Next Article in Journal
Yuccalechins A–C from the Yucca schidigera Roezl ex Ortgies Bark: Elucidation of the Relative and Absolute Configurations of Three New Spirobiflavonoids and Their Cholinesterase Inhibitory Activities
Next Article in Special Issue
Synthesis and Antimicrobial Activity of Some New Substituted Quinoxalines
Previous Article in Journal
In Silico Molecular Studies of Antiophidic Properties of the Amazonian Tree Cordia nodosa Lam.
Previous Article in Special Issue
A Simple, Efficient, and Eco-Friendly Method for the Preparation of 3-Substituted-2,3-dihydroquinazolin-4(1H)-one Derivatives
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 24
Issue 22
10.3390/molecules24224161
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Pyrido[2,3-d]pyrimidin-7(8H)-ones: Synthesis and Biomedical Applications

by
Guillem Jubete
,
Raimon Puig de la Bellacasa
,
Roger Estrada-Tejedor
,
Jordi Teixidó
and
José I. Borrell
*
Grup de Química Farmacèutica, IQS School of Engineering, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(22), 4161; https://doi.org/10.3390/molecules24224161
Submission received: 22 September 2019 / Revised: 11 November 2019 / Accepted: 13 November 2019 / Published: 16 November 2019
(This article belongs to the Collection Heterocyclic Compounds)
Browse Figures
Versions Notes

Abstract

:
Pyrido[2,3-d]pyrimidines (1) are a type of privileged heterocyclic scaffolds capable of providing ligands for several receptors in the body. Among such structures, our group and others have been particularly interested in pyrido[2,3-d]pyrimidine-7(8H)-ones (2) due to the similitude with nitrogen bases present in DNA and RNA. Currently there are more than 20,000 structures 2 described which correspond to around 2900 references (half of them being patents). Furthermore, the number of references containing compounds of general structure 2 have increased almost exponentially in the last 10 years. The present review covers the synthetic methods used for the synthesis of pyrido[2,3-d]pyrimidine-7(8H)-ones (2), both starting from a preformed pyrimidine ring or a pyridine ring, and the biomedical applications of such compounds.

1. Introduction

Pyridopyrimidines are ortho-fused bicyclic heterocyclic structures formed by the fusion of a pyridine and a pyrimidine ring. There are four possible isomeric pyridopyrimidines [1,2] and one of them is pyrido[2,3-d]pyrimidines (1,3,8-triazanaphtalenes) 1 shown in Figure 1. Such structure is included in the concept of privileged heterocyclic scaffolds, introduced by Evans in the late 80s [3] and recently revised by Altomare [4], for drug discovery probably due to their resemblance with DNA bases. Some examples of drugs based on such structure that have reached the market are piritrexim isethionate (treatment of bladder cancer and urethral cancer) and pipemidic acid (antibiotic active against Gram-negative and some Gram-positive bacteria) [5].
Among these bicyclic heterocyclic compounds, our group has been especially interested in the pyrido[2,3-d]pyrimidin-7(8H)-ones (2) (Figure 1) since the initial synthetic approach of Victory et al. to 2,4-diamino-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (7) obtained by reaction of 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles (5), prepared upon treatment of an α,β-unsaturated ester (3) with malononitrile (4) in the presence of NaOMe/MeOH, and guanidine (6) (Figure 2) [6]. Since then, our group has developed synthetic methodologies allowing to access systems 2 with up to five diversity centers (C2, C4, C5, C6, and N8) and two degrees of unsaturation C5-C6 (note: during the rest of the review substituents at positions C2, C4, C5, C6, and N8 will be depicted as G2, G4, R5, R6 and R8 for a better comparison of the structures).
A preliminary search carried out in SciFinder [7] has revealed that there are more than 20,000 compounds which include the substructure 2 (both with a C5-C6 single and double bond) and more than 2900 references. Moreover, the number of references including such substructure has almost exponentially increased during the past 10 years showing the interest for such kind of systems and their potential biomedical applications.
However, if the total number of references is filtered to select the Reviews, the number is reduced to around 180. An inspection of such references indicates that most of them are reviews on the biological activity of pyrido[2,3-d]pyrimidin-7(8H)-ones (2) (mainly as kinase inhibitors [8,9], anti-leukemic [10], against breast cancer [11], antihypertensives [12], etc.) or about the compound palbociclib (8) approved for the treatment of breast cancer (Figure 3) [13].
The lack of a specific revision on pyrido[2,3-d]pyrimidin-7(8H)-ones (2) impelled us to review the literature covering structural, synthetic, and biological aspects.

2. Structural Features of Pyrido[2,3-d]pyrimidin-7(8H)-ones: Substitution Patterns and Degree of Unsaturation C5-C6

One of the interesting aspects to be included in a review of a given substructure is to have an idea of the variety of substituents that have been introduced in each diversity center of the molecule. This information is useful to know the diversity already covered in a Markush formula based on such substructure, particularly when a new project related to it has to begin looking for new biological activities and a patent. Before the introduction of computerized databases, such as SciFinder, this information was virtually inaccessible by requiring the review of hundreds of articles.
To carry out such analysis for the pyrido[2,3-d]pyrimidin-7(8H)-ones (2), the first step was to determine the total number of structures 2 present in the database. For this purpose, we used in the substructural search the Unspecified bond tool between C5 and C6 (depicted by a discontinuous line in 9, Figure 4) that includes single, double, or triple bonds between those positions. The search gave a total number of 21,571 pyrido[2,3-d]pyrimidin-7(8H)-ones (2), a number that is slowly but continuously growing (search carried out in May 2019). Then we carried out the searches with a C5-C6 double bond 10 (14,448 structures) and a C5-C6 single bond 11 (9183 structures) (Figure 4). A quick initial search related to the single bond retrieved 9183 results but, surprisingly, it included some double-bonded structures, so it was curated by means of the Exclude command of the Combine Answer Sets tool in SciFinder to obtain the final set of 7303 molecules. It is interesting to note that from the total number of structures 2 included in SciFinder roughly 2/3 (67%) correspond to structures presenting a C5-C6 double bond. Such a 2:1 ratio in favor of the C5-C6 double bond can be due both to a structural requirement for the biological activity of compounds 2 (mostly used as tyrosine kinase inhibitors as described later) or to the easier synthetic approaches for such unsaturated structures also described later.
The structures 10 presenting a C5-C6 double bond are contained in around 2500 references which include around 1100 patents (43.6%) showing the great interest of such kind of structures. On the other hand, the structures 11 with a C5-C6 single bond appear in less than 500 references (a number clearly lower than the preceding one) although 60% are patents.
The huge number of compounds retrieved makes it impossible to download the structures from the database to perform a diversity analysis with specialized software (SciFinder allows the creation of an SDFile with the structures retrieved on a search but it is limited to 500 compounds). Consequently, we decided to explore one by one the substitution patterns at positions C2, C4, C5, C6, and N8 for each degree of unsaturation C5-C6 to have a picture of the diversity covered by the substances already described.

2.1. Substitution Pattern at C2 and C4

Concerning positions C2 and C4 we searched the structures presenting H, C (either alkyl groups or aromatic rings), N (primary amines, aminoalkyl or aminoaryl groups or heterocyclic rings connected by the nitrogen atom), O (hydroxy group probably as the carbonyl tautomer, ethers or ester groups), and S (thiol groups, thioethers, or SO2Me groups used for the subsequent nucleophilic substitution) as possible substituents both for the C5-C6 single and double bonds. The results obtained are included in Table 1 and Table 2, respectively, which include also examples of references containing such substitution patterns.
Concerning 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (11) (Table 1), the inspection of the percentages reveals that the nitrogen-based substituents at position C2 are the majority (more than 43%) followed by the carbon substituents (around 30%) and sulfur substituents (21%). On the other hand, the oxygen substituents, particularly as a carbonyl group, prevailed at position C4 (around 63%) followed also by the carbon substituents (almost 26%). It is interesting to note that the added percentages at position C2 cover 99.63% of the diversity at such position while in the case of C4 reach 98.99%. We also carried out a search corresponding to the combination of nitrogen substituent at C2 and oxygen substituent at C4 which covers the 37.97% of the total diversity, but includes only around 30 references. Such percentage is high enough taking into account that it corresponds to one of the 20 combinations (5 × 4) possible and can be interpreted on the basis of the similarity of the resulting structures with guanine. In the case of the double nitrogen substitution at C2 and C4, the total number of structures covers 4.30% of the total diversity, the corresponding references coming from our group of research.
In the case of pyrido[2,3-d]pyrimidin-7(8H)-ones (10) with a C5-C6 double bond (Table 2), the analysis of the substitution pattern at C2 indicates the nitrogen substituents are absolutely predominant (near 76%), very far from the other possible substitutions. Similarly, in the case of C4, the presence of a hydrogen atom represents 78% of the situations followed by the carbon substituents (near 18%). Now the addition of the percentages of the different substituents considered reaches 89.34% and 99.64% for C2 and C4, respectively. The combination of a nitrogen substituent at C2 and a hydrogen atom at C4 covers the 63.72% of the total diversity, thus revealing that such combination has been largely explored in connection with the biological activity of these structures as antineoplastic drugs that will be discussed later.

2.2. Substitution Pattern at C5 and C6

While the combination of substituents at C2 and C4 of pyrido[2,3-d]pyrimidin-7(8H)-ones (2) is normally in correlation with the biological activity desired for such heterocycles (as it happens in the case of tyrosine kinase inhibitors), the substitution pattern at C5 and C6 is responsible usually for the selectivity of one receptor with respect to other one. In this context, it is interesting to note (as it will be described later in the biological part) that the 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (11) with a C5-C6 single bond and the pyrido[2,3-d]pyrimidin-7(8H)-ones (10) with a C5-C6 double bond have been focused in very different biological targets and, consequently, the substitution pattern at C5 and C6 is quite different.
Thus, in the case of the structures 11 (C5-C6 single bond), 53.12% present at least a substituent at C5 and a CH2 at C6 (in most of them a carbon substituent [29,30] and, more precisely, a phenyl ring in one half of the structures [50,51]) while only 3.19% present a substituent at C6 and a CH2 at C5 (in this case most structures present a carbon substituent [52,53] which is a phenyl ring in also one half of them [31,42]). Finally, 20.86% of the structures do not present substituents at C5 or C6 [20,54]. These three substitution patterns cover 84.87% of the total diversity.
On the contrary, in the case of the structures 10 (C5-C6 double bond), 53.53% present only a substituent at C6 (R5 = H) with the following distribution referring to the total number of structures: 44.46% carbon substituent [55,56] (32.12% phenyl ring [42,57,58]), 4.70% oxygen substituent [59,60], and 1.00% nitrogen substituent [32,61]. In 7.05% of the structures there is a substituent at C5 (R6 = H) with the following distribution referring to the total number of structures: 4.16% carbon substituent [62,63] (0.10% phenyl ring [16,56]), 0.47% oxygen substituent [56,64], and 2.39% nitrogen substituent [64,65]. There is 7.75% of structures in which R5 = R6 = H [66,67].
These results clearly point out that 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (11, C5-C6 single bond) have been mainly substituted at C5 while pyrido[2,3-d]pyrimidin-7(8H)-ones (10, C5-C6 double bond) at C6.

