RU2801664C2 - PHOSPHATE AND PHOSPHONATE DERIVATIVES OF 7-AMINO-5-THIOTHIAZOLO[4,5-d]PYRIMIDINES AND THEIR USE FOR THE TREATMENT OF PATHOLOGICAL CONDITIONS ASSOCIATED WITH ELEVATED LEVELS OF CX3CR1 AND/OR CX3CL1 - Google Patents

Abstract

FIELD: organic chemistry; pharmaceuticals.

SUBSTANCE: group of inventions is directed to the treatment of diseases and disorders associated with elevated levels of CX3CR1 and/or CX3CL1. Compound of formula I, where the values of the radicals R¹, R², Q¹ are as defined in paragraph 1 of the claims is disclosed. Also the following is disclosed: a pharmaceutical composition based on a compound of formula (I) having fractalkine receptor antagonist activity, a method of treating or preventing a disease or disorder associated with elevated levels of CXCR1 and/or CX3CL1, and the use of the above compounds for the manufacture of a medicinal product. Also a method of preparing compounds represented by the general formula (I) is disclosed.

EFFECT: group of inventions provides an effective antagonistic effect of the fractalkine receptor with high stability and bioavailability.

36 cl, 8 tbl, 7 ex

Description

Technical field

This invention relates to new pharmaceutically active compounds, to pharmaceutical compositions containing said compounds, as well as to their pharmaceutical use. In particular, this invention relates to fractalkine receptor antagonists and their use in the treatment of diseases and disorders associated with elevated levels of CX3CR1 and/or CX3CL1.

State of the art

In this description, the listing or discussion of previously explicitly published documents should not necessarily be understood as an admission that this document is part of the prior art or general knowledge.

7-Amino-5-thiothiazolo[4,5- d ]pyrimidines such as (2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]thio}[1,3]thiazolo [4,5- d ]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (A) and 5-{[(1 S )-1-(5-chloropyridin-2-yl)ethyl]sulfanyl }-7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5- d ]pyrimidin-2(3 H )-one (B), are known fractalkine receptor antagonists ( et al . J. Med. Chem. , 2013, 56, 3177-3190).

(A) (B)

However, these compounds are poorly soluble in water, which makes it difficult to obtain suitable pharmaceutical dosage forms.

Detailed description of the invention

Surprisingly, certain phosphate derivatives of compounds such as Compounds A and B have been found to have certain advantages over known fractalkine receptor antagonists. In addition to a significant improvement in water solubility, such compounds are also significantly more stable during long-term storage in an aqueous environment and provide higher plasma concentrations than with the introduction of known compounds.

Without being limited by theory, it can be assumed that due to the higher plasma concentrations that are achieved with the use of these compounds, there is reason to believe that they are likely to cause less stress on the liver during first-pass metabolism after oral administration, compared with the administration of known antagonists. Thus, these compounds may be better tolerated at higher doses and/or over a longer period of treatment than known fractalkine receptor antagonists.

In a first aspect of the present invention, there is provided a compound of formula I,

(I)

Where

R ¹ is aryl (eg phenyl) or pyridyl, both of which are optionally substituted with one or more groups selected from halo, -CN, -C(O)NR ³ R ⁴ , -S(O) ₂ R ⁵ , C _{1 -6} alkyl, C _2-6 alkenyl or C _2-6 alkynyl, the last three groups being optionally substituted with one or more F;

R ² is H or C _1-6 alkyl optionally substituted with one or more F;

R ³ and R ⁴ are each independently H or C _1-6 alkyl optionally substituted with one or more F;

R ⁵ is C _1-6 alkyl optionally substituted with one or more F;

represents , or ,

Where means the point of attachment to the rest of the molecule;

Q ¹ and Q ² are each independently H or -PO(OR ⁶ )(OR ⁷ );

Q ³ is H or -CH ₂ OPO(OR ⁶ )(OR ⁷ ); And

Q ⁴ is -CH ₂ OPO(OR ⁶ )(OR ⁷ );

where R ⁶ and R ⁷ each independently represent H, C _1-4 alkyl or C _2-4 alkenyl;

wherein at least one of Q ¹ and Q ² , Q ³ or Q ⁴ is -PO(OR ⁶ )(OR ⁷ ) or -CH ₂ OPO(OR ⁶ )(OR ⁷ );

or a pharmaceutically acceptable salt thereof, and said compounds (including pharmaceutically acceptable salts) may be referred to herein as "compounds of this invention".

For the avoidance of doubt, those skilled in the art should understand that, in this context, reference to compounds from specific aspects of this invention (e.g., from the first aspect of this invention, i.e., reference to compounds of formula I as defined in the first aspect of this invention) includes references to all embodiments and specific features thereof, and combinations of such implementation options and specific features may form additional embodiments and features of the present invention.

Unless otherwise indicated, all technical and scientific terms used in this context have their usual meaning as understood by those skilled in the art to which this invention pertains.

Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts may be prepared by conventional means, for example, by reacting the free acid form or free base form of a compound of this invention with one or more equivalents of the appropriate acid or base, optionally in a solvent or medium in which the salt is insoluble, followed by removal of said salt. solvent or specified medium using standard techniques (eg in vacuo , freeze drying or filtration). Salts can also be prepared using techniques known to those skilled in the art, such as exchanging a counterion of a compound of this invention in salt form for another counterion, for example using a suitable ion exchange resin.

Particular acid addition salts that may be mentioned include salts formed by reaction with the appropriate acids resulting in the protonation of the compound of this invention to form carboxylate salts (e.g., formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate , caprylate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, α-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxy benzoate, methoxybenzoate, dinitrobenzoate, o -acetoxybenzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, hippurate, phthalate or terephthalate salts), halide salts (e.g. chloride, bromide or iodine ide salts), sulfonate salts (e.g. benzenesulfonate, methyl, bromo or chlorobenzenesulfonate, xylenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, hydroxyethanesulfonate, 1- or 2-naphthalenesulfonate or 1,5-naphthalenesulfonate salts) or sulfate, pyrosulfate, bisulfate atnyh, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate or nitrate salts, and the like.

Particular base addition salts that may be mentioned include those formed by reacting with the corresponding bases resulting in the removal of a proton atom from the compounds of this invention to form salts with alkali metals (such as Na and K salts), alkaline earth metals (such as Mg and Ca salts), organic bases (such as ethanolamine, diethanolamine, triethanolamine and tromethamine) and inorganic bases (such as ammonia).

More specific salts that may be mentioned include Li, Na, K and ammonium salts (including monosalts and disalts). In particular, for compounds of this invention in which each R ⁶ and R ⁷ is H, specific salts that may be mentioned include diammonium salts, disodium salts, dilithium salts and dipotassium salts.

For the avoidance of doubt, the compounds of this invention may exist in solid form and, therefore, the scope of this invention includes all of their amorphous, crystalline and partially crystalline forms, and they may also exist in the form of an oily substance. If the compounds of this invention exist in crystalline and partially crystalline forms, then such forms may include solvates, which are included in the scope of this invention.

For the avoidance of doubt, the compounds of this invention may also exist in solution (ie, in solution in a suitable solvent). For example, the compounds of this invention may exist in aqueous solution, in which case the compounds of this invention may exist in the form of their hydrates.

The compounds of this invention may contain double bonds and therefore, unless otherwise indicated, may exist as E ( entgegen ) and Z ( zusammen ) geometric isomers with respect to each individual double bond. Unless otherwise indicated, all such isomers and mixtures thereof are within the scope of this invention.

The compounds of this invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are within the scope of this invention (in particular those that are sufficiently stable to allow their isolation).

The compounds of this invention may also contain one or more asymmetric carbon atoms and, therefore, may exhibit optical isomerism and/or diastereoisomerism (ie, exist in enantiomeric or diastereomeric forms). Diastereoisomers can be separated using conventional techniques such as chromatography or fractional crystallization. Various stereoisomers (ie enantiomers) can be isolated by separation of a racemic or other mixture of compounds using conventional techniques such as fractional crystallization or HPLC. Alternatively, the desired enantiomer or diastereoisomer can be obtained from the respective optically active starting materials under conditions that do not lead to racemization or epimerization (i.e., the “chiral pooling” method) by reacting the corresponding starting material with a “chiral auxiliary agent” that can then be removed at a suitable stage, by derivatization (i.e. separation, including dynamic separation; for example, with a homochiral acid followed by separation of diastereomeric derivatives by conventional methods such as chromatography), or by reaction with an appropriate chiral reagent or chiral catalyst, and all of these methods and processes can be carried out under conditions known to those skilled in the art. Unless otherwise indicated, all stereoisomers and mixtures thereof are within the scope of this invention.

Unless otherwise noted, C _1-z alkyl groups (where z is the upper end of the range) as defined herein may be straight chain or, if there is a sufficient number (i.e., at least two or three, depending on the specific case) carbon atoms, may be branched and/or cyclic (forming a C _3-z cycloalkyl group). If there are a sufficient number (ie, at least four) carbon atoms, such groups may also be partially cyclic (forming a C _4-z partially cycloalkyl group). For example, cycloalkyl groups that may be mentioned include cyclopropyl, cyclopentyl, and cyclohexyl. Similarly, partially cyclic alkyl groups (which may also be described as "partially cycloalkyl" groups) that may be mentioned include cyclopropylmethyl. If there are sufficient carbon atoms, such groups may also be polycyclic (eg, bicyclic or tricyclic) and/or spirocyclic. For the avoidance of doubt, specific alkyl groups that may be mentioned include straight chain (ie straight and/or cyclic) alkyl groups.

Unless otherwise noted, C _2-z alkenyl groups (where z is the upper end of the range) as defined herein may be straight chain or, if there are a sufficient number (i.e., at least three) carbon atoms, may be branched and/or cyclic (forming a C _4-z cycloalkenyl group). If there are a sufficient number (ie, at least five) carbon atoms, such groups may also be partially cyclic. For example, partially cyclic alkenyl groups (which may also be described as "partially cycloalkenyl" groups) that may be mentioned include cyclopentenylmethyl and cyclohexenylmethyl. If a sufficient number of carbon atoms exist, such groups may also be polycyclic (eg, bicyclic or tricyclic) or spirocyclic. For the avoidance of doubt, specific alkenyl groups that may be mentioned include straight chain (ie straight and/or cyclic) alkenyl groups.

Unless otherwise noted, C _2-z alkynyl groups (where z is the upper end of the range) as defined herein may be straight chain or, if there are a sufficient number (i.e., at least four) carbon atoms, may be branched . For the avoidance of doubt, specific alkynyl groups that may be mentioned include straight alkynyl groups (ie straight chain and/or cyclic).

For the avoidance of doubt, unless otherwise indicated, groups described herein as "alkyl", "alkenyl", and/or "alkynyl" are to be understood in relation to the highest degree of bond unsaturation present in such groups. For example, such a group containing a carbon-carbon double bond and a carbon-carbon triple bond in the same group is referred to as "alkynyl". Alternatively, such groups may be specifically stated to contain only the indicated degree of unsaturation (ie, in one or more bonds per group, as the case may be; eg, in one bond per group).

For the avoidance of doubt, the alkyl, alkenyl, and alkynyl groups described herein may also act as linker groups (i.e., groups linking two or more parts of the described compound), in which case such groups may be described as "alkylene ”, “alkenylene” and/or “alkynylene” groups, respectively.

The term "aryl", which can be used in this context, may refer to C _6-14 (eg, C _6-10 ) aromatic groups. Such groups may be monocyclic or bicyclic, and in the case of bicyclic groups, they may be fully or partially aromatic. C _6-10 aryl groups that may be mentioned include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, and the like. (eg phenyl, naphthyl, etc.). For the avoidance of doubt, the point of attachment of substituents on aryl groups may be at any suitable carbon atom of the ring system.

For the avoidance of doubt, those skilled in the art should understand that the aryl groups that may form part of the compounds of this invention are those that can be obtained by chemical means known to those skilled in the art. Specific aryl groups that may be mentioned include phenyl and naphthyl, eg phenyl.

For the avoidance of doubt, reference to polycyclic (e.g., bicyclic or tricyclic) groups (e.g., when used in the context of heterocyclyl or cycloalkyl groups (e.g., heterocyclyl groups)) refers to ring systems in which at least two cuts must be made to convert such rings into a non-cyclic (i.e., straight or branched) chain, with the minimum number of such cuts corresponding to the number of said rings (for example, the term "bicyclic" may mean that at least two cuts are needed to convert said rings into a straight chain). For the avoidance of doubt, the term "bicyclic" (for example, when used in the context of alkyl groups) may refer to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring, to groups in which two non-adjacent atoms are bonded by an alkyl (which, when linking two fragments, may be referred to as an alkylene) group (optionally containing one or more heteroatoms), the latter groups may be referred to as bridged, or to groups in which the second ring is attached to one atom, and such groups may be referred to as spirocyclic compounds.

This invention also includes isotopically labeled compounds of this invention which are identical to those described herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. (or the most common in nature). All isotopes of any particular atom or element referred to in this context are included within the scope of the compounds of this invention. Thus, the compounds of this invention also include deuterated compounds, i. compounds of this invention in which one or more hydrogen atoms have been replaced by the hydrogen isotope deuterium.

In addition, for the avoidance of doubt, when indicating that the substituent itself is optionally substituted with one or more substituents (for example, C _1-3 alkyl optionally substituted with one or more F), these substituents, if possible, may be located on one or different atoms. Such optional substituents may be present in any suitable amount (eg, the group in question may be substituted with one or more such substituents, eg, one such substituent).

For the avoidance of doubt, when referring in this context to groups that are optionally substituted, it is expressly provided that such optional substituents may be omitted (i.e., mention of such optional substituents may be omitted), in which case the optionally substituted group may be described as unsubstituted.

When used, a wavy connection (i.e. or similar designation) can mean the point of attachment of the substituent in question to the central molecule (ie, to the compound of formula I to which this substituent is attached).

For the avoidance of doubt, those skilled in the art should understand that the compounds of this invention that are the subject of this invention include those that are suitable for preparation, i.e. those that can be obtained in a stable form. That is, the compounds of this invention include compounds that are strong enough to withstand isolation, for example, from a reaction mixture, to an acceptable degree of purity.

In specific embodiments of the compounds of this invention that may be mentioned, R ¹ is phenyl or pyridyl, both of which are optionally substituted with one or more (for example, one) fluorine, chlorine, bromine, -CN, -C(O)NR ³ R ⁴ , -S(O) ₂ R ⁵ , C _1-4 alkyls (eg C _1-3 alkyls, eg C _1-2 alkyls), C _2-6 alkenyls (eg C _2-3 alkenyls, eg ethenyls) or C _2-4 alkynyls (eg C _2-3 alkenyls, eg ethynyls), the last three groups being optionally substituted with one or more F, wherein R ³ , R ⁴ and R ⁵ are as described herein .

In additional specific embodiments, R ¹ is phenyl or pyridyl, both of which are optionally substituted with one or more fluorine, chlorine, bromine, -CN, -C(O)NR ³ R ⁴ or -S(O) ₂ Me groups, where R ³ and R ⁴ are as described in this document.

In further specific embodiments, R ¹ is phenyl or pyridyl, both of which are optionally substituted with one or more (eg, one) fluorine, chlorine, bromine, or methyl groups.

In further specific embodiments, R ¹ is phenyl or pyridyl, both of which are optionally substituted with one or more (eg, one) fluorine, chlorine, bromine groups.

In additional specific embodiments, R ¹ is selected from

Where " " means the point of attachment to the rest of the molecule.

In further specific embodiments, R ¹ is phenyl or pyridyl, both of which are optionally substituted with one or more (eg, one) chlorine groups.

In more specific embodiments, R ¹ is phenyl (ie, unsubstituted) or 5-chloropyridin-2-yl (eg, phenyl).

In specific embodiments, R ² is C _1-6 alkyl optionally substituted with one or more F.

In specific embodiments, R ² is C _1-6 alkyl (ie, is unsubstituted). In more specific embodiments, R ² is C _1-3 alkyl optionally substituted with one or more F (eg, is unsubstituted). In even more specific embodiments, R ² is trifluoromethyl, difluoromethyl, fluoromethyl, or in particular methyl.

In further specific embodiments, R ² is H, or in particular methyl.

In specific embodiments, R ³ and R ⁴ are each independently H or C _1-6 alkyl (ie, unsubstituted). In more specific embodiments, R ³ and R ⁴ are each independently C _1-3 alkyl optionally substituted with one or more F (eg, are unsubstituted). In even more specific embodiments, R ³ and R ⁴ are each independently H, trifluoromethyl, difluoromethyl, fluoromethyl, or methyl. In additional specific embodiments, both R ³ and R ⁴ are H.

In specific embodiments, R ⁵ is C _1-6 alkyl (ie, is unsubstituted). In more specific embodiments, R ⁵ is C _1-3 alkyl optionally substituted with one or more F (eg, is unsubstituted). In even more specific embodiments, R ⁵ is trifluoromethyl, difluoromethyl, fluoromethyl, or in particular methyl.

In the compounds of this invention, at least one of Q ¹ and Q ² , Q ³ or Q ⁴ (ie at least one of Q ¹ and Q ² ; or Q ¹ and Q ³ ; or Q ¹ and Q ⁴ , as the case may be) is -PO(OR ⁶ )(OR ⁷ ) or -CH ₂ OPO(OR ⁶ )(OR ⁷ ). Thus, the compounds of this invention may contain one or two phosphate or phosphoramide acid groups, or groups of their esters (-OPO(OR ⁶ )(OR ⁷ ) or -NHPO(OR ⁶ )(OR ⁷ )/-NR ^x PO (OR ⁶ )(OR ⁷ ), where R ^x is a carbon group (eg, alkyl)) (i.e., one or two of Q ¹ and Q ² , Q ³ or Q ⁴ may be -PO(OR ⁶ )(OR ⁷ ) or -CH ₂ OP(OR ⁶ )(OR ⁷ ) (as applicable)). If one of Q ¹ and Q ² , Q ³ or Q ⁴ is -PO(OR ⁶ )(OR ⁷ ) or -CH ₂ OP(OR ⁶ )(OR ⁷ ), the rest of the group is H.

In more specific embodiments, one of Q ¹ and Q ² , Q ³ or Q ⁴ is -PO(OR ⁶ )(OR ⁷ ) or -CH ₂ OPO(OR ⁶ )(OR ⁷ ) and the other is Q ¹ , and (if present) Q ² or Q ³ is H (Q ⁴ is —CH ₂ OPO(OR ⁶ )(OR ⁷ ) or absent).

Specific compounds of this invention that may be mentioned include compounds in which

represents , or .

Specific compounds of this invention that may be mentioned include compounds in which if

represents or ,

then one of Q ¹ and Q ² or Q ³ is -PO(OR ⁶ )(OR ⁷ ) or -CH ₂ OPO(OR ⁶ )(OR ⁷ ) and the other of Q ¹ and Q ² or Q ³ is H; And

If represents ,

then Q ¹ is H and Q ⁴ is -CH ₂ OPO(OR ⁶ )(OR ⁷ ).

In specific implementations that may be mentioned, represents

or .

In more specific implementations represents .

In alternative specific implementations represents .

In particular embodiments that may be mentioned, Q ¹ is -PO(OR ⁶ )(OR ⁷ ).

In specific implementations that may be mentioned,

represents or ; And

Q ¹ is -PO(OR ⁶ )(OR ⁷ ).

In additional specific implementations in which represents or ,

Q ¹ is -PO(OR ⁶ )(OR ⁷ );

and each Q ² or Q ³ (as the case may be) is H.

In specific embodiments, Q ¹ is -PO(OR ⁶ )(OR ⁷ ).

In specific embodiments, Q ² is -PO(OR ⁶ )(OR ⁷ ).

In more specific implementations, in which represents ,

Q ² is -PO(OR ⁶ )(OR ⁷ ); And

Q ¹ is H.

In specific embodiments, Q ³ is -CH ₂ PO(OR ⁶ )(OR ⁷ ).

In more specific implementations, in which represents ,

Q ³ is -CH ₂ PO(OR ⁶ )(OR ⁷ ); And

Q ¹ is H.

In specific implementations in which represents ,

Q ¹ is H.

In particular embodiments, Q ² is H.

In particular embodiments, Q ³ is H.

In additional specific embodiments, Q ² , Q ³ , or Q ⁴ (as the case may be) is H.

In specific implementations that may be mentioned,

Q ¹ is -PO(OR ⁶ )(OR ⁷ ) (eg -PO(OH) ₂ );

represents or ; or

Q ¹ is H, and

represents , where Q ⁴ represents -CH ₂ OPO(OR ⁶ )(OR ⁷ ) (for example, -CH ₂ OPO(OH) ₂ );

and R ¹ and R ² are as described herein.

In specific embodiments that may be mentioned, R ⁶ and R ⁷ are each independently C _1-3 alkyl (eg, C _1-2 alkyl) or H. In more specific embodiments, each R ⁶ and R ⁷ is H.

In further embodiments, R ⁶ and R ⁷ are each methyl, or each is ethyl.

In additional specific embodiments, R ⁶ is iso -propyl and R ⁷ is H.

In particular embodiments that may be mentioned, the compound of formula I is a compound of formula Ia,

(Ia)

where R ¹ , R ² , Q ¹ and Q ² are as defined above, or a pharmaceutically acceptable salt thereof.

In particular embodiments of a compound of formula Ia that may be mentioned,

Q ¹ is -PO(OR ⁶ )(OR ⁷ );

Q ² is H;

R ¹ is phenyl or pyridyl, both of which are optionally substituted with one or more (eg one) groups selected from the group consisting of chlorine, fluoro, -CN, -CONH ₂ and -SO ₂ Me (particularly phenyl ( i.e. unsubstituted));

R ² is H or C _1-3 alkyl (eg methyl);

R ⁶ and R ⁷ are each independently C _1-3 alkyl (eg Me) or H; more specifically, R ⁶ is iso -propyl and R ⁷ is H, or each R ⁶ and R ⁷ is H (eg, each R ⁶ and R ⁷ is H).

In additional specific embodiments of the compounds of formula Ia that may be mentioned,

Q ¹ is -PO(OR ⁶ )(OR ⁷ );

Q ² is H;

R ¹ is phenyl or pyridyl, both of which are optionally substituted with one or more (eg one) chlorine atoms (in particular phenyl, ie unsubstituted));

R ² is C _1-3 alkyl (eg methyl);

R ⁶ and R ⁷ are each independently C _1-2 alkyl (eg Me) or in particular H.

In other specific embodiments of a compound of formula Ia

Q ¹ is H;

Q ² is -PO(OR ⁶ )(OR ⁷ );

R ¹ is phenyl or pyridyl, both of which are optionally substituted with one or more (eg one) groups selected from the group consisting of fluorine, chlorine or —CN (particularly phenyl (ie unsubstituted));

R ² is C _1-3 alkyl (eg methyl);

R ⁶ and R ⁷ are each independently C _1-3 alkyl (eg Me) or in particular H.

In additional specific embodiments of a compound of formula Ia

Q ¹ is H;

Q ² is -PO(OR ⁶ )(OR ⁷ );

R ¹ is phenyl or pyridyl, both of which are optionally substituted with one or more (eg one) chlorine atoms (in particular phenyl, ie unsubstituted));

R ² is C _1-3 alkyl (eg methyl);

R ⁶ and R ⁷ are each independently C _1-2 alkyl (eg Me) or in particular H.

In other specific embodiments that may be mentioned, the compound of formula I is a compound of formula Ib,

(IB)

where R ¹ , R ² , Q ¹ , Q ⁴ are as defined above, or a pharmaceutically acceptable salt thereof.

