- Design, synthesis and evaluation of pyrrolo[2,3-d]pyrimidine-phenylamide hybrids as potent Janus kinase 2 inhibitors
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Janus kinase 2 (JAK2) plays an essential role in the signaling of hormone-like cytokines and growth factors, which has been convinced as an important target of myeloproliferative neoplasms (MPNs) therapy. In this study, a series of novel pyrrolo[2,3-d]pyr
- Wang, Tingfang,Liu, Xiaofei,Hao, Meixi,Qiao, Jianan,Ju, Caoyun,Xue, Lingjing,Zhang, Can
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Read Online
- Structure-based discovery of novel 4,5,6-trisubstituted pyrimidines as potent covalent Bruton's tyrosine kinase inhibitors
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A series of novel 4,5,6-trisubstituted pyrimidines were designed as potent covalent Bruton's tyrosine kinase (BTK) inhibitors based on the structure of ibrutinib by using a ring-opening strategy. Among these derivatives, compound I1 exhibited the most potent inhibitory activity with an IC50 value of 0.07 μM. The preliminary structure-activity relationship was discussed and the primary amino group at the C-4 position of pyrimidine was crucial for maintaining BTK activity. Furthermore, molecular dynamics simulations and binding free energy calculations were performed for three inhibitor-BTK complexes to determine the probable binding model, which provided a comprehensive guide for further structural modification and optimization.
- Zou, Yi,Xiao, Jianhu,Tu, Zhengchao,Zhang, Yingyi,Yao, Kun,Luo, Minghao,Ding, Ke,Zhang, Yihua,Lai, Yisheng
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Read Online
- PROCESS AND INTERMEDIATES FOR PREPARING A JAK INHIBITOR
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The present invention is related to processes for preparing ruxolitinib, or a salt thereof, and related synthetic intermediates related thereto.
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- PROCESS AND INTERMEDIATES FOR PREPARING A JAK1 INHIBITOR
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The present invention is related to processes for preparing itacitinib, or a salt thereof, and related synthetic intermediates related thereto.
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- 1H-PYRAZOLO[3,4-D]PYRIMIDINE COMPOUNDS USEFUL FOR THE TREATMENT OF PLATINUM-RESISTANT CANCER
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The invention relates to compounds of formula (I) and related compounds and their use in the treatment of cancer, especially platinum resistant cancer. The invention also provides a treatment comprising administration of a compound of formula (I) and a pl
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Page/Page column 54
(2021/06/26)
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- PROCESSES AND INTERMEDIATES FOR MAKING A JAK INHIBITOR
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This invention relates to processes and intermediates for making {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, useful in the treatment of diseases related to the activity of Janus kinases (JAK) including inflammatory disorders, autoimmune disorders, cancer, and other diseases.
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Paragraph 0125; 0126
(2019/08/22)
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- HETEROARYL DERIVATIVE OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, PREPARATION METHOD THEREFOR, AND PHARMACEUTICAL COMPOSTION FOR PREVENTING OR TREATING DISEASES ASSOCIATED WITH PI3 KINASES, CONTAINING SAME AS ACTIVE INGREDIENT
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The present invention relates to a heteroaryl derivative or a pharmaceutically acceptable salt thereof, a preparation method therefor, and a pharmaceutical composition for preventing or treating diseases associated with PI3 kinases, containing the same as an active ingredient. The heteroaryl derivative according to the present invention has an excellent effect of selectively inhibiting PI3 kinases, thereby being useful in preventing or treating PI3 kinase diseases such as: cancers, autoimmune diseases, and respiratory diseases.
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Paragraph 0797-0799
(2018/04/26)
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- Preparation methods of JAK inhibitor and salt thereof
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The present invention relates to preparation methods of a JAK inhibitor and a salt thereof. The preparation method comprises: (1) carrying out a Suzuki coupling reaction on (R)-3-(4-boronic acid-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile and 6-halogen-5-(2-methoxyvinyl)pyrimidin-4-ylamine to generate (3R)-cyclopentyl-3-[4-(5-(2-methoxyvinyl)pyrimidin-4-ylamine)pyrazol-1-yl]propionitrile; and (2)carrying out a protection group removing and ring-closure reaction on the (3R)-cyclopentyl-3-[4-(5-(2-methoxyvinyl)pyrimidin-4-ylamine)pyrazol-1-yl]propionitrile to generate a JAK inhibitor ruxolitinib. According to the present invention, the new ruxolitinib preparation route is provided, wherein each reaction of the route has the high yield, the total yield of the route is high, the purity of theobtained product is good, the post-treatment of the reaction is simple, and column chromatography is not required; by adopting the route, the required raw materials or catalysts and other materials are relatively easy to obtain; and compared to the method in the prior art, the method of the present invention is economical and is suitable for industrial production.