2.3. Substitution Pattern at N8

Similarly to what has been observed for the substitution pattern at C5 and C6, the substitution pattern at N8 is clearly different between the C5-C6 single bond compounds 11 and the C5-C6 double bond compounds 10. As it can be easily deduced from Table 3, compounds 11 have been left usually unsubstituted at N8 (R8 = H) while compounds 10 are usually substituted at such position, R8 = Me and R8 = cyclopentyl being the most used substituents. Once more, such pattern substitution relates to the different biological activities these two families of structures have been oriented towards.
In summary, the combinations of substituents apparently more widely explored in literature for both structures are
(a)
In 14.08% of the 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (11): G2 = nitrogen substituent, G4 = oxygen substituent (in particular as a carbonyl group), R5 = phenyl group, R6 = H, N8 = H.
(b)
In 7.84% of the pyrido[2,3-d]pyrimidin-7(8H)-ones (10): G2 = nitrogen substituent, G4 = H, R5 = H, R6 = phenyl group, N8 = Me.
A more visual comparison of the diversities covered by the substituents present at positions C2, C4, C5, C6, and N8 of the 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (11) and pyrido[2,3-d]pyrimidin-7(8H)-ones (10) included in SciFinder is included in Figure 5 and Figure 6.
Although the differences in the substitution pattern of 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (11) and pyrido[2,3-d]pyrimidin-7(8H)-ones (10) could be attributed initially to the greater or lesser synthetic accessibility of some types of substituents, the different orientation of the biological activities sought for each structure seem to be the ultimate reason for such diversity.

3. Synthetic Approaches to Pyrido[2,3-d]pyrimidin-7(8H)-ones

Although for a bicyclic heterocyclic system, such as the pyrido[2,3-d]pyrimidin-7(8H)-ones (2), it is possible to envisage several possible synthetic approaches, in this review we concentrated on two major alternative protocols: (a) construction from a preformed pyrimidine and (b) construction from a preformed pyridone (Figure 7).
SciFinder offers two different ways of retrieving synthetic routes for a given general structure:
(1)
Search through Reaction Structure: in which it is possible to draw either two general starting products and the reaction arrow not drawing the reaction product or to draw a possible general starting material and the reaction arrow followed by the structure of the reaction product. Such approaches are very convenient once the possible starting products are known.
(2)
Retrosynthetic analysis: drawing the structure of the general final product indicating with a small arrow included in the structure editor the bonds to be broken. Such an approach is more useful when several possible synthetic approaches must be considered.
In this work, we used a combination of both methodologies to draw a picture of the synthetic approaches used for the preparation of pyrido[2,3-d]pyrimidin-7(8H)-ones (2).

3.1. Synthesis from a Preformed Pyrimidine

The searches carried out using the methodologies described above revealed that, in the case of preformed pyrimidines as precursors, two main approaches have been used:
(a) In the first one, an adequately substituted 4-amino-5-bromopyrimidine (12) is used as the starting material. Such an approach corresponds to the disconnection of the C4a-C5 and C7-N8 bonds of the pyridopyrimidine ring (Figure 8). Compounds 12 are usually synthesized from the corresponding 5-bromo-4-chloropyridimine by reaction with the adequate amine (R-NH2). The search carried out in SciFinder indicated that there are 2563 reactions of that type which appear in 36 references, most of them patents. As for the yields of such approach, in 101 cases of the 116 fully described reactions (87.07%) they are higher than 60%.
(b) In the second one, a preformed N-substituted pyrimidine-4-amine (13) is used as starting material, which bears a carbon functional group G (CHO, COOR, or CN) at position C5 of the pyrimidine ring. Such precursor is usually formed from the corresponding 4-chloro substituted pyrimidine 14 by nucleophilic substitution with the desired amine. This synthetic approach corresponds to the disconnection of the C5-C6 and C7-N8 bonds of the pyridopyrimidine system (Figure 9). In the case of the CHO group, there are 7248 reactions included in 93 references, 3174 reactions (78 references) for the COOR group, and 115 reactions (seven references) for the CN group. Once more, most of the references are patents. In this synthetic approach, yields are higher than 60% in 840 cases of the 1476 reactions fully described (56.91%).
A nice example of the first synthetic strategy is the synthesis of 19, an intermediate in the synthesis of palbociclib [90], starting from 5-bromo-2,4-dichloropyrimidine (15) which is substituted by cyclopentyl amine (16) to afford 17 which undergoes a palladium-catalyzed coupling with crotonic acid (18) followed by an intramolecular cyclization to yield the pyridopyrimidine system 19 (Figure 10).
Concerning the second synthetic strategy, an example of the use of a pyrimidine aldehyde for the construction of the pyridone ring is the synthesis of compound 23 [57], an intermediate for the synthesis of a series of tyrosine kinase inhibitors, starting from the aldehyde 20 which is condensed with the appropriate nitrile 21 to give the 7-iminopyridopyrimidine 22 that is subsequently transformed in the corresponding pyrido[2,3-d]pyrimidin-7(8H)-one (23) (Figure 11). The oxidation of the 2-methylthio substituent to a sulfone allows the introduction of arylamino substituents in such a position. In some cases, a carboxylic ester is used as a precursor of the aldehyde [91].
An example of the direct use of a pyrimidine ester is the formation of the 5-hydroxy substituted compound 26 starting from the ester 24 upon condensation with ethyl acetate (25) in a multistep protocol for which the yield is not described (Figure 12) [92].
Finally, an example of the use of a pyrimidine nitrile as a precursor is the synthesis of the 5-amino substituted compound 29 by condensation of the nitrile substituted pyrimidine 27 with diethyl malonate (28) in the presence of Na/EtOH (Figure 13) [93].
The preceding synthetic protocols have two major drawbacks: on one side, it is difficult to introduce substituents in position C4 of the resulting pyridopyrimidine unless they are groups that cannot participate in the cyclization of the pyridone ring (for this reason they have mainly been used in cases that the substituent at position C4 is a hydrogen atom) and, on the other side, they afford pyrido[2,3-d]pyrimidin-7(8H)-ones (10) with a C5-C6 double bond.
The first limitation has been recently partially solved in the synthesis of the 4-chloro substituted pyridopyrimidine 33 from the chloro substituted pyrimidine aldehyde 30 (Figure 14) [33]. The presence of the 4-chloro substituent allows the ulterior substitution by nitrogen nucleophiles.
Our group has also contributed a complementary methodology that allows the synthesis of pyridopyrimidines with a wide range of substituents at C2 and C4 and two levels of unsaturation at C5-C6 (Figure 15) [31]. Starting from the pyrimidinone 35, the Michael addition with a 2-aryl substituted methyl acrylate (35) affords the 4-oxopyridopyrimidine 36 which undergoes oxidation to the sulfone 37 that can be substituted by different nucleophiles to yield the corresponding 38. Its reaction with benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) affords 39 that can be again substituted by a wide variety of nucleophiles to afford the 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one 40. Finally, the oxidation of 40 affords the pyrido[2,3-d]pyrimidin-7(8H)-one 41. The formation of the pyridopyrimidine structure proceeds normally with yields higher than 80%.

3.2. Synthesis from a Preformed Pyridone

In this second synthetic approach, we considered two possible disconnections: (a) in between C8a-N1 and C4-C4a and (b) in between C8a-N1 and N3-C4 (Figure 16).
Only one example of the first kind of disconnection was found in SciFinder, the synthesis of compound 44 [94], an intermediate in the synthesis of pobosaibu, from pyridone 42 upon treatment with S-methylisothiourea (43) and DMF (N,N-Dimethylformamide) which provides the C4 carbon atom (yield not available) (Figure 17).
However, there are many examples of the second disconnection option shown in Figure 16. In this context, our group has a broad experience in the synthesis of 5,6-dihydropyrido[2,3-d]pyrimidin-7-(8H)-ones (50; R4 = NH2) and (51; R4 = OH) from α,β-unsaturated esters (45) (Figure 18). Thus, in the so-called cyclic strategy 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles (47) are obtained by reaction of an α,β-unsaturated ester (45) and malononitrile (46, G = CN) in NaOMe/MeOH (usually yields are above 60% although it depends on the nature and position of the substituents at C5 and C6 [95,96]). Treatment of pyridones 47 with guanidine systems (49, R2 = H, alkyl) affords 4-amino-pyrido[2,3-d]pyrimidines (50, R4 = NH2) [95,96]. On the other hand, we described an acyclic variation of the above protocol for the synthesis of pyridopyrimidines (50, R4 = NH2) based on the isolation of the corresponding Michael adduct (48, G = CN) and later cyclization with a guanidine 49 [24]. Similarly, 4-oxopyrido[2,3-d]pyrimidines (here depicted as the hydroxyl tautomer 51, R3 = OH) are obtained by treating intermediates (48, G = CO2Me), the result of a Michael addition between 45 and methyl cyanoacetate (46, G = CO2Me), with guanidines 49 [97]. Such acyclic protocol was amenable to a multicomponent microwave-assisted cyclocondensation to afford compounds 50 and 51 via Michael adducts 48 [50,98]. We also achieved 4-unsubstituted 5,6-dihydropyrido[2,3-d]pyrimidines (55; R4 = H) through the Michael addition of 2-aryl substituted acrylates (45; R6 = aryl, R5 = H) and 3,3-dimethoxypropanenitrile (52) which leads, depending on the reaction temperature (60 or −78 °C, respectively), to a 4-methoxymethylene substituted 4-cyanobutyric ester (54) or to a 4-dimethoxymethyl 4-cyanobutyric ester (53). These compounds are subsequently converted to the desired 4-unsubstituted compound (55; R4 = H) upon treatment with a guanidine carbonate 49 under microwave irradiation [99]. We completed our approach to totally dehydrogenated pyrido[2,3-d]pyrimidin-7(8H)-ones (56–58) and (17; R4 = H) by using several oxidation protocols [16]. The construction of the pyridopyrimidine structure from pyridone 47 usually proceeds with yields higher than 70% but is mainly dependent on the nature and position of the substituents present in the pyridone ring.
Our interest in tyrosine kinase inhibitors, led us to develop a methodology for the synthesis of 6-aryl-2-arylamino substituted 4-amino-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (59, R2 = aryl) via the corresponding 3-aryl substituted pyridopyrimidines 60, formed upon treatment of pyridones 47 with an arylsubstituted guanidine 49 in dioxane, which underwent the Dimroth rearrangement to the desired 4-aminopyridopyrimidines (59, R2 = aryl) with NaOMe/MeOH. The overall yields of such a two-step protocol are in general higher than the direct reaction between pyridones 47 and an arylsubstituted guanidine 49 (Figure 19) [28].
Outside of these two main methodologies, the rest of the literature concerning the synthesis of pyrido[2,3-d]pyrimidine-7(8H)-ones is devoted to the manipulation of the substituents present in the bicyclic ring, mainly at C2 and C4, by using nucleophilic substitutions of halogen atoms at such positions by nitrogen or oxygen nucleophiles. Thus, there are more than 2000 examples of the substitution of a 2-chloropyridopyrimidine by nitrogen nucleophiles in good yields [62] but fewer of the substitution of a 2-bromo substituted compound [100]. Similarly, the substitution of the corresponding 4-chloropyrimidine by nitrogen nucleophiles appears in more than 1800 examples [33] but the same reaction carried out with 4-bromo derivatives only appears in a reference of our research group [52]. Even more frequently, the introduction of nitrogen or oxygen substituents at position C2 is carried out in a two steps protocol in which a methyl thioether is oxidized to the corresponding methyl sulfonyl group (usually with m-CPBA) and subsequently substituted by the nitrogen or oxygen nucleophile. On example of such two steps protocol, used in more than 2000 reactions in the literature, is depicted in Figure 15.
On the other hand, two miscellaneous protocols for the formation of the pyrido[2,3-d]pyrimidine-7(8H)-one scaffold include a Diels-Alder reaction between diethyl acetylenedicarboxylate and a 6-amino-4-oxopyrimidine ring [101] and the photochemical cyclization of N-(pyrimidin-4-yl)methacrylamide [14], however, both methodologies proceed in very low yields (1% and 21% respectively).