In particular embodiments of compounds of formula Ib that may be mentioned,

Q ⁴ is -CH ₂ OPO(OR ⁶ )(OR ⁷ );

Q ¹ is H;

R ¹ is phenyl or pyridyl, both of which are optionally substituted with one or more (eg one) groups selected from fluorine, chlorine and —CN (particularly phenyl (ie unsubstituted));

R ² is C _1-3 alkyl (eg methyl); And

R ⁶ and R ⁷ are each independently C _1-2 alkyl (eg Me) or in particular H.

In additional specific embodiments of the compounds of formula Ib that may be mentioned,

Q ⁴ is -CH ₂ OPO(OR ⁶ )(OR ⁷ );

Q ¹ is H;

R ¹ is phenyl or pyridyl, both of which are optionally substituted with one or more (eg one) chlorine atoms (in particular phenyl, ie unsubstituted));

R ² is C _1-3 alkyl (eg methyl); And

R ⁶ and R ⁷ are each independently C _1-2 alkyl (eg Me) or in particular H.

In other specific embodiments that may be mentioned, the compound of formula I is a compound of formula Ic,

(ic)

where R ¹ , R ² , Q ¹ and Q ³ are as defined above, or a pharmaceutically acceptable salt thereof.

In specific embodiments of compounds of formula Ic that may be mentioned,

Q ¹ is -PO(OR ⁶ )(OR ⁷ );

Q ³ is H;

R ¹ is phenyl optionally substituted with one or more (eg one) groups selected from the group consisting of chlorine, -SO ₂ Me, -CN and -CONH ₂ ; or in particular pyridyl optionally substituted with one or more (eg one) chlorine atoms (eg 5-chloropyridin-2-yl);

R ² is C _1-3 alkyl (eg methyl); And

R ⁶ and R ⁷ are each independently C _1-2 alkyl (eg Me) or in particular H.

In additional specific embodiments of the compounds of formula Ic that may be mentioned,

Q ¹ is -PO(OR ⁶ )(OR ⁷ );

Q ³ is H;

R ¹ is phenyl optionally substituted with one or more (eg one) chlorine atoms, or in particular pyridyl optionally substituted with one or more (eg one) chlorine atoms (eg 5-chloropyridin-2-yl);

R ² is C _1-3 alkyl (eg methyl); And

R ⁶ and R ⁷ are each independently C _1-2 alkyl (eg Me) or in particular H.

In other specific embodiments of the compounds of formula Ic that may be mentioned,

Q ¹ is H;

Q ³ is -CH ₂ OPO(OR ⁶ )(OR ⁷ );

R ¹ is phenyl optionally substituted with one or more (eg one) chlorine atoms, or in particular pyridyl optionally substituted with one or more (eg one) chlorine atoms (eg 5-chloropyridin-2-yl);

R ² is C _1-3 alkyl (eg methyl); And

R ⁶ and R ⁷ are each independently C _1-2 alkyl (eg Me) or in particular H.

In additional specific embodiments, a compound of formula I is a compound of formula IA

(IA)

where R ¹ , R ² , Q ¹ and are as defined above, or a pharmaceutically acceptable salt thereof.

Those skilled in the art will appreciate that a compound of formula IA is one enantiomer of a compound of formula I. By convention, wedge and dashed bonds signify essentially no other stereochemistry at each stereocenter.

In additional specific embodiments, a compound of formula IA is a compound of formula IAa, IAb, or IAc,

(IAa),

(IAb),

(IAc)

where (for each of the compounds IAa, IAb and IAc), R ¹ , R ² , Q ¹ , Q ² , Q ³ and Q ⁴ are as defined herein, in particular in relation to compounds of formula Ia, Ib and Ic, respectively, or a pharmaceutically acceptable salt thereof.

In additional specific embodiments, the compound of formula I is a compound of formula IB or IC.

(IB)

where R ¹ , R ² , Q ¹ , Q ² , Q ³ and Q ⁴ are as defined herein, in particular with respect to compounds of formula Ia, Ib and Ic.

(IC)

where R ¹ , R ² , Q ¹ , Q ² , Q ³ and Q ⁴ are as defined herein, in particular with respect to compounds of formula Ia, Ib and Ic.

Specific compounds of this invention that may be mentioned include those described in the examples provided herein and their pharmaceutically acceptable salts. For the avoidance of doubt, if said compounds of this invention include compounds in a specific salt form, then compounds of this invention include said compounds in non-salt form and in the form of any pharmaceutically acceptable salt (which may include the salt form shown in these examples).

More specific compounds of this invention that may be mentioned include:

(2 R )-2-[(2-Amino-5-{[(1 S )-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]- 4-methylpentyl dihydrogen phosphate,

[7-{[(1 R )-1-(Hydroxymethyl)-3-methylbutyl]amino}-2-imino-5-{[(1 S )-1-phenylethyl]sulfanyl}[1,3]thiazolo[4 ,5- d ]pyrimidin-3(2 H )-yl]methyl-dihydrophosphate and

(2 R )-2-[(5-{[(1 S )-1-(5-Chloropyridin-2-yl)ethyl]sulfanyl}-2-oxo-2,3-dihydro[1,3]thiazolo[ 4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate,

and their pharmaceutically acceptable salts.

Pharmaceutically acceptable salts

As mentioned above, the compounds of this invention may be in the form of pharmaceutically acceptable salts.

In specific embodiments, the pharmaceutically acceptable salt is a base addition salt.

In more specific embodiments, particularly those in which R ⁶ and R ⁷ are each H (i.e., in compounds containing phosphate groups -OPO(OH) ₂ ), the pharmaceutically acceptable salt is the double addition salt grounds.

In this context, the expression "double base addition salt" can be understood to mean a salt formed by reacting an acidic compound (such as a compound of this invention where R ⁶ and R ⁷ each is H) with two moles of the corresponding base.

In specific embodiments, the pharmaceutically acceptable salt is an ammonium salt or an alkali metal (Li, K, or in particular Na) salt (including monosalts and disalts). In more specific embodiments, the salt is a diammonium or disodium salt.

medical application

As noted herein, the compounds of this invention, and therefore compositions and kits containing them, are useful as pharmaceuticals. In particular, the compounds of this invention and their derivatives are modulators of fractalkine receptor (CX3CR1) activity and, therefore, they can be used to treat and/or prevent diseases or disorders associated with elevated levels of the fractalkine receptor (CX3CR1) and/or its associated ligand. fractalkyne (CX3CL1).

Thus, in accordance with the second aspect of the present invention, there is provided a compound of the present invention as defined above (i.e., a compound as defined in the first aspect of the present invention, including all embodiments and specific features), for use as pharmaceutical product (or for use in medicine).

For the avoidance of doubt, references to compounds defined in the first aspect of this invention include references to compounds of formula I (including all their embodiments, such as compounds of formulas Ia, Ib, Ic, IA, IAa, IAb, IAc, IB, IC) and their pharmaceutically acceptable salts.

Thus, for the avoidance of doubt, the compounds of this invention are useful because they have pharmacological activity and/or are metabolized in the body after oral or parenteral administration to form compounds that have pharmacological activity.

As described herein, the compounds of this invention may be particularly useful in the treatment and/or prevention of diseases or disorders associated with elevated levels of CX3CR1 and/or CX3CL1.

Thus, in a third aspect of the present invention, there is provided a compound of the present invention, as defined above, for use in the treatment and/or prevention of a disease or disorder associated with elevated levels of CX3CR1 and/or CX3CL1.

In an alternative third aspect of the invention, there is provided a method for treating and/or preventing a disease or disorder associated with elevated levels of CX3CR1 and/or CX3CL1, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention as defined above.

In a further alternative third aspect of the present invention, there is provided the use of a compound of the present invention as defined above for the manufacture of a medicament for the treatment and/or prevention of a disease or disorder associated with elevated levels of CX3CR1 and/or CX3CL1.

Those skilled in the art will appreciate that reference to the treatment of a specific pathological condition (or also the therapy of said condition) has a conventional meaning in the medical field. In particular, these terms may refer to achieving a reduction in the severity and/or frequency of occurrence of one or more clinical symptoms associated with a pathological condition, as determined by the physician attending a patient suffering from or predisposed to such symptoms. For example, in the case of cancer, the term may refer to achieving a reduction in the number of cancer cells present (eg, in the case of a cancer forming a solid tumor, this is indicated by a reduction in tumor volume).

In this context, the term "prevention" (and likewise prevention) includes an indication of the prevention of a disease or disorder (and vice versa). Therefore, an indication of a warning can also mean an indication of a prevention, and vice versa. In particular, such terms may refer to achieving a reduction (e.g., reduction of at least 10%, e.g., reduction of at least 20%, 30%, or 40%, e.g., reduction of at least 50%) in the likelihood of developing of a patient (or healthy subject) of a given pathological condition (which can be understood as denoting that the patient's condition changes in such a way that the doctor diagnoses the patient with the corresponding disease or disorder, for example, requiring treatment).

As used herein, reference to a patient (or patients) refers to living subjects being treated, including mammalian patients (eg, humans). In particular, reference to a patient refers to human patients.

For the avoidance of doubt, it will be understood by those skilled in the art that such treatment or prevention is provided to a patient (or subject) in need thereof. The patient's (or subject's) need for such treatment or prevention can be ascertained by one of ordinary skill in the art by standard means.

In this context, the terms "disease" and "disorder" (and, likewise, the terms "pathological condition", "illness", "medical problem", etc.) can be used interchangeably.

In this context, the term "effective amount" refers to the amount of the compound, which provides a therapeutic effect in the patient undergoing treatment. Said effect can be observed objectively (eg, the effect can be measured by some test or marker) or subjectively (ie, the subject shows signs and/or feels the effect). In particular, said effect can be observed (eg, measured) objectively using appropriate tests known to those skilled in the art.

Diseases and disorders known to be associated with elevated levels of CX3CR1 and/or CX3CL1 include acute and/or chronic inflammation, eye disease (such as macular degeneration), lung disease (such as pulmonary arterial hypertension, asthma, and pulmonary fibrosis). ), skin diseases (such as atopic dermatitis and pruritis), joint and/or bone diseases (such as osteoarthritis, osteoporosis, and aplastic anemia), autoimmune diseases (such as ankylosing spondylitis, multiple sclerosis, systemic sclerosis, and rheumatoid arthritis), cardiovascular and metabolic diseases (such as stroke and arteriosclerosis (including atherosclerosis), unstable angina, myocardial infarction, carotid artery disease, chronic heart failure, inflammatory cardiomyopathy, peripheral arterial disease, and diabetes), brain and neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease and traumatic brain injury), pain (such as chronic pain, fibromyalgia, neuropathic pain, pain associated with chemotherapy, and pain due to herniated discs), cancer (such as ovarian cancer, lung cancer, prostate cancer, liver cancer, pancreatic cancer, B-cell lymphoma, and breast cancer), liver disease (such as cirrhosis), kidney disease (such as IgA nephropathy, kidney inflammation, lupus, ischemic reperfusion injury, ischemic acute kidney failure, and contrast-induced kidney injury ), gastrointestinal diseases (such as colitis, Crohn's disease, inflammatory bowel disease, and pancreatitis), human immunodeficiency virus (HIV) (such as HIV-1 and HIV-associated dementia), and mood disorders (such as depression, anxiety, schizophrenia and autism spectrum disorders).

Specific diseases and disorders known to be associated with elevated levels of CX3CR1 and/or CX3CL1 that may be mentioned include eye diseases (such as macular degeneration), lung diseases (such as pulmonary arterial hypertension, asthma, and pulmonary fibrosis), skin diseases (such as atopic dermatitis and pruritis), joint and/or bone diseases (such as osteoarthritis, osteoporosis, and aplastic anemia), autoimmune diseases (such as ankylosing spondylitis, multiple sclerosis, systemic sclerosis, and rheumatoid arthritis), cardiovascular and metabolic diseases (such as arteriosclerosis (including atherosclerosis), unstable angina, myocardial infarction, carotid disease, chronic heart failure and diabetes), brain and neurodegenerative diseases (such as Alzheimer's disease and traumatic brain injury), pain (such as chronic pain , fibromyalgia, neuropathic pain, chemotherapy-associated pain, and herniated disc pain), cancer (such as ovarian cancer, lung cancer, prostate cancer, liver cancer, pancreatic cancer, B-cell lymphoma, and breast cancer), liver disease (such as cirrhosis), kidney disease (such as IgA nephropathy, kidney inflammation, lupus, and ischemic reperfusion injury), gastrointestinal diseases (such as colitis, inflammatory bowel disease, and pancreatitis), and human immunodeficiency virus (HIV) ( such as HIV-1 and HIV-associated dementia).

In specific embodiments (i.e., in some embodiments of the third aspect of the present invention), the disease or disorder associated with elevated levels of CX3CR1 and/or CX3CL1 is selected from diseases of the eye, diseases of the lungs, diseases of the skin, diseases of the joints and/or bones, autoimmune disease, cardiovascular disease, metabolic disease, brain disease, neurodegenerative disease, pain, cancer, liver disease, kidney disease, gastrointestinal disease, and human immunodeficiency virus.

In specific embodiments (i.e., in some embodiments of the third aspect of the present invention), the disease or disorder associated with elevated levels of CX3CR1 and/or CX3CL1 is selected from diseases of the eye, diseases of the lungs, diseases of the skin, diseases of the joints and/or bones, autoimmune disease, cardiovascular disease, metabolic disease, brain disease, neurodegenerative disease, pain, cancer, liver disease, kidney disease, gastrointestinal disease, human immunodeficiency virus, and mood disorders.

In more specific embodiments, the disease or disorder associated with fractalkin and elevated levels of CX3CR1 and/or CX3CL1 is selected from macular degeneration, pulmonary arterial hypertension, asthma, pulmonary fibrosis, atopic dermatitis, pritis, osteoarthritis, osteoporosis, aplastic anemia, ankylosing spondylitis , multiple sclerosis, systemic sclerosis, rheumatoid arthritis, arteriosclerosis, unstable angina, myocardial infarction, carotid artery disease, chronic heart failure, diabetes, Alzheimer's disease, traumatic brain injury, chronic pain, fibromyalgia, neuropathic pain, chemotherapy-induced pain, pain with herniated discs, cancer (eg, ovarian cancer, lung cancer, liver cancer, pancreatic cancer, B-cell lymphoma, and breast cancer), liver cirrhosis, IgA nephropathy, kidney inflammation, lupus, ischemic reperfusion injury, colitis, inflammatory bowel disease, pancreatitis, human immunodeficiency virus-1 and human immunodeficiency virus dementia, stroke, Parkinson's disease, depression, anxiety, schizophrenia and autism spectrum disorders.

In more specific embodiments, the disease or disorder associated with fractalkin and elevated levels of CX3CR1 and/or CX3CL1 is selected from macular degeneration, pulmonary arterial hypertension, asthma, pulmonary fibrosis, atopic dermatitis, pritis, osteoarthritis, osteoporosis, aplastic anemia, ankylosing spondylitis , multiple sclerosis, systemic sclerosis, rheumatoid arthritis, arteriosclerosis, unstable angina, myocardial infarction, carotid artery disease, chronic heart failure, diabetes, Alzheimer's disease, traumatic brain injury, chronic pain, fibromyalgia, neuropathic pain, chemotherapy-induced pain, pain with herniated discs, cancer (eg, ovarian cancer, lung cancer, liver cancer, pancreatic cancer, B-cell lymphoma, and breast cancer), liver cirrhosis, IgA nephropathy, kidney inflammation, lupus, ischemic reperfusion injury, colitis, inflammatory bowel disease, pancreatitis, human immunodeficiency virus-1 and human immunodeficiency virus dementia.

In more specific embodiments, the disease or disorder associated with elevated levels of CX3CR1 and/or CX3CL1 is selected from atopic dermatitis, multiple sclerosis, rheumatoid arthritis, atherosclerosis, myocardial infarction, chronic heart failure, inflammatory cardiomyopathy, fibromyalgia, neuropathic pain, pain due to chemotherapy, B-cell lymphoma, breast cancer, IgA nephropathy, lupus, ischemic acute renal failure and pancreatitis.

In even more specific embodiments, the disease or disorder associated with elevated levels of CX3CR1 and/or CX3CL1 is selected from myocardial infarction, arteriosclerosis, multiple sclerosis, rheumatoid arthritis, Crohn's disease, pancreatitis, neuropathic pain, pain associated with chemotherapy, and cancer (e.g. , ovarian cancer, lung cancer, liver cancer, pancreatic cancer, B-cell lymphoma, and breast cancer).

In specific embodiments, a disease or disorder associated with elevated levels of CX3CR1 and/or CX3CL1 is treated in a patient with substantially elevated plasma levels of CX3CL1. For example, in such patients, the plasma concentration of CX3CL1 may be greater than about 300 picograms per milliliter (pg/mL). In particular, in such patients, the plasma concentration of CX3CL1 can range from about 350 pg/ml to about 600 pg/ml.

Pharmaceutical compositions

As described herein, the compounds of this invention are useful as pharmaceuticals. Such compounds can be administered separately, or they can be administered as known pharmaceutical compositions/dosage forms.

In a fourth aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention described herein, and optionally one or more pharmaceutically acceptable excipients.

As used herein, the term "pharmaceutically acceptable excipients" includes liquid media, adjuvants, carriers, diluents, pH adjusting and buffering agents, tonicity agents, stabilizers, wetting agents, and the like. In particular, such excipients may include adjuvants, diluents or carriers.

In a specific embodiment of the fourth aspect of this invention, the pharmaceutical composition contains at least one pharmaceutically acceptable excipient.

For the avoidance of doubt, in this context, the indication of the compounds of this invention intended for a specific use (and, likewise, uses and methods of use relating to the compounds of this invention) may also refer to pharmaceutical compositions containing the compounds of this invention, described in this context.

Thus, in a fifth aspect of the present invention, there is provided a pharmaceutical composition as defined in the fourth aspect of the present invention, for use in the treatment of fractalkine related diseases (described herein in relation to the third aspect of the present invention and all its embodiments).

Those skilled in the art will recognize that the compounds of this invention act systemically and/or locally (ie, at a specific site) and therefore can be administered by suitable routes known to those of skill in the art.

Those skilled in the art will appreciate that the compounds and compositions described herein are generally administered orally, intravenously, intraocularly, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, intranasally, topically, by any other parenteral route, or by inhalation, in a pharmaceutically acceptable dosage form. In particular, the proposed compounds can be administered orally (ie, through the introduction through the mouth) or intravenously.

Pharmaceutical compositions described herein include compositions in the form of tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral (eg, intravenous) or intramuscular administration, and the like.

Thus, specific embodiments provide a pharmaceutical composition in a pharmaceutically acceptable dosage form, including tablets or capsules, oral or injectable liquid forms, suppositories, creams, gels, foams, or inhalants (e.g., for intranasal administration), or forms for topical use (eg eye drops). For the avoidance of doubt, in such embodiments, the compounds of this invention may be presented in solid (eg, in the form of a dispersion of solid particles), liquid (eg, in solution), or other forms, eg, in the form of micelles.

For example, in the preparation of pharmaceutical dosage forms for oral administration, the compound may be mixed with solid powder ingredients such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or other suitable ingredient, as well as disintegrants and lubricants such as as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The resulting mixtures can then be processed into granules or compressed into tablets.

Soft gelatin capsules can be prepared with capsules containing one or more active compounds (for example, compounds according to the first and therefore the second and third aspects of this invention, and optionally additional therapeutic agents), together with, for example, vegetable oil, fat or other suitable carrier for soft gelatin capsules. Similarly, hard gelatin capsules may contain such compound(s) in combination with solid powder ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.

Unit dosage forms for rectal administration may be prepared (i) in the form of suppositories which contain the compound(s) mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule which contains the active substance in admixture with vegetable oil, paraffin oil or other suitable carrier for gelatin rectal capsules; (iii) in the form of ready-made microclysters; or (iv) in the form of a dry microenema composition to be reconstituted in a suitable solvent immediately prior to administration.

Liquid preparations for oral administration may be in the form of syrups or suspensions, for example solutions or suspensions, containing the compound(s) and the remainder of the composition being sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, saccharin and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder for reconstitution with a suitable solvent prior to use.

Solutions for parenteral administration can be prepared as a solution of the compound(s) in a pharmaceutically acceptable solvent (eg water). These solutions may also contain stabilizing agents and/or buffer ingredients and are divided into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation for reconstitution with a suitable solvent immediately prior to use.

Depending on, for example, the potency and physical properties of the compound of this invention (i.e. active ingredient), pharmaceutical dosage forms that may be mentioned include those in which the active ingredient is present in an amount of at least 1% (or at least at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to other components (i.e., additional adjuvant, diluent, and carrier) of the pharmaceutical composition is at least 1:99 (or at least 10:90, at least 30:70, or at least 50 :50) by weight.

Those skilled in the art will recognize that the compounds of this invention may be administered (eg, in the dosage forms described above) at various dosages, and suitable dosages can be readily ascertained by one of skill in the art. Oral, pulmonary, and topical dosage forms (as well as subcutaneous dosage forms, although such doses may be relatively smaller) can range from about 0.01 mg/kg body weight per day (mg/kg/day) to about 30 mg/kg/day. day, preferably from about 0.1 to about 5.0 mg/kg/day, and more preferably from about 0.5 to about 3.0 mg/kg/day. For example, when administered orally, treatment with such compounds may include administration of dosage forms typically containing from about 0.01 mg to about 5000 mg, for example, from about 0.1 mg to about 500 mg, or from about 1 mg to about 400 mg (for example , from about 20 mg to about 200 mg) of the active ingredient(s). When administered intravenously, the most preferred doses are from about 0.001 to about 10 mg/kg/hour during infusion at a constant rate. Advantageously, treatment may include administering such compounds and compositions in a single daily dose, or the total daily dose may be administered in divided doses two, three, or four times daily (e.g., twice daily for the doses described herein, e.g., dose 25 mg, 50 mg, 100 mg or 200 mg twice a day).

When used herein in relation to a particular value (such as an amount), the term "about" (or similar terms such as "approximately") should be understood to mean that such values may vary by up to 10% (in particular, up to 5%, for example, up to 1%) of the indicated value. It is envisaged that, in each case, such terms may be replaced by the indication “±10%” or similar indications (or an indication of the amount of deviation from a particular value calculated from the corresponding value). It is also provided that in each case the said terms may be deleted.

For the avoidance of doubt, one of skill in the art (e.g. a physician) can determine the actual dose that will be most appropriate for a particular patient, which is likely to vary depending on the route of administration, the type and severity of the condition being treated, as well as species, age, weight. , sex, renal function, hepatic function and response of the particular patient to be treated. While the above doses are illustrative of the average case, there may, of course, be individual cases in which higher or lower dose ranges are appropriate, and such doses are within the scope of this invention.

The compounds of this invention exhibit significantly improved aqueous solubility compared to known fractalkine receptor antagonists, as well as significantly improved long term aqueous storage stability.

Accordingly, in specific embodiments, compounds containing one or more (eg, one) compounds of this invention further contain water.

In more specific embodiments, the implementation of the proposed pharmaceutical composition containing one or more (for example, one) compounds according to this invention is presented in the form of an aqueous solution.

Those skilled in the art will understand that the reference to pharmaceutical compositions presented in the form of an aqueous solution refers to compositions in which the active ingredient and optionally one or more pharmaceutically acceptable excipients are dissolved in water.

The greatly improved aqueous solubility and storage stability in an aqueous medium allows the compounds of this invention to be formulated into aqueous compositions (eg, in the form of aqueous solutions) without the need to include solubilizing auxiliaries.