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Paragraph 0105-0109
(2018/03/24)
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- Intermediate of JAK inhibitor, and preparation method thereof
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The present invention relates to a novel key intermediate of a JAK inhibitor ruxolitinib, and a preparation method thereof, wherein the chemical name of the intermediate is (R)-3-(4-boric acid-1H-pyrazole-1-yl)-3-cyclopentylpropionitrile. According to the present invention, the new ruxolitinib preparation route is provided, wherein each reaction of the route has the high yield, the total yield ofthe route is high, the purity of the obtained product is good, the post-treatment of the reaction is simple, and column chromatography is not required; by adopting the route, the required raw materials or catalysts and other materials are relatively easy to obtain; and compared to the method in the prior art, the method of the present invention is economical and is suitable for industrial production.
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Paragraph 0110
(2018/03/24)
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- 4-Aminopyrimidine compound, and preparation method and medicinal use thereof
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The invention belongs to the field of medicines, and concretely relates to a 4-aminopyrimidine compound having a structural represented by formula (I), or pharmaceutically acceptable salts thereof, a preparation method of the compound, and a use of the compound and the salts as a Bruton tyrosine kinase (BTK) inhibitor. A result of experiments shows that the compound has a significant inhibition effect on the BTK, and can be used for treating thromboembolism, inflammatory disorders, autoimmune diseases, Waldenstrom macroglobulinemia, B cell lymphomas and other diseases.
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Paragraph 0085; 0086
(2017/09/01)
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- PYRAZOLOPYRIMIDINE ANTIBACTERIAL AGENTS
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Pyrazolopyrimidine compounds for inhibition of isoprenoid biosynthesis have a formula (I) or a pharmaceutically acceptable salt thereof. In formula (I), R1 includes an alkyl group and R2 includes an optionally substituted moiety selected from the group consisting of an optionally substituted benzyl group, an optionally substituted phenethyl group, an optionally substituted ethanol group, an optionally substituted ethyl acetate group, an optionally substituted methyl furan group, an optionally substituted 3-ethyl indole group, and a lower alkyl group. Compositions containing pyrazolopyrimidine compounds and methods for using pyrazolopyrimidine compounds are described.
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Paragraph 0099
(2018/01/14)
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- Design, synthesis and biological evaluation of 4-aminopyrimidine-5-cabaldehyde oximes as dual inhibitors of c-Met and VEGFR-2
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The synergistically collaboration of c-Met/HGF and VEGFR-2/VEGF leads to development of tumor angiogenesis and progression of various human cancers. Therefore, inhibiting both HGF/c-Met and VEGF/VEGFR signaling may provide a novel and effective therapeutic approach for treating patients with abroad spectrum of tumors. Toward this goal, we designed and synthesized a series of derivatives bearing 4-aminopyrimidine-5-cabaldehyde oxime scaffold as potent dual inhibitors of c-Met and VEGFR-2. The cell proliferation assay in vitro demonstrated most target compounds have inhibition potency both on c-Met and VEGFR-2 with IC50values in nanomolar range, especially compound 14i, 18a and 18b. Based on the further enzyme assay in vitro, compound 18a was considered as the most potent one, the IC50s of which were 210?nM and 170?nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 10 and 18a with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogs. All the results indicate that 18a is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.
