ES2356502T3 - PURINE DERIVATIVES AS IMMUNOMODULAR. - Google Patents

Abstract

A compound of formula (I): ** Formula ** in which R 1 is (C 1-8 alkyl) amino, C 1-8 alkoxy, (C 3-7 cycloalkyl) (C 1-6 alkyl) amino, (C 35-7 cycloalkyl) ) C1-6 alkoxy, (C1-3 alkoxy) C2-3 alkoxy, or Hetb-C1-3 alkoxy; Hetb is a saturated 5- or 6-membered aliphatic heterocycle containing an oxygen atom; R2 is - (CH2) n-Het; n is an integer that has a value from 1 to 4; Het is a saturated 5- or 6-membered aliphatic heterocycle containing an oxygen heteroatom, a heterocycle that may be substituted with one or two C1-4 alkyl groups; or its salts or solvates.

Description

Background of the invention

The present invention relates to compounds, processes for their preparation, compositions containing them, for use in the treatment of various disorders, in particular infectious diseases, cancer, and allergic diseases and other inflammatory conditions, for example allergic rhinitis and asthma. , and as vaccine adjuvants.

Vertebrates are constantly threatened by the invasion of microorganisms and have developed immune defense mechanisms to eliminate infectious pathogens. In mammals, this immune system comprises two branches; innate immunity and acquired immunity. The first line of defense of the host is the innate immune system, which is mediated by macrophages and dendritic cells. Acquired immunity involves the elimination of pathogens in the last stages of the infection and also allows the generation of immunological memory. Acquired immunity is very specific, due to the wide repertoire of lymphocytes with specific antigen receptors that have undergone gene rearrangement. fifteen

Initially it was thought that the innate immune response was nonspecific, but currently it is known that it is capable of discriminating between the same and a variety of pathogens. The innate immune system recognizes microbes through a number of pattern recognition receptors encoded by germ lines (PRR) that have a number of important characteristics. PRRs recognize the microbial components, known as pathogen-associated molecular patterns (PAMP), that are essential for the survival of the microorganism. PRRs are constitutively expressed in the host in all cells of a given type and are independent of immunological memory. These receptors include newly identified Toll type receptors (TLRs), nucleotide oligomerization domain type receptors (NLRs) and retinoic acid inducible gene type receptors (RLRs) (Creagh EM, O'Neill LA., Trends Immunol. 2006 27 (8): 352-7).

Key to the generation of an effective innate immune response in mammals are the mechanisms that cause the induction of interferons and other cytokines that act on the cells inducing a series of effects. These effects may include activation of anti-infective gene expression, activation of antigen presentation in cells to cause potent antigen-specific immunity and stimulation of phagocytosis in phagocytic cells.

Interferon was first described as a substance that could protect cells from viral infection (Isaacs & Lindemann, J. Virus Interference. Proc. R. Soc. Lon. Ser. 35

B. Biol. Sci. 1957, 147: 258-267). In man, type I interferons are a family of related proteins encoded by genes on chromosome 9 and that encode at least 13 interferon alpha isoforms (IFNα) and an interferon beta isoform (IFNβ). Recombinant IFNα was the first authorized biological therapeutic substance and has become an important treatment for viral infections and cancer. In addition to direct antiviral activity in cells, interferons are known to be potent modulators of the immune response and act on cells of the immune system.

As a first-line treatment against hepatitis C virus (HCV) disease, interferon combinations can be very effective in reducing viral load and in some subjects in eliminating viral replication. However, 10 many patients fail to maintain a sustained antiviral response and in these patients the viral load cannot be controlled. In addition, treatment with injected interferon may be associated with a number of unwanted adverse effects that have been shown to affect therapeutic compliance (Dudley T, O'Donnell K, Haydon G, Mutimer D. Gut. 2006 55 (9): 1362- 3). fifteen

