Review on the Synthesis and Therapeutic Potential of Pyrido[2,3- d], [3,2- d], [3,4- d] and [4,3- d]pyrimidine Derivatives

Abstract

The objective of this review is to list the structures composed of a pyridopyrimidine moiety which have shown a therapeutic interest or have already been approved for use as therapeutics. We consider all the synthetic protocols to prepare these pyridopyrimidine derivatives. The review is organized into four sections, successively pyrido[2,3-d]pyrimidines, pyrido[3,4-d]pyrimidines, pyrido[4,3-d]pyrimidines and pyrido[3,2-d]pyrimidines. For each compound we present the biological activity and the synthetic route reported. To produce this manuscript, the bibliographic research was done using Reaxys and Scifinder for each kind of pyridopyrimidine.

Keywords: N-heterocycles; biological activity; pyridopyrimidines; synthesis.

Figure 1

Various pyridopyrimidine structures types.

Figure 2

Examples of interesting molecules. Palbociclib: breast cancer drug developed by Pfizer and Dilmapimod: potential activity against rheumatoid arthritis.

Scheme 1

Synthesis of pyrido[2,3-d]pyrimidine-2,4-diamine (4) by Kisliuk et al. [6].

Scheme 2

Synthesis of pyrido[2,3-d]pyrimidine-2,4-diamine (9) by Kisliuk et al. [19].

Scheme 3

Synthesis of N6-[(2,5-dimethoxyphenyl)methyl]-N6-methylpyrido[2,3-d]pyrimidine-2,4,6-triamine (12) by Queener et al. [18].

Scheme 4

Synthesis of 6-[(2,5-dimethoxyphenyl)methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine (18) by Grivsky, Sigel et al. [24].

Scheme 5

Synthesis of 6-[(2,5-dimethoxyphenyl)methyl]-5-methylpyrido[2,3-d]pyrimidine-2-amine (28) by Chan and Rosowsky [21].

Scheme 6

Synthesis of 6-(2,6-dichlorophenyl)-2-([3-(hydroxymethyl)phenyl]amino)-8-ethyl-7H,8H-pyrido[2,3-d]pyrimidin-7-one (43) [25].

Scheme 7

Synthesis of 6-(2,6-dichlorophenyl)-8-methyl-2-([3-(methylsulfanyl)phenyl]amino)-7H,8H-pyrido [2,3-d]pyrimidin-7-one (47), PD-173955 [17].

Scheme 8

Synthesis of 6-(2,4-difluorophenoxy)-8-methyl-2-[(oxan-4-yl)amino]-7H,8H-pyrido[2,3-d]pyrimidin-7-one (58) [29].

Scheme 9

Synthesis of 3-[(2R)-2,3-dihydroxypropyl]-6-fluoro-5-[(2-fluoro-4-iodophenyl)amino]-8-methyl-3H,4H,7H,8H-pyrido[2,3-d]pyrimidine-4,7-dione (72) [33].

Scheme 10

Synthesis of 6-acetyl-8-cyclopentyl-5-methyl-2-([5-(piperazin-1-yl)pyridin-2-yl]amino)-7H,8H-pyrido[2,3-d]pyrimidin-7-one (88), Palbociclib [38].

Scheme 11

Synthesis of 3-(2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl)-N-methylbenzamide (99) [40].

Scheme 12

Synthesis of 8-(2,6-difluorophenyl)-2-[(1,3-dihydroxypropan-2-yl)amino]-4-(4-fluoro-2-methylphenyl)-7H,8H-pyrido[2,3-d]pyrimidin-7-one, Dilmapimod (110) [47].

Scheme 13

Synthesis of 2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)-7H,8H-pyrido[2,3-d]pyrimidin-7-one, Voxtalisib (123) [49].

Scheme 14

Synthesis of (5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (134), AZD8055 [51].

Scheme 15

6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-1H,2H-pyrido[2,3-d]pyrimidin-2-one (150), AMG-510 [56].

Scheme 16

Synthesis of 6-(2,6-dibromophenyl)pyrido[2,3-d]pyrimidine-2,7-diamine (159) [57].

Scheme 17

Synthesis of 6-(2,6-dimethoxyphenyl)pyrido[2,3-d]pyrimidine-2,7-diamine (161) [25,58].

Scheme 18

(2S)-2-[(4S)-4-carboxy-4-[(2S)-2-([hydroxy(([(2R,3S,4S)-2,3,4-trihydroxy-5-(8-hydroxy-2,4-dioxo-2H,3H,4H,10H-pyrimido[4,5-b]quinolin-1-yl)pentyl]oxy))phosphoryl]oxy)propanamido]butanamido]pentanedioic acid (179) [59].

Scheme 18

(2S)-2-[(4S)-4-carboxy-4-[(2S)-2-([hydroxy(([(2R,3S,4S)-2,3,4-trihydroxy-5-(8-hydroxy-2,4-dioxo-2H,3H,4H,10H-pyrimido[4,5-b]quinolin-1-yl)pentyl]oxy))phosphoryl]oxy)propanamido]butanamido]pentanedioic acid (179) [59].

Scheme 19

[(2E)-3-({4-[(3-bromo-4-chlorophenyl)amino]pyrido[3,4-d]pyrimidin-6-yl}carbamoyl)prop-2-en-1-yl]dimethyl[(1-methyl-4-nitro-1H-imidazol-5-yl)methyl]azanium (194) [61].

Scheme 20

N8-(2,2-dimethylpropyl)-N2-[2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine (200), BOS172722 [62].

Scheme 21

Synthesis of N-(3-(3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-1H,2H,3H,4H,6H,7H-pyrido[4,3-d]pyrimidin-1-yl)phenyl)acetamid, Trametinib (209) [69].

Scheme 22

Synthesis of 3-[8-chloro-3-[(1R)-2,2,2-trifluoro-1-([pyrido[3,2-d]pyrimidin-4-yl]amino)ethyl]quinolin-2-yl]pyridin-1-ium-1-olate (229) [71].

Scheme 23

(2S)-2-([2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl]amino)-2-methylhexan-1-ol (233) [73].

Scheme 24

Synthesis of (2S)-2-((4-[(2E)-N-((2-amino-4-oxo-1H,4H-pyrido[3,2-d]pyrimidin-6-yl)methyl)-3-{4-carbamoyl-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(phosphonooxy)methyl]oxolan-2-yl]-1H-imidazol-5-yl)prop-2-enamido]phenyl)formamido)pentanedioic acid (238) [74].