－7.00(m,1H),7.05(dd,J＝8.09,1.47 Hz,1H),7.19(s,1H),7.26(d,J＝8.82 Hz,2H),7.56(d,J＝8.82 Hz,2H),8.09(d,J＝5.15 Hz,1H),8.20(s,1H),8.80(s,1H),10.04(s,1H)；MS(ESI＋ )m/z 404.1(M＋H)＋ .Example 8d N-{4-[4-Methyl-2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-4-ylamino)-phenylthio]-phenyl }-acetamide The product of Example 8c (47.3 mg, 0.282 mmol), the product of Example 7b (84.6 mg, 0.310 mmol), Pd 2 (dba) 3 (12.9 mg, 0.0141 mmol), Sodium tert-butoxide (67.8 mg, 0.706 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphinobicyclo[3,3,3] The mixture of undecane (19.3 mg, 0.0564 mmol) in toluene (4 mL) was degassed, placed under a positive pressure of nitrogen and heated under reflux for 2 hours. Additional amounts of Pd 2 (dba) 3 (4.0 mg, 0.0044 mmol) and PN3 (4.5 mg, 0.013 mmol) were added and the reaction mixture was heated at reflux for a further 2 hours. The mixture was then cooled to room temperature and partitioned between ethyl acetate (30 mL) and water (30 mL). The aqueous phase was extracted with ethyl acetate and the combined organic phases dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was purified by chromatography on silica in 5% MeOH / CH 2 Cl 2 eluting provide the title compound (0.0195 g, 17% yield). 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 2.03 (s, 3H), 2.29 (s, 3H), 4.11 (s, 3H), 5.97 (d, J = 5.15 Hz, 1H), 6.94 7.00 (m, 1H), 7.05 (dd, J = 8.09, 1.47 Hz, 1H), 7.19 (s, 1H), 7.26 (d, J = 8.82 Hz, 2H), 7.56 (d, J = 8.82 Hz, 2H) ), 8.09 (d, J = 5.15 Hz, 1H), 8.20 (s, 1H), 8.80 (s, 1H), 10.04 (s, 1H); MS (ESI + ) m/z 404.1 (M+H) + .
4－[4－甲基－2－(2－甲基－2H－吡唑并[3,4－b]吡啶－4－基胺基)－苯基硫基]－酚將實例8c之產物(62.1毫克，0.371毫莫耳)、實例6c之產物(85.7毫克，0.371毫莫耳)、Pd2 (dba)3 (16.9毫克，0.0185毫莫耳)、第三－丁醇鈉(89.0毫克，0.926毫莫耳)及2,8,9－三異丁基－2,5,8,9－四氮－1－磷雙環并[3,3,3]十一烷(25.4毫克，0.0741毫莫耳)在甲苯(3毫升)中之混合物脫氣，留置於氮正壓力下，並在回流下加熱2小時。添加另外量之Pd2 (dba)3 (7.0毫克，0.0076毫莫耳)與2,8,9－三異丁基－2,5,8,9－四氮－1－磷雙環并[3,3,3]十一烷(15毫克，0.044毫莫耳)，將反應混合物於回流下再加熱2小時。然後使混合物冷卻至室溫，並於醋酸乙酯(30毫升)與水(30毫升)之間作分液處理。以醋酸乙酯萃取水相，並以鹽水洗滌合併之有機相，以無水硫酸鎂脫水乾燥，過濾，及在減壓下蒸發。使殘留物於矽膠上藉層析純化，以2－5% MeOH/CH2 Cl2 梯度液溶離，提供標題化合物(0.0279克，21%產率)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：2.27(s,3H),4.11(s,3H),5.92(d,J＝5.15 Hz,1H),6.75－6.85(m,3H),7.02(dd,J＝8.27,0.92 Hz,1H),7.14(s,1H),7.18－7.27(m,2H),8.09(d,J＝5.15 Hz,1H),8.20(s,1H),8.77(s,1H),9.82(s,1H)；MS(ESI＋ )m/z 363.0(M＋H)＋ (ESI－ )m/z 360.9(M－H)－ .4-[4-Methyl-2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-4-ylamino)-phenylthio]-phenol The product of Example 8c ( 62.1 mg, 0.371 mmol, product of Example 6c (85.7 mg, 0.371 mmol), Pd 2 (dba) 3 (16.9 mg, 0.015 mmol), sodium tris-butoxide (89.0 mg, 0.926) Millol) and 2,8,9-triisobutyl-2,5,8,9-tetrazo-1-phosphabicyclo[3,3,3]undecane (25.4 mg, 0.0741 mmol) The mixture in toluene (3 ml) was degassed, left under a positive pressure of nitrogen and heated under reflux for 2 hours. Add another amount of Pd 2 (dba) 3 (7.0 mg, 0.0076 mmol) to 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphinobicyclo[3, 3,3]undecane (15 mg, 0.044 mmol), and the reaction mixture was heated under reflux for additional 2 hours. The mixture was then cooled to room temperature and partitioned between ethyl acetate (30 mL) and water (30 mL). The aqueous phase was extracted with EtOAc. EtOAc (EtOAc)EtOAc. The residue was purified by chromatography on silica to 2-5% MeOH / CH 2 Cl 2 eluting with a gradient, to provide the title compound (0.0279 g, 21% yield). 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 2.27 (s, 3H), 4.11 (s, 3H), 5.92 (d, J = 5.15 Hz, 1H), 6.75-6.85 (m, 3H), 7.02 (dd, J=8.27, 0.92 Hz, 1H), 7.14 (s, 1H), 7.18-7.27 (m, 2H), 8.09 (d, J = 5.15 Hz, 1H), 8.20 (s, 1H), 8.77 (s, 1H), 9.82 (s, 1H); MS (ESI + ) m/z 363.0 (M+H) + (ESI - ) m/z 360.9 (M-H) - .
4－[4－(4－甲氧基－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚實例10A 2－胺基－6－甲基－菸鹼腈於130℃下，使2－氯基－6－甲基－菸鹼腈(25克，0.164莫耳)與液態氨(250毫升)在500毫升乙醇中，於密封高壓容器中反應20小時。在真空下濃縮反應混合物，並以水(2 x 50毫升)洗滌殘留物，然後於真空烘箱中乾燥24小時，提供標題化合物，為淡黃色固體(18克，82%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：2.30(s,3H),6.52(d,J＝7.7 Hz,1H),6.78(s,2H),7.73(d,J＝7.7 Hz,1H).4-[4-(4-Methoxy-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol Example 10A 2-Amino-6-methyl-nicotinonitrile The 2-chloro-6-methyl-nicotinonitrile (25 g, 0.164 mol) was combined with liquid ammonia (250 mL) at 130 °C. The reaction was carried out in a sealed high pressure vessel for 20 hours in 500 ml of ethanol. The reaction mixture was concentrated with EtOAc EtOAc m. 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 2.30 (s, 3H), 6.52 (d, J = 7.7 Hz, 1H), 6.78 (s, 2H), 7.73 (d, J = 7.7 Hz, 1H).
實例10B N'－(3－氰基－6－甲基－吡啶－2－基)－N,N－二甲基－甲脒將實例10A之產物(10克，75.19毫莫耳)與N,N－二甲基甲醯胺二甲基縮醛(11毫升，82.71毫莫耳)在甲苯(100毫升)中之溶液於回流下加熱6小時。於冷卻至室溫後，使溶液在真空下濃縮，提供標題化合物，為黃色固體(13.78克，98%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：2.41(s,3H),3.06(s,3H),3.14(s,3H),6.87(d,J＝7.7 Hz,1H),7.89(d,J＝8.1 Hz,1H),8.59(s,1H).Example 10B N'-(3-Cyano-6-methyl-pyridin-2-yl)-N,N-dimethyl-methylhydrazine The product of Example 10A (10 g, 75.19 mmol) and N, A solution of N-dimethylformamide dimethyl acetal (11 ml, 82.71 mmol) in toluene (100 mL) was evaporated. After cooling to rt, EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 2.41 (s, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 6.87 (d, J = 7.7 Hz, 1H), 7.89 ( d, J = 8.1 Hz, 1H), 8.59 (s, 1H).
實例10C 1－氯基－4－(4－甲氧基－苄氧基)－2－硝基－苯將4－氯基－3－硝基－酚(0.5克，2.88毫莫耳)、1－氯基甲基－4－甲氧基－苯(0.496克，3.17毫莫耳)、碳酸鉀(1.19克，8.64毫莫耳)及碘化四丁基銨(0.005克，0.0135毫莫耳)在N,N－二甲基甲醯胺(5毫升)中之溶液，於室溫下攪拌16小時。然後將冰水(10毫升)添加至溶液中，並藉過濾收集所形成之固體，且在真空烘箱中乾燥，提供標題化合物(0.812克，96%)。Example 10C 1-Chloro-4-(4-methoxy-benzyloxy)-2-nitro-benzene 4-chloro-3-nitro-phenol (0.5 g, 2.88 mmol), 1 -Chloromethyl-4-methoxy-benzene (0.496 g, 3.17 mmol), potassium carbonate (1.19 g, 8.64 mmol) and tetrabutylammonium iodide (0.005 g, 0.0135 mmol) A solution of N,N-dimethylformamide (5 ml) was stirred at room temperature for 16 h. The ice water (10 mL) was then added to a solution.
實例10D 4－[4－(4－甲氧基－苄氧基)－2－硝基－苯基硫基]－酚將實例10C之產物(0.812克，2.76毫莫耳)、4－羥基硫酚(0.419，3.32毫莫耳)及碳酸銫(2.16克，6.64毫莫耳)在N,N－二甲基甲醯胺(5毫升)中之溶液加熱至100℃，歷經16小時。於冷卻至室溫後，將混合物倒入冰水(20毫升)中，並以1N鹽酸水溶液使所形成之溶液酸化。然後以醋酸乙酯(3 x 10毫升)萃取溶液，使合併之萃液以硫酸鎂脫水乾燥，過濾，及在真空下濃縮，提供標題化合物(1.06克，100%)。Example 10D 4-[4-(4-Methoxy-benzyloxy)-2-nitro-phenylthio]-phenol The product of Example 10C (0.812 g, 2.76 mmol), 4-hydroxy sulphur A solution of phenol (0.419, 3.32 mmol) and cesium carbonate (2.16 g, 6.64 mmol) in N,N-dimethylformamide (5 mL) was heated to 100 ° C for 16 h. After cooling to room temperature, the mixture was poured into ice water (20 ml), and the resulting solution was acidified with 1N aqueous hydrochloric acid. The solution was extracted with EtOAc (EtOAc (EtOAc)EtOAc.
實例10E 4－[2－胺基－4－(4－甲氧基－苄氧基)－苯基硫基]－酚將實例10D之產物(1.06克，2.76毫莫耳)、鐵粉(0.63克，11.04毫莫耳)及氯化銨(0.18克，3.31毫莫耳)在甲醇(18毫升)、四氫呋喃(18毫升)及水(6毫升)溶液中之溶液加熱至回流，歷經3小時。以甲醇(50毫升)稀釋所形成之混合物，並經過矽藻土墊過濾。使濾液在真空下濃縮成體積10毫升，以水(50毫升)稀釋溶液，並以醋酸乙酯(2 x 50毫升)萃取。使合併之萃液以硫酸鎂脫水乾燥，過濾，及在真空下濃縮，提供標題化合物(0.99克，100%)。Example 10E 4-[2-Amino-4-(4-methoxy-benzyloxy)-phenylsulfanyl]-phenol The product of Example 10D (1.06 g, 2.76 mmol), iron powder (0.63) A solution of EtOAc (1. <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; The resulting mixture was diluted with methanol (50 mL) and filtered through a pad of Celite. The filtrate was concentrated in vacuo to a volume of 10 mL, diluted with water (50 mL) andEtOAc. The combined extracts were dried with EtOAc EtOAc.
實例10F 4－[4－(4－甲氧基－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚將實例10B之產物(28.4毫克，0.151毫莫耳)與實例10E之產物(53.3毫克，0.151毫莫耳)在醋酸(1毫升)中之溶液，於預熱至130℃之油浴中攪拌20分鐘。然後使混合物冷卻至室溫，在真空下移除醋酸，並將所形成之殘留物以甲醇研製，提供標題化合物，為黃褐色固體(26.5毫克，35%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：9.92(s,1H),9.63(s,1H),8.70(d,J＝8.09 Hz,1H),8.55(s,1H),7.52(d,J＝8.46 Hz,1H),7.38(d,J＝8.82 Hz,2H),7.27(s,1H),7.06－7.18(m,3H),6.94(d,J＝8.46 Hz,3H),6.61－6.72(m,2H),5.02(s,2H),3.75(s,3H),2.66(s,3H)；MS(ESI＋)m/z 497.2(M＋H)＋,(ESI－)m/z 495.3(M－H)－.Example 10F 4-[4-(4-Methoxy-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio] - a solution of the product of Example 10B (28.4 mg, 0.151 mmol) and the product of Example 10E (53.3 mg, 0.151 mmol) in acetic acid (1 mL) in an oil bath preheated to 130 ° C Stir for 20 minutes. The mixture was then cooled to rt. EtOAc (EtOAc)EtOAc. 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 9.92 (s, 1H), 9.63 (s, 1H), 8.70 (d, J = 8.09 Hz, 1H), 8.55 (s, 1H), 7.52 ( d, J = 8.46 Hz, 1H), 7.38 (d, J = 8.82 Hz, 2H), 7.27 (s, 1H), 7.06-7.18 (m, 3H), 6.94 (d, J = 8.46 Hz, 3H), 6.61-6.72(m,2H),5.02(s,2H),3.75(s,3H),2.66(s,3H);MS(ESI+)m/z 497.2(M+H)+, (ESI-)m/z 495.3(M-H)-.
3－[4－(4－羥基－苯基硫基)－3－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基甲基]－苯甲腈3-[4-(4-Hydroxy-phenylthio)-3-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl]-benzene Nitrile
實例11A 3－[3－胺基－4－(4－羥基－苯基硫基)－苯氧基甲基]－苯甲腈使4－氯基－3－硝基－酚之溶液與3－溴基甲基－苯甲腈反應，使用實例10C中所述之條件，提供3－(4－氯基－3－硝基－苯氧基甲基)－苯甲腈，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 11A 3-[3-Amino-4-(4-hydroxy-phenylsulfanyl)-phenoxymethyl]-benzonitrile A solution of 4-chloro-3-nitro-phenol with 3- Reaction of bromomethyl-benzonitrile, using the conditions described in Example 10C, provided 3-(4-chloro-3-nitro-phenoxymethyl)-benzonitrile, which was obtained from an example The 10D and 10E programs continue processing to provide the title product.
實例11B 3－[4－(4－羥基－苯基硫基)－3－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基甲基]－苯甲腈使實例11A之產物與實例10B之產物反應，使用實例10F之程序，以實例11A之產物取代實例10E之產物，提供粗製標題化合物，使其在Waters Symmetry C8管柱上藉逆相預備HPLC(25毫米x 100毫米，7微米粒子大小)純化，使用10%至100%乙腈/0.1%三氟醋酸在水中之梯度液，歷經8分鐘(10分鐘操作時間)，於流率40毫升/分鐘下，提供標題化合物，為三氟醋酸鹽(20毫克，23%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：11.39(s,1H),9.70(s,1H),8.89(d,J＝8.46 Hz,1H),8.77(s,1H),7.92(s,1H),7.75－7.86(m,3H),7.62(t,J＝7.72 Hz,1H),7.18－7.29(m,2H),7.03－7.14(m,3H),6.55－6.69(m,2H),5.18(s,2H),2.74(s,3H)；MS(ESI＋)m/z 492.1(M＋H)＋(ESI－)m/z 490.2(M－H)－.Example 11B 3-[4-(4-Hydroxy-phenylthio)-3-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl] -benzonitrile The product of Example 11A was reacted with the product of Example 10B, using the procedure of Example 10F, substituting the product of Example 11A for the product of Example 10E to provide the crude title compound to afford reverse phase on a Waters Symmetry C8 column. Prepare HPLC (25 mm x 100 mm, 7 micron particle size) and use a gradient of 10% to 100% acetonitrile / 0.1% trifluoroacetic acid in water over 8 minutes (10 min operation time) at a flow rate of 40 ml The title compound was provided as trifluoroacetate (20 mg, 23%). 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 11.39 (s, 1H), 9.70 (s, 1H), 8.89 (d, J = 8.46 Hz, 1H), 8.77 (s, 1H), 7.92 ( s, 1H), 7.75-7.86 (m, 3H), 7.62 (t, J = 7.72 Hz, 1H), 7.18-7.29 (m, 2H), 7.03-7.14 (m, 3H), 6.55-6.69 (m, 2H), 5.18 (s, 2H), 2.74 (s, 3H); MS (ESI+) m/z 492.1 (M+H) + (ESI-) m/z 490.2 (M-H)-.
4－[2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－(吡啶－2－基甲氧基)－苯基硫基]－酚4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(pyridin-2-ylmethoxy)-phenylthio]-phenol
實例12A 4－[2－胺基－4－(吡啶－2－基甲氧基)－苯基硫基]－酚使4－氯基－3－硝基－酚之溶液與2－溴基甲基－吡啶氫溴酸鹽反應，使用實例10C中所述之條件，提供2－(4－氯基－3－硝基－苯氧基甲基)－吡啶，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 12A 4-[2-Amino-4-(pyridin-2-ylmethoxy)-phenylthio]-phenol A solution of 4-chloro-3-nitro-phenol with 2-bromomethyl The pyridine-pyridine hydrobromide reaction was carried out using the conditions described in Example 10C to provide 2-(4-chloro-3-nitro-phenoxymethyl)-pyridine, which was obtained from Examples 10D and 10E. The program continues processing to provide the title product.
實例12B 4－[2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－(吡啶－2－基甲氧基)－苯基硫基]－酚使實例12A之產物與實例10B之產物反應，使用實例10F之程序，以實例12A之產物取代實例10E之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(15毫克，17%)。1 H NMR(300 MHz,DMSO－D6 )δ ppm2.76(s,3H)5.19(s,2H)6.63(d,J＝8.82 Hz,2H)6.98－7.17(m,3H)7.20(d,J＝2.57 Hz,1H)7.22－7.30(m,1H)7.38(dd,J＝6.43,4.96 Hz,1H)7.53(d,J＝7.72 Hz,1H)7.71－7.94(m,2H)8.58(d,J＝4.04 Hz,1H)8.82(s,1H)8.93(d,J＝7.72 Hz,1H)9.71(br s,1H)11.66(br s,1H)；MS(ESI＋)m/z 468(M＋H)＋.Example 12B 4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(pyridin-2-ylmethoxy)-phenylthio]- The phenol was reacted with the product of Example </RTI><RTIID=0.0>#</</RTI></RTI> Acetate (15 mg, 17%). 1 H NMR (300 MHz, DMSO-D 6 ) δ ppm 2.76 (s, 3H) 5.19 (s, 2H) 6.63 (d, J = 8.82 Hz, 2H) 6.98-7.17 (m, 3H) 7.20 (d, J=2.57 Hz,1H)7.22-7.30(m,1H)7.38(dd,J=6.43,4.96 Hz,1H)7.53(d,J=7.72 Hz,1H)7.71-7.94(m,2H)8.58(d , J=4.04 Hz,1H)8.82(s,1H)8.93(d,J=7.72 Hz,1H)9.71(br s,1H)11.66(br s,1H);MS(ESI+)m/z 468(M+H )+.
4－[4－(4－第三－丁基－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(4-Terti-butyl-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio] -phenol
實例13A 4－[2－胺基－4－(4－第三－丁基－苄氧基)－苯基硫基]－酚使4－氯基－3－硝基－酚之溶液與1－溴基甲基－4－第三－丁基－苯反應，使用實例10C中所述之條件，提供4－(4－第三－丁基－苄氧基)－1－氯基－2－硝基－苯，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 13A 4-[2-Amino-4-(4-t-butyl-benzyloxy)-phenylsulfanyl]-phenol A solution of 4-chloro-3-nitro-phenol with 1- Reaction of bromomethyl-4-tert-butyl-benzene using the conditions described in Example 10C to provide 4-(4-tri-butyl-benzyloxy)-1-chloro-2-nitrate The base-benzene was further processed using the procedures from Examples 10D and 10E to provide the title product.
實例13B 4－[4－(4－第三－丁基－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚使實例13A之產物與實例10B之產物反應，使用實例10F之程序，以實例13A之產物取代實例10E之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(52毫克，36%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.28(s,9H)2.74(s,3H)5.06(s,2H)6.63(d,J＝8.46 Hz,2H)7.00－7.12(m,3H)7.15－7.27(m,2H)7.30－7.47(m,5H)7.79(d,J＝8.46 Hz,1H)8.77(s,1H)8.89(d,J＝8.46 Hz,1H)9.69(s,1H)；MS(ESI＋)m/z 523(M＋H)＋.Example 13B 4-[4-(4-Terti-butyl-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfide The product of Example 13A was reacted with the product of Example 10B to give the title compound as It was trifluoroacetate (52 mg, 36%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.28 (s, 9H) 2.74 (s, 3H) 5.06 (s, 2H) 6.63 (d, J = 8.46 Hz, 2H) 7.00-7.12 (m, 3H) ) 7.15-7.27(m,2H)7.30-7.47(m,5H)7.79(d,J=8.46 Hz,1H)8.77(s,1H)8.89(d,J=8.46 Hz,1H)9.69(s,1H ); MS (ESI +) m / z 523 (M + H) +.
4－[4－(2－溴－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(2-Bromo-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
實例14A 4－[2－胺基－4－(2－溴－苄氧基)－苯基硫基]－酚使4－氯基－3－硝基－酚之溶液與1－溴基－2－溴基甲基－苯反應，使用實例10C中所述之條件，提供4－(2－溴－苄氧基)－1－氯基－2－硝基－苯，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 14A 4-[2-Amino-4-(2-bromo-benzyloxy)-phenylsulfanyl]-phenol A solution of 4-chloro-3-nitro-phenol with 1-bromo-2 -Bromomethyl-benzene reaction, using the conditions described in Example 10C, provided 4-(2-bromo-benzyloxy)-1-chloro-2-nitro-benzene, which was obtained from Example 10D Continue processing with the 10E program to provide the title product.
實例14B 4－[4－(2－溴－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚使實例14A之產物與實例10B之產物反應，使用實例10F之程序，以實例14A之產物取代實例10E之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(42毫克，39%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.68(s,3H)5.13(s,2H)6.67(m,2H)6.96(d,J＝7.68 Hz,1H)7.14(m,3H)7.30(m,2H)7.44(m,1H)7.59(m,2H)7.68(d,J＝7.68 Hz,1H)8.59(s,1H)8.73(d,J＝8.09 Hz,1H)9.66(s,1H)10.27(s,1H)；MS(ESI＋)m/z 545,547(M＋H)＋.Example 14B 4-[4-(2-Bromo-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol The product of Example 14A was reacted with the product of Example <RTI ID=0.0># </ </RTI> Salt (42 mg, 39%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.68 (s, 3H) 5.13 (s, 2H) 6.67 (m, 2H) 6.96 (d, J = 7.68 Hz, 1H) 7.14 (m, 3H) 7.30 (m, 2H) 7.44 (m, 1H) 7.59 (m, 2H) 7.68 (d, J = 7.68 Hz, 1H) 8.59 (s, 1H) 8.73 (d, J = 8.09 Hz, 1H) 9.66 (s, 1H) ) 10.27 (s, 1H); MS (ESI +) m / z 545, 547 (M + H) +.
4－[4－(3－溴－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(3-Bromo-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
實例15A 4－[2－胺基－4－(3－溴－苄氧基)－苯基硫基]－酚使4－氯基－3－硝基－酚之溶液與1－溴基－3－溴基甲基－苯反應，使用實例10C中所述之條件，提供4－(3－溴－苄氧基)－1－氯基－2－硝基－苯，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 15A 4-[2-Amino-4-(3-bromo-benzyloxy)-phenylsulfanyl]-phenol A solution of 4-chloro-3-nitro-phenol with 1-bromo-3 -Bromomethyl-benzene reaction, using the conditions described in Example 10C, provided 4-(3-bromo-benzyloxy)-1-chloro-2-nitro-benzene, which was obtained from Example 10D Continue processing with the 10E program to provide the title product.
實例15B 4－[4－(3－溴－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚使實例15A之產物與實例10B之產物反應，使用實例10F之程序，以實例15A之產物取代實例10E之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(25毫克，23%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.72(s,3H)5.13(s,2H)6.65(m,2H)7.11(m,5H)7.40(m,2H)7.54(d,J＝7.72 Hz,1H)7.66(s,1H)7.72(d,J＝8.82 Hz,1H)8.71(s,1H)8.84(d,J＝8.09 Hz,1H)9.68(s,1H),11.04(m,1H)；MS(ESI＋)m/z 545,547(M＋H)＋.Example 15B 4-[4-(3-Bromo-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)phenylsulfanyl]-phenol The product of Example 15A was reacted with the product of Example </RTI><RTIID=0.0></RTI></RTI></RTI> Salt (25 mg, 23%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.72 (s, 3H) 5.13 (s, 2H) 6.65 (m, 2H) 7.11 (m, 5H) 7.40 (m, 2H) 7.54 (d, J = 7.72 Hz,1H)7.66(s,1H)7.72(d,J=8.82 Hz,1H)8.71(s,1H)8.84(d,J=8.09 Hz,1H)9.68(s,1H),11.04(m, 1H); MS (ESI+) m/z 545, 547 (M+H)+.
4－[4－(4－溴－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(4-Bromo-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
實例16A 4－[2－胺基－4－(4－溴－苄氧基)－苯基硫基]－酚使4－氯基－3－硝基－酚之溶液與1－溴基－4－溴基甲基－苯反應，使用實例10C中所述之條件，提供4－(4－溴－苄氧基)－1－氯基－2－硝基－苯，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 16A 4-[2-Amino-4-(4-bromo-benzyloxy)-phenylthio]-phenol A solution of 4-chloro-3-nitro-phenol with 1-bromo-4 -Bromomethyl-benzene reaction, using the conditions described in Example 10C, provided 4-(4-bromo-benzyloxy)-1-chloro-2-nitro-benzene, which was obtained from Example 10D Continue processing with the 10E program to provide the title product.
實例16B 4－[4－(4－溴－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚使實例16A之產物與實例10B之產物反應，使用實例10F之程序，以實例16A之產物取代實例10E之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(19毫克，17%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.72(s,3H)5.13(s,2H)6.63(m,2H)7.03(dd,J＝8.82,2.57 Hz,1H)7.10(m,2H)7.21(d,J＝8.46 Hz,2H)7.40(m,2H)7.54(d,J＝8.09 Hz,1H)7.66(s,1H)7.73(d,J＝8.46 Hz,1H)8.72(s,1H)8.84(d,J＝8.46 Hz,1H)9.69(s,1H)11.08(m,1H)；MS(ESI＋)m/z 545,547(M＋H)＋.Example 16B 4-[4-(4-Bromo-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)phenylsulfanyl]-phenol The product of Example 16A was reacted with the product of Example </RTI><RTIID=0.0>#</</RTI> Salt (19 mg, 17%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.72 (s, 3H) 5.13 (s, 2H) 6.63 (m, 2H) 7.03 (dd, J = 8.82, 2.57 Hz, 1H) 7.10 (m, 2H) ) 7.21 (d, J = 8.46 Hz, 2H) 7.40 (m, 2H) 7.54 (d, J = 8.09 Hz, 1H) 7.66 (s, 1H) 7.73 (d, J = 8.46 Hz, 1H) 8.72 (s, 1H) 8.84 (d, J = 8.46 Hz, 1H) 9.69 (s, 1H) 11.08 (m, 1H); MS (ESI+) m/z 545, 547 (M+H)+.
4－[4－(2－甲基－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(2-Methyl-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
實例17A 4－[2－胺基－4－(2－甲基－苄氧基)－苯基硫基]－酚使4－氯基－3－硝基－酚之溶液與1－溴基甲基－2－甲基－苯反應，使用實例10C中所述之條件，提供1－氯基－4－(2－甲基－苄氧基)－2－硝基－苯，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 17A 4-[2-Amino-4-(2-methyl-benzyloxy)-phenylsulfanyl]-phenol A solution of 4-chloro-3-nitro-phenol with 1-bromomethyl 2-methyl-benzene reaction, using the conditions described in Example 10C, provided 1-chloro-4-(2-methyl-benzyloxy)-2-nitro-benzene, which was obtained from The procedures of Examples 10D and 10E continue processing to provide the title product.
實例17B 4－[4－(2－甲基－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚使實例17A之產物與實例10B之產物反應，使用實例10F之程序，以實例17A之產物取代實例10E之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(35毫克，36%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.32(s,3H)2.71(s,3H)5.09(s,2H)6.65(m,2H)7.03(dd,J＝8.82,2.57 Hz,1H)7.11(m,2H)7.24(m,5H)7.41(d,J＝6.99 Hz,1H)7.69(d,J＝8.46 Hz,1H)8.69(s,1H)8.82(d,J＝8.82 Hz,1H)9.67(s,1H)10.84(s,1H)；MS(ESI＋)m/z 481(M＋H)＋.Example 17B 4-[4-(2-Methyl-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]- The phenol was reacted with the product of Example <RTI ID=0.0># </RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; Acetate (35 mg, 36%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.32 (s, 3H) 2.71 (s, 3H) 5.09 (s, 2H) 6.65 (m, 2H) 7.03 (dd, J = 8.82, 2.57 Hz, 1H 7.11 (m, 2H) 7.24 (m, 5H) 7.41 (d, J = 6.99 Hz, 1H) 7.69 (d, J = 8.46 Hz, 1H) 8.69 (s, 1H) 8.82 (d, J = 8.82 Hz, 1H) 9.67 (s, 1H) 10.84 (s, 1H); MS (ESI+) m/z 481 (M+H)+.
4－[4－(3－甲基－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(3-Methyl-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
實例18A 4－[2－胺基－4－(3－甲基－苄氧基)－苯基硫基]－酚使4－氯基－3－硝基－酚之溶液與1－溴基甲基－3－甲基－苯反應，使用實例10C中所述之條件，提供1－氯基－4－(3－甲基－苄氧基)－2－硝基－苯，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 18A 4-[2-Amino-4-(3-methyl-benzyloxy)-phenylthio]-phenol A solution of 4-chloro-3-nitro-phenol with 1-bromomethyl 3-methyl-benzene reaction, using the conditions described in Example 10C, provided 1-chloro-4-(3-methyl-benzyloxy)-2-nitro-benzene, which was obtained from The procedures of Examples 10D and 10E continue processing to provide the title product.
實例18B 4－[4－(3－甲基－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚使實例18A之產物與實例10B之產物反應，使用實例10F之程序，以實例18A之產物取代實例10E之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(37毫克，39%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.31(s,3H)2.73(s,3H)5.07(s,2H)6.64(m,2H)7.16(m,9H)7.75(d,J＝8.46 Hz,1H)8.73(s,1H)8.86(d,J＝8.46 Hz,1H)9.69(s,1H)11.16(s,1H)；MS(ESI＋)m/z 481(M＋H)＋.Example 18B 4-[4-(3-Methyl-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]- The phenol was reacted with the product of Example </RTI><RTIID=0.0>#</RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; Acetate (37 mg, 39%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.31 (s, 3H) 2.73 (s, 3H) 5.07 (s, 2H) 6.64 (m, 2H) 7.16 (m, 9H) 7.75 (d, J = 8.46 Hz,1H)8.73(s,1H)8.86(d,J=8.46 Hz,1H)9.69(s,1H)11.16(s,1H);MS(ESI+)m/z 481(M+H)+.
4－[4－(4－甲基－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(4-Methyl-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
實例19A 4－[2－胺基－4－(4－甲基－苄氧基)－苯基硫基]－酚使4－氯基－3－硝基－酚之溶液與1－溴基甲基－4－甲基－苯反應，使用實例10C中所述之條件，提供1－氯基－4－(4－甲基－苄氧基)－2－硝基－苯，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 19A 4-[2-Amino-4-(4-methyl-benzyloxy)-phenylthio]-phenol A solution of 4-chloro-3-nitro-phenol with 1-bromomethyl The benzyl-4-methyl-benzene reaction was carried out using the conditions described in Example 10C to provide 1-chloro-4-(4-methyl-benzyloxy)-2-nitro-benzene. The procedures of Examples 10D and 10E continue processing to provide the title product.
實例19B 4－[4－(4－甲基－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚使實例19A之產物與實例10B之產物反應，使用實例10F之程序，以實例19A之產物取代實例10E之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(29毫克，30%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.30(s,3H)2.67(s,3H)5.05(s,2H)6.64(m,2H)6.94(d,J＝7.38 Hz,1H)7.17(m,6H)7.33(d,J＝8.09 Hz,2H)7.56(d,J＝8.46 Hz,1H)8.57(s,1H)8.72(d,J＝8.09 Hz,1H)9.63(s,1H)10.12(s,1H)；MS(ESI＋)m/z 481(M＋H)＋.Example 19B 4-[4-(4-Methyl-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]- The phenol was reacted with the product of Example 19A to give the title compound as the title compound. Acetate (29 mg, 30%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.30 (s, 3H) 2.67 (s, 3H) 5.05 (s, 2H) 6.64 (m, 2H) 6.94 (d, J = 7.38 Hz, 1H) 7.17 (m, 6H) 7.33 (d, J = 8.09 Hz, 2H) 7.56 (d, J = 8.46 Hz, 1H) 8.57 (s, 1H) 8.72 (d, J = 8.09 Hz, 1H) 9.63 (s, 1H) 10.12(s,1H); MS(ESI+)m/z 481(M+H)+.
2－[4－(4－羥基－苯基硫基)－3－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基甲基]－苯甲腈2-[4-(4-Hydroxy-phenylsulfanyl)-3-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl]-benzene Nitrile
實例20A 2－[3－胺基－4－(4－羥基－苯基硫基)－苯氧基甲基]－苯甲腈使4－氯基－3－硝基－酚之溶液與2－溴基甲基－苯甲腈反應，使用實例10C中所述之條件，提供2－(4－氯基－3－硝基－苯氧基甲基)－苯甲腈，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 20A 2-[3-Amino-4-(4-hydroxy-phenylsulfanyl)-phenoxymethyl]-benzonitrile A solution of 4-chloro-3-nitro-phenol with 2- Reaction of bromomethyl-benzonitrile, using the conditions described in Example 10C, provided 2-(4-chloro-3-nitro-phenoxymethyl)-benzonitrile, which was obtained from an example The 10D and 10E programs continue processing to provide the title product.
實例20B 2－[4－(4－羥基－苯基硫基)－3－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基甲基]－苯甲腈使實例20A之產物與實例10B之產物反應，使用實例10F之程序，以實例20A之產物取代實例10E之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(21毫克，16%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：9.93(s,1H),9.63(s,1H),8.75(d,J＝8.46 Hz,1H),8.57(s,1H),7.60(d,J＝8.09 Hz,1H),7.38(d,J＝8.46 Hz,2H),7.27(s,1H),7.05－7.19(m,3H),6.85－7.00(m,3H),6.67(d,J＝8.82 Hz,2H),5.02(s,2H),3.75(s,3H),3.14－3.28(m,1H),1.32(d,J＝6.62 Hz,6H)；MS(ESI＋)m/z 492.2(M＋H)＋(ESI－)m/z 490.2(M－H)－.Example 20B 2-[4-(4-Hydroxy-phenylthio)-3-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl] -benzonitrile The product of Example 20A was reacted with the product of Example 10B, using the procedure of Example 10F, to give the title compound as the title compound. It was trifluoroacetate (21 mg, 16%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 9.93 (s, 1H), 9.63 (s, 1H), 8.75 (d, J = 8.46 Hz, 1H), 8.57 (s, 1H), 7.60 (d) , J=8.09 Hz, 1H), 7.38 (d, J=8.46 Hz, 2H), 7.27 (s, 1H), 7.05-7.19 (m, 3H), 6.85-7.00 (m, 3H), 6.67 (d, J = 8.82 Hz, 2H), 5.02 (s, 2H), 3.75 (s, 3H), 3.14 - 3.28 (m, 1H), 1.32 (d, J = 6.62 Hz, 6H); MS (ESI+) m/z 492.2(M+H)+(ESI-)m/z 490.2(M-H)-.
4－[4－(4－羥基－苯基硫基)－3－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基甲基]－苯甲腈4-[4-(4-Hydroxy-phenylsulfanyl)-3-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl]-benzene Nitrile
實例21A 4－[3－胺基－4－(4－羥基－苯基硫基)－苯氧基甲基]－苯甲腈使4－氯基－3－硝基－酚之溶液與4－溴基甲基－苯甲腈反應，使用實例10C中所述之條件，提供4－(4－氯基－3－硝基－苯氧基甲基)－苯甲腈，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 21A 4-[3-Amino-4-(4-hydroxy-phenylsulfanyl)-phenoxymethyl]-benzonitrile. 4-Chloro-3-nitro-phenol solution and 4- Reaction of bromomethyl-benzonitrile, using the conditions described in Example 10C, provided 4-(4-chloro-3-nitro-phenoxymethyl)-benzonitrile, which was obtained from an example The 10D and 10E programs continue processing to provide the title product.
實例21B 4－[4－(4－羥基－苯基硫基)－3－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基甲基]－苯甲腈使實例21A之產物與實例10B之產物反應，使用實例10F之程序，以實例21A之產物取代實例10E之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(15毫克，14%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：11.69(s,1H),9.72(s,1H),8.94(d,J＝8.46 Hz,1H),8.83(s,1H),7.78－7.96(m,3H),7.63(d,J＝8.46 Hz,2H),7.22－7.27(m,1H),7.18(d,J＝2.57 Hz,1H),7.06－7.13(m,3H),6.59－6.66(m,2H),5.23(s,2H),2.76(s,3H)；MS(ESI＋)m/z 492.1(M＋H)＋(ESI－)m/z 490.1(M－H)－.Example 21B 4-[4-(4-Hydroxy-phenylsulfanyl)-3-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl] -benzonitrile The product of Example 21A was reacted with the product of Example </RTI><RTIID=0.0></RTI> It was trifluoroacetate (15 mg, 14%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 11.69 (s, 1H), 9.72 (s, 1H), 8.94 (d, J = 8.46 Hz, 1H), 8.83 (s, 1H), 7.78-7.96 (m, 3H), 7.63 (d, J = 8.46 Hz, 2H), 7.22-7.27 (m, 1H), 7.18 (d, J = 2.57 Hz, 1H), 7.06-7.13 (m, 3H), 6.59- 6.66 (m, 2H), 5.23 (s, 2H), 2.76 (s, 3H); MS (ESI+) m/z 492.1 (M+H) + (ESI-) m/z 490.1 (M-H)-.
4－[4－[1－(4－溴苯基)－乙氧基]－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-[1-(4-bromophenyl)-ethoxy]-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfide Phenol
實例22A 1－溴基－4－(1－溴－乙基)－苯使1－(4－溴苯基)－乙醇(4.21克，20.9毫莫耳)在15毫升CH2 Cl2 中之溶液，與15毫升CH2 Cl2 中之1.0M PBr3 於室溫下反應4小時。藉由倒入冰中使反應淬滅，並以5% NaHCO3 水溶液調整至pH 9。以CH2 Cl2 萃取，並以Na2 SO4 脫水乾燥，過濾，及在真空下濃縮，獲得標題化合物(4.1克，75%)。Examples. 22A 1-bromo-4- (1-bromo - ethyl) - benzene 1- (4-bromophenyl) - ethanol (4.21 g, 20.9 mmol) in 15 ml of CH 2 Cl 2 solution of It was reacted with 1.0 M PBr 3 in 15 ml of CH 2 Cl 2 at room temperature for 4 hours. The reaction was poured into ice by manipulation quenched and adjusted to pH 9 to 5% NaHCO 3 aq. 2 extracted with CH 2 Cl, Na 2 SO 4 and is dried, filtered, and concentrated in vacuo to give the title compound (4.1 g, 75%).
實例22B 4－[1－(4－溴苯基)－乙氧基]－1－氯基－2－硝基－苯於80℃下，使得自實例22A之產物(995毫克，3.77毫莫耳)與4－氯基－3－硝基－酚(650毫克，3.77毫莫耳)在15毫升具有K2 CO3 之DMF(10.4克，3.77毫莫耳)中反應3小時。冷卻至室溫，並以水稀釋。以CH2 Cl2 萃取，以水洗滌四次。以Na2 SO4 脫水乾燥，過濾，及在真空下濃縮，獲得標題化合物(1.24克，92%)。Example 22B 4-[1-(4-Bromophenyl)-ethoxy]-1-chloro-2-nitro-benzene at 80 ° C to give the product from Example 22A (995 mg, 3.77 mmol) And 4-chloro-3-nitro-phenol (650 mg, 3.77 mmol) was reacted in 15 ml of DMF (10.4 g, 3.77 mmol) with K 2 CO 3 for 3 hours. Cool to room temperature and dilute with water. Extract with CH 2 Cl 2 and wash four times with water. In Na 2 SO 4 dried, filtered, and concentrated in vacuo to give the title compound (1.24 g, 92%).
實例22C 4－{4－[1－(4－溴苯基)－乙氧基]－2－硝基－苯基硫基}－酚於80℃下，使得自實例22B之產物(1.15克，3.22毫莫耳)與4－巰基－酚(403毫克，3.22毫莫耳)及K2 CO3 (890毫克，6.44毫莫耳)在25毫升DMF中反應18小時。冷卻至室溫，並倒入水中。以CH2 Cl2 萃取，並以水洗滌數次。以Na2 SO4 脫水乾燥，過濾，及在真空下濃縮，獲得標題化合物(980毫克，68%)。Example 22C 4-{4-[1-(4-Bromophenyl)-ethoxy]-2-nitro-phenylthio}-phenol at 80 ° C to give the product from Example 22B (1.15 g, 3.22 mmoles was reacted with 4-mercapto-phenol (403 mg, 3.22 mmol) and K 2 CO 3 (890 mg, 6.44 mmol) in 25 mL of DMF for 18 hours. Cool to room temperature and pour into water. Extract with CH 2 Cl 2 and wash several times with water. In Na 2 SO 4 dried, filtered, and concentrated in vacuo to give the title compound (980 mg, 68%).
實例22D 4－[2－胺基－4－(1－苯基－乙氧基)－苯基硫基]－酚使得自實例22C之產物(560毫克，1.25毫莫耳)與Fe(279毫克，5.0毫莫耳)及NH4 Cl(76毫克，1.40毫莫耳)在5毫升MeOH/5毫升THF/2.5毫升水中反應，按照得自實例10E之程序，獲得標題化合物，為固體(439毫克，84%)。Example 22D 4-[2-Amino-4-(1-phenyl-ethoxy)-phenylsulfanyl]-phenol The product from Example 22C (560 mg, 1.25 mmol) and Fe (279 mg) , 5.0 mmol) and NH 4 Cl (76 mg, 1.40 mmol) in MeOH the reaction 5 ml / 5 ml THF / 2.5 ml of water, according to the procedure from example 10E, the title compound was obtained as a solid (439 mg , 84%).
實例22E 4－[4－[1－(4－溴苯基)－乙氧基]－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚使得自實例22D之產物(204毫克，0.49毫莫耳)與得自實例10B之產物(93毫克，0.49毫莫耳)反應，按照得自實例10F之程序，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(38毫克，12%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：11.24(br s,1H)9.70(s,1H)8.83(d,J＝8.09 Hz,1H)8.74(s,1H)7.76(d,J＝8.45 Hz,1H)7.55(d,J＝8.46 Hz,2H)7.37(d,J＝8.46 Hz,2H)7.09(m,4H)6.93(dd,J＝6.62 Hz,J＝2.20 Hz,1H)6.63(d,J＝8.82 Hz,2H)5.51(q,J＝6.25 Hz,2H)2.73(s,3H),1.53(d,J＝6.25 Hz,3H)；MS(ESI＋)m/z 559,561(m,＋H－TFA)＋；(ESI－)m/z 557,559(M－H－TFA)－.Example 22E 4-[4-[1-(4-Bromophenyl)-ethoxy]-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzene The thiol]-phenol was reacted with the product from Example 22D (204 mg, 0.49 mmol) and product from Example 10B (93 mg, 0.49 mmol). The title compound was obtained from EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 11.24 (br s, 1H) 9.70 (s, 1H) 8.83 (d, J = 8.09 Hz, 1H) 8.74 (s, 1H) 7.76 (d, J = 8.45 Hz, 1H) 7.55 (d, J = 8.46 Hz, 2H) 7.37 (d, J = 8.46 Hz, 2H) 7.09 (m, 4H) 6.93 (dd, J = 6.62 Hz, J = 2.20 Hz, 1H) 6.63 (d, J = 8.82 Hz, 2H) 5.51 (q, J = 6.25 Hz, 2H) 2.73 (s, 3H), 1.53 (d, J = 6.25 Hz, 3H); MS (ESI+) m/z 559, 561 ( m,+H-TFA)+;(ESI-)m/z 557,559(M-H-TFA)-.
4－[4－[1－(4－氟苯基)－乙氧基]－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-[1-(4-Fluorophenyl)-ethoxy]-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfide Phenol
實例23A 4－{2－胺基－4－[1－(4－氟苯基)－乙氧基]－苯基硫基}－酚使用實例22A中所述之條件，使1－(4－氟苯基)－乙醇之溶液轉化成1－(1－溴－乙基)－4－氟－苯，將其使用得自實例22B－22D之程序繼續處理，提供標題產物。Example 23A 4-{2-Amino-4-[1-(4-fluorophenyl)-ethoxy]-phenylthio}-phenol Using the conditions described in Example 22A, 1-(4- A solution of fluorophenyl)-ethanol was converted to 1-(1-bromo-ethyl)-4-fluoro-benzene which was purified using the procedure from Example 22B-22D to afford the title product.
實例23B 4－[4－[1－(4－氟苯基)－乙氧基]－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚將得自實例23A之產物(207毫克，0.584毫莫耳)與得自實例10B之產物(110毫克，0.584毫莫耳)反應，按照得自實例10F之程序，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(30毫克，35%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：1.54(d,J＝6.25 Hz,3H)2.73(s,3H)5.53(q,J＝6.13 Hz,1H)6.63(d,J＝8.82 Hz,2H)6.93(dd,J＝8.82,2.57 Hz,1H)7.05－7.14(m,4H)7.18(t,J＝9.01 Hz,2H)7.41－7.49(m,2H)7.76(d,J＝8.46 Hz,1H)8.73(s,1H)8.84(d,J＝8.46 Hz,1H)9.71(s,1H)；MS(ESI＋)m/z 497(MH)－.Example 23B 4-[4-[1-(4-Fluorophenyl)-ethoxy]-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzene The thiol]-phenol was obtained by reacting the product from Example 23A (207 mg, 0.584 mmol) with the product from Example 10B (110 mg, 0.584 mmol). The title compound was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 1.54 (d, J = 6.25 Hz, 3H) 2.73 (s, 3H) 5.53 (q, J = 6.13 Hz, 1H) 6.63 (d, J = 8.82) Hz, 2H) 6.93 (dd, J = 8.82, 2.57 Hz, 1H) 7.05-7.14 (m, 4H) 7.18 (t, J = 9.01 Hz, 2H) 7.41 - 7.49 (m, 2H) 7.76 (d, J = 8.46 Hz,1H)8.73(s,1H)8.84(d,J=8.46 Hz,1H)9.71(s,1H);MS(ESI+)m/z 497(MH)-.
4－[4－[1－(3－氟苯基)－乙氧基]－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-[1-(3-fluorophenyl)-ethoxy]-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfide Phenol
實例24A 4－{2－胺基－4－[1－(3－氟苯基)－乙氧基]－苯基硫基}－酚使用實例22A中所述之條件，使1－(3－氟苯基)－乙醇之溶液轉化成1－(1－溴－乙基)－3－氟－苯，將其使用得自實例22B－22D之程序繼續處理，提供標題產物。Example 24A 4-{2-Amino-4-[1-(3-fluorophenyl)-ethoxy]-phenylthio}-phenol Using the conditions described in Example 22A, 1-(3- A solution of fluorophenyl)-ethanol was converted to 1-(1-bromo-ethyl)-3-fluoro-benzene, which was worked up using the procedure from Example 22B-22D to afford title product.
實例24B 4－[4－[1－(3－氟苯基)－乙氧基]－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚使得自實例24A之產物(226毫克，0.637毫莫耳)與得自實例10B之產物(120毫克，0.637毫莫耳)反應，按照得自實例10F之程序，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(87毫克，22%)。1 H (300 MHz,DMSO－D6)δ ppm：1.55(d,J＝6.62 Hz,3H)2.72(s,3H)5.54(q,J＝6.13 Hz,1H)6.64(d,J＝8.46 Hz,2H)6.91(dd,J＝8.82,2.57 Hz,1H)7.06－7.15(m,5H)7.20－7.28(m,2H)7.35－7.44(m,1H)7.70(d,J＝8.46 Hz,1H)8.68(s,1H)8.81(d,J＝8.46 Hz,1H)9.73(s,1H)；MS(ESI＋)m/z 499(M＋H)＋.Example 24B 4-[4-[1-(3-Fluorophenyl)-ethoxy]-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzene The thiol]-phenol was reacted with the product from Example 24A (226 mg, 0.637 mmol) from the product from Example 10B (120 mg, 0.637 mmol). The title compound was obtained from EtOAc (EtOAc) 1 H (300 MHz, DMSO-D6) δ ppm: 1.55 (d, J = 6.62 Hz, 3H) 2.72 (s, 3H) 5.54 (q, J = 6.13 Hz, 1H) 6.64 (d, J = 8.46 Hz, 2H) 6.91 (dd, J=8.82, 2.57 Hz, 1H) 7.06-7.15 (m, 5H) 7.20-7.28 (m, 2H) 7.35-7.44 (m, 1H) 7.70 (d, J = 8.46 Hz, 1H) 8.68(s,1H)8.81(d,J=8.46 Hz,1H)9.73(s,1H);MS(ESI+)m/z 499(M+H)+.
4－[4－(2－氯－噻唑－5－基甲氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(2-Chloro-thiazol-5-ylmethoxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio ]-phenol
實例25A 4－[2－胺基－4－(2－氯－噻唑－5－基甲氧基)－苯基硫基]－酚使4－氯基－3－硝基－酚之溶液與5－溴基甲基－2－氯－噻唑(根據Kim,H.－J.,Liu,S.,Keum,Y.－S.,Qing,X.J.Agric.Food Chem. 2003,51 ,1823－1830之方法製成)反應，使用實例10C中所述之條件，提供2－氯基－5－(4－氯基－3－硝基－苯氧基甲基)－噻唑，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 25A 4-[2-Amino-4-(2-chloro-thiazol-5-ylmethoxy)-phenylthio]-phenol A solution of 4-chloro-3-nitro-phenol with 5 -Bromomethyl-2-chloro-thiazole (according to Kim, H.-J., Liu, S., Keum, Y.-S., Qing, X. J. Agric. Food Chem. 2003, 51 , 1823 The method of -1830 was prepared to give 2-chloro-5-(4-chloro-3-nitro-phenoxymethyl)-thiazole using the conditions described in Example 10C. The process from Examples 10D and 10E continues processing to provide the title product.
實例25B 4－[4－(2－氯－噻唑－5－基甲氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚使實例25A之產物與實例10B之產物反應，使用實例10F之程序，以實例25A之產物取代實例10E之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.71(s,3H)5.34(s,2H)6.66(d,J＝8.46 Hz,2H)7.01(dd,J＝8.64,2.02 Hz,1H)7.06－7.28(m,4H)7.68(d,J＝8.46 Hz,1H)7.80(s,1H)8.67(s,1H)8.82(d,J＝8.46 Hz,1H)9.70(s,1H),10.81(bs1H)；MS(ESI＋)m/z 508(M＋H)＋.Example 25B 4-[4-(2-Chloro-thiazol-5-ylmethoxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl The thio]-phenol was reacted with the product of Example </RTI><RTIID=0.0>#</RTI></RTI></RTI> , is trifluoroacetate. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.71 (s, 3H) 5.34 (s, 2H) 6.66 (d, J = 8.46 Hz, 2H) 7.01 (dd, J = 8.64, 2.02 Hz, 1H) 7.06-7.28(m,4H)7.68(d,J=8.46 Hz,1H) 7.80(s,1H)8.67(s,1H)8.82(d,J=8.46 Hz,1H)9.70(s,1H),10.81 (bs1H); MS (ESI+) m/z 508 (M+H)+.
4－[2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－(3－三氟甲基－苄氧基)－苯基硫基]－酚4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(3-trifluoromethyl-benzyloxy)-phenylthio]- phenol
實例26A 4－[2－胺基－4－(3－三氟甲基－苄氧基)－苯基硫基]－酚使4－氯基－3－硝基－酚之溶液與1－氯基甲基－3－三氟甲基－苯反應，使用實例10C中所述之條件，提供1－氯基－2－硝基－4－(3－三氟甲基－苄氧基)－苯，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 26A 4-[2-Amino-4-(3-trifluoromethyl-benzyloxy)-phenylsulfanyl]-phenol A solution of 4-chloro-3-nitro-phenol with 1-chloro Reaction with methyl-3-trifluoromethyl-benzene, using the conditions described in Example 10C to provide 1-chloro-2-nitro-4-(3-trifluoromethyl-benzyloxy)-benzene It was processed using the procedures from Examples 10D and 10E to provide the title product.
實例26B 4－[2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－(3－三氟甲基－苄氧基)－苯基硫基]－酚使實例26A之產物與實例10B之產物反應，使用實例10F之程序，以實例26A之產物取代實例10E之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(9.9毫克，9%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.74(s,3H),5.22(s,2H),6.64(d,J＝8.46 Hz,2H),7.10(d,J＝8.82 Hz,3H),7.19－7.30(m,2H),7.62－7.72(m,J＝7.35 Hz,2H),7.72－7.84(m,4H),8.75(s,1H),8.88(d,J＝7.35 Hz,1H),9.69(s,1H)；MS ESI＋ m/z 535(M＋H)＋,ESI－ m/z 533(M－H)－.Example 26B 4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(3-trifluoromethyl-benzyloxy)-phenylthio The phenol was reacted with the product of Example </RTI></RTI><RTIID=0.0> Trifluoroacetate (9.9 mg, 9%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.74 (s, 3H), 5.22 (s, 2H), 6.64 (d, J = 8.46 Hz, 2H), 7.10 (d, J = 8.82 Hz, 3H ), 7.19-7.30 (m, 2H), 7.62-7.72 (m, J = 7.35 Hz, 2H), 7.72-7.84 (m, 4H), 8.75 (s, 1H), 8.88 (d, J = 7.35 Hz, 1H), 9.69 (s, 1H); MS ESI+ m/z 535 (M+H)+, ESI- m/z 533 (M-H)-.
4－[4－苄氧基－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚實例27A 4－(2－胺基－4－苄氧基－苯基硫基)－酚使4－氯基－3－硝基－酚之溶液與溴基甲基－苯反應，使用實例10C中所述之條件，提供4－苄氧基－1－氯基－2－硝基－苯，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。4-[4-Benzyloxy-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol Example 27A 4-(2-amine 4-benzyloxy-phenylthio)-phenol reacts a solution of 4-chloro-3-nitro-phenol with bromomethyl-benzene using the conditions described in Example 10C to provide 4- Benzyloxy-1-chloro-2-nitro-benzene, which was further processed using procedures from Examples 10D and 10E afforded the title product.
實例27B 4－[4－苄氧基－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚使實例27A之產物與實例10B之產物反應，使用實例10F之程序，以實例27A之產物取代實例10E之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(73毫克，25%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.70(s,3H)5.11(s,2H)6.65(d,J＝8.46 Hz,2H)6.98(d,J＝7.72 Hz,1H)7.10(d,J＝8.46 Hz,2H)7.18(d,J＝8.46 Hz,1H)7.24(s,1H)7.28－7.51(m,5H)7.63(d,J＝8.82 Hz,1H)8.64(s,1H)8.78(d,J＝8.82 Hz,1H)9.65(s,1H)10.56(br s,1H)；MS(ESI＋)m/z 467(M＋H)＋.Example 27B 4-[4-Benzyloxy-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol gave the product of Example 27A The product of Example 10B was taken from the titled compound from EtOAc (EtOAc) %). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.70 (s, 3H) 5.11 (s, 2H) 6.65 (d, J = 8.46 Hz, 2H) 6.98 (d, J = 7.72 Hz, 1H) 7.10 ( d, J = 8.46 Hz, 2H) 7.18 (d, J = 8.46 Hz, 1H) 7.24 (s, 1H) 7.28 - 7.51 (m, 5H) 7.63 (d, J = 8.82 Hz, 1H) 8.64 (s, 1H) 8.78 (d, J = 8.82 Hz, 1H) 9.65 (s, 1H) 10.56 (br s, 1H); MS (ESI+) m/z 467 (M+H)+.
4－[4－(3－氟－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－“苯基硫基]－酚4-[4-(3-Fluoro-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-"phenylthio]-phenol
實例28A 4－[2－胺基－4－(3－氟－苄氧基)－苯基硫基]－酚使4－氯基－3－硝基－酚之溶液與1－溴基甲基－3－氟－苯反應，使用實例10C中所述之條件，提供1－氯基－4－(3－氟－苄氧基)－2－硝基－苯，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 28A 4-[2-Amino-4-(3-fluoro-benzyloxy)-phenylthio]-phenol A solution of 4-chloro-3-nitro-phenol with 1-bromomethyl 3-fluoro-benzene reaction, using the conditions described in Example 10C, provided 1-chloro-4-(3-fluoro-benzyloxy)-2-nitro-benzene, which was obtained from Example 10D. The 10E program continues to process and provides the title product.
實例28B 4－[4－(3－氟－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－“苯基硫基]－酚使實例28A之產物與實例10B之產物反應，使用實例10F之程序，以實例28A之產物取代實例10E之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(41毫克，42%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.72(s,3H)5.14(s,2H)6.65(m,2H)7.02(dd,J＝8.64,2.76 Hz,1H)7.10(m,2H)7.23(m,5H)7.44(m,1H)7.71(d,J＝8.46 Hz,1H)8.69(s,1H)8.83(d,J＝8.46 Hz,1H)9.69(s,1H)10.96(s,1H)；MS(ESI＋)m/z 485(M＋H)＋.Example 28B 4-[4-(3-Fluoro-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-"phenylthio]- The phenol was reacted with the product of Example </RTI><RTIID=0.0>#</RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; acetate (41 mg, 42%) 1 H NMR ( 300 MHz, DMSO-D6) δ ppm:. 2.72 (s, 3H) 5.14 (s, 2H) 6.65 (m, 2H) 7.02 (dd, J = 8.64, 2.76 Hz,1H)7.10(m,2H)7.23(m,5H)7.44(m,1H)7.71(d,J=8.46 Hz,1H)8.69(s,1H)8.83(d,J=8.46 Hz,1H ) 9.69 (s, 1H) 10.96 (s, 1H); MS (ESI +) m / z 485 (M + H) +.
4－[2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－(四氫－呋喃－2－基甲氧基)－苯基硫基]－酚4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(tetrahydro-furan-2-ylmethoxy)-phenylthio] -phenol
實例29A 4－[2－胺基－4－(四氫－呋喃－2－基甲氧基)－苯基硫基]－酚使4－氯基－3－硝基－酚之溶液與2－溴基甲基－四氫－呋喃反應，使用實例10C中所述之條件，提供2－(4－氯基－3－硝基－苯氧基甲基)－四氫－呋喃，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 29A 4-[2-Amino-4-(tetrahydro-furan-2-ylmethoxy)-phenylthio]-phenol A solution of 4-chloro-3-nitro-phenol with 2- Reaction with bromomethyl-tetrahydro-furan, using the conditions described in Example 10C, provided 2-(4-chloro-3-nitro-phenoxymethyl)-tetrahydro-furan, which was used The process from Examples 10D and 10E continues processing to provide the title product.
實例29B 4－[2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－(四氫－呋喃－2－基甲氧基)－苯基硫基]－酚使實例29A之產物與實例10B之產物反應，使用實例10F之程序，以實例29A之產物取代實例10E之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(29毫克，17%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.55－1.84(m,1H)1.84－2.07(m,1H)2.67(s,3H)3.59－3.71(m,2H)3.73－3.83(m,1H)3.85－4.02(m,2H)4.15(dd,J＝6.43,4.23 Hz,2H)6.66(d,J＝8.46 Hz,2H)6.87(dd,J＝8.64,2.76 Hz,1H)7.02－7.15(m,2H)7.12－7.24(m,2H)7.53(d,J＝8.46 Hz,1H)8.56(s,1H)8.71(d,J＝8.46 Hz,1H)9.62(s,1H)9.92(s,1H)；MS(ESI＋)m/z 461(M＋H)＋.Example 29B 4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(tetrahydro-furan-2-ylmethoxy)-phenylsulfide The product of Example 29A was reacted with the product of Example </RTI><RTIID=0.0>#</RTI> It was trifluoroacetate (29 mg, 17%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.55-1.84 (m, 1H): s.sup.1, s. 1H) 3.85-4.02 (m, 2H) 4.15 (dd, J = 6.43, 4.23 Hz, 2H) 6.66 (d, J = 8.46 Hz, 2H) 6.87 (dd, J = 8.64, 2.76 Hz, 1H) 7.02-7.15 (m,2H)7.12-7.24(m,2H)7.53(d,J=8.46 Hz,1H)8.56(s,1H)8.71(d,J=8.46 Hz,1H)9.62(s,1H)9.92(s ,1H);MS(ESI+)m/z 461(M+H)+.
4－[2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－(萘－1－基甲氧基)－苯基硫基]－酚4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(naphthalen-1-ylmethoxy)-phenylthio]-phenol
實例30A 4－[2－胺基－4－(萘－1－基甲氧基)－苯基硫基]－酚使4－氯基－3－硝基－酚之溶液與1－氯基甲基－萘反應，使用實例10C中所述之條件，提供1－(4－氯基－3－硝基－苯氧基甲基)－萘，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 30A 4-[2-Amino-4-(naphthalen-1-ylmethoxy)-phenylsulfanyl]-phenol A solution of 4-chloro-3-nitro-phenol with 1-chloromethyl The quinone-naphthalene reaction, using the conditions described in Example 10C, provided 1-(4-chloro-3-nitro-phenoxymethyl)-naphthalene, which was processed using the procedures from Examples 10D and 10E. , providing the title product.
實例30B 4－[2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－(萘－1－基甲氧基)－苯基硫基]－酚使實例30A之產物與實例10B之產物反應，使用實例10F之程序，以實例30A之產物取代實例10E之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(31毫克，25%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.68(s,3H)5.56(s,2H)6.67(d,J＝8.82 Hz,2H)7.01－7.16(m,3H)7.16－7.24(m,1H)7.35(s,1H)7.45－7.64(m,4H)7.69(d,J＝6.62 Hz,1H)7.87－8.02(m,2H)8.05－8.14(m,1H)8.59(s,1H)8.74(d,J＝8.46 Hz,1H)9.65(s,1H)10.23(s,1H)；MS(ESI＋)517(M＋H)＋.Example 30B 4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(naphthalen-1-ylmethoxy)-phenylthio]- The phenol was reacted with the product of Example </RTI><RTIID=0.0>#</RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; Acetate (31 mg, 25%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.68 (s, 3H) 5.56 (s, 2H) 6.67 (d, J = 8.82 Hz, 2H) 7.01-7.16 (m, 3H) 7.16-7.24 (m ,1H)7.35(s,1H)7.45-7.64(m,4H)7.69(d,J=6.62 Hz,1H)7.87-8.02(m,2H)8.05-8.14(m,1H)8.59(s,1H) 8.74 (d, J = 8.46 Hz, 1H) 9.65 (s, 1H) 10.23 (s, 1H); MS (ESI+) 517 (M+H) +.
4－[4－(3－甲氧基－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(3-Methoxy-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
實例31A 4－[2－胺基－4－(3－甲氧基－苄氧基)－苯基硫基]－酚使4－氯基－3－硝基－酚之溶液與1－氯基甲基－3－甲氧基－苯反應，使用實例10C中所述之條件，提供1－氯基－4－(3－甲氧基－苄氧基)－2－硝基－苯，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 31A 4-[2-Amino-4-(3-methoxy-benzyloxy)-phenylthio]-phenol A solution of 4-chloro-3-nitro-phenol with 1-chloro Methyl-3-methoxy-benzene reaction, using the conditions described in Example 10C, provided 1-chloro-4-(3-methoxy-benzyloxy)-2-nitro-benzene, Processing was continued using the procedures from Examples 10D and 10E to provide the title product.
實例31B 4－[4－(3－甲氧基－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚使實例31A之產物與實例10B之產物反應，使用實例10F之程序，以實例31A之產物取代實例10E之產物，提供固體，將其以甲醇研製，提供標題化合物(24毫克，26%)。1 H NMR(300 MHz,DMSO－D6)δ ppm 9.93(s,1H),9.63(s,1H),8.71(d,J＝8.09 Hz,1H),8.55(s,1H),7.53(d,J＝8.09 Hz,1H),7.26－7.35(m,2H),7.15(d,J＝8.46 Hz,1H),7.07－7.13(m,2H),6.98－7.04(m,J＝5.15 Hz,2H),6.96(s,1H),6.90(dd,J＝8.09,2.57 Hz,1H),6.62－6.71(m,2H),5.08(s,2H),3.75(s,3H),2.67(s,3H)；MS(ESI＋)m/z 497.2(M＋H)＋(ESI－)m/z 495.2(M－H)－.Example 31B 4-[4-(3-Methoxy-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio] - phenol The product of Example 31A was reacted with the product of Example </RTI><RTIID=0.0>#</RTI></RTI></RTI></RTI></RTI></RTI></RTI> . 1 H NMR (300 MHz, DMSO-D6) δ ppm 9.93 (s, 1H), 9.63 (s, 1H), 8.71 (d, J = 8.09 Hz, 1H), 8.55 (s, 1H), 7.53 (d, J=8.09 Hz, 1H), 7.26-7.35 (m, 2H), 7.15 (d, J = 8.46 Hz, 1H), 7.07-7.13 (m, 2H), 6.98-7.04 (m, J = 5.15 Hz, 2H) ), 6.96 (s, 1H), 6.90 (dd, J = 8.09, 2.57 Hz, 1H), 6.62-6.71 (m, 2H), 5.08 (s, 2H), 3.75 (s, 3H), 2.67 (s, 3H); MS (ESI+) m/z 497.2 (M+H) + (ESI-) m/z 495.2 (M-H)-.
4－[2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－(喹啉－2－基甲氧基)－苯基硫基]－酚4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(quinolin-2-ylmethoxy)-phenylthio]-phenol
實例32A 4－[2－胺基－4－(喹啉－2－基甲氧基)－苯基硫基]－酚使4－氯基－3－硝基－酚之溶液與2－氯基甲基－喹啉鹽酸鹽反應，使用實例10C中所述之條件，提供2－(4－氯基－3－硝基－苯氧基甲基)－喹啉，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 32A 4-[2-Amino-4-(quinolin-2-ylmethoxy)-phenylsulfanyl]-phenol A solution of 4-chloro-3-nitro-phenol with 2-chloro Methyl-quinoline hydrochloride reaction, using the conditions described in Example 10C, provided 2-(4-chloro-3-nitro-phenoxymethyl)-quinoline, which was obtained from Example 10D Continue processing with the 10E program to provide the title product.
實例32B 4－[2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－(喹啉－2－基甲氧基)－苯基硫基]－酚使實例32A之產物與實例10B之產物反應，使用實例10F之程序，以實例32A之產物取代實例10E之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(13毫克，27%)。1 H NMR(500 MHz,DMSO－D6)δ ppm：2.75(s,3H)5.39(s,2H)6.62(d,J＝8.54 Hz,2H)7.09(d,J＝8.54 Hz,2H)7.14(dd,J＝8.54,2.44 Hz,1H)7.22－7.28(m,2H)7.63(t,J＝7.93 Hz,1H)7.68(d,J＝8.54 Hz,1H)7.74－7.81(m,1H)7.83(d,J＝8.54 Hz,1H)8.00(t,J＝7.93 Hz,2H)8.44(d,J＝8.54 Hz,1H)8.76(s,1H)8.92(d,J＝8.54 Hz,1H)9.68(s,1H)11.64(br s,1H)；MS(ESI＋)518(M＋H)＋.Example 32B 4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(quinolin-2-ylmethoxy)-phenylthio] The phenol was reacted with the product of Example </RTI><RTIID=0.0>#</RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI> Fluoroacetate (13 mg, 27%). 1 H NMR (500 MHz, DMSO-D6) δ ppm: 2.75 (s, 3H) 5.39 (s, 2H) 6.62 (d, J = 8.54 Hz, 2H) 7.09 (d, J = 8.54 Hz, 2H) 7.14 ( Dd,J=8.54,2.44 Hz,1H)7.22-7.28(m,2H)7.63(t,J=7.93 Hz,1H)7.68(d,J=8.54 Hz,1H)7.74-7.81(m,1H)7.83 (d, J = 8.54 Hz, 1H) 8.00 (t, J = 7.93 Hz, 2H) 8.44 (d, J = 8.54 Hz, 1H) 8.76 (s, 1H) 8.92 (d, J = 8.54 Hz, 1H) 9.68 (s, 1H) 11.64 (br s, 1H); MS (ESI+) 518 (M+H) +.
4－[4－(聯苯－4－基甲氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚將實例16B之產物(自由態鹽形式，0.055克，0.1毫莫耳)、苯基二羥基硼烷(0.017克，0.14毫莫耳)、碳酸銫(0.05克，0.15毫莫耳)及二氯雙(三苯膦)鈀(II)(0.007克，0.01毫莫耳)在N,N－二甲基甲醯胺(1毫升)中合併，並加熱至100℃，歷經24小時。於冷卻至室溫後，將混合物倒入冰水(20毫升)中，並以1N鹽酸水溶液使所形成之溶液酸化。然後以醋酸乙酯(3 x 10毫升)萃取溶液，使合併之萃液以硫酸鈉脫水乾燥，過濾，及在真空下濃縮。使粗產物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(10毫克，15%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.67(s,3H),5.16(s,2H),6.60－6.72(m,2H),6.98(d,J＝8.09 Hz,1H),7.06－7.22(m,3H),7.27－7.41(m,2H),7.47(t,J＝7.54 Hz,2H),7.54(d,J＝8.46 Hz,3H),7.60－7.73(m,4H),8.58(s,1H),8.72(d,J＝8.09 Hz,1H),9.64(s,1H),10.08(s,1H)；MS(ESI＋)m/z 543(M＋H＋)＋.4-[4-(biphenyl-4-ylmethoxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol The product of Example 16B (free salt form, 0.055 g, 0.1 mmol), phenyldihydroxyborane (0.017 g, 0.14 mmol), cesium carbonate (0.05 g, 0.15 mmol) and dichloro Bis(triphenylphosphine)palladium(II) (0.007 g, 0.01 mmol) was combined in N,N-dimethylformamide (1 mL) and heated to 100 ° C for 24 hours. After cooling to room temperature, the mixture was poured into ice water (20 ml), and the resulting solution was acidified with 1N aqueous hydrochloric acid. The solution was then extracted with ethyl acetate (3 x 10 mL). The crude product was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.67 (s, 3H), 5.16 (s, 2H), 6.60-6.72 (m, 2H), 6.98 (d, J = 8.09 Hz, 1H), 7.06 -7.22 (m, 3H), 7.27-7.41 (m, 2H), 7.47 (t, J = 7.54 Hz, 2H), 7.54 (d, J = 8.46 Hz, 3H), 7.60-7.73 (m, 4H), 8.58(s,1H), 8.72(d,J=8.09 Hz,1H), 9.64(s,1H), 10.08(s,1H);MS(ESI+)m/z 543(M+H+)+.
4－[4－(5－氯－噻吩－2－基甲氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(5-Chloro-thiophen-2-ylmethoxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio ]-phenol
實例34A 4－[2－胺基－4－(5－氯－噻吩－2－基甲氧基)－苯基硫基]－酚使4－氯基－3－硝基－酚之溶液與2－氯基－5－氯基甲基－噻吩反應，使用實例10C中所述之條件，提供2－氯基－5－(4－氯基－3－硝基－苯氧基甲基)－噻吩，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 34A 4-[2-Amino-4-(5-chloro-thiophen-2-ylmethoxy)-phenylthio]-phenol A solution of 4-chloro-3-nitro-phenol with 2 -Chloro-5-chloromethyl-thiophene reaction, using the conditions described in Example 10C to provide 2-chloro-5-(4-chloro-3-nitro-phenoxymethyl)-thiophene It was processed using the procedures from Examples 10D and 10E to provide the title product.
實例34B 4－[4－(5－氯－噻吩－2－基甲氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚苯基硫基]－酚使實例34A之產物與實例10B之產物反應，使用實例10F之程序，以實例34A之產物取代實例10E之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(6.6毫克，10%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.72(s,3H)5.25(s,2H)6.65(d,J＝8.46 Hz,2H)6.97－7.14(m,4H)7.19(d,J＝8.46 Hz,2H)7.72(d,J＝8.09 Hz,1H)8.71(s,1H)8.84(d,J＝8.46 Hz,1H)9.69(s,1H)11.01(br s,1H)；MS(ESI＋)m/z 543(M＋H)＋.Example 34B 4-[4-(5-Chloro-thiophen-2-ylmethoxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl The thiol]-phenol phenyl thio]-phenol was reacted with the product of Example </RTI></RTI></RTI><RTIID=0.0> Purified by TFA to provide the title compound as EtOAc. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.72 (s, 3H) 5.25 (s, 2H) 6.65 (d, J = 8.46 Hz, 2H) 6.97-7.14 (m, 4H) 7.19 (d, J =8.46 Hz, 2H) 7.72 (d, J = 8.09 Hz, 1H) 8.71 (s, 1H) 8.84 (d, J = 8.46 Hz, 1H) 9.69 (s, 1H) 11.01 (br s, 1H); MS ( ESI+)m/z 543(M+H)+.
4－[4－(4－氟－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(4-Fluoro-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
實例35A 4－[2－胺基－4－(4－氟－苄氧基)－苯基硫基]－酚使4－氯基－3－硝基－酚之溶液與1－溴基甲基－4－氟－苯反應，使用實例10C中所述之條件，提供1－氯基－4－(4－氟－苄氧基)－2－硝基－苯，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 35A 4-[2-Amino-4-(4-fluoro-benzyloxy)-phenylthio]-phenol A solution of 4-chloro-3-nitro-phenol with 1-bromomethyl 4-fluoro-benzene reaction, using the conditions described in Example 10C, provided 1-chloro-4-(4-fluoro-benzyloxy)-2-nitro-benzene, which was obtained from Example 10D. The 10E program continues to process and provides the title product.
實例35B 4－[4－(4－氟－苄氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚使實例35A之產物與實例10B之產物反應，使用實例10F之程序，以實例35A之產物取代實例10E之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(40毫克，41%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.69(s,3H)5.09(s,2H)6.65(m,2H)6.97(dd,J＝8.64,2.39 Hz,1H)7.09(m,2H)7.21(m,4H)7.50(m,2H)7.61(d,J＝8.46 Hz,1H)8.61(s,1H)8.75(d,J＝8.46 Hz,1H)9.65(s,1H)10.41(s,1H)；MS(ESI＋)m/z 485(M＋H)＋.Example 35B 4-[4-(4-Fluoro-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol The product of Example </RTI><RTIID=0.0></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; Salt (40 mg, 41%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.69 (s, 3H) 5.09 (s, 2H) 6.65 (m, 2H) 6.97 (dd, J = 8.64, 2.39 Hz, 1H) 7.09 (m, 2H) 7.21(m,4H)7.50(m,2H)7.61(d,J=8.46 Hz,1H)8.61(s,1H)8.75(d,J=8.46 Hz,1H)9.65(s,1H)10.41(s ,1H);MS(ESI+)m/z 485(M+H)+.
3－[4－(4－羥基－苯基硫基)－3－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基甲基]－苯甲腈3-[4-(4-Hydroxy-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl]- Benzoonitrile
實例36A 4－甲基－3－酮基－戊醛鈉鹽將裝有25－毫升添液漏斗之經火焰乾燥過之100－毫升燒瓶以氮氣滌氣，並添加無水***(40毫升)，接著添加鈉絲條(1.65克，0.0725莫耳)。使反應混合物冷卻至冰/水浴溫度，並在0℃下，慢慢逐滴添加甲基異丙基酮(6.244克，0.0725莫耳)與甲酸乙酯(5.481克，0.0725莫耳)在無水***(5毫升)中之溶液，歷經1.5小時。在添加完成後，移除冷卻浴，並將反應混合物於室溫下攪拌過夜。然後添加另外之醚(10毫升)，以使所形成之沉澱物破碎，並藉真空過濾迅速單離固體。以少量之醚沖洗固體，接著在真空中乾燥器中乾燥一小時，提供標題產物，為灰白色固體(5.35克，54%產率)。將此物質用於下一步驟，無需進一步純化。Example 36A 4-methyl-3-keto-valeraldehyde sodium salt A flame-dried 100-ml flask equipped with a 25-mL addition funnel was purged with nitrogen and anhydrous diethyl ether (40 mL) was then added. Add sodium silk (1.65 g, 0.0725 mol). The reaction mixture was cooled to ice/water bath temperature and methyl isopropyl ketone (6.244 g, 0.0725 mol) and ethyl formate (5.481 g, 0.0725 mol) in anhydrous ether were slowly added dropwise at 0 °C. The solution in (5 ml) was passed over 1.5 hours. After the addition was complete, the cooling bath was removed and the reaction mixture was stirred at room temperature overnight. Additional ether (10 mL) was then added to break up the formed precipitate and rapidly separate the solid by vacuum filtration. The solid was washed with a small portion of EtOAc (EtOAc). This material was used in the next step without further purification.
實例36B 6－異丙基－2－酮基1,2－二氫－吡啶－3－甲腈將實例36A之產物(5.35克，0.0393莫耳)與2－氰基乙醯胺(3.47克，0.0413莫耳)在水(35毫升)中之溶液，於室溫下攪拌10分鐘。於此混合物中，添加2.5毫升儲備六氫吡啶醋酸鹽溶液(製自9.8毫升六氫吡啶、6毫升醋酸及10毫升水)，並將溶液於回流下加熱2小時。然後使混合物冷卻至室溫，並藉由添加冰醋酸帶至pH 4。藉真空過濾單離所形成之淡黃色固體，以水(2 x 30毫升)沖洗，並在真空下乾燥，提供標題產物(4.36克，68%)。Example 36B 6-Isopropyl-2-keto 1,2-dihydro-pyridine-3-carbonitrile The product of Example 36A (5.35 g, 0.0393 m) and 2-cyanoacetamide (3.47 g, A solution of 0.0413 moles in water (35 mL) was stirred at room temperature for 10 min. To this mixture, 2.5 ml of a stock solution of hexahydropyridine salt (from 9.8 ml of hexahydropyridine, 6 ml of acetic acid and 10 ml of water) was added, and the solution was heated under reflux for 2 hours. The mixture was then allowed to cool to room temperature and brought to pH 4 by the addition of glacial acetic acid. The resulting pale yellow solid was isolated by EtOAc (EtOAc) (EtOAc)
實例36C 2－溴基－6－異丙基－菸鹼腈於實例36B之產物(4.35克，0.0269莫耳)、第三丁基溴化銨(10.4克，0.0323莫耳)及五氧化二磷(8.01克，1.05莫耳)在甲苯(80毫升)中之溶液內，於回流下加熱5小時。然後使反應混合物冷卻至室溫，添加水(80毫升)，並將混合物在室溫下攪拌2小時。以甲苯(20毫升)稀釋反應混合物，並分離有機層。以甲苯(50毫升)洗滌水層，並以鹽水(50毫升)洗滌合併之有機層，以無水硫酸鎂脫水乾燥，過濾，及在真空下濃縮，提供標題產物，為黃色油(5.64克，93%)。Example 36C 2-Bromo-6-isopropyl-nicotinonitrile The product of Example 36B (4.35 g, 0.0269 m), <RTI ID=0.0> (8.01 g, 1.05 mol) in a solution of toluene (80 mL). The reaction mixture was then cooled to room temperature, water (EtOAc) was evaporated. The reaction mixture was diluted with toluene (20 mL) and organic layer was separated. The aqueous layer was washed with EtOAc EtOAc (EtOAc (EtOAc) %).
實例36D 2－胺基－6－異丙基－菸鹼腈使實例36C之產物(21克，0.093莫耳)與液態氨(250毫升)在500毫升乙醇中之溶液，於密封高壓容器中，在130℃下反應20小時。在真空下濃縮反應混合物，並將殘留物研磨成微細粉末，然後以水(2 x 50毫升)洗滌，及在真空烘箱中乾燥24小時，提供標題化合物，為米黃色固體(14克，93%)。Example 36D 2-Amino-6-isopropyl-nicotinic nitrile A solution of the product of Example 36C (21 g, 0.093 m) and liquid ammonia (250 mL) in 500 mL of ethanol, in a sealed high pressure vessel, The reaction was carried out at 130 ° C for 20 hours. The reaction mixture was concentrated with EtOAc (EtOAc m. ).
實例36E N'－(3－氰基－6－異丙基－吡啶－2－基)－N－N－二甲基－甲脒將實例36D之產物(7.1克，0.044莫耳)與N,N－二甲基甲醯胺二甲基縮醛(6.44毫升，0.0484莫耳)在甲苯(100毫升)中之溶液，於回流下加熱3小時。使所形成之溶液冷卻至室溫，並在真空下濃縮，提供標題化合物(9.5克，100%)，為濃稠褐色油，其在靜置時固化。雖然藉由NMR顯示此物質為純的，但其含有少量高度帶有顏色之雜質。可使其在矽膠上層析(醋酸乙酯/己烷梯度液)，提供微黃色油，其在靜置時固化(約70%自層析回收)。Example 36E N'-(3-Cyano-6-isopropyl-pyridin-2-yl)-N-N-dimethyl-methylhydrazine The product of Example 36D (7.1 g, 0.044 m) and N, A solution of N-dimethylformamide dimethyl acetal (6.44 mL, 0.0484 mol) in toluene (100 mL). The resulting solution was cooled to room temperature and concentrated in vacuo to afford title compound (l. Although this material was shown to be pure by NMR, it contained a small amount of highly colored impurities. It was chromatographed on silica gel (ethyl acetate/hexane gradient) to provide a slightly yellow oil which solidified upon standing (about 70% from chromatography).
實例36F 3－(4－氯基－3－硝基－苯氧基甲基)－苯甲腈標題化合物係根據實例10C之程序，以3－溴基甲基－苯甲腈取代1－氯基甲基－4－甲氧基－苯而製成(0.813克，98%)。Example 36F 3-(4-Chloro-3-nitro-phenoxymethyl)-benzonitrile The title compound was replaced by 3-bromomethyl-benzonitrile in the procedure of Example 10C. Made of methyl-4-methoxy-benzene (0.813 g, 98%).
實例36G 3－[4－(4－羥基－苯基硫基)－3－硝基－苯氧基甲基]－苯甲腈標題化合物係根據實例10D之程序，以3－(4－氯基－3－硝基－苯氧基甲基)－苯甲腈取代1－氯基－4－(4－甲氧基－苄氧基)－2－硝基－苯而製成(1.07克，100%)。Example 36G 3-[4-(4-Hydroxy-phenylsulfanyl)-3-nitro-phenoxymethyl]-benzonitrile The title compound was obtained according to the procedure of Example 10D. -3-Nitro-phenoxymethyl)-benzonitrile is substituted for 1-chloro-4-(4-methoxy-benzyloxy)-2-nitro-benzene (1.07 g, 100 %).
實例36H 3－[3－胺基－4－(4－羥基－苯基硫基)－苯氧基甲基]－苯甲腈標題化合物係根據實例10E之程序，以3－[4－(4－羥基－苯基硫基)－3－硝基－苯氧基甲基]－苯甲腈取代4－[4－(4－甲氧基－苄氧基)－2－硝基－苯基硫基]－酚而製成(0.97克，98%)。Example 36H 3-[3-Amino-4-(4-hydroxy-phenylsulfanyl)-phenoxymethyl]-benzonitrile The title compound was obtained according to the procedure of Example 10E to 3-[4-(4 -Hydroxy-phenylthio)-3-nitro-phenoxymethyl]-benzonitrile substituted 4-[4-(4-methoxy-benzyloxy)-2-nitro-phenylsulfide Made of phenol - (0.97 g, 98%).
實例36I 3－[4－(4－羥基－苯基硫基)－3－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基甲基]－苯甲腈將實例36E之產物(47.4毫克，0.219毫莫耳)與實例36H之產物(76.3毫克，0.219毫莫耳)在醋酸(1毫升)中之溶液，於預熱至130℃之油浴中攪拌15分鐘。然後使混合物冷卻至室溫，在真空下移除醋酸，並使所形成之殘留物於Waters Symmetry C8管柱上藉逆相預備HPLC(25毫米x 100毫米，7微米粒子大小)純化，使用10%至100%乙腈/0.1%三氟醋酸在水中之梯度液，歷經8分鐘(10分鐘操作時間)，於流率40毫升/分鐘下，提供標題化合物，為三氟醋酸鹽(14毫克，10%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：10.94(s,1H),9.69(s,1H),8.88(d,J＝8.46 Hz,1H),8.70(s,1H),7.92(s,1H),7.72－7.87(m,3H),7.62(t,J＝7.72 Hz,1H),7.15－7.28(m,J＝8.82 Hz,2H),7.08－7.15(m,2H),6.99－7.06(m,1H),6.61－6.72(m,2H),5.18(s,2H),3.19－3.30(m,1H),1.34(d,J＝6.99 Hz,6H)；MS(ESI)m/z 520.3(M＋H)＋,(ESI－)m/z 518.3(M－H)－.Example 36I 3-[4-(4-Hydroxy-phenylthio)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl - Benzoonitrile A solution of the product of Example 36E (47.4 mg, 0.219 mmol) and product of Example 36H (76.3 mg, 0.219 mmol) in acetic acid (1 mL), preheated to 130 ° C Stir in the oil bath for 15 minutes. The mixture was then allowed to cool to room temperature, the acetic acid was removed under vacuum, and the residue formed was purified on a Waters Symmetry C8 column by reverse phase preparative HPLC (25 mm x 100 mm, 7 micron particle size) using 10 A gradient of % to 100% acetonitrile / 0.1% trifluoroacetic acid in water over 8 min (10 mins). %). 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 10.94 (s, 1H), 9.69 (s, 1H), 8.88 (d, J = 8.46 Hz, 1H), 8.70 (s, 1H), 7.92 ( s, 1H), 7.72-7.87 (m, 3H), 7.62 (t, J = 7.72 Hz, 1H), 7.15-7.28 (m, J = 8.82 Hz, 2H), 7.08-7.15 (m, 2H), 6.99 -7.06 (m, 1H), 6.61-6.72 (m, 2H), 5.18 (s, 2H), 3.19-3.30 (m, 1H), 1.34 (d, J = 6.99 Hz, 6H); MS (ESI) m /z 520.3(M+H)+, (ESI-)m/z 518.3(M-H)-.
4－[2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－(2－甲氧基－苄氧基)－苯基硫基]－酚4-[2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(2-methoxy-benzyloxy)-phenylthio]- phenol
實例37A 4－[2－胺基－4－(2－甲氧基－苄氧基)－苯基硫基]－酚使4－氯基－3－硝基－酚之溶液與1－溴基甲基－2－甲基－苯反應，使用實例10C中所述之條件，提供1－氯基－4－(2－甲基－苄氧基)－2－硝基－苯，將其使用得自實例10D與10E之程序繼續處理，提供標題產物。Example 37A 4-[2-Amino-4-(2-methoxy-benzyloxy)-phenylthio]-phenol A solution of 4-chloro-3-nitro-phenol with 1-bromo Methyl-2-methyl-benzene reaction, using the conditions described in Example 10C, provided 1-chloro-4-(2-methyl-benzyloxy)-2-nitro-benzene, which was used The process from Examples 10D and 10E continues processing to provide the title product.