4. Biomedical Applications of Pyrido[2,3-d]pyrimidin-7(8H)-ones

SciFinder is a very useful tool when one is interested in the biological activity or uses of a single compound but renders it difficult to retrieve biological information for a family of compounds. Certainly, it is possible to retrieve all the references including biological data for a set of structures (Biological Study) but it only retrieves the references that later must be examined one by one (in the case of the 14,448 structures with a C5-C6 double bond reduces the number by 10%). For this reason, we used the tool Index Term to obtain a list, ordered by frequency, of the indexed terms (keywords) that appear in the references in order to get a general picture of the biological activities of 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (11) and pyrido[2,3-d]pyrimidin-7(8H)-ones (10). Table 4 shows the 10 first index terms obtained for compounds 11 (C5-C6 single bond) and 10 (C5-C6 double bond).
The simple inspection of Table 4 clearly indicates that the intended uses of both families of compounds are totally different. On one side, 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (11) have been applied for cardiovascular diseases: antihypertensive agents (as angiotensin II receptor antagonists), antidiabetics, etc., although also as antitumor agents. In particular, there are circa 150 references including the index term antihypertensives [102,103]. On the other side, pyrido[2,3-d]pyrimidin-7(8H)-ones (10) have been focused on antitumor agents: mammary neoplasms, neoplasms, signal transduction, etc., in particular as tyrosine kinase inhibitors (around 430 references) [104,105].
In this context, our group has described in the past years several 4-amino and 4-oxo substituted pyrido[2,3-d]pyrimidin-7(8H)-ones (R4 = NH2, OH) (Figure 18 and Figure 19 with up to five diversity centers which, contrary to compounds bearing R4 = H, render these compounds, in general, nontoxic for normal cells. Consequently, an adequate decoration of these structures has allowed us to describe compounds with activities in the nanomolar range as BCR kinase (Breakpoint Cluster Region protein) inhibitors for B lymphoid malignancies (compound 62) [42], DDR2 (Discoidin Domain-containing Receptor 2) inhibitors for treatment of lung cancer (compound 63) [106], and even as HCV (Hepatitis C Virus) inhibitors (compound 64) [31], and others (Figure 20). In fact, we are convinced that an adequate decoration of pyrido[2,3-d]pyrimidin-7(8H)-one scaffolds should allow targeting very diverse biological receptors such, in our case, tyrosine kinases and HCV NS5B polymerase.
Reaching this point, it would be highly interesting to know how many 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (11) and pyrido[2,3-d]pyrimidin-7(8H)-ones (10) have reached the market. SciFinder is not the right tool to find this information since it does not incorporate, at least with clarity, commercial information or the stage of development of a drug candidate. Consequently, we used a second database called Drugbank [107] (https://www.drugbank.ca/) for searching the market situation of compounds 10 and 11.
The search showed that in the case of 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (11) a single compound is included in the database. Tasosartan (65, CAS 145733-36-4, Figure 21), patented by American Home Products Corporation and developed by Wyeth as an angiotensin II receptor antagonist, did not reach the market since it was withdrawn by the manufacturer during the Clinical Phase III due to the detection of elevated transaminase levels (as a sign of possible liver toxicity) in a high number of participants in the study.
On the other hand, in the case of pyrido[2,3-d]pyrimidin-7(8H)-ones (10), there are eight structures in various stages of development. Two of them are classified as Experimental, a category that according to Drugbank corresponds to potential drugs in the Discovery Phase. Five more in the Investigational category, which means that for these compounds an IND (Investigative New Drug) application has been submitted to the FDA (Food and Drug Administration) indicating that they have initiated Clinical Phases. Finally, there is a single compound approved by the FDA, the already mentioned palbociclib (8, CAS 571190-30-2, Figure 3). All these structures have a nitrogen substituent at C2 and hydrogen at C4 in line with the structural searches carried out in this work.
Palbociclib was patented by Warner-Lambert in 2003 [108]. Palbociclib [109,110] is a pyrido[2,3-d]pyrimidin-7(8H)-one that acts in the cell cycle machinery [111]. It is a second inhibitor of CD4 kinase and was selected from a group of pyridopyrimidines due to its favorable physical and pharmaceutical properties. Palbociclib was developed by Pfizer Inc after the discovery that identified cyclin-dependent kinases as key regulators of cell growth. It was approved by the FDA in March 2015 for the treatment of breast cancer positive for HR, advanced HER2-negative, or metastatic. The indications were updated in April 2019 to include male patients based on the results of post-marketing reports that demonstrate clinical safety and efficacy.
As for the rest of pyrido[2,3-d]pyrimidin-7(8H)-ones (10) under development (Figure 22), it is interesting to note that the list includes some of the most important pharmaceutical companies (Takeda, Pfizer, SmithKline Beecham, etc.) thus confirming the interest of structures 10 as scaffolds for the development of new drugs.
Compound 66 (CAS 260415-63-2) was patented by the Scripps Research Institute in 2001 [112] as an Abl1/Src kinase inhibitor mainly oriented to leukemia treatment although more recent papers and patents seem to address this compound also to neuromuscular disorders. To the best of our knowledge, this compound has not yet reached the market.
Dilmapimod (67, CAS 444606-18-2) is a p38 MAP-kinase inhibitor with potential uses in rheumatoid arthritis that was patented by SmithKline Beecham Corporation (GSK-681323) in 2001 [113] and has been involved in clinical trials for inflammation, neuropathic pain, and heart diseases but was finally discontinued due to liver toxicity.
Compound 68 (CAS 1013101-36-4) was patented by Pfizer in 2007 [114] as a 1 phosphatidylinositol 3 kinase inhibitor and MTOR protein inhibitor. It reached Phase II clinical trial for endometrial cancer treatment but was discontinued in 2012. N68 has also been involved in clinical trials for early breast cancer (Phase 2), and advanced breast cancer (Phase 1b). More than 180 publications including many patents, some of them very recent, seem to indicate that there is still an interest of Pfizer for such compounds.
TAK-733 (69, CAS 1035555-63-5) is a compound developed and patented by Takeda Pharmaceutical Company in 2007 [115] as an inhibitor of MEK1 and MEK2 (MEK1/2) that was tested in clinical trials for advanced metastatic melanoma and advanced nonhematologic malignancies. TAK-733 was tested against non-small cell lung cancer reaching Phase I but was discontinued in 2015.
Compound 70 (CAS 449811-92-1), patented by Hoffmann-La Roche (R-1487) in 2002 [116] for the treatment of p38 mediated disorders, was investigated for use/treatment in rheumatoid arthritis but was discontinued in 2004.
Compound 71 (CAS 185039-91-2) was patented by Warner-Lambert Company in 1996 [117]. Warner-Lambert was very active in the field of pyrido[2,3-d]pyrimidin-7(8H)-ones (10) in the late 90s. Such company was bought by Pfizer in 2000 and this fact seems to have stopped the development of such compound.
Finally, Voxtalisib (72, CAS 934493-76-2) was patented by Exelis (XL-765) in 2006 [118] as an inhibitor of phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) kinases in the PI3K/mTOR signaling pathway. 72 was licensed to Sanofi-Aventis (SAR-245409) in 2009 in a deal for the development PI3K inhibitors with an upfront payment of $140 million and guaranteed research funding. In 2018, Voxtalisib was discontinued in Phase I/II for solid tumors (breast and ovarian cancer) both as monotherapy and combined therapy.

5. Conclusions

In this paper, we reviewed the substitution patterns of 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (11) and pyrido[2,3-d]pyrimidin-7(8H)-ones (10) establishing the kind of substituents mainly used at positions C2, C4, C5, C6, and N8 of such systems. For compounds 11, we established that the most used combination of substituents is G2 = nitrogen substituent, G4 = oxygen substituent (in particular as a carbonyl group), R5 = phenyl group, R6 = H, N8 = H. In the case of compounds 10, it is G2 = nitrogen substituent, G4 = H, R5 = H, R6 = phenyl group, N8 = methyl.
We established the main synthetic strategies for the synthesis of such compounds starting from a preformed pyrimidine or pyridone and demonstrated that compounds 11 have been mainly used in the area of cardiovascular diseases while compounds 10 have been focused in antitumor agents, mainly as tyrosine kinase inhibitors.

Author Contributions

Conceptualization, J.I.B. and R.P.d.l.B.; writing—original draft preparation, G.J. and J.I.B.; validation, R.E.-T. and J.T.; writing—review and editing, J.I.B.; All authors read and approved the final manuscript.