The administration of a compound of small molecules that could stimulate the innate immune response, including the activation of type I interferons and other cytokines, would be an important strategy for the treatment or prevention of human diseases including viral infections. This type of immunomodulatory strategy has the potential to identify compounds that may be useful not only in infectious diseases but in cancer (Krieg. Curr. Oncol. Rep. 2004; 6 (2): 88-95), allergic diseases (Moisan et al., Am. J. Physiol. Lung Cell Mol. Physiol. 2005; 290 (5): L987-95), other inflammatory conditions such as irritable bowel disease (Rakoff-Nahoum S., Cell. 2004, 23; 118 (2): 229-41), and as vaccine adjuvants (Persing et al. Trends Microbiol. 2002; 10 (10 Supl): S32-7). 25

The mechanisms that lead to the induction of type I interferons are only partially understood. One mechanism that can lead to the induction of interferon in many cell types is the recognition of double stranded viral RNA by RIG-I and MDA5 helicase RNAs. It is believed that this mechanism is the primary mechanism by which interferons are induced in the infection of cells by Sendai virus. 30

Other mechanisms for the induction of interferons act through TLR-dependent signaling events. In man, plasmacytoid dendritic cells (pDC) are professional interferon producing cells, capable of producing large amounts of interferons in response, for example, to viral infection. It has been shown that these pDCs preferably express TLR7 and TLR9 and the stimulation of these 35

receptors with viral RNA or DNA can respectively induce the expression of interferon alfa.

TLR7 and TLR9 oligonucleotide agonists and purine-based agonists of small TLR7 molecules that can induce alpha interferon in these cell types in animals and man have been described (Takeda K. et al., Annu. Rev. Immunol., 2003 , 21: 335-5 76). TLR7 agonists include imidazoquinoline compounds such as imiquimod and resiquimod, oxoadenin analogs and also nucleoside analogs such as loxoribin and 7-thia-8-oxoguanosine that have long been known to induce interferon alpha.

It remains unclear how purine compounds of small molecules 10 can induce type I interferons and other cytokines since the molecular targets of these known inducers have not been identified. However, an assay strategy has been developed to characterize small molecule inducers of human IFNα interferon (regardless of mechanism) that is based on the stimulation of primary human donor cells with compounds, and is disclosed herein. fifteen

Brief Description of the Invention

The compounds of the invention have been shown to be inducers of human interferon and may have an improved profile with respect to known human interferon inducers, for example enhanced potency. Compounds that induce human interferon may be useful in the treatment of various disorders, for example the treatment of infectious diseases, cancer, and allergic diseases and other inflammatory conditions such as allergic rhinitis and asthma, and may also be useful as adjuvants of vaccines

Summary of the invention

In a first aspect, compounds of the formula (I) are provided:

in which

R1 is (C1-8 alkyl) amino, C1-8 alkoxy, (C3-7 cycloalkyl) (C1-6 alkyl) amino, (C3-7 cycloalkyl) C1-6 alkoxy, (C1-3 alkoxy) C2-3 alkoxy , or Hetb-C1-3 alkoxy;

Hetb is a saturated 5- or 6-membered aliphatic heterocycle containing an oxygen atom;

R2 is - (CH2) n-Het;

n is an integer that has a value from 1 to 4;

Het is a saturated 5- or 6-membered aliphatic heterocycle containing an oxygen heteroatom, a heterocycle that may be substituted by one or two C1-4 alkyl groups;

and its salts and solvates. 5

In a further embodiment, R1 is (C1-6 alkyl) amino, C1-8 alkoxy, (C3-7 cycloalkyl) amino, (C3-7 cycloalkyl) C1-6 alkoxy, (C1-3 alkoxy ) C2-3 alkoxy, or Hetb-C1-3 alkoxy.

In a further embodiment, R1 is n-butoxy, n-butylamino, 2,2-dimethylpentyloxy, n-pentylamino, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 2-methylbutylamino, 3-methylbutylamino, 1-methylbutylamino, 2 - (cyclopropyl) ethoxy, 2- (ethoxy) ethoxy, (1-methyl-2-methoxy) ethoxy, cyclohexylmethylamino, 10 cyclopentylmethylamino, 2- (cyclopropyl) ethylamino, 2- (methyl) propoxy, cyclohexylmethoxy, methoxyethoxy, (2- tetrahydrofuranyl) methoxy, (2-tetrahydro-2H-pyranyl) methoxy, or 2- (isopropoxy) ethoxy.

