cas 93683-65-9, 6-CHLORO-2-CYANO-3-NITROPYRIDINE

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Optimization of 4,6-Disubstituted Pyrido[3,2-d]pyrimidines as Dual MNK/PIM Inhibitors to Inhibit Leukemia Cell Growth
Mitogen-activated protein kinase-interacting kinases (MNKs) and provirus integration in maloney murine leukemia virus kinases (PIMs) are downstream enzymes of cell proliferation signaling pathways associated with the resistance of tyrosine kinase inhibitors. MNKs and PIMs have complementary effects to regulate cap-dependent translation of oncoproteins. Dual inhibitors of MNKs and PIMs have not been developed. We developed a novel 4,6-disubstituted pyrido[3,2-d]pyrimidine compound 21o with selective inhibition of MNKs and PIMs. The IC50’s of 21o to inhibit MNK1 and MNK2 are 1 and 7 nM and those to inhibit PIM1, PIM2, and PIM3 are 43, 232, and 774 nM, respectively. 21o inhibits the growth of myeloid leukemia K562 and MOLM-13 cells with GI50’s of 2.1 and 1.2 μM, respectively. 21o decreases the levels ofp-eIF4E andp-4EBP1, the downstream products of MNKs and PIMs, as well as cap-dependent proteins c-myc, cyclin D1, and Mcl-1. 21o inhibits the growth of MOLM-13 cell xenografts without causing evident toxicity. 21o represents an innovative dual MNK/PIM inhibitor with a good pharmacokinetic profile.
Han, Yu,Zhang, Huimin,Wang, Shuxiang,Li, Bo,Xing, Kun,Shi, Yuntao,Cao, Hongxue,Zhang, Jian,Tong, Tong,Zang, Jie,Guan, Lihong,Gao, Xiaoxiao,Wang, Yuetong,Liu, Dan,Huang, Min,Jing, Yongkui,Zhao, Linxiang
p. 13719 - 13735
(2021/10/01)

4, 6-disubstituted pyridine [3, 2-d] pyrimidine compound as well as preparation and application thereof
The invention belongs to the technical field of medicines. The invention relates to the field of pharmaceutical chemistry, in particular to a 4, 6-disubstituted pyridine [3, 2-d] pyrimidine compound and pharmaceutically acceptable salt thereof, a preparation method of the compound, a pharmaceutical composition taking the compound as an active ingredient, and application of the compound in preparation of an MNK inhibitor and drugs for treating and/or preventing various cancers and/or metabolic diseases. The present invention relates to compounds represented by formulas I, II, III or IV, and pharmaceutically acceptable salts, hydrates, solvates and metabolites thereof, wherein the variables are described in the claims and the description.
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(2020/04/02)

Development of substituted pyrido[3,2-d]pyrimidines as potent and selective dihydrofolate reductase inhibitors for pneumocystis pneumonia infection
Pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii (pj) can lead to serious health consequences in patients with an immunocompromised system. Trimethoprim (TMP), used as first-line therapy in combination with sulfamethoxazole, is a selective but only moderately potent pj dihydrofolate reductase (pjDHFR) inhibitor, whereas non-clinical pjDHFR inhibitors, such as, piritrexim and trimetrexate are potent but non-selective pjDHFR inhibitors. To meet the clinical needs for a potent and selective pjDHFR inhibitor for PCP treatment, fourteen 6-substituted pyrido[3,2-d]pyrimidines were developed. Comparison of the amino acid residues in the active site of pjDHFR and human DHFR (hDHFR) revealed prominent amino acid differences which could be exploited to structurally design potent and selective pjDHFR inhibitors. Molecular modeling followed by enzyme assays of the compounds revealed 15 as the best compound of the series with an IC50 of 80 nM and 28-fold selectivity for inhibiting pjDHFR over hDHFR. Compound 15 serves as the lead analog for further structural variations to afford more potent and selective pjDHFR inhibitors.
Shah, Khushbu,Queener, Sherry,Cody, Vivian,Pace, Jim,Gangjee, Aleem
p. 1874 - 1880
(2019/06/08)