Thus, specific embodiments provide a pharmaceutical composition comprising one or more (e.g., one) compounds of this invention, water, and less than 20% (w/w) solubilizing excipients (e.g., less than 10%, e.g., less than 5 %, for example, less than 1%). In more specific embodiments, such a composition is in the form of an aqueous solution.

In this context, the expression "solubilizing excipients" can be understood as an indication of (pharmaceutically acceptable) excipients that are used to solubilize organic compounds in an aqueous medium (for example, in an aqueous pharmaceutical composition), to obtain a stable solution or suspension of the active ingredient. Such solubilizing adjuvants include water-miscible/water-soluble solvents and water-soluble surfactants. Examples of such excipients include ethanol, polyethylene glycol (PEG) (PEG 400, PEG 300), polysorbates, cyclodextrins, dimethyl sulfoxide, polysorbate 80 (Tween 80), propylene glycol, ethylene glycol, glycerin, dimethylacetamide, polyoxyethylated castor oils (e.g. Chremophor), polyoxyethylated glycerides, stearyl alcohol, oleyl alcohol.

In alternative embodiments, pharmaceutical compositions containing the compounds of this invention are in the form of a (dry) powder (ie, a powder containing the compounds of this invention and optionally one or more pharmaceutically acceptable excipients). As described above, it is contemplated that such a powder may be diluted with a suitable liquid (particularly water, optionally in the form of an aqueous solution of pharmaceutically acceptable excipients) to form a liquid dosage form (eg, an aqueous solution) prior to administration.

In specific embodiments, compositions containing the compounds of this invention (and/or pharmaceutical compositions containing them) are presented in a dosage form suitable for oral or intravenous administration (eg oral administration).

Combinations and sets of components

Those skilled in the art will recognize that treatment with the compounds of this invention may further comprise (ie, it may be combined with) additional treatment(s) or methods of preventing the same condition. In particular, treatment with the compounds of this invention may be combined with treatments for a fractalkine related disease described herein, e.g., an inflammatory disease, an autoimmune disease, cancer, and/or a cardiovascular disease, e.g. agents useful in the treatment or prevention of a disease associated with fractalkin, and/or one or more physical methods used for treatment (such as treatment through surgery) known to those skilled in the art.

As described herein, the compounds of this invention may also be combined with one or more (i.e., other) therapeutic agents (i.e., agents that are not compounds of this invention) useful in the treatment and/or prevention of a disease. associated with fractalkin. Such combination products are provided for administering a compound of this invention in combination with one or more other therapeutic agents, or may be presented as separate dosage forms, wherein at least one of such dosage forms contains a compound of this invention and at least at least one contains another therapeutic agent, or may be presented (i.e., formulated) as a combination preparation (i.e., presented as a single dosage form containing a compound of this invention and one or more other therapeutic agents).

Thus, according to the sixth aspect of the present invention, there is provided a combination product comprising:

(I) a compound of this invention as defined above (ie, in the first aspect of the invention, including all embodiments and specific features thereof); And

(II) one or more other therapeutic agents useful in the treatment and/or prevention of a disease or disorder associated with elevated levels of CX3CR1 and/or CX3CL1 (such as eye disease, lung disease, skin disease, joint and/or bone disease, autoimmune diseases, cardiovascular disease, metabolic disease, brain disease, neurodegenerative disease, pain, cancer, liver disease, kidney disease, gastrointestinal disease, and human immunodeficiency virus, as described herein),

wherein each of components (I) and (II) is formulated as a mixture, optionally with one or more pharmaceutically acceptable excipients.

In the seventh aspect of the present invention, a set of components is provided, comprising:

(a) a pharmaceutical dosage form as defined above (ie in the fourth aspect of the invention); And

(b) one or more other therapeutic agents useful in the treatment or prevention of a disease or disorder associated with elevated levels of CX3CR1 and/or CX3CL1 (such as eye disease, lung disease, skin disease, joint and/or bone disease, autoimmune disease, cardiovascular diseases, metabolic diseases, brain diseases, neurodegenerative diseases, pain, cancer, liver diseases, kidney diseases, gastrointestinal diseases and human immunodeficiency virus, as described herein), optionally in admixture with one or more pharmaceutically acceptable carriers,

and both components (a) and (b) are presented in a form suitable for administration in combination (ie, simultaneously or sequentially) with another component.

With respect to the sets of components described herein, "administration in combination with" (and likewise "introduced in combination with") includes the administration of the respective dosage forms sequentially, separately, or simultaneously, as part of a medical intervention aimed at treating a relevant condition.

Thus, in relation to this invention, the term "administration in combination with" (and similarly "administered in combination with") includes the administration (optionally multiple) of two active ingredients (i.e., a compound of this invention and an additional agent for treatment and/or prevention of diseases associated with fractalkine, or compositions containing them) together or close enough in time to provide a beneficial effect on the patient, that is, an effect that is higher during the course of treatment and / or prevention of the relevant condition than when administered (optionally multiple times) any of the agents alone, without the other component, during the same course of treatment and/or prevention. Determining whether a combination provides an enhanced beneficial effect in relation to and during the course of treatment and/or prevention of a particular condition depends on the condition being treated and/or prevention, but can be routinely carried out by a person skilled in the art.

In addition, in the context of this invention, the term "in combination with" includes the possibility of introducing (optionally multiple) one or the other of the two dosage forms before, after and/or at the same time as the introduction of the other component. When used in this context, the terms "administered simultaneously" and "administered at the same time" include situations in which separate doses of a compound of this invention and an additional compound for the treatment of a disease or disorder associated with elevated levels of CX3CR1 and/or CX3CL1, or pharmaceutically acceptable salts are administered within 48 hours (eg, within 24 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes or 10 minutes) relative to each other.

In this context, the indication of other therapeutic agents that are "suitable" in a certain way (for example, for the treatment of a particular disease or disorder) refers to agents that are known to be suitable for use in this way (for example, to agents commonly used for this goals). Thus, these references may be replaced by indications of agents "fit for" the respective purpose.

Other therapeutic agents suitable for the treatment and/or prevention of diseases associated with fractalkin (such as those described herein) are well known to those skilled in the art. For example, these other therapeutic agents may include:

anti-inflammatory drugs (such as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and targeted anti-inflammatory antibodies);

anticancer agents (such as alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, mitotic inhibitors, immunomodulators, targeted therapeutics (eg kinase inhibitors) and drugs that interfere with DNA repair);

compounds for the treatment of cardiovascular diseases (such as ACE inhibitors (angiotensin-converting enzyme inhibitors), anti-arrhythmia drugs, anticoagulants, antiplatelet agents, beta-blockers, calcium channel blockers, cholesterol-lowering drugs (such as statins) and acetylsalicylic acid.

Preparation of compounds/compositions

Pharmaceutical compositions/dosage forms, combination products and kits described herein can be obtained in accordance with standard and/or accepted pharmaceutical practice.

Thus, in a further aspect of the present invention, there is provided a process for the preparation of a pharmaceutical composition/dosage form as defined above, which comprises contacting a compound of the invention as defined above with one or more pharmaceutically acceptable excipients.

In additional aspects of the present invention, there is provided a method for preparing a combination product or set of components as defined above, which comprises contacting a compound of this invention, as defined above, with another therapeutic agent useful in treating the disease or disorder in question, and at least at least one pharmaceutically acceptable excipient.

In this context, the mention of bringing into contact means ensuring the suitability of the two components for the introduction in combination with each other.

Thus, in relation to the method of obtaining a set of components, as defined above, by bringing "in contact" of two components with each other means that the two components of the set of components can be:

(i) presented as separate dosage forms (ie, independently of each other), which are then brought into contact for use in combination with each other in combination therapy; or

(ii) packaged and presented together as separate components of a "combination package" for use in combination with each other in combination therapy.

The compounds of this invention described herein can be prepared according to methods well known to those skilled in the art, such as those described in the examples below.

Precursor compounds for the compounds of this invention (such as (2 R )-2-[(2-amino-5-{[(1 S )-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentan-1-ol hydrochloride and 5-{[(1 S )-1-(5-chloropyridin-2-yl)ethyl]sulfanyl}-7-{[( 1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5- d ]pyrimidin-2( 3H )-one (compounds of formula II)) can be prepared by methods known in the art, such as those described in Karlström S., et al., ( J. Med. Chem ., 2013 , 56 , 3177-3190 (including related information)), WO 2006/107258 and WO 2008/039138.

According to the eighth aspect of the present invention, there is provided a process for preparing the compound of the present invention as defined above, comprising:

(a) for compounds in which Q ¹ is -PO(OR ⁶ )(OR ⁷ ), where R ⁶ and R ⁷ are as described herein,

(i) reacting a compound of formula II

(II)

where R ¹ and R ² are as described herein; And

represents or ;

with phosphorus oxychloride in the presence of a suitable solvent (eg tetrahydrofuran, diethyl ether or methyl tert -butyl ether) and a suitable base (eg pyridine or triethylamine); then

(ii) adding water or R ⁶ OH/R ⁷ OH to the reaction mixture;

(b) for compounds in which Q ² is -PO(OR ⁶ )(OR ⁷ );

bringing into interaction the compounds of formula III

(III)

Where:

R ¹ and R ² are as described herein;

PG ¹ is a suitable oxygen protecting group (eg a silyl protecting group, eg trimethylsilyl, t -butyldimethylsilyl or triisopropylsilyl);

in the presence of phosphorus pentachloride, a suitable solvent (eg dichloromethane) and optionally a suitable base (eg pyridine),

(c) for compounds in which Q ³ or Q ⁴ is -CH ₂ OPO(OR ⁶ )(OR ⁷ ) and at least one of R ⁶ and R ⁷ is C _1-4 alkyl or C _2-4 alkenyl,

bringing into interaction the compounds of formula II

(II)

where R ¹ and R ² are as described herein; And

represents or ;

with compound of formula IV

(iv)

where R ⁶ and R ⁷ are as described herein, provided that at least one of R ⁶ and R ⁷ is C _1-4 alkyl or C _2-4 alkenyl, and LG ¹ is a suitable leaving a group (such as halogen (eg Cl, Br));

in the presence of a suitable base (eg K ₂ CO ₃ ) and a suitable solvent (eg acetonitrile);

(d) for compounds in which Q ³ or Q ⁴ is -CH ₂ OPO(OH) ₂ ,

(i) reacting a compound of formula II

(II)

where R ¹ and R ² are as described herein; And

represents or ;

with a compound of formula V

(V)

where R ⁸ and R ⁹ are C _1-6 alkyl, LG ² is a suitable leaving group (such as halo (eg Cl, Br));

in the presence of a suitable base (eg K ₂ CO ₃ ) and a suitable solvent (eg acetonitrile); And

(ii) reacting the resulting product in the presence of a suitable acid (eg HCl) and a suitable solvent (eg dioxane).

Compounds of formulas II - V are either commercially available or known from the literature, or can be prepared by analogy with the methods described herein or conventional synthetic methods according to standard procedures from available starting materials using appropriate reagents and reaction conditions. In this respect, those skilled in the art may refer,interalia, to publication"Comprehensive Organic Synthesis”, B. M. Trost and I. Fleming, Pergamon Press, 1991. Additional sources that may be consulted include “Heterocyclic Chemistry”, J. A. Joule, K. Mills and G. F. Smith, 3^e edition published by Chapman & Hall, “Comprehensive Heterocyclic Chemistry II”, A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon Press, 1996, and “Science of Synthesis”, volumes 9-17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006.

Those skilled in the art will appreciate that the substituents described herein and their substitutions may be modified one or more times, after or during the methods described above, to obtain the compounds of this invention using methods well known to those skilled in the art. this field of technology. Examples of such methods include substitution, reduction, oxidation, dehydrogenation, alkylation, dealkylation, acylation, hydrolysis, esterification, esterification, halogenation, and nitration. Precursor groups may be replaced by other such groups, or by groups defined in formula I, at any time during the course of the reaction sequence. Those skilled in the art may also refer to Comprehensive Organic Functional Group Transformations , AR Katritzky, O. Meth-Cohn and CW Rees, Pergamon Press, 1995, and/or Comprehensive Organic Transformations , RC Larock, Wiley-VCH , 1999.

The compounds of this invention can be isolated from their reaction mixtures and, if necessary, purified using conventional techniques known to those skilled in the art. Thus, methods for preparing compounds of this invention described herein may include, as a last step, isolation and optional purification of a compound of this invention.

Those skilled in the art will appreciate that in the methods described herein, the functional groups of intermediates may need to be protected with protective groups. Protection and deprotection of functional groups can be carried out before or after the reaction in the above schemes.

The compounds of formulas III, IV and V are characterized by the presence of protective groups. Protecting groups can be installed and removed in accordance with techniques well known to those skilled in the art and described below. For example, the protected compounds/intermediates described herein can be chemically converted to unprotected compounds using standard deprotection techniques. The type of chemical transformation determines the need and type of protective groups, as well as the sequence of the synthesis. The use of protecting groups is described in detail in " Protective Groups in Organic Synthesis ", 3rd edition, TW Greene & PGM Wutz, Wiley-Interscience (1999), the contents of which are incorporated herein by reference.

In particular, silyl ether protecting groups for oxygen atoms can be introduced by reacting the appropriate alcohol with a suitable trialkylsilyl halide (eg trimethylsilyl chloride or t -butyldimethylsilyl chloride) in the presence of a suitable base (eg N,N -diisopropylethylamine, triethylamine or N,N -dimethylaminopyridine). Silyl ether protecting groups can be removed in the presence of a suitable fluoride source (eg, tetrabutylammonium fluoride). Carbamate nitrogen protecting groups may be introduced by reacting the appropriate amino group with a suitable chloroformate or carbonate anhydride (eg, di- tert -butyl dicarbonate), optionally in the presence of a suitable base, and may be removed under appropriate acidic or basic conditions known in the art. specialists in this field of technology. Benzyl protecting groups may be introduced by reacting the relevant nitrogen atom with a suitable benzyl halide in the presence of a suitable base, and may be removed under appropriate conditions known to those skilled in the art (e.g., the 2,4-dimethoxybenzyl group may be removed in the presence of nitrate ammonium-cerium and a suitable solvent).

It can be assumed that the compounds of this invention provide significant advantages over known fractalkine receptor antagonists in terms of water solubility and storage stability in an aqueous medium.

The compounds of this invention may have the advantage that they may be more effective, less toxic, longer acting, may cause fewer side effects, may be more easily absorbed, and/or may have a better pharmacokinetic profile (e.g., higher oral bioavailability and/or or lower clearance), and/or may have other useful pharmacological, physical or chemical properties compared to prior art compounds when used for the above indications or otherwise. In particular, the compounds of this invention may have the advantage of being more potent and/or showing advantageous properties in vivo .

In particular, it can be contemplated that the compounds of this invention may provide the possibility of treatment with higher doses and/or longer therapeutic regimens than known fractalkine receptor antagonists, and therefore provide a significant advantage in terms of treatment options available. for the patient.

Examples

General methods

The following abbreviations are used in this context:

DXM - dichloromethane

DMAP - 4-dimethylaminopyridine

DMF - N,N -dimethylformamide

DMSO - dimethyl sulfoxide

ESI - electrospray ionization

EtOAc - ethyl acetate

EtOH - ethanol

HPLC - high performance liquid chromatography

MeOH - methanol

MS - mass spectrometry

NMR - nuclear magnetic resonance.

Spectra¹H NMR and¹³C NMR was recorded on a Varian Inova 600 instrument equipped with a triple resonance probe. All spectra were recorded using the proton resonance of the residual solvent as an internal standard. Analytical HPLC was performed on an Agilent Series 1100 system using a Kinetex C18 column (2.6 µm, 3.0x50 mm) with 0.1% formic acid in MilliQ H₂O/CH₃CN as mobile phase (acid system) or Kinetex EVO column (2.6 µm 3.0x50 mm) with 10 mM, pH10, NH₄HCO₃ /CH₃CN as mobile phase (basic system). Electrospray mass spectrometry (ES-MS) was performed on an Agilent 1100 Series Mass Selective Detector (MSD) liquid chromatograph to obtain the pseudomolecular ion [M+H]⁺ required molecules. Preparative HPLC was performed on a Gilson 306 HPLC system using a Kinetex C18 column (5 µm, 21x100 mm) with 0.1% TFA in MilliQ H₂O/CH₃CN as mobile phase (acid system) or Gemini NX column (5 µm, 21x100 mm) with 50 mM, pH10, NH₄HCO₃/CH₃CN as mobile phase (basic system). Fractions were collected based on the UV signal at the maximum wavelength for the compound in question. Preparative flash chromatography was performed on Merck 60 silica gel (230-400 mesh) or YMC 120Å S-150 µm gel. Microwave reactions were performed on a Biotage Initiator using 0.5-2 ml or 2-5 ml Biotage Process flasks fitted with aluminum caps and a septum. Compound names were obtained using ACD Labs 10.0 software.

Example 1

Getting (2 R )-2-[(2-amino-5-{[(1 S )-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate

Phosphorus oxychloride (337 mg, 2.2 mmol) was dissolved in THF (0.75 ml) and water (25 mg, 1.4 mmol) was added. The mixture was cooled in an ice bath and pyridine (111 mg, 113 μl, 1.4 mmol) was added followed by ( 2R )-2-[(2-amino-5-{[( 1S )-1-phenylethyl]sulfanyl} [1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentan-1-ol hydrochloride (110 mg, 0.25 mmol) ( S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258). The reaction mixture was stirred at ice bath temperature for 1 hour. Pyridine (111 mg, 113 μl, 1.4 mmol) was added to a mixture of phosphorus oxychloride (337 mg, 2.2 mmol) and water (25 mg, 1.4 mmol) in THF at ice bath temperature. Half of the resulting mixture was added to the reaction mixture described above. The reaction mixture was stirred at ice bath temperature for an additional 1 hour. Water (3 ml) was added and the reaction mixture was stirred for 15 minutes at ice bath temperature and for 20 minutes at room temperature. DCM (3 ml) was added and the phases were separated. The aqueous phase was extracted with an additional portion of DCM (3 ml) and the organic phases were combined. At this time, the product began to precipitate as a pale yellow gum in the organic phase. MeOH was added and the now homogeneous solution was transferred to a round bottom flask and evaporated to give 120 mg of the crude product, which, according to HPLC, was about 93% pure. The crude material was dissolved in MeOH/water and the pH was adjusted to about 6-7 with 1M NaOH. The material was purified by preparative HPLC (basic method). Pure fractions were combined, evaporated and dried in vacuo. After purification, the product was considered a diammonium salt. ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.43 - 7.47 (m, 2 H) 7.30 - 7.35 (m, 2 H) 7.20 - 7.24 (m, 1 H) 5.08 (k, J = 7.03 Hz, 1 H) 4.59 - 4.68 (m, 1 H) 3.92 (ddd, J = 10.12, 5.67, 4.30 Hz, 1 H) 3.88 (dt, J = 10.12, 4.94 Hz, 1 H) 1.74 (d, J =7.03 Hz, 3 H) 1.71 - 1.79 (m, 1 H) 1.68 (ddd, J =13 .87, 9.54, 5.67 Hz, 1 H) 1.57 (ddd, J = 13.87, 8.54, 5.33 Hz, 1 H) 0.98 (d, J = 6.71 Hz, 3 H) 0.96 (d, J = 6.56 Hz, 3 H). MS (ESI+) m/z 484 [M+H] ⁺ .

Example 1b

(2 R )-2-[(2-Amino-5-{[1-(2-fluorophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate

The title compound was synthesized from ( 2R )-2-[(2-amino-5-{[1-(2-fluorophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidine-7 -yl)amino]-4-methylpentan-1-ol ( S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) in 55% yield using the method described for example 1. The product was a mixture of two diastereomers. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ _H ppm 7.98 (ws, 4 H) 8.09 (ws, 2 H) 7.50 - 7.57 (m, 2 H) 7.26 - 7.32 (m, 2 H) 7.15 - 7, 20 (m, 4 H) 7.30 (ws, 4 H) 5.25 (k, J = 7.0 Hz, 1 H) 5.24 (k, J = 7.2 Hz, 1 H) 4, 22 - 4.30 (m, 1 H) 4.14 - 4.25 (m, 1 H) 3.75 - 3.82 (m, 1 H) 3.65 - 3.76 (m, 3 H) 1.69 (d, J =7.0 Hz, 3 H) 1.66 (d, J =7.2 Hz, 3 H) 1.56 - 1.65 (m, 2 H) 1.46 - 1 .57 (m, 2 H) 1.41 (ddd, J = 13.4, 6.9, 6.8 Hz, 2 H) 0.88 (d, J = 6.6 Hz, 3 H) 0, 88 (d, J =6.6 Hz, 3 H) 0.85 (d, J =6.7 Hz, 3 H) 0.84 (d, J =6.7 Hz, 3 H). MS (ESI+) m/z 502 [M+H] ⁺ .

Example 1c

(2 R )-2-[(2-Amino-5-{[1-(2-chlorophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate

The title compound was synthesized from ( 2R )-2-[(2-amino-5-{[1-(2-chlorophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidine-7 -yl)amino]-4-methylpentan-1-ol ( S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) in 55% yield using the method described for example 1. The product was a mixture of two diastereomers. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ _H ppm 8.31 (ws, 2 H) 7.95 (ws, 4 H) 7.61 (dd, J =7.8, 1.8 Hz, 1 H) 7.60 (dd, J =7.8, 1.8 Hz, 1 H) 7.45 (dd, J =8.0, 1.4 Hz, 1 H) 7.45 (dd, J =8.0, 1.4 Hz, 1 H) 7, 35 (ddd, J =7.8, 7.3, 1.4 Hz, 1 H) 7.34 (ddd, J =7.8, 7.3, 1.4 Hz, 1 H) 7.28 ( ddd, J = 8.0, 7.3, 1.8 Hz, 1 H) 7.28 (ddd, J = 8.0, 7.3, 1.8 Hz, 1 H) 6.77 - 7, 56 (m, 4 H) 5.42 (k, J = 6.9 Hz, 1 H) 5.36 (k, J = 6.9 Hz, 1 H) 4.16 - 4.29 (m, 2 H) 3.76 - 3.84 (m, 1 H) 3.64 - 3.76 (m, 3 H) 1.71 (d, J = 6.9 Hz, 3 H) 1.67 (d, J = 6.9 Hz, 3 H) 1.49 - 1.65 (m, 4 H) 1.37 - 1.45 (m, 2 H) 0.89 (d, J = 6.4 Hz, 3 H) 0.88 (d, J =6.4Hz, 3H) 0.87 (d, J =6.6Hz, 3H) 0.83 (d, J =6.1Hz, 3H) . MS (ESI+) m/z 518 [M+H] ⁺ .

