- Design of pyrido[2,3-d]pyrimidin-7-one inhibitors of receptor interacting protein kinase-2 (RIPK2) and nucleotide-binding oligomerization domain (NOD) cell signaling
-
Receptor interacting protein kinase-2 (RIPK2) is an enzyme involved in the transduction of pro-inflammatory nucleotide-binding oligomerization domain (NOD) cell signaling, a pathway implicated in numerous chronic inflammatory conditions. Herein, a pyrido[
- Nikhar, Sameer,Siokas, Ioannis,Schlicher, Lisa,Lee, Seungheon,Gyrd-Hansen, Mads,Degterev, Alexei,Cuny, Gregory D.
-
-
- SALT FORM AND CRYSTAL FORM OF NOVEL AZATRICYCLIC COMPOUND AND USE THEREOF
-
A maleate, mesylate, benzene sulfonate, hydrochloride, phosphate, L-tartrate, L-malate, citrate, and fumarate of a compound represented by structural formula I, various crystal forms of each salt form, and a preparation method and application thereof.
- -
-
-
- Pyrido[2,3-d]pyrimidin-7(8H)-one derivatives and Composition for skin whitening and Pharmaceutical composition for use in preventing or treating disorders of Melanin Hyperpigmentation containing the same as an active ingredient
-
The present invention relates to a pyrido[2,3-d]pyrimidin-7(8H)-one derivative, and to a composition for skin whitening comprising the same as an active ingredient. Since the derivative exhibits an effect of inhibiting the production of melanin even when
- -
-
-
- FGFR INHIBITOR AND APPLICATION THEREOF
-
An azatricyclic compound (as represented by formula I) which acts as an inhibitor of fibroblast growth factor receptors (FGFR), as well as a pharmaceutical composition thereof, a preparation method, and a use therefor in the treatment of FGFR-mediated diseases. The azatricyclic compound exerts an effect by means of participating in the regulation of a plurality of processes such as cell proliferation, apoptosis, migration, neovascularization, and the like. AA%%%Formula (I).
- -
-
-
- PROTEIN KINASE INHIBITORS AND USES THEREOF FOR THE TREATMENT OF DISEASES AND CONDITIONS
-
Identified compounds demonstrate protein kinase inhibitory activity. More specifically, the compounds are demonstrated to inhibit receptor interacting kinase 2 (RIPK2) and/or Activin-like kinase 2 (ALK2) and/or receptor interacting kinase 3 (RIPK3). Compounds that are either dual RIPK2/ALK2 inhibitors or that preferentially inhibit RIPK2 or ALK2 or RIPK3 could provide therapeutic benefit. Compounds that function as RIPK3 inhibitors provide therapeutic benefit in the treatment of inflammatory and degenerative conditions.
- -
-
-
- PYRIDO[2,3-D]PYRIMIDIN-7ONES AND RELATED COMPOUNDS AS INHIBITORS OF PROTEIN KINASES
-
Identified compounds demonstrate protein kinase inhibitory activity. More specifically, the compounds having the structures below (I) are demonstrated to inhibit receptor interacting kinase 2 (RIPK2) and/or Activin-like kinase 2 (ALK2). Compounds that are either dual RIPK2/ ALK2 inhibitors or that preferentially inhibit RIPK2 or ALK2 could provide therapeutic benefit.
- -
-
-
- CHEMICAL COMPOUNDS AS H-PGDS INHIBITORS
-
A compound of formula (I) wherein R1, R2, R3, R4, X, Y, and A are as defined herein. The compounds of the present invention are inhibitors of hematopoietic prostaglandin D synthase (H-PGDS) and can be useful in the treatment of Duchenne muscular dystrophy. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting H-PGDS activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
- -
-
-
- 7-PHENYLETHYLAMINO-4H-PYRIMIDO[4,5-D][1,3]OXAZIN-2-ONE COMPOUNDS AND THEIT USE AS MUTANT IDH1 INHIBITORS
-
Phenylethylamino-4H-pyrimido[4,5-d][1,3]oxazin-2-one compounds of Formula I, formulations containing those compounds, and their use as mutant isocitrate dehydrogenase 1 enzyme inhibitors.