Funding

This research was funded by Ministerio de Ciencia, Innovación y Universidades, Proyectos de I+D+I “Retos Investigación” del Programa Estatal de I+D+I orientada a los Retos de la Sociedad, grant number RTI2018-096455-B-I00.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Sako, M. Product class 19: Pyridopyrimidines. Sci. Synth. 2004, 16, 1155–1267. [Google Scholar]
  2. Akssira, M.; Guillaumet, G.; Routier, S. Recent advances in the chemistry and biology of pyridopyrimidines. Eur. J. Med. Chem. 2015, 95, 76–95. [Google Scholar]
  3. Evans, B.E.; Rittle, K.E.; Bock, M.G.; DiPardo, R.M.; Freidinger, R.M.; Whitter, W.L.; Lundell, G.F.; Veber, D.F.; Anderson, P.S.; Chang, R.S. Methods for drug discovery: Development of potent, selective, orally effective cholecystokinin antagonists. J. Med. Chem 1988, 31, 2235–2246. [Google Scholar] [CrossRef]
  4. Altomare, C.D. Privileged heterocyclic scaffolds in chemical biology and drug discovery: Synthesis and bioactivity. Chem. Heterocycl. Compd. 2017, 53, 239. [Google Scholar]
  5. Theivendren, P.S.; Caiado, R.J.; Phadte, V.D.; Silveira, K.V. A mini review of pyrimidine and fused pyrimidine marketed drugs. Res. Pharm. 2012, 2, 1–9. [Google Scholar]
  6. Victory, P.; Jover, J.M.; Nomen, R. The 3-cyano-2-methoxy-2,3-dehydropiperidin-6-ones as starting materials in synthesis. Synthesis of heterocycles. I. Sect. Title Heterocycl. Compd. 1981, 38, 497–500. [Google Scholar]
  7. Chemical Abstracts Service. Scifinder, Version 2019; Chemical Abstracts Service: Columbus, OH, USA, 2019. [Google Scholar]
  8. Wu, P.; Choudhary, A. Kinase Inhibitor Drugs; Wiley-VCH GmbH & Co. KGaA: Weinheim, Germany, 2018; Volume 3, pp. 65–93. [Google Scholar]
  9. Dickson, M.A. Molecular Pathways: CDK4 Inhibitors for Cancer Therapy. Clin. Cancer Res. 2014, 20, 3379–3383. [Google Scholar] [CrossRef]
  10. Robak, P.; Robak, T. Novel synthetic drugs currently in clinical development for chronic lymphocytic leukemia. Expert Opin. Investig. Drugs 2017, 26, 1249–1265. [Google Scholar] [CrossRef]
  11. Miller, S.M.; Goulet, D.R.; Johnson, G.L. Targeting the Breast Cancer Kinome. J. Cell. Physiol. 2017, 232, 53–60. [Google Scholar] [CrossRef]
  12. Schmidt, B.; Schieffer, B. Angiotensin II AT1 Receptor Antagonists. J. Med. Chem. 2003, 46, 2261–2270. [Google Scholar] [CrossRef]
  13. Lu, J. Palbociclib: A first-in-class CDK4/CDK6 inhibitor for the treatment of hormone-receptor positive advanced breast cancer. J. Hematol. Oncol. 2015, 8, 1–3. [Google Scholar] [CrossRef] [PubMed]
  14. Mallory, F.B.; Mallory, C.W. Photocyclization of Stilbenes and Related Molecules. In Organic Reactions; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 1984; pp. 1–456. [Google Scholar]
  15. Choi, Y.; Kim, H.; Shin, Y.H.; Park, S.B. Diverse display of non-covalent interacting elements using pyrimidine-embedded polyheterocycles. Chem. Commun. 2015, 51, 13040–13043. [Google Scholar] [CrossRef] [PubMed]
  16. Perez-Pi, I.; Berzosa, X.; Galve, I.; Teixido, J.; Borrell, J.I. Dehydrogenation of 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones: A convenient last step for a synthesis of pyrido[2,3-d]pyrimidin-7(8H)-ones. Heterocycles 2010, 82, 581–591. [Google Scholar] [CrossRef]
  17. Singh, S.B.; Kaelin, D.E.; Wu, J.; Miesel, L.; Tan, C.M.; Gill, C.; Black, T.; Nargund, R.; Meinke, P.T.; Olsen, D.B.; et al. Hydroxy tricyclic 1,5-naphthyridinone oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents-SAR of RHS moiety (Part-3). Bioorg. Med. Chem. Lett. 2015, 25, 2473–2478. [Google Scholar] [CrossRef] [PubMed]
  18. Rana, P.; Will, Y.; Nadanaciva, S.; Jones, L.H. Development of a cell viability assay to assess drug metabolite structure–toxicity relationships. Bioorg. Med. Chem. Lett. 2016, 26, 4003–4006. [Google Scholar] [CrossRef] [PubMed]
  19. Teraoka, Y.; Kume, S.; Lin, Y.; Atsuji, S.; Inui, T. Comprehensive Evaluation of the Binding of Lipocalin-Type Prostaglandin D Synthase to Poorly Water-Soluble Drugs. Mol. Pharm. 2017, 14, 3558–3567. [Google Scholar] [CrossRef] [PubMed]
  20. Ellingboe, J.W.; Antane, M.; Nguyen, T.T.; Collini, M.D.; Antane, S.; Bender, R.; Hartupee, D.; White, V.; McCallum, J.; Park, C.H.; et al. Pyrido[2,3-d]pyrimidine Angiotensin II Antagonists. J. Med. Chem. 1994, 37, 542–550. [Google Scholar] [CrossRef]
  21. Gentile, G.; Ceccarelli, M.; Micheli, L.; Tirone, F.; Cavallaro, S. Functional genomics identifies Tis21-dependent mechanisms and putative cancer drug targets underlying medulloblastoma shh-type development. Front. Pharmacol. 2016, 7, 449. [Google Scholar] [CrossRef]
  22. Tu, S.; Li, C.; Shi, F.; Zhou, D.; Shao, Q.; Cao, L.; Jiang, B. An efficient chemoselective synthesis of pyrido[2,3-d]pyrimidine derivatives under microwave irradiation. Synthesis 2008, 2008, 369–376. [Google Scholar] [CrossRef]
  23. Camarasa, M.; Barnils, C.; Puig de la Bellacasa, R.; Teixido, J.; Borrell, J.I. A new and practical method for the synthesis of 6-aryl-5,6-dihydropyrido[2,3-d]pyrimidine-4,7(3H,8H)-diones. Mol. Divers. 2013, 17, 525–536. [Google Scholar] [CrossRef]
  24. Borrell, J.I.; Teixido, J.; Matallana, J.L.; Martinez-Teipel, B.; Colominas, C.; Costa, M.; Balcells, M.; Schuler, E.; Castillo, M.J. Synthesis and Biological Activity of 7-Oxo Substituted Analogues of 5-Deaza-5,6,7,8-tetrahydrofolic Acid (5-DATHF) and 5,10-Dideaza-5,6,7,8-tetrahydrofolic Acid (DDATHF). J. Med. Chem. 2001, 44, 2366–2369. [Google Scholar] [CrossRef] [PubMed]
  25. Moradi, S.; Zolfigol, M.A.; Zarei, M.; Alonso, D.A.; Khoshnood, A.; Tajally, A. An efficient catalytic method for the synthesis of pyrido[2,3-d]pyrimidines as biologically drug candidates by using novel magnetic nanoparticles as a reusable catalyst. Appl. Organomet. Chem. 2018, 32, e4043. [Google Scholar] [CrossRef]
  26. Uitdehaag, J.C.M.; de Man, J.; Willemsen-Seegers, N.; Prinsen, M.B.W.; Libouban, M.A.A.; Sterrenburg, J.G.; de Wit, J.J.P.; de Vetter, J.R.F.; de Roos, J.A.D.M.; Buijsman, R.C.; et al. Target Residence Time-Guided Optimization on TTK Kinase Results in Inhibitors with Potent Anti-Proliferative Activity. J. Mol. Biol. 2017, 429, 2211–2230. [Google Scholar] [CrossRef] [PubMed]
  27. El-Naggar, A.M.; Khalil, A.K.; Zeidan, H.M.; El-Sayed, W.M. Eco-friendly Synthesis of Pyrido[2,3-d]pyrimidine Analogs and Their Anticancer and Tyrosine Kinase Inhibition Activities. Anticancer. Agents Med. Chem. 2018, 17, 1644–1651. [Google Scholar] [CrossRef]
  28. Galve, I.; Puig de la Bellacasa, R.; Sanchez-Garcia, D.; Batllori, X.; Teixido, J.; Borrell, J.I. Synthesis of 2-arylamino substituted 5,6-dihydropyrido[2,3-d]pyrimidine-7(8H)-ones from arylguanidines. Mol. Divers. 2012, 16, 639–649. [Google Scholar] [CrossRef]
  29. Parthasarathy, S.; Henry, K.; Pei, H.; Clayton, J.; Rempala, M.; Johns, D.; De Frutos, O.; Garcia, P.; Mateos, C.; Pleite, S.; et al. Discovery of chiral dihydropyridopyrimidinones as potent, selective and orally bioavailable inhibitors of AKT. Bioorg. Med. Chem. Lett. 2018, 28, 1887–1891. [Google Scholar] [CrossRef]
  30. Sakamoto, T.; Koga, Y.; Hikota, M.; Matsuki, K.; Mochida, H.; Kikkawa, K.; Fujishige, K.; Kotera, J.; Omori, K.; Morimoto, H.; et al. 8-(3-Chloro-4-methoxybenzyl)-8H-pyrido[2,3-d]pyrimidin-7-one derivatives as potent and selective phosphodiesterase 5 inhibitors. Bioorg. Med. Chem. Lett. 2015, 25, 1431–1435. [Google Scholar] [CrossRef]
  31. Camarasa, M.; Puig de la Bellacasa, R.; González, À.L.; Ondoño, R.; Estrada, R.; Franco, S.; Badia, R.; Esté, J.; Martínez, M.Á.; Teixidó, J. Design, synthesis and biological evaluation of pyrido[2,3-d]pyrimidin-7-(8H)-ones as HCV inhibitors. Eur. J. Med. Chem. 2016, 115, 463–483. [Google Scholar] [CrossRef]
  32. Zinchenko, A.N.; Muzychka, L.V.; Biletskii, I.I.; Smolii, O.B. Synthesis of new 4-amino-substituted 7-iminopyrido[2,3-d]pyrimidines. Chem. Heterocycl. Compd. 2017, 53, 589–596. [Google Scholar] [CrossRef]
  33. Zinchenko, A.M.; Muzychka, L.V.; Kucher, O.V.; Sadkova, I.V.; Mykhailiuk, P.K.; Smolii, O.B. One-Pot Synthesis of 6-Aminopyrido[2,3-d]pyrimidin-7-ones. Eur. J. Org. Chem. 2018, 2018, 6519–6523. [Google Scholar] [CrossRef]