實例37B 4－[2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－(2－甲氧基－苄氧基)－苯基硫基]－酚使實例37A之產物與實例36E之產物反應，使用實例36I之程序，以實例37A之產物取代實例36H之產物，提供固體，將其以甲醇研製，提供標題化合物(31毫克，31%)。1 H NMR(500 MHz,DMSO－D6)δ ppm：9.88(s,1H),9.57(s,1H),8.73(d,J＝5.49 Hz,1H),8.56(s,1H),7.58(d,J＝7.32 Hz,1H),7.40(dd,J＝7.63,1.53 Hz,1H),7.31－7.37(m,1H),7.30(s,1H),7.18(d,J＝6.10 Hz,1H),7.11(d,J＝8.54 Hz,2H),7.05(d,J＝7.93 Hz,1H),6.97(t,J＝7.32 Hz,1H),6.93(s,1H),6.67(d,J＝8.54 Hz,2H),5.06(s,2H),3.80(s,3H),3.16－3.25(m,1H),1.33(d,J＝6.71 Hz,6H)；MS(ESI＋)m/z 525.2(M＋H)＋(ESI－)m/z 523.2(M－H)－.Example 37B 4-[2-(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(2-methoxy-benzyloxy)-phenylthio The product of Example 37A was reacted with the product of Example 36A. ). 1 H NMR (500 MHz, DMSO-D6) δ ppm: 9.88 (s, 1H), 9.57 (s, 1H), 8.73 (d, J = 5.49 Hz, 1H), 8.56 (s, 1H), 7.58 (d) , J = 7.32 Hz, 1H), 7.40 (dd, J = 7.63, 1.53 Hz, 1H), 7.31-7.37 (m, 1H), 7.30 (s, 1H), 7.18 (d, J = 6.10 Hz, 1H) , 7.11 (d, J = 8.54 Hz, 2H), 7.05 (d, J = 7.93 Hz, 1H), 6.97 (t, J = 7.32 Hz, 1H), 6.93 (s, 1H), 6.67 (d, J = 8.54 Hz, 2H), 5.06 (s, 2H), 3.80 (s, 3H), 3.16-3.25 (m, 1H), 1.33 (d, J = 6.71 Hz, 6H); MS (ESI+) m/z 525.2 ( M+H)+(ESI-)m/z 523.2(M-H)-.
4－[2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－(4－甲氧基－苄氧基)－苯基硫基]－酚4-[2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(4-methoxy-benzyloxy)-phenylthio]- phenol
使得自實例10E之產物與實例36E之產物反應，按照實例36I之程序，以實例10E之產物取代實例36H之產物，提供固體，將其以甲醇研製，提供標題化合物(43毫克，49%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：9.93(s,1H),9.63(s,1H),8.75(d,J＝8.46 Hz,1H),8.57(s,1H),7.60(d,J＝8.09 Hz,1H),7.38(d,J＝8.46 Hz,2H),7.27(s,1H),7.05－7.19(m,3H),6.85－7.00(m,3H),6.67(d,J＝8.82 Hz,2H),5.02(s,2H),3.75(s,3H),3.14－3.28(m,1H),1.32(d,J＝6.62Hz6H)；MS(ESI＋)m/z 525.3(M＋H)＋(ESI－)m/z 523.3(M－H)－.The product from Example 10E was reacted with the product from Example </RTI><RTIID=0.0></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; 1 H NMR (300 MHz, DMSO-D6) δ ppm: 9.93 (s, 1H), 9.63 (s, 1H), 8.75 (d, J = 8.46 Hz, 1H), 8.57 (s, 1H), 7.60 (d) , J=8.09 Hz, 1H), 7.38 (d, J=8.46 Hz, 2H), 7.27 (s, 1H), 7.05-7.19 (m, 3H), 6.85-7.00 (m, 3H), 6.67 (d, J = 8.82 Hz, 2H), 5.02 (s, 2H), 3.75 (s, 3H), 3.14 - 3.28 (m, 1H), 1.32 (d, J = 6.62 Hz 6H); MS (ESI+) m/z 525.3 ( M+H)+(ESI-)m/z 523.3(M-H)-.
4－[2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－(1－苯基－乙氧基)－苯基硫基]－酚4-[2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(1-phenyl-ethoxy)-phenylthio]-phenol
實例39A 4－[2－胺基－4－(1－苯基－乙氧基)－苯基硫基]－酚使1－(3－氟苯基)－乙醇之溶液轉化成1－(1－溴－乙基)－3－氟－苯，使用實例22A中所述之條件，將其使用得自實例22B－22D之程序繼續處理，提供標題產物。Example 39A 4-[2-Amino-4-(1-phenyl-ethoxy)-phenylthio]-phenol converts a solution of 1-(3-fluorophenyl)-ethanol to 1-(1 -Bromo-ethyl)-3-fluoro-benzene, using the conditions described in Example 22A, was worked up using the procedure from Example 22B-22D to afford title product.
實例39B 4－[2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－(1－苯基－乙氧基)－苯基硫基]－酚使得自實例39A之產物與得自實例36E之產物反應，按照得自實例36I之程序，以實例39A之產物取代實例36H之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.34(d,J＝6.99 Hz,6H)1.55(d,J＝6.25 Hz,3H)3.14－3.29(m,1H)5.49(q,J＝6.37 Hz,1H)6.63(d,J＝8.82 Hz,2H)6.89(dd,J＝8.82,2.57 Hz,1H)7.09(dd,J＝9.01,2.76 Hz,3H)7.19－7.48(m,6H)7.75(d,J＝8.82 Hz,1H)8.67(s,1H)8.83(d,J＝8.46 Hz,1H)9.67(s,1H)10.85(s,1H)；MS ESI＋(m/z)509,ESI－(m/z)507.Example 39B 4-[2-(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(1-phenyl-ethoxy)-phenylthio] - Phenol, the product from Example 39A was reacted with the product from Example 36E, and the product of Example 36H was taken from the product from Example 39A to afford the crude title compound. The title compound is trifluoroacetate. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J = 6.99 Hz, 6H) 1.55 (d, J = 6.25 Hz, 3H) 3.14 - 3.29 (m, 1H) 5.49 (q, J = 6.37 Hz, 1H) 6.63 (d, J = 8.82 Hz, 2H) 6.89 (dd, J = 8.82, 2.57 Hz, 1H) 7.09 (dd, J = 9.01, 2.76 Hz, 3H) 7.19-7.48 (m, 6H) 7.75 (d, J = 8.82 Hz, 1H) 8.67 (s, 1H) 8.83 (d, J = 8.46 Hz, 1H) 9.67 (s, 1H) 10.85 (s, 1H); MS ESI + (m/z) 509, ESI-(m/z)507.
4－[4－[1－(4－溴苯基)－乙氧基]－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-[1-(4-Bromophenyl)-ethoxy]-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl Thio]-phenol
使得自實例22D之產物(211毫克，0.506毫莫耳)與得自實例36E之產物(109毫克，0.506毫莫耳)反應，按照得自實例36I之程序，以實例22D之產物取代實例36H之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(150毫克，42%)。1 H NMR(300 MHz,DMSOD6)δ ppm：10.87(br s,1H)9.68(s,1H)8.83(d,J＝8.45 Hz,1H)8.67(s,1H)7.75(d,J＝7.72 Hz,1H)7.55(d,J＝8.46 Hz,2H)7.37(d,J＝8.46 Hz,2H)7.09(m,4H)6.89(dd,J＝8.46 Hz,J＝2.20 Hz,1H)6.66(d,J＝8.82 Hz,2H)5.50(q,J＝6.25 Hz,2H)3.25(七重峰,J＝6.99 Hz,1H)1.53(d,J＝6.25 Hz,3H)1.34(d,J＝6.99 Hz,6H).MS(ESI＋)m/z 587,589(M＋H－TFA)＋；(ESI－)m/z 585,587(M－H－TFA)－.The product from Example 22D (211 mg, 0.506 mmol) was reacted with the product from Example 36E (109 mg, 0.506 mmol), and the product of Example 22D was used to replace Example 36H. The title compound was obtained from EtOAc EtOAc. 1 H NMR (300 MHz, DMSO D6) δ ppm: 10.87 (br s, 1H) 9.68 (s, 1H) 8.83 (d, J = 8.45 Hz, 1H) 8.67 (s, 1H) 7.75 (d, J = 7.72 Hz , 1H) 7.55 (d, J = 8.46 Hz, 2H) 7.37 (d, J = 8.46 Hz, 2H) 7.09 (m, 4H) 6.89 (dd, J = 8.46 Hz, J = 2.20 Hz, 1H) 6.66 (d , J=8.82 Hz, 2H) 5.50 (q, J=6.25 Hz, 2H) 3.25 (seven peak, J=6.99 Hz, 1H) 1.53 (d, J=6.25 Hz, 3H) 1.34 (d, J=6.99 Hz , 6H). MS (ESI+) m/z 587, 589 (M+H-TFA)+; (ESI-) m/z 585, 587 (M-H-TFA)-.
4－[4－[1－(3－氟苯基)－乙氧基]－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-[1-(3-Fluorophenyl)-ethoxy]-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl Thio]-phenol
使得自實例24A之產物(197毫克，0.555毫莫耳)與得自實例36E之產物(120毫克，0.555毫莫耳)反應，按照得自實例36I之程序，以實例24A之產物取代實例36H之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(100毫克，28%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.34(d,J＝6.99 Hz,6H)1.55(d,J＝6.62 Hz,3H)3.19－3.32(m,J＝13.70,6.94,6.94 Hz,1H)5.53(q,J＝6.62 Hz,1H)6.64(d,J＝8.46 Hz,2H)6.91(dd,J＝8.82,2.57 Hz,1H)7.09(d,J＝8.46 Hz,5H)7.19－7.29(m,2H)7.39(dd,J＝8.09,5.88 Hz,1H)7.78(d,J＝8.46 Hz,1H)8.68(s,1H)8.85(d,J＝8.46 Hz,1H)9.70(s,1H)；MS(ESI＋)m/z 527(M＋H)＋.The product from Example 24A (197 mg, 0.555 mmol) was reacted with the product from Example 36E (120 mg, 0.555 mmol), substituting the product of Example </RTI> The title compound was obtained from EtOAc EtOAc. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J = 6.99 Hz, 6H) 1.55 (d, J = 6.62 Hz, 3H) 3.19-3.32 (m, J = 13.70, 6.94, 6.94 Hz , 1H) 5.53 (q, J = 6.62 Hz, 1H) 6.64 (d, J = 8.46 Hz, 2H) 6.91 (dd, J = 8.82, 2.57 Hz, 1H) 7.09 (d, J = 8.46 Hz, 5H) 7.19 - 7.29 (m, 2H) 7.39 (dd, J = 8.09, 5.88 Hz, 1H) 7.78 (d, J = 8.46 Hz, 1H) 8.68 (s, 1H) 8.85 (d, J = 8.46 Hz, 1H) 9.70 ( s, 1H); MS (ESI+) m/z 527 (M+H)+.
4－[2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－(3－三氟甲基－苄氧基)－苯基硫基]－酚4-[2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(3-trifluoromethyl-benzyloxy)-phenylthio] -phenol
使得自實例26A之產物與得自實例36E之產物反應，按照得自實例36I之程序，以實例26A之產物取代實例36H之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(22毫克，21%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.34(d,J＝6.99 Hz,6H),5.22(s,2H),6.65(d,J＝8.46 Hz,2H),7.01－7.13(m,3H),7.20(d,J＝8.82 Hz,2H),7.66(d,J＝7.35 Hz,1H),7.70－7.82(m,4H),8.68(s,1H),8.87(d,J＝8.46 Hz,1H),9.68(s,1H)；MS ESI＋ m/z 563(M＋H)＋,ESI－ m/z 561(M－H)－.The product from Example 26A was reacted with the product from Example 36. mp. , is trifluoroacetate (22 mg, 21%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J = 6.99 Hz, 6H), 5.22 (s, 2H), 6.65 (d, J = 8.46 Hz, 2H), 7.01 - 7.13 (m) , 3H), 7.20 (d, J = 8.82 Hz, 2H), 7.66 (d, J = 7.35 Hz, 1H), 7.70-7.82 (m, 4H), 8.68 (s, 1H), 8.87 (d, J = 8.46 Hz, 1H), 9.68 (s, 1H); MS ESI+ m/z 563 (M+H)+, ESI- m/z 561 (M-H)-.
4－[4－(3－氟－苄氧基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(3-Fluoro-benzyloxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使得自實例57D之產物與得自實例36E之產物反應，按照實例36I之程序，以實例57D之產物取代實例36H之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(26毫克，51%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.35(d,J＝6.99 Hz,6H)3.28(m,1H)5.14(s,2H)6.65(m,2H)7.16(m,8H)7.44(m,1H)7.81(d,J＝8.46 Hz,1H)8.73(s,1H)8.90(d,J＝8.46 Hz,1H)9.69(s,1H)11.08(s,1H)；MS(ESI＋)m/z 513(M＋H)＋.The product from Example 57D was reacted with the product from Example </RTI><RTIID=0.0> Trifluoroacetate (26 mg, 51%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.99 Hz, 6H) 3.28 (m, 1H) 5.14 (s, 2H) 6.65 (m, 2H) 7.16 (m, 8H) 7.44 (m, 1H) 7.81 (d, J = 8.46 Hz, 1H) 8.73 (s, 1H) 8.90 (d, J = 8.46 Hz, 1H) 9.69 (s, 1H) 11.08 (s, 1H); MS (ESI+) m/z 513(M+H)+.
4－[4－(4－氟－苄氧基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(4-Fluoro-benzyloxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使實例35A之產物與實例36E之產物反應，使用實例36I之程序，以實例35A之產物取代實例36H之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(23毫克，45%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.35(d,J＝6.99 Hz,6H)3.26(m,1H)5.09(s,2H)6.62(m,2H)7.14(m,7H)7.48(m,2H)7.81(d,J＝8.46 Hz,1H)8.73(s,1H)8.90(d,J＝8.46 Hz,1H)9.68(s,1H)11.12(s,1H)；MS(ESI＋)m/z 513(M＋H)＋.The product of Example 35A was reacted with the product of Example 36 </ RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI> Salt (23 mg, 45%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.99 Hz, 6H) 3.26 (m, 1H) 5.09 (s, 2H) 6.62 (m, 2H) 7.14 (m, 7H) 7.48 (m, 2H) 7.81 (d, J = 8.46 Hz, 1H) 8.73 (s, 1H) 8.90 (d, J = 8.46 Hz, 1H) 9.68 (s, 1H) 11.12 (s, 1H); MS (ESI+) m/z 513(M+H)+.
4－[4－[1－(4－氟苯基)－乙氧基]－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚使得自實例23A之產物(180毫克，0.510毫莫耳)與得自實例36E之產物(110毫克，0.510毫莫耳)反應，按照得自實例36I之程序，以實例23A之產物取代實例36H之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(35毫克，12%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.35(d,J＝6.99 Hz,6H)1.54(d,J＝6.62 Hz,3H)3.23－3.34(m,1H)5.52(q,J＝5.88 Hz,1H)6.63(d,J＝8.82 Hz,2H)6.94(dd,J＝8.82,2.57 Hz,1H)7.08(m,J＝8.82 Hz,4H)7.14(d,J＝4.78 Hz,1H)7.17－7.21(m,1H)7.41－7.49(m,2H)7.86(d,J＝8.82 Hz,1H)8.76(s,1H)8.91(d,J＝8.46 Hz,1H)；MS(ESI＋)m/z 527(M＋H)＋.4-[4-[1-(4-Fluorophenyl)-ethoxy]-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl The thio]-phenol was reacted with the product from Example 23A (180 mg, 0.510 mmol) from the product from Example 36E (110 mg, 0.510 mmol), according to procedure from Example 36, The product was replaced with the title compound, mp. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.99 Hz, 6H) 1.54 (d, J = 6.62 Hz, 3H) 3.23-3.34 (m, 1H) 5.52 (q, J = 5.88 Hz, 1H) 6.63 (d, J = 8.82 Hz, 2H) 6.94 (dd, J = 8.82, 2.57 Hz, 1H) 7.08 (m, J = 8.82 Hz, 4H) 7.14 (d, J = 4.78 Hz, 1H) 7.17-7.21(m,1H)7.41-7.49(m,2H)7.86(d,J=8.82 Hz,1H)8.76(s,1H)8.91(d,J=8.46 Hz,1H);MS(ESI+) m/z 527(M+H)+.
4－[2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－(3－甲氧基－苄氧基)－苯基硫基]－酚4-[2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(3-methoxy-benzyloxy)-phenylthio]- phenol
使實例31A之產物與實例36E之產物反應，使用實例36I之程序，以實例31A之產物取代實例36H之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(23毫克，45%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：10.98(s,1H),9.67(s,1H),8.88(d,J＝8.09 Hz,1H),8.70(s,1H),7.78(d,J＝8.09 Hz,1H),7.31(t,J＝8.09 Hz,1H),7.15－7.24(m,J＝8.82 Hz,2H),7.06－7.15(m,2H),6.95－7.05(m,J＝6.62 Hz,3H),6.90(dd,J＝7.72,2.21 Hz,1H),6.54－6.73(m,2H),5.09(s,2H),3.75(s,3H),3.19－3.28(m,1H),1.34(d,J＝6.99 Hz,6H)；MS(ESI＋)m/z 525.2(M＋H)＋(ESI－)m/z 523.2(M－H)－.The product of Example </RTI><RTIID=0.0>#</RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; Salt (23 mg, 45%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 10.98 (s, 1H), 9.67 (s, 1H), 8.88 (d, J = 8.09 Hz, 1H), 8.70 (s, 1H), 7.78 (d) , J=8.09 Hz, 1H), 7.31 (t, J=8.09 Hz, 1H), 7.15-7.24 (m, J=8.82 Hz, 2H), 7.06-7.15 (m, 2H), 6.95-7.05 (m, J=6.62 Hz, 3H), 6.90 (dd, J=7.72, 2.21 Hz, 1H), 6.54-6.73 (m, 2H), 5.09 (s, 2H), 3.75 (s, 3H), 3.19-3.28 (m) , 1H), 1.34 (d, J = 6.99 Hz, 6H); MS (ESI+) m/z 525.2 (M+H) + (ESI-) m/z 523.2 (M-H)-.
4－[4－(3－溴－苄氧基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(3-Bromo-benzyloxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使實例15A之產物與實例36E之產物反應，使用實例36I之程序，以實例15A之產物取代實例36H之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(16毫克，28%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.33(d,J＝6.62 Hz,6H)3.21(m,1H)5.13(s,2H)6.68(d,J＝8.82 Hz,2H)6.95(dd,J＝8.64,2.76 Hz,1H)7.12(m,3H)7.34(m,2H)7.50(m,2H)7.60(d,J＝8.82 Hz,1H)(s,1H)8.57(s,1H)8.76(d,J＝8.46 Hz,1H)9.65(s,1H)9.95(s,1H)；MS(ESI＋)m/z 573,575(M＋H)＋.The product of Example 15A was reacted with the product of Example 36A, and the title compound was obtained from the product of Example </RTI><RTIgt; Salt (16 mg, 28%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.33 (d, J = 6.62 Hz, 6H) 3.21 (m, 1H) 5.13 (s, 2H) 6.68 (d, J = 8.82 Hz, 2H) 6.95 ( Dd, J=8.64, 2.76 Hz, 1H) 7.12 (m, 3H) 7.34 (m, 2H) 7.50 (m, 2H) 7.60 (d, J = 8.82 Hz, 1H) (s, 1H) 8.57 (s, 1H) 8.76 (d, J = 8.46 Hz, 1H) 9.65 (s, 1H) 9.95 (s, 1H); MS (ESI+) m/z 573,575 (M+H)+.
4－[4－(4－溴－苄氧基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(4-Bromo-benzyloxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使實例16A之產物與實例36E之產物反應，使用實例36I之程序，以實例16A之產物取代實例36H之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(28毫克，49%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.32(d,J＝6.99 Hz,6H)3.22(m,1H)5.10(s,2H)6.67(d,J＝8.46 Hz,2H)6.94(dd,J＝8.82,2.57 Hz,1H)7.12(m,3H)7.28(d,J＝2.57 Hz,1H)7.41(d,J＝8.46 Hz,2H)7.59(m,3H)8.56(s,1H)8.75(d,J＝8.46 Hz,1H)9.65(s,1H)9.94(s,1H)；MS(ESI＋)m/z 573,575(M＋H)＋.The product of Example 16A was reacted with the product of Example 36 </ RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI> Salt (28 mg, 49%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.32 (d, J = 6.99 Hz, 6H) 3.22 (m, 1H) 5.10 (s, 2H) 6.67 (d, J = 8.46 Hz, 2H) 6.94 ( Dd, J = 8.82, 2.57 Hz, 1H) 7.12 (m, 3H) 7.28 (d, J = 2.57 Hz, 1H) 7.41 (d, J = 8.46 Hz, 2H) 7.59 (m, 3H) 8.56 (s, 1H) 8.75 (d, J = 8.46 Hz, 1H) 9.65 (s, 1H) 9.94 (s, 1H); MS (ESI+) m/z 573,575 (M+H)+.
4－[4－(4－羥基－苯基硫基)－3－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基甲基]－苯甲腈4-[4-(4-Hydroxy-phenylthio)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl]- Benzoonitrile
使實例21A之產物與實例36E之產物反應，使用實例36I之程序，以實例21A之產物取代實例36H之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(32毫克，26%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：10.91(s,1H),9.69(s,1H),8.87(d,J＝9.19 Hz,1H),8.69(s,1H),7.88(d,J＝8.09 Hz,2H),7.77(d,J＝8.46 Hz,1H),7.64(d,J＝8.46 Hz,2H),7.15－7.26(m,J＝8.82 Hz,2H),7.08－7.15(m,2H),7.01(d,J＝8.82 Hz,1H),6.58－6.72(m,2H),5.23(s,2H),3.20－3.31(m,1H),1.34(d,J＝6.99 Hz,6H)；MS(ESI＋)m/z 520.2(M＋H)＋(ESI－)m/z 518.2(M－H)－.The product of Example 21A was reacted with the product of Example 36A, and the product of Example 36A was used to give the title compound as the product of Example 21A. Salt (32 mg, 26%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 10.91 (s, 1H), 9.69 (s, 1H), 8.87 (d, J = 9.19 Hz, 1H), 8.69 (s, 1H), 7.88 (d) , J=8.09 Hz, 2H), 7.77 (d, J=8.46 Hz, 1H), 7.64 (d, J=8.46 Hz, 2H), 7.15-7.26 (m, J=8.82 Hz, 2H), 7.08-7.15 (m, 2H), 7.01 (d, J = 8.82 Hz, 1H), 6.58-6.72 (m, 2H), 5.23 (s, 2H), 3.20-3.31 (m, 1H), 1.34 (d, J = 6.99) Hz,6H); MS (ESI+) m/z 520.2 (M+H) + (ESI-) m/z 518.2 (M-H)-.
2－[4－(4－羥基－苯基硫基)－3－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基甲基]－苯甲腈2-[4-(4-Hydroxy-phenylthio)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl]- Benzoonitrile
使實例20A之產物與實例36E之產物反應，使用實例36I之程序，以實例20A之產物取代實例36H之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(11毫克，9%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：11.30(s,1H),9.71(s,1H),8.93(d,J＝8.82 Hz,1H),8.76(s,1H),7.92(d,J＝7.35 Hz,1H),7.84(d,J＝8.82 Hz,1H),7.72－7.80(m,2H),7.59(ddd,J＝7.72,6.25,2.58 Hz,1H),7.19－7.28(m,2H),7.06－7.17(m,3H),6.64－6.69(m,2H),5.25(s,2H),3.22－3.33(m,1H),1.35(d,J＝6.99 Hz,6H)；MS(ESI＋)m/z 520.2(M＋H)＋(ESI－)m/z 518.2(M－H)－.The product of Example 20A was reacted with the product of Example 36A, and the title compound was obtained from the product of Example </ RTI></RTI> Salt (11 mg, 9%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 11.30 (s, 1H), 9.71 (s, 1H), 8.93 (d, J = 8.82 Hz, 1H), 8.76 (s, 1H), 7.92 (d) , J = 7.35 Hz, 1H), 7.84 (d, J = 8.82 Hz, 1H), 7.72-7.80 (m, 2H), 7.59 (ddd, J = 7.72, 6.25, 2.58 Hz, 1H), 7.19-7.28 ( m, 2H), 7.06-7.17 (m, 3H), 6.64-6.69 (m, 2H), 5.25 (s, 2H), 3.22-3.33 (m, 1H), 1.35 (d, J = 6.99 Hz, 6H) ;MS(ESI+) m/z 520.2 (M+H)+ (ESI-) m/z 518.2 (M-H)-.
4－[4－苄氧基－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-Benzyloxy-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使實例27A之產物與實例36E之產物反應，使用實例36I之程序，以實例27A之產物取代實例36H之產物，提供固體，將其以甲醇研製，提供標題化合物。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.32(d,J＝6.62 Hz,6H)3.10－3.30(m,1H)5.11(s,2H)6.67(d,J＝8.82 Hz,2H)6.90－6.99(m,1H)7.07－7.19(m,1H)7.11(d,J＝8.82 Hz,2H)7.23－7.52(m,6H)7.59(d,J＝8.09 Hz,1H)8.56(s,1H)8.75(d,J＝8.09 Hz,1H)9.64(s,1H)9.95(s,1H)；MS(DCI/NH3)m/z 495(M＋H)＋.The product of Example 27A was reacted with the product of Example 36 </ RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.32 (d, J = 6.62 Hz, 6H) 3.10-3.30 (m, 1H) 5.11 (s, 2H) 6.67 (d, J = 8.82 Hz, 2H) 6.90-6.99(m,1H)7.07-7.19(m,1H)7.11(d,J=8.82 Hz,2H)7.23-7.52(m,6H)7.59(d,J=8.09 Hz,1H)8.56(s, 1H) 8.75 (d, J = 8.09 Hz, 1H) 9.64 (s, 1H) 9.95 (s, 1H); MS (DCI / NH3) m / z 495 (M + H) +.
3－[3－[7－(1－羥基－1－甲基－乙基)－吡啶并[2,3－d]嘧啶－4－基胺基]－4－(4－羥基－苯基硫基)－苯氧基甲基]－苯甲腈於油浴中，將得自實例36E之產物(45.9毫克，0.212毫莫耳)與得自實例36H之產物(73.5毫克，0.212毫莫耳)在醋酸(1毫升)中逐漸從室溫加熱至130℃，歷經15分鐘期間，接著於130℃下再加熱1.5小時。然後使混合物冷卻至室溫，於真空下濃縮，提供粗製標題化合物，使其在Waters Symmetry C8管柱上藉逆相預備HPLC(25毫米x 100毫米，7微米粒子大小)純化，使用10%至100%乙腈/0.1%三氟醋酸在水中之梯度液，歷經8分鐘(10分鐘操作時間)，於流率40毫升/分鐘下，提供標題化合物，為三氟醋酸鹽(22毫克，20%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：11.76(s,1H),9.72(s,1H),9.06(d,J＝8.09 Hz,1H),8.83(s,1H),8.20(d,J＝8.46 Hz,1H),7.92(s,1H),7.75－7.88(m,2H),7.63(t,J＝7.72 Hz,1H),7.21－7.26(m,1H),7.19(d,J＝2.57 Hz,1H),7.07－7.15(m,3H),6.64(d,J＝8.46 Hz,2H),5.18(s,2H),1.56(s,6H)；MS(ESI)m/z 536.2(M＋H)＋,(ESI－)m/z 534.2(M－H)－.3-[3-[7-(1-Hydroxy-1-methyl-ethyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-4-(4-hydroxy-phenylsulfide The product from Example 36E (45.9 mg, 0.212 mmol) and the product from Example 36H (73.5 mg, 0.212 mmol). It was gradually heated from room temperature to 130 ° C in acetic acid (1 ml) over a period of 15 minutes, followed by heating at 130 ° C for an additional 1.5 hours. The mixture was then cooled to room temperature and concentrated in vacuo to give title crystalljjjjjjjjjjjjjjjjjjjjjjj A gradient of 100% acetonitrile / 0.1% trifluoroacetic acid in EtOAc (EtOAc) (EtOAc) . 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 11.76 (s, 1H), 9.72 (s, 1H), 9.06 (d, J = 8.09 Hz, 1H), 8.83 (s, 1H), 8.20 ( d, J = 8.46 Hz, 1H), 7.92 (s, 1H), 7.75-7.88 (m, 2H), 7.63 (t, J = 7.72 Hz, 1H), 7.21 - 7.26 (m, 1H), 7.19 (d , J=2.57 Hz, 1H), 7.07-7.15 (m, 3H), 6.64 (d, J = 8.46 Hz, 2H), 5.18 (s, 2H), 1.56 (s, 6H); MS (ESI) m/ z 536.2(M+H)+, (ESI-)m/z 534.2(M-H)-.
2－[3－[7－(1－羥基－1－甲基－乙基)－吡啶并[2,3－d]嘧啶－4－基胺基]－4－(4－羥基－苯基硫基)－苯氧基甲基]－苯甲腈2-[3-[7-(1-hydroxy-1-methyl-ethyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-4-(4-hydroxy-phenylsulfide Phenoxymethyl]-benzonitrile
使實例20A之產物與實例36E之產物反應，使用實例52之程序，以實例20A之產物取代實例36H之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(11毫克，11%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：11.73(s,1H),9.75(s,1H),9.05(d,J＝8.46 Hz,1H),8.84(s,1H),8.20(d,J＝8.82 Hz,1H),7.92(d,J＝7.35 Hz,1H),7.69－7.84(m,2H),7.54－7.64(m,1H),7.23－7.27(m,1H),7.21(d,J＝2.57 Hz,1H),7.10－7.17(m,3H),6.64－6.69(m,2H),5.25(s,2H),1.56(s,6H)；MS(ESI＋)m/z 536.2(M＋H)＋(ESI－)m/z 534.3(M－H).The product of Example 20A was reacted with the product of Example <RTI ID=0.0># </ </RTI> Salt (11 mg, 11%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 11.73 (s, 1H), 9.75 (s, 1H), 9.05 (d, J = 8.46 Hz, 1H), 8.84 (s, 1H), 8.20 (d) , J=8.82 Hz, 1H), 7.92 (d, J=7.35 Hz, 1H), 7.69-7.84 (m, 2H), 7.54-7.64 (m, 1H), 7.23-7.27 (m, 1H), 7.21 ( d, J=2.57 Hz, 1H), 7.10-7.17 (m, 3H), 6.64-6.69 (m, 2H), 5.25 (s, 2H), 1.56 (s, 6H); MS (ESI+) m/z 536.2 (M+H)+(ESI-)m/z 534.3(M-H).
4－[3－[7－(1－羥基－1－甲基－乙基)－吡啶并[2,3－d]嘧啶－4－基胺基]－4－(4－羥基－苯基硫基)－苯氧基甲基]－苯甲腈4-[3-[7-(1-hydroxy-1-methyl-ethyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-4-(4-hydroxy-phenylsulfide Phenoxymethyl]-benzonitrile
使實例21A之產物與實例36E之產物反應，使用實例52之程序，以實例21A之產物取代實例36H之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(10毫克，10%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：11.64(s,1H),9.73(s,1H),9.05(s,1H),8.82(s,1H),8.19(d,J＝8.82 Hz,1H),7.88(d,J＝8.09 Hz,2H),7.64(d,J＝8.46 Hz,2H),7.23(d,J＝8.82 Hz,1H),7.18(d,J＝2.57 Hz,1H),7.04－7.15(m,3H),6.62－6.69(m,2H),5.23(s,2H),2.54(s,1H),1.56(s,6H)；MS(ESI＋)m/z 536.2(M＋H)＋(ESI－)m/z 534.2(M－H)－.The product of Example 21A was reacted with the product of Example </RTI><RTIID=0.0> Salt (10 mg, 10%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 11.64 (s, 1H), 9.73 (s, 1H), 9.05 (s, 1H), 8.82 (s, 1H), 8.19 (d, J = 8.82 Hz , 1H), 7.88 (d, J = 8.09 Hz, 2H), 7.64 (d, J = 8.46 Hz, 2H), 7.23 (d, J = 8.82 Hz, 1H), 7.18 (d, J = 2.57 Hz, 1H) ), 7.04-7.15 (m, 3H), 6.62-6.69 (m, 2H), 5.23 (s, 2H), 2.54 (s, 1H), 1.56 (s, 6H); MS (ESI+) m/z 536.2 ( M+H)+(ESI-)m/z 534.2(M-H)-.
4－[2－[7－(1－羥基－1－甲基－乙基)－吡啶并[2,3－d]嘧啶－4－基胺基]－4－(2－甲氧基－苄氧基)－苯基硫基]－酚4-[2-[7-(1-Hydroxy-1-methyl-ethyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-4-(2-methoxy-benzyl Oxy)-phenylthio]-phenol
使實例37A之產物與實例36E之產物反應，使用實例52之程序，以實例37A之產物取代實例36H之產物，提供固體，將其以甲醇研製，提供標題化合物(8毫克，8%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：11.81(s,1H),9.40－9.95(m,1H),9.06(d,J＝8.46 Hz,1H),8.85(s,1H),8.21(d,J＝8.46 Hz,1H),7.31－7.44(m,2H),7.25(d,J＝8.46 Hz,1H),7.15(d,J＝2.57 Hz,1H),7.02－7.14(m,4H),6.97(t,J＝7.54 Hz,1H),6.61－6.67(m,2H),5.05(s,2H),3.80(s,3H),2.54(s,1H),1.56(s,6H)；MS(ESI＋)m/z 541.2(M＋H)＋(ESI－)m/z 539.2(M－H)－.The product of Example 37A was obtained from the title compound (8 mg, 8%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 11.81 (s, 1H), 9.40-9.95 (m, 1H), 9.06 (d, J = 8.46 Hz, 1H), 8.85 (s, 1H), 8.21. (d, J = 8.46 Hz, 1H), 7.31 - 7.44 (m, 2H), 7.25 (d, J = 8.46 Hz, 1H), 7.15 (d, J = 2.57 Hz, 1H), 7.02-7.14 (m, 4H), 6.97 (t, J = 7.54 Hz, 1H), 6.61-6.67 (m, 2H), 5.05 (s, 2H), 3.80 (s, 3H), 2.54 (s, 1H), 1.56 (s, 6H) MS(ESI+) m/z 541.2 (M+H) + (ESI-) m/z 539.2 (M-H)-.
4－{4－(4－溴－苄氧基)－2－[7－(1－羥基－1－甲基－乙基)－吡啶并[2,3－d]嘧啶－4－基胺基]－苯基硫基}－酚4-{4-(4-Bromo-benzyloxy)-2-[7-(1-hydroxy-1-methyl-ethyl)-pyrido[2,3-d]pyrimidin-4-ylamino ]-phenylthio}-phenol
使實例16A之產物與實例36E之產物反應，使用實例52之程序，以實例16A之產物取代實例36H之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(8毫克，13%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.55(s,6H)2.08(s,1H)5.10(s,2H)6.65(d,J＝8.46 Hz,2H)7.13(m,5H)7.41(d,J＝8.46 Hz,2H)7.60(d,J＝8.09 Hz,2H)8.15(d,J＝8.46 Hz,1H)8.77(s,1H)9.00(d,J＝8.46 Hz,1H)9.70(s,1H)11.43(s,1H)；MS(ESI＋)m/z 589,591(M＋H)＋.The product of Example 16A was reacted with the product of Example 36 </ RTI></RTI></RTI></RTI></RTI></RTI></RTI> Salt (8 mg, 13%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.55 (s, 6H) 2.08 (s, 1H) 5.10 (s, 2H) 6.65 (d, J = 8.46 Hz, 2H) 7.13 (m, 5H) 7.41 (d, J = 8.46 Hz, 2H) 7.60 (d, J = 8.09 Hz, 2H) 8.15 (d, J = 8.46 Hz, 1H) 8.77 (s, 1H) 9.00 (d, J = 8.46 Hz, 1H) 9.70 (s, 1H) 11.43 (s, 1H); MS (ESI+) m/z 589, 591 (M+H)+.
4－[4－(3－氟－苄氧基)－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(3-Fluoro-benzyloxy)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
實例57A N'－(3－氰基－吡啶－2－基)－N,N－二甲基－甲脒將2－胺基－菸鹼腈(5克，42毫莫耳)與N,N－二甲基甲醯胺二甲基縮醛(6.13毫升，46.2毫莫耳)在甲苯(20毫升)中之溶液，於回流下加熱3小時。於冷卻至室溫後，使溶液在真空下濃縮，提供標題化合物(7.3克，100%)。Example 57A N'-(3-Cyano-pyridin-2-yl)-N,N-dimethyl-formamidine 2-Amino-nicotinonitrile (5 g, 42 mmol) with N,N A solution of dimethylformamide dimethyl acetal (6.13 ml, 46.2 mmol) in toluene (20 mL). After cooling to rt, EtOAc (EtOAc)
實例57B 1－氯基－4－(3－氟－苄氧基)－2－硝基－苯標題化合物係根據實例10C之程序，以1－溴基甲基－3－氟－苯取代1－氯基甲基－4－甲氧基－苯而製成(0.56克，100%)。Example 57B 1-Chloro-4-(3-fluoro-benzyloxy)-2-nitro-benzene title compound was replaced by 1-bromomethyl-3-fluoro-benzene according to the procedure of Example 10C. Made of chloromethyl-4-methoxy-benzene (0.56 g, 100%).
實例57C 4－[4－(3－氟－苄氧基)－2－硝基－苯基硫基]－酚標題化合物係根據實例10D之程序，以1－氯基－4－(3－氟－苄氧基)－2－硝基－苯取代1－氯基－4－(4－甲氧基－苄氧基)－2－硝基－苯而製成(0.57克，77%)。Example 57C 4-[4-(3-Fluoro-benzyloxy)-2-nitro-phenylthio]-phenol The title compound is 1-chloro-4-(3-fluoro) according to the procedure of Example 10D. (Benzyloxy)-2-nitro-benzene was substituted with 1-chloro-4-(4-methoxy-benzyloxy)-2-nitro-benzene to give (0.57 g, 77%).
實例57D 4－[2－胺基－4－(3－氟－苄氧基)－苯基硫基]－酚標題化合物係根據實例10E之程序，以4－[4－(3－氟－苄氧基)－2－硝基－苯基硫基]－酚取代4－[4－(4－甲氧基－苄氧基)－2－硝基－苯基硫基]－酚而製成(0.501克，96%)。Example 57D 4-[2-Amino-4-(3-fluoro-benzyloxy)-phenylsulfanyl]-phenol The title compound was obtained using 4-[4-(3-fluoro-benzyl) according to procedure of Example 10E. Oxy)-2-nitro-phenylthio]-phenol is substituted for 4-[4-(4-methoxy-benzyloxy)-2-nitro-phenylthio]-phenol ( 0.501 g, 96%).
實例57E 4－[4－(3－氟－苄氧基)－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚將得自實例57A之產物(35毫克，0.2毫莫耳)與得自實例57D之產物(68毫克，0.2毫莫耳)在醋酸(1毫升)中之溶液，於油浴中逐漸從室溫加熱至130℃，歷經15分鐘期間，接著於130℃下再加熱1.5小時。然後使混合物冷卻至室溫，於真空下濃縮，提供粗製標題化合物，使其在Waters Symmetry C8管柱上藉逆相預備HPLC(25毫米x 100毫米，7微米粒子大小)純化，使用10%至100%乙腈/0.1%三氟醋酸在水中之梯度液，歷經8分鐘(10分鐘操作時間)，於流率40毫升/分鐘下，提供標題化合物，為三氟醋酸鹽(28毫克，30%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：5.14(s,2H)6.65(m,2H)7.14(m,8H)7.49(m,1H)7.66(m,1H)8.61(s,1H)8.88(d,J＝7.47 Hz,1H)9.07(s,1H)9.65(s,1H)10.34(s,1H)；MS(ESI)m/z 471(M＋H)＋.Example 57E 4-[4-(3-Fluoro-benzyloxy)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol will be obtained from Example 57A The product (35 mg, 0.2 mmol) and the product from Example 57D (68 mg, 0.2 mmol) in acetic acid (1 mL) was then warmed from room temperature to 130 ° C in an oil bath. Over a period of 15 minutes, it was then heated at 130 ° C for an additional 1.5 hours. The mixture was then cooled to room temperature and concentrated in vacuo to give title crystalljjjjjjjjjjjjjjjjjjjjjjj A gradient of 100% acetonitrile / 0.1% trifluoroacetic acid in EtOAc (EtOAc (EtOAc) . 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 5.14 (s, 2H) 6.65 (m, 2H) 7.14 (m, 8H) 7.49 (m, 1H) 7.66 (m, 1H) 8.61 (s, 1H) 8.88 (d, J = 7.47 Hz, 1H) 9.07 (s, 1H) 9.65 (s, 1H) 10.34 (s, 1H); MS (ESI) m/z 471 (M+H)+.
4－[4－(2－甲基－苄氧基)－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(2-methyl-benzyloxy)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使實例17A之產物與實例57A之產物反應，使用實例57E之程序，以實例17A之產物取代實例57D之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(50毫克，54%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.31(s,3H)5.09(s,2H)6.66(m,2H)7.01(m,1H)7.19(m,7H)7.42(d,J＝6.99 Hz,1H)7.71(dd,J＝7.91,4.23 Hz,1H)8.63(s,1H)8.89(d,J＝7.35 Hz,1H)9.09(s,1H)9.66(s,1H)10.50(s,1H)；MS(ESI＋)m/z 467(M＋H)＋.The product of Example 17A was reacted with the product of Example 57A, and the product of Example 57A was used to afford the product of Example 57A. Salt (50 mg, 54%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.31 (s, 3H) 5.09 (s, 2H) 6.66 (m, 2H) 7.01 (m, 1H) 7.19 (m, 7H) 7.42 (d, J = 6.99 Hz, 1H) 7.71 (dd, J = 7.91, 4.23 Hz, 1H) 8.63 (s, 1H) 8.89 (d, J = 7.35 Hz, 1H) 9.09 (s, 1H) 9.66 (s, 1H) 10.50 (s ,1H);MS(ESI+)m/z 467(M+H)+.
4－[4－(4－甲基－苄氧基)－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(4-Methyl-benzyloxy)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使實例19A之產物與實例57A之產物反應，使用實例57E之程序，以實例19A之產物取代實例57D之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(45毫克，48%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.30(s,3H)5.05(s,2H)6.65(m,2H)7.10(m,7H)7.33(d,J＝8.07 Hz,2H)7.69(dd,J＝8.27,4.23 Hz,1H)8.62(s,1H)8.87(d,J＝7.72 Hz,1H)9.07(s,1H)9.64(s,1H)10.42(s,1H)；MS(ESI＋)m/z 467(M＋H)＋.The product of Example 19A was reacted with the product of Example 57A to give the title compound as the product of Example </RTI><RTIgt; Salt (45 mg, 48%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.30 (s, 3H) 5.05 (s, 2H) 6.65 (m, 2H) 7.10 (m, 7H) 7.33 (d, J = 8.07 Hz, 2H) 7.69 (dd, J = 8.27, 4.23 Hz, 1H) 8.62 (s, 1H) 8.87 (d, J = 7.72 Hz, 1H) 9.07 (s, 1H) 9.64 (s, 1H) 10.42 (s, 1H); ESI+)m/z 467(M+H)+.
4－[4－(2－溴－苄氧基)－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(2-Bromo-benzyloxy)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)phenylsulfanyl]-phenol
使實例14A之產物與實例57A之產物反應，使用實例57E之程序，以實例14A之產物取代實例57D之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(40毫克，38%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：5.13(s,2H)6.66(m,2H)6.99(d,J＝8.43 Hz,1H)7.15(m,3H)7.35(m,3H)7.64(m,3H)8.60(s,1H)8.85(d,J＝7.32 Hz,1H)9.07(s,1H)9.66(s,1H)10.28(s,1H)；MS(ESI＋)m/z 531,533(M＋H)＋.The product of Example 14A was reacted with the product of Example 57A to give the title compound as the product of Example 14A. Salt (40 mg, 38%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 5.13 (s, 2H) 6.66 (m, 2H) 6.99 (d, J = 8.43 Hz, 1H) 7.15 (m, 3H) 7.35 (m, 3H) 7.64 (m, 3H) 8.60 (s, 1H) 8.85 (d, J = 7.32 Hz, 1H) 9.07 (s, 1H) 9.66 (s, 1H) 10.28 (s, 1H); MS (ESI+) m/z 531, 533 ( M+H)+.
3－[4－(4－羥基－苯基硫基)－3－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基甲基]－苯甲腈3-[4-(4-Hydroxy-phenylthio)-3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl]-benzonitrile
使得自實例36H之產物與得自實例57A之產物反應，根據實例57E中之程序，以實例36H之產物取代實例57D之產物，提供固體，將其以甲醇研製，提供標題化合物(44毫克，44%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：10.08(s,1H),9.65(s,1H),9.06(s,1H),8.86(s,1H),8.58(s,1H),7.92(s,1H),7.77－7.86(m,2H),7.54－7.70(m,J＝7.72,7.72 Hz,2H),7.28(s,1H),7.07－7.19(m,3H),6.97(s,1H),6.63－6.72(m,2H),5.18(s,2H)；MS(ESI＋)m/z 478.2(M＋H)＋,(ESI－)m/z 476.1(M－H)－.The product from Example 36H was reacted with the product from Example 57A. %). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 10.08 (s, 1H), 9.65 (s, 1H), 9.06 (s, 1H), 8.86 (s, 1H), 8.58 (s, 1H), 7.92 (s, 1H), 7.77-7.86 (m, 2H), 7.54-7.70 (m, J = 7.72, 7.72 Hz, 2H), 7.28 (s, 1H), 7.07-7.19 (m, 3H), 6.97 (s , 1H), 6.63-6.72 (m, 2H), 5.18 (s, 2H); MS (ESI+) m/z 478.2 (M+H)+, (ESI-) m/z 476.1 (M-H)-.
4－[4－(3－甲基－苄氧基)－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(3-Methyl-benzyloxy)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使實例18A之產物與實例57A之產物反應，使用實例57E之程序，以實例18A之產物取代實例57D之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(50毫克，54%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.31(s,3H)5.07(s,2H)6.65(m,2H)7.12(m,9H)7.78(dd,J＝8.10 Hz,4.77 Hz,1H)8.72(s,1H)8.94(d,J＝7.47 Hz,1H)9.12(d,J＝3.15 Hz,1H)9.67(s,1H)11.03(s,1H)；MS(ESI＋)m/z 467(M＋H)＋.The product of Example 18A was reacted with the product of Example </RTI><RTIID=0.0></RTI></RTI> Salt (50 mg, 54%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.31 (s, 3H) 5.07 (s, 2H) 6.65 (m, 2H) 7.12 (m, 9H) 7.78 (dd, J = 8.10 Hz, 4.77 Hz, 1H) 8.72 (s, 1H) 8.94 (d, J = 7.47 Hz, 1H) 9.12 (d, J = 3.15 Hz, 1H) 9.67 (s, 1H) 11.03 (s, 1H); MS (ESI+) m/z 467(M+H)+.
4－[4－(4－甲氧基－苄氧基)－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(4-Methoxy-benzyloxy)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使得自實例10E之產物與得自實例57A之產物反應，根據實例57E中之程序，以實例10E之產物取代實例57D之產物，提供固體，將其以甲醇研製，提供標題化合物(49毫克，55%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：10.07(s,1H),9.63(s,1H),9.05(s,1H),8.83(s,1H),8.58(s,1H),7.64(s,1H),7.38(d,J＝8.46 Hz,2H),7.20－7.29(m,1H),7.12－7.18(m,1H),7.06－7.12(m,2H),6.90－6.99(m,3H),6.62－6.69(m,2H),5.02(s,2H),3.75(s,3H)；MS(ESI＋)m/z 483.2(M＋H)＋,(ESI－)m/z 481.2(M－H)－.The product from Example 10E was reacted with the product from Example 57A, and the product from Example 57D was used to afford the product from Example 57D to afford the title compound. %). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 10.07 (s, 1H), 9.63 (s, 1H), 9.05 (s, 1H), 8.83 (s, 1H), 8.58 (s, 1H), 7.64 (s, 1H), 7.38 (d, J = 8.46 Hz, 2H), 7.20-7.29 (m, 1H), 7.12-7.18 (m, 1H), 7.06-7.12 (m, 2H), 6.90-6.99 (m , 3H), 6.62-6.69 (m, 2H), 5.02 (s, 2H), 3.75 (s, 3H); MS (ESI+) m/z 483.2 (M+H)+, (ESI-) m/z 481.2 (M -H)-.
4－[4－(2－甲氧基－苄氧基)－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(2-methoxy-benzyloxy)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使實例37A之產物與實例57A之產物反應，使用實例57E之程序，以實例37A之產物取代實例57D之產物，提供固體，將其以甲醇研製，提供標題化合物(47毫克，56%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：10.08(s,1H),9.63(s,1H),9.07(s,1H),8.85(d,J＝6.62 Hz,1H),8.59(s,1H),7.64(s,1H),7.41(dd,J＝7.35,1.47 Hz,1H),7.30－7.38(m,1H),7.24(s,1H),7.16(d,J＝8.46 Hz,1H),7.08－7.14(m,2H),7.05(d,J＝8.09 Hz,1H),6.89－7.01(m,J＝7.54,7.54 Hz,2H),6.61－6.71(m,2H),5.05(s,2H),3.80(s,3H)；MS(ESI＋)m/z 483.2(M＋H)＋,(ESI－)m/z 481.2(M－H)－.The product of Example 37A was obtained from the title compound (47 mg, 56%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 10.08 (s, 1H), 9.63 (s, 1H), 9.07 (s, 1H), 8.85 (d, J = 6.62 Hz, 1H), 8.59 (s) , 1H), 7.64 (s, 1H), 7.41 (dd, J = 7.35, 1.47 Hz, 1H), 7.30-7.38 (m, 1H), 7.24 (s, 1H), 7.16 (d, J = 8.46 Hz, 1H), 7.08-7.14 (m, 2H), 7.05 (d, J = 8.09 Hz, 1H), 6.89-7.01 (m, J = 7.54, 7.54 Hz, 2H), 6.61-6.71 (m, 2H), 5.05 (s, 2H), 3.80 (s, 3H); MS (ESI+) m/z 483.2 (M+H)+, (ESI-) m/z 481.2 (M-H)-.
4－[4－(4－羥基－苯基硫基)－3－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基甲基]－苯甲腈4-[4-(4-Hydroxy-phenylthio)-3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl]-benzonitrile
使實例21A之產物與實例57A之產物反應，使用實例57E之程序，以實例21A之產物取代實例57D之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(6毫克，6%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：11.17(s,1H),9.69(s,1H),9.09－9.20(m,J＝3.68 Hz,1H),8.97(d,J＝8.82 Hz,1H),8.74(s,1H),7.78－7.96(m,3H),7.64(d,J＝8.46 Hz,2H),7.20(d,J＝8.46 Hz,2H),7.07－7.16(m,2H),7.03(d,J＝6.25 Hz,1H),6.57－6.70(m,2H),5.23(s,2H)；MS(ESI＋)m/z 478.2(M＋H)＋,(ESI－)m/z 476.2(M－H)－.The product of Example 21A was reacted with the product of Example </RTI><RTIID=0.0>#</</RTI> Salt (6 mg, 6%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 11.17 (s, 1H), 9.69 (s, 1H), 9.09-9.20 (m, J = 3.68 Hz, 1H), 8.97 (d, J = 8.82 Hz , 1H), 8.74 (s, 1H), 7.78-7.96 (m, 3H), 7.64 (d, J = 8.46 Hz, 2H), 7.20 (d, J = 8.46 Hz, 2H), 7.07-7.16 (m, 2H), 7.03 (d, J = 6.25 Hz, 1H), 6.57-6.70 (m, 2H), 5.23 (s, 2H); MS (ESI+) m/z 478.2 (M+H)+, (ESI-) m/ z 476.2(M-H)-.
4－[4－(3－甲氧基－苄氧基)－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(3-methoxy-benzyloxy)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使得自實例31A之產物與得自實例57A之產物反應，根據實例57E中之程序，以實例31A之產物取代實例57D之產物，提供固體，將其以甲醇研製，提供標題化合物(38毫克，45%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：10.07(s,1H),9.63(s,1H),9.07(s,1H),8.86(d,J＝7.72 Hz,1H),8.59(s,1H),7.64(s,1H),7.23－7.36(m,2H),7.16(dd,J＝8.64,1.65 Hz,1H),7.07－7.13(m,2H),6.93－7.05(m,3H),6.89(dd,J＝8.27,2.02 Hz,1H),6.61－6.71(m,2H),5.08(s,2H),3.75(s,3H)；MS(ESI＋)m/z 483.2(M＋H)＋,(ESI－)m/z 481.2(M－H)－.The product from Example 31A was reacted with the product from Example </RTI><RTIID=0.0>#</</RTI> %). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 10.07 (s, 1H), 9.63 (s, 1H), 9.07 (s, 1H), 8.86 (d, J = 7.72 Hz, 1H), 8.59 (s) , 1H), 7.64 (s, 1H), 7.23 - 7.36 (m, 2H), 7.16 (dd, J = 8.64, 1.65 Hz, 1H), 7.07-7.13 (m, 2H), 6.93-7.05 (m, 3H) ), 6.89 (dd, J = 8.27, 2.02 Hz, 1H), 6.61-6.71 (m, 2H), 5.08 (s, 2H), 3.75 (s, 3H); MS (ESI+) m/z 483.2 (M+H) +,(ESI-)m/z 481.2(M-H)-.
4－[4－(4－溴－苄氧基)－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(4-Bromo-benzyloxy)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使得自實例16A之產物與得自實例57A之產物反應，根據實例57E中之程序，以實例16A之產物取代實例57D之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(11毫克，16%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：5.09(s,2H),6.66(d,J＝8.46 Hz,2H),6.94(s,1H),7.11(d,J＝8.46 Hz,3H),7.25(s,1H),7.41(d,J＝8.09 Hz,2H),7.57－7.69(m,3H),8.59(s,1H),8.84(s,1H),9.06(s,1H),9.64(s,1H),10.07(s,1H)；MS ESI＋ m/z 531(M＋H)＋,ESI－ m/z 529(M－H)－.The product from Example 16A was reacted with the product from Example 57A to give the title compound as the title compound. It was trifluoroacetate (11 mg, 16%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 5.09 (s, 2H), 6.66 (d, J = 8.46 Hz, 2H), 6.94 (s, 1H), 7.11 (d, J = 8.46 Hz, 3H ), 7.25 (s, 1H), 7.41 (d, J = 8.09 Hz, 2H), 7.57-7.69 (m, 3H), 8.59 (s, 1H), 8.84 (s, 1H), 9.06 (s, 1H) , 9.64(s,1H), 10.07(s,1H);MS ESI+ m/z 531(M+H)+,ESI- m/z 529(M-H)-.
4－[4－(3－溴－苄氧基)－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(3-Bromo-benzyloxy)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使得自實例15A之產物與得自實例57A之產物反應，根據實例57E中之程序，以實例15A之產物取代實例57D之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(40毫克，16%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：5.12(s,2H),6.67(d,J＝8.46 Hz,2H),6.94(s,1H),7.12(d,J＝8.46 Hz,3H),7.26(s,1H),7.36(t,J＝7.72 Hz,1H),7.45(s,1H),7.54(d,J＝6.62 Hz,1H),7.66(s,2H),8.57(s,1H),8.83(s,1H),9.04(s,1H),9.64(s,1H),10.08(s,1H)；MS ESI＋ m/z 531(M＋H)＋,ESI－ m/z 529(M－H)－.The product from Example 15A was reacted with the product from Example 57A to give the title compound as the title compound. It was trifluoroacetate (40 mg, 16%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 5.12 (s, 2H), 6.67 (d, J = 8.46 Hz, 2H), 6.94 (s, 1H), 7.12 (d, J = 8.46 Hz, 3H ), 7.26 (s, 1H), 7.36 (t, J = 7.72 Hz, 1H), 7.45 (s, 1H), 7.54 (d, J = 6.62 Hz, 1H), 7.66 (s, 2H), 8.57 (s) , 1H), 8.83 (s, 1H), 9.04 (s, 1H), 9.64 (s, 1H), 10.08 (s, 1H); MS ESI+ m/z 531 (M+H)+, ESI- m/z 529 ( M-H)-.
4－[4－苄氧基－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-Benzyloxy-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使得自實例27A之產物與得自實例57A之產物反應，根據實例57E中之程序，以實例27A之產物取代實例57D之產物，提供標題化合物，其係被單離為醋酸鹽(79毫克，48%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：5.10(s,3H),6.61－6.72(m,2H),6.93(d,J＝9.56 Hz,1H),7.11(d,J＝8.46 Hz,4H),7.24(s,1H),7.32－7.47(m,5H),7.59－7.68(m,1H),8.54(s,1H),8.83(d,J＝9.56 Hz,1H),9.04(s,1H)；ESI＋ m/z 453(M＋H)＋,ESI－ m/z 451(M－H)－.The product from Example 27A was reacted with the product from Example 57A, substituting the product of Example 57A to the product of Example 57D to afford the title compound, which was isolated as acetate (79 mg, 48%). ). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 5.10 (s, 3H), 6.61-6.72 (m, 2H), 6.93 (d, J = 9.56 Hz, 1H), 7.11 (d, J = 8.46 Hz , 4H), 7.24 (s, 1H), 7.32-7.47 (m, 5H), 7.59-7.68 (m, 1H), 8.54 (s, 1H), 8.83 (d, J = 9.56 Hz, 1H), 9.04 ( s,1H); ESI+ m/z 453(M+H)+, ESI- m/z 451(M-H)-.
4－[4－[1－(4－溴苯基)－乙氧基]－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-[1-(4-bromophenyl)-ethoxy]-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使得自實例22D之產物(153毫克，0.367毫莫耳)與得自實例57A之產物(63毫克，0.367毫莫耳)反應，按照得自實例57E之程序，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(97毫克，40%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：10.60(br s,1H)9.67(s,1H)9.09(s,1H)8.88(d,J＝8.46 Hz,1H)8.64(s,1H)7.73(m,J＝3.31 Hz,1H)7.54(d,J＝8.46 Hz,2H)7.36(d,J＝8.46 Hz,2H)7.11(m,4H)6.86(d,J＝9.19 Hz,1H)6.64(d,J＝8.46 Hz,2H)5.51(q,J＝6.62 Hz,1H)1.53(d,J＝6.62 Hz,3H)；MS(ESI＋)m/z 545,547(M＋H－TFA)＋；(ESI－)m/z 543,545(M－H－TFA)－.The product from Example 22D (153 mg, 0.367 mmol) was obtained from EtOAc (EtOAc: EtOAc: Purification by TFA afforded the title compound as a m. 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 10.60 (br s, 1H) 9.67 (s, 1H) 9.09 (s, 1H) 8.88 (d, J = 8.46 Hz, 1H) 8.64 (s, 1H) ) 7.73 (m, J = 3.31 Hz, 1H) 7.54 (d, J = 8.46 Hz, 2H) 7.36 (d, J = 8.46 Hz, 2H) 7.11 (m, 4H) 6.86 (d, J = 9.19 Hz, 1H) 6.64 (d, J = 8.46 Hz, 2H) 5.51 (q, J = 6.62 Hz, 1H) 1.53 (d, J = 6.62 Hz, 3H); MS (ESI+) m/z 545, 547 (M+H-TFA)+; (ESI-)m/z 543,545(M-H-TFA)-.
4－[4－[1－(4－氟苯基)－乙氧基]－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-[1-(4-Fluorophenyl)-ethoxy]-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使得自實例23A之產物(180毫克，0.803毫莫耳)與得自實例57A之產物(140毫克，0.803毫莫耳)反應，按照得自實例57E之程序，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(60毫克，12%)。1 H NMR(500 MHz,DMSO－D6)δ ppm：1.53(d,J＝6.35 Hz,3H)5.51(q,1H)6.61(d,J＝8.79 Hz,2H)6.74－6.82(m,1H)6.93(dd,J＝8.79,2.44 Hz,1H)7.06－7.09(m,3H)7.11－7.19(m,2H)7.44(dd,J＝8.54,5.62 Hz,2H)7.83－7.86(m,J＝8.54,5.13 Hz,1H)8.75(s,1H)8.96(d,J＝7.32 Hz,1H)9.14(d,J＝2.93 Hz,1H)；MS(ESI＋)m/z 485.The product from Example 23A (180 mg, <RTI ID=0.0></RTI></RTI><RTIgt;</RTI><RTIgt; Purified by TFA to provide the title compound, m. 1 H NMR (500 MHz, DMSO-D6) δ ppm: 1.53 (d, J = 6.35 Hz, 3H) 5.51 (q, 1H) 6.61 (d, J = 8.79 Hz, 2H) 6.74-6.82 (m, 1H) 6.93 (dd, J=8.79, 2.44 Hz, 1H) 7.06-7.09 (m, 3H) 7.11-7.19 (m, 2H) 7.44 (dd, J = 8.54, 5.62 Hz, 2H) 7.83-7.86 (m, J = 8.54, 5.13 Hz, 1H) 8.75 (s, 1H) 8.96 (d, J = 7.32 Hz, 1H) 9.14 (d, J = 2.93 Hz, 1H); MS (ESI+) m/z 485.
4－[4－[1－(3－氟苯基)－乙氧基]－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-[1-(3-fluorophenyl)-ethoxy]-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使得自實例24A之產物(285毫克，0.80毫莫耳)與得自實例57A之產物(140毫克，0.803毫莫耳)反應，按照得自實例57E之程序，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(150毫克，31%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.55(d,J＝6.25 Hz,3H)5.53(q,J＝6.13 Hz,1H)6.65(d,J＝8.46 Hz,2H)6.85(d,J＝6.99 Hz,1H)7.03－7.18(m,4H)7.21－7.29(m,2H)7.37－7.45(m,1H)7.67(dd,J＝8.09,4.41 Hz,1H)8.57(s,1H)8.81(s,1H)9.06(s,1H)9.66(s,1H)；MS(ESI＋)m/z 485(M＋H)＋.The product from Example 24A (285 mg, <RTI ID=0.0></RTI></RTI><RTIgt; Purified by TFA to provide the title compound, m. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.55 (d, J = 6.25 Hz, 3H) 5.53 (q, J = 6.13 Hz, 1H) 6.65 (d, J = 8.46 Hz, 2H) 6.85 (d , J=6.99 Hz, 1H) 7.03-7.18(m,4H)7.21-7.29(m,2H)7.37-7.45(m,1H)7.67(dd,J=8.09,4.41 Hz,1H)8.57(s,1H 8.81(s,1H)9.06(s,1H)9.66(s,1H);MS(ESI+)m/z 485(M+H)+.
(5－苄氧基－4－氯基－2－氟苯基)－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺(5-Benzyloxy-4-chloro-2-fluorophenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
實例73A碳酸2－氯基－4－氟苯基酯乙酯於2－氯基－4－氟－酚(0.8毫升，7.64毫莫耳)與三乙胺(1.3毫升，9.16毫莫耳)在二氯甲烷(10毫升)中之溶液內，在0℃下，逐滴添加氯甲酸乙酯(0.9毫升，9.16毫莫耳)。移除冰浴，並使溶液溫熱至室溫，且再攪拌16小時。然後將二氯甲烷(20毫升)添加至混合物中，以鹽水(50毫升)洗滌有機溶液，以無水硫酸鎂脫水乾燥，過濾，及在真空下濃縮，提供標題產物，為油狀物(1.65克，100%)。Example 73A 2-Chloro-4-fluorophenylethyl ester carbonate in 2-chloro-4-fluoro-phenol (0.8 mL, 7.64 mmol) and triethylamine (1.3 mL, 9.16 mmol) Ethyl chloroformate (0.9 mL, 9.16 mmol) was added dropwise at 0 ° C in dichloromethane (10 mL). The ice bath was removed and the solution was allowed to warm to rt and stirred for a further 16 h. Dichloromethane (20 mL) was then added to EtOAc (EtOAc) (EtOAc) , 100%).
實例73B碳酸2－氯基－4－氟基－5－硝基－苯酯乙酯於得自實例73A之產物(0.88克，4.03毫莫耳)在濃硫酸(2毫升)中之已於冰浴中冷卻之溶液內，慢慢添加發煙硝酸(0.27毫升，6.45毫莫耳)，以保持溫度在0℃下。將混合物再攪拌2小時，然後將冰水(10毫升)添加至溶液中，並藉過濾收集所形成之固體，以水洗滌，且在真空烘箱中乾燥，提供標題化合物(0.87克，82%)。Example 73B 2-Chloro-4-fluoro-5-nitro-phenyl ester ethyl carbonate was obtained from the product from Example 73A (0.88 g, 4.03 mmol) in concentrated sulfuric acid (2 mL). To the cooled solution in the bath, fuming nitric acid (0.27 ml, 6.45 mmol) was slowly added to maintain the temperature at 0 °C. The mixture was stirred for additional 2 hours, then ice water (10 mL) was evaporated, evaporated. .
實例73C 2－氯基－4－氟基－5－硝基－酚於得自實例73B之產物(0.87克，3.30毫莫耳)在甲醇(20毫升)與水(1毫升)中之溶液內，添加碳酸氫鈉(2.22克，26.4毫莫耳)，並將混合物於室溫下攪拌16小時。然後在真空下移除甲醇，將二氯甲烷(20毫升)添加至混合物中，以鹽水(50毫升)洗滌有機溶液，以無水硫酸鎂脫水乾燥，過濾，及在真空下濃縮，提供標題產物(0.62克，98%)。Example 73C 2-Chloro-4-fluoro-5-nitro-phenol in a solution of the product from Example 73B (0.87 g, 3.30 mmol) in methanol (20 mL) Sodium bicarbonate (2.22 g, 26.4 mmol) was added and the mixture was stirred at room temperature for 16 h. Methanol was then removed in vacuo, EtOAc (EtOAc (EtOAcMeOHMeOHMeOHMeOH 0.62 g, 98%).
實例73D 1－苄氧基－2－氯基－4－氟基－5－硝基－苯標題化合物係根據實例10C之程序，以溴化苄與得自實例73C之產物取代1－氯基甲基－4－甲氧基－苯與4－氯基－3－硝基－酚而製成(0.72克，79%)。Example 73D 1-Benzyloxy-2-chloro-4-fluoro-5-nitro-benzene title compound was obtained according to the procedure of Example 10C, substituting chlorobenzyl bromide with the product from Example 73C. Made of 4-methoxy-benzene and 4-chloro-3-nitro-phenol (0.72 g, 79%).
實例73E 5－苄氧基－4－氯基－2－氟苯基胺標題化合物係根據實例10D之程序，以得自實例73D之產物取代1－氯基－4－(4－甲氧基－苄氧基)－2－硝基－苯而製成(77毫克，100%)。Example 73E 5-Benzyloxy-4-chloro-2-fluorophenylamine The title compound was obtained according to the procedure of Example 10D, substituting 1-chloro-4-(4-methoxy- Made of benzyloxy)-2-nitro-benzene (77 mg, 100%).
實例73F(5－苄氧基－4－氯基－2－氟苯基)－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺將實例10B之產物(17毫克，0.0927毫莫耳)與實例73E之產物(28毫克，0.111毫莫耳)在醋酸(1毫升)中之溶液，於預熱至130℃之油浴中攪拌15分鐘。然後使混合物冷卻至室溫，在真空下移除醋酸，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(8.1毫克，17%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：2.72(s,3H),5.19(s,2H),7.28－7.53(m,6H),7.66(d,J＝9.56 Hz,1H),7.70(d,J＝8.82 Hz,1H),8.73(s,1H),8.84(d,J＝8.09 Hz,1H),10.85(s,1H)；MS(ESI)m/z 395(M＋H)＋.Example 73F (5-Benzyloxy-4-chloro-2-fluorophenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine The product of Example 10B ( A solution of the product of Example 73E (28 mg, 0.11 mmol) in EtOAc (1 mL) was stirred for 15 minutes in an oil bath preheated to 130 °C. The mixture was then cooled to rt. EtOAc (EtOAc m. 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 2.72 (s, 3H), 5.19 (s, 2H), 7.28-7.53 (m, 6H), 7.66 (d, J = 9.56 Hz, 1H), 7.70 (d, J = 8.82 Hz, 1H), 8.73 (s, 1H), 8.84 (d, J = 8.09 Hz, 1H), 10.85 (s, 1H); MS (ESI) m/z 395 (M+H)+ .
(5－苄氧基－4－氯基－2－氟苯基)－吡啶并[2,3－d]嘧啶－4－基－胺(5-Benzyloxy-4-chloro-2-fluorophenyl)-pyrido[2,3-d]pyrimidin-4-yl-amine
標題化合物係根據實例73F之程序，以得自實例57A之產物取代得自實例10B之產物而製成(7.9毫克，19%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：5.19(s,2H),7.20－7.54(m,6H),7.65(d,J＝9.56 Hz,1H),7.78(dd,J＝8.27,4.60 Hz,1H),8.73(s,1H),8.95(d,J＝8.09 Hz,1H),9.12(d,J＝3.31 Hz,1H),10.82(s,1H)；MS(ESI＋)m/z 381(M＋H)＋.The title compound was prepared according to the procedure of Example 73F, which was obtained from the product from Example 57A (yield: 7.9 mg, 19%). 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 5.19 (s, 2H), 7.20-7.54 (m, 6H), 7.65 (d, J = 9.56 Hz, 1H), 7.78 (dd, J = 8.27) , 4.60 Hz, 1H), 8.73 (s, 1H), 8.95 (d, J = 8.09 Hz, 1H), 9.12 (d, J = 3.31 Hz, 1H), 10.82 (s, 1H); MS (ESI+) m /z 381(M+H)+.
(5－苄氧基－2,4－二氟－苯基)－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺(5-Benzyloxy-2,4-difluoro-phenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
實例75A碳酸2,4－二氟－苯酯乙酯標題化合物係根據實例73A之程序，以2,4－二氟－酚取代2－氯基－4－氟－酚而製成(1.48克，96%)。Example 75A 2,4-difluoro-phenylethyl ester carbonate The title compound was prepared according to the procedure of Example 73A, substituting 2,4-difluoro-phenol for 2-chloro-4-fluoro-phenol (1.48 g, 96%).
實例75B碳酸2,4－二氟－5－硝基－苯酯乙酯標題化合物係根據實例73B之程序製成。Example 75B 2,4-Difluoro-5-nitro-phenyl ester ethyl carbonate The title compound was prepared according to the procedure of Example 73B.
實例75C 2,4－二氟－5－硝基－酚標題化合物係根據實例73C之程序，以得自實例73B之產物取代313B之產物而製成(0.59克，89%)。Example 75C 2,4-Difluoro-5-nitro-phenol title compound (0.59 g, 89%) was obtained from the product from s.
實例75D 1－苄氧基－2,4－二氟－5－硝基－苯標題化合物係根據實例73D之程序，以得自實例75C之產物取代313C之產物而製成(0.56克，63%)。Example 75D 1-Benzyloxy-2,4-difluoro-5-nitro-benzene titled compound was obtained according to the procedure of Example 73D, substituting the product from Example 75C to the product of 313C (0.56 g, 63% ).
實例75E 5－苄氧基－2,4－二氟－苯胺標題化合物係根據實例73E之程序，以得自實例75D之產物取代313D之產物而製成(89毫克，100%)。Example 75E 5-Benzyloxy-2,4-difluoro-phenylamine The title compound was obtained (yield: 89 mg, 100%).
實例75F(5－苄氧基－2,4－二氟－苯基)－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺標題化合物係根據實例73F之程序，以得自實例75E之產物取代實例73E之產物而製成。使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(7.4毫克，16%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：2.72(s,3H),5.17(s,2H),7.19－7.60(m,7H),7.71(d,J＝8.46 Hz,1H),8.75(s,1H),8.85(d,J＝8.46 Hz,1H),10.84(s,1H)；MS(ESI)m/z 379(M＋H)＋.Example 75F (5-Benzyloxy-2,4-difluoro-phenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine The title compound is according to Example 73F The procedure was carried out by substituting the product of Example 75E for the product of Example 73E. The resulting residue was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 2.72 (s, 3H), 5.17 (s, 2H), 7.19-7.60 (m, 7H), 7.71 (d, J = 8.46 Hz, 1H), 8.75 (s, 1H), 8.85 (d, J = 8.46 Hz, 1H), 10.84 (s, 1H); MS (ESI) m/z 379 (M+H)+.
(5－苄氧基－2,4－二氟－苯基)－吡啶并[2,3－d]嘧啶－4－基－胺(5-Benzyloxy-2,4-difluoro-phenyl)-pyrido[2,3-d]pyrimidin-4-yl-amine
將實例57A之產物(17毫克，0.099毫莫耳)與實例73E之產物(28毫克，0.119毫莫耳)在醋酸(1毫升)中之溶液，於預熱至130℃之油浴中攪拌15分鐘。然後使混合物冷卻至室溫，在真空下移除醋酸，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(21.4毫克，45%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：5.17(s,2H)7.19－7.61(m,7H)7.80(dd,J＝8.09,4.41 Hz,1H)8.77(s,1H)8.97(d,J＝7.35 Hz,1H)9.14(d,J＝2.94 Hz,1H)10.88(s,1H)；MS(ESI＋)m/z 365(M＋H)＋.A solution of the product from Example 57A (17 mg, <RTI ID=0.0></RTI></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; minute. The mixture was then cooled to rt. EtOAc (EtOAc)EtOAc. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 5.17 (s, 2H) 7.19-7.61 (m, 7H) 7.80 (dd, J = 8.09, 4.41 Hz, 1H) 8.77 (s, 1H) 8.97 (d) , J=7.35 Hz, 1H) 9.14 (d, J=2.94 Hz, 1H) 10.88 (s, 1H); MS (ESI+) m/z 365 (M+H)+.
4－{2－[苄基－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺基]－4－苄氧基－苯基硫基}－酚4-{2-[Benzyl-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amino]-4-benzyloxy-phenylsulfanyl}-phenol
將實例27之產物(26.3毫克，0.062毫莫耳)、溴化苄(0.0075毫升，0.062毫莫耳)及碳酸鉀(8.6毫克，0.062毫莫耳)在N,N－二甲基甲醯胺(0.5毫升)中之溶液，於室溫下攪拌16小時。然後將混合物倒入冰水(10毫升)中，並以1N鹽酸水溶液使所形成之溶液酸化。接著以醋酸乙酯(3 x 10毫升)萃取溶液，使合併之萃液以硫酸鎂脫水乾燥，過濾，及在真空下濃縮，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(6.7毫克，18%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.74(s,3H)5.10(s,2H)5.69(s,1H)6.65(d,J＝8.82 Hz,2H)7.02－7.18(m,2H)7.14－7.26(m,1H)7.26－7.58(m,12H)7.86(s,1H)8.93(s,1H)9.23(s,1H)9.73(s,1H)12.09(s,1H)；MS(ESI＋)m/z 557(M＋H)＋.The product of Example 27 (26.3 mg, 0.062 mmol), benzyl bromide (0.0075 mL, 0.062 mmol) and potassium carbonate (8.6 mg, 0.062 mmol) in N,N-dimethylformamide The solution in (0.5 ml) was stirred at room temperature for 16 hours. The mixture was poured into ice water (10 ml) and the resulting solution was acidified with 1N aqueous hydrochloric acid. The solution is then extracted with ethyl acetate (3×10 mL), EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH It was trifluoroacetate (6.7 mg, 18%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.74 (s, 3H) 5.10 (s, 2H) 5.69 (s, 1H) 6.65 (d, J = 8.82 Hz, 2H) 7.02-7.18 (m, 2H) 7.14-7.26(m,1H)7.26-7.58(m,12H)7.86(s,1H)8.93(s,1H)9.23(s,1H)9.73(s,1H)12.09(s,1H);MS( ESI+)m/z 557(M+H)+.
(5－苄氧基－2－溴苯基)－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺(5-benzyloxy-2-bromophenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
實例78A 5－苄氧基－2－溴苯基胺標題化合物係根據以下之方法製成：Boger,D.L.,Wysocki,R.J.,Ishizaki,T.J.Am.Chem.Soc. 112,1990,第5230－5240頁。所獲得之量為4.58克，48%。Example 78A 5-Benzyloxy-2-bromophenylamine The title compound was prepared according to the following procedure: Boger, DL, Wysocki, RJ, Ishizaki, T. J. Am. Chem. Soc. 112, 1990, 5230 -5240 pages. The amount obtained was 4.58 g, 48%.
實例78B(5－苄氧基－2－溴苯基)－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺於油浴中，將得自實例78A之產物(2.0克，7.19毫莫耳)與得自實例10B之產物(1.35克，7.19毫莫耳)在醋酸(15毫升)中，逐漸從室溫加熱至130℃，歷經15分鐘期間，接著於130℃下再加熱1.5小時。然後使混合物冷卻至室溫，於真空下濃縮，提供粗製標題化合物(3.4克黏性紅色漿液，100%)，使其一部份藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(81毫克)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：2.74(s,3H),5.14(s,2H),7.06(dd,J＝8.8,2.9 Hz,1H),7.23(m,1H),7.41(m,5H),7.70(d,J＝8.8 Hz,1H),7.78(d,J＝8.5 Hz,1H),8.79(s,1H),8.91(d,J＝8.8 Hz,1H),11.40(bs,1H)；MS(ESI＋)m/z 421/423(M＋H)＋.Example 78B (5-benzyloxy-2-bromophenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine in an oil bath, obtained from Example 78A The product (2.0 g, 7.19 mmol) and the product from Example 10B (1.35 g, 7.19 mmol) in acetic acid (15 mL), gradually warmed from room temperature to 130 ° C over 15 min. Heat at 130 ° C for an additional 1.5 hours. The mixture was then cooled to EtOAc (3HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 81 mg). 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 2.74 (s, 3H), 5.14 (s, 2H), 7.06 (dd, J = 8.8, 2.9 Hz, 1H), 7.23 (m, 1H), 7.41 (m, 5H), 7.70 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 8.79 (s, 1H), 8.91 (d, J = 8.8 Hz, 1H), 11.40 (bs, 1H); MS (ESI+) m/z 421/423 (M+H)+.
2－氯－N－[3－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基]－苯甲醯胺2-Chloro-N-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-benzamide
實例79A N－(3－胺基－苯基)－2－氯－苯甲醯胺標題化合物係根據實例254A之程序，以氯化2－氯－苯甲醯取代氯化4－溴－苯甲醯，接著為硝基之還原作用，使用得自實例255B之程序製成，以提供標題產物。Example 79A N-(3-Amino-phenyl)-2-chloro-benzimidamide The title compound was obtained by substituting 2-chloro-benzhydrin chloride for 4-bromo-benzoic acid according to the procedure of Example 254A. Hydrazine, followed by reduction of the nitro group, was prepared using the procedure from Example 255B to afford the title product.
實例79B 2－氯－N－[3－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基]－苯甲醯胺使得自實例79A之產物與得自實例57A之產物反應，使用得自實例254C之程序，以得自實例79A之產物取代得自實例254B之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(18毫克，22%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：7.45－7.54(m,4H),7.56－7.62(m,3H),7.83－7.90(m,1H),8.25－8.29(m,1H),8.93(s,1H),9.12－9.18(m,2H),10.70(s,1H),11.23(s,1H)；MS ESI＋ m/z 376(M＋H)＋,ESI－ m/z 374(M－H)－.Example 79B 2-Chloro-N-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-benzamide The product from Example 79A was obtained from Example 57A. The product was reacted, using the procedure from Example 254 C, to give the product from Example s. ,twenty two%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 7.45-7.54 (m, 4H), 7.56-7.62 (m, 3H), 7.83-7.90 (m, 1H), 8.25-8.29 (m, 1H), 8.93(s,1H), 9.12-9.18(m,2H), 10.70(s,1H),11.23(s,1H);MS ESI+ m/z 376(M+H)+,ESI- m/z 374(M- H)-.
2－溴－N－[3－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基]－苯甲醯胺2-bromo-N-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-benzamide
實例80A N－(3－胺基－苯基)－2－溴－苯甲醯胺標題化合物係根據實例254A之程序，以氯化2－溴－苯甲醯取代氯化4－溴－苯甲醯，接著為硝基之還原作用，使用得自實例255B之程序製成，以提供標題產物。Example 80A N-(3-Amino-phenyl)-2-bromo-benzimidamide The title compound was obtained by substituting 2-bromo-benzhydrazyl chloride with 4-bromo-benzoic acid according to the procedure of Example 254A. Hydrazine, followed by reduction of the nitro group, was prepared using the procedure from Example 255B to afford the title product.
實例80B 2－溴－N－[3－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基]－苯甲醯胺使得自實例80A之產物與得自實例57A之產物反應，使用得自實例254C之程序，以得自實例80A之產物取代得自實例254B之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(18毫克，22%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：7.44－7.54(m,4H),7.56－7.60(m,2H),7.74(dd,J＝7.91,0.92 Hz,1H),7.82－7.89(m,1H),8.27(s,1H),8.92(s,1H),9.11－9.19(m,2H),10.68(s,1H),11.20(s,1H)；MS ESI＋ m/z 420(M＋H)＋,ESI－ m/z 418(M－H)－.Example 80B 2-Bromo-N-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-benzamide The product from Example 80A was obtained from Example 57A. The product was reacted, using the procedure from Example 254 C, to give the product from Example </RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI> ,twenty two%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 7.44 - 7.54 (m, 4H), 7.56-7.60 (m, 2H), 7.74 (dd, J = 7.91, 0.92 Hz, 1H), 7.82-7.89 ( m,1H), 8.27(s,1H),8.92(s,1H),9.11-9.19(m,2H), 10.68(s,1H),11.20(s,1H);MS ESI+ m/z 420(M+H )+,ESI- m/z 418(M-H)-.
2－甲氧基－N－[3－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基]－苯甲醯胺2-methoxy-N-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-benzamide
實例81A N－(3－胺基－苯基)－2－甲氧基－苯甲醯胺標題化合物係根據實例254A之程序，以氯化2－甲氧基－苯甲醯取代氯化4－溴－苯甲醯，接著為硝基之還原作用，使用得自實例255B之程序製成，以提供標題產物。Example 81A N-(3-Amino-phenyl)-2-methoxy-benzimidamide The title compound was obtained according to the procedure of Example 254A. Bromo-benzamide, followed by reduction of the nitro group, was prepared using the procedure from Example 255B to afford the title product.
實例81B 2－甲氧基－N－[3－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基]－苯甲醯胺使得自實例81A之產物與得自實例57A之產物反應，使用得自實例254C之程序，以得自實例81A之產物取代得自實例254B之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(26毫克，33%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：3.90(s,3H),7.08(t,J＝6.99 Hz,1H),7.20(d,J＝8.46 Hz,1H),7.41－7.56(m,4H),7.62(dd,J＝7.54,1.65 Hz,1H),7.88(dt,1H),8.28(s,1H),8.94(s,1H),9.12－9.19(m,2H),10.30(s,1H),11.30(s,1H)；MS ESI＋ m/z 372(M＋H)＋,ESI－ m/z 370(M－H)－.Example 81B 2-Methoxy-N-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-benzamide The product from Example 81A was obtained from an example The product of 57A was obtained from the titled compound from y. 26 mg, 33%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 3.90 (s, 3H), 7.08 (t, J = 6.99 Hz, 1H), 7.20 (d, J = 8.46 Hz, 1H), 7.41 - 7.56 (m) , 4H), 7.62 (dd, J = 7.54, 1.65 Hz, 1H), 7.88 (dt, 1H), 8.28 (s, 1H), 8.94 (s, 1H), 9.12-9.19 (m, 2H), 10.30 ( s,1H),11.30(s,1H);MS ESI+ m/z 372(M+H)+,ESI- m/z 370(M-H)-.
3－甲氧基－N－[3－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基]－苯甲醯胺實例82A N－(3－胺基－苯基)－3－甲氧基－苯甲醯胺標題化合物係根據實例254A之程序，以氯化3－甲氧基－苯甲醯取代氯化4－溴－苯甲醯，接著為硝基之還原作用，使用得自實例255B之程序製成，以提供標題產物。3-methoxy-N-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-benzimidamide Example 82A N-(3-Amino-phenyl The title compound of 3-methoxy-benzamide is a 4-bromo-benzhydryl chloride substituted with 3-methoxy-benzhydryl chloride according to the procedure of Example 254A, followed by reduction of the nitro group. The effect was made using the procedure from Example 255B to provide the title product.
實例82B 3－甲氧基－N－[3－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基]－苯甲醯胺使得自實例82A之產物與得自實例57A之產物反應，使用得自實例254C之程序，以得自實例82A之產物取代得自實例254B之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(35毫克，45%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：3.85(s,3H),7.18(dd,J＝7.54,2.02 Hz,1H),7.42－7.51(m,3H),7.53－7.61(m,3H),7.82(dd,J＝7.72,5.15 Hz,1H),8.32(t,J＝1.84 Hz,1H),8.89(s,1H),9.09－9.17(m,2H),10.38(s,1H),10.99(s,1H)；MS ESI＋ m/z 372(M＋H)＋,ESI－ m/z 370(M＋H)－.Example 82B 3-Methoxy-N-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-benzamide derived from the product of Example 82A The product of 57A was obtained from the titled compound, mp. 35 mg, 45%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 3.85 (s, 3H), 7.18 (dd, J = 7.54, 2.02 Hz, 1H), 7.42-7.51 (m, 3H), 7.53-7.61 (m, 3H), 7.82 (dd, J = 7.72, 5.15 Hz, 1H), 8.32 (t, J = 1.84 Hz, 1H), 8.89 (s, 1H), 9.09-9.17 (m, 2H), 10.38 (s, 1H) ),10.99(s,1H);MS ESI+ m/z 372(M+H)+,ESI- m/z 370(M+H)-.
3－氟－N－[3－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基]－苯甲醯胺實例83A3-fluoro-N-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-benzimidamide Example 83A
N－(3－胺基－苯基)－3－氟－苯甲醯胺標題化合物係根據實例254A之程序，以氯化3－氟－苯甲醯取代氯化4－溴－苯甲醯，接著為硝基之還原作用，使用得自實例255B之程序製成，以提供標題產物。The title compound of N-(3-amino-phenyl)-3-fluoro-benzamide was replaced by 3-fluoro-benzidin chloride 4-bromo-benzamide according to the procedure of Example 254A. Subsequent reduction of the nitro group was made using the procedure from Example 255B to provide the title product.
實例83B 3－氟－N－[3－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基]－苯甲醯胺使得自實例83A之產物與得自實例57A之產物反應，使用得自實例254C之程序，以得自實例83A之產物取代得自實例254B之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(21毫克，28%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：7.41－7.53(m,2H),7.54－7.65(m,3H),7.77－7.86(m,3H),8.33(s,1H),8.89(s,1H),9.10－9.16(m,2H),10.48(s,1H),10.97(s,1H)；MS ESI＋ m/z 360(M＋H)＋,ESI－ m/z 358(M－H)－.Example 83B 3-Fluoro-N-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-benzamide The product from Example 83A was obtained from Example 57A. The product was reacted, using the procedure from Example 254 C, to give the product from Example </RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI> , 28%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 7.41-7.53 (m, 2H), 7.54-7.65 (m, 3H), 7.77-7.86 (m, 3H), 8.33 (s, 1H), 8.89 ( s,1H), 9.10-9.16(m,2H), 10.48(s,1H), 10.97(s,1H);MS ESI+ m/z 360(M+H)+,ESI- m/z 358(M-H) -.
