CN109422749B - Pyrimidinedione derivative for inhibiting monocarboxylic acid transporter - Google Patents

Pyrimidinedione derivative for inhibiting monocarboxylic acid transporter Download PDF

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CN109422749B
CN109422749B CN201710716695.7A CN201710716695A CN109422749B CN 109422749 B CN109422749 B CN 109422749B CN 201710716695 A CN201710716695 A CN 201710716695A CN 109422749 B CN109422749 B CN 109422749B
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methyl
pyrimidine
pyrrolo
dihydro
carbonyl
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CN109422749A (en
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徐立炎
廖勇
刘才平
雷皇书
邓杰
邹艳冶
雷文波
周昌兵
何志琴
吴坤灿
袁泉
樊斌
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Chongqing Pharmaceutical Research Institute Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The present invention relates to pyrimidinedione derivatives that inhibit a monocarboxylic acid transporter, which are compounds of formula (I) and/or pharmaceutically acceptable salts thereof, and/or stereoisomers thereof, and/or solvates thereof, which compounds have monocarboxylic acid transporter inhibiting activity, pharmaceutical compositions containing the compounds of formula (I) and their use in therapy.

Description

Pyrimidinedione derivative for inhibiting monocarboxylic acid transporter
Technical Field
The present invention relates to a class of compounds and/or pharmaceutically acceptable salts capable of inhibiting the activity of monocarboxylate transporters (MCT 1 s), pharmaceutical compositions containing them and their use in therapy, such as cancer and autoimmune diseases.
Background
Monocarboxylic acid transporters (MCTs) are a class of transmembrane transporters widely distributed in the human cell membrane, a family of proteins that transport lactic acid and other small monocarboxylic acids, and are important for cellular glycolytic metabolism, particularly lactate metabolism. Upon activation of T lymphocytes or cancer cells, MCT1 expression is rapidly upregulated to meet the requirement for lactate efflux due to increased glycolysis rates. MCT1 inhibitors inhibit feedback from glycolysis by blocking lactate transport, leading to intracellular accumulation of lactic acid, ultimately rendering rapid cell division untenable. Therefore, the inhibitor has the functions of immunosuppression and cancer resistance.
Among current MCT1 inhibitors, aslicon, inc. developed AZD-3965, which is a selective inhibitor of MCT1, and has entered clinical phase I trials for lymphoma treatment. The chemical structural formula is shown as follows.
Figure 726742DEST_PATH_IMAGE001
。
MCT1 inhibition is an attractive therapeutic approach, and there is a need to develop MCT1 inhibitors that have advantages in at least one of therapeutic efficacy, stability, selectivity, safety, pharmacodynamic or pharmacokinetic properties. Thus, a novel MCT1 inhibitor is provided.
Disclosure of Invention
The present invention has various embodiments, one embodiment of which provides at least one compound of formula (I), and/or a pharmaceutically acceptable salt, and/or a stereoisomer, and/or a solvate thereof.
Figure 526070DEST_PATH_IMAGE002
。
Wherein:
a is selected from aryl and heteroaryl;
R 1 selected from hydrogen, C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 4-14 Heterocyclic group, C 4-14 Heterocyclyl radical C 1-6 Alkyl radical, C 6-14 Aryl radical, C 6-14 Aryl radical C 1-6 Alkyl radical, C 5-14 Heteroaryl group, C 5-14 Heteroaryl C 1-6 Alkyl, wherein each of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstitutedSubstituted or substituted by at least one, such as 1,2 or 3, W groups;
R 2 selected from hydrogen, C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 4-14 Heterocyclic group, C 4-14 Heterocyclyl radical C 1-6 Alkyl radical, C 6-14 Aryl radical, C 6-14 Aryl radical C 1-6 Alkyl radical, C 5-14 Heteroaryl group, C 5-14 Heteroaryl C 1-6 Alkyl, wherein each of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted with at least one, such as 1,2 or 3, groups W;
each R 3 Each independently selected from halogen, C 1-6 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-10 Cycloalkoxy, C 1-6 Alkylamino radical, C 3-10 Cycloalkylamino, C 4-14 Heterocyclic group, C 4-14 Heterocyclyl radical C 1-6 Alkyl radical, C 6-14 Aryl radical, C 6-14 Aryl radical C 1-6 Alkyl radical, C 5-14 Heteroaryl group, C 5-14 Heteroaryl C 1-6 Alkyl, -NR a R b 、-S(CR a R b ) r CR a R b 、-S(CR a R b ) r C(O)R a 、-S(CR a R b ) r NR c R d 、-S(CR a R b ) r C(O)NR c R d 、-S(O) r (CR a R b ) r NR c R d 、-S(O) r O(CR a R b ) r NR c R d 、-C(O) (CR a R b ) r NR c R d 、-(CR a R b ) r NR c R d 、-OC(O) NR c R d 、-C(O)O(CR a R b ) r NR c R d Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylamino, heterocyclyl, aryl, heteroaryl is independently unsubstituted orSubstituted by at least one, such as 1,2,3 or 4, W group;
each R 4 Each independently selected from halogen, C 1-6 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-10 Cycloalkoxy, C 1-6 Alkylamino radical, C 3-10 Cycloalkylamino, C 4-14 Heterocyclic group, C 4-14 Heterocyclyl radical C 1-6 Alkyl radical, C 6-14 Aryl radical, C 6-14 Aryl radical C 1-6 Alkyl radical, C 5-14 Heteroaryl group, C 5-14 Heteroaryl C 1-6 Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylamino, heterocyclyl, aryl, heteroaryl is each unsubstituted or substituted with at least one, such as 1,2,3 or 4, W group;
each R 5 And R 6 Independently selected from hydrogen, halogen, C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one, such as 1,2 or 3, W groups;
or R 5 And R 6 Together with the C atom to which they are attached form a 3-7 membered ring containing 0, 1 or 2 heteroatoms independently selected from O, S and N, and optionally substituted with 0, 1,2 or 3W;
each R a 、R b 、R c And R d Each independently selected from hydrogen, hydroxy, halogen, C 1-6 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-10 Cycloalkoxy, C 1-6 Alkylamino radical, C 3-10 Cycloalkylamino, C 4-14 Heterocyclic group, C 4-14 Heterocyclyl radical C 1-6 Alkyl radical, C 6-14 Aryl radical, C 6-14 Aryl radical C 1-6 Alkyl radical, C 5-14 Heteroaryl group, C 5-14 Heteroaryl C 1-6 Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkaneOxy, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one, such as 1,2,3 or 4, W groups;
or, each "R a And R b ”、“R c And R d "together with the N atom to which they are attached form a 4-12 membered ring which also contains 0, 1 or 2 further heteroatoms independently selected from O, S and N, and which is optionally substituted with 1,2 or 3W groups;
each W is independently selected from hydrogen, nitro, cyano, amino, hydroxy, carboxy, halogen, oxo, thio, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-8 Cycloalkyl radical, C 1-6 Alkylamino radical, C 3-8 Cycloalkylamino group, (C) 1-6 Alkyl radical) 2 Amino, halogeno C 1-6 Alkyl, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxyalkyl group, C 2-6 Alkanoyl radical, C 1-6 Alkylthio radical, C 1-6 Alkoxycarbonyl group, C 1-6 Alkylsulfonyl radical, C 1-6 Alkylsulfinyl, carbamoyl, C 1-6 Alkylcarbamoyl, di- (C) 1-6 Alkyl) carbamoyl, C 2-8 Alkenyl and C 2-8 An alkynyl group;
m is selected from 1,2 and 3;
n is selected from 1,2 and 3;
r is selected from 0, 1,2 and 3.
In another embodiment, a pharmaceutical composition is provided, which comprises at least one compound of formula (I), and/or a pharmaceutically acceptable salt thereof, and/or a stereoisomer thereof, and/or a solvate thereof, in a pharmaceutical formulation in any pharmaceutically acceptable dosage form, together with one or more pharmaceutically acceptable carriers and/or diluents.
In another embodiment, there is provided a pharmaceutically acceptable dosage form comprising at least one compound of formula (I), and/or a pharmaceutically acceptable salt thereof, and/or a stereoisomer thereof, and/or a solvate thereof, together with one or more pharmaceutically acceptable carriers and/or diluents.
In another embodiment, there is provided a method of immunosuppression comprising administering to a patient a therapeutically effective amount of at least one compound of formula (I), and/or a pharmaceutically acceptable salt thereof, and/or a stereoisomer thereof, and/or a solvate thereof.
Alternatively, there is provided the use of at least one compound of formula (I) and/or a pharmaceutically acceptable salt thereof, and/or a stereoisomer thereof, and/or a solvate thereof, for the manufacture of a medicament for immunosuppression.
In another embodiment, a method of inhibiting cancer cells is provided comprising administering to a patient a therapeutically effective amount of at least one compound of formula (I), and/or a pharmaceutically acceptable salt thereof, and/or a stereoisomer thereof, and/or a solvate thereof.
Alternatively, there is provided the use of at least one compound of formula (I) and/or a pharmaceutically acceptable salt thereof, and/or a stereoisomer thereof, and/or a solvate thereof, for the manufacture of a medicament for inhibiting cancer cells.
In another embodiment, there is provided a method of treating and reducing the risk of an obstructive airways disease in a patient that is at risk of the obstructive airways disease in a patient that comprises administering to the patient a therapeutically effective amount of at least one compound of formula (I), and/or a pharmaceutically acceptable salt thereof, and/or a stereoisomer thereof, and/or a solvate thereof.
Alternatively, there is provided the use of at least one compound of formula (I) and/or a pharmaceutically acceptable salt thereof, and/or a stereoisomer thereof, and/or a solvate thereof, for the manufacture of a medicament for the treatment of an obstructive airways disease and for reducing the risk of an obstructive airways disease in a patient at risk.
Definition of terms
In order to make the objects, technical solutions and advantages of the embodiments more clear, the technical solutions of the embodiments are described below clearly and completely. It should be apparent that the described embodiments are only some of the embodiments of the present invention, and not all of them. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention without any inventive step, are within the scope of protection of the invention.
The "halogen" includes fluorine atom, chlorine atom, bromine atom and iodine atom.
The "alkyl group" means a straight chain or branched alkyl group derived from an alkane having 1 to 18 carbon atoms partially removed one hydrogen atom, and examples thereof include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 5364 zxft 64-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimetylpropyl, 3525-trimethylpropyl, 1-ethyl-1-methylpropyl, and 1-ethylpropyl, and the like. The term "C 1-18 Alkyl group "," C 1-6 Alkyl group and C 1-4 Alkyl group "," C 1-3 Alkyl "refers to the specific examples containing 1 to 18, 1 to 6, 1 to 4, 1 to 3 carbon atoms in the above examples.
The "alkenyl group" means a straight-chain or branched-chain or cyclic alkenyl group having 2 to 8 carbon atoms and containing at least one double bond, and includes, for example, "C 2-8 Alkenyl group, "C 2-6 Alkenyl group "," C 2-4 Alkenyl group "," C 2-3 Alkenyl group and C 3-6 Cycloalkenyl ", and the like, examples include, but are not limited to: vinyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 2-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 2-pentenyl, and the like 1-methyl-2-pentenyl, 3-methyl-2-pentenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-1-butenyl, 2-ethyl-1-butenyl, 2-ethylhexyleneThe group consisting of 3-butenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 4-octenyl, 1,3-butadienyl, 2,4-pentadienyl, 1,4-hexadienyl, 2,4-hexadienyl, 1,5-heptadienyl, 2,5-heptadienyl, 2,6-octadienyl, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadienyl, cycloheptenyl, 1,4-cycloheptadienyl, cyclooctenyl, and the like. The term "C 2-4 The alkenyl group "means a specific example having 2 to 4 carbon atoms among the above examples.
The "alkynyl" refers to a straight chain or branched alkynyl group having 2 to 8 carbon atoms and containing a triple bond, and includes, for example, "C 2-8 Alkynyl group "," C 2-6 Alkynyl group "," C 2-4 Alkynyl group "," C 2-3 Alkynyl "and the like, examples include but are not limited to: ethynyl, 1-propynyl, 2-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1,1-dimethyl-3-butynyl, 2-ethyl-3-butynyl, 2-heptynyl, 3-heptynyl, 4-methyl-2-hexynyl, 5-methyl-2-hexynyl, 2-methyl-3-hexynyl, 5-methyl-3-hexynyl, 2-methyl-4-hexynyl, 4-methyl-5-hexynyl, 2-octynyl, 3-octynyl, 4-methyl-2-heptynyl, 5-methyl-3-heptynyl, 6-methyl-3-heptynyl, 2-methyl-3-heptynyl, 6-methyl-3-heptynyl, and the like. The term "C 2-4 Alkynyl "refers to the specific examples containing 2 to 4 carbon atoms in the above examples.
Said "C 3-8 Cycloalkyl "refers to a cyclic alkyl group derived from an alkane moiety of 3 to 8 carbon atoms with one hydrogen atom removed, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
"C" according to the invention 6-14 Aryl "means an aromatic cyclic group having 6 to 14 carbon atoms, specifically, for example, benzene, pentalene, indene, naphthalene, cyclopenta cycloheptatriene, heptatriene, biphenylene, benzindene, acenaphthylene, fluorene, and the like,phenalene, phenanthrene, anthracene, and the like.
Said "C 5-14 The heteroaryl group is an aromatic cyclic group having 5 to 14 ring atoms, and the atomic species of the ring constituting the cyclic group include 1 or more heteroatoms such as nitrogen atom, sulfur atom and oxygen atom. Specifically, nitrogen-containing aromatic heterocyclic rings such as a pyrrole ring, a pyridine ring, a pyridone ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a pyrazole ring, an imidazole ring, a triazole ring, a tetrazole ring, an indole ring, an isoindole ring, a indolizine ring, a purine ring, an indazole ring, a quinoline ring, an isoquinoline ring, a quinoline ring, a phthalazine ring, a naphthyridine ring, a quinoxaline ring, a quinazoline ring, a cinnoline ring, a pteridine ring, an imidazopyridine ring, an imidazotriazine ring, a pyrazinopyridazine ring, an acridine ring, a phenanthridine ring, a carbazolyl ring, a hexahydrocarbazolyl ring, a perimidine ring, a phenanthroline ring, a phenazine ring, an oxadiazole ring, a benzimidazole, a pyrrolopyridine ring, a pyrrolopyrimidine ring, and a pyridopyrimidine ring; sulfur-containing aromatic heterocycles such as a thiophene ring and a benzothiophene ring; oxygen-containing aromatic heterocycles such as furan ring, pyran ring, cyclopentapyrane ring, benzofuran ring and isobenzofuran ring; an aromatic heterocyclic ring containing 2 or more heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as a thiazole ring, a thiadiazole ring, an isothiazole ring, a benzothiazole ring, a benzothiadiazole ring, a phenothiazine ring, an isoxazole ring, a phenazine ring, a pyrazolozole ring, an imidazothiazole ring, a thienofuran ring, a furopyrrole ring, a pyridooxazine ring, a furopyridine ring, a furopyrimidine ring, a thienopyrimidine ring and an oxazole ring.
Said "C" is 4-14 The heterocyclic group "means a non-aromatic cyclic group in which the number of atoms constituting the ring of the cyclic group is 4 to 14 and the kind of atoms constituting the ring of the cyclic group includes at least 1 hetero atom such as a nitrogen atom, a sulfur atom and an oxygen atom. Specifically, for example, pyrrolidinyl, pyrrolinyl, piperidyl, piperazinyl, N-methylpiperazinyl, imidazolinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl, oxathiolanyl (oxathiolanyl), pyridone ring, 2-pyrrolidone ring, ethyleneurea ring1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, phthalimide ring, succinimide ring and other non-aromatic heterocyclic groups.
The "hetero atom" is specifically exemplified by oxygen atom, sulfur atom, nitrogen atom, phosphorus, arsenic, antimony, silicon, germanium, tin, lead, boron, mercury, etc.
Said "C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, (C) 1-6 Alkyl radical) 2 Amino group, C 1-6 Alkylthio radical, C 1-6 Alkylcarbonyl group, C 1-6 Alkylsulfonylamino group, C 1-6 Alkylaminosulfonyl, (C) 1-6 Alkyl radical) 2 Aminosulfonyl radical, C 1-6 Alkylsulfonyl radical, C 1-6 Alkylcarbonyloxy "means substituted with C 1-6 alkyl-O-, C 1-6 alkyl-NH-, (C) 1-6 Alkyl radical) 2 -N-、C 1-6 alkyl-S-, C 1-6 alkyl-C (O) -, C 1-6 alkyl-SO 2 NH-、C 1-6 alkyl-NHSO 2 -、（C 1-6 Alkyl radical) 2 -NSO 2 -、C 1-6 alkyl-SO 2 -、C 1-6 Radicals formed by alkyl-C (O) -O-systems, in which "C" is 1-6 Alkyl "is as defined above.
Said "halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl, hydroxy C 2-8 Alkenyl, carboxyl C 2-8 Alkenyl, hydroxy C 2-8 Alkynyl, carboxyl C 2-8 Alkynyl, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkoxy, hydroxy C 1-6 Alkylamino "means one to more than one, e.g., 1-4, 1-3, 1-2 halogen atoms, hydroxy, amino, carboxy, C 1-6 Alkoxy radicals each being substituted for C 1-6 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 1-6 Alkoxy radical, C 1-6 A group formed by a hydrogen atom in an alkylamino group.
Said "C 1-6 Alkoxy "means" C "as defined above 1-6 Alkyl radical'Examples of the substituent resulting from the combination with an oxygen atom include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, n-pentoxy, i-pentoxy, sec-pentoxy, t-pentoxy, neopentoxy, 1-methylbutoxy, 2-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, n-hexoxy, i-hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 1,1-dimethylbutoxy, 4232-dimethylbutoxy, 2,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 3579-trimethylpropoxy, 3525-trimethylpropoxy, 1-methylpropoxy, methyl-1-methylpropoxy, and the like.
Said "C 1-6 Alkoxycarbonyl "means a radical which is identical to the above-mentioned" C 1-6 Alkoxy "bonded carbonyl, examples include but are not limited to methoxy carbonyl, ethoxy carbonyl, n-propoxy carbonyl, i-propoxy carbonyl, sec-propoxy carbonyl, n-butoxy carbonyl, i-butoxy carbonyl, 1,2-two methyl propoxy carbonyl, 2-ethyl propoxy carbonyl.
Said "halo C 1-6 Alkyl "means C substituted by at least one halogen 1-6 An alkyl group; in particular, monohaloalkyl, dihaloalkyl, trihaloalkyl, examples of which include but are not limited to: fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
Said "halo C 1-6 Alkoxy "means C substituted by at least one halogen 1-6 An alkoxy group; examples include, but are not limited to, fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, and fluoropropoxy.
Said "hydroxy group C 1-6 Alkyl "refers to an alkyl group substituted with at least one hydroxyl group, examples of which include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropylHydroxy-butyl, dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2, 3-hydroxybutyl, 3,4-hydroxybutyl and 2- (hydroxymethyl) hydroxy-propyl.
Said "C 2-6 Alkanoyl "is a group derived from an aliphatic carboxylic acid having 2 to 6 carbon atoms, examples of which include, but are not limited to, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, and the like.
The term "n-" refers to a primary or normal chain substituent, "sec-" refers to a secondary substituent, "t-" refers to a tertiary substituent, and "i-" refers to a heterochain substituent.
The salts used in the pharmaceutical composition are pharmaceutically acceptable salts, but other salts may be used to produce the compound of formula (1) and pharmaceutically acceptable salts thereof. For example, pharmaceutically acceptable salts of the invention include acid addition salts of the compounds of formula (1) as defined above, which compounds of formula (1) are sufficiently basic to form said acid addition salts. Such acid addition salts include, for example, salts with inorganic or organic acids which provide pharmaceutically acceptable anions, for example, salts with hydrogen halides (particularly hydrochloric or hydrobromic acids, with hydrochloric acid being particularly preferred), sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid or maleic acid. Suitable salts include hydrochloride, hydrobromide, phosphate, sulphate, bisulphate, alkylsulphonate, arylsulphonate, acetate, benzoate, citrate, maleate, fumarate, succinate, lactate and tartrate salts. In addition, when the compounds of formula (I) are sufficiently acidic, pharmaceutically acceptable salts may be formed with inorganic or organic bases which provide pharmaceutically acceptable cations. Such salts with inorganic or organic bases include, for example, alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts or salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine, for example.
Preferred salts include acid addition salts, for example, the hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citric acid, oxalate, methanesulfonate or p-toluenesulfonate salts or alkali metal salts, such as sodium or potassium salts.
When the compound of the present invention is a base, it is necessary to prepare a salt thereof with at least one pharmaceutically acceptable non-toxic acid selected from inorganic and organic acids. For example, selected from acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid. In some embodiments, these acids may be selected, for example: citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid, tartaric acid.
"leaving group" means a group well known in the art, see, for example, "Advanced organic chemistry", "Jersey Ma Ji (Jerry March), 5th edition, pages 351-357, john Wiley parent-publishing company (John Wiley and Sons), new York (N. Y). The leaving group includes, but is not limited to, halogen, alkoxy, sulfonyloxy, optionally substituted alkylsulfonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, and diazo moieties. Examples of suitable leaving groups include chloro, iodo, bromo, fluoro, acetoxy, methanesulfonyloxy (methanesulfonyloxy), toluenesulfonyloxy, trifluoromethanesulfonyloxy, nitro-phenylsulfonyloxy (nitrobenzenesulfonyloxy), and bromo-phenylsulfonyloxy (bromobenzenesulfonyloxy).
"protecting group" (Pg) refers to a class of substituents used to block or protect a particular functional group by reacting with other functional groups on a compound. For example, "amino protecting group" refers to a substituent attached to an amino group that blocks or protects the amino functionality on a compound. Suitable amino protecting groups include acetyl, trifluoro, tert-Butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyl chloroformate (Fmoc). Similarly, "hydroxy protecting group" refers to a class of hydroxy substituents that are effective in blocking or protecting the hydroxy function. Suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to a class of carboxy substituents that function effectively to block or protect a carboxy group. Common carboxyl protecting groups include-CH 2CH2SO2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonamide) ethyl, 2- (p-nitrophenylthio) ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like. For general description and instructions for use of protecting groups, see references: greene, protective Groups in Organic Synthesis, john Wiley & Sons, new York,1991.
The "composition" includes: the invention may take the form of a kit, article of manufacture, or any combination thereof. The pharmaceutical composition comprises: products comprising the active ingredient and an inert ingredient as a carrier, as well as products produced by any two or more of the ingredients, directly or indirectly, by combination, complexation or aggregation, or by dissociation of one or more of the ingredients, or by other types of reactions or interactions of one or more of the ingredients.