- Qiang, Hao,Gu, Weijie,Huang, DanDan,Shi, Wei,Qiu, Qianqian,Dai, Yuxuan,Huang, Wenlong,Qian, Hai
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supporting information
p. 3353 - 3358
(2016/07/20)
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- Method for synthesizing ibrutinib
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The invention provides a method for synthesizing ibrutinib. The method takes 4,6-dihydroxypyrimidine as an initial raw material, the material is subjected to formylation and chlorination to obtain a compound in a formula 3; the compound in the formula 3 and a compound in a formula 4 are subjected to a reaction to obtain a compound in a formula 5; the compound in the formula 5 is subjected to oxidation to obtain a compound in a formula 6; the compound in the formula 6 is subjected to ammonification to obtain a compound in a formula 7; the compound in the formula 7 and hydrazine hydrate are subjected to a reaction for closing pyrazole ring to obtain a compound in a formula 8; the compound in the formula 8 and a compound in a formula 9 are subjected to an alkylation reaction to obtain a compound in a formula 10; the compound in the formula 10 is subjected to acid deprotection to obtain a compound in a formula 11; and the compound in the formula 11 and acryloyl chloride are subjected to the reaction to obtain ibrutinib. The invention also discloses an ibrutinib intermediate. The raw materials have the advantages of low cost and easy acquisition, no dangerous highly-toxic product, mild reaction condition, no requirement of cryogenic cooling and high temperature, and simple operation, and is suitable for industrial production.
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Paragraph 0109; 0148; 0149; 0150; 0151; 0152; 0153
(2016/10/09)
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- Preparation of 8-Aza-7-deazaaristeromycin and -neplanocin A and Their 5′-Homologs
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The synthesis of new members of the aristeromycin and neplaoncin A families of carbocyclic nucleosides possessing the 1H-pyrazolo[3,4-d]pyrimidine ring is reported. For this purpose, an adapted route to 4-amino-1H-pyrazolo[3,4-d]pyrimidine is described.
- Wang, Haisheng,Zhang, Yan,Ye, Wei,Schneller, Stewart W.
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p. 1132 - 1135
(2015/08/06)
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- PROCESSES AND INTERMEDIATES FOR MAKING A JAK INHIBITOR
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This invention relates to processes and intermediates for making {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, useful in the treatment of diseases related to the activity of Janus kinases (JAK) including inflammatory disorders, autoimmune disorders, cancer, and other diseases.
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Paragraph 0168
(2014/09/29)
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- QUINOLINE DERIVATIVES AS PIK3 INHIBITORS
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Substituted bicyclic heteroaryls having the general formula (I) and compositions containing them, for the treatment of general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, including but not restricted to autoimmune diseases such as systemic lupus erythematosis (SLE), myestenia gravis, rheumatoid arthritis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiples sclerosis, Sjoegren's syndrome and autoimmune hemolytic anemia, allergic conditions including all forms of hypersensitivity, The present invention also enables methods for treating cancers that are mediated, dependent on or associated with pl 108 activity, including but not restricted to leukemias, such as Acute Myeloid leukaemia (AML), Myelodysplastic syndrome (MDS), myeio-proiiferative diseases (MPD), Chronic Myeloid Leukemia (CML), T-cell Acute Lymphoblastic leukaemia (T-ALL), B-cell Acute Lymphoblastic leukaemia (B-ALL), Non Hodgkins Lymphoma (NHL), B-cell lymphoma and solid tumors, such as breast cancer.
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Page/Page column 28
(2012/06/01)
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- Synthesis and SAR development of novel mGluR1 antagonists for the treatment of chronic pain
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High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1 = 10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic
- Brumfield, Stephanie,Korakas, Peter,Silverman, Lisa S.,Tulshian, Deen,Matasi, Julius J.,Qiang, Li,Bennett, Chad E.,Burnett, Duane A.,Greenlee, William J.,Knutson, Chad E.,Wu, Wen-Lian,Sasikumar, T. K.,Domalski, Martin,Li, Cheng,Bertorelli, Rosalia,Grilli, Mariagrazia,Lozza, Gianluca,Reggiani, Angelo
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p. 7223 - 7226,4
(2012/12/12)
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- HETEROCYCLIC COMPOUNDS AND THEIR USES
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Substituted bicyclic heteroaryls and compositions containing them, for the treatment of general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, including but not restricted to autoimmune diseases such as systemic lupus erythematosis (SLE), myestenia gravis, rheumatoid arthritis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiples sclerosis, Sjoegren's syndrome and autoimmune hemolytic anemia, allergic conditions including all forms of hypersensitivity, The present invention also enables methods for treating cancers that are mediated, dependent on or associated with p110δ activity, including but not restricted to leukemias, such as Acute Myeloid leukaemia (AML) Myelo-dysplastic syndrome (MDS) myelo-proliferative diseases (MPD) Chronic Myeloid Leukemia (CML) T-cell Acute Lymphoblastic leukaemia (T-ALL) B-cell Acute Lymphoblastic leukaemia (B-ALL) Non Hodgkins Lymphoma (NHL) B-cell lymphoma and solid tumors, such as breast cancer.