4－[4－苄胺基－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-Benzylamino-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
實例84A 4－(4－胺基－2－硝基－苯基硫基)－酚將4－氯基－3－硝基苯胺(1.0克，5.79毫莫耳)、4－羥基硫酚(0.75克，6.00毫莫耳)、碳酸銫(3.9克，12毫莫耳)在二甲亞碸(10毫升)中之溶液，於100℃下加熱16小時。然後將冰水(50毫升)添加至溶液中，並將所形成之漿液以醋酸乙酯(100毫升)處理。分離液層，並以10%碳酸氫鈉與10%氯化鈉洗滌有機層，然後以無水硫酸鈉脫水乾燥。過濾乾燥劑，並在真空下移除溶劑，留下紅色固體，為標題化合物(1.45克，92%)。Example 84A 4-(4-Amino-2-nitro-phenylthio)-phenol 4-Chloro-3-nitroaniline (1.0 g, 5.79 mmol), 4-hydroxythiophenol (0.75)克, 6.00 mmol, cesium carbonate (3.9 g, 12 mmol) in dimethyl hydrazine (10 mL), heated at 100 ° C for 16 h. Ice water (50 ml) was then added to the solution and the resulting syrup was treated with ethyl acetate (100 mL). The liquid layer was separated, and the organic layer was washed with 10% sodium hydrogen carbonate and 10% sodium chloride, and then dried over anhydrous sodium sulfate. The <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0>
實例84B 4－(4－苄胺基－2－硝基－苯基硫基)－酚將實例84A之產物(0.63克，2.4毫莫耳)、苯甲醛(0.24克，2.3毫莫耳)及氰基硼氫化鈉(0.15克，2.4毫莫耳)在含有1%醋酸之甲醇(10毫升)中之溶液，於室溫下攪拌16小時。以水(20毫升)使反應混合物淬滅，並使所形成之溶液於真空下濃縮成黃色固體。使固體溶於醋酸乙酯(50毫升)中，並以水、10%碳酸氫鈉及10%氯化鈉洗滌。使有機層以無水硫酸鈉脫水乾燥，過濾，及在真空下移除溶劑，留下淡黃色油。使此油藉矽膠層析純化，以二氯甲烷中之1%甲醇溶離，提供標題化合物(0.63克，77%)。Example 84B 4-(4-Benzylamino-2-nitro-phenylsulfanyl)-phenol The product of Example 84A (0.63 g, 2.4 mmol), benzaldehyde (0.24 g, 2.3 mmol) A solution of sodium cyanoborohydride (0.15 g, 2.4 mmol) in EtOAc (EtOAc) The reaction mixture was quenched with water (20 mL). The solid was dissolved in ethyl acetate (50 mL) and washed with water, 10% sodium hydrogen carbonate and 10% sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The oil was purified by EtOAc (EtOAc) elut elut elut elut
實例84C 4－(2－胺基－4－苄胺基－苯基硫基)－酚將實例84B之產物(0.5克，1.4毫莫耳)、鐵粉(0.49克，8.74毫莫耳)及氯化銨(0.50克，9.3毫莫耳)在甲醇(10毫升)、四氫呋喃(10毫升)及水(5毫升)溶液中之溶液加熱至回流，歷經1.5小時。以甲醇(50毫升)稀釋所形成之混合物，並經過矽藻土墊過濾。使濾液在真空下濃縮成體積10毫升，以水(50毫升)稀釋溶液，並以醋酸乙酯(2 x 50毫升)萃取。以10%氯化鈉洗滌合併之萃液，然後以硫酸鎂脫水乾燥，過濾，及在真空下濃縮，提供標題化合物(0.30克，66%)。Example 84C 4-(2-Amino-4-benzylamino-phenylthio)-phenol The product of Example 84B (0.5 g, 1.4 mmol), iron powder (0.49 g, 8.74 m. A solution of ammonium chloride (0.50 g, 9.3 mmol) in methanol (10 mL), EtOAc (EtOAc) The resulting mixture was diluted with methanol (50 mL) and filtered through a pad of Celite. The filtrate was concentrated in vacuo to a volume of 10 mL, diluted with water (50 mL) andEtOAc. The combined extracts were washed with EtOAc EtOAc EtOAc.
實例84D 4－[4－苄胺基－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚將得自實例10B之產物(30毫克，0.159毫莫耳)與得自實例84C之產物(56.5毫克，0.17毫莫耳)在醋酸(2毫升)中之溶液，於預熱至130℃之油浴中攪拌20分鐘。然後使混合物冷卻至室溫，在真空下移除醋酸，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(12毫克，10%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.71(s,3H),4.50(s,2H),6.60－6.69(m,2H),6.73－6.85(m,2H),7.04－7.29(m,6H),7.31－7.40(m,2H),7.46(d,J＝7.35 Hz,2H),8.54(s,1H),8.75(s,1H),9.74(s,1H)；MS(ESI)m/z 466(M＋H)＋,(ESI－)m/z 464(M－H)－.Example 84D 4-[4-Benzylamino-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol will be obtained from Example 10B. A solution of the product (30 mg, 0.159 mmol) from EtOAc (EtOAc) (EtOAc) The mixture was then cooled to rt. EtOAc (EtOAc m. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.71 (s, 3H), 4.50 (s, 2H), 6.60-6.69 (m, 2H), 6.73-6.85 (m, 2H), 7.04-7.29 ( m,6H), 7.31-7.40 (m, 2H), 7.46 (d, J = 7.35 Hz, 2H), 8.54 (s, 1H), 8.75 (s, 1H), 9.74 (s, 1H); MS (ESI) m/z 466(M+H)+, (ESI-)m/z 464(M-H)-.
N1－苄基－4－(4－苄氧基－苯基硫基)－N3－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－苯－1,3－二胺N1-benzyl-4-(4-benzyloxy-phenylsulfanyl)-N3-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-benzene-1,3- Diamine
實例85A 4－(2－胺基－4－硝基－苯基硫基)－酚將2－氯基－5－硝基苯胺(3克，17.4毫莫耳)、4－羥基硫酚(2.4克，19.0毫莫耳)、碳酸銫(12.35克，38毫莫耳)在二甲基甲醯胺(35毫升)中之溶液，於100℃下加熱16小時。然後將冰水(200毫升)添加至溶液中，並於所形成之漿液中，添加醋酸乙酯(200毫升)。分離液層，並以10%碳酸氫鈉與10%氯化鈉洗滌有機層，以無水硫酸鈉脫水乾燥。過濾乾燥劑，及在真空下移除溶劑，留下黃色油。使油藉矽膠層析純化，以二氯甲烷/甲醇(97：3)溶離，提供黃色固體，為標題化合物(2.1克，46%)。Example 85A 4-(2-Amino-4-nitro-phenylthio)-phenol 2-Chloro-5-nitroaniline (3 g, 17.4 mmol), 4-hydroxythiophenol (2.4 A solution of ruthenium carbonate (19.0 mmol), cesium carbonate (12.35 g, 38 mmol) in dimethylformamide (35 mL) was heated at 100 ° C for 16 h. Ice water (200 ml) was then added to the solution, and ethyl acetate (200 ml) was added to the formed slurry. The liquid layer was separated, and the organic layer was washed with 10% sodium hydrogen carbonate and 10% sodium chloride and dried over anhydrous sodium sulfate. The desiccant was filtered and the solvent was removed under vacuum to leave a yellow oil. The oil was purified by EtOAc EtOAc (EtOAc:EtOAc:
實例85B 2－(4－苄氧基－苯基硫基)－5－硝基－苯胺將含有得自實例85A之產物(0.2克，0.763毫莫耳)與碳酸銫(0.25克，0.763毫莫耳)在二甲基甲醯胺(5毫升)中之漿液，以溴化苄(0.091毫升，0.763毫莫耳)處理，並將所形成之漿液於室溫下攪拌18小時。然後將冰水(50毫升)添加至溶液中，並於所形成之漿液中，添加醋酸乙酯(50毫升)。分離液層，並以10%碳酸氫鈉與10%氯化鈉洗滌有機層，以無水硫酸鈉脫水乾燥。過濾乾燥劑，及在真空下移除溶劑，留下黃色固體，為標題化合物(0.24克，89%)。Example 85B 2-(4-Benzyloxy-phenylsulfanyl)-5-nitro-phenylamine will contain the product from Example 85A (0.2 g, 0.763 mmol) and bismuth carbonate (0.25 g, 0.763 mmol) The slurry was treated with benzyl bromide (0.091 mL, 0.763 m.m. Ice water (50 ml) was then added to the solution, and ethyl acetate (50 ml) was added to the formed slurry. The liquid layer was separated, and the organic layer was washed with 10% sodium hydrogen carbonate and 10% sodium chloride and dried over anhydrous sodium sulfate. The <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0>
實例85C[2－(4－苄氧基－苯基硫基)－5－硝基－苯基]－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺將得自實例10B之產物(62毫克，0.331毫莫耳)與實例85B之產物(120毫克，0.331毫莫耳)在醋酸(1毫升)中之溶液，於預熱至130℃之油浴中攪拌20分鐘。然後使混合物冷卻至室溫，在真空下移除醋酸，留下褐色油，為標題化合物(0.15克，92%)。將化合物用於下一步驟，無需純化。Example 85C [2-(4-Benzyloxy-phenylsulfanyl)-5-nitro-phenyl]-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine A solution of the product from Example 10B (62 mg, 0.331 mmol) and the product of Example 85B (120 mg, 0.331 mmol) in acetic acid (1 mL) in an oil bath preheated to 130 ° C Stir for 20 minutes. The mixture was then cooled to rt. EtOAc (EtOAc) The compound was used in the next step without purification.
實例85D 4－(4－苄氧基－苯基硫基)－N3－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－苯－1,3－二胺將得自實例85C之產物(0.150克，0.303毫莫耳)、鐵粉(0.10克，1.86毫莫耳)及氯化銨(0.10克，1.98毫莫耳)在甲醇(2毫升)、四氫呋喃(2毫升)及水(1毫升)溶液中之溶液加熱至回流，歷經1.5小時。以甲醇(50毫升)稀釋所形成之混合物，並經過矽藻土墊過濾。使濾液在真空下濃縮成體積10毫升，以水(50毫升)稀釋溶液，並以醋酸乙酯(2 x 50毫升)萃取。以10%氯化鈉洗滌合併之萃液，接著以硫酸鎂脫水乾燥，過濾，及在真空下濃縮，提供標題化合物(0.06克，42%)。Example 85D 4-(4-Benzyloxy-phenylsulfanyl)-N3-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-benzene-1,3-diamine The product from Example 85C (0.150 g, 0.303 mmol), iron powder (0.10 g, 1.86 mmol) and ammonium chloride (0.10 g, 1.98 mmol) in methanol (2 mL), tetrahydrofuran (2) The solution in milliliters and water (1 ml) was heated to reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 mL) and filtered through a pad of Celite. The filtrate was concentrated in vacuo to a volume of 10 mL, diluted with water (50 mL) andEtOAc. The combined extracts were washed with EtOAc EtOAc EtOAc.
實例85E N1－苄基－4－(4－苄氧基－苯基硫基)－N3－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－苯－1,3－二胺將實例85D中製成之化合物(0.06克，0.130毫莫耳)、苯甲醛(0.013克，0.130毫莫耳)及氰基硼氫化鈉(0.0081克，0.13毫莫耳)在甲醇(1毫升)中之含有1滴醋酸之混合物，於室溫下攪拌18小時。在真空下移除溶劑，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(12毫克，17%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.69(s,3H),4.30(s,2H),4.96(s,2H),6.60(dd,J＝8.46,2.57 Hz,1H),6.72－6.89(m,3H),6.94－7.09(m,2H),7.19－7.29(m,1H),7.29－7.46(m,11H),7.63(d,J＝8.46 Hz,1H),8.61(s,1H),8.71(d,J＝8.82 Hz,1H),10.69(s,1H).Example 85E N1-benzyl-4-(4-benzyloxy-phenylsulfanyl)-N3-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-benzene-1, 3-Diamine The compound prepared in Example 85D (0.06 g, 0.130 mmol), benzaldehyde (0.013 g, 0.130 mmol) and sodium cyanoborohydride (0.0081 g, 0.13 mmol) in methanol A mixture of 1 drop of acetic acid (1 ml) was stirred at room temperature for 18 hours. The solvent was removed in vacuo and EtOAcqqqqqqqq 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.69 (s, 3H), 4.30 (s, 2H), 4.96 (s, 2H), 6.60 (dd, J = 8.46, 2.57 Hz, 1H), 6.72 -6.89(m,3H),6.94-7.09(m,2H),7.19-7.29(m,1H), 7.29-7.46(m,11H),7.63(d,J=8.46 Hz,1H),8.61(s , 1H), 8.71 (d, J = 8.82 Hz, 1H), 10.69 (s, 1H).
4－[4－[(呋喃－3－基甲基)－胺基]－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-[(furan-3-ylmethyl)-amino]-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio ]-phenol
實例86A 4－[2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－硝基－苯基硫基]－酚將得自實例10B之產物(340毫克，1.80毫莫耳)與實例85A之產物(480毫克，1.80毫莫耳)在醋酸(10毫升)中之溶液，於預熱至130℃之油浴中攪拌30分鐘。然後使混合物冷卻至室溫，在真空下移除醋酸，留下褐色油，為標題化合物(0.65克，89%)。Example 86A 4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-nitro-phenylthio]-phenol will be obtained from the product of Example 10B (340 mg, 1.80 mmol) and a solution of the product from Example 85A (480 mg, 1. <RTI ID=0.0></RTI> </RTI> <RTIgt; The mixture was then cooled to rt. EtOAc (EtOAc)
實例86B 4－[4－胺基－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚將得自實例86A之產物(0.19克，0.469毫莫耳)與10% Pd/C(0.025克)在醋酸(3毫升)中之漿液置於氫大氣下，並於室溫下攪拌2小時。過濾漿液，並在真空下移除溶劑，留下褐色固體，為標題化合物之醋酸鹽(0.21克，91%)。Example 86B 4-[4-Amino-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol will be obtained from the product of Example 86A A slurry of (0.19 g, 0.469 mmol) and 10% Pd/C (0.025 g) in acetic acid (3 ml) was placed under hydrogen atmosphere and stirred at room temperature for 2 hr. The syrup was filtered, and the solvent was evaporated.
實例86C 4－[4－[(呋喃－3－基甲基)－胺基]－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚將得自實例86B之產物(69.7毫克，0.141毫莫耳)、3－呋喃醛(13.5毫克，0.141毫莫耳)及氰基硼氫化鈉(8.7毫克，0.141毫莫耳)在2毫升甲醇中之溶液，於室溫下攪拌18小時。在真空下蒸發溶劑，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(16毫克，14%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.75(s,3H),3.85(s,1H),4.09(s,2H),6.47(s,1H),6.53(d,J＝8.82 Hz,2H),6.62－6.75(m,2H),6.94(d,J＝8.46 Hz,3H),7.21－7.32(m,1H),7.61(s,1H),7.83(d,J＝8.46 Hz,1H),8.77(s,1H),8.88(s,1H),9.51(s,1H),11.68(s,1H).Example 86C 4-[4-[(Furan-3-ylmethyl)-amino]-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl Thio]-phenol will be obtained from the product of Example 86B (69.7 mg, 0.141 mmol), 3-furanal (13.5 mg, 0.141 mmol) and sodium cyanoborohydride (8.7 mg, 0.141 mmol) The solution in 2 ml of methanol was stirred at room temperature for 18 hours. The solvent was evaporated under EtOAc (EtOAc m. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.75 (s, 3H), 3.85 (s, 1H), 4.09 (s, 2H), 6.47 (s, 1H), 6.53 (d, J = 8.82 Hz , 2H), 6.62-6.75 (m, 2H), 6.94 (d, J = 8.46 Hz, 3H), 7.21-7.32 (m, 1H), 7.61 (s, 1H), 7.83 (d, J = 8.46 Hz, 1H), 8.77 (s, 1H), 8.88 (s, 1H), 9.51 (s, 1H), 11.68 (s, 1H).
4－{2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－[(噻吩－3－基甲基)－胺基]－苯基硫基}－酚4-{2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-[(thiophen-3-ylmethyl)-amino]-phenylthio }-phenol
使得自實例86B之產物溶液與3－噻吩羧醛之反應，根據得自實例86C之程序，以3－噻吩羧醛取代3－呋喃醛，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(26毫克，37%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.74(s,3H),3.74(s,1H),4.26(s,2H),6.52(d,J＝8.82 Hz,3H),6.64－6.76(m,1H),6.86－6.99(m,3H),7.02－7.14(m,1H),7.19－7.34(m,1H),7.42－7.54(m,1H),7.82(d,J＝8.09 Hz,1H),8.76(s,1H),8.90(s,1H),9.51(s,1H),11.65(s,1H).The product from Example 86B was reacted with 3-thiophenecarboxaldehyde, and the 3-furanaldehyde was replaced with 3-thiophenecarboxaldehyde according to the procedure from Example 86C to afford crude product. The compound was trifluoroacetate (26 mg, 37%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.74 (s, 3H), 3.74 (s, 1H), 4.26 (s, 2H), 6.52 (d, J = 8.82 Hz, 3H), 6.64-6.76 (m, 1H), 6.86-6.99 (m, 3H), 7.02-7.14 (m, 1H), 7.19-7.34 (m, 1H), 7.42-7.54 (m, 1H), 7.82 (d, J = 8.09 Hz , 1H), 8.76 (s, 1H), 8.90 (s, 1H), 9.51 (s, 1H), 11.65 (s, 1H).
4－{2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－[(萘－1－基甲基)－胺基]－苯基硫基}－酚4-{2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-[(naphthalen-1-ylmethyl)-amino]-phenylthio }-phenol
使得自實例86B之產物溶液與1－萘甲醛之反應，根據得自實例86C之程序，以1－萘甲醛取代3－呋喃醛，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(18毫克，12%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.73(s,3H),4.73(s,1H),6.39(s,1H),6.45－6.60(m,2H),6.67－6.80(m,1H),6.88－6.98(m,2H),7.17－7.34(m,1H),7.43－7.54(m,1H),7.51－7.71(m,4H),7.71－7.83(m,1H),7.83(d,J＝8.82 Hz,1H),7.95－8.09(m,2H),8.10－8.18(m,1H),8.22(d,J＝8.09 Hz,1H),8.76(s,1H),8.82－8.89(m,1H),9.51(s,1H),11.64(s,1H).The reaction of the product from Example 86B with 1-naphthaldehyde was used to give the title compound as the title compound. It was trifluoroacetate (18 mg, 12%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.73 (s, 3H), 4.73 (s, 1H), 6.39 (s, 1H), 6.45-6.60 (m, 2H), 6.67-6.80 (m, 1H), 6.88-6.98 (m, 2H), 7.17-7.34 (m, 1H), 7.43-7.54 (m, 1H), 7.51-7.71 (m, 4H), 7.71-7.83 (m, 1H), 7.83 ( d, J = 8.82 Hz, 1H), 7.95-8.09 (m, 2H), 8.10-8.18 (m, 1H), 8.22 (d, J = 8.09 Hz, 1H), 8.76 (s, 1H), 8.82-8.89 (m, 1H), 9.51 (s, 1H), 11.64 (s, 1H).
4－[4－[(呋喃－2－基甲基)－胺基]－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-[(furan-2-ylmethyl)-amino]-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio ]-phenol
使得自實例86B之產物溶液與2－呋喃醛之反應，根據得自實例86C之程序，以2－呋喃醛取代3－呋喃醛，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(18毫克，16%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.69－2.81(m,3H),4.26(s,2H),6.27－6.44(m,1H),6.45－6.59(m,2H),6.46－6.60(m,3H),6.68－6.78(m,2H),6.89－7.00(m,2H),7.20－7.33(m,1H),7.59(s,1H),7.84(d,J＝8.09 Hz,1H),8.77(s,1H),8.89(s,1H),11.73(s,1H).The reaction of the product from Example 86B with 2-furanaldehyde afforded the title compound as the title compound. It was trifluoroacetate (18 mg, 16%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.69-2.81 (m, 3H), 4.26 (s, 2H), 6.27-6.44 (m, 1H), 6.45-6.59 (m, 2H), 6.46- 6.60 (m, 3H), 6.68-6.78 (m, 2H), 6.89-7.00 (m, 2H), 7.20-7.33 (m, 1H), 7.59 (s, 1H), 7.84 (d, J = 8.09 Hz, 1H), 8.77 (s, 1H), 8.89 (s, 1H), 11.73 (s, 1H).
4－{2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－[(噻吩－2－基甲基)－胺基]－苯基硫基}－酚4-{2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-[(thiophen-2-ylmethyl)-amino]-phenylthio }-phenol
使得自實例86B之產物溶液與2－噻吩羧醛之反應，根據得自實例86C之程序，以2－噻吩羧醛取代3－呋喃醛，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(11毫克，16%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.64－2.86(m,3H),4.47(s,2H),6.46－6.57(m,2H),6.64－6.78(m,3H),6.87－7.00(m,3H),7.02－7.13(m,2H),7.19－7.31(m,2H),7.32－7.48(m,1H),7.82(d,J＝8.82 Hz,1H),8.77(s,1H),8.89(s,1H),9.50(s,1H),11.68(s,1H).Reaction of the product from Example 86B with 2-thiophenecarboxaldehyde, 3-furanaldehyde was replaced with 2-thiophenecarboxaldehyde according to the procedure from Example 86C to afford crude product which was purified by HPLC to afford title The compound was trifluoroacetate (11 mg, 16%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.64 - 2.86 (m, 3H), 4.47 (s, 2H), 6.46-6.57 (m, 2H), 6.64 - 6.78 (m, 3H), 6.87- 7.00 (m, 3H), 7.02-7.13 (m, 2H), 7.19-7.31 (m, 2H), 7.32-7.48 (m, 1H), 7.82 (d, J = 8.82 Hz, 1H), 8.77 (s, 1H), 8.89 (s, 1H), 9.50 (s, 1H), 11.68 (s, 1H).
4－[4－(4－溴－苄胺基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(4-Bromo-benzylamino)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
實例91A 4－[4－(4－溴－苄胺基)－2－硝基－苯基硫基]－酚使得自實例84A之產物溶液與4－溴基苯甲醛之反應，根據得自實例84B之程序，以4－溴基苯甲醛取代得自實例84A之產物，提供粗產物，使其藉矽膠層析純化，以二氯甲烷中之2%甲醇溶離，提供標題化合物，為黃色固體(0.11克，73%)。Example 91A 4-[4-(4-Bromo-benzylamino)-2-nitro-phenylthio]-phenol is allowed to react from the product of Example 84A with 4-bromobenzaldehyde, according to the obtained example The title compound was obtained as a yellow solid (yield: 0.11 g, 73%).
實例91B 4－[2－胺基－4－(4－溴－苄胺基)－苯基硫基]－酚使得自實例91A產物之溶液反應，根據得自實例84C之程序，提供標題化合物(0.17克，76%)。Example 91B 4-[2-Amino-4-(4-bromo-benzylamino)-phenylthio]-phenol was allowed to react from a solution of the product of Example 91A. 0.17 g, 76%).
實例91C 4－[4－(4－溴－苄胺基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚將實例10B之產物(50毫克，0.266毫莫耳)與實例91B之產物(110毫克，0.266毫莫耳)在醋酸(2毫升)中之溶液，於預熱至130℃之油浴中攪拌20分鐘。然後使混合物冷卻至室溫，在真空下移除醋酸，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(22毫克，15%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.73(s,3H),4.26(s,2H),6.53(d,J＝8.46 Hz,2H),6.54－6.69(m,2H),6.85－7.03(m,2H),7.23(d,J＝8.46 Hz,1H),7.30(d,J＝8.46 Hz,3H),7.46－7.61(m,2H),7.78(d,J＝8.46 Hz,1H),8.73(s,1H),8.89(d,J＝19.12 Hz,1H),9.51(s,1H),11.46(s,1H).Example 91C 4-[4-(4-Bromo-benzylamino)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)phenylsulfanyl]-phenol A solution of the product from Example 10B (50 mg, 0.266 mmol) eluted with EtOAc (EtOAc (EtOAc) minute. The mixture was then cooled to rt. EtOAc (EtOAc)EtOAc. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.73 (s, 3H), 4.26 (s, 2H), 6.53 (d, J = 8.46 Hz, 2H), 6.54-6.69 (m, 2H), 6.85 -7.03 (m, 2H), 7.23 (d, J = 8.46 Hz, 1H), 7.30 (d, J = 8.46 Hz, 3H), 7.46-7.61 (m, 2H), 7.78 (d, J = 8.46 Hz, 1H), 8.73 (s, 1H), 8.89 (d, J = 19.12 Hz, 1H), 9.51 (s, 1H), 11.46 (s, 1H).
N1－苄基－4－(4－甲氧基－苯基硫基)－N3－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－苯－1,3－二胺N1-benzyl-4-(4-methoxy-phenylthio)-N3-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-benzene-1,3- Diamine
實例92A 4－(4－甲氧基－苯基硫基)－3－硝基－苯胺將4－氯基－3－硝基苯胺(1.0克，5.79毫莫耳)、4－甲氧基硫酚(0.84克，6.00毫莫耳)、碳酸銫(1.95克，6.00毫莫耳)在二甲基甲醯胺(10毫升)中之溶液，於100℃下加熱16小時。然後將冰水(50毫升)添加至溶液中，並將所形成之漿液以醋酸乙酯(100毫升)處理。分離液層，並以10%碳酸氫鈉與10%氯化鈉洗滌有機層，接著以無水硫酸鈉脫水乾燥。過濾乾燥劑，及在真空下移除溶劑，留下紅色固體，為標題化合物(1.5克，94%)。Example 92A 4-(4-Methoxy-phenylthio)-3-nitro-phenylamine 4-Chloro-3-nitroaniline (1.0 g, 5.79 mmol), 4-methoxy sulphur A solution of phenol (0.84 g, 6.00 mmol), cesium carbonate (1.95 g, 6.00 mmol) in dimethylformamide (10 mL) was heated at 100 ° C for 16 h. Ice water (50 ml) was then added to the solution and the resulting syrup was treated with ethyl acetate (100 mL). The liquid layer was separated, and the organic layer was washed with 10% sodium hydrogen carbonate and 10% sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was filtered, and the solvent was evaporated.
實例92B苄基－[4－(4－甲氧基－苯基硫基)－3－硝基－苯基]－胺將實例92A之產物(0.50克，1.81毫莫耳)、苯甲醛(0.19克，1.81毫莫耳)及氰基硼氫化鈉(0.11克，1.8毫莫耳)在含有1%醋酸之甲醇(10毫升)中之溶液，於室溫下攪拌16小時。以水(20毫升)使反應混合物淬滅，並使所形成之溶液於真空下濃縮成黃色固體。使固體溶於醋酸乙酯(50毫升)中，並以水、10%碳酸氫鈉及10%氯化鈉洗滌。使有機層以無水硫酸鈉脫水乾燥，過濾，及在真空下移除溶劑，留下淡黃色油。使油藉矽膠層析純化，以二氯甲烷中之1%甲醇溶離，提供標題化合物，為磚紅色固體(0.62克，91%)。Example 92B Benzyl-[4-(4-methoxy-phenylthio)-3-nitro-phenyl]-amine The product of Example 92A (0.50 g, 1.81 mmol), benzaldehyde (0.19 </RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The reaction mixture was quenched with water (20 mL). The solid was dissolved in ethyl acetate (50 mL) and washed with water, 10% sodium hydrogen carbonate and 10% sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The oil was purified by EtOAc EtOAc (EtOAc)
實例92C N1－苄基－4－(4－甲氧基－苯基硫基)－苯－1,3－二胺使實例92B產物之溶液反應，根據得自實例84C之程序，提供標題化合物(0.49克，89%)。Example 92C N1-Benzyl-4-(4-methoxy-phenylsulfanyl)-benzene-1,3-diamine The solution of the product of Example 92B was obtained. 0.49 g, 89%).
實例92D N1－苄基－4－(4－甲氧基－苯基硫基)－N3－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－苯－1,3－二胺將實例10B之產物(27.8毫克，0.148毫莫耳)與實例92C之產物(49毫克，0.148毫莫耳)在醋酸(2毫升)中之溶液，於預熱至130℃之油浴中攪拌20分鐘。然後使混合物冷卻至室溫，在真空下移除醋酸，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(15毫克，14%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.64－2.81(m,3H),3.56－3.71(m,3H),4.29(s,2H),6.61－6.75(m,3H),6.95－7.07(m,2H),7.16－7.45(m,8H),7.76(d,J＝8.46 Hz,1H),8.69(s,1H),8.80(d,1H),11.34(s,1H).Example 92D N1-benzyl-4-(4-methoxy-phenylthio)-N3-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-benzene-1, 3-Diamine A solution of the product from Example 10B (27.8 mg, 0.148 mmol) and the product from Example 92C (49 mg, 0.148 mmol) in acetic acid (2 mL). Stir in the bath for 20 minutes. The mixture was then cooled to rt. EtOAc (EtOAc m. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.64-2.81 (m, 3H), 3.56-3.71 (m, 3H), 4.29 (s, 2H), 6.61-6.75 (m, 3H), 6.95- 7.07 (m, 2H), 7.16-7.45 (m, 8H), 7.76 (d, J = 8.46 Hz, 1H), 8.69 (s, 1H), 8.80 (d, 1H), 11.34 (s, 1H).
N1－苄基－4－(4－甲氧基－苯氧基)－N3－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－苯－1,3－二胺N1-benzyl-4-(4-methoxy-phenoxy)-N3-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-benzene-1,3-di amine
實例93A 4－(4－甲氧基－苯氧基)－3－硝基－苯胺將4－氯基－3－硝基苯胺(1.0克，5.79毫莫耳)、4－甲氧基酚(0.74克，6.00毫莫耳)、碳酸銫(1.95克，6.00毫莫耳)在二甲基甲醯胺(10毫升)中之溶液，於100℃下加熱16小時。然後將冰水(50毫升)添加至溶液中，並將所形成之漿液以醋酸乙酯(100毫升)處理。分離液層，並以10%碳酸氫鈉與10%氯化鈉洗滌有機層，然後以無水硫酸鈉脫水乾燥。過濾乾燥劑，及在真空下移除溶劑，留下紅色固體，為標題化合物(1.1克，73%)。Example 93A 4-(4-Methoxy-phenoxy)-3-nitro-phenylamine 4-Chloro-3-nitroaniline (1.0 g, 5.79 mmol), 4-methoxyphenol ( A solution of 0.74 g, 6.00 mmol, cesium carbonate (1.95 g, 6.00 mmol) in dimethylformamide (10 mL) was heated at 100 ° C for 16 h. Ice water (50 ml) was then added to the solution and the resulting syrup was treated with ethyl acetate (100 mL). The liquid layer was separated, and the organic layer was washed with 10% sodium hydrogen carbonate and 10% sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was filtered, and the solvent was evaporated.
實例93B N1－苄基－4－(4－甲氧基－苯氧基)－苯－1,3－二胺使得自實例93A產物之溶液反應，根據得自實例92B之程序，以得自實例93A之產物取代得自實例92A之產物，將其根據得自實例84C之程序還原，提供標題化合物(0.05克，12%)。Example 93B N1-benzyl-4-(4-methoxy-phenoxy)-benzene-1,3-diamine was allowed to react from a solution of the product of Example 93A, according to the procedure from Example 92B, The product from Example </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt;
實例93C N1－苄基－4－(4－甲氧基－苯氧基)－N3－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－苯－1,3－二胺使實例10B之產物與得自實例93B之產物溶液反應，根據得自實例92D之程序，以得自實例93B之產物取代得自實例92C之產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(8毫克，18%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.55－2.68(m,3H),3.61(s,3H),4.26(d,J＝5.88 Hz,2H),6.27(t,J＝5.88 Hz,1H),6.50(dd,J＝8.64,2.76 Hz,1H),6.64－6.87(m,6H),7.18－7.45(m,6H),8.48(s,1H),8.57(d,J＝8.46 Hz,1H),9.59(s,1H).Example 93C N1-benzyl-4-(4-methoxy-phenoxy)-N3-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-benzene-1,3 - Diamine The product of Example 10B was reacted with the product from Example 93B, and the product from Example 92C was substituted from the product from Example </RTI> The title compound was trifluoroacetate (8 mg, 18%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.55-2.68 (m, 3H), 3.61 (s, 3H), 4.26 (d, J = 5.88 Hz, 2H), 6.27 (t, J = 5.88 Hz , 1H), 6.50 (dd, J=8.64, 2.76 Hz, 1H), 6.64-6.87 (m, 6H), 7.18-7.45 (m, 6H), 8.48 (s, 1H), 8.57 (d, J = 8.46) Hz, 1H), 9.59 (s, 1H).
N1－苄基－4－(4－苄氧基－苯氧基)－N3－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－苯－1,3－二胺N1-benzyl-4-(4-benzyloxy-phenoxy)-N3-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-benzene-1,3-di amine
實例94A 4－(4－苄氧基－苯氧基)－3－硝基－苯胺將4－氯基－3－硝基苯胺(2.0克，11.16毫莫耳)、4－苄氧基酚(2.55克，12.76毫莫耳)、粉末狀氫氧化鉀(0.94克，16.80毫莫耳)在二甲基甲醯胺(15毫升)中之溶液，於120℃下加熱20小時。然後將冰水(50毫升)添加至溶液中，並將所形成之漿液以醋酸乙酯(100毫升)處理。分離液層，並以10%碳酸氫鈉與10%氯化鈉洗滌有機層，然後以無水硫酸鈉脫水乾燥。過濾乾燥劑，及在真空下移除溶劑，留下深紅色固體，為標題化合物(2.07克，53%)。Example 94A 4-(4-Benzyloxy-phenoxy)-3-nitro-phenylamine 4-Chloro-3-nitroaniline (2.0 g, 11.16 mmol), 4-benzyloxyphenol ( 2.55 g, 12.76 mmol, a solution of powdered potassium hydroxide (0.94 g, 16.80 mmol) in dimethylformamide (15 mL). Ice water (50 ml) was then added to the solution and the resulting syrup was treated with ethyl acetate (100 mL). The liquid layer was separated, and the organic layer was washed with 10% sodium hydrogen carbonate and 10% sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was filtered, and the solvent was evaporated,jjjjjjjj
實例94B N1－苄基－4－(4－苄氧基－苯氧基)－苯－1,3－二胺使得自實例94A產物之溶液反應，根據得自實例92B之程序，以得自實例94A之產物取代得自實例92A之產物，將其根據得自實例84C之程序還原，提供標題化合物(0.6克，91%)。Example 94B N1-benzyl-4-(4-benzyloxy-phenoxy)-benzene-1,3-diamine was allowed to react from a solution of the product of Example 94A, from the procedure obtained from Example 92B. The product from <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> <RTI ID=0.0>
實例94C N1－苄基－4－(4－苄氧基－苯氧基)－N3－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－苯－1,3－二胺使實例10B之產物與得自實例94B之產物溶液反應，根據得自實例92D之程序，以得自實例94B之產物取代得自實例92C之產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(12毫克，10%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.70(s,3H),4.27(s,2H),4.94(s,2H),4.99－5.12(m,1H),6.64(dd,J＝8.82,2.94 Hz,1H),6.70－6.92(m,9H),6.90－7.00(m,1H),7.16－7.29(m,1H),7.31－7.42(m,5H),7.70(d,J＝8.46 Hz,1H),8.67－8.86(m,2H),11.22(s,1H).Example 94C N1-benzyl-4-(4-benzyloxy-phenoxy)-N3-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-benzene-1,3 - Diamine The product of Example 10B was reacted with a solution of the product from Example 94B, and the product from Example 92C was substituted from the product from Example 94. The title compound was trifluoroacetate (12 mg, 10%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.70 (s, 3H), 4.27 (s, 2H), 4.94 (s, 2H), 4.99-5.12 (m, 1H), 6.64 (dd, J = 8.82, 2.94 Hz, 1H), 6.70-6.92 (m, 9H), 6.90-7.00 (m, 1H), 7.16-7.29 (m, 1H), 7.31-7.42 (m, 5H), 7.70 (d, J = 8.46 Hz, 1H), 8.67-8.86 (m, 2H), 11.22 (s, 1H).
4－[4－胺基－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-Amino-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
實例95A 4－[2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－硝基－苯基硫基]－酚將得自實例10B之產物(340毫克，2.31毫莫耳)與實例85A之產物(610毫克，2.30毫莫耳)在醋酸(10毫升)中之溶液，於預熱至130℃之油浴中攪拌10分鐘。然後使混合物冷卻至室溫，在真空下移除醋酸，提供褐色油，為標題化合物(0.92克，92%)。Example 95A 4-[2-(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-nitro-phenylthio]-phenol will be obtained from Example 10B. A solution of the product (340 mg, 2.31 mmol) and EtOAc (EtOAc: EtOAc (EtOAc) The mixture was then cooled to rt. EtOAc (EtOAc)
實例95B 4－[4－胺基－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚將實例95A中所製成之化合物(0.7克，1.73毫莫耳)與10% Pd/C(100毫克)在醋酸(10毫升)與甲醇(10毫升)中之漿液置於氫氣瓶大氣下，並於室溫下攪拌20小時。過濾漿液，並在真空下移除溶劑，提供標題化合物，為醋酸鹽(540毫克，63%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.35(d,J＝7.0 Hz,6H),1.91(s,6H),3.27(m,1H),6.55(d,J＝8.8 Hz,2H),6.62(m,1H),6.69(m,1H),6.95(d,J＝8.8 Hz,2H),7.20(d,J＝8.5 Hz,1H),7.87(d,J＝8.5 Hz,1H),7.95(s,1H),8.75(s,1H),8.99(m,1H),9.52(s,1H),11.57(bs,1H)；MS(ESI＋)m/z 404(M＋H)＋.Example 95B 4-[4-Amino-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-phenol was prepared as in Example 95A A slurry of the compound (0.7 g, 1.73 mmol) and 10% Pd/C (100 mg) in acetic acid (10 ml) and methanol (10 ml) was placed under a hydrogen atmosphere and stirred at room temperature. 20 hours. The syrup was filtered and the title title compound was crystalljjjjjjj 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 7.0 Hz, 6H), 1.91 (s, 6H), 3.27 (m, 1H), 6.55 (d, J = 8.8 Hz, 2H ), 6.62 (m, 1H), 6.69 (m, 1H), 6.95 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H) ), 7.95 (s, 1H), 8.75 (s, 1H), 8.99 (m, 1H), 9.52 (s, 1H), 11.57 (bs, 1H); MS (ESI+) m/z 404 (M+H)+.
4－[2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－苯乙基胺基－苯基硫基]－酚4-[2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-phenylethylamino-phenylthio]-phenol
將含有得自實例95B之產物(65毫克，0.124毫莫耳)、苯乙醛(15毫克，0.124毫莫耳)及氰基硼氫化鈉(10毫克，0.199毫莫耳)在2毫升甲醇中之溶液，於室溫下攪拌18小時。在真空下蒸發溶劑，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(25毫克，32%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.28(d,6H),2.31－2.48(m,1H),2.78－2.93(m,2H),3.16－3.35(m,2H),4.17－4.36(m,2H),4.73－4.91(m,1H),6.47－6.59(m,2H),6.61－6.74(m,1H),6.86－7.01(m,2H),7.10(d,J＝6.99 Hz,1H),7.15－7.27(m,1H),7.19－7.39(m,6H),7.89(d,J＝8.46 Hz,1H),8.77(s,1H),8.96(s,1H),9.50(s,1H),11.61(s,1H).The product from Example 95B (65 mg, 0.124 mmol), phenylacetaldehyde (15 mg, 0.124 mmol) and sodium cyanoborohydride (10 mg, 0.199 mmol) in 2 mL of methanol The solution was stirred at room temperature for 18 hours. The solvent was evaporated under EtOAc (EtOAc m. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.28 (d, 6H), 2.31-2.48 (m, 1H), 2.78-2.93 (m, 2H), 3.16-3.35 (m, 2H), 4.17- 4.36 (m, 2H), 4.73-4.91 (m, 1H), 6.47-6.59 (m, 2H), 6.61-6.74 (m, 1H), 6.86-7.01 (m, 2H), 7.10 (d, J = 6.99) Hz, 1H), 7.15-7.27 (m, 1H), 7.19-7.39 (m, 6H), 7.89 (d, J = 8.46 Hz, 1H), 8.77 (s, 1H), 8.96 (s, 1H), 9.50 (s, 1H), 11.61 (s, 1H).
4－[4－(環戊基甲基－胺基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(cyclopentylmethyl-amino)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使含有得自實例95B產物之溶液與環戊烷羧甲醛反應，根據得自實例96之程序，以環戊烷羧甲醛取代苯乙醛，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(11毫克，9%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.26－1.43(m,6H),1.53(s,4H),1.75(d,J＝3.31 Hz,4H),2.01－2.19(m,1H),2.92(d,J＝6.99 Hz,2H),3.20－3.36(m,1H),6.53(d,J＝8.82 Hz,2H),6.58－6.73(m,1H),6.87－7.00(m,2H),6.98－7.13(m,1H),7.17－7.36(m,1H),7.89(s,1H),8.15(s,1H),8.77(s,1H),8.95(s,1H),9.49(s,1H),10.98(s,1H),11.68(s,1H).The solution containing the product from Example 95B was reacted with cyclopentanecarboxaldehyde, and phenylacetaldehyde was replaced with cyclopentanecarboxycarboxaldehyde according to the procedure from Example 96. Fluoroacetate (11 mg, 9%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.26-1.43 (m, 6H), 1.53 (s, 4H), 1.75 (d, J = 3.31 Hz, 4H), 2.01-2.19 (m, 1H) , 2.92 (d, J = 6.99 Hz, 2H), 3.20-3.36 (m, 1H), 6.53 (d, J = 8.82 Hz, 2H), 6.58-6.73 (m, 1H), 6.87-7.00 (m, 2H) ), 6.98-7.13 (m, 1H), 7.17-7.36 (m, 1H), 7.89 (s, 1H), 8.15 (s, 1H), 8.77 (s, 1H), 8.95 (s, 1H), 9.49 ( s, 1H), 10.98 (s, 1H), 11.68 (s, 1H).
N1－苄基－N3－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－4－(4－甲氧基－苯基硫基)－苯－1,3－二胺N1-benzyl-N3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-4-(4-methoxy-phenylthio)-benzene-1,3 -diamine
將得自實例36E之產物(40.4毫克，0.187毫莫耳)與實例92C之產物(62.8毫克，0.187毫莫耳)在醋酸(2毫升)中之溶液，於預熱至140℃之油浴中攪拌45分鐘。使反應物冷卻至室溫，以己烷(50毫升)稀釋，藉迴轉式蒸發濃縮，並與二氯甲烷/己烷共蒸發(4x)。使殘留物在真空下乾燥，接著藉矽膠急驟式層析之純化，使用15%至20%醋酸乙酯/二氯甲烷之梯度液作為溶離劑，而得標題化合物，為黃色固體(29.6毫克，31%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.31(d,J＝6.99 Hz,6H)3.11－3.26(m,1H)3.64(s,3H)4.30(d,J＝5.88 Hz,2H)6.53(dd,J＝8.46,2.57 Hz,1H)6.66－6.78(m,3H)6.95(d,J＝2.21 Hz,1H)7.03(d,J＝8.82 Hz,2H)7.12－7.28(m,2H)7.28－7.44(m,4H)7.54(d,J＝8.46 Hz,1H)8.50(s,1H)8.65(d,J＝8.46 Hz,1H)9.75(s,1H)；MS(DCI/NH3 )m/z 508(M＋H)＋ .A solution of the product from Example 36E (40.4 mg, 0.187 mmol) and the product of Example 92C (62.8 mg, 0.187 mmol) in acetic acid (2 mL) in an oil bath preheated to 140 ° C Stir for 45 minutes. The reaction was cooled to room rt, diluted with EtOAc EtOAc EtOAc. The residue was dried with EtOAc (EtOAc m. 31%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.31 (d, J = 6.99 Hz, 6H) 3.11-3.26 (m, 1H) 3.64 (s, 3H) 4.30 (d, J = 5.88 Hz, 2H) 6.53 (dd, J = 8.46, 2.57 Hz, 1H) 6.66-6.78 (m, 3H) 6.95 (d, J = 2.21 Hz, 1H) 7.03 (d, J = 8.82 Hz, 2H) 7.12-7.28 (m, 2H) ) 7.28-7.44 (m, 4H) 7.54 (d, J = 8.46 Hz, 1H) 8.50 (s, 1H) 8.65 (d, J = 8.46 Hz, 1H) 9.75 (s, 1H); MS (DCI/NH 3 ) m/z 508 (M+H) + .
4－[2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－吡咯－1－基－苯基硫基]－酚4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-pyrrol-1-yl-phenylthio]-phenol
於得自實例86B之產物(50毫克，0.101毫莫耳)與琥珀酸二醛(40%，在水溶液中)(0.065毫升，0.303毫莫耳)在甲苯(5毫升)與甲醇(3毫升)中之溶液內，添加4A分子篩(100毫克)。然後將混合物加熱至60℃，歷經7小時，冷卻至室溫，在真空下移除溶劑，添加0.1N鹽酸水溶液(20毫升)，並以二氯甲烷(2 x 25毫升)與二氧陸圜(25毫升)萃取混合物。使合併之有機萃液脫水乾燥，及在真空下濃縮，接著使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(14毫克，26%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.68(s,3H),6.26(m,2H),6.77(d,J＝8.5 Hz,2H),7.05(d,J＝8.5 Hz,1H),7.24(d,J＝8.5 Hz,2H),7.37(m,2H),7.48(dd,J＝8.6,2.4 Hz,1H),7.57(d,J＝8.5 Hz,1H),7.73(d,J＝2.6 Hz,1H),8.57(s,1H),8.80(d,J＝8.4 Hz,1H),9.81(s,1H),10.11(s,1H)；MS(ESI＋)m/z 426(M＋H)＋.The product from Example 86B (50 mg, 0.101 mmol) and succinic acid dialdehyde (40% in aqueous) (0.065 mL, 0.303 mmol) in toluene (5 mL) and methanol (3 mL) Into the solution, 4A molecular sieve (100 mg) was added. The mixture was then heated to 60 ° C for 7 hours, cooled to room temperature, the solvent was removed in vacuo and aq. 0.1N aqueous hydrochloric acid (20 mL) and dichloromethane (2 x 25 mL) and dioxane (25 ml) extract the mixture. The combined organic extracts were dried <RTI ID=0.0> 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.68 (s, 3H), 6.26 (m, 2H), 6.77 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.5 Hz, 1H) ), 7.24 (d, J = 8.5 Hz, 2H), 7.37 (m, 2H), 7.48 (dd, J = 8.6, 2.4 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.73 (d) , J = 2.6 Hz, 1H), 8.57 (s, 1H), 8.80 (d, J = 8.4 Hz, 1H), 9.81 (s, 1H), 10.11 (s, 1H); MS (ESI+) m/z 426 (M+H)+.
4－[2,4－雙－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[2,4-bis-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
將得自實例86B之產物(50毫克，0.101毫莫耳)與得自實例10B之產物(19毫克，0.101毫莫耳)在醋酸(1毫升)中之溶液加熱至120℃，歷經2小時。於冷卻至室溫後，在真空下移除溶劑，並添加甲醇(2毫升)。收集所形成之固體，並以甲醇研製，提供標題化合物，為淡褐色固體(12毫克，23%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.67(s,3H),2.68(m,3H),6.75(d,J＝8.8 Hz,2H),6.83(m,1H),7.12(m,1H),7.21(d,J＝8.8 Hz,2H),7.34(m,1H),7.58(m,J＝8.8 Hz,2H),8.73(s,1H),8.81(m,1H),8.88(m,1H),9.76(s,1H),10.13(s,1H),11.95(bs,1H)；MS(ESI＋)m/z 519(M＋H)＋.A solution of the product from Example 86B (50 mg, 0.11 <RTI ID=0.0></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI></RTI></RTI></RTI><RTIgt; After cooling to room temperature, the solvent was removed in vacuo and methanol (2 mL) was evaporated. The resulting solid was collected and purified with EtOAc EtOAcjjjjj 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.67 (s, 3H), 2.68 (m, 3H), 6.75 (d, J = 8.8 Hz, 2H), 6.83 (m, 1H), 7.12 (m) , 1H), 7.21 (d, J = 8.8 Hz, 2H), 7.34 (m, 1H), 7.58 (m, J = 8.8 Hz, 2H), 8.73 (s, 1H), 8.81 (m, 1H), 8.88 (m, 1H), 9.76 (s, 1H), 10.13 (s, 1H), 11.95 (bs, 1H); MS (ESI+) m/z 519 (M+H)+.
4－[4－(4－溴－苄胺基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(4-Bromo-benzylamino)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使含有得自實例95B產物之溶液與4－溴－苯甲醛反應，根據得自實例96之程序，以4－溴－苯甲醛取代苯乙醛，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(7毫克，3%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.35(d,J＝6.6 Hz,6H),3.30(m,1H),6.55(d,J＝8.5 Hz,2H),6.68(m,1H),6.76(d,J＝8.8 Hz,2H),6.91(m,1H),6.98(d,J＝8.5 Hz,2H),7.27(d,J＝8.8 Hz,2H),7.32(m,1H),7.56(m,2H),8.78(s,1H),9.53(m,1H)；MS(ESI＋)m/z 574(M＋H)＋.The solution containing the product from Example 95B was reacted with 4-bromo-benzaldehyde, and phenylacetaldehyde was replaced with 4-bromo-benzaldehyde according to the procedure from Example 96. It is trifluoroacetate (7 mg, 3%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.6 Hz, 6H), 3.30 (m, 1H), 6.55 (d, J = 8.5 Hz, 2H), 6.68 (m, 1H) ), 6.76 (d, J = 8.8 Hz, 2H), 6.91 (m, 1H), 6.98 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 7.32 (m, 1H) ), 7.56 (m, 2H), 8.78 (s, 1H), 9.53 (m, 1H); MS (ESI+) m/z 574 (M+H)+.
4－[4－甲基－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-methyl-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
將得自實例10B之產物(100毫克，0.575毫莫耳)與得自實例6c之產物(146毫克，0.632毫莫耳)在醋酸(1毫升)中之溶液，於130℃下加熱1小時。然後使混合物冷卻至室溫，接著將甲醇(5毫升)添加至溶液中，並收集所形成之固體，且以甲醇洗滌，提供標題化合物(120毫克，56%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.29(s,3H),2.66(s,3H),6.73(d,J＝8.8 Hz,2H),6.93(m,1H),7.03(m,1H),7.18(d,J＝8.5 Hz,2H),7.26(s,1H),7.53(d,J＝8.5 Hz,1H),8.53(s,1H),8.77(m,1H),9.76(bs,1H),9.96(bs,1H)；MS(ESI)＋ m/z 375(M＋H)＋.A solution of the product from Example 10B (100 mg, 0.575 mmol) eluted from EtOAc (EtOAc: EtOAc) The mixture was then cooled to rt then MeOH (5 mL) was evaporated. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.29 (s, 3H), 2.66 (s, 3H), 6.73 (d, J = 8.8 Hz, 2H), 6.93 (m, 1H), 7.03 (m) , 1H), 7.18 (d, J = 8.5 Hz, 2H), 7.26 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 8.53 (s, 1H), 8.77 (m, 1H), 9.76 (bs, 1H), 9.96 (bs, 1H); MS (ESI) + m/z 375 (M+H)+.
(5－甲基－2－苯基硫基－苯基)－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺(5-Methyl-2-phenylthio-phenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
將得自實例10B之產物(90毫克，0.517毫莫耳)與得自實例5I之產物(122毫克，0.569毫莫耳)在醋酸(1毫升)中之溶液，於130℃下加熱1小時。然後使混合物冷卻至室溫，收集所形成之固體，並以甲醇洗滌，接著在二氧陸圜(2毫升)中溶解50毫克物質，且添加鹽酸，接著在真空下移除溶劑，提供標題化合物，為鹽酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.37(s,3H),2.74(s,3H),7.18(m,5H),7.24(m,1H),7.37(m,2H),7.81(d,J＝8.5 Hz,1H),8.80(s,1H),8.99(d,J＝8.5 Hz,1H),11.82(bs,1H)；MS(ESI)＋ m/z 359(M＋H)＋.A solution of the product from Example 10B (90 mg, 0.517 mmol) eluted from EtOAc (EtOAc) The mixture was then cooled to room temperature, the solid formed was collected, washed with methanol, then 50 mg of material was dissolved in dioxane (2 mL) and hydrochloric acid was added, then solvent was evaporated in vacuo to afford title compound , is the hydrochloride salt. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.37 (s, 3H), 2.74 (s, 3H), 7.18 (m, 5H), 7.24 (m, 1H), 7.37 (m, 2H), 7.81 (d, J = 8.5 Hz, 1H), 8.80 (s, 1H), 8.99 (d, J = 8.5 Hz, 1H), 11.82 (bs, 1H); MS (ESI) + m/z 359 (M+H)+ .
[3－(3－溴－苯氧基甲基)－苯基]－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺[3-(3-Bromo-phenoxymethyl)-phenyl]-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
實例104A 1－硝基－3－(3－溴－苯氧基甲基)－苯將氯化3－硝基苄(1.0克，5.83毫莫耳)、3－溴酚(1.01克，5.83毫莫耳)及碳酸鉀(806毫克，5.83毫莫耳)在丙酮(25毫升)中之溶液加熱至回流，歷經23小時。於冷卻後，濾出固體，並使濾液在真空下濃縮成黃色殘留物，使其溶於醋酸乙酯(50毫升)中，且以1N氫氧化鈉水溶液(25毫升)與水(25毫升)洗滌，然後脫水乾燥，及在真空下濃縮成標題化合物，為白色固體(1.64克，91%)。Example 104A 1-Nitro-3-(3-bromo-phenoxymethyl)-benzene will be 3-nitrobenzyl chloride (1.0 g, 5.83 mmol), 3-bromophenol (1.01 g, 5.83 m) A solution of potassium carbonate (80 mg, 5.83 mmol) in acetone (25 mL) was heated to reflux for 23 h. After cooling, the solid was filtered, EtOAcjjjjjjjjjjjj After washing, it was dried over EtOAcqqqqqqqq
實例104B 3－(3－溴－苯氧基甲基)－苯胺將得自實例104A之產物(1.64克，5.32毫莫耳)、鐵粉(1.49克，26.62毫莫耳)與氯化銨(430毫克，7.98毫莫耳)在四氫呋喃(20毫升)、水(6毫升)及乙醇(20毫升)之混合物中之溶液加熱至回流，歷經3小時。使混合物冷卻至室溫，經過矽藻土墊過濾，將其以乙醇洗滌，並在真空下濃縮所形成之濾液。然後使物質溶於水(50毫升)中，並以醋酸乙酯(50毫升)萃取，使有機層脫水乾燥，及在真空下濃縮，提供標題化合物，為黃色油(1.43克，97%)。Example 104B 3-(3-Bromo-phenoxymethyl)-phenylamine The product from Example 104A (1.64 g, 5.32 mmol), iron powder (1.49 g, 26.62 mmol) and ammonium chloride ( A solution of 430 mg, 7.98 mmol, in a mixture of tetrahydrofuran (20 mL), water (6 mL) and ethanol (20 mL). The mixture was allowed to cool to room temperature, filtered through a pad of Celite, washed with ethanol, and concentrated. The material was then taken up in EtOAc EtOAc (EtOAc)
實例104C[3－(3－溴－苯氧基甲基)－苯基]－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺將得自實例10C之產物(50毫克，0.266毫莫耳)與得自實例104B之產物(74毫克，0.266莫耳)在醋酸(3毫升)中之溶液加熱至130℃，歷經30分鐘。於冷卻至室溫後，使溶液在真空下濃縮，並藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(62毫克，44%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.71(s,3H),5.20(s,2H),7.05(m,1H),7.16(m,1H),7.24(m,2H),7.33(m,1H),7.49(t,J＝7.7 Hz,1H),7.70(d,J＝8.5 Hz,1H),7.79(m,1H),7.84(s,1H),8.83(s,1H),8.96(d,J＝8.4 Hz,1H),10.75(bs,1H)；MS(ESI)＋ m/z 421/423(M＋H)＋.Example 104C [3-(3-Bromo-phenoxymethyl)-phenyl]-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine will be obtained from Example 10C. A solution of the product (50 mg, 0.266 mmol) from EtOAc (EtOAc) After cooling to rt, EtOAc (EtOAc m. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.71 (s, 3H), 5.20 (s, 2H), 7.05 (m, 1H), 7.16 (m, 1H), 7.24 (m, 2H), 7.33 (m, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.79 (m, 1H), 7.84 (s, 1H), 8.83 (s, 1H) , 8.96 (d, J = 8.4 Hz, 1H), 10.75 (bs, 1H); MS (ESI) + m/z 421/423 (M+H)+.
(3'－甲氧基－5－甲基－聯苯－3－基)－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺(3'-Methoxy-5-methyl-biphenyl-3-yl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
實例105A 3－溴基－5－甲基－苯胺標題化合物係使用得自實例104B之條件，製自3－溴基－5－硝基甲苯(1.08克，5.0毫莫耳)，提供標題化合物，為橘色油(0.8克，86%)。Example 105A 3-bromo-5-methyl-phenylamine the title compound was obtained from the title compound from EtOAc (EtOAc: EtOAc: It is an orange oil (0.8 g, 86%).
實例105B(3－溴基－5－甲基－苯基)－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺使得自實例105A之產物(0.8克，4.3毫莫耳)與得自實例10C之產物反應，使用得自實例104C之程序，以得自實例105A之產物取代得自實例104B之產物，提供粗製殘留物，使其在矽膠上藉層析純化，以99：1二氯甲烷/甲醇溶離，提供標題化合物，為黃色粉末(1.1克，77%)。Example 105B (3-bromo-5-methyl-phenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine gave the product from Example 105A (0.8 g, 4.3 mmoles of the product from Example 10C, using the procedure from Example 104C, substituting the product from Example 105A from the product from Example 104B to provide a crude residue which was taken on a silica gel. Purification, eluting with EtOAc (MeOH:MeOH)
實例105C(3'－甲氧基－5－甲基－聯苯－3－基)－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺將實例105B之產物(0066克，0.2毫莫耳)、3－甲氧苯基二羥基硼烷(0.043克，0.28毫莫耳)、碳酸銫(0.1克，0.3毫莫耳)及二氯雙(三苯膦)鈀(II)(0.014克，0.02毫莫耳)在N,N－二甲基甲醯胺(1毫升)中合併，並加熱至100℃，歷經24小時。於冷卻至室溫後，將混合物倒入冰水(20毫升)中，並以1N鹽酸水溶液使所形成之溶液酸化。然後以醋酸乙酯(3 x 10毫升)萃取溶液，使合併之萃液以硫酸鈉脫水乾燥，過濾，及在真空下濃縮。使粗產物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(12毫克，13%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.45(s,3H),2.75(s,3H),3.83(s,3H),6.98(dd,J＝7.72,2.21 Hz,1H),7.20(d,J＝2.21 Hz,1H),7.25(d,J＝8.09 Hz,1H),7.41(t,J＝7.91 Hz,1H),7.48(s,1H),7.56(s,1H),7.82(d,J＝5.15 Hz,1H),7.83(d,J＝3.31 Hz,1H),8.96(s,1H),9.03(d,J＝8.46 Hz,1H),11.34(s,1H)；MS(ESI)＋ m/z 357(M＋H)＋.Example 105C (3'-Methoxy-5-methyl-biphenyl-3-yl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine Example 105B Product (0066 g, 0.2 mmol), 3-methoxyphenyldihydroxyborane (0.043 g, 0.28 mmol), cesium carbonate (0.1 g, 0.3 mmol) and dichlorobis(triphenylphosphine) Palladium (II) (0.014 g, 0.02 mmol) was combined in N,N-dimethylformamide (1 mL) and heated to 100 ° C for 24 hours. After cooling to room temperature, the mixture was poured into ice water (20 ml), and the resulting solution was acidified with 1N aqueous hydrochloric acid. The solution was then extracted with ethyl acetate (3 x 10 mL). The crude product was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.45 (s, 3H), 2.75 (s, 3H), 3.83 (s, 3H), 6.98 (dd, J = 7.72, 2.21 Hz, 1H), 7.20 (d, J = 2.21 Hz, 1H), 7.25 (d, J = 8.09 Hz, 1H), 7.41 (t, J = 7.91 Hz, 1H), 7.48 (s, 1H), 7.56 (s, 1H), 7.82 (d, J = 5.15 Hz, 1H), 7.83 (d, J = 3.31 Hz, 1H), 8.96 (s, 1H), 9.03 (d, J = 8.46 Hz, 1H), 11.34 (s, 1H); MS (ESI)+ m/z 357(M+H)+.
{2－2－(4－甲氧基－苯基)－乙基]－5－甲基－苯基)－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)胺{2-2-(4-Methoxy-phenyl)-ethyl]-5-methyl-phenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl) amine
實例106A 1－[2－(4－甲氧基－苯基)－乙烯基－4－甲基－2－硝基－苯將1－溴基－4－甲基－2－硝基－苯(0.76克，3.5毫莫耳)、1－甲氧基－4－乙烯基－苯(0.59克，4.4毫莫耳)、三乙胺(0.88克，8.8毫莫耳)、三－鄰－甲苯基膦(0.022克)及醋酸鈀(0.008克)在N,N－二甲基甲醯胺(7毫升)中之溶液置於高壓管件中，並以氮滌氣10分鐘。將管件密封，並於120℃下加熱，歷經16小時。將混合物以水與醋酸乙酯分配，調整pH至3。以鹽水洗滌有機層，脫水乾燥(硫酸鈉)，並經過矽膠填充柱過濾。在真空下蒸發濾液，並將殘留物以己烷/醋酸乙酯(9：1)研製，提供標題化合物(0.55克，58%)。Example 106A 1-[2-(4-Methoxy-phenyl)-vinyl-4-methyl-2-nitro-benzene 1-bromo-4-methyl-2-nitro-benzene ( 0.76 g, 3.5 mmol, 1-methoxy-4-vinyl-benzene (0.59 g, 4.4 mmol), triethylamine (0.88 g, 8.8 mmol), tri-o-tolyl A solution of phosphine (0.022 g) and palladium acetate (0.008 g) in N,N-dimethylformamide (7 ml) was placed in a high pressure tube and purged with nitrogen for 10 min. The tube was sealed and heated at 120 ° C for 16 hours. The mixture was partitioned between water and ethyl acetate to adjust pH to 3. The organic layer was washed with brine, dried (sodium sulfate) and filtered over silica gel. The filtrate was evaporated <RTI ID=0.0></RTI>
實例106B 2－[2－(4－甲氧基－苯基)－乙基]－5－甲基－苯胺使得自實例106A之產物(164毫克，0.6毫莫耳)與10%鈀/炭(50毫克)在乙醇(20毫升)中之溶液以氫氣瓶氫化三天。使溶劑經過矽藻土過濾，以乙醇洗滌，並在真空下蒸發，提供標題化合物(140毫克，97%)。Example 106B 2-[2-(4-Methoxy-phenyl)-ethyl]-5-methyl-phenylamine gave the product from Example 106A (164 mg, 0.6 m. A solution of 50 mg) in ethanol (20 ml) was hydrogenated in a hydrogen cylinder for three days. The solvent was filtered through EtOAc (EtOAc)EtOAcEtOAc
實例106C{2－2－(4－甲氧基－苯基)－乙基]－5－甲基－苯基}－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)胺使得自實例106B之產物與得自實例10C之產物反應，使用得自實例104C之程序，以得自實例106B之產物取代得自實例104B之產物，提供粗製殘留物，使其在矽膠上藉層析純化，以99：1二氯甲烷/甲醇溶離，提供標題化合物(53毫克，69%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.30(s,3H),2.69(m,7H),3.64(s,3H),6.69(d,J＝8.8 Hz,2H),6.89(d,J＝8.8 Hz,2H),7.08(d,J＝7.7 Hz,1H),7.13(s,1H),7.22(d,J＝7.7 Hz,1H),7.53(d,J＝8.5 Hz,1H),8.50(s,1H),8.79(d,J＝8.5 Hz,1H),9.83(s,1H)；(ESI＋)m/z 385(M＋H)＋.Example 106C {2-2-(4-Methoxy-phenyl)-ethyl]-5-methyl-phenyl}-(7-methyl-pyrido[2,3-d]pyrimidine-4- The amine was allowed to react with the product from Example 106C, using the procedure from Example 104C, substituting the product from Example 106B from the product from Example 104B to afford a crude residue. The title compound (53 mg, 69%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.30 (s, 3H), 2.69 (m, 7H), 3.64 (s, 3H), 6.69 (d, J = 8.8 Hz, 2H), 6.89 (d) , J = 8.8 Hz, 2H), 7.08 (d, J = 7.7 Hz, 1H), 7.13 (s, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H) ), 8.50 (s, 1H), 8.79 (d, J = 8.5 Hz, 1H), 9.83 (s, 1H); (ESI+) m/z 385 (M+H)+.
4－[4－甲基－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-methyl-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使得自實例6c之產物與得自實例57A之產物反應，使用得自實例10F之程序，以得自實例6c之產物取代得自實例10E之產物，並以得自實例57A之產物取代得自實例10B之產物，提供粗製殘留物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.31(s,3H),6.61－6.78(m,2H),7.02(d,J＝8.09 Hz,1H),7.11－7.20(m,3H),7.24(s,1H),7.87(dd,J＝8.46,4.41 Hz,1H),8.79(s,1H),9.03(d,J＝8.46 Hz,1H),9.14－9.19(m,1H),9.79(s,1H)；MS(ESI＋)m/z 361(M＋H)＋.The product from Example 6c was reacted with the product from Example 57A, using the procedure from Example 10F, substituting the product from Example 6c for the product from Example 10E, and substituting the product from Example 57A The product of <RTI ID=0.0></RTI></RTI><RTIgt; 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.31 (s, 3H), 6.61-6.78 (m, 2H), 7.02 (d, J = 8.09 Hz, 1H), 7.11 - 7.20 (m, 3H) , 7.24 (s, 1H), 7.87 (dd, J = 8.46, 4.41 Hz, 1H), 8.79 (s, 1H), 9.03 (d, J = 8.46 Hz, 1H), 9.14 - 9.19 (m, 1H), 9.79(s,1H);MS(ESI+)m/z 361(M+H)+.
(5－甲基－2－苯基硫基－苯基)－吡啶并[2,3－d]嘧啶－4－基－胺(5-Methyl-2-phenylthio-phenyl)-pyrido[2,3-d]pyrimidin-4-yl-amine
使得自實例5I之產物與得自實例57A之產物反應，使用得自實例10F之程序，以得自實例5I之產物取代得自實例10E之產物，並以得自實例57A之產物取代得自實例10B之產物，提供粗製殘留物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.37(s,3H),7.09－7.27(m,6H),7.35(d,J＝7.72 Hz,2H),7.83(dd,J＝8.09,4.41 Hz,1H),8.75(s,1H),8.96(d,J＝7.72 Hz,1H),9.13(d,J＝3.31 Hz,1H)；MS(ESI＋)m/z 345(M＋H)＋The product from Example 5I was reacted with the product from Example 57A, using the procedure from Example 10F, substituting the product from Example 5I for the product from Example 10E, and substituting the product from Example 57A. The product of <RTI ID=0.0></RTI></RTI><RTIgt; 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.37 (s, 3H), 7.09-7.27 (m, 6H), 7.35 (d, J = 7.72 Hz, 2H), 7.83 (dd, J = 8.09, 4.41 Hz, 1H), 8.75 (s, 1H), 8.96 (d, J = 7.72 Hz, 1H), 9.13 (d, J = 3.31 Hz, 1H); MS (ESI+) m/z 345 (M+H)+
N－{4－[4－甲基－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－苯基}－乙醯胺N-{4-[4-methyl-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenyl}-acetamide
使得自實例7b之產物與得自實例57A之產物反應，使用得自實例10F之程序，以得自實例7b之產物取代得自實例10E之產物，並以得自實例57A之產物取代得自實例10B之產物，提供粗製殘留物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.02(s,3H),2.34(s,3H),7.13－7.35(m,5H),7.46(d,J＝8.46 Hz,2H),7.87(dd,J＝8.09,4.41 Hz,1H),8.80(s,1H),9.01(d,J＝8.09 Hz,1H),9.15(d,J＝3.31 Hz,1H),9.99(s,1H)；MS(ESI＋)m/z 402(M＋H)＋.The product from Example 7b was reacted with the product from Example 57A using the procedure from Example 10F, substituting the product from Example 7b from the product from Example 10E, and substituting the product from Example 57A. The product of <RTI ID=0.0></RTI></RTI><RTIgt; 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.02 (s, 3H), 2.34 (s, 3H), 7.13 - 7.35 (m, 5H), 7.46 (d, J = 8.46 Hz, 2H), 7.87 (dd, J=8.09, 4.41 Hz, 1H), 8.80 (s, 1H), 9.01 (d, J=8.09 Hz, 1H), 9.15 (d, J=3.31 Hz, 1H), 9.99 (s, 1H) ;MS(ESI+)m/z 402(M+H)+.
4－[2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－酚4-[2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-phenol
使得自實例6c之產物與得自實例36E之產物反應，使用得自實例36I之程序，以得自實例6c之產物取代得自實例36H之產物，提供粗製殘留物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.35(d,J＝6.62 Hz,6H),2.31(s,3H),3.29(t,J＝6.89 Hz,1H),6.70(d,J＝8.82 Hz,2H),7.01(d,J＝8.09 Hz,1H),7.17(d,J＝8.82 Hz,2H),7.13－7.22(m,2H),7.23(s,1H),7.87(d,J＝8.82 Hz,1H),8.79(s,1H),8.97(d,J＝8.82 Hz,1H),9.80(s,1H),11.42(s,1H)；MS(ESI＋)m/z 403(M＋H)＋.The product from Example 6c was reacted with the product from Example 36E, using the procedure from Example 36I, substituting the product from Example 6c to the product from Example 36H to afford crude residue. The title compound is provided as the trifluoroacetate salt. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.62 Hz, 6H), 2.31 (s, 3H), 3.29 (t, J = 6.89 Hz, 1H), 6.70 (d, J) =8.82 Hz, 2H), 7.01 (d, J = 8.09 Hz, 1H), 7.17 (d, J = 8.82 Hz, 2H), 7.13 - 7.22 (m, 2H), 7.23 (s, 1H), 7.87 (d , J=8.82 Hz, 1H), 8.79 (s, 1H), 8.97 (d, J = 8.82 Hz, 1H), 9.80 (s, 1H), 11.42 (s, 1H); MS (ESI+) m/z 403 (M+H)+.
2－氯基－4－[2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－酚2-Chloro-4-[2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-phenol
於得自實例110之產物(50毫克，0.124毫莫耳)在醋酸(1.5毫升)中之溶液內，在室溫下，逐滴添加二氯化硫醯(0.01毫升，0.124毫莫耳)。將混合物再攪拌30分鐘，然後於真空下濃縮，並藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(19毫克，28%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.35(d,J＝6.6 Hz,6H),2.34(s,3H),3.30(m,1H),6.82(d,J＝8.5 Hz,1H),7.08(dd,J＝8.5,2.2 Hz,1H),7.17(m,1H),7.24(m,3H),8.74(s,1H),8.94(d,J＝8.5 Hz,1H),10.50(s,1H),11.42(bs,1H)；MS(ESI＋)m/z 437(M＋H)＋.To a solution of the product from Example 110 (50 mg, 0.124 m. The mixture was stirred for additional 30 min then EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.6 Hz, 6H), 2.34 (s, 3H), 3.30 (m, 1H), 6.82 (d, J = 8.5 Hz, 1H) ), 7.08 (dd, J = 8.5, 2.2 Hz, 1H), 7.17 (m, 1H), 7.24 (m, 3H), 8.74 (s, 1H), 8.94 (d, J = 8.5 Hz, 1H), 10.50 (s, 1H), 11.42 (bs, 1H); MS (ESI+) m/z 437 (M+H)+.
2,6－二氯－4－[2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－酚2,6-Dichloro-4-[2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-phenol
於得自實例110之產物(50毫克，0.124毫莫耳)在醋酸(1.5毫升)中之溶液內，在室溫下，逐滴添加二氯化硫醯(0.02毫升，0.248毫莫耳)。將混合物再攪拌30分鐘，然後於真空下濃縮，並藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(17毫克，23%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.35(d,J＝6.6 Hz,6H),2.37(s,3H),3.28(m,1H),7.12(s,1H),7.28(m,2H),7.46(d,J＝8.1 Hz,1H),7.83(d,J＝8.5 Hz,1H),8.70(s,1H),8.88(d,J＝8.8 Hz,1H),10.38(s,1H),11.22(bs,1H)；MS(ESI＋)m/z 472(M＋H)＋.To a solution of the product from Example 110 (50 mg, <RTI ID=0.0></RTI></RTI><RTIgt; The mixture was stirred for a further 30 min then EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.6 Hz, 6H), 2.37 (s, 3H), 3.28 (m, 1H), 7.12 (s, 1H), 7.28 (m) , 2H), 7.46 (d, J = 8.1 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 8.70 (s, 1H), 8.88 (d, J = 8.8 Hz, 1H), 10.38 (s , 1H), 11.22 (bs, 1H); MS (ESI+) m/z 472 (M+H)+.
4－[4－羥甲基－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-Hydroxymethyl-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
實例113A 4－(4－羥基－苯基硫基)－3－硝基－苯甲酸甲酯於室溫下，將4－氯基－3－硝基－苯甲酸甲酯(4.0克，18.55毫莫耳)在無水N,N－二甲基甲醯胺(25毫升)中之溶液，以4－巰基酚(2.34克，18.55毫莫耳)與碳酸銫(9.07克，27.83毫莫耳)處理23小時。然後藉迴轉式蒸發在真空下移除溶劑，使殘留物溶於水(100毫升)中，並以1N HCl水溶液將pH調整至3。以醋酸乙酯(2 x 100毫升)萃取水溶液，並以鹽水(50毫升)洗滌合併之有機萃液。將有機層以硫酸鎂脫水乾燥，過濾，及藉迴轉式蒸發濃縮，提供產物，為被N,N－二甲基甲醯胺污染之橘色油(7.28克)。Example 113A 4-(4-Hydroxy-phenylsulfanyl)-3-nitro-benzoic acid methyl ester 4-methyl-3-nitro-benzoic acid methyl ester (4.0 g, 18.55 m) a solution of anhydrous nonylphenol (2.34 g, 18.55 mmol) and cesium carbonate (9.07 g, 27.83 mmol) in anhydrous N,N-dimethylformamide (25 ml) 23 hours. The solvent was then removed in vacuo by rotary evaporation, the residue dissolved in water (100 mL) The aqueous solution was extracted with ethyl acetate (2 x 100 mL) and brine and evaporated. The organic layer was dried over MgSO4, filtered, and evaporated eluting with EtOAc EtOAc EtOAc
實例113B 3－胺基－4－(4－羥基－苯基硫基)－苯甲酸甲酯將實例113A之產物(為單DMF加成物)(7.25克，19.23毫莫耳)、氯化銨(1.54克，28.8毫莫耳)及鐵粉(5.37克，96.15毫莫耳)在四氫呋喃(75毫升)、水(25毫升)及乙醇(75毫升)中之懸浮液，於回流下加熱3小時。使反應物冷卻至室溫，並使混合物經過矽藻土墊過濾，然後將其以甲醇洗滌，及在真空下使濾液濃縮成固體。接著使殘留物溶於水(100毫升)中，並以二氯甲烷(2 x 50毫升)萃取。以鹽水(25毫升)洗滌合併之有機萃液，以硫酸鎂脫水乾燥，過濾，及在真空下濃縮，提供標題化合物，為白色固體(4.2克，79%)。Example 113B 3-Amino-4-(4-hydroxy-phenylsulfanyl)-benzoic acid methyl ester The product of Example 113A (as a single DMF adduct) (7.25 g, 19.23 mmol), ammonium chloride (1.54 g, 28.8 mmol) and a suspension of iron powder (5.37 g, 96.15 mmol) in tetrahydrofuran (75 ml), water (25 ml) and ethanol (75 ml), heated under reflux for 3 h . The reaction was allowed to cool to room temperature and the mixture was filtered thru a pad of Celite, then washed with methanol and the filtrate was concentrated to a solid. The residue was dissolved in water (100 mL) andEtOAcEtOAc The combined organic extracts were washed with EtOAc EtOAc m.
實例113C 4－(2－胺基－4－羥甲基－苯基硫基)－酚於四氫呋喃(50毫升)中之得自實例113B之產物(500毫克，1.82毫莫耳)內，在室溫下，逐滴添加氫化鋰鋁之溶液(1.0M，在THF中，1.8毫升，1.82毫莫耳)，接著將混合物加熱至70℃，歷經4小時。然後將水(25毫升)小心地添加至溶液中，並分離有機層，脫水乾燥，及在真空下濃縮，提供標題化合物(295毫克，66%)。Example 113C 4-(2-Amino-4-hydroxymethyl-phenylsulfanyl)-phenol in tetrahydrofuran (50 mL) obtained from product of Example 113B (500 mg, 1.82 m. A solution of lithium aluminum hydride (1.0 M in THF, 1.8 mL, 1.82 mmol) was then added dropwise, and then the mixture was warmed to 70 ° C for 4 hr. Water (25 mL) was then added to EtOAc (EtOAc).
實例113D 4－[4－羥甲基－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚使得自實例113C之產物與得自實例36E之產物反應，使用得自實例36I之程序，以得自實例113C之產物取代得自實例36H之產物，提供粗製殘留物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(30毫克，31%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.36(d,J＝7.0 Hz,6H),3.30(m,1H),4.50(s,2H),6.72(d,J＝8.5 Hz,2H),7.05(d,J＝8.1 Hz,1H),7.19(d,J＝8.5 Hz,2H),7.27(m,1H),7.35(s,1H),7.87(d,J＝8.5 Hz,1H),8.79(s,1H),8.98(m,1H),9.82(s,1H),11.43(bs,1H)；MS(ESI＋)m/z 419(M＋H)＋.Example 113D 4-[4-Hydroxymethyl-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol is rendered from Example 113C The product was reacted with the product from Example 36, using the procedure from Example 36I. It was trifluoroacetate (30 mg, 31%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (d, J = 7.0 Hz, 6H), 3.30 (m, 1H), 4.50 (s, 2H), 6.72 (d, J = 8.5 Hz, 2H ), 7.05 (d, J = 8.1 Hz, 1H), 7.19 (d, J = 8.5 Hz, 2H), 7.27 (m, 1H), 7.35 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H) ), 8.79 (s, 1H), 8.98 (m, 1H), 9.82 (s, 1H), 11.43 (bs, 1H); MS (ESI+) m/z 419 (M+H)+.
醋酸4－(4－羥基－苯基硫基)－3－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苄4-(4-Hydroxy-phenylthio)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzyl acetate
使得自實例113C之產物與得自實例36E之產物反應，使用得自實例36I之程序，以得自實例113C之產物取代得自實例36H之產物，提供粗製殘留物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(12毫克，11%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.36(d,J＝6.6 Hz,6H),2.05(s,3H),3.30(m,1H),5.07(s,2H),6.71(d,J＝8.5 Hz,2H),7.03(d,J＝8.1 Hz,1H),7.19(d,J＝8.5 Hz,2H),7.27(m,1H),7.40(m,1H),7.95(d,J＝8.8 Hz,1H),8.89(s,1H),9.02(d,J＝8.8 Hz,1H),9.75(bs,1H),11.79(bs,1H)；MS(ESI＋)m/z 461(M＋H)＋.The product from Example 113C was reacted with the product from Example 36, using the procedure from Example 36I to afford the product from Example <RTI ID=0.0>#</RTI> The title compound was obtained as trifluoroacetate (12 mg, 11%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (d, J = 6.6 Hz, 6H), 2.05 (s, 3H), 3.30 (m, 1H), 5.07 (s, 2H), 6.71 (d) , J=8.5 Hz, 2H), 7.03 (d, J=8.1 Hz, 1H), 7.19 (d, J=8.5 Hz, 2H), 7.27 (m, 1H), 7.40 (m, 1H), 7.95 (d , J = 8.8 Hz, 1H), 8.89 (s, 1H), 9.02 (d, J = 8.8 Hz, 1H), 9.75 (bs, 1H), 11.79 (bs, 1H); MS (ESI+) m/z 461 (M+H)+.
N－{4－[2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－苯基}－乙醯胺N-{4-[2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-phenyl}-acetamidine amine
使得自實例7b之產物與得自實例36E之產物反應，使用得自實例36I之程序，以得自實例7b之產物取代得自實例36H之產物，提供粗製殘留物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.35(d,J＝6.99 Hz,6H),2.02(s,3H),2.33(s,3H),3.28(t,J＝6.89 Hz,1H),7.18(s,1H),7.20(d,J＝8.46 Hz,2H),7.28(s,1H),7.46(d,J＝8.46 Hz,2H),7.86(d,J＝8.46 Hz,1H),8.79(s,1H),8.93(d,J＝8.82 Hz,1H),9.99(s,1H),11.46(s,1H)；MS(ESI＋)m/z 444(M＋H)＋.The product from Example 7b was reacted with the product from Example 36E, using the procedure from Example 36I, substituting the product from Example 7b from the product from Example 36H to afford crude residue. The title compound is provided as the trifluoroacetate salt. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.99 Hz, 6H), 2.02 (s, 3H), 2.33 (s, 3H), 3.28 (t, J = 6.89 Hz, 1H) ), 7.18 (s, 1H), 7.20 (d, J = 8.46 Hz, 2H), 7.28 (s, 1H), 7.46 (d, J = 8.46 Hz, 2H), 7.86 (d, J = 8.46 Hz, 1H) ), 8.79 (s, 1H), 8.93 (d, J = 8.82 Hz, 1H), 9.99 (s, 1H), 11.46 (s, 1H); MS (ESI+) m/z 444 (M+H)+.
(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－[2－(4－甲氧基－苯氧基)－5－甲基－苯基]－胺(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-[2-(4-methoxy-phenoxy)-5-methyl-phenyl]-amine
實例116A 1－(4－甲氧基－苯氧基)－4－甲基－2－硝基－苯使4－甲氧基－酚與1－氟基－4－甲基－2－硝基苯反應，根據得自實例122a之程序，以4－甲氧基－酚取代對苯二酚，提供標題化合物。Example 116A 1-(4-Methoxy-phenoxy)-4-methyl-2-nitro-benzene 4-methoxy-phenol and 1-fluoro-4-methyl-2-nitro The benzene reaction, substituting hydroquinone with 4-methoxy-phenol according to the procedure from Example 122a afforded the title compound.
實例116B 2－(4－甲氧基－苯氧基)－5－甲基－苯胺將得自實例116A之產物根據實例104B之程序還原，以得自實例116A之產物取代得自實例104A之產物，提供標題化合物。Example 116B 2-(4-Methoxy-phenoxy)-5-methyl-phenylamine The product from Example 116A was reduced according to the procedure of Example 104B, substituting the product from Example 116A for the product from Example 104A. , providing the title compound.
實例116C(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－[2－(4－甲氧基－苯氧基)－5－甲基－苯基]－胺使得自實例116B之產物與得自實例36E之產物反應，使用得自實例36I之程序，以得自實例116B之產物取代得自實例36H之產物，提供粗製殘留物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.33(d,J＝6.99 Hz,6H),2.33(s,3H),3.26(dt,J＝13.74,6.85 Hz,1H),3.67(s,3H),6.77－6.96(m,5H),7.18(dd,J＝8.46,2.21 Hz,1H),7.33(d,J＝1.84 Hz,1H),7.83(d,J＝8.46 Hz,1H),8.84(s,1H),8.91(d,J＝8.82 Hz,1H),11.33(s,1H)；MS(ESI)＋ m/z 401(M＋H)＋.Example 116C (7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-[2-(4-methoxy-phenoxy)-5-methyl-phenyl]-amine The product from Example 116B was reacted with the product from Example 36E, using the procedure from Example 36I, substituting the product from Example 116B from the product from Example 36H to afford crude residue. The title compound is provided as the trifluoroacetate salt. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.33 (d, J = 6.99 Hz, 6H), 2.33 (s, 3H), 3.26 (dt, J = 13.74, 6.85 Hz, 1H), 3.67 (s) , 3H), 6.77-6.96 (m, 5H), 7.18 (dd, J = 8.46, 2.21 Hz, 1H), 7.33 (d, J = 1.84 Hz, 1H), 7.83 (d, J = 8.46 Hz, 1H) , 8.84 (s, 1H), 8.91 (d, J = 8.82 Hz, 1H), 11.33 (s, 1H); MS (ESI) + m / z 401 (M + H) +.
4－[2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－甲基－苯氧基]－酚4-[2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenoxy]-phenol
使得自實例122b之產物與得自實例36E之產物反應，使用得自實例36I之程序，以得自實例122b之產物取代得自實例36H之產物，提供粗製殘留物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.33(d,J＝6.99 Hz,6H),2.32(s,3H),3.27(t,J＝6.89 Hz,1H),6.67(m,2H),6.75－6.85(m,3H),7.16(dd,J＝8.46,1.84 Hz,1H),7.31(d,J＝1.47 Hz,1H),7.84(d,J＝8.46 Hz,1H),8.85(s,1H),8.94(d,J＝8.46 Hz,1H),9.28(s,1H)；MS(ESI)＋ m/z 387(M＋H)＋.The product from Example 122b was reacted with the product from Example 36E, using the procedure from Example 36I, and the product from Example </RTI> The title compound is provided as the trifluoroacetate salt. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.33 (d, J = 6.99 Hz, 6H), 2.32 (s, 3H), 3.27 (t, J = 6.89 Hz, 1H), 6.67 (m, 2H) ), 6.75-6.85 (m, 3H), 7.16 (dd, J = 8.46, 1.84 Hz, 1H), 7.31 (d, J = 1.47 Hz, 1H), 7.84 (d, J = 8.46 Hz, 1H), 8.85 (s, 1H), 8.94 (d, J = 8.46 Hz, 1H), 9.28 (s, 1H); MS (ESI) + m/z 387 (M+H)+.
(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－[2－(4－甲氧基－苯基硫基)－5－甲基－苯基]－胺(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-[2-(4-methoxy-phenylthio)-5-methyl-phenyl]-amine
使得自實例6a之產物(5.0克，175毫莫耳)與4－甲氧基－苯硫醇(2.45克，175毫莫耳)反應18小時，按照得自實例6b之程序，獲得1－(4－甲氧基－苯基硫基)－4－甲基－2－硝基－苯，使其按照得自實例5I之程序以SnCl2 還原，獲得2－(4－甲氧基－苯基硫基)－5－甲基－苯胺。The product from Example 6a (5.0 g, 175 mmol) was reacted with 4-methoxy-benzenethiol (2.45 g, 175 mmol) for 18 hours, according to the procedure from Example 6b. 4-methoxy-phenylthio)-4-methyl-2-nitro-benzene, which was reduced with SnCl 2 according to the procedure from Example 5I to give 2-(4-methoxy-phenyl Thio)-5-methyl-aniline.
使2－(4－甲氧基－苯基硫基)－5－甲基－苯胺與得自實例36E之產物反應，使用得自實例36I之程序，以2－(4－甲氧基－苯基硫基)－5－甲基－苯胺取代得自實例36H之產物，提供粗製殘留物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.35(d,J＝6.62 Hz,6H),2.33(s,3H),3.28(t,J＝6.89 Hz,1H),3.69(s,3H),6.81(d,J＝9.19 Hz,2H),7.06－7.20(m,2H),7.23(d,J＝8.82 Hz,2H),7.26(s,1H),7.85(d,J＝8.46 Hz,1H),8.76(s,1H),8.94(d,J＝8.46 Hz,1H),11.36(s,1H)；MS(ESI)＋ m/z 417(M＋H)＋.2-(4-Methoxy-phenylsulfanyl)-5-methyl-phenylamine was reacted with the product from Example 36E using the procedure from Example 36I to 2-(4-methoxy-benzene The thiol)-5-methyl-aniline compound was obtained from the title compound. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.62 Hz, 6H), 2.33 (s, 3H), 3.28 (t, J = 6.89 Hz, 1H), 3.69 (s, 3H) ), 6.81 (d, J = 9.19 Hz, 2H), 7.06-7.20 (m, 2H), 7.23 (d, J = 8.82 Hz, 2H), 7.26 (s, 1H), 7.85 (d, J = 8.46 Hz) , 1H), 8.76 (s, 1H), 8.94 (d, J = 8.46 Hz, 1H), 11.36 (s, 1H); MS (ESI) + m/z 417 (M+H) +.