Example 1d

(2 R )-2-[(2-Amino-5-{[1-(5-chloropyridin-2-yl)ethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate

The title compound was synthesized from ( 2R )-2-[(2-amino-5-{[1-(5-chloropyridin-2-yl)ethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentan-1-ol ( S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) in 16% yield using the method described for example 1. The product was a mixture of two diastereomers. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ _H ppm 8.57 (dd, J =2.5, 0.7 Hz, 1 H) 8.55 (dd, J =2.5, 0.7 Hz, 1 H) 8.02 (shs, 4 H) 7 .88 (dd, J =8.5, 2.5 Hz, 1 H) 7.84 (dd, J =8.4, 2.5 Hz, 1 H) 7.58 (dd, J =8.5 , 0.7 Hz, 1 H) 7.56 (dd, J = 8.5, 0.7 Hz, 1 H) 6.93 - 7.51 (m, 4 H) 5.14 (k, J = 7.2 Hz, 1 H) 5.07 (k, J =7.2 Hz, 1 H) 4.40 - 4.51 (m, 1 H) 4.15 - 4.26 (m, 1 H) 3.74 - 3.82 (m, 3 H) 3.71 (dt, J =10.3, 6.0 Hz, 1 H) 1.66 (d, J =7.2 Hz, 3 H) 1 .64 (d, J = 7.2 Hz, 3 H) 1.54 - 1.65 (m, 2 H) 1.44 - 1.54 (m, 2 H) 1.40 (ddd, J = 13 .7, 8.9, 4.8 Hz, 1 H) 1.35 (ddd, J = 13.7, 8.7, 4.7 Hz, 1 H) 0.87 (d, J = 6.7 Hz, 3 H) 0.85 (d, J =6.4 Hz, 3 H) 0.84 (d, J =6.5 Hz, 3 H) 0.76 (d, J =6.6 Hz, 3H). MS (ESI+) m/z 519 [M+H] ⁺ .

Example 1e

(2 R )-2-[(2-Amino-5-{[1-(3-fluoropyridin-2-yl)ethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate

The title compound was synthesized from ( 2R )-2-[(2-amino-5-{[1-(3-fluoropyridin-2-yl)ethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentan-1-ol ( S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) in 7% yield using the method described for example 1. The product was a mixture of two diastereomers. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ _H ppm 8.75 (ws, 1 H) 8.39 - 8.42 (m, 2 H) 7.95 (ws, 4 H) 7.68 - 7.74 (m, 2 H) 7.36 - 7, 43 (m, 2 H) 7.15 (brw, 5 H) 5.49 (k, J = 6.9 Hz, 1 H) 5.45 (k, J = 6.9 Hz, 1 H) 4, 13 - 4.33 (m, 2 H) 3.74 - 3.85 (m, 2 H) 3.67 - 3.75 (m, 2 H) 1.71 (d, J = 6.9 Hz, 3 H) 1.68 (d, J = 6.9 Hz, 3 H) 1.58 - 1.67 (m, 2 H) 1.48 - 1.59 (m, 2 H) 1.40 - 1 .48 (m, 2 H) 0.90 (d, J =6.5 Hz, 3 H) 0.90 (d, J =6.5 Hz, 3 H) 0.87 (d, J =6, 7 Hz, 3 H) 0.86 (d, J = 6.7 Hz, 3 H). MS (ESI+) m/z 503 [M+H] ⁺ .

Example 1f

(2 R )-2-[(2-Amino-5-{[1-(3-cyanophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate

The title compound was synthesized from 3-{1-[(2-amino-7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5- d ]pyrimidin-5-yl)sulfanyl]ethyl}benzonitrile ( S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) in 50% yield using the method described for example 1. The product was a mixture of two diastereomers. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ _H ppm 8.17 (ws, 1 H) 7.99 (ws, 4 H) 8.04 (ws, 1 H) 7.92 (t, J =1.6 Hz, 1 H) 7.90 (t, J =1.7 Hz, 1 H) 7.80 - 7.85 (m, 2 H) 7.67 - 7.70 (m, 2 H) 7.56 (t, J = 7.8 Hz, 1 H ) 7.51 (t, J = 7.8 Hz, 1 H) 7.26 (ws, 4 H) 5.03 (k, J = 7.2 Hz, 1 H) 5.03 (k, J = 7.2 Hz, 1 H) 4.18 - 4.29 (m, 1 H) 4.06 - 4.16 (m, 1 H) 3.64 - 3.74 (m, 4 H) 1.66 (d, J =7.2 Hz, 3 H) 1.65 (d, J =7.2 Hz, 3 H) 1.53 - 1.62 (m, 2 H) 1.37 - 1.51 ( m, 4 H) 0.88 (d, J =6.6 Hz, 3 H) 0.86 (d, J =6.5 Hz, 3 H) 0.85 (d, J =6.5 Hz, 3 H) 0.78 (d, J = 6.5 Hz, 3 H). MS (ESI+) m/z 509 [M+H] ⁺ .

Example 1g

(2 R )-2-[(2-Amino-5-{[1-(3-carbamoylphenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate

The title compound was synthesized from 3-{1-[(2-amino-7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5- d ]pyrimidin-5-yl)sulfanyl]ethyl}benzamide ( S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) as a single diastereomer, in 17% yield using the method described for example 1. The product was a single diastereomer. ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 8.03 (t, J =1.85 Hz, 1 H) 7.75 (ddd, J =7.70, 1.85, 1.10 Hz, 1 H) 7.71 (ddd, J =7, 70, 1.85, 1.10, 0.42 Hz, 1 H) 7.42 (t, J =7.70 Hz, 1 H) 5.14 (k, J =7.19 Hz, 1 H) 4.35 - 4.43 (m, 1 H) 3.98 (ddd, J =9.85, 5.11, 4.37 Hz, 1 H) 3.91 (ddd, J =9.85, 5 .20, 5.02 Hz, 1 H) 1.73 (d, J = 7.19 Hz, 3 H) 1.58 - 1.67 (m, 2 H) 1.48 - 1.55 (m, 1 H) 0.91 (d, J =6.39 Hz, 3 H) 0.76 (d, J =6.39 Hz, 3 H). MS (ESI+) m/z 527 [M+H] ⁺ .

Example 1h

(2 R )-2-{[2-Amino-5-({1-[4-(methylsulfonyl)phenyl]ethyl}sulfanyl)[1,3]thiazolo[4,5- d ]pyrimidin-7-yl]amino}-4-methylpentyl dihydrogen phosphate

The title compound was synthesized from ( 2R )-2-{[2-amino-5-({1-[4-(methylsulfonyl)phenyl]ethyl}sulfanyl)[1,3]thiazolo[4,5- d ] pyrimidin-7-yl]amino}-4-methylpentan-1-ol ( S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) as a single diastereomer, in 39% yield using the method described for example 1. The product was a single diastereomer. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ _H ppm 8.22 (brw, 2H) 7.83 - 7.88 (m, 2H) 7.73 - 7.78 (m, 2H) 7.34 (brw, 1H) 5.08 (k, J = 7.3 Hz, 1 H) 4.22 - 4.33 (m, 1 H) 3.88 (dt, J = 9.9, 5.4 Hz, 1 H) 3.76 (td, J =9.9, 6.1 Hz, 1 H) 3.18 (s, 3 H) 1.64 (d, J = 7.3 Hz, 3 H) 1.53 - 1.61 (m, 1 H ) 1.51 (ddd, J =13.6, 10.3, 4.9 Hz, 1 H) 1.37 (ddd, J =13.6, 9.2, 4.3 Hz, 1 H) 0 .85 (d, J =6.6 Hz, 3 H) 0.72 (d, J =6.6 Hz, 3 H). MS (ESI+) m/z 562 [M+H] ⁺ .

Example 1i

(2 R )-2-[(2-Amino-5-{[4-(methylsulfonyl)benzyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate

The title compound was synthesized from ( 2R )-2-[(2-amino-5-{[4-(methylsulfonyl)benzyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl )amino]-4-methylpentan-1-ol ( S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) in 22% yield using the method described for example 1. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ _H ppm. 8.02 (ws, 2 H) 7.81 - 7.86 (m, 2 H) 7.66 - 7.71 (m, 2 H) 7.17 (ws, 2 H) 4.45 (d, J = 14.3 Hz, 1 H) 4.39 (d, J = 14.3 Hz, 1 H) 4.20 - 4.34 (m, 1 H) 3.67 - 3.76 (m, 2 H) 3.17 (s, 3 H) 1.52 - 1.61 (m, 1 H) 1.46 (ddd, J = 13.7, 9.0, 6.0 Hz, 1 H) 1, 38 (ddd, J =13.7, 8.1, 5.5 Hz, 1 H) 0.83 (d, J =6.6 Hz, 3 H) 0.78 (d, J =6.4 Hz , 3H). MS (ESI+) m/z 548 [M+H] ⁺ .

Example 1j

(2 R )-2-({2-Amino-5-[(1-pyridin-2-ylethyl)sulfanyl][1,3]thiazolo[4,5- d ]pyrimidin-7-yl}amino)-4-methylpentyl dihydrogen phosphate

The title compound was synthesized from ( 2R )-2-({2-amino-5-[(1-pyridin-2-ylethyl)sulfanyl][1,3]thiazolo[4,5- d ]pyrimidin-7- yl}amino)-4-methylpentan-1-ol ( S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) in 43% yield using the method described for example 1. The product was a mixture of two diastereomers. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ _H ppm 8.51 (ddd, J =4.8, 1.9, 1.0 Hz, 1 H) 8.51 (ddd, J =4.8, 1.9, 1.0 Hz, 1 H) 8, 00 (ws, 4 H) 7.74 (ddd, J =7.9, 7.4, 1.9 Hz, 1 H) 7.73 (ddd, J =7.9, 7.4, 1.9 Hz, 1 H) 7.51 (dt, J =7.9, 1.0 Hz, 1 H) 7.49 (dt, J =7.9, 1.0 Hz, 1 H) 7.47 (ws , 1 H) 7.25 (ddd, J =7.4, 4.8, 1.0 Hz, 1 H) 7.23 (ddd, J =7.4, 4.8, 1.0 Hz, 1 H) 7.17 (brw, 4 H) 5.13 (k, J = 7.0 Hz, 1 H) 5.09 (k, J = 7.0 Hz, 1 H) 4.34 - 4.48 (m, 1 H) 4.15 - 4.29 (m, 1 H) 3.66 - 3.83 (m, 4 H) 1.67 (d, J = 7.0 Hz, 3 H) 1, 66 (d, J = 7.0 Hz, 3 H) 1.54 - 1.66 (m, 2 H) 1.45 - 1.54 (m, 2 H) 1.41 (ddd, J = 13, 8, 8.5, 5.3 Hz, 1 H) 1.39 (ddd, J =13.8, 8.5, 5.3 Hz, 1 H) 0.88 (d, J =6.6 Hz , 3 H) 0.86 (d, J =6.7 Hz, 3 H) 0.85 (d, J =6.6 Hz, 3 H) 0.78 (d, J =6.6 Hz, 3 H). MS (ESI+) m/z 485 [M+H] ⁺ .

Example 1k

(2 R )-2-[(2-Amino-5-{[(1 S )-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl-dimethylphosphate

The title compound was synthesized from ( 2R )-2-[(2-amino-5-{[( 1S )-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidine-7 -yl)amino]-4-methylpentan-1-ol ( S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) in 27% yield using the method described for Example 1, except that MeOH was added instead of THF and water after 1 hour at ice bath temperature. ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.45 - 7.48 (m, 2 H) 7.30 - 7.34 (m, 2 H) 7.20 - 7.24 (m, 1 H) 5.06 (k, J = 7.1 Hz, 1 H) 4.67 - 4.74 (m, 1 H) 3.97 (ddd, J =10.2, 6.6, 5.7 Hz, 1 H) 3.94 (ddd, J = 10.2, 6.5, 4.9 Hz, 1 H) 3.68 (d, J =11.1 Hz, 3 H) 3.63 (d, J =11.1 Hz, 3 H) 1, 72 - 1.79 (m, 1 H) 1.72 (d, J = 7.1 Hz, 3 H) 1.62 (ddd, J = 13.9, 10.5, 5.0 Hz, 1 H ) 1.42 (ddd, J =13.9, 9.3, 4.4 Hz, 1 H) 0.99 (d, J =6.7 Hz, 3 H) 0.97 (d, J =6 .6 Hz, 3 H). MS (ESI+) m/z 512 [M+H] ⁺ .

Example 1l

(2 R )-2-[(2-Amino-5-{[(1 S )-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl-diethyl phosphate

The title compound was synthesized from ( 2R )-2-[(2-amino-5-{[( 1S )-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidine-7 -yl)amino]-4-methylpentan-1-ol ( S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) in 68% yield using the method described for Example 1, except that EtOH was added instead of THF and water after 1 hour at ice bath temperature. ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.45 - 7.48 (m, 2 H) 7.29 - 7.34 (m, 2 H) 7.20 - 7.24 (m, 1 H) 5.05 (k, J = 7.1 Hz, 1 H) 4.66 - 4.74 (m, 1 H) 4.01 (dc, J = 8.2, 7.1 Hz, 2 H) 3.93 - 3.98 (m, J = 8.0, 7.0, 7.0, 7.0, 3.4Hz, 2H) 3.92 - 3.95 (m, 2H) 1.72 - 1.79 (m, 1H) 1.72 (d, J =7.1 Hz, 3 H) 1.62 (ddd, J =13.8, 10.4, 5.0 Hz, 1 H) 1.41 (ddd, J =13, 8, 9.2, 4.5 Hz, 1 H) 1.23 (td, J =7.1, 1.0 Hz, 3 H) 1.16 (td, J =7.0, 1.0 Hz , 3 H) 0.99 (d, J =6.7 Hz, 3 H) 0.97 (d, J =6.6 Hz, 3 H). MS (ESI+) m/z 540 [M+H] ⁺ .

Example 1m

(2 R )-2-[(2-Amino-5-{[(1 S )-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl-bis(1-methylethyl)phosphate

The title compound was synthesized from ( 2R )-2-[(2-amino-5-{[( 1S )-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidine-7 -yl)amino]-4-methylpentan-1-ol ( S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) in 29% yield using the method described for Example 1, except that i-PrOH was added instead of THF and water after 1 hour at ice bath temperature. The product was a mixture of mono- and diisopropyl phosphate esters, which were separated by preparative HPLC. ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.47 (dd, J =8.1, 1.1 Hz, 2 H) 7.30 - 7.35 (m, 2 H) 7.23 (tt, J =7.2, 1.4 Hz, 1 H) 5.06 (k, J = 7.2 Hz, 1 H) 4.71 (brs, 1 H) 4.51 (sextet, J = 6.3 Hz, 1 H) 4.44 (sextet, J = 6.3 Hz, 1 H) 3.85 - 3.95 (m, 2 H) 1.73 - 1.79 (m, 1 H) 1.72 (d, J = 7.0 Hz, 3 H) 1.62 (ddd, J =13.7, 10.4, 5.2 Hz, 1 H) 1.41 (ddd, J =13.8, 9.2, 4.4 Hz, 1 H) 1.24 (d, J =6.1 Hz, 3 H) 1.21 (d, J =6.1 Hz, 3 H) 1.19 (d, J =6.1 Hz, 3 H) 1, 13 (d, J =6.1 Hz, 3 H) 0.99 (d, J =6.7 Hz, 3 H) 0.98 (d, J =6.7 Hz, 3 H). MS (ESI+) m/z 540 [M+H] ⁺ .

Example 1n

(2 R )-2-[(2-Amino-5-{[(1 S )-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl-1-methylethyl hydrogen phosphate

The title compound was synthesized from ( 2R )-2-[(2-amino-5-{[( 1S )-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidine-7 -yl)amino]-4-methylpentan-1-ol ( S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) in 37% yield using the method described for Example 1, except that i-PrOH was added instead of THF and water after 1 hour at ice bath temperature. The product was a mixture of mono- and diisopropyl phosphate esters, which were separated by preparative HPLC. ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.47 (dd, J =8.2, 1.2 Hz, 2 H) 7.32 - 7.38 (m, 2 H) 7.26 (tt, J =7.4, 1.5 Hz, 1 H) 5.13 (k, J = 7.0 Hz, 1 H) 4.68 (brw, 1 H) 4.31 - 4.38 (m, 1 H) 3.81 - 3.89 (m , 2 H) 1.78 (d, J = 7.0 Hz, 3 H) 1.67 - 1.77 (m, 2 H) 1.50 - 1.56 (m, 1 H) 1.18 ( d, J =6.1 Hz, 3 H) 1.11 (d, J =6.4 Hz, 3 H) 0.99 (d, J =6.4 Hz, 3 H) 0.97 (d, J = 6.7 Hz, 3 H). MS (ESI+) m/z 526 [M+H] ⁺ .

Example 1o

(2 R )-2-[(2-Amino-5-{[1-(2-fluorophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl-diethyl phosphate

The title compound was synthesized from ( 2R )-2-[(2-amino-5-{[1-(2-fluorophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidine-7 -yl)amino]-4-methylpentan-1-ol ( S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) in 46% yield using the method described for Example 1, except that EtOH was added instead of THF and water after 1 hour at ice bath temperature. The product was a mixture of two diastereomers. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ _H ppm 8.06 (s, 4 H) 7.53 - 7.58 (m, 2 H) 7.27 - 7.33 (m, 2 H) 7.12 - 7.20 (m, 6 H) 5, 22 (k, J = 7.0 Hz, 2 H) 4.38 - 4.55 (m, 2 H) 3.81 - 4.00 (m, 12 H) 1.67 (d, J = 7, 0 Hz, 3 H) 1.65 (d, J =7.0 Hz, 3 H) 1.58 - 1.66 (m, 2 H) 1.54 (ddd, J =18.7, 5.3 , 5.0 Hz, 2 H) 1.28 - 1.36 (m, 2 H) 1.16 (td, J = 7.0, 0.7 Hz, 3 H) 1.15 (td, J = 7.0, 0.7 Hz, 3 H) 1.11 (td, J =7.0, 0.8 Hz, 6 H) 0.89 (d, J =6.6 Hz, 3 H) 0, 88 (d, J =6.6 Hz, 3 H) 0.86 (d, J =6.6 Hz, 3 H) 0.81 (d, J =6.6 Hz, 3 H). MS (ESI+) m/z 558 [M+H] ⁺ .

Example 1p

(2 R )-2-[(2-Amino-5-{[1-(2-chlorophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl-diethyl phosphate

The title compound was synthesized from ( 2R )-2-[(2-amino-5-{[1-(2-chlorophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidine-7 -yl)amino]-4-methylpentan-1-ol ( S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) in 36% yield using the method described for Example 1, except that EtOH was added instead of THF and water after 1 hour at ice bath temperature. The two diastereomers were separated by preparative HPLC (basic method).

Diastereomer A: ¹ H NMR (600 MHz, DMSO- d ₆ ) δ _H ppm 8.06 (s, 2 H) 7.63 (dd, J =7.8, 1.7 Hz, 1 H) 7.45 (dd, J =8.0, 1.3 Hz, 1 H) 7 .34 (ddd, J = 7.8, 7.4, 1.3 Hz, 1 H) 7.28 (ddd, J = 8.0, 7.4, 1.7 Hz, 1 H) 7.15 (d, J = 8.2 Hz, 1 H) 5.35 (k, J = 7.0 Hz, 1 H) 4.41 - 4.52 (m, 1 H) 3.95 - 4.01 ( m, 1 H) 3.86 - 3.96 (m, 5 H) 1.67 (d, J = 7.0 Hz, 3 H) 1.58 - 1.65 (m, 1 H) 1.55 (ddd, J =13.5, 10.4, 5.0 Hz, 1 H) 1.30 (ddd, J =13.5, 9.2, 4.5 Hz, 1 H) 1.15 (td , J =7.1, 0.7 Hz, 3 H) 1.11 (td, J =7.1, 0.7 Hz, 3 H) 0.87 (d, J =6.6 Hz, 3 H ) 0.78 (d, J = 6.6 Hz, 3 H). MS (ESI+) m/z 574 [M+H] ⁺ . Diastereomer B: ¹ H NMR (600 MHz, DMSO- d ₆ ) δ _H ppm 8.06 (s, 2 H) 7.63 (dd, J =7.8, 1.7 Hz, 1 H) 7.45 (dd, J =7.9, 1.3 Hz, 1 H) 7 .35 (ddd, J = 7.8, 7.4, 1.3 Hz, 1 H) 7.28 (ddd, J = 7.9, 7.4, 1.7 Hz, 1 H) 7.17 (d, J = 8.2 Hz, 1 H) 5.36 (k, J = 7.1 Hz, 1 H) 4.42 - 4.54 (m, 1 H) 3.93 (dc, J = 8.2, 7.1 Hz, 2 H) 3.84 - 3.92 (m, 2 H) 3.78 - 3.86 (m, 2 H) 1.65 (d, J =7.0 Hz , 3 H) 1.60 - 1.70 (m, 1 H) 1.57 (ddd, J =13.7, 10.2, 4.8 Hz, 1 H) 1.32 (ddd, J =13 .7, 9.1, 4.4 Hz, 1 H) 1.15 (td, J =7.1, 0.8 Hz, 3 H) 1.09 (td, J =7.1, 0.8 Hz, 3 H) 0.90 (d, J =6.6 Hz, 3 H) 0.87 (d, J =6.6 Hz, 3 H). MS (ESI+) m/z 574 [M+H] ⁺ .

Example 1q

(2 R )-2-[(2-Amino-5-{[1-(5-chloropyridin-2-yl)ethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl-diethyl phosphate

The title compound was synthesized from ( 2R )-2-[(2-amino-5-{[1-(5-chloropyridin-2-yl)ethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentan-1-ol ( S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) in 27% yield using the method described for Example 1, except that EtOH was added instead of THF and water after 1 hour at ice bath temperature. After preparative HPLC purification (acid method), the product was isolated in the form of a TFA salt. The product was a mixture of two diastereomers. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ _H ppm 8.58 (dd, J =2.6, 0.7 Hz, 1 H) 8.57 (dd, J =2.6, 0.7 Hz, 1 H) 8.36 (brs, 2 H) 8 .34 (ws, 2 H) 7.89 (dd, J =8.5, 2.6 Hz, 1 H) 7.88 (dd, J =8.5, 2.6 Hz, 1 H) 7, 60 (dd, J =8.5, 0.7 Hz, 1 H) 7.57 (dd, J =8.5, 0.7 Hz, 1 H) 7.58 (shs, 2 H) 5.16 (k, J = 7.1 Hz, 1 H) 5.09 (k, J = 7.2 Hz, 1 H) 4.51 - 4.62 (m, 1 H) 4.30 - 4.40 ( m, 1 H) 3.83 - 4.02 (m, 12 H) 1.67 (d, J =7.1 Hz, 3 H) 1.66 (d, J =7.1 Hz, 3 H) 1.57 - 1.67 (m, 2 H) 1.49 - 1.57 (m, 2 H) 1.35 (ddd, J =13.6, 9.1, 4.3 Hz, 1 H) 1.31 (ddd, J =13.6, 9.1, 4.3 Hz, 1 H) 1.15 (dt, J =7.1, 0.8 Hz, 3 H) 1.15 (td, J = 7.1, 0.8 Hz, 3 H) 1.12 (td, J = 7.1, 0.8 Hz, 3 H) 1.11 (td, J = 7.1, 0.8 Hz , 3 H) 0.90 (d, J =6.7 Hz, 3 H) 0.87 (d, J =6.6 Hz, 6 H) 0.76 (d, J =6.5 Hz, 3 H). MS (ESI+) m/z 575 [M+H] ⁺ .