- -
-
-
- QUINOLONE DERIVATIVES AS FIBROBLAST GROWTH FACTOR RECEPTOR INHIBITORS
-
Compounds of formula (I) that are Fibroblast Growth Factor Inhibitors (FGFR) and are therefore useful for the treatment of diseases treatable by inhibition of FGFR are disclosed. Also disclosed are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
- -
-
-
- Chemically Diverse Group i p21-Activated Kinase (PAK) Inhibitors Impart Acute Cardiovascular Toxicity with a Narrow Therapeutic Window
-
p21-activated kinase 1 (PAK1) has an important role in transducing signals in several oncogenic pathways. The concept of inhibiting this kinase has garnered significant interest over the past decade, particularly for targeting cancers associated with PAK1 amplification. Animal studies with the selective group I PAK (pan-PAK1, 2, 3) inhibitor G-5555 from the pyrido[2,3-d]pyrimidin-7-one class uncovered acute toxicity with a narrow therapeutic window. To attempt mitigating the toxicity, we introduced significant structural changes, culminating in the discovery of the potent pyridone side chain analogue G-9791. Mouse tolerability studies with this compound, other members of this series, and compounds from two structurally distinct classes revealed persistent toxicity and a correlation of minimum toxic concentrations and PAK1/2 mediated cellular potencies. Broad screening of selected PAK inhibitors revealed PAK1, 2, and 3 as the only overlapping targets. Our data suggest acute cardiovascular toxicity resulting from the inhibition of PAK2, which may be enhanced by PAK1 inhibition, and cautions against continued pursuit of pan-group I PAK inhibitors in drug discovery.
- Rudolph, Joachim,Murray, Lesley J.,Ndubaku, Chudi O.,O'Brien, Thomas,Blackwood, Elizabeth,Wang, Weiru,Aliagas, Ignacio,Gazzard, Lewis,Crawford, James J.,Drobnick, Joy,Lee, Wendy,Zhao, Xianrui,Hoeflich, Klaus P.,Favor, David A.,Dong, Ping,Zhang, Haiming,Heise, Christopher E.,Oh, Angela,Ong, Christy C.,La, Hank,Chakravarty, Paroma,Chan, Connie,Jakubiak, Diana,Epler, Jennifer,Ramaswamy, Sreemathy,Vega, Roxanne,Cain, Gary,Diaz, Dolores,Zhong, Yu
-
p. 5520 - 5541
(2016/07/06)
-
- SERINE/THREONINE KINASE INHIBITORS
-
Compounds having the formula I wherein R1, R2, R3, R4, R5, Ra, Rb, Rc, Rd, Re, n, r, s and t are as defined herein and which compounds are inhibitors of PAK1. Also disclosed are compositions and methods for treating cancer and hyperproliferative disorders.
- -
-
-
- Pyridopyrimidinone derivatives as potent and selective c-jun N-terminal kinase (JNK) inhibitors
-
A novel series of 2-aminopyridopyrimidinone based JNK (c-jun N-terminal kinase) inhibitors were discovered and developed. Structure-activity relationships (SARs) were systematically developed utilizing biochemical and cell based assays and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies. Through the optimization of lead compound 1, several potent and selective JNK inhibitors with high oral bioavailability were developed. Inhibitor 13 was a potent JNK3 inhibitor (IC50 = 15 nM), had high selectivity against p38 (IC50 > 10 μM), had high potency in functional cell based assays, and had high stability in human liver microsome (t1/2 = 76 min), a clean CYP-450 inhibition profile, and excellent oral bioavailability (%F = 87). Moreover, cocrystal structures of compounds 13 and 22 in JNK3 were solved at 2.0 ?. These structures elucidated the binding mode (Type-I binding) and can pave the way for further inhibitor design of this pyridopyrimidinone scaffold for JNK inhibition.
- Zheng, Ke,Park, Chul Min,Iqbal, Sarah,Hernandez, Pamela,Park, Hajeung,Lograsso, Philip V.,Feng, Yangbo
-
p. 413 - 418
(2015/04/27)
-
- NOVEL COMPOUNDS AS JNK KINASE INHIBITORS
-
The present invention is directed to modulators, such as inhibitors, of JNK isoform 2 (JNK2) or isoform 3 (JNK3) comprising compounds of formula (I) or formula (II) as described herein. Compounds of the invention can be used for treatment of a medical dis
- -
-
-
- Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3- d ]pyrimidin-6-yl)phenyl)urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical activation and activity against BRAF or RAS mutant tumor cells
-
The RAS-RAF-MEK-MAPK cascade is an essential signaling pathway, with activation typically mediated through cell surface receptors. The kinase inhibitors vemurafenib and dabrafenib, which target oncogenic BRAF V600E, have shown significant clinical efficac
- Henry, James R.,Kaufman, Michael D.,Peng, Sheng-Bin,Ahn, Yu Mi,Caldwell, Timothy M.,Vogeti, Lakshminarayana,Telikepalli, Hanumaiah,Lu, Wei-Ping,Hood, Molly M.,Rutkoski, Thomas J.,Smith, Bryan D.,Vogeti, Subha,Miller, David,Wise, Scott C.,Chun, Lawrence,Zhang, Xiaoyi,Zhang, Youyan,Kays, Lisa,Hipskind, Philip A.,Wrobleski, Aaron D.,Lobb, Karen L.,Clay, Julia M.,Cohen, Jeffrey D.,Walgren, Jennie L.,McCann, Denis,Patel, Phenil,Clawson, David K.,Guo, Sherry,Manglicmot, Danalyn,Groshong, Chris,Logan, Cheyenne,Starling, James J.,Flynn, Daniel L.