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Page/Page column 14-15
(2011/07/06)
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- HETEROARYL BTK INHIBITORS
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The present invention provides compounds useful as inhibitors of Btk, compositions thereof, and methods of using the same.
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Page/Page column 126
(2011/04/14)
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- HETEROCYCLIC COMPOUNDS AND THEIR USES
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Substituted bicyclic heteroaryls and compositions containing them, for the treatment of general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, including but not restricted to autoimmune diseases such as systemic lupus erythematosis (SLE), myestenia gravis, rheumatoid arthritis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiples sclerosis, Sjoegren's syndrome and autoimmune hemolytic anemia, allergic conditions including all forms of hypersensitivity, The present invention also enables methods for treating cancers that are mediated, dependent on or associated with p110δ activity, including but not restricted to leukemias, such as Acute Myeloid leukaemia (AML) Myelo-dysplastic syndrome (MDS) myelo-proliferative diseases (MPD) Chronic Myeloid Leukemia (CML) T-cell Acute Lymphoblastic leukaemia (T-ALL) B-cell Acute Lymphoblastic leukaemia (B-ALL) Non Hodgkins Lymphoma (NHL) B-cell lymphoma and solid tumors, such as breast cancer.
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Page/Page column 14
(2011/10/13)
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- Design, synthesis, and structure-activity relationship studies of novel 2,4,6-trisubstituted-5-pyrimidinecarboxylic acids as peroxisome proliferator-activated receptor γ (PPARγ) partial agonists with comparable antidiabetic efficacy to rosiglitazone
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A series of novel 2,4,6-trisubstitutedpyrimidine-5-carboxylic acid derivatives were designed and synthesized with the intent of producing a peroxisome proliferator-activated receptor γ (PPARγ) partial agonist for antidiabetic agents. A pharmacophore-driven approach of in-house screening identified compound 7, which led to the identification of compound 9 featuring a 2,4,6-trisubstituted pyrimidine-5-carboxylic acid core. Structure-activity relationship studies of 9 resulted in identifying 4,6-bisbenzylthio-2- methylthiopyrimidine-5-carboxylic acid (50) as the most attractive of all the screened compounds. The X-ray cocrystal structure of 50 bound on PPARγ revealed that the key hydrogen bond interactions, which are not related to the activation function 2 (AF-2) site, are different from those of the full agonist. Compound 50 showed typical PPARγ partial agonist properties in the PPARγ-GAL4 functional assay and weaker differentiation of adipocytes in 3T3-L1 cells than observed with rosiglitazone. Furthermore, 50 displayed comparable antidiabetic efficacy with rosiglitazone in db/db mice, although its potency is 10-fold weaker than that of rosiglitazone.
- Seto, Shigeki,Okada, Kyoko,Kiyota, Koichi,Isogai, Shigeki,Iwago, Maki,Shinozaki, Takehiro,Kitamura, Yoshiaki,Kohno, Yasushi,Murakami, Koji
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experimental part
p. 5012 - 5024
(2010/09/05)
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- PROCESSES FOR PREPARING JAK INHIBITORS AND RELATED INTERMEDIATE COMPOUNDS
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The present invention is related to processes for preparing chiral substituted pyrazolyl pyrrolo[2,3-d]pyrimidines of Formula III, and related synthetic intermediate compounds. The chiral substituted pyrazolyl pyrrolo[2,3-d]pyrimidines are useful as inhibitors of the Janus Kinase family of protein tyrosine kinases (JAKs) for treatment of inflammatory diseases, myeloproliferative disorders, and other diseases.
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Page/Page column 101-102
(2010/08/07)
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- HETEROCYCLIC COMPOUNDS AND THEIR USES
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Substituted bicyclic heteroaryls and compositions containing them, for the treatment of general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, including but not restricted to autoimmune diseases such as systemic lupus erythematosis (SLE), myestenia gravis, rheumatoid arthritis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiples sclerosis, Sjoegren's syndrome and autoimmune hemolytic anemia, allergic conditions including all forms of hypersensitivity, The present invention also enables methods for treating cancers that are mediated, dependent on or associated with p110 activity, including but not restricted to leukemias, such as Acute Myeloid leukaemia (AML) Myelo-dysplastic syndrome (MDS) myelo-proliferative diseases (MPD) Chronic Myeloid Leukemia (CML) T-cell Acute Lymphoblastic leukaemia ( T-ALL) B-cell Acute Lymphoblastic leukaemia (B-ALL) Non Hodgkins Lymphoma (NHL) B-cell lymphoma and solid tumors, such as breast cancer.