Example 1r

(2 R )-2-[(2-Amino-5-{[1-(3-fluoropyridin-2-yl)ethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl-diethyl phosphate

The title compound was synthesized from ( 2R )-2-[(2-amino-5-{[1-(3-fluoropyridin-2-yl)ethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentan-1-ol ( S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) in 47% yield using the method described for Example 1, except that EtOH was added instead of THF and water after 1 hour at ice bath temperature. After preparative HPLC purification (acid method), the product was isolated in the form of a TFA salt. The product was a mixture of two diastereomers. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ _H ppm 8.48 (ws, 2 H) 8.46 (ws, 2 H) 8.41 - 8.43 (m, 2 H) 7.74 (ddd, J =10.1, 8.4, 1.4 Hz, 1 H) 7.79 (ws, 2 H) 7.74 (ddd, J =10.1, 8.4, 1.4 Hz, 1 H) 7.44 (ddd, J =8.4, 4.4, 3.2 Hz, 1 H) 7.43 (ddd, J = 8.4, 4.4, 3.2 Hz, 1 H) 5.47 (c, J = 6.9 Hz, 1 H) 5.46 (k, J = 6.9 Hz, 1 H) 4.51 - 4.64 (m, 2 H) 3.99 - 4.05 (m, 1 H) 3.85 - 4, 00 (m, 11 H) 1.72 (d, J = 7.0 Hz, 3 H) 1.70 (d, J = 7.0 Hz, 3 H) 1.60 - 1.69 (m, 2 H) 1.57 (ddd, J =13.6, 10.0, 5.0 Hz, 2 H) 1.37 (ddd, J =13.6, 9.2, 4.5 Hz, 1 H) 1.37 (ddd, J =13.6, 9.2, 4.5 Hz, 1 H) 1.16 (td, J =7.0, 0.7 Hz, 3 H) 1.15 (td, J =7.0, 0.7Hz, 3H) 1.12 (td, J =7.0, 0.7Hz, 3H) 1.10 (td, J =7.0, 0.7Hz , 3 H) 0.91 (d, J =6.6 Hz, 3 H) 0.91 (d, J =6.6 Hz, 3 H) 0.88 (d, J =6.6 Hz, 3 H) 0.86 (d, J = 6.6 Hz, 3 H). MS (ESI+) m/z 558 [M+H] ⁺ .

Example 1s

(2 R )-2-[(2-Amino-5-{[1-(3-cyanophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl-diethyl phosphate

The title compound was synthesized from 3-{1-[(2-amino-7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5- d ]pyrimidin-5-yl)sulfanyl]ethyl}benzonitrile ( S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) in 50% yield using the method described for Example 1, except that EtOH was added instead of THF and water after 1 hour at ice bath temperature. After preparative HPLC purification (acid method), the product was isolated in the form of a TFA salt. The product was a mixture of two diastereomers. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ _H ppm 8.36 (ws, 4 H) 7.95 (dd, J =1.8, 1.2 Hz, 1 H) 7.93 (dd, J =1.9, 1.2 Hz, 1 H) 7 .84 (ddd, J =7.8, 1.8, 1.5 Hz, 1 H) 7.83 (ddd, J =7.8, 1.8, 1.5 Hz, 1 H) 7.72 (ddd, J =7.7, 1.5, 1.2 Hz, 1 H) 7.71 (ddd, J =7.7, 1.5, 1.2 Hz, 1 H) 7.55 (dd , J = 7.8, 7.7 Hz, 1 H) 7.53 (dd, J = 7.8, 7.7 Hz, 1 H) 5.08 (c, J = 7.2 Hz, 1 H ) 5.06 (k, J = 7.2 Hz, 1 H) 4.45 - 4.56 (m, 1 H) 4.30 - 4.40 (m, 1 H) 3.84 - 3.99 (m, 12 H) 1.68 (d, J =7.2 Hz, 3 H) 1.65 (d, J =7.2 Hz, 3 H) 1.49 - 1.65 (m, 4 H ) 1.34 (ddd, J =13.6, 9.1, 4.3 Hz, 1 H) 1.31 (ddd, J =13.6, 9.1, 4.3 Hz, 1 H) 1 .16 (td, J =7.1, 0.6 Hz, 6 H) 1.13 (td, J =7.1, 0.8 Hz, 3 H) 1.10 (td, J =7.1 , 0.7 Hz, 3 H) 0.90 (d, J =6.6 Hz, 3 H) 0.86 (d, J =6.5 Hz, 3 H) 0.86 (d, J =6 .5 Hz, 3 H) 0.73 (d, J = 6.5 Hz, 3 H). MS (ESI+) m/z 565 [M+H] ⁺ .

Example 2

Getting [7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}-2-imino-5-{[(1 S )-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidine-3(2 H )-yl]methyl dihydrogen phosphate

To a mixture of (2 R )-2-[(2-amino-5-{[(1 S )-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino ]-4-methylpentan-1-ol (Karlström S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) (40 mg, 0.10 mmol), K ₂ CO ₃ (28 mg, 0.20 mmol) and sodium iodide (22 mg, 0.15 mmol) in CH ₃ CN were added di- tert -butylchloromethyl phosphate (39 mg, 0.15 mmol). The reaction mixture was stirred at 50°C for 21 hours. The reaction mixture was evaporated and DCM (5 ml) and water (2 ml) were added. The phases were separated and the organic phase was washed with water (2×2 ml) and brine (2 ml), dried over MgSO ₄ , filtered and evaporated to give 60 mg of the crude product as an orange solid. To the crude material in dioxane (1.5 ml) was added conc. HCl (30 μl, 0.38 mmol) and the mixture was stirred at room temperature for 2 hours. To the resulting mixture was added 2 M NaOH (300 μl), resulting in a pH of about 7. The mixture was diluted with MeOH, DMSO and water, filtered and purified by preparative HPLC (basic method). Pure fractions were combined, evaporated and dried in vacuo to give 7.2 mg (14%) of pure product as a white solid. After purification, the product was considered a diammonium salt. ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.46 - 7.50 (m, 2 H) 7.30 - 7.35 (m, 2 H) 7.20 - 7.24 (m, 1 H) 5.86 - 5.93 (m, 2 H) 5.02 (k, J = 7.12 Hz, 1 H) 4.42 - 4.57 (m, 1 H) 3.53 (dd, J = 11.11, 5.42 Hz, 1 H ) 3.50 (dd, J =11.11, 5.32 Hz, 1 H) 1.72 (d, J =7.12 Hz, 3 H) 1.62 - 1.71 (m, 1 H) 1.53 (ddd, J =13.95, 10.10, 4.87 Hz, 1 H) 1.45 (ddd, J =13.95, 9.18, 4.58 Hz, 1 H) 0, 96 (d, J =6.71 Hz, 3 H) 0.94 (d, J =6.60 Hz, 3 H). MS (ESI+) m/z 514 [M+H] ⁺ .

Example 2b

[5-{[1-(2-Fluorophenyl)ethyl]sulfanyl}-7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}-2-imino[1,3]thiazolo[4,5- d ]pyrimidine-3(2 H )-yl]methyl dihydrogen phosphate

The title compound was synthesized from (2R)-2-[(2-amino-5-{[1-(2-fluorophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO 2006/107258) in 12% yield using the method described for example 2. The product was a mixture of two diastereomers.¹H NMR (600 MHz, CD₃OD) δ_H ppm 7.54 - 7.60 (m, 2 H) 7.23 - 7.29 (m, 2 H) 7.12 - 7.17 (m, 2 H) 7.06 - 7.13 (m, 2 H) 5.87 - 5.96 (m, 4 H) 5.32 (k,J\u003d 7.17 Hz, 1 H) 5.31 (k,J=7.17 Hz, 1 H) 4.46 - 4.53 (m, 1 H) 4.41 - 4.48 (m, 1 H) 3.62 (dd,J=11.20, 5.08 Hz, 1 H) 3.55 (dd,J=11.20, 5.56 Hz, 1 H) 3.51 (dd,J=11.20, 5.12 Hz, 1 H) 3.47 (dd,J=11.20, 4.97 Hz, 1 H) 1.72 (d,J=7.17 Hz, 3 H) 1.71 (d,J=7.17 Hz, 3 H) 1.60 - 1.69 (m, 2 H) 1.51 - 1.59 (m, 2 H) 1.43 (ddd,J=13.97, 9.06, 4.46 Hz, 1 H) 1.42 (ddd,J=13.79, 9.06, 4.46 Hz, 1 H) 0.96 (d,J=6.71 Hz, 3 H) 0.94 (d,J=6.70 Hz, 3 H) 0.94 (d,J=6.50 Hz, 3 H) 0.89 (d,J=6.56 Hz, 3 H). MS (ESI+) m/z 532 [M+H]⁺.

Example 2c

[5-{[1-(2-Chlorophenyl)ethyl]sulfanyl}-7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}-2-imino[1,3]thiazolo[4,5- d ]pyrimidine-3(2 H )-yl]methyl dihydrogen phosphate

The title compound was synthesized from (2R)-2-[(2-amino-5-{[1-(2-chlorophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO 2006/107258) in 12% yield using the method described for example 2. The product was a mixture of two diastereomers.¹H NMR (600 MHz, CD₃OD) δ_H ppm 7.67 (dd,J=7.78, 1.70 Hz, 1 H) 7.66 (dd,J=7.78, 1.70 Hz, 1 H) 7.43 (dd,J=7.94, 1.35 Hz, 1 H) 7.42 (dd,J=7.94, 1.35 Hz, 1 H) 7.29 (ddd,J=7.78, 7.42, 1.35Hz, 2H) 7.24 (ddd,J=7.94, 7.42, 1.70 Hz, 1 H) 7.23 (ddd,J=7.94, 7.42, 1.70 Hz, 1 H) 5.86 - 5.94 (m, 4 H) 5.48 (k,J\u003d 7.14 Hz, 1 H) 5.48 (k,J=7.14 Hz, 1 H) 4.43 - 4.54 (m, 2 H) 3.64 (dd,J=11.20, 4.93 Hz, 1 H) 3.56 (dd,J=11.22, 5.51 Hz, 1 H) 3.48 (dd,J=11.29, 4.80 Hz, 1 H) 3.42 (dd,J=11.20, 4.93 Hz, 1 H) 1.71 (d,J=7.14 Hz, 3 H) 1.69 (d,J=7.14 Hz, 3 H) 1.53 - 1.70 (m, 4 H) 1.41 (ddd,J=13.69, 9.15, 4.48 Hz, 1 H) 1.40 (ddd,J=13.69, 9.15, 4.48 Hz, 1 H) 0.96 (d,J=6.56 Hz, 3 H) 0.95 (d,J=6.56 Hz, 3 H) 0.93 (d,J=6.71 Hz, 3 H) 0.85 (d,J=6.56 Hz, 3 H). MS (ESI+) m/z 548 [M+H]⁺.

Example 2d

[5-{[1-(5-Chloropyridin-2-yl)ethyl]sulfanyl}-7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}-2-imino[1,3]thiazolo[4,5- d ]pyrimidine-3(2 H )-yl]methyl dihydrogen phosphate

The title compound was synthesized from (2R)-2-[(2-amino-5-{[1-(5-chloropyridin-2-yl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO 2006/107258) in 6% yield using the method described for example 2. The product was a mixture of two diastereomers.¹H NMR (600 MHz, CD₃OD) δ_H ppm 8.49 (dd,J=2.46, 0.70 Hz, 1 H) 8.48 (dd,J=2.46, 0.70 Hz, 1 H) 7.83 (dd,J= 8.41, 2.46 Hz, 1 H) 7.83 (dd,J= 8.41, 2.46 Hz, 1 H) 7.68 (dd,J=8.41, 0.70 Hz, 1 H) 7.67 (dd,J=8.41, 0.70 Hz, 1 H) 5.87 - 5.94 (m, 2 H) 5.81 - 5.87 (m, 2 H) 5.15 (k,J\u003d 7.23 Hz, 1 H) 5.12 (k,J=7.23 Hz, 1 H) 4.41 - 4.50 (m, 1 H) 4.25 - 4.35 (m, 1 H) 3.54 (d,J=5.49 Hz, 2 H) 3.45 - 3.52 (m, 2 H) 1.71 (d,J=7.23 Hz, 3 H) 1.70 (d,J=7.23 Hz, 3 H) 1.56 - 1.69 (m, 2 H) 1.47 - 1.54 (m, 2 H) 1.42 (ddd,J=13.81, 9.23, 4.43 Hz, 1 H) 1.41 (ddd,J=13.81, 9.23, 4.43 Hz, 1 H) 0.95 (d,J=6.71 Hz, 3 H) 0.92 (d,J=6.71 Hz, 3 H) 0.92 (d,J=6.41 Hz, 3 H) 0.83 (d,J=6.56 Hz, 3 H). MS (ESI+) m/z 549 [M+H]⁺.

Example 2e

[7-{[(1 R )-1-(Hydroxymethyl)-3-methylbutyl]amino}-2-imino-5-[(1-pyridin-2-ylethyl)sulfanyl][1,3]thiazolo[4,5- d ]pyrimidine-3(2 H )-yl]methyl dihydrogen phosphate

The title compound was synthesized from (2R)-2-({2-amino-5-[(1-pyridin-2-ylethyl)sulfanyl][1,3]thiazolo[4,5-d]pyrimidin-7-yl}amino)-4-methylpentan-1-ol (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO 2006/107258) in 4% yield using the method described for example 2. The two diastereomers were separated by preparative HPLC (basic method).

Diastereomer A: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 8.49 (ddd, J =4.95, 1.85, 1.00 Hz, 1 H) 7.83 (ddd, J =7.89, 7.54, 1.85 Hz, 1 H) 7, 67 (ddd, J =7.89, 1.10, 1.00 Hz, 1 H) 7.29 (ddd, J =7.54, 4.95, 1.10 Hz, 1 H) 5.86 ( dd, J =10.74, 9.88 Hz, 1 H) 5.81 (dd, J =10.74, 9.65 Hz, 1 H) 5.15 (c, J =7.28 Hz, 1 H) 4.42 - 4.51 (m, 1 H) 3.50 (dd, J =11.15, 5.52 Hz, 1 H) 3.46 (dd, J =11.15, 5.46 Hz, 1 H) 1.72 (d, J = 7.28 Hz, 3 H) 1.58 - 1.68 (m, 1 H) 1.51 (ddd, J = 13.94, 10.22, 4.87 Hz, 1 H) 1.43 (ddd, J =13.94, 9.20, 4.45 Hz, 1 H) 0.94 (d, J =6.56 Hz, 3 H) 0, 92 (d, J = 6.56 Hz, 3 H). MS (ESI+) m/z 515 [M+H] ⁺ .

Diastereomer B: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 8.49 (ddd, J =4.95, 1.85, 1.00 Hz, 1 H) 7.82 (ddd, J =7.89, 7.54, 1.85 Hz, 1 H) 7, 68 (ddd, J =7.89, 1.10, 1.00 Hz, 1 H) 7.29 (ddd, J =7.54, 4.95, 1.10 Hz, 1 H) 5.87 ( dd, J =10.74, 9.88 Hz, 1 H) 5.81 (dd, J =10.74, 9.65 Hz, 1 H) 5.13 (c, J =7.28 Hz, 1 H) 4.28 - 4.37 (m, 1 H) 3.56 (dd, J =11.15, 5.46 Hz, 1 H) 3.52 (dd, J =11.15, 5.57 Hz, 1 H) 1.71 (d, J = 7.28 Hz, 3 H) 1.57 - 1.68 (m, 1 H) 1.50 (ddd, J = 13.94, 10.22, 4.87 Hz, 1 H) 1.42 (ddd, J =13.94, 9.20, 4.45 Hz, 1 H) 0.92 (d, J =6.71 Hz, 3 H) 0, 84 (d, J = 6.56 Hz, 3 H). MS (ESI+) m/z 515 [M+H] ⁺ .

Example 2f

[5-{[1-(3-Fluoropyridin-2-yl)ethyl]sulfanyl}-7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}-2-imino[1,3]thiazolo[4,5- d ]pyrimidine-3(2 H )-yl]methyl dihydrogen phosphate

The title compound was synthesized from (2R)-2-[(2-amino-5-{[1-(3-fluoropyridin-2-yl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO 2006/107258) in 19% yield using the method described for example 2. The two diastereomers were separated by preparative HPLC (basic method).

Diastereomer A: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 8.33 (dt, J = 4.74, 1.32 Hz, 1 H) 7.65 (ddd, J = 9.96, 8.39, 1.32 Hz, 1 H) 7.36 (ddd, J = 8.39, 4.74, 4.12 Hz, 1 H) 5.89 (t, J = 10.40 Hz, 1 H) 5.83 (t, J = 10.40 Hz, 1 H) 5.48 (k, J = 7.15 Hz, 1 H) 4.45 - 4.53 (m, 1 H) 3.54 (dd, J = 11.22, 5.44 Hz, 1 H) 3 .52 (dd, J = 11.22, 5.29 Hz, 1 H) 1.73 (d, J = 7.15 Hz, 3 H) 1.62 - 1.70 (m, 1 H) 1, 54 (ddd, J =13.85, 10.11, 5.01 Hz, 1 H) 1.43 (ddd, J =13.85, 9.19, 4.52 Hz, 1 H) 0.95 ( d, J =6.71 Hz, 3 H) 0.93 (d, J =6.56 Hz, 3 H). MS (ESI+) m/z 533 [M+H] ⁺ .

Diastereomer B: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 8.34 (dt, J =4.7, 1.3 Hz, 1 H) 7.64 (ddd, J =10.0, 8.4, 1.3 Hz, 1 H) 7.36 (ddd, J = 8.4, 4.7, 4.1 Hz, 1 H) 5.89 (dd, J = 10.7, 10.1 Hz, 1 H) 5.83 (dd, J = 10.7, 10.1 Hz, 1 H) 5.48 (k, J = 7.2 Hz, 1 H) 4.41 - 4.53 (m, 1 H) 3.59 (dd, J = 11.2.5 .3 Hz, 1 H) 3.56 (dd, J = 11.2, 5.6 Hz, 1 H) 1.75 (d, J = 7.2 Hz, 3 H) 1.62 - 1.70 (m, 1 H) 1.54 (ddd, J =13.9, 10.1, 5.0 Hz, 1 H) 1.43 (ddd, J =13.9, 9.2, 4.5 Hz , 1 H) 0.95 (d, J =6.7 Hz, 3 H) 0.92 (d, J =6.7 Hz, 3 H). MS (ESI+) m/z 533 [M+H] ⁺ .

Example 2g

[5-{[1-(3-Cyanophenyl)ethyl]sulfanyl}-7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}-2-imino[1,3]thiazolo[4,5- d ]pyrimidine-3(2 H )-yl]methyl dihydrogen phosphate

The title compound was synthesized from 3-{1-[(2-amino-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-5-yl)sulfanyl]ethyl}benzonitrile (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO 2006/107258) in 22% yield using the method described for example 2. The two diastereomers were separated by preparative HPLC (basic method).

Diastereomer A: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.85 - 7.88 (m, 2 H) 7.59 (dt, J = 7.76, 1.38 Hz, 1 H) 7.54 (dd, J = 8.44, 7.76 Hz, 1 H) 5.83 (d, J = 9.82 Hz, 2 H) 5.09 (k, J = 7.21 Hz, 1 H) 4.40 - 4.49 (m, 1 H) 3, 51 (dd, J =11.13, 5.49 Hz, 1 H) 3.46 (dd, J =11.13, 5.35 Hz, 1 H) 1.71 (d, J =7.21 Hz , 3 H) 1.60 - 1.68 (m, 1 H) 1.52 (ddd, J =13.85, 10.25, 4.91 Hz, 1 H) 1.43 (ddd, J =13 .85, 9.19, 4.35 Hz, 1 H) 0.95 (d, J =6.71 Hz, 3 H) 0.93 (d, J =6.56 Hz, 3 H). MS (ESI+) m/z 539 [M+H] ⁺ .

Diastereomer B: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.86 - 7.89 (m, 2 H) 7.58 (dt, J = 7.8, 1.4 Hz, 1 H) 7.53 (dd, J = 8.4, 7.8 Hz, 1 H) 5.83 (dd, J = 10.6, 9.7 Hz, 1 H) 5.81 (dd, J = 10.6, 9.6 Hz, 1 H) 5.08 (k, J =7.3 Hz, 1 H) 4.28 - 4.38 (m, 1 H) 3.57 (dd, J =11.4, 5.6 Hz, 1 H) 3.55 (dd, J = 11.4, 5.7 Hz, 1 H) 1.70 (d, J =7.3 Hz, 3 H) 1.57 - 1.66 (m, 1 H) 1.50 (ddd, J =13 .9, 10.4, 5.0 Hz, 1 H) 1.41 (ddd, J =13.9, 9.3, 4.3 Hz, 1 H) 0.92 (d, J =6.7 Hz, 3 H) 0.82 (d, J = 6.6 Hz, 3 H). MS (ESI+) m/z 539 [M+H] ⁺ .

Example 2h

[5-{[(1 S )-1-(5-Chloropyridin-2-yl)ethyl]sulfanyl}-7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}-2-oxo[1,3]thiazolo[4,5- d ]pyrimidine-3(2 H )-yl]methyl dihydrogen phosphate

The title compound was synthesized from 5-{[(1 S )-1-(5-chloropyridin-2-yl)ethyl]sulfanyl}-7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl] amino}[1,3]thiazolo[4,5- d ]pyrimidin-2( 3H )-one (Karlström S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO2008/ 039138) in 39% yield using the method described for Example 2. ¹ H NMR (600 MHz, CD3OD) δ _H ppm. 8.49 (dd, J =2.53, 0.66 Hz, 1 H) 7.86 (dd, J =8.47, 2.53 Hz, 1 H) 7.77 (dd, J =8, 47, 0.66Hz, 1H) 5.67 (dd, J =9.30, 5.92Hz, 1H) 5.63 (dd, J =9.30, 5.83Hz, 1H) 5.23 (k, J = 7.32 Hz, 1 H) 4.35 - 4.48 (m, 1 H) 3.51 (dd, J = 11.06, 5.53 Hz, 1 H) 3 .45 (dd, J = 11.06, 5.65 Hz, 1 H) 1.68 (d, J = 7.32 Hz, 3 H) 1.58 - 1.66 (m, 1 H) 1, 49 (ddd, J =13.87, 10.27, 4.85 Hz, 1 H) 1.41 (ddd, J =13.87, 9.27, 4.36 Hz, 1 H) 0.93 ( e, J =6.68 Hz, 3 H) 0.90 (d, J =6.56 Hz, 3 H). MS (ESI+) m/z 550 [M+H] ⁺ .

Example 3

Getting (2 R )-2-[(5-{[(1 S )-1-(5-chloropyridin-2-yl)ethyl]sulfanyl}-2-oxo-2,3-dihydro[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate

Phosphorus oxychloride (383 mg, 2.5 mmol) was dissolved in THF (0.75 ml) and water (28 mg, 1.58 mmol) was added. The mixture was cooled in an ice bath and pyridine (125 mg, 127 μl, 1.58 mmol) was added followed by 5-{[(1 S )-1-(5-chloropyridin-2-yl)ethyl]sulfanyl}-7-{ [(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5- d ]pyrimidin-2( 3H )-one (Karlström S., et al., J Med. Chem ., 2013 , 56 , 3177-3190; WO2008/039138) (110 mg, 0.25 mmol). The reaction mixture was stirred at ice bath temperature for 2 hours. Water (4 ml) was added and the mixture was stirred at room temperature for 1 hour. The pH was adjusted to 11-12 with 5 M NaOH (ca. 2.8 ml) and the mixture was washed with DCM (3x4 ml). The pH of the aqueous phase was adjusted to 1 by adding conc. HCl (about 300 µl), causing the crude product to precipitate. The mixture was centrifuged and the supernatant was discarded. The remaining solid was washed with water (2 ml), centrifuged and the supernatant was discarded. The remaining solid was dissolved in MeOH and evaporated to give 47 mg of product in 90% purity. The crude material was dissolved in DMSO/water and adjusted to pH about 7 and purified by preparative HPLC (basic method). Pure fractions were combined, evaporated and dried in vacuo to give 34 mg (24%) of pure product as an off-white solid. After purification, the product was considered a diammonium salt. ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 8.47 (dd, J =2.54, 0.48 Hz, 1 H) 7.84 (dd, J =8.42, 2.54 Hz, 1 H) 7.62 (dd, J =8, 42, 0.48 Hz, 1 H) 5.17 (k, J = 7.20 Hz, 1 H) 4.53 - 4.68 (m, 1 H) 3.88 (dt, J = 10.13 , 5.09 Hz, 1 H) 3.83 (dt, J = 10.13, 5.25 Hz, 1 H) 1.72 (d, J = 7.20 Hz, 3 H) 1.65 - 1 .73 (m, 1 H) 1.60 (ddd, J = 13.86, 9.91, 5.20 Hz, 1 H) 1.54 (ddd, J = 13.86, 9.04, 4, 93 Hz, 1 H) 0.96 (d, J =6.63 Hz, 3 H) 0.94 (d, J =6.53 Hz, 3 H). MS (ESI+) m/z 520 [M+H] ⁺ .