(7－環丙基－吡啶并[2,3－d]嘧啶－4－基)－(5－甲基－2－苯基硫基－苯基)－胺(7-Cyclopropyl-pyrido[2,3-d]pyrimidin-4-yl)-(5-methyl-2-phenylthio-phenyl)-amine
實例119A N'－(3－氰基－6－環丙基－吡啶－2－基)－N,N－二甲基－甲脒使環丙基甲基酮根據實例36A－36E中所述之程序反應，提供標題化合物。Example 119A N'-(3-cyano-6-cyclopropyl-pyridin-2-yl)-N,N-dimethyl-formamidine Cyclopropylmethyl ketone as described in Examples 36A-36E The program reacts to provide the title compound.
實例119B(7－環丙基－吡啶并[2,3－d]嘧啶－4－基)－(5－甲基－2－苯基硫基－苯基)－胺使得自實例5I之產物與得自實例119A之產物反應，使用得自實例102之程序，以得自實例5I之產物取代得自實例6c之產物，並以得自實例119A之產物取代得自實例10B之產物，提供粗製殘留物，使其藉由以甲醇研製而純化，提供標題化合物。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.05－1.19(m,4H),2.22－2.41(m,1H),2.35(s,3H),7.05－7.31(m,7H),7.37(s,1H),7.58(d,J＝8.46 Hz,1H),8.50(s,1H),8.65(d,J＝8.46 Hz,1H),10.21(s,1H)；MS(ESI)＋ m/z 385(M＋H)＋.Example 119B (7-cyclopropyl-pyrido[2,3-d]pyrimidin-4-yl)-(5-methyl-2-phenylthio-phenyl)-amine is obtained from the product of Example 5I The product from Example 119A was obtained using the procedure from Example 102, substituting the product from Example 5I from the product from Example 6c, and substituting the product from Example 119A from the product from Example 10B to afford crude residue. Purification by purification in methanol afforded the title compound. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.05-1.19 (m, 4H), 2.22-2.41 (m, 1H), 2.35 (s, 3H), 7.05-7.31 (m, 7H), 7.37 ( s, 1H), 7.58 (d, J = 8.46 Hz, 1H), 8.50 (s, 1H), 8.65 (d, J = 8.46 Hz, 1H), 10.21 (s, 1H); MS (ESI) + m/ z 385(M+H)+.
4－[2－(7－環丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－酚4-[2-(7-cyclopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-phenol
使得自實例6c之產物與得自實例119A之產物反應，使用得自實例102之程序，以得自實例119A之產物取代得自實例10B之產物，提供粗製殘留物，使其藉由以甲醇研製而純化，提供標題化合物。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.05－1.22(m,J＝1.84 Hz,4H),2.24－2.39(m,1H),2.29(s,3H),6.73(d,J＝8.82 Hz,2H),6.91(d,J＝8.09 Hz,1H),7.04(dd,J＝8.09,1.47 Hz,1H),7.17(d,J＝8.82 Hz,2H),7.25(s,1H),7.57(d,J＝8.82 Hz,1H),8.49(s,1H),8.71(d,J＝8.46 Hz,1H),9.74(s,1H),9.92(s,1H)；MS(ESI)＋ m/z 401(M＋H)＋.The product from Example 6c was reacted with the product from Example 119A, using the procedure from Example 102, substituting the product from Example 119A from the product from Example 10B to provide a crude residue which was developed from methanol. Purified to provide the title compound. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.05-1.22 (m, J = 1.84 Hz, 4H), 2.24 - 2.39 (m, 1H), 2.29 (s, 3H), 6.73 (d, J = 8.82 Hz, 2H), 6.91 (d, J = 8.09 Hz, 1H), 7.04 (dd, J = 8.09, 1.47 Hz, 1H), 7.17 (d, J = 8.82 Hz, 2H), 7.25 (s, 1H) , 7.57 (d, J = 8.82 Hz, 1H), 8.49 (s, 1H), 8.71 (d, J = 8.46 Hz, 1H), 9.74 (s, 1H), 9.92 (s, 1H); MS (ESI) + m/z 401(M+H)+.
N－{4－[2－(7－環丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－苯基}－乙醯胺N-{4-[2-(7-Cyclopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylsulfanyl]-phenyl}-acetamidine amine
使得自實例7b之產物與得自實例119A之產物反應，使用得自實例102之程序，以得自實例7b之產物取代得自實例6c之產物，並以得自實例119A之產物取代得自實例10B之產物，提供粗製殘留物，使其藉由以甲醇研製而純化，提供標題化合物。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.13(d,J＝6.25 Hz,4H),2.02(s,3H),2.22－2.38(m,1H),2.31(s,3H),7.07(s,2H),7.20(d,J＝8.82 Hz,2H),7.30(s,1H),7.50(d,J＝8.82 Hz,2H),7.56(d,J＝8.46 Hz,1H),8.49(s,1H),8.68(d,J＝8.82 Hz,1H),9.99(s,2H)；MS(ESI＋)m/z 442(M＋H)＋.The product from Example 7b was reacted with the product from Example 119A, using the procedure from Example 102, substituting the product from Example 7b for the product from Example 6c, and substituting the product from Example 119A The product was purified by EtOAc (EtOAc): 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.13 (d, J = 6.25 Hz, 4H), 2.02 (s, 3H), 2.22 - 2.38 (m, 1H), 2.31 (s, 3H), 7.07 (s, 2H), 7.20 (d, J = 8.82 Hz, 2H), 7.30 (s, 1H), 7.50 (d, J = 8.82 Hz, 2H), 7.56 (d, J = 8.46 Hz, 1H), 8.49 (s, 1H), 8.68 (d, J = 8.82 Hz, 1H), 9.99 (s, 2H); MS (ESI+) m/z 442 (M+H)+.
4－[2－(7－環丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－甲基－苯氧基]－酚實例122a4-[2-(7-Cyclopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenoxy]-phenol Example 122a
4－(4－甲基－2－硝基苯氧基)酚將對苯二酚(3.2克，29.0毫莫耳)與K2 CO3 (8.0克，54.0毫莫耳)在40毫升DMF中之溶液，於100℃下與1－氟基－4－甲基－2－硝基苯(3.0克，19.3毫莫耳)一起加熱，並攪拌24小時。冷卻至室溫，並以EtOAc稀釋。以水洗滌，並以有機層MgSO4 脫水乾燥。過濾，及在真空下濃縮，獲得標題化合物，使其藉矽膠管柱層析純化，以5% EtOAc/己烷溶離，獲得橘色油(1.89克，40%)。4-(4-Methyl-2-nitrophenoxy)phenol with hydroquinone (3.2 g, 29.0 mmol) and K 2 CO 3 (8.0 g, 54.0 mmol) in 40 mL DMF The solution was heated with 1-fluoro-4-methyl-2-nitrobenzene (3.0 g, 19.3 mmol) at 100 ° C and stirred for 24 hours. Cooled to room temperature and diluted with EtOAc. It was washed with water and dried over anhydrous MgSO 4 . Filtration and EtOAc (EtOAc)EtOAc.
實例122b 4－(2－胺基－4－甲基苯氧基)酚按照得自實例5I之程序，使得自實例122a之產物(1.89克，7.71毫莫耳)以SnCl2 還原，獲得標題化合物，為白色固體(1.42克，86%)。Example 122b 4- (2- amino-4-methylphenoxy) phenol according to the procedure from Example 5I, the product from Example 122a of such (1.89 g, 7.71 mmol) SnCl 2 reduction to obtain the title compound , as a white solid (1.42 g, 86%).
實例122c 4－(2－(7－環丙基吡啶并[2,3－d]嘧啶－4－基胺基)－4－甲基苯氧基)酚使得自實例122b之產物與得自實例119A之產物反應，使用得自實例102之程序，以得自實例122b之產物取代得自實例6c之產物，並以得自實例119A之產物取代得自實例10B之產物，提供粗製殘留物，使其藉由以甲醇研製而純化，提供標題化合物。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.03－1.18(m,J＝6.25 Hz,4H),2.20－2.35(m,1H),2.30(s,3H),6.57－6.85(m,5H),7.03(dd,J＝8.27,1.65 Hz,1H),7.36(d,J＝1.84 Hz,1H),7.52(d,J＝8.46 Hz,1H),8.50(s,1H),8.65(d,J＝8.46 Hz,1H),9.18(s,1H),9.70(s,1H)；MS(ESI)＋ m/z 385(M＋H)＋.Example 122c 4-(2-(7-Cyclopropylpyrido[2,3-d]pyrimidin-4-ylamino)-4-methylphenoxy)phenol from the product of Example 122b. The product of 119A was reacted, using the procedure from Example 102, substituting the product from Example 122b from the product from Example 6c, and substituting the product from Example 119A from the product from Example 10B to provide a crude residue. It was purified by trituration with methanol to afford the title compound. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.03-1.18 (m, J = 6.25 Hz, 4H), 2.20-2.35 (m, 1H), 2.30 (s, 3H), 6.57-6.85 (m, 5H), 7.03 (dd, J = 8.27, 1.65 Hz, 1H), 7.36 (d, J = 1.84 Hz, 1H), 7.52 (d, J = 8.46 Hz, 1H), 8.50 (s, 1H), 8.65 ( d, J = 8.46 Hz, 1H), 9.18 (s, 1H), 9.70 (s, 1H); MS (ESI) + m/z 385 (M+H) +.
(7－環丙基－吡啶并[2,3－d]嘧啶－4－基)－[2－(4－甲氧基－苯氧基)－5－甲基－苯基]－胺(7-Cyclopropyl-pyrido[2,3-d]pyrimidin-4-yl)-[2-(4-methoxy-phenoxy)-5-methyl-phenyl]-amine
使得自實例116B之產物與得自實例119A之產物反應，使用得自實例102之程序，以得自實例116B之產物取代得自實例6c之產物，並以得自實例119A之產物取代得自實例10B之產物，提供粗製殘留物，使其藉由以甲醇研製而純化，提供標題化合物。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.02－1.20(m,J＝6.25 Hz,4H),2.21－2.37(m,1H),2.31(s,3H),3.66(s,3H),6.75－6.92(m,5H),7.06(dd,J＝8.64,0.92 Hz,1H),7.37(s,1H),7.51(d,J＝8.46 Hz,1H),8.49(s,1H),8.63(d,J＝8.82 Hz,1H),9.74(s,1H)；MS(ESI)＋ m/z 399(M＋H)＋.The product from Example 116B was reacted with the product from Example 119A, using the procedure from Example 102, substituting the product from Example 116B for the product from Example 6c, and substituting the product from Example 119A. The product was purified by EtOAc (EtOAc): 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.02-1.20 (m, J = 6.25 Hz, 4H), 2.21-2.37 (m, 1H), 2.31 (s, 3H), 3.66 (s, 3H) , 6.75-6.92 (m, 5H), 7.06 (dd, J = 8.64, 0.92 Hz, 1H), 7.37 (s, 1H), 7.51 (d, J = 8.46 Hz, 1H), 8.49 (s, 1H), 8.63 (d, J = 8.82 Hz, 1H), 9.74 (s, 1H); MS (ESI) + m/z 399 (M+H)+.
(7－環丙基－吡啶并[2,3－d]嘧啶－4－基)－[2－(4－氟苯基硫基)－5－甲基－苯基]－胺(7-Cyclopropyl-pyrido[2,3-d]pyrimidin-4-yl)-[2-(4-fluorophenylthio)-5-methyl-phenyl]-amine
按照得自實例5H之程序，使得自實例6a之產物(5.00克，17.53毫莫耳)與4－氟基硫酚(2.24克，17.53毫莫耳)取代硫酚反應18小時，獲得1－(4－氟苯基硫基)－4－甲基－2－硝基－苯，使其藉矽膠管柱層析純化，以5% EtOAc/己烷溶離，提供固體(3.39克，74%)。按照得自實例5I之程序，使1－(4－氟苯基硫基)－4－甲基－2－硝基－苯以SnCl2 還原，獲得2－(4－氟苯基硫基)－5－甲基－苯胺。The product from Example 6a (5.00 g, 17.53 mmol) was reacted with 4-fluorothiophenol (2.24 g, 17.53 mmol) in place of thiophenol for 18 hours according to the procedure from Example 5H. 4-Fluorophenylsulfanyl)-4-methyl-2-nitro-benzene was purified by EtOAc (EtOAc) elute According to the procedure from Example 5I, 1-(4-fluorophenylthio)-4-methyl-2-nitro-benzene was reduced with SnCl 2 to give 2-(4-fluorophenylthio)- 5-methyl-aniline.
使2－(4－氟苯基硫基)－5－甲基－苯胺與得自實例119A之產物反應，使用得自實例102之程序，以2－(4－氟苯基硫基)－5－甲基－苯胺取代得自實例6c之產物，並以得自實例119A之產物取代得自實例10B之產物，提供粗製殘留物，使其藉由以甲醇研製而純化，提供標題化合物。1 H NMR(300 MHz,DMSO－D6)δ ppm：0.96－1.19(m,J＝6.25 Hz,4H),2.22－2.42(m,1H),2.33(s,3H),7.02－7.28(m,6H),7.33(s,1H),7.56(d,J＝8.46 Hz,1H),8.46(s,1H),8.66(d,J＝8.09 Hz,1H),10.03(s,1H)；MS(ESI)＋ m/z 403(M＋H)＋.2-(4-Fluorophenylthio)-5-methyl-phenylamine was reacted with the product from Example 119A using the procedure from Example 102 to 2-(4-fluorophenylthio)-5 -Methyl-aniline was substituted for the product from Example 6c, and the product from Example 10B was obtained from the product from Example 119A. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 0.96-1.19 (m, J = 6.25 Hz, 4H), 2.22-2.42 (m, 1H), 2.33 (s, 3H), 7.02-7.28 (m, 6H), 7.33 (s, 1H), 7.56 (d, J = 8.46 Hz, 1H), 8.46 (s, 1H), 8.66 (d, J = 8.09 Hz, 1H), 10.03 (s, 1H); MS ( ESI)+ m/z 403(M+H)+.
(7－環丙基－吡啶并[2,3－d]嘧啶－4－基)－[2－(4－甲氧基－苯基硫基)－5－甲基－苯基]－胺(7-Cyclopropyl-pyrido[2,3-d]pyrimidin-4-yl)-[2-(4-methoxy-phenylthio)-5-methyl-phenyl]-amine
使2－(4－甲氧基－苯基硫基)－5－甲基－苯胺(實例118)與得自實例119A之產物反應，使用得自實例102之程序，以2－(4－甲氧基－苯基硫基)－5－甲基－苯胺取代得自實例6c之產物，並以得自實例119A之產物取代得自實例10B之產物，提供粗製殘留物，使其藉由以甲醇研製而純化，提供標題化合物。1 H NMR(300 MHz,DMSO－D6)δ ppm：0.96－1.30(m,J＝5.52 Hz,4H),2.21－2.42(m,1H),2.31(s,3H),3.71(s,3H),6.85(d,J＝8.82 Hz,2H),6.99－7.12(m,2H),7.24(d,J＝8.82 Hz,2H),7.63(d,J＝8.46 Hz,1H),8.53(s,1H),8.72(d,J＝8.46 Hz,1H),10.33(s,1H)；MS(ESI)＋ m/z 415(M＋H)＋.2-(4-Methoxy-phenylsulfanyl)-5-methyl-phenylamine (Example 118) was reacted with the product from Example 119A using the procedure from Example 102 to 2-(4- Oxy-phenylthio)-5-methyl-aniline was substituted for the product from Example 6c, and the product from Example 10B was substituted with the product from Example 119A to provide a crude residue. Purified by purification to provide the title compound. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 0.96-1.30 (m, J = 5.52 Hz, 4H), 2.21-2.42 (m, 1H), 2.31 (s, 3H), 3.71 (s, 3H) , 6.85 (d, J = 8.82 Hz, 2H), 6.99-7.12 (m, 2H), 7.24 (d, J = 8.82 Hz, 2H), 7.63 (d, J = 8.46 Hz, 1H), 8.53 (s, 1H), 8.72 (d, J = 8.46 Hz, 1H), 10.33 (s, 1H); MS (ESI) + m/z 415 (M+H) +.
[2－(4－甲氧基－苯氧基)－5－甲基－苯基]－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺[2-(4-Methoxy-phenoxy)-5-methyl-phenyl]-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
使得自實例116B之產物與得自實例10C之產物反應，使用得自實例104C之程序，以得自實例116B之產物取代得自實例104B之產物，提供粗製殘留物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.33(s,3H),2.72(s,3H),3.68(s,3H),6.80－6.95(m,5H),7.18(dd,J＝8.46,2.21 Hz,1H),7.34(d,J＝1.84 Hz,1H),7.76(d,J＝8.46 Hz,1H),8.85(s,2H),11.32(s,1H).The product from Example 116B was reacted with the product from Example 10C, using the procedure from Example 104C, substituting the product from Example 116B from the product from Example 104B to afford crude residue. The title compound is provided as the trifluoroacetate salt. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.33 (s, 3H), 2.72 (s, 3H), 3.68 (s, 3H), 6.80-6.95 (m, 5H), 7.18 (dd, J = 8.46, 2.21 Hz, 1H), 7.34 (d, J = 1.84 Hz, 1H), 7.76 (d, J = 8.46 Hz, 1H), 8.85 (s, 2H), 11.32 (s, 1H).
4－[2－(7－第三－丁基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－酚4-[2-(7-Third-butyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-phenol
實例127A N'－(6－第三－丁基－3－氰基－吡啶－2－基)－N,N－二甲基－甲脒使3,3－二甲基－2－丁酮根據實例36A－36E中所述之程序反應，提供標題化合物。Example 127A N'-(6-Third-butyl-3-cyano-pyridin-2-yl)-N,N-dimethyl-methylhydrazine gives 3,3-dimethyl-2-butanone according to The procedure described in Examples 36A-36E was carried out to provide the title compound.
實例127B 4－[2－(7－第三－丁基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－酚使得自實例6c之產物與得自實例127A之產物反應，使用得自實例36I之程序，以得自實例6c之產物取代得自實例36H之產物，並以得自實例127A之產物取代得自276E之產物，提供粗製殘留物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(40毫克，29%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.44(s,9H),2.31(s,3H),6.71(d,J＝8.5 Hz,2H),7.00(d,J＝8.1 Hz,1H),7.16(m,1H),7.18(d,J＝8.8 Hz,2H),7.23(s,1H),8.01d,J＝7.6 Hz,1H),8.75(s,1H),8.97(d,J＝8.8 Hz,1H),9.79(s,1H),11.22(bs,1H)；MS(ESI)＋ m/z 417(M＋H)＋.Example 127B 4-[2-(7-T-butyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylsulfanyl]-phenol is rendered from Example 6c The product was reacted with the product from Example 127A, using the procedure from Example 36I, substituting the product from Example 6c for the product from Example 36H, and substituting the product from Example 127A for the product from 276E. The residue was purified by EtOAc EtOAc EtOAc EtOAc 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.44 (s, 9H), 2.31 (s, 3H), 6.71 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 8.1 Hz, 1H) ), 7.16 (m, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.23 (s, 1H), 8.01d, J = 7.6 Hz, 1H), 8.75 (s, 1H), 8.97 (d, J = 8.8 Hz, 1H), 9.79 (s, 1H), 11.22 (bs, 1H); MS (ESI) + m/z 417 (M+H) +.
(5－甲基－2－苯基硫基－苯基)－(7－丙基－吡啶并[2,3－d]嘧啶－4－基)－胺(5-Methyl-2-phenylthio-phenyl)-(7-propyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
產物係使用得自實例36A之程序，以2－戊酮取代甲基異丙基酮，獲得中間物，然後使其根據得自實例36A－36E之連續程序反應而製成。The product was prepared using the procedure from Example 36A, substituting 2-pentanone with methyl isopropyl ketone to afford intermediates which were then reacted according to the continuous procedure from Example 36A-36E.
實例128A N'－(3－氧基－6－丙基－吡啶－2－基)－N,N－二甲基－甲脒產物係使用得自實例36A之程序，以2－戊酮取代甲基異丙基酮，獲得中間物，然後使其根據得自實例36A－36E之連續程序反應而製成。Example 128A N'-(3-Oxo-6-propyl-pyridin-2-yl)-N,N-dimethyl-formamidine product was obtained using the procedure from Example 36A. Isopropyl ketone, an intermediate was obtained which was then prepared according to the continuous procedure from Examples 36A-36E.
實例128B(5－甲基－2－苯基硫基－苯基)－(7－丙基－吡啶并[2,3－d]嘧啶－4－基)－胺使得自實例5I之產物(49毫克0.231毫莫耳)與得自實例128A之產物(50毫克，0.231毫莫耳)溶於醋酸(1毫升)中，並加熱至130℃，歷經1.5小時。於冷卻至室溫後，固體在醋酸溶劑中出現，將其藉過濾收集，提供標題化合物，為醋酸鹽(68毫克，62%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：0.94(t,J＝7.4 Hz,3H),1.79(m,2H),1.88(s,6H),2.35(s,3H),2.88(t,J 7.6 Hz,2H),7.18(m,5H),7.23(m,2H),7.37(s,1H),7.51(d,J＝8.1 Hz,1H),8.48(s,1H),8.69(d,J＝8.5 Hz,1H)；MS(ESI)＋ m/z 387(M＋H)＋.Example 128B (5-methyl-2-phenylsulfanyl-phenyl)-(7-propyl-pyrido[2,3-d]pyrimidin-4-yl)-amine as a product from Example 5I (49 The mg of the product from Example 128A (50 mg, 0.231 mmol) was dissolved in acetic acid (1 mL) and heated to 130 ° C for 1.5 h. After cooling to rt, EtOAc (EtOAc:EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 0.94 (t, J = 7.4 Hz, 3H), 1.79 (m, 2H), 1.88 (s, 6H), 2.35 (s, 3H), 2.88 (t) , J 7.6 Hz, 2H), 7.18 (m, 5H), 7.23 (m, 2H), 7.37 (s, 1H), 7.51 (d, J = 8.1 Hz, 1H), 8.48 (s, 1H), 8.69 ( d, J = 8.5 Hz, 1H); MS (ESI) + m/z 387 (M+H) +.
3－[4－甲基－2－(7－丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚3-[4-Methyl-2-(7-propyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使得自實例6a之產物(10.14克，35.6毫莫耳)與3－(4－甲基－2－硝基－苯基硫基)－酚(4.48克，35.6毫莫耳)反應18小時，按照得自實例6b之程序，獲得3－(4－甲基－2－硝基－苯基硫基)－酚(7.88克，85%)，使其按照得自實例5I之程序以SnCl2 還原，獲得3－(2－胺基－4－甲基－苯基硫基)－酚。The product from Example 6a (10.14 g, 35.6 mmol) was reacted with 3-(4-methyl-2-nitro-phenylthio)-phenol (4.48 g, 35.6 mmol) for 18 hours. From the procedure of Example 6b, 3-(4-methyl-2-nitro-phenylsulfanyl)-phenol (7.88 g, 85%) was obtained, which was purified from SnCl 2 according to the procedure from Example 5I. 3-(2-Amino-4-methyl-phenylthio)-phenol was obtained.
使3－(2－胺基－4－甲基－苯基硫基)－酚(49毫克0.231毫莫耳)與得自實例128A之產物(50毫克，0.231毫莫耳)溶於醋酸(1毫升)中，並加熱至130℃，歷經1.5小時。於冷卻至室溫後，固體在醋酸溶劑中出現，將其藉過濾收集，提供標題化合物，為醋酸鹽(78毫克，68%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：0.95(t,J＝7.3 Hz,3H),1.79(m,2H),1.88(s,6H),2.40(s,3H),2.88(t,J＝7.6 Hz,2H),6.57(m,3H),7.00(t,J＝7.7 Hz,1H),7.13(m,1H),7.26(d,J＝7.7 Hz,1H),7.38(s,1H),7.51(d,J＝8.5 Hz,1H),8.50(s,1H),8.70(d,J＝8.5 Hz,1H)；MS(ESI)＋ m/z 403(M＋H)＋.3-(2-Amino-4-methyl-phenylsulfanyl)-phenol (49 mg 0.231 mmol) and the product from Example 128A (50 mg, 0.231 mmol) dissolved in acetic acid (1) In milliliters) and heated to 130 ° C for 1.5 hours. After cooling to rt, EtOAc (EtOAc:EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 0.95 (t, J = 7.3 Hz, 3H), 1.79 (m, 2H), 1.88 (s, 6H), 2.40 (s, 3H), 2.88 (t) , J=7.6 Hz, 2H), 6.57 (m, 3H), 7.00 (t, J = 7.7 Hz, 1H), 7.13 (m, 1H), 7.26 (d, J = 7.7 Hz, 1H), 7.38 (s , 1H), 7.51 (d, J = 8.5 Hz, 1H), 8.50 (s, 1H), 8.70 (d, J = 8.5 Hz, 1H); MS (ESI) + m/z 403 (M+H) +.
N－{4－[4－甲基－2－(7－丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－苯基}－乙醯胺N-{4-[4-Methyl-2-(7-propyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenyl}-acetamide
使得自實例7b之產物(49毫克0.231毫莫耳)與得自實例128A之產物(50毫克，0.231毫莫耳)溶於醋酸(1毫升)中，並加熱至130℃，歷經1.5小時。於冷卻至室溫後，並在真空下移除醋酸溶劑，將甲醇(3毫升)添加至油中，其造成固體形成，將其以甲醇研製，提供標題化合物(80毫克，78%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：0.95(t,J＝7.4 Hz,3H),1.89(m,2H),2.02(s,3H),2.32(s,3H),2.89(t,J＝7.5 Hz,2H),7.06(s,2H),7.21(t,J＝8.5 Hz,2H),7.30(s,1H),7.50(d,J＝8.8 Hz,2H),7.52(m,1H),8.52(s,1H),8.74(d,J＝7.7 Hz,1H),10.00(s,1H)；MS(ESI)＋ m/z 444(M＋H)＋.The product from Example 7b (49 mg 0.231 mmol) and product from Example 128A (50 mg, 0.231 mmol) was dissolved in acetic acid (1 mL) and heated to 130 ° C for 1.5 hours. After chilling to rt, EtOAc (3 mL). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 0.95 (t, J = 7.4 Hz, 3H), 1.89 (m, 2H), 2.02 (s, 3H), 2.32 (s, 3H), 2.89 (t) , J = 7.5 Hz, 2H), 7.06 (s, 2H), 7.21 (t, J = 8.5 Hz, 2H), 7.30 (s, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.52 (m , 1H), 8.52 (s, 1H), 8.74 (d, J = 7.7 Hz, 1H), 10.00 (s, 1H); MS (ESI) + m/z 444 (M+H)+.
4－[4－甲基－2－(7－丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-Methyl-2-(7-propyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使得自實例6c之產物(49毫克0.231毫莫耳)與得自實例128A之產物(50毫克，0.231毫莫耳)溶於醋酸(1毫升)中，並加熱至130℃，歷經1.5小時。於冷卻至室溫後，固體在醋酸溶劑中出現，將其藉過濾收集，提供標題化合物，為醋酸鹽(77毫克，68%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：0.96(t,J＝7.4 Hz,3H),1.80(m,2H),1.88(s,6H),2.40(s,3H),2.90(t,J＝7.6 Hz,2H),6.74(d,J＝8.5 Hz,2H),6.90(d,J＝8.1 Hz,1H),7.03(m,1H),7.18(d,J＝8.8 Hz,2H),7.22(s,1H),7.54(d,J＝8.1 Hz,1H),8.53(s,1H),8.78(d,J＝8.5 Hz,1H)；MS(ESI)＋ m/z 403(M＋H)＋.The product from Example 6c (49 mg 0.231 mmol) and product from Example 128A (50 mg, 0.231 mmol) was dissolved in acetic acid (1 mL) and heated to 130 ° C for 1.5 hours. After cooling to rt, EtOAc (EtOAc:EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 0.96 (t, J = 7.4 Hz, 3H), 1.80 (m, 2H), 1.88 (s, 6H), 2.40 (s, 3H), 2.90 (t) , J=7.6 Hz, 2H), 6.74 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.1 Hz, 1H), 7.03 (m, 1H), 7.18 (d, J=8.8 Hz, 2H ), 7.22 (s, 1H), 7.54 (d, J = 8.1 Hz, 1H), 8.53 (s, 1H), 8.78 (d, J = 8.5 Hz, 1H); MS (ESI) + m/z 403 ( M+H)+.
N－{4－[5－羥基－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－苯基}－乙醯胺N-{4-[5-Hydroxy-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-phenyl }-acetamide
將2－甲基－4－硝基－5－氯酚(1.5克，8.0毫莫耳)、4－乙醯胺基硫酚(1.6克，8.8毫莫耳)及碳酸銫(5.74克，17.6毫莫耳)在DMF(10毫升)中之混合物，於100℃下加熱2.5小時。使混合物冷卻，以醋酸乙酯(100毫升)稀釋，並以水與10%氯化鈉水溶液洗滌有機層，然後以無水硫酸鈉脫水乾燥。過濾乾燥劑，及在真空下移除溶劑，留下N－[4－(5－羥基－4－甲基－2－硝基－苯基硫基)－苯基]－乙醯胺，為固體(2.5克，81%)。將N－[4－(5－羥基－4－甲基－2－硝基－苯基硫基)－苯基]－乙醯胺(2.5克，6.45毫莫耳)、鐵粉(1.79克，32毫莫耳)及氯化銨(0.514克，9.6毫莫耳)在甲醇(10毫升)、四氫呋喃(10毫升)及水(5毫升)溶液中之溶液加熱至回流，歷經1.5小時。以甲醇(50毫升)稀釋所形成之混合物，並經過矽藻土墊過濾。使濾液在真空下濃縮成體積10毫升，以水(50毫升)稀釋溶液，並以醋酸乙酯(2 x 50毫升)萃取。以10%氯化鈉洗滌合併之萃液，接著以硫酸鎂脫水乾燥，過濾，及在真空下濃縮，提供N－[4－(2－胺基－5－羥基－4－甲基－苯基硫基)－苯基]－乙醯胺(1.7克，91%)。2-Methyl-4-nitro-5-chlorophenol (1.5 g, 8.0 mmol), 4-acetamidothiophenol (1.6 g, 8.8 mmol) and cesium carbonate (5.74 g, 17.6) Mixture of the mixture in DMF (10 mL) was heated at 100 ° C for 2.5 h. The mixture was cooled, diluted with ethyl acetate (100 mL), and then evaporated and evaporated. Filter the desiccant and remove the solvent under vacuum to leave N-[4-(5-hydroxy-4-methyl-2-nitro-phenylsulfanyl)-phenyl]-acetamide as a solid (2.5 grams, 81%). N-[4-(5-Hydroxy-4-methyl-2-nitro-phenylsulfanyl)-phenyl]-acetamide (2.5 g, 6.45 mmol), iron powder (1.79 g, A solution of 32 mmol of ammonium chloride (0.514 g, 9.6 mmol) in methanol (10 mL), THF (10 mL) The resulting mixture was diluted with methanol (50 mL) and filtered through a pad of Celite. The filtrate was concentrated in vacuo to a volume of 10 mL, diluted with water (50 mL) andEtOAc. The combined extracts were washed with 10% aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford N-[4-(2-amino-5-hydroxy-4-methyl-phenyl Thio)-phenyl]-acetamide (1.7 g, 91%).
使N－[4－(2－胺基－5－羥基－4－甲基－苯基硫基)－苯基]－乙醯胺與得自實例36E之產物反應，使用得自實例36I之程序，以N－[4－(2－胺基－5－羥基－4－甲基－苯基硫基)－苯基]－乙醯胺取代得自實例36H之產物，提供粗製殘留物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.34(d,J＝6.99 Hz,6H),2.03(s,3H),2.11(s,3H),3.27(s,1H),6.63(s,1H),7.12(s,1H),7.25(d,J＝8.82 Hz,2H),7.51(d,J＝8.82 Hz,2H),7.85(d,J＝8.46 Hz,1H),8.80(s,1H),8.94(d,J＝8.46 Hz,1H),9.75(s,1H),10.02(s,1H),11.36(s,1H)；MS(ESI)＋ m/z 460(M＋H)＋.N-[4-(2-Amino-5-hydroxy-4-methyl-phenylsulfanyl)-phenyl]-acetamide was reacted with the product from Example 36E using the procedure from Example 36. Substituting the product from Example 36H with N-[4-(2-amino-5-hydroxy-4-methyl-phenylsulfanyl)-phenyl]-acetamide afforded a crude residue. Purification by TFA by HPLC afforded the title compound as trifluoroacetate. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J = 6.99 Hz, 6H), 2.03 (s, 3H), 2.11 (s, 3H), 3.27 (s, 1H), 6.63 (s) , 1H), 7.12 (s, 1H), 7.25 (d, J = 8.82 Hz, 2H), 7.51 (d, J = 8.82 Hz, 2H), 7.85 (d, J = 8.46 Hz, 1H), 8.80 (s) , 1H), 8.94 (d, J = 8.46 Hz, 1H), 9.75 (s, 1H), 10.02 (s, 1H), 11.36 (s, 1H); MS (ESI) + m/z 460 (M+H)+ .
N1 －(4－苄氧基－苯基)－N2 －(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－4,N1 －二甲基－苯－1,2－二胺N 1 -(4-Benzyloxy-phenyl)-N 2 -(7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-4,N 1 -dimethyl-benzene -1,2-diamine
實例133A(4－苄氧基－苯基)－(4－甲基－2－硝基－苯基)－胺將4－甲基－2－硝基苯胺(1.006克，6.612毫莫耳)、4－苄氧基溴苯(5.794克，22.02毫莫耳)、碘化亞銅(62.9毫克，0.3306毫莫耳)、碳酸鉀(0.914克，6.612毫莫耳)及無水鄰－二甲苯(18毫升)之混合物，在150°下加熱24小時。添加另外之碘化亞銅(30毫克)，並於160°下再加熱6小時。使反應物冷卻至室溫，並在真空下藉迴轉式蒸發移除溶劑。使殘留物藉矽膠急驟式層析純化，使用1：1二氯甲烷/己烷作為溶離劑，而得標題化合物，為紅色油，其係慢慢地結晶(1.23克，56%)。Example 133A (4-benzyloxy-phenyl)-(4-methyl-2-nitro-phenyl)-amine 4-methyl-2-nitroaniline (1.006 g, 6.612 mmol), 4-benzyloxybromobenzene (5.794 g, 22.02 mmol), cuprous iodide (62.9 mg, 0.3306 mmol), potassium carbonate (0.914 g, 6.612 mmol) and anhydrous o-xylene (18) A mixture of ml) was heated at 150 ° for 24 hours. Additional cuprous iodide (30 mg) was added and heated at 160 for an additional 6 hours. The reaction was allowed to cool to room temperature and the solvent was removed by rotary evaporation under vacuum. The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut
實例133B(4－苄氧基－苯基)－甲基－(4－甲基－2－硝基－苯基)－胺於室溫及氮大氣下，將得自實例133A之產物(229.4毫克，0.6861毫莫耳)在無水N,N－二甲基甲醯胺(3毫升)中之溶液，添加至氫化鈉(在礦油中之60%分散液，55毫克，1.372毫莫耳)在N,N－二甲基甲醯胺(3毫升)中之懸浮液內。將反應物在室溫下攪拌1小時，然後添加碘化甲烷(0.171毫升，2.744毫莫耳)，並將其在室溫下攪拌2小時。在真空下藉迴轉式蒸發移除溶劑。使殘留物溶於水(30毫升)中，並以二氯甲烷(50毫升)萃取。以水(30毫升)洗滌有機相，以無水硫酸鎂脫水乾燥，過濾，及在真空下藉迴轉式蒸發濃縮，而得標題化合物，為帶有栗色之固體(239毫克，100%)。Example 133B (4-benzyloxy-phenyl)-methyl-(4-methyl-2-nitro-phenyl)-amine The product from Example 133A (229.4 mg. , 0.6861 mmol) in anhydrous N,N-dimethylformamide (3 mL), added to sodium hydride (60% dispersion in mineral oil, 55 mg, 1.372 mmol) In a suspension of N,N-dimethylformamide (3 ml). The reaction was stirred at room temperature for 1 hr then methylene iodide (0.171 mL, 2.344 m. The solvent was removed by rotary evaporation under vacuum. The residue was dissolved in water (30 mL) The organic phase was washed with EtOAc EtOAc m.
實例133C(4－苄氧基－苯基)－甲基－(4－甲基－2－胺基－苯基)－胺將得自實例133B之產物(129.4毫克，0.3714毫莫耳)、鐵粉(128毫克，2.284毫莫耳)、氯化銨(130毫克，2.433毫莫耳)在水(1毫升)與乙醇(2毫升)中之混合物，於70°及氮大氣下加熱1小時。使反應物冷卻至室溫，並真空過濾，以甲醇洗滌殘留物。在真空下濃縮濾液，並與甲苯(50毫升)共沸。使殘留物藉矽膠急驟式層析純化，使用二氯甲烷作為溶離劑，提供標題化合物，為蠟狀固體(85毫克，72%)。Example 133C (4-benzyloxy-phenyl)-methyl-(4-methyl-2-amino-phenyl)-amine The product from Example 133B (129.4 mg, 0.3714 m. A mixture of powder (128 mg, 2.284 mmol), ammonium chloride (130 mg, 2.433 mmol) in water (1 ml) and ethanol (2 ml) was heated at 70 ° under a nitrogen atmosphere for 1 hour. The reaction was cooled to room temperature and filtered under vacuum and the residue was washed with methanol. The filtrate was concentrated under vacuum and azeotroped with toluene (50 mL). The residue was purified by flash chromatography eluting elut elut elut elut
實例133D N1 －(4－苄氧基－苯基)－N2 －(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－4,N1 －二甲基－苯－1,2－二胺將得自實例36E之產物(28毫克，0.1297毫莫耳)與得自實例133C之產物(41.3毫克，0.1297毫莫耳)在醋酸(1毫升)中之溶液，於預熱至140℃之油浴中攪拌1小時。使反應物冷卻至室溫，以己烷(50毫升)稀釋，在真空下藉迴轉式蒸發濃縮，並與二氯甲烷/己烷共蒸發(4x)。使殘留物乾燥，然後藉矽膠急驟式層析純化，使用20%醋酸乙酯/二氯甲烷作為溶離劑，而得標題化合物，為黃色固體(35毫克，55%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.27(d,J＝6.62 Hz,6H),2.34(s,3H),3.08(s,3H),3.06－3.22(m,1H),4.79(s,2H),6.50(d,J＝9.19 Hz,2H),6.60(d,J＝8.82 Hz,2H),7.05－7.17(m,2H),7.25－7.37(m,5H),7.41(d,J＝8.46 Hz,1H),7.47(s,1H),8.42(d,J＝8.46 Hz,1H),8.52(s,1H),9.33(s,1H)；MS(DCI/NH3 )m/z 490(M＋H)＋ .Example 133D N 1 -(4-Benzyloxy-phenyl)-N 2 -(7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-4,N 1 -dimethyl - Benzene-1,2-diamine. A solution of the product from Example 36E (28 mg, 0.1297 mmol) and the product from Example 133C (41.3 mg, 0.1297 mmol) in acetic acid (1 mL) It was stirred for 1 hour in an oil bath preheated to 140 °C. The reaction was cooled to room temperature, diluted with EtOAc EtOAc (EtOAc) The residue was dried and purified with EtOAc EtOAc EtOAc EtOAc 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.27 (d, J = 6.62 Hz, 6H), 2.34 (s, 3H), 3.08 (s, 3H), 3.06-3.22 (m, 1H), 4.79 (s, 2H), 6.50 (d, J = 9.19 Hz, 2H), 6.60 (d, J = 8.82 Hz, 2H), 7.05-7.17 (m, 2H), 7.25-7.37 (m, 5H), 7.41 ( d, J = 8.46 Hz, 1H), 7.47 (s, 1H), 8.42 (d, J = 8.46 Hz, 1H), 8.52 (s, 1H), 9.33 (s, 1H); MS (DCI/NH 3 ) m/z 490 (M+H) + .
(2－苄基－5－甲基－苯基)－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺(2-Benzyl-5-methyl-phenyl)-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
實例134A 2－苄基－5－甲基－苯胺於氮大氣下，將氫化鋰鋁在四氫呋喃中之溶液(1.0M，2.54毫升，2.54毫莫耳)經由注射器添加至含有氯化鋁(534毫克，4.005毫莫耳)之燒瓶中，並於0°浴液中冷卻。使混合物冷卻5分鐘後，於0°下，慢慢逐滴添加2－胺基－4－甲基二苯甲酮(200毫克，0.9467毫莫耳)在四氫呋喃(4毫升)中之溶液。然後將反應物於50°下加熱30分鐘。使反應物冷卻至室溫，並添加潮濕***(5毫升)。將反應物小心地倒入水(20毫升)中，並以***(2 x 50毫升)萃取。以鹽水(20毫升)洗滌合併之含醚萃液，以無水硫酸鈉脫水乾燥，過濾，及在真空下藉迴轉式蒸發濃縮。藉矽膠急驟式層析之純化，使用40：60己烷/二氯甲烷作為溶離劑，提供標題化合物，為油狀物(94毫克，50%)。Example 134A 2-Benzyl-5-methyl-phenylamine A solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 2.54 mL, 2.54 mmol) was added via syringe to aluminum chloride (534 mg). , 4.005 mmol) in a flask and cooled in a 0 ° bath. After allowing the mixture to cool for 5 minutes, a solution of 2-amino-4-methylbenzophenone (200 mg, 0.9467 mmol) in tetrahydrofuran (4 mL) was slowly added dropwise. The reaction was then heated at 50 for 30 minutes. The reaction was cooled to rt and EtOAc (5 mL) was evaporated. The reaction was poured into water (20 mL) EtOAc. The combined ether extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated. Purification by flash chromatography eluting with EtOAc (EtOAc)
實例134B(2－苄基－5－甲基－苯基)－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺將得自實例36E之產物(34.6毫克，0.160毫莫耳)與得自實例134A之產物(31.6毫克，0.160毫莫耳)在醋酸(1毫升)中之溶液，於預熱至140℃之油浴中攪拌1小時。使反應物冷卻至室溫，以己烷(50毫升)稀釋，在真空下藉迴轉式蒸發濃縮，並與二氯甲烷/己烷共蒸發(4x)。使殘留物乾燥，然後藉矽膠急驟式層析純化，使用2%甲醇/二氯甲烷作為溶離劑，提供標題化合物，為淡黃色固體(50毫克，85%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.32(d,J＝6.99 Hz,6H)2.30(s,3H)3.12－3.28(m,1H)3.87(s,2H)6.95－7.20(m,8H)7.57(s,1H)8.47(s,1H)8.74(d,J＝8.46 Hz,1H)9.81(s,1H)；MS(DCI/NH3 )m/z 369(M＋H)＋ .Example 134B (2-benzyl-5-methyl-phenyl)-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-amine The product from Example 36E (34.6 A solution of the product from Example 134A (31.6 mg, 0.160 mmol) in acetic acid (1 mL) was stirred for 1 hour in an oil bath preheated to 140 °C. The reaction was cooled to room temperature, diluted with EtOAc EtOAc (EtOAc) The residue was dried with EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.32 (d, J = 6.99 Hz, 6H) 2.30 (s, 3H) 3.12-3.28 (m, 1H) 3.87 (s, 2H) 6.95-7.20 (m , 8H) 7.57 (s, 1H) 8.47 (s, 1H) 8.74 (d, J = 8.46 Hz, 1H) 9.81 (s, 1H); MS (DCI / NH 3 ) m / z 369 (M + H) + .
(7－環己基－吡啶并[2,3－d]嘧啶－4－基)－(5－甲基－2－苯基硫基－苯基)－胺(7-Cyclohexyl-pyrido[2,3-d]pyrimidin-4-yl)-(5-methyl-2-phenylthio-phenyl)-amine
實例135A N'－(3－氰基－6－環己基－吡啶－2－基)－N,N－二甲基－甲脒使1－環己基－乙酮根據實例36A－36E中所述之程序反應，提供標題化合物。Example 135A N'-(3-Cyano-6-cyclohexyl-pyridin-2-yl)-N,N-dimethyl-formamidine 1-cyclohexyl-ethanone as described in Examples 36A-36E The program reacts to provide the title compound.
實例135B(7－環己基－吡啶并[2,3－d]嘧啶－4－基)－(5－甲基－2－苯基硫基－苯基)－胺於得自實例135A之產物(56.0毫克，0.2322毫莫耳)在醋酸(4毫升)中之溶液內，添加得自實例5I之產物(50.0毫克’0.2322毫莫耳)，並將混合物於預熱至130℃之油浴中攪拌15分鐘。然後使混合物冷卻至室溫，在真空下移除醋酸，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(20毫克，20%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.38－1.51(m,2H),1.57－1.69(m,2H),1.70－1.80(m,2H),1.80－1.99(m,6H),2.33－2.40(m,3H),7.12－7.17(m,1H),7.12－7.26(m,3H),7.30－7.33(m,1H),7.33－7.38(m,2H),8.68－8.75(m,1H),8.82－8.90(m,1H)；MS(DCI/NH3)m/z 427(M＋H)＋.Example 135B (7-cyclohexyl-pyrido[2,3-d]pyrimidin-4-yl)-(5-methyl-2-phenylsulfanyl-phenyl)-amine from the product from Example 135A ( 56.0 mg, 0.2322 mmol; in a solution of acetic acid (4 ml), the product from Example 5I (50.0 mg < 15 minutes. After the mixture was cooled to room temperature, the title compound was obtained from EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.38-1.51 (m, 2H), 1.57-1.69 (m, 2H), 1.70-1.80 (m, 2H), 1.80-1.99 (m, 6H), 2.33-2.40(m,3H),7.12-7.17(m,1H),7.12-7.26(m,3H),7.30-7.33(m,1H),7.33-7.38(m,2H),8.68-8.75(m , 1H), 8.82-8.90 (m, 1H); MS (DCI/NH3) m/z 427 (M+H)+.
4－[2－(7－環己基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－酚4-[2-(7-Cyclohexyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-phenol
使得自實例135A之產物與得自實例6c之產物反應，根據得自實例135B之程序，以得自實例6c之產物取代得自實例5I之產物，提供標題化合物，為三氟醋酸鹽(20毫克，20%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.38－1.52(m,2H),1.55－1.80(m,3H),1.80－1.91(m,2H),1.91－2.03(m,3H),2.30(s,3H),3.26－3.47(m,1H),6.66－6.74(m,2H),6.74－6.81(m,1H),6.96－7.03(m,1H),7.10－7.14(m,1H),7.14－7.21(m,3H),7.21－7.26(m,1H),8.72－8.80(m,1H),8.90－8.97(m,1H),9.78(s,1H)；MS(DCI/NH3)m/z 443(M＋H)＋.The product from Example 135A was reacted with the product from Example 6c to give the title compound as a trifluoroacetate (20 mg). , 20%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.38-1.52 (m, 2H), 1.55-1.80 (m, 3H), 1.80-1.91 (m, 2H), 1.91-2.03 (m, 3H), 2.30(s,3H), 3.26-3.47(m,1H),6.66-6.74(m,2H),6.74-6.81(m,1H),6.96-7.03(m,1H),7.10-7.14(m,1H ), 7.14-7.21 (m, 3H), 7.21-7.26 (m, 1H), 8.72-8.80 (m, 1H), 8.90-8.97 (m, 1H), 9.78 (s, 1H); MS (DCI/NH3) )m/z 443(M+H)+.
N－{4－[2－(7－環己基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－苯基}－乙醯胺N-{4-[2-(7-Cyclohexyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylsulfanyl]-phenyl}-acetamide
使得自實例135A之產物與得自實例7b之產物反應，根據得自實例135B之程序，以得自實例7b之產物取代得自實例5I之產物，提供標題化合物，為三氟醋酸鹽(21毫克，25%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.28－1.52(m,3H),1.53－1.79(m,3H),1.79－1.97(m,4H),2.02(s,3H),2.32(s,3H),2.79－2.94(m,1H),7.03－7.12(m,1H),7.20(d,J＝8.46 Hz,2H),7.31(s,1H),7.50(d,J＝8.82 Hz,2H),7.56(d,J＝8.46 Hz,1H),8.54(s,1H),8.76(d,J＝8.82 Hz,1H),9.99(s,2H)；MS(DCI/NH3)m/z 484(M＋H)＋.The product from Example 135A was reacted with the product from Example 7b to give the title compound as a trifluoroacetic acid salt (21 mg) from the product from Example 7b. , 25%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.28-1.52 (m, 3H), 1.53-1.79 (m, 3H), 1.79-1.97 (m, 4H), 2.02 (s, 3H), 2.32 ( s, 3H), 2.79-2.94 (m, 1H), 7.03-7.12 (m, 1H), 7.20 (d, J = 8.46 Hz, 2H), 7.31 (s, 1H), 7.50 (d, J = 8.82 Hz , 2H), 7.56 (d, J = 8.46 Hz, 1H), 8.54 (s, 1H), 8.76 (d, J = 8.82 Hz, 1H), 9.99 (s, 2H); MS (DCI/NH3) m/ z 484(M+H)+.
N－{4－[2－(7－環丁基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－苯基}－乙醯胺N-{4-[2-(7-Cyclobutyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-phenyl}-acetamidine amine
實例138A N'－(3－氰基－6－環丁基－吡啶－2－基)－N,N－二甲基－甲脒使1－環丁基－乙酮根據實例36A－36E中所述之程序反應，提供標題化合物。Example 138A N'-(3-Cyano-6-cyclobutyl-pyridin-2-yl)-N,N-dimethyl-formamidine 1-cyclobutyl-ethanone according to Examples 36A-36E The procedure described provides the title compound.
實例138B N－{4－[2－(7－環丁基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－苯基}－乙醯胺使得自實例138A之產物與得自實例7b之產物反應，根據得自實例135B之程序，以得自實例7b之產物取代得自實例5I之產物，並以得自實例138A之產物取代得自實例135A之產物，提供標題化合物，為三氟醋酸鹽(30毫克，36%產率)。1 H NMR(500 MHz,DMSO－D6)δ ppm：0.86(t,J＝7.02 Hz,1H),1.86－1.98(m,1H),2.02(s,3H),2.06－2.18(m,1H),2.34(s,3H),2.37－2.47(m,4H),3.80－4.02(m,1H),7.13－7.25(m,4H),7.29(s,1H),7.45(d,J＝8.54 Hz,2H),7.78(d,J＝8.54 Hz,1H),8.80(s,1H),8.92(d,J＝8.54 Hz,1H),9.98(s,1H)；MS(DCI/NH4 )m/z 456(M＋H)＋.Example 138B N-{4-[2-(7-Cyclobutyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-phenyl}- The acetamide was reacted with the product from Example 138A from the product from Example 7b, substituting the product from Example 7b from the product from Example 7b, and substituting the product from Example 138A. The title compound was obtained as the title compound (30 mg, 36% yield). 1 H NMR (500 MHz, DMSO-D6) δ ppm: 0.86 (t, J = 7.02 Hz, 1H), 1.86-1.98 (m, 1H), 2.02 (s, 3H), 2.06-2.18 (m, 1H) , 2.34 (s, 3H), 2.37-2.47 (m, 4H), 3.80-4.02 (m, 1H), 7.13 - 7.25 (m, 4H), 7.29 (s, 1H), 7.45 (d, J = 8.54 Hz , 2H), 7.78 (d, J = 8.54 Hz, 1H), 8.80 (s, 1H), 8.92 (d, J = 8.54 Hz, 1H), 9.98 (s, 1H); MS (DCI/NH 4 ) m /z 456(M+H)+.
4－[2－(7－環丁基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－酚使得自實例138A之產物與得自實例6c之產物反應，根據得自實例135B之程序，以得自實例6c之產物取代得自實例5I之產物，並以得自實例138A之產物取代得自實例135A之產物，提供標題化合物，為三氟醋酸鹽(30毫克，33%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.85－2.01(m,1H),2.03－2.24(m,1H),2.31(s,3H),2.36－2.46(m,4H),3.81－4.13(m,2H),6.70(d,J＝8.46 Hz,2H),7.02(d,J＝8.09 Hz,1H),7.17(d,J＝8.46 Hz,3H),7.24(s,1H),7.82(d,J＝8.46 Hz,1H),8.82(s,1H),8.97(d,J＝8.46 Hz,1H),9.72－9.93(m,1H)；MS(DCI/NH4 )m/z 415(M＋H)＋.4-[2-(7-Cyclobutyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylsulfanyl]-phenol gave the product from Example 138A From the product of Example 6c, substituting the product from Example </RTI></RTI><RTIgt; It was trifluoroacetate (30 mg, 33%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.85-2.01 (m, 1H), 2.03-2.24 (m, 1H), 2.31 (s, 3H), 2.36-2.46 (m, 4H), 3.81 4.13(m, 2H), 6.70 (d, J = 8.46 Hz, 2H), 7.02 (d, J = 8.09 Hz, 1H), 7.17 (d, J = 8.46 Hz, 3H), 7.24 (s, 1H), 7.82 (d, J = 8.46 Hz, 1H), 8.82 (s, 1H), 8.97 (d, J = 8.46 Hz, 1H), 9.72 - 9.93 (m, 1H); MS (DCI/NH 4 ) m/z 415 (M+H)+.
(7－第二－丁基－吡啶并[2,3－d]嘧啶－4－基)－(5－甲基－2－苯基硫基－苯基)－胺(7-second-butyl-pyrido[2,3-d]pyrimidin-4-yl)-(5-methyl-2-phenylthio-phenyl)-amine
實例140A N'－(6－第二－丁基－3－氰基－吡啶－2－基)－N,N－二甲基－甲脒使3－甲基－戊烷－2－酮根據實例36A－36E中所述之程序反應，提供標題化合物。Example 140A N'-(6-Second-butyl-3-cyano-pyridin-2-yl)-N,N-dimethyl-formamidine 3-methyl-pentan-2-one according to an example The procedure described in 36A-36E provides the title compound.
實例140B(7－第二－丁基－吡啶并[2,3－d]嘧啶－4－基)－(5－甲基－2－苯基硫基－苯基)－胺使得自實例140A之產物與得自實例5I之產物反應，根據得自實例135B之程序，以得自實例140A之產物取代得自實例135A之產物，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：0.83(t,J＝7.35 Hz,3H),1.32(d,J＝6.99 Hz,3H),1.59－1.75(m,1H),1.75－1.95(m,1H),2.37(s,3H),2.95－3.12(m,2H),7.11－7.22(m,5H),7.25(d,J＝6.62 Hz,1H),7.31－7.46(m,2H),7.81(d,J＝8.82 Hz,1H),8.76(s,1H),8.91(d,J＝8.46 Hz,1H)；MS(DCI/NH4 )m/z 401(M＋H)＋.Example 140B (7-second-butyl-pyrido[2,3-d]pyrimidin-4-yl)-(5-methyl-2-phenylthio-phenyl)-amine is rendered from Example 140A The product was reacted with the product from Example </RTI><RTIID=0.0> 1 H NMR (300 MHz, DMSO-D6) δ ppm: 0.83 (t, J = 7.35 Hz, 3H), 1.32 (d, J = 6.99 Hz, 3H), 1.59-1.75 (m, 1H), 1.75-1.95 (m, 1H), 2.37 (s, 3H), 2.95-3.12 (m, 2H), 7.11-7.22 (m, 5H), 7.25 (d, J = 6.62 Hz, 1H), 7.31-7.46 (m, 2H) ), 7.81 (d, J = 8.82 Hz, 1H), 8.76 (s, 1H), 8.91 (d, J = 8.46 Hz, 1H); MS (DCI/NH 4 ) m/z 401 (M+H) +.
N－{4－[2－(7－第二－丁基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－苯基}－乙醯胺N-{4-[2-(7-Second-butyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-phenyl}- Acetamine
使得自實例140A之產物與得自實例7b之產物反應，根據得自實例135B之程序，以得自實例7b之產物取代得自實例5I之產物，並以得自實例140A之產物取代得自實例135A之產物，提供標題化合物，為三氟醋酸鹽(37毫克，45%)。1 H NMR(500 MHz,DMSO－D6)δ ppm：0.84(t,J＝7.32 Hz,3H),1.33(d,J＝6.71 Hz,3H),1.62－1.76(m,1H),1.77－1.91(m,1H),2.34(s,3H),2.49(s,3H),2.96－3.14(m,1H),7.11－7.25(m,4H),7.28(s,1H),7.46(d,J＝9.16 Hz,2H),7.83(d,J＝8.54 Hz,1H),8.79(s,1H),8.94(d,J＝7.93 Hz,1H),9.97(s,1H),11.31－11.69(m,1H)；MS(DCI/NH4 )m/z 458(M＋H)＋.The product from Example 140A was reacted with the product from Example 7b, substituting the product from Example 7b from the product from Example 7b and substituting the product from Example 140A. The title compound was obtained as the title compound, mp. 1 H NMR (500 MHz, DMSO-D6) δ ppm: 0.84 (t, J = 7.32 Hz, 3H), 1.33 (d, J = 6.71 Hz, 3H), 1.62-1.76 (m, 1H), 1.77-1.91 (m,1H), 2.34(s,3H), 2.49(s,3H),2.96-3.14(m,1H),7.11-7.25(m,4H),7.28(s,1H),7.46(d,J = 9.16 Hz, 2H), 7.83 (d, J = 8.54 Hz, 1H), 8.79 (s, 1H), 8.94 (d, J = 7.93 Hz, 1H), 9.97 (s, 1H), 11.31-11.69 (m ,1H);MS(DCI/NH 4 )m/z 458(M+H)+.
N－(4－{4－甲基－2－[7－(1－甲基－環丙基)－吡啶并[2,3－d]嘧啶－4－基胺基]－苯基硫基}－苯基)－乙醯胺N-(4-{4-Methyl-2-[7-(1-methyl-cyclopropyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-phenylthio} -phenyl)-acetamide
實例142A N'－[3－氰基－6－(1－甲基－環丙基)－吡啶－2－基]－N,N－二甲基－甲脒使1－(1－甲基－環丙基)－乙酮根據實例36A－36E中所述之程序反應，提供標題化合物。Example 142A N'-[3-Cyano-6-(1-methyl-cyclopropyl)-pyridin-2-yl]-N,N-dimethyl-formamidine 1-(1-methyl- The cyclopropyl)-ethanone was reacted according to the procedure described in Example 36A-36E to provide the title compound.
實例142B N－(4－{4－甲基－2－[7－(1－甲基－環丙基)－吡啶并[2,3－d]嘧啶－4－基胺基]－苯基硫基}－苯基)－乙醯胺Example 142B N-(4-{4-methyl-2-[7-(1-methyl-cyclopropyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-phenylsulfide }--phenyl)-acetamide
使得自實例142A之產物與得自實例7b之產物反應，根據得自實例135B之程序，以得自實例7b之產物取代得自實例5I之產物，並以得自實例142A之產物取代得自實例135A之產物，提供標題化合物，為三氟醋酸鹽(30毫克，50%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：0.79－0.91(m,1H),1.08－1.19(m,2H),1.19－1.30(m,1H),1.37－1.50(m,2H),1.61(s,3H),2.02(s,1H),2.33(s,3H),7.10－7.24(m,4H),7.28(s,1H),7.45(d,J＝8.82 Hz,2H),7.85(d,J＝8.46 Hz,1H),8.78(s,1H),8.89(d,J＝9.19 Hz,1H),9.99(s,1H)；MS(DCI/NH4 )m/z 456(M＋H)＋.The product from Example 142A was reacted with the product from Example 7b, substituting the product from Example 7b from the product from Example 7b and substituting the product from Example 142A. The title compound was obtained as the title compound (30 mg, 50%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 0.79-0.91 (m, 1H), 1.08-1.19 (m, 2H), 1.19-1.30 (m, 1H), 1.37-1.50 (m, 2H), 1.61 (s, 3H), 2.02 (s, 1H), 2.33 (s, 3H), 7.10-7.24 (m, 4H), 7.28 (s, 1H), 7.45 (d, J = 8.82 Hz, 2H), 7.85 (d, J = 8.46 Hz, 1H), 8.78 (s, 1H), 8.89 (d, J = 9.19 Hz, 1H), 9.99 (s, 1H); MS (DCI/NH 4 ) m/z 456 (M+H )+.
4－{4－甲基－2－[7－(1－甲基－環丙基)－吡啶并[2,3－d]嘧啶－4－基胺基]－苯基硫基}－酚4-{4-methyl-2-[7-(1-methyl-cyclopropyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-phenylthio}-phenol
使得自實例142A之產物與得自實例6c之產物反應，根據得自實例135B之程序，以得自實例6c之產物取代得自實例5I之產物，並以得自實例142A之產物取代得自實例135A之產物，提供標題化合物，為三氟醋酸鹽(20毫克，37%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：0.77－0.91(m,1H),1.07－1.18(m,2H),1.38－1.52(m,2H),1.61(s,3H),2.31(s,3H),6.70(d,J＝8.46 Hz,2H),7.02(d,J＝8.09 Hz,1H),7.10－7.21(m,J＝8.46 Hz,3H),7.23(s,1H),7.86(d,J＝8.82 Hz,1H),8.78(s,1H),8.93(d,J＝8.82 Hz,1H),9.82(s,1H)；MS(DCI/NH4 )m/w415(M＋H)＋.The product from Example 142A was reacted with the product from Example 6c, substituting the product from Example 6c, sub. The title compound was obtained as the title compound as a trifluoroacetate (20 mg, 37%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 0.77-0.91 (m, 1H), 1.07-1.18 (m, 2H), 1.38-1.52 (m, 2H), 1.61 (s, 3H), 2.31 ( s, 3H), 6.70 (d, J = 8.46 Hz, 2H), 7.02 (d, J = 8.09 Hz, 1H), 7.10 - 7.21 (m, J = 8.46 Hz, 3H), 7.23 (s, 1H), 7.86 (d, J = 8.82 Hz, 1H), 8.78 (s, 1H), 8.93 (d, J = 8.82 Hz, 1H), 9.82 (s, 1H); MS (DCI/NH 4 ) m/w 415 (M+H )+.
3－{4－甲基－2－[7－(1－甲基－環丙基)－吡啶并[2,3－d]嘧啶－4－基胺基]－苯基硫基}－酚3-{4-methyl-2-[7-(1-methyl-cyclopropyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-phenylthio}-phenol
使得自實例142A之產物與3－(2－胺基－4－甲基－苯基硫基)－酚(實例129)反應，根據得自實例135B之程序，以3－(2－胺基－4－甲基－苯基硫基)－酚取代得自實例5I之產物，並以得自實例142A之產物取代得自實例135A之產物，提供標題化合物，為三氟醋酸鹽(20毫克，37%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：0.77－0.92(m,1H),1.35－1.48(m,2H),1.60(s,3H),2.36(s,3H),6.41－6.68(m,3H),6.90－7.05(m,1H),7.23(d,J＝6.62 Hz,1H),7.29－7.42(m,2H),7.77(d,J＝9.56 Hz,1H),8.68(s,1H),8.82(d,J＝7.72 Hz,1H),9.52(s,1H)；MS(DCI/NH4 )m/z 415(M＋H)＋.The product from Example 142A was reacted with 3-(2-amino-4-methyl-phenylsulfanyl)-phenol (Example 129), according to the procedure from Example 135B, 3-(2-amino- 4-Methyl-phenylthio)-phenol was substituted for the product from Example 5I, and the product from Example </RTI></RTI></RTI></RTI> %). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 0.77-0.92 (m, 1H), 1.35-1.48 (m, 2H), 1.60 (s, 3H), 2.36 (s, 3H), 6.41-6.68 ( m, 3H), 6.90-7.05 (m, 1H), 7.23 (d, J = 6.62 Hz, 1H), 7.29-7.42 (m, 2H), 7.77 (d, J = 9.56 Hz, 1H), 8.68 (s) , 1H), 8.82 (d, J = 7.72 Hz, 1H), 9.52 (s, 1H); MS (DCI / NH 4 ) m / z 415 (M + H) +.
(7－乙基－吡啶并[2,3－d]嘧啶－4－基)－(5－甲基－2－苯基硫基－苯基)－胺(7-Ethyl-pyrido[2,3-d]pyrimidin-4-yl)-(5-methyl-2-phenylthio-phenyl)-amine
實例145A N'－(3－氰基－6－乙基－吡啶－2－基)－N,N－二甲基－甲脒使得自實例10B之產物(0.942克，5.0毫莫耳)在無水四氫呋喃(50毫升)中之溶液，於氮大氣下冷卻至－78℃。於此溶液中，慢慢逐滴添加鋰二異丙基胺之溶液(3.0毫升甲苯/己烷/庚烷中之2.0M溶液，6.0毫莫耳，1.2當量)。在添加完成後，將反應混合物於－78℃下攪拌1小時，然後逐滴添加碘化甲烷(1.42克，10.0毫莫耳，2.0當量)。將反應混合物於－78℃下再攪拌1.5小時，於此段時間內，所有固體均溶解。接著將反應燒瓶自冷卻浴移離，並添加飽和氯化銨水溶液(25毫升)與水(25毫升)。以醋酸乙酯(3 x 100毫升)萃取反應混合物，並以鹽水洗滌合併之有機層，以無水硫酸鎂脫水乾燥，過濾，及在真空下蒸發。使殘留物於矽膠上藉層析純化，以3/2己烷：醋酸乙酯溶離，提供標題化合物(0.87克，86%產率)。Example 145A N'-(3-Cyano-6-ethyl-pyridin-2-yl)-N,N-dimethyl-carboxamidine The product from Example 10B (0.942 g, 5.0 mmol) The solution in tetrahydrofuran (50 mL) was cooled to -78 °C under nitrogen atmosphere. To this solution, a solution of lithium diisopropylamine (3.0 M solution in 3.0 ml of toluene/hexane/heptane, 6.0 mmol, 1.2 eq.) was slowly added dropwise. After the addition was completed, the reaction mixture was stirred at -78 ° C for 1 hour, then methylene iodide (1.42 g, 10.0 mmol, 2.0 eq.) was added dropwise. The reaction mixture was stirred at -78 ° C for an additional 1.5 hours during which time all solids dissolved. The reaction flask was then removed from the cooling bath and saturated aqueous ammonium chloride (25 mL) and water (25 mL). The reaction mixture was extracted with EtOAc (EtOAc)EtOAc. The residue was purified by chromatography EtOAcjjjjjjjj
實例145B(7－乙基－吡啶并[2,3－d]嘧啶－4－基)－(5－甲基－2－苯基硫基－苯基)－胺使得自實例145A之產物與得自實例5I之產物反應，根據得自實例135B之程序，以得自實例145A之產物取代得自實例135A之產物，提供標題化合物，為三氟醋酸鹽(20毫克，33%)。1 H NMR(500 MHz,DMSO－D6)δ ppm：1.34(t,J＝7.93 Hz,3H),2.35(s,3H),3.01(q,J＝7.93 Hz,2H),7.09－7.29(m,6H),7.36(s,1H),7.78(d,J＝8.54 Hz,1H),8.75(s,1H),8.88(d,J＝8.54 Hz,1H)；MS(DCI/NH4 )m/z 373(M＋H)＋.Example 145B (7-ethyl-pyrido[2,3-d]pyrimidin-4-yl)-(5-methyl-2-phenylthio-phenyl)-amine gave the product from Example 145A The product from Example 5I was obtained from the titled </RTI><RTIID=0.0> 1 H NMR (500 MHz, DMSO-D6) δ ppm: 1.34 (t, J = 7.93 Hz, 3H), 2.35 (s, 3H), 3.01 (q, J = 7.93 Hz, 2H), 7.09-7.29 (m) ,6H),7.36(s,1H),7.78(d,J=8.54 Hz,1H),8.75(s,1H),8.88(d,J=8.54 Hz,1H);MS(DCI/NH 4 )m /z 373(M+H)+.
N－{4－[2－(7－乙基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－苯基}－乙醯胺N-{4-[2-(7-ethyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylsulfanyl]-phenyl}-acetamide
使得自實例145A之產物與得自實例7b之產物反應，根據得自實例135B之程序，以得自實例7b之產物取代得自實例5I之產物，並以得自實例145A之產物取代得自實例135A之產物，提供標題化合物，為三氟醋酸鹽(20毫克，29%)。1 H NMR(500 MHz,DMSO－D6)δ ppm：1.34(m,3H),2.37(s,3H),3.01(q,J＝7.93 Hz,2H),7.12－7.28(m,5H),7.35(s,1H),7.36(s,1H),7.78(d,J＝8.54 Hz,1H),8.75(s,1H),8.88(d,J＝8.54 Hz,1H)；MS(DCI/NH4 )m/z 430(M＋H)＋.The product from Example 145A was reacted with the product from Example 7b, substituting the product from Example 7b from the product from Example 7b, and substituting the product from Example 145A. The title compound was obtained as the title compound, mp. 1 H NMR (500 MHz, DMSO-D6) δ ppm: 1.34 (m, 3H), 2.37 (s, 3H), 3.01 (q, J = 7.93 Hz, 2H), 7.12-7.28 (m, 5H), 7.35 (s, 1H), 7.36 (s, 1H), 7.78 (d, J = 8.54 Hz, 1H), 8.75 (s, 1H), 8.88 (d, J = 8.54 Hz, 1H); MS (DCI/NH 4 )m/z 430(M+H)+.
4－[4－(6－溴基－1H－苯并咪唑－2－基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基]－酚4-[4-(6-Bromo-1H-benzimidazol-2-yl)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzene Oxy]-phenol
實例147A 4－(4－苄氧基－苯氧基)－3－硝基－苯甲醛將4－氯基－3－硝基苯甲醛(1.00克，5.389毫莫耳)、4－(苄氧基)酚(1.187克，5.928毫莫耳)及碳酸鉀(0.744克，5.389毫莫耳)在無水吡啶(10毫升)中之混合物，於回流及氮大氣下加熱30分鐘。使反應物冷卻至室溫，並在真空下藉迴轉式蒸發移除溶劑。使殘留物溶於醋酸乙酯(100毫升)中，並以1N鹽酸水溶液(2 x 50毫升)、水(50毫升)及鹽水(50毫升)洗滌。使有機相以無水硫酸鈉脫水乾燥，過濾，及在真空下濃縮。藉矽膠急驟式層析之純化，使用二氯甲烷作為溶離劑，提供標題化合物，為黃色固體(1.625克，86%)。Example 147A 4-(4-Benzyloxy-phenoxy)-3-nitro-benzaldehyde 4-Chloro-3-nitrobenzaldehyde (1.00 g, 5.389 mmol), 4-(benzyloxy) A mixture of phenol (1.187 g, 5.928 mmol) and potassium carbonate (0.744 g, 5.389 mmol) in anhydrous pyridine (10 mL). The reaction was allowed to cool to room temperature and the solvent was removed by rotary evaporation under vacuum. The residue was dissolved in ethyl acetate (EtOAc) (EtOAc)EtOAc. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The title compound was obtained as a yellow solid (1.625 g, 86%).
實例147B 2－[4－(4－苄氧基－苯氧基)－3－硝基－苯基]－6－溴基－1H－苯并咪唑將4－溴基－1,2－苯二胺(214毫克，1.145毫莫耳)在含有水(0.4毫升)之N,N－二甲基甲醯胺(12毫升)中之溶液，以實例147A之產物(400毫克，1.145毫莫耳)與OXONE(458毫克，0.7443毫莫耳)處理，並將反應物於室溫下攪拌30分鐘。然後添加水(40毫升)，並將反應物攪拌10分鐘。真空過濾混合物，且以水洗滌固體，接著在真空下乾燥。藉矽膠層析之純化，使用3%至4%醋酸乙酯/二氯甲烷之梯度液作為溶離劑，提供標題化合物，為黃色固體(305毫克，51%)。Example 147B 2-[4-(4-Benzyloxy-phenoxy)-3-nitro-phenyl]-6-bromo-1H-benzimidazole 4-bromo-1,2-benzene A solution of the amine (214 mg, 1.145 mmol) in N,N-dimethylformamide (12 mL) EtOAc (EtOAc) Treat with OXONE (458 mg, 0.7443 mmol) and stir the reaction at room temperature for 30 min. Water (40 mL) was then added and the reaction was stirred for 10 min. The mixture was vacuum filtered and the solid was washed with water then dried under vacuum. The title compound was obtained as a yellow solid (m.
實例147C 2－(4－苄氧基－苯氧基)－5－(6－溴基－1H－苯并咪唑－2－基)－苯胺於80°下，將實例147B之產物(374毫克，0.723毫莫耳)、鐵粉(248毫克，4.45毫莫耳)及氯化銨(253毫克，4.74毫莫耳)在水(5毫升)與乙醇(10毫升)中加熱45分鐘。使反應混合物冷卻至室溫，以醋酸乙酯(100毫升)稀釋，並以水(2 x 50毫升)與鹽水(50毫升)洗滌。使有機相以無水硫酸鈉脫水乾燥，過濾，及在真空下藉迴轉式蒸發濃縮，提供標題化合物，為金色固體(327毫克，93%)。Example 147C 2-(4-Benzyloxy-phenoxy)-5-(6-bromo-1H-benzimidazol-2-yl)-phenylamine The product of Example 147B (374 mg, 0.723 mmol, iron powder (248 mg, 4.45 mmol) and ammonium chloride (253 mg, 4.74 mmol) were heated in water (5 mL) and ethanol (10 mL) for 45 min. The reaction mixture was cooled to room temperature, diluted with EtOAc EtOAc (EtOAc) The org. <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0>
實例147D[2－(4－苄氧基－苯氧基)－5－(6－溴基－1H－苯并咪唑－2－基)－苯基]－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺將得自實例36E之產物(26.7毫克，0.123毫莫耳)與實例147C之產物(60毫克，0.123毫莫耳)在醋酸(2毫升)中之溶液，於預熱至140℃之油浴中攪拌30分鐘。使反應物冷卻至室溫，以己烷(50毫升)稀釋，在真空下藉迴轉式蒸發濃縮，並與二氯甲烷/己烷共蒸發(4x)。使殘留物在真空下乾燥，然後藉矽膠層析純化，使用3%甲醇/二氯甲烷作為溶離劑，提供標題化合物，為灰白色固體(59毫克，73%)。Example 147D [2-(4-Benzyloxy-phenoxy)-5-(6-bromo-1H-benzimidazol-2-yl)-phenyl]-(7-isopropyl-pyridino[ 2,3-d]pyrimidin-4-yl)-amine The product from Example 36E (26.7 mg, 0.123 mmol) and the product from Example 147C (60 mg, 0.123 mmol) in acetic acid (2 mL) The solution was stirred in an oil bath preheated to 140 ° C for 30 minutes. The reaction was cooled to room temperature, diluted with EtOAc EtOAc (EtOAc) The residue was dried with EtOAc (EtOAc)
實例147E 4－[4－(6－溴基－1H－苯并咪唑－2－基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基]－酚將得自實例147D之產物(38.8毫克，0.059毫莫耳)與五甲基苯(87毫克，0.5901毫莫耳)在三氟醋酸(5毫升)中之溶液，於室溫下攪拌2小時。在真空下藉迴轉式蒸發移除溶劑，並與二氯甲烷/己烷共蒸發(2x)。將所形成之固體以己烷研製(3x)，並藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(22毫克，47%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.36(d,J＝6.99 Hz,6H),3.20－3.39(m,1H),6.78(d,J＝8.82 Hz,2H),6.95(d,J＝9.19 Hz,2H),7.02(d,J＝8.82 Hz,1H),7.36(dd,J＝8.64,2.02 Hz,1H),7.55(d,J＝8.46 Hz,1H),7.78(d,J＝1.47 Hz,1H),7.91(d,J＝8.82 Hz,1H),8.11(dd,J＝8.64,2.02 Hz,1H),8.35(d,J＝1.84 Hz,1H),8.94(s,1H),9.03(d,J＝8.82 Hz,1H),9.46(br s,1H),11.63(br s,1H)；MS(APCI＋)m/z 567/569(M＋H)＋ .Example 147E 4-[4-(6-Bromo-1H-benzimidazol-2-yl)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino) -Phenoxy]-phenol The solution of the product from Example 147D (38.8 mg, 0.059 mmol) and pentamethylbenzene (87 mg, 0.5901 mmol) in trifluoroacetic acid (5 mL) Stir at room temperature for 2 hours. The solvent was removed by rotary evaporation under vacuum and co-evaporated with dichloromethane / hexane (2x). The resulting solid was triturated with EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (d, J = 6.99 Hz, 6H), 3.20-3.39 (m, 1H), 6.78 (d, J = 8.82 Hz, 2H), 6.95 (d) , J = 9.19 Hz, 2H), 7.02 (d, J = 8.82 Hz, 1H), 7.36 (dd, J = 8.64, 2.02 Hz, 1H), 7.55 (d, J = 8.46 Hz, 1H), 7.78 (d , J = 1.47 Hz, 1H), 7.91 (d, J = 8.82 Hz, 1H), 8.11 (dd, J = 8.64, 2.02 Hz, 1H), 8.35 (d, J = 1.84 Hz, 1H), 8.94 (s , 1H), 9.03 (d, J = 8.82 Hz, 1H), 9.46 (br s, 1H), 11.63 (br s, 1H); MS (APCI+) m/z 567/569 (M+H) + .
4－[4－(6－溴基－1H－苯并咪唑－2－基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基]－酚4-[4-(6-Bromo-1H-benzimidazol-2-yl)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxy Phenol
使得自實例147C之產物與得自實例10B之產物反應，使用實例147D中所述之程序，以得自實例10B之產物取代得自實例36E之產物，提供[2－(4－苄氧基－苯氧基)－5－(6－溴基－1H－苯并咪唑－2－基)－苯基]－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺，使其根據實例147E中所述之程序脫苄基化，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.74(s,3H),6.77(d,J＝9.19 Hz,2H),6.95(d,J＝8.82 Hz,2H),7.01(d,J＝8.82 Hz,1H),7.35(dd,J＝8.46,1.84 Hz,1H),7.54(d,J＝8.82 Hz,1H),7.74－7.85(m,2H),8.10(dd,J＝8.82,2.21 Hz,1H),8.36(d,J＝2.21 Hz,1H),8.90(s,1H),8.95(d,J＝8.46 Hz,1H),9.45(bs,1H),11.35(bs,1H)；MS(ESI＋)m/z 539/541(M＋H)＋.The product from Example 147C was reacted with the product from Example 10B, using the procedure described in Example 147D, substituting the product from Example 10B to afford the product from Example 36E to provide [2-(4-benzyloxy). Phenoxy)-5-(6-bromo-1H-benzimidazol-2-yl)-phenyl]-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)- The title compound was obtained as a trifluoroacetic acid salt. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.74 (s, 3H), 6.77 (d, J = 9.19 Hz, 2H), 6.95 (d, J = 8.82 Hz, 2H), 7.01 (d, J) =8.82 Hz, 1H), 7.35 (dd, J = 8.46, 1.84 Hz, 1H), 7.54 (d, J = 8.82 Hz, 1H), 7.74 - 7.85 (m, 2H), 8.10 (dd, J = 8.82, 2.21 Hz, 1H), 8.36 (d, J = 2.21 Hz, 1H), 8.90 (s, 1H), 8.95 (d, J = 8.46 Hz, 1H), 9.45 (bs, 1H), 11.35 (bs, 1H) ;MS(ESI+)m/z 539/541(M+H)+.
4－(4－胺基－苯基硫基)－N－(4－溴苯基)－3－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯磺醯胺4-(4-Amino-phenylthio)-N-(4-bromophenyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino) - benzenesulfonamide
實例149A N－(4－溴苯基)－4－氯基－3－硝基－苯磺醯胺將氯化4－氯基－3－硝基苯磺醯(2.561克，10毫莫耳)在醋酸(20毫升)中之溶液，以4－溴基苯胺(1.72克，10毫莫耳)與無水醋酸鈉(1.23克，15毫莫耳)處理，然後於100°下加熱30分鐘。使反應物冷卻至室溫，並在真空下藉迴轉式蒸發移除醋酸。使殘留物溶於醋酸乙酯(100毫升)中，並以水(2 x 25毫升)與鹽水(25毫升)洗滌。使有機相以無水硫酸鈉脫水乾燥，過濾，及在真空下濃縮，與二氯甲烷/己烷共蒸發該油。藉矽膠層析之純化，使用二氯甲烷，接著是5%醋酸乙酯/二氯甲烷作為溶離劑，提供標題化合物，為黃色固體(2.038克，52%)。Example 149A N-(4-bromophenyl)-4-chloro-3-nitro-benzenesulfonamide chlorinated 4-chloro-3-nitrobenzenesulfonate (2.561 g, 10 mmol) The solution in acetic acid (20 mL) was treated with 4-bromoaniline (1.72 g, 10 mmol) and anhydrous sodium acetate (1.23 g, 15 m.m. The reaction was allowed to cool to room temperature and the acetic acid was removed by rotary evaporation under vacuum. The residue was dissolved in ethyl acetate (EtOAc) (EtOAc) The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The title compound was obtained as a yellow solid (m.
實例149B 4－(4－胺基－苯基硫基)－N－(4－溴苯基)－3－硝基－苯磺醯胺將實例149A之產物(500毫克，1.277毫莫耳)、4－胺基硫酚(240毫克，1.915毫莫耳)及無水醋酸鈉(524毫克，6.384毫莫耳)在無水乙醇(9毫升)中之混合物，於回流及氮大氣下加熱1小時。使反應物冷卻至室溫，並在真空下藉迴轉式蒸發移除乙醇。使殘留物溶於醋酸乙酯(100毫升)中，並以水(2 x 50毫升)與鹽水(50毫升)洗滌。使有機相以無水硫酸鈉脫水乾燥，過濾，及在真空下濃縮，與二氯甲烷/己烷共蒸發該油，獲得標題化合物，為橘色泡沫物(613毫克，100%)。Example 149B 4-(4-Amino-phenylsulfanyl)-N-(4-bromophenyl)-3-nitro-benzenesulfonamide The product of Example 149A (500 mg, 1.277 mmol), A mixture of 4-aminothiophenol (240 mg, 1.915 mmol) and anhydrous sodium acetate (524 mg, 6.384 mmol) in dry ethanol (9 mL). The reaction was allowed to cool to room temperature and the ethanol was removed by rotary evaporation under vacuum. The residue was dissolved in ethyl acetate (EtOAc) (EtOAc) The organic phase was dried with EtOAc EtOAc EtOAc.
實例149C{4－[4－(4－溴苯基胺磺醯基)－2－硝基－苯基硫基]－苯基}－胺甲基酸第三－丁酯於室溫下，將實例149B之產物(613毫克，1.277毫莫耳)在無水1,4－二氧陸圜(10毫升)中之溶液，以二碳酸二－第三－丁酯(418毫克，1.92毫莫耳)處理，然後將反應物於回流及氮大氣下加熱3小時。使反應物冷卻至室溫，添加另外之二碳酸二－第三－丁酯(500毫克)，並使反應物回流17小時。使反應物冷卻至室溫，並在真空下藉迴轉式蒸發移除溶劑。殘留物藉矽膠層析之純化，使用3%醋酸乙酯/二氯甲烷作為溶離劑，提供標題化合物，為黃色固體(512毫克，69%)。Example 149C {4-[4-(4-bromophenylaminesulfonyl)-2-nitro-phenylthio]-phenyl}-amine methyl acid tert-butyl ester at room temperature, A solution of the product of Example 149B (613 mg, 1.277 mmol) in anhydrous 1,4-dioxane (10 mL) as di-tris-butyl-dicarbonate (418 mg, 1.92 mmol) The reaction was then heated to reflux under nitrogen atmosphere for 3 h. The reaction was allowed to cool to room temperature and additional di-t-butyl-dicarbonate (500 mg) was added and the mixture was refluxed for 17 h. The reaction was allowed to cool to room temperature and the solvent was removed by rotary evaporation under vacuum. The residue was purified by EtOAc EtOAc EtOAc EtOAc
實例149D{4－[2－胺基－4－(4－溴苯基胺磺醯基)－苯基硫基]－苯基}－胺甲基酸第三－丁酯於80°下，將實例149C之產物(510毫克，0.879毫莫耳)、鐵粉(302毫克，5.40毫莫耳)及氯化銨(308毫克，5.76毫莫耳)在水(4毫升)與乙醇(8毫升)中加熱40分鐘。使反應物冷卻至室溫，以醋酸乙酯(100毫升)稀釋，並以水(2 x 50毫升)與鹽水(50毫升)洗滌。使有機相以無水硫酸鈉脫水乾燥，過濾，及在真空下藉迴轉式蒸發濃縮，提供標題化合物，為白色泡沫物(436毫克，90%)。Example 149D {4-[2-Amino-4-(4-bromophenylamine sulfonyl)-phenylthio]-phenyl}-amine methyl acid tert-butyl ester at 80 °, Example 149C product (510 mg, 0.879 mmol), iron powder (302 mg, 5.40 mmol) and ammonium chloride (308 mg, 5.76 mmol) in water (4 ml) and ethanol (8 ml) Heat in 40 minutes. The reaction was cooled to room temperature, diluted with ethyl EtOAc (EtOAc)EtOAc. The org. <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0>
實例149E{4－[4－(4－溴苯基胺磺醯基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－苯基}－胺甲基酸第三－丁酯將得自實例36E之產物(59毫克，0.2725毫莫耳)與得自實例149D之產物(150毫克，0.2725毫莫耳)在醋酸(4毫升)中之溶液，於預熱至140℃之油浴中攪拌25分鐘。使反應物冷卻至室溫，以己烷(100毫升)稀釋，在真空下藉迴轉式蒸發濃縮，並與二氯甲烷/己烷共蒸發(4x)。使殘留物在真空下乾燥，然後藉矽膠層析純化，使用4%甲醇/二氯甲烷作為溶離劑，提供標題化合物，為黃褐色固體(67毫克，34%)。Example 149E {4-[4-(4-Bromophenylaminesulfonyl)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfide The base product of the compound of Example 36E (59 mg, 0.2725 mmol) and the product from Example 149D (150 mg, 0.2725 mmol) in acetic acid. The solution in (4 ml) was stirred in an oil bath preheated to 140 ° C for 25 minutes. The reaction was cooled to room rt, diluted with EtOAc EtOAc (EtOAc) The residue was dried with EtOAc (EtOAc m.
實例149F 4－(4－胺基－苯基硫基)－N－(4－溴苯基)－3－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯磺醯胺於室溫下，將得自實例149E之產物(44毫克，0.061毫莫耳)以三氟醋酸(2毫升)在二氯甲烷(2毫升)中處理30分鐘。在真空下藉迴轉式蒸發移除溶劑，並使殘留油於高真空下乾燥。藉矽膠層析之純化，使用5%甲醇/二氯甲烷作為溶離劑，提供標題化合物，為三氟醋酸鹽(25毫克，48%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.35(d,J＝6.62 Hz,6H),3.13－3.38(m,1H),6.63(d,J＝8.46 Hz,2H),6.87(d,J＝7.72 Hz,1H),7.01－7.09(d,J＝8.82 Hz,2H),7.12(d,J＝8.46 Hz,2H),7.44(d,J＝8.82 Hz,2H),7.61(dd,J＝7.72,1.47 Hz,1H),7.71(s,1H),7.81(dd,J＝6.62,1.47 Hz,1H),8.66－8.80(m,1H),8.90(d,J＝6.99 Hz,1H),10.55(s,1H)；MS(ESI＋)m/z 621/623(M＋H)＋ .Example 149F 4-(4-Amino-phenylthio)-N-(4-bromophenyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamine The product from Example 149E (44 mg, EtOAc, m. The solvent was removed by rotary evaporation under vacuum and the residual oil was dried under high vacuum. The title compound was obtained as a trifluoroacetic acid salt (25 mg, 48%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.62 Hz, 6H), 3.13 - 3.38 (m, 1H), 6.63 (d, J = 8.46 Hz, 2H), 6.87 (d) , J=7.72 Hz, 1H), 7.01-7.09 (d, J=8.82 Hz, 2H), 7.12 (d, J=8.46 Hz, 2H), 7.44 (d, J=8.82 Hz, 2H), 7.61 (dd , J=7.72, 1.47 Hz, 1H), 7.71 (s, 1H), 7.81 (dd, J=6.62, 1.47 Hz, 1H), 8.66-8.80 (m, 1H), 8.90 (d, J = 6.99 Hz, 1H), 10.55 (s, 1H); MS (ESI+) m/z 621/623 (M+H) + .