  34. Thibault, S.; Hu, W.; Hirakawa, B.; Kalabat, D.; Franks, T.; Sung, T.; Khoh-Reiter, S.; Lu, S.; Finkelstein, M.; Jessen, B.; et al. Intestinal Toxicity in Rats Following Administration of CDK4/6 Inhibitors Is Independent of Primary Pharmacology. Mol. Cancer Ther. 2018, 18, 257–266. [Google Scholar] [CrossRef] [PubMed]
  35. Poratti, M.; Marzaro, G. Third-generation CDK inhibitors: A review on the synthesis and binding modes of Palbociclib, Ribociclib and Abemaciclib. Eur. J. Med. Chem. 2019, 172, 143–153. [Google Scholar] [CrossRef] [PubMed]
  36. Salman, A.S. Utility of Activated Nitriles in the Synthesis of Novel Heterocyclic Compounds with Antitumor Activity. Org. Chem. Int. 2013, 2013, 1–9. [Google Scholar] [CrossRef] [PubMed]
  37. Murphy-Benenato, K.E.; Gingipalli, L.; Boriack-Sjodin, P.A.; Martinez-Botella, G.; Carcanague, D.; Eyermann, C.J.; Gowravaram, M.; Harang, J.; Hale, M.R.; Ioannidis, G.; et al. Negishi cross-coupling enabled synthesis of novel NAD+-dependent DNA ligase inhibitors and SAR development. Bioorg. Med. Chem. Lett. 2015, 25, 5172–5177. [Google Scholar] [CrossRef]
  38. Coussy, F.; de Koning, L.; Lavigne, M.; Bernard, V.; Ouine, B.; Boulai, A.; El Botty, R.; Dahmani, A.; Montaudon, E.; Assayag, F.; et al. A large collection of integrated genomically characterized patient-derived xenografts highlighting the heterogeneity of triple-negative breast cancer. Int. J. Cancer 2019. [Google Scholar] [CrossRef]
  39. Liu, L.; Chen, X.; Liu, W.; Yu, H.; Liu, F. Statistical analysis and heuristic identification of unexpected interactions from the neurokinase-inhibitor interactome in trigeminal neuralgia pharmacological intervention. J. Chemom. 2019, 33, e3126. [Google Scholar] [CrossRef]
  40. Wendling, D.; Prati, C. Kinases inhibitors and small molecules: A new treatment tool for axial spondyloarthropathy? Jt. Bone Spine 2016, 83, 473–475. [Google Scholar] [CrossRef]
  41. Warth, B.; Palermo, A.; Rattray, N.J.W.; Lee, N.V.; Zhu, Z.; Hoang, L.T.; Cai, Y.; Mazurek, A.; Dann, S.; Vanarsdale, T.; et al. Palbociclib and fulvestrant act in synergy to modulate central carbon metabolism in breast cancer cells. Metabolites 2019, 9, 7. [Google Scholar] [CrossRef] [Green Version]
  42. Puig de la Bellacasa, R.; Roue, G.; Balsas, P.; Perez-Galan, P.; Teixido, J.; Colomer, D.; Borrell, J.I. 4-Amino-2-arylamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7-(8H)-ones as BCR kinase inhibitors for B lymphoid malignancies. Eur. J. Med. Chem. 2014, 86, 664–675. [Google Scholar] [CrossRef]
  43. Dong, J.; Zhao, H.; Zhou, T.; Spiliotopoulos, D.; Rajendran, C.; Li, X.D.; Huang, D.; Caflisch, A. Structural analysis of the binding of type I, I1/2, and II inhibitors to Eph tyrosine kinases. ACS Med. Chem. Lett. 2015, 6, 79–83. [Google Scholar] [CrossRef] [Green Version]
  44. Li, J.J.; Tian, Y.L.; Zhai, H.L.; Lv, M.; Zhang, X.Y. Insights into mechanism of pyrido[2,3-d]pyrimidines as DYRK1A inhibitors based on molecular dynamic simulations. Proteins Struct. Funct. Bioinf. 2016, 84, 1108–1123. [Google Scholar] [CrossRef] [PubMed]
  45. Panda, S.; Roy, A.; Deka, S.J.; Trivedi, V.; Manna, D. Fused Heterocyclic Compounds as Potent Indoleamine-2,3-dioxygenase 1 Inhibitors. ACS Med. Chem. Lett. 2016, 7, 1167–1172. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Melik-Ohanjanyan, R.G.; Hovsepyan, T.R.; Israelyan, S.G.; Hakobyan, M.R.; Tamazyan, R.A.; Ayvazyan, A.G. Synthesis and X-ray analysis of some pyrido[2,3-d]pyrimidines. Russ. J. Org. Chem. 2014, 50, 913–915. [Google Scholar] [CrossRef]
  47. Okram, B.; Nagle, A.; Adrián, F.J.; Lee, C.; Ren, P.; Wang, X.; Sim, T.; Xie, Y.; Wang, X.; Xia, G.; et al. A General Strategy for Creating “Inactive-Conformation” Abl Inhibitors. Chem. Biol. 2006, 13, 779–786. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  48. Brameld, K.A.; Owens, T.D.; Verner, E.; Venetsanakos, E.; Bradshaw, J.M.; Phan, V.T.; Tam, D.; Leung, K.; Shu, J.; Lastant, J.; et al. Discovery of the Irreversible Covalent FGFR Inhibitor 8-(3-(4-Acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PRN1371) for the Treatment of Solid Tumors. J. Med. Chem. 2017, 60, 6516–6527. [Google Scholar] [CrossRef] [PubMed]
  49. Komkov, A.V.; Yakovlev, I.P.; Dorokhov, V.A. Synthesis of pyrido[2,3-d]pyrimidin-7(8H)-one derivatives from 5-acetyl-4-aminopyrimidines and β-dicarbonyl compounds. Russ. Chem. Bull. 2005, 54, 784–788. [Google Scholar] [CrossRef]
  50. Mont, N.; Teixido, J.; Borrell, J.I.; Kappe, C.O. A three-component synthesis of pyrido[2,3-d]pyrimidines. Tetrahedron Lett. 2003, 44, 5385–5387. [Google Scholar] [CrossRef]
  51. Shi, H.; Zhou, L.; Bao, G.; Yi, Q.; Zhou, S.; Tian, Y.; Li, X. Identification of Potential MEK1 Inhibitors by Pharmacophore-based Virtual Screening and MD Simulations. Lett. Drug Des. Discov. 2014, 11, 894–907. [Google Scholar] [CrossRef]
  52. Mont, N.; Carrion, F.; Borrell, J.I.; Teixido, J. Cyclization of 5-cyano-6-cyanoimino-3,4-dihydropyridin-2(1H)-ones with amines. Heterocycles 2010, 81, 329–347. [Google Scholar]
  53. Harutyunyan, A.A.; Panosyan, G.A.; Chishmarityan, S.G.; Paronikyan, R.V.; Stepanyan, H.M. Synthesis and properties of derivatives of pyrimidin-5-ylpropanoic acids and 8-aryl-4-methyl- and 4,6-dimethyl-2-phenyl-5,6,7,8-tetrahydropyrido-[2,3-d]pyrimidin-7-ones. Russ. J. Org. Chem. 2015, 51, 705–710. [Google Scholar] [CrossRef]
  54. Mont, N.; Fernandez-Megido, L.; Teixido, J.; Kappe, C.O.; Borrell, J.I. A diversity-oriented, microwave-assisted synthesis of 4-oxo and 4-chloropyrido[2,3-d]pyrimidin-7(8H)-ones. QSAR Comb. Sci. 2004, 23, 836–849. [Google Scholar] [CrossRef]
  55. Adcock, J.; Gibson, C.L.; Huggan, J.K.; Suckling, C.J. Diversity oriented synthesis: Substitution at C5 in unreactive pyrimidines by Claisen rearrangement and reactivity in nucleophilic substitution at C2 and C4 in pteridines and pyrido[2,3-d]pyrimidines. Tetrahedron 2011, 67, 3226–3237. [Google Scholar] [CrossRef] [Green Version]
  56. Xu, T.; Peng, T.; Ren, X.; Zhang, L.; Yu, L.; Luo, J.; Zhang, Z.; Tu, Z.; Tong, L.; Huang, Z.; et al. C5-substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific kinase inhibitors targeting the clinical resistance-related EGFRT790M mutant. Medchemcomm 2015, 6, 1693–1697. [Google Scholar] [CrossRef]
  57. Boschelli, D.H.; Wu, Z.; Klutchko, S.R.; Showalter, H.D.H.; Hamby, J.M.; Lu, G.H.; Major, T.C.; Dahring, T.K.; Batley, B.; Panek, R.L.; et al. Synthesis and tyrosine kinase inhibitory activity of a series of 2- amino-8H-pyrido[2,3-d]pyrimidines: Identification of potent, selective platelet-derived growth factor receptor tyrosine kinase inhibitors. J. Med. Chem. 1998, 41, 4365–4377. [Google Scholar] [CrossRef]
  58. Kalyukina, M.; Yosaatmadja, Y.; Middleditch, M.J.; Patterson, A.V.; Smaill, J.B.; Squire, C.J. TAS-120 Cancer Target Binding: Defining Reactivity and Revealing the First Fibroblast Growth Factor Receptor 1 (FGFR1) Irreversible Structure. ChemMedChem 2019, 14, 494–500. [Google Scholar] [CrossRef]
  59. Apsunde, T.; Wurz, R.P. Pyridin-2-one synthesis using ester enolates and aryl aminoaldehydes and ketones. J. Org. Chem. 2014, 79, 3260–3266. [Google Scholar] [CrossRef]
  60. Simon-Szabó, L.; Kokas, M.; Greff, Z.; Boros, S.; Bánhegyi, P.; Zsákai, L.; Szántai-Kis, C.; Vantus, T.; Mandl, J.; Bánhegyi, G.; et al. Novel compounds reducing IRS-1 serine phosphorylation for treatment of diabetes. Bioorg. Med. Chem. Lett. 2016, 26, 424–428. [Google Scholar] [CrossRef] [Green Version]
  61. Anderson, K.; Chen, Y.; Chen, Z.; Dominique, R.; Glenn, K.; He, Y.; Janson, C.; Luk, K.C.; Lukacs, C.; Polonskaia, A.; et al. Pyrido[2,3-d]pyrimidines: Discovery and preliminary SAR of a novel series of DYRK1B and DYRK1A inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 6610–6615. [Google Scholar] [CrossRef]
  62. Yu, L.; Huang, M.; Xu, T.; Tong, L.; Yan, X.E.; Zhang, Z.; Xu, Y.; Yun, C.; Xie, H.; Ding, K.; et al. A structure-guided optimization of pyrido[2,3-d]pyrimidin-7-ones as selective inhibitors of EGFRL858R/T790Mmutant with improved pharmacokinetic properties. Eur. J. Med. Chem. 2017, 126, 1107–1117. [Google Scholar] [CrossRef]
  63. Parsons, A.T.; Kubryk, M.; Hedley, S.J.; Thiel, O.R.; Bauer, D.; Potter-Racine, M.S.; Lin, Z. An Improved Process for the Preparation of a Covalent Kinase Inhibitor through a C-N Bond-Forming SNAr Reaction. Org. Process. Res. Dev. 2018, 22, 898–902. [Google Scholar] [CrossRef]