In a further embodiment, R1 is n-butylamino, n-butoxy, or 2- (cyclopropyl) ethoxy.

In a further embodiment, R1 is n-butylamino, n-butoxy, (R) -1-methylbutyloxy, (S) -1-methylbutyloxy, or 2- (cyclopropyl) ethoxy. fifteen

In a further embodiment, n is 1.

In a further embodiment, n is 2.

In a further embodiment, n is 3.

In a further embodiment, n is 4.

In a further embodiment, Het is tetrahydrofuran-3-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydrofuran-2-yl, 2,2-dimethyltetrahydro-2H-pyran- 4-yl, or tetrahydro-2H-pyran-2-yl.

In a further embodiment, Het is tetrahydro-2H-pyran-4-yl, tetrahydrofuran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-piran-2-yl, or tetrahydrofuran-3-yl.

In a further embodiment, Het is tetrahydro-2H-pyran-3-yl. 25

In a further embodiment, Het is tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-2-yl, 2,2-dimethyltetrahydro-2H-pyran-4-yl , tetrahydrofuran-3-yl or tetrahydro-2H-pyran-2-yl.

In a further embodiment, when n is 1, then Het is tetrahydrofuran-3-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydrofuran-2-yl, 2,2-dimethyltetrahydro -2H-30 pyran-4-yl, or tetrahydro-2H-pyran-2-yl.

In a further embodiment, when n is 2, then Het is tetrahydro-2H-pyran-4-yl, tetrahydrofuran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-2-yl, or tetrahydrofuran-3-yl.

In a further embodiment, when n is 3, then Het is tetrahydro-2H-pyran-3-yl.

In a further embodiment, when n is 4, then Het is tetrahydro-2H-pyran-3-yl. 35

In a further embodiment, when n is 1, then R2 is tetrahydro-2H-pyran-4-yl or tetrahydrofuran-3-yl.

In a further embodiment, when n is 2, then Het is tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-2-yl, 2,2-dimethyltetrahydro-2H -piran-4-yl, tetrahydrofuran-3-yl, or tetrahydrofuran-2-yl. 5

In a further embodiment, when n is 3, then Het is tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-2-yl, 2,2-dimethyltetrahydro-2H -piran-4-yl, tetrahydrofuran-3-yl, or tetrahydrofuran-2-yl.

In a further embodiment, when n is 4, then Het is tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-2-yl, 2,2-dimethyltetrahydro-2H -piran-4-yl, tetrahydrofuran-3-yl, or tetrahydrofuran-2-yl.

In a further aspect of the invention, a subset of compounds of the formula (I) are provided, which are compounds of the formula (I ’):

in which 15

R1 ’is n-butylamino, n-butoxy, or cyclopropylethoxy;

R2 ’is - (CH2) n’-Het’;

n ’is 1;

Het ’is tetrahydro-2H-pyran-4-yl or tetrahydro-3-furanyl;

and its salts and solvates. twenty

In a further aspect of the invention, a subset of compounds of the formula (I) are provided, which are compounds of the formula (I ''):

in which

R1 '' is n-butylamino, n-butoxy, (R) -1-methylbutyloxy, (S) -1-methylbutyloxy, or 2- (cyclopropyl) ethoxy; 25

R2 '' is - (CH2) n '' - Het '';

n '' is 2, 3 or 4;

Het '' is tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-2-yl, 2,2-dimethyltetrahydro-2H-pyran-4-yl, tetrahydrofuran- 3-yl, or tetrahydrofuran-2-yl;

and its salts and solvates.

In a further aspect of the invention, a subset of compounds of the formula (I) is provided, the compounds of the formula (IA) being:

wherein R1A is (C1-6 alkyl) amino, or C1-6 alkoxy;

R2A is - (CH2) nA-HetA;

nA is an integer that has a value of 1 to 4;

HetA is a saturated 5- or 6-membered aliphatic heterocycle containing an oxygen heteroatom;

and its salts and solvates.