4－(4－胺基－苯基硫基)－N－(4－溴苯基)－3－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯磺醯胺4-(4-Amino-phenylthio)-N-(4-bromophenyl)-3-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)- Phenylsulfonamide
使得自實例149D之產物與得自實例10B之產物反應，使用實例149E中所述之程序，以得自實例10B之產物取代得自實例36E之產物，提供{4－[4－(4－溴苯基胺磺醯基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－苯基}－胺甲基酸第三－丁酯，使其根據實例149F中所述之程序去除保護，接著為矽膠層析，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.74(s,3H),6.64(d,J＝8.46 Hz,2H),6.89(d,J＝8.09 Hz,1H),7.05(d,J＝9.19 Hz,2H),7.12(d,J＝8.82 Hz,2H),7.44(d,J＝8.82 Hz,2H),7.63(dd,J＝7.72,0.74 Hz,1H),7.74(s,1H),7.79(dd,J＝7.72,1.10 Hz,1H),8.70－8.83(m,1H),8.88(d,J＝8.09 Hz,1H),10.55(s,1H)；MS(ESI＋)m/z 593/595(M＋H)＋.The product from Example 149D was reacted with the product from Example 10B, using the procedure described in Example 149E, substituting the product from Example 10B to afford the product from Example 36E to provide {4-[4-(4-bromo) Phenylamine sulfonyl)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenyl}-amine methyl acid The butyl ester was deprotected according to the procedure described in Example 149F, followed by silica gel chromatography to afford the title compound as trifluoroacetate. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.74 (s, 3H), 6.64 (d, J = 8.46 Hz, 2H), 6.89 (d, J = 8.09 Hz, 1H), 7.05 (d, J) = 9.19 Hz, 2H), 7.12 (d, J = 8.82 Hz, 2H), 7.44 (d, J = 8.82 Hz, 2H), 7.63 (dd, J = 7.72, 0.74 Hz, 1H), 7.74 (s, 1H) ), 7.79 (dd, J = 7.72, 1.10 Hz, 1H), 8.70-8.83 (m, 1H), 8.88 (d, J = 8.09 Hz, 1H), 10.55 (s, 1H); MS (ESI+) m/ z 593/595(M+H)+.
4－[4－氯基－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基]－酚實例151A4-[4-Chloro-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxy]-phenol Example 151A
4－(4－氯基－2－硝基－苯氧基)－酚將對苯二酚(1.21克，0.011莫耳)與氫氧化鉀(0.894克，0.0159莫耳)在無水二甲亞碸(7毫升)中之溶液，於120°及氮大氣下加熱30分鐘。於120°下，逐滴添加2,5－二氯硝基苯(1.90克，0.0099莫耳)在二甲亞碸(3毫升)中之溶液，歷經30分鐘期間，然後將反應物在相同溫度下攪拌1小時。接著使反應物於冰浴中冷卻，並倒入30毫升冰水中。以濃鹽酸使混合物酸化至pH 1，並以***(2 x 50毫升)萃取。以水(3 x 150毫升)洗滌合併之含醚萃液，以無水硫酸鈉脫水乾燥，過濾，及在真空下藉迴轉式蒸發濃縮。殘留物藉矽膠層析之純化，使用二氯甲烷作為溶離劑，提供產物，為黃褐色固體(1.34克，51%)。4-(4-Chloro-2-nitro-phenoxy)-phenol with hydroquinone (1.21 g, 0.011 mol) and potassium hydroxide (0.894 g, 0.0159 mol) in anhydrous dimethyl hydrazine The solution in (7 ml) was heated at 120 ° and nitrogen for 30 minutes. A solution of 2,5-dichloronitrobenzene (1.90 g, 0.0099 mol) in dimethyl hydrazine (3 ml) was added dropwise at 120 ° for a period of 30 minutes and then the reaction was at the same temperature. Stir under 1 hour. The reaction was then cooled in an ice bath and poured into 30 mL of ice water. The mixture was acidified to pH 1 with EtOAc (EtOAc) (EtOAc) The combined ether extracts were washed with water (3 x 150 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by EtOAc EtOAc (EtOAc)
實例151B 4－(2－胺基－4－氯－苯氧基)－酚將實例151A之產物(400毫克，1.506毫莫耳)與鐵粉(336毫克，6.02毫莫耳)在醋酸(10毫升)與乙醇(10毫升)中之混合物，於回流及氮大氣下加熱25分鐘。使反應物冷卻至室溫，以水(50毫升)稀釋，並以固體碳酸鈉處理，直到pH值為6為止。以醋酸乙酯(2 x 50毫升)萃取，並以鹽水(50毫升)洗滌有機物，以無水硫酸鈉脫水乾燥，過濾，及在真空下藉迴轉式蒸發濃縮。與二氯甲烷/己烷共蒸發所形成之油，提供標題化合物，為黃褐色固體(355毫克，100%)。Example 151B 4-(2-Amino-4-chloro-phenoxy)-phenol The product of Example 151A (400 mg, 1.506 mmol) and iron powder (336 mg, 6.02 mmol) in acetic acid (10) A mixture of ML) and ethanol (10 mL) was heated under reflux for a period of 25 min. The reaction was cooled to room rt, diluted with water (50 mL) and dried over Nat. Extracted with ethyl acetate (2 x 50 mL), EtOAc (EtOAc) elute The oil was formed by EtOAc (EtOAc) elute
實例151C 4－[4－氯基－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基]－酚將得自實例36E之產物(38毫克，0.177毫莫耳)與得自實例151B之產物(42毫克，0.177毫莫耳)在醋酸(2毫升)中之溶液，於預熱至140℃之油浴中攪拌1.5小時。使反應物冷卻至室溫，以己烷(100毫升)稀釋，在真空下藉迴轉式蒸發濃縮，並與二氯甲烷/己烷共蒸發(4x)。使殘留物在高真空下乾燥，然後藉由以40%醋酸乙酯/二氯甲烷研製而純化，提供標題化合物，為米黃色固體(49毫克，65%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.31(d,J＝6.99 Hz,6H),3.10－3.29(m,1H),6.70(d,J＝8.82 Hz,2H),6.76－6.90(m,3H),7.24(dd,J＝8.64,2.39 Hz,1H),7.55(d,J＝8.82 Hz,1H),7.71(bs,1H),8.59(bs,1H),8.73(d,J＝8.09 Hz,1H),9.31(bs,1H),9.89(bs,1H)；MS(DCI/NH3 )m/z 407(M＋H)＋.Example 151C 4-[4-Chloro-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxy]-phenol The product from Example 36E A solution of (38 mg, 0.177 mmol) from EtOAc (EtOAc m. The reaction was cooled to room rt, diluted with EtOAc EtOAc (EtOAc) The residue was dried with EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.31 (d, J = 6.99 Hz, 6H), 3.10-3.29 (m, 1H), 6.70 (d, J = 8.82 Hz, 2H), 6.76-6.90 (m, 3H), 7.24 (dd, J = 8.64, 2.39 Hz, 1H), 7.55 (d, J = 8.82 Hz, 1H), 7.71 (bs, 1H), 8.59 (bs, 1H), 8.73 (d, J=8.09 Hz, 1H), 9.31 (bs, 1H), 9.89 (bs, 1H); MS (DCI/NH 3 ) m/z 407 (M+H)+.
4－(4－羥基－苯氧基)－3－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯甲腈4-(4-Hydroxy-phenoxy)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzonitrile
實例152A 4－(4－羥基－苯氧基)－3－硝基－苯甲腈將對苯二酚(1.21克，0.011莫耳)與氫氧化鉀(0.894克，0.0159莫耳)在無水二甲亞碸(8毫升)中之溶液，於90℃及氮大氣下加熱30分鐘。於90°下，逐滴添加4－氯基－3－硝基苯甲腈(1.806克，0.0099莫耳)在二甲亞碸(8毫升)中之溶液，歷經30分鐘期間，然後將反應物在相同溫度下攪拌1小時。接著使反應物於冰浴中冷卻，並倒入30毫升冰水中。使混合物以濃鹽酸酸化至pH 3，並以***(3 x 100毫升)萃取。以水(3 x 150毫升)與鹽水(50毫升)洗滌合併之含醚萃液，以無水硫酸鈉脫水乾燥，過濾，及在真空下藉迴轉式蒸發濃縮。藉矽膠層析之純化，使用4%醋酸乙酯/二氯甲烷作為溶離劑，提供產物，為橘色固體(0.984克，39%)。Example 152A 4-(4-Hydroxy-phenoxy)-3-nitro-benzonitrile Hydroquinone (1.21 g, 0.011 mol) and potassium hydroxide (0.894 g, 0.0195 mol) in anhydrous The solution in yamidine (8 ml) was heated at 90 ° C for 30 minutes under a nitrogen atmosphere. A solution of 4-chloro-3-nitrobenzonitrile (1.806 g, 0.0099 mol) in dimethyl hydrazine (8 ml) was added dropwise at 90° over a period of 30 min. Stir at the same temperature for 1 hour. The reaction was then cooled in an ice bath and poured into 30 mL of ice water. The mixture was acidified to pH 3 with cone. EtOAc (EtOAc)EtOAc. The combined ether extracts were washed with water (3 x 150 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The product was obtained as an orange solid (0.984 g, 39%).
實例152B 3－胺基－4－(4－羥基－苯氧基)－苯甲腈使實例152A之產物(500毫克，1.952毫莫耳)在甲醇(20毫升)中，以氫(1大氣壓，氣瓶)與10%鈀/碳(50毫克)氫化30分鐘。使反應物經過0.45 μPTFE薄膜真空過濾，並以甲醇洗滌觸媒。使濾液在真空下藉迴轉式蒸發濃縮，提供標題化合物，為略帶粉紅色－米黃色固體(437毫克，99%)。Example 152B 3-Amino-4-(4-hydroxy-phenoxy)-benzonitrile The product of Example 152A (500 mg, 1.952 mmol) in methanol (20 mL) Gas cylinder) was hydrogenated with 10% palladium on carbon (50 mg) for 30 minutes. The reaction was vacuum filtered through a 0.45 μ PTFE membrane and the catalyst was washed with methanol. The filtrate was concentrated with EtOAc (EtOAc) elute
實例152C 4－(4－羥基－苯氧基)－3－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯甲腈得自實例36E之產物(41毫克，0.1896毫莫耳)與得自實例152B之產物(42.9毫克，0.1896毫莫耳)在醋酸(2毫升)中之溶液，於預熱至140℃之油浴中攪拌1.5小時。使反應物冷卻至室溫，以己烷(100毫升)稀釋，在真空下藉迴轉式蒸發濃縮，並與二氯甲烷/己烷共蒸發(4x)。使殘留物在高真空下乾燥。藉矽膠層析之純化，使用30%醋酸乙酯/二氯甲烷作為溶離劑，提供標題化合物，為白色固體(16毫克，21%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.31(d,J＝6.99 Hz,6H),3.11－3.28(m,1H),6.77(d,J＝8.82 Hz,2H),6.85(d,J＝8.46 Hz,1H),6.93(d,J＝8.46 Hz,2H),7.64(dd,J＝17.28,8.46 Hz,2H),8.12(s,1H),8.66(s,1H),8.81(d,J＝8.09 Hz,1H),9.47(s,1H),9.99(s,1H)；MS(DCI/NH3 )m/z 398(M＋H)＋.Example 152C 4-(4-Hydroxy-phenoxy)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzonitrile from the product of Example 36E A solution of the product from Example 152B (42.9 mg, 0.1896 mmol) in EtOAc (2 mL). The reaction was cooled to room rt, diluted with EtOAc EtOAc (EtOAc) The residue was dried under high vacuum. The title compound was obtained as a white solid (16 mg, 21%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.31 (d, J = 6.99 Hz, 6H), 3.11-3.28 (m, 1H), 6.77 (d, J = 8.82 Hz, 2H), 6.85 (d) , J = 8.46 Hz, 1H), 6.93 (d, J = 8.46 Hz, 2H), 7.64 (dd, J = 17.28, 8.46 Hz, 2H), 8.12 (s, 1H), 8.66 (s, 1H), 8.81 (d, J=8.09 Hz, 1H), 9.47 (s, 1H), 9.99 (s, 1H); MS (DCI/NH 3 ) m/z 398 (M+H)+.
(5－溴基－2－苯氧基－苯基)－吡啶并[2,3－d]嘧啶－4－基－胺(5-bromo-2-phenoxy-phenyl)-pyrido[2,3-d]pyrimidin-4-yl-amine
使5－溴基－2－苯氧基苯胺與得自實例57A之產物反應，使用實例57E中所述之程序，以5－溴基－2－苯氧基苯胺取代得自實例57D之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：6.94－7.03(m,J＝8.09,5.88 Hz,3H),7.07(t,J＝7.35 Hz,1H),7.24－7.36(m,2H),7.54(dd,J＝8.82,2.21 Hz,1H),7.77(dd,J＝8.46,4.41 Hz,1H),7.83(d,J＝2.21 Hz,1H),8.82(s,1H),8.89(d,J＝7.35 Hz,1H),9.10(d,J＝2.57 Hz,1H)；MS(ESI)＋ m/z 394(m,＋2)＋.5-Bromo-2-phenoxyaniline was reacted with the product from Example 57A using the procedure described in Example 57E, substituting 5-bromo-2-phenoxyaniline from the product from Example 57D. The crude product was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 6.94-7.03 (m, J = 8.09, 5.88 Hz, 3H), 7.07 (t, J = 7.35 Hz, 1H), 7.24 - 7.36 (m, 2H) , 7.54 (dd, J = 8.82, 2.21 Hz, 1H), 7.77 (dd, J = 8.46, 4.41 Hz, 1H), 7.83 (d, J = 2.21 Hz, 1H), 8.82 (s, 1H), 8.89 ( d, J = 7.35 Hz, 1H), 9.10 (d, J = 2.57 Hz, 1H); MS (ESI) + m/z 394 (m, +2) +.
(5－氯基－2－苯氧基－苯基)－吡啶并[2,3－d]嘧啶－4－基－胺(5-chloro-2-phenoxy-phenyl)-pyrido[2,3-d]pyrimidin-4-yl-amine
使5－氯基－2－苯氧基－苯胺與得自實例57A之產物反應，使用實例57E中所述之程序，以5－氯基－2－苯氧基－苯胺取代得自實例57D之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：6.97(d,J＝7.72 Hz,2H),7.00－7.11(m,2H),7.24－7.34(m,J＝8.09,8.09 Hz,2H),7.41(dd,J＝8.82,2.57 Hz,1H),7.69－7.77(m,2H),8.77(s,1H),8.85(d,J＝8.46 Hz,1H),9.08(d,J＝3.31 Hz,1H)；MS(ESI)＋ m/z 349(M＋H)＋.5-Chloro-2-phenoxy-phenylamine was reacted with the product from Example 57A using the procedure described in Example 57E, substituting 5-chloro-2-phenoxy-phenylamine from Example 57D. The product was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 6.97 (d, J = 7.72 Hz, 2H), 7.00-7.11 (m, 2H), 7.24 - 7.34 (m, J = 8.09, 8.09 Hz, 2H) , 7.41 (dd, J = 8.82, 2.57 Hz, 1H), 7.69-7.77 (m, 2H), 8.77 (s, 1H), 8.85 (d, J = 8.46 Hz, 1H), 9.08 (d, J = 3.31) Hz, 1H); MS (ESI) + m/z 349 (M+H)+.
1－{3－[4－氯基－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基]－苯基}－乙醇1-{3-[4-Chloro-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxy]-phenyl}-ethanol
使1－[4－(2－胺基－4－氯－苯氧基)－苯基]－乙醇與得自實例36E之產物反應，根據得自實例152C之程序，以1－[4－(2－胺基－4－氯－苯氧基)－苯基]－乙醇取代得自實例152B之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.16(d,J＝6.62 Hz,3H),1.31(d,J＝6.99 Hz,6H),3.17－3.28(m,1H),4.60(q,1H),6.81(m,1H),6.94(s,1H),7.01(d,J＝7.72 Hz,1H),7.06(d,J＝8.82 Hz,1H),7.23(t,J＝7.91 Hz,1H),7.43(dd,J＝8.82,2.57 Hz,1H),7.72(m,1H),7.76(s,1H),8.79(s,1H),8.82(s,1H)；MS(ESI－)m/z 433(M－H)－.1-[4-(2-Amino-4-chloro-phenoxy)-phenyl]-ethanol was reacted with the product from Example 36E, according to the procedure from Example 152C, 1-[4-( Substituting 2-amino-4-chloro-phenoxy)-phenyl]-ethanol to give the title compound as a trifluoroacetic acid salt. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.16 (d, J = 6.62 Hz, 3H), 1.31 (d, J = 6.99 Hz, 6H), 3.17 - 3.28 (m, 1H), 4.60 (q) , 1H), 6.81 (m, 1H), 6.94 (s, 1H), 7.01 (d, J = 7.72 Hz, 1H), 7.06 (d, J = 8.82 Hz, 1H), 7.23 (t, J = 7.91 Hz) , 1H), 7.43 (dd, J = 8.82, 2.57 Hz, 1H), 7.72 (m, 1H), 7.76 (s, 1H), 8.79 (s, 1H), 8.82 (s, 1H); MS (ESI- )m/z 433(M-H)-.
4－[2－(7－乙基硫基－嘧啶并[4,5－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－酚4-[2-(7-Ethylthio-pyrimido[4,5-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-phenol
實例156A 4－胺基－2－乙基硫基－嘧啶－5－甲腈將2－乙基－2－硫基假脲氫溴酸鹽(1.52克，8.19毫莫耳)、(乙氧基亞甲基)丙二腈(1.0克，8.19毫莫耳)及N,N－二異丙基乙胺(3.57毫升，20.05毫莫耳)在乙醇(20毫升)中之溶液，於室溫下攪拌3.5小時。收集所形成之固體，以乙醇洗滌，並在真空下乾燥，提供標題化合物，為淡黃色固體(580毫克，39%)。Example 156A 4-Amino-2-ethylsulfanyl-pyrimidine-5-carbonitrile 2-ethyl-2-thiopyuryl hydrobromide (1.52 g, 8.19 mmol), (ethoxy) a solution of methylene)malononitrile (1.0 g, 8.19 mmol) and N,N-diisopropylethylamine (3.57 ml, 20.05 mmol) in ethanol (20 mL) at room temperature Stir for 3.5 hours. The resulting solid was collected, washed with EtOAc EtOAcjjjjjj
實例156B N'－(5－氰基－2－乙基硫基－嘧啶－4－基)－N,N－二甲基－甲脒使得自實例156A之產物(200毫克，1.11毫莫耳)與N,N－二甲基甲醯胺二甲基縮醛(0.15毫升，1.11毫莫耳)在甲苯(10毫升)中之溶液回流2.5小時。於冷卻至室溫後，使溶液在真空下濃縮，提供標題化合物，為無色固體(260毫克，100%)。Example 156B N'-(5-Cyano-2-ethylsulfanyl-pyrimidin-4-yl)-N,N-dimethyl-methylhydrazine as a product from Example 156A (200 mg, 1.11 mmol) A solution of N,N-dimethylformamide dimethyl acetal (0.15 mL, 1.11 mmol) in toluene (10 mL) After cooling to rt, EtOAc (EtOAc)
實例156C 4－[2－(7－乙基硫基－嘧啶并[4,5－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－酚將得自實例6c之產物(54毫克，0.234毫莫耳)與得自實例156B之產物(50毫克，0.213毫莫耳)在醋酸(2毫升)中之溶液，於130℃下加熱1.5小時。然後使溶液冷卻至室溫，在真空下移除醋酸，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(51毫克，45%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：1.38(t,J＝7.4 Hz,3H),2.30(s,3H),3.23(q,J＝7.3 Hz,2H),6.72(d,J＝8.8 Hz,2H),6.98(d,J＝8.1 Hz,1H),7.10(m,1H),7.18(d,J＝8.7 Hz,2H),7.21(s,1H),8.62(s,1H),9.70(s,1H),9.78(bs,1H),10.85(s,1H)；MS(ESI)＋ m/z 422(M＋H)＋.Example 156C 4-[2-(7-Ethylthio-pyrimido[4,5-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-phenol will be obtained from Example 6c A solution of the product (54 mg, 0.234 m. The solution was then cooled to rt. EtOAc (EtOAc m. 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 1.38 (t, J = 7.4 Hz, 3H), 2.30 (s, 3H), 3.23 (q, J = 7.3 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.1 Hz, 1H), 7.10 (m, 1H), 7.18 (d, J = 8.7 Hz, 2H), 7.21 (s, 1H), 8.62 (s, 1H), 9.70 (s, 1H), 9.78 (bs, 1H), 10.85 (s, 1H); MS (ESI) + m/z 422 (M+H)+.
(7－乙基硫基－嘧啶并[4,5－d]嘧啶－4－基)－[5－甲基－2－(4－苯氧基－苯基硫基)－苯基]－胺(7-Ethylthio-pyrimido[4,5-d]pyrimidin-4-yl)-[5-methyl-2-(4-phenoxy-phenylsulfanyl)-phenyl]-amine
實例157a 5－甲基－2－(4－苯氧基－苯基硫基)－苯胺使得自實例6c之產物(0.500克，1.91毫莫耳)伴隨著苯基二羥基硼烷(0.701克，5.74毫莫耳)、醋酸銅(II)(0.659克，3.83毫莫耳)及三乙胺(0.387克，3.83毫莫耳)溶於CH2 Cl2 中。在室溫下攪拌48小時，此時再添加各2當量之試劑。於室溫下再攪拌16小時，此時添加另一份各2當量之試劑。於室溫下再攪拌16小時。以水稀釋反應物，並以醋酸乙酯萃取，以Na2 SO4 脫水乾燥，過濾，及在真空下濃縮，獲得粗產物，使其藉矽膠管柱層析純化，以20% EtOAc/己烷溶離(0.100克，15%)。使產物按照得自實例5I之程序以SnCl2 還原，而得標題化合物(90毫克，98%)。Example 157a 5-Methyl-2-(4-phenoxy-phenylsulfanyl)-phenylamine afforded the product from Example 6c (0.500 g, 1.91 mmol) with phenyldihydroxyborane (0.701 g, 5.74 mmol), copper (II) acetate (0.659 g, 3.83 mmol) and triethylamine (0.387 g, 3.83 mmol) was dissolved in CH 2 Cl 2. Stir at room temperature for 48 hours at which time each additional 2 equivalents of reagent was added. Stirring was continued for a further 16 hours at room temperature, at which time another 2 equivalents of each reagent was added. Stir for a further 16 hours at room temperature. The reaction was diluted with water, and extracted with ethyl acetate, to Na 2 SO 4 dried, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography, in 20% EtOAc / hexanes Dissolution (0.100 g, 15%). The product obtained according to the procedure from Example 5I of SnCl 2 reduction to give the title compound (90 mg, 98%).
實例157b 7－(乙硫基)－N－(5－甲基－2－(4－苯氧基苯硫基)苯基)嘧啶并[4,5－d]嘧啶－4－胺使得自實例156B之產物與得自實例157a之產物溶液反應，根據得自實例156C之程序，以得自實例157a之產物取代得自實例6c之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(16毫克，21%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.37(t,J＝7.35 Hz,3H),2.34(s,3H),3.22(q,J＝7.35 Hz,2H),6.82(m,2H),6.93(m,2H),7.29(m,8H),8.57(s,1H),9.64(s,1H),10.66(s,1H)；MS(ESI＋)m/z 498(M＋H)＋.Example 157b 7-(ethylthio)-N-(5-methyl-2-(4-phenoxyphenylthio)phenyl)pyrimido[4,5-d]pyrimidin-4-amine The product of 156B was reacted with a product solution from Example 157a. The compound was trifluoroacetate (16 mg, 21%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.37 (t, J = 7.35 Hz, 3H), 2.34 (s, 3H), 3.22 (q, J = 7.35 Hz, 2H), 6.82 (m, 2H) ), 6.93 (m, 2H), 7.29 (m, 8H), 8.57 (s, 1H), 9.64 (s, 1H), 10.66 (s, 1H); MS (ESI+) m/z 498 (M+H)+.
4－[4－甲基－2－(7－六氫吡啶－1－基－嘧啶并[4,5－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-Methyl-2-(7-hexahydropyridin-1-yl-pyrimido[4,5-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使得自實例156C之產物(42毫克，0.1毫莫耳)在六氫吡啶(1毫升)中之溶液，於180℃下微波(CEM Discover微波)2小時。在真空下濃縮溶液，並使殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(17毫克，38%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.64(m,6H),2.30(s,3H),3.96(m,4H),6.72(m,2H),7.01(d,J＝7.72 Hz,1H),7.17(m,4H),8.59(s,1H),9.53(s,1H),9.83(s,1H),11.43(s,1H)；(ESI＋)m/z 445(M＋H)＋.A solution of the product from Example 156C (42 mg, 0.1 mmol) in hexanes (1 mL) The solution was concentrated in EtOAc (EtOAc)EtOAc. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.64 (m, 6H), 2.30 (s, 3H), 3.96 (m, 4H), 6.72 (m, 2H), 7.01 (d, J = 7.72 Hz , 1H), 7.17 (m, 4H), 8.59 (s, 1H), 9.53 (s, 1H), 9.83 (s, 1H), 11.43 (s, 1H); (ESI+) m/z 445 (M+H)+ .
丙烷－2－磺酸4－[2－(7－乙基硫基－嘧啶并[4,5－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－苯酯Propane-2-sulfonic acid 4-[2-(7-ethylthio-pyrimido[4,5-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-phenyl ester
將得自實例156C之產物(0.042克，0.1毫莫耳)、氯化異丙基磺醯(0.014克，0.105毫莫耳)、4－二甲胺基吡啶(0.002克，0.01毫莫耳)及二異丙基乙胺(0.04克，0.3毫莫耳)在1,2－二氯乙烷(2.0毫升)中攪拌1小時，倒入水(20毫升)中，並以醋酸乙酯(3 x 10毫升)萃取。使合併之萃液以硫酸鈉脫水乾燥，過濾，及在真空下濃縮。使粗產物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(15毫克，23%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.27－1.46(m,9H),2.37(s,3H),3.20(q,J＝7.35 Hz,2H),3.56－3.70(m,1H),7.09－7.20(m,2H),7.19－7.29(m,3H),7.34(s,1H),7.39(d,J＝8.09 Hz,2H),8.56(s,1H),9.61(s,1H),10.72(s,1H)；MS(ESI)＋ m/z 528(M＋H)＋.The product from Example 156C (0.042 g, 0.1 mmol), isopropylsulfonium chloride (0.014 g, 0.105 mmol), 4-dimethylaminopyridine (0.002 g, 0.01 mmol) And diisopropylethylamine (0.04 g, 0.3 mmol) was stirred in 1,2-dichloroethane (2.0 mL) for 1 hour, poured into water (20 mL) and ethyl acetate (3) x 10 ml) extraction. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.27-1.46 (m, 9H), 2.37 (s, 3H), 3.20 (q, J = 7.35 Hz, 2H), 3.56-3.70 (m, 1H) , 7.09-7.20 (m, 2H), 7.19-7.29 (m, 3H), 7.34 (s, 1H), 7.39 (d, J = 8.09 Hz, 2H), 8.56 (s, 1H), 9.61 (s, 1H) ), 10.72 (s, 1H); MS (ESI) + m / z 528 (M + H) +.
4－乙醯胺基－苯磺酸4－[2－(7－乙基硫基－嘧啶并[4,5－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－苯酯4-Ethylamino-benzenesulfonic acid 4-[2-(7-ethylthio-pyrimido[4,5-d]pyrimidin-4-ylamino)-4-methyl-phenylthio ]-phenyl ester
使得自實例156C之產物與氯化4－乙醯胺基－苯磺醯反應，根據得自實例159之程序，以氯化4－乙醯胺基－苯磺醯取代氯化異丙基磺醯，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(31毫克，50%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.36(t,J＝7.35 Hz,3H),2.10(s,3H),2.35(s,3H),3.20(q,J＝7.35 Hz,2H),6.85(d,J＝8.82 Hz,2H),7.13(d,J＝8.82 Hz,2H),7.26(m,3H),7.71(m,2H),7.81(m,2H),8.52(s,1H),9.59(s,1H),10.48(s,1H),10.71(s,1H)；MS(ESI＋)m/z 619(M＋H)＋.The product from Example 156C was reacted with 4-ethylguanidinyl-benzenesulfonium chloride, and isopropylsulfonium chloride was replaced with 4-ethylguanidino-benzenesulfonyl chloride according to the procedure from Example 159. The crude product was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (t, J = 7.35 Hz, 3H), 2.10 (s, 3H), 2.35 (s, 3H), 3.20 (q, J = 7.35 Hz, 2H) ), 6.85 (d, J = 8.82 Hz, 2H), 7.13 (d, J = 8.82 Hz, 2H), 7.26 (m, 3H), 7.71 (m, 2H), 7.81 (m, 2H), 8.52 (s) , 1H), 9.59 (s, 1H), 10.48 (s, 1H), 10.71 (s, 1H); MS (ESI+) m/z 619 (M+H)+.
4－[4－甲基－2－(7－嗎福啉－4－基－嘧啶并[4,5－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-Methyl-2-(7-morpholine-4-yl-pyrimido[4,5-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使得自實例156C之產物在嗎福啉中之溶液(1毫升)，於180℃下微波(CEM Discover微波)2小時。使溶液在真空下濃縮，並使殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(29毫克，65%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.30(s,3H),3.73(t,J＝4.41 Hz,4H),3.94(bs,4H),6.72(d,J＝8.82 Hz,2H),7.02(d,J＝8.09 Hz,1H),7.18(m,4H),8.61(s,1H),9.57(s,1H),9.85(s,1H),11.47(s,1H)；MS(ESI＋)m/z 447(M＋H)＋.A solution (1 mL) of the product from Example 156C in morpholine was taken and then microwaved (CEM Discover Microwave) at 180 °C for 2 hours. The solution was concentrated in EtOAc (EtOAc)EtOAc. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.30 (s, 3H), 3.73 (t, J = 4.41 Hz, 4H), 3.94 (bs, 4H), 6.72 (d, J = 8.82 Hz, 2H ), 7.02 (d, J = 8.09 Hz, 1H), 7.18 (m, 4H), 8.61 (s, 1H), 9.57 (s, 1H), 9.85 (s, 1H), 11.47 (s, 1H); (ESI+) m/z 447 (M+H)+.
苯磺酸4－[2－(7－乙基硫基－嘧啶并[4,5－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－苯酯4-[2-(7-ethylthio-pyrimido[4,5-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-phenyl benzenesulfonate
使得自實例156C之產物與氯化苯磺醯反應，根據得自實例159之程序，以氯化苯磺醯取代氯化異丙基磺醯，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(27毫克，48%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.36(t,J＝7.35 Hz,3H),2.36(s,3H),3.20(q,J＝7.35 Hz,2H),6.85(m,2H),7.11(m,2H),7.20(d,J＝7.72 Hz,1H),7.35(m,2H),7.65(m,2H),7.86(m,3H),8.51(s,1H),9.58(s,1H),10.65(s,1H)；MS(ESI＋)562(M＋H)＋.The product from Example 156C was reacted with phenylsulfonium chloride, and the isopropylsulfonium chloride was replaced with phenylsulfonium chloride according to the procedure from Example 159 to provide crude product which was purified by HPLC with TFA. The title compound was trifluoroacetate (27 mg, 48%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (t, J = 7.35 Hz, 3H), 2.36 (s, 3H), 3.20 (q, J = 7.35 Hz, 2H), 6.85 (m, 2H) ), 7.11 (m, 2H), 7.20 (d, J = 7.72 Hz, 1H), 7.35 (m, 2H), 7.65 (m, 2H), 7.86 (m, 3H), 8.51 (s, 1H), 9.58 (s, 1H), 10.65 (s, 1H); MS (ESI+) 562 (M+H)+.
4－溴－苯磺酸4－[2－(7－乙基硫基－嘧啶并[4,5－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－苯酯4-bromo-benzenesulfonic acid 4-[2-(7-ethylthio-pyrimido[4,5-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-benzene ester
使得自實例156C之產物與氯化4－溴－苯磺醯反應，根據得自實例159之程序，以氯化4－溴－苯磺醯取代氯化異丙基磺醯，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.36(t,J＝7.35 Hz,3H),2.37(s,3H),3.20(q,J＝7.35 Hz,2H),6.87(m,2H),7.12(m,2H),7.19(d,J＝7.05 Hz,1H),7.36(m,2H),7.71(m,2H),7.87(m,2H),8.51(s,1H),9.60(s,1H),10.61(s,1H)；MS(ESI＋)m/z 640/642(M＋H)＋.The product from Example 156C was reacted with 4-bromo-benzenesulfonium chloride, and the chlorosulfonium chloride was replaced with 4-bromo-benzenesulfonyl chloride according to the procedure from Example 159 to provide crude product. Purification by TFA by HPLC afforded the title compound as trifluoroacetate. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (t, J = 7.35 Hz, 3H), 2.37 (s, 3H), 3.20 (q, J = 7.35 Hz, 2H), 6.87 (m, 2H) ), 7.12 (m, 2H), 7.19 (d, J = 7.05 Hz, 1H), 7.36 (m, 2H), 7.71 (m, 2H), 7.87 (m, 2H), 8.51 (s, 1H), 9.60 (s, 1H), 10.61 (s, 1H); MS (ESI+) m/z 640/642 (M+H)+.
(7－乙基硫基－嘧啶并[4,5－d]嘧啶－4－基)－[2－(4－羥基－苯基硫基)－5－甲基－苯基]－胺甲基酸第三－丁酯(7-Ethylthio-pyrimido[4,5-d]pyrimidin-4-yl)-[2-(4-hydroxy-phenylsulfanyl)-5-methyl-phenyl]-aminomethyl Acidic third-butyl ester
於室溫下，使實例156C之產物與二碳酸二－第三－丁酯及三乙胺在四氫呋喃中反應16小時。然後將混合物倒入水(10毫升)中，並以醋酸乙酯(3 x 10毫升)萃取所形成之溶液，使合併之萃液以硫酸鎂脫水乾燥，過濾，及在真空下濃縮，提供標題化合物。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.52(t,J＝7.35 Hz,3H),1.62(s,9H),2.50(s,3H),3.35(q,J＝7.35 Hz,2H),7.21(d,J＝8.46 Hz,2H),7.41(m,5H),8.71(s,1H),9.80(s,1H),10.72(s,1H)；MS(ESI＋)m/z 522(M＋H)＋.The product of Example 156C was reacted with di-tert-butyl dicarbonate and triethylamine in tetrahydrofuran for 16 hours at room temperature. The mixture was poured into water (10 mL). EtOAc (EtOAc m. Compound. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.52 (t, J = 7.35 Hz, 3H), 1.62 (s, 9H), 2.50 (s, 3H), 3.35 (q, J = 7.35 Hz, 2H ), 7.21 (d, J = 8.46 Hz, 2H), 7.41 (m, 5H), 8.71 (s, 1H), 9.80 (s, 1H), 10.72 (s, 1H); MS (ESI+) m/z 522 (M+H)+.
{4－[2－(7－乙基硫基－嘧啶并[4,5－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－苯氧基}－乙腈{4-[2-(7-Ethylthio-pyrimido[4,5-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-phenoxy}-acetonitrile
於室溫下，將得自實例164之產物(52毫克，0.1毫莫耳)、溴－乙腈(0.008毫升，0.12毫莫耳)、碳酸銫(0.065克，0.2毫莫耳)及碘化四丁基銨(0.001克)在N,N－二甲基甲醯胺(2毫升)中攪拌2小時。使混合物於水與醋酸乙酯之間作分液處理。以鹽水洗滌有機層，脫水乾燥(硫酸鈉)，過濾，並在真空下蒸發。於殘留物中，添加二氯甲烷(2.5毫升)與三氟醋酸(2.5毫升)，然後於室溫下攪拌1小時。在真空下蒸發溶劑，並使殘留物藉HPLC以TFA純化，提供標題化合物(9毫克，20%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.42(t,J＝7.35 Hz,3H),2.24(s,3H),3.29(q,J＝7.35 Hz,2H),5.25(s,2H),6.81(m,5H),7.20(d,J＝8.46 Hz,2H),8.34(s,1H),9.25(s,1H),9.75(s,1H)；MS(ESI＋)m/z 461(M＋H)＋.The product from Example 164 (52 mg, 0.1 mmol), bromo-acetonitrile (0.008 mL, 0.12 mmol), cesium carbonate (0.065 g, 0.2 mmol) and iodinated at room temperature Butylammonium (0.001 g) was stirred in N,N-dimethylformamide (2 mL) for 2 h. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered and evaporated. Dichloromethane (2.5 ml) and trifluoroacetic acid (2.5 ml) were added and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under EtOAcqqqqm 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.42 (t, J = 7.35 Hz, 3H), 2.24 (s, 3H), 3.29 (q, J = 7.35 Hz, 2H), 5.25 (s, 2H) ), 6.81 (m, 5H), 7.20 (d, J = 8.46 Hz, 2H), 8.34 (s, 1H), 9.25 (s, 1H), 9.75 (s, 1H); MS (ESI+) m/z 461 (M+H)+.
[2－(4－苄氧基－苯基硫基)－5－甲基－苯基]－(7－乙基硫基－嘧啶并[4,5－d]嘧啶－4－基)－胺[2-(4-Benzyloxy-phenylsulfanyl)-5-methyl-phenyl]-(7-ethylsulfanyl-pyrimido[4,5-d]pyrimidin-4-yl)-amine
使得自實例164之產物與溴化苄反應，根據得自實例165之程序，以溴化苄取代溴－乙腈，提供粗產物，使其藉矽膠層析純化，使用98/2二氯甲烷/甲醇作為溶離劑，提供標題化合物(15毫克，29%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.20(t,J＝7.35 Hz,3H),2.27(s,3H),3.08(q,J＝7.35 Hz,2H),5.44(s,2H),6.74(d,J＝8.46 Hz,2H),6.95(m,3H),7.20(d,J＝8.46 Hz,2H),7.35(m,5H),8.77(s,1H),9.42(s,1H),9.81(s,1H)；MS(ESI＋)m/z 512(M＋H)＋.The product from Example 164 was reacted with benzyl bromide, and bromo-acetonitrile was substituted with benzyl bromide according to the procedure from Example 165 to afford crude product. The title compound (15 mg, 29%) was obtained as a solvent. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.20 (t, J = 7.35 Hz, 3H), 2.27 (s, 3H), 3.08 (q, J = 7.35 Hz, 2H), 5.44 (s, 2H) ), 6.74 (d, J = 8.46 Hz, 2H), 6.95 (m, 3H), 7.20 (d, J = 8.46 Hz, 2H), 7.35 (m, 5H), 8.77 (s, 1H), 9.42 (s) , 1H), 9.81 (s, 1H); MS (ESI+) m/z 512 (M+H)+.
4－[4－(3－溴－苄氧基)－2－(2－甲硫基－噻唑并[4,5－d]嘧啶－7－基胺基)－苯基硫基]－酚4-[4-(3-Bromo-benzyloxy)-2-(2-methylthio-thiazolo[4,5-d]pyrimidin-7-ylamino)-phenylthio]-phenol
實例167A N'－(5－氰基－2－甲硫基－噻唑－4－基)－N,N－二甲基－甲脒標題化合物係製自4－胺基－2－甲硫基－噻唑－5－甲腈與N,N－二甲基甲醯胺二甲基縮醛之反應，使用得自實例156B之程序，提供標題化合物，為白色泡沫物(0.132克，99%)。Example 167A N'-(5-Cyano-2-methylthio-thiazol-4-yl)-N,N-dimethyl-methylindole title compound from 4-amino-2-methylthio- Reaction of the thiazole-5-carbonitrile with N,N-dimethylformamide dimethyl acetal, using the procedure from Example 156B to give the title compound as white foam (0.132 g, 99%).
實例167B 4－[4－(3－溴－苄氧基)－2－(2－甲硫基－噻唑并[4,5－d]嘧啶－7－基胺基)－苯基硫基]－酚將得自實例167A之產物(66.0毫克，0.29毫莫耳)與得自實例15A之產物(118毫克，0.29毫莫耳)在醋酸(1毫升)中之溶液，於經預熱140℃之油浴中攪拌20分鐘。使混合物冷卻，及在真空下濃縮。然後使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(34毫克，17%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.75(s,3H),5.12(s,2H),6.70(d,J＝8.82 Hz,1H),6.96－7.05(m,2H),7.07－7.16(m,3H),7.33(t,J＝7.72 Hz,1H),7.41－7.46(m,1H),7.51(d,J＝7.72 Hz,1H),7.63(s,1H),8.47(s,1H),9.73(s,2H)；MS(ESI)＋ m/z 583/585(M＋H)＋.Example 167B 4-[4-(3-Bromo-benzyloxy)-2-(2-methylthio-thiazolo[4,5-d]pyrimidin-7-ylamino)-phenylthio]- The phenol was obtained from the product of Example 167A (66.0 mg, 0.29 mmol) and the product from Example 15A (118 mg, 0.29 mmol) in acetic acid (1 mL). Stir in the oil bath for 20 minutes. The mixture was allowed to cool and concentrated under vacuum. The resulting residue was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.75 (s, 3H), 5.12 (s, 2H), 6.70 (d, J = 8.82 Hz, 1H), 6.96-7.05 (m, 2H), 7.07 -7.16(m,3H),7.33(t,J=7.72 Hz,1H), 7.41-7.46(m,1H),7.51(d,J=7.72 Hz,1H), 7.63(s,1H),8.47( s,1H),9.73(s,2H);MS(ESI)+ m/z 583/585(M+H)+.
4－[4－(4－溴－苄氧基)－2－(2－甲硫基－噻唑并[4,5－d]嘧啶－7－基胺基)－苯基硫基]－酚4-[4-(4-Bromo-benzyloxy)-2-(2-methylthio-thiazolo[4,5-d]pyrimidin-7-ylamino)-phenylthio]-phenol
使得自實例167A之產物溶液與得自實例16A之產物反應，根據得自實例167B之程序，以得自實例16A之產物取代得自實例15A之產物，提供粗製物質，使其藉由以甲醇研製而純化，提供標題化合物，為白色固體(46毫克，27%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.76(s,3H),5.09(s,2H),6.70(d,J＝8.46 Hz,2H),6.91－7.24(m,5H),7.38(d,J＝8.09 Hz,2H),7.56(d,J＝8.09 Hz,2H),8.46(s,1H),9.71(s,2H)；MS(ESI)＋ m/z 583/585(M＋H)＋.The product from Example 167A was reacted with the product from Example 16A, and the product from Example 15A was replaced with the product from Example 16A according to the procedure from Example 167B to afford crude material. The title compound was obtained as a white solid (46 mg, 27%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.76 (s, 3H), 5.09 (s, 2H), 6.70 (d, J = 8.46 Hz, 2H), 6.91-7.24 (m, 5H), 7.38 (d, J = 8.09 Hz, 2H), 7.56 (d, J = 8.09 Hz, 2H), 8.46 (s, 1H), 9.71 (s, 2H); MS (ESI) + m/z 583/585 (M+H )+.
4－[4－甲基－2－(2－甲硫基－噻唑并[4,5－d]嘧啶－7－基胺基)－苯基硫基]－酚4-[4-Methyl-2-(2-methylthio-thiazolo[4,5-d]pyrimidin-7-ylamino)-phenylthio]-phenol
使得自實例167A之產物溶液與得自實例6c之產物反應，根據得自實例167B之程序，以得自實例6c之產物取代得自實例15A之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(17毫克，11%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.27(s,3H),2.76(s,3H),6.76(d,J＝8.46 Hz,2H),6.82(d,J＝8.09 Hz,1H),7.06－7.22(m,4H),8.49(s,1H),9.86(s,2H)；MS(ESI)＋ m/z 413(M＋H)＋.The product from Example 167A was reacted with the product from Example 6c, and the product from Example 15A was substituted from the product from Example 6c according to the procedure from Example 167B to afford crude material. The title compound was obtained as trifluoroacetate (17 mg, 11%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.27 (s, 3H), 2.76 (s, 3H), 6.76 (d, J = 8.46 Hz, 2H), 6.82 (d, J = 8.09 Hz, 1H) ), 7.06-7.22 (m, 4H), 8.49 (s, 1H), 9.86 (s, 2H); MS (ESI) + m/z 413 (M+H)+.
N－{4－[4－甲基－2－(2－甲硫基－噻唑并[4,5－d]嘧啶－7－基胺基)－苯基硫基]－苯基}－乙醯胺N-{4-[4-Methyl-2-(2-methylthio-thiazolo[4,5-d]pyrimidin-7-ylamino)-phenylthio]-phenyl}-acetamidine amine
使得自實例167A之產物溶液與得自實例7b之產物反應，根據得自實例167B之程序，以得自實例7b之產物取代得自實例15A之產物，提供粗製物質，使其藉由以甲醇研製而純化，提供標題化合物(110毫克，83%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.03(s,3H),2.29(s,3H),2.76(s,3H),6.96(d,J＝8.09 Hz,1H),7.14(d,J＝8.09 Hz,1H),7.18－7.26(m,J＝8.82 Hz,3H),7.54(d,J＝8.46 Hz,2H),8.45(s,1H),9.74(s,1H),10.04(s,1H)；MS(ESI)＋ m/z 454(M＋H)＋.The product from Example 167A was reacted with the product from Example 7b, and the product from Example 15A was replaced with the product from Example 7b according to the procedure from Example 167B to afford crude material. Purified to provide the title compound (110 mg, < 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.03 (s, 3H), 2.29 (s, 3H), 2.76 (s, 3H), 6.96 (d, J = 8.09 Hz, 1H), 7.14 (d) , J=8.09 Hz, 1H), 7.18-7.26 (m, J=8.82 Hz, 3H), 7.54 (d, J=8.46 Hz, 2H), 8.45 (s, 1H), 9.74 (s, 1H), 10.04 (s, 1H); MS (ESI) + m/z 454 (M+H)+.
N－{4－[2－(1－第三－丁基－1H－吡唑并[3,4－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－苯基}－乙醯胺N-{4-[2-(1-Terve-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-benzene }--acetamide
實例171A N'－(2－第三－丁基－4－氰基－2H－吡唑－3－基)－N,N－二甲基－甲脒標題化合物係製自5－胺基－1－第三－丁基－1H－吡唑－4－甲腈與N,N－二甲基甲醯胺二甲基縮醛之反應，使用得自實例156B之程序，提供標題化合物。Example 171A N'-(2-Terti-butyl-4-cyano-2H-pyrazol-3-yl)-N,N-dimethyl-methylindole title compound from 5-amino-1 Reaction of <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt;
實例171B N－{4－[2－(1－第三－丁基－1H－吡唑并[3,4－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－苯基}－乙醯胺使得自實例171A之產物溶液與得自實例7b之產物反應，根據得自實例167B之程序，以得自實例7b之產物取代得自實例15A之產物，並以得自實例171A之產物取代得自實例167A之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(54毫克，32%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.74(s,9H),2.03(s,3H),2.41(s,3H),7.13(d,J＝8.82 Hz,2H),7.49(m,4H),7.62(s,1H),8.41(s,1H),8.47(s,1H),8.76(s,1H),10.06(s,1H),10.39(s,1H)；MS(ESI＋)m/z 447(M＋H)＋.Example 171B N-{4-[2-(1-Terti-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-4-methyl-phenylthio] -Phenyl}-acetamide to react the product from Example 171A with the product from Example 7b, substituting the product from Example 7b for the product from Example 15A according to the procedure from Example 167B. The product from Example 171A was obtained from the titled </RTI></RTI><RTIID=0.0></RTI><RTIgt; 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.74 (s, 9H), 2.03 (s, 3H), 2.41 (s, 3H), 7.13 (d, J = 8.82 Hz, 2H), 7.49 (m) , 4H), 7.62 (s, 1H), 8.41 (s, 1H), 8.47 (s, 1H), 8.76 (s, 1H), 10.06 (s, 1H), 10.39 (s, 1H); MS (ESI+) m/z 447(M+H)+.
實例172 4－[2－(1－第三－丁基－1H－吡唑并[3,4－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－酚使得自實例171A之產物溶液與得自實例6c之產物反應，根據得自實例167B之程序，以得自實例6c之產物取代得自實例15A之產物，並以得自實例171A之產物取代得自實例167A之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(40毫克，25%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.76(s,9H),2.38(s,3H),6.67(d,J＝8.82 Hz,2H),7.07(d,J＝8.82 Hz,2H),7.34(d,J＝8.09 Hz,1H),7.50(d,J＝8.09 Hz,1H),7.58(s,1H),8.43(s,1H),8.49(s,1H),8.75(s,1H),9.91(s,1H),10.40(s,1H)；MS(ESI＋)m/z 406(M＋H)＋.Example 172 4-[2-(1-Terve-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-4-methyl-phenylsulfanyl]-phenol The product solution from Example 171A was reacted with the product from Example 6c. The product from Example 15A was substituted from the product from Example 6c according to the procedure from Example 167B, and the product obtained from Example 171A was substituted from the example. The product was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.76 (s, 9H), 2.38 (s, 3H), 6.67 (d, J = 8.82 Hz, 2H), 7.07 (d, J = 8.82 Hz, 2H) ), 7.34 (d, J = 8.09 Hz, 1H), 7.50 (d, J = 8.09 Hz, 1H), 7.58 (s, 1H), 8.43 (s, 1H), 8.49 (s, 1H), 8.75 (s) , 1H), 9.91 (s, 1H), 10.40 (s, 1H); MS (ESI+) m/z 406 (M+H)+.
4－[2－(7－異丙基－嘧啶并[4,5－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－酚4-[2-(7-isopropyl-pyrimido[4,5-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-phenol
實例173A N'－(5－氰基－2－異丙基－嘧啶－4－基)－N,N－二甲基－甲脒標題化合物係製自4－胺基－2－異丙基－嘧啶－5－甲腈與N,N－二甲基甲醯胺二甲基縮醛之反應，使用得自實例156B之程序，提供標題化合物。Example 173A N'-(5-Cyano-2-isopropyl-pyrimidin-4-yl)-N,N-dimethyl-methylhydrazine the title compound was obtained from 4-amino-2-isopropyl- Reaction of the pyrimidine-5-carbonitrile with N,N-dimethylformamide dimethyl acetal using the procedure from Example 156B afforded the title compound.
實例173B 4－[2－(7－異丙基－嘧啶并[4,5－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－酚使得自實例173A之產物溶液與得自實例6c之產物反應，根據得自實例167B之程序，以得自實例6c之產物取代得自實例15A之產物，並以得自實例173A之產物取代得自實例167A之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(39毫克，38%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.36(d,J＝6.62 Hz,6H),2.30(s,3H),3.29(m,1H),6.70(d,J＝8.46 Hz,2H),6.98(d,J＝8.09 Hz,1H),7.17(m,4H),8.72(s,1H),9.76(s,1H),9.90(s,1H),11.13(s,1H)；MS(ESI＋)m/z 404(M＋H)＋.Example 173B 4-[2-(7-isopropyl-pyrimido[4,5-d]pyrimidin-4-ylamino)-4-methyl-phenylsulfanyl]-phenol was obtained as a product from Example 173A The solution was reacted with the product from Example 6c, substituting the product from Example 6c to afford the product from Example 15A, and substituting the product from Example 173A from the product from Example 167A. The crude material was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (d, J = 6.62 Hz, 6H), 2.30 (s, 3H), 3.29 (m, 1H), 6.70 (d, J = 8.46 Hz, 2H ), 6.98 (d, J = 8.09 Hz, 1H), 7.17 (m, 4H), 8.72 (s, 1H), 9.76 (s, 1H), 9.90 (s, 1H), 11.13 (s, 1H); (ESI+)m/z 404(M+H)+.
4－[4－苄氧基－2－(7－異丙基－嘧啶并[4,5－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-Benzyloxy-2-(7-isopropyl-pyrimido[4,5-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使得自實例173A之產物溶液與得自實例27A之產物反應，根據得自實例167B之程序，以得自實例27A之產物取代得自實例15A之產物，並以得自實例173A之產物取代得自實例167A之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(10毫克，20%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.35(d,J＝6.99 Hz,6H),3.27(m,1H),5.11(s,2H),6.64(d,J＝8.46 Hz,2H),7.06(m,5H),7.40(m,5H),8.64(s,1H),9.65(s,1H),9.84(s,1H),10.88(s,1H)；MS(ESI＋)m/z 496(M＋H)＋.The product from Example 173A was reacted with the product from Example 27A, substituting the product from Example 27A to afford the product from Example 15A and substituting the product from Example 173A. The product of Example 167A, EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.99 Hz, 6H), 3.27 (m, 1H), 5.11 (s, 2H), 6.64 (d, J = 8.46 Hz, 2H ), 7.06 (m, 5H), 7.40 (m, 5H), 8.64 (s, 1H), 9.65 (s, 1H), 9.84 (s, 1H), 10.88 (s, 1H); MS (ESI+) m/ z 496(M+H)+.
N－{4－[2－(7－乙基硫基－5－甲硫基－嘧啶并[4,5－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－苯基}－乙醯胺N-{4-[2-(7-Ethylthio-5-methylthio-pyrimido[4,5-d]pyrimidin-4-ylamino)-4-methyl-phenylthio] -phenyl}-acetamide
實例175A N'－(5－氰基－2－乙基硫基－6－甲硫基－嘧啶－4－基)－N,N－二甲基－甲脒標題化合物係製自4－胺基－2－乙基硫基－6－甲硫基－嘧啶－5－甲腈與N,N－二甲基甲醯胺二甲基縮醛之反應，使用得自實例156B之程序，提供標題化合物。Example 175A N'-(5-Cyano-2-ethylsulfanyl-6-methylsulfanyl-pyrimidin-4-yl)-N,N-dimethyl-methylindole title compound from 4-amino Reaction of 2-ethylthio-6-methylthio-pyrimidine-5-carbonitrile with N,N-dimethylformamide dimethyl acetal using the procedure from Example 156B to provide the title compound .
實例175B N－{4－[2－(7－乙基硫基－5－甲硫基－嘧啶并[4,5－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－苯基}－乙醯胺使得自實例175A之產物溶液與得自實例7b之產物反應，根據得自實例167B之程序，以得自實例7b之產物取代得自實例15A之產物，並以得自實例175A之產物取代得自實例167A之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(23毫克，35%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.36(t,J＝7.35 Hz,3H),2.03(s,3H),2.24(s,3H),2.40(s,3H),3.18(q,J＝7.35 Hz,2H),6.84(m,3H),7.19(d,J＝8.46 Hz,2H),7.49(d,J＝8.46 Hz,2H),7.82(s,1H),9.97(s,1H),12.25(s,1H)；MS(ESI＋)m/z 509(M＋H)＋.Example 175B N-{4-[2-(7-Ethylthio-5-methylthio-pyrimido[4,5-d]pyrimidin-4-ylamino)-4-methyl-phenylsulfide The base product of Example 175A was reacted with the product from Example 7b, and the product from Example 15A was replaced with the product from Example 7b according to the procedure from Example 167B. The product from Example 167A was obtained from the titled </RTI></RTI><RTIID=0.0></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (t, J = 7.35 Hz, 3H), 2.03 (s, 3H), 2.24 (s, 3H), 2.40 (s, 3H), 3.18 (q) , J = 7.35 Hz, 2H), 6.84 (m, 3H), 7.19 (d, J = 8.46 Hz, 2H), 7.49 (d, J = 8.46 Hz, 2H), 7.82 (s, 1H), 9.97 (s , 1H), 12.25 (s, 1H); MS (ESI+) m/z 509 (M+H)+.
4－[2－(7－乙基硫基－5－甲硫基－嘧啶并[4,5－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－酚4-[2-(7-ethylthio-5-methylthio-pyrimido[4,5-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-phenol
使得自實例175A之產物溶液與得自實例6c之產物反應，根據得自實例167B之程序，以得自實例6c之產物取代得自實例15A之產物，並以得自實例175A之產物取代得自實例167A之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(19毫克，31%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.36(t,J＝7.35 Hz,3H),2.21(s,3H),2.44(s,3H),3.19(q,J＝7.11 Hz,2H),6.70(m,5H),7.18(d,J＝8.46 Hz,2H),7.84(s,1H),9.67(s,1H),12.24(s,1H)；MS(ESI＋)m/z 468(M＋H)＋.The product from Example 175A was reacted with the product from Example 6c, and the product from Example 15A was substituted from the product from Example 6c according to the procedure from Example 167B, and was obtained from the product from Example 175A. The product of </RTI></RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI><RTIgt;</RTI><RTIgt; 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (t, J = 7.35 Hz, 3H), 2.21 (s, 3H), 2.44 (s, 3H), 3.19 (q, J = 7.11 Hz, 2H) ), 6.70 (m, 5H), 7.18 (d, J = 8.46 Hz, 2H), 7.84 (s, 1H), 9.67 (s, 1H), 12.24 (s, 1H); MS (ESI+) m/z 468 (M+H)+.
N－{4－[2－(2－氰基甲硫基－噻唑并[4,5－d]嘧啶－7－基胺基)－4－甲基－苯基硫基]－苯基}－乙醯胺N-{4-[2-(2-Cyanomethylthio-thiazolo[4,5-d]pyrimidin-7-ylamino)-4-methyl-phenylthio]-phenyl}- Acetamine
實例177A N'－(5－氰基－2－氰基甲硫基－噻唑－4－基)－N,N－二甲基－甲脒標題化合物係製自4－胺基－2－氰基甲硫基－噻唑－5－甲腈與N,N－二甲基甲醯胺二甲基縮醛之反應，使用得自實例156B之程序，提供標題化合物。Example 177A N'-(5-Cyano-2-cyanomethylthio-thiazol-4-yl)-N,N-dimethyl-methylindole title compound from 4-amino-2-cyano Reaction of methylthio-thiazole-5-carbonitrile with N,N-dimethylformamide dimethyl acetal using the procedure from Example 156B afforded the title compound.
實例177B N－{4－[2－(2－氰基甲硫基－噻唑并[4,5－d]嘧啶－7－基胺基)－4－甲基－苯基硫基]－苯基}－乙醯胺使得自實例177A之產物溶液與得自實例7b之產物反應，根據得自實例167B之程序，以得自實例7b之產物取代得自實例15A之產物，並以得自實例177A之產物取代得自實例167A之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(64毫克，52%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.03(s,3H),2.30(s,3H),4.54(s,2H),6.95(d,J＝8.09 Hz,1H),7.15(d,J＝8.09 Hz,1H),7.23(m,3H),7.55(d,J＝8.46 Hz,2H),8.51(s,1H),9.91(s,1H),10.04(s,1H)；MS(ESI＋)m/z 479(M＋H)＋.Example 177B N-{4-[2-(2-Cyanomethylthio-thiazolo[4,5-d]pyrimidin-7-ylamino)-4-methyl-phenylthio]-phenyl The test product from Example 177A was reacted with the product from Example 7b, and the product from Example 15A was replaced with the product from Example 7b according to the procedure from Example 167B, and obtained from Example 177A. The product was obtained from the titled </RTI><RTIID=0.0></RTI></RTI></RTI><RTIgt; 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.03 (s, 3H), 2.30 (s, 3H), 4.54 (s, 2H), 6.95 (d, J = 8.09 Hz, 1H), 7.15 (d) , J=8.09 Hz, 1H), 7.23 (m, 3H), 7.55 (d, J=8.46 Hz, 2H), 8.51 (s, 1H), 9.91 (s, 1H), 10.04 (s, 1H); MS (ESI+) m/z 479(M+H)+.
{7－[2－(4－羥基－苯基硫基)－5－甲基－苯基胺基]－噻唑并[4,5－d]嘧啶－2－基硫基}－乙腈{7-[2-(4-Hydroxy-phenylthio)-5-methyl-phenylamino]-thiazolo[4,5-d]pyrimidin-2-ylthio}-acetonitrile
使得自實例177A之產物溶液與得自實例6c之產物反應，根據得自實例167B之程序，以得自實例6c之產物取代得自實例15A之產物，並以得自實例177A之產物取代得自實例167A之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(62毫克，56%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.27(s,3H),4.54(s,2H),6.77(m,3H),7.18(m,4H),8.53(s,1H),9.85(s,1H),9.97(s,1H)；MS(ESI＋)m/z 438(M＋H)＋.The product from Example 177A was reacted with the product from Example 6c, substituting the product from Example 6c to afford the product from Example 15A, and substituting the product from Example 177A. The product of </RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.27 (s, 3H), 4.54 (s, 2H), 6.77 (m, 3H), 7.18 (m, 4H), 8.53 (s, 1H), 9.85 (s, 1H), 9.97 (s, 1H); MS (ESI+) m/z 438 (M+H)+.
4－[4－苄氧基－2－(7－七氟丙基－嘧啶并[4,5－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-Benzyloxy-2-(7-heptafluoropropyl-pyrimido[4,5-d]pyrimidin-4-ylamino)-phenylthio]-phenol
實例179A N'－(5－氰基－2－七氟丙基－嘧啶－4－基)－N,N－二甲基－甲脒標題化合物係製自4－胺基－2－七氟丙基－嘧啶－5－甲腈與N,N－二甲基甲醯胺二甲基縮醛之反應，使用得自實例156B之程序，提供標題化合物。Example 179A N'-(5-Cyano-2-heptafluoropropyl-pyrimidin-4-yl)-N,N-dimethyl-methylindole title compound from 4-amino-2-heptafluoropropane Reaction of the pyridine-pyrimidine-5-carbonitrile with N,N-dimethylformamide dimethyl acetal using the procedure from Example 156B afforded the title compound.
實例179B 4－[4－苄氧基－2－(7－七氟丙基－嘧啶并[4,5－d]嘧啶－4－基胺基)－苯基硫基]－酚使得自實例179A之產物溶液與得自實例27A之產物反應，根據得自實例167B之程序，以得自實例27A之產物取代得自實例15A之產物，並以得自實例179A之產物取代得自實例167A之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(24毫克，39%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：5.11(s,2H),6.61(d,J＝8.46 Hz,2H),7.04(dd,J＝8.82,2.57 Hz,1H),7.10(d,J＝8.46 Hz,2H),7.17(d,J＝2.57 Hz,1H),7.23(d,J＝8.82 Hz,1H),7.40(m,5H),8.79(s,1H),9.63(s,1H),10.12(s,1H),11.01(s,1H)；MS(ESI＋)m/z 622(M＋H)＋.Example 179B 4-[4-Benzyloxy-2-(7-heptafluoropropyl-pyrimido[4,5-d]pyrimidin-4-ylamino)-phenylthio]-phenol is rendered from Example 179A The product solution was reacted with the product from Example 27A, substituting the product from Example 27A to afford the product from Example 15A, and substituting the product from Example 179A to the product from Example 167A. The crude material was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 5.11 (s, 2H), 6.61 (d, J = 8.46 Hz, 2H), 7.04 (dd, J = 8.82, 2.57 Hz, 1H), 7.10 (d) , J = 8.46 Hz, 2H), 7.17 (d, J = 2.57 Hz, 1H), 7.23 (d, J = 8.82 Hz, 1H), 7.40 (m, 5H), 8.79 (s, 1H), 9.63 (s , 1H), 10.12 (s, 1H), 11.01 (s, 1H); MS (ESI+) m/z 622 (M+H)+.
(7－異丙基－嘧啶并[4,5－d]嘧啶－4－基)－[5－甲基－2－(4－苯氧基－苯基硫基)－苯基]－胺(7-Isopropyl-pyrimido[4,5-d]pyrimidin-4-yl)-[5-methyl-2-(4-phenoxy-phenylthio)-phenyl]-amine
使得自實例173A之產物溶液與得自實例157a之產物反應，根據得自實例167B之程序，以得自實例157a之產物取代得自實例15A之產物，並以得自實例173A之產物取代得自實例167A之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.34(d,J＝6.99 Hz,6H),2.34(s,3H),3.24(m,1H),6.81(d,J＝8.82 Hz,2H),6.94(d,J＝7.72 Hz,2H),7.28(m,8H),8.63(s,1H),9.83(s,1H),10.78(s,1H)；MS(ESI＋)m/z 480(M＋H)＋.The product from Example 173A was reacted with the product from Example 157a, substituting the product from Example 157a to afford the product from Example 15A and substituting the product from Example 173A. The product of Example 167A, mp. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J = 6.99 Hz, 6H), 2.34 (s, 3H), 3.24 (m, 1H), 6.81 (d, J = 8.82 Hz, 2H ), 6.94 (d, J = 7.72 Hz, 2H), 7.28 (m, 8H), 8.63 (s, 1H), 9.83 (s, 1H), 10.78 (s, 1H); MS (ESI+) m/z 480 (M+H)+.
(7－乙基硫基－嘧啶并[4,5－d]嘧啶－4－基)－[3－(4－甲氧基－苯基硫基)－5－甲基－苯基]－胺(7-Ethylthio-pyrimido[4,5-d]pyrimidin-4-yl)-[3-(4-methoxy-phenylthio)-5-methyl-phenyl]-amine
實例181A 1－(4－甲氧基－苯基硫基)－3－甲基－5－硝基－苯將4－甲氧基硫酚亞銅(0.94克，4.63毫莫耳)，其係經由使過量4－甲氧基硫酚與氧化銅在乙醇中回流過夜，並藉過濾單離所要之產物而製成，與3－溴基－5－硝基甲苯(1.0克，4.63毫莫耳)，其係按J.Am.Chem.Soc.第78卷,第1992,1956頁中所述，以兩個步驟製自3－硝基－4－甲苯胺，在喹啉(5毫升)與吡啶(1毫升)之混合物中加熱至165℃，歷經2小時。以HCl水溶液使反應淬滅後，所要之產物係於矽膠上藉層析單離，使用醋酸乙酯/己烷作為溶離劑，提供標題化合物(0.96克，75%)。Example 181A 1-(4-Methoxy-phenylthio)-3-methyl-5-nitro-benzene 4-methoxythiophenol cuprous (0.94 g, 4.63 mmol), Prepared by refluxing excess 4-methoxythiophenol with copper oxide in ethanol overnight and by filtration to separate the desired product with 3-bromo-5-nitrotoluene (1.0 g, 4.63 mmol) ), which is prepared in two steps from 3-nitro-4-toluidine in quinoline (5 ml) according to J. Am. Chem. Soc., vol. 78, p. 1992, p. The mixture of pyridine (1 mL) was heated to 165 ° C for 2 hours. After the reaction was quenched with EtOAcqqqqqqqm
實例181B 3－(4－甲氧基－苯基硫基)－5－甲基－苯胺將得自實例181A之產物根據得自實例147C之程序還原，以得自實例181A之產物取代得自實例147B之產物，提供標題化合物。Example 181B 3-(4-Methoxy-phenylsulfanyl)-5-methyl-phenylamine The product from Example 181A was purified according to the procedure from Example 147 C. The product of 147B provides the title compound.
實例181C(7－乙基硫基－嘧啶并[4,5－d]嘧啶－4－基)－[3－(4－甲氧基－苯基硫基)－5－甲基－苯基]－胺使得自實例181B之產物與得自實例156B之產物反應，根據得自實例156C之程序，以得自實例181B之產物取代得自實例6c之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(500 MHz,DMSO－D6)δ ppm：1.37(t,J＝7.32 Hz,3H),2.28(s,3H),3.21(q,J＝7.32 Hz,2H),3.79(s,3H),6.83(s,1H),7.03(d,J＝9.16 Hz,2H),7.42－7.53(m,4H),8.71(s,1H),9.72(s,1H),10.39(s,1H)；MS(ESI＋)m/z 436(M＋H)＋.Example 181C (7-Ethylthio-pyrimido[4,5-d]pyrimidin-4-yl)-[3-(4-methoxy-phenylthio)-5-methyl-phenyl] -Amine The product from Example 181B was reacted with the product from Example 156B, and the product from Example 6c was substituted from the product from Example </RTI> Purification afforded the title compound as trifluoroacetate. 1 H NMR (500 MHz, DMSO-D6) δ ppm: 1.37 (t, J = 7.32 Hz, 3H), 2.28 (s, 3H), 3.21. (q, J = 7.32 Hz, 2H), 3.79 (s, 3H) ), 6.83 (s, 1H), 7.03 (d, J = 9.16 Hz, 2H), 7.42 - 7.53 (m, 4H), 8.71 (s, 1H), 9.72 (s, 1H), 10.39 (s, 1H) ;MS(ESI+)m/z 436(M+H)+.
(7－乙基硫基－嘧啶并[4,5－d]嘧啶－4－基)－[3－(3－甲氧基－苯基硫基)－5－甲基－苯基]－胺(7-Ethylthio-pyrimido[4,5-d]pyrimidin-4-yl)-[3-(3-methoxy-phenylthio)-5-methyl-phenyl]-amine
實例182A 3－(3－甲氧基－苯基硫基)－5－甲基－苯胺使3－甲氧基硫酚亞銅與3－溴基－5－硝基甲苯反應，根據得自實例181A之程序，以3－甲氧基硫酚亞銅取代4－甲氧基硫酚亞銅，提供1－(3－甲氧基－苯基硫基)－3－甲基－5－硝基－苯，將其根據得自實例181B之程序還原，提供標題化合物。Example 182A 3-(3-Methoxy-phenylthio)-5-methyl-phenylamine The reaction of 3-methoxythiophenol cuprous with 3-bromo-5-nitrotoluene, according to the example Procedure for 181A, substituting 4-methoxythiophenol cuprous with copper 4-methoxythiophenol to provide 1-(3-methoxy-phenylthio)-3-methyl-5-nitro - Benzene, which was reduced according to the procedure from Example 181B to afford the title compound.
實例182B(7－乙基硫基－嘧啶并[4,5－d]嘧啶－4－基)－[3－(3－甲氧基－苯基硫基)－5－甲基－苯基]－胺使得自實例182A之產物與得自實例156B之產物反應，根據得自實例156C之程序，以得自實例182A之產物取代得自實例6c之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.37(t,J＝7.35 Hz,3H),2.33(s,3H),3.21(q,J＝7.11 Hz,2H),3.74(s,3H),6.84－6.96(m,J＝1.10 Hz,3H),7.05(s,1H),7.32(dd,J＝9.01,7.17 Hz,1H),7.60(s,1H),7.65(s,1H),8.74(s,1H),9.74(s,1H),10.47(s,1H)；MS(ESI＋)m/z 436(M＋H)＋.Example 182B (7-ethylthio-pyrimido[4,5-d]pyrimidin-4-yl)-[3-(3-methoxy-phenylthio)-5-methyl-phenyl] -Amine The product from Example 182A was reacted with the product from Example 156B. The product from Example </RTI></RTI></RTI> Purification afforded the title compound as trifluoroacetate. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.37 (t, J = 7.35 Hz, 3H), 2.33 (s, 3H), 3.21. (q, J = 7.11 Hz, 2H), 3.74 (s, 3H) ), 6.84-6.96 (m, J = 1.10 Hz, 3H), 7.05 (s, 1H), 7.32 (dd, J = 9.01, 7.17 Hz, 1H), 7.60 (s, 1H), 7.65 (s, 1H) , 8.74(s,1H), 9.74(s,1H), 10.47(s,1H);MS(ESI+)m/z 436(M+H)+.
(7－苄基硫基－嘧啶并[4,5－d]嘧啶－4－基)－(5－乙基－2－苯基硫基－苯基)－胺(7-Benzylthio-pyrimido[4,5-d]pyrimidin-4-yl)-(5-ethyl-2-phenylthio-phenyl)-amine
實例183A 5－乙基－2－苯基硫基－苯胺使硫酚鈉與1－氯基－4－乙基－2－硝基－苯反應，根據得自實例5H之程序，以1－氯基－4－乙基－2－硝基－苯取代4－氯基－3－硝基甲苯，提供4－乙基－2－硝基－1－苯基硫基－苯，將其根據得自實例5I之程序還原，提供標題化合物。Example 183A 5-Ethyl-2-phenylthio-aniline was reacted with sodium thiophene and 1-chloro-4-ethyl-2-nitro-benzene according to the procedure from Example 5H to 1-chloro 4-ethyl-2-nitro-benzene substituted 4-chloro-3-nitrotoluene to provide 4-ethyl-2-nitro-1-phenylthio-benzene, which is obtained according to The procedure of Example 5I was reduced to provide the title compound.
實例183B 4－胺基－2－苄基硫基－嘧啶－5－甲腈將2－苄基－2－硫基假脲鹽酸鹽(5.0克，24.67毫莫耳)、(乙氧基亞甲基)丙二腈(3.01克，24.67毫莫耳)及N,N－二異丙基乙胺(10.75毫升，61.68毫莫耳)在乙醇(50毫升)中之溶液，於室溫下攪拌18小時。收集所形成之固體，以乙醇洗滌，並在真空下乾燥，提供標題化合物(2.69克，45%)。Example 183B 4-Amino-2-benzylthio-pyrimidine-5-carbonitrile 2-Benzyl-2-thio pseudourea hydrochloride (5.0 g, 24.67 mmol), (E. a solution of methyl)malononitrile (3.01 g, 24.67 mmol) and N,N-diisopropylethylamine (10.75 ml, 61.68 mmol) in ethanol (50 ml), stirred at room temperature 18 hours. The resulting solid was collected, washed with EtOAc EtOAcjjjjjj
實例183C N'－(2－苄基硫基－5－氰基－嘧啶－4－基)－N,N－二甲基－甲脒使得自實例183B產物之溶液與N,N－二甲基甲醯胺二甲基縮醛反應，根據得自實例156B之程序，以得自實例183B之產物取代得自實例156B之產物，提供標題化合物。Example 183C N'-(2-Benzylthio-5-cyano-pyrimidin-4-yl)-N,N-dimethyl-formamidine as a solution of the product from Example 183B with N,N-dimethyl The product of Example 156B was substituted with the product from Example 183B to afford the title compound.
實例183D(7－苄基硫基－嘧啶并[4,5－d]嘧啶－4－基)－(5－乙基－2－苯基硫基－苯基)－胺使得自實例183A之產物與得自實例183C之產物反應，根據得自實例156C之程序，以得自實例183A之產物取代得自實例6c之產物，並以得自實例183C之產物取代得自實例156B之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。MS(ESI＋)m/z 482(M＋H)＋.Example 183D (7-Benzylthio-pyrimido[4,5-d]pyrimidin-4-yl)-(5-ethyl-2-phenylsulfanyl-phenyl)-amine from the product of Example 183A Reaction with the product from Example 183C, substituting the product from Example </RTI> </RTI> <RTI ID=0.0> The product was purified by EtOAc (EtOAc) elut MS (ESI+) m/z 482 (M+H)+.
(7－苄基硫基－嘧啶并[4,5－d]嘧啶－4－基)－[2－(4－甲氧基－苯基硫基)－5－甲基－苯基]－胺(7-Benzylthio-pyrimido[4,5-d]pyrimidin-4-yl)-[2-(4-methoxy-phenylthio)-5-methyl-phenyl]-amine
使得自實例183C之產物與2－(4－甲氧基－苯基硫基)－5－甲基－苯胺(實例118)反應，根據得自實例156C之程序，以2－(4－甲氧基－苯基硫基)－5－甲基－苯胺取代得自實例6c之產物，並以得自實例183C之產物取代得自實例156B之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。MS(ESI＋)m/z 498(M＋H)＋.The product from Example 183C was reacted with 2-(4-methoxy-phenylsulfanyl)-5-methyl-phenylamine (Example 118) according to the procedure from Example 156C to 2-(4-methoxy Substituting the product from Example 6c, and substituting the product from Example </RTI> </RTI> </RTI> <RTI ID=0.0> The title compound is provided as the trifluoroacetate salt. MS (ESI+) m/z 498 (M+H)+.
(7－苄基硫基－嘧啶并[4,5－d]嘧啶－4－基)－(5－氟基－2－苯基硫基－苯基)－胺(7-Benzylthio-pyrimido[4,5-d]pyrimidin-4-yl)-(5-fluoro-2-phenylthio-phenyl)-amine
實例185A 5－氟基－2－苯基硫基－苯胺使4－氟基－2－硝基酚根據類似實例6a、6b及6c中所述之程序反應，以苯硫醇取代4－巰基酚，並以4－氟基－2－硝基酚取代4－甲基－2－硝基酚，提供標題化合物。Example 185A 5-Fluoro-2-phenylthio-aniline 4-Fluoro-2-nitrophenol was reacted according to the procedures described in Examples 6a, 6b and 6c to replace 4-nonylphenol with phenylthiol And the 4-methyl-2-nitrophenol was replaced by 4-fluoro-2-nitrophenol to provide the title compound.
實例185B(7－苄基硫基－嘧啶并[4,5－d]嘧啶－4－基)－(5－氟基－2－苯基硫基－苯基)－胺使得自實例185A之產物與得自實例203A之產物反應，根據得自實例156C之程序，以得自實例203A之產物取代得自實例6c之產物，並以得自實例185A之產物取代得自實例156B之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。MS(ESI＋)m/z 472(M＋H)＋.Example 185B (7-Benzylthio-pyrimido[4,5-d]pyrimidin-4-yl)-(5-fluoro-2-phenylthio-phenyl)-amine from the product of Example 185A Reaction with the product from Example 203A, substituting the product from Example </RTI> </RTI> <RTI ID=0.0> The product was purified by EtOAc (EtOAc) elut MS (ESI+) m/z 472 (M+H)+.
(7－苄基硫基－嘧啶并[4,5－d]嘧啶－4－基)－[2－(4－氟苯基硫基)－5－甲基－苯基]－胺(7-Benzylthio-pyrimido[4,5-d]pyrimidin-4-yl)-[2-(4-fluorophenylthio)-5-methyl-phenyl]-amine
使得自實例183C之產物與2－(4－氟苯基硫基)－5－甲基－苯胺(實例124)反應，根據得自實例156C之程序，以2－(4－氟苯基硫基)－5－甲基－苯胺取代得自實例6c之產物，並以得自實例183C之產物取代得自實例156B之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。MS(ESI＋)m/z 486(M＋H)＋.The product from Example 183C was reacted with 2-(4-fluorophenylsulfanyl)-5-methyl-phenylamine (Example 124), according to the procedure from Example 156C, 2-(4-fluorophenylthio). -5-Methyl-aniline was substituted for the product from Example 6c, and the product from Example </RTI> </RTI> </RTI> Fluoroacetate. MS (ESI+) m/z 486 (M+H)+.
(7－苄基硫基－嘧啶并[4,5－d]嘧啶－4－基)－(5－甲基－2－間－甲苯基硫基－苯基)－胺(7-Benzylthio-pyrimido[4,5-d]pyrimidin-4-yl)-(5-methyl-2-m-tolylthio-phenyl)-amine
使得自實例183C之產物與5－甲基－2－間－甲苯基硫基－苯胺反應，根據得自實例156C之程序，以5－甲基－2－間－甲苯基硫基－苯胺取代得自實例6c之產物，並以得自實例183C之產物取代得自實例156B之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。MS(ESI＋)m/z 482(M＋H)＋.The product from Example 183C was reacted with 5-methyl-2-m-tolylthio-aniline, substituting 5-methyl-2-m-tolylthio-aniline according to the procedure from Example 156C. The product from Example 6c was obtained from the titled compound from </RTI> <RTI ID=0.0></RTI> MS (ESI+) m/z 482 (M+H)+.
(7－苄基硫基－嘧啶并[4,5－d]嘧啶－4－基)－(5－甲基－2－苯基硫基－苯基)－胺(7-Benzylthio-pyrimido[4,5-d]pyrimidin-4-yl)-(5-methyl-2-phenylthio-phenyl)-amine
使得自實例183C之產物與得自實例5I之產物反應，根據得自實例156C之程序，以得自實例5I之產物取代得自實例6c之產物，並以得自實例183C之產物取代得自實例156B之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。MS(ESI＋)m/z 468(M＋H)＋.The product from Example 183C was reacted with the product from Example 5I, substituting the product from Example 5I from the product from Example </RTI> </RTI> </RTI> The product was purified by EtOAc (EtOAc) MS (ESI+) m/z 468 (M+H)+.
3－[2－(7－苄基硫基－嘧啶并[4,5－d]嘧啶－4－基胺基)－4－甲基－苯基硫基]－酚3-[2-(7-Benzylthio-pyrimido[4,5-d]pyrimidin-4-ylamino)-4-methyl-phenylthio]-phenol
使得自實例183C之產物與3－(2－胺基－4－甲基－苯基硫基)－酚(實例129)反應，根據得自實例156C之程序，以3－(2－胺基－4－甲基－苯基硫基)－酚取代得自實例6c之產物，並以得自實例183C之產物取代得自實例156B之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。MS(ESI＋)m/z 484(M＋H)＋.The product from Example 183C was reacted with 3-(2-amino-4-methyl-phenylsulfanyl)-phenol (Example 129), according to the procedure from Example 156C, 3-(2-amino- 4-methyl-phenylthio)-phenol was substituted for the product from Example 6c, and the product from Example </RTI> </RTI> </RTI> The compound is a trifluoroacetate salt. MS (ESI+) m/z 484 (M+H)+.
(7－苄基硫基－嘧啶并[4,5－d]嘧啶－4－基)－[3－(3－甲氧基－苯基硫基)－5－甲基－苯基]－胺(7-Benzylthio-pyrimido[4,5-d]pyrimidin-4-yl)-[3-(3-methoxy-phenylthio)-5-methyl-phenyl]-amine
使得自實例183C之產物與得自實例182A之產物反應，根據得自實例156C之程序，以得自實例182A之產物取代得自實例6c之產物，並以得自實例183C之產物取代得自實例156B之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.34(s,3H),3.74(s,3H),4.52(s,2H),6.84－6.97(m,J＝1.10 Hz,3H),7.05(s,1H),7.21－7.39(m,4H),7.46－7.53(m,2H),7.61(s,1H),7.66(s,1H),8.76(s,1H),9.77(s,1H),10.47(s,1H)；MS(ESI＋)m/z＝498(M＋H)＋.The product from Example 183C was reacted with the product from Example 182A. The product from Example 6c was substituted from the product from Example </RTI></RTI> The product was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.34 (s, 3H), 3.74 (s, 3H), 4.52 (s, 2H), 6.84-6.97 (m, J = 1.10 Hz, 3H), 7.05 (s, 1H), 7.21-7.39 (m, 4H), 7.46-7.53 (m, 2H), 7.61 (s, 1H), 7.66 (s, 1H), 8.76 (s, 1H), 9.77 (s, 1H) ), 10.47 (s, 1H); MS (ESI+) m / z = 498 (M + H) +.
(7－苄基硫基－嘧啶并[4,5－d]嘧啶－4－基)－[3－(4－甲氧基－苯基硫基)－5－甲基－苯基]－胺(7-Benzylthio-pyrimido[4,5-d]pyrimidin-4-yl)-[3-(4-methoxy-phenylthio)-5-methyl-phenyl]-amine
使得自實例183C之產物與得自實例181B之產物反應，根據得自實例156C之程序，以得自實例181B之產物取代得自實例6c之產物，並以得自實例183C之產物取代得自實例156B之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.28(s,3H),3.79(s,3H),4.52(s,2H),6.83(s,1H),7.04(d,J＝8.82 Hz,2H),7.19－7.38(m,2H),7.41－7.55(m,5H),8.74(s,1H),9.75(s,1H),10.42(s,1H)；MS(ESI＋)m/z 497(M＋H)＋.The product from Example 183C was reacted with the product from Example 181B. The product from Example 6c was substituted from the product from Example </RTI></RTI> The product was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.28 (s, 3H), 3.79 (s, 3H), 4.52 (s, 2H), 6.83 (s, 1H), 7.04 (d, J = 8.82 Hz , 2H), 7.19-7.38 (m, 2H), 7.41-7.55 (m, 5H), 8.74 (s, 1H), 9.75 (s, 1H), 10.42 (s, 1H); MS (ESI+) m/z 497(M+H)+.
(7－苄基硫基－嘧啶并[4,5－d]嘧啶－4－基)－[2－(4－甲氧基－苯氧基)－5－甲基－苯基]－胺(7-Benzylthio-pyrimido[4,5-d]pyrimidin-4-yl)-[2-(4-methoxy-phenoxy)-5-methyl-phenyl]-amine
使得自實例183C之產物與得自實例116B之產物反應，根據得自實例156C之程序，以得自實例116B之產物取代得自實例6c之產物，並以得自實例183C之產物取代得自實例156B之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。MS(ESI＋)m/z 482(M＋H)＋.The product from Example 183C was reacted with the product from Example 116B, substituting the product from Example </RTI> </RTI> </RTI> </RTI> C. The product was purified by EtOAc (EtOAc) MS (ESI+) m/z 482 (M+H)+.
(7－苄基硫基－嘧啶并[4,5－d]嘧啶－4－基)－(5－甲基－2－對－甲苯基硫基－苯基)－胺(7-Benzylthio-pyrimido[4,5-d]pyrimidin-4-yl)-(5-methyl-2-p-tolylthio-phenyl)-amine
使得自實例183C之產物與5－甲基－2－對－甲苯基硫基－苯胺反應，根據得自實例156C之程序，以5－甲基－2－對－甲苯基硫基－苯胺取代得自實例6c之產物，並以得自實例183C之產物取代得自實例156B之產物，提供粗產物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。MS(ESI＋)m/z 482(M＋H)＋.The product from Example 183C was reacted with 5-methyl-2-p-tolylthio-aniline, substituting 5-methyl-2-p-tolylthio-aniline according to the procedure from Example 156C. The product from Example 6c was obtained from the titled compound from </RTI> <RTI ID=0.0></RTI> MS (ESI+) m/z 482 (M+H)+.
4－[4－(3－溴－苄氧基)－2－(嘧啶并[4,5－d]嘧啶－4－基胺基)－苯基硫基]－酚實例194A4-[4-(3-Bromo-benzyloxy)-2-(pyrimido[4,5-d]pyrimidin-4-ylamino)-phenylthio]-phenol Example 194A
N'－(5－氰基－嘧啶－4－基)－N,N－二甲基－甲脒標題化合物係製自4－胺基－5－嘧啶甲腈(Aldrich)與N,N－二甲基甲醯胺二甲基縮醛之反應，使用得自實例156B之程序，提供標題化合物。N'-(5-Cyano-pyrimidin-4-yl)-N,N-dimethyl-methylhydrazine the title compound is prepared from 4-amino-5-pyrimidinecarbonitrile (Aldrich) and N,N-di Reaction of methylformamide dimethyl acetal using the procedure from Example 156B provided the title compound.
實例194B 4－[4－(3－溴－苄氧基)－2－(嘧啶并[4,5－d]嘧啶－4－基胺基)－苯基硫基]－酚使得自實例194A之產物與得自實例15A之產物反應，根據得自實例156C之程序，以得自實例15A之產物取代得自實例6c之產物，並以得自實例194A之產物取代得自實例156B之產物，提供粗產物，使其藉HPLC以NH4OAc純化，提供標題化合物。1 H NMR(300 MHz,DMSO－D6)δ ppm：5.12(s,2H),6.64(d,J＝8.82 Hz,2H),6.93－7.04(m,1H),7.10(d,J＝8.82 Hz,2H),7.14－7.23(m,2H),7.36(t,J＝7.72 Hz,1H),7.43－7.49(m,1H),7.54(dt,J＝7.81,1.61 Hz,1H),7.65(d,J＝1.47 Hz,1H),9.04(m,1H),9.63(s,1H),10.29(m,1H)；MS(ESI－)m/z 531(M－H)－.Example 194B 4-[4-(3-Bromo-benzyloxy)-2-(pyrimido[4,5-d]pyrimidin-4-ylamino)-phenylthio]-phenol is rendered from Example 194A The product was reacted with the product from Example 15A, substituting the product from Example 15A to afford the product from Example 6c, and substituting the product from Example 194A from the product from Example 156B. The crude product was purified with EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 5.12 (s, 2H), 6.64 (d, J = 8.82 Hz, 2H), 6.93-7.04 (m, 1H), 7.10 (d, J = 8.82 Hz , 2H), 7.14 - 7.23 (m, 2H), 7.36 (t, J = 7.72 Hz, 1H), 7.43 - 7.49 (m, 1H), 7.54 (dt, J = 7.81, 1.61 Hz, 1H), 7.65 ( d, J = 1.47 Hz, 1H), 9.04 (m, 1H), 9.63 (s, 1H), 10.29 (m, 1H); MS (ESI-) m/z 531 (M-H)-.