-
p. 4165 - 4179
(2015/06/08)
-
- QUINOLONE DERIVATIVES AS FIBROBLAST GROWTH FACTOR RECEPTOR INHIBITORS
-
Compounds that are Fibroblast Growth Factor Inhibitors (FGFR) and are therefore useful for the treatment of diseases treatable by inhibition of FGFR are disclosed. Also disclosed are pharmaceutical compositions containing such compounds and processes for
- -
-
-
- Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-pKa Polar Moiety
-
Signaling pathways intersecting with the p21-activated kinases (PAKs) play important roles in tumorigenesis and cancer progression. By recognizing that the limitations of FRAX1036 (1) were chiefly associated with the highly basic amine it contained, we devised a mitigation strategy to address several issues such as hERG activity. The 5-amino-1,3-dioxanyl moiety was identified as an effective means of reducing pKa and logP simultaneously. When positioned properly within the scaffold, this group conferred several benefits including potency, pharmacokinetics, and selectivity. Mouse xenograft PK/PD studies were carried out using an advanced compound, G-5555 (12), derived from this approach. These studies concluded that dose-dependent pathway modulation was achievable and paves the way for further in vivo investigations of PAK1 function in cancer and other diseases.
- Ndubaku, Chudi O.,Crawford, James J.,Drobnick, Joy,Aliagas, Ignacio,Campbell, David,Dong, Ping,Dornan, Laura M.,Duron, Sergio,Epler, Jennifer,Gazzard, Lewis,Heise, Christopher E.,Hoeflich, Klaus P.,Jakubiak, Diana,La, Hank,Lee, Wendy,Lin, Baiwei,Lyssikatos, Joseph P.,Maksimoska, Jasna,Marmorstein, Ronen,Murray, Lesley J.,O'Brien, Thomas,Oh, Angela,Ramaswamy, Sreemathy,Wang, Weiru,Zhao, Xianrui,Zhong, Yu,Blackwood, Elizabeth,Rudolph, Joachim
-
p. 1241 - 1246
(2015/12/23)
-
- Discovery of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7- oxo-7,8-dihydro-pyrido[2,3- d ]pyrimidine-6-carbonitrile (7x) as a potent inhibitor of cyclin-dependent kinase 4 (CDK4) and AMPK-related kinase 5 (ARK5)
-
The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multikinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure-activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8-cyclopentyl-2-[4-(4-methyl- piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6- carbonitrile (7x), was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30-100 nM. In vitro kinase profiling revealed that 7x is a multikinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARK5 kinases. Here, we report the synthesis, structure-activity relationship, kinase inhibitory profile, in vitro cytotoxicity, and in vivo tumor regression studies by this lead compound.
- Reddy, M. V. Ramana,Akula, Balireddy,Cosenza, Stephen C.,Athuluridivakar, Saikrishna,Mallireddigari, Muralidhar R.,Pallela, Venkat R.,Billa, Vinay K.,Subbaiah, D. R. C. Venkata,Bharathi, E. Vijaya,Vasquez-Del Carpio, Rodrigo,Padgaonkar, Amol,Baker, Stacey J.,Reddy, E. Premkumar
-
p. 578 - 599
(2014/03/21)
-
- PYRIMIDINE COMPOUNDS AS KINASE INHIBITORS
-
This disclosure relates to compounds, methods for their preparation, pharmaceutical compositions including these compounds and methods for the treatment of cellular proliferative disorders, including, but not limited to, cancer.
- -
-
-
- HETEROARYL COMPOUNDS AND USES THEREOF
-
The present invention relates to compounds useful as inhibitors of protein kinases, containing a cysteine residue in the ATP binding site. The invention further provides for pharmaceutically acceptable compositions comprising therapeutically effective amounts of one or more of the protein kinase inhibitor compounds and methods of using said compositions in the treatment of cancers and carcinomas.