  64. Boros, E.E.; Wood, E.R.; McDonald, O.B.; Spitzer, T.D.; Sefler, A.M.; Reep, B.R.; Thompson, J.B. Tandem Michael-addition/cyclization synthesis and EGFR kinase inhibition activity of pyrido[2,3-d]pyrimidin-7(8H)-ones. J. Heterocycl. Chem. 2004, 41, 355–358. [Google Scholar] [CrossRef]
  65. Dong, Q.; Dougan, D.R.; Gong, X.; Halkowycz, P.; Jin, B.; Kanouni, T.; O’Connell, S.M.; Scorah, N.; Shi, L.; Wallace, M.B.; et al. Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer. Bioorg. Med. Chem. Lett. 2011, 21, 1315–1319. [Google Scholar] [CrossRef] [PubMed]
  66. Zhang, J.; Lu, D.; Wei, H.X.; Gu, Y.; Selkoe, D.J.; Wolfe, M.S.; Augelli-Szafran, C.E. Part 3: Notch-sparing γ-secretase inhibitors: SAR studies of 2-substituted aminopyridopyrimidinones. Bioorg. Med. Chem. Lett. 2016, 26, 2138–2141. [Google Scholar] [CrossRef] [PubMed]
  67. Blades, K.; Glossop, S. A Three-Step Protocol towards N-8-(2,2-Dimethoxyethyl)-2-methylsulfanylpyrido[2,3-d]pyrimidin-7-one. Synthesis 2016, 49, 554–556. [Google Scholar] [CrossRef]
  68. Aryan, R.; Beyzaei, H.; Nojavan, M.; Pirani, F.; Samareh Delarami, H.; Sanchooli, M. Expedient multicomponent synthesis of a small library of some novel highly substituted pyrido[2,3-d]pyrimidine derivatives mediated and promoted by deep eutectic solvent and in vitro and quantum mechanical study of their antibacterial and antifungal activ. Mol. Divers. 2019, 23, 93–105. [Google Scholar] [CrossRef]
  69. Baker, B.R.; Almaula, P.I. Analogs of tetrahydrofolic acid. XIX. On the mode of binding of the pyrimidyl moiety of n-(2-amino-4-hydroxy-6-methyl-5-pyrimidylpropionyl)-P-aminobenzoyl-l-glutamic acid to 5,10-methylenetetrahydrofolate dehydrogenase. J. Heterocycl. Chem. 1964, 1, 263–270. [Google Scholar] [CrossRef]
  70. Balsas, P.; Esteve-Arenys, A.; Roldán, J.; Jiménez, L.; Rodríguez, V.; Valero, J.G.; Chamorro-Jorganes, A.; Puig de la Bellacasa, R.; Teixidó, J.; Matas-Céspedes, A.; et al. Activity of the novel BCR kinase inhibitor IQS019 in preclinical models of B-cell non-Hodgkin lymphoma. J. Hematol. Oncol. 2017, 10, 80. [Google Scholar] [CrossRef] [Green Version]
  71. Lang, J.D.; Hendricks, W.P.D.; Orlando, K.A.; Yin, H.; Kiefer, J.; Ramos, P.; Sharma, R.; Pirrotte, P.; Raupach, E.A.; Sereduk, C.; et al. Ponatinib shows potent antitumor activity in small cell carcinoma of the ovary hypercalcemic type (SCCOHT) through multikinase inhibition. Clin. Cancer Res. 2018, 24, 1932–1943. [Google Scholar] [CrossRef] [Green Version]
  72. Boschelli, D.H.; Dobrusin, E.M.; Doherty, A.M.; Fattacy, A.; Fry, D.W.; Barvian, M.R.; Kallmeyer, S.T.; Wu, Z. Preparation of Pyrido[2,3-d]Pyrimidines and 4-Aminopyrimidines as Inhibitors of Cellular Proliferation. WO Patent 9833798A2, 26 January 1998. [Google Scholar]
  73. Aftab, D.T.; Laird, D.A.; Lamb, P.; Martini, J.-F.A. Preparation of Azetidine MEK Kinase Inhibitors and Pyridopyrimidine and Quinoxaline and Analog PI3K Inhibitors and Methods of Using MEK Inhibitors in Combination with PI3K Inhibitors for the Treatment of Proliferative Diseases, Especially Cancer. WO Patent 9833798A2, 16 August 2008. [Google Scholar]
  74. Rudolph, J.; Murray, L.J.; Ndubaku, C.O.; O’Brien, T.; Blackwood, E.; Wang, W.; Aliagas, I.; Gazzard, L.; Crawford, J.J.; Drobnick, J.; et al. Chemically Diverse Group i p21-Activated Kinase (PAK) Inhibitors Impart Acute Cardiovascular Toxicity with a Narrow Therapeutic Window. J. Med. Chem. 2016, 59, 5520–5541. [Google Scholar] [CrossRef]
  75. Semenova, G.; Stepanova, D.S.; Dubyk, C.; Handorf, E.; Deyev, S.M.; Lazar, A.J.; Chernoff, J. Targeting group i p21-activated kinases to control malignant peripheral nerve sheath tumor growth and metastasis. Oncogene 2017, 36, 5421–5431. [Google Scholar] [CrossRef] [Green Version]
  76. Le, P.T.; Cheng, H.; Ninkovic, S.; Plewe, M.; Huang, X.; Wang, H.; Bagrodia, S.; Sun, S.; Knighton, D.R.; Lafleur Rogers, C.M.; et al. Design and synthesis of a novel pyrrolidinyl pyrido pyrimidinone derivative as a potent inhibitor of PI3Kα and mTOR. Bioorg. Med. Chem. Lett. 2012, 22, 5098–5103. [Google Scholar] [CrossRef] [PubMed]
  77. Reddy, M.V.R.; Akula, B.; Jatiani, S.; Vasquez-Del Carpio, R.; Billa, V.K.; Mallireddigari, M.R.; Cosenza, S.C.; Venkata Subbaiah, D.R.C.; Bharathi, E.V.; Pallela, V.R.; et al. Discovery of 2-(1H-indol-5-ylamino)-6-(2,4-difluorophenylsulfonyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (7ao) as a potent selective inhibitor of Polo like kinase 2 (PLK2). Bioorg. Med. Chem. 2016, 24, 521–544. [Google Scholar] [CrossRef] [PubMed]
  78. Xu, X. Method for Preparation of Palbociclib. WO Patent 2016082604A1, 16 September 2016. [Google Scholar]
  79. Shu, Y. Process for Preparation of Compound for Inhibiting and Degrading Cdk. WO Patent 2019052535A1, 14 September 2019. [Google Scholar]
  80. Thomas, N.A.; Abraham, R.G.; Dedi, B.; Krucher, N.A. Targeting retinoblastoma protein phosphorylation in combination with EGFR inhibition in pancreatic cancer cells. Int. J. Oncol. 2019, 54, 527–536. [Google Scholar] [PubMed]
  81. Bronner, S.M.; Merrick, K.A.; Murray, J.; Salphati, L.; Moffat, J.G.; Pang, J.; Sneeringer, C.J.; Dompe, N.; Cyr, P.; Purkey, H.; et al. Design of a Brain-Penetrant CDK4/6 Inhibitor for Glioblastoma. Bioorg. Med. Chem. Lett. 2019. [Google Scholar] [CrossRef]
  82. Barvian, M.; Boschelli, D.H.; Cossrow, J.; Dobrusin, E.; Fattaey, A.; Fritsch, A.; Fry, D.; Harvey, P.; Keller, P.; Garrett, M.; et al. Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases. J. Med. Chem. 2000, 43, 4606–4616. [Google Scholar] [CrossRef]
  83. Kumar, B.V.S.; Lakshmi, N.; Kumar, M.; Rambabu, G.; Manjashetty, T.; Arunasree, K.; Sriram, D.; Ramkumar, K.; Neamati, N.; Dayam, R.; et al. Design, Synthesis and Screening Studies of Potent Thiazol-2-Amine Derivatives as Fibroblast Growth Factor Receptor 1 Inhibitors. Curr. Top. Med. Chem. 2014, 14, 2031–2041. [Google Scholar] [CrossRef]
  84. Shanmugasundaram, P.; Harikrishnan, N.; Aanandini, M.V.; Kumar, M.S.; Sateesh, J.N. Synthesis and biological evaluation of pyrido(2,3-d)pyrimidine-carboxylate derivatives. Indian J. Chem. Sect. B Org. Chem. Incl. Med. Chem. 2011, 50B, 284–289. [Google Scholar]
  85. Harutyunyan, A.A.; Panosyan, H.A.; Chishmarityan, S.G.; Tamazyan, R.A.; Ayvazyan, A.G. One-step synthesis of pyrido[2,3-d]pyrimidines, amides, and benzoxazolylethylpyrimidine by condensation of substituted 3-(2-phenylpyrimidin-5-yl)propanoic acids with aromatic amines in polyphosphoric acid. Russ. J. Org. Chem. 2015, 51, 357–360. [Google Scholar] [CrossRef]
  86. Wurz, R.P.; Pettus, L.H.; Ashton, K.; Brown, J.; Chen, J.J.; Herberich, B.; Hong, F.T.; Hu-Harrington, E.; Nguyen, T.; St. Jean, D.J.; et al. Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors. ACS Med. Chem. Lett. 2015, 6, 987–992. [Google Scholar] [CrossRef] [Green Version]
  87. Schoop, A.; Backes, A.; Vogt, J.; Neumann, L.; Eickhoff, J.; Hannus, S.; Hansen, K.; Amon, P.; Ivanov, I.; Borgmann, M.; et al. Preparation of pyrido[2,3-d]pyrimidin-7-one derivatives as Raf inhibitors for the treatment of cancer. Eur. Pat. Appl. 2009, 71. [Google Scholar]
  88. Kawai, H.; Murata, D.; Suzumura, Y. Preparation of 1-Hydroxypyrimido[4,5-d]Pyrimidin-2(1H)-One and 8-Hydroxypyrido[2,3-d]Pyrimidin-7(8H)-One Derivatives Having Anti-HIV Activity. WO Patent 2013115265A1, 30 January 2013. [Google Scholar]
  89. Allam, Y.A. Cyanoacetylurea in heterocyclic synthesis: Part III: Simple synthesis of uracil derivatives. Afinidad 2003, 60, 300–302. [Google Scholar]
  90. Duan, S.; Place, D.; Perfect, H.H.; Ide, N.D.; Maloney, M.; Sutherland, K.; Price Wiglesworth, K.E.; Wang, K.; Olivier, M.; Kong, F.; et al. Palbociclib Commercial Manufacturing Process Development. Part I: Control of Regioselectivity in a Grignard-Mediated SNAr Coupling. Org. Process. Res. Dev. 2016, 20, 1191–1202. [Google Scholar] [CrossRef]
  91. Reddy, M.V.R.; Akula, B.; Cosenza, S.C.; Athuluridivakar, S.; Mallireddigari, M.R.; Pallela, V.R.; Billa, V.K.; Subbaiah, D.R.C.V.; Bharathi, E.V.; Vasquez-Del Carpio, R.; et al. 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). J. Med. Chem. 2014, 57, 578–599. [Google Scholar] [CrossRef] [PubMed]