4－[4－苄氧基－2－(嘧啶并[4,5－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-Benzyloxy-2-(pyrimido[4,5-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使得自實例194A之產物與得自實例27A之產物反應，根據得自實例156C之程序，以得自實例27A之產物取代得自實例6c之產物，並以得自實例194A之產物取代得自實例156B之產物，提供粗產物，使其藉HPLC以NH4OAc純化，提供標題化合物。1 H NMR(300 MHz,DMSO－D6)δ ppm：5.10(s,2H),6.63(d,J＝8.46 Hz,2H),6.94－7.05(m,1H),7.10(d,J＝8.82 Hz,2H),7.18(d,J＝7.72 Hz,2H),7.29－7.51(m,5H),9.05(m,1H),9.63(s,1H),9.92(s,1H),10.66(s,1H)；MS(ESI－)m/z 452(M－H)－.The product from Example 194A was reacted with the product from Example 27A, substituting the product from Example 27A from the product from Example 27A and substituting the product from Example 194A. The product was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 5.10 (s, 2H), 6.63 (d, J = 8.46 Hz, 2H), 6.94-7.05 (m, 1H), 7.10 (d, J = 8.82 Hz , 2H), 7.18 (d, J = 7.72 Hz, 2H), 7.29-7.51 (m, 5H), 9.05 (m, 1H), 9.63 (s, 1H), 9.92 (s, 1H), 10.66 (s, 1H); MS (ESI-) m/z 452 (M-H)-.
(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－[3－(4－甲氧基－苯基硫基)－5－甲基－苯基]－胺(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-[3-(4-methoxy-phenylthio)-5-methyl-phenyl]-amine
使得自實例181B之產物與得自實例36E之產物反應，使用得自實例36I之程序，以得自實例181B之產物取代得自實例36H之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(500 MHz,DMSO－D6)δ ppm：1.33(d,J＝6.71 Hz,6H),2.29(s,3H)3.25(qq,J＝7.02,6.90 Hz,1H),3.79(s,3H),6.88(s,1H),7.03(d,J＝9.16 Hz,2H),7.42(d,J＝7.93 Hz,2H),7.45(d,J＝8.54 Hz,2H),7.77(d,J＝8.54 Hz,1H),8.81(s,1H),8.95(d,J＝8.54 Hz,1H),10.74(s,1H)；MS(ESI＋)m/z 417(M＋H)＋.The product from Example 181B was reacted with the product from Example 36E, using the procedure from Example 36I, substituting the product from Example 181B from the product from Example 36H to afford crude material, The title compound is provided as the trifluoroacetate salt. 1 H NMR (500 MHz, DMSO-D6) δ ppm: 1.33 (d, J = 6.71 Hz, 6H), 2.29 (s, 3H) 3.25 (qq, J = 7.02, 6.90 Hz, 1H), 3.79 (s, 3H), 6.88 (s, 1H), 7.03 (d, J = 9.16 Hz, 2H), 7.42 (d, J = 7.93 Hz, 2H), 7.45 (d, J = 8.54 Hz, 2H), 7.77 (d, J = 8.54 Hz, 1H), 8.81 (s, 1H), 8.95 (d, J = 8.54 Hz, 1H), 10.74 (s, 1H); MS (ESI+) m/z 417 (M+H)+.
4－[3－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－5－甲基－苯基硫基]－酚實例197A4-[3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-5-methyl-phenylthio]-phenol Example 197A
4－(3－胺基－5－甲基－苯基硫基)－酚將二氯甲烷中之得自實例181B之產物(0.5克，2.0毫莫耳)，在室溫下，以三溴化硼(10毫莫耳)處理1小時。以水萃取溶液，然後使有機溶液脫水乾燥，並濃縮，提供標題化合物。4-(3-Amino-5-methyl-phenylsulfanyl)-phenol The product from Example 181B (0.5 g, 2.0 mmol) from dichloromethane. Boron (10 mmol) was treated for 1 hour. The solution was extracted with water and the organic solution was dried <RTI ID=0.0>
實例197B 4－[3－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－5－甲基－苯基硫基]－酚使得自實例197A之產物與得自實例36E之產物反應，使用得自實例36I之程序，以得自實例197A之產物取代得自實例36H之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.35(s,3H),1.33(s,3H),2.28(s,3H),3.27(qq,J＝6.86 Hz,1H),6.79－6.91(m,1H),6.86(d,J＝8.82 Hz,2H),7.30(s,1H),7.36(d,J＝8.46 Hz,2H),7.35(s,1H),7.83(d,J＝8.46 Hz,1H),8.87(s,1H),8.98(d,J＝8.82 Hz,1H),9.92(s,1H),11.06(s,1H)；MS(ESI－)m/z 403(M＋H)＋.Example 197B 4-[3-(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-5-methyl-phenylthio]-phenol from the product of Example 197A Reaction with the product from Example 36E, using the procedure from Example 36I, mp. Fluoroacetate. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (s, 3H), 1.33 (s, 3H), 2.28 (s, 3H), 3.27 (qq, J = 6.86 Hz, 1H), 6.79-6.91 (m, 1H), 6.86 (d, J = 8.82 Hz, 2H), 7.30 (s, 1H), 7.36 (d, J = 8.46 Hz, 2H), 7.35 (s, 1H), 7.83 (d, J = 8.46 Hz, 1H), 8.87 (s, 1H), 8.98 (d, J = 8.82 Hz, 1H), 9.92 (s, 1H), 11.06 (s, 1H); MS (ESI-) m/z 403 (M+H) )+.
4－[5－(3－氟－苄氧基)－2－(4－羥基－苯基硫基)－苯基胺基]－7－甲基－吡啶并[2,3－d]嘧啶－6－甲腈4-[5-(3-Fluoro-benzyloxy)-2-(4-hydroxy-phenylsulfanyl)-phenylamino]-7-methyl-pyrido[2,3-d]pyrimidine- 6-carbonitrile
實例198A N'－(3,5－二氰基－6－甲基－吡啶－2－基)－N,N－二甲基－甲脒將2－胺基－6－甲基－吡啶－3,5－二甲腈(0.158克，1.0毫莫耳)與N,N－二甲基甲醯胺二甲基縮醛(0.119克，1.0毫莫耳)在甲苯(10毫升)中之溶液，於回流下加熱6小時。於冷卻至室溫後，使溶液在真空下濃縮，提供標題化合物，為褐色固體(0.2克，94%)。Example 198A N'-(3,5-Dicyano-6-methyl-pyridin-2-yl)-N,N-dimethyl-formamidine 2-Amino-6-methyl-pyridine-3 a solution of 5-dicarbonitrile (0.158 g, 1.0 mmol) and N,N-dimethylformamide dimethyl acetal (0.119 g, 1.0 mmol) in toluene (10 mL). Heat under reflux for 6 hours. After cooling to rt, EtOAc (EtOAc)
實例198B 4－[5－(3－氟－苄氧基)－2－(4－羥基－苯基硫基)－苯基胺基]－7－甲基－吡啶并[2,3－d]嘧啶－6－甲腈使實例198A之產物與實例10B之產物反應，使用實例10F之程序，以實例198A之產物取代實例10E之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(18毫克，29%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.82(s,3H),5.13(s,2H),6.64(d,J＝8.46 Hz,2H),6.99(d,J＝9.56 Hz,1H),7.09(d,J＝8.82 Hz,2H),7.12－7.21(m,3H),7.29(d,J＝7.72 Hz,2H),7.39－7.53(m,1H),8.63(s,1H),9.36(s,1H),9.64(s,1H),10.33(s,1H).Example 198B 4-[5-(3-Fluoro-benzyloxy)-2-(4-hydroxy-phenylthio)-phenylamino]-7-methyl-pyrido[2,3-d] Pyrimidine-6-carbonitrile The product of Example 198A was reacted with the product of Example 10B, using the procedure of Example 10F, substituting the product of Example 198A. , is trifluoroacetate (18 mg, 29%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.82 (s, 3H), 5.13 (s, 2H), 6.64 (d, J = 8.46 Hz, 2H), 6.99 (d, J = 9.56 Hz, 1H) ), 7.09 (d, J = 8.82 Hz, 2H), 7.12 - 7.21 (m, 3H), 7.29 (d, J = 7.72 Hz, 2H), 7.39 - 7.53 (m, 1H), 8.63 (s, 1H) , 9.36 (s, 1H), 9.64 (s, 1H), 10.33 (s, 1H).
[3－(3－氟－苄氧基)－苯基]－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺實例199A[3-(3-Fluoro-benzyloxy)-phenyl]-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine Example 199A
(3－氟－苄氧基)－3－硝基－苯將3－硝基－酚(0.278克，2.0毫莫耳)、1－溴基甲基－3－氟－苯(0.258毫升，2.1毫莫耳)、碳酸鉀(0.553克，4.0毫莫耳)及碘化四丁基銨(0.001克)在N,N－二甲基甲醯胺(5毫升)中之溶液，於室溫下攪拌16小時。然後將冰水(10毫升)添加至溶液中，並藉過濾收集所形成之固體，且在真空烘箱中乾燥，以定量產率提供標題化合物。(3-Fluoro-benzyloxy)-3-nitro-benzene 3-nitro-phenol (0.278 g, 2.0 mmol), 1-bromomethyl-3-fluoro-benzene (0.258 ml, 2.1 a solution of potassium carbonate (0.553 g, 4.0 mmol) and tetrabutylammonium iodide (0.001 g) in N,N-dimethylformamide (5 ml) at room temperature Stir for 16 hours. Ice water (10 mL) was then added to the solution and the solid formed was collected by filtration and dried in vacuo to afford title compound.
實例199B(3－氟－苄氧基)－3－胺基－苯將得自實例199A之產物(0.494克，2.0毫莫耳)、鐵粉(0.56克，10.0毫莫耳)及氯化銨(0.54克，10.0毫莫耳)在甲醇(20毫升)、四氫呋喃(20毫升)及水(10毫升)溶液中之溶液加熱至回流，歷經2小時。使所形成之混合物經過矽藻土墊過濾，並濃縮濾液。然後添加醋酸乙酯，攪拌30分鐘，過濾，及在真空下濃縮，提供標題化合物(0.405克，93%)。Example 199B (3-fluoro-benzyloxy)-3-amino-benzene The product from Example 199A (0.494 g, 2.0 mmol), iron powder (0.56 g, 10.0 mmol) and ammonium chloride A solution of (0.54 g, 10.0 mmol) in methanol (20 mL), EtOAc (EtOAc) The resulting mixture was filtered through a pad of Celite and concentrated. Ethyl acetate was then added, stirred for 30 min.
實例199C[3－(3－氟－苄氧基)－苯基]－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺使實例199B之產物與實例10B之產物反應，使用實例10F之程序，以實例199B之產物取代實例10E之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(32毫克，89%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.74(s,3H),5.18(s,2H),6.98(m,1H),7.18(m,1H),7.42(m,6H),7.79(d,J＝8.46 Hz,1H),8.92(s,1H),9.00(d,J＝8.82 Hz,1H),11.16(s,1H)；MS(ESI＋)m/z 361(M＋H)＋.Example 199C [3-(3-Fluoro-benzyloxy)-phenyl]-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine The product of Example 199B and Example 10B The product was reacted, the product of Example </RTI><RTIID=0.0>#</RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI> 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.74 (s, 3H), 5.18 (s, 2H), 6.98 (m, 1H), 7.18 (m, 1H), 7.42 (m, 6H), 7.79 (d, J = 8.46 Hz, 1H), 8.92 (s, 1H), 9.00 (d, J = 8.82 Hz, 1H), 11.16 (s, 1H); MS (ESI+) m/z 361 (M+H)+.
[3－(3－氟－苄氧基)－苯基]－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺[3-(3-Fluoro-benzyloxy)-phenyl]-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
使得自實例199B之產物與得自實例36E之產物反應，使用得自實例36I之程序，以得自實例199B之產物取代得自實例36H之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.34(d,J＝6.99 Hz,6H),3.26(m,1H),5.18(s,2H),6.93(m,1H),7.17(m,1H),7.42(m,6H),7.79(d,J＝8.46 Hz,1H),8.85(s,1H),9.00(d,J＝8.46 Hz,1H),10.76(s,1H)；MS(ESI＋)m/z 389(M＋H)＋.The product from Example 199B was reacted with the product from Example 36E, using the procedure from Example 36I. The title compound is provided as the trifluoroacetate salt. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J = 6.99 Hz, 6H), 3.26 (m, 1H), 5.18 (s, 2H), 6.93 (m, 1H), 7.17 (m) , 1H), 7.42 (m, 6H), 7.79 (d, J = 8.46 Hz, 1H), 8.85 (s, 1H), 9.00 (d, J = 8.46 Hz, 1H), 10.76 (s, 1H); MS (ESI+) m/z 389 (M+H)+.
[3－(3－氟－苄氧基)－苯基]－吡啶并[2,3－d]嘧啶－4－基－胺[3-(3-Fluoro-benzyloxy)-phenyl]-pyrido[2,3-d]pyrimidin-4-yl-amine
使實例199B之產物與實例57A之產物反應，使用實例57E之程序，以實例199B之產物取代實例57D之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：5.18(s,2H),6.98(m,1H),7.18(m,1H),7.42(m,6H),7.87(dd,J＝8.27,4.60 Hz,1H),8.93(s,1H),9.14(m,2H),11.12(s,1H)；MS(ESI＋)m/z 347(M＋H)＋.The product of Example 199B was reacted with the product of Example </RTI><RTIID=0.0></RTI></RTI> salt. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 5.18 (s, 2H), 6.98 (m, 1H), 7.18 (m, 1H), 7.42 (m, 6H), 7.78 (dd, J = 8.27, 4.60 Hz, 1H), 8.93 (s, 1H), 9.14 (m, 2H), 11.12 (s, 1H); MS (ESI+) m/z 347 (M+H)+.
[3－(4－氟－苄氧基)－苯基]－吡啶并[2,3－d]嘧啶－4－基－胺[3-(4-Fluoro-benzyloxy)-phenyl]-pyrido[2,3-d]pyrimidin-4-yl-amine
實例202A 3－(4－氟－苄氧基)－苯胺使3－硝基－酚與1－溴基甲基－4－氟－苯反應，根據得自實例199A之程序，以1－溴基甲基－4－氟－苯取代1－溴基甲基－3－氟－苯，然後根據得自實例199B之程序還原，提供標題化合物。Example 202A 3-(4-Fluoro-benzyloxy)-phenylamine 3-nitro-phenol was reacted with 1-bromomethyl-4-fluoro-benzene according to the procedure from Example 199A, 1-bromo. Methyl-4-fluoro-benzene was substituted for 1-bromomethyl-3-fluoro-benzene, which was then purified according to the procedure from Example 199.
實例202B[3－(4－氟－苄氧基)－苯基]－吡啶并[2,3－d]嘧啶－4－基－胺使實例202A之產物與實例57A之產物反應，使用實例57E之程序，以實例202A之產物取代實例57D之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(20毫克，58%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：5.13(s,2H),6.92(m,1H),7.24(m,2H),7.38(m,2H),7.55(m,3H),7.80(dd,J＝8.27,4.60 Hz,1H),8.87(s,1H),9.07(dd,J＝8.27,1.65 Hz,1H),9.12(dd,J＝4.41,1.84 Hz,1H),10.69(s,1H)；MS(ESI＋)m/z 347(M＋H)＋.Example 202B [3-(4-Fluoro-benzyloxy)-phenyl]-pyrido[2,3-d]pyrimidin-4-yl-amine The product of Example 202A was reacted with the product of Example 57A using Example 57E </RTI></RTI><RTIID=0.0></RTI></RTI></RTI><RTIgt;</RTI><RTIgt; 1 H NMR (300 MHz, DMSO-D6) δ ppm: 5.13 (s, 2H), 6.92 (m, 1H), 7.24 (m, 2H), 7.38 (m, 2H), 7.55 (m, 3H), 7.80 (dd, J = 8.27, 4.60 Hz, 1H), 8.87 (s, 1H), 9.07 (dd, J = 8.27, 1.65 Hz, 1H), 9.12 (dd, J = 4.41, 1.84 Hz, 1H), 10.69 ( s, 1H); MS (ESI+) m/z 347 (M+H)+.
[3－(3,5－二氟－苄氧基)－苯基]－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺[3-(3,5-Difluoro-benzyloxy)-phenyl]-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
實例203A 3－(3,5－二氟－苄氧基)－苯胺使3－硝基－酚與1－溴基甲基－3,5－二氟－苯反應，根據得自實例199A之程序，以1－溴基甲基－3,5－二氟－苯取代1－溴基甲基－3－氟－苯，然後根據得自實例199B之程序還原，提供標題化合物。Example 203A 3-(3,5-Difluoro-benzyloxy)-phenylamine The 3-nitro-phenol was reacted with 1-bromomethyl-3,5-difluoro-benzene according to the procedure from Example 199A. Substituting 1-bromomethyl-3,5-difluoro-benzene for 1-bromomethyl-3-fluoro-benzene followed by reduction according to the procedure obtained from Example 199B afforded the title compound.
實例203B[3－(3,5－二氟－苄氧基)－苯基]－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺使得自實例203A之產物與得自實例36E之產物反應，使用得自實例36I之程序，以得自實例203A之產物取代得自實例36H之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(26毫克，67%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.35(d,J＝6.99 Hz,6H),3.26(m,1H),5.19(s,2H),6.95(m,1H),7.20(m,3H),7.38(m,2H),7.54(s,1H),7.82(d,J＝8.46 Hz,1H),8.86(s,1H),9.02(d,J＝8.46 Hz,1H),10.89(s,1H)；MS(ESI＋)m/z 407(M＋H)＋.Example 203B [3-(3,5-Difluoro-benzyloxy)-phenyl]-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-amine is rendered from Example 203A The product was reacted with the product from Example 36, using the procedure from Example 36I. It was trifluoroacetate (26 mg, 67%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.99 Hz, 6H), 3.26 (m, 1H), 5.19 (s, 2H), 6.95 (m, 1H), 7.20 (m) , 3H), 7.38 (m, 2H), 7.54 (s, 1H), 7.82 (d, J = 8.46 Hz, 1H), 8.86 (s, 1H), 9.02 (d, J = 8.46 Hz, 1H), 10.89 (s, 1H); MS (ESI+) m/z 407 (M+H)+.
[3－(3,5－二氟－苄氧基)－苯基]－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺[3-(3,5-Difluoro-benzyloxy)-phenyl]-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
使實例203A之產物與實例10B之產物反應，使用實例10F之程序，以實例203A之產物取代實例10E之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.73(s,3H),5.19(s,2H),6.95(m,1H),7.21(m,3H),7.38(m,2H),7.55(s,1H),7.75(d,J＝8.46 Hz,1H),8.87(s,1H),8.98(d,J＝8.46 Hz,1H),10.90(s,1H)；MS(ESI＋)m/z 379(M＋H)＋.The product of Example 203A was reacted with the product of Example </RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI> . 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.73 (s, 3H), 5.19 (s, 2H), 6.95 (m, 1H), 7.21 (m, 3H), 7.38 (m, 2H), 7.55 (s, 1H), 7.75 (d, J = 8.46 Hz, 1H), 8.87 (s, 1H), 8.98 (d, J = 8.46 Hz, 1H), 10.90 (s, 1H); MS (ESI+) m/ z 379(M+H)+.
[3－(3,5－二氟－苄氧基)－苯基]－吡啶并[2,3－d]嘧啶－4－基－胺[3-(3,5-Difluoro-benzyloxy)-phenyl]-pyrido[2,3-d]pyrimidin-4-yl-amine
使實例203A之產物與實例57A之產物反應，使用實例57E之程序，以實例203A之產物取代實例57D之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：5.19(s,2H),6.94(m,1H),7.21(m,3H),7.39(d,J＝5.15 Hz,2H),7.58(s,1H),7.81(dd,J＝8.09,4.41 Hz,1H),8.87(s,1H),9.10(m,2H),10.79(s,1H)；MS(ESI＋)m/z 365(M＋H)＋.The product of Example 203A was reacted with the product of Example </RTI><RTIID=0.0></RTI></RTI> salt. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 5.19 (s, 2H), 6.94 (m, 1H), 7.21 (m, 3H), 7.39 (d, J = 5.15 Hz, 2H), 7.58 (s) ,1H), 7.81 (dd, J=8.09, 4.41 Hz, 1H), 8.87 (s, 1H), 9.10 (m, 2H), 10.79 (s, 1H); MS (ESI+) m/z 365 (M+H) +.
4－[3－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基甲基]－苯甲腈4-[3-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl]-benzonitrile
實例206A 4－(3－胺基－苯氧基甲基)－苯甲腈使3－硝基－酚與4－溴基甲基－苯甲腈反應，根據得自實例199A之程序，以4－溴基甲基－苯甲腈取代1－溴基甲基－3－氟－苯，然後根據得自實例199B之程序還原，提供標題化合物。Example 206A 4-(3-Amino-phenoxymethyl)-benzonitrile The 3-nitro-phenol was reacted with 4-bromomethyl-benzonitrile according to the procedure from Example 199A. -Bromomethyl-benzonitrile was substituted for 1-bromomethyl-3-fluoro-benzene and then purified according to the procedure obtained from Example 199B.
實例206B 4－[3－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基甲基]－苯甲腈使實例206A之產物與實例10B之產物反應，使用實例10F之程序，以實例206A之產物實例10E之產物取代，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.71(s,3H),5.27(s,2H),6.92(m,1H),7.38(m,2H),7.59(s,1H),7.68(m,3H),7.89(d,J＝8.46 Hz,2H),8.83(s,1H),8.95(d,J＝8.82 Hz,1H),10.64(s,1H)；MS(ESI＋)m/z 368(M＋H)＋.Example 206B 4-[3-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl]-benzonitrile The product of Example 206A and Example 10B The product was subjected to the title compound, mp. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.71 (s, 3H), 5.27 (s, 2H), 6.92 (m, 1H), 7.38 (m, 2H), 7.59 (s, 1H), 7.68 (m, 3H), 7.89 (d, J = 8.46 Hz, 2H), 8.83 (s, 1H), 8.95 (d, J = 8.82 Hz, 1H), 10.64 (s, 1H); MS (ESI+) m/ z 368(M+H)+.
4－[3－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基甲基]－苯甲腈4-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl]-benzonitrile
使實例206A之產物與實例57A之產物反應，使用實例57E之程序，以實例206A之產物取代實例57D之產物，提供粗製標題化合物，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：5.27(s,2H),6.93(m,1H),7.38(m,2H)7.60(s,1H),7.67(d,J＝8.46 Hz,2H),7.80(dd,J＝8.46,4.41 Hz,1H),7.90(d,J＝8.46 Hz,2H),8.86(s,1H),9.07(dd,J＝8.46,1.65 Hz,1H),9.13(dd,J＝4.41,1.65 Hz,1H),10.72(s,1H)；MS(ESI＋)m/z 354(M＋H)＋.The product of Example </RTI><RTIID=0.0></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; salt. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 5.27 (s, 2H), 6.93 (m, 1H), 7.38 (m, 2H) 7.60 (s, 1H), 7.67 (d, J = 8.46 Hz, 2H), 7.80 (dd, J = 8.46, 4.41 Hz, 1H), 7.90 (d, J = 8.46 Hz, 2H), 8.86 (s, 1H), 9.07 (dd, J = 8.46, 1.65 Hz, 1H), 9.13 (dd, J = 4.41, 1.65 Hz, 1H), 10.72 (s, 1H); MS (ESI+) m/z 354 (M+H)+.
3－[3－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基甲基]－苯甲腈3-[3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl]-benzonitrile
實例208A 3－(3－胺基－苯氧基甲基)－苯甲腈使3－硝基－酚與3－溴基甲基－苯甲腈反應，根據得自實例199A之程序，以3－溴基甲基－苯甲腈取代1－溴基甲基－3－氟－苯，然後根據得自實例199B之程序還原，提供標題化合物。Example 208A 3-(3-Amino-phenoxymethyl)-benzonitrile The 3-nitro-phenol was reacted with 3-bromomethyl-benzonitrile according to the procedure from Example 199A. -Bromomethyl-benzonitrile was substituted for 1-bromomethyl-3-fluoro-benzene and then purified according to the procedure obtained from Example 199B.
實例208B 3－[3－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基甲基]－苯甲腈使得自實例208A之產物與得自實例36E之產物反應，使用得自實例36I之程序，以得自實例208A之產物取代得自實例36H之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(22毫克，56%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.34(d,J＝6.99 Hz,6H),3.26(m,1H),5.22(s,2H),6.93(m,1H),7.38(m,2H),7.62(m,2H),7.77(d,J＝8.46 Hz,1H),7.84(m,2H),7.95(s,1H),8.83(s,1H),8.99(d,J＝8.46 Hz,1H),10.67(s,1H)；MS(ESI＋)m/z 396(M＋H)＋.Example 208B 3-[3-(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl]-benzonitrile afforded the product from Example 208A From the product of Example 36E, the title compound was obtained from trifluoroacetic acid. Salt (22 mg, 56%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J = 6.99 Hz, 6H), 3.26 (m, 1H), 5.22 (s, 2H), 6.93 (m, 1H), 7.38 (m) , 2H), 7.62 (m, 2H), 7.77 (d, J = 8.46 Hz, 1H), 7.84 (m, 2H), 7.95 (s, 1H), 8.83 (s, 1H), 8.99 (d, J = 8.46 Hz, 1H), 10.67 (s, 1H); MS (ESI+) m/z 396 (M+H)+.
2－[3－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基甲基]－苯甲腈2-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl]-benzonitrile
實例209A 2－(3－胺基－苯氧基甲基)－苯甲腈使3－硝基－酚與2－溴基甲基－苯甲腈反應，根據得自實例199A之程序，以2－溴基甲基－苯甲腈取代1－溴基甲基－3－氟－苯，然後根據得自實例199B之程序還原，提供標題化合物。Example 209A 2-(3-Amino-phenoxymethyl)-benzonitrile The 3-nitro-phenol was reacted with 2-bromomethyl-benzonitrile according to the procedure from Example 199A. -Bromomethyl-benzonitrile was substituted for 1-bromomethyl-3-fluoro-benzene and then purified according to the procedure obtained from Example 199B.
實例209B 2－[3－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基甲基]－苯甲腈使得自實例209A之產物與得自實例36E之產物反應，使用得自實例36I之程序，以得自實例209A之產物取代得自實例36H之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：5.30(s,2H),7.02(m,1H),7.42(m,2H),7.59(m,2H),7.78(m,2H),7.85(dd,J＝8.46,4.41 Hz,1H),7.94(d,J＝7.72 Hz,1H),8.92(s,1H),9.14(m,2H),11.03(s,1H)；MS(ESI＋)m/z 354(M＋H)＋.Example 209B 2-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl]-benzonitrile was allowed to react from the product from Example 209A with the product from Example 36. The title compound was obtained as the trifluoroacetic acid salt from the titled compound. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 5.30 (s, 2H), 7.02 (m, 1H), 7.42 (m, 2H), 7.59 (m, 2H), 7.78 (m, 2H), 7.85 (dd, J=8.46, 4.41 Hz, 1H), 7.94 (d, J=7.72 Hz, 1H), 8.92 (s, 1H), 9.14 (m, 2H), 11.03 (s, 1H); MS (ESI+) m/z 354(M+H)+.
(3－苄氧基－苯基)－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺(3-benzyloxy-phenyl)-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
實例210A 3－苄氧基－苯胺使3－硝基－酚與溴基甲基－苯反應，根據得自實例199A之程序，以溴基甲基－苯取代1－溴基甲基－3－氟－苯，然後根據得自實例199B之程序還原，提供標題化合物。Example 210A 3-Benzyloxy-phenylamine The 3-nitro-phenol was reacted with bromomethyl-benzene, and 1-bromomethyl-3- was substituted with bromomethyl-benzene according to the procedure from Example 199A. Fluorine-benzene was then reduced according to the procedure from Example 199B to provide the title compound.
實例210B(3－苄氧基－苯基)－(7－異丙基－吡啶并[2.3－d]嘧啶－4－基)－胺使得自實例210A之產物與得自實例36E之產物反應，使用得自實例36I之程序，以得自實例210A之產物取代得自實例36H之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(5毫克，10%)。1 H NMR(500 MHz,DMSO－D6)δ ppm：1.33(d,J＝6.84 Hz,6H),3.25(qt,J＝6.84 Hz,1H),5.13(s,2H),6.89－6.94(m,J＝2.20,2.20 Hz,1H),7.33－7.41(m,5H),7.45－7.48(m,J＝7.32 Hz,2H),7.54－7.58(m,J＝2.44,2.44 Hz,1H),7.76(d,J＝8.30 Hz,1H),8.84(s,1H),9.02(d,J＝8.30 Hz,1H)；MS ESI＋ m/z 371(M＋H)＋,ESI－ m/z 369(M－H)－.Example 210B (3-benzyloxy-phenyl)-(7-isopropyl-pyrido[2.3-d]pyrimidin-4-yl)-amine allowed the product from Example 210A to react with the product from Example 36E. The product from Example 36I was used to give the title compound as a trifluoroacetate (5 mg, 10%). ). 1 H NMR (500 MHz, DMSO-D6) δ ppm: 1.33 (d, J = 6.84 Hz, 6H), 3.25 (qt, J = 6.84 Hz, 1H), 5.13 (s, 2H), 6.89-6.94 (m) , J=2.20, 2.20 Hz, 1H), 7.33-7.41 (m, 5H), 7.45-7.48 (m, J=7.32 Hz, 2H), 7.54-7.58 (m, J=2.44, 2.44 Hz, 1H), 7.76 (d, J = 8.30 Hz, 1H), 8.84 (s, 1H), 9.02 (d, J = 8.30 Hz, 1H); MS ESI+ m/z 371 (M+H)+, ESI- m/z 369 (M -H)-.
[3－(3－溴－苄氧基)－苯基]－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺[3-(3-Bromo-benzyloxy)-phenyl]-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
實例211A 3－(3－溴－苄氧基)－苯胺使3－硝基－酚與1－溴基－3－溴基甲基－苯反應，根據得自實例199A之程序，以1－溴基－3－溴基甲基－苯取代1－溴基甲基－3－氟－苯，然後根據得自實例199B之程序還原，提供標題化合物。Example 211A 3-(3-Bromo-benzyloxy)-aniline 3-nitro-phenol was reacted with 1-bromo-3-bromomethyl-benzene according to the procedure from Example 199A to 1-bromo The benzyl-3-bromomethyl-benzene was substituted for 1-bromomethyl-3-fluoro-benzene, which was then purified according to the procedure obtained from Example 199B.
實例211B[3－(3－溴－苄氧基)－苯基]－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺使得自實例211A之產物與得自實例36E之產物反應，使用得自實例36I之程序，以得自實例211A之產物取代得自實例36H之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(1毫克，1%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.34(d,J＝6.9wHz,6H),5.16(s,2H),6.94(td,J＝4.50,2.39 Hz,1H),7.39(td,J＝7.63,3.86 Hz,3H),7.46－7.51(m,1H),7.53－7.57(m,2H),7.69(s,1H),7.80(d,J＝8.46 Hz,1H),8.86(s,1H),9.01(d,J＝8.46 Hz,1H),10.84(s,1H)；MS ESI＋ m/z 451(M＋H)＋,ESIwm/z 449(M－H)－.Example 211B [3-(3-Bromo-benzyloxy)-phenyl]-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-amine was obtained from the product of Example 211A The product from Example 36E was used to give the title compound as a trifluorobenzene. Acetate (1 mg, 1%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J = 6.9 wHz, 6H), 5.16 (s, 2H), 6.94 (td, J = 4.50, 2.39 Hz, 1H), 7.39 (td) , J=7.63, 3.86 Hz, 3H), 7.46-7.51 (m, 1H), 7.53-7.57 (m, 2H), 7.69 (s, 1H), 7.80 (d, J = 8.46 Hz, 1H), 8.86 ( s, 1H), 9.01 (d, J = 8.46 Hz, 1H), 10.84 (s, 1H); MS ESI+ m/z 451 (M+H)+, ESIwm/z 449 (M-H)-.
(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－[3－(3－甲氧基－苄氧基)－苯基]－胺(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-[3-(3-methoxy-benzyloxy)-phenyl]-amine
實例212A 3－(3－甲氧基－苄氧基)－苯胺使3－硝基－酚與1－溴基甲基－3－甲氧基－苯反應，根據得自實例199A之程序，以1－溴基甲基－3－甲氧基－苯取代1－溴基甲基－3－氟－苯，然後根據得自實例199B之程序還原，提供標題化合物。Example 212A 3-(3-Methoxy-benzyloxy)-phenylamine The 3-nitro-phenol was reacted with 1-bromomethyl-3-methoxy-benzene according to the procedure from Example 199A. 1-Bromomethyl-3-methoxy-benzene was substituted for 1-bromomethyl-3-fluoro-benzene, which was then purified according to the procedure from Example 199.
實例212B(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－[3－(3－甲氧基－苄氧基)－苯基]－胺使得自實例212A之產物與得自實例36E之產物反應，使用得自實例36I之程序，以得自實例212A之產物取代得自實例36H之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(8毫克，9%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.35(d,J＝6.99 Hz,6H),3.76(s,3H),5.12(s,2H),6.87－6.98(m,2H),7.00－7.06(m,2H),7.36(dt,J＝19.85,8.09 Hz,3H),7.52(s,1H),7.82(d,J＝8.82 Hz,1H),8.88(s,1H),9.02(d,J＝8.46 Hz,1H),10.94(s,1H)；MS ESI＋ m/z 401(M＋H)＋,ESI－ m/z 399(M－H)－.Example 212B (7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-[3-(3-methoxy-benzyloxy)-phenyl]-amine is rendered from Example 212A The product was reacted with the product from Example 36, using the procedure from Example 36I. Trifluoroacetate (8 mg, 9%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.99 Hz, 6H), 3.76 (s, 3H), 5.12 (s, 2H), 6.87-6.98 (m, 2H), 7.00 -7.06 (m, 2H), 7.36 (dt, J = 19.85, 8.09 Hz, 3H), 7.52 (s, 1H), 7.82 (d, J = 8.82 Hz, 1H), 8.88 (s, 1H), 9.02 ( d, J = 8.46 Hz, 1H), 10.94 (s, 1H); MS ESI + m/z 401 (M+H) +, ESI- m/z 399 (M-H)-.
[3－(4－溴－苄氧基)－苯基]－吡啶并[2,3－d]嘧啶－4－基－胺[3-(4-Bromo-benzyloxy)-phenyl]-pyrido[2,3-d]pyrimidin-4-yl-amine
實例213A 3－(4－溴－苄氧基)－苯胺使3－硝基－酚與1－溴基－4－溴基甲基－苯反應，根據得自實例199A之程序，以1－溴基－4－溴基甲基－苯取代1－溴基甲基－3－氟－苯，然後根據得自實例199B之程序還原，提供標題化合物。Example 213A 3-(4-Bromo-benzyloxy)-aniline 3-nitro-phenol was reacted with 1-bromo-4-bromomethyl-benzene according to the procedure from Example 199A to 1-bromo Substituted 4-bromomethyl-benzene substituted 1-bromomethyl-3-fluoro-benzene, which was then purified according to the procedure from Example 199B to afford the title compound.
實例213B[3－(4－溴－苄氧基)－苯基]－吡啶并[2,3－d]嘧啶－4－基－胺使得自實例213A之產物與得自實例36E之產物反應，使用得自實例36I之程序，以得自實例213A之產物取代得自實例36H之產物，提供粗製物質，使其藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：5.13(s,2H),6.82(dd,J＝8.09,1.84 Hz,1H),7.32(t,J＝8.09 Hz,1H),7.45(d,J＝8.46 Hz,3H),7.61(d,J＝8.46 Hz,2H),7.64－7.71(m,2H),9.01(dd,J＝8.46,1.84 Hz,1H),9.08(dd,J＝4.23,1.65 Hz,1H),10.01(s,1H)；MS ESI＋ m/z 407(M＋H)＋,ESI＋ m/z 429(M＋Na)＋,ESI－ m/z 405(M－H)－.Example 213B [3-(4-Bromo-benzyloxy)-phenyl]-pyrido[2,3-d]pyrimidin-4-yl-amine allowed the product from Example 213A to react with the product from Example 36E. The title compound was obtained as the trifluoroacetic acid salt from the titled compound. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 5.13 (s, 2H), 6.82 (dd, J = 8.09, 1.84 Hz, 1H), 7.32 (t, J = 8.09 Hz, 1H), 7.45 (d) , J=8.46 Hz, 3H), 7.61 (d, J=8.46 Hz, 2H), 7.64-7.71 (m, 2H), 9.01 (dd, J=8.46, 1.84 Hz, 1H), 9.08 (dd, J= 4.23, 1.65 Hz, 1H), 10.01 (s, 1H); MS ESI+ m/z 407 (M+H)+, ESI+ m/z 429 (M+Na)+, ESI- m/z 405 (M-H)-.
[2－(4－胺基－苯基硫基)－5－苄氧基－苯基]－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺[2-(4-Amino-phenylthio)-5-benzyloxy-phenyl]-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
實例214A 4－苄氧基－1－氯基－2－硝基－苯將4－氯基－3－硝基－酚(2.0克，11.5毫莫耳)、1－溴基甲基－苯(2.01克，11.5毫莫耳)、碳酸鉀(1.65克，12.0毫莫耳)及碘化四丁基銨(0.005克，0.0135毫莫耳)在N,N－二甲基甲醯胺(5毫升)中之溶液，於室溫下攪拌16小時。然後將冰水(10毫升)添加至溶液中，並藉過濾收集所形成之固體，且在真空烘箱中乾燥，提供標題化合物(3.0克，99%)。Example 214A 4-Benzyloxy-1-chloro-2-nitro-benzene 4-chloro-3-nitro-phenol (2.0 g, 11.5 mmol), 1-bromomethyl-benzene ( 2.01 g, 11.5 mmol, potassium carbonate (1.65 g, 12.0 mmol) and tetrabutylammonium iodide (0.005 g, 0.0135 mmol) in N,N-dimethylformamide (5 ml) The solution was stirred at room temperature for 16 hours. Ice water (10 mL) was then added to the solution, and the solid formed was collected by filtration and dried in vacuo to afford title compound (3.0 g, 99%).
實例214B 4－(4－苄氧基－2－硝基－苯基硫基)－苯胺將實例214A中所製成之化合物(1.0克，3.80毫莫耳)、4－胺基硫酚(0.5克，4.00毫莫耳)、碳酸銫(1.3克，4毫莫耳)在二甲基甲醯胺(10毫升)中之溶液，於40℃下加熱16小時。然後將冰水(50毫升)添加至溶液中，並將所形成之漿液以醋酸乙酯(100毫升)處理。分離液層，並以10%碳酸氫鈉與10%氯化鈉洗滌有機層，接著以無水硫酸鈉脫水乾燥。過濾乾燥劑，及在真空下移除溶劑，留下橘色油，為標題化合物(1.1克，83%)。Example 214B 4-(4-Benzyloxy-2-nitro-phenylsulfanyl)-phenylamine The compound prepared in Example 214A (1.0 g, 3.80 mmol), 4-aminothiophenol (0.5) A solution of ketone (4.00 mmol), cesium carbonate (1.3 g, 4 mmol) in dimethylformamide (10 mL) Ice water (50 ml) was then added to the solution and the resulting syrup was treated with ethyl acetate (100 mL). The liquid layer was separated, and the organic layer was washed with 10% sodium hydrogen carbonate and 10% sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was filtered, and the solvent was evaporated.
實例214C[4－(4－苄氧基－2－硝基－苯基硫基)－苯基]－胺甲基酸第三－丁酯將得自實例214B化合物之溶液(1.1克，3.1毫莫耳)以Boc酐(0.9克，4.00毫莫耳)在二氧陸圜(15毫升)中處理，並於回流下加熱數小時。隔天，在真空下移除溶劑，留下標題化合物，為淡黃褐色油(1.4克，100%)。Example 214C [4-(4-Benzyloxy-2-nitro-phenylsulfanyl)-phenyl]-aminomethyl acid tert-butyl ester A solution of the compound from Example 214B (1.1 g, 3.1 m. Mohr) was treated with Boc anhydride (0.9 g, 4.00 mmol) in dioxane (15 mL) and heated under reflux for several hours. The solvent was removed in vacuo to give the title compound as a pale brown oil (1. 4g, 100%).
實例214D[4－(2－胺基－4－苄氧基－苯基硫基)－苯基]－胺甲基酸第三－丁酯將實例214C之產物(1.4克，3.09毫莫耳)、鐵粉(0.70克，12毫莫耳)及氯化銨(0.18克，3.41毫莫耳)在甲醇(10毫升)、四氫呋喃(10毫升)及水(5毫升)溶液中之溶液加熱至回流，歷經1.5小時。以甲醇(50毫升)稀釋所形成之混合物，並經過矽藻土墊過濾。使濾液在真空下濃縮成體積10毫升，以水(50毫升)稀釋溶液，並以醋酸乙酯(2 x 50毫升)萃取。以10%氯化鈉洗滌合併之萃液，然後以硫酸鎂脫水乾燥，過濾，及在真空下濃縮，提供標題化合物(1.1克，90%)。Example 214D [4-(2-Amino-4-benzyloxy-phenylsulfanyl)-phenyl]-aminomethyl acid tert-butyl ester The product of Example 214C (1.4 g, 3.09 mmol) , iron powder (0.70 g, 12 mmol) and ammonium chloride (0.18 g, 3.41 mmol) in a solution of methanol (10 ml), tetrahydrofuran (10 ml) and water (5 ml) was heated to reflux After 1.5 hours. The resulting mixture was diluted with methanol (50 mL) and filtered through a pad of Celite. The filtrate was concentrated in vacuo to a volume of 10 mL, diluted with water (50 mL) andEtOAc. The combined extracts were washed with EtOAc EtOAc EtOAc EtOAc.
實例214E[2－(4－胺基－苯基硫基)－5－苄氧基－苯基]－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺將得自實例10B之產物(67毫克，0.355毫莫耳)與得自實例214D之產物(150毫克，0.355毫莫耳)在醋酸(1毫升)中之溶液，於預熱至130℃之油浴中攪拌10分鐘。然後使混合物冷卻至室溫，在真空下移除醋酸，並於室溫下，將所形成之殘留物以CH2 Cl2 中之50% TFA(2毫升)處理30分鐘。在真空下蒸發溶劑，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(25毫克，12%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.76(s,3H),5.10(s,2H),6.46－6.61(m,2H),6.97－7.12(m,3H),7.10－7.22(m,2H),7.29－7.51(m,6H),7.85(d,J＝8.46 Hz,1H),8.80－8.90(m,2H),8.95(d,J＝8.46 Hz,1H),11.70(s,1H).Example 214E [2-(4-Amino-phenylthio)-5-benzyloxy-phenyl]-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine A solution of the product from Example 10B (67 mg, 0.355 mmol) and the product from Example 214D (150 mg, 0.355 mmol) in acetic acid (1 mL). Stir in the bath for 10 minutes. The mixture was then cooled to room temperature, acetic acid is removed under vacuum and at room temperature, the thus formed residue was treated for 30 minutes in CH 2 Cl 2 of 50% TFA (2 mL). The solvent was evaporated under EtOAc (EtOAc m. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.76 (s, 3H), 5.10 (s, 2H), 6.46-6.61 (m, 2H), 6.97-7.12 (m, 3H), 7.10-7.22 ( m, 2H), 7.29-7.51 (m, 6H), 7.85 (d, J = 8.46 Hz, 1H), 8.80-8.90 (m, 2H), 8.95 (d, J = 8.46 Hz, 1H), 11.70 (s , 1H).
[2－(4－胺基－苯基硫基)－5－苄氧基－苯基]－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺[2-(4-Amino-phenylthio)-5-benzyloxy-phenyl]-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
將得自實例36E之產物(80毫克，0.368毫莫耳)與得自實例214D之產物(160毫克，0.368毫莫耳)在醋酸(2毫升)中之溶液，於預熱至130℃之油浴中攪拌10分鐘。然後使混合物冷卻至室溫，在真空下移除醋酸，並於室溫下，將殘留物以CH2 Cl2 中之50% TFA(2毫升)處理30分鐘。在真空下蒸發溶劑，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(22毫克，10%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.36(d,J＝6.62 Hz,6H),3.19－3.38(m,1H),5.10(s,2H),6.41－6.61(m,2H),6.92－7.18(m,5H),7.27－7.52(m,6H),7.91(d,J＝8.46 Hz,1H),8.84(s,1H),9.01(s,1H),11.64(s,2H).A solution of the product from Example 36E (80 mg, 0.368 mmol) and the product from Example 214D (160 mg, 0.368 mmol) in acetic acid (2 mL). Stir in the bath for 10 minutes. The mixture was then cooled to room temperature, acetic acid removed in vacuo at room temperature and the residue was treated in CH 2 Cl 2 in the 50% TFA (2 mL) for 30 min. The solvent was evaporated under EtOAc (EtOAc m. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (d, J = 6.62 Hz, 6H), 3.19-3.38 (m, 1H), 5.10 (s, 2H), 6.41-6.61 (m, 2H) , 6.92-7.18 (m, 5H), 7.27-7.52 (m, 6H), 7.91 (d, J = 8.46 Hz, 1H), 8.84 (s, 1H), 9.01 (s, 1H), 11.64 (s, 2H) ).
[2－(4－胺基－苯基硫基)－5－(1－苯基－乙氧基)－苯基]－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺[2-(4-Amino-phenylthio)-5-(1-phenyl-ethoxy)-phenyl]-(7-isopropyl-pyrido[2,3-d]pyrimidine- 4-yl)-amine
實例216A 1－氯基－2－硝基－4－(1－苯基－乙氧基)－苯將4－氯基－3－硝基－酚(2.0克，11.5毫莫耳)、1－溴基乙基－苯(3.2克，17.3毫莫耳)、碳酸鈉(1.80克，17.0毫莫耳)在丙酮(20毫升)中之溶液，於回流下加熱18小時。使反應混合物冷卻，濾出固體，及在真空下使濾液濃縮成濃稠漿液。使殘留物溶於醚(80毫升)中，並以水(20毫升)與30% KOH溶液(2 x 20毫升)洗滌，且於真空下濃縮溶劑，留下油狀殘留物，為標題化合物(3.01克，94%)。Example 216A 1-Chloro-2-nitro-4-(1-phenyl-ethoxy)-benzene 4-chloro-3-nitro-phenol (2.0 g, 11.5 mmol), 1- A solution of bromoethyl-benzene (3.2 g, 17.3 mmol), sodium carbonate (1.80 g, 17.0 mmol) in acetone (20 mL). The reaction mixture was allowed to cool, the solid was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (EtOAc (EtOAcMeOHMeOHMeOHMeOH 3.01 g, 94%).
實例216B 4－[2－硝基－4－(1－苯基－乙氧基)－苯基硫基]－苯胺將得自實例216A之化合物(1.86克，6.95毫莫耳)、4－胺基硫酚(0.88克，7.00毫莫耳)、碳酸銫(2.3克，7.00毫莫耳)在二甲基甲醯胺(10毫升)中之溶液，於40℃下加熱16小時。然後將冰水(50毫升)添加至溶液中，並將所形成之漿液以醋酸乙酯(100毫升)處理。分離液層，並以10%碳酸氫鈉與10%氯化鈉洗滌有機層，且以無水硫酸鈉脫水乾燥。過濾乾燥劑，及在真空下移除溶劑，留下橘色油，為標題化合物(2.35克，92%)。Example 216B 4-[2-Nitro-4-(1-phenyl-ethoxy)-phenylsulfanyl]-aniline Compound from Example 216A (1.86 g, 6.95 mmol), 4-amine A solution of thiophenol (0.88 g, 7.00 mmol), cesium carbonate (2.3 g, 7.00 mmol) in dimethylformamide (10 ml) was heated at 40 ° C for 16 h. Ice water (50 ml) was then added to the solution and the resulting syrup was treated with ethyl acetate (100 mL). The liquid layer was separated, and the organic layer was washed with 10% sodium hydrogen carbonate and 10% sodium chloride and dried over anhydrous sodium sulfate. The desiccant was filtered, and the solvent was evaporated,jjjjjjjj
實例216C{4－[2－硝基－4－(1－苯基－乙氧基)－苯基硫基]－苯基}－胺甲基酸第三－丁酯將得自實例216B化合物之溶液(2.35克，6.4毫莫耳)以Boc酐(1.7克，7.70毫莫耳)在二氧陸圜(20毫升)中處理，並於回流下加熱18小時。隔天，在真空下移除溶劑，留下標題化合物，為淡黃褐色油(1.78克，60%)。Example 216C {4-[2-Nitro-4-(1-phenyl-ethoxy)-phenylsulfanyl]-phenyl}-aminomethyl-acid tri-butyl ester will be obtained from the compound of Example 216B The solution (2.35 g, 6.4 mmol) was treated with EtOAc (EtOAc (EtOAc) The solvent was removed in vacuo to give the title compound as a pale brown oil (1.78 g, 60%).
實例216D{4－[2－胺基－4－(1－苯基－乙氧基)－苯基硫基]－苯基}－胺甲基酸第三－丁酯將得自實例216C之產物(1.78克，3.80毫莫耳)、鐵粉(0.85克，15.3毫莫耳)及氯化銨(0.25克，4.57毫莫耳)在甲醇(10毫升)、四氫呋喃(10毫升)及水(5毫升)溶液中之溶液加熱至回流，歷經1.5小時。以甲醇(50毫升)稀釋所形成之混合物，並經過矽藻土墊過濾。使濾液在真空下濃縮成體積10毫升，以水(50毫升)稀釋溶液，並以醋酸乙酯(2 x 50毫升)萃取。以10%氯化鈉洗滌合併之萃液，然後以硫酸鎂脫水乾燥，過濾，及在真空下濃縮，提供標題化合物(0.53克，32%)。Example 216D {4-[2-Amino-4-(1-phenyl-ethoxy)-phenylsulfanyl]-phenyl}-aminomethyl-acid tri-butyl ester. Product from Example 216C (1.78 g, 3.80 mmol), iron powder (0.85 g, 15.3 mmol) and ammonium chloride (0.25 g, 4.57 mmol) in methanol (10 ml), tetrahydrofuran (10 ml) and water (5) The solution in the milliliter solution was heated to reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 mL) and filtered through a pad of Celite. The filtrate was concentrated in vacuo to a volume of 10 mL, diluted with water (50 mL) andEtOAc. The combined extracts were washed with EtOAc EtOAc EtOAc.
實例216E[2－(4－胺基－苯基硫基)－5－(1－苯基－乙氧基)－苯基]－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺將得自實例36E之產物(57毫克，0.265毫莫耳)與得自實例216D之產物(116毫克，0.265毫莫耳)在醋酸(2毫升)中之溶液，於預熱至130℃之油浴中攪拌10分鐘。然後使混合物冷卻至室溫，在真空下移除醋酸，並於室溫下，將殘留物以CH2 Cl2 中之50% TFA(2毫升)處理30分鐘。在真空下蒸發溶劑，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(18毫克，11%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.30(m,3H),1.31(d,6H),3.18－3.34(m,1H),5.48(s,1H),6.50(s,1H),6.86－7.08(m,3H),7.10(d,J＝5.15 Hz,2H),7.22－7.50(m,5H),7.86(s,1H),8.37(s,1H),8.48(s,1H),8.78(s,1H),8.94(s,1H),11.19(s,1H).Example 216E [2-(4-Amino-phenylthio)-5-(1-phenyl-ethoxy)-phenyl]-(7-isopropyl-pyrido[2,3-d] Pyrimidine-4-yl)-amine A solution of the product from Example 36E (57 mg, 0.265 mmol) eluted from the product from Example 216D (116 mg, 0.265 mmol) in acetic acid (2 mL). Stir for 10 minutes in an oil bath preheated to 130 °C. The mixture was then cooled to room temperature, acetic acid removed in vacuo at room temperature and the residue was treated in CH 2 Cl 2 in the 50% TFA (2 mL) for 30 min. The solvent was evaporated under EtOAc (EtOAc m. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.30 (m, 3H), 1.31 (d, 6H), 3.18-3.34 (m, 1H), 5.48 (s, 1H), 6.50 (s, 1H) , 6.86-7.08 (m, 3H), 7.10 (d, J = 5.15 Hz, 2H), 7.22-7.50 (m, 5H), 7.86 (s, 1H), 8.37 (s, 1H), 8.48 (s, 1H) ), 8.78 (s, 1H), 8.94 (s, 1H), 11.19 (s, 1H).
[2－(2－胺基－6－氯－嘧啶－4－基硫基)－5－苄氧基－苯基]－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺[2-(2-Amino-6-chloro-pyrimidin-4-ylthio)-5-benzyloxy-phenyl]-(7-methyl-pyrido[2,3-d]pyrimidine-4 -based)-amine
實例217A 4－苄氧基－2－硝基－苯胺將含有4－胺基－3－硝基酚(1.09克，7.07毫莫耳)、溴化苄(1.28克，7.5毫莫耳)及碳酸銫(2.43克，7.5毫莫耳)之溶液，於室溫下攪拌4天。在反應完成後，將反應混合物倒入冰水(500毫升)中，攪拌1小時，並過濾所形成之固體，及在真空下乾燥，提供標題化合物(1.1克，64%)。Example 217A 4-Benzyloxy-2-nitro-phenylamine will contain 4-amino-3-nitrophenol (1.09 g, 7.07 mmol), benzyl bromide (1.28 g, 7.5 mmol) and carbonic acid. A solution of hydrazine (2.43 g, 7.5 mmol) was stirred at room temperature for 4 days. After the reaction was completed, EtOAc m m m m m m
實例217B 4－苄氧基－2－硝基苯重氮四氟硼酸鹽使得自實例217A之產物(0.5克，2.05毫莫耳)溶於THF(10毫升)中，並逐滴添加至含有三氟化硼醚化物(1.1毫升，8.20毫莫耳)與亞硝酸第三－丁酯(0.6毫升，4.92毫莫耳)之冷(－20℃)溶液中，歷經5分鐘期間。將所形成之混合物於－20℃下攪拌10分鐘，然後在10℃下2小時。接著將反應混合物倒入己烷(100毫升)中，並過濾固體，以醚洗滌，及在真空下乾燥，提供標題化合物(0.61克，87%)。Example 217B 4-Benzyloxy-2-nitrobenzenediazonium tetrafluoroborate The product from Example 217A (0.5 g, 2.05 mmol) was dissolved in THF (10 mL). A solution of boron fluoride etherate (1.1 mL, 8.20 mmol) with a cold (-20 ° C) solution of 1,3-nitrate (0.6 mL, 4.92 mmol) was applied over a period of 5 min. The resulting mixture was stirred at -20 ° C for 10 minutes and then at 10 ° C for 2 hours. The reaction mixture was poured into EtOAc EtOAc m.
實例217C 4－(4－苄氧基－2－硝基－苯基硫基)－6－氯－嘧啶－2－基胺將得自實例217B之產物(0.1克，0.290毫莫耳)在二甲亞碸(1毫升)中之溶液，逐滴添加至含有硫代醋酸鉀(0.04克，0.350毫莫耳)在二甲亞碸(1毫升)中之溶液內。反應混合物立即開始起泡。當起泡已消退時，將混合物於室溫下攪拌90分鐘。然後將所形成之深綠色混合物以3M氫氧化鉀水溶液(0.1毫升)處理，並再攪拌80分鐘，此時添加固體4,6二氯－2－胺基嘧啶，且將混合物再攪拌60分鐘。以醋酸乙酯(50毫升)稀釋反應混合物，以水(20毫升)、10%碳酸氫鈉及10%氯化鈉溶液洗滌，以硫酸鈉脫水乾燥，過濾，及在真空下移除溶劑，提供黃褐色固體，為標題化合物(0.1克，88%)。Example 217C 4-(4-Benzyloxy-2-nitro-phenylsulfanyl)-6-chloro-pyrimidin-2-ylamine The product from Example 217B (0.1 g, 0.290 mmol) A solution of hydrazine (1 ml) was added dropwise to a solution containing potassium thioacetate (0.04 g, 0.350 mmol) in dimethylhydrazine (1 mL). The reaction mixture immediately started to foam. When the foaming had subsided, the mixture was stirred at room temperature for 90 minutes. The dark green mixture formed was then treated with 3M aqueous potassium hydroxide (0.1 mL) and stirred for a further 80 min at which time solid 4,6dichloro-2-aminopyrimidine was added and the mixture was stirred for a further 60 min. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (20 ml), 10% sodium hydrogen carbonate and 10% sodium chloride, dried over sodium sulfate, filtered and evaporated The title compound (0.1 g, 88%).
實例217D 4－(2－胺基－4－苄氧基－苯基硫基)－6－氯－嘧啶－2－基胺將得自實例217C之產物(0.1克，0.257毫莫耳)、鐵粉(0.058克，1.03毫莫耳)及氯化銨(0.017克，0.310毫莫耳)在甲醇(5毫升)、四氫呋喃(5毫升)及水(2毫升)溶液中之溶液加熱至回流，歷經1.5小時。以甲醇(50毫升)稀釋所形成之混合物，並經過矽藻土墊過濾。使濾液在真空下濃縮成體積10毫升，以水(50毫升)稀釋溶液，並以醋酸乙酯(2 x 50毫升)萃取。以10%氯化鈉洗滌合併之萃液，然後以硫酸鎂脫水乾燥，過濾，及在真空下濃縮，提供標題化合物(0.04克，43%)。Example 217D 4-(2-Amino-4-benzyloxy-phenylsulfanyl)-6-chloro-pyrimidin-2-ylamine The product from Example 217C (0.1 g, 0.257 mmol). A solution of the powder (0.058 g, 1.03 mmol) and ammonium chloride (0.017 g, 0.310 mmol) in methanol (5 ml), tetrahydrofuran (5 ml) and water (2 ml) 1.5 hours. The resulting mixture was diluted with methanol (50 mL) and filtered through a pad of Celite. The filtrate was concentrated in vacuo to a volume of 10 mL, diluted with water (50 mL) andEtOAc. The combined extracts were washed with EtOAc EtOAc EtOAc EtOAc
實例217E[2－(2－胺基－6－氯－嘧啶－4－基硫基)－5－苄氧基－苯基]－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺將得自實例10B之產物(21毫克，0.112毫莫耳)與得自實例217D之產物(40毫克，0.112毫莫耳)在醋酸(1毫升)中之溶液，於預熱至130℃之油浴中攪拌10分鐘。然後使混合物冷卻至室溫，在真空下移除醋酸，並於室溫下，將所形成之殘留物以CH2 Cl2 中之50% TFA(2毫升)處理30分鐘。在真空下蒸發溶劑，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(5毫克，7%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.66(s,J＝6.25 Hz,3H),5.21(s,2H),6.53(s,1H),7.07(s,1H),7.14(dd,J＝8.64,2.76 Hz,1H),7.25－7.61(m,6H),7.62－7.72(m,1H),8.52(s,1H),8.66(d,J＝8.82 Hz,1H),8.71(s,1H),8.88(d,J＝8.46 Hz,1H),10.05(s,1H).Example 217E [2-(2-Amino-6-chloro-pyrimidin-4-ylthio)-5-benzyloxy-phenyl]-(7-methyl-pyrido[2,3-d]pyrimidine -4-yl)-amine a solution of the product from Example 10B (21 mg, 0.112 mmol) eluted from the product from Example 217D (40 mg, 0.112 mmol) in acetic acid (1 mL) Stir for 10 minutes in an oil bath preheated to 130 °C. The mixture was then cooled to room temperature, acetic acid is removed under vacuum and at room temperature, the thus formed residue was treated for 30 minutes in CH 2 Cl 2 of 50% TFA (2 mL). The solvent was evaporated in vacuo and EtOAcqqqqqqqq 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.66 (s, J = 6.25 Hz, 3H), 5.21 (s, 2H), 6.53 (s, 1H), 7.07 (s, 1H), 7.14 (dd , J=8.64, 2.76 Hz, 1H), 7.25-7.61 (m, 6H), 7.62-7.72 (m, 1H), 8.52 (s, 1H), 8.66 (d, J = 8.82 Hz, 1H), 8.71 ( s, 1H), 8.88 (d, J = 8.46 Hz, 1H), 10.05 (s, 1H).
4－[4－(3－溴－苄氧基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基]－酚4-[4-(3-Bromo-benzyloxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxy]-phenol
實例218A 4－[4－(3－溴－苄氧基)－2－硝基－苯氧基]－酚將對苯二酚(276.4毫克，2.510毫莫耳)在無水3.64毫莫耳)中之溶液，於氮大氣及120°下加熱30分鐘。在120°下，自添液漏斗逐滴添加4－(3－溴－苄氧基)－1－氯基－2－硝基－苯(得自實例15A)(774毫克，2.259毫莫耳)在二甲亞碸(4毫升)中之溶液，歷經30分鐘期間，然後將混合物在此溫度下攪拌1小時。使反應物於冰浴中冷卻，接著倒入冰水(20毫升)中，並以濃鹽酸調整pH至2。以***(3 x 100毫升)萃取混合物，以水(3 x 100毫升)與鹽水(50毫升)洗滌合併之含醚萃液，以無水硫酸鈉脫水乾燥，過濾，及於真空下藉迴轉式蒸發濃縮，殘留物藉矽膠急驟式層析之純化，使用3%醋酸乙酯/二氯甲烷作為溶離劑，獲得標題化合物，為深黃色固體(386毫克，0.927毫莫耳，41%)。Example 218A 4-[4-(3-Bromo-benzyloxy)-2-nitro-phenoxy]-phenol. Hydroquinone (276.4 mg, 2.510 mmol) in anhydrous 3.64 mmol. The solution was heated in a nitrogen atmosphere at 120 ° for 30 minutes. 4-(3-Bromo-benzyloxy)-1-chloro-2-nitro-benzene (from Example 15A) (774 mg, 2.259 mmol) was added dropwise from the addition funnel at 120 °. The solution in dimethyl hydrazine (4 ml) was allowed to stand at this temperature for 1 hour over a period of 30 minutes. The reaction was cooled in an ice-bath, then poured into ice water (20 mL) and then adjusted to 2 with concentrated hydrochloric acid. The mixture was extracted with diethyl ether (3×100 mL), EtOAc (EtOAc) (EtOAc) The residue was purified by EtOAc EtOAc EtOAc.
實例218B 4－[2－胺基－4－(3－溴－苄氧基)－苯氧基]－酚將得自實例218A之產物(384.6毫克，0.924毫莫耳)、鐵粉(317.4毫克，5.683毫莫耳)及氯化銨(323.7毫克，6.052毫莫耳)在水(3毫升)與乙醇(6毫升)中之混合物，於70°及氮大氣下加熱1小時。使反應物冷卻至室溫，並真空過濾，以甲醇洗滌殘留物。在真空下濃縮濾液，並與甲苯(50毫升)共沸。使殘留物藉矽膠急驟式層析純化，使用7%至10%醋酸乙酯/二氯甲烷之梯度液作為溶離劑，提供標題化合物，為米黃色固體(272毫克，0.704毫莫耳，76%)。Example 218B 4-[2-Amino-4-(3-bromo-benzyloxy)-phenoxy]-phenol The product from Example 218A (384.6 mg, 0.924 mmol), iron powder (317.4 mg) A mixture of ammonium chloride (323.7 mg, 6.052 mmol) in water (3 ml) and ethanol (6 ml) was heated at 70 ° under nitrogen atmosphere for 1 hour. The reaction was cooled to room temperature and filtered under vacuum and the residue was washed with methanol. The filtrate was concentrated under vacuum and azeotroped with toluene (50 mL). The residue was purified by flash chromatography eluting EtOAc EtOAc EtOAc ).
實例218C 4－[4－(3－溴－苄氧基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基]－酚將得自實例36E之產物(25毫克，0.116毫莫耳)與得自實例218B之產物(44.6毫克，0.116毫莫耳)在醋酸(1毫升)中之溶液，於預熱至140℃之油浴中攪拌1小時。使反應物冷卻至室溫，以己烷(50毫升)稀釋，藉迴轉式蒸發濃縮，並與二氯甲烷/己烷共蒸發(4x)。使殘留物在高真空下乾燥過夜，然後藉矽膠急驟式層析純化，使用3%甲醇/二氯甲烷作為溶離劑，提供標題化合物，為淡黃色固體(34毫克，0.0613毫莫耳，53%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.30(d,J＝6.62 Hz,6H),3.09－3.28(m,1H),5.12(s,2H),6.62(d,J＝9.20 Hz,2H),6.76(d,J＝8.82 Hz,2H),6.82－6.97(m,2H),7.32－7.36(m,1H),7.39(d,J＝7.72 Hz,1H),7.45－7.58(m,3H),7.68(s,1H),8.57(s,1H),8.72(d,J＝8.82 Hz,1H),9.14(s,1H),9.75(s,1H)；MS(ESI＋)m/z 557/559(M＋H)＋.Example 218C 4-[4-(3-Bromo-benzyloxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxy]-phenol A solution of the product from Example 36E (25 mg, 0.116 mmol) and the product from Example 218B (44.6 mg, 0.116 mmol) in acetic acid (1 mL). Stir in the bath for 1 hour. The reaction was cooled to room rt, diluted with EtOAc EtOAc EtOAc. The residue was dried under EtOAc (EtOAc) EtOAc (EtOAc) ). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.30 (d, J = 6.62 Hz, 6H), 3.09 - 3.28 (m, 1H), 5.12 (s, 2H), 6.62 (d, J = 9.20 Hz , 2H), 6.76 (d, J = 8.82 Hz, 2H), 6.82-6.97 (m, 2H), 7.32-7.36 (m, 1H), 7.39 (d, J = 7.72 Hz, 1H), 7.45-7.58 ( m, 3H), 7.68 (s, 1H), 8.57 (s, 1H), 8.72 (d, J = 8.82 Hz, 1H), 9.14 (s, 1H), 9.75 (s, 1H); MS (ESI+) m /z 557/559(M+H)+.
4－[4－(4－溴－苄氧基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基]－酚4-[4-(4-Bromo-benzyloxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxy]-phenol
實例219A 4－[2－胺基－4－(4－溴－苄氧基)－苯氧基]－酚使4－(4－溴－苄氧基)－1－氯基－2－硝基－苯(得自實例16A)與對苯二酚反應，根據得自實例39A之程序，並根據得自實例39B之程序還原，提供標題產物。Example 219A 4-[2-Amino-4-(4-bromo-benzyloxy)-phenoxy]-phenol 4-(4-bromo-benzyloxy)-1-chloro-2-nitro - Benzene (from Example 16A) was reacted with hydroquinone, according to the procedure from Example 39A, and purified according to procedure from Example 39B to afford title product.
實例219B 4－[4－(4－溴－苄氧基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基]－酚使得自實例219A之產物與得自實例36E之產物反應，根據得自實例39C之程序，以得自實例219A之產物取代得自實例218B之產物，於矽膠層析後，提供標題化合物(38毫克59%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.30(d,J＝6.99 Hz,6H),3.10－3.27(m,1H),5.09(s,2H),6.56－6.66(m,2H),6.70－6.79(m,2H),6.81－6.97(m,2H),7.32(d,J＝2.57 Hz,1H),7.43(d,J＝8.46 Hz,2H),7.53(d,J＝8.46 Hz,1H),7.60(d,J＝8.46 Hz,2H),8.57(s,1H),8.72(d,J＝8.46 Hz,1H),9.14(s,1H),9.74(s,1H)；MS(ESI＋)m/z 557/559(M＋H)＋.Example 219B 4-[4-(4-Bromo-benzyloxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxy]-phenol The product from Example 219A was reacted with the product from Example </RTI><RTIID=0.0>#</RTI></RTI> 59%). 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.30 (d, J = 6.99 Hz, 6H), 3.10-3.27 (m, 1H), 5.09 (s, 2H), 6.56-6.66 (m, 2H) , 6.70-6.79 (m, 2H), 6.81-6.97 (m, 2H), 7.32 (d, J = 2.57 Hz, 1H), 7.43 (d, J = 8.46 Hz, 2H), 7.53 (d, J = 8.46) Hz, 1H), 7.60 (d, J = 8.46 Hz, 2H), 8.57 (s, 1H), 8.72 (d, J = 8.46 Hz, 1H), 9.14 (s, 1H), 9.74 (s, 1H); MS (ESI+) m/z 557/559 (M+H)+.
4－[4－苄氧基－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基]－酚4-[4-Benzyloxy-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxy]-phenol
實例220A 4－(2－胺基－4－苄氧基－苯氧基)－酚使4－苄氧基－1－氯基－2－硝基－苯(得自實例27A)與對苯二酚反應，根據得自實例39A之程序，並根據得自實例39B之程序還原，提供標題產物。Example 220A 4-(2-Amino-4-benzyloxy-phenoxy)-phenol 4-benzyloxy-1-chloro-2-nitro-benzene (from Example 27A) and p-phenylene The phenol reaction, according to the procedure from Example 39A, was purified according to procedure from Example 39B to afford title product.
實例220B 4－[4－苄氧基－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯氧基]－酚使得自實例220A之產物與得自實例36E之產物反應，根據得自實例39C之程序，以得自實例220A之產物取代得自實例218B之產物，於矽膠層析後，提供標題化合物(58毫克，65%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.30(d,J＝6.99 Hz,6H),3.08－3.27(m,1H),5.10(s,2H),6.62(d,J＝9.2 Hz,2H),6.74(d,J＝9.2 Hz,2H),6.81－6.98(m,2H),7.26－7.61(m,7H),8.57(s,1H),8.72(d,J＝8.46 Hz,1H),9.13(s,1H),9.75(s,1H)；MS(DCI/NH3 )m/z 479(M＋H)＋.Example 220B 4-[4-Benzyloxy-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxy]-phenol as a product from Example 220A The title compound (58 mg, 65%) was obtained from the titled compound mp. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.30 (d, J = 6.99 Hz, 6H), 3.08-3.27 (m, 1H), 5.10 (s, 2H), 6.62 (d, J = 9.2 Hz , 2H), 6.74 (d, J = 9.2 Hz, 2H), 6.81-6.98 (m, 2H), 7.26-7.61 (m, 7H), 8.57 (s, 1H), 8.72 (d, J = 8.46 Hz, 1H), 9.13 (s, 1H), 9.75 (s, 1H); MS (DCI / NH 3 ) m / z 479 (M + H) +.
4－[4－苄氧基－2－(7－乙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-Benzyloxy-2-(7-ethyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使得自實例27A之產物與得自實例145A之產物反應，使用得自實例10F之程序，以得自實例27A之產物取代得自實例10E之產物，並以得自實例145A之產物取代得自實例10B之產物，提供標題產物。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.32(t,J＝7.72 Hz,3H),2.95(q,J＝7.72 Hz,2H),5.11(s,2H),6.65(d,J＝8.82 Hz,2H),6.91－7.05(m,1H),7.10(d,J＝8.46 Hz,2H),7.32－7.50(m,6H),8.12(d,J＝6.99 Hz,1H),8.66－8.77(m,1H),9.04(d,J＝8.82 Hz,1H),9.63(s,1H),10.28(s,1H)；MS(APCI)m/z 481(M＋H)＋.The product from Example 27A was reacted with the product from Example 145A, using the procedure from Example 10F, substituting the product from Example 27A for the product from Example 10E, and substituting the product from Example 145A from the example. The product of 10B provides the title product. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.32 (t, J = 7.72 Hz, 3H), 2.95 (q, J = 7.72 Hz, 2H), 5.11 (s, 2H), 6.65 (d, J) =8.82 Hz, 2H), 6.91-7.05 (m, 1H), 7.10 (d, J = 8.46 Hz, 2H), 7.32-7.50 (m, 6H), 8.12 (d, J = 6.99 Hz, 1H), 8.66 -8.77 (m, 1H), 9.04 (d, J = 8.82 Hz, 1H), 9.63 (s, 1H), 10.28 (s, 1H); MS (APCI) m/z 481 (M+H)+.
4－[4－苄氧基－2－(7－環己基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-Benzyloxy-2-(7-cyclohexyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使得自實例27A之產物與得自實例135A之產物反應，使用得自實例10F之程序，以得自實例27A之產物取代得自實例10E之產物，並以得自實例135A之產物取代得自實例10B之產物，提供標題產物。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.23－1.51(m,4H),1.53－1.79(m,4H),1.80－2.00(m,2H),2.77－3.02(m,1H),5.10(s,2H),6.67(d,J＝8.46 Hz,2H),6.88－7.01(m,1H),7.11(d,J＝8.82 Hz,2H),7.22－7.31(m,1H),7.32－7.49(m,6H),7.56(d,J＝7.72 Hz,1H),8.55(s,1H),8.73(d,J＝8.09 Hz,1H),9.94(s,1H)；MS(APCI)m/z 535(M＋H)＋.The product from Example 27A was reacted with the product from Example 135A, using the procedure from Example 10F, substituting the product from Example 27A for the product from Example 10E, and substituting the product from Example 135A from the example. The product of 10B provides the title product. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.23-1.51 (m, 4H), 1.53-1.79 (m, 4H), 1.80-2.00 (m, 2H), 2.77-3.02 (m, 1H), 5.10(s, 2H), 6.67 (d, J = 8.46 Hz, 2H), 6.88-7.01 (m, 1H), 7.11 (d, J = 8.82 Hz, 2H), 7.22 - 7.31 (m, 1H), 7.32 -7.49 (m, 6H), 7.56 (d, J = 7.72 Hz, 1H), 8.55 (s, 1H), 8.73 (d, J = 8.09 Hz, 1H), 9.94 (s, 1H); MS (APCI) m/z 535(M+H)+.
4－[4－苄氧基－2－(7－第二－丁基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-Benzyloxy-2-(7-second-butyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
使得自實例27A之產物與得自實例140A之產物反應，使用得自實例10F之程序，以得自實例27A之產物取代得自實例10E之產物，並以得自實例140A之產物取代得自實例10B之產物，提供標題產物。1 H NMR(300 MHz,DMSO－D6)δ ppm：0.82(t,J＝7.35 Hz,3H),1.30(d,J＝6.62 Hz,3H),1.58－1.73(m,1H),1.75－1.87(m,1H),2.89－3.08(m,1H),5.11(s,2H),6.67(d,J＝8.82 Hz,2H),6.85－7.03(m,1H),7.11(d,J＝8.46 Hz,2H),7.30－7.50(m,6H),7.56(d,J＝8.82 Hz,1H),8.56(s,1H),8.75(d,J＝8.46 Hz,1H),9.64(s,1H),9.95(s,1H)；MS(APCI)m/zThe product from Example 27A was reacted with the product from Example 140A, using the procedure from Example 10F, substituting the product from Example 27A for the product from Example 10E, and substituting the product from Example 140A The product of 10B provides the title product. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 0.82 (t, J = 7.35 Hz, 3H), 1.30 (d, J = 6.62 Hz, 3H), 1.58-1.73 (m, 1H), 1.75-1.87 (m, 1H), 2.89-3.08 (m, 1H), 5.11 (s, 2H), 6.67 (d, J = 8.82 Hz, 2H), 6.85-7.03 (m, 1H), 7.11 (d, J = 8.46) Hz, 2H), 7.30-7.50 (m, 6H), 7.56 (d, J = 8.82 Hz, 1H), 8.56 (s, 1H), 8.75 (d, J = 8.46 Hz, 1H), 9.64 (s, 1H) ), 9.95 (s, 1H); MS (APCI) m / z
4－[4－(2－氯－噻唑－5－基甲氧基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(2-Chloro-thiazol-5-ylmethoxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfide Phenol
實例224A 4－[2－胺基－4－(2－氯－噻唑－5－基甲氧基)－苯基硫基]－酚標題化合物係按實例16A中所述，以2－氯基－5－溴基甲基噻唑取代溴化苄而製成，以提供標題化合物(0.38克，64%)。Example 224A 4-[2-Amino-4-(2-chloro-thiazol-5-ylmethoxy)-phenylsulfanyl]-phenol The title compound was obtained as described in Example 16A with 2-chloro- 5-Bromomethylthiazole was substituted for benzyl bromide to give the title compound (0.38 g, 64%).
實例224b 4－[4－(2－氯－噻唑－5－基甲氧基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)苯基硫基]－酚將實例36E之產物(40.4毫克，0.187毫莫耳)與實例224A之產物(68毫克，0.187毫莫耳)在醋酸(1毫升)中之溶液，於預熱至130℃之油浴中攪拌10分鐘。然後使混合物冷卻至室溫，在真空下移除醋酸，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(31毫克，30%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：1.35(d,J＝6.99 Hz,6H)3.17－3.36(m,1H)5.35(s,2H)6.55(d,J＝7.72 Hz,1H)6.58－6.74(m,2H)7.00－7.30(m,4H)7.68－7.95(m,2H)8.76(s,1H)8.94(d,J＝8.46 Hz,1H)9.73(s,1H)11.34(s,1H)；MS(ESI＋)m/z 536(M＋H)＋,(ESI－)m/z 534(M－H)－.Example 224b 4-[4-(2-Chloro-thiazol-5-ylmethoxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)phenyl Thio]-phenol A solution of the product of Example 36E (40.4 mg, 0.187 mmol) and the product of Example 224A (68 mg, 0.187 mmol) in acetic acid (1 mL), preheated to 130 ° C Stir in the oil bath for 10 minutes. The mixture was then cooled to rt. EtOAc (EtOAc m. 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 1.35 (d, J = 6.99 Hz, 6H) 3.17-3.36 (m, 1H) 5.35 (s, 2H) 6.55 (d, J = 7.72 Hz, 1H) 6.58-6.74(m,2H)7.00-7.30(m,4H)7.68-7.95(m,2H)8.76(s,1H)8.94(d,J=8.46 Hz,1H)9.73(s,1H)11.34( s,1H);MS(ESI+)m/z 536(M+H)+, (ESI-)m/z 534(M-H)-.
4－[4－(6－氯－吡啶－2－基甲氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(6-Chloro-pyridin-2-ylmethoxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio ]-phenol
實例225a 4－[2－胺基－4－(6－氯－吡啶－2－基甲氧基)－苯基硫基]－酚標題化合物係按實例16A中所述，以2－氯基－5－溴基甲基吡啶取代溴化苄而製成，以提供標題化合物(0.63克，73%)。Example 225a 4-[2-Amino-4-(6-chloro-pyridin-2-ylmethoxy)-phenylsulfanyl]-phenol title compound as described in Example 16A, with 2-chloro- Substituting 5-bromomethylpyridine for benzyl bromide to give the title compound (0.63 g, 73%).
實例225b 4－[4－(6－氯－吡啶－2－基甲氧基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚將實例10B之產物(37毫克，0.197毫莫耳)與實例225a之產物(70.7毫克，0.197毫莫耳)在醋酸(2毫升)中之溶液，於預熱至130℃之油浴中攪拌20分鐘。然後使混合物冷卻至室溫，在真空下移除醋酸，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(20毫克，20%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：2.70(s,3H)5.18(s,2H)6.65(d,J＝8.82 Hz,2H)7.02(d,J＝8.09 Hz,1H)7.11(d,J＝8.82 Hz,2H)7.19(d,J＝8.82 Hz,1H)7.25(s,1H)7.52(dd,J＝13.60,7.72 Hz,2H)7.67(d,J＝8.09 Hz,1H)7.93(t,J＝7.72 Hz,2H)8.65(s,1H)8.80(d,J＝8.09 Hz,1H)9.68(s,1H)；MS(ESI＋)m/z 502(M＋H)＋,(ESI－)m/z 500(M－H)－.Example 225b 4-[4-(6-Chloro-pyridin-2-ylmethoxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl Thio]-phenol The solution of the product of Example 10B (37 mg, 0.197 mmol) and the product of Example 225a (70.7 mg, 0.197 mmol) in acetic acid (2 mL) was preheated to 130 ° C Stir in the oil bath for 20 minutes. After the mixture was cooled to room temperature, the title compound was obtained from EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 2.70 (s, 3H) 5.18 (s, 2H) 6.65 (d, J = 8.82 Hz, 2H) 7.02 (d, J = 8.09 Hz, 1H) 7.11 (d, J = 8.82 Hz, 2H) 7.19 (d, J = 8.82 Hz, 1H) 7.25 (s, 1H) 7.52 (dd, J = 13.60, 7.72 Hz, 2H) 7.67 (d, J = 8.09 Hz, 1H 7.93 (t, J = 7.72 Hz, 2H) 8.65 (s, 1H) 8.80 (d, J = 8.09 Hz, 1H) 9.68 (s, 1H); MS (ESI+) m/z 502 (M+H)+, ( ESI-)m/z 500(M-H)-.
4－[4－(6－氯－吡啶－2－基甲氧基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(6-Chloro-pyridin-2-ylmethoxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfide Phenol
將實例36E之產物(36毫克，0.168毫莫耳)與實例225a之產物(60毫克，0.168毫莫耳)在醋酸(1毫升)中之溶液，於預熱至130℃之油浴中攪拌10分鐘。然後使混合物冷卻至室溫，在真空下移除醋酸，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(31毫克，30%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：1.16(d,J＝6.99 Hz,3H)1.36(d,J＝6.62 Hz,3H)3.20－3.40(m,1H)5.18(s,1H)6.55(d,J＝7.72 Hz,1H)6.64(d,J＝8.82 Hz,2H)6.77(s,1H)7.04－7.18(m,2H)7.15－7.29(m,2H)7.52(dd,J＝10.48,7.91 Hz,2H)7.77(d,J＝7.72 Hz,1H)7.93(t,J＝7.72 Hz,2H)8.82(s,1H)8.97(s,1H)9.72(s,1H)11.66(s,1H)；MS(ESI＋)m/z 530(M＋H)＋,(ESI－)m/z 528(M－H)－.A solution of the product from Example 36E (36 mg, 0.168 mmol) eluted with the product of Example 225a (60 mg, 0.168 mM) in acetic acid (1 mL) and stirred in an oil bath preheated to 130 ° C 10 minute. The mixture was then cooled to rt. EtOAc (EtOAc m. 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 1.16 (d, J = 6.99 Hz, 3H) 1.36 (d, J = 6.62 Hz, 3H) 3.20-3.40 (m, 1H) 5.18 (s, 1H) 6.55 (d, J = 7.72 Hz, 1H) 6.64 (d, J = 8.82 Hz, 2H) 6.77 (s, 1H) 7.04-7.18 (m, 2H) 7.15-7.29 (m, 2H) 7.52 (dd, J = 10.48, 7.91 Hz, 2H) 7.77 (d, J = 7.72 Hz, 1H) 7.93 (t, J = 7.72 Hz, 2H) 8.82 (s, 1H) 8.97 (s, 1H) 9.72 (s, 1H) 11.66 ( s,1H);MS(ESI+)m/z 530(M+H)+, (ESI-)m/z 528(M-H)-.
4－[2－(7－第三－丁基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－(3－氟－苄氧基)－苯基硫基]－酚4-[2-(7-Third-butyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(3-fluoro-benzyloxy)-phenylthio]- phenol
使得自實例127A之產物(110毫克，0.478毫莫耳)與得自實例28A之產物(164毫克，0.48毫莫耳)在1毫升冰醋酸中及應，於120℃下加熱13分鐘。冷卻至室溫，並在真空下移除醋酸。使粗產物藉HPLC以TFA純化，而得標題化合物，為三氟醋酸鹽(134毫克，44%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：1.43(s,9H)5.14(s,2H)6.65(d,J＝8.45 Hz,2H)7.17(m,4H)7.29(d,J＝8.45 Hz,2H)7.44(d,J＝8.45 Hz,2H)7.99(d,J＝7.80 Hz,1H)8.72(s,1H)8.93(d,J＝8.45 Hz,1H)9.68(s,1H)10.90(br s,1H)；MS(ESI＋)m/z 527(M＋H－TFA)＋；(ESI－)m/z 525(M－H－TFA)－.The product from Example 127A (110 mg, 0.478 mmol) was obtained from the product from Example 28A (164 mg, 0.48 mmol) in 1 ml of glacial acetic acid and heated at 120 ° C for 13 minutes. Cool to room temperature and remove the acetic acid under vacuum. The crude product was purified by EtOAc EtOAc EtOAc EtOAc 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 1.43 (s, 9H) 5.14 (s, 2H) 6.65 (d, J = 8.45 Hz, 2H) 7.17 (m, 4H) 7.29 (d, J = 8.45 Hz, 2H) 7.44 (d, J = 8.45 Hz, 2H) 7.99 (d, J = 7.80 Hz, 1H) 8.72 (s, 1H) 8.93 (d, J = 8.45 Hz, 1H) 9.68 (s, 1H) 10.90(br s,1H);MS(ESI+)m/z 527(M+H-TFA)+; (ESI-)m/z 525(M-H-TFA)-.
4－[4－[1－(3－溴苯基)－乙氧基]－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-[1-(3-Bromophenyl)-ethoxy]-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
實例228a 1－(1－溴－乙基)－4－氟－苯於1－(3－溴苯基)－乙醇(7.0克，34.0毫莫耳)在二氯甲烷(40毫升)中之溶液內，逐滴添加三溴化磷(77克，34.0毫莫耳)。將混合物於室溫下攪拌16小時。將反應物傾倒在冰/水上。以碳酸氫鈉使水相呈鹼性。以二氯甲烷萃取水相。以水、鹽水洗滌有機相，並以硫酸鈉脫水乾燥，過濾，及在真空下濃縮，獲得標題化合物(7.8克，80%)。Example 228a a solution of 1-(1-bromo-ethyl)-4-fluoro-benzene in 1-(3-bromophenyl)-ethanol (7.0 g, 34.0 mmol) in dichloromethane (40 mL) Inside, phosphorus tribromide (77 g, 34.0 mmol) was added dropwise. The mixture was stirred at room temperature for 16 hours. The reaction was poured onto ice/water. The aqueous phase was made alkaline with sodium bicarbonate. The aqueous phase was extracted with dichloromethane. The organic phase was washed with EtOAc EtOAc m.
實例228b 4－[1－(3－溴苯基)－乙氧基]－1－氯基－2－硝基－苯於DMF(50毫升)中之實例228a(7.8克，30毫莫耳)內，添加4－氯基－3－硝基－酚(5.14克，30.0毫莫耳)與K2 CO3 (8.18克，60毫莫耳)。將混合物在80℃下加熱16小時。使反應物冷卻，並倒入水中。以醋酸乙酯萃取水相(2x)，並以水、鹽水洗滌合併之液相，且以硫酸鈉脫水乾燥。在減壓下濃縮有機相。使殘留物藉矽膠層析純化，以(己烷/醋酸乙酯90：10)溶離，而得標題化合物(7.0克，66%)。Example 228b Example 228a (7.8 g, 30 mmol) of 4-[1-(3-bromophenyl)-ethoxy]-1-chloro-2-nitro-benzene in DMF (50 mL) Inside, 4-chloro-3-nitro-phenol (5.14 g, 30.0 mmol) was added with K 2 CO 3 (8.18 g, 60 mmol). The mixture was heated at 80 ° C for 16 hours. The reaction was allowed to cool and poured into water. The aqueous phase was extracted with ethyl acetate (2×), and the combined liquid phase was washed with water and brine and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAcjjjjjj
實例228c 4－{4－[1－(3－溴苯基)－乙氧基]－2－硝基－苯基硫基}－酚於DMF(50毫升)中之實例228b(5.0克，14.0毫莫耳)內，添加4－巰基酚(1.7克，14.0毫莫耳)與K2 CO3 (3.8克，28毫莫耳)。將混合物在80℃下加熱16小時。使反應物冷卻，並倒入水中。以醋酸乙酯萃取水相(2x)，並以水、鹽水洗滌合併之液相，且以硫酸鈉脫水乾燥。在減壓下濃縮有機相。使殘留物藉矽膠層析純化，以(己烷/醋酸乙酯/甲醇75：15：5)溶離，而得標題化合物(5.2克，83%)。Example 228c Example 228b of 4-{4-[1-(3-bromophenyl)-ethoxy]-2-nitro-phenylsulfanyl}-phenol in DMF (50 mL) (5.0 g, 14.0 Within the millimolar, 4-nonylphenol (1.7 g, 14.0 mmol) was added with K 2 CO 3 (3.8 g, 28 mmol). The mixture was heated at 80 ° C for 16 hours. The reaction was allowed to cool and poured into water. The aqueous phase was extracted with ethyl acetate (2×), and the combined liquid phase was washed with water and brine and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAcjjjjjj
實例228d 4－{2－胺基－4－[1－(3－溴苯基)－乙氧基]－苯基硫基}－酚按實例10E中所述，使得自實例228c之產物(5.4克，12.2毫莫耳)與Fe及NH4 Cl反應，而得標題化合物(3.6克，76%)。Example 228d 4-{2-Amino-4-[1-(3-bromophenyl)-ethoxy]-phenylsulfanyl}-phenol as described in Example 10E, afforded product from Example 228. g, 12.2 mmol) and the reaction Fe and NH 4 Cl, to give the title compound (3.6 g, 76%).