Example 3b

(2 R )-4-Methyl-2-({2-oxo-5-[(1-pyridin-2-ylethyl)sulfanyl]-2,3-dihydro[1,3]thiazolo[4,5- d ]pyrimidin-7-yl}amino)pentyl dihydrogen phosphate

The title compound was synthesized from 7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-5-{[1-pyridin-2-ylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-she (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO2008/039138) in 2% yield using the method described for Example 3. The product was a mixture of two diastereomers.¹H NMR (600 MHz, DMSO-d ₆) δ_H ppm 12.36 (ws, 2 H) 8.52 (ddd,J=1.97, 0.97 Hz, 1 H) 8.52 (ddd,J=1.87, 0.97 Hz, 1 H) 7.76 (ddd,J=7.80, 7.59, 1.87 Hz, 1 H) 7.75 (ddd,J=7.80, 7.59, 1.87 Hz, 1 H) 7.53 (dt,J=7.80, 0.97Hz, 1H) 7.50 (dt,J=7.80, 0.97 Hz, 1 H) 7.27 (ddd,J=7.59, 4.87, 0.97 Hz, 1 H) 7.25 (ddd,J=7.59, 4.87, 0.97 Hz, 1 H) 7.11 (br, 1 H) 5.11 (k,J\u003d 7.07 Hz, 1 H) 5.06 (k,J=7.07 Hz, 1 H) 4.37 - 4.51 (m, 1 H) 4.16 - 4.30 (m, 1 H) 3.73 - 3.85 (m, 3 H) 3, 67 - 3.73 (m, 1 H) 1.67 (d,J=7.07 Hz, 3 H) 1.66 (d,J=7.07 Hz, 3 H) 1.54 - 1.64 (m, 2 H) 1.45 - 1.54 (m, 2 H) 1.34 - 1.45 (m, 2 H) 0, 89 (d,J=6.56 Hz, 3 H) 0.87 (d,J=6.71 Hz, 3 H) 0.86 (d,J=6.56 Hz, 3 H) 0.78 (d,J=6.26 Hz, 3 H). MS (ESI+) m/z 486 [M+H]⁺.

Example 3c

(2 R )-4-Methyl-2-{[5-({1-[4-(methylsulfonyl)phenyl]ethyl}sulfanyl)-2-oxo-2,3-dihydro[1,3]thiazolo[4,5- d ]pyrimidin-7-yl]amino}pentyl dihydrogen phosphate

The title compound was synthesized from 7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-5-({1-[4-(methylsulfonyl)phenyl]ethyl}sulfanyl)[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-she (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO2008/039138) as a single diastereomer, in 43% yield using the method described for Example 3. The product was a single diastereomer.¹H NMR (600 MHz, DMSO-d ₆) δ_H ppm 8.41 (brw, 1H) 7.83 - 7.87 (m, 2H) 7.73 - 7.77 (m, 2H) 7.30 (brw, 2H) 5.04 (k,J=7.18 Hz, 1 H) 4.07 - 4.16 (m, 1 H) 3.67 - 3.77 (m, 2 H) 3.19 (s, 3 H) 1.67 (d,J=7.18 Hz, 3 H) 1.51 - 1.60 (m, 1 H) 1.47 (ddd,J=13.50, 8.30, 6.70 Hz, 1 H) 1.37 - 1.44 (m, 1 H) 0.85 (d,J=6.56 Hz, 3 H) 0.77 (d,J=6.26 Hz, 3 H). MS (ESI+) m/z 563 [M+H]⁺.

Example 3d

(2 R )-2-[(5-{[1-(3-Carbamoylphenyl)ethyl]sulfanyl}-2-oxo-2,3-dihydro[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate

The title compound was synthesized from 3-{1-[(7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-2-oxo-2,3-dihydro[1,3]thiazolo[4,5-d]pyrimidin-5-yl)sulfanyl]ethyl}benzamide (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO2008/039138) as a single diastereomer, in 20% yield using the method described for Example 3. The product was a single diastereomer.¹H NMR (600 MHz, DMSO-d ₆) δ_H ppm 8.33 (ws, 1 H) 8.46 (ws, 1 H) 8.06 (ws, 1 H) 7.76 (ddd,J=7.70, 1.68, 1.22 Hz, 1 H) 7.58 (ddd,J=7.70, 1.51, 1.22 Hz, 1 H) 7.41 (t,J=7.70 Hz, 1 H) 7.30 (ws, 1 H) 7.23 (ws, 3 H) 5.07 (k,J=7.04 Hz, 1 H) 4.25 - 4.42 (m, 1 H) 3.74 (td,J=10.15, 4.82 Hz, 1 H) 3.65 - 3.71 (m, 1 H) 1.70 (d,J=7.04 Hz, 3 H) 1.57 - 1.66 (m, 1 H) 1.40 - 1.51 (m, 2 H) 0.89 (d,J=6.56 Hz, 3 H) 0.85 (d,J=6.56 Hz, 1 H). MS (ESI+) m/z 528 [M+H]⁺.

Example 3e

(2 R )-2-[(5-{[1-(2-Chlorophenyl)ethyl]sulfanyl}-2-oxo-2,3-dihydro[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate

The title compound was synthesized from 5-{[1-(2-chlorophenyl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-she (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO2008/039138) in 49% yield using the method described for example 3. The two diastereomers were separated by preparative HPLC (basic method).

Diastereomer A: ¹ H NMR (600 MHz, DMSO- d ₆ ) δ _H ppm 8.43 (ws, 2 H) 7.61 (dd, J =7.75, 1.65 Hz, 1 H) 7.47 (dd, J =7.88, 1.30 Hz, 1 H) 7 .36 (ddd, J =7.75, 7.40, 1.60 Hz, 1 H) 7.29 (ddd, J =7.88, 7.40, 1.65 Hz, 1 H) 6.57 - 8.60 (m, 3 H) 5.34 (k, J = 6.93 Hz, 1 H) 4.17 - 4.27 (m, 1 H) 3.77 - 3.83 (m, 1 H) 3.70 (td, J =10.07, 3.66 Hz, 1 H) 1.74 (d, J =6.93 Hz, 3 H) 1.57 - 1.65 (m, 1 H ) 1.49 - 1.61 (m, 1 H) 1.38 - 1.46 (m, 1 H) 0.86 (d, J = 7.00 Hz, 3 H) 0.82 (d, J =6.16 Hz, 3 H). MS (ESI+) m/z 519 [M+H] ⁺ .

Diastereomer B: ¹ H NMR (600 MHz, DMSO- d ₆ ) δ _H ppm 8.90 (ws, 1 H) 7.60 (dd, J =7.82, 1.72 Hz, 1 H) 7.46 (dd, J =7.96, 1.30 Hz, 1 H) 7 .36 (ddd, J =7.82, 7.50, 1.30 Hz, 1 H) 7.30 (ddd, J =7.96, 7.50, 1.72 Hz, 1 H) 6.46 - 8.26 (m, 3 H) 5.42 (k, J = 6.99 Hz, 1 H) 4.15 - 4.25 (m, 1 H) 3.70 - 3.76 (m, 1 H) 3.66 (td, J =11.41, 4.35 Hz, 1 H) 1.69 (d, J =6.99 Hz, 3 H) 1.56 - 1.65 (m, 1 H ) 1.52 (dt, J =13.28, 7.48 Hz, 1 H) 1.43 (dt, J =13.28, 7.02 Hz, 1 H) 0.89 (d, J =6 .71 Hz, 3 H) 0.87 (d, J = 6.56 Hz, 3 H). MS (ESI+) m/z 519 [M+H] ⁺ .

Example 3f

(2 R )-2-[(5-{[1-(3-Cyanophenyl)ethyl]sulfanyl}-2-oxo-2,3-dihydro[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate

The title compound was synthesized from 3-{1-[(7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-2-oxo-2,3-dihydro[1,3]thiazolo[4,5-d]pyrimidin-5-yl)sulfanyl]ethyl}benzonitrile (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO2008/039138) in 49% yield using the method described for example 3. The two diastereomers were separated by preparative HPLC (basic method).

Diastereomer A: ¹ H NMR (600 MHz, DMSO- d ₆ ) δ _H ppm 7.93 (dd, J =1.80, 1.36 Hz, 1 H) 7.83 (dd, J =7.95, 1.80, 1.36 Hz, 1 H) 7.68 (dt, J = 7.68, 1.36 Hz, 1 H) 7.51 (dd, J = 7.95, 7.68 Hz, 1 H) 7.44 (brw, 4 H) 5.00 (k, J =7.15 Hz, 1 H) 4.05 - 4.13 (m, 1 H) 3.61 - 3.71 (m, 2 H) 1.65 (d, J = 7.15 Hz, 3 H) ) 1.52 - 1.62 (m, 1 H) 1.36 - 1.48 (m, 2 H) 0.85 (d, J = 6.58 Hz, 3 H) 0.78 (d, J =6.58 Hz, 3 H). MS (ESI+) m/z 510 [M+H] ⁺ .

Diastereomer B: ¹ H NMR (600 MHz, DMSO- d ₆ ) δ _H ppm 8.55 (ws, 1 H) 7.94 (dd, J =1.80, 1.36 Hz, 1 H) 7.83 (ddd, J =7.95, 1.80, 1.36 Hz, 1 H) 7.69 (dt, J = 7.68, 1.36 Hz, 1 H) 7.56 (dd, J = 7.95, 7.68 Hz, 1 H) 7.37 (ws, 3 H) 5.00 (k, J = 7.19 Hz, 1 H) 4.15 - 4.24 (m, 1 H) 3.63 - 3.73 (m, 2 H) 1.67 (d, J = 7.19 Hz, 3 H) 1.54 - 1.63 (m, 1 H) 1.39 - 1.48 (m, 2 H) 0.89 (d, J = 6.56 Hz, 3 H) 0.86 (d, J = 6.56 Hz, 3 H). MS (ESI+) m/z 510 [M+H] ⁺ .

Example 3g

(2 R )-2-[(5-{[(1 S )-1-(5-Chloropyridin-2-yl)ethyl]sulfanyl}-2-oxo-2,3-dihydro[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl-dimethylphosphate

The title compound was synthesized from 5-{[(1S)-1-(5-chloropyridin-2-yl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-she (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO2008/039138) in 27% yield using the method described for Example 3, except that MeOH was added instead of water after 2 hours at ice bath temperature.¹H NMR (600 MHz, DMSO-d ₆) δ_H ppm 8.48 (d,J=2.4 Hz, 1 H) 7.79 (d,J=7.9 Hz, 1 H) 7.61 (d,J\u003d 8.2 Hz, 1 H) 5.09 (k,J=7.3 Hz, 1 H) 4.63 (br, 1 H) 3.89 - 3.97 (m, 2 H) 3.70 (d,J=11.3 Hz, 3 H) 3.67 (d,J=11.3 Hz, 3 H) 1.69 (d, 3 H) 1.64 - 1.73 (m, 1 H) 1.58 (ddd,J=14.0, 10.5, 4.9 Hz, 1 H) 1.38 (ddd,J=13.8, 9.4, 4.3 Hz, 1 H) 0.96 (d,J=6.7 Hz, 3 H) 0.94 (d,J=6.7 Hz, 3 H). MS (ESI+) m/z 548 [M+H]⁺.

Example 3h

(2 R )-2-[(5-{[(1 S )-1-(5-Chloropyridin-2-yl)ethyl]sulfanyl}-2-oxo-2,3-dihydro[1,3]thiazolo[4,5- d ]pyrimidin-7-yl)amino]-4-methylpentyl-diethyl phosphate

The title compound was synthesized from 5-{[(1S)-1-(5-chloropyridin-2-yl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidine-2(3H)-she (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO2008/039138) in 20% yield using the method described for example 3, except that 2-methyl-THF was used as solvent and EtOH was added instead of water after 2 hours at ice bath temperature.¹H NMR (600 MHz, DMSO-d ₆) δ_H ppm 8.47 (d,J=1.2 Hz, 1 H) 7.78 (d,J=7.0 Hz, 1 H) 7.61 (d,J\u003d 7.0 Hz, 1 H) 5.09 (k,J=7.0 Hz, 1 H) 4.63 (br, 1 H) 3.96 - 4.14 (m, 4 H) 3.89 - 3.95 (m, 2 H) 1.68 (d,J=7.0 Hz, 3 H) 1.63 - 1.67 (m, 1 H) 1.58 (ddd,J=13.8, 10.6, 4.9 Hz, 1 H) 1.35 - 1.40 (m, 1 H) 1.26 (td,J=7.2, 0.9 Hz, 3 H) 1.20 (td,J=7.0, 0.9 Hz, 3 H) 0.96 (d,J=6.4 Hz, 3 H) 0.94 (d,J=6.4 Hz, 3 H). MS (ESI+) m/z 576 [M+H]⁺.

Example 4

(7-{[(1 R )-1-(Hydroxymethyl)-3-methylbutyl]amino}-5-{[(1 S )-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-2-yl)phosphoramidic acid

The title product was synthesized from hydrochloride (2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO 2006/107258) in two stages.

Stage 1: N ⁷ -[(1R)-1-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-3-methylbutyl]-5-{[(1S)-1-phenylethyl]sulfanyl}[1 ,3]thiazolo[4,5-d]pyrimidine-2,7-diamine

To a solution of (2 R )-2-[(2-amino-5-{[(1 S )-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-7-yl) hydrochloride solution amino]-4-methylpentan-1-ol ^1,2 (605 mg, 1.50 mmol), tert -butyldimethylsilyl chloride (520 mg, 3.46 mmol) and DMAP (92 mg, 0.75 mmol) in DCM (5 ml) was added Et3N (630 μl, 5.50 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. DCM (25 ml) was added and the resulting organic phase was washed with 2 M citric acid solution (2x5 ml) and water (5 ml), dried over Na2SO4, filtered and evaporated to give 969 mg of the crude material. The crude product was purified by flash chromatography (silica, 3-4% MeOH in DCM) and the pure fractions were combined and evaporated to give 741 mg (95%) >99% pure product as a white solid.

¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.44 (dd, J =8.2, 0.9 Hz, 2 H) 7.28 - 7.32 (m, 2 H) 7.19 - 7.24 (m, 1 H) 5.07 ( k, J = 7.2 Hz, 1 H) 4.51 (ws, 1 H) 3.59 (dd, J = 10.1, 5.5 Hz, 1 H) 3.50 (dd, J = 9 .9, 6.0 Hz, 1 H) 1.74 (d, J = 7.0 Hz, 3 H) 1.70 - 1.79 (m, 1 H) 1.49 - 1.55 (m, 1 H) 1.43 - 1.49 (m, 1 H) 0.97 (d, J = 6.7 Hz, 3 H) 0.95 (d, J = 6.4 Hz, 3 H) 0, 84 (s, 9 H) 0.03 (s, 3 H) 0.01 (s, 3 H). MS (ESI+) m/z 518 [M+H]+.

Stage 2:

N ⁷ -[(1 R )-1-({[ tert- Butyl(dimethyl)silyl]oxy}methyl)-3-methylbutyl]-5-{[(1 S )-1-phenylethyl]sulfanyl}[1, 3]thiazolo[4,5- d ]pyrimidine-2,7-diamine (115 mg, 0.22 mmol) in DCM (1.5 ml) was added to a mixture of phosphorus pentachloride (92 mg, 0.44 mmol) and pyridine (53 mg, 0.67 mmol) in DCM (0.5 ml) at ice bath temperature. The reaction mixture was stirred at ice bath temperature for 60 minutes. Water (1 ml) and DMSO (1 ml) were added and the reaction mixture was stirred at 50°C for 1.5 hours. The reaction mixture was filtered through a 0.45 µm Agilent nylon disc filter and the crude mixture was purified by preparative HPLC (basic method) to give 49 mg (43%) of the pure title product as a white solid. After purification, the product was considered a diammonium salt. ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.44 - 7.48 (m, 2 H) 7.27 - 7.33 (m, 2 H) 7.21 (tt, J = 7.3, 1.2 Hz, 1 H) 5.09 ( k, J =7.0 Hz, 1 H) 4.51 (ws, 1 H) 3.57 (dd, J =11.0, 5.2 Hz, 1 H) 3.49 (dd, J =11 .1, 5.6 Hz, 1 H) 1.73 (d, J = 7.0 Hz, 3 H) 1.70 - 1.78 (m, 1 H) 1.54 - 1.61 (m, 1 H) 1.46 - 1.53 (m, 1 H) 0.97 (d, J =6.7 Hz, 3 H) 0.95 (d, J =6.7 Hz, 3 H). MS (ESI+) m/z 484 [M+H]+.

Example 4b

(5-{[1-(2-Chlorophenyl)ethyl]sulfanyl}-7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5- d ]pyrimidin-2-yl)phosphoramidic acid

The title product was synthesized from (2R)-2-[(2-amino-5-{[1-(2-chlorophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO 2006/107258) in two stages, using the method described for Example 4. Overall yield over two stages: 62%.

Step 1: N 7-[(1 R )-1-({[ tert -Butyl(dimethyl)silyl]oxy}methyl)-3-methylbutyl]-5-{[1-(2-chlorophenyl)ethyl]sulfanyl} [1,3]thiazolo[4,5- d ]pyrimidine-2,7-diamine

The product was a mixture of two diastereomers. ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.67 (dd, J =7.8, 1.7 Hz, 1 H) 7.64 (dd, J =7.8, 1.7 Hz, 1 H) 7.39 (dd, J =7, 8, 1.2 Hz, 1 H) 7.39 (dd, J =7.8, 1.2 Hz, 1 H) 7.29 (td, J =7.6, 1.2 Hz, 2 H) 7.22 (tt, J =7.7, 1.5 Hz, 2 H) 5.52 (k, J =7.0 Hz, 1 H) 5.50 (k, J =7.0 Hz, 1 H) 4.51 (ws, 2 H) 3.67 (dd, J =10.1, 5.5 Hz, 1 H) 3.63 (dd, J =9.8, 5.8 Hz, 1 H ) 3.49 (dd, J =10.1, 4.3 Hz, 1 H) 3.37 (dd, J =10.1, 4.9 Hz, 1 H) 1.73 (d, J =7 .0 Hz, 3 H) 1.68 (d, J = 7.0 Hz, 3 H) 1.64 - 1.76 (m, 2 H) 1.56 - 1.62 (m, 1 H) 1 .49 - 1.55 (m, 1 H) 1.41 (dddd, J = 13.7, 9.3, 4.2, 2.4 Hz, 2 H) 0.97 (d, J = 6, 7 Hz, 3 H) 0.96 (d, J =6.7 Hz, 3 H) 0.92 (d, J =6.7 Hz, 3 H) 0.84 (s, 9 H) 0.81 (s, 9 H) 0.03 (s, 3 H) 0.00 (s, 3 H) -0.06 (s, 3 H) -0.07 (s, 3 H). MS (ESI+) m/z 552 [M+H]+.

Step 2: The two diastereomers were separated by preparative HPLC (basic method).

Diastereomer A: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.66 (dd, J =7.8, 1.7 Hz, 1 H) 7.42 (dd, J =7.9, 1.2 Hz, 1 H) 7.31 (td, J =7, 6, 1.4 Hz, 1 H) 7.25 (td, J = 7.7, 1.7 Hz, 1 H) 5.57 (c, J = 7.0 Hz, 1 H) 4.54 ( ws, 1 H) 3.49 (dd, J =11.3, 4.3 Hz, 1 H) 3.40 (dd, J =11.1, 4.7 Hz, 1 H) 1.72 (d , J =7.0 Hz, 3 H) 1.60 - 1.78 (m, 2 H) 1.44 (ddd, J = 13.7, 9.2, 4.6 Hz, 1 H) 0, 98 (d, J =6.7 Hz, 3 H) 0.96 (d, J =6.7 Hz, 3 H). MS (ESI+) m/z 518 [M+H]+.

Diastereomer B: ¹ H NMR (600 MHz, CD ₃ OD) 7.65 (dd, J =7.8, 1.7 Hz, 1 H) 7.39 (dd, J =7.9, 1.5 Hz , 1 H) 7.29 (td, J = 7.3, 1.2 Hz, 1 H) 7.22 (td, J = 7.7, 1.5 Hz, 1 H) 5.53 (c, J = 7.0 Hz, 1 H) 4.46 (ws, 1 H) 3.67 (dd, J = 11.0, 5.2 Hz, 1 H) 3.60 (dd, J = 11.3 , 4.9 Hz, 1 H) 1.74 (d, J = 7.0 Hz, 3 H) 1.56 - 1.73 (m, 2 H) 1.37 - 1.42 (m, 1 H ) 0.92 (d, J =6.7 Hz, 3 H) 0.82 (d, J =6.7 Hz, 3 H). MS (ESI+) m/z 518 [M+H]+.

Example 4c

(7-{[(1 R )-1-(Hydroxymethyl)-3-methylbutyl]amino}-5-[(1-pyridin-2-ylethyl)sulfanyl][1,3]thiazolo[4,5- d ]pyrimidin-2-yl)phosphoramidic acid

The title product was synthesized from ( 2R )-2-({2-amino-5-[(1-pyridin-2-ylethyl)sulfanyl][1,3]thiazolo[4,5- d ]pyrimidin-7- yl}amino)-4-methylpentan-1-ol (Karlström S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) in two steps using the method described for example 4. The overall yield for two stages: 29%.

Stage 1: N 7-[(1 R )-1-({[ tert- Butyl(dimethyl)silyl]oxy}methyl)-3-methylbutyl]-5-[(1-pyridin-2-ylethyl)sulfanyl][ 1,3]thiazolo[4,5- d ]pyrimidine-2,7-diamine

The product was a mixture of two diastereomers. ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 8.45 - 8.50 (m, 2 H) 7.77 (td, J =7.9, 1.8 Hz, 1 H) 7.76 (td, J =7.7, 1.8 Hz, 1 H) 7.60 (d, J =7.9 Hz, 2 H) 7.28 (dt, J =4.9, 1.2 Hz, 1 H) 7.27 (dt, J =4.9 , 1.2 Hz, 1 H) 5.19 (k, J = 7.2 Hz, 1 H) 5.18 (k, J = 7.2 Hz, 1 H) 4.42 (br, 2 H) 3.60 - 3.67 (m, 2 H) 3.54 (dd, J =10.1, 5.2 Hz, 1 H) 3.44 (dd, J =9.9, 5.6 Hz, 1 H) 1.76 (d, J = 7.0 Hz, 3 H) 1.74 (d, J = 7.0 Hz, 3 H) 1.66 - 1.73 (m, 2 H) 1, 47 - 1.55 (m, 2 H) 1.39 - 1.46 (m, 2 H) 0.96 (d, J = 6.7 Hz, 3 H) 0.95 (d, J = 6, 7 Hz, 3 H) 0.94 (d, J =6.7 Hz, 3 H) 0.86 (d, J =6.4 Hz, 3 H) 0.83 (s, 18 H) 0.02 (s, 3H) 0.01 (s, 3H) 0.00 (s, 3H) -0.01 (s, 3H). MS (ESI+) m/z 519 [M+H]+.