In a further embodiment, R1A is n-butoxy or n-butylamino.

In a further embodiment, nA is 1 or 2.

In a further embodiment, when nA is 1, then HetA is tetrahydrofuran-3-yl, tetrahydro-2H-pyran-3-yl, or tetrahydro-2H-pyran-4-yl.

Examples of compounds of the formula (I) are provided in the following list and form a further aspect of the invention:

6-amino-2-butoxy-9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2-butoxy-9- (tetrahydro-2H-pyran-2-ylmethyl) -7,9-dihydro-8H-purin-8-one; twenty

6-amino-2-butoxy-9- (tetrahydrofuran-2-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2-butylamino-9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2-butylamino-9- (tetrahydro-2H-pyran-2-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2-butylamino-9- (tetrahydrofuran-2-ylmethyl) -7,9-dihydro-8H-purin-8-one;

 6-amino-2-butylamino-9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-8-one; 25

6-amino-2-butylamino-9- (tetrahydrofuran-3-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2-butylamino-9- (tetrahydro-2H-pyran-3-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2-butoxy-9- (tetrahydrofuran-3-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2-butoxy-9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2-butoxy-9- (tetrahydro-2H-pyran-3-ylmethyl) -7,9-dihydro-8H-purin-8-one; 30

6-amino-2-butoxy-9- [2- (tetrahydrofuran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2-butylamino-9- [2- (tetrahydrofuran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2-butoxy-9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2-butylamino-9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(2,2-dimethylpentyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; 5

6-amino-2- (pentylamino) -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(3-methylbutyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(2-methylbutyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(1-methylbutyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(2-methylbutyl) amino] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-10 one;

6-amino-2 - [(3-methylbutyl) amino] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(1-methylbutyl) amino] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; fifteen

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2-butyloxy-9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2-butyloxy-9 - [(2,2-dimethyltetrahydro-2H-pyran-4-yl) methyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butylamino) -9 - [(2,2-dimethyltetrahydro-2H-pyran-4-yl) methyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2-butyloxy-9- [2- (tetrahydro-3-furanyl) ethyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butylamino) -9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butylamino) -9- [2- (tetrahydro-3-furanyl) ethyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butyloxy) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one, isomer 1; 25

6-amino-2- (butyloxy) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one, isomer 2;

 6-amino-2 - {[2- (ethyloxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2 - {[1-methyl-2- (methoxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; 30

6-amino-2 - {[2- (ethyloxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-3-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2 - {[1-methyl-2- (methoxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-3-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(cyclohexylmethyl) amino] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; 35

6-amino-2 - [(cyclopentylmethyl) amino] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(2-cyclopropylethyl) amino] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butylamino) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one, isomer 1;

6-amino-2- (butylamino) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one, isomer 2;

6-amino-2 - [(2-methylpropyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-10 one;

6-amino-2 - [(cyclohexylmethyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2 - {[2- (methoxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; fifteen

6-amino-2 - {[2- (methoxy) ethyl] oxy} -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(tetrahydro-2-furanylmethyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butylamino) -9- [3- (tetrahydro-2H-pyran-3-yl) propyl] -7,9-dihydro-8H-purin-8-one;

6-amino-9- (tetrahydro-2H-pyran-4-ylmethyl) -2 - [(tetrahydro-2H-pyran-2-ylmethoxy] -7,9-dihydro-20 8H-purin-8-one;

6-amino-2 - ({2 - [(1-methyl ethyl) oxy] ethyl} oxy) -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one ;

6-amino-2- (butylamino) -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(2-cyclopropylethyl) amino] -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-25 one;

6-amino-2 - [(2-cyclopropylethyl) amino] -9- (tetrahydro-2H-pyran-3-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one, isomer 1, and 30

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [tetrahydro-3-furanylmethyl] -7,9-dihydro-8H-purin-8-one, isomer 2;

and its salts and solvates.