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Page/Page column 56
(2011/01/12)
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- GPR119 Receptor Agonists
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Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of metabolic diseases and disorders such as, for example, type II diabetes mellitus.
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Page/Page column 23
(2009/12/05)
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- COMPOUNDS USEFUL AS RAF KINASE INHIBITORS
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The present invention provides compounds useful as inhibitors of Raf protein kinase. The present invention also provides compositions thereof, and methods of treating Raf-mediated diseases.
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Page/Page column 39
(2009/03/07)
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- Synthesis and substitution of 8-(4,6-Dichloropyrimidin-5-yl)-BODIPY
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meso-Dichloropyrimidyl-BODIPY dyes are readily substituted by nucleophiles or through palladium-catalysed coupling reactions, while retaining excellent quantum yields of fluorescence.
- Leen, Volker,Schevenels, Florian,Cui, Jie,Xu, Chan,Yang, Wensheng,Tang, Xiaoliang,Liu, Weisheng,Qin, Wenwu,De Borggraeve, Wim M.,Boens, Noel,Dehaen, Wim
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scheme or table
p. 5920 - 5926
(2010/02/16)
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- P70 S6 KINASE INHIBITORS
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The present invention provides p70 S6 kinase inhibitors of the formula: pharmaceutical formulations comprising them, and methods for their use.
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Page/Page column 37
(2009/01/20)
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- An efficient synthesis of an NMDA receptor antagonist via stereoselective fluorination
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Herein is described the development and use of a novel bis(dialkylamino) sulfur difluoride reagent to effect the stereoselective conversion of a benzylic alcohol into a benzylic fluoride. A new method for the synthesis of 1H-pyrazolo[3,4-d]pyrimidin-4-ami
- Bio, Matthew M.,Waters, Marjorie,Javadi, Gary,Song, Zhiguo Jake,Zhang, Fei,Thomas, Dave
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p. 891 - 896
(2008/09/21)
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- Fused tricyclic mGIuR1 antagonists as therapeutic agents
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In its many embodiments, the present invention provides tricyclic compounds of formula I (wherein J1-J3, X, Z, and R1, R3, and R4 are as defined herein) useful as metabotropic glutamate receptor (mGlu
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Page/Page column 33; 21
(2010/11/26)
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- SUBSTITUTED THIENOPYRIMIDINE KINASE INHIBITORS
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The present invention is directed to thienopyrimidine compounds of formula (I): and forms thereof, their synthesis and use for treating, preventing or ameliorating a chronic or acute protein kinase mediated disease, disorder or condition.
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Page/Page column 41
(2010/11/28)
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- AMINOPYRIMIDINES AS KINASE MODULATORS
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Abstract The invention is directed to aminopyrimidine compounds of Formula I: where R3, B, Z, r and R1 are as defined herein, the use of such compounds as protein tyrosine kinase modulators, particularly inhibitors of FLT3 and/or c-kit and/or TrkB, the use of such compounds to reduce or inhibit kinase activity of FLT3 and/or c-kit and/or TrkB in a cell or a subject, and the use of such compounds for preventing or treating in a subject a cell proliferative disorder and/or disorders related to FLT3 and/or c-kit and/or TrkB . The present invention is further directed to pharmaceutical compositions comprising the compounds of the present invention and to methods for treating conditions such as cancers and other cell proliferative disorders.
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Page/Page column 46-47
(2008/06/13)
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- THIA-TETRAAZAACENAPHTHYLENE KINASE INHIBITORS
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The present invention is directed to novel thia-tetraazaacenaphthylene compounds of Formula (I): and pharmaceutically acceptable forms thereof and their synthesis and use as inhibitors of ATP-protein kinase interactions.