- -
-
-
- QUINOLONE DERIVATIVES AS FIBROBLAST GROWTH FACTOR INHIBITORS
-
Compounds of formula (Ι') that are Fibroblast Growth Factor Inhibitors (FGFR) and are therefore useful for the treatment of diseases treatable by inhibition of FGFR are disclosed. Also disclosed are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
- -
-
-
- 2-AMINO, 6-PHENYL SUBSTITUTED PYRIDO [2, 3 - D] PYRIMIDINE DERIVATIVES USEFUL AS RAF KINASE INHIBITORS
-
The present invention provides the compound l-(3,3-Dimethylbutyl) -3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea or a pharmaceutically acceptable salt thereof, that inhibits Raf and, therefore, may be useful in tr
- -
-
-
- Synthesis and biological evaluation of a triazole-based library of pyrido[2,3-d]pyrimidines as FGFR3 tyrosine kinase inhibitors
-
A library of pyrido[2,3-d]pyrimidines was designed as inhibitors of FGFR3 tyrosine kinase allowing possible interactions with an unexploited region of the ATP binding-site. This library was built-up with an efficient step of click-chemistry giving easy access to triazole-based compounds bearing a large panel of substituents. Among the 27 analogues synthesized, more than half exhibited 55-89% inhibition of in vitro FGFR3 kinase activity at 2 μM and one (19g) was able to inhibit auto-phosphorylation of mutant FGFR3-K650M in transfected HEK cells.
- Le Corre, Laurent,Girard, Anne-Lise,Aubertin, Johannes,Radvanyi, Franois,Benoist-Lasselin, Catherine,Jonquoy, Aurelie,Mugniery, Emilie,Legeai-Mallet, Laurence,Busca, Patricia,Le Merrer, Yves
-
scheme or table
p. 2164 - 2173
(2010/07/04)
-
- Derivatives of Pyrido[2,3-d]pyrimidine, the Preparation Thereof, and the Therapeutic Application of the Same
-
The invention relates to derivatives of pyrido[2,3-d]pyrimidine, to the preparation thereof, and to the therapeutic application of the same.
- -
-
Page/Page column 4
(2008/12/07)
-
- PYRIDO-PYRIDIMIDINE DERIVATIVES USEFUL AS ANTIINFLAMMATORY AGENTS
-
Provided are novel pyrido-pyrimidine derivatives, having the structure of Formula (I): which can be used as anti-inflammatory agents. Also provided are pharmaceutical compositions comprising one or more pyrido-pyrimidine derivatives, as well as methods of
- -
-
Page/Page column 55-56
(2008/06/13)
-
- Pyrido-pyrimidine derivatives, preparation thereof, and therapeutic use thereof
-
The disclosure concerns pyrido[2,3-d]pyrimidine derivatives, their preparation and their therapeutic application, of general formula (I) and acid addition salts, hydrates and solvates thereof, as well as in the form of enantiomers, diastereoisomers and mixtures thereof. The disclosure also concerns methods for preparing said derivatives, pharmaceutical compositions containing a compound of general formula (I), and their therapeutic use.
- -
-
Page/Page column 4
(2008/06/13)
-
- Pyrido[2,3-d]pyrimidin-7-ones as specific inhibitors of cyclin-dependent kinase 4
-
Inhibition of the cell cycle kinase, cyclin-dependent kinase-4 (Cdk4), is expected to provide an effective method for the treatment of proliferative diseases such as cancer. The pyrido[2,3-d]-pyrimidin-7-one template has been identified previously as a privileged structure for the inhibition of ATP-dependent kinases, and good potency against Cdks has been reported for representative examples. Obtaining selectivity for individual Cdk enzymes, particularly Cdk4, has been challenging. Here, we report that the introduction of a methyl substituent at the C-5 position of the pyrido[2,3-d]pvrimidin-7-one template is sufficient to confer excellent selectivity for Cdk4 vs other Cdks and representative tyrosine kinases. Further optimization led to the identification of highly potent and selective inhibitors of Cdk4 that exhibit potent antiproliferative activity against human tumor cells in vitro. The most selective Cdk4 inhibitors were evaluated for antitumor activity against MDA-MB-435 human breast carcinoma xenografts in mice.
- VanderWel, Scott N.,Harvey, Patricia J.,McNamara, Dennis J.,Repine, Joseph T.,Keller, Paul R.,Quin III, John,Booth, R. John,Elliott, William L.,Dobrusin, Ellen M.,Fry, David W.,Toogood, Peter L.