The following compounds of the formula (I) form a further aspect of the invention:

6-amino-2- (butyloxy) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one, isomer 1;

6-amino-2-butylamino-9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butyloxy) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one, isomer 2;

6-amino-2- (butylamino) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one, isomer 1; 5

6-amino-2- (butylamino) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one, isomer 2;

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one, isomer 1, and;

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [tetrahydro-3-furanylmethyl] -7,9-dihydro-8H-purin-8-one, isomer 2;

and its salts and solvates.

The following compounds of the formula (I) form a further aspect of the invention:

6-amino-2-butoxy-9- [2- (tetrahydrofuran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one, isomer 1; fifteen

6-amino-2-butoxy-9- [2- (tetrahydrofuran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one, isomer 2;

6-amino-2-butylamino-9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin-8-one, isomer 1;

6-amino-2-butylamino-9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin-8-one, isomer 2; twenty

6-amino-2-butyloxy-9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one, isomer 1;

6-amino-2-butyloxy-9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one, isomer 2;

6-amino-2-butyloxy-9 - [(2,2-dimethyltetrahydro-2H-pyran-4-yl) methyl] -7,9-dihydro-8H-purin-8-25 one, isomer 1;

6-amino-2-butyloxy-9 - [(2,2-dimethyltetrahydro-2H-pyran-4-yl) methyl] -7,9-dihydro-8H-purin-8-one, isomer 2;

6-amino-2- (butylamino) -9- [3- (tetrahydro-2-furanyl) propyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butylamino) -9- [4- (tetrahydro-2-furanyl) butyl] -7,9-dihydro-8H-purin-8-one; 30

6-amino-2- (butylamino) -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butylamino) -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butylamino) -9- [3- (tetrahydro-3-furanyl) propyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butylamino) -9- [4- (tetrahydro-3-furanyl) butyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butylamino) -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -7,9-dihydro-8H-purin-8-one; 35

6-amino-2- (butylamino) -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butylamino) -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butylamino) -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butylamino) -9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-8-one; 5

6-amino-2- (butylamino) -9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butylamino) -9- [4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butyloxy) -9- [3- (tetrahydro-2-furanyl) propyl] -7,9-dihydro-8H-purin-8-one; 10

6-amino-2- (butyloxy) -9- [4- (tetrahydro-2-furanyl) butyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butyloxy) -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butyloxy) -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butyloxy) -9- [3- (tetrahydro-3-furanyl) propyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butyloxy) -9- [4- (tetrahydro-3-furanyl) butyl] -7,9-dihydro-8H-purin-8-one; fifteen

6-amino-2- (butyloxy) -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butyloxy) -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butyloxy) -9- [3- (tetrahydro-2H-pyran-3-yl) propyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butyloxy) -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butyloxy) -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8-one; twenty

6-amino-2- (butyloxy) -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butyloxy) -9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2- (butyloxy) -9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8-one; 25

6-amino-2- (butyloxy) -9- [4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [2- (tetrahydro-2-furanyl) ethyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [3- (tetrahydro-2-furanyl) propyl] -7,9-dihydro-8H-purin-8-one; 30

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [4- (tetrahydro-2-furanyl) butyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [2- (tetrahydro-3-furanyl) ethyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8-one; 35

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [3- (tetrahydro-3-furanyl) propyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [4- (tetrahydro-3-furanyl) butyl] -7,9-dihydro-8H-purin-8-5 one;

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -7,9-dihydro-8H-purin-8-one; 10

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -7,9-dihydro-8H-purin-15 8-one;

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8-one; twenty

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-8- ona;

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -7.9-25 dihydro-8H-purin-8 -one;

6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8- ona;

6-amino-2 - {[(1 S) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2-furanyl) ethyl] -7,9-dihydro-8H-purin-8-one; 30

6-amino-2 - {[(1 S) -1-methylbutyl] oxy} -9- [3- (tetrahydro-2-furanyl) propyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8- ona;

6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-35

8-one;