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Page/Page column 87
(2008/06/13)
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- SYNERGISTIC MODULATION OF FLT3 KINASE USING AMINOPYRIMIDINES KINASE MODULATORS
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The invention is directed to a method of inhibiting FLT3 tyrosine kinase activity or expression or reducing FLT3 kinase activity or expression in a cell or a subject comprising the administration of a farnesyl transferase inhibitor and a FLT3 kinase inhibitor selected from aminopyrimidine compounds of Formula I′: where R3, B, Z, Q, p, q and R1 are as defined herein. Included within the present invention is both prophylactic and therapeutic methods for treating a subject at risk of (or susceptible to) developing a cell proliferative disorder or a disorder related to FLT3.
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Page/Page column 34
(2010/11/25)
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- SYNERGISTIC MODULATION OF FLT3 KINASE USING AMINOPYRIMIDINES KINASE MODULATORS
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The invention is directed to a method of inhibiting FLT3 tyrosine kinase activity or expression or reducing FLT3 kinase activity or expression in a cell or a subject comprising the administration of a farnesyl transferase inhibitor and a FLT3 kinase inhibitor selected from aminopyrimidine compounds of Formula I′: where R3, B, Z, r and R1 are as defined herein. Included within the present invention is both prophylactic and therapeutic methods for treating a subject at risk of (or susceptible to) developing a cell proliferative disorder or a disorder related to FLT3.
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Page/Page column 40
(2010/11/25)
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- AMINOPYRIMIDINES AS KINASE MODULATORS
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The invention is directed to aminopyrimidine compounds of Formula I: where R3, B, Z, Q, p, q and R1 are as defined herein, the use of such compounds as protein tyrosine kinase modulators, particularly inhibitors of FLT3 and/or c-kit and/or TrkB, the use of such compounds to reduce or inhibit kinase activity of FLT3 and/or c-kit and/or TrkB in a cell or a subject, and the use of such compounds for preventing or treating in a subject a cell proliferative disorder and/or disorders related to FLT3 and/or c-kit and/or TrkB. The present invention is further directed to pharmaceutical compositions comprising the compounds of the present invention and to methods for treating conditions such as cancers and other cell proliferative disorders.
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Page/Page column 25
(2010/11/25)
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- PYRIDO PYRIMIDINONES, DIHYDRO PYRIMIDO PYRIMIDINONES AND PTERIDINONES USEFUL AS RAF KINASE INHIBITORS
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The present invention provides compounds having the formula: (I) wherein A-B together represents one of the following structures; (II), (III), (IV) and n, R1, R2, R3, R4, L1, L2, Y and Z are as defined in classes and subclasses herein, and pharmaceutical compositions thereof, as described generally and in subclasses herein, which compounds are useful as inhibitors of protein kinase (e.g., RAF), and thus are useful, for example, for the treatment of RAF mediated diseases.
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Page/Page column 94
(2010/11/08)
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- TRISUBSTITUTED ARYL AND HETEROARYL DERIVATIVES AS MODULATORS OF METABOLISM AND THE PROPHYLAXIS AND TREATMENT OF DISORDERS RELATED THERETO
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The present invention relates to certain trisubstituted aryl and heteroaryl derivatives of Formula (I) that are modulators of metabolism. Accordingly, compounds of the present invention are useful in the prophylaxis or treatment of metabolic disorders and complications thereof, such as, diabetes and obesity.
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Page/Page column 164
(2008/06/13)
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- THERAPEUTIC AGENTS USEFUL FOR TREATING PAIN
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The Invention provides a compound of formula (I), (where A, X, Y, Z, R3, R4, R5, R6, m and n are disclosed herein) or a pharmaceutically acceptable salt thereof (the compound or pharmaceutically acceptable salt thereof being a "Piperazine Compound"); phar
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Page/Page column 108
(2010/02/12)
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- PHENYL OR HETEROARYL AMINO ALKANE DERIVATIVES AS IP RECEPTOR ANTAGONIST
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The present invention relates to a phenyl or heteroaryl amino alkane derivatives which are useful as an active ingredient of pharmaceutical preparations. The phenyl or heteroaryl amino alkanes of the present invention have IP receptor antagonistic activity, and can be used for the prophylaxis and treatment of diseases associated with IP receptor antagonistic activity. Such diseases include urological diseases or disorder as follows: bladder outlet obstruction, overactive bladder, urinary incontinence, detrusor hyper-reflexia, detrusor instability, reduced bladder capacity, frequency of micturition, urge incontinence, stress incontinence, bladder hyperreactivity, benighn prostatic hypertrophy (BPH), prostatitis, urinary frequency, nocturia, urinary urgency, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis, or idiophatic bladder hypersensitivity. The compounds of the present invention are also useful for treatment of pain including, but not limited to inflammatory pain, neuropathic pain, acute pain, chronic pain, dental pain, premenstrual pain, visceral pain, headaches, and the like; hypotension; hemophilia and hemorrhage; and inflammation, since the diseases also is alleviated by treatment with an IP receptor antagonist.