Step 2: The two diastereomers were separated by preparative HPLC (basic method).

Diastereomer A: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 8.47 (dt, J =5.0, 0.9 Hz, 1 H) 7.78 (td, J =7.7, 1.7 Hz, 1 H) 7.64 (dt, J =7, 9, 1.0 Hz, 1 H) 7.28 (ddd, J =7.3, 4.9, 0.9 Hz, 1 H) 5.24 (c, J =7.3 Hz, 1 H) 4.50 (ws, 1 H) 3.52 (dd, J =11.0, 5.5 Hz, 1 H) 3.42 (dd, J =11.1, 5.6 Hz, 1 H) 1 .75 (d, J = 7.0 Hz, 3 H) 1.68 - 1.73 (m, 1 H) 1.51 - 1.60 (m, 1 H) 1.43 - 1.51 (m , 1 H) 0.97 (d, J =6.7 Hz, 3 H) 0.95 (d, J =6.7 Hz, 3 H). MS (ESI+) m/z 485 [M+H]+.

Diastereomer B: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 8.47 (dt, J =5.0, 0.9 Hz, 1 H) 7.78 (td, J =7.8, 1.8 Hz, 1 H) 7.66 (d, J =7, 9 Hz, 1 H) 7.26 - 7.29 (m, 1 H) 5.17 (k, J = 7.2 Hz, 1 H) 4.24 (ws, 1 H) 3.65 (dd, J = 11.0, 4.9 Hz, 1 H) 3.52 (dd, J = 11.0, 6.1 Hz, 1 H) 1.73 (d, J = 7.3 Hz, 3 H) 1.60 - 1.67 (m, 1 H) 1.51 - 1.59 (m, 1 H) 1.43 - 1.51 (m, 1 H) 0.91 (d, J = 6.4 Hz, 3 H) 0.77 (d, J =6.4 Hz, 3 H). MS (ESI+) m/z 485 [M+H]+.

Example 4d

(5-{[1-(3-Cyanophenyl)ethyl]sulfanyl}-7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5- d ]pyrimidin-2-yl)phosphoramidic acid

The title compound was synthesized from 3-{1-[(2-amino-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-5-yl)sulfanyl]ethyl}benzonitrile (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO 2006/107258) in two stages, using the method described for example 4. Total yield for two stages: 47%.

Step 1: 3-{1-[(2-Amino-7-{[(1 R )-1-({[ tert- butyl(dimethyl)silyl]oxy}methyl)-3-methylbutyl]amino}[1, 3]thiazolo[4,5- d ]pyrimidin-5-yl)sulfanyl]ethyl}benzonitrile

The product was a mixture of two diastereomers. ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.80 - 7.88 (m, 4 H) 7.59 (dt, J =6.1, 1.2 Hz, 1 H) 7.58 (dt, J =6.1, 1.2 Hz, 1 H) 7.49 (k, J = 7.5 Hz, 2 H) 5.10 (k, J = 7.3 Hz, 2 H) 4.44 (shs, 1 H) 4.35 (shs, 1 H) 3.68 (dd, J =9.8, 5.8 Hz, 1 H) 3.58 (dd, J =9.8, 6.1 Hz, 1 H) 3.54 (dd, J =9.9, 5.3 Hz, 1 H) 3.43 - 3.48 (m, 1 H) 1.71 (d, J = 7.3 Hz, 3 H) 1.70 (d, J = 7.3 Hz, 3 H) 1.63 - 1.75 (m, 2 H) 1.39 - 1.55 (m, 4 H) 0.97 (d, J =6.7 Hz, 3 H) 0.96 (d, J =6.7 Hz, 3 H) 0.93 (d, J =6.7 Hz, 3 H) 0.85 (s, 9 H) 0.81 (s, 9 H) 0.81 (d, J =6.4 Hz, 3 H) 0.05 (s, 3 H) 0.03 (s, 3 H) 0.00 (s, 3 H) -0.02 (s, 3H). MS (ESI+) m/z 543 [M+H]+.

Step 2: The two diastereomers were separated by preparative HPLC (basic method).

Diastereomer A: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.87 (s, 1 H) 7.85 (dd, J =7.8, 1.1 Hz, 1 H) 7.57 (dd, J =7.6, 1.5 Hz, 1 H) 7 .49 (t, J = 7.8 Hz, 1 H) 5.13 (k, J = 7.2 Hz, 1 H) 4.29 (shs, 1 H) 3.63 (dd, J = 11, 0, 5.2 Hz, 1 H) 3.55 (dd, J =10.7, 5.8 Hz, 1 H) 1.70 (d, J =7.3 Hz, 3 H) 1.61 - 1.68 (m, 1 H) 1.49 - 1.57 (m, 1 H) 1.41 - 1.48 (m, 1 H) 0.92 (d, J =6.7 Hz, 3 H ) 0.80 (d, J = 6.7 Hz, 3 H). MS (ESI+) m/z 509 [M+H]+.

Diastereomer B: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.86 (s, 1 H) 7.84 (dd, J = 7.9, 1.5 Hz, 1 H) 7.58 (d, J = 7.9 Hz, 1 H) 7.49 (t , J = 7.8 Hz, 1 H) 5.12 (k, J = 7.0 Hz, 1 H) 4.44 (ws, 1 H) 3.53 (dd, J = 11.0, 5, 2 Hz, 1 H) 3.43 (dd, J =11.0, 5.5 Hz, 1 H) 1.71 (d, J =7.3 Hz, 3 H) 1.67 - 1.74 ( m, 1 H) 1.51 - 1.60 (m, 1 H) 1.43 - 1.51 (m, 1 H) 0.97 (d, J =6.7 Hz, 3 H) 0.95 (d, 3H). MS (ESI+) m/z 509 [M+H]+.

Example 4e

(5-{[1-(3-Fluoropyridin-2-yl)ethyl]sulfanyl}-7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5- d ]pyrimidin-2-yl)phosphoramidic acid

The title compound was synthesized from (2R)-2-[(2-amino-5-{[1-(3-fluoropyridin-2-yl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO 2006/107258) in two stages, using the method described for example 4. Total yield for two stages: 55%.

Stage 1: N 7-[(1 R )-1-({[ tert- Butyl(dimethyl)silyl]oxy}methyl)-3-methylbutyl]-5-{[1-(3-fluoropyridin-2-yl) ethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidine-2,7-diamine

The product was a mixture of two diastereomers. ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 8.35 (d, J =1.2 Hz, 1 H) 8.34 (d, J =0.9 Hz, 1 H) 7.59 (dt, J =8.5, 1.2 Hz, 1 H) 7.57 (dt, J = 8.2, 1.2 Hz, 1 H) 7.34 - 7.39 (m, 2 H) 5.59 (k, J = 7.0 Hz, 2 H ) 4.54 (ws, 2 H) 3.65 (d, J =5.8 Hz, 2 H) 3.62 (dd, J =10.1, 5.5 Hz, 1 H) 3.57 ( dd, J =10.1, 5.8 Hz, 1 H) 1.79 (d, J =7.0 Hz, 3 H) 1.77 (d, J =7.0 Hz, 3 H) 1, 70 - 1.76 (m, 2 H) 1.50 - 1.57 (m, 2 H) 1.42 - 1.50 (m, 2 H) 0.98 (d, J = 6.7 Hz, 3 H) 0.96 (d, J =6.7 Hz, 3 H) 0.96 (d, J =6.4 Hz, 3 H) 0.93 (d, J =6.4 Hz, 3 H) ) 0.83 (s, 9 H) 0.82 (s, 9 H) 0.03 (s, 3 H) 0.02 (s, 3 H) 0.00 (s, 3 H) -0.01 (s, 3H). MS (ESI+) m/z 537 [M+H]+.

Step 2: The two diastereomers were separated by preparative HPLC (basic method).

Diastereomer A: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 8.33 (dd, J =4.9, 1.5 Hz, 1 H) 7.59 (t, J =9.4 Hz, 1 H) 7.34 - 7.38 (m, 1 H) 5 .62 (k, J = 7.1 Hz, 1 H) 4.53 (shs, 1 H) 3.59 (dd, J = 11.0, 4.9 Hz, 1 H) 3.54 (d, J = 11.0, 4.9 Hz, 1 H) 1.77 (d, J = 7.3 Hz, 3 H) 1.70 - 1.75 (m, 1 H) 1.55 - 1.64 (m, 1 H) 1.45 - 1.52 (m, 1 H) 0.98 (d, J =6.4 Hz, 3 H) 0.96 (d, J =6.4 Hz, 3 H) ). MS (ESI+) m/z 503 [M+H]+.

Diastereomer B: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 8.34 (dt, J = 4.9, 1.2 Hz, 1 H) 7.58 (ddd, J = 9.8, 8.4, 1.2 Hz, 1 H) 7.34 - 7, 38 (m, 1 H) 5.60 (k, J = 7.0 Hz, 1 H) 4.49 (ws, 1 H) 3.63 (dd, J = 5.2, 1.5 Hz, 2 H) 1.79 (d, J = 7.0 Hz, 3 H) 1.70 - 1.75 (m, 1 H) 1.55 - 1.64 (m, 1 H) 1.44 - 1, 52 (m, 1 H) 0.97 (d, J =7.0 Hz, 3 H) 0.91 (d, J =6.7 Hz, 3 H). MS (ESI+) m/z 503 [M+H]+.

Example 4f

Diethyl-(7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}-5-{[(1 S )-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-2-yl)amidophosphate

The title product was synthesized from hydrochloride (2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO 2006/107258) in two steps using the method described for example 4, except that EtOH was added instead of water and DMSO after 1 hour at ice bath temperature in step 2.

The starting material for Step 2 was the same as in Example 4. Overall yield for the two steps: 71%.

Stage 2: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.44 - 7.47 (m, 2 H) 7.29 - 7.34 (m, 2 H) 7.22 (tt, J = 7.3, 1.5 Hz, 1 H) 5.05 ( k, J = 7.0 Hz, 1 H) 4.51 (ws, 1 H) 4.08 - 4.17 (m, 4 H) 3.55 (dd, J = 11.0, 5.2 Hz , 1 H) 3.49 (dd, J = 11.0, 5.5 Hz, 1 H) 1.73 (d, J = 7.0 Hz, 3 H) 1.67 - 1.72 (m, 1 H) 1.53 - 1.59 (m, 1 H) 1.44 - 1.50 (m, 1 H) 1.34 (tdd, J = 7.0, 2.1, 0.61 Hz, 6 H) 0.97 (d, J =6.7 Hz, 3 H) 0.95 (d, J =6.7 Hz, 3 H). MS (ESI+) m/z 540 [M+H]+.

4g example

Dimethyl-(7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}-5-{[(1 S )-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidin-2-yl)amidophosphate

The title product was synthesized from hydrochloride (2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO 2006/107258) in two steps using the method described for example 4, except that MeOH was added instead of water and DMSO after 1 hour at ice bath temperature in step 2.

The starting material for Step 2 was the same as in Example 4. Overall yield for the two steps: 75%.

Stage 2: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.43 - 7.47 (m, 2 H) 7.29 - 7.33 (m, 2 H) 7.22 (tt, J = 7.4, 1.5 Hz, 1 H) 5.04 ( k, J =7.1 Hz, 1 H) 4.50 (ws, 1 H) 3.76 (d, J =10.7 Hz, 6 H) 3.55 (dd, J =11.0.5 .5 Hz, 1 H) 3.49 (dd, J =11.0, 5.5 Hz, 1 H) 1.73 (d, J =7.0 Hz, 3 H) 1.66 - 1.75 (m, 1 H) 1.52 - 1.58 (m, 1 H) 1.44 - 1.50 (m, 1 H) 0.97 (d, J = 6.7 Hz, 3 H) 0, 94 (d, J = 6.7 Hz, 3 H). MS (ESI+) m/z 512 [M+H]+.

Example 4h

Diethyl-(5-{[1-(2-chlorophenyl)ethyl]sulfanyl}-7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5- d ]pyrimidin-2-yl)amidophosphate

The title product was synthesized from (2R)-2-[(2-amino-5-{[1-(2-chlorophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO 2006/107258) in two steps using the method described for example 4, except that water and DMSO were replaced after 1 hour at ice bath temperature in step 2.

The starting material for step 2 was the same as in example 4b. The product was a mixture of two diastereomers. Overall yield for two stages: 73%.

Step 2: The two diastereomers were separated by preparative HPLC (basic method).

Diastereomer A: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.64 (dd, J =7.6, 1.5 Hz, 1 H) 7.41 (dd, J =7.9, 1.2 Hz, 1 H) 7.30 (td, J =7, 6, 1.4 Hz, 1 H) 7.23 (td, J = 7.8, 1.7 Hz, 1 H) 5.50 (k, J = 7.0 Hz, 1 H) 4.50 ( ws, 1 H) 4.08 - 4.16 (m, 4 H) 3.48 (dd, J =11.0, 4.6 Hz, 1 H) 3.39 (dd, J =11.3, 4.9 Hz, 1 H) 1.70 (d, J =7.0 Hz, 3 H) 1.67 - 1.75 (m, 1 H) 1.59 - 1.66 (m, 1 H) 1.41 (ddd, J =13.7, 9.2, 4.6 Hz, 1 H) 1.34 (td, J =7.1, 1.7 Hz, 6 H) 0.97 (d, J = 6.7 Hz, 3 H) 0.95 (d, J = 6.7 Hz, 3 H). MS (ESI+) m/z 574 [M+H]+.

Diastereomer B: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.63 (dd, J =7.8, 1.7 Hz, 1 H) 7.39 (dd, J =7.9, 1.2 Hz, 1 H) 7.30 (td, J =7, 6, 1.2 Hz, 1 H) 7.23 (td, J = 7.8, 1.4 Hz, 1 H) 5.50 (c, J = 7.0 Hz, 1 H) 4.45 ( ws, 1 H) 4.08 - 4.16 (m, 4 H) 3.64 (dd, J =11.3, 5.2 Hz, 1 H) 3.58 (dd, J =11.0, 5.2 Hz, 1 H) 1.74 (d, J =7.0 Hz, 3 H) 1.63 - 1.69 (m, 1 H) 1.56 - 1.63 (m, 1 H) 1.38 - 1.44 (m, 1 H) 1.34 (t, J = 7.2 Hz, 6 H) 0.93 (d, J = 6.4 Hz, 3 H) 0.83 (d , J = 6.4 Hz, 3 H). MS (ESI+) m/z 574 [M+H]+.

Example 4i

Diethyl-(7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}-5-[(1-pyridin-2-ylethyl)sulfanyl][1,3]thiazolo[4,5- d ]pyrimidin-2-yl)amidophosphate

The title product was synthesized from ( 2R )-2-({2-amino-5-[(1-pyridin-2-ylethyl)sulfanyl][1,3]thiazolo[4,5- d ]pyrimidin-7- yl}amino)-4-methylpentan-1-ol (Karlström S., et al., J. Med. Chem ., 2013 , 56 , 3177-3190; WO 2006/107258) in two steps using the method described for example 4, except that instead of water and DMSO, EtOH was added after 1 hour at the temperature of the ice bath in step 2.

The starting material for step 2 was the same as in example 4c. The product was a mixture of two diastereomers. Overall yield for two stages: 31%.

Step 2: The two diastereomers were separated by preparative HPLC (basic method).

Diastereomer A: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 8.47 (dt, J =4.9, 0.8 Hz, 1 H) 7.79 (td, J =7.7, 1.4 Hz, 1 H) 7.62 (d, J =7, 3 Hz, 1 H) 7.28 (dd, J = 7.6, 4.9 Hz, 1 H) 5.19 (k, J = 7.3 Hz, 1 H) 4.48 (brs, 1 H ) 4.06 - 4.16 (m, 4 H) 3.51 (dd, J =11.1, 5.3 Hz, 1 H) 3.43 (dd, J =11.0, 5.5 Hz , 1 H) 1.74 (d, J = 7.3 Hz, 3 H) 1.65 - 1.72 (m, 1 H) 1.51 - 1.57 (m, 1 H) 1.42 - 1.48 (m, 1 H) 1.33 (t, J =7.0 Hz, 6 H) 0.96 (d, J =6.4 Hz, 3 H) 0.94 (d, J =6 .7 Hz, 3 H). MS (ESI+) m/z 541 [M+H]+.

Diastereomer B: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 8.47 (dd, J =5.1, 0.9 Hz, 1 H) 7.78 (td, J =7.9, 1.8 Hz, 1 H) 7.65 (d, J =7, 9 Hz, 1 H) 7.27 - 7.29 (m, 1 H) 5.14 (k, J = 7.3 Hz, 1 H) 4.25 (br, 1 H) 4.07 - 4, 14 (m, 4 H) 3.61 (dd, J =11.0, 5.2 Hz, 1 H) 3.51 (dd, J =11.0, 5.8 Hz, 1 H) 1.72 (d, J = 7.3 Hz, 3 H) 1.59 - 1.66 (m, 1 H) 1.49 - 1.54 (m, 1 H) 1.41 - 1.46 (m, 1 H) 1.33 (t, J =7.0 Hz, 6 H) 0.92 (d, J =6.4 Hz, 3 H) 0.79 (d, J =6.7 Hz, 3 H) . MS (ESI+) m/z 541 [M+H]+.

Example 4j

Diethyl-(5-{[1-(3-cyanophenyl)ethyl]sulfanyl}-7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5- d ]pyrimidin-2-yl)amidophosphate

The title product was synthesized from 3-{1-[(2-amino-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-5-yl)sulfanyl]ethyl}benzonitrile (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO 2006/107258) in two steps using the method described for example 4, except that EtOH was added instead of water and DMSO after 1 hour at ice bath temperature in step 2.

The starting material for step 2 was the same as in example 4d. The product was a mixture of two diastereomers. Total yield for two stages: 60%.

Step 2: The two diastereomers were separated by preparative HPLC (basic method).

Diastereomer A: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.86 (t, J =1.7 Hz, 1 H) 7.84 (dt, J =7.9, 1.4 Hz, 1 H) 7.58 (dt, J =7.6, 1, 4 Hz, 1 H) 7.49 (t, J = 7.8 Hz, 1 H) 5.08 (c, J = 7.2 Hz, 1 H) 4.30 (br, 1 H) 4.07 - 4.16 (m, 4 H) 3.59 (dd, J =11.0, 5.5 Hz, 1 H) 3.55 (dd, J =11.0, 5.8 Hz, 1 H) 1.70 (d, J = 7.3 Hz, 3 H) 1.59 - 1.67 (m, 1 H) 1.49 - 1.55 (m, 1 H) 1.40 - 1.46 ( m, 1 H) 1.33 (td, J =7.1, 0.8 Hz, 6 H) 0.92 (d, J =6.7 Hz, 3 H) 0.80 (d, J =6 .4 Hz, 3 H). MS (ESI+) m/z 565 [M+H]+.

Diastereomer B: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 7.86 (t, J =1.7 Hz, 1 H) 7.83 (dt, J =7.9, 1.4 Hz, 1 H) 7.59 (dt, J =7.6, 1, 4 Hz, 1 H) 7.50 (t, J = 7.8 Hz, 1 H) 5.09 (k, J = 7.2 Hz, 1 H) 4.45 (br, 1 H) 4.07 - 4.16 (m, 4 H) 3.52 (dd, J =11.0, 5.2 Hz, 1 H) 3.44 (dd, J =11.0, 5.5 Hz, 1 H) 1.71 (d, J = 7.3 Hz, 3 H) 1.65 - 1.70 (m, 1 H) 1.51 - 1.57 (m, 1 H) 1.42 - 1.49 ( m, 1 H) 1.33 (t, J =7.0 Hz, 6 H) 0.96 (d, J =6.7 Hz, 3 H) 0.94 (d, J =6.4 Hz, 3H). MS (ESI+) m/z 565 [M+H]+.

4k example

Diethyl-(5-{[1-(3-fluoropyridin-2-yl)ethyl]sulfanyl}-7-{[(1 R )-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5- d ]pyrimidin-2-yl)amidophosphate

The title product was synthesized from (2R)-2-[(2-amino-5-{[1-(3-fluoropyridin-2-yl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (Karlström S.,et al., J. Med. Chem.,2013,56, 3177-3190; WO 2006/107258) in two steps using the method described for example 4, except that EtOH was added instead of water and DMSO after 1 hour at ice bath temperature in step 2.

The starting material for step 2 was the same as in example 4e. The product was a mixture of two diastereomers. Overall yield for two stages: 56%.

Step 2: The two diastereomers were separated by preparative HPLC (basic method).

Diastereomer A: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 8.34 (dt, J =4.9, 1.2 Hz, 1 H) 7.60 (ddd, J =9.8, 8.5, 1.2 Hz, 1 H) 7.37 (dt, J = 8.5, 4.3 Hz, 1 H) 5.56 (k, J = 7.1 Hz, 1 H) 4.52 (br, 1 H) 4.07 - 4.17 (m, 4 H) 3.57 (dd, J =11.0, 5.2 Hz, 1 H) 3.53 (dd, J =11.0, 5.5 Hz, 1 H) 1.76 (d, J = 7.0 Hz, 3 H) 1.67 - 1.74 (m, 1 H) 1.55 - 1.61 (m, 1 H) 1.46 (ddd, J =13.7, 9.2, 4.6 Hz, 1 H) 1.34 (td, J = 7.2, 1.8 Hz, 6 H) 0.97 (d, J = 6.7 Hz, 3 H) 0.95 (d, J = 6.7 Hz, 3 H). MS (ESI+) m/z 559 [M+H]+.

Diastereomer B: ¹ H NMR (600 MHz, CD ₃ OD) δ _H ppm 8.35 (dt, J =4.9, 1.2 Hz, 1 H) 7.59 (ddd, J =9.8, 8.4, 1.4 Hz, 1 H) 7.37 (ddd, J = 8.4, 4.4, 4.3 Hz, 1 H) 5.55 (k, J = 7.0 Hz, 1 H) 4.48 (br, 1 H) 4.08 - 4.16 (m, 4 H) 3.61 (d, J =5.5 Hz, 2 H) 1.78 (d, J =7.0 Hz, 3 H) 1.67 - 1.74 (m, 1 H ) 1.54 - 1.61 (m, 1 H) 1.43 - 1.50 (m, 1 H) 1.34 (t, J = 7.0 Hz, 6 H) 0.97 (d, J =6.4 Hz, 3 H) 0.92 (d, J =6.4 Hz, 3 H). MS (ESI+) m/z 559 [M+H]+.

Example 5 Comparative Kinetic Solubility of Example 1 and Compound A

Samples of the compound from Example 1 and (2 R )-2-[(2-amino-5-{[(1 S )-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5- d ]pyrimidine-7 -yl)amino]-4-methylpentan-1-ol. HCl (compounds A) was diluted to a nominal concentration of 250 μm in 50 mm phosphate buffer pH 7.4, then stirred for 1 hour and filtered.

Received standard solutions of the two indicated compounds at concentrations of 25 and 250 μm in 50:50 mixture of acetonitrile:water.

The solutions were then analyzed by reverse phase HPLC with UV detection, and the solubility was determined from the ratio of the sample peaks to the standard curve. The results are presented in the following table.