By "administering" or "administering" at least one compound and/or at least one pharmaceutically acceptable salt thereof is meant providing at least one compound and/or at least one pharmaceutically acceptable salt thereof to an individual in need of treatment.
The terms "treating", "treating" and "treatment" refer to a method of reducing or eliminating a disease and/or its attendant symptoms.
The terms "preventing", "preventing" and "prevention" refer to a method of preventing the occurrence of a disease and/or its attendant symptoms (onset), or preventing a subject from suffering from a disease. As used herein, "preventing" and "prevention" also include delaying the onset of a disease and/or its attendant symptoms and reducing the risk of a subject suffering from a disease.
An "effective amount" is an amount of at least one compound and/or at least one pharmaceutically acceptable salt thereof that is capable of eliciting a biological or medical response in a cell, tissue, system, animal or human that is observable by a researcher, veterinarian, clinician, or other clinician.
By "pharmaceutically acceptable" is meant compatible with the other ingredients of the formulation and not unacceptably toxic to the user.
The term "modulate" refers to the ability of a compound to increase or decrease the function or activity of a kinase. As used herein, various forms of "modulation" include antagonism, agonism, partial antagonism and/or partial agonism of the activity associated with the kinase. Kinase inhibitors are compounds that, for example, partially or completely block stimulation, reduce, prevent, delay activation, inactivate, or down regulate signal transduction. Kinase activators are compounds that, for example, stimulate, increase, open, activate, promote, increase activation, sensitize or up regulate signal transduction.
The term "composition" as used herein includes a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant that the carrier, diluent or excipient must not be incompatible with the other ingredients of the formulation and not deleteriously affect the recipient thereof.
As defined herein, a "patient" includes an animal, such as a mammal, including but not limited to: primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like. In a preferred embodiment, the patient is a human.
Compound (I)
Geometric isomers may be present in the compounds of the present invention. The compounds of the present invention may contain carbon-carbon double bonds or carbon-nitrogen double bonds in either the E or Z configuration, where the term "E" indicates that the substituents in higher order are on opposite sides of a carbon-carbon or carbon-nitrogen double bond and the term "Z" indicates that the substituents in higher order are on the same side of a carbon-carbon or carbon-nitrogen double bond, as determined according to Cahn-Ingold-Prelog priority rules. The compounds of the invention may also exist as mixtures of "E" and "Z" isomers. Substituents around a cycloalkyl or heterocycloalkyl group may also be referred to as being in the cis or trans configuration.
The compounds of the invention may contain asymmetrically substituted carbon atoms in the R or S configuration, where the terms "R" and "S" are as defined in IUPAC 1974 for part E, the basic stereochemistry recommended, pure Appl. chem. (1976) 45, 13-10. Compounds with asymmetrically substituted carbon atoms and with the same number of R and S configurations are racemic at those carbon atoms. An excess of atoms in one configuration relative to another is referred to as a configuration present in a higher amount, preferably a configuration present in an excess of about 85% to 90%, more preferably about 95% to 99%, and still more preferably a higher amount greater than about 99%. Thus, the present invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.
The compounds of formula (I) may contain one or more asymmetrically substituted atoms. The compounds of formula (I) may also exist as individual stereoisomers (including enantiomers and diastereomers) and mixtures thereof. The individual stereoisomers of the compounds of formula (I) may be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers or by preparing racemic mixtures and then resolving the individual stereoisomers using methods known to those of ordinary skill in the art. Examples of resolution are, for example, (i) linking of enantiomeric mixtures with chiral auxiliary substances, separation of the resulting diastereomeric mixtures by recrystallization or chromatography, followed by liberation of the optically pure product; or (ii) separating a mixture of enantiomers or diastereomers on a chiral chromatography column.
The compounds of formula (I) may also include various geometric isomers and mixtures thereof resulting from the placement of substituents around a carbon-carbon double bond, a carbon-nitrogen double bond, a cycloalkyl group, or a heterocycloalkyl group. Substituents around a carbon-carbon double bond or a carbon-nitrogen double bond are referred to as Z or E configuration, and substituents around a cycloalkyl or heterocycloalkyl are referred to as cis or trans configuration.
Within the present invention, it is understood that the compounds disclosed herein may exhibit tautomerism and that all tautomers are included within the scope of the present invention.
Thus, the general formula within this specification may represent only one of the possible tautomeric, geometric or stereoisomeric forms, it being understood that the invention encompasses any tautomeric, geometric or stereoisomeric form and mixtures thereof and should not be limited only to any one tautomeric, geometric or stereoisomeric form used within the general formula.
Isotopically enriched or labelled compounds
The compounds of the present invention may exist in isotopically-labeled or-enriched forms, containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. The isotope may be a radioactive or non-radioactive isotope. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to, 2 H、 3 H、 13 C、 14 C、 15 N、 18 O、 32 P、 35 S、 18 F、 36 cl and 125 I. compounds containing other isotopes of these and/or other atoms are within the scope of this invention.
In another embodiment, the isotopically-labeled compound comprises deuterium (b) 2 H) Tritium (a) 3 H) Or 14 Isotope of C. Isotopically-labeled compounds of the present invention can be prepared by conventional methods well known to those skilled in the art. The steps disclosed in the examples and Schemes (Schemes) disclosed herein may be conveniently carried out by substituting a readily available isotopically labeled reagent for the unlabeled reagent to prepare such isotopically labeled compounds. In some cases, the compound may be treated with an isotopically-labeled reagent to exchange a normal atom for its isotope, e.g., by deuterium acid, such as D 2 SO 4 /D 2 By the action of O, hydrogen can be exchanged for deuterium. In addition to the above, for example, in Lizondo, J et al, drugs Fut,21 (11), 1116 (1996); brickner, S J et al, J Med Chem,39 (3), 673 (1996); mallesham, B et al, org Lett,5 (7), 963 (2003); PCT publications WO1997010223, WO2005099353, WO1995007271, WO2006008754; U.S. patent nos. 7538189;7534814;7531685;7528131;7521421;7514068;7511013; and U.S. patent application publication nos. 20090137457;20090131485;20090131363;20090118238;20090111840;20090105338;20090105307;20090105147;20090093422;20090088416; and 20090082471, which methods are incorporated herein by reference.
Isotopically-labeled compounds of the present invention are useful as standards for determining the efficacy of BET bromodomain inhibitors in binding assays. Isotopically-containing compounds have been used in pharmaceutical research to study the in vivo metabolic fate of the parent non-isotopically-labelled compound by assessing the mechanism of action and metabolic pathways of the compound (Blake et al, j. Pharm. Sci. 64,3, 367-391 (1975)). Such metabolic studies are important in the design of safe and effective therapeutic drugs because the active compound administered to the patient in vivo or because metabolites produced by the parent compound have been shown to be toxic or carcinogenic (Foster et al, advances in Drug Research Vol. 14, pages 2-36, academic press, london,1985, kato et al, J. Labelled Comp. Radiopharmaceut.,36 (10): 927-932 (1995); kushner et al, can. J. Physiol. Pharmacol.,77, 79-88 (1999)).
In addition, non-radioisotope containing drugs, such as deuterated drugs known as "heavy drugs," can be used to treat diseases and conditions associated with BET bromodomain activity. Increasing the amount of isotope present in a compound above its natural abundance is referred to as enrichment. Examples of enrichment amounts include from about 0.5, 1,2,3,4, 5,6,7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96 to about 100 mole%. The lowest side effects have been observed in mammals, including rodents and canines, during which up to about 15% of normal atoms have been replaced with heavy isotopes and maintained for days to weeks (Czajka D M and Finkel a J, ann. N.y. Acad. Sci. 1960 84 770. Acute replacement of deuterium by up to 15-23% in human body fluids has not been found to cause toxicity (Blagojevic N et al in "Dosimetry & Treatment Planning for Neutron Capture Therapy", zamenhof R, solares G and Harling O eds. 1994. Advanced Medical Publishing, madison Wis. Pp. 125-134; diabetes metals. 251. 23 (1997)).
The stable isotope labeling of the drug can change its physicochemical properties such as pKa and lipid solubility. If isotopic substitutions act on regions involved in ligand-receptor interactions, these effects and changes can affect the pharmacodynamic response of the drug molecule. Although some of the physical properties of stable isotope-labeled molecules differ from those of unlabeled ones, the chemical and biological properties are the same, with one important exception: due to the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom. Thus, incorporation of isotopes at the site of metabolic or enzymatic conversion will slow the reaction, potentially altering the pharmacokinetic profile or potency compared to non-isotopic compounds.
Detailed Description
In some embodiments, there is provided at least one compound of formula (i), and/or, a pharmaceutically acceptable salt thereof, and/or, a stereoisomer thereof and/or a solvate thereof:
Figure 49456DEST_PATH_IMAGE002
wherein:
a is selected from aryl and heteroaryl;
R 1 selected from hydrogen, C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 4-14 Heterocyclic group, C 4-14 Heterocyclyl radical C 1-6 Alkyl radical, C 6-14 Aryl radical, C 6-14 Aryl radical C 1-6 Alkyl radical, C 5-14 Heteroaryl group, C 5-14 Heteroaryl C 1-6 Alkyl, wherein each of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted with at least one, such as 1,2 or 3, groups W;
R 2 selected from hydrogen,C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 4-14 Heterocyclic group, C 4-14 Heterocyclyl radical C 1-6 Alkyl radical, C 6-14 Aryl radical, C 6-14 Aryl radical C 1-6 Alkyl radical, C 5-14 Heteroaryl group, C 5-14 Heteroaryl C 1-6 Alkyl, wherein each of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted with at least one, such as 1,2 or 3, groups W;
each R 3 Each independently selected from halogen, C 1-6 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-10 Cycloalkoxy, C 1-6 Alkylamino radical, C 3-10 Cycloalkylamino, C 4-14 Heterocyclic group, C 4-14 Heterocyclyl radical C 1-6 Alkyl radical, C 6-14 Aryl radical, C 6-14 Aryl radical C 1-6 Alkyl radical, C 5-14 Heteroaryl group, C 5-14 Heteroaryl C 1-6 Alkyl, -NR a R b 、-S(CR a R b ) r CR a R b 、-S(CR a R b ) r C(O)R a 、-S(CR a R b ) r NR c R d 、-S(CR a R b ) r C(O)NR c R d 、-S(O) r (CR a R b ) r NR c R d 、-S(O) r O(CR a R b ) r NR c R d 、-C(O) (CR a R b ) r NR c R d 、-(CR a R b ) r NR c R d 、-OC(O) NR c R d 、-C(O)O(CR a R b ) r NR c R d Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylamino, heterocyclyl, aryl, heteroaryl is independently unsubstituted or substituted with at least one, such as 1,2,3 or 4, group W;
each R 4 Each is independent of othersSelected from halogen and C 1-6 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-10 Cycloalkoxy, C 1-6 Alkylamino radical, C 3-10 Cycloalkylamino, C 4-14 Heterocyclic group, C 4-14 Heterocyclyl radical C 1-6 Alkyl radical, C 6-14 Aryl radical, C 6-14 Aryl radical C 1-6 Alkyl radical, C 5-14 Heteroaryl group, C 5-14 Heteroaryl C 1-6 Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylamino, heterocyclyl, aryl, heteroaryl is each unsubstituted or substituted with at least one, such as 1,2,3 or 4, W group;
each R 5 And R 6 Independently selected from hydrogen, halogen, C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one, such as 1,2 or 3, W groups.
Or R 5 And R 6 Together with the C atom to which they are attached, form a 3-7 membered ring containing 0, 1 or 2 heteroatoms independently selected from O, S and N, and optionally substituted with 0, 1,2 or 3W.
Each R a 、R b 、R c And R d Each independently selected from hydrogen, hydroxy, halogen, C 1-6 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-10 Cycloalkoxy, C 1-6 Alkylamino radical, C 3-10 Cycloalkylamino, C 4-14 Heterocyclic group, C 4-14 Heterocyclyl radical C 1-6 Alkyl radical, C 6-14 Aryl radical, C 6-14 Aryl radical C 1-6 Alkyl radical, C 5-14 Heteroaryl group, C 5-14 Heteroaryl C 1-6 Alkyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted with at least one, such as 1,23 or 4, substituted with a W group;
or, each "R a And R b ”、“R c And R d "together with the N atom to which they are attached form a 4-12 membered ring which also contains 0, 1 or 2 further heteroatoms independently selected from O, S and N, and which is optionally substituted with 1,2 or 3W groups;
each W is independently selected from hydrogen, nitro, cyano, amino, hydroxy, carboxy, halogen, oxo, thio, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-8 Cycloalkyl radical, C 1-6 Alkylamino radical, C 3-8 Cycloalkylamino, (C) 1-6 Alkyl radical) 2 Amino, halogeno C 1-6 Alkyl, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxyalkyl group, C 2-6 Alkanoyl radical, C 1-6 Alkylthio radical, C 1-6 Alkoxycarbonyl group, C 1-6 Alkylsulfonyl radical, C 1-6 Alkylsulfinyl, carbamoyl, C 1-6 Alkylcarbamoyl, di- (C) 1-6 Alkyl) carbamoyl, C 2-8 Alkenyl and C 2-8 Alkynyl.
m is selected from 1,2 and 3;
n is selected from 1,2 and 3;
r is independently selected from 0, 1,2, 3.
In some embodiments, a is heteroaryl.
In some embodiments, a is selected from
Figure 292349DEST_PATH_IMAGE003
。
In some embodiments, a is selected from
Figure 533975DEST_PATH_IMAGE004
。
In some embodiments, R 1 Is selected from C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl, each alkyl and cycloalkyl being unsubstituted or substituted by at least one, such as 1,2,3 or 4, W.
In some embodiments, R 1 Selected from the group consisting of methyl, ethyl, isobutyl, cyclopropylmethyl, isopropyl and isopentyl, each unsubstituted or substituted with at least one hydroxyl group.
In some embodiments, R 2 Is independently selected from C 1-6 Alkyl radical, C 3-8 Cycloalkyl and C 3-8 Cycloalkyl radical C 1-6 An alkyl group.
In some embodiments, R 2 Selected from methyl or isobutyl.
In some embodiments, R 3 Selected from the group consisting of-C (O) (CR) a R b ) r NR c R d 、-S(CR a R b ) r CR a R b and-S (CR) a R b ) r C(O)R a Each of which is unsubstituted or substituted by at least one W group.
In some embodiments, R 3 Selected from-C (O) (CR) a R b ) r NR c R d 、-S(CR a R b ) r CR a R b and-S (CR) a R b ) r C(O)R a Each of which is unsubstituted or substituted by at least one member selected from the group consisting of hydroxy, C 1-6 Alkyl radical, C 3-8 Cycloalkyl and hydroxy C 1-6 Alkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with at least one W group.
In some embodiments, R 3 Is selected from
Figure 871415DEST_PATH_IMAGE005
Each of which is unsubstituted or substituted with at least one group independently selected from methyl, hydroxy and hydroxymethyl.
In some embodiments, R 4 Is selected from C 6-14 Aryl and C 5-14 Heteroaryl, wherein aryl and heteroaryl are unsubstituted or substituted with at least one W group.
In some embodiments, R 4 Is selected from C 6-14 Aryl and C 5-14 Heteroaryl, wherein aryl and heteroarylUnsubstituted or substituted by at least one member selected from cyano, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-8 Cycloalkyl and halo C 1-6 Alkyl, wherein alkyl, alkoxy and cycloalkyl are unsubstituted or substituted with at least one W group.
In some embodiments, R 4 Selected from the group consisting of phenyl, naphthalen-1-yl, pyridin-4-yl, pyridin-2-yl, and quinolin-5-yl, wherein phenyl, naphthyl, pyridinyl, and quinolinyl are unsubstituted or substituted with at least one group independently selected from the group consisting of methyl, methoxy, cyano, fluoro, and trifluoromethyl.
In some embodiments, R 5 And R 6 Independently selected from hydrogen and C1-6 alkyl, wherein alkyl is unsubstituted or substituted with at least one, such as 1,2,3 or 4, W groups.
In some embodiments, R 5 And R 6 Selected from hydrogen.
In some embodiments, m is 1.
In some embodiments, n is 1.
At least one compound, and/or a pharmaceutically acceptable salt thereof, and/or a stereoisomer thereof, and/or a solvate thereof, selected from:
(S) -5- (4-hydroxyisoxazolidine-2-carbonyl) -1-ethyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxyisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxyisoxazolidine-2-carbonyl) -1-cyclopropylmethyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxyisoxazolidine-2-carbonyl) -1-isopentyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxyisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (2- (trifluoromethyl) benzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isopropyl-3-methyl-6- (2,6-dimethylbenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isopropyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isopropyl-3-methyl-6- (3,5-difluoro-2-methoxybenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxy-4-methyl isoxazolidine-2-carbonyl) -1-isopropyl-3-methyl-6- (2,3-dimethylbenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isopropyl-3-methyl-6- (2- (trifluoromethyl) benzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (2,4,5-trifluorobenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (2,3-dimethylbenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (2,6-dimethylbenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1,3-diisobutyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(R) -5- (2- (hydroxymethyl) pyrrolidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (2- (hydroxymethyl) pyrrolidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(R) -5- (3-hydroxypyrrolidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
n- ((1-hydroxycyclopropyl) methyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo [3,4-d ] pyrimidine-5-carboxamide;
5- (4-hydroxypiperidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(R) -5- (2- (hydroxymethyl) azetidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
5- (3-hydroxyazetidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (2- (hydroxymethyl) azetidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione.
The compounds of the invention are useful because they provide compounds having pharmaceutical activity in both human and non-human animals. The compounds of the invention are useful as medicaments for the (prophylactic) treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases, as well as immune-mediated diseases, including transplant organ or tissue rejection and acquired immunodeficiency syndrome (AIDS).
Examples of such diseases are:
(1) (respiratory) airway diseases including Chronic Obstructive Pulmonary Disease (COPD); asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, especially chronic or adult asthma (e.g. late asthma and airway hyperresponsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis includes fibrinous rhinitis, croupus rhinitis, pseudoabdominal rhinitis and tuberculous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis (sarcodosis), farmer's lung and related diseases, fibrotic lung and idiopathic interstitial pneumonia.
(2) Rheumatoid arthritis (bone and joint), seronegative spondyloarthopathies (including ankylosing spondylitis, psoriatic arthritis and reiter's disease), behcet's disease, sjogren's syndrome and systemic sclerosis.
(3) (skin) psoriasis, allergic dermatitis, contact dermatitis and other eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigus, epidermolysis bullosa, urticaria, angioedema, vasculitis (illness), erythema, cutaneous eosinophilia, uveitis, topical alopecia and vernal conjunctivitis.
(4) (gastrointestinal tract) abdominal diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, crohn's disease, ulcerative colitis, food-related allergies having an effect distant from the intestine, such as migraine, rhinitis and eczema.
(5) (other tissue and systemic diseases) multiple sclerosis, atherosclerosis, acquired Immune Deficiency Syndrome (AIDS), lupus erythematosus, systemic lupus erythematosus, hashimoto's thyroiditis, thymic hyperplasia, type I diabetes, nephrotic syndrome, eosinophilic fasciitis, high IgE syndrome, leprosy, zeyland's syndrome, and idiopathic thrombocytopenic purpura.
(6) (allograft rejection) chronic and acute following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease; and
(7) Cancer.
In another aspect, the invention relates to a pharmaceutical composition comprising as an active ingredient a compound according to any one of the above embodiments and variants. In a particular variant, the composition is a solid formulation suitable for oral administration. In another particular variant, the composition is a liquid formulation suitable for oral administration. In another particular variant, the composition is a tablet. In yet another particular variant, the composition is a liquid formulation suitable for parenteral administration.
In another aspect, a pharmaceutical composition is contemplated, which composition comprises a compound of any of the above embodiments and variations, wherein the composition is suitable for different routes of administration, including oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposomal, via inhalation, vaginal, intraocular, via local delivery (e.g., by catheter or stent), subcutaneous injection, intralipid injection, intraarticular injection, and intrathecal injection.
In another aspect, a kit (kit) is provided comprising a compound according to any one of the above embodiments and variations, and instructions for use comprising information on one or more components, including a disease state indication suitable for administration of the composition, composition storage information, administration information, and instructions on how to use the composition. In a particular variation, the kit comprises multiple dosage forms of the compound.
In another aspect, an article of manufacture is provided that includes the compound of any of the above embodiments and variations and a packaging material. In one variation, the packaging material includes a container containing the compound. In a particular variation, the container contains a label with information including a disease state presentation for the appropriate composition to take, stored information, administration information, and instructions on how to use the composition. In another variation, the article of manufacture comprises multiple dosage forms of the compound.
In another aspect, there is provided a method of treatment comprising administering to a subject a compound of any one of the above embodiments and variations.
In another aspect, there is provided a method of immunosuppression comprising the interaction of a compound of any one of the above examples and modifications with MCT 1.
In another aspect, there is provided a method of inhibiting cancer cells, the method comprising administering to a patient a compound of any one of the above embodiments and variations.
In another aspect, there is provided a method of treating and reducing the risk of an obstructive airways disease in a patient that comprises administering to the patient a compound of any one of the above embodiments and modifications.
Administration and pharmaceutical combinations
Generally, the compounds of the present invention will be administered in a therapeutically effective amount via any of the usual and acceptable means known in the art, alone or in combination with one or more therapeutic agents. The therapeutically effective amount may vary widely depending on the severity of the disease, age and relative health of the subject, the potency of the compound used and other general skills known in the art. For example, for the treatment of neoplastic diseases and immune system diseases, the required dosage will vary depending upon the mode of administration, the particular condition being treated and the effect desired.
In general, satisfactory results are achieved at daily dosages of from 0.001 to 100mg/kg body weight, in particular from about 0.03 to 2.5mg/kg body weight. Daily doses for larger mammals, such as humans, may be administered in a convenient form, for example in divided doses up to four times a day or in sustained release form, from about 0.5mg to about 2000mg, or more specifically, from 0.5mg to 100 mg. Suitable unit dosage forms for oral administration contain from about 1 to 50mg of the active ingredient.
The compounds of the invention may be administered in the form of pharmaceutical compositions, by any conventional route; e.g., enterally, e.g., orally, e.g., in the form of tablets or capsules, parenterally, e.g., in the form of injectable solutions or suspensions; or topically, e.g., as a lotion, gel, ointment or cream, or in nasal or suppository form.