實例228e 4－[4－[1－(3－溴苯基)－乙氧基]－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚於125℃下，使得自實例57A之產物(125毫克，0.72毫莫耳)與實例228d(298毫克，0.72毫莫耳)在醋酸(10毫升)中，於密封管中反應5分鐘，獲得粗製標題化合物，使其藉HPLC以TFA純化，提供產物，為三氟醋酸(120毫克，31%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：1.54(d,J＝6.25 Hz,3H)5.52(q,J＝6.25 Hz,1H)6.66(d,J＝8.82 Hz,2H)6.85(s,1H)7.07－7.12(m,3H)7.19(s,1H)7.32(t,J＝7.72 Hz,1H)7.39－7.49(m,2H)7.61(s,2H)8.57(s,1H)8.80(s,1H)9.06(s,1H)9.65(s,1H)；MS(ESI－)m/z 545(M－H)－.Example 228e 4-[4-[1-(3-Bromophenyl)-ethoxy]-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]- The phenol was reacted at 125 ° C from the product of Example 57A (125 mg, 0.72 mmol) and Example 228d (298 mg, 0.72 mmol) in acetic acid (10 mL). The title compound was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 1.54 (d, J = 6.25 Hz, 3H) 5.52 (q, J = 6.25 Hz, 1H) 6.66 (d, J = 8.82 Hz, 2H) 6.85 ( s,1H)7.07-7.12(m,3H)7.19(s,1H)7.32(t,J=7.72 Hz,1H)7.39-7.49(m,2H)7.61(s,2H)8.57(s,1H)8.80 (s, 1H) 9.06 (s, 1H) 9.65 (s, 1H); MS (ESI-) m/z 545 (M-H)-.
4－[4－[1－(3－溴苯基)－乙氧基]－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-[1-(3-Bromophenyl)-ethoxy]-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfide Phenol
於125℃下，使得自實例10B之產物(110毫克，0.58毫莫耳)與實例228d(243毫克，0.58毫莫耳)在醋酸(10毫升)中，於密封管中反應5分鐘，獲得粗製標題化合物，使其藉HPLC以TFA純化，提供產物，為三氟醋酸(100毫克，30%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：1.33(d,J＝6.25 Hz,3H)2.53(s,3H)5.31(q,J＝6.43 Hz,1H)6.44(d,J＝8.82 Hz,2H)6.68(dd,J＝8.82,2.57 Hz,1H)6.85－6.92(m,3H)6.95(d,J＝2.57 Hz,1H)7.11(t,J＝7.72 Hz,1H)7.19－7.27(m,2H)7.40(s,1H)7.44(d,J＝8.46 Hz,1H)8.44(s,1H)8.56(d,J＝8.46 Hz,1H)；MS(ESI＋)m/z 560(M＋H)＋.The product from Example 10B (110 mg, 0.58 mmol) and 228d (243 mg, 0.58 mmol) in acetic acid (10 mL) were reacted in a sealed tube for 5 minutes at 125 ° C to obtain crude. The title compound was purified by EtOAc (EtOAc) elute 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 1.33 (d, J = 6.25 Hz, 3H) 2.53 (s, 3H) 5.31 (q, J = 6.43 Hz, 1H) 6.44 (d, J = 8.82) Hz, 2H) 6.68 (dd, J = 8.82, 2.57 Hz, 1H) 6.85-6.92 (m, 3H) 6.95 (d, J = 2.57 Hz, 1H) 7.11 (t, J = 7.72 Hz, 1H) 7.19-7.27 (m, 2H) 7.40 (s, 1H) 7.44 (d, J = 8.46 Hz, 1H) 8.44 (s, 1H) 8.56 (d, J = 8.46 Hz, 1H); MS (ESI+) m/z 560 (M+H) )+.
4－[4－[1－(3－溴苯基)－乙氧基]－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-[1-(3-Bromophenyl)-ethoxy]-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl Thio]-phenol
於125℃下，使得自實例36E之產物(130毫克，0.60毫莫耳)與實例228d(250毫克，0.60毫莫耳)在醋酸(10毫升)中，於密封管中反應5分鐘，獲得粗製標題化合物，使其藉HPLC以TFA純化，提供產物，為三氟醋酸(140毫克，39%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：1.34(d,J＝6.99 Hz,6H)1.54(d,J＝6.25 Hz,3H)3.26(q,1H)5.52(q,J＝6.62 Hz,1H)6.65(d,J＝8.46 Hz,2H)6.92(dd,J＝8.82,2.94 Hz,1H)7.10(m,4H)7.32(t,J＝7.72 Hz,1H)7.39－7.50(m,2H)7.60(s,1H)7.79(d,J＝8.46 Hz,1H)8.70(s,1H)8.86(d,J＝8.46 Hz,1H)9.72(s,1H)；MS(ESI＋)m/z 588(M＋H)＋.The product from Example 36E (130 mg, 0.60 mmol) and 228d (250 mg, 0.60 mmol) in acetic acid (10 mL) were reacted in a sealed tube for 5 minutes at 125 ° C to obtain crude. The title compound was purified by EtOAc EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 1.34 (d, J = 6.99 Hz, 6H) 1.54 (d, J = 6.25 Hz, 3H) 3.26 (q, 1H) 5.52 (q, J = 6.62) Hz, 1H) 6.65 (d, J = 8.46 Hz, 2H) 6.92 (dd, J = 8.82, 2.94 Hz, 1H) 7.10 (m, 4H) 7.32 (t, J = 7.72 Hz, 1H) 7.39-7.50 (m , 2H) 7.60 (s, 1H) 7.79 (d, J = 8.46 Hz, 1H) 8.70 (s, 1H) 8.86 (d, J = 8.46 Hz, 1H) 9.72 (s, 1H); MS (ESI+) m/ z 588(M+H)+.
4－[4－(3－溴－苄氧基)－2－(7－第三－丁基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(3-Bromo-benzyloxy)-2-(7-tris-butyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]- phenol
將得自實例127A之產物(147毫克，0.63毫莫耳)與得自實例15A之產物(256毫克，0.63毫莫耳)在2毫升冰醋酸中，於120℃下加熱15分鐘。冷卻至室溫，並在真空下移除醋酸。使粗產物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽45毫克，10%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：1.43(s,9H)5.139(s,2H)6.66(d,J＝8.83 Hz,2H)7.01(d,J＝6.62 Hz,1H)7.11(d,J＝8.83 Hz,2H)7.19(m,1H)7.37(m,1H)7.46(d,J＝7.72 Hz,1H)7.54(d,J＝6.62 Hz,1H)7.66(s,1H)7.95(d,J＝8.09 Hz,1H)8.69(s,1H)8.88(d,J＝8.83 Hz,1H)9.68(s,1H)；MS(ESI＋)m/z 587,589(M＋H－TFA)＋；(ESI－)m/z 585,587(M－H－TFA)－.The product from Example 127A (147 mg, 0.63 mmol) was obtained from the product from Example 15A (256 mg, 0.63 m. Cool to room temperature and remove the acetic acid under vacuum. The crude product was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 1.43 (s, 9H) 5.139 (s, 2H) 6.66 (d, J = 8.83 Hz, 2H) 7.01 (d, J = 6.62 Hz, 1H) 7.11 (d, J = 8.83 Hz, 2H) 7.19 (m, 1H) 7.37 (m, 1H) 7.46 (d, J = 7.72 Hz, 1H) 7.54 (d, J = 6.62 Hz, 1H) 7.66 (s, 1H) 7.95 (d, J = 8.09 Hz, 1H) 8.69 (s, 1H) 8.88 (d, J = 8.83 Hz, 1H) 9.68 (s, 1H); MS (ESI+) m/z 587, 589 (M+H-TFA)+; (ESI-)m/z 585,587 (M-H-TFA)-.
4－[4－(3－溴－苯氧基甲基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(3-Bromo-phenoxymethyl)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]- phenol
實例232A 4－[2－胺基－4－(3－溴－苯氧基甲基)－苯基硫基]－酚將4－[4－(3－溴－苯氧基甲基)－2－硝基－苯基硫基]－酚(325毫克，0.752毫莫耳)、鐵粉(210毫克，3.76毫莫耳)及氯化銨(60毫克，1.13毫莫耳)在四氫呋喃(5毫升)、水(1.5毫升)及乙醇(5毫升)中之溶液，於回流下加熱2.5小時。於冷卻至室溫後，使溶液經過矽藻土墊過濾，其以甲醇洗滌。然後在真空下濃縮濾液，接著溶於水(20毫升)中，並以醋酸乙酯(2 x 20毫升)萃取。使有機萃液脫水乾燥，及在真空下濃縮，提供標題化合物，為淡黃色固體(240毫克，79%)。Example 232A 4-[2-Amino-4-(3-bromo-phenoxymethyl)-phenylthio]-phenol 4-[4-(3-bromo-phenoxymethyl)-2 -Nitro-phenylthio]-phenol (325 mg, 0.752 mmol), iron powder (210 mg, 3.76 mmol) and ammonium chloride (60 mg, 1.13 mmol) in tetrahydrofuran (5 ml) A solution of water (1.5 ml) and ethanol (5 ml) was heated under reflux for 2.5 hours. After cooling to room temperature, the solution was filtered through a pad of Celite, which was washed with methanol. The filtrate was concentrated in vacuo then EtOAc (EtOAc)EtOAc. The organic extract was dried with EtOAc (EtOAc)
實例232B 4－[4－(3－溴－苯氧基甲基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚將得自實例232A之產物(85毫克，0.211毫莫耳)與得自實例36E之產物(46毫克，0.211毫莫耳)在醋酸(3毫升)中之溶液，於130℃下加熱15分鐘。然後使溶液冷卻至室溫，在真空下移除醋酸，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(63毫克，43%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：1.35(d,J＝7.0 Hz,6H),3.25(m,1H),5.13(s,2H),6.77(d,J＝8.8 Hz,2H),7.02(d,J＝8.1 Hz,2H),7.15(m,1H),7.23(m,4H),7.36(m,1H),7.46(s,1H),7.83(d,J＝8.8 Hz,1H),8.76(s,1H),8.95(d,J＝8.8 Hz,1H),9.88(s,1H),11.22(bs,1H)；MS(ESI)＋m/z 573/575(M＋H)＋.Example 232B 4-[4-(3-Bromo-phenoxymethyl)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio The phenol was obtained from a solution of the product from Example 232A (85 mg, 0.211 mmol) and the product from Example 36E (46 mg, 0.211 mmol) in acetic acid (3 mL). 15 minutes. The solution was then cooled to rt. EtOAc (EtOAc)EtOAc. 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 1.35 (d, J = 7.0 Hz, 6H), 3.25 (m, 1H), 5.13 (s, 2H), 6.77 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.1 Hz, 2H), 7.15 (m, 1H), 7.23 (m, 4H), 7.36 (m, 1H), 7.46 (s, 1H), 7.83 (d, J = 8.8 Hz, 1H), 8.76 (s, 1H), 8.95 (d, J = 8.8 Hz, 1H), 9.88 (s, 1H), 11.22 (bs, 1H); MS (ESI) + m/z 573/575 (M+H )+.
4－[4－(3－溴－苯氧基甲基)－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(3-Bromo-phenoxymethyl)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
將得自實例232A之產物(60毫克，0.149毫莫耳)與得自實例10B之產物(28毫克，0.149毫莫耳)在醋酸(3毫升)中之溶液，於130℃下加熱15分鐘。然後使溶液冷卻至室溫，在真空下移除醋酸，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(46毫克，47%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：2.72(s,3H),5.12(s,2H),6.77(d,J＝8.5 Hz,2H),7.02(m,2H),7.16(m,1H),7.23(m,4H),7.36(m,1H),7.47(s,1H),7.70(d,J＝8.8 Hz,1H),8.70(s,1H),8.86(d,J＝8.5 Hz,1H),9.87(s,1H),10.95(bs,1H)；MS(ESI)＋ m/z 545/547(M＋H)＋.A solution of the product from Example 232A (60 mg, 0.149 mmol) eluted from EtOAc (EtOAc) The solution was then cooled to rt. EtOAc (EtOAc m. 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 2.72 (s, 3H), 5.12 (s, 2H), 6.77 (d, J = 8.5 Hz, 2H), 7.02 (m, 2H), 7.16 ( m,1H), 7.23 (m, 4H), 7.36 (m, 1H), 7.47 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 8.70 (s, 1H), 8.86 (d, J) = 8.5 Hz, 1H), 9.87 (s, 1H), 10.95 (bs, 1H); MS (ESI) + m/z 545/547 (M+H)+.
4－[4－(2,5－二氟－苄氧基)－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(2,5-Difluoro-benzyloxy)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
實例234a 2－溴基甲基－1,4－二氟－苯於(2,5－二氟－苯基)－甲醇(4.8克，33.6毫莫耳)在二氯甲烷(40毫升)中之溶液內，逐滴添加三溴化磷(94克，33.6毫莫耳)。將混合物於室溫下攪拌16小時。將反應物傾倒在冰/水上。以碳酸氫鈉使水相呈鹼性。以二氯甲烷萃取水相。在減壓下濃縮有機相。使殘留物藉矽膠層析純化，以(己烷/醋酸乙酯90：10)溶離，而得標題化合物(3.5克，50%)。Example 234a 2-Bromomethyl-1,4-difluoro-benzene in (2,5-difluoro-phenyl)-methanol (4.8 g, 33.6 mmol) in dichloromethane (40 mL) Phosphorus tribromide (94 g, 33.6 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 16 hours. The reaction was poured onto ice/water. The aqueous phase was made alkaline with sodium bicarbonate. The aqueous phase was extracted with dichloromethane. The organic phase was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc elut elut elut elut elut
實例234b 1－氯基－4－(2,5－氟－苄氧基)－2－硝基－苯於DMF(50毫升)中之實例234a(2.2克，10.4毫莫耳)內，添加4－氯基－3－硝基－酚(1.8克，10.4毫莫耳)與K2 CO3 (2.87克，20.8毫莫耳)。將混合物在80℃下加熱16小時。使反應物冷卻，並倒入水中。以醋酸乙酯萃取水相(2x)，並以水、鹽水洗滌合併之液相，且以硫酸鈉脫水乾燥。在減壓下濃縮有機相。使殘留物藉矽膠層析純化，以(己烷/醋酸乙酯90：10)溶離，而得標題化合物(2.48克，66%)。Example 234b 1-Chloro-4-(2,5-fluoro-benzyloxy)-2-nitro-benzene in Example 234a (2.2 g, 10.4 mmol) in DMF (50 mL) -Chloro-3-nitro-phenol (1.8 g, 10.4 mmol) with K 2 CO 3 (2.87 g, 20.8 mmol). The mixture was heated at 80 ° C for 16 hours. The reaction was allowed to cool and poured into water. The aqueous phase was extracted with ethyl acetate (2×), and the combined liquid phase was washed with water and brine and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc elut elut elut elut elut
實例234c 4－[4－(2,5－二氟－苄氧基)－2－硝基－苯基硫基]－酚於DMF(50毫升)中之實例234b(2.5克，8.3毫莫耳)內，添加4－巰基酚(1.0克，8.3毫莫耳)與K2 CO3 (2.3克，16.5毫莫耳)。將混合物在80℃下加熱16小時。使反應物冷卻，並倒入水中。以醋酸乙酯萃取水相(2x)，並以水、鹽水洗滌合併之液相，且以硫酸鈉脫水乾燥。在減壓下濃縮有機相。使殘留物藉急驟式層析純化，以(己烷/醋酸乙酯/甲醇75：15：5)溶離，而得標題化合物(1.7克，52%)。Example 234c Example 234b (2.5 g, 8.3 mmol) of 4-[4-(2,5-difluoro-benzyloxy)-2-nitro-phenylthio]-phenol in DMF (50 mL) Within the mixture, 4-nonylphenol (1.0 g, 8.3 mmol) and K 2 CO 3 (2.3 g, 16.5 mmol) were added. The mixture was heated at 80 ° C for 16 hours. The reaction was allowed to cool and poured into water. The aqueous phase was extracted with ethyl acetate (2×), and the combined liquid phase was washed with water and brine and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography eluting elut elut elut elut elut elut
實例234d 4－[2－胺基－4－(2,5－二氟－苄氧基)－苯基硫基]－酚按實例10E中所述，使得自實例234c之產物(1.70克，4.2毫莫耳)與Fe及NH4 Cl反應，而得標題化合物(1.3克，84%)。Example 234d 4-[2-Amino-4-(2,5-difluoro-benzyloxy)-phenylsulfanyl]-phenol as described in Example 10E, yielded product from Example 234c (1.70 g, 4.2 mmol) and the reaction Fe and NH 4 Cl, to give the title compound (1.3 g, 84%).
實例234e 4－[4－(2,5－二氟－苄氧基)－2－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚於125℃下，使得自實例57A之產物(100毫克，0.57毫莫耳)與實例234d(206毫克，0.57毫莫耳)在醋酸(10毫升)中，於密封管中反應5分鐘，獲得粗製標題化合物，使其藉HPLC以TFA純化，提供產物，為三氟醋酸(140毫克，39%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：5.13(s,2H)6.67(d,J＝8.46 Hz,2H)6.93－7.01(m,1H)7.10－7.16(m,3H)7.22－7.37(m,4H)7.41－7.52(m,J＝5.79,5.79,2.76 Hz,1H)7.64(dd,J＝8.09,4.41 Hz,1H)8.53(s,1H)8.84(d,J＝7.72 Hz,1H)9.05(s,1H)；MS(ESI＋)m/z 489(M＋H)＋.Example 234e 4-[4-(2,5-Difluoro-benzyloxy)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol at 125 The product from Example 57A (100 mg, 0.57 mmol) was obtained from m. The product was purified by TFA to give the product as trifluoroacetic acid (140 mg, 39%). 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 5.13 (s, 2H) 6.67 (d, J = 8.46 Hz, 2H) 6.93-7.01 (m, 1H) 7.10-7.16 (m, 3H)7.22- 7.37 (m, 4H) 7.41 - 7.52 (m, J = 5.79, 5.79, 2.76 Hz, 1H) 7.64 (dd, J = 8.09, 4.41 Hz, 1H) 8.53 (s, 1H) 8.84 (d, J = 7.72 Hz) ,1H)9.05(s,1H);MS(ESI+)m/z 489(M+H)+.
4－[4－(2,5－二氟－苄氧基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(2,5-Difluoro-benzyloxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio] -phenol
於125℃下，使得自實例36E之產物(100毫克，0.46毫莫耳)與實例234d(206毫克，0.46毫莫耳)在醋酸(10毫升)中，於密封管中反應5分鐘，獲得粗製標題化合物，使其藉HPLC以TFA純化，提供產物，為三氟醋酸(140毫克，39%)。1 HNMR(300 MHz,DMSO－d6 )δ ppm：1.34(d,J＝6.62 Hz,6H)5.14(s,2H)6.66(d,J＝8.46 Hz,2H)7.06(d,J＝2.57 Hz,1H)7.12(d,J＝8.46 Hz,2H)7.21－7.35(m,4H)7.44(s,1H)7.77(d,J＝8.46 Hz,1H)8.69(s,1H)8.88(d,J＝8.46 Hz,1H)9.70(s,1H)；MS(ESI＋)m/z 531(M＋H)＋.The product from Example 36E (100 mg, 0.46 mmol) and 234d (206 mg, 0.46 mmol) in acetic acid (10 mL) were reacted in a sealed tube for 5 minutes at 125 ° C to obtain crude. The title compound was purified by EtOAc EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 1.34 (d, J = 6.62 Hz, 6H) 5.14 (s, 2H) 6.66 (d, J = 8.46 Hz, 2H) 7.06 (d, J = 2.57 Hz ,1H)7.12(d,J=8.46 Hz,2H)7.21-7.35(m,4H)7.44(s,1H)7.77(d,J=8.46 Hz,1H)8.69(s,1H)8.88(d,J =8.46 Hz, 1H) 9.70 (s, 1H); MS (ESI+) m/z 531 (M+H)+.
4－[4－(2－氯基－5－氟－苄氧基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-(2-Chloro-5-fluoro-benzyloxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfide Phenol
實例236a 2－溴基甲基－1－氯基－4－氟－苯於(2－氯基－5－氟苯基)－甲醇(5.0克，31.1毫莫耳)在二氯甲烷(40毫升)中之溶液內，逐滴添加三溴化磷(87克，31.1毫莫耳)。將混合物於室溫下攪拌16小時。將反應物傾倒在冰/水上。以碳酸氫鈉使水相呈鹼性。以二氯甲烷萃取水相。在減壓下濃縮有機相。使殘留物藉矽膠層析純化，以(己烷/醋酸乙酯90：10)溶離，而得標題化合物(5.75克，82.5%)。Example 236a 2-Bromomethyl-1-chloro-4-fluoro-benzene in (2-chloro-5-fluorophenyl)-methanol (5.0 g, 31.1 mmol) in dichloromethane (40 mL In the solution in the solution, phosphorus tribromide (87 g, 31.1 mmol) was added dropwise. The mixture was stirred at room temperature for 16 hours. The reaction was poured onto ice/water. The aqueous phase was made alkaline with sodium bicarbonate. The aqueous phase was extracted with dichloromethane. The organic phase was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc elutcd
實例236b 1－氯基－4－(2－氯基－5－氟－苄氧基)－2－硝基－苯於DMF(50毫升)中之實例236a(5.7克，25.7毫莫耳)內，添加4－氯基－3－硝基－酚(4.46克，25.7毫莫耳)與K2 CO3 (7.10克，51.4毫莫耳)。將混合物在80℃下加熱16小時。使反應物冷卻，並倒入水中。以醋酸乙酯萃取水相(2x)，並以水、鹽水洗滌合併之液相，且以硫酸鈉脫水乾燥。在減壓下濃縮有機相。使殘留物藉矽膠層析純化，以(己烷/醋酸乙酯90：10)溶離，而得標題化合物(7.0克，86%)。Example 236b 1-Chloro-4-(2-chloro-5-fluoro-benzyloxy)-2-nitro-benzene in Example 236a (5.7 g, 25.7 mmol) in DMF (50 mL) 4-Chloro-3-nitro-phenol (4.46 g, 25.7 mmol) was added with K 2 CO 3 (7.10 g, 51.4 mmol). The mixture was heated at 80 ° C for 16 hours. The reaction was allowed to cool and poured into water. The aqueous phase was extracted with ethyl acetate (2×), and the combined liquid phase was washed with water and brine and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjj:
實例236c 4－[4－(2－氯基－5－氟－苄氧基)－2－硝基－苯基硫基]－酚於DMF(50毫升)中之實例236b(2.5克，8.3毫莫耳)內，添加4－巰基酚(1.0克，8.3毫莫耳)與K2 CO3 (2.3克，16.5毫莫耳)。將混合物在80℃下加熱16小時。使反應物冷卻，並倒入水中。以醋酸乙酯萃取水相(2x)，並以水、鹽水洗滌合併之液相，且以硫酸鈉脫水乾燥。在減壓下濃縮有機相。使殘留物藉矽膠層析純化，以(己烷/醋酸乙酯/甲醇(70：25：5)溶離，而得標題化合物(5.0克，78%)。Example 236c Example 236b of 4-[4-(2-chloro-5-fluoro-benzyloxy)-2-nitro-phenylsulfanyl]-phenol in DMF (50 mL) (2.5 g, 8.3 m Within the moles, 4-nonylphenol (1.0 g, 8.3 mmol) and K 2 CO 3 (2.3 g, 16.5 mmol) were added. The mixture was heated at 80 ° C for 16 hours. The reaction was allowed to cool and poured into water. The aqueous phase was extracted with ethyl acetate (2×), and the combined liquid phase was washed with water and brine and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAcjjjjjj
實例236d 4－[2－胺基－4－(2－氯基－5－氟－苄氧基)－苯基硫基]－酚按實例10E中所述，使得自實例236c之產物(4.2克，10.2毫莫耳)與Fe及NH4 Cl反應，而得標題化合物(3.0克，77%)。Example 236d 4-[2-Amino-4-(2-chloro-5-fluoro-benzyloxy)-phenylsulfanyl]-phenol as described in Example 10E, yielded product from Example 236. , 10.2 mmol) and the reaction Fe and NH 4 Cl, to give the title compound (3.0 g, 77%).
實例236e 4－[4－(2－氯基－5－氟－苄氧基)－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚於125℃下，使得自實例36E之產物(125毫克，0.72毫莫耳)與實例236d(298毫克，0.72毫莫耳)在醋酸(10毫升)中，於密封管中反應5分鐘，獲得粗製標題化合物，藉由添加***至殘留物中使其純化，提供所要之產物，為醋酸(225毫克，66%)。1 H NMR(300 MHz,DMSO－d6 )δ ppm：1.32(d,J＝6.99 Hz,6H)3.21(q,1H)5.15(s,2H)6.69(d,J＝8.46 Hz,2H)6.99(dd,1H)7.13(d,J＝8.46 Hz,4H)7.25－7.35(m,2H)7.49(dd,J＝9.38,3.13 Hz,1H)7.54－7.62(m,J＝8.82,5.15 Hz,3H)8.55(1H,s)18.74(s,1H)9.66(s,1H)9.98(s,1H)；MS(ESI－)m/z 547(M＋H)＋.Example 236e 4-[4-(2-Chloro-5-fluoro-benzyloxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzene The thiol]-phenol at 125 ° C, the product from Example 36E (125 mg, 0.72 mmol) and Example 236d (298 mg, 0.72 mmol) in acetic acid (10 mL) in a sealed tube The reaction was carried out for 5 minutes to give the title compound. 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm: 1.32 (d, J = 6.99 Hz, 6H) 3.21 (q, 1H) 5.15 (s, 2H) 6.69 (d, J = 8.46 Hz, 2H) 6.99 (dd, 1H) 7.13 (d, J = 8.46 Hz, 4H) 7.25-7.35 (m, 2H) 7.49 (dd, J = 9.38, 3.13 Hz, 1H) 7.54 - 7.62 (m, J = 8.82, 5.15 Hz, 3H) 8.55 (1H, s) 18.74 (s, 1H) 9.66 (s, 1H) 9.98 (s, 1H); MS (ESI-) m/z 547 (M+H)+.
4－[5－苄氧基－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[5-Benzyloxy-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
實例237A 4－苄氧基－2－氟基－1－硝基－苯將3－氟基－4－硝基酚(0.30克，1.91毫莫耳)、溴化苄(0.36克，2.10毫莫耳，1.1當量)、碳酸鉀(0.792克，5.73毫莫耳，3.0當量)及碘化四丁基銨(5.0毫克，0.014毫莫耳，0.007當量)在二甲基甲醯胺(5毫升)中之混合物，於室溫下攪拌16小時。將水(20毫升)添加至反應混合物中，並藉真空過濾單離所形成之固體沉澱物，及乾燥，提供標題化合物(0.455克，96%)，為黃色固體。Example 237A 4-Benzyloxy-2-fluoro-1-nitro-benzene 3-fluoro-4-nitrophenol (0.30 g, 1.91 mmol), benzyl bromide (0.36 g, 2.10 mmol) Ears, 1.1 equivalents), potassium carbonate (0.792 g, 5.73 mmol, 3.0 equivalents) and tetrabutylammonium iodide (5.0 mg, 0.014 mmol, 0.007 equivalent) in dimethylformamide (5 mL) The mixture was stirred at room temperature for 16 hours. Water (20 mL) was added to EtOAc m.
實例237B 4－(5－苄氧基－2－硝基－苯基硫基)－酚將實例237A之產物(0.301克，1.22毫莫耳)、4－巰基酚(0.184克，1.46毫莫耳，1.2當量)及碳酸銫(0.952克，2.92毫莫耳，2.4當量)在二甲基甲醯胺(10毫升)中，於100℃油浴中加熱3小時，然後冷卻至室溫。添加水(20毫升)，並將混合物於室溫下攪拌2小時，且藉真空過濾單離所形成之固體，及乾燥，提供標題化合物(0.405克，94%)，為黃色固體。Example 237B 4-(5-Benzyloxy-2-nitro-phenylsulfanyl)-phenol The product of Example 237A (0.301 g, 1.22 mmol), 4-nonylphenol (0.184 g, 1.46 mmol) , 1.2 equivalents) and cesium carbonate (0.952 g, 2.92 mmol, 2.4 eq.) were heated in dimethylformamide (10 mL) in a 100 ° C oil bath for 3 h and then cooled to room temperature. Water (20 mL) was added and the~~~~~~~~~~~~~~~~~~~~~~~~~~~
實例237C 4－(2－胺基－5－苄氧基－苯基硫基)－酚將實例237B之產物(0.390克，1.10毫莫耳)、鐵粉(0.248克，4.41毫莫耳，4.0當量)及氯化銨(0.071克，1.32毫莫耳，1.2當量)在四氫呋喃(6毫升)、甲醇(6毫升)及水(2毫升)中，於回流下加熱16小時，然後冷卻至室溫。使反應混合物經過矽藻土過濾，以甲醇沖洗，並在減壓下蒸發濾液，提供標題化合物(0.340克，95%)，為灰色粉末，將其用於後續反應中，無需進一步純化。Example 237C 4-(2-Amino-5-benzyloxy-phenylsulfanyl)-phenol The product of Example 237B (0.390 g, 1.10 mmol), iron powder (0.248 g, 4.41 m. Equivalent) and ammonium chloride (0.071 g, 1.32 mmol, 1.2 eq.) in tetrahydrofuran (6 ml), methanol (6 ml) and water (2 ml). . The reaction mixture was taken from EtOAc EtOAc EtOAc.
實例237D 4－[5－苄氧基－2－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚將實例237C之產物(0.0908克，0.281毫莫耳)與實例36E之產物(0.0607克，0.281毫莫耳)在冰醋酸(2毫升)中，於140℃油浴中加熱10分鐘，冷卻至室溫，及在減壓下蒸發。使殘留物於矽膠上藉管柱層析純化，以5%甲醇/氯甲烷溶離，提供標題化合物(0.0368克，27%)，為黃褐色固體。1 H NMR(300 MHz,DMSO－D6)δ ppm：9.88(s,2H),8.82(d,J＝8.46 Hz,1H),8.52(s,1H),7.58(d,J＝8.46 Hz,1H),7.28－7.42(m,5H),7.19－7.28(m,3H),6.87(dd,J＝8.64,2.76 Hz,1H),6.75－6.84(m,2H),6.38(d,J＝2.57 Hz,1H),4.99(s,2H),3.14－3.27(m,1H),1.32(d,J＝6.99 Hz,6H)；MS(ESI＋ )m/z 495.2(M＋H)＋ ,(ESI－ )m/z 493.2(M－H)－ .Example 237D 4-[5-Benzyloxy-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol The product of Example 237C (0.0908 g, 0.281 mmol) and the product of Example 36E (0.0607 g, 0.281 mmol) in glacial acetic acid (2 mL), heated in an oil bath of 140 ° C for 10 min, cooled to room temperature, and reduced Press down to evaporate. The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut 1 H NMR (300 MHz, DMSO-D6) δ ppm: 9.88 (s, 2H), 8.82 (d, J = 8.46 Hz, 1H), 8.52 (s, 1H), 7.58 (d, J = 8.46 Hz, 1H ), 7.28-7.42 (m, 5H), 7.19-7.28 (m, 3H), 6.87 (dd, J = 8.64, 2.76 Hz, 1H), 6.75-6.84 (m, 2H), 6.38 (d, J = 2.57) Hz, 1H), 4.99 (s, 2H), 3.14 - 3.27 (m, 1H), 1.32 (d, J = 6.99 Hz, 6H); MS (ESI + ) m/z 495.2 (M+H) + , (ESI - ) m/z 493.2(M-H) - .
4－[2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－苯乙烯基－苯基硫基]－酚4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-styryl-phenylthio]-phenol
實例238A 4－(4－溴基－2－硝基－苯基硫基)－酚將4－溴基－1－氟基－2－硝基苯(0.44克，2.0毫莫耳)、4－巰基酚(0.303克，2.4毫莫耳)及碳酸銫(1.56克，4.8毫莫耳，2.4當量)在二甲基甲醯胺(10毫升)中之混合物，於100℃油浴中加熱3小時，然後冷卻至室溫。將反應混合物傾倒於冰水(50毫升)上，藉由添加1N鹽酸水溶液調整至pH 3，並以醋酸乙酯(3 x 100毫升)萃取。使合併之有機層以無水硫酸鎂脫水乾燥，過濾，並蒸發，提供標題化合物，為濃稠黃色油(0.70克，>100%)，使用之而無需進一步純化。Example 238A 4-(4-Bromo-2-nitro-phenylthio)-phenol 4-bromo-1-fluoro-2-nitrobenzene (0.44 g, 2.0 mmol), 4- a mixture of nonylphenol (0.303 g, 2.4 mmol) and cesium carbonate (1.56 g, 4.8 mmol, 2.4 eq.) in dimethylformamide (10 mL), heated in a 100 ° C oil bath for 3 h Then cooled to room temperature. The reaction mixture was poured into ice water (50 ml), and then evaporated toEtOAc. The combined organic layers were dried with EtOAc EtOAc.
實例238B 4－(2－胺基－4－溴苯基硫基)－酚將得自實例238A之產物(0.302克，0.926毫莫耳)、鐵粉(0.208克，3.7毫莫耳，4.0當量)及氯化銨(0.059克，1.11毫莫耳，1.2當量)在甲醇(6毫升)、四氫呋喃(6毫升)及水(2毫升)之混合物中之混合物，於回流下加熱5小時，然後冷卻至室溫。使反應混合物經過矽藻土過濾，並以甲醇(25毫升)沖洗過濾墊。在減壓下蒸發濾液，留下褐色玻璃態固體(0.27克，99%)，使用之而無需進一步純化。Example 238B 4-(2-Amino-4-bromophenylthio)-phenol The product from Example 238A (0.302 g, 0.926 mmol), iron powder (0.208 g, 3.7 mmol, 4.0 eq. And a mixture of ammonium chloride (0.059 g, 1.11 mmol, 1.2 eq.) in a mixture of methanol (6 ml), tetrahydrofuran (6 ml) and water (2 ml), heated under reflux for 5 hours, then cooled To room temperature. The reaction mixture was filtered through EtOAc (EtOAc) (EtOAc) The filtrate was evaporated under reduced pressure to leave a brown brown solid (0.27 g, 99%).
實例238C 4－[4－溴基－2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚將之產物得自實例238B(0.158克，0.533毫莫耳)與得自實例10B之產物(0.100克，0.533毫莫耳)在冰醋酸(2毫升)中之混合物，於130℃油浴中加熱30分鐘。添加另一數量之得自實例10B之產物(0.060克，0.319毫莫耳)，並將反應混合物於130℃下再加熱30分鐘。然後使反應混合物冷卻至室溫，並在減壓下蒸發溶劑。將殘留物以2－丙醇研製，且藉真空過濾單離所形成之固體，及乾燥，提供標題化合物(0.083克，36%產率)，為米黃色固體。Example 238C 4-[4-Bromo-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)phenylsulfanyl]-phenol was obtained from Example 238B (0.158 g, 0.533 mmol) and a mixture of the product from Example 10B (0.100 g, 0.533 mmol) in EtOAc (2 mL). Another amount of product from Example 10B (0.060 g, 0.319 mmol) was added and the reaction mixture was then warmed for 30 min. The reaction mixture was then cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was triturated with EtOAc (EtOAc)EtOAc.
實例238D 4－[2－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－苯乙烯基－苯基硫基]－酚將得自實例238C之產物(0.0791克，0.180毫莫耳)、苯乙烯(0.176克，1.69毫莫耳，9.4當量)、醋酸鈀(II)(6.2毫克，0.0276毫莫耳，0.15當量)、三－鄰－甲苯基膦(13.3毫克，0.0437毫莫耳，0.24當量)及二－異丙基乙胺(0.697克，0.539毫莫耳，3.0當量)在二甲基甲醯胺(2毫升)中之混合物，於130℃油浴中加熱98小時。然後使混合物冷卻至室溫，並在氮氣流下蒸發溶劑。使殘留物於醋酸乙酯與水之間作分液處理，並以醋酸乙酯進一步萃取水層。使合併之有機層以無水硫酸鎂脫水乾燥，過濾，及蒸發。使殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(6.1毫克，10%產率)。1 H NMR(300 MHz,DMSO－D6)δ ppm：11.27(s,1H),9.89(s,1H),8.93(d,J＝8.09 Hz,1H),8.79(s,1H),7.78(d,J＝8.82 Hz,1H),7.66(s,1H),7.58(d,J＝7.35 Hz,2H),7.52(dd,J＝8.09,1.47 Hz,1H),7.37(t,J＝7.35 Hz,2H),7.19－7.31(m,5H),7.00(d,J＝8.09 Hz,1H),6.73－6.81(m,2H),2.75(s,3H).Example 238D 4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-styryl-phenylthio]-phenol will be obtained from Example 238C Product (0.0791 g, 0.180 mmol), styrene (0.176 g, 1.69 mmol, 9.4 equivalent), palladium (II) acetate (6.2 mg, 0.0276 mmol, 0.15 equivalent), tri-o-tolyl a mixture of phosphine (13.3 mg, 0.0437 mmol, 0.24 eq.) and di-isopropylethylamine (0.697 g, 0.539 mmol, 3.0 eq.) in dimethylformamide (2 mL) Heat in a °C oil bath for 98 hours. The mixture was then cooled to room temperature and the solvent was evaporated under a stream of nitrogen. The residue was partitioned between ethyl acetate and water, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 11.27 (s, 1H), 9.89 (s, 1H), 8.93 (d, J = 8.09 Hz, 1H), 8.79 (s, 1H), 7.78 (d) , J = 8.82 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J = 7.35 Hz, 2H), 7.52 (dd, J = 8.09, 1.47 Hz, 1H), 7.37 (t, J = 7.35 Hz , 2H), 7.19-7.31 (m, 5H), 7.00 (d, J = 8.09 Hz, 1H), 6.73-6.81 (m, 2H), 2.75 (s, 3H).
(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－(2－苯基硫基－5－苯乙烯基－苯基)－胺(7-Methyl-pyrido[2,3-d]pyrimidin-4-yl)-(2-phenylthio-5-styryl-phenyl)-amine
實例239A(5－溴基－2－苯基硫基－苯基)－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺5－溴基－2－(苯硫基)苯胺係根據類似實例6a、6b及6c中所述之程序，以苯硫醇取代4－巰基酚，並以4－溴基－2－硝基酚取代4－甲基－2－硝基酚製成。Example 239A (5-bromo-2-phenylthio-phenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine 5-bromo-2-( Phenylthio)aniline was substituted for 4-nonylphenol with benzenethiol and 4-methyl-2- with 4-bromo-2-nitrophenol according to procedures similar to those described in Examples 6a, 6b and 6c. Made of nitrophenol.
將得自實例10B之產物(0.188克，1.0毫莫耳)與5－溴基－2－(苯硫基)苯胺(0.280克，1.0毫莫耳)在冰醋酸(2毫升)中之混合物，於130℃油浴中加熱30分鐘。然後使反應混合物冷卻至室溫，並在減壓下蒸發溶劑。將殘留物以甲醇研製，並藉真空過濾單離所形成之固體，且乾燥，提供標題化合物(0.276克，65%產率)，為米黃色固體。A mixture of the product from Example 10B (0.188 g, 1.0 mmol) and 5-bromo-2-(phenylthio)aniline (0.280 g, 1.0 mmol) in EtOAc (2 mL) Heat in a 130 ° C oil bath for 30 minutes. The reaction mixture was then cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was triturated with EtOAc (EtOAc m.
實例239B(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－(2－苯基硫基－5－苯乙烯基－苯基)－胺將得自實例239A之產物(0.127克，0.30毫莫耳)、苯乙烯(0.133克，1.27毫莫耳，4.3當量)、醋酸鈀(II)(5.3毫克，0.0236毫莫耳，0.08當量)、三－鄰－甲苯基膦(17.7毫克，0.058毫莫耳，0.19當量)及三乙胺(0.0913克，0.90毫莫耳，3.0當量)在二甲基甲醯胺(3毫升)中之混合物，於130℃油浴中加熱98小時。然後使混合物冷卻至室溫，並在氮氣流下蒸發溶劑。使殘留物於醋酸乙酯與水之間作分液處理，並以醋酸乙酯進一步萃取水層。使合併之有機層以無水硫酸鎂脫水乾燥，過濾，並蒸發。使殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(4.0毫克，2.4%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：11.21(s,1H),8.85(d,J＝8.46 Hz,1H),8.74(s,1H),7.68－7.78(m,2H),7.55－7.65(m,J＝7.35 Hz,3H),7.19－7.46(m,11H),2.72(s,3H)；MS(ESI＋ )m/z 447.2(M＋H)＋ ,(ESI－ )m/z 445.2(M－H)－ .Example 239B (7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-(2-phenylsulfanyl-5-styryl-phenyl)-amine will be obtained from the product of Example 239A (0.127 g, 0.30 mmol), styrene (0.133 g, 1.27 mmol, 4.3 equivalents), palladium (II) acetate (5.3 mg, 0.0236 mmol, 0.08 equivalent), tri-o-tolylphosphine (17.7 mg, 0.058 mmol, 0.19 eq.) and a mixture of triethylamine (0.0913 g, 0.90 mmol, 3.0 eq.) in dimethylformamide (3 mL). 98 hours. The mixture was then cooled to room temperature and the solvent was evaporated under a stream of nitrogen. The residue was partitioned between ethyl acetate and water, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 11.21 (s, 1H), 8.85 (d, J = 8.46 Hz, 1H), 8.74 (s, 1H), 7.68-7.78 (m, 2H), 7.55 -7.65 (m, J = 7.35 Hz, 3H), 7.19-7.46 (m, 11H), 2.72 (s, 3H); MS (ESI + ) m/z 447.2 (M+H) + , (ESI - ) m/z 445.2 (M-H) - .
(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－(3－苯乙烯基－苯基)－胺(7-Methyl-pyrido[2,3-d]pyrimidin-4-yl)-(3-styryl-phenyl)-amine
實例240A(3－溴苯基)－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺將得自實例10B之產物(0.206克，1.09毫莫耳)與3－溴基苯胺(0.188克，1.09毫莫耳)在冰醋酸(1毫升)中之混合物，於130℃油浴中加熱15分鐘。然後使反應混合物冷卻至室溫，並在減壓下蒸發溶劑。將殘留物以甲醇研製，並藉真空過濾單離所形成之固體，及乾燥，提供標題化合物(0.126克，37%)，為米黃色固體。Example 240A (3-bromophenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine The product from Example 10B (0.206 g, 1.09 mmol) A mixture of 3-bromoaniline (0.188 g, 1.09 mmol) in glacial acetic acid (1 mL). The reaction mixture was then cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was triturated with EtOAc EtOAc m.
實例240B(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－(3－苯乙烯基－苯基)－胺將得自實例240A之產物(0.063克，0.20毫莫耳)、苯乙烯(0.0412克，0.40毫莫耳，2.0當量)、醋酸鈀(II)(0.9毫克，0.004毫莫耳，0.02當量)、三－鄰－甲苯基膦(2.4毫克，0.008毫莫耳，0.04當量)及三乙胺(0.0607克，0.60毫莫耳，3.0當量)在二甲基甲醯胺(2毫升)中之混合物，於120℃油浴中加熱4小時。然後使混合物冷卻至室溫，並在氮氣流下蒸發溶劑。使殘留物於醋酸乙酯與水之間作分液處理，並以醋酸乙酯進一步萃取水層。使合併之有機層以無水硫酸鎂脫水乾燥，過濾，並蒸發。使殘留物自甲醇再結晶，及乾燥，提供標題化合物，為黃色結晶(11.8毫克，17%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：10.01(s,1H),8.89(d,J＝8.46 Hz,1H),8.72(s,1H),8.03(s,1H),7.72－7.85(m,J＝6.07,2.76 Hz,1H),7.64(d,J＝6.99 Hz,2H),7.57(d,J＝8.82 Hz,1H),7.35－7.49(m,4H),7.24－7.35(m,3H),2.63－2.74(m,3H)；MS(ESI＋ )m/z 339.1(M＋H)＋ ,(ESI－ )m/z 337.1(M－H)－ .Example 240B (7-Methyl-pyrido[2,3-d]pyrimidin-4-yl)-(3-styryl-phenyl)-amine The product from Example 240A (0.063 g, 0.20 mmol) Ear), styrene (0.0412 g, 0.40 mmol, 2.0 equivalents), palladium (II) acetate (0.9 mg, 0.004 mmol, 0.02 equivalent), tri-o-tolylphosphine (2.4 mg, 0.008 mmol) The mixture was stirred in an oil bath at 120 ° C for 4 hours. A mixture of EtOAc (EtOAc, EtOAc) The mixture was then cooled to room temperature and the solvent was evaporated under a stream of nitrogen. The residue was partitioned between ethyl acetate and water, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was recrystallized from EtOAc (EtOAc m. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 10.01 (s, 1H), 8.89 (d, J = 8.46 Hz, 1H), 8.72 (s, 1H), 8.03 (s, 1H), 7.72-7.85 (m, J = 6.07, 2.76 Hz, 1H), 7.64 (d, J = 6.99 Hz, 2H), 7.57 (d, J = 8.82 Hz, 1H), 7.35-7.49 (m, 4H), 7.24 - 7.35 ( m, 3H), 2.63 - 2.74 (m, 3H); MS (ESI + ) m/z 339.1 (M+H) + , (ESI - ) m/z 337.1 (M-H) - .
(2－甲基－5－苯乙基－苯基)－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺(2-methyl-5-phenethyl-phenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
實例241A 1－甲基－2－硝基－4－苯乙烯基－苯將4－溴基－2－硝基甲苯(0.432克，2.0毫莫耳)、苯乙烯(0.250克，2.40毫莫耳，1.2當量)、醋酸鈀(II)(4.5毫克，0.020毫莫耳，0.01當量)、三－鄰－甲苯基膦(12.2毫克，0.04毫莫耳，0.02當量)及三乙胺(0.405克，4.0毫莫耳，2.0當量)在二甲基甲醯胺(2毫升)中之混合物，於120℃油浴中加熱4小時。然後使混合物冷卻至室溫，並在氮氣流下蒸發溶劑。使殘留物於醋酸乙酯與水之間作分液處理，並以醋酸乙酯進一步萃取水層。使合併之有機層以無水硫酸鎂脫水乾燥，過濾，並蒸發。使殘留物於矽膠上藉層析純化，以己烷/醋酸乙酯梯度液溶離，提供標題化合物，為黃色固體(166毫克，35%產率)。Example 241A 1-methyl-2-nitro-4-styryl-benzene 4-bromo-2-nitrotoluene (0.432 g, 2.0 mmol), styrene (0.250 g, 2.40 mmol) , 1.2 equivalents), palladium (II) acetate (4.5 mg, 0.020 mmol, 0.01 equivalent), tri-o-tolylphosphine (12.2 mg, 0.04 mmol, 0.02 equivalent) and triethylamine (0.405 g, A mixture of 4.0 mmoles, 2.0 eq. in dimethylformamide (2 mL) was heated in a 120 ° C oil bath for 4 h. The mixture was then cooled to room temperature and the solvent was evaporated under a stream of nitrogen. The residue was partitioned between ethyl acetate and water, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by chromatography EtOAcjjjjjjjj
實例241B 2－甲基－5－苯乙基－苯胺將得自實例241A之產物(0.166克，0.694毫莫耳)與10%鈀/炭(18.4毫克，0.025當量)在乙醇(10毫升)中之混合物，於一大氣壓之氫氣下攪拌16小時。然後使反應混合物經過矽藻土過濾，並在減壓下蒸發溶劑，提供標題化合物，為微紅色油(0.141克，96%產率)。Example 241B 2-Methyl-5-phenethyl-phenylamine The product from Example 241A (0.166 g, 0.694 mmol) and 10% palladium/carbon (18.4 mg, 0.025 eq.) in ethanol (10 mL) The mixture was stirred under atmospheric pressure of hydrogen for 16 hours. The reaction mixture was filtered with EtOAc EtOAc (EtOAc)
實例241C(2－甲基－5－苯乙基－苯基)－(7－甲基－吡啶并[2,3－d]嘧啶－4－基)－胺將得自實例10B之產物(0.041克，0.22毫莫耳)與得自實例241B之產物(0.046克，0.22毫莫耳)在冰醋酸(1毫升)中之混合物，於130℃油浴中加熱15分鐘。然後使反應混合物冷卻至室溫，並在減壓下蒸發溶劑。將殘留物以甲醇研製，並藉真空過濾單離所形成之固體，及乾燥，提供標題化合物(0.0121克，16%產率)，為微橘色固體。1 H NMR(300 MHz,CHCl3 －d)δ ppm：8.84(s,1H),8.23(d,J＝8.46 Hz,1H),7.44(s,1H),7.15－7.37(m,8H),7.07(dd,J＝7.72,1.47 Hz,1H),2.93(s,4H),2.78(s,3H),2.28(s,3H)；MS(ESI＋ )m/z 355.3(M＋H)＋ ,(ESI－ )m/z 353.2(M－H)－ .Example 241C (2-methyl-5-phenethyl-phenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine The product from Example 10B (0.041 A mixture of the product from Example 241B (0.046 g, 0.22 mmol) in EtOAc (EtOAc) The reaction mixture was then cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was triturated with EtOAc (EtOAc m. 1 H NMR (300 MHz, CHCl 3 -d) δ ppm: 8.84 (s, 1H), 8.23 (d, J = 8.46 Hz, 1H), 7.44 (s, 1H), 7.15-7.37 (m, 8H), 7.07 (dd, J=7.72, 1.47 Hz, 1H), 2.93 (s, 4H), 2.78 (s, 3H), 2.28 (s, 3H); MS (ESI + ) m/z 355.3 (M+H) + , ( ESI - ) m/z 353.2(M-H) - .
(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－(2－甲基－5－苯乙基－苯基)－胺(7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-(2-methyl-5-phenethyl-phenyl)-amine
將得自實例241B之產物(46.2毫克，0.219毫莫耳)與得自實例36E之產物(47.3毫克，0.219毫莫耳)在冰醋酸(1毫升)中之混合物，於130℃油浴中加熱15分鐘。然後使反應混合物冷卻至室溫，並在減壓下蒸發溶劑。使殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(0.0131克，10%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：11.09(s,1H),8.94(d,J＝8.46 Hz,1H),8.74(s,1H),7.82(d,J＝8.46 Hz,1H),7.12－7.35(m,8H),3.21－3.33(m,1H),2.89(s,4H),2.15(s,3H),1.35(d,J＝6.62 Hz,6H)；MS(ESI＋ )m/z 383.2(M＋H)＋ ,(ESI－ )m/z 381.3(M－H)－ .A mixture of the product from Example 241B (46.2 mg, 0.219 mmol) eluted from the product from Example 36E (47.3 mg, 0.219 mmol) in EtOAc (EtOAc) 15 minutes. The reaction mixture was then cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 11.09 (s, 1H), 8.94 (d, J = 8.46 Hz, 1H), 8.74 (s, 1H), 7.82 (d, J = 8.46 Hz, 1H ), 7.12-7.35 (m, 8H), 3.21-3.33 (m, 1H), 2.89 (s, 4H), 2.15 (s, 3H), 1.35 (d, J = 6.62 Hz, 6H); MS (ESI + m/z 383.2 (M+H) + , (ESI - ) m/z 381.3 (M-H) - .
(5－甲基－2－苯基硫基－苯基)－(7－丙基－喋啶－4－基)－胺實例243A(5-Methyl-2-phenylthio-phenyl)-(7-propyl-acridin-4-yl)-amine Example 243A
N'－(3－氰基－6－丙基吡－2－基)－N,N－二甲基甲脒將3－胺基－5－丙基吡－2－甲腈(0.140克，0.863毫莫耳)(根據Taylor與LaMattina,JOC 1977,47,1523之方法製成)與二甲基甲醯胺二甲基縮醛(0.123克，1.04毫莫耳，1.2當量)在甲苯(10毫升)中之混合物，於回流下加熱2小時。使混合物冷卻至室溫，並在減壓下蒸發溶劑，提供標題化合物(0.188毫克，100%)，為濃稠油。N'-(3-cyano-6-propylpyrazine 2-yl)-N,N-dimethylformamidine 3-amino-5-propylpyridinium 2-carbonitrile (0.140 g, 0.863 mmol) (made according to Taylor and LaMattina, JOC 1977, 47, 1523) with dimethylformamide dimethyl acetal (0.123 g, 1.04 mmol) A mixture of 1.2 eq. in toluene (10 mL) was evaporated. The mixture was cooled to rt EtOAc (EtOAc m.
實例243B(5－甲基－2－苯基硫基－苯基)－(7－丙基－喋啶－4－基)－胺將得自實例243A之產物(38.2毫克，0.176毫莫耳)與實例5I之產物(41.6毫克，0.193毫莫耳，1.1當量)在醋酸(1毫升)中之混合物，於回流下加熱1.5小時。使反應混合物冷卻至室溫，並在減壓下蒸發溶劑。將所形成之殘留物以甲醇研製，提供標題化合物(19毫克，28%產率)，為米黃色固體。1 H NMR(300 MHz,DMSO－D6)δ ppm：0.97(t,J＝7.35 Hz,3H),1.76－1.90(m,2H),2.42(s,3H),2.94－3.05(m,2H),7.08－7.28(m,6H),7.55(d,J＝8.09 Hz,1H),8.45(s,1H),8.81(s,1H),8.89(s,1H),10.32(s,1H).MS(ESI＋ )m/z 388.1(M＋H)＋ (ESI－ )m/z 386.1(M－H)－ .Example 243B (5-methyl-2-phenylsulfanyl-phenyl)-(7-propyl-acridin-4-yl)-amine The product from Example 243A (38.2 mg, 0.176 mmol) A mixture of the product of Example 5I (41.6 mg, EtOAc, m. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The resulting residue was purified with EtOAc EtOAcjjjjj 1 H NMR (300 MHz, DMSO-D6) δ ppm: 0.97 (t, J = 7.35 Hz, 3H), 1.76-1.90 (m, 2H), 2.42 (s, 3H), 2.94-3.05 (m, 2H) , 7.08-7.28 (m, 6H), 7.55 (d, J = 8.09 Hz, 1H), 8.45 (s, 1H), 8.81 (s, 1H), 8.89 (s, 1H), 10.32 (s, 1H). MS (ESI + ) m/z 388.1 (M+H) + (ESI - ) m/z 386.1 (M-H) -
4－[4－苄氧基－2－(7－異丙基－喋啶－4－基胺基)－苯基硫基]－酚4-[4-Benzyloxy-2-(7-isopropyl-acridin-4-ylamino)-phenylthio]-phenol
實例244A 3－胺基－5－異丙基－4－氧基－吡－2－甲腈將2－羥亞胺基－3－甲基丁醛(1.93克，16.8毫莫耳)(經由Nakamura,Agric.Biol.Chem.1961,25,665－670之程序製成)與2－胺基丙二腈甲苯磺酸鹽(4.25克，16.8毫莫耳)在異－丙醇(40毫升)中之混合物，於室溫下攪拌18小時。藉真空過濾單離所形成之固體，並以異－丙醇沖洗，且風乾，提供標題化合物(0.525克，18%產率)，為白色固體。Example 244A 3-Amino-5-isopropyl-4-oxy-pyridyl 2-carbonitrile 2-hydroxyimino-3-methylbutanal (1.93 g, 16.8 mmol) (made by Nakamura, Agric. Biol. Chem. 1961, 25, 665-670) and 2 A mixture of aminal malononitrile tosylate (4.25 g, 16.8 mmol) in iso-propanol (40 mL) was stirred at room temperature for 18 h. The resulting solid was isolated by EtOAc (EtOAc m.)
實例244B 3－胺基－5－異丙基－吡－2－甲腈將得自實例244A之產物(0.525克，2.95毫莫耳)在四氫呋喃(30毫升)中之溶液，於冰水浴溫下攪拌。於此溶液中，逐滴迅速地添加三氯化磷(4.0克，2.6毫升，29.5毫莫耳，10當量)。將反應混合物在室溫下攪拌16小時，然後蒸發溶劑與過量試劑。使所形成之殘留物於醋酸乙酯與半飽和碳酸氫鈉水溶液之間作分液處理。以醋酸乙酯(3 x 100毫升)萃取水相，並使合併之有機層以無水硫酸鎂脫水乾燥，過濾，及蒸發，提供標題化合物(0.370克，77%產率)，為淡褐色固體。Example 244B 3-Amino-5-isopropyl-pyridyl A solution of the product from Example 244A (0.525 g, 2.95 mmol) in THF (30 mL). In this solution, phosphorus trichloride (4.0 g, 2.6 ml, 29.5 mmol, 10 equivalents) was rapidly added dropwise. The reaction mixture was stirred at room temperature for 16 hours then the solvent was evaporated and excess reagent. The resulting residue was partitioned between ethyl acetate and a half saturated aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted with EtOAc (EtOAc m.
實例244C N'－(3－氰基－6－異丙基－吡－2－基)－N,N－二甲基－甲脒將得自實例244B之產物(0.37克，2.28毫莫耳)與二甲基甲醯胺二甲基縮醛(0.30克，2.5毫莫耳，1.1當量)在甲苯(25毫升)中之混合物，於回流下加熱1.75小時。然後使反應混合物冷卻至室溫，並在減壓下蒸發溶劑，提供標題化合物(0.50克，100%)，為濃稠紅/褐色油，將其使用於後續反應中，無需進一步純化。Example 244C N'-(3-Cyano-6-isopropyl-pyridyl 2-yl)-N,N-dimethyl-formamidine The product from Example 244B (0.37 g, 2.28 mmol) and dimethylformamide dimethyl acetal (0.30 g, 2.5 m) A mixture of MeOH (1.1 mL) in EtOAc (EtOAc) The reaction mixture was then cooled to EtOAc EtOAc m.
實例244D 4－[4－苄氧基－2－(7－異丙基－喋啶－4－基胺基)－苯基硫基]－酚將得自實例244C之產物(56.2毫克，0.259毫莫耳)與得自實例27A之產物在醋酸(1毫升)中之混合物，於回流下加熱2小時。使反應混合物冷卻至室溫，並在減壓下蒸發。將所形成之殘留物以甲醇研製，提供標題化合物(55.5毫克，53%產率)，為米黃色固體。1 H NMR(300 MHz,DMSO－D6)δ ppm：10.37(s,1H),9.65(s,1H),9.03(s,1H),8.80(s,1H),8.31(s,1H),7.38(d,J＝8.09 Hz,1H),7.21(d,J＝8.82 Hz,2H),7.03(dd,J＝8.09,1.47 Hz,1H),6.68(d,J＝8.82 Hz,2H),3.35－3.46(m,1H),2.37(s,3H),1.38(d,J＝6.62 Hz,6H).MS(ESI＋ )m/z 404.2(M＋H)＋ (ESI－ )m/z 402.3(M－H)－ .Example 244D 4-[4-Benzyloxy-2-(7-isopropyl-azino-4-ylamino)-phenylsulfanyl]-phenol The product from Example 244C (56.2 mg, 0.259 A mixture of the product from Example 27A in acetic acid (1 mL) was evaporated. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The resulting residue was crystalljjjjjjjjjj 1 H NMR (300 MHz, DMSO-D6) δ ppm: 10.37 (s, 1H), 9.65 (s, 1H), 9.03 (s, 1H), 8.80 (s, 1H), 8.31 (s, 1H), 7.38 (d, J = 8.09 Hz, 1H), 7.21 (d, J = 8.82 Hz, 2H), 7.03 (dd, J = 8.09, 1.47 Hz, 1H), 6.68 (d, J = 8.82 Hz, 2H), 3.35 -3.46(m,1H), 2.37(s,3H), 1.38 (d,J=6.62 Hz,6H). MS (ESI + ) m/z 404.2 (M+H) + (ESI - ) m/z 402.3 (M -H) - .
[2－(4－胺基－苯氧基)－5－(6－溴基－1H－苯并咪唑－2－基)－苯基]－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺[2-(4-Amino-phenoxy)-5-(6-bromo-1H-benzimidazol-2-yl)-phenyl]-(7-isopropyl-pyrido[2,3 -d]pyrimidin-4-yl)-amine
實例245A[4－(4－甲醯基－2－硝基－苯氧基)－苯基]－胺甲基酸第三－丁酯使4－氯基－3－硝基苯甲醛與(4－羥基－苯基)－胺甲基酸第三－丁酯之混合物在DMSO中一起反應，伴隨著添加KOH，提供標題產物。Example 245A [4-(4-Methyl fluorenyl-2-nitro-phenoxy)-phenyl]-aminomethyl acid tert-butyl ester 4-chloro-3-nitrobenzaldehyde with (4 A mixture of -hydroxy-phenyl)-amine methyl acid tert-butyl ester was reacted together in DMSO with the addition of KOH to provide the title product.
實例245B{4－[2－胺基－4－(6－溴基－1H－苯并咪唑－2－基)－苯氧基]－苯基}－胺甲基酸第三－丁酯使得自實例245A之產物根據得自實例147B與147C之程序反應，提供標題產物。Example 245B {4-[2-Amino-4-(6-bromo-1H-benzimidazol-2-yl)-phenoxy]-phenyl}-amine methyl acid tert-butyl ester The product of Example 245A was reacted according to the procedure from Example 147B and 147C to afford the title product.
實例245C[2－(4－胺基－苯氧基)－5－(6－溴基－1H－苯并咪唑－2－基)－苯基]－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺使得自實例245B之產物與得自實例36E之產物在HOAc中反應，並置於經預熱120℃之油浴中。於N2 氣流下移除溶劑。使產物藉由溶解於TFA在DCM中之1：1混合物內而去除保護，並在室溫下攪拌。使粗製物質藉HPLC以TFA純化，提供標題產物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.35(d,J＝6.99 Hz,6H)3.21－3.39(m,1H)6.87－7.04(m,4H)7.09(d,J＝8.46 Hz,1H)7.36(dd,J＝8.82,1.84 Hz,1H)7.56(d,J＝8.46 Hz,1H)7.78(d,J＝1.47 Hz,1H)7.89(d,J＝8.46 Hz,1H)8.14(dd,J＝8.82,1.84 Hz,1H)8.37(d,J＝1.84 Hz,1H)8.90(s,1H)9.00(d,J＝8.09 Hz,1H)；MS(ESI＋)m/z 568.2(M＋H)＋.Example 245C [2-(4-Amino-phenoxy)-5-(6-bromo-1H-benzimidazol-2-yl)-phenyl]-(7-isopropyl-pyrido[2] , 3-d]pyrimidin-4-yl)-amine The product from Example 245B was reacted with the product from Example 36E in HOAc and placed in an oil bath preheated at 120 °C. The solvent was removed under N 2 stream. The product was deprotected by dissolving in a 1:1 mixture of TFA in DCM and stirred at room temperature. The crude material was purified by EtOAc (EtOAc) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J = 6.99 Hz, 6H) 3.21-3.39 (m, 1H) 6.87-7.04 (m, 4H) 7.09 (d, J = 8.46 Hz, 1H) 7.36 (dd, J = 8.82, 1.84 Hz, 1H) 7.56 (d, J = 8.46 Hz, 1H) 7.78 (d, J = 1.47 Hz, 1H) 7.89 (d, J = 8.46 Hz, 1H) 8.14 ( Dd, J = 8.82, 1.84 Hz, 1H) 8.37 (d, J = 1.84 Hz, 1H) 8.90 (s, 1H) 9.00 (d, J = 8.09 Hz, 1H); MS (ESI+) m/z 568.2 (M+H )+.
4－[4－苄氧基－2－(7－第三－丁基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基硫基]－酚4-[4-Benzyloxy-2-(7-tris-butyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylthio]-phenol
於130℃下，將得自實例27A之產物在醋酸中與得自實例127A之產物一起加熱15分鐘，然後使混合物冷卻至室溫，移除溶劑，並使殘留物於矽膠上藉管柱層析純化，提供標題產物。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.38(s,9H)5.11(s,2H)6.60－6.74(m,2H)6.94(d,J＝7.35 Hz,1H)7.06－7.19(m,3H)7.27－7.50(m,6H)7.78(d,J＝8.09 Hz,1H)8.56(s,1H)8.75(s,1H)9.64(s,1H)9.95(s,1H)；MS(ESI＋)m/z 509(M＋H)＋.The product from Example 27A was heated in acetic acid with the product from Example 127A for 15 minutes at 130 ° C, then the mixture was allowed to cool to room temperature, solvent was removed, and the residue was applied to the silica gel. The purification was carried out to provide the title product. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.38 (s, 9H) 5.11 (s, 2H) 6.60-6.74 (m, 2H) 6.94 (d, J = 7.35 Hz, 1H) 7.06-7.19 (m ,3H)7.27-7.50(m,6H)7.78(d,J=8.09 Hz,1H)8.56(s,1H)8.75(s,1H)9.64(s,1H)9.95(s,1H);MS(ESI+ )m/z 509(M+H)+.
2－(4－胺基－苯基硫基)－5－(2－氯－噻唑－5－基甲氧基)－苯基]－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺2-(4-Amino-phenylthio)-5-(2-chloro-thiazol-5-ylmethoxy)-phenyl]-(7-isopropyl-pyrido[2,3-d Pyrimidin-4-yl)-amine
實例247A{4－[2－胺基－4－(2－氯－噻唑－5－基甲氧基)－苯基硫基]－苯基}－胺甲基酸第三－丁酯於回流及氮大氣下，使2－氯基－5－(4－氯基－3－硝基－苯氧基甲基)－噻唑(得自實例25A)與4－胺基硫酚在無水乙醇中反應。使反應物冷卻至室溫，並藉迴轉式蒸發移除乙醇。使殘留物溶於水中，並以醋酸乙酯萃取。以鹽水洗滌合併之有機萃液，以無水硫酸鈉脫水乾燥，過濾，及在真空中濃縮。固體以4%醋酸乙酯/二氯甲烷研製，獲得4－(4－((2－氯基噻唑－5－基)甲氧基)－2－硝基苯基硫基)苯胺。將4－(4－((2－氯基噻唑－5－基)甲氧基)－2－硝基苯基硫基)苯胺與二碳酸二－第三－丁酯在1,4－二氧陸圜中之混合物，於回流及氮大氣下加熱，然後添加另外之Boc酐，並使反應物回流。使反應物冷卻至室溫，並在真空中藉迴轉式蒸發移除溶劑。將所形成之固體以2.5%醋酸乙酯/二氯甲烷研製，獲得4－(4－((2－氯基噻唑－5－基)甲氧基)－2－硝基苯基硫基)苯基胺基甲酸第三－丁酯。將4－(4－((2－氯基噻唑－5－基)甲氧基)－2－硝基苯基硫基)苯基胺基甲酸酯、鐵粉及氯化銨在水與乙醇中之懸浮液加熱。使反應物冷卻至室溫。以醋酸乙酯稀釋混合物，並以水及鹽水洗滌。使有機相脫水乾燥，過濾，及在真空下濃縮，提供標題化合物。Example 247A {4-[2-Amino-4-(2-chloro-thiazol-5-ylmethoxy)-phenylthio]-phenyl}-aminomethyl acid tert-butyl ester at reflux 2-Chloro-5-(4-chloro-3-nitro-phenoxymethyl)-thiazole (from Example 25A) was reacted with 4-aminothiophenol in absolute ethanol under nitrogen atmosphere. The reaction was allowed to cool to room temperature and the ethanol was removed by rotary evaporation. The residue was dissolved in water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate. The solid was triturated with 4% ethyl acetate in dichloromethane to afford 4-(4-((2-chlorothiathiazol-5-yl)methoxy)-2-nitrophenylthio)phenylamine. 4-(4-((2-Chlorothiazol-5-yl)methoxy)-2-nitrophenylthio)phenylamine and di-tertiary-butyl phthalate in 1,4-dioxane The mixture in radix was heated under reflux and nitrogen atmosphere, then additional Boc anhydride was added and the reaction was refluxed. The reaction was allowed to cool to room temperature and the solvent was removed by rotary evaporation in vacuo. The solid formed was triturated with 2.5% ethyl acetate in dichloromethane to give 4-(4-((2-chlorothiazol-5-yl)methoxy)-2-nitrophenylthio)benzene. Tert-butyl ester of carbamic acid. 4-(4-((2-Chlorothiazol-5-yl)methoxy)-2-nitrophenylthio)phenylcarbamate, iron powder and ammonium chloride in water and ethanol The suspension is heated. The reaction was allowed to cool to room temperature. The mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried <RTI ID=0.0>
實例247B[2－(4－胺基－苯基硫基)－5－(2－氯－噻唑－5－基甲氧基)－苯基]－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺於130℃下，將得自實例247A之產物在醋酸中與得自實例36E之產物一起加熱15分鐘，然後使混合物冷卻至室溫，在真空下移除溶劑，並添加二氯甲烷/三氟醋酸1/1之混合物，然後將殘留物於室溫下攪拌2小時，接著在真空下移除溶劑，並使殘留物藉HPLC以TFA純化，提供標題產物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.36(d,J＝6.99 Hz,6H)3.20－3.37(m,1H)3.75(s,2H)5.33(s,2H)6.53(d,J＝8.46 Hz,2H)6.99－7.12(m,5H)7.14(s,1H)7.80(s,1H)7.92(d,J＝8.82 Hz,1H)8.83(s,1H)9.01(s,1H)11.62(s,1H)；MS(ESI＋)m/z 535(M＋H)＋.Example 247B [2-(4-Amino-phenylthio)-5-(2-chloro-thiazol-5-ylmethoxy)-phenyl]-(7-isopropyl-pyrido[2, 3-d]pyrimidin-4-yl)-amine The product from Example 247A was heated in acetic acid with the product from Example 36E for 15 minutes at 130 ° C, then the mixture was cooled to room temperature under vacuum The solvent was removed and a mixture of dichloromethane / trifluoroacetic acid 1 / 1 was added, then the residue was stirred at room temperature for 2 hr then solvent was evaporated and the residue was purified by HPLC The title product is trifluoroacetate. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (d, J = 6.99 Hz, 6H) 3.20-3.37 (m, 1H) 3.75 (s, 2H) 5.33 (s, 2H) 6.53 (d, J =8.46 Hz,2H)6.99-7.12(m,5H)7.14(s,1H)7.80(s,1H)7.92(d,J=8.82 Hz,1H)8.83(s,1H)9.01(s,1H)11.62 (s, 1H); MS (ESI+) m/z 535 (M+H)+.
{4－[2－(7－第三－丁基－吡啶并[2,3－d]嘧啶－4－基胺基)－4－(2－氯－噻唑－5－{4-[2-(7-Terve-butyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(2-chloro-thiazole-5-
基甲氧基)－苯基硫基]－苯基}－胺甲基酸第三－丁酯於130℃下，將得自實例247A之產物在醋酸中與得自實例127A之產物一起加熱15分鐘，然後使混合物冷卻至室溫，移除溶劑，並使殘留物藉HPLC以TFA純化，提供標題產物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.43(d,J＝11.40 Hz,15H)2.73(s,1H)5.36(s,2H)7.00(d,1H)7.13(d,J＝8.46 Hz,2H)7.25(d,1H)7.33(d,J＝8.46 Hz,3H)7.81(s,2H)8.62(s,1H)8.78(s,1H)9.39(s,1H)10.49(bs,1H)；MS(ESI＋)m/z 649(M＋H)＋.The methoxy-)phenylphenyl]-phenyl}-amine methyl acid tert-butyl ester was heated at 130 ° C with the product from Example 247A in acetic acid with the product from Example 127A. The mixture was cooled to rt. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.43 (d, J = 11.40 Hz, 15H) 2.73 (s, 1H) 5.36 (s, 2H) 7.00 (d, 1H) 7.13 (d, J = 8.46) Hz,2H)7.25(d,1H)7.33(d,J=8.46 Hz,3H)7.81(s,2H)8.62(s,1H)8.78(s,1H)9.39(s,1H)10.49(bs,1H ); MS (ESI+) m/z 649 (M+H)+.
[2－(4－胺基－苯基硫基)－5－(2－氯－噻唑－5－基甲氧基)－苯基]－(7－第三－丁基－吡啶并[2,3－d]嘧啶－4－基)－胺[2-(4-Amino-phenylthio)-5-(2-chloro-thiazol-5-ylmethoxy)-phenyl]-(7-tri-butyl-pyrido[2, 3-d]pyrimidin-4-yl)-amine
將得自實例248之產物添加至二氯甲烷/三氟醋酸1/1之混合物中，並將溶液於室溫下攪拌2小時，接著在真空下移除溶劑，且使所形成之殘留物藉HPLC以TFA純化，提供標題產物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.44(s,6H)2.51－2.59(m,1H)3.72(s,2H)5.33(s,2H)6.24(dd,J＝8.82,2.94 Hz,1H)6.42(d,J＝2.94 Hz,1H)6.53(d,J＝8.46 Hz,2H)6.98－7.12(m,3H)7.14(s,1H)7.74－7.85(m,1H)8.09(d,J＝8.46 Hz,1H)8.83(s,1H)9.03(s,1H)11.65(s,1H)；MS(ESI＋)m/z 549(M＋H)＋.The product from Example 248 was added to a mixture of dichloromethane/trifluoroacetic acid 1/1, and the solution was stirred at room temperature for 2 hours, then the solvent was removed under vacuum and the residue formed was taken The HPLC was purified by TFA to afford the title product as trifluoroacetate. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.44 (s, 6H) 2.51-2.59 (m, 1H) 3.72 (s, 2H) 5.33 (s, 2H) 6.24 (dd, J = 8.82, 2.94 Hz ,1H)6.42(d,J=2.94 Hz,1H)6.53(d,J=8.46 Hz,2H)6.98-7.12(m,3H)7.14(s,1H)7.74-7.85(m,1H)8.09(d , J=8.46 Hz, 1H)8.83(s,1H)9.03(s,1H)11.65(s,1H);MS(ESI+)m/z 549(M+H)+.
[2－(4－胺基－苯基硫基)－5－(6－溴基－1H－苯并咪唑－2－基)－苯基]－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺[2-(4-Amino-phenylthio)-5-(6-bromo-1H-benzimidazol-2-yl)-phenyl]-(7-isopropyl-pyrido[2, 3-d]pyrimidin-4-yl)-amine
實例250A[4－(4－甲醯基－2－硝基－苯基硫基)－苯基]－胺甲基酸第三－丁酯根據實例216B之程序，以4－氯基－3－硝基苯甲醛取代得自實例216A之產物，使4－氯基－3－硝基苯甲醛與4－胺基硫酚之混合物一起反應，然後使其接受得自實例216C之條件，提供標題產物。Example 250A [4-(4-Methylmethyl-2-nitro-phenylthio)-phenyl]-aminomethyl acid tert-butyl ester according to the procedure of Example 216B, 4-chloro-3- Nitrobenzaldehyde was substituted for the product from Example 216A, and the mixture of 4-chloro-3-nitrobenzaldehyde and 4-aminothiophenol was reacted and then subjected to the conditions obtained from Example 216C to provide the title product. .
實例250B[2－(4－胺基－苯基硫基)－5－(6－溴基－1H－苯并咪唑－2－基)－苯基]－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺使得自實例250A之產物根據得自實例147B、147C及147C之程序反應，提供粗製殘留物，使其藉HPLC以TFA純化，提供標題產物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.38(d,J＝6.62 Hz,6H)3.26－3.40(m,1H)6.64(d,J＝8.46 Hz,2H)7.03(d,J＝8.46 Hz,1H)7.17(d,J＝8.46 Hz,2H)7.35(dd,J＝8.46,1.84 Hz,1H)7.54(d,J＝8.82 Hz,1H)7.77(d,J＝1.84 Hz,1H)7.94(d,J＝8.46 Hz,1H)8.03(dd,J＝8.46,1.84 Hz,1H)8.18(s,1H)8.89(s,1H)9.05(d,J＝8.82 Hz,1H)；MS(ESI＋)m/z 584(M＋H)＋.Example 250B [2-(4-Amino-phenylthio)-5-(6-bromo-1H-benzimidazol-2-yl)-phenyl]-(7-isopropyl-pyridin[ 2,3-d]pyrimidin-4-yl)-amine was allowed to react from the product of Example </RTI></RTI><RTIID=0.0> It is a trifluoroacetate salt. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.38 (d, J = 6.62 Hz, 6H) 3.26 - 3.40 (m, 1H) 6.64 (d, J = 8.46 Hz, 2H) 7.03 (d, J = 8.46 Hz, 1H) 7.17 (d, J = 8.46 Hz, 2H) 7.35 (dd, J = 8.46, 1.84 Hz, 1H) 7.54 (d, J = 8.82 Hz, 1H) 7.77 (d, J = 1.84 Hz, 1H) 7.94 (d, J = 8.46 Hz, 1H) 8.03 (dd, J = 8.46, 1.84 Hz, 1H) 8.18 (s, 1H) 8.89 (s, 1H) 9.05 (d, J = 8.82 Hz, 1H); MS (ESI+)m/z 584(M+H)+.
[2－(4－胺基－苯基硫基)－5－(3－氟－苄氧基)－苯基]－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺[2-(4-Amino-phenylthio)-5-(3-fluoro-benzyloxy)-phenyl]-(7-isopropyl-pyrido[2,3-d]pyrimidine-4 -based)-amine
實例251A{4－[2－胺基－4－(3－氟－苄氧基)－苯基硫基]－苯基}－胺甲基酸第三－丁酯使得自實例57B之產物與4－胺基硫酚反應，根據得自實例214B之程序，接著為根據得自實例214C與214D程序之反應，提供標題產物。Example 251A {4-[2-Amino-4-(3-fluoro-benzyloxy)-phenylthio]-phenyl}-aminomethyl-tert-butyl-butyrate from the product of Example 57B - Aminothiophenol reaction, according to the procedure from Example 214B, followed by the reaction according to the procedure from Example 214C and 214D afforded the title product.
實例251B[2－(4－胺基－苯基硫基)－5－(3－氟－苄氧基)－苯基]－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺於130℃下，將得自實例251A之產物在醋酸中與得自實例36E之產物一起加熱15分鐘，接著使混合物冷卻至室溫，在真空下移除溶劑，並添加二氯甲烷/三氟醋酸1/1之混合物，然後將殘留物於室溫下攪拌2小時，接著在真空下移除溶劑，且使殘留物於矽膠上藉管柱層析純化，提供標題產物。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.26－1.44(d,6H)3.23－3.37(m,1H)5.13(s,2H)6.44－6.61(m,2H)6.96－7.10(m,3H)7.10－7.22(m,2H)7.24－7.35(m,3H)7.35(d,J＝6.25 Hz,1H)7.43(dd,J＝7.91,5.70 Hz,2H)7.92(s,1H)8.18(d,J＝8.82 Hz,1H)8.83(s,1H)9.03(s,1H)；MS(ESI＋)m/z 512(M＋H)＋.Example 251B [2-(4-Amino-phenylthio)-5-(3-fluoro-benzyloxy)-phenyl]-(7-isopropyl-pyrido[2,3-d]pyrimidine -4-yl)-amine The product from Example 251A was heated in acetic acid with the product from Example 36E for 15 minutes at 130 ° C, then the mixture was cooled to room temperature and solvent was removed under vacuum. A mixture of dichloromethane/trifluoroacetic acid 1/1 was added, then the residue was stirred at room temperature for 2 hr then solvent was evaporated and the residue was purified eluting product. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.26-1.44 (d, 6H) 3.23-3.37 (m, 1H) 5.13 (s, 2H) 6.44-6.61 (m, 2H) 6.96-7.10 (m, 3H) 7.10-7.22 (m, 2H) 7.24 - 7.35 (m, 3H) 7.35 (d, J = 6.25 Hz, 1H) 7.43 (dd, J = 7.91, 5.70 Hz, 2H) 7.92 (s, 1H) 8.18 ( d, J = 8.82 Hz, 1H) 8.83 (s, 1H) 9.03 (s, 1H); MS (ESI+) m/z 512 (M+H)+.
[2－(4－胺基－苯基硫基)－5－(3－氟－苄氧基)－苯基]－(7－第三－丁基－吡啶并[2,3－d]嘧啶－4－基)－胺[2-(4-Amino-phenylthio)-5-(3-fluoro-benzyloxy)-phenyl]-(7-tri-butyl-pyrido[2,3-d]pyrimidine -4-yl)-amine
於130℃下，將得自實例251A之產物在醋酸中與得自實例127A之產物一起加熱15分鐘，接著使混合物冷卻至室溫，在真空下移除溶劑，並添加二氯甲烷/三氟醋酸1/1之混合物，然後將殘留物於室溫下攪拌2小時，接著在真空下移除溶劑，且使殘留物藉HPLC以TFA純化，提供標題產物，為三氟醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.38－1.50(m,9H)5.12(s,2H)6.44－6.61(m,3H)6.96－7.12(m,3H)7.19(s,3H)7.23－7.33(m,3H)7.38－7.50(m,2H)8.00(s,1H)8.76(s,1H)8.96(s,1H)；MS(ESI＋)m/z 526(M＋H)＋.The product from Example 251A was heated in acetic acid with the product from Example 127A for 15 minutes at 130 ° C, then the mixture was cooled to room temperature, solvent was removed in vacuo and dichloromethane/trifluoro A mixture of 1/1 of EtOAc, EtOAc (EtOAc)EtOAc. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.38-1.50 (m, 9H) 5.12 (s, 2H) 6.44-6.61 (m, 3H) 6.96-7.12 (m, 3H) 7.19 (s, 3H) 7.23-7.33(m,3H)7.38-7.50(m,2H)8.00(s,1H)8.76(s,1H)8.96(s,1H);MS(ESI+)m/z 526(M+H)+.
[5－苄氧基－2－(4－二甲胺基－苯基硫基)－苯基]－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺[5-Benzyloxy-2-(4-dimethylamino-phenylthio)-phenyl]-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)- amine
實例253A 5－苄氧基－2－(4－二甲胺基－苯基硫基)－苯胺將得自實例214B之產物(1.0克，0.284毫莫耳)，伴隨著甲酸(5毫升)、二氧陸圜(5毫升)及37%甲醛水溶液(5毫升)置於管件中。將管件密封，並加熱至110℃，歷經20分鐘。使混合物冷卻至室溫，移除溶劑，並使所形成之殘留物於矽膠上以管柱層析純化，接著為硝基之還原作用，根據實例214D之程序，提供標題產物(411毫克，43%)。Example 253A 5-Benzyloxy-2-(4-dimethylamino-phenylsulfanyl)-phenylamine The product from Example 214B (1.0 g, 0.284 m.m. Dioxane (5 ml) and 37% aqueous formaldehyde (5 ml) were placed in the tube. The tube was sealed and heated to 110 ° C for 20 minutes. The mixture was allowed to cool to room temperature, the solvent was removed, and the residue was purified eluted eluted eluted elut elut elut elut %).
實例253B[5－苄氧基－2－(4－二甲胺基－苯基硫基)－苯基]－(7－異丙基－吡啶并[2,3－d]嘧啶－4－基)－胺將得自實例253A之產物與得自實例36E之產物在冰醋酸中之混合物，於經預熱130℃之油浴中加熱20分鐘。然後使反應混合物冷卻至室溫，並在真空下蒸發溶劑，提供標題化合物，為醋酸鹽。1 H NMR(300 MHz,DMSO－D6)δ ppm：1.36(d,J＝7.0 Hz,6H),2.81(s,6H),3.30(m,1H),5.10(s,2H),6.45(d,J＝9.2 Hz,2H),7.07(d,J＝8.8 Hz,2H),7.12(m,2H),7.25(d,J＝8.8 Hz,1H),7.40(m,5H),7.94(m,1H),8.78(s,1H),8.99(m,1H),11.70(bs,1H)；MS(ESI)m/z 522(M＋H)＋.Example 253B [5-Benzyloxy-2-(4-dimethylamino-phenylthio)-phenyl]-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl The amine was obtained from a mixture of the product from Example 253A and the product from Example 36E in glacial acetic acid and heated in an oil bath preheated at < The reaction mixture was then cooled to rt. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 1.36 (d, J = 7.0 Hz, 6H), 2.81 (s, 6H), 3.30 (m, 1H), 5.10 (s, 2H), 6.45 (d) , J=9.2 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 7.12 (m, 2H), 7.25 (d, J = 8.8 Hz, 1H), 7.40 (m, 5H), 7.94 (m) , 1H), 8.78 (s, 1H), 8.99 (m, 1H), 11.70 (bs, 1H); MS (ESI) m/z 522 (M+H)+.
4－溴－N－[3－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基]－苯甲醯胺4-bromo-N-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-benzamide
實例254A 4－溴－N－(3－硝基－苯基)－苯甲醯胺標題化合物係根據實例255A之程序，以3－硝基－苯胺取代4－氟基－3－硝基－苯胺，並以氯化4－溴－苯甲醯取代氯化3－三氟甲基－苯甲醯製成，以提供標題產物(3.373克，90%)。Example 254A 4-bromo-N-(3-nitro-phenyl)-benzimidamide The title compound was obtained by substituting 3-nitro-aniline for 4-fluoro-3-nitro-aniline according to the procedure of Example 255A. The title product (3.373 g, 90%) was obtained eluted with 4-bromo-benzhydrazyl chloride.
實例254B 4－溴－N－(3－胺基－苯基)－苯甲醯胺標題化合物係根據實例255B之程序，以得自實例254A之產物取代得自實例255A之產物製成，以提供標題產物(1.8克，80%)。Example 254B 4-bromo-N-(3-Amino-phenyl)-benzamide The title compound was obtained according to the procedure of Example 255B, substituting the product from Example 254A from the product from Example 255A to provide The title product (1.8 g, 80%).
實例254C 4－溴－N－[3－(吡啶并[2,3－d]嘧啶－4－基胺基)－苯基]－苯甲醯胺將得自實例57A之產物(40.0毫克，0.212毫莫耳)與實例254B之產物(61.0毫克，0.212毫莫耳)在醋酸(1毫升)中之溶液，於預熱至130℃之油浴中攪拌20分鐘。然後使混合物冷卻至室溫，在真空下移除醋酸，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(25.0毫克，30%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：7.45(t,J＝8.09 Hz,1H),7.52－7.61(m,2H),7.74－7.86(m,3H),7.94(d,J＝8.82 Hz,2H),8.33(t,J＝1.84 Hz,1H),8.88(s,1H),9.09－9.17(m,2H),10.48(s,1H),10.94(s,1H)；MS(ESI＋)m/z 420(M＋H)＋,(ESI－)m/z 417(M－H)－.Example 254C 4-bromo-N-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-benzamide The product from Example 57A (40.0 mg, 0.212 A solution of the product from Example 254B (61.0 mg, 0.212 mmol) inEtOAc (1 mL). The mixture was then cooled to room temperature. EtOAc (EtOAc m.) 1 H NMR (300 MHz, DMSO-D6) δ ppm: 7.45 (t, J = 8.09 Hz, 1H), 7.52-7.61 (m, 2H), 7.74-7.86 (m, 3H), 7.94 (d, J = 8.82 Hz, 2H), 8.33 (t, J = 1.84 Hz, 1H), 8.88 (s, 1H), 9.09-9.17 (m, 2H), 10.48 (s, 1H), 10.94 (s, 1H); MS ( ESI+)m/z 420(M+H)+, (ESI-)m/z 417(M-H)-.