Preparation method of novel substituted pyridine pyrimidine compound
The invention belongs to the field of pharmaceutical and chemical industry, and provides a preparation method of a novel substituted pyridine pyrimidine compound. The pyridine pyrimidine compound is of great significance to medical research and new drug development. The problem that an amide compound is easily destroyed by strong alkalis in a synthesis process under a high temperature condition issolved, and meanwhile the problem that a pyrimidine 4-amino group is difficult to react to synthesize amide due to poorer amino activity is solved. Moreover, a two-step reaction for reducing a nitrogroup into an amino group and hydrolyzing cyano group into the amide group is completed in a one-step reaction, thereby simplifying the reaction flow. The invention provides a preparation method of the compound. The compound provides important support for the application of the compound in the field of new drug development in the future in terms of synthesis conditions, methods and processes.
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Paragraph 0026; 0027; 0028

(2018/10/27)

MONOCYCLIC, THIENO, PYRIDO, AND PYRROLO PYRIMIDINE COMPOUNDS AND METHODS OF USE AND MANUFACTURE OF THE SAME
The present invention provides monocyclic, thieno, pyrido and pyrrolo pyrimidine compounds. Pharmaceutical compositions comprising one or more of these compounds and optionally comprising a pharmaceutically acceptable salt or hydrate of one or more of the compounds are provided. Preferably, these pharmaceutical compositions further comprise at least one pharmaceutically acceptable carrier. Methods of treating a patient having cancer are provided wherein a therapeutically effective amount of one or more of these compounds or pharmaceutical compositions are administered to the patient.
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(2017/03/21)

QUINOLINES AND RELATED ANALOGS AS SIRTUIN MODULATORS
Provided herein are novel sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.
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Paragraph 0334; 0335

(2016/08/17)

Design and synthesis of substituted pyrido[3,2-d]-1,2,3-triazines as potential Pim-1 inhibitors
A novel series of substituted pyrido[3,2-d]-1,2,3-triazines were designed and synthesized as Pim-1 inhibitors through scaffold hopping. Most of the derivatives showed potent in vitro Pim-1 inhibitory activities and anti-proliferative effects toward prosta
Fan, Yin-Bo,Li, Kun,Huang, Min,Cao, Yu,Li, Ying,Jin, Shu-Yu,Liu, Wen-Bing,Wen, Jia-Chen,Liu, Dan,Zhao, Lin-Xiang
supporting information
p. 1224 - 1228
(2016/02/23)

Cyclohexylpropionic polypyridine deriv.
A problem of the present invention is to provide a new compound which has NK 1 receptor antagonist activity ,whose CYP3A4 inhibitory activity is reduced compared to aprepitant, and which are useful for the prevention or treatment of cancer-chemotherapy-induced nausea and vomiting. That is, the present invention relates to cyclohexyl pyridine derivatives represented by the following formula (I) or a pharmaceutically acceptable salt thereof. wherein, ring A is 4-fluoro-2-methylphenyl or the like; X is a hydrogen atom or the like; R 1 is carboxymethyl or the like; R 2 is alkyl or the like; Y is 0-2 or the like; U is-N(CH 3 )COC(CH 3 ) 2 -3,5-bistrifluoromethylphenyl or the like.
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Paragraph 0060

(2016/10/27)

Carboxymethyl piperidine derivative
The present invention provides a novel compound useful in the prevention or treatment of nausea and vomiting associated with the administration of antineoplastics, the compound having an NK1 receptor-antagonizing effect, and an inhibitory effect on CYP3A4 that is attenuated to a greater extent than in aprepitant. Specifically, the present invention relates to a carboxymethyl piperidine derivative represented by formula (I) or a pharmacologically acceptable salt thereof. In the formula, ring A is a benzene ring or the like, ring B is a pyridine ring or the like, R1 is a C1-6 alkyl or C1-6 alkoxy, R2 and R3 are hydrogen atoms or methyl, and n represents an integer of from 0 to 5.
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Paragraph 0063

(2016/10/31)

CARBOXYMETHYL PIPERIDINE DERIVATIVE
The present invention provides a new compound which has NK1 receptor antagonist activity, whose CYP3A4 inhibitory activity is reduced compared to aprepitant, and which are useful for the prevention or treatment of cancer-chemotherapy-induced nausea and vomiting. That is, the present invention relates to carboxymethyl piperidine derivatives represented by the following formula (I) or a pharmaceutically acceptable salt thereof. Wherein, ring A is a benzene ring or the like; ring B is a pyridine ring or the like; R1 is C1-6 alkyl or C1-6 alkoxy; R2 and R3 are a hydrogen atom or methyl; and n is an integral number from 0 to 5.
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Paragraph 0113; 0114