Pharmaceutical compositions comprising a compound of the invention in free base or pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent may be manufactured in conventional manner by means of mixing, granulating, coating, dissolving or lyophilizing processes. For example, pharmaceutical compositions comprising a compound of the invention in combination with at least one pharmaceutically acceptable carrier or diluent may be formulated in conventional manner by admixture with a pharmaceutically acceptable carrier or diluent. Unit dosage forms for oral administration contain, for example, from about 0.1mg to about 500mg of active substance.
In one embodiment, the pharmaceutical composition is a solution of the active ingredient, including a suspension or dispersion, such as an isotonic aqueous solution. In the case of lyophilized compositions comprising the active ingredient alone or in admixture with a carrier such as mannitol, the dispersion or suspension may be replenished prior to use. The pharmaceutical compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solubility promoters, salts for regulating the osmotic pressure and/or buffers. Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid, microbicides such as sorbic acid or benzoic acid. The solution or suspension may also contain viscosity increasing agents including, but not limited to, sodium carboxymethylcellulose, dextran, polyvinylpyrrolidone, gelatin, or solubilizing agents, such as tween 80 (polyoxyethylene (20) sorbitan monooleate).
Suspensions may contain vegetable oils, synthetic or semi-synthetic oils, as the oily component in the oil, commonly used for injection purposes. Examples include liquid fatty acid esters containing as the acid component a long chain fatty acid having from 8 to 22 carbon atoms, or in some embodiments, from 12 to 22 carbon atoms. Suitable liquid fatty acid esters include, but are not limited to, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, such as oleic acid, elaidic acid, erucic acid, brassidic acid and linoleic acid, which may, if desired, contain antioxidants, such as vitamin E, 3-carotene or 3,5 di-tert-butyl-hydroxytoluene. The alcohol component of these fatty acid esters may have six carbon atoms and may be a monovalent or polyvalent, e.g. mono-, di-or trivalent, alcohol. Suitable alcohol components include, but are not limited to, methanol, ethanol, propanol, butanol or pentanol or isomers thereof, ethylene glycol and glycerol.
Other suitable fatty acid esters include, but are not limited to, ethyl oleate, isopropyl myristate, isopropyl palmitate, LABRAFIL M2375, (polyoxyethylene glycerol), LABRAFIL M1944 CS (unsaturated polyglycolized glycerides by alcoholysis of almond oil and containing glycerides and polyethylene glycol esters), LABRAS0L (saturated polyglycolized glycerides prepared by alcoholysis of TCM and containing glycerides and polyethylene glycol esters; all available from GaKefosse, france), and/or MI Y0L _12 (saturated fatty acid triglycerides of chain length C8 to C12, hills AG, germany), and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil or peanut oil.
Pharmaceutical compositions for oral administration may be obtained, for example, by mixing the active ingredient with one or more solid carriers, if desired granulating a resulting mixture, and processing the mixture or granules by adding further excipients, in the form of tablets or tablet cores.
Suitable carriers include, but are not limited to, fillers, for example sugars, such as lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, for example starches, such as corn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrants, such as the above-mentioned starches, carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional excipients include flow-regulating agents and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
The tablet cores may be provided with a suitable, optionally enteric, coating by using, inter alia, concentrated sugar solutions, which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for enteric coatings, the preparation of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate solutions. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.
Pharmaceutical compositions for oral administration may also include hard capsules, including gelatin or soft, sealed capsules containing gelatin and a plasticizer, such as glycerol or sorbitol. Hard capsules may contain the active ingredients in the form of granules, for example in admixture with fillers such as corn starch, binders and/or glidants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the fatty acid ester type of polyoxyethylene sorbitol, may also be added.
Pharmaceutical compositions suitable for rectal administration, for example suppositories, comprise a combination of the active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
Pharmaceutical compositions suitable for parenteral administration may contain the active ingredient in water-soluble form, for example as a water-soluble salt or as an aqueous injection suspension containing a viscosity-increasing substance, for example sodium carboxymethylcellulose, an aqueous solution of sorbitol and/or dextran, and, if desired, a stabilizer. The active ingredient, optionally together with excipients, may also be in a lyophilized form and may be prepared as a solution by addition of a suitable solvent prior to parenteral administration. The solutions used, for example, for parenteral administration, can also be used as infusion solutions. Injectable preparations are generally prepared under sterile conditions, and filled, for example, in ampoules or vials, and in sealed containers.
Combination therapy
The invention further provides methods of using the compounds or compositions of the invention in combination with one or more other active agents.
The compounds of formula (I) are expected to be effective when used together with the following.
Alkylating agents, angiogenesis inhibitors, antibodies, metabolic antagonists, antimitotic agents, antiproliferative agents, other apoptosis promoter (e.g., bcl-xL, bcl-w and Bfl-1) inhibitors, bcr-Abl kinase inhibitors, biTE (bispecific T cell engage) antibodies, aurora kinase inhibitors, biological response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVD's, leukemia virus oncogene homolog (ErbB 2) receptor inhibitors, growth factor inhibitors, heat shock protein HSP (HSP) -90 inhibitors, histone Deacetylase (HDAC) inhibitors, hormone therapy, immunity, inhibitors of antibiotic-embedded apoptosis proteins (siRNA's), kinase inhibitors, mammalian targets of rapamycin inhibitors, mitogen-activated extracellular signal-regulated kinase inhibitors of small RNAs, multivalent binding proteins, non-steroidal anti-inflammatory drugs (aids nss), poly (adenosine diphosphate) -polymerase (PARP) inhibitors, polo drugs, inhibitors of picornase (pds), retinoid-like kinase inhibitors, topoisomerase inhibitors of nucleic acid kinase, topoisomerase inhibitors, and the like receptor (delta kinase inhibitors), and the like.
BiTE antibodies are bispecific antibodies that direct T cells to attach to cancer cells while allowing both cells to bind. The T cells then attack the targeted cancer cells. Exemplary BiTE antibodies include: adermumab (ademight) (Micromet MT 201), blinatumomab (Micromet MT 103), and the like.
SiRNA's are molecules with endogenous RNA bases or chemically regulated nucleotides. The modification does not abolish cellular activity, but can improve stabilityAnd/or increase cell potency. Examples of chemical modifications include phosphorothioate groups, 2 '-deoxynucleotides, containing 2' -OCH 3 -ribonucleotides, 2 '-F-ribonucleotides, 2' -methoxyethyl ribonucleotides or combinations thereof. sirnas can have varying lengths (e.g., 10-200 bps) and structures (e.g., hairpin, single/double stranded, convex, concave/notch, non-overlapping) and are processed in cells to provide active gene silencing. In certain embodiments, double stranded siRNA (dsRNA) have the same number of nucleotides on each strand (blunt end) or asymmetric end (overhang). An overhang of 1-2 nucleotides may be present on the sense strand and/or the antisense strand, as well as on the 5 '-and/or 3' -end of the resulting strand.
Multivalent binding proteins are binding proteins that comprise two or more antigen binding sites. Multivalent binding proteins can preferably be designed to have three or more antigen binding sites and are not normally naturally occurring antibodies. The term "multispecific binding protein" refers to a binding protein capable of binding two or more related or unrelated targets. Dual variable region (DVD) binding proteins are tetravalent or multivalent binding proteins that comprise two or more antigen binding sites. Such DVDs can be monospecific (i.e., capable of binding one antigen) or multispecific (i.e., capable of binding two or more antigens). A DVD-binding protein comprising two heavy chain DVD polypeptides and two light chain DVD polypeptides is referred to as DVD Ig. Each half of the DVD Ig contains a heavy chain DVD polypeptide, a light chain DVD polypeptide, and two antigen binding sites. Each binding site comprises a heavy chain variable domain and a light chain variable domain, and each antigen binding site has a total of 6 CDRs involved in antigen binding.
Alkylating agents include: altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brositallicin, busulfan, carboquone, carmustine (BCNU), chlorambucil, cloretazone @ (lamotrigine (larmoustine), VNP 40101M), cyclophosphamide, desclohydroxyzine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), macsfamide (mafosfamide), melphalan, dibromomannitol, dibromodulcitol, pyrimidinenitrosourea, azoneMustard N-oxide, ranimustine (Ranimustine), temozolomide, thiotepa, TREANDA @ (bendamustine), troosulfan, rofesfamide, and the like.
Angiogenesis inhibitors include: endothelial-specific receptor tyrosine kinase (Tie-2) inhibitors, epidermal Growth Factor Receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, platelet growth factor receptor (PDGFR) inhibitors, thrombospondin analogs, vascular endothelial growth factor receptor tyrosine kinase (VEGFR) inhibitors, and the like.
Metabolic antagonists include: ALIMTA @ (pemetrexed disodium, LY231514, MTA), 5-azacitidine, XELODA @ (Capecitabine), carmofur, LEUSTAT @ (cladribine), clofarabine (clofarabine), cytarabine sodium octadecyl phosphate, cytarabine, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR (5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide), enocitabine, ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination with folinic acid, GEMZAR @ (Gemcitabine), hydroxyurea, ALKERAN @ (melphalan), mercaptopurine, 6-mercaptopurine ribonucleosides, methotrexate, mycophenolic acid, nelarabine (nelarabine), nolatrexed, sodium octadecyl phosphate, pyridine Li Qusuo (pellitrexol), pentostatin, raltitrexed (raltitrexed), ribavirin, triapine, trimetrexate, S-1, thiazolofuran, tegafur, TS-1, vidarabine, UFT, and the like.
Aurora kinase inhibitors include: AZD-1152, MLN-8054, VX-680, ABT-348, and the like.
Bcl-2 protein inhibitors include: AT-101 ((-) gossypol), GENASENSE @ (G3139 or oblimersen) (Bcl-2-targeting antisense oligonucleotide)), IPI-194, IPI-565, N- (4- (4- ((4 '-chloro (1,1' -biphenyl) -2-yl) methyl) piperazin-1-yl) benzoyl) -4- (((1R) -3- (dimethylamino) -1- ((phenylsulfanyl) methyl) propyl) amino) -3-nitrobenzenesulfonamide) (ABT-737), N- (4- (4-((2- (4-chlorophenyl) -5,5-dimethyl-1-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoyl) -4- (((1R) -3- (morpholin-4-yl) -1- ((phenylsulfanyl) methyl) propyl) amino) -3- ((trifluoromethyl) sulfonyl) benzenesulfonamide (ABT-263), GX-070 (obatoclax), and the like.
Bcr-Abl kinase inhibitors include: DASATINIB @ (BMS-354825)，GLEEVEC @ (imatinib), and the like.
CDK inhibitors include: AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, frazidine (flavopiridol), GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202, R-roscovine), ZK-304709, and the like.
COX-2 inhibitors include: ABT-963, ARCOXIA @ (muskon), BEXTRA @ (valdecoxib), BMS347070, CELEBREX @ (celecoxib), COX-189 (lumiracoxib), CT-3, DERAMAXX @ (deracoxib), JTE-522, 4-methyl-2- (3,4-dimethylphenyl) -1- (4-sulfamoylphenyl-1H-pyrrole), MK-663 (merxadon), NS-398, parricombin, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T-614, VIOXX, VIOXY, and VIO @ (rofecoxib), and the like.
EGFR inhibitors include: ABX-EGF, anti-EGFR immunoliposome, EGF-vaccine, EMD-7200, ERBITIX @ (cetuximab), HR3, igA antibody, IRESSA @ (Gefitinib), TARCEVA @ (erlotinib or OSI-774), TP-38, EGFR fusion protein, TYKERB @ (lapatinib) and the like.
ErbB2 receptor inhibitors include: CP-724-714, CI-1033 (canertinib), HERCEPTIN @ (trastuzumab), TYKERB @ (lapatinib), OMNITARG @ (2C 4, pertuzumab (pertuzumab)), TAK-165, GW-572016 (ionofanib), GW-282974, EKB-569, PI-166, dHER2 (HER 2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2 neu bispecific antibody, B7.HER2IgG3, AS HER2 trifunctional bispecific antibody, mAB AR-209, mAB 2B-1, and the like.
Histone deacetylase inhibitors include: depsipeptides, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid, and the like.
HSP-90 inhibitors include: 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB @ (human recombinant antibody to HSP-90), NCS-683664, PU24FCl, PU-3, radicicol, SNX-2112, STA-9090 VER49009, and the like.
Inhibitors of apoptosis proteins include: apoMab (fully human affinity-mature IgG1 monoclonal antibody), antibodies targeting TRAIL or death receptors (e.g., PRO-apoptotic receptor agonists DR4 and DR 5), conatumumab, ETR2-ST01, GDC0145, (lexatuzumab), HGS-1029, LBY-135, PRO-1762, and trastuzumab (trastuzumab).
MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059, and the like.
mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, sirolimus (temsirolimus), and the like.
Non-steroidal anti-inflammatory drugs include: AMIGESC @ (disalicylate), DOLOBID @ (diflunisal), MOTRIN @ (ibuprofen), ORUDIS @ (ketoprofen), RELAFEN @ (Nabumetone), felden @ (piroxicam), ibuprofen cream, ALEVE @ (naproxen) and NAPROSYN @ (naproxen), VOLTAREN @ (diclofenac), INDOCIN @ (anti-inflammatory pain) CLINORIL @ (sulindac), toleclin @ (toluoylpyridine acid), LODINE @ (Etodolac), toradol @ (ketorolac), DAYPRO @ (oxaprozin), and the like.
PDGFR inhibitors include C-451, CP-673, CP-868596, and the like.
Platinum chemotherapeutic agents include: cisplatin, ELOXATIN @ (oxaliplatin) eptaplatin, ledaplatin, nedaplatin, paraplatin @ (carboplatin), satraplatin (satraplatin), and the like.
Polo-like kinase inhibitors include BI-2536 and the like.
Thrombospondin analogs include ABT-510, ABT-567, TSP-1 and the like.
VEGFR inhibitors include: AVASTIN @ (bevacizumab), ABT-869, AEE-788, ANGIOZYME TM (ribozymes (Boulder, CO.) and Chiron (Emeryville, CA) which inhibit angiogenesis), axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptanib), NEXAVAR @ (sorafenib, BAY 43-9006), pazopanib (pazopanib) (GW-786034), vatalanib (vatalanib) (PTK-787, ZK-222584), SUTENT @ (Sunitinib, SU-11248), VEGF trap, ZACTIMA TM (vandetanib), ZD-6474) and the like.
The antibiotics include: embedded antitumor (antitumor) antibiotics aclarubicin, actinomycin D, amrubicin, anthracycline (annamycin), doxorubicin, BLENOXANE @ (bleomycin), daunorubicin, CAELYX @ Or MYOCET @ (Liposomal doxorubicin), elsamitrucin, epirubicin (epinbucin), glarbuiin, ZAVEDOS @ (idarubicin), mitomycin C, nemorubicin, neocarzinostatin, pellomycin sulfate, pirarubicin, rebeccamycin, netastatin (stimamer), streptozotocin, VALSTAR @ (valrubicin), neocarzinostain, and the like.
Topoisomerase inhibitors include: aclarubicin, 9-aminocamptothecin, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR @ (irinotecan hydrochloride), camptothecin, and CARDIOXANE @ (dexpropizone), difluotecan (diflomotecan), idocanol (edotecarin), elence @ Or PHARMOUBICIN @ (epirubicin), etoposide, exatecan (exatecan), 10-hydroxycamptothecin, gemmacetan, lurotecan, mitoxantrone, rubitecan (orathecin), pirarubicin (pirarubicin), pixantrone, rubitecan, sobuzosin, SN-38, afluposide, topotecan, and the like.
The antibody comprises: AVASTIN @ (bevacizumab), CD 40-specific antibody, chTNT-1/B, denosumab、ERBITUX @ (cetuximab), HUMAX-CD4 @ (zanolimumab), IGF 1R-specific antibody, linotuzumab, PANOREX @ (Eycolub), RENCAREX @ (WX G250)、RITUXAN @ (rituximab), ticilimumab, trastuzimab, and the like.
Hormone therapy includes: ARIMIDEX @ (anastrozole), AROMASIN @ (exemestane), arzoxifene (arzoxifene), CASODEX @ (bicalutamide), cettrotide @ (cetrorelix), degarelix, deslorelin, DESOPAN @ (trilostane), dexamethasone, DROGENIL @ (Flutamide), EVISTA @ (Ranoxiphenol), AFEMA TM (fadrozole), farest on @ (toremifene citrate), FASLODEX @ (fulvestrant), FEMARA @ (letrozole), formestane, glucocorticoids, hectone @ (doxercalciferol), RENAGEL @ Sevelamer carbonate, lasofoxifene, leuprolide acetate, MEGACE @ (megestrol), MIFEPREX @ (Mesopridone), NILANDRON TM (nilutamide), NOLVADEX @ (tamoxifen citrate), PLENAXIS TM (aberelix), dehydrocortisone, PROPECIA @ (finasteride), rilostate, SUPREFACT @ (buserelin), TRELSTRAR @ (luteinizing hormone releasing hormone (LHRH)), VANTAS @ (Histrelin) implant), VETORYL @ (trilostane or modastane), ZOLADEX @ (fosrelin, goserelin) and the like.
Trigonal alkaloids (Deltoids) and retinoids include: seocalcitol (EB 1089, CB 1093), lexacalcitol (KH 1060), fenretinide (fenretinide), PANRETIN @ (aliretinoin)、ATRAGEN @ (Liposomal retinoic acid), TARGRETIN @ (bexarotene), LGD-1550, and the like.
PARP inhibitors include: ABT-888, olaparib, KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231, and the like.
Plant alkaloids include, but are not limited to: vincristine, vinblastine, desacetylvinblastine, vinorelbine, and the like.
Proteasome inhibitors include: VELCADE @ (bortezomib), MG132, NPI-0052, PR-171, and the like.
Examples of immunity include interferon and other immune enhancing agents. The interferon includes interferon alpha, interferon alpha-2 a, interferon alpha-2 b, interferon beta, interferon gamma-1 a, and activimtone @ (interferon gamma-1 b), or interferon gamma-n 1, combinations thereof, and the like. Other agents include: ALFAFERONE @ IFN-alpha, BAM-002 (oxidized glutathione), BEROMIN @ (tasonermin), BEXXAR @ (tositumomab), CAMPATH @ (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), desoxyzine, denim interleukin (denileukin), epratuzumab, GRANOCYTE @ (leguminose), lentinan, leukocyte interferon-alpha, imiquimod, MDX-010 (anti-CTLA-4), melanoma vaccine, mi Tuomo monoclonal antibody (mitomamab), morastim, MYLOTARG TM (gemtuzumab ozolomide Mi Xing (gemtuzumab ozogamicin)), NEUPOGEN @ (filgrastim), oncovac-CL, OVAREX @ (oregovomab)、pemtumomab(Y-muHMFG1)、PROVENGE @ (sipuleucel-T), sargaramostim, sizofilan, tecelin interleukin (teceleukin), THERACYS @ (BCG), ubenimex, VIRULIZIN @ (immunotherapeutic agents, lorus Pharmaceuticals), Z-100 (Maruyama's Specific Substance (SSM)), WF-10 (Tetrachlorodecaoxide (TCDO)), PROLEUKIN @ (aldesleukin), ZADAXIN @ (thymalfasin), ZENAPAX @ (Darkizumab), ZEVALIN @ (90Y-Ibritumomab tiuxetan), and the like.
Bioresponse modifiers are agents which regulate the defense mechanisms or biological responses of the organism (e.g. survival, growth or differentiation of tissue cells) and thus confer them antitumor activity, and include coriolus versicolor polysaccharide K (krestin), lentinan, cezopyran, streptolysin (picibanil) PF-3512676 (CpG-8954), ubenimex and the like.
Pyrimidine analogs include: cytarabine (ara C or arabinoside C), cytarabine, doxifluridine, FLUDARA @ (fludarabine), 5-FU (5-fluorouracil), azauridine, GEMZAR @ (Gemcitabine), TOMUDEX @ (ratitrexed)、TROXATYL TM (triacetyluridine troxacitabine (troxacitabine)), and the like.
Purine analogs include: lanvis @ (thioguanine) and PURI-NETHOL @ (mercaptopurine).
Anti-mitotic agents include: barbitubulin (batabulin), epothilone D (KOS-862), N- (2- ((4-hydroxyphenyl) amino) pyridin-3-yl) -4-methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, TAXOTERE @ (docetaxel), PNU100940 (109881), ixabepilone (patupilone), XRP-9881 (larotaxel), vinflunine, ZK-EPO (synthetic epothilones), and the like.
The compounds of the present invention may also be used as radiosensitizers to improve the efficacy of radiotherapy. Examples of radiotherapy include: external beam radiotherapy, teletherapy, brachytherapy and sealed, unsealed source radiotherapy, and the like.