N－[4－(4－羥基－苯基硫基)－3－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基]－3－三氟甲基－苯甲醯胺N-[4-(4-Hydroxy-phenylthio)-3-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-3-trifluoro Methyl-benzamide
實例255A N－(4－氟基－3－硝基－苯基)－3－三氟甲基－苯甲醯胺將4－氟基－3－硝基－苯胺(2.00克，12.8毫莫耳)、氯化3－三氟甲基－苯甲醯(1.895毫升，12.8毫莫耳)、Hunig氏鹼(4.463毫升，25.6毫莫耳)在四氫呋喃(50毫升)中之溶液，於室溫下攪拌1小時。然後將水(450毫升)添加至溶液中，並藉過濾收集所形成之固體，且在真空烘箱中乾燥，提供標題化合物(3.311克，97%)。Example 255A N-(4-Fluoro-3-nitro-phenyl)-3-trifluoromethyl-benzamide The 4-fluoro-3-nitro-aniline (2.00 g, 12.8 mmol) a solution of 3-trifluoromethyl-benzamide (1.895 ml, 12.8 mmol), Hunig's base (4.463 ml, 25.6 mmol) in tetrahydrofuran (50 ml) at room temperature Stir for 1 hour. Water (450 mL) was then added to a solution.
實例255B N－[4－(4－羥基－苯基硫基)－3－硝基－苯基]－3－三氟甲基－苯甲醯胺將實例255A之產物(2.00克，5.80毫莫耳)、4－羥基硫酚(0.732克，5.80毫莫耳)及碳酸鉀(1.604克，11.6毫莫耳)在N,N－二甲基甲醯胺(40毫升)中之溶液加熱至80℃，歷經2小時。於冷卻至室溫後，將混合物倒入冰水(100毫升)中。然後以醋酸乙酯(3 x 150毫升)萃取溶液，使合併之萃液以硫酸鎂脫水乾燥，過濾，及在真空下濃縮，提供標題化合物(2.52克，100%)。Example 255B N-[4-(4-Hydroxy-phenylsulfanyl)-3-nitro-phenyl]-3-trifluoromethyl-benzamide The product of Example 255A (2.00 g, 5.80 mmol) a solution of 4-hydroxythiophenol (0.732 g, 5.80 mmol) and potassium carbonate (1.604 g, 11.6 mmol) in N,N-dimethylformamide (40 mL). °C, after 2 hours. After cooling to room temperature, the mixture was poured into ice water (100 mL). The solution was extracted with EtOAc (EtOAc (EtOAc)EtOAc.
實例255C N－[3－胺基－4－(4－羥基－苯基硫基)－苯基]－3－三氟甲基－苯甲醯胺將實例255B之產物(0.660克，1.52毫莫耳)、鐵粉(0.339克，6.07毫莫耳)及氯化銨(0.099克，1.82毫莫耳)在四氫呋喃(18毫升)與水(6毫升)溶液中之溶液加熱至回流，歷經3小時。以甲醇(50毫升)稀釋所形成之混合物，並經過矽藻土墊過濾。以水(50毫升)稀釋濾液，並以二氯甲烷(2 x 100毫升)萃取。使合併之萃液以硫酸鎂脫水乾燥，過濾，及在真空下濃縮，提供標題化合物(0.60克，97%)。Example 255C N-[3-Amino-4-(4-hydroxy-phenylsulfanyl)-phenyl]-3-trifluoromethyl-benzamide The product of Example 255B (0.660 g, 1.52 mmol) a solution of iron powder (0.339 g, 6.07 mmol) and ammonium chloride (0.099 g, 1.82 mmol) in tetrahydrofuran (18 ml) and water (6 ml) . The resulting mixture was diluted with methanol (50 mL) and filtered through a pad of Celite. The filtrate was diluted with water (50 mL) and extracted with dichloromethane (2x 100 mL). The combined extracts were dried with EtOAc EtOAc EtOAc EtOAc
實例255D N－[4－(4－羥基－苯基硫基)－3－(7－甲基－吡啶并[2,3－d]嘧啶－4－基胺基)－苯基]－3－三氟甲基－苯甲醯胺將得自實例10B之產物(40.0毫克，0.212毫莫耳)與得自實例255C之產物(86.0毫克，0.212毫莫耳)在醋酸(1毫升)中之溶液，於預熱至130℃之油浴中攪拌20分鐘。然後使混合物冷卻至室溫，在真空下移除醋酸，並使所形成之殘留物藉HPLC以TFA純化，提供標題化合物，為三氟醋酸鹽(11毫克，10%)。1 H NMR(300 MHz,DMSO－D6)δ ppm：2.74(s,3H),6.70(d,J＝8.82 Hz,2H),7.18(d,J＝8.46 Hz,3H),7.64(dd,J＝8.46,2.21 Hz,1H),7.79(t,J＝7.72 Hz,2H),7.93－8.07(m,J＝6.62 Hz,2H),8.21－8.30(m,2H),8.78(s,1H),8.92(d,J＝7.72 Hz,1H),9.79(s,1H),10.67(s,1H),11.17－11.50(m,1H)MS(ESI＋)m/z 548.2(M＋H)＋,(ESI－)m/z 546.2(M－H)－.Example 255D N-[4-(4-Hydroxy-phenylthio)-3-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-3- Trifluoromethyl-benzamide The solution from the product of Example 10B (40.0 mg, 0.212 mmol) and the product from Example 255C (86.0 mg, 0.212 mmol) in acetic acid (1 mL) It was stirred for 20 minutes in an oil bath preheated to 130 °C. The mixture was then cooled to room temperature. EtOAc (EtOAc) was evaporated. 1 H NMR (300 MHz, DMSO-D6) δ ppm: 2.74 (s, 3H), 6.70 (d, J = 8.82 Hz, 2H), 7.18 (d, J = 8.46 Hz, 3H), 7.64 (dd, J =8.46, 2.21 Hz, 1H), 7.79 (t, J = 7.72 Hz, 2H), 7.93 - 8.07 (m, J = 6.62 Hz, 2H), 8.21 - 8.30 (m, 2H), 8.78 (s, 1H) , 8.92 (d, J = 7.72 Hz, 1H), 9.79 (s, 1H), 10.67 (s, 1H), 11.17-11.50 (m, 1H) MS (ESI+) m/z 548.2 (M+H)+, (ESI) -)m/z 546.2(M-H)-.
本發明之代表性化合物係根據下文所述之檢測分析。Representative compounds of the invention are analyzed according to the assays described below.
下列頭字語係於本文中使用：IC50 50%抑制濃度TC50 50%毒性濃度DMEM Dulbecco氏變性必須培養基TM RNA 核糖核酸RT－PCR 反轉錄酶聚合酶連鎖反應SEAP 分泌之鹼性磷酸酶The following initial words are used herein: IC 50 50% inhibitory concentration TC 50 50% toxic concentration DMEM Dulbecco's denaturing essential medium TM RNA ribonucleic acid RT-PCR reverse transcriptase polymerase chain reaction SEAP secretion of alkaline phosphatase
C型肝炎病毒基因組係使大的多蛋白編碼，其在處理後，會產生必須之功能性成份，以合成後代RNA。會產生高且持續含量之亞基因組HCV RNA(複製子)之可選擇細胞系，已被衍生自人類肝細胞瘤細胞(Huh7)，如Ikeda等人,J.VIROLOGY ,76(6)：2997－3006(2002)與Blight等人,SCIENCE ,290：1972－1974(2000)中所述。在此等細胞系中RNA複製之機制，係被視為與全長HCV RNA在受感染肝細胞中之複製相同。本發明化合物在下文所述之複製子檢測系統中，係為HCV RNA複製之抑制劑。The hepatitis C virus genome encodes large polyproteins that, upon processing, produce the necessary functional components to synthesize progeny RNA. A selectable cell line that produces a high and sustained amount of subgenomic HCV RNA (replicon) that has been derived from human hepatoma cells (Huh7), such as Ikeda et al, J. VIROLOGY , 76(6): 2997- 3006 (2002) and Blight et al, SCIENCE , 290: 1972-1974 (2000). The mechanism of RNA replication in these cell lines is considered to be identical to the replication of full-length HCV RNA in infected liver cells. The compounds of the invention are inhibitors of HCV RNA replication in the replicon detection system described below.
HCV抑制劑在HCV複製子中之評估 評估本發明之代表性化合物，關於其對於HCV基因型1a與1b複製子之抑制作用。其亦藉由MTT檢測評估，關於對宿主細胞之細胞毒性。此等細胞系係根據由Yi等人,VIROLOGY ,304(2)：197－210(2002)所述之方法被保持著。 Evaluation of HCV Inhibitors in HCV Replicons The representative compounds of the invention were evaluated for their inhibition of HCV genotypes 1a and 1b replicons. It is also assessed by MTT assay for cytotoxicity to host cells. These cell lines are maintained according to the method described by Yi et al., VIROLOGY , 304(2): 197-210 (2002).
A. RNA檢測與SEAP檢測 此等檢測之目的係為評估化合物在活體外抑制HCV基因型1a與1b複製子之複製上之功效。 A. RNA Detection and SEAP Testing The purpose of these tests was to evaluate the efficacy of compounds in inhibiting the replication of HCV genotype 1a and 1b replicons in vitro.
將基因型1a及/或1b複製子細胞在每井3－5 x 103 個細胞下，覆蓋於96－井板中，在含有5%牛胎兒血清之DMEM培養基內。隔天，移除培養基，並以含有化合物之八次連續稀釋液之新培養基置換。將未經處理之對照培養物以相同方式處理，惟未將抑制劑添加至培養基中。將板在CO2 培養器中，於37℃下培養。於第4天，在移除培養基後，將100微升溶胞緩衝劑(RTL)(Qiagen)添加至各井中。RNA係根據製造者之建議(Qiagen RNAeasy)純化，並以200微升水溶離。HCV RNA含量係自一部份(5微升，來自200微升)經純化之RNA，藉由即時RT－PCR方法定量。引物與探測物係衍生自5'－未轉譯區域(5'UTR)中之特定順序。RT－PCR反應係在48℃下進行30分鐘，接著為經設定至95℃，15秒；54℃，30秒；及72℃，40秒之40次循環。或者，SEAP之活性係在與化合物之四天培養後，根據製造者之說明書，於各培養物上層清液中度量。計算HCV RNA或SEAP於化合物存在下之降低百分比，而50%抑制濃度(IC50 )係藉由非線性回歸分析，使用Prism程式(4.0版,GraphPad軟體,San Diego,CA)計算。Genotype 1a and/or 1b replicon cells were plated in 96-well plates at 3-5 x 10 3 cells per well in DMEM medium containing 5% fetal serum. The next day, the medium was removed and replaced with new medium containing eight serial dilutions of the compound. Untreated control cultures were treated in the same manner except that no inhibitor was added to the medium. The plates were incubated at 37 ° C in a CO 2 incubator. On day 4, after the medium was removed, 100 microliters of lysis buffer (RTL) (Qiagen) was added to each well. The RNA was purified according to the manufacturer's recommendations (Qiagen RNAeasy) and dissolved in 200 μl of water. The HCV RNA content was quantified from a portion (5 microliters from 200 microliters) of purified RNA by real-time RT-PCR. Primers and probes are derived from a specific sequence in the 5'-untranslated region (5' UTR). The RT-PCR reaction was carried out at 48 ° C for 30 minutes, followed by 40 cycles of setting to 95 ° C, 15 seconds; 54 ° C, 30 seconds; and 72 ° C, 40 seconds. Alternatively, the activity of SEAP is measured in the supernatant of each culture after incubation with the compound for four days, according to the manufacturer's instructions. Calculation HCV RNA or SEAP in the presence of the compound under the percent reduction, and the 50% inhibitory concentration (IC 50) by non-linear regression analysis based calculated using Prism program (version 4.0, GraphPad Software, San Diego, CA).
當使用上述方法測試時，本發明之代表性化合物會抑制HCV複製子複製，具有IC50 值在約0.3 nM至約100 μM之範圍內。When tested using the method described above, representative compounds of this invention inhibit HCV replicon replication, with IC 50 values in the range of about 0.3 nM to about 100 μM of.
B.細胞毒性檢測 此項檢測之目的係為測定化合物在活體外對於病毒宿主細胞之毒性。 B. Cytotoxicity assay The purpose of this assay is to determine the toxicity of a compound to a viral host cell in vitro.
化合物之細胞毒性係使用粒線體酵素為基礎之細胞增生/存活力檢測，在複製子細胞中度量。簡言之，係將HCV複製子細胞在每井3－5 x 103 個細胞下，覆蓋於96－井板中，在含有5% FCS之DMEM培養基內。於第1天，移除培養基，並以含有化合物之八次連續稀釋液之新培養基置換。將未經處理之對照培養物以相同方式處理，惟未將抑制劑添加至培養基中。將板在CO2 培養器中，於37℃下培養。於第4天，將四銼鹽MTT之儲備溶液(4毫克/毫升，在PBS中，Sigma目錄#M 2128)添加至各井中，在每井25微升下。將板進一步培養4小時，以20% SDS加上0.02 N HCl在每井50微升下處理，以溶解細胞。於過夜培養後，藉由在570/650毫微米波長下讀取板，度量光密度。計算所形成福嗎簡(formazan)藍色相對於對照組之降低百分比，而50%毒性濃度(TC50 )係藉由非線性回歸分析，使用Prism程式(4.0版,GraphPad軟體,San Diego,CA)計算。The cytotoxicity of the compounds is measured in granulocyte enzyme-based cell proliferation/viability assays in replicon cells. Briefly, HCV replicon cells were plated in 96-well plates at 3-5 x 10 3 cells per well in DMEM medium containing 5% FCS. On day 1, the medium was removed and replaced with new medium containing eight serial dilutions of the compound. Untreated control cultures were treated in the same manner except that no inhibitor was added to the medium. The plates were incubated at 37 ° C in a CO 2 incubator. On day 4, a stock solution of tetrasodium salt MTT (4 mg/ml in PBS, Sigma Catalog #M 2128) was added to each well at 25 microliters per well. The plates were further incubated for 4 hours and treated with 20% SDS plus 0.02 N HCl at 50 microliters per well to lyse the cells. After overnight incubation, the optical density was measured by reading the plate at a wavelength of 570/650 nm. Fu it Jane (formazan) is calculated with respect to the blue form of the percentage reduction in the control group, while 50% toxicity concentration (TC 50) lines by nonlinear regression analysis using the Prism program (version 4.0, GraphPad Software, San Diego, CA) Calculation.
當使用上述方法測試時，本發明代表性化合物之TC50 值係大於此等化合物之相應IC50 值。When using the test methods described above, TC 50 Representative compounds of the present invention, the IC 50 value is greater than the corresponding system values of these compounds.
本發明之特徵為包含本發明化合物之醫藥組合物。作為非限制性實例，本發明之醫藥組合物係包括一或多種本發明之化合物，其中各化合物係獨立選自式I、II、III、IV、V、VI、VII或VIII。各化合物較佳係獨立選自實例1－255。The invention features a pharmaceutical composition comprising a compound of the invention. By way of non-limiting example, the pharmaceutical compositions of the present invention comprise one or more compounds of the invention, wherein each compound is independently selected from Formula I, II, III, IV, V, VI, VII or VIII. Preferably, each compound is independently selected from the examples 1-255.
本發明之特徵亦為包含本發明化合物之藥學上可接受鹽、溶劑合物或前體藥物之醫藥組合物。藥學上可接受之鹽可為兩性離子，或衍生自藥學上可接受之無機或有機酸或鹼。本發明化合物之藥學上可接受鹽較佳係保留該化合物之自由態酸或鹼之生物有效性，而無不當毒性、刺激性或過敏性回應，具有合理利益/風險比，且係對其所意欲之用途有效，及不會在生物學上或在其他方面是不期望的。藥學上可接受鹽之非限制性實例包括但不限於下列：醋酸鹽、己二酸鹽、海藻酸鹽、檸檬酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、酸性硫酸鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、二葡萄糖酸鹽、環戊烷丙酸鹽、十二基硫酸鹽、乙烷磺酸鹽、葡萄糖庚酸鹽、甘油磷酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、反丁烯二酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽、2－羥基－乙烷磺酸鹽(羥乙磺酸鹽)、乳酸鹽、順丁烯二酸鹽、甲烷磺酸鹽、菸鹼酸鹽、2－萘磺酸鹽、草酸鹽、雙羥萘酸鹽、果膠酯酸鹽、過硫酸鹽、3－苯基丙酸鹽、苦味酸鹽、三甲基醋酸鹽、丙酸鹽、琥珀酸鹽、酒石酸鹽、硫氰酸鹽、對－甲苯磺酸鹽及十一烷酸鹽。鹼性含氮基團亦可以作用劑四級化，譬如低碳烷基鹵化物(例如甲基、乙基、丙基或丁基氯化物、溴化物或碘化物)、二烷基硫酸鹽(例如二甲基、二乙基、二丁基或二戊基硫酸鹽)、長鏈鹵化物(例如癸基、月桂基、肉豆蔻基或硬脂基氯化物、溴化物或碘化物)、芳烷基鹵化物(例如苄基或苯乙基溴化物)。可用於本發明之其他鹽包括與鹼金屬或鹼土金屬譬如鈉、鉀、鈣或鎂，或與有機鹼之鹽。可用以形成藥學上可接受酸加成鹽類之酸類之實例，包括但不限於鹽酸、硫酸、磷酸、草酸、順丁烯二酸、琥珀酸、檸檬酸或其他適當無機或有機酸類。A feature of the invention is also a pharmaceutical composition comprising a pharmaceutically acceptable salt, solvate or prodrug of a compound of the invention. The pharmaceutically acceptable salt can be a zwitterion or be derived from a pharmaceutically acceptable inorganic or organic acid or base. Preferably, the pharmaceutically acceptable salt of a compound of the invention retains the biological effectiveness of the free acid or base of the compound without undue toxicity, irritation or allergic response, has a reasonable benefit/risk ratio, and is The intended use is effective and will not be biologically or otherwise undesirable. Non-limiting examples of pharmaceutically acceptable salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, acid sulfate Salt, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentane propionate, dodecyl sulfate, ethanesulfonate, glucose heptanoate, glycerol phosphate, hemisulfuric acid Salt, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate (glycidyl), lactate , maleic acid salt, methane sulfonate, nicotinic acid salt, 2-naphthalene sulfonate, oxalate, pamoate, pectin ester, persulfate, 3-phenyl propyl Acid, picrate, trimethylacetate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. The basic nitrogen-containing group can also be tetracyclized, such as a lower alkyl halide (such as methyl, ethyl, propyl or butyl chloride, bromide or iodide), dialkyl sulfate ( For example, dimethyl, diethyl, dibutyl or dipentyl sulfate), long chain halides (such as decyl, lauryl, myristyl or stearyl chloride, bromide or iodide), aromatic An alkyl halide (such as benzyl or phenethyl bromide). Other salts which may be used in the present invention include salts with alkali or alkaline earth metals such as sodium, potassium, calcium or magnesium, or with organic bases. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, maleic acid, succinic acid, citric acid or other suitable inorganic or organic acids.
本發明之進一步特徵為包含本發明化合物(或其鹽、溶劑合物或前體藥物)與另一種治療劑之醫藥組合物。在一項非限制性實例中，本發明之醫藥組合物係包含1、2、3或更多種本發明化合物(或其鹽、溶劑合物或前體藥物)，與1、2、3或更多種其他治療劑。藉由說明而非限制，此等其他治療劑可選自抗病毒劑(例如抗－HIV劑或其他抗－HCV劑)、免疫調制劑、抗癌或化學治療劑或消炎劑。此等其他治療劑之特殊實例包括但不限於***核苷；干擾素(例如IFN α2a或2b)；蛋白酶抑制劑；免疫抑制劑；抗體(例如治療用之單株或嵌合抗體)；反有意義劑或siRNA；HIV抑制劑；B型肝炎(HBV)抑制劑；用於治療肝硬化與肝臟發炎之藥劑；ω IFN(生物醫學公司,Emeryville,CA)；BILN－2061絲胺酸蛋白酶抑制劑(Boehringer Ingelheim Pharma KG,Ingelheim,Germany)；Summetrel抗病毒(Endo Pharmaceuticals Holdings公司,Chadds Ford,PA)；Roferon A IFN－α2a(F.Hoffmann－La Roche公司,Basel,Switzerland)；Pegasys經PEG化之IFN－α2a(F.Hoffmann－La Roche公司,Basel,Switzerland)；Pegasys與***核苷經PEG化之IFN－α2a/***核苷(F.Hoffmann－La Roche公司,Basel,Switzerland)；CellCept HCV IgG免疫抑制劑(F.Hoffmann－La Roche公司,Basel,Switzerland)；Wellferon類淋巴胚細胞IFN－αn1(GlaxoSmithKline plc,Uxbridge,UK)；阿布非隆(Albuferon)－α白蛋白IFN－α2b(人類基因組科學公司,Rockville,MD)；列弗維林(Levovirin)***核苷(ICN醫藥,Costa Mesa,CA)；IDN－6556卡斯蛋白酶抑制劑(Idun醫藥公司,San Diego,CA)；IP－501抗纖維變性劑(Indevus醫藥公司,Lexington,MA)；Actimmune INF－γ(InterMune公司,Brisbane,CA)；干擾原(Infergen)A IFN alfacon－1(InterMune醫藥公司,Brisbane,CA)；ISIS 14803反有意義劑(ISIS醫藥公司,Carlsbad,CA/Elan醫藥公司,New York,NY)；JTK－003 RdRp抑制劑(日本煙草公司,Tokyo,Japan)；Pegasys與西普連(Ceplene)經PEG化之IFN－α2a/免疫調制劑(Maxim醫藥公司,San Diego,CA)；西普連(Ceplene)免疫調制劑(Maxim醫藥公司,San Diego,CA)；Civacir HCV IgG免疫抑制劑(Nabi生物醫藥公司,Boca Raton,FL)；Intron A與札遲辛(Zadaxin)IFN－α2b/α1－胸腺素(RegeneRx Biopharmiceuticals公司,Bethesda,MD/SciClone醫藥公司,San Mateo,CA)；列弗維林(Levovirin)IMPDH抑制劑(Ribapharm公司,Costa Mesa,CA)；維拉嘧啶(Viramidine)IMPDH抑制劑(Ribapharm公司,Costa Mesa,CA)；賀普塔酶(Heptazyme)核糖酵素(Ribozyme醫藥公司,Boulder,CO)；Intron A IFN－α2b(Schering－Plough公司,Kenilworth,NJ)；PEG－Intron經PEG化之IFN－α 2b(Schering－Plough公司,Kenilworth,NJ)；Rebetron IFN－α2b/***核苷(Schering－Plough公司,Kenilworth,NJ)；***核苷(Schering－Plough公司,Kenilworth,NJ)；PEG－Intron/***核苷經PEG化之IFN－α 2b/***核苷(Schering－Plough公司,Kenilworth,NJ)；Zadazim免疫調制劑(SciClone醫藥公司,San Mateo,CA)；Rebif IFN－β1a(Serono,Geneva,Switzerland)；IFN－β與EMZ701 IFN－β及EMZ701(轉移治療劑公司,Ontario,Canada)；T67 β－微管蛋白抑制劑(Tularik公司,South San Francisco,CA)；VX－497 IMPDH抑制劑(Vertex醫藥公司,Cambridge,MA)；VX－950/LY－570310絲胺酸蛋白酶抑制劑(Vertex醫藥公司,Cambridge,MA/Eli Lilly公司,Indianapolis,IN)；Omniferon天然IFN－α(Viragen公司,Plantation,FL)；XTL－002單株抗體(XTL生物醫藥)；(後文化合物VX－950,Vertex醫藥公司)；(後文化合物SCH503034,Schering－Plough公司)；及(後文化合物GS9137,Gilead科學公司,Foster City,CA)。任何其他所要之治療劑亦可被加入本發明之醫藥組合物中。A further feature of the invention is a pharmaceutical composition comprising a compound of the invention (or a salt, solvate or prodrug thereof) and another therapeutic agent. In one non-limiting example, the pharmaceutical composition of the invention comprises 1, 2, 3 or more compounds of the invention (or a salt, solvate or prodrug thereof), with 1, 2, 3 or More kinds of other therapeutic agents. By way of illustration and not limitation, such other therapeutic agents may be selected from antiviral agents (eg, anti-HIV agents or other anti-HCV agents), immunomodulators, anti-cancer or chemotherapeutic agents or anti-inflammatory agents. Specific examples of such other therapeutic agents include, but are not limited to, triazole nucleosides; interferons (e.g., IFN alpha 2a or 2b); protease inhibitors; immunosuppressive agents; antibodies (e.g., therapeutic single or chimeric antibodies); Significance agent or siRNA; HIV inhibitor; Hepatitis B (HBV) inhibitor; Agent for the treatment of cirrhosis and liver inflammation; ω IFN (Biomedical company, Emeryville, CA); BILN-2061 serine protease inhibitor (Boehringer Ingelheim Pharma KG, Ingelheim, Germany); Summetrel antiviral (Endo Pharmaceuticals Holdings, Chadds Ford, PA); Roferon A IFN-α2a (F. Hoffmann-La Roche, Basel, Switzerland); Pegasys PEGylated IFN-α2a (F. Hoffmann-La Roche, Basel, Switzerland); Pegasys and ribavirin PEGylated IFN-α2a/triazole nucleoside (F.Hoffmann-La Roche, Basel, Switzerland); CellCept HCV IgG immunosuppressant (F. Hoffmann-La Roche, Basel, Switzerland); Wellferon lymphoid blast cell IFN-αn1 (GlaxoSmithKline plc, Uxbridge, UK); Albuflon-alpha albumin IFN-α2b ( Human Genome Sciences, Rockville, MD); Levovirin triazole nucleoside (ICN Pharmaceuticals, Costa Mesa, CA); IDN-6556 caspase inhibitor (Idun Pharmaceuticals, San Diego, CA); IP-501 anti-fibres Denaturant (Indevus Pharmaceuticals, Lexington, MA); Actimmune INF-γ (InterMune, Brisbane, CA); Interferon (Infergen) A IFN alfacon-1 (InterMune Pharmaceuticals, Brisbane, CA); ISIS 14803 anti-sense agent (ISIS Pharmaceuticals, Carlsbad, CA/Elan Pharmaceuticals, New York, NY); JTK-003 RdRp Inhibitor (Japan Tobacco Company, Tokyo, Japan); Pegasys and Ceplene PEGylated IFN-α2a /immunomodulant (Maxim Pharmaceuticals, San Diego, CA); Ceplene immunomodulator (Maxim Pharmaceuticals, San Diego, CA); Civacir HCV IgG immunosuppressant (Nabi Biopharma, Boca Raton, FL); Intron A and Zadaxin IFN-α2b/α1-thymosin (RegeneRx Biopharmiceuticals, Bethesda, MD/SciClone Pharmaceuticals, San Mateo, CA); Levovirin IMPDH inhibitor ( Ribapharm, Costa Mesa, CA); Viramidine IMPDH inhibitor (Ribapharm, Costa Mesa, CA) Heptazyme ribozyme (Ribozyme Pharmaceuticals, Boulder, CO); Intron A IFN-α2b (Schering-Plough, Kenilworth, NJ); PEG-Intron PEGylated IFN-α 2b (Schering-Plough) Company, Kenilworth, NJ); Rebetron IFN-α2b/triazole nucleoside (Schering-Plough, Kenilworth, NJ); triazole nucleoside (Schering-Plough, Kenilworth, NJ); PEG-Intron/triazole nucleoside PEGylated IFN-α 2b/triazole nucleoside (Schering-Plough, Inc., Kenilworth, NJ); Zadazim immunomodulator (SciClone Pharmaceuticals, San Mateo, CA); Rebif IFN-β1a (Serono, Geneva, Switzerland) IFN-β with EMZ701 IFN-β and EMZ701 (Transfer Therapeutics Inc., Ontario, Canada); T67 β-tubulin inhibitor (Tularik, South San Francisco, CA); VX-497 IMPDH inhibitor (Vertex Pharmaceuticals) Company, Cambridge, MA); VX-950/LY-570310 serine protease inhibitor (Vertex Pharmaceuticals, Cambridge, MA/Eli Lilly, Indianapolis, IN); Omniferon natural IFN-α (Viragen, Plantation, FL) ); XTL-002 monoclonal antibody (XTL biomedicine); (hereinafter compound VX-950, Vertex Pharmaceuticals); (hereinafter compound SCH503034, Schering-Plough Company); and (hereinafter compound GS9137, Gilead Scientific, Foster City, CA). Any other desired therapeutic agent can also be incorporated into the pharmaceutical compositions of the present invention.
於一項具體實施例中，本發明之醫藥組合物包含一或多種本發明化合物(或其鹽、溶劑合物或前體藥物)，與一或多種其他抗病毒劑。In a specific embodiment, the pharmaceutical compositions of the present invention comprise one or more compounds of the invention (or a salt, solvate or prodrug thereof), together with one or more other antiviral agents.
於另一項具體實施例中，本發明之醫藥組合物包含一或多種本發明化合物(或其鹽、溶劑合物或前體藥物)，與一或多種其他抗－HCV劑。在一項實例中，各本發明化合物係獨立選自式I、II、III、IV、V、VI、VII或VIII或實例1－255，而各其他抗－HCV劑係獨立選自HCV RNA依賴性RNA聚合酶抑制劑(例如核苷或非核苷類型聚合酶抑制劑)、HCV蛋白酶抑制劑或HCV解螺旋酶抑制劑。In another specific embodiment, the pharmaceutical compositions of the present invention comprise one or more compounds of the invention (or a salt, solvate or prodrug thereof), together with one or more other anti-HCV agents. In one embodiment, each of the compounds of the invention is independently selected from Formula I, II, III, IV, V, VI, VII or VIII or Examples 1-255, and each of the other anti-HCV agents are independently selected from HCV RNA dependent An inhibitor of RNA polymerase (eg, a nucleoside or non-nucleoside type polymerase inhibitor), an HCV protease inhibitor, or an HCV helicase inhibitor.
於進一步具體實施例中，本發明之醫藥組合物包含一或多種本發明化合物(或其鹽、溶劑合物或前體藥物)，與兩種或多種其他抗－HCV抑制劑。各本發明化合物較佳係獨立選自式I、II、III、IV、V、VI、VII或VIII或得自實例1－255。該其他抗－HCV抑制劑可選自相同抑制劑種類(例如其全部均選自HCV RNA依賴性RNA聚合酶抑制劑或HCV蛋白酶抑制劑)，或選自不同抑制劑種類(例如一或多種係選自HCV RNA依賴性RNA聚合酶抑制劑，而另一種或其他係選自HCV蛋白酶抑制劑)。In further embodiments, the pharmaceutical compositions of the present invention comprise one or more compounds of the invention (or a salt, solvate or prodrug thereof), and two or more other anti-HCV inhibitors. Each of the compounds of the invention is preferably independently selected from Formula I, II, III, IV, V, VI, VII or VIII or from Examples 1-255. The other anti-HCV inhibitor may be selected from the same inhibitor class (eg, all selected from HCV RNA-dependent RNA polymerase inhibitors or HCV protease inhibitors), or selected from different inhibitor species (eg, one or more lines) It is selected from the group consisting of HCV RNA-dependent RNA polymerase inhibitors and the other or other is selected from HCV protease inhibitors.
於又再另一項具體實施例中，本發明之醫藥組合物包含至少一種本發明化合物(或其鹽、溶劑合物或前體藥物)，與至少一種HCV RNA依賴性RNA聚合酶抑制劑。各本發明化合物較佳係獨立選自式I、II、III、IV、V、VI、VII或VIII或實例1－255。In still another embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention (or a salt, solvate or prodrug thereof), and at least one HCV RNA-dependent RNA polymerase inhibitor. Preferably, each compound of the invention is independently selected from Formula I, II, III, IV, V, VI, VII or VIII or Examples 1-255.
於另一項具體實施例中，本發明之醫藥組合物包含至少一種本發明化合物(或其鹽、溶劑合物或前體藥物)，與至少一種HCV蛋白酶抑制劑。本發明化合物較佳係選自式I、II、III、IV、V、VI、VII或VIII或實例1－255。In another specific embodiment, the pharmaceutical composition of the invention comprises at least one compound of the invention (or a salt, solvate or prodrug thereof), and at least one HCV protease inhibitor. Preferably, the compounds of the invention are selected from Formula I, II, III, IV, V, VI, VII or VIII or Examples 1-255.
於又另一項具體實施例中，本發明之醫藥組合物包含至少一種本發明化合物(或其鹽、溶劑合物或前體藥物)，至少一種HCV RNA依賴性RNA聚合酶抑制劑，及至少一種HCV蛋白酶抑制劑。本發明化合物較佳係選自式I、II、III、IV、V、VI、VII或VIII或實例1－255。In still another specific embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention (or a salt, solvate or prodrug thereof), at least one HCV RNA-dependent RNA polymerase inhibitor, and at least one An HCV protease inhibitor. Preferably, the compounds of the invention are selected from Formula I, II, III, IV, V, VI, VII or VIII or Examples 1-255.
於又再另一項具體實施例中，本發明之醫藥組合物包含至少一種本發明化合物(或其鹽、溶劑合物或前體藥物)，與兩種或多種抗－HCV劑，其每一種係獨立選自HCV RNA依賴性RNA聚合酶抑制劑或HCV蛋白酶抑制劑。本發明化合物較佳係選自式I、II、III、IV、V、VI、VII或VIII或實例1－255。In still another specific embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention (or a salt, solvate or prodrug thereof), and two or more anti-HCV agents, each of which The lines are independently selected from HCV RNA-dependent RNA polymerase inhibitors or HCV protease inhibitors. Preferably, the compounds of the invention are selected from Formula I, II, III, IV, V, VI, VII or VIII or Examples 1-255.
於又再另一項具體實施例中，本發明之醫藥組合物包含至少一種本發明化合物(或其鹽、溶劑合物或前體藥物)，與三種或更多種其他抗－HCV劑，其每一種係獨立選自HCV RNA依賴性RNA聚合酶抑制劑或HCV蛋白酶抑制劑。本發明化合物較佳係選自式I、II、III、IV、V、VI、VII或VIII或實例1－255。In still another specific embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention (or a salt, solvate or prodrug thereof), and three or more other anti-HCV agents, Each line is independently selected from an HCV RNA-dependent RNA polymerase inhibitor or an HCV protease inhibitor. Preferably, the compounds of the invention are selected from Formula I, II, III, IV, V, VI, VII or VIII or Examples 1-255.
HCV RNA依賴性RNA聚合酶抑制劑之非限制性實例包括在WO0190121(A2),US6348587B1,WO0160315,WO0132153,EP1162196A1及WO0204425中所述者。HCV蛋白酶抑制劑之非限制性實例包括BILN－2061,VX－950及SCH503034。Non-limiting examples of HCV RNA-dependent RNA polymerase inhibitors include those described in WO 0190121 (A2), US Pat. No. 6,348,587 B1, WO 0,160,315, WO 0132153, EP 1 162 196 A1 and WO 0 022 425. Non-limiting examples of HCV protease inhibitors include BILN-2061, VX-950 and SCH503034.
於另一項具體實施例中，本發明之醫藥組合物包含至少一種本發明化合物(或其鹽、溶劑合物或前體藥物)，與一或多種其他抗病毒劑，譬如抗－HBV或抗－HIV劑。抗－HBV劑之非限制性實例包括阿迪弗伐(adefovir)、拉米五定(lamivudine)及天諾弗伐(tenofovir)。抗－HIV藥物之非限制性實例包括利托那伯(ritonavir)、洛平那伯(lopinavir)、因地那伯(indinavir)、尼爾非那伯(nelfinavir)、沙昆那伯(saquinavir)、安普瑞那伯(amprenavir)、阿塔那伯(atazanavir)、提普蘭那伯(tipranavir)、TMC－114、弗山普那伯(fosamprenavir)、寄多夫定(zidovudine)、拉米五定(lamivudine)、二丹諾辛(didanosine)、史塔五定(stavudine)、天諾弗伐(tenofovir)、佳西塔賓(zalcitabine)、阿巴卡伐(abacavir)、依發伯恩姿(efavirenz)、聶伯拉平(nevirapine)、迪拉伯汀(delavirdine)、TMC－125、L－870812、S－1360、恩弗維太(enfuvirtide)、T－1249，及其他HIV蛋白酶、反轉錄酶、整合酶或融合抑制劑。其他所要之抗病毒劑亦可被加入本發明之醫藥組合物中，如熟諳此藝者所明瞭。In another specific embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention (or a salt, solvate or prodrug thereof), together with one or more other antiviral agents, such as anti-HBV or anti- - HIV agent. Non-limiting examples of anti-HBV agents include adefovir, lamivudine, and tenofovir. Non-limiting examples of anti-HIV drugs include ritonavir, lopinavir, indinavir, nelfinavir, saquinavir ,amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lambat five Lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, escarpment Efavirenz), nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide, T-1249, and other HIV proteases, reverse transcriptase , integrase or fusion inhibitor. Other desired antiviral agents can also be incorporated into the pharmaceutical compositions of the present invention, as will be apparent to those skilled in the art.
於一項具體實施例中，本發明之醫藥組合物包含至少一種本發明化合物，選自式I、II、III、IV、V、VI、VII或VIII或得自實例1－255，或其鹽、溶劑合物或前體藥物，與至少一種抗－HBV劑。於另一項具體實施例中，本發明之醫藥組合物包含至少一種本發明化合物，選自式I、II、III、IV、V、VI、VII或VIII或得自實例1－255，或其鹽、溶劑合物或前體藥物，與至少一種抗－HIV劑。於又另一項具體實施例中，本發明之醫藥組合物包含至少一種本發明化合物，選自式I、II、III、IV、V、VI、VII或VIII或得自實例1－255，或其鹽、溶劑合物或前體藥物，與至少一種抗－A型肝炎、抗－D型肝炎、抗－E型肝炎或抗－G型肝炎劑。In a specific embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the invention selected from Formula I, II, III, IV, V, VI, VII or VIII or from Example 1-255, or a salt thereof a solvate or prodrug, with at least one anti-HBV agent. In another specific embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the invention selected from Formula I, II, III, IV, V, VI, VII or VIII or from Example 1-255, or a salt, solvate or prodrug, and at least one anti-HIV agent. In still another specific embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the invention selected from Formula I, II, III, IV, V, VI, VII or VIII or from Example 1-255, or a salt, solvate or prodrug thereof, and at least one anti-A hepatitis, anti-D hepatitis, anti-E hepatitis or anti-G hepatitis agent.
於又再另一項具體實施例中，本發明之醫藥組合物包含至少一種本發明化合物，選自式I、II、III、IV、V、VI、VII或VIII或得自實例1－255，或其鹽、溶劑合物或前體藥物，與至少一種適合治療肝臟發炎之藥劑。In still another specific embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the invention selected from Formula I, II, III, IV, V, VI, VII or VIII or from Example 1-255. Or a salt, solvate or prodrug thereof, and at least one agent suitable for treating inflammation of the liver.
本發明之醫藥組合物典型上包含藥學上可接受之載劑或賦形劑。適當藥學上可接受之載劑/賦形劑之非限制性實例包括糖類(例如乳糖、葡萄糖或蔗糖)、澱粉(例如玉米澱粉或馬鈴薯澱粉)、纖維素或其衍生物(例如羧甲基纖維素鈉、乙基纖維素或纖維素醋酸酯)、油類(例如花生油、棉籽油、紅花油、芝麻油、橄欖油、玉米油或大豆油)、二醇類(例如丙二醇)、緩衝劑(例如氫氧化鎂或氫氧化鋁)、瓊脂、海藻酸、粉末狀西黃蓍樹膠、麥芽、明膠、滑石、可可豆脂、不含熱原水、等滲鹽水、林格氏溶液、乙醇或磷酸鹽緩衝溶液。潤滑劑、著色劑、離型劑、塗覆劑，增甜、矯味或芳香劑，防腐劑或抗氧化劑，亦可被加入本發明之醫藥組合物中，如一般熟諳此項技藝者所明瞭。Pharmaceutical compositions of the invention typically comprise a pharmaceutically acceptable carrier or excipient. Non-limiting examples of suitable pharmaceutically acceptable carriers/excipients include saccharides (such as lactose, glucose or sucrose), starch (such as corn starch or potato starch), cellulose or derivatives thereof (such as carboxymethyl fibers). Sodium, ethyl cellulose or cellulose acetate), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil or soybean oil), glycols (such as propylene glycol), buffers (for example Magnesium hydroxide or aluminum hydroxide), agar, alginic acid, powdered sassafras gum, malt, gelatin, talc, cocoa butter, pyrogen-free water, isotonic saline, Ringer's solution, ethanol or phosphate Buffer solution. Lubricants, colorants, release agents, coating agents, sweetening, flavoring or perfuming agents, preservatives or antioxidants may also be incorporated into the pharmaceutical compositions of the present invention, as will be apparent to those skilled in the art.
本發明之醫藥組合物可經由多種途徑投予有需要之病患，譬如口服、非經腸方式、舌下方式、直腸方式、局部方式或藉由吸入噴霧。局部投藥可涉及利用經皮投藥，譬如經皮貼藥或離子電滲裝置。非經腸投藥包括但不限於皮下、靜脈內、肌內或胸骨內注射及灌注技術。The pharmaceutical compositions of the present invention can be administered to a patient in need thereof by a variety of routes, such as orally, parenterally, sublingually, rectally, topically, or by inhalation spray. Topical administration may involve the use of transdermal administration, such as transdermal patches or iontophoresis devices. Parenteral administration includes, but is not limited to, subcutaneous, intravenous, intramuscular or intrasternal injection and perfusion techniques.
本發明之醫藥組合物可以其投藥途徑為基礎，使用此項技藝中所習知之方法調配。例如，無菌可注射製劑可使用適當分散或潤濕劑與懸浮劑，製成無菌可注射水性或油性懸浮液。供直腸投藥用之栓劑可經由將藥物與適當無刺激性賦形劑譬如可可豆脂或聚乙二醇混合而製成，該賦形劑在一般溫度下為固體，但在直腸溫度下為液體，因此將在直腸中熔解並釋出藥物。供口服投藥之固體劑型可為膠囊、片劑、丸劑、粉末或顆粒。在此種固體劑型中，可將活性化合物與至少一種惰性稀釋劑譬如蔗糖、乳糖或澱粉互混。除了惰性稀釋劑以外，固體劑型亦可包含其他物質，譬如潤滑劑。在膠囊、片劑及丸劑之情況中，該劑型亦可包含緩衝劑。片劑與丸劑可另外被製成具有腸溶性塗層。供口服投藥之液體劑型，可包括藥學上可接受之乳化液、溶液、懸浮液、糖漿或酏劑，含有此項技藝中常用之惰性稀釋劑。液體劑型亦可包含潤濕、乳化、懸浮、增甜、矯味或芳香劑。本發明之醫藥組合物亦可以微脂粒形式投藥，如在美國專利6,703,403中所述者。可應用於本發明之藥物配方係一般性地討論於例如Hoover,John E.,Remington氏醫藥科學 (Mack出版公司(Easton,PA)：1975)與LachmanL.編著,醫藥劑型 (Marcel Decker,New York,N.Y.,1980)中。The pharmaceutical compositions of the present invention can be formulated on the basis of their route of administration using methods known in the art. For example, a sterile injectable preparation may be in the form of a sterile injectable aqueous or oily suspension using suitable dispersing or wetting agents and suspending agents. A suppository for rectal administration can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter or polyethylene glycol which is solid at ordinary temperatures but liquid at rectal temperature Therefore, the drug will be melted and released in the rectum. The solid dosage form for oral administration can be a capsule, tablet, pill, powder or granule. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. In addition to the inert diluent, the solid dosage form may also contain other materials such as a lubricant. In the case of capsules, tablets and pills, the dosage form may also contain a buffer. Tablets and pills may additionally be formulated with an enteric coating. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs containing inert diluents conventional in the art. Liquid dosage forms can also include wetting, emulsifying, suspending, sweetening, flavoring or flavoring agents. The pharmaceutical compositions of the present invention may also be administered in the form of a liposome, as described in U.S. Patent No. 6,703,403. Pharmaceutical formulations that can be used in the present invention are generally discussed, for example, in Hoover, John E., Remington Medical Sciences (Mack Publishing Company (Easton, PA): 1975) and Lachman L., Medical Formula (Marcel Decker, New York). , NY, 1980).
本發明之進一步特徵為使用本發明化合物(或其鹽、溶劑合物或前體藥物)以抑制HCV複製之方法。於一項具體實施例中，此等方法包括使HCV病毒與有效量之本發明化合物(或其鹽、溶劑合物或前體藥物)接觸，藉以抑制HCV病毒之複製。於另一項具體實施例中，此等方法包括使已被HCV病毒感染之細胞與有效量之本發明化合物(或其鹽、溶劑合物或前體藥物)接觸，藉以抑制HCV病毒在細胞中之複製。於又再另一項具體實施例中，此等方法包括使HCV病毒或受感染細胞與有效量之兩種或多種本發明之化合物(或其鹽、溶劑合物或前體藥物)接觸，藉以抑制HCV病毒之複製。於本文中使用之"抑制"係意謂顯著地降低或廢除正被抑制之活性(例如病毒複製)。在許多情況中，本發明之代表性化合物可降低HCV病毒之複製(例如，在如上文所述之HCV複製子檢測中)達至少10%、20%、30%、40%、50%、60%、70%、80%、90%、95%或更多。A further feature of the invention is the use of a compound of the invention (or a salt, solvate or prodrug thereof thereof) to inhibit HCV replication. In a specific embodiment, the methods comprise contacting the HCV virus with an effective amount of a compound of the invention (or a salt, solvate or prodrug thereof thereof) to inhibit replication of the HCV virus. In another embodiment, the methods comprise contacting a cell that has been infected with an HCV virus with an effective amount of a compound of the invention (or a salt, solvate or prodrug thereof thereof) thereby inhibiting HCV virus in the cell Copy. In yet another specific embodiment, the methods comprise contacting an HCV virus or infected cell with an effective amount of two or more compounds of the invention (or a salt, solvate or prodrug thereof), thereby Inhibition of replication of HCV virus. As used herein, "inhibiting" means significantly reducing or abolishing the activity being inhibited (eg, viral replication). In many cases, representative compounds of the invention reduce replication of the HCV virus (eg, in the HCV replicon assay as described above) by at least 10%, 20%, 30%, 40%, 50%, 60. %, 70%, 80%, 90%, 95% or more.
本發明化合物可抑制所有HCV亞型。易於接受本發明之HCV亞型之實例包括但不限於HCV基因型1、2、3、4、5及6，包括HCV基因型1a、1b、2a、2b、2c或3a。於一項具體實施例中，係使用一或多種本發明化合物(或其鹽、溶劑合物或前體藥物)以抑制HCV基因型1a之複製。於另一項具體實施例中，係使用一或多種本發明化合物(或其鹽、溶劑合物或前體藥物)以抑制HCV基因型1b之複製。於又再另一項具體實施例中，係使用一或多種本發明化合物(或其鹽、溶劑合物或前體藥物)以抑制HCV基因型1a與1b兩者之複製。The compounds of the invention inhibit all HCV subtypes. Examples of HCV subtypes that are susceptible to the present invention include, but are not limited to, HCV genotypes 1, 2, 3, 4, 5, and 6, including HCV genotypes 1a, 1b, 2a, 2b, 2c, or 3a. In one embodiment, one or more compounds of the invention (or a salt, solvate or prodrug thereof thereof) are used to inhibit replication of HCV genotype 1a. In another specific embodiment, one or more compounds of the invention (or a salt, solvate or prodrug thereof thereof) are used to inhibit replication of HCV genotype 1b. In yet another embodiment, one or more compounds of the invention (or a salt, solvate or prodrug thereof thereof) are used to inhibit replication of both HCV genotypes 1a and 1b.
本發明之特徵亦為使用本發明化合物(或其鹽、溶劑合物或前體藥物)以治療HCV感染之方法。此等方法典型上包括對HCV病患投予治療有效量之本發明化合物(或其鹽、溶劑合物或前體藥物)，藉以降低病患之血液或肝臟中之HCV病毒含量。於本文中使用之"治療"一詞係指逆轉、減輕、抑制或預防此種術語所適用之病症或症狀或此種病症或症狀之一或多種病徵之進展。"治療法"一詞係指治療行為。於一項具體實施例中，此等方法係包括對HCV病患投予治療有效量之兩種或多種本發明化合物(或其鹽、溶劑合物或前體藥物)，藉以降低病患之血液或肝臟中之HCV病毒含量。被採用於此等方法中之化合物，較佳係具有式I、II、III、IV、V、VI、VII或VIII，或係選自實例1－255，或為其鹽、溶劑合物或前體藥物。A feature of the invention is also a method of treating a HCV infection using a compound of the invention (or a salt, solvate or prodrug thereof). Such methods typically involve administering a therapeutically effective amount of a compound of the invention (or a salt, solvate or prodrug thereof) to a HCV patient to reduce the level of HCV virus in the blood or liver of the patient. The term "treatment" as used herein refers to the reversal, alleviation, inhibition or prevention of a condition or symptom to which such a term applies or the progression of one or more of such a condition or symptom. The term "therapeutic method" refers to the treatment behavior. In a specific embodiment, the methods comprise administering to the HCV patient a therapeutically effective amount of two or more compounds of the invention (or a salt, solvate or prodrug thereof thereof) to reduce blood of the patient Or the amount of HCV virus in the liver. The compounds employed in such methods preferably have the formula I, II, III, IV, V, VI, VII or VIII, or are selected from the examples 1-255, or are their salts, solvates or former Body medicine.
於另一方面，本發明之特徵為使用本發明之醫藥組合物以治療HCV感染之方法。本文中所述之任何醫藥組合物均可用於此項目的。此等方法典型上包括對HCV病患投予治療有效量之本發明醫藥組合物，藉以降低病患之血液或肝臟中之HCV病毒含量。在該醫藥組合物包含其他治療劑之情況下，其亦可在病患中治療其他疾病、病症或症狀。In another aspect, the invention features a method of using the pharmaceutical composition of the invention to treat an HCV infection. Any of the pharmaceutical compositions described herein can be used in this project. Such methods typically comprise administering to the HCV patient a therapeutically effective amount of a pharmaceutical composition of the invention to reduce the level of HCV virus in the blood or liver of the patient. Where the pharmaceutical composition comprises other therapeutic agents, it can also treat other diseases, conditions or conditions in the patient.
於一項具體實施例中，被投予之醫藥組合物係包含至少一種本發明化合物，選自式I、II、III、IV、V、VI、VII或VIII或得自實例1－255，或其鹽、溶劑合物或前體藥物，與至少另一種抗－HCV劑，選自HCV RNA依賴性RNA聚合酶抑制劑、HCV蛋白酶抑制劑或HCV解螺旋酶抑制劑。於另一項具體實施例中，被投予之醫藥組合物係包含至少一種本發明化合物，選自式I、II、III、IV、V、VI、VII或VIII或得自實例1－255，或其鹽、溶劑合物或前體藥物，與至少兩種其他抗－HCV劑，其每一種係獨立選自HCV RNA依賴性RNA聚合酶抑制劑、HCV蛋白酶抑制劑或HCV解螺旋酶抑制劑。於又再另一項具體實施例中，被投予之醫藥組合物係包含至少一種本發明化合物，選自式I、II、III、IV、V、VI、VII或VIII或得自實例1－255，或其鹽、溶劑合物或前體藥物，與1、2或更多種HCV RNA依賴性RNA聚合酶抑制劑(例如在WO0190121(A2),US6348587B1,WO0160315,WO0132153,EP1162196A1及WO0204425中所述者)。於又另一項具體實施例中，被投予之醫藥組合物係包含至少一種本發明化合物，選自式I、II、III、IV、V、VI、VII或VIII或得自實例1－255，或其鹽、溶劑合物或前體藥物，與1、2或更多種HCV蛋白酶抑制劑(例如BILN－2061,VX－950及SCH503034)。In a specific embodiment, the pharmaceutical composition to be administered comprises at least one compound of the invention selected from Formula I, II, III, IV, V, VI, VII or VIII or from Example 1-255, or A salt, solvate or prodrug thereof, and at least another anti-HCV agent, selected from the group consisting of an HCV RNA-dependent RNA polymerase inhibitor, an HCV protease inhibitor, or an HCV helicase inhibitor. In another specific embodiment, the pharmaceutical composition to be administered comprises at least one compound of the invention selected from Formula I, II, III, IV, V, VI, VII or VIII or from Example 1-255. Or a salt, solvate or prodrug thereof, and at least two other anti-HCV agents, each of which is independently selected from the group consisting of an HCV RNA-dependent RNA polymerase inhibitor, an HCV protease inhibitor or a HCV helicase inhibitor . In still another specific embodiment, the pharmaceutical composition to be administered comprises at least one compound of the invention selected from Formula I, II, III, IV, V, VI, VII or VIII or from Example 1 255, or a salt, solvate or prodrug thereof, with 1, 2 or more HCV RNA-dependent RNA polymerase inhibitors (for example, in WO0190121 (A2), US Pat. No. 6,348,587 B1, WO 0160315, WO 0132153, EP 1 162 196 A1 and WO 0204425 Said). In yet another embodiment, the pharmaceutical composition to be administered comprises at least one compound of the invention selected from Formula I, II, III, IV, V, VI, VII or VIII or from Example 1-255. Or a salt, solvate or prodrug thereof, with 1, 2 or more HCV protease inhibitors (eg, BILN-2061, VX-950 and SCH503034).
於進一步具體實施例中，被投予之醫藥組合物係包含至少一種本發明化合物，選自式I、II、III、IV、V、VI、VII或VIII或得自實例1－255，或其鹽、溶劑合物或前體藥物，與至少一種抗病毒劑，選自抗－HIV劑、抗－HBV劑、抗－A型肝炎劑、抗－D型肝炎劑、抗－E型肝炎劑或抗－G型肝炎劑。In a further embodiment, the pharmaceutical composition to be administered comprises at least one compound of the invention selected from Formula I, II, III, IV, V, VI, VII or VIII or from Example 1-255, or a salt, solvate or prodrug, and at least one antiviral agent selected from the group consisting of an anti-HIV agent, an anti-HBV agent, an anti-A hepatitis agent, an anti-D hepatitis agent, an anti-hepatitis E agent, or Anti-G hepatitis agent.
於又另一方面，本發明係提供使用本發明化合物與另一種治療劑以治療HCV感染之方法。此等方法包括對HCV病患投予治療有效量之本發明化合物與另一種治療劑，藉以降低病患之血液或肝臟中之HCV病毒含量。各本發明化合物(或其鹽、溶劑合物或前體藥物)與該其他治療劑可被合併在單一配方中，且同時投予病患。其亦可同時投予，但在不同配方中。此外，其可相繼地投予。In yet another aspect, the invention provides a method of using a compound of the invention and another therapeutic agent to treat an HCV infection. Such methods include administering to a HCV patient a therapeutically effective amount of a compound of the invention and another therapeutic agent to reduce the amount of HCV virus in the blood or liver of the patient. Each of the compounds of the invention (or a salt, solvate or prodrug thereof) and the other therapeutic agent can be combined in a single formulation and administered to the patient at the same time. It can also be administered at the same time, but in different formulations. Furthermore, it can be administered sequentially.
於一項具體實施例中，被投予之本發明化合物係包括一或多種化合物，選自式I、II、III、IV、V、VI、VII或VIII或得自實例1－255，或其鹽、溶劑合物或前體藥物，而被投予之其他治療劑係包括一或多種藥劑，選自HCV RNA依賴性RNA聚合酶抑制劑、HCV蛋白酶抑制劑或HCV解螺旋酶抑制劑。於另一項具體實施例中，被投予之本發明化合物係包括一或多種化合物，選自式I、II、III、IV、V、VI、VII或VIII或得自實例1－255，或其鹽、溶劑合物或前體藥物，而被投予之其他治療劑係包括兩種或多種藥劑，選自HCV RNA依賴性RNA聚合酶抑制劑、HCV蛋白酶抑制劑或HCV解螺旋酶抑制劑。於又另一項具體實施例中，被投予之本發明化合物係包括一或多種化合物，選自式I、II、III、IV、V、VI、VII或VIII或得自實例1－255，或其鹽、溶劑合物或前體藥物，而被投予之其他治療劑係包括一、二或更多種HCV RNA依賴性RNA聚合酶抑制劑(例如在WO0190121(A2),US6348587B1,WO0160315,WO0132153,EP1162196A1及WO0204425中所述者)。於又再另一項具體實施例中，被投予之本發明化合物係包括一或多種化合物，選自式I、II、III、IV、V、VI、VII或VIII或得自實例1－255，或其鹽、溶劑合物或前體藥物，而被投予之其他治療劑係包括一、二或更多種HCV蛋白酶抑制劑(例如BILN－2061,VX－950及SCH503034)。In a specific embodiment, the compound of the invention to be administered comprises one or more compounds selected from Formula I, II, III, IV, V, VI, VII or VIII or from Examples 1-255, or A salt, solvate or prodrug, and the other therapeutic agent to be administered comprises one or more agents selected from the group consisting of HCV RNA-dependent RNA polymerase inhibitors, HCV protease inhibitors or HCV helicase inhibitors. In another embodiment, the compound of the invention to be administered comprises one or more compounds selected from Formula I, II, III, IV, V, VI, VII or VIII or from Examples 1-255, or a salt, solvate or prodrug thereof, and other therapeutic agents to be administered include two or more agents selected from the group consisting of HCV RNA-dependent RNA polymerase inhibitors, HCV protease inhibitors or HCV helicase inhibitors . In yet another embodiment, the compound of the invention to be administered comprises one or more compounds selected from Formula I, II, III, IV, V, VI, VII or VIII or from Examples 1-255. Or a salt, solvate or prodrug thereof, and the other therapeutic agent to be administered comprises one, two or more HCV RNA-dependent RNA polymerase inhibitors (for example, in WO0190121 (A2), US Pat. No. 6,348,587 B1, WO 0160315, WO0132153, EP 1 162 196 A1 and WO 0 022 425). In still another specific embodiment, the compound of the invention to be administered comprises one or more compounds selected from Formula I, II, III, IV, V, VI, VII or VIII or from Example 1-255. Or a salt, solvate or prodrug thereof, and other therapeutic agents to be administered include one, two or more HCV protease inhibitors (e.g., BILN-2061, VX-950 and SCH503034).
本發明化合物(或其鹽、溶劑合物或前體藥物)亦可與其他所要之藥物共同投予，譬如抗－HIV劑、抗－HBV劑、抗－A型肝炎劑、抗－D型肝炎劑、抗－E型肝炎劑、抗－G型肝炎劑或其他抗病毒藥物。The compound of the present invention (or a salt, solvate or prodrug thereof) can also be administered together with other desired drugs, such as an anti-HIV agent, an anti-HBV agent, an anti-A hepatitis agent, and an anti-D type hepatitis. Agent, anti-E hepatitis agent, anti-G hepatitis agent or other antiviral drugs.
本發明化合物(或其鹽、溶劑或前體藥物)可以單一劑量或分離劑量投予病患。典型日服劑量範圍可為但不限於0.1至200毫克/公斤體重，譬如0.25至100毫克/公斤體重。單一劑量組合物可含有此等量或其約數，以構成日服劑量。各劑量較佳係含有足量之本發明化合物，其係有效降低病患之血液或肝臟中之HCV病毒負載。活性成份或合併之活性成份產生單一劑型之量，可依待治療之宿主及特定投藥模式而改變。應明瞭的是，對任何特定病患之特定劑量程度係依多種因素而定，包括所採用特定化合物之活性、年齡、體重、一般健康狀態、性別、飲食、投藥時間、投藥途徑、***速率、藥物組合及接受治療之特定疾病之嚴重性。The compounds of the invention (or salts, solvents or prodrugs thereof) can be administered to a patient in a single dose or in divided doses. A typical daily dosage range can be, but is not limited to, 0.1 to 200 mg/kg body weight, such as 0.25 to 100 mg/kg body weight. A single dose composition may contain such equal amounts or submultiples thereof to constitute a daily dose. Each dose preferably contains a sufficient amount of a compound of the invention which is effective to reduce the HCV viral load in the blood or liver of the patient. The amount of active ingredient or combined active ingredient produced in a single dosage form will vary depending upon the host to be treated and the particular mode of administration. It should be understood that the specific dosage level for any particular patient will depend on a number of factors, including the activity of the particular compound employed, age, weight, general health status, sex, diet, time of administration, route of administration, rate of excretion, The combination of the drug and the severity of the particular disease being treated.
於又另一方面，式I、II、III、IV、V、VI、VII或VIII化合物，或其藥學上可接受之鹽、立體異構物或互變異構物可以單獨活性藥劑，或併用一或多種其他藥劑投藥，以治療與其他含RNA病毒有關聯之感染或病徵。In yet another aspect, the compound of Formula I, II, III, IV, V, VI, VII or VIII, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, may be the active agent alone or in combination Or a variety of other agents to treat infections or signs associated with other RNA-containing viruses.
因含RNA病毒所造成之感染，其治療或預防可藉由組合療法提供，其包含治療上有效量之第一種抗病毒劑，由一或多種式I、II、III、IV、V、VI、VII或VIII化合物或其鹽提供，伴隨著治療上有效量之第二種藥劑，由一或多種化合物提供，選自包括另一種抗病毒劑；宿主免疫調制劑；干擾素衍生物，譬如干擾素－α、經PEG化之干擾素－α、干擾素－β及干擾素－γ；細胞活素；疫苗；核苷類似物；會造成HCV機能障礙之關鍵酵素之抑制劑，此種酵素之實例為HCV金屬蛋白酶、HCV絲胺酸蛋白酶、肌苷單磷酸鹽脫氫酶(IMPDH)及HCV解螺旋酶；病毒粒子蛋白質之抑制劑，譬如HCV NS4B蛋白質與HCV NS5a蛋白質；及會抑制HCV功能之藥劑，該功能譬如HCV進入、HCV組裝及HCV流出。亦被包含者為疫苗，包括HCV抗原或針對抵抗HCV之抗原佐劑組合。進一步被包含者為會與宿主細胞成份交互作用以阻斷病毒蛋白質合成之藥劑，其方式是抑制HCV病毒複製之內部核糖體進入位置(IRES)所引發之轉譯步驟，或使用針對膜蛋白質之病毒孢素族群例如HCV P7作為標的之藥劑以阻斷病毒粒子成熟與釋出。For infection by an RNA-containing virus, the treatment or prevention thereof may be provided by a combination therapy comprising a therapeutically effective amount of a first antiviral agent, one or more of Formulas I, II, III, IV, V, VI a compound of VII or VIII or a salt thereof, provided with a therapeutically effective amount of a second agent, provided by one or more compounds, selected from the group consisting of another antiviral agent; a host immunomodulator; an interferon derivative, such as interference -α, PEGylated interferon-α, interferon-β and interferon-γ; cytokines; vaccines; nucleoside analogues; inhibitors of key enzymes that cause HCV dysfunction, such enzymes Examples are HCV metalloproteinases, HCV serine proteases, inosine monophosphate dehydrogenases (IMPDH) and HCV helicase; inhibitors of virion proteins such as HCV NS4B protein and HCV NS5a protein; and inhibition of HCV function The agent, such as HCV entry, HCV assembly, and HCV outflow. Also included are vaccines, including HCV antigens or antigen adjuvant combinations against HCV. Further included is an agent that interacts with host cell components to block viral protein synthesis by a translation step initiated by inhibition of the internal ribosome entry site (IRES) of HCV viral replication, or by use of a virus against membrane proteins. The spore group, such as HCV P7, acts as the target agent to block virion maturation and release.
於一項具體實施例中，本發明係針對一種治療或預防因含RNA病毒所造成感染之方法，其包括對需要此種治療之病患投予治療上有效量之式I、II、III、IV、V、VI、VII或VIII化合物，或其藥學上可接受之鹽。In a specific embodiment, the invention is directed to a method of treating or preventing an infection caused by an RNA-containing virus, comprising administering to a patient in need of such treatment a therapeutically effective amount of Formulas I, II, III, A compound of IV, V, VI, VII or VIII, or a pharmaceutically acceptable salt thereof.
於另一項具體實施例中，本發明係針對一種治療或預防因含RNA病毒所造成感染之方法，其包括對需要此種治療之病患共同投予一或多種藥劑，選自包括宿主免疫調制劑，與第二種抗病毒劑，或其組合，伴隨著治療上有效量之式I、II、III、IV、V、VI、VII或VIII化合物，或其藥學上可接受之鹽。In another embodiment, the invention is directed to a method of treating or preventing an infection caused by an RNA-containing virus, comprising co-administering one or more agents to a patient in need of such treatment, selected from the group consisting of: The modulator, and the second antiviral agent, or a combination thereof, is accompanied by a therapeutically effective amount of a compound of formula I, II, III, IV, V, VI, VII or VIII, or a pharmaceutically acceptable salt thereof.
於又另一項具體實施例中，本發明係針對一種治療或預防因含RNA病毒所造成感染之方法，其包括對需要此種治療之病患共同投予一或多種藥劑，選自包括干擾素－α、經PEG化之干擾素－α、干擾素－β、干擾素－γ、細胞活素、疫苗及包含抗原與佐劑之疫苗，與第二種抗病毒劑，或其組合，伴隨著治療上有效量之式I、II、III、IV、V、VI、VII或VIII化合物，或其藥學上可接受之鹽。In yet another embodiment, the invention is directed to a method of treating or preventing an infection caused by an RNA-containing virus, comprising co-administering one or more agents to a patient in need of such treatment, selected from the group consisting of including interference -α, PEGylated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants, and second antiviral agents, or combinations thereof, A therapeutically effective amount of a compound of formula I, II, III, IV, V, VI, VII or VIII, or a pharmaceutically acceptable salt thereof.
於又再另一項具體實施例中，本發明係提供一種治療或預防因含RNA病毒所造成感染之方法，其包括對需要此種治療之病患共同投予一或多種藥劑，選自包括宿主免疫調制劑，與第二種抗病毒劑，其係藉由抑制與病毒複製有關聯之宿主細胞功能而抑制HCV複製，或其組合，伴隨著治療上有效量之式I、II、III、IV、V、VI、VII或VIII化合物，或其藥學上可接受之鹽。In still another specific embodiment, the present invention provides a method of treating or preventing an infection caused by an RNA-containing virus, comprising co-administering one or more agents to a patient in need of such treatment, selected from the group consisting of a host immune modulator, and a second antiviral agent that inhibits HCV replication by inhibiting host cell function associated with viral replication, or a combination thereof, with a therapeutically effective amount of Formula I, II, III, A compound of IV, V, VI, VII or VIII, or a pharmaceutically acceptable salt thereof.
於進一步具體實施例中，本發明係提供一種治療或預防因含RNA病毒所造成感染之方法，其包括對需要此種治療之病患共同投予可治療或減輕HCV感染之病徵包括肝硬化與肝臟發炎之藥劑或藥劑組合，伴隨著治療上有效量之式I、II、III、IV、V、VI、VII或VIII化合物，或其藥學上可接受之鹽。In a further embodiment, the invention provides a method of treating or preventing an infection caused by an RNA-containing virus, comprising co-administering a condition for treating or ameliorating HCV infection, including cirrhosis, and a patient in need of such treatment An agent or combination of agents for inflammation of the liver, accompanied by a therapeutically effective amount of a compound of formula I, II, III, IV, V, VI, VII or VIII, or a pharmaceutically acceptable salt thereof.
於另一項具體實施例中，本發明係提供一種治療或預防因含RNA病毒所造成感染之方法，其包括對需要此種治療之病患共同投予一或多種治療因B型肝炎(HBV)感染所造成疾病之病患之藥劑，伴隨著治療上有效量之式I、II、III、IV、V、VI、VII或VIII化合物，或其藥學上可接受之鹽。In another embodiment, the invention provides a method of treating or preventing an infection caused by an RNA-containing virus, comprising co-administering one or more treatments for hepatitis B (HBV) to a patient in need of such treatment. An agent for a disease in which the disease is caused is accompanied by a therapeutically effective amount of a compound of formula I, II, III, IV, V, VI, VII or VIII, or a pharmaceutically acceptable salt thereof.
於又另一項具體實施例中，本發明係提供一種治療或預防因含RNA病毒所造成感染之方法，其包括對需要此種治療之病患共同投予一或多種治療因人類免疫不全病毒(HIV)感染所造成疾病之病患之藥劑，伴隨著治療上有效量之式I、II、III、IV、V、VI、VII或VIII化合物，或其藥學上可接受之鹽。In yet another embodiment, the invention provides a method of treating or preventing an infection caused by an RNA-containing virus, comprising co-administering one or more therapeutic human immunodeficiency viruses to a patient in need of such treatment An agent for a disease caused by (HIV) infection, accompanied by a therapeutically effective amount of a compound of formula I, II, III, IV, V, VI, VII or VIII, or a pharmaceutically acceptable salt thereof.
"組合療法"(或"共同療法")之措辭，係意欲包括各藥劑以相繼方式在服用法中之投藥，其將提供藥物組合之有利作用，且亦意欲包括此等藥劑以實質上同時方式之共同投藥，譬如藉由口服攝食具有固定比例之此等活性劑之單一膠囊，或攝食多次各藥劑之個別膠囊。"組合療法"亦包括藉由口服、靜脈內、肌內或其他非經腸途徑之同時或相繼投藥至身體中，包括直接吸收經過黏膜組織，如在竇通路中所發現者。相繼投藥亦包括藥物組合，其中個別藥劑可在不同時間下及/或藉由不同途徑投予，但其係以組合發生作用，以提供有利作用，例如藉由各藥劑之藥物動力學或藥藥力效果之共作用。The wording of "combination therapy" (or "common therapy") is intended to include the administration of each agent in a sequential manner, which will provide a beneficial effect of the combination of drugs, and is also intended to include such agents in a substantially simultaneous manner. Co-administration, for example, by oral ingestion of a single capsule having a fixed ratio of such active agents, or ingesting individual capsules of each of the multiple agents. "Combination therapy" also includes simultaneous or sequential administration to the body by oral, intravenous, intramuscular or other parenteral routes, including direct absorption through mucosal tissue, as found in the sinus pathway. Successive administration also includes a combination of drugs, wherein individual agents can be administered at different times and/or by different routes, but they act in combination to provide a beneficial effect, for example by pharmacokinetics or pharmacodynamics of each agent. The effect of the effect.
本發明之特徵亦為本發明化合物或其藥學上可接受鹽、溶劑合物或前體藥物於藥劑製造上之用途，該藥劑係用於治療HCV或其他病毒感染。於一項具體實施例中，本發明之特徵為本發明化合物，選自式I、II、III、IV、V、VI、VII或VIII，或其鹽、溶劑合物或前體藥物，於藥劑製造上之用途，該藥劑係用於治療HCV感染。於另一項具體實施例中，本發明之特徵為兩種或多種本發明之化合物(或其鹽、溶劑合物或前體藥物)於藥劑製造上之用途，該藥劑係用於治療HCV感染，其中該兩種或多種化合物之每一種係獨立選自式I、II、III、IV、V、VI、VII或VIII。A feature of the invention is also the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the manufacture of a medicament for the treatment of HCV or other viral infections. In a specific embodiment, the invention features a compound of the invention, selected from Formula I, II, III, IV, V, VI, VII or VIII, or a salt, solvate or prodrug thereof, in a medicament For manufacturing purposes, the agent is used to treat HCV infection. In another embodiment, the invention features the use of two or more compounds of the invention (or a salt, solvate or prodrug thereof) for the manufacture of a medicament for the treatment of HCV infection Wherein each of the two or more compounds is independently selected from Formula I, II, III, IV, V, VI, VII or VIII.
於又再另一項具體實施例中，本發明之特徵為至少一種本發明化合物(或其鹽、溶劑合物或前體藥物)與至少一種其他治療劑於藥劑製造上之用途，該藥劑係用於治療HCV感染。本發明化合物較佳係選自式I、II、III、IV、V、VI、VII或VIII，而其他治療劑，藉由說明而非限制，可選自抗病毒劑(例如抗－HIV劑或其他抗－HCV劑)、免疫調制劑、抗癌或化學治療劑及消炎劑。其他治療劑之特殊實例包括但不限於***核苷；干擾素(例如IFN α2a或2b)；蛋白酶抑制劑；免疫抑制劑；抗體(例如治療用之單株或嵌合抗體)；反有意義劑或siRNA；HIV抑制劑；B型肝炎(HBV)抑制劑；用於治療肝硬化與肝臟發炎之藥劑；ω IFN(生物醫學公司,Emeryville,CA)；BILN－2061絲胺酸蛋白酶抑制劑(Boehringer Ingelheim Pharma KG,Ingelheim,Germany)；Summetrel抗病毒(Endo Pharmaceuticals Holdings公司,Chadds Ford,PA)；Roferon A IFN－α2a(F.Hoffmann－La Roche公司,Basel,Switzerland)；Pegasys經PEG化之IFN－α2a(F.Hoffmann－La Roche公司,Basel,Switzerland)；Pegasys與***核苷經PEG化之IFN－α2a/***核苷(F.Hoffmann－La Roche公司,Basel,Switzerland)；CellCept HCV IgG免疫抑制劑(F.Hoffmann－La Roche公司,Basel,Switzerland)；Wellferon類淋巴胚細胞IFN－α n1(GlaxoSmithKline plc,Uxbridge,UK)；阿布非隆(Albuferon)－α白蛋白IFN－α2b(人類基因組科學公司,Rockville,MD)；列弗維林(Levovirin)***核苷(ICN醫藥,Costa Mesa,CA)；IDN－6556卡斯蛋白酶抑制劑(Idun醫藥公司,San Diego,CA)；IP－501抗纖維變性劑(Indevus醫藥公司,Lexington,MA)；Actimmune INF－γ(InterMune公司,Brisbane,CA)；干擾原(Infergen)A IFN alfacon－1(InterMune醫藥公司,Brisbane,CA)；ISIS 14803反有意義劑(ISIS醫藥公司,Carlsbad,CA/Elan醫藥公司,New York,NY)；JTK－003 RdRp抑制劑(日本煙草公司,Tokyo,Japan)；Pegasys與西普連(Ceplene)經PEG化之IFN－α2a/免疫調制劑(Maxim醫藥公司,San Diego,CA)；西普連(Ceplene)免疫調制劑(Maxim醫藥公司,San Diego,CA)；Civacir HCV IgG免疫抑制劑(Nabi生物醫藥公司,Boca Raton,FL)；Intron A與札遲辛(Zadaxin)IFN－α2b/α1－胸腺素(RegeneRx Biopharmiceuticals公司,Bethesda,MD/SciClone醫藥公司,San Mateo,CA)；列弗維林(Levovirin)IMPDH抑制劑(Ribapharm公司,Costa Mesa,CA)；維拉嘧啶(Viramidine)IMPDH抑制劑(Ribapharm公司,Costa Mesa,CA)；賀普塔酶(Heptazyme)核糖酵素(Ribozyme醫藥公司,Boulder,CO)；Intron A IFN－α2b(Schering－Plough公司,Kenilworth,NJ)；PEG－Intron經PEG化之IFN－α2b(Schering－Plough公司,Kenilworth,NJ)；Rebetron IFN－α2b/***核苷(Schering－Plough公司,Kenilworth,NJ)；***核苷(Schering－Plough公司,Kenilworth,NJ)；PEG－Intron/***核苷經PEG化之IFN－α2b/***核苷(Schering－Plough公司,Kenilworth,NJ)；Zadazim免疫調制劑(SciClone醫藥公司,San Mateo,CA)；Rebif IFN－β1a(Serono,Geneva,Switzerland)；IFN－β與EMZ701 IFN－β及EMZ701(轉移治療劑公司,Ontario,Canada)；T67 β－微管蛋白抑制劑(Tularik公司,South San Francisco,CA)；VX－497 IMPDH抑制劑(Vertex醫藥公司,Cambridge,MA)；VX－950/LY－570310絲胺酸蛋白酶抑制劑(Vertex醫藥公司,Cambridge,MA/Eli Lilly公司,Indianapolis,IN)；Omniferon天然IFN－α(Viragen公司,Plantation,FL)；XTL－002單株抗體(XTL生物醫藥)；化合物VX－950(Vertex醫藥公司)；化合物SCH503034(Schering－Plough公司)；及化合物GS9137(Gilead科學公司,Foster City,CA)。In yet another specific embodiment, the invention features the use of at least one compound of the invention (or a salt, solvate or prodrug thereof thereof) and at least one additional therapeutic agent in the manufacture of a medicament For the treatment of HCV infection. Preferably, the compounds of the invention are selected from Formula I, II, III, IV, V, VI, VII or VIII, and other therapeutic agents, by way of illustration and not limitation, may be selected from antiviral agents (eg, anti-HIV agents or Other anti-HCV agents), immunomodulators, anti-cancer or chemotherapeutic agents, and anti-inflammatory agents. Specific examples of other therapeutic agents include, but are not limited to, triazole nucleosides; interferons (e.g., IFN alpha 2a or 2b); protease inhibitors; immunosuppressive agents; antibodies (e.g., therapeutic single or chimeric antibodies); Or siRNA; HIV inhibitor; hepatitis B (HBV) inhibitor; agent for the treatment of cirrhosis and liver inflammation; omega IFN (Biomedical Company, Emeryville, CA); BILN-2061 serine protease inhibitor (Boehringer) Ingelheim Pharma KG, Ingelheim, Germany); Summetrel antiviral (Endo Pharmaceuticals Holdings, Chadds Ford, PA); Roferon A IFN-α2a (F. Hoffmann-La Roche, Basel, Switzerland); Pegasys PEGylated IFN- 22a (F. Hoffmann-La Roche, Basel, Switzerland); Pegasys and ribavirin PEGylated IFN-α2a/triazole nucleoside (F.Hoffmann-La Roche, Basel, Switzerland); CellCept HCV IgG Immunosuppressant (F. Hoffmann-La Roche, Basel, Switzerland); Wellferon lymphoid blast cell IFN-α n1 (GlaxoSmithKline plc, Uxbridge, UK); Albuflon-alpha albumin IFN-α2b (human Genomics Science Corporation, Rockv Lille, MD); Levovirin triazole nucleoside (ICN Pharmaceuticals, Costa Mesa, CA); IDN-6556 caspase inhibitor (Idun Pharmaceuticals, San Diego, CA); IP-501 anti-fibres Denaturant (Indevus Pharmaceuticals, Lexington, MA); Actimmune INF-γ (InterMune, Brisbane, CA); Interferon (Infergen) A IFN alfacon-1 (InterMune Pharmaceuticals, Brisbane, CA); ISIS 14803 anti-sense agent (ISIS Pharmaceuticals, Carlsbad, CA/Elan Pharmaceuticals, New York, NY); JTK-003 RdRp Inhibitor (Japan Tobacco Company, Tokyo, Japan); Pegasys and Ceplene PEGylated IFN-α2a /immunomodulant (Maxim Pharmaceuticals, San Diego, CA); Ceplene immunomodulator (Maxim Pharmaceuticals, San Diego, CA); Civacir HCV IgG immunosuppressant (Nabi Biopharma, Boca Raton, FL); Intron A and Zadaxin IFN-α2b/α1-thymosin (RegeneRx Biopharmiceuticals, Bethesda, MD/SciClone Pharmaceuticals, San Mateo, CA); Levovirin IMPDH inhibitor ( Ribapharm, Costa Mesa, CA); Viramidine IMPDH inhibitor (Ribapharm, Costa Mesa, CA); Heptazyme ribozyme (Ribozyme Pharmaceuticals, Boulder, CO); Intron A IFN-α2b (Schering-Plough, Kenilworth, NJ); PEG-Intron PEGylated IFN-α2b (Schering-Plough, Kenilworth , NJ); Rebetron IFN-α2b/triazole nucleoside (Schering-Plough, Kenilworth, NJ); triazole nucleoside (Schering-Plough, Kenilworth, NJ); PEG-Intron/triazole nucleoside via PEGylation IFN-α2b/triazole nucleoside (Schering-Plough, Kenilworth, NJ); Zadazim immunomodulator (SciClone Pharmaceuticals, San Mateo, CA); Rebif IFN-β1a (Serono, Geneva, Switzerland); IFN-β With EMZ701 IFN-β and EMZ701 (Transfer Therapeutics Inc., Ontario, Canada); T67 β-tubulin inhibitor (Tularik, South San Francisco, CA); VX-497 IMPDH inhibitor (Vertex Pharmaceuticals, Cambridge, MA); VX-950/LY-570310 serine protease inhibitor (Vertex Pharmaceuticals, Inc., Cambridge, MA/Eli Lilly, Inc., Indianapolis, IN); Omniferon native IFN-α (Viragen, Plantation, FL); XTL- 002 monoclonal antibody (XTL biomedicine); compound VX-950 (Vertex Pharmaceutical Co., Ltd.) Compound SCH503034 (Schering-Plough Company); and compound GS9137 (Gilead Scientific, Foster City, CA).
於又另一項具體實施例中，本發明之特徵為至少一種本發明化合物(或其鹽、溶劑合物或前體藥物)與至少一種其他抗病毒劑於藥劑製造上之用途，該藥劑係用於治療病毒感染。本發明化合物較佳係選自式I、II、III、IV、V、VI、VII或VIII，而其他抗病毒劑可選自但不限於抗－HCV或抗－HIV劑。在一項實例中，本發明之特徵為至少一種本發明化合物，選自式I、II、III、IV、V、VI、VII或VIII(或其鹽、溶劑合物或前體藥物)，與至少一種其他抗－HCV劑於藥劑製造上之用途，該藥劑係用於治療HCV感染。抗－HCV劑之非限制性實例包括HCV RNA依賴性RNA聚合酶抑制劑(例如核苷或非核苷類型聚合酶抑制劑)或HCV蛋白酶抑制劑。在另一項實例中，本發明之特徵為至少一種本發明化合物，選自式I、II、III、IV、V、VI、VII或VIII(或其鹽、溶劑合物或前體藥物)與至少兩種或更多種其他抗－HCV劑於藥劑製造上之用途，該藥劑係用於治療HCV感染。各其他抗－HCV劑可獨立選自HCV RNA依賴性RNA聚合酶抑制劑或HCV蛋白酶抑制劑。In yet another embodiment, the invention features the use of at least one compound of the invention (or a salt, solvate or prodrug thereof thereof) and at least one other antiviral agent for the manufacture of a medicament For the treatment of viral infections. Preferably, the compounds of the invention are selected from Formula I, II, III, IV, V, VI, VII or VIII, and other antiviral agents may be selected from, but not limited to, anti-HCV or anti-HIV agents. In one embodiment, the invention features at least one compound of the invention selected from Formula I, II, III, IV, V, VI, VII or VIII (or a salt, solvate or prodrug thereof), and Use of at least one other anti-HCV agent for the manufacture of a medicament for the treatment of HCV infection. Non-limiting examples of anti-HCV agents include HCV RNA-dependent RNA polymerase inhibitors (eg, nucleoside or non-nucleoside type polymerase inhibitors) or HCV protease inhibitors. In another embodiment, the invention features at least one compound of the invention selected from Formula I, II, III, IV, V, VI, VII or VIII (or a salt, solvate or prodrug thereof) The use of at least two or more other anti-HCV agents for the manufacture of a medicament for the treatment of HCV infection. Each of the other anti-HCV agents can be independently selected from an HCV RNA-dependent RNA polymerase inhibitor or an HCV protease inhibitor.
於又再另一項具體實施例中，本發明之特徵為至少一種本發明化合物，選自式I、II、III、IV、V、VI、VII或VIII(或其鹽、溶劑合物或前體藥物)，與至少一種抗－HIV劑於藥劑製造上之用途，該藥劑係用於治療HIV或HCV感染。於更又再另一項具體實施例中，本發明之特徵為至少一種本發明化合物，選自式I、II、III、IV、V、VI、VII或VIII(或其鹽、溶劑合物或前體藥物)，及至少一種抗－A型肝炎、抗B型肝炎、抗－D型肝炎、抗－E型肝炎或抗－G型肝炎劑於藥劑製造上之用途，該藥劑係用於治療病毒肝炎。於進一步具體實施例中，本發明之特徵為至少一種本發明化合物，選自式I、II、III、IV、V、VI、VII或VIII(或其鹽、溶劑合物或前體藥物)，與至少一種治療肝臟發炎之藥劑，於藥劑製造上之用途，該藥劑係用於治療C型肝炎。In yet another specific embodiment, the invention features at least one compound of the invention selected from Formula I, II, III, IV, V, VI, VII or VIII (or a salt, solvate or former thereof) And a use of at least one anti-HIV agent for the manufacture of a medicament for the treatment of HIV or HCV infection. In still another embodiment, the invention features at least one compound of the invention selected from Formula I, II, III, IV, V, VI, VII or VIII (or a salt, solvate thereof or Prodrug), and at least one anti-A hepatitis, anti-B hepatitis, anti-D hepatitis, anti-E hepatitis or anti-G hepatitis agent for the manufacture of a medicament for the treatment Viral hepatitis. In a further embodiment, the invention features at least one compound of the invention selected from Formula I, II, III, IV, V, VI, VII or VIII (or a salt, solvate or prodrug thereof), And the use of at least one agent for treating inflammation of the liver for the manufacture of a medicament for the treatment of hepatitis C.
本發明之前述描述文係提供說明與描述，但並非意欲為毫無遺漏地，或將本發明限制於明確之所揭示者。修正與變型在明白上述陳述內容後是可能的，或可獲取自本發明之實施。因此，應注意的是，本發明之範圍係由請求項及其等效事物所界定。The above description of the present invention is intended to be illustrative, and not restrictive. The modifications and variations are possible after the above statements are apparent, or may be obtained from the practice of the invention. Therefore, it should be noted that the scope of the invention is defined by the claims and their equivalents.
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| TW095148301A TW200738707A (en) | 2005-12-21 | 2006-12-21 | Anti-viral compounds |
| TW95148302A TWI392676B (en) | 2005-12-21 | 2006-12-21 | Anti-viral compounds,process for preparation and uses thereof |
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| TW (3) | TW200738707A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200738707A (en) * | 2005-12-21 | 2007-10-16 | Abbott Lab | Anti-viral compounds |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997013771A1 (en) * | 1995-10-11 | 1997-04-17 | Glaxo Group Limited | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
| WO1998013350A1 (en) * | 1996-09-25 | 1998-04-02 | Zeneca Limited | Qinoline derivatives inhibiting the effect of growth factors such as vegf |
| WO1998023613A1 (en) * | 1996-11-27 | 1998-06-04 | Pfizer Inc. | Fused bicyclic pyrimidine derivatives |
| WO2004087056A2 (en) * | 2003-03-28 | 2004-10-14 | Scios Inc. | BI-CYCLIC PYRIMIDINE INHIBITORS OF TGFβ |
| WO2005047288A1 (en) * | 2003-11-10 | 2005-05-26 | Arrow Therapeutics Limited | Pyrazolopyrimidines as anti - hepatits c agents |
| TW200745107A (en) * | 2005-12-21 | 2007-12-16 | Abbott Lab | Anti-viral compounds |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9127252D0 (en) * | 1991-12-23 | 1992-02-19 | Boots Co Plc | Therapeutic agents |
| GB9312891D0 (en) * | 1993-06-22 | 1993-08-04 | Boots Co Plc | Therapeutic agents |
-
2006
- 2006-12-21 TW TW095148301A patent/TW200738707A/en unknown
- 2006-12-21 TW TW95148302A patent/TWI392676B/en not_active IP Right Cessation
- 2006-12-21 TW TW95148303A patent/TWI392677B/en not_active IP Right Cessation
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997013771A1 (en) * | 1995-10-11 | 1997-04-17 | Glaxo Group Limited | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
| WO1998013350A1 (en) * | 1996-09-25 | 1998-04-02 | Zeneca Limited | Qinoline derivatives inhibiting the effect of growth factors such as vegf |
| WO1998023613A1 (en) * | 1996-11-27 | 1998-06-04 | Pfizer Inc. | Fused bicyclic pyrimidine derivatives |
| WO2004087056A2 (en) * | 2003-03-28 | 2004-10-14 | Scios Inc. | BI-CYCLIC PYRIMIDINE INHIBITORS OF TGFβ |
| WO2005047288A1 (en) * | 2003-11-10 | 2005-05-26 | Arrow Therapeutics Limited | Pyrazolopyrimidines as anti - hepatits c agents |
| TW200745107A (en) * | 2005-12-21 | 2007-12-16 | Abbott Lab | Anti-viral compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| TW200745107A (en) | 2007-12-16 |
| TW200800991A (en) | 2008-01-01 |
| TW200738707A (en) | 2007-10-16 |
| TWI392676B (en) | 2013-04-11 |
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