6-amino-2 - {[(1 S) -1-methylbutyl] oxy} -9- [3- (tetrahydro-3-furanyl) propyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2 - {[(1 S) -1-methylbutyl] oxy} -9- [4- (tetrahydro-3-furanyl) butyl] -7,9-dihydro-8H-purin-8-one; 5

6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -7,9-dihydro-8H-purin-8- ona;

6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -7,9-dihydro-8H-purin-8- ona;

6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -7,9-dihydro-8H-purin-10 8 -one;

6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin-8- ona;

6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -7,9-dihydro-8H-purin-8- ona; fifteen

6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-8- ona;

6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8- ona;

6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-20 8 -one;

6-amino-9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -2 - {[(1S) -1-methylbutyl] oxy} -7,9-dihydro-8H- purin-8-one;

6-amino-9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -2 - {[(1S) -1-methylbutyl] oxy} -7,9-dihydro-8H- purin-8-one; 25

6-amino-9- [4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) butyl] -2 - {[(1S) -1-methylbutyl] oxy} -7,9-dihydro-8H- purin-8-one;

6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2-furanyl) ethyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [3- (tetrahydro-2-furanyl) propyl] -7,9-dihydro-8H-purin-8-30 one;

6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8- ona;

6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8- ona; 35

6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [3- (tetrahydro-3-furanyl) propyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [4- (tetrahydro-3-furanyl) butyl] -7,9-dihydro-8H-purin-8-one;

6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -7,9-dihydro-8H-purin-5 8 -one;

6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -7,9-dihydro-8H-purin-8- ona;

6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -7,9-dihydro-8H-purin-8- ona; 10

6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin-8- ona;

6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -7,9-dihydro-8H-purin-8- ona;

6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-15 8 -one;

6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8- ona;

6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8- ona; twenty

6-amino-9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -2 - {[(1R) -1-methylbutyl] oxy} -7,9-dihydro-8H- purin-8-one;

6-amino-9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -2 - {[(1R) -1-methylbutyl] oxy} -7,9-dihydro-8H- purin-8-one;

6-amino-9- [4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) butyl] -2 - {[(1R) -1-methylbutyl] oxy} -7.9-25 dihydro-8H -purin-8-one;

and its salts and solvates.

A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic agent is thus provided as an additional aspect of the invention. 30

A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, is therefore also provided for use in the treatment of infectious diseases, cancer, allergic diseases and other inflammatory conditions.

A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, is therefore also provided for use as a vaccine adjuvant. 35

The use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, is also provided for the manufacture of a medicament for the treatment of infectious diseases, cancer, allergic diseases and other inflammatory conditions.

In a further aspect of the invention, there is provided a method for the treatment of infectious diseases, cancer, allergic diseases and other inflammatory conditions, a method comprising administering an effective amount of a compound of the formula (I), or a salt or pharmaceutically acceptable solvate thereof.

The invention thus provides, in a further aspect, a combination comprising at least one compound of the formula (I), or pharmaceutically acceptable salts or solvates thereof, together with at least one other therapeutically active agent.

A pharmaceutical composition is further provided comprising a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, and optionally one or more pharmaceutically acceptable diluents or carriers.

A method is also provided for preparing a pharmaceutical composition comprising mixing a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, with one or more pharmaceutically acceptable diluents or carriers.

The compounds of the formula (I) and their salts and solvates can be prepared according to the methodology described herein, and constitutes an additional aspect of the present invention. twenty

Accordingly, a process is provided for the preparation of a compound of the formula (I), a process comprising deprotection of a compound of the formula (IIA):

wherein R1 and R2 are as defined hereinbefore for a compound of the formula (I) and R3 is C1-6 alkyl, and thereafter, if necessary, perform one or more of the following optional stages:

(i). converting a compound of formula (I) into another compound of formula (I);

(ii). Prepare a salt or solvate of the compound so formed.

In one aspect of the invention, a compound of the formula (IIA) can be prepared by reacting a compound of the formula (II):

wherein R1 is as defined hereinbefore for a compound of formula (I) and R3 is as defined hereinbefore for a compound of formula (IIA), with a compound of formula (IIB):

 5

wherein R2 is as defined hereinbefore for a compound of formula (I) and L is a suitable leaving group, for example an alkylsulfonyloxy group such as a methanesulfonyloxy group or a halogen atom, such as bromine .