In addition, the compounds of formula (I) may be combined with other chemotherapeutic agents, such as ABRAXANE TM (ABI-007), ABT-100 (farnesyltransferase inhibitors), ADVEXIN @ (Ad 5CMV-p53 vaccine), ALOCOR @ Or MEVACOR @ (lovastatin), AMPLIGEN @ (poly I: poly C12U, synthetic RNA), APTOSYN @ (Exisulin (exisulind)), AREDIA @ (pamidronic acid), arglabin, L-asparaginase, atamestan (1-methyl-3,17-dione-androstane-1,4-diene), AVAGE @ (vitamin A acid (tazarotene)), AVE-8062 (combretastatin derivative) BEC2 (mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin (vaccine), CEAVAC @ (cancer vaccine), CELEUK @ (west Mo Bai Interleukin), CEPLENE @ (formula II dihydrochloride), cervarix @ (human papilloma virus vaccine), CHOP @ (C: CYTOXAN @ (cyclophosphamide); h, ADRIAMYCIN @ (hydroxydoxorubicin); vincristine (ONCOVIN) @ ) (ii) a P is dehydrocortisone), CYPAT TM (Semipron acetate), combretastatin A4P, DAB (389) EGF (catalytic and migratory region of diphtheria toxin fused to human epidermal growth factor via His-Ala linker) or TransMID-107R TM (diphtheria toxin), dacarbazine, actinomycin, 5,6-dimethyl
Figure 325006DEST_PATH_IMAGE006
Xanthone-4-acetic acid (DMXAA), eniluracil, EVIZON TM (squalamine lactate), DIMERICINE @ (T4N 5 liposome lotion), discodermolide, DX-8951f (irinotecan mesylate), enzastaurin, EPO906 (epithilone B), GARDASIL @ (tetravalent human papilloma virus (type 6, 11, 16, 18) recombinant vaccine), GASTRIMMUNE @ 、GENASENSE @ GMK (ganglioside conjugate vaccine), GVAX @ (prostate cancer vaccine), halofuginone (halofuginone), histerelin (histerelin), hydroxyurea, ibandronic acid, IGN-101, IL-13-PE38QQR (cindrekin bestudox), IL-13-Pseudomonas exotoxin, interferon-alpha, interferon-gamma, JUNOVAN TM Or MEPACT TM (mivawood peptide (mifamurtide)), lonafarnib (lonafarnib), 5,10-methylenetetrahydrofolic acid, mi Tefu octan (hexadecylphosphocholine), NEOVASTAT @ (AE-941)、NEUTREXIN @ (Trimethoxsuprate), NIPENT @ (pentostatin), ONCONASE @ (ribonuclease), ONCOPHAGE @ (melanoma vaccine therapy), ONCOVAX @ (IL-2 vaccine), ORATHECIN TM (rubitecan), OSIDE EM @ (antibody-based cellular pharmaceuticals), OVAREX @ MAb (murine monoclonal antibody), paclitaxel (paclitaxel), PANDIMEX TM (aglycone sapogenin derived from ginseng, comprising 20 (S) protopanaxadiol (aPPD) and 20 (S) protopanaxatriol (aPPT)), panitumumab (panitumumab), PANVAC @ VF (cancer vaccine investigated), pegapase, PEG interferon A, phenoxadiol, procarbazine, remamastat, REMOVAB @ (catumaxomab)、REVLIMID @ (lenalidomide), RSR13 (efaproxil), SOMATULINE @ LA (lanreotide), SORIATANE @ (Avermectin A), staurosporine (Streptomyces stellate spore), talabostat (PT 100), TARGRETIN @ (bexarotene), TAXOPREXIN @ (DHA-Pacific Taxol), TELCYTA @ (canfosfamide、TLK286)、temilifene、TEMODAR @ (temozolomide), telimifene (tesmilifene), thalidomide, THERATOPE @ (STn-KLH), thymogitaq (2-amino-3,4-dihydro-6-methyl-4-oxo-5- (4-pyridylthio) quinazoline dihydrochloride), TNFaradE TM (adenovirus vector: DNA vector containing tumor necrosis factor Gene-alpha), TRACLEER @ Or ZAVESCA @ (bosentan), tretinoin (Retin-A), tetrandrine, TRISENOX @ (arsenic trioxide) and Virulizin @ Ukrain (alkaloid derivative derived from celandine plant), vitaxin (anti-alphavbeta 3 antibody), XCYTRIN @ (motexfin) gadolinium), XINLAY TM (atrasentan), XYOTAX TM (paclitaxel (paclitaxel poliglumex)), YONDELIS @ (trabectedin), ZD-6126, ZINECARD @ (dexrazoxane), ZOMETA @ (zoledronic acid), zolpidem, and the like.
Examples
There are various methods for synthesizing at least one compound represented by formula (I) or at least one pharmaceutically acceptable salt thereof. In this example, typical methods are listed. It is to be noted, however, that at least one compound of formula (I) or at least one pharmaceutically acceptable salt thereof may also be obtained synthetically by other synthetic routes.
In certain compounds of formula (I), the atom-to-atom linkage may result in the presence of a particular stereoisomer (e.g., a chiral center). The synthesis of at least one compound of formula (I) or at least one pharmaceutically acceptable salt thereof may result in a mixture of different isomers (enantiomers, diastereomers). Unless a particular configuration is specified, all recited compounds include all possible stereoisomers thereof.
At least one compound of formula (I) may be prepared as a pharmaceutically acceptable acid addition salt thereof, for example, by reacting the free base form of the compound of the invention with a pharmaceutically acceptable inorganic or organic acid. Or reacting the free acid form of the compound represented by the formula (I) with a pharmaceutically acceptable inorganic or organic base to prepare a pharmaceutically acceptable base addition salt. Inorganic and organic acids and bases suitable for the preparation of pharmaceutically acceptable salts of the compounds of formula (I) are described in the definitions section of this application. In addition, salt forms of the compounds of formula (I) can also be prepared by using salts of starting materials or intermediates.
The free acid or the free base of the compound of formula (I) may be prepared from the corresponding base addition salt or acid addition salt thereof. For example, an acid addition salt form of a compound of formula (I) can be converted to the corresponding free base by treatment with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). A base addition salt form of a compound of formula (I) can be converted to the corresponding free acid by treatment with a suitable acid such as hydrochloric acid or the like.
The N-oxide of at least one compound of formula (I) or at least one pharmaceutically acceptable salt thereof may be prepared by conventional methods known in the art. For example, the N-oxide can be obtained by reacting a non-oxidized form of a compound represented by the formula (I) with an oxidizing agent (e.g., trifluoroperacetic acid, peroxymaleic acid, perbenzoic acid, peracetic acid, m-chloroperoxybenzoic acid, etc.) in an inert organic solvent (e.g., halogenated hydrocarbon such as dichloromethane, etc.) at a temperature of approximately 0 to 80 ℃. In addition, the N-oxides of the compounds can also be prepared from the N-oxides of the starting materials.
The non-oxidized form of the compound represented by formula (I) can be prepared by reacting the N-oxide with a reducing agent (such as sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide and the like) at 0 to 80 ℃ in a corresponding inert organic solvent (such as acetonitrile, ethanol, dioxane aqueous solution and the like).
Protected derivatives of the compounds of formula (I) may be prepared by methods well known to those skilled in the art. For a detailed technical description of the addition and removal of protecting Groups see Wuts, peter G. M., greene's Protective Groups in Organic Synthesis, 5th Edition, john Wiley & Sons, inc. 2014.
The symbols and general knowledge, charts and cases used in these reactions are consistent with the current scientific literature, e.g., the journal of the American chemical Association or the journal of biochemistry. Unless otherwise indicated, standard single or three letter abbreviations in the L-configuration generally refer to amino acid residues. All starting materials used were purchased from commercial suppliers and used without further purification unless otherwise indicated. For example, the following abbreviations are used in the examples and throughout the specification: g (g), mg (mg), L (L), mL (mL), μ L (μ L), psi (pounds per square inch), M (mol), mM (mmol), i.v. (i.v.), hz (hertz), MHz (megahertz), mol (mol), mmol (mmol), RT (room temperature), min (min), h (h), mp (melting point), TLC (thin layer chromatography), RT (retention time), RP (reversed phase), meOH (methanol), NEt (NEt) 3 <xnotran> (), TFA ( ), THF ( ), DMSO ( ), etOAc ( ), DCM (), meCN (), DMF (N, N- ), acOH (), BOC ( ), ac (), atm ( ), TIPS ( ), TBS ( ), DMAP (4- ), me (), OMe (), et (), t-Bu ( ), HPLC ( ), TBAF ( ), tosMIC ( ), TIPSCl ( ), TBTU (</xnotran>Obenzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate), NBS (N-bromosuccinimide), N-BuLi (N-butyllithium), DIPEA (diisopropylethylamine), LDA (diisopropylaminolithium), nosCl (m-nitrobenzenesulfonyl chloride)），NHP（N-hydroxyphthalimide), con. Hcl (concentrated hydrochloric acid).
Ether or Et 2 O is all ether; brine is then a saturated aqueous NaCl solution. Unless otherwise indicated, all temperatures refer to degrees Celsius (degrees Celsius) and all reactions are carried out in an inert atmosphere at room temperature.
1 H NMR spectra were recorded using a Bruker-AM 600 (600 MHz) nuclear magnetic resonance spectrometer. Chemical shifts are expressed in ppm. The coupling constants are all in hertz (Hz). Apparent diversity is described in the split mode and is assigned as s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), sex (sextet), sept (heptaplex), m (multiplet), br (generalized peak).
Low resolution Mass Spectrometry (MS) and compound purity data were from a single stage quadrupole system of Shimadzu mass spectrometry (LCMS-2020).
Synthetic route
The preparation of the compounds of the invention is illustrated by the following schemes and examples, starting materials are either commercially available or can be prepared according to known methods or methods exemplified herein.
In some cases, the order of carrying out the reactions shown in the above schemes may be adjusted to ensure that the reactions proceed or to avoid side reactions. The following examples are for a full understanding of the present invention and are not to be construed as limiting the invention in any way.
Preparation of intermediates
1-Ethyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (intermediate a).
Figure 988068DEST_PATH_IMAGE007
。
Step A
3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (A-1).
N-methylurea (20 g, 270 mmol) was weighed into a 500ml round bottom flaskAdding diethylenone (29 ml, 380 mmol) and glacial acetic acid 200ml, stirring in 90 deg.C oil bath for 3 hr, then stirring at 110 deg.C for 1 hr, concentrating the reaction solution under reduced pressure, crystallizing the residue with ethyl acetate and cyclohexane to obtain off-white solid 3,6-dimethylpyrimidine-2,4 (1)H, 3H) -diketones and 1,6-dimethylpyrimidine-2,4 (1)H, 3H) 14.2g of a mixture of diketones.
The product (14.2 g, 91 mmol) was added to 37% formaldehyde (24.8 ml, 320 mmol), 1N aqueous sodium hydroxide (143 ml, 143 mmol) and stirred at room temperature overnight.
The reaction solution was neutralized with 2M hydrochloric acid and 2% potassium carbonate, then 60g of ammonium ceric nitrate was added in portions, after the disappearance of red color, extraction was repeated with dichloromethane until little monitoring by organic layer TLC, and then drying with anhydrous sodium sulfate, filtration, and concentration under reduced pressure were performed. The crude product was dry loaded and column chromatographed using eluent (cyclohexane: ethyl acetate 2:1, then 1.5, and finally 1:1) to give a pale yellow solid 3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (3.9 g, 23 mmol) (A-1). MS-ESI (m/z) 169.0[ m + H ]] + 。
Step B
3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (a-2).
3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (A-1) (2.0 g, 11.9 mmol) is weighed and dissolved in 120ml of trichloromethane, the internal temperature is raised to 50 ℃, 12ml of 1M bromine-trichloromethane solution is slowly dripped, the reaction is continued for 0.5 hour, then 1ml of 1M bromine-trichloromethane solution is additionally dripped, and the mixture is slowly cooled to the room temperature after dripping.
Then, the reaction solution was cooled in an ice bath, and triethylamine (4 ml, 28.9 mmol) and naphthalenemethylamine trifluoroacetate (3.23 g, 11.9 mmol) were added thereto and stirred at room temperature overnight. The reaction solution was concentrated by addition of silica gel, and the product was dry-loaded, column chromatographed, and eluted with an eluent (dichloromethane: isopropanol =150:1 to 100H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (A-2) (3).1g, 10.1mmol）。MS-ESI（m/z）:306.0[M+H] + 。
Step C
1-Ethyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (intermediate a).
Weighing intermediate 3-methyl-6- (naphthalene-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) Diketon (A-2) (500 mg, 1.6 mmol) and potassium carbonate (875mg, 6.3mmol) were added to dimethyl sulfoxide (5 ml), and the mixture was stirred uniformly, followed by addition of ethyl iodide (500. Mu.l, 5.9 mmol), and reacted at 60 ℃ overnight. The reaction solution was diluted with water, extracted with ethyl acetate three times, the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography (eluent dichloromethane: ethyl acetate =20H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -dione (intermediate a) (210 mg, yield 38%). MS-ESI (m/z) 334.0[ m ] +H] + 。
1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (intermediate B).
Figure 451411DEST_PATH_IMAGE008
。
And (3) replacing iodoethane in the step C with iodoisobutane by referring to the synthesis method of the intermediate A to prepare an intermediate B. MS-ESI (m/z) 362.0[ m ] +H] + 。
1-cyclopropylmethyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (intermediate C).
Figure 343274DEST_PATH_IMAGE009
。
Prepared by replacing ethyl iodide in the step C with bromomethyl cyclopropane according to the synthesis method of the intermediate ATo intermediate C. MS-ESI (m/z) 360.0[ m ] +H] + 。
1-isopentyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (intermediate D).
Figure 841252DEST_PATH_IMAGE010
。
Referring to the synthesis method of the intermediate A, the iodoethane in the step C is replaced by 1-bromoisopentane to prepare an intermediate D. MS-ESI (m/z) 376.0[ m + H ]] + 。
1-isobutyl-3-methyl-6- (2- (trifluoromethyl) benzyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (intermediate E).
Figure 675216DEST_PATH_IMAGE011
。
And (3) according to the synthesis method of the intermediate A, the naphthyl methylamine trifluoroacetate in the step B is replaced by 2-trifluoromethyl benzylamine, and the iodoethane in the step C is replaced by iodoisobutane to prepare an intermediate E. MS-ESI (m/z) 380.0[ m + H ]] + 。
1-isopropyl-3-methyl-6- (2,6-dimethylbenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (intermediate F).
Figure 438903DEST_PATH_IMAGE012
。
Step A
3-methylpyrimidine-2,4 (1)H, 3H) -a diketone (F-1).
Weighing 6-chloro-3-methyluracil (20 g, 125 mmol) in a 500ml round-bottom flask, adding 10% Pd/C (5.1 g), anhydrous methanol 300ml and triethylamine 18ml, replacing with N2 for 2 times, stirring by H2 at room temperature for 8 hours, monitoring by TLC that the raw material reaction is complete, filtering, concentrating the reaction solution under reduced pressure, and separating the residue by column chromatography (eluent)Pure ethyl acetate) to obtain a light yellow solid, namely 3-methylpyrimidine-2,4 (1)H, 3H) -diketone (F-1) (15 g, 119 mmol). MS-ESI (m/z) 127.0[ m ] +H] + 。
Step B
1-isopropyl-3-methylpyrimidine-2,4 (1)H, 3H) -a diketone (F-2).
Weighing 3-methylpyrimidine-2,4 (1)H, 3H) -diketone (F-1) (11.9 g, 94.36 mmol) and isopropyl iodide (24 g, 141.2 mmol) were dissolved in 120ml of dimethyl sulfoxide, and potassium carbonate (26 g, 188 mmol) was added thereto and the reaction was stirred at 60 ℃ overnight. TLC to monitor the reaction completion of the starting material, then 240ml of water was added, extracted 6 times with 250ml each time of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was dry loaded and column chromatographed using eluent (petroleum ether: ethyl acetate first 10, then 5:1, and finally 1:1) to give a pale yellow solid (15.4 g, 91.56 mmol), i.e., 1-isopropyl-3-methylpyrimidine-2,4 (1H, 3H) -a diketone (F-2). MS-ESI (m/z) 169.0[ m + H ]] + 。
Step C
1-isopropyl-3-methyl-1,6-dihydro-2HPyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (F-3).
50ml of tetrahydrofuran was charged into a 250ml single-neck flask, cooled in an ice-water bath, and stirred at low temperature by adding 60% NaH (4 g, 100 mmol) in portions. Weighing 1-isopropyl-3-methylpyrimidine-2,4 (1)H, 3H) -diketone (F-2) (5 g, 29.73 mmol) and p-toluenesulfonylmethylisonitrile (8.8 g, 45 mmol) were dissolved in 80ml tetrahydrofuran, slowly added dropwise to the above 60% NaH tetrahydrofuran system in an ice water bath, removed from the ice water bath after completion of the addition, and reacted for 4 hours with stirring at room temperature. Dripping 5ml water via dropper to extract out, adding 120ml saturated sodium bicarbonate solution, extracting with ethyl acetate for 3 times (150 ml each time), mixing organic layers, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure. Pulping the crude product with 30ml of ethyl acetate for 30 minutes, and filtering to obtain 1-isopropyl-3-methyl-1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (F-3). MS-ESI (m/z) 208.0[ 2 ], [ M + H ]] + 。
Step D
1-isopropyl-3-methyl-6- (2,6-dimethylbenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (intermediate F).
Weighing 1-isopropyl-3-methyl-1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketone (F-3) (1 g, 4.83 mmol) and potassium carbonate (2 g, 14.5 mmol) in N, N-dimethylformamide 10ml, 2,6-dimethylbenzyl bromide (1.15 g, 5.8 mmol) was added, stirring was carried out overnight at room temperature, TLC monitored for completion of the starting material reaction, then 15ml of water was added, extraction was carried out 2 times with ethyl acetate, 20ml each time, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude column was chromatographed, eluting with eluent (petroleum ether: ethyl acetate first 15, then 10, then 5:1) to give a pale yellow solid (1.25 g, 3.84 mmol), i.e., 1-isopropyl-3-methyl-6- (2,6-dimethylbenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (intermediate F). MS-ESI (M/z) 326.0[ M + H [ ]] + 。
1-isopropyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2HPyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (intermediate G).
Figure 383726DEST_PATH_IMAGE013
。
Referring to the synthesis method of the intermediate F, 2,6-dimethylbenzyl bromide in the step D is replaced by naphthylmethyl bromide to prepare the intermediate G. MS-ESI (m/z) 348.0[ m ] +H] + 。
1-isopropyl-3-methyl-6- (3,5-difluoro-2-methoxybenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (intermediate H).
Figure 736210DEST_PATH_IMAGE014
。
Reference to the Synthesis of intermediate F, step D thereof2,6-dimethylbenzyl bromide was replaced with 3,5-difluoro-2-methoxybenzyl bromide to afford intermediate H. MS-ESI (m/z) 364.0[ 2 ], [ M + H ]] + 。
1-isopropyl-3-methyl-6- (2,3-dimethylbenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (intermediate I).
Figure 491807DEST_PATH_IMAGE015
。
Referring to the synthesis method of the intermediate F, 2,6-dimethylbenzyl bromide in the step D is replaced by 2,3-dimethylbenzyl bromide to prepare the intermediate I. MS-ESI (m/z) 326.0[ m ] +H] + 。
1-isopropyl-3-methyl-6- (2- (trifluoromethyl) benzyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (intermediate J).
Figure 929742DEST_PATH_IMAGE016
。
Referring to the synthesis method of the intermediate F, 2,6-dimethylbenzyl bromide in the step D is replaced by 2- (trifluoromethyl) benzyl bromide to prepare an intermediate J. MS-ESI (m/z) 366.0[ 2 ] M + H] + 。
1-isobutyl-3-methyl-6- (2,4,5-trifluorobenzyl) -1,6-dihydro-2HPyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (intermediate K).
Figure 412676DEST_PATH_IMAGE017
。
Referring to the synthesis method of the intermediate F, isopropyl iodide in the step B is replaced by iodo-isobutane, and 2,6-dimethylbenzyl bromide in the step D is replaced by 2,4,5-trifluorobenzyl bromide to prepare the intermediate K. MS-ESI (m/z) 366.0[ 2 ], [ M ] +H] + 。
1-isobutyl-3-methyl-6- (2,3-dimethylbenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (intermediate L).
Figure 695365DEST_PATH_IMAGE018
。
And (3) replacing isopropyl iodide in the step B with iodoisobutane by referring to the synthesis method of the intermediate F, and replacing 2,6-dimethyl benzyl bromide with 2,3-dimethyl benzyl bromide in the step D to prepare the intermediate L. MS-ESI (m/z) 340.0[ m ] +H] + 。
1-isobutyl-3-methyl-6- (2,6-dimethylbenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (intermediate M).
Figure 808814DEST_PATH_IMAGE019
。
And (4) replacing the isopropyl iodide in the step B with iodoisobutane by referring to the synthesis method of the intermediate F to prepare the intermediate M. MS-ESI (m/z) 340.0[ m ] +H] + 。
1,3-diisobutylpyrimidine-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (intermediate N)
Figure 530783DEST_PATH_IMAGE020
。
Step A
6-chloro-1,3-diisobutylpyrimidine-2,4 (1)H, 3H) -diketones (N-1).
6-chlorouracil (2.0 g, 13.7 mmol) and iodoisobutane (7.5 g, 41.0 mmol) were weighed out and dissolved in 30ml of dimethyl sulfoxide, and potassium carbonate (5.6 g, 41.0 mmol) was added and the reaction was stirred at 60 ℃ overnight. TLC monitored the starting material reaction was complete, then diluted with water, extracted 6 times with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was column chromatographed to give a pale yellow solid (1.8 g,7.0 mmol), i.e., 6-chloro-1,3-diisobutylpyrimidine-2,4 (1)H, 3H) -a diketone.
Step B
1,3-diisobutylpyrimidine-2,4 (1)H, 3H) -diketones (N-2).
The 6-chloro-1,3-diisobutylpyrimidine-2,4 (1)H, 3H) -Dione (N-1) (1.8 g,7.0 mmol) was added 10% Pd/C (360 mg), anhydrous ethanol 9ml, anhydrous tetrahydrofuran 9ml and triethylamine 710mg, N2 substitution was 2 times by stirring at room temperature for 4 hours by H2, TLC monitored that the raw materials reacted completely, followed by filtration, the reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography to give 1,3-diisobutylpyrimidine-2,4 (1.8 g,7.0 mmol) as a pale yellow solidH, 3H) -diketone (1.5 g,7.0 mmol). MS-ESI (m/z) 225.0[ 2 ], [ M + H ]] + 。
Steps C and D
1,3-diisobutylpyrimidine-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (intermediate N).
Referring to the synthetic procedure steps C and D of intermediate F, 1-isopropyl-3-methylpyrimidine-2,4 (1) of step C was preparedH, 3H) Replacement of-dione (F-2) with 1,3-diisobutylpyrimidine-2,4 (1)H, 3H) -diketone (N-2), 2,6-dimethylbenzyl bromide was replaced with naphthylmethyl bromide in step D to prepare intermediate N. MS-ESI (m/z) 404.0[ m ] +H] + 。
1- (1- ((triisopropylsilyl) oxy) propan-2-yl) -3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (intermediate O).
Figure 568140DEST_PATH_IMAGE021
。
Step A
(2-Bromopropoxy) triisopropylsilane (O-1).
1,2-propanediol (1.0 g, 13.6 mmol), imidazole (1.0 g, 14.9 mmol) were dissolved in acetonitrile (10 ml), followed by the addition of triisopropylchlorosilane (2.6 g, 13.6 mmol) for 2 hours at room temperature. The reaction solution was concentrated under reduced pressure, then diluted with water, extracted with ethyl acetate 2 times, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3.35g of a crude product of 1- ((triisopropylsilyl) oxy) propan-2-ol.
3.35g of crude 1- ((triisopropylsilyl) oxy) propan-2-ol was added triphenylphosphine (4.3 g, 16.3 mmol) and dissolved in 50ml of dichloromethane, and N-bromosuccinimide (2.9 g, 16.3 mmol) was added in portions, followed by stirring at room temperature for 2 hours. The reaction solution was directly concentrated and subjected to column chromatography (eluent: pure petroleum ether) to obtain 3.5g of (2-bromopropoxy) triisopropylsilane (O-1) as a product.
1- (1- ((triisopropylsilyl) oxy) propan-2-yl) -3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -diketones (intermediate O).