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- 1,2,3-TRISUBSTITUTED ARYL AND HETEROARYL DERIVATIVES AS MODULATORS OF METABOLISM AND THE PRPPHYLAXIS AND TREATMENT OF DISORDERS RELATED THERETO SUCH AS DIABETES AND HYPERGLYCEMIA
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The present invention relates to certain 1,2,3-trisubstituted aryl and heteroaryl derivatives of Fomula (Ia) that are modulators of metabolism. Accordingly, compounds of the present invention are useful in the prophylaxis or treatment of metabolic disorde
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- NOVEL TYROSINE KINASE INHIBITORS
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The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof. The formula (I) compounds inhibit tyrosine kinase enzymes thereby making them useful as anti-cancer agents.
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- Novel tyrosine kinase inhibitors
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The present invention provides compounds of formula I and pharmaceutically acceptable salts thereof. The formula I compounds inhibit tyrosine kinase enzymes thereby making them useful as anti-cancer agents. The formula I compounds are also useful for the treatment of other diseases which can be treated by inhibiting tyrosine kinase enzymes.
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- PYRIMIDINE DERIVATIVES AND HERBICIDES CONTAINING THE SAME
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The present invention provides a pyrimidine derivative represented by the formula: wherein R1p and R1q are the same or different, and each represents (1)hydrogen, (2)halogen, (3) a C1-6alkyl group which may be substituted or (4) a C1-6alkoxy group, and so on, R2 is halogen, a C1-6alkyl group, cyano group, and so on, Ar is a phenyl group which may be substituted or is a condensed hetero ring which may be substituted, which has excellent selective herbicidal activity, and a herbicide containing the derivative.
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- Design, synthesis, and structure-activity relationship of 6-alkynylpyrimidines as potent adenosine kinase inhibitors
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Adenosine (ADO) is an extracellular signaling molecule within the central and peripheral nervous system. Its concentration is increased at sites of tissue injury and inflammation. One of the mechanisms by which antinociceptive and antiinflammatory effects of ADO can be enhanced consists of inhibition of adenosine kinase (AK), the primary metabolic enzyme for ADO. Novel nonnucleoside AK inhibitors based on 4-amino-6-alkynylpyrimidines were prepared, and the importance of the length of the linker at the 5-position for high affinity AK inhibition was demonstrated. Compounds with 2- and 3-atom linkers were the most potent AK inhibitors. Optimization of their physicochemical properties led to 31a and 37a that effectively reduced pain and inflammation in animal models.
- Gomtsyan, Arthur,Didomenico, Stanley,Lee, Chih-Hung,Matulenko, Mark A.,Kim, Ki,Kowaluk, Elizabeth A.,Wismer, Carol T.,Mikusa, Joe,Yu, Haixia,Kohlhaas, Kathy,Jarvis, Michael F.,Bhagwatt, Shripad S.
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p. 3639 - 3648
(2007/10/03)
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- Diastereoselective intramolecular hetero Diels-Alder approach towards polycyclic heterocycles
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Several different heterocyclic aldehydes, derived from pyrazole, pyrimidine, pyridine, indole and thiazole, were converted to polyheterocyclic compounds containing four to seven rings. The key steps in the sequence were a Knoevenagel condensation of the aldehyde and a heterocyclic carbonyl compound, such as pyrazolone and isoxazolone, followed by an intramolecular hetero Diels-Alder reaction. Most final products were isolated with high yield and diastereoselecivity. The isoxazolo fused cycloadducts formed interesting spiro-adducts upon heating. The cis nature of the bridging hydrogens of the heterocycles was evidenced by X-ray diffraction analysis.
- Ceulemans, Erik,Voets, Marieke,Emmers, Sabine,Uytterhoeven, Koen,Meervelt, Luc Van,Dehaen, Wim
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p. 531 - 544
(2007/10/03)
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