(2016/10/27)

COMPOUND OF CAMPTOTHECIN AND PREPARATION AND USE THEREOF
The present disclosure relates to a compound of formula I, a pharmaceutical composition thereof and the use thereof as an anti-tumor drug.
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Paragraph 0128; 0129

(2015/05/05)

COMPOUND OF CAMPTOTHECIN AND PREPARATION AND USE THEREOF
The present disclosure relates to a compound of formula I, a pharmaceutical composition thereof and the use thereof as an anti-tumor drug.
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Paragraph 0181; 0182

(2015/06/24)

DERIVATIVES OF AZAINDAZOLE OR DIAZAINDAZOLE TYPE FOR TREATING A CANCER OVEREXPRESSING TRK
The present invention relates to a compound of following formula (I) or a pharmaceutically acceptable salt or solvate of same, a tautomer of same, or a stereoisomer or mixture of stereoisomers of same in any proportions, such as a mixture of enantiomers, notably a racemic mixture, as well as pharmaceutical composition comprising such a compound, for use in the treatment of a cancer associated with the overexpression of at least one Trk protein.
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Page/Page column 61-62

(2014/02/16)

QUINAZOLINES AND AZAQUINAZOLINES AS DUAL INHIBITORS OF RAS/RAF/MEK/ERK AND PI3K/AKT/PTEN/MTOR PATHWAYS
The present application provides novel quinazolines and azaquinazolines and pharmaceutically acceptable salts thereof. Also provided are methods for preparing these compounds. These compounds are useful in for co-regulating RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways by administering a therapeutically effective amount of one or more of the compounds of formula (I), wherein X, Y, T and R4, and R6 to R8' are defined herein, to a patient. By doing so, these compounds are effective in treating conditions associated with the dysregulation of the RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways. A variety of conditions can be treated using these compounds and include diseases which are characterized by abnormal cellular proliferation. In one embodiment/ the disease is cancer.
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Page/Page column 77

(2014/10/29)

DERIVATIVES OF AZAINDAZOLE OR DIAZAINDAZOLE TYPE AS MEDICAMENT
The present invention relates to a compound of following formula (I): or a pharmaceutically acceptable salt or solvate of same, a tautomer of same, or a stereoisomer or mixture of stereoisomers of same in any proportions, such as a mixture of enantiomers, notably a racemic mixture; as well as to the use of same as a drug, notably intended for the treatment of cancer, inflammation and neurodegenerative diseases such as Alzheimer's disease; to the use of same as a kinase inhibitor; to the pharmaceutical compositions comprising same; and to methods for the preparation of same.
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Paragraph 0350; 0351

(2013/04/13)

Synthesis and biological evaluation of substituted 1,2,3-benzotriazines and pyrido[3,2-d]-1,2,3-triazines as inhibitors of vascular endothelial growth factor receptor-2
A novel series of substituted 1,2,3-benzotriazines and pyrido[3,2-d]-1,2,3- triazines were synthesized. The abilities of these compounds to inhibit the VEGFR-2 kinase activity and the proliferation of human microvascular endothelial cells (MVECs) were det
Zhao, Xing-Wang,Liu, Dan,Luan, Sheng-Lin,Hu, Guo-Dong,Lv, Jin-Ling,Jing, Yong-Kui,Zhao, Lin-Xiang
p. 7807 - 7815
(2014/01/06)

NOVEL PYRIDOPYRIMIDINE DERIVATIVES AND USE THEREOF
The invention provides novel substituted pyridopyrimidines represented by Formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, and a composition comprising these compounds. The compounds provided can be used as inhibitors of the phosphoinositide 3′ OH kinase family (PI3K) for the treatment of inflammatory diseases, cancer, cardiovascular diseases, allergy, asthma and autoimmune disorders.
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Page/Page column 15

(2012/09/25)

AROMATIC RING FUSED TRIAZINE DERIVATIVES AND USES THEREOF
The invention belongs to pharmaceutical field. The invention relates to the compounds according to Formula I, including their optically active forms, pharmaceutically acceptable salts or hydrates, and the pharmaceutical composition comprising thereof as a
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Page/Page column 12

(2011/08/06)

NEW CHEMICAL COMPOUNDS
The present invention encompasses compounds of general formula (1) while the groups R4 to R7 and the units W, L, Qa and QH are defined as in claim 1, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and their use as medicaments having the above-mentioned properties.
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Page/Page column 83-84