Referring to the synthesis method of intermediate F, isopropyl iodide in step B is replaced by (2-bromopropoxy) triisopropylsilane (O-1), and 2,6-dimethylbenzyl bromide in step D is replaced by naphthylmethyl bromide to prepare intermediate O. MS-ESI (m/z) 520.0[ m ] +H] + 。
Example 1
(S) -5- (4-hydroxyisoxazolidine-2-carbonyl) -1-ethyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione (1).
Figure 895216DEST_PATH_IMAGE022
。
Step A
1-Ethyl-3-methyl-6- (naphthalen-1-ylmethyl) -2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo [3,4-d]Pyrimidine-5-carbaldehyde (1 a).
Dissolving intermediate A (210 mg, 0.63 mmol) in anhydrous tetrahydrofuran (2.5 ml), cooling to-78 deg.C in liquid nitrogen acetone bath, adding 2.5M n-butyllithium solution (378 μ l, 0.95 mmol) dropwise, activating for 10min, adding anhydrous dimethylformamide 400 μ l, slowly raising to room temperature, diluting with water, extracting with ethyl acetate for three times, combining organic layers, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressureColumn chromatography (eluent cyclohexane: ethyl acetate =10:1 to 8:1 then 7:1) gave the yellow product (155.1 mg, 68% yield), i.e. 1-ethyl-3-methyl-6- (naphthalen-1-ylmethyl) -2,4-dioxo-2,3,4,6-tetrahydro-1%H-pyrrolo [3,4-d]Pyrimidine-5-carbaldehyde (1 a). MS-ESI (m/z) 362.0[ m ] +H] + 。
Step B
1-Ethyl-3-methyl-6- (naphthalen-1-ylmethyl) -2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo [3,4-d]Pyrimidine-5-carboxylic acid (1 b).
1-ethyl-3-methyl-6- (naphthalen-1-ylmethyl) -2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo [3,4-d]Adding ethanol (6.0 ml) into pyrimidine-5-formaldehyde (1 a) (155 mg), stirring uniformly, adding 1N sodium hydroxide (1.5 ml) and 30% hydrogen peroxide (1.5 ml), reacting at 40 ℃ for 1 hour, supplementing 30% hydrogen peroxide every other hour, supplementing 4 times (1.5 ml multiplied by 4), finally adding 1N sodium hydroxide (1.5 ml) and stirring at 40 ℃ for 1 hour. The reaction was concentrated under reduced pressure to remove ethanol, acidified with 2M hydrochloric acid, extracted three times with ethyl acetate, the organic layers combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and column chromatographed (eluent petroleum ether: ethyl acetate =8:1 to 5:1 and then 1:1) to give a yellow solid (54 mg, yield 33%) that was 1-ethyl-3-methyl-6- (naphthalen-1-ylmethyl) -2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo [3,4-d]Pyrimidine-5-carboxylic acid (1 b). MS-ESI (m/z) 378.0[ 2 ], [ M + H ]] + 。
Step C
（S) Isoxazolidin-4-ol hydrochloride (1 c).
Weighing N-hydroxyphthalimide (15 g, 92 mmol) and epichlorohydrin (7.5 ml), dissolving in N, N-dimethylformamide (100 ml), adding triethylamine (15 ml), heating to 50 ℃, stirring for reaction for 30 hours, monitoring by TLC that raw materials are completely reacted, adding anhydrous methanol (70 ml) and triethylamine (15 ml), continuing to react for 20 hours at 50 ℃, directly concentrating under reduced pressure while cooling, dissolving with saturated sodium bicarbonate (100 ml), extracting with ethyl acetate for 5 times (100 ml each time), combining organic layers, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure. The crude product is treated with acetic acidPulping 10ml of ethyl ester for 30 minutes, and filtering to obtain (A), (B)S) Methyl (4-hydroxyisoxazolidine-2-carbonyl) -2- (4-hydroxyisoxazolidine) -benzoate (3 g, 11.94 mmol).
Will (a) toS) Methyl (3 g, 11.94 mmol) 2- (4-hydroxyisoxazolidine-2-carbonyl) benzoate was added 4M hydrochloric acid (25 ml), warmed to 95 ℃ and refluxed for 7 hours, then cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was recrystallized from isopropanol (10 ml) to give a white solid (S) Isoxazolidine-4-ol hydrochloride (1 c) (1.1 g, 8.8 mmol).
Step D
1-ethyl-3-methyl-6- (naphthalen-1-ylmethyl) -2,4-dioxo-2,3,4,6-tetrahydro-1HPyrrolo [3,4-d]Pyrimidine-5-carboxylic acid (1 b) (54 mg, 0.14 mmol), (b), (c) and (d)S) Isoxazolidin-4-ol hydrochloride (1 c) (36 mg, 0.29 mmol),Oto benzotriazol-N, N, N ', N' -tetramethyluronium tetrafluoroborate (92 mg, 0.29 mmol) was added dichloromethane (1 ml), and after stirring well, diisopropylethylamine (125. Mu.l) was added and stirred at room temperature for 3 hours. The reaction solution was diluted with dichloromethane, washed three times with 2% aqueous potassium carbonate solution, once with 2% aqueous phosphoric acid solution, and the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by thin layer chromatography (developing solvent ethyl acetate: dichloromethane = 2:1) to give an off-white solid (30 mg, yield 46%). That is toS) -5- (4-hydroxyisoxazolidine-2-carbonyl) -1-ethyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (1). MS-ESI (m/z) 449.0[ m + H ]] + 。
1 H NMR （600MHz, CHLOROFORM-d） δ = 8.05 - 7.94 （m, 1H）, 7.86 （s, 2H）, 7.53 （ddd, J=2.2, 4.0, 6.2 Hz, 2H）, 7.47 - 7.42 （m, 1H）, 7.24 - 7.19 （m, 1H）, 6.27 （br s, 1H）, 5.74 （br s, 2H）, 4.71 （br s, 1H）, 4.53 - 4.41 （m, 1H）, 4.19 （br d, J=8.1 Hz, 1H）, 4.07 - 3.96 （m, 1H）, 3.81 - 3.68 （m, 3H）, 3.58 - 3.50 （m, 1H）, 3.37 （s, 3H）, 1.21 - 1.13 （m, 3H）。
Example 2
（S）-5- (4-hydroxyisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (2).
Figure 507463DEST_PATH_IMAGE023
。
Example 2 the title compound (2) was prepared following the procedure of example 1 substituting intermediate a of step a for intermediate B. MS-ESI (m/z) 477.0[ m + H ]] + 。
1 H NMR （600MHz, CHLOROFORM-d） δ = 7.96 （br s, 1H）, 7.92 - 7.88 （m, 1H）, 7.87 - 7.84 （m, 1H）, 7.58 - 7.50 （m, 2H）, 7.44 （s, 1H）, 7.19 - 7.13 （m, 1H）, 6.25 （br s, 1H）, 5.74 （br d, J=16.5 Hz, 2H）, 4.77 - 4.64 （m, 1H）, 4.57 - 4.39 （m, 1H）, 4.24 - 4.12 （m, 1H）, 4.08 - 3.95 （m, 1H）, 3.64 - 3.43 （m, 3H）, 3.37 （s, 3H）, 2.14 - 2.05 （m, 1H）, 0.94 - 0.78 （m, 6H）。
Example 3
（S) -5- (4-hydroxyisoxazolidine-2-carbonyl) -1-cyclopropylmethyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (3).
Figure 201881DEST_PATH_IMAGE024
。
Example 3 the title compound (3) was prepared following the procedure of example 1 substituting intermediate a of step a for intermediate C. MS-ESI (m/z) 475.0[ 2 ], [ M + H ]] + 。
1 H NMR （600MHz, CHLOROFORM-d） δ = 8.00 - 7.94 （m, 1H）, 7.92 - 7.84 （m, 2H）, 7.58 - 7.49 （m, 2H）, , 7.48 - 7.41 （m, 1H）, 7.20 （br d, J=6.6 Hz, 1H）, 6.24 （br s, 1H）, 5.71 - 5.62 （m, 1H）, 5.00 - 4.89 （m, 1H）, 4.72 （br s, 1H）, 4.53 - 4.45 （m, 1H）, 4.19 （br d, J=7.7 Hz, 1H）, 4.07 - 4.00 （m, 1H）, 3.82 - 3.68 （m, 2H）, 3.52 （br s, 1H）, 3.37 （s, 3H）, 2.41 - 2.30 （m, 1H）, 1.60 （br d, J=7.0 Hz, 1H）, 1.28 - 1.21 （m, 3H）。
Example 4
（S) -5- (4-hydroxyisoxazolidine-2-carbonyl) -1-isopentyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2HPyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (4).
Figure 229880DEST_PATH_IMAGE025
。
Example 4 the title compound (4) was prepared following the procedure of example 1 substituting intermediate a of step a for intermediate D. MS-ESI (m/z) 491.0[ 2 ], [ M ] +H] + 。
1 H NMR （600MHz, CHLOROFORM-d） δ = 7.97 （br s, 1H）, 7.92 - 7.88 （m, 1H）, 7.88 - 7.84 （m, 1H）, 7.58 - 7.49 （m, 2H）, 7.48 - 7.40 （m, 1H）, 7.21 （br d, J=5.9 Hz, 1H）, 6.23 （br s, 1H）, 5.74 （br s, 2H）, 4.71 （br s, 1H）, 4.48 （br d, J=7.0 Hz, 1H）, 4.17 （br s, 1H）, 4.02 （br s, 1H）, 3.76 - 3.63 （m, 3H）, 3.57 - 3.50 （m, 1H）, 3.40 - 3.34 （m, 3H）, 1.30 - 1.17 （m, 3H）, 0.84 （br d, J=4.0 Hz, 6H）。
Example 5
（S) -5- (4-hydroxyisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (2- (trifluoromethyl) benzyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (5).
Figure 473779DEST_PATH_IMAGE026
。
Example 5 the title compound (5) was prepared following the procedure of example 1 substituting intermediate a of step a for intermediate E. MS-ESI (m/z) 495.0[ m ] +H] + 。
1 H NMR （600MHz, CHLOROFORM-d） δ = 7.70 （br d, J=7.7 Hz, 1H）, 7.49 （br s, 1H）, 7.42 （br s, 1H）, 7.06 - 6.99 （m, 1H）, 6.30 （s, 1H）, 5.62 - 5.51 （m, 1H）, 5.44 - 5.36 （m, 1H）, 4.73 （br s, 1H）, 4.53 - 4.42 （m, 1H）, 4.25 - 4.15 （m, 1H）, 4.12 - 4.04 （m, 1H）, 3.75 - 3.68 （m, 1H）, 3.66 - 3.53 （m, 2H）, 3.39 （s, 3H）, 2.16 （br s, 1H）, 0.93 （br d, J=6.2 Hz, 6H）。
Example 6
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isopropyl-3-methyl-6- (2,6-dimethylbenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione (6).
Figure 742081DEST_PATH_IMAGE027
。
Step A
1-isopropyl-3-methyl-6- (2,6-dimethylbenzyl) -2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo [3,4-d]Pyrimidine-5-carbaldehyde (6 a).
1-isopropyl-3-methyl-6- (2,6-dimethylbenzyl) -2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo [3,4-d ] was prepared by substituting intermediate A for intermediate F according to the procedure of example 1, step A]Pyrimidine-5-carbaldehyde (6 a). MS-ESI (m/z) 354.0[ m ] +H] + 。
Step B
1-isopropyl-3-methyl-6- (2,6-dimethylbenzyl) -2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo [3,4-d]Pyrimidine-5-carboxylic acid (6 b).
Weighing 1-isopropyl-3-methyl-6- (2,6-dimethylbenzyl) -2,4-dioxo-2,3,4,6-tetrahydro-1HPyrrolo [3,4-d]Pyrimidine-5-carbaldehyde (6 a) (0.4 g, 1.13 mmol) was dissolved in anhydrous methanol (20 ml) in 35
Figure 641903DEST_PATH_IMAGE028
Freshly prepared silver oxide (2.08 g, 8.98 mmol) was added with stirring and then added dropwise3.75N sodium hydroxide (4.4 ml, 16.5 mmol), stirred at 35 deg.C for 3 hours, monitored by TLC for incomplete reaction, supplemented with silver oxide (1.6 g, 6.9 mmol) and 3.75N sodium hydroxide (2 ml, 7.5 mmol), and held at 35 deg.C for 2 hours. Filtering, concentrating the mother liquor under reduced pressure, extracting with ethyl acetate for 3 times (10 ml each time), mixing the organic layers, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure. The crude column was chromatographed using an eluent (petroleum ether: ethyl acetate first 10, then 5:1, and finally 3:1) to give a pale yellow solid (108 mg, 0.29 mmol), i.e., 1-isopropyl-3-methyl-6- (2,6-dimethylbenzyl) -2,4-dioxo-2,3,4,6-tetrahydro-1-tetrahydro-8H-pyrrolo [3,4-d]Pyrimidine-5-carboxylic acid (6 b). MS-ESI (m/z) 370.0[ m + H ], [] + 。
Step C
(S) -4-methyl isoxazolidine-4-ol hydrochloride (6 c).
Adding a 4A molecular sieve (100 g) into dichloromethane (400 ml), and cooling to an internal temperature of-30 to-35 under the protection of nitrogen
Figure 270331DEST_PATH_IMAGE028
Is then weighedDAdding diethyl (24.7 g, 0.6 mol) tartrate and isopropyl titanate (24.3 ml, 0.207 mol) into a reaction bottle, maintaining the temperature, stirring, adding methyl allyl alcohol (15.0 g, 207 mmol), slowly dropwise adding tert-phenylpropyl hydroperoxide (67 ml, 0.454 mol), maintaining the temperature, stirring for 1 hour after the addition is finished, and heating to-20%
Figure 382119DEST_PATH_IMAGE028
Stir overnight. The reaction was complete by TLC. Adding triethyl phosphite (60.2 g, 0.362 mol) dropwise to quench reaction, then adding DMAP (3.0 g, 0.024 mol) and triethylamine (43.8 ml, 0.31 mol), finally adding a dichloromethane solution (400 ml) of m-nitrobenzenesulfonyl chloride (40.5 g, 0.182 mol), keeping the whole process at-25 to-20 ℃, and heating to-13 to-10 ℃ after the dropwise addition is finished to react overnight. TLC detection of reaction completion, washing the mixture with 10% aqueous tartaric acid (500 ml), saturated sodium bicarbonate (300 ml), and saturated brine (300 ml), separating the organic layer and using anhydrousAnd (4) drying by using sodium sulfate. The crude product was purified by column chromatography (eluent dichloromethane: petroleum ether =2:1 to 4) to collect 34.3g of a pale yellow oil, that is, (dichloromethane: petroleum ether = 2)S) - (2-methyloxiran-2-yl) methyl 3-nitrobenzenesulfonate.
Will (a) toS) - (2-Methyloxieth-2-yl) methyl 3-nitrobenzenesulfonate (15.0 g, 0.055 mol) was dissolved in dichloromethane (50 ml), and N-hydroxyphthalimide (11.7 g, 0.071 mol) and triethylamine (24 ml, 0.17 mol) were added in that order, followed by stirring overnight at 30 ℃ and completion of the reaction detected by TLC. The reaction solution was washed with a saturated aqueous solution of sodium bicarbonate (60 ml), and the organic layer was directly concentrated under reduced pressure and purified by column chromatography (eluent dichloromethane: petroleum ether =1 to 1)S) -2- ((2-methyloxiran-2-yl) methoxy) isoindoline-1,3-dione.
Will (a) toS) -2- ((2-Methyloxieth-2-yl) methoxy) isoindoline-1,3-dione (7.0 g, 0.03 mol) was dissolved in concentrated hydrochloric acid (30 ml), rapidly dissolved at 30 ℃ and stirred for 2h, and the reaction was checked by TLC to completion. Then, water (60 ml) was slowly added to dilute and quench the reaction, and then dichloromethane (80 ml) was added to extract, and the organic layer was separated and dried over anhydrous sodium sulfate and column chromatography purification (eluent ethyl acetate: dichloromethane =1S) -2- (3-chloro-2-hydroxy-2-methylpropoxy) isoindoline-1,3-dione.
Will (a) toS) -2- (3-chloro-2-hydroxy-2-methylpropoxy) isoindoline-1,3-dione (2.7 g, 0.1 mol) was dissolved in methanol (20 ml), triethylamine (2.6 ml) was added, the temperature was raised to 75 ℃ and the reaction was refluxed for 2 hours, and the reaction was completed as checked by TLC. After the reaction solution is concentrated, the reaction solution is directly recrystallized for 2 times by using acetonitrile, the dosage of each time is about 8ml, and 2.01g of white solid product is obtained in total collection (namely: (S) -methyl 2- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) benzoate.
Will (a) toS) Methyl (2.01 g, 0.007 mol) 2- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) benzoate was added with 2N HCl (15 ml), heated to 105 ℃ for reflux reaction for 5hMS detection essentially complete. Cooling the reaction solution to room temperature, filtering, discarding the solid, concentrating the water layer under reduced pressure to dryness, recrystallizing with acetonitrile-methyl tert-butyl ether =1:5 to obtain a white solid product, and weighing 940mgS) -4-methyl isoxazolidine-4-ol hydrochloride (6 c).
Step D
The title compound (6) was prepared by substituting compound 1b for compound 6b and compound 1c for compound 6c according to the procedure of example 1, step D. MS-ESI (m/z) 455.0[ deg. ] M + H] + 。
1 H NMR （600MHz, CHLOROFORM-d） δ = 7.24 - 7.18 （m, 1H）, 7.14 - 7.08 （m, 2H）, 6.01 - 5.92 （m, 1H）, 5.49 - 5.38 （m, 1H）, 5.18 - 5.05 （m, 1H）, 4.68 - 4.52 （m, 1H）, 4.50 - 4.36 （m, 1H）, 4.18 - 4.08 （m, 1H）, 3.93 - 3.82 （m, 1H）, 3.52 - 3.38 （m, 1H）, 3.34 （s, 3H）, 2.30 （s, 6H）, 1.54 （br s, 3H）, 1.33 （br d, J=6.6 Hz, 6H）。
Example 7
（S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isopropyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (7).
Figure 8272DEST_PATH_IMAGE029
。
Example 7 the title compound (7) was prepared following the procedure for example 6 substituting intermediate F of step a for intermediate G. MS-ESI (m/z) 477.0[ M + H ]] + 。
1 H NMR （600MHz, CHLOROFORM-d） δ = 8.03 - 7.95 （m, 1H）, 7.92 - 7.88 （m, 1H）, 7.88 - 7.84 （m, 1H）, 7.54 （br s, 2H）, 7.44 （s, 1H）, 7.18 （br d, J=6.6 Hz, 1H）, 6.41 - 6.30 （m, 1H）, 5.74 （br d, J=19.1 Hz, 2H）, 4.73 - 4.59 （m, 1H）, 4.44 - 4.34 （m, 1H）, 4.11 （br d, J=7.0 Hz, 1H）, 3.82 （br d, J=7.7 Hz, 1H）, 3.35 （s, 4H）, 1.50 （br s, 3H）, 1.35 （br d, J=4.8 Hz, 6H）。
Example 8
（S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isopropyl-3-methyl-6- (3,5-difluoro-2-methoxybenzyl) -1,6-dihydro-2-carbonylH-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (8).
Figure 926550DEST_PATH_IMAGE030
。
Example 8 the title compound (8) was prepared following the procedure for example 6 substituting intermediate F of step a with intermediate H. MS-ESI (m/z) 493.0[ m + H ]] + 。
1 H NMR （600MHz, CHLOROFORM-d） δ = 7.00 （br s, 1H）, 6.89 （br t, J=9.9 Hz, 1H）, 6.54 （br s, 1H）, 5.35 （br d, J=15.0 Hz, 1H）, 5.12 （br d, J=14.7 Hz, 1H）, 4.83 - 4.69 （m, 1H）, 4.44 （br d, J=11.0 Hz, 1H）, 4.10 （br d, J=7.7 Hz, 1H）, 3.90 - 3.78 （m, 4H）, 3.45 - 3.39 （m, 1H）, 3.34 （s, 3H）, 1.53 （br s, 3H）, 1.46 （br d, J=6.2 Hz, 6H）。
Example 9
（S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isopropyl-3-methyl-6- (2,3-dimethylbenzyl) -1,6-dihydro-2HPyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (9).
Figure 109401DEST_PATH_IMAGE031
。
Example 9 the title compound (9) was prepared following the procedure for example 6 substituting intermediate F of step a for intermediate I. MS-ESI (m/z) 455.0[ deg. ] M + H] + 。
1 H NMR （600MHz, CHLOROFORM-d） δ = 7.15 （br d, J=7.3 Hz, 1H）, 7.12 - 7.03 （m, 1H）, 6.83 - 6.74 （m, 1H）, 6.32 （br s, 1H）, 5.39 - 5.31 （m, 1H）, 5.26 - 5.17 （m, 1H）, 4.80 - 4.65 （m, 1H）, 4.42 - 4.33 （m, 1H）, 4.15 - 4.05 （m, 1H）, 3.85 - 3.77 （m, 1H）, 3.42 - 3.32 （m, 4H）, 2.30 （s, 3H）, 2.17 （s, 3H）, 1.50 （br s, 3H）, 1.41 （br s, 6H）。
Example 10
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isopropyl-3-methyl-6- (2- (trifluoromethyl) benzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione (10).
Figure 265575DEST_PATH_IMAGE032
。
Step A
1-isopropyl-3-methyl-6- (2- (trifluoromethyl) benzyl) -2,4-dioxo-2,3,4,6-tetrahydro-1HPyrrolo [3,4-d]Pyrimidine-5-carboxylic acid (10 a).
Weighing intermediate J (284 mg, 0.78 mmol), dissolving in tetrahydrofuran 4ml, cooling to-78 deg.C with liquid nitrogen, adding 2.5M n-butyl lithium (600 ul, 1.5 mmol) dropwise, stirring for 20 min, introducing carbon dioxide continuously, and reacting at naturally elevated temperature (-78 deg.C to room temperature) for 3 h. Adding 5ml of water for extraction and sterilization reaction, adjusting the pH value to 3 by using 2M hydrochloric acid, extracting for 2 times by using ethyl acetate, 10ml of each time, combining organic layers, drying by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a crude product (90 mg), namely 1-isopropyl-3-methyl-6- (2- (trifluoromethyl) benzyl) -2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo [3,4-d]Pyrimidine-5-carboxylic acid (10 a). MS-ESI (m/z) 410.0[ m ] +H] + 。
Step B
The title compound (10) was prepared by the method of example 1, step D, substituting compound 1b for compound 10a and compound 1c for compound 6 c. MS-ESI (m/z) 495.0[ m ] +H] + 。
1 H NMR （600MHz, CHLOROFORM-d） δ = 7.74 - 7.67 （m, 1H）, 7.52 - 7.47 （m, 1H）, 7.46 - 7.38 （m, 1H）, 7.12 - 7.03 （m, 1H）, 6.41 （s, 1H）, 5.62 - 5.50 （m, 1H）, 5.43 - 5.33 （m, 1H）, 4.83 - 4.70 （m, 1H）, 4.43 - 4.33 （m, 1H）, 4.16 - 4.08 （m, 1H）, 3.90 - 3.82 （m, 1H）, 3.44 - 3.28 （m, 4H）, 1.51 （br s, 3H）, 1.43 （br d, J=5.9 Hz, 6H）。
Example 11
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (2,4,5-trifluorobenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione (11).