In one aspect of the invention, a compound of the formula (II) is used in the form of a salt, for example the trifluoroacetate salt. This salt comes from the deprotection of a compound 10 of formula (III), for example, with trifluoroacetic acid, as described hereinafter.

Alternatively, a compound of formula (I) can be prepared by reacting a compound of formula (II) as defined hereinbefore, usually in the form of a salt, for example the trifluoroacetate salt, with a Compound of formula (IIB) as defined hereinbefore, without isolating the intermediate compound (IIA).

In one aspect of the invention, a compound of the formula (II) can be prepared by reacting a compound of formula (III):

 twenty

wherein R1 is as defined hereinbefore for a compound of formula (I), P is a protective group, usually a tetrahydro-2H-pyran-2-yl group, and R3 is as described above. defined hereinbefore for a compound of formula (IIA), with a suitable deprotection agent, for example trifluoroacetic acid (the use of trifluoroacetic acid involves the formation of a compound of the formula (II) in the form of a salt trifluoroacetate).

In one aspect of the invention, a compound of formula (IIB) in which L is an atom

Halogen can be prepared by reacting a compound of formula (IX):

wherein R2 is as defined hereinbefore for a compound of the formula (I) and OG is a leaving group, for example an alkanesulfonate group such as a methanesulfonate group, with an anhydrous alkali metal halide such 5 as anhydrous lithium bromide.

In one aspect of the invention, a compound of the formula (IX), or a compound of the formula (IIB) in which L is an alkylsulfonyl group, can be prepared by reacting a compound of the formula (X):

R2-OH (X) 10

wherein R2 is as defined hereinbefore for a compound of the formula (I), with a suitable activating agent, for example an alkylsufonyl halide such as methanesufonyl chloride.

In one aspect of the invention, a compound of the formula (X) can be prepared by reacting a compound of the formula (XI):

Het- (CH2) (n-1) -COO-C1-6 alkyl (XI)

wherein Het and n are as defined hereinbefore for a compound of formula (I) with a suitable reducing agent, such as lithium aluminum hydride.

In one aspect of the invention, a compound of the formula (X) in which Het is 3-20 tetrahydropyranyl and n is an integer having a value of 2 can be prepared by reacting the compound of the formula (XII):

wherein Het is 3-tetrahydropyranyl, with a suitable reducing agent, for example sodium borohydride. 25

In one aspect of the invention, a compound of the formula (XII) can be prepared by reacting a compound of the formula (XIII):

Het-CH = CH (O-C1-6 alkyl) (XIII)

wherein Het is 3-tetrahydropyranyl, with a suitable mineral acid, for example hydrochloric acid. 30

In one aspect of the invention, a compound of the formula (XIII) can be prepared by reacting the compound of formula (XIV):

wherein Het is 3-tetrahydropyranyl, with a compound of the formula (XV):

(C1-6 alkoxy) - (CH2) -P + (Ph) 3 Cl- (XV)

In one aspect of the invention, a compound of formula (XIV) can be prepared by hydrogenation of the compound of formula (XVI):

In one aspect of the invention, a compound of the formula (III) can be prepared by reacting a compound of the formula (IV):

wherein R1 is as defined hereinbefore for a compound of the formula (I), P is as defined hereinbefore for a compound of the formula (III), and X is a halogen atom, for example 10 bromine, with an alkali metal alkoxide, for example sodium methoxide.

In one aspect of the invention, a compound of the formula (IV) can be prepared by reacting a compound of the formula (V):

wherein R1 is as defined hereinbefore for a compound of the formula (I) and P is as defined hereinbefore for a compound of the formula (III), with a suitable halogenating agent, for example N-bromosuccinimide.