(2010/04/03)

NEW CHEMICAL COMPOUNDS
The present invention encompasses compounds of general formula (1) wherein the units W, A, L, Q1 and QH are defined as in claim 1, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and their use as medicaments having the above-mentioned properties.
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Page/Page column 117-118

(2010/04/03)

THE AROMATIC RING TRIAZINE DERIVATIVES AND THE USES THEREOF
The invention belongs to pharmaceutical field. The invention relates to the compounds according to Formula I. including their optically active forms, pharmaceutically acceptable salts or hydrates, and the pharmaceutical composition comprising thereof as a
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Page/Page column 17

(2010/12/01)

Synthesis of benzo[1,2-d;3,4-d′]diimidazole and 1H-pyrazolo[4,3-b] pyridine as putative A2A receptor antagonists
The synthesis and the binding affinity for the putative adenosine receptor antagonist 6-methyl-7-[1,2,3]triazol-2-yl-1,6-dihydrobenzo[1,2-d;3,4-d′] diimidazole (10) and 5-oxazol-2-yl-1H-pyrazolo[4,3-b]pyridin-3-ylamine (16) are reported. The title compounds were prepared from commercially available 1-chloro-2,4-dinitrobenzene (1) and 2-chloro-6-methoxy-3nitropyridine (11), respectively, but proved devoid of affinity for the adenosine A1 and A2A receptors. The Royal Society of Chemistry.
Piersanti, Giovanni,Giorgi, Luca,Bartoccini, Francesca,Tarzia, Giorgio,Minetti, Patrizia,Gallo, Grazia,Giorgi, Fabrizio,Castorina, Massimo,Ghirardi, Orlando,Carminati, Paolo
p. 2567 - 2571
(2008/03/14)

COMPOUNDS AND METHODS FOR TREATING DYSLIPIDEMIA
The present invention discloses compounds of formula I wherein A, n, m, j, q, K, W, X, K, Z, R1, R2, R3, R4, R5, and R6 are as defined herein and their pharmaceutical compositions and methods of use are disclosed as useful for treating dyslipidemia and its sequelae.
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Page/Page column 48-49

(2008/06/13)

Cyclic urea and cyclic amide derivatives
This invention provides compounds of the formula: wherein: A, B and D are N or CH, with the proviso that A, B and D can not all be CH; R1and R2are independent substituents selected from H, CORA, NRBCORA, or optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or groups; or R1and R2are fused to form an optionally substituted 3 to 8 membered spirocyclic or heterocyclic ring; RAis H or optionally substituted alkyl, aryl, alkoxy, or aminoalkyl; RBis H, C1to C3alkyl, or substituted C1to C3alkyl; R3is H, OH, NH2, or optionally substituted alkyl, or alkenyl, or CORC; RCis H or optionally substituted alkyl, aryl, alkoxy, or aminoalkyl; R4is a substituted benzene ring or a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO, SO2or NR5; RFis H or optionally substituted alkyl, aryl, alkoxy, or aminoalkyl; RGis H, alkyl, or substituted alkyl; R5is H or alkyl; Q is O, S, NR6, or CR7R8; R6is CN, SO2CF3, or optionally substituted alkyl, cycloalkyl, aryl, or heterocyclic ring; R7and R8are H, NO2, CN CO2R9, or optionally substituted alkyl, cycloalkyl, aryl, or heterocyclic; R9is C1to C3alkyl; or CR7R8form a six membered ring of the structure below: W is O or a chemical bond; or a pharmaceutically acceptable salt thereof, as well as their use and pharmaceutical compositions as agonists and antagonists of the progesterone receptor.
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(2008/06/13)

Cyclic regimens using cyclic urea and cyclic amide derivatives
This invention concerns cyclic combination therapies using progestational agents and indoline derivatives which are progesterone receptor antagonists of the general structure: wherein: A, B and D are N or CH, though not all can be CH; R1and R2are H, CORA, NRBCORA, or optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, or aryl groups; or R1and R2form a spirocyclic ring; RAis H or optionally substituted alkyl aryl, alkoxy, or aminoalkyl; RBis H, alkyl alkyl; R3is H, OH, NH2, alkyl, alkenyl, or CORC; RCis H, alkyl, aryl, alkoxy, or aminoalkyl; R4is benzene or a 5 or 6 membered heteroaromatic ring; RFis H, alkyl, aryl, alkoxy, or aminoalkyl; RGis H or alkyl; R5is H or alkyl; W is O or a chemical bond; or a pharmaceutically acceptable salt thereof. These methods may be used for contraception.
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(2008/06/13)