Figure 124947DEST_PATH_IMAGE033
。
Step A
1-isobutyl-3-methyl-6- (2,4,5-trifluorobenzyl) -2,4-dioxo-2,3,4,6-tetrahydro-1HPyrrolo [3,4-d]Pyrimidine-5-carbaldehyde (11 a)
Preparation of 1-isobutyl-3-methyl-6- (2,4,5-trifluorobenzyl) -2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo [3,4-d by substituting intermediate A with intermediate K and n-butyllithium with lithium diisopropylamide following the procedure of step A of example 1]Pyrimidine-5-carbaldehyde (11 a). MS-ESI (m/z) 394.0[ m ] +H] + 。
Step B
1-isobutyl-3-methyl-6- (2,4,5-trifluorobenzyl) -2,4-dioxo-2,3,4,6-tetrahydro-1HPyrrolo [3,4-d]Pyrimidine-5-carboxylic acid (11 b)
Compound 11a (250 mg, 0.65 mmol) was dissolved in acetonitrile (12 ml), cooled in an ice-water bath, and then sodium chlorite (3.9 ml, 3.91 mmol) and sodium dihydrogen phosphate (78.3 mg, 0.65 mmol) were added, and the mixture was reacted at 0~3 ℃ for 3 hours, followed by TLC detection of substantial completion of the reaction. Adding saturated Na into the reaction solution 2 S 2 O 3 Quenching reaction with water solution (3 ml), extracting with ethyl acetate twice (10 ml each time), mixing organic layers, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with crude column chromatography (eluent is ethyl acetate: petroleum ether = 1:5) to obtain pale yellow solid product 54mg, i.e. pale yellow solid product1-isobutyl-3-methyl-6- (2,4,5-trifluorobenzyl) -2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo [3,4-d]Pyrimidine-5-carboxylic acid (11 b). MS-ESI (m/z) 410.0[ m ] +H] + 。
Step C
The title compound (11) was prepared by the method of example 1 step D, substituting compound 1b for compound 11b and substituting compound 1c for compound 6 c. MS-ESI (m/z) 495.0[ m ] +H] + 。
1 H NMR （600MHz, CHLOROFORM-d） δ = 7.09 （br d, J=8.8 Hz, 1H）, 7.02 - 6.92 （m, 1H）, 6.40 （s, 1H）, 5.39 （br d, J=15.4 Hz, 1H）, 5.12 （br d, J=15.4 Hz, 1H）, 4.40 （br d, J=10.6 Hz, 1H）, 4.11 （br d, J=6.6 Hz, 1H）, 3.86 （br d, J=7.0 Hz, 1H）, 3.65 （br d, J=7.3 Hz, 1H）, 3.61 - 3.53 （m, 1H）, 3.47 - 3.39 （m, 1H）, 3.37 （s, 3H）, 2.21 - 2.13 （m, 1H）, 1.53 （br s, 3H）, 0.95 （br d, J=5.9 Hz, 6H）。
Example 12
（S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (2,3-dimethylbenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (12).
Figure 546832DEST_PATH_IMAGE034
。
Example 12 the title compound (12) was prepared following the procedure for example 6 substituting intermediate F of step a for intermediate L. MS-ESI (m/z) 469.0[ 2 ], [ M + H ]] + 。
1 H NMR （600MHz, CHLOROFORM-d） δ = 7.15 （br d, J=7.3 Hz, 1H）, 7.08 （br d, J=7.7 Hz, 1H）, 6.80 - 6.68 （m, 1H）, 6.21 （br s, 1H）, 5.41 - 5.17 （m, 2H）, 4.43 - 4.30 （m, 1H）, 4.13 - 4.04 （m, 1H）, 3.84 - 3.76 （m, 1H）, 3.66 - 3.56 （m, 1H）, 3.55 - 3.45 （m, 1H）, 3.37 （s, 4H）, 2.30 （s, 3H）, 2.16 （s, 4H）, 1.54 - 1.44 （m, 3H）, 0.91 （br d, J=5.1 Hz, 6H）。
Example 13
（S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (2,6-dimethylbenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (13).
Figure 517062DEST_PATH_IMAGE035
。
Example 13 the title compound (13) was prepared following the procedure for example 6 substituting intermediate F of step a for intermediate M. MS-ESI (m/z) 469.0[ 2 ], [ M + H ]] + 。
1 H NMR （600MHz, CHLOROFORM-d） δ = 7.24 - 7.20 （m, 1H）, 7.11 （br d, J=7.0 Hz, 2H）, 5.89 - 5.82 （m, 1H）, 5.49 - 5.40 （m, 1H）, 5.17 - 5.08 （m, 1H）, 4.51 - 4.42 （m, 1H）, 4.17 - 4.09 （m, 1H）, 3.94 - 3.85 （m, 1H）, 3.59 - 3.32 （m, 6H）, 2.28 （br s, 6H）, 2.07 - 2.02 （m, 1H）, 1.54 （br s, 3H）, 0.91 - 0.78 （m, 6H）。
Example 14
（S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2HPyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (14).
Figure 527744DEST_PATH_IMAGE036
。
Example 14 the title compound (14) was prepared following the procedure for example 6 substituting intermediate F of step a for intermediate B. MS-ESI (m/z) 491.0[ m + H ], [] + 。
1 H NMR （600MHz, CHLOROFORM-d） δ = 8.00 - 7.93 （m, 1H）, 7.92 - 7.88 （m, 1H）, 7.88 - 7.83 （m, 1H）, 7.56 - 7.49 （m, 2H）, 7.46 - 7.41 （m, 1H）, 7.18 - 7.12 （m, 1H）, 6.28 - 6.20 （m, 1H）, 5.82 - 5.68 （m, 2H）, 4.45 - 4.34 （m, 1H）, 4.11 （br d, J=7.3 Hz, 1H）, 3.81 （br d, J=7.7 Hz, 1H）, 3.62 - 3.51 （m, 1H）, 3.51 - 3.43 （m, 1H）, 3.37 （s, 4H）, 2.08 （br d, J=5.5 Hz, 1H）, 1.50 （br s, 3H）, 0.93 - 0.81 （m, 6H）。
Example 15
（S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1,3-diisobutyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (15).
Figure 308749DEST_PATH_IMAGE037
。
Example 15 the title compound (15) was prepared following the procedure for example 10 substituting intermediate J of step a with intermediate N. MS-ESI (m/z) 533.0[ m + H ], [] + 。
1 H NMR （600MHz, CHLOROFORM-d） δ = 8.03 - 7.94 （m, 1H）, 7.93 - 7.88 （m, 1H）, 7.88 - 7.83 （m, 1H）, 7.58 - 7.49 （m, 2H）, 7.48 - 7.41 （m, 1H）, 7.20 - 7.13 （m, 1H）, 6.25 - 6.19 （m, 1H）, 5.81 - 5.66 （m, 2H）, 4.44 - 4.36 （m, 1H）, 4.09 - 4.01 （m, 1H）, 3.90 - 3.77 （m, 3H）, 3.63 - 3.54 （m, 1H）, 3.48 - 3.41 （m, 1H）, 3.40 - 3.34 （m, 1H）, 2.15 - 2.05 （m, 2H）, 1.49 （s, 3H）, 0.98 - 0.78 （m, 12H）。
Example 16
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1- (1-hydroxypropan-2-yl) -3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione (16).
Figure 404881DEST_PATH_IMAGE038
。
Step A
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1- (1- ((triisopropylsilyl) oxy) propan-2-yl) -3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2HPyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (16 a).
Compound 16a was prepared according to the procedure for example 10 substituting intermediate J of step a for intermediate O to afford compound 16a. MS-ESI (m/z) 649.0[ m + H ], [ solution of calcium ] and] + 。
step B
Compound 16a (177 mg; 0.27 mmol) was dissolved in anhydrous tetrahydrofuran (11 ml), tetrabutylammonium fluoride (430 mg, 1.64 mmol) was added, and the mixture was stirred at room temperature overnight. Directly concentrating the reaction solution, separating by column chromatography, and separating by thin layer chromatography to obtain 73mg of product (i.e., (S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1- (1-hydroxypropan-2-yl) -3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (16). MS-ESI (m/z) 493.0[ m + H ]] + 。
1 H NMR (600 MHz, Chloroform-d) δ 7.99 (s, 1H), 7.92 – 7.85 (m, 2H), 7.57 – 7.50 (m, 2H), 7.45 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 6.32 (s, 1H), 5.72 (s, 2H), 4.40 (s, 1H), 4.21 – 4.08 (m, 2H), 3.94 (s, 1H), 3.86 – 3.76 (m, 2H), 3.48 – 3.38 (m, 1H), 3.34 (s, 3H), 1.51 (s, 3H), 1.36 (s, 3H)。
Example 17
（R) -5- (2- (hydroxymethyl) pyrrolidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (17).
Figure 178802DEST_PATH_IMAGE039
。
Example 17 is a procedure as in example 6, substituting intermediate F for intermediate B and compound 6c for intermediate B in step aR-prolinol to prepare the title compound (17).MS-ESI（m/z）:489.0[M+H] + 。
1 H NMR (600 MHz, Chloroform-d) δ 7.99 – 7.92 (m, 1H), 7.91 – 7.84 (m, 2H), 7.52 (dd, J = 6.4, 3.3 Hz, 2H), 7.44 (t, J = 7.7 Hz, 1H), 7.33 (d, J = 7.0 Hz, 1H), 6.49 (s, 1H), 5.84 (d, J = 15.1 Hz, 1H), 5.58 (d, J = 15.1 Hz, 1H), 4.36 – 4.31 (m, 1H), 4.01 (t, J = 7.8 Hz, 1H), 3.69 (dd, J = 13.8, 7.7 Hz, 1H), 3.57 (dd, J = 13.7, 7.3 Hz, 1H), 3.39 (d, J = 12.0 Hz, 1H), 3.34 (s, 3H), 3.21 (s, 2H), 2.42 (t, J = 8.0 Hz, 1H), 2.23 – 2.16 (m, 1H), 2.00 – 1.92 (m, 1H), 1.84 – 1.75 (m, 1H), 1.62 (s, 1H), 0.98 – 0.93 (m, 6H)。
Example 18
（S) -5- (2- (hydroxymethyl) pyrrolidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (18).
Figure 119688DEST_PATH_IMAGE040
。
Example 18 is a procedure as in example 6, substituting intermediate F for intermediate B and compound 6c for intermediate B in step aS-prolinol to give the title compound (18). MS-ESI (m/z) 489.0[ m + H ], [ solution of calcium and calcium ]] + 。
1 H NMR (600 MHz, Chloroform-d) δ 7.98 – 7.93 (m, 1H), 7.92 – 7.84 (m, 2H), 7.55 – 7.49 (m, 2H), 7.47 – 7.42 (m, 1H), 7.33 (d, J = 7.0 Hz, 1H), 6.49 (s, 1H), 5.84 (d, J = 15.2 Hz, 1H), 5.58 (d, J = 15.1 Hz, 1H), 4.34 (dd, J = 11.5, 2.4 Hz, 1H), 4.01 (t, J = 8.0 Hz, 1H), 3.69 (dd, J = 13.7, 7.6 Hz, 1H), 3.57 (dd, J = 13.8, 7.3 Hz, 1H), 3.39 (dd, J = 12.0, 2.4 Hz, 1H), 3.34 (s, 3H), 3.25 – 3.19 (m, 2H), 2.46 – 2.39 (m, 1H), 2.25 – 2.15 (m, 1H), 2.02 – 1.92 (m, 1H), 1.83 – 1.74 (m, 1H), 1.66 – 1.59 (m, 1H), 0.98 – 0.92 (m, 6H)。
Example 19
（R）-5-(3-hydroxypyrrolidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2HPyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (19).
Figure 320863DEST_PATH_IMAGE041
。
Example 19 is a procedure as in example 6, substituting intermediate F of step a with intermediate B, and substituting compound 6c with (B)R) -3-hydroxypyrrolidine hydrochloride to thereby prepare the title compound (19). MS-ESI (m/z) 475.0[ m + H ]] + 。
1 H NMR (600 MHz, Chloroform-d) δ 7.99 – 7.82 (m, 3H), 7.56 – 7.49 (m, 2H), 7.47 – 7.41 (m, 1H), 7.25 – 7.19 (m, 1H), 6.49 (s, 1H), 5.88 – 5.78 (m, 1H), 5.63 – 5.56 (m, 1H), 4.26 (d, J = 12.8 Hz, 1H), 4.10 – 3.38 (m, 6H), 3.34 (s, 3H), 2.23 – 2.16 (m, 1H), 2.06 – 1.75 (m, 2H), 0.94 (dd, J = 6.5, 2.9 Hz, 6H)。
Example 20
N- ((1-Hydroxycyclopropyl) methyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo [3,4-d]Pyrimidine-5-carboxamide (20).
Figure 638712DEST_PATH_IMAGE042
。
Example 20 the title compound (20) was prepared according to the procedure for example 6 substituting intermediate F of step a for intermediate B and compound 6c for 1- (aminomethyl) cyclopropanol. MS-ESI (m/z) 475.0[ 2 ], [ M + H ]] + 。
1 H NMR (600 MHz, Chloroform-d) δ 11.10 (s, 1H), 7.94 – 7.87 (m, 2H), 7.84 (d, J = 8.2 Hz, 1H), 7.55 – 7.50 (m, 2H), 7.41 (t, J = 7.7 Hz, 1H), 6.97 (d, J = 7.0 Hz, 1H), 6.40 (s, 2H), 6.31 (s, 1H), 3.59 (d, J = 5.1 Hz, 2H), 3.52 (d, J = 7.3 Hz, 2H), 3.45 (s, 3H), 2.08 – 1.96 (m, 1H), 0.85 (s, 2H), 0.80 (d, J = 6.6 Hz, 6H), 0.65 (s, 2H)。
Example 21
5- (4-hydroxypiperidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2HPyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (21).
Figure 967056DEST_PATH_IMAGE043
。
Example 21 the title compound (21) was prepared according to the procedure for example 6 substituting intermediate F of step a for intermediate B and compound 6c for 4-hydroxypiperidine hydrochloride. MS-ESI (m/z) 489.0[ m + H ], [ solution of calcium and calcium ]] + 。
1 H NMR (600 MHz, Chloroform-d) δ 7.97 – 7.93 (m, 1H), 7.93 – 7.82 (m, 2H), 7.56 – 7.49 (m, 2H), 7.47 – 7.39 (m, 1H), 7.24 (d, J = 7.1 Hz, 1H), 6.48 (s, 1H), 5.89 – 5.79 (m, 1H), 5.54 – 5.47 (m, 1H), 4.17 (d, J = 13.3 Hz, 1H), 3.96 – 3.50 (m, 4H), 3.34 (s, 3H), 3.28 – 3.11 (m, 2H), 2.27 – 2.13 (m, 1H), 1.67 – 1.44 (m, 4H), 0.95 (dd, J = 6.9, 3.6 Hz, 6H)。
Example 22
（R) -5- (2- (hydroxymethyl) azetidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2HPyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (22).
Figure 14646DEST_PATH_IMAGE044
。
Example 22 the title compound (22) was prepared following the procedure for example 6 substituting intermediate F of step a with intermediate B and compound 6c with (R) -2-hydroxymethylazetidine. MS-ESI (m/z) 475.0[ m + H ]] + 。
1 H NMR (600 MHz, Chloroform-d) δ 7.94 – 7.87 (m, 3H), 7.57 – 7.50 (m, 2H), 7.47 (t, J = 7.7 Hz, 1H), 7.20 (d, J = 7.0 Hz, 1H), 6.47 (s, 1H), 5.85 – 5.64 (m, 2H), 4.50 – 3.49 (m, 7H), 3.37 (s, 3H), 2.25 – 1.99 (m, 3H), 0.93 (d, J = 6.6 Hz, 6H)。
Example 23
5- (3-hydroxyazetidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (23).
Figure 324405DEST_PATH_IMAGE045
。
Example 23 the title compound (23) was prepared according to the procedure for example 6 substituting intermediate F of step a with intermediate B and compound 6c with 3-hydroxyazetidine hydrochloride. MS-ESI (m/z) 461.0[ m ] +H] + 。
1 H NMR (600 MHz, Chloroform-d) δ 7.94 – 7.85 (m, 3H), 7.56 – 7.50 (m, 2H), 7.46 (t, J = 7.7 Hz, 1H), 7.19 (d, J = 7.1 Hz, 1H), 6.44 (s, 1H), 5.73 (s, 2H), 4.46 – 3.68 (m, 5H), 3.59 (d, J = 8.2 Hz, 2H), 3.36 (s, 3H), 2.22 – 2.13 (m, 1H), 0.92 (d, J = 6.5 Hz, 6H)。
Example 24
（S) -5- (2- (hydroxymethyl) azetidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3)H) -a diketone (24).
Figure 942599DEST_PATH_IMAGE046
。
Example 24 the title compound (24) was prepared following the procedure for example 6 substituting intermediate F of step a with intermediate B and compound 6c with (S) -2-hydroxymethylazetidine. MS-ESI (m/z) 475.0[ m + H ]] + 。
1 H NMR (600 MHz, Chloroform-d) δ 7.94 – 7.87 (m, 3H), 7.57 – 7.50 (m, 2H), 7.47 (t, J = 7.7 Hz, 1H), 7.20 (d, J = 7.0 Hz, 1H), 6.47 (s, 1H), 5.85 – 5.64 (m, 2H), 4.50 – 3.49 (m, 7H), 3.37 (s, 3H), 2.25 – 1.99 (m, 3H), 0.93 (d, J = 6.6 Hz, 6H)。
Example 25
(S) -6- ([ 1,1' -biphenyl ] -4-ylmethyl) -5- (4-hydroxy-4-methyl isoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione (25).
Figure 996006DEST_PATH_IMAGE047
。
Step A
Figure 898103DEST_PATH_IMAGE048
。
1-isobutyl-3-methyl-1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione (P-1).
And (3) replacing isopropyl iodide in the step B with iodoisobutane by referring to the synthesis method of the intermediate F, the step A, B and the step C to prepare the P-1.MS-ESI (m/z) 222.0[ m ] +H] + 。
1-isobutyl-3-methyl-6- (phenylsulfonyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione (intermediate P).
Figure 191812DEST_PATH_IMAGE049
。
Weighing intermediate P-1 (12.4 g, 56 mmol) in N, N-dimethylformamide 120ml, cooling with ice water to 0 deg.C, adding 60% NaH (3.5 g, 84 mmol) in portions, stirring for 10min, then adding benzenesulfonyl chloride (12.0 g, 67mmol) dropwise at 0 deg.C, moving to room temperature, stirring for 1h, adding 500ml of water, extracting for quenching reaction, extracting with ethyl acetate for 3 times (300 ml each time), combining organic layers, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure. The crude column was chromatographed using eluent (petroleum ether: ethyl acetate 5:1 followed by dichloromethane and finally petroleum ether: ethyl acetate 1:1) to give a pale yellow solid (15.9 g, 44 mmol) as intermediate P.MS-ESI(m/z):362.0[M+H] + 。
Weighing intermediate P (3 g, 8.3 mmol), dissolving in tetrahydrofuran 33ml, cooling with liquid nitrogen to-78 deg.C, dropwise adding lithium diisopropylamide (6.5ml, 13mmol), stirring for 50 min, introducing carbon dioxide without interruption, and naturally heating to (-78 deg.C to room temperature) for reaction for 4 hr. 40ml of water was added to the reaction mixture, the pH was adjusted to 3 with 2N hydrochloric acid, and the mixture was extracted 2 times with 50ml of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
Dissolving the residue in anhydrous methanol 130ml, adding potassium carbonate (2.2 g,15.9 mmol), stirring at room temperature for 3 hr, directly concentrating the reaction solution, adding water 40ml, adjusting pH to 3 with 2N hydrochloric acid, extracting with ethyl acetate for 2 times (50 ml each time), combining organic layers, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain crude product 1.5g, i.e. 1-isobutyl-3-methyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo [3,4-d]Pyrimidine-5-carboxylic acid (25 b). MS-ESI (m/z) 266.0[ 2 ], [ M + H ]] + 。
Step B
Dichloromethane (25 ml) was added to compound 25b (520 mg, 2.0 mmol), (S) -isoxazolidine-4-methyl-4-ol hydrochloride (360 mg, 2.6 mmol), and O-benzotriazole-N, N' -tetramethyluronium tetrafluoroborate (945 mg, 2.9 mmol), and after stirring, diisopropylethylamine (2.7 ml) was added thereto, and the mixture was stirred at room temperature for 3 hours. The reaction was directly concentrated and the residue was column chromatographed using eluent (petroleum ether: ethyl acetate 5:1, then petroleum ether: ethyl acetate 1:1, finally ethyl acetate: methanol 10) to give a tan oil (630mg, 1.8mmol), i.e. (S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3H) -dione (25 c). MS-ESI (m/z) 351.0[ 2 ], [ M ] +H] + 。
Step C
Weighing the compound (25 c) (100 mg, 0.29 mmol) in the step B and potassium carbonate (119 mg, 0.86 mmol) in N, N-dimethylformamide (4 ml), adding 4-bromomethylbiphenyl (106 mg, 0.43 mmol), stirring at room temperature overnight, monitoring the completion of the raw material reaction by TLC, adding 20ml of water, extracting with dichloromethane for 3 times (8 ml each), combining the organic layers, extracting with 8ml of water for 1 time, drying the organic layer,Filtering, and concentrating under reduced pressure. The crude column chromatography, eluting with eluent (petroleum ether: dichloromethane first 10, then dichloromethane, finally dichloromethane: methanol 20) gave 130mg of tan oil, which was then separated by thin layer chromatography (developing solvent dichloromethane: ethyl acetate = 2:1) 2 times to give 44mg of a light yellow solid, i.e. (S) -6- ([ 1,1' -biphenyl]-4-ylmethyl) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-1,6-dihydro-2H-pyrrolo [3,4-d]Pyrimidine-2,4 (3H) -dione (25). MS-ESI (m/z) 517.0[ m ] +H] + 。
1 H NMR (600 MHz, Chloroform-d) δ 7.56 (t, J = 7.2 Hz, 5H), 7.44 (t, J = 7.7 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.28 (s, 1H), 6.39 (s, 1H), 5.41 (d, J = 15.3 Hz, 1H), 5.18 (d, J = 15.3 Hz, 1H), 4.39 (d, J = 11.4 Hz, 1H), 4.09 (d, J = 8.2 Hz, 1H), 3.80 (d, J = 8.2 Hz, 1H), 3.69 – 3.64 (m, 1H), 3.58 – 3.53 (m, 1H), 3.40 (d, J = 11.9 Hz, 1H), 3.37 (s, 3H), 2.21 – 2.15 (m, 1H), 1.52 – 1.45 (m, 3H), 0.94 (dd, J = 6.8, 3.2 Hz, 6H)。
Example 26
(S) -6- (cyclohexylmethyl) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione (26).