  92. Brookfield, F.; Eustache, F.; Dillon, M.P.; Goldstein, D.M.; Gong, L.; Han, X.; Hogg, J.H.; Park, J.; Reuter, D.C.; Sjogren, E.B. Preparation of Pyrimidinyl Pyridone as Therapeutic Inhibitors of JNK Kinases. U.S. Patent 20090270389A1, 29 April 2009. [Google Scholar]
  93. Cacciari, B.; Spalluto, G. Facile and versatile route to the synthesis of fused 2-pyridones: Useful intermediates for polycyclic sytems. Synth. Commun. 2006, 36, 1177–1183. [Google Scholar] [CrossRef]
  94. Qi, Y.; Wang, C.; Chen, J.; Ju, L.; Li, X. The method for preparing pabosaibu. Faming Zhuanli Shenqing 2015, 12. [Google Scholar]
  95. Victory, P.; Nomen, R.; Colomina, O.; Garriga, M.; Crespo, A. New synthesis of pyrido[2,3-d]pyrimidines. I. Reaction of 6-alkoxy-5-cyano-3,4-dihydro-2-pyridones with guanidine and cyanamide. Sect. Title Heterocycl. Compd. 1985, 23, 1135–1141. [Google Scholar] [CrossRef]
  96. Martinez-Teipel, B.; Teixido, J.; Pascual, R.; Mora, M.; Pujola, J.; Fujimoto, T.; Borrell, J.I.; Michelotti, E.L. 2-Methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles: Versatile Starting Materials for the Synthesis of Libraries with Diverse Heterocyclic Scaffolds. J. Comb. Chem. 2005, 7, 436–448. [Google Scholar] [CrossRef]
  97. Borrell, J.I.; Teixido, J.; Martinez-Teipel, B.; Serra, B.; Matallana, J.L.; Costa, M.; Batllori, X. An unequivocal synthesis of 4-amino-1,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-2,7-diones and 2-amino-3,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-4,7-diones. Collect. Czechoslov. Chem. Commun. 1996, 61, 901–909. [Google Scholar] [CrossRef]
  98. Mont, N.; Teixido, J.; Kappe, C.O.; Borrell, J.I. A one-pot microwave-assisted synthesis of pyrido[2,3-d]pyrimidines. Mol. Divers. 2003, 7, 153–159. [Google Scholar] [CrossRef]
  99. Berzosa, X.; Bellatriu, X.; Teixido, J.; Borrell, J.I. An Unusual Michael Addition of 3,3-Dimethoxypropanenitrile to 2-Aryl Acrylates: A Convenient Route to 4-Unsubstituted 5,6-Dihydropyrido[2,3-d]pyrimidines. J. Org. Chem. 2010, 75, 487–490. [Google Scholar] [CrossRef]
  100. Victory, P.; Crespo, A.; Garriga, M.; Nomen, R. New synthesis of pyrido[2,3-d]pyrimidines. III. Nucleophilic substitution on 4-amino-2-halo and 2-amino-4-halo-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones. J. Heterocycl. Chem. 1988, 25, 245–247. [Google Scholar] [CrossRef]
  101. Cobo, J.; García, C.; Melguizo, M.; Sánchez, A.; Nogueras, M. Reactivity of 6-aminopyrimidin-4(3H)-ones towards dimethyl acetylenedicarboxylate (DMAD). Tandem diels-alder/retro diels-alder (DA/RDA) reaction in the synthesis of 2-aminopyridines. Tetrahedron 1994, 50, 10345–10358. [Google Scholar] [CrossRef]
  102. Hines, J.; Fluharty, S.J.; Sakai, R.R. The angiotensin AT1 receptor antagonist irbesartan has near-peptide affinity and potently blocks receptor signaling. Eur. J. Pharmacol. 1999, 384, 81–89. [Google Scholar] [CrossRef]
  103. Jain, S.; Yadav, A. Ab initio study of non-peptidic antihypertensives. Chem. Biol. Drug Des. 2007, 69, 251–257. [Google Scholar] [CrossRef] [PubMed]
  104. Boschelli, D. Dual Inhibitors of Src and Abl Tyrosine Kinases. Drug Des. Rev. Online 2005, 1, 203–214. [Google Scholar] [CrossRef]
  105. Leijen, S.; H Beijnen, J.; HM Schellens, J. Abrogation of the G2 Checkpoint by Inhibition of Wee-1 Kinase Results in Sensitization of p53-Deficient Tumor Cells to DNA-Damaging Agents. Curr. Clin. Pharmacol. 2010, 5, 186–191. [Google Scholar] [CrossRef] [PubMed]
  106. Molina Vila, M.A.; Garcia Roman, S.; Borrell Bilbao, J.I.; Teixido Closa, J.; Estrada Tejedor, R.; Puig de la Bellacasa, R. Use of 4-Amino-6-(2,6-Dichlorophenyl)-8-Methyl-2-(Phenylamino)-Pyrido[2,3-d]Pyrimidin-7(8H)-One in Formulations for Treatment of Solid Tumors. EP Patent 3120851A1, 21 July 2017. [Google Scholar]
  107. Wishart, D.S.; Knox, C.; Guo, A.C.; Shrivastava, S.; Hassanali, M.; Stothard, P.; Chang, Z.; Woolsey, J. DrugBank: A comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res. 2006, 34, D668–D672. [Google Scholar] [CrossRef]
  108. Barvian, M.R.; Booth, R.J.; Quin, J., III; Repine, J.T.; Sheehan, D.J.; Toogood, P.L.; Vanderwel, S.N.; Zhou, H. Preparation of Pyrido[2,3-d]Pyrimidin-7-Ones as Cdk4 Inhibitors. WO Patent 2003062236A1, 10 January 2003. [Google Scholar]
  109. Beaver, J.A.; Amiri-Kordestani, L.; Charlab, R.; Chen, W.; Palmby, T.; Tilley, A.; Zirkelbach, J.F.; Yu, J.; Liu, Q.; Zhao, L.; et al. FDA approval: Palbociclib for the treatment of postmenopausal patients with estrogen receptor-positive, HER2-negative metastatic breast cancer. Clin. Cancer Res. 2015, 21, 4760–4766. [Google Scholar] [CrossRef]
  110. Rocca, A.; Schirone, A.; Maltoni, R.; Bravaccini, S.; Cecconetto, L.; Farolfi, A.; Bronte, G.; Andreis, D. Progress with palbociclib in breast cancer: Latest evidence and clinical considerations. Ther. Adv. Med. Oncol. 2017, 9, 83–105. [Google Scholar] [CrossRef] [Green Version]
  111. Cadoo, K.A.; Gucalp, A.; Traina, T.A. Palbociclib: An evidence-based review of its potential in the treatment of breast cancer. Breast Cancer Targets Ther. 2014, 6, 123–133. [Google Scholar]
  112. Cheresh, D.A.; Eliceiri, B.; Paul, R. Angiogenesis and Vascular Permeability Modulators and Inhibitors. WO Patent 2001045751A1, 22 December 2001. [Google Scholar]
  113. Adams, J.L.; Boehm, J.C.; Hall, R.; Jin, Q.; Kasparec, J.; Silva, D.J.; Taggart, J.J. Preparation of 2,4,8-Trisubstituted-8H-Pyrido[2,3-d]Pyrimidin-7-Ones as CSBP/RK/p38 Kinase Inhibitors. WO Patent 2002059083A2, 23 October 2002. [Google Scholar]
  114. Cheng, H.; Bhumralkar, D.; Dress, K.R.; Hoffman, J.E.; Johnson, M.C.; Kania, R.S.; Le, P.T.Q.; Nambu, M.D.; Pairish, M.A.; Plewe, M.B.; et al. Pyrido[2,3-d]Pyrimidinone Compounds as PI3 Inhibitors and Their Preparation, Pharmaceutical Compositions and Use in the Treatment of Abnormal Cell Growth. WO Patent 2008032162A1, 3 September 2008. [Google Scholar]
  115. Dong, Q.; Gong, X.; Kaldor, S.W.; Kanouni, T.; Scorah, N.; Wallace, M.B.; Zhou, F. Preparation of Phenylamino Pyridopyrimidinediones as MAPK/ERK Kinase Inhibitors. WO Patent 2008079814A2, 18 December 2008. [Google Scholar]
  116. Chen, J.J.; Dunn, J.P.; Goldstein, D.M.; Stahl, C.M. Preparation of 2,6-Disubstituted 7-Oxopyrido[2,3-d]Pyrimidines for Treating p38 Mediated Disorders. WO Patent 2002064594A2, 4 February 2002. [Google Scholar]
  117. Blankley, C.J.; Boschelli, D.H.; Doherty, A.M.; Hamby, J.M.; Klutchko, S.; Panek, R.L. Preparation of Pyrido[2,3-d]Pyrimidines as Protein Tyrosine Kinase Mediated Cell Proliferation Inhibitors. WO Patent 9634867A1, 26 April 1996. [Google Scholar]
  118. Baik, T.-G.; Buhr, C.A.; Lara, K.; Ma, S.; Wang, L.; Yeung, B.K.S. Preparation of Pyridopyrimidinone Derivatives as Inhibitors of PI3Kα. WO Patent 2007044698A1, 9 October 2006. [Google Scholar]
Molecules 24 04161 g001 550
Figure 1. Structures of the pyrido[2,3-d]pyrimidine ring system (1) and pyrido[2,3-d]pyrimidin-7(8H)-ones (2).
Figure 1. Structures of the pyrido[2,3-d]pyrimidine ring system (1) and pyrido[2,3-d]pyrimidin-7(8H)-ones (2).
Molecules 24 04161 g001
Molecules 24 04161 g002 550
Figure 2. Synthesis of 2,4-diamino-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (7) from 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles (5).
Figure 2. Synthesis of 2,4-diamino-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (7) from 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles (5).
Molecules 24 04161 g002
Molecules 24 04161 g003 550
Figure 3. Structure of palbociclib (8) approved for the treatment of breast cancer.
Figure 3. Structure of palbociclib (8) approved for the treatment of breast cancer.
Molecules 24 04161 g003
Molecules 24 04161 g004 550
Figure 4. Number of pyrido[2,3-d]pyrimidin-7(8H)-ones (2) retrieved using an undefined bond (9), double bond (10) and single bond (11) between C5 and C6, respectively.
Figure 4. Number of pyrido[2,3-d]pyrimidin-7(8H)-ones (2) retrieved using an undefined bond (9), double bond (10) and single bond (11) between C5 and C6, respectively.
Molecules 24 04161 g004
Molecules 24 04161 g005 550
Figure 5. Diversity analysis of the substituents present at positions C2, C4, C5, C6, and N8 of 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (11) included in Scifinder.
Figure 5. Diversity analysis of the substituents present at positions C2, C4, C5, C6, and N8 of 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (11) included in Scifinder.