-
p. 2371 - 2387
(2007/10/03)
-
- Pyridopyrimidinone derivatives for treatment of neurodegenerative disease
-
This invention provides pyridopyrimidines and 4-aminopyrimidines that are useful for treating cell proliferatives disorders, such as cancer and restenosis. We have now discovered a group of 7,8-dihydro-2 (amino and thio)pyrido[2,3-d]pyrimidines and 2,4-di
- -
-
-
- Pyrido[2,3-d]pyrimidine-2,7-diamine kinase inhibitors
-
Disclosed are compounds of the formula (I) wherein: R2, R7, RI3, R14 and R15 are independently hydrogen, or (un)substituted lower alkyl, (un)substitued lower alkenyl, (un)substituted lower alkynyl, or (un)substituted —(CH2)nR12; R5 is halogen, cyano, nitro, —R9, —NR9R10, or —OR9; R6 is halogen, cyano, nitro, —R9, —NR9R10, —OR9, —Co2R9, —COR9, —CONR9R10, —NR9COR10, (un)substiuted lower alkenyl, or (un)substituted lower alkynyl; R8 is —CO2R13, —COR13, —CONR13R14, —CSNR13R14, —C(NR13)NR14R15, —SO3R13, —SO2R13, —SO2NR13R14, —PO3R13R14, —POR13R14, —PO(NR13R14)2; R9 and R10 are independently hydrogen or (un)substituted lower alkyl; R11 is a heteroaryl or a heterocyclic group; R12 is a cycloalkyl, a heterocyclic, an aryl, or a heteroaryl group; and n is 0,1,2, or 3. These compounds and their pharmaceutical compositions are useful for treating cell proliferative disorders, such as cancer and restenosis. These compounds are potent inhibitors of cdks and growth factor-mediated kinases.
- -
-
-
- PYRIDOPYRIMIDINE OR NAPHTHYRIDINE DERIVATIVE
-
A pyridopyrimidine or a naphthyridine derivative of the formula (I): wherein R1 is an optionally substituted nitrogen-containing heterocyclic group, etc.; R2 is H or a lower alkyl group; R3 is H or an optionally substitute
- -
-
Page/Page column 22
(2010/02/07)
-
- Pyrido[2,3-D]pyrimidines and 4-aminopyrimidines as inhibitors of cellular proliferation
-
This invention provides pyridopyrimidines and 4-aminopyrimidines that are useful for treating cell proliferative disorders, such as cancer and restenosis. We have now discovered a group of 7,8-dihydro-2-(amino and thio)pyrido[2,3-d]pyrimidines and 2,4-dia
- -
-
-
- 7-oxo-pyridopyrimidines (II)
-
The present invention provides compounds of the formula: a prodrug or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3 and Ar1 are those defined herein, and methods for preparation and uses thereof
- -
-
-
- Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases
-
The identification of 8-ethyl-2-phenylamino-8H-pyrido [2,3-d]pyrimidin-7-one (1) as an inhibitor of Cdk4 led to the initiation of a program to evaluate related pyrido [2,3-d]pyrimidin-7-ones for inhibition of cyclin-dependent kinases (Cdks). Analysis of m
- Barvian,Boschelli,Cossrow,Dobrusin,Fattaey,Fritsch,Fry,Harvey,Keller,Garrett,La,Leopold,McNamara,Quin,Trumpp-Kallmeyer,Toogood,Wu,Zhang
-
p. 4606 - 4616
(2007/10/03)
-
- Bicyclic nitrogen heterocycles
-
Amino-substituted dihydropyrimido[4,5-d]pyrimidinones of the formula in which R1 represents hydrogen, lower alkyl, aryl, aryl-lower alkyl, heteroaryl, heteroaryl-lower alkyl, lower cycloalkyl or lower cycloalkyl-lower alkyl, R2 represents lower alkyl, aryl, aryl-lower alkyl, heteroaryl, heteroaryl-lower alkyl, lower cycloalkyl or lower cycloalkyl-lower alkyl, and R3 represents hydrogen, lower alkyl, aryl, aryl-lower alkyl, heteroaryl, heteroaryl-lower alkyl, lower cycloalkyl, lower cycloalkenyl or lower cycloalkyl-lower alkyl, and pharmaceutically acceptable salts thereof are protein kinase inhibitors. They can be used in the treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular disorders, in the treatment of asthma, central nervous system disorders or diabetic complications or for the prevention of graft rejection following transplant surgery.
- -
-
-