Figure 749832DEST_PATH_IMAGE050
。
Example 26 the title compound (26) was prepared by the method of example 25 substituting 4-bromomethylbiphenyl of step C with bromomethylcyclohexane. MS-ESI (m/z) 447.0[ m ] +H] + 。
1 H NMR (600 MHz, Chloroform-d) δ 6.35 (s, 1H), 4.42 (d, J = 11.3 Hz, 1H), 4.13 – 4.01 (m, 2H), 3.89 (d, J = 8.1 Hz, 1H), 3.79 – 3.67 (m, 2H), 3.62 – 3.52 (m, 1H), 3.46 (d, J = 11.5 Hz, 1H), 3.36 (s, 3H), 2.25 – 2.17 (m, 1H), 1.81 – 1.57 (m, 5H), 1.53 (s, 3H), 1.29 – 1.12 (m, 4H), 0.97 (dd, J = 6.7, 3.2 Hz, 6H), 0.95 – 0.81 (m, 2H)。
Example 27
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (pyridin-4-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione (27).
Figure 403667DEST_PATH_IMAGE051
。
Example 27 the title compound (27) was prepared according to the procedure for example 25 substituting 4- (bromomethyl) pyridylbenzyl for 4-bromomethyl biphenyl of step C. MS-ESI (m/z) 442.0[ m ] +H] + 。
1 H NMR (600 MHz, Chloroform-d) δ 8.59 (s, 2H), 7.07 (s, 2H), 6.39 (s, 1H), 5.46 (d, J = 16.6 Hz, 1H), 5.16 (d, J = 16.4 Hz, 1H), 4.34 (d, J = 11.3 Hz, 1H), 4.11 (d, J = 8.5 Hz, 1H), 3.82 (d, J = 8.2 Hz, 1H), 3.71 – 3.64 (m, 1H), 3.61 – 3.55 (m, 1H), 3.38 (s, 3H), 3.35 (d, J = 11.5 Hz, 1H), 2.24 – 2.14 (m, 1H), 1.50 (s, 3H), 0.95 (dd, J = 6.9, 3.7 Hz, 6H)。
Example 28
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (quinolin-8-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione (28).
Figure 173653DEST_PATH_IMAGE052
。
Example 28 the title compound (28) was prepared by the method of example 25 substituting 4-bromomethylbiphenyl of step C with 8-bromomethylquinoline. MS-ESI (m/z) 492.0[ m ] +H] + 。
1 H NMR (600 MHz, Chloroform-d) δ 8.97 (s, 1H), 8.23 (d, J = 8.3 Hz, 1H), 7.81 (s, 1H), 7.51 (s, 3H), 6.71 (s, 1H), 6.12 (d, J = 15.8 Hz, 1H), 5.88 (d, J = 15.7 Hz, 1H), 4.41 (d, J = 11.3 Hz, 1H), 4.09 (d, J = 7.8 Hz, 1H), 3.83 (d, J = 8.0 Hz, 1H), 3.63 – 3.59 (m, 1H), 3.58 – 3.54 (m, 1H), 3.45 – 3.40 (m, 1H), 3.36 (s, 3H), 2.14 (dt, J = 13.9, 7.0 Hz, 1H), 1.51 (s, 3H), 0.91 (d, J = 6.7 Hz, 6H)。
Example 29
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (pyridin-2-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione (29).
Figure 825214DEST_PATH_IMAGE053
。
Example 29 the title compound (29) was prepared according to the procedure for example 25 substituting 4-bromomethylbiphenyl of step C with 2- (bromomethyl) pyridylbromide. MS-ESI (m/z) 442.0[ 2 ], [ M ] +H] + 。
1 H NMR (600 MHz, Chloroform-d) δ 8.50 (s, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.19 – 7.15 (m, 2H), 6.48 (s, 1H), 5.37 (d, J = 15.7 Hz, 1H), 5.21 (d, J = 15.3 Hz, 1H), 4.33 (d, J = 11.3 Hz, 1H), 4.06 – 4.02 (m, 1H), 3.78 (d, J = 8.0 Hz, 1H), 3.60 – 3.56 (m, 1H), 3.54 – 3.49 (m, 1H), 3.35 (d, J = 11.2 Hz, 1H), 3.30 (s, 3H), 2.16 – 2.07 (m, 1H), 1.45 (s, 3H), 0.87 (d, J = 6.7 Hz, 6H)。
Example 30
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (4-fluoro-2-cyanobenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione (30).
Figure 667268DEST_PATH_IMAGE054
。
Example 30 the title compound (30) was prepared according to the procedure for example 25 substituting 4-bromomethylbiphenyl of step C with 4-fluoro-2-cyanobenzyl bromide. MS-ESI (m/z) 484.0[ 2 ], [ M ] +H] + 。
1 H NMR (600 MHz, Chloroform-d) δ 7.40 (dd, J = 7.7, 2.7 Hz, 1H), 7.37 – 7.32 (m, 1H), 7.31 – 7.27 (m, 1H), 6.48 (s, 1H), 5.54 (d, J = 16.0 Hz, 1H), 5.36 (d, J = 15.8 Hz, 1H), 4.38 (d, J = 11.4 Hz, 1H), 4.12 (dd, J = 8.2, 5.2 Hz, 1H), 3.86 (d, J = 8.2 Hz, 1H), 3.62 (d, J = 7.5 Hz, 2H), 3.41 (d, J = 11.3 Hz, 1H), 3.37 (s, 3H), 2.18 (dq, J = 13.7, 7.1 Hz, 1H), 1.53 (s, 3H), 0.95 (dd, J = 6.7, 2.7 Hz, 6H)。
Example 31
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (benzo [ d ] thiazol-2-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione (31).
Figure 875527DEST_PATH_IMAGE055
。
Example 31 the title compound (31) was prepared by the method of example 25 substituting 4-bromomethylbiphenyl of step C with 2- (bromomethyl) benzothiazole. MS-ESI (m/z) 498.0[ m ] +H] + 。
1 H NMR (600 MHz, Chloroform-d) δ 8.03 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 6.63 (s, 1H), 5.79 (d, J = 15.8 Hz, 1H), 5.58 (d, J = 15.8 Hz, 1H), 4.41 (d, J = 11.1 Hz, 1H), 4.16 – 4.12 (m, 1H), 3.93 – 3.88 (m, 1H), 3.68 – 3.60 (m, 2H), 3.51 – 3.46 (m, 1H), 3.37 (s, 3H), 2.21 – 2.14 (m, 1H), 1.53 (s, 3H), 0.94 (d, J = 6.7 Hz, 6H)。
Example 32
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (2-fluoro-3-methylbenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione (32).
Figure 689899DEST_PATH_IMAGE056
。
Example 32 the title compound (32) was prepared according to the procedure for example 25 substituting 4-bromomethylbiphenyl of step C with 2-fluoro-3-methylbenzyl bromide. MS-ESI (m/z) 473.0[ m ] +H] + 。
1 H NMR (600 MHz, Chloroform-d) δ 7.15 (s, 1H), 6.99 (d, J = 7.0 Hz, 2H), 6.42 (s, 1H), 5.44 (d, J = 15.4 Hz, 1H), 5.17 (d, J = 15.4 Hz, 1H), 4.39 (d, J = 11.3 Hz, 1H), 4.08 (d, J = 8.0 Hz, 1H), 3.81 (d, J = 8.1 Hz, 1H), 3.67 (s, 1H), 3.55 (d, J = 10.3 Hz, 1H), 3.42 (d, J = 11.5 Hz, 1H), 3.36 (s, 3H), 2.28 (s, 3H), 2.17 (dt, J = 13.8, 6.8 Hz, 1H), 1.51 (s, 3H), 0.94 (d, J = 6.8 Hz, 6H)。
Example 33
(S) -5- (4-hydroxy-4-methyl isoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (3,5-difluoro-2-methoxybenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione (33).
Figure 574678DEST_PATH_IMAGE057
。
Example 33 the title compound (33) was prepared according to the procedure for example 25 substituting 3,5-difluoro-2-methoxybenzyl bromide for 4-bromomethylbiphenyl of step C. MS-ESI (m/z) 507.0[ m ] +H] + 。
1 H NMR (600 MHz, Chloroform-d) δ 6.95 (t, J = 7.8 Hz, 1H), 6.89 (t, J = 10.0 Hz, 1H), 6.41 (s, 1H), 5.36 (d, J = 15.2 Hz, 1H), 5.12 (d, J = 15.3 Hz, 1H), 4.43 (d, J = 11.4 Hz, 1H), 4.11 (d, J = 8.1 Hz, 1H), 3.82 (d, J = 32.9 Hz, 4H), 3.61 (t, J = 8.8 Hz, 2H), 3.42 (d, J = 11.7 Hz, 1H), 3.36 (s, 3H), 2.17 (dp, J = 13.8, 6.6 Hz, 1H), 1.53 (s, 3H), 0.95 (d, J = 6.7 Hz, 6H)。
Example 34
(S) -5- (4-hydroxy-4-methyl isoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (2,6-difluorobenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione (34).
Figure 654761DEST_PATH_IMAGE058
。
Example 34 the title compound was prepared according to the procedure for example 25 substituting 4-bromomethylbiphenyl of step C with 2,6-difluorobenzyl bromide（34）。MS-ESI(m/z):477.0[M+H] + 。
1 H NMR (600 MHz, Chloroform-d) δ 7.34 (t, J = 7.5 Hz, 1H), 6.98 – 6.92 (m, 2H), 6.42 (s, 1H), 5.58 (d, J = 14.9 Hz, 1H), 5.20 (d, J = 14.9 Hz, 1H), 4.42 (d, J = 11.3 Hz, 1H), 4.07 (d, J = 8.2 Hz, 1H), 3.86 (d, J = 8.1 Hz, 1H), 3.72 – 3.67 (m, 1H), 3.53 – 3.46 (m, 2H), 3.34 (s, 3H), 2.15 (dq, J = 13.8, 6.9 Hz, 1H), 1.54 (s, 3H), 0.95 – 0.91 (m, 6H)。
Example 35
(S) -3- (4-hydroxyisoxazolidine-2-carbonyl) -7-isopropyl-5-methyl-2- (naphthalen-1-ylmethyl) -2,7-dihydro-4H-pyrazolo [3,4-d ] pyrimidine-4,6 (5H) -dione (35).
Figure 853661DEST_PATH_IMAGE059
。
Step A
6-chloro-1-isopropyl-3-methyluracil (35 a).
Weighing 6-chloro-3-methyl uracil (30 g, 187 mmol) into a 500ml round bottom flask, adding potassium carbonate (52 g,374 mmol), isopropyl iodide (64g, 374mmol) and dimethyl sulfoxide (300ml), stirring overnight at 60 ℃ in an oil bath, adding ice water (800 ml) to the reaction solution, quenching, extracting with ethyl acetate (3 times 400 ml) each time, combining the organic layers, concentrating under reduced pressure, adding 2N HCl (150ml) and 1,4-dioxane (120ml) to the residue, stirring overnight at 60 ℃ in an oil bath, directly concentrating the reaction solution to about half volume, extracting with ethyl acetate (3 times 200ml each time, combining the organic layers, washing with 2% potassium carbonate (2 times 300ml each time), washing the organic layer with saturated saline (300 ml), drying the organic layer with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a pale yellow solid, namely 6-chloro-1-isopropyl-3-methyl uracil (35 a) (9.6 g, 47.4 mmol). MS-ESI (m/z) 203.0[ 2 ], [ M + H ]] + 。
Step B
1-isopropyl-3-methyl-6- (2- (naphthalen-1-ylmethylene) hydrazino) pyrimidine-2,4 (1)H,3H) -a diketone (35 b).
6-chloro-1-isopropyl-3-methyluracil from step A (4.0 g, 19.7 mmol) was weighed out and dissolved in 20ml of absolute ethanol, followed by addition of 2.8ml of hydrazine hydrate and heating to 75 ℃ and refluxing for 5 hours.
Then the reaction liquid is cooled to room temperature, and is directly decompressed and concentrated, the residue is dissolved in 220ml of warm methanol, then 4ml of 1-naphthaldehyde is added, the mixture is stirred for 2 hours at room temperature, the precipitated solid is filtered, the toluene is used for beating for 2 times, 30ml is added for each time, and the light yellow solid, namely 1-isopropyl-3-methyl-6- (2- (naphthalene-1-yl methylene) hydrazino) pyrimidine-2,4 (1) is obtained by filteringH,3H) -diketone (35 b) (2.3g, 6.84mmol). MS-ESI (m/z) 337.0[ deg. ] M + H] + 。
Step C
7-isopropyl-5-methyl-2- (naphthalen-1-ylmethyl) -4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo [3,4-d]Pyrimidine-3-carboxylic acid ethyl ester (35 c).
Weighing 1-isopropyl-3-methyl-6- (2- (naphthalene-1-ylmethylene) hydrazino) pyrimidine-2,4 (1) in step BH,3H) Diketone (1.9 g, 5.65 mmol) and ethyl glyoxylate (713mg, 7.0 mmol), 100ml of N, N-dimethylformamide are added, the temperature is raised to 100 ℃ and stirring is carried out for 16 hours, then cooling is carried out to room temperature, 200ml of ethyl acetate are added, then washing is carried out twice with 0.5N of hydrochloric acid, 100ml each time, the organic layers are combined, washing is carried out twice with a saturated sodium bicarbonate solution, 150ml each time, and finally washing is carried out once with 150ml of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and column chromatographed (eluent petroleum ether: ethyl acetate =10: 1) to give 7-isopropyl-5-methyl-2- (naphthalen-1-ylmethyl) -4,6-dioxo-4,5,6,7-tetrahydro-2-tetrahydro-5H-pyrazolo [3,4-d]Pyrimidine-3-carboxylic acid ethyl ester (35 c) (1.4 g, yield 59%). MS-ESI (m/z) 421.0[ 2 ], [ M ] +H] + 。
Step D
7-isopropyl-5-methyl-2- (naphthalen-1-ylmethyl) -4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo [3,4-d]Pyrimidine-3-carboxylic acid (35 d)
The 7-isopropyl-5-methyl-2- (naphthalen-1-ylmethyl) -4,6-dioxo-4,5,6,7-tetrahydro-2 of step CH-pyrazolo [3,4-d]Pyrimidine-3-carboxylic acid ethyl ester (1.4 g, 3.33 mmol) was dissolved in 30ml of tetrahydrofuran and 30ml of water, and lithium hydroxide (280mg, 6.67mmol) was added thereto, followed byStirring at room temperature overnight, adjusting pH =3 with 2N HCl, separating out solids, directly filtering, washing the filter cake with isopropanol to obtain a white solid (1.04 g, 79.6% yield) 7-isopropyl-5-methyl-2- (naphthalen-1-ylmethyl) -4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo [3,4-d]Pyrimidine-3-carboxylic acid (35 d). MS-ESI (m/z) 393.0[ m ] +H] + 。
Step E
(S) -3- (4-hydroxyisoxazolidine-2-carbonyl) -7-isopropyl-5-methyl-2- (naphthalen-1-ylmethyl) -2,7-dihydro-4H-pyrazolo [3,4-d]Pyrimidine-4,6 (5)H) -a diketone (35).
The 7-isopropyl-5-methyl-2- (naphthalen-1-ylmethyl) -4,6-dioxo-4,5,6,7-tetrahydro-2-carbonyl of step DH-pyrazolo [3,4-d]Pyrimidine-3-carboxylic acid (48 mg, 0.12 mmol), (b), (c) and (d)S) Isoxazolidine-4-ol hydrochloride (23 mg, 0.18 mmol),Odichloromethane (2 ml) was added to benzotriazol-N, N, N ', N' -tetramethyluronium tetrafluoroborate (59 mg, 0.18 mmol), and after stirring uniformly, diisopropylethylamine (148. Mu.l) was added thereto and stirred at room temperature for 3 hours. The reaction solution was diluted with dichloromethane, washed three times with 2% aqueous potassium carbonate solution, once with 2% aqueous phosphoric acid solution, and the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by thin layer chromatography (developing solvent ethyl acetate: dichloromethane = 2:1) to give an off-white solid (23 mg, yield 40%). I.e. (S) -3- (4-hydroxyisoxazolidine-2-carbonyl) -7-isopropyl-5-methyl-2- (naphthalen-1-ylmethyl) -2,7-dihydro-4H-pyrazolo [3,4-d]Pyrimidine-4,6 (5)H) -a diketone (35). MS-ESI (m/z) 464.0[ m ] +H] + 。
1 H NMR (600MHz, CHLOROFORM-d) δ = 8.21 - 8.16 (m, 1H), 7.91 - 7.79 (m, 2H), 7.57 - 7.48 (m, 2H), 7.45 - 7.38 (m, 1H), 7.30 - 7.27 (m, 1H), 5.92 (q, J=15.5 Hz, 2H), 5.13 (td, J=6.6, 13.7 Hz, 1H), 4.69 - 4.58 (m, 1H), 4.37 (br d, J=12.1 Hz, 1H), 4.01 (br d, J=8.4 Hz, 1H), 3.69 (br d, J=5.9 Hz, 1H), 3.45 - 3.37 (m, 1H), 3.37 - 3.27 (m, 3H), 1.67 - 1.49 (m, 6H)。
Example 36
(S) -3- (4-hydroxyisoxazolidine-2-carbonyl) -7-isobutyl-5-methyl-2- (naphthalene-1-ylmethyl) -2,7-dihydro-4H-pyrazolo [3,4-d]Pyrimidine-4,6 (5)H) -a diketone (36).
Figure 584857DEST_PATH_IMAGE060
。
Example 36 the title compound (36) was prepared by the method of example 35 substituting isopropyl iodide for iodo-isobutane in step a. MS-ESI (m/z) 478.0[ 2 ] M + H] + 。
1 H NMR (600MHz, CHLOROFORM-d) δ = 8.13 (br d, J=7.7 Hz, 1H), 7.88 - 7.79 (m, 2H), 7.51 (quin, J=6.7 Hz, 2H), 7.40 (br t, J=7.3 Hz, 1H), 7.24 (br d, J=5.9 Hz, 1H), 5.92 (q, J=15.3 Hz, 2H), 4.61 (br s, 1H), 4.33 (br d, J=11.7 Hz, 1H), 4.00 (br d, J=7.7 Hz, 1H), 3.87 (br d, J=7.3 Hz, 2H), 3.65 (br s, 1H), 3.40 (br d, J=10.3 Hz, 1H), 3.35 (s, 3H), 2.34 - 2.23 (m, 1H), 1.07 - 0.91 (m, 6H)。
Example 37
(S) -3- (4-hydroxyisoxazolidine-2-carbonyl) -7-isopropyl-5-methyl-2- (2- (trifluoromethyl) benzyl) -2,7-dihydro-4H-pyrazolo [3,4-d ] pyrimidine-4,6 (5H) -dione (37).
Figure 391270DEST_PATH_IMAGE061
。
Example 37 the title compound (37) was prepared by the method of example 35 substituting 1-naphthaldehyde from step B with o-trifluorobenzaldehyde. MS-ESI (m/z) 482.0[ m ] +H] + 。
1H NMR (600MHz, CHLOROFORM-d) δ = 7.70 (br d, J=7.7 Hz, 1H), 7.53 - 7.45 (m, 1H), 7.42 (br d, J=7.3 Hz, 1H), 6.99 (br d, J=7.3 Hz, 1H), 5.73 (br d, J=16.1 Hz, 1H), 5.65 - 5.49 (m, 1H), 5.14 - 5.02 (m, 1H), 4.75 (br s, 1H), 4.48 (br d, J=11.4 Hz, 1H), 4.27 - 4.18 (m, 1H), 4.08 (br s, 1H), 3.56 - 3.46 (m, 1H), 3.37 (s, 3H), 1.50 (br d, J=6.6 Hz, 6H)。
Example 38
(S) -3- (4-hydroxyisoxazolidine-2-carbonyl) -7-isobutyl-5-methyl-2- (2- (trifluoromethyl) benzyl) -2,7-dihydro-4H-pyrazolo [3,4-d]Pyrimidine-4,6 (5)H) -a diketone (38).
Figure 145599DEST_PATH_IMAGE062
。
Example 38 the title compound (38) was prepared according to the procedure for example 35 substituting isopropyl iodide for iodo-isobutane in step a and 1-naphthaldehyde for o-trifluorobenzaldehyde in step B. MS-ESI (m/z) 496.0[ 2 ], [ M ] +H] + 。
1 H NMR (600MHz, CHLOROFORM-d) δ = 7.69 (br d, J=7.7 Hz, 1H), 7.46 (br s, 1H), 7.41 (br d, J=7.3 Hz, 1H), 6.92 (br d, J=7.7 Hz, 1H), 5.73 (br d, J=16.1 Hz, 1H), 5.65 - 5.47 (m, 1H), 4.76 (br s, 1H), 4.54 - 4.39 (m, 1H), 4.22 (br s, 1H), 4.15 - 3.99 (m, 1H), 3.91 - 3.77 (m, 2H), 3.60 - 3.44 (m, 1H), 3.39 (s, 3H), 2.25 (qt, J=6.8, 13.5 Hz, 1H), 0.91 (d, J=6.6 Hz, 6H)。
Example 39
(S) -3- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -7-isopropyl-5-methyl-2- (naphthalen-1-ylmethyl) -2,7-dihydro-4H-pyrazolo [3,4-d]Pyrimidine-4,6 (5)H) -a diketone (39).