Compound Solubility (µM) Example 1 (diammonium salt) 118 Compound A (HCl salt) 5

Example 6 Comparative Stability of Solutions of Example 1 and Compound A

An aqueous solution of the compound of Example 1 (diammonium salt) was prepared in MilliQ water at a concentration of 1.7 mg/mL, and the long-term storage stability of the compound in aqueous solution was determined by analyzing the solution by HPLC-MS over an extended period of time.

The results of this study are presented in table 1.

Table 1. Stability of example 1 in aqueous solution (1.7 mg/ml) at room temperature (room temperature).

Experiment Storage days Example 1
% area 1 0 99.6 2 4 99.6 3 13 99.6 4 20 99.6 5 40 99.6

It was not possible to dissolve Compound A in pure water, so several solutions were prepared with different co-solvents, and the long-term storage stability of the compound in aqueous solution was determined by analyzing the solution with HPLC-MS over an extended period of time. The results of the experiments are presented in tables 2-4.

Table 2. Stability of compound A in water + 20% MeOH (1.75 mg/ml) at room temperature

Experiment days Compound A
% area 1 0 98.4% 2 4 96.7%

Table 3 shows the stability of compound A in an aqueous solution containing various amounts of this compound and added polyethylene glycol.

Table 3 Stability of compound A in water containing various amounts of polyethylene glycol at room temperature

Experiment days Compound A
(1.22 mg/ml) Compound A
(2.25 mg/ml) Compound A
(1.18 mg/ml) Polyethylene glycol concentration (v/v) 24% 26% 24% 1 Remaining compound A, % 0 98.6 98.5 98.5 2 Remaining compound A, % 3 98.0 97.7 97.7 3 Remaining compound A, % 56 31 35 28

Table 3 shows the stability of compound A in an aqueous solution containing various amounts of this compound and added polyethylene glycol and ethanol.

Table 4 Stability of compound A in water containing polyethylene glycol and ethanol at room temperature

Experiment days Compound A
(3.2 mg/ml) Compound A
(4.0 mg/ml) Polyethylene glycol concentration (v/v) 28% 25% Ethanol (v/v) 0 3% 1 Remaining compound A, % 0 98.4 98.4 2 Remaining compound A, % 14 88.1 92.3 3 Remaining compound A, % 70 60.7 75.1

Aqueous compositions of Compound A require additional co-solvents such as polyethylene glycol and/or ethanol to solubilize the compound. Such compositions have proven to be unstable when stored at room temperature, and a relatively rapid degradation of the compound has been observed. In contrast, Example 1 not only showed improved water solubility (without the need for co-solvents), but also unexpectedly pronounced stability compared to Compound A in aqueous solutions.

The degradation products observed for Compound A were mostly debenzylated thiol and the corresponding disulfide along with phenylethanol and a small amount of styrene.

Surprisingly, these degradation products were not observed when Example 1 was stored in aqueous solution.

Example 6 Additional Stability Studies

Received aqueous solutions of several exemplary compounds at concentrations of 1.2 mg/ml (10 mg/ml for example 1 (not salt)) in accordance with the following methods.

i) Examples 1b, 2h and 3 (diammonium salts) were dissolved in pure water.

ii) Examples 1d (diammonium salt) and 1n (monoammonium salt) were suspended in water and Na ₂ HPO ₃ was added until the compound went into solution.

iii) Examples 1q, 4f and 4g (not salts) were dissolved in water with the addition of DMSO (100 μl) and (2-hydroxypropyl)-β-cyclodextrin was added until the compound was completely in solution.

The stability of the compounds during long-term storage in aqueous solution at room temperature and/or at 40°C was then determined by analyzing the solution with HPLC-MS after 60 days.

Table 5. Stability of aqueous solutions after storage at room temperature for 60 days

Example % area by HPLC (60 days) 1b (diammonium salt) 100 1d (diammonium salt) 98.0 1n (monoammonium salt) 98.2 1q 63.1 2h (diammonium salt) 92.3 3 (diammonium salt) 99.6 4f 95.7 4g 91.6

Table 6. Stability of aqueous solutions after storage at 40°C for 60 days.

Example % area by HPLC (60 days) 1b (diammonium salt) 100 1d (diammonium salt) 99.7 1n (monoammonium salt) 100 1q 0 2h (diammonium salt) 82.2 3 (diammonium salt) 100 4f 82.1 4g 45.1 1 (10 mg/ml) 100

The data obtained demonstrate that the compounds of this invention are generally stable when stored in an aqueous solution, including under conditions of accelerated aging at 40°C.

Example 7 Plasma concentration comparison of Example 1 and Compound A in mice after intravenous and oral administration.

Compound A

An oral dose solution of compound A (12 mg/ml) in 30% HP-β-CD in 10 mM Na ₂ PO ₄ and an intravenous dose solution of compound A (2.5 mg/ml) in 30% HP- β-CD in 10 mM Na ₂ PO ₄ in DPBS. The intravenous dosing solution was administered to male CD1 mice (weighing 28-30 g) via intravenous injection (25 mg/kg), and the oral dosing solution was administered to male CD1 mice (weighing 28-30 g) via a gastric tube (120 mg/kg). kg).

Animal blood was collected at time points 0.083, 0.25, 0.5, 1, 2, 4, 6, 12, and 24 hours and analyzed for plasma concentration, and used the data to calculate the area under the curve (AUC) values represented by in table 5.

Hydrochloride salt of compound A

An oral dose solution of the HCl salt of compound A (12 mg/ml) in 30% HP-β-CD in 10 mM Na ₂ PO ₄ and a solution for an intravenous dose of the HCl salt of compound A (2.5 mg/ml) in 30% HP-β-CD in 10 mM Na ₂ PO ₄ in DPBS. The intravenous dosing solution was administered to male CD1 mice (weighing 28-30 g) via intravenous injection (25 mg/kg), and the oral dosing solution was administered to male CD1 mice (weighing 28-30 g) via gavage (125 mg/kg). kg).

Animal blood was collected at time points 0.083, 0.25, 0.5, 1, 2, 4, 6, 12, and 24 hours and analyzed for plasma concentration, and used the data to calculate the area under the curve (AUC) values represented by in table 7.

Disodium salt of example 1

An oral dose solution of the disodium salt of Example 1 in water (15.4 mg/ml) at pH 7.18 and an intravenous dose solution of the disodium salt of Example 1 in water (6.4 mg/ml) at pH 7.11 were prepared. by dissolving the diammonium salt of Example 1 in water and adjusting the pH with 0.1 M NaOH solution. The intravenous dosing solution was administered to male CD1 mice (weighing 24-25 g) via tail injection (32 mg/kg), and the oral dosing solution was administered to male CD1 mice (weighing 24-25 g) via gavage (154 mg /kg).

Animal blood was collected at time points 0.083, 0.25, 0.5, 1, 2, 4, 6, 12, and 24 hours and analyzed for plasma concentration, and used the data to calculate the area under the curve (AUC) values represented by in table 7.

Table 7. Comparison of the area under the plasma concentration curve for Compound A and Example 1.

Injected compound Compound A in plasma ID Method of administration Dose Dose AUC Dose selection according to AUC (mg/kg) (µmol/kg) (h*µM) (h*µM) Compound A IV 25 62 45.92 0.74 Compound A.HCl 25 57 50.07 0.88 Example 1.2Na 32 62 55.44 0.90 Compound A PO 120 297 92.57 0.31 Compound A.HCl 125 284 170.19 0.60 Example 1.2Na 154 298 230.80 0.78

Claims (135)

1. Compound of formula I Where R ¹ is phenyl or pyridyl, both of which are optionally substituted with one(oh) fluorine, chlorine, bromine, -CN, -C(O)NR ³ R ⁴ or -S(O) ₂ Me group; R ² is H or C _1-6 alkyl; R ³ and R ⁴ are each H; represents or Where means the point of attachment to the rest of the molecule; Q ¹ and Q ² are each independently H or -PO(OR ⁶ )(OR ⁷ ); Q ³ is H or -CH ₂ OPO(OR ⁶ )(OR ⁷ ); And Q ⁴ is -CH ₂ OPO(OR ⁶ )(OR ⁷ ); where R ⁶ and R ⁷ are each independently H or C _1-4 alkyl; wherein at least one of Q ¹ and Q ² , Q ³ or Q ⁴ is -PO(OR ⁶ )(OR ⁷ ) or -CH ₂ OPO(OR ⁶ )(OR ⁷ ); or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein R ¹ is phenyl or pyridyl, both of which are optionally substituted with one fluorine, chlorine or bromine atom. 3. A compound according to claim 2, characterized in that R ¹ is phenyl or 5-chloropyridyl-2-yl. 4. The connection according to any one of paragraphs. 1-3, characterized in that R ² is C _1-6 alkyl. 5. Connection according to any one of paragraphs. 1-4, characterized in that R ² is C _1-3 alkyl. 6. A compound according to claim 5, characterized in that R ² is methyl. 7. Connection according to any one of paragraphs. 1-6, characterized in that one of Q ¹ and Q ² , Q ³ or Q ⁴ is -PO(OR ⁶ )(OR ⁷ ) or -CH ₂ OPO(OR ⁶ )(OR ⁷ ), and the others from Q ¹ and (if any) Q ² or Q ³ are H. 8. Connection according to any one of paragraphs. 1-7, characterized in that represents 9. Connection according to claim 8, characterized in that represents 10. Connection according to claim 8, characterized in that represents 11. The connection according to any one of paragraphs. 8-10, characterized in that Q ¹ is -PO(OR ⁶ )(OR ⁷ ). 12. A compound according to claim 8 or 9, characterized in that Q ² is —PO(OR ⁶ )(OR ⁷ ). 13. A compound according to claim 8 or 10, wherein Q ³ is -CH ₂ OPO(OR ⁶ )(OR ⁷ ). 14. Connection according to any one of paragraphs. 1-7, characterized in that represents 15. Connection according to any one of paragraphs. 1-14, characterized in that said compound is a compound of formula IA where R ¹ , R ² , Q ¹ , Q ² and are as defined in any of the preceding paragraphs, or a pharmaceutically acceptable salt thereof. 16. Connection according to any one of paragraphs. 1-15, characterized in that each R ⁶ and R ⁷ is independently C _1-3 alkyl or H. 17. The compound according to claim 16, characterized in that each R ⁶ and R ⁷ is H. 18. The compound according to claim 16, characterized in that each R ⁶ and R ⁷ is methyl, or each of them is ethyl. 19. The compound according to claim 16, characterized in that R ⁶ is isopropyl and R ⁷ is H. 20. A compound according to claim 1 or 15, selected from the group consisting of: (2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4- methylpentyl dihydrogen phosphate; (2R)-2-[(2-amino-5-{[1-(2-fluorophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4 -methylpentyl dihydrogen phosphate; (2R)-2-[(2-amino-5-{[1-(2-chlorophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4 -methylpentyl dihydrogen phosphate; (2R)-2-[(2-amino-5-{[1-(5-chloropyridin-2-yl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl) amino]-4-methylpentyl dihydrogen phosphate; (2R)-2-[(2-amino-5-{[1-(3-fluoropyridin-2-yl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl) amino]-4-methylpentyl dihydrogen phosphate; (2R)-2-[(2-amino-5-{[1-(3-cyanophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4 -methylpentyl dihydrogen phosphate; (2R)-2-[(2-amino-5-{[1-(3-carbamoylphenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4 -methylpentyl dihydrogen phosphate; (2R)-2-{[2-amino-5-({1-[4-(methylsulfonyl)phenyl]ethyl}sulfanyl)-[1,3]thiazolo[4,5-d]pyrimidin-7-yl] amino}-4-methylpentyl dihydrogen phosphate; (2R)-2-[(2-amino-5-{[4-(methylsulfonyl)benzyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl]amino}-4-methylpentyl -dihydrophosphate; (2R)-2-({2-amino-5-[(1-pyridin-2-ylethyl)sulfanyl][1,3]thiazolo[4,5-d]pyrimidin-7-yl}amino)-4- methylpentyl dihydrogen phosphate; (2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4- methylpentyl dimethyl phosphate; (2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4- methylpentyl diethyl phosphate; (2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4- methylpentyl bis(1-methylethyl)phosphate; (2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4- methylpentyl-1-methylethyl hydrogen phosphate; (2R)-2-[(2-amino-5-{[1-(2-fluorophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4 -methylpentyl-diethyl phosphate; (2R)-2-[(2-amino-5-{[1-(2-chlorophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4 -methylpentyl-diethyl phosphate; (2R)-2-[(2-amino-5-{[1-(5-chloropyridin-2-yl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl) amino]-4-methylpentyl diethyl phosphate; (2R)-2-[(2-amino-5-{[1-(3-fluoropyridin-2-yl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl) amino]-4-methylpentyl diethyl phosphate; (2R)-2-[(2-amino-5-{[1-(3-cyanophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4 -methylpentyl-diethyl phosphate; [7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-2-imino-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5 -d]pyrimidin-3(2H)-yl]methyl dihydrogen phosphate; [5-{[1-(2-fluorophenyl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-2-imino[1,3]thiazolo[4, 5-d]pyrimidin-3(2H)-yl]methyl dihydrogen phosphate; [5-{[1-(2-chlorophenyl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-2-imino[1,3]thiazolo[4, 5-d]pyrimidin-3(2H)-yl]methyl dihydrogen phosphate; [5-{[1-(5-chloropyridin-2-yl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-2-imino[1,3] thiazolo[4,5-d]pyrimidin-3(2H)-yl]methyl dihydrogen phosphate; [7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-2-imino-5-[(1-pyridin-2-ylethyl)sulfanyl][1,3]thiazolo[4,5 -d]pyrimidin-3(2H)-yl]methyl dihydrogen phosphate; [5-{[1-(3-Fluoropyridin-2-yl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-2-imino[1,3] thiazolo[4,5-d]pyrimidin-3(2H)-yl]methyl dihydrogen phosphate; [5-{[1-(3-cyanophenyl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-2-imino[1,3]thiazolo[4, 5-d]pyrimidin-3(2H)-yl]methyl dihydrogen phosphate; [5-{[(1S)-1-(5-chloropyridin-2-yl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-2-oxo[ 1,3]thiazolo[4,5-d]pyrimidin-3(2H)-yl]methyl dihydrogen phosphate; (2R)-2-[(5-{[(1S)-1-(5-chloropyridin-2-yl)ethyl]sulfanyl}-2-oxo-2,3-dihydro[1,3]thiazolo[4, 5-d]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate; (2R)-4-methyl-2-({2-oxo-5-[(1-pyridin-2-ylethyl)sulfanyl]-2,3-dihydro[1,3]thiazolo[4,5-d]pyrimidine -7-yl}amino)pentyl dihydrogen phosphate; (2R)-4-methyl-2-{[5-({1-[4-(methylsulfonyl)phenyl]ethyl}sulfanyl)-2-oxo-2,3-dihydro[1,3]thiazolo[4,5 -d]pyrimidin-7-yl]amino}pentyl dihydrogen phosphate; (2R)-2-[(5-{[1-(3-carbamoylphenyl)ethyl]sulfanyl}-2-oxo-2,3-dihydro[1,3]thiazolo[4,5-d]pyrimidine-7- yl)amino]-4-methylpentyl dihydrogen phosphate; (2R)-2-[(5-{[1-(2-chlorophenyl)ethyl]sulfanyl}-2-oxo-2,3-dihydro[1,3]thiazolo[4,5-d]pyrimidine-7- yl)amino]-4-methylpentyl dihydrogen phosphate; (2R)-2-[(5-{[1-(3-cyanophenyl)ethyl]sulfanyl}-2-oxo-2,3-dihydro[1,3]thiazolo[4,5-d]pyrimidine-7- yl)amino]-4-methylpentyl dihydrogen phosphate; (2R)-2-[(5-{[(1S)-1-(5-chloropyridin-2-yl)ethyl]sulfanyl}-2-oxo-2,3-dihydro[1,3]thiazolo[4, 5-d]pyrimidin-7-yl)amino]-4-methylpentyl-dimethylphosphate; (2R)-2-[(5-{[(1S)-1-(5-chloropyridin-2-yl)ethyl]sulfanyl}-2-oxo-2,3-dihydro[1,3]thiazolo[4, 5-d]pyrimidin-7-yl)amino]-4-methylpentyldiethyl phosphate; (7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidine -2-yl)phosphoramide acid; (5-{[1-(2-chlorophenyl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d] pyrimidin-2-yl)phosphoramide acid; (7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-5-[(1-pyridin-2-ylethyl)sulfanyl][1,3]thiazolo[4,5-d]pyrimidine -2-yl)phosphoramide acid; (5-{[1-(3-cyanophenyl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d] pyrimidin-2-yl)phosphoramide acid; (5-{[1-(3-Fluoropyridin-2-yl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4, 5-d]pyrimidin-2-yl)phosphoramide acid; diethyl-(7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d ]pyrimidin-2-yl)amidophosphate; dimethyl-(7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d ]pyrimidin-2-yl)amidophosphate; diethyl-(5-{[1-(2-chlorophenyl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5- d]pyrimidin-2-yl)amidophosphate; diethyl-(7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-5-[(1-pyridin-2-ylethyl)sulfanyl][1,3]thiazolo[4,5-d ]pyrimidin-2-yl)amidophosphate; diethyl-(5-{[1-(3-cyanophenyl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5- d]pyrimidin-2-yl)amidophosphate; And diethyl-(5-{[1-(3-fluoropyridin-2-yl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[ 4,5-d]pyrimidin-2-yl)amidophosphate, or a pharmaceutically acceptable salt thereof. 21. The compound according to claim 1 or 15, which is (2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d ]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof. 22. Connection according to any one of paragraphs. 1-21, characterized in that the pharmaceutically acceptable salt is a base addition salt. 23. A compound according to claim 22, wherein the pharmaceutically acceptable salt is an ammonium salt or an alkali metal salt. 24. Pharmaceutical composition having the activity of fractalkin receptor antagonists, which contains an effective amount of the compound according to any one of paragraphs. 1-23, including its pharmaceutically acceptable salts, in admixture with one or more pharmaceutically acceptable excipients. 25. Pharmaceutical composition according to claim 24, characterized in that said pharmaceutical composition additionally contains water and less than 20% (w/w) solubilizing excipients. 26. A pharmaceutical composition according to claim 24, characterized in that said pharmaceutical composition is in the form of an aqueous solution. 27. A pharmaceutical composition according to claim 24, characterized in that said composition is in the form of a powder. 28. Connection according to any one of paragraphs. 1-23, including its pharmaceutically acceptable salts, or a pharmaceutical composition according to any one of paragraphs. 24-27 for use in medicine. 29. Connection according to any one of paragraphs. 1-23, including its pharmaceutically acceptable salts, or a pharmaceutical composition according to any one of paragraphs. 24-27 for use in the treatment and/or prevention of a disease or disorder associated with elevated levels of CX3CR1 and/or CX3CL1. 30. A method of treating and/or preventing a disease or disorder associated with elevated levels of CX3CR1 and/or CX3CL1, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of paragraphs. 1-23, including its pharmaceutically acceptable salts, or a pharmaceutical composition according to any one of paragraphs. 24-27. 31. The use of a compound according to any one of paragraphs. 1-23, including its pharmaceutically acceptable salts, or a pharmaceutical composition according to any one of paragraphs. 24-27 for the manufacture of a medicament for the treatment and/or prevention of a disease or disorder associated with elevated levels of CX3CR1 and/or CX3CL1. 32. Connection for use, method or application according to any one of paragraphs. 29-31, characterized in that said disease or disorder associated with elevated levels of CX3CR1 and/or CX3CL1 is selected from acute and/or chronic inflammation, eye diseases, lung diseases, skin diseases, diseases of the joints and/or bones, autoimmune diseases , cardiovascular disease, metabolic disease, brain disease, neurodegenerative disease, pain, cancer, liver disease, kidney disease, gastrointestinal disease, human immunodeficiency virus, and mood disorders. 33. Connection for use, method or application according to any one of paragraphs. 29-32, characterized in that said disease or disorder associated with elevated levels of CX3CR1 and/or CX3CL1 is selected from macular degeneration, pulmonary arterial hypertension, asthma, pulmonary fibrosis, atopic dermatitis, pritis, osteoarthritis, osteoporosis, aplastic anemia, ankylosing spondylitis, multiple sclerosis, systemic sclerosis, rheumatoid arthritis, atherosclerosis, unstable angina, myocardial infarction, carotid artery disease, chronic heart failure, inflammatory cardiomyopathy, peripheral arterial disease, diabetes, Alzheimer's disease, traumatic brain injury, chronic pain, fibromyalgia, neuropathic pain, chemotherapy-induced pain, herniated disc pain, cancer, liver cirrhosis, IgA nephropathy, kidney inflammation, lupus, ischemic reperfusion injury, ischemic acute kidney injury, contrast-induced kidney injury, colitis, Crohn's disease, inflammatory disease bowel disease, pancreatitis, human immunodeficiency virus-1, human immunodeficiency virus dementia, stroke, Parkinson's disease, depression, anxiety, schizophrenia and autism spectrum disorders. 34. Connection for use, method or application according to any one of paragraphs. 29-33, characterized in that said disease or disorder associated with elevated levels of CX3CR1 and/or CX3CL1 is selected from myocardial infarction, arteriosclerosis, multiple sclerosis, rheumatoid arthritis, Crohn's disease, pancreatitis, neuropathic pain, chemotherapy-induced pain, and cancer. 35. Connection for use, method or application according to any one of paragraphs. 29-33, characterized in that said disease or disorder associated with elevated levels of CX3CR1 and/or CX3CL1 is selected from atopic dermatitis, multiple sclerosis, rheumatoid arthritis, atherosclerosis, myocardial infarction, congestive heart failure, inflammatory cardiomyopathy, fibromyalgia, neuropathic pain , chemotherapy-induced pain, B-cell lymphoma, breast cancer, IgA nephropathy, lupus, ischemic acute renal failure, and pancreatitis. 36. A method of obtaining a compound according to any one of paragraphs. 1-23, including: (a) for compounds in which Q ¹ is -PO(OR ⁶ )(OR ⁷ ), where R ⁶ and R ⁷ are as defined in any of the preceding paragraphs, (i) reacting a compound of formula II where R ¹ and R ² are as defined in any of the preceding paragraphs; And represents or with phosphorus oxychloride in the presence of a suitable solvent and a suitable base; then (ii) adding water or R ⁶ OH/R ⁷ OH to the reaction mixture; (b) for compounds in which Q ² is -PO(OR ⁶ )(OR ⁷ ), bringing into interaction the compounds of formula III Where: R ¹ and R ² are as defined in any of the preceding paragraphs; And PG ¹ is a suitable protecting group for an oxygen atom; in the presence of phosphorus pentachloride, a suitable solvent, and optionally a suitable base; (c) for compounds in which Q ³ or Q ⁴ is -CH ₂ OPO(OR ⁶ )(OR ⁷ ) and at least one of R ⁶ and R ⁷ is C _1-4 alkyl, bringing into interaction the compounds of formula II where R ¹ and R ² are as described herein; And represents or with compound of formula IV where R ⁶ and R ⁷ are as defined in any of the preceding paragraphs, provided that at least one of R ⁶ and R ⁷ is C _1-4 alkyl and LG ¹ is a suitable leaving group; in the presence of a suitable base and a suitable solvent; (d) for compounds in which Q ³ or Q ⁴ is -CH ₂ OPO(OH) ₂ , (i) reacting a compound of formula II where R ¹ and R ² are as described herein; And represents or with a compound of formula V where R ⁸ and R ⁹ are C _1-6 alkyl and LG ² is a suitable leaving group; in the presence of a suitable base and a suitable solvent; And (ii) bringing into interaction the resulting product in the presence of a suitable acid and a suitable solvent.