6-Substituted 2,4-diaminopyrido[3,2-d]pyrimidine analogues of piritrexim as inhibitors of dihydrofolate reductase from rat liver, Pneumocystis carinii, and Toxoplasma gondii and as antitumor agents
The synthesis and biological activity are reported for 21 6-substituted 2,4-diaminopyrido[3,2-d]pyrimidine analogues (4-24) of piritrexim (PTX) as inhibitors of dihydrofolate reductase (DHFR) and as antitumor agents. Recombinant DHFR from Pneumocystis carinii (pc) and native DHFR from Toxoplasma gondii (tg) were the target enzymes tested; these organisms are responsible for fatal opportunistic infections in AIDS patients. Rat liver (rl) DHFR served as the mammalian reference enzyme to determine selectivity for the pathogenic DHFR. The synthesis of S9-bridged compounds 4-6 was achieved by aryl displacement of 2,4-diamino-6-chloropyrido[3,2-d]pyrimidine (27) with thiol nucleophiles. Oxidation of 4-6 with hydrogen peroxide in glacial acetic acid afforded the corresponding sulfone analogues 7-9. The N9- bridged compounds 10-24 were synthesized from their precursor 3-amino-6- (arylamino)-2-pyridinecarbonitriles via a thermal cyclization with chloroformamidine hydrochloride. Unlike the S9-bridged compounds, the arylamino side chains of the N9-bridged analogues were introduced prior to the formation of the 2,4-diaminopyrido[3,2-d]pyrimidine nucleus. A reversed two-atom-bridged analogue (25) was also synthesized using a synthetic strategy similar to that utilized for compounds 10-24. The IC50 values of these compounds against pcDHFR ranged from 0.0023 x 10-6 M for 2,4-diamino- 6-(N-methyl-3',4'-dimethoxyanilino)pyrido[3,2-d]pyrimidine (21), which was the most potent, to 90.4 x 10-6 M for 2,4-diamino-6-(4'-methoxyanilino)- pyrido[3,2-d]pyrimidine (12), which was the least potent. The three S9- bridged compounds tested were more potent than the corresponding sulfone- bridged compounds for all three DHFRs. N9-Methylation increased the potency by as much as 17 000-fold (compounds 15 and 21). None of the analogues were selective for pcDHFR. Against tgDHFR the most potent analogue was again 21 with an IC50 value of 0.00088 x 10-6 M and the least potent was 12 with an IC50 of 2.8 x 10-6 M. N9-Methylation afforded an increase in potency of up to 770-fold (compound 15 NH vs 21 N-CH3) compared to the corresponding N9-H analogue. In contrast to pcDHFR, several analogues had a greater selectivity ratio for tgDHFR compared to trimetrexate (TMQ) or PTX, most notably 2,4-diamino-6-[(3',4'-dimethoxyphenyl)thio]pyrido[3,2-d]pyrimidine (4), 2,4-diamino-6-[(2'-methoxyphenyl)sulfonyl]pyrido[3,2-d]pyrimidine (7), and 2,4-diamino-6-(2',5'-dimethoxyanilino)pyrido[3,2-d]pyrimidine (14) which combined relatively high potency at 10-7-10-8 M along with selectivity ratios of 3.97, 6.67, and 4.93, respectively. Several analogues synthesized had better selectivity ratios than TMQ or PTX for both pcDHFR and tgDHFR, and the potencies of the N9-methylated compounds were comparable to or greater than that of TMQ or PTX. Selected compounds were evaluated as inhibitors of the growth of a variety of tumor cells in culture. The N9-CH3 analogues were, in general, highly potent with GI50 values in the nanomolar range. The N9-H and S9 analogues were less potent with GI50 values in the millimolar to micromolar range.
Gangjee, Aleem,Zhu, Yuanming,Queener, Sherry F.
p. 4533 - 4541
(2007/10/03)

Synthesis and antimalarial properties of 2,4-diamino-6-[(aryl)thio,sulfinyl, and sulfonyl]pyrido[3,2-d]pyrimidines [1,2]
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Colbry,Elslager,Werbel
p. 1521 - 1525
(2007/10/02)