Molecules 24 04161 g005
Molecules 24 04161 g006 550
Figure 6. Diversity analysis of the substituents present at positions C2, C4, C5, C6, and N8 of pyrido[2,3-d]pyrimidin-7(8H)-ones (10) included in Scifinder.
Figure 6. Diversity analysis of the substituents present at positions C2, C4, C5, C6, and N8 of pyrido[2,3-d]pyrimidin-7(8H)-ones (10) included in Scifinder.
Molecules 24 04161 g006
Molecules 24 04161 g007 550
Figure 7. Synthetic approaches for pyrido[2,3-d]pyrimidin-7(8H)-ones (2): (a) from a preformed pyrimidine and (b) from a preformed pyridone.
Figure 7. Synthetic approaches for pyrido[2,3-d]pyrimidin-7(8H)-ones (2): (a) from a preformed pyrimidine and (b) from a preformed pyridone.
Molecules 24 04161 g007
Molecules 24 04161 g008 550
Figure 8. Synthetic approach for pyrido[2,3-d]pyrimidin-7(8H)-ones (2) from a preformed 4-amino-5-bromopyrimidine (12).
Figure 8. Synthetic approach for pyrido[2,3-d]pyrimidin-7(8H)-ones (2) from a preformed 4-amino-5-bromopyrimidine (12).
Molecules 24 04161 g008
Molecules 24 04161 g009 550
Figure 9. Synthetic approach for pyrido[2,3-d]pyrimidin-7(8H)-ones (2) from a preformed N-substituted pyrimidine-4-amine (13) bearing a carbon functional group G.
Figure 9. Synthetic approach for pyrido[2,3-d]pyrimidin-7(8H)-ones (2) from a preformed N-substituted pyrimidine-4-amine (13) bearing a carbon functional group G.
Molecules 24 04161 g009
Molecules 24 04161 g010 550
Figure 10. Synthesis of the palbociclib intermediate 19 from 5-bromo-2,4-dichloropyrimidine (15).
Figure 10. Synthesis of the palbociclib intermediate 19 from 5-bromo-2,4-dichloropyrimidine (15).
Molecules 24 04161 g010
Molecules 24 04161 g011 550
Figure 11. Synthesis of the pyrido[2,3-d]pyrimidin-7(8H)-one (23) from pyrimidine aldehyde (20).
Figure 11. Synthesis of the pyrido[2,3-d]pyrimidin-7(8H)-one (23) from pyrimidine aldehyde (20).
Molecules 24 04161 g011
Molecules 24 04161 g012 550
Figure 12. Synthesis of the 5-hydroxy substituted pyrido[2,3-d]pyrimidin-7(8H)-one (26) from pyrimidine ester (24).
Figure 12. Synthesis of the 5-hydroxy substituted pyrido[2,3-d]pyrimidin-7(8H)-one (26) from pyrimidine ester (24).
Molecules 24 04161 g012
Molecules 24 04161 g013 550
Figure 13. Synthesis of the 5-amino substituted pyrido[2,3-d]pyrimidin-7(8H)-one (29) from the nitrile substituted pyrimidine (27).
Figure 13. Synthesis of the 5-amino substituted pyrido[2,3-d]pyrimidin-7(8H)-one (29) from the nitrile substituted pyrimidine (27).
Molecules 24 04161 g013
Molecules 24 04161 g014 550
Figure 14. Synthesis of the 4-chloro substituted pyrido[2,3-d]pyrimidin-7(8H)-one (33) from the chloro substituted pyrimidine aldehyde (30).
Figure 14. Synthesis of the 4-chloro substituted pyrido[2,3-d]pyrimidin-7(8H)-one (33) from the chloro substituted pyrimidine aldehyde (30).
Molecules 24 04161 g014
Molecules 24 04161 g015 550
Figure 15. Synthesis of the substituted pyrido[2,3-d]pyrimidin-7(8H)-one (41) from the pyrimidinone 35.
Figure 15. Synthesis of the substituted pyrido[2,3-d]pyrimidin-7(8H)-one (41) from the pyrimidinone 35.
Molecules 24 04161 g015
Molecules 24 04161 g016 550
Figure 16. Synthetic approaches for pyrido[2,3-d]pyrimidin-7(8H)-ones (2) from a preformed pyridone.
Figure 16. Synthetic approaches for pyrido[2,3-d]pyrimidin-7(8H)-ones (2) from a preformed pyridone.
Molecules 24 04161 g016
Molecules 24 04161 g017 550
Figure 17. Synthesis of the substituted pyrido[2,3-d]pyrimidin-7(8H)-one (44) from the pyridone 42.
Figure 17. Synthesis of the substituted pyrido[2,3-d]pyrimidin-7(8H)-one (44) from the pyridone 42.
Molecules 24 04161 g017
Molecules 24 04161 g018 550
Figure 18. Synthesis of 5,6-dihydropyrido[2,3-d]pyrimidin-7-(8H)-ones and pyrido[2,3-d]pyrimidin-7-(8H)-ones from α,β-unsaturated esters (45).
Figure 18. Synthesis of 5,6-dihydropyrido[2,3-d]pyrimidin-7-(8H)-ones and pyrido[2,3-d]pyrimidin-7-(8H)-ones from α,β-unsaturated esters (45).
Molecules 24 04161 g018
Molecules 24 04161 g019 550
Figure 19. Synthesis of 6-aryl-2-arylamino substituted 4-amino-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (59) from α,β-unsaturated esters (45).
Figure 19. Synthesis of 6-aryl-2-arylamino substituted 4-amino-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (59) from α,β-unsaturated esters (45).
Molecules 24 04161 g019
Molecules 24 04161 g020 550
Figure 20. Pyrido[2,3-d]pyrimidin-7(8H)-ones with nM biological activities as BCR kinase inhibitor (62), DDR2 inhibitor (63), and HCV NS5B polymerase inhibitor (64).
Figure 20. Pyrido[2,3-d]pyrimidin-7(8H)-ones with nM biological activities as BCR kinase inhibitor (62), DDR2 inhibitor (63), and HCV NS5B polymerase inhibitor (64).
Molecules 24 04161 g020
Molecules 24 04161 g021 550
Figure 21. Tasosartan (65).
Figure 21. Tasosartan (65).
Molecules 24 04161 g021
Molecules 24 04161 g022 550
Figure 22. Structures of pyrido[2,3-d]pyrimidin-7(8H)-ones (10) included in Drugbank which are in different phases of development.
Figure 22. Structures of pyrido[2,3-d]pyrimidin-7(8H)-ones (10) included in Drugbank which are in different phases of development.
Molecules 24 04161 g022
Table
Table 1. Substitution pattern at C2 and C4 of 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (11) with a C5-C6 single bond.
Table 1. Substitution pattern at C2 and C4 of 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (11) with a C5-C6 single bond.
Molecules 24 04161 i001
SubstituentG2G4
Structures (%)ReferencesStructures (%)References
H4.8722 [14,15]2.9648 [16,17]
C29.10335 [18,19]25.80317 [20,21]
N43.7880 [22,23]7.5357 [24,25]
O0.8825 [26,27]62.70317 [28,29]
S21.0218 [30,31]0-
Table
Table 2. Substitution pattern at C2 and C4 of pyrido[2,3-d]pyrimidin-7(8H)-ones (10) with a C5-C6 double bond.
Table 2. Substitution pattern at C2 and C4 of pyrido[2,3-d]pyrimidin-7(8H)-ones (10) with a C5-C6 double bond.
Molecules 24 04161 i002
SubstituentG2G4
Structures (%)ReferencesStructures (%)References
H5.48108 [32,33]78.101946 [34,35]
C3.8693 [36,37]17.42447 [38,39]
N75.552220 [40,41]2.2592 [42,43]
O2.4598 [44,45]1.8293 [27,46]
S9.84243 [47,48]0.053 [37,49]
Table
Table 3. Substitution pattern at N8 of 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (11) with a C5-C6 single bond and the pyrido[2,3-d]pyrimidin-7(8H)-ones (10) with a C5-C6 double bond.
Table 3. Substitution pattern at N8 of 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (11) with a C5-C6 single bond and the pyrido[2,3-d]pyrimidin-7(8H)-ones (10) with a C5-C6 double bond.
R8Structures 11 (%)ReferencesStructures 10 (%)References
H72.37[29,31]6.71[44,68]
Me2.62[42,69]15.48[70,71]
Et0.11[72,73]7.03[74,75]
Molecules 24 04161 i0030.29-0.84[76,77]
Molecules 24 04161 i0040.74[78,79]15.95[80,81]
Molecules 24 04161 i0050.04[73]0.78[82,83]
Ph0.77[84,85]15.01[62,86]
OR--5.52[87,88]
NR0.03[89]0.73[36,76]
Table
Table 4. Index terms in SciFinder for compounds 10 and 11.
Table 4. Index terms in SciFinder for compounds 10 and 11.
Compounds 11Compounds 10
Index TermFrequencyIndex TermFrequency
Human170Human1300
Antihypertensives150Antitumor agents1028
Hypertension120Mammary gland neoplasm535
Combination chemotherapy96Neoplasm523
Angiotensin II receptor antagonists95Combination chemotherapy503
Drug delivery systems90Piperazines385
Cardiovascular agents66Pyridines380
Diabetes mellitus62Signal transduction365
Heart failure61Cell proliferation346
Antitumor agents61Proteins345

Share and Cite

MDPI and ACS Style

Jubete, G.; Puig de la Bellacasa, R.; Estrada-Tejedor, R.; Teixidó, J.; Borrell, J.I. Pyrido[2,3-d]pyrimidin-7(8H)-ones: Synthesis and Biomedical Applications. Molecules 2019, 24, 4161. https://doi.org/10.3390/molecules24224161

AMA Style

Jubete G, Puig de la Bellacasa R, Estrada-Tejedor R, Teixidó J, Borrell JI. Pyrido[2,3-d]pyrimidin-7(8H)-ones: Synthesis and Biomedical Applications. Molecules. 2019; 24(22):4161. https://doi.org/10.3390/molecules24224161

Chicago/Turabian Style

Jubete, Guillem, Raimon Puig de la Bellacasa, Roger Estrada-Tejedor, Jordi Teixidó, and José I. Borrell. 2019. "Pyrido[2,3-d]pyrimidin-7(8H)-ones: Synthesis and Biomedical Applications" Molecules 24, no. 22: 4161. https://doi.org/10.3390/molecules24224161

Article Metrics

Back to TopTop