Figure 210507DEST_PATH_IMAGE063
。
Example 39 is a process according to example 35, step E (S) -isoxazolidine-4-alkoxide with (S) -4-methylisoxazolidine-4-ol hydrochloride to prepare the title compound (39). MS-ESI (m/z) 478.0[ 2 ], [ M ] +H] + 。
1 H NMR (600 MHz, Chloroform-d) δ 8.18 (d, J = 8.3 Hz, 1H), 7.88 – 7.81 (m, 2H), 7.57 – 7.48 (m, 3H), 7.41 (t, J = 7.7 Hz, 1H), 5.96 (d, J = 15.3 Hz, 1H), 5.90 (d, J = 15.3 Hz, 1H), 5.13 (p, J = 7.0 Hz, 1H), 4.28 (d, J= 11.4 Hz, 1H), 3.92 (d, J = 8.2 Hz, 1H), 3.49 (d, J = 8.4 Hz, 1H), 3.33 (s, 3H), 3.25 (d, J = 11.3 Hz, 1H), 1.56 – 1.51 (m, 6H), 1.44 (s, 3H)。
Example 40
(S) -3- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -7-isobutyl-5-methyl-2- (naphthalen-1-ylmethyl) -2,7-dihydro-4H-pyrazolo [3,4-d]Pyrimidine-4,6 (5)H) -a diketone (40).
Figure 544012DEST_PATH_IMAGE064
。
Example 40 is a method as in example 35, substituting isopropyl iodide for iodoisobutane in step A, and (of step E)S) -isoxazolidine-4-alkoxide is replaced by (S) -4-methylisoxazolidine-4-ol hydrochloride to prepare the title compound (40). MS-ESI (m/z) 492.0[ m ] +H] + 。
1 H NMR (600MHz, CHLOROFORM-d) δ = 8.15 - 8.09 (m, 1H), 7.89 - 7.84 (m, 1H), 7.84 - 7.80 (m, 1H), 7.55 - 7.48 (m, 2H), 7.42 - 7.37 (m, 1H), 7.24 - 7.19 (m, 1H), 5.96 (br d, J=15.4 Hz, 1H), 5.93 - 5.85 (m, 1H), 4.26 (br d, J=11.4 Hz, 1H), 3.97 - 3.89 (m, 1H), 3.87 (br d, J=7.3 Hz, 2H), 3.48 - 3.43 (m, 1H), 3.35 (s, 3H), 3.26 - 3.20 (m, 1H), 2.28 (td, J=6.7, 13.3 Hz, 1H), 1.44 (s, 3H), 0.99 - 0.89 (m, 6H)。
EXAMPLE 41
(S) -3- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -7-isopropyl-5-methyl-2- (2- (trifluoromethyl) benzyl) -2,7-dihydro-4H-pyrazolo [3,4-d]Pyrimidine-4,6 (5)H) -a diketone (41).
Figure 770594DEST_PATH_IMAGE065
。
Example 41 is toFollowing the procedure of example 35, the 1-naphthaldehyde from step B was replaced with o-trifluorobenzaldehyde and step E thereof (S) -isoxazolidine-4-alkoxide with (S) -4-methylisoxazolidine-4-ol hydrochloride to prepare the title compound (41). MS-ESI (m/z) 496.0[ 2 ], [ M ] +H] + 。
1 H NMR (600 MHz, Chloroform-d) δ 7.70 (d, J = 7.8 Hz, 1H), 7.47 (t, J= 7.9 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 5.74 (d, J= 16.7 Hz, 1H), 5.56 (d, J = 16.6 Hz, 1H), 5.09 (q, J = 7.2 Hz, 1H), 4.39 (d, J = 11.4 Hz, 1H), 4.13 (d, J = 8.1 Hz, 1H), 3.86 (d, J = 8.1 Hz, 1H), 3.37 (s, 4H), 2.81 (s, 3H), 1.49 (d, J = 6.8 Hz, 6H)。
Example 42
(S) -3- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -7-isobutyl-5-methyl-2- (2- (trifluoromethyl) benzyl) -2,7-dihydro-4H-pyrazolo [3,4-d]Pyrimidine-4,6 (5)H) -a diketone (42).
Figure 12219DEST_PATH_IMAGE066
。
Example 42 is a process as in example 35, substituting isopropyl iodide for iodo-isobutane in step A, substituting 1-naphthalene formaldehyde for o-trifluorobenzaldehyde in step B, and substituting (c) of step ES) -isoxazolidine-4-alkoxide with (S) -4-methylisoxazolidine-4-ol hydrochloride to prepare the title compound (42). MS-ESI (m/z) 510.0[ 2 ], [ M + H ]] + 。
1 H NMR (600 MHz, Chloroform-d) δ 7.69 (d, J = 7.7 Hz, 1H), 7.49 – 7.43 (m, 1H), 7.43 – 7.38 (m, 1H), 6.92 (d, J = 7.7 Hz, 1H), 5.74 (d, J = 16.9 Hz, 1H), 5.56 (d, J = 16.6 Hz, 1H), 4.40 – 4.35 (m, 1H), 4.13 (s, 1H), 3.88 – 3.81 (m, 3H), 3.42 – 3.35 (m, 4H), 2.25 (dt, J = 14.3, 7.3 Hz, 1H), 1.52 (s, 3H), 0.94 – 0.88 (m, 6H)。
Example 43
(S) -3- (3-hydroxypyrrolidine-1-carbonyl) -7-isopropyl-5-methyl-2- (2- (trifluoromethyl) benzyl) -2,7-dihydro-4HPyrazolo [3,4-d]Pyrimidine-4,6 (5)H) -a diketone (43).
Figure 365972DEST_PATH_IMAGE067
。
Example 43 is a process as in example 35, substituting the 1-naphthaldehyde from step B with o-trifluorobenzaldehyde and step E with: (S) -isoxazolidine-4-alkoxide with (S) -3-hydroxypyrrolidine, thereby preparing the title compound (43). MS-ESI (m/z) 480.0[ m ] +H] + 。
1 H NMR (600 MHz, Chloroform-d) δ 7.70 (d, J = 7.8 Hz, 1H), 7.55 – 7.48 (m, 1H), 7.47 – 7.39 (m, 1H), 7.22 – 7.15 (m, 1H), 5.78 – 5.69 (m, 1H), 5.56 – 5.47 (m, 1H), 5.13 – 5.08 (m, 1H), 4.46 – 3.42 (m, 5H), 3.36 (s, 3H), 2.23 – 1.75 (m, 2H), 1.56 – 1.45 (m, 6H)。
Example 44
(S) -3- (3-hydroxypyrrolidine-1-carbonyl) -7-isopropyl-5-methyl-2- (naphthalen-1-ylmethyl) -2,7-dihydro-4H-pyrazolo [3,4-d]Pyrimidine-4,6 (5)H) -a diketone (44).
Figure 743863DEST_PATH_IMAGE068
。
Example 44 is a process according to example 35, which is stage E ofS) -isoxazolidine-4-alkoxide with (S) -3-hydroxypyrrolidine, thereby preparing the title compound (44) MS-ESI (m/z): 462.0, [ M ] +H] + 。
1 H NMR (600 MHz, Chloroform-d) δ 8.26 – 8.06 (m, 1H), 7.89 – 7.81 (m, 2H), 7.55 – 7.39 (m, 4H), 5.99 – 5.82 (m, 2H), 5.21 (p, J = 7.1 Hz, 1H), 4.45 – 3.36 (m, 4H), 3.31 – 3.22 (m, 4H), 2.02 – 1.72 (m, 2H), 1.69 – 1.60 (m, 6H)。
Example 45
5- ((3-hydroxypropyl) thio) -1-isopropyl-3-methyl-6- (2- (trifluoromethyl) benzyl) pyrido [2,3-d]Pyrimidine-2,4 (1)H, 3H) -a diketone (45).
Figure 406926DEST_PATH_IMAGE069
。
Step A
6-chloro-3-methyluracil (40 g, 249 mmol) and isopropyl iodide (68 g, 399 mmol) were weighed out and dissolved in 350ml of dimethyl sulfoxide, and potassium carbonate (70 g, 498 mmol) was added thereto and the reaction was stirred at 60 ℃ overnight. TLC monitors the reaction of the raw materials is complete, then 1000ml water is added, extraction with ethyl acetate is carried out for 4 times, organic layers are combined, then 700ml water and 600ml saturated sodium chloride aqueous solution are respectively washed once, and the organic layers are dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 25.1g of crude oily matter. Then, 25.1g of the crude product was added to 200ml of 1,4-dioxane and 250ml of 2N aqueous hydrochloric acid solution, and the mixture was stirred at 60 ℃ overnight. The mixture was concentrated under reduced pressure to remove 1,4-dioxane, and then extracted with ethyl acetate 4 times at 200ml each time. The organic layers were combined, washed with a 2% aqueous solution of potassium carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 12.4g of a crude oily substance. The crude column was chromatographed, eluting with eluent (petroleum ether: ethyl acetate first 200, then 20, then 1, finally 10) to give a pale yellow solid (12.3 g, 60.7 mmol), i.e. 6-chloro-1-isopropyl-3-methylpyrimidine-2,4 (1H, 3H) -a diketone.
Weighing 6-chloro-1-isopropyl-3-methylpyrimidine-2,4 (1)H, 3H) Adding (3.6 g, 17.8 mmol) of-diketone (3.6 g) into a sealed tube, adding 10ml of acetonitrile and 20ml of 28% ammonia water, sealing at 80 ℃ for reaction for 2 hours, then supplementing 20ml of 28% ammonia water, sealing for reaction overnight, then concentrating the reaction solution under reduced pressure, recrystallizing and filtering with methanol-methyl tert-butyl ether, and drying a filter cake in vacuum to obtain 3.6g of light pink solid, namely 6-amino-1-isopropyl-3-methylpyrimidine-2,4 (1)H, 3H) -a diketone. MS-ESI (m/z) 184.0[ m ] +H] + 。
Step B
After cooling triethylamine 27ml in an ice bath, formic acid 18.5ml was added dropwise, o-trifluoromethylbenzaldehyde (10.5 g, 60.3 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (10.0 g, 69.4 mmol) were added and the reaction was refluxed at 100 ℃ for 2.5 hours. Then the reaction was cooled to room temperature, 100ml of water was added, the pH was adjusted to 3 with 2N hydrochloric acid, extracted three times with dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried under vacuum to give 14.3g of a solid, i.e., o-trifluoromethylphenylpropionic acid.
Adding 14.3g of o-trifluoromethylphenylpropionic acid into 37ml of dichloromethane, cooling in an ice bath, adding 33.3ml of thionyl chloride, dripping 1 drop of dimethylformamide, refluxing for 1 hour, and concentrating the reaction solution under reduced pressure until the volume is not reduced any more to obtain a crude product. Namely o-trifluoromethylphenylpropionyl chloride.
The 6-amino-1-isopropyl-3-methylpyrimidine-2,4 (1)H, 3H) 3.6g of the-diketone was dissolved in 15ml of pyridine, 6.0g of o-trifluoromethylphenylpropanoyl chloride was added thereto, and the reaction was stirred at 90 ℃ for 2 hours. The reaction solution was diluted with 100ml of 2N aqueous hydrochloric acid, extracted with ethyl acetate 3 times, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried under vacuum to give 3.0g of a yellow solid, i.e., 6-amino-1-isopropyl-3-methyl-5- (3- (2- (trifluoromethyl) phenyl) propionyl) pyrimidine-2,4 (1)H, 3H) -a diketone. MS-ESI (m/z) 384.0[ 2 ], [ M ] +H] + 。
Step C
The 6-amino-1-isopropyl-3-methyl-5- (3- (2- (trifluoromethyl) phenyl) propionyl) pyrimidine-2,4 (1)H, 3H) The diketone (1.7 g, 4.44 mmol) was dissolved in 20ml of dimethylformamide, 0.8ml of N-dimethylformamide dimethyl acetal was added, and the reaction was carried out overnight at 100 ℃. Cooling the reaction solution to room temperature, adding saturated sodium chloride solution, extracting with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain crude product, separating by chromatography, eluting with eluent (petroleum ether: ethyl acetate 6:1) to obtain 1.6g of 5-hydroxy-1-isopropyl-3-methyl-6- (2- (trifluoromethyl) benzyl) pyrido [2,3-d]Pyrimidine-2,4 (1)H, 3H) -a diketone. MS-ESI (m/z) 394.0[ 2 ], [ M + H ]] + 。
Step D
5-hydroxy-1-isopropyl-3-methyl-6- (2- (trifluoromethyl) benzyl) pyrido [2,3-d]Pyrimidine-2,4 (1)H, 3H) Adding 5ml of phosphorus oxychloride into the diketone, reacting at 100 ℃ for 24 hours, concentrating the reaction solution under reduced pressure to a small volume, slowly dripping the reaction solution into a potassium carbonate aqueous solution, extracting twice with ethyl acetate, washing an organic layer once with a saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a crude product of 780mg, namely 5-chloro-1-isopropyl-3-methyl-6- (2- (trifluoromethyl) benzyl) pyrido [2,3-d]Pyrimidine-2,4 (1)H, 3H) -a diketone. ESI (m/z) 412.0, 414.0[ M ] +H] + 。
Step E
5-chloro-1-isopropyl-3-methyl-6- (2- (trifluoromethyl) benzyl) pyrido [2,3-d]Pyrimidine-2,4 (1)H, 3H) 60mg of-diketone was dissolved in 5ml of dimethylformamide, 50mg of potassium carbonate was added, and 0.575M of 3-mercapto-1-propanol was further added to react at 100 ℃ for 2 hours. Cooling the reaction solution to room temperature, adding water for dilution, extracting twice with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain crude product, and separating by thin layer chromatography to obtain 29.4mg of 5- ((3-hydroxypropyl) thio) -1-isopropyl-3-methyl-6- (2- (trifluoromethyl) benzyl) pyrido [2,3-d]Pyrimidine-2,4 (1)H, 3H) -a diketone. ESI (m/z) 412.0, 468.0[ M ] +H] + 。
1 H NMR (600 MHz, Chloroform-d) δ 8.18 (s, 1H), 7.72 (d, J = 8.1, 1H), 7.45 – 7.39 (m, 1H), 7.35 (t, J = 7.7 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H), 5.81 – 5.72 (br s, 1H), 4.51 (s, 2H), 3.76 – 3.68 (m, 3H), 3.46 (s, 3H), 3.10 – 3.05 (m, 2H), 1.82 – 1.77 (m, 2H), 1.59 – 1.53 (m, 6H)。
Biological activity assay
1. Inhibition of K562 cell proliferation
Materials and reagents
MTS detection kit (Promega), RPMI-1640 culture medium (GIBCO), fetal bovine serum (BI), penicillin (Sigma), streptomycin (Sigma), and dimethyl sulfoxide (Sigma).
Cell proliferation inhibitory Activity
The inhibition of K562 cell proliferation by compounds was tested for MCT1 inhibition. K562 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum. After collecting and counting cells, 60000 cell suspensions were prepared in 2% serum medium, mixed well and seeded into 96-well plates (i.e., 3000 cells/well in plating) at 50. Mu.L/well and 37 ℃ in 5% CO 2 After 2h was incubated in the incubator, compounds of different concentrations prepared in serum-free medium (final concentrations: 0.3, 3, 30, 300, 3000, 30000 nM, respectively) were added and the mixture was incubated at 37 ℃ with 5% CO 2 After 72 h was incubated in the incubator, 10. Mu.L of MTS was added to each well and incubated for 2h, and OD was measured at 490 nm. EC was calculated using GraphPad Prism 5.0 50 The value is obtained.
Biological data of the Compounds
Selected compounds prepared as described above were tested according to the biological methods described in the examples of the present invention. The results are shown in the following table.
Figure 683317DEST_PATH_IMAGE070
。
2. Inhibition of DOHH-2 cell proliferation
Materials and reagents
MTS detection kit (Promega), RPMI-1640 medium (GIBCO), fetal bovine serum (BI), penicillin (Sigma), streptomycin (Sigma), DMSO (Sigma), and sodium pyruvate (VWR).
Cell proliferation inhibitory Activity
The inhibitory effect of the compound on MCT1 was examined by measuring the inhibition of cell proliferation by DOHH-2. DOHH-2 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum. Collecting cells, counting, preparing 80000 cell suspensions/ml with 10% serum culture medium, mixing, inoculating 100 μ L/well into 96-well plate (the number of plated cells is 8000), adding compound solutions of different concentrations prepared with 10% serum culture medium 100 μ L/well (final concentrations are 0, 0.08, 0.4, 1.9, 9.6, 48, 240, 1200, 6000, 30000 nM), incubating at 37 deg.C and 5% CO2 incubatorAfter 120 h, 10. Mu.L of MTS was added to each well and incubated for 2h, and OD was measured at 490 nm. Calculation of EC for GraphPad Prism 5.0 50 The value is obtained.
Biological data of the Compound
Selected compounds prepared as described above were tested according to the biological methods described in the examples of the present invention. The results are shown in the following table.
Figure 27711DEST_PATH_IMAGE071
。
3. Inhibition of Raji cell proliferation
Materials and reagents
MTS detection kit (Promega), RPMI-1640 medium (GIBCO), fetal bovine serum (BI), penicillin (Sigma), streptomycin (Sigma), DMSO (Sigma), and sodium pyruvate (VWR).
Cell proliferation inhibitory Activity
The inhibition of the compound on Raji cell proliferation was tested by measuring its inhibition on MCT 1. Raji cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum. After collecting and counting cells, 30000 cell suspensions per ml are prepared by 10% serum culture medium, after mixing evenly, the cells are inoculated on a 96-well plate according to 100 muL per well (namely, the number of the plated cells is 3000 per well), then compound solutions with different concentrations prepared by 10% serum culture medium are added, 100 muL per well (the final concentrations are respectively 0, 0.08, 0.4, 1.9, 9.6, 48, 240, 1200, 6000 and 30000 nM), the mixture is placed in a 37 ℃,5% CO2 incubator to incubate 72 h, 10 muL MTS is added into each well to incubate for 2h, and the OD value is measured under the wavelength of 490 nm. Calculation of EC for GraphPad Prism 5.0 50 The value is obtained.
Biological data of the Compound
Selected compounds prepared as described above were tested according to the biological methods described in the examples of the present invention. The results are shown in the following table.
Figure 322426DEST_PATH_IMAGE072
。

Claims (8)

1. A compound represented by the formula (I) and/or a pharmaceutically acceptable salt thereof,
Figure 88574DEST_PATH_IMAGE001
wherein:
a is selected from
Figure 840629DEST_PATH_IMAGE002
；
R1 is selected from C1-6 alkyl, C3-8 cycloalkyl C1-6 alkyl, wherein each alkyl, cycloalkyl is independently unsubstituted or substituted with at least one W group;
r2 is selected from C1-6 alkyl;
each R3 is independently selected from:
Figure 663092DEST_PATH_IMAGE003
each of which is unsubstituted or substituted with at least one group independently selected from methyl, hydroxy and hydroxymethyl;
each R4 is independently selected from phenyl, naphthalen-1-yl, pyridin-4-yl, pyridin-2-yl, and quinolin-5-yl, wherein phenyl, naphthyl, pyridinyl, and quinolinyl are unsubstituted or substituted with at least one group independently selected from methyl, methoxy, cyano, fluoro, and trifluoromethyl;
each R5 and R6 is independently selected from hydrogen;
each W is independently selected from the group consisting of hydrogen, nitro, cyano, amino, hydroxy, carboxy, halogen, oxo, thio, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, C1-6 alkylamino, C3-8 cycloalkylamino, (C1-6 alkyl) 2 amino, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, C1-6 alkoxyalkyl, C2-6 alkanoyl, C1-6 alkylthio, C1-6 alkoxycarbonyl, C1-6 alkylsulfonyl, C1-6 alkylsulfinyl, carbamoyl, C1-6 alkylcarbamoyl, di- (C1-6 alkyl) carbamoyl, C2-8 alkenyl, and C2-8 alkynyl;
m is selected from 1,2 and 3;
n is selected from 1,2 and 3;
r is independently selected from 0, 1,2, 3.
2. The compound of claim 1, and/or a pharmaceutically acceptable salt thereof, wherein R1 is selected from methyl, ethyl, isobutyl, cyclopropylmethyl, isopropyl, or isopentyl, each unsubstituted or substituted with at least one hydroxyl group.
3. The compound of claim 2, and/or a pharmaceutically acceptable salt thereof, wherein R2 is selected from methyl or isobutyl.
4. The compound of any one of claims 1-3, and/or a pharmaceutically acceptable salt thereof, wherein m is 1.
5. A compound according to any one of claims 1 to 3, and/or a pharmaceutically acceptable salt thereof, in particular selected from the following compounds:
(S) -5- (4-hydroxyisoxazolidine-2-carbonyl) -1-ethyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxyisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxyisoxazolidine-2-carbonyl) -1-cyclopropylmethyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxyisoxazolidine-2-carbonyl) -1-isopentyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxyisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (2- (trifluoromethyl) benzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isopropyl-3-methyl-6- (2,6-dimethylbenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isopropyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isopropyl-3-methyl-6- (3,5-difluoro-2-methoxybenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isopropyl-3-methyl-6- (2,3-dimethylbenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isopropyl-3-methyl-6- (2- (trifluoromethyl) benzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (2,4,5-trifluorobenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (2,3-dimethylbenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (2,6-dimethylbenzyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxy-4-methyl isoxazolidine-2-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (4-hydroxy-4-methylisoxazolidine-2-carbonyl) -1,3-diisobutyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(R) -5- (2- (hydroxymethyl) pyrrolidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (2- (hydroxymethyl) pyrrolidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(R) -5- (3-hydroxypyrrolidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
n- ((1-hydroxycyclopropyl) methyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo [3,4-d ] pyrimidine-5-carboxamide;
5- (4-hydroxypiperidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(R) -5- (2- (hydroxymethyl) azetidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
5- (3-hydroxyazetidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione;
(S) -5- (2- (hydroxymethyl) azetidine-1-carbonyl) -1-isobutyl-3-methyl-6- (naphthalen-1-ylmethyl) -1,6-dihydro-2H-pyrrolo [3,4-d ] pyrimidine-2,4 (3H) -dione.
6. A pharmaceutical composition comprising a compound of any one of claims 1-5, and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
7. A pharmaceutical formulation of a compound of any one of claims 1 to 5 and/or a pharmaceutically acceptable salt thereof in any one of pharmaceutically acceptable dosage forms, together with one or more pharmaceutically acceptable carriers and/or diluents.
8. Use of a compound of any one of claims 1-5 and/or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting cell proliferation.
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