In one aspect of the invention, a compound of the formula (V), wherein R 1 is C 1-8 alkoxy, (C 3-7 cycloalkyl), C 1-6 alkoxy, (C 1-6 alkoxy) C 1-6 alkoxy, or Hetb C1-3alkoxy, 20 can be prepared by reacting a compound of the formula (VI):

wherein P is as defined hereinbefore for a compound of the formula (III) and Y is a halogen atom, for example chlorine, with a compound of the formula (VIA):

 5

wherein R1 is C1-8 alkoxy, (C3-7 cycloalkyl) C1-6 alkoxy, (C1-6 alkoxy) C1-6 alkoxy, or Hetb-C1-3 alkoxy, in the presence of a strong base of suitable potency, for example sodium metal, sodium hydride, or sodium tert-butoxide.

In one aspect of the invention, a compound of the formula (V), wherein R 1 is (C 1-8 alkyl) amino or (C 3-7 cycloalkyl) (C 1-6 alkyl) amino can be prepared by reacting a compound. of the formula (VI) as defined hereinbefore, with a compound of the formula (VIB):

wherein R1 is (C1-6 alkyl) amino or (C3-7 cycloalkyl) (C1-6 alkyl) amino.

In one aspect of the invention, a compound of the formula (VI) can be prepared by reacting a compound of the formula (VII):

wherein P is as defined hereinbefore for a compound of formula (III), Y is as defined hereinbefore for a compound of formula (VI), and Z is a halogen atom, for example 20 chlorine, with an alcoholic ammonia solution.

In one aspect of the invention, a compound of the formula (VII) can be prepared from a compound of the formula (VIII):

wherein Y is as defined hereinbefore for a compound of the formula (VI) and Z is as defined hereinbefore for a compound of the formula (VII), by reaction with a suitable protective reagent, for example 3,4-dihydro-2H-pyran. 5

In a further aspect of the invention, there is also provided a process for the preparation of a compound of the formula (I), a process comprising the hydrolysis of a compound of the formula (XXI):

wherein R1 and R2 are as defined hereinbefore for a compound of the formula (I) and X is as defined hereinbefore for a compound of the formula (IV).

In one aspect of the invention, a compound of the formula (XXI) can be prepared by halogenating a compound of the formula (XX):

 fifteen

wherein R1 and R2 are as defined hereinbefore for a compound of the formula (I).

In one aspect of the present invention, a compound of the formula (XX), wherein R 1 is C 1-8 alkoxy, (C 3-7 cycloalkyl) C 1-6 alkoxy, (C 1-6 alkoxy) C 1-6 alkoxy, or Hetb-C1-3 alkoxy can be prepared by reacting a compound of the formula (XIX):

wherein Y is as defined hereinbefore for a compound of the formula (VI) and R2 is as defined hereinbefore for a compound of the formula (I), with a compound of the formula (VIA) as defined hereinbefore. 5

In one aspect of the invention, a compound of the formula (XIX) can be prepared by reacting a compound of the formula (XVIII):

wherein Y is as defined hereinbefore for a compound of the formula (VI), Z is as defined hereinbefore for a compound of the formula (VII), and R2 it is as defined hereinbefore for a compound of the formula (I), with ammonia.

A compound of the formula (XIX) can also be prepared by reacting a compound of the formula (XVII):

 fifteen

wherein Y is as defined hereinbefore for a compound of the formula (VI), with a compound of the formula (IIB) as defined hereinbefore.

In one aspect of the invention, a compound of the formula (XVIII) can be prepared by reacting a compound of the formula (VIII) as defined hereinbefore with a compound of the formula R2-OH, in which R2 is as defined hereinbefore for a compound of the formula (I).

In one aspect of the invention, a compound of the formula (XVII) can be prepared

by reaction of a compound of the formula (VIII) as defined hereinbefore with ammonia.

In a further aspect of the invention, a compound of the formula (I), wherein R 1 is (C 1-8 alkyl) amino or (C 3-7 cycloalkyl) (C 1-6 alkyl) amino, can be prepared by reacting a compound of the formula (XXIII): 5

wherein Y is as defined hereinbefore for a compound of the formula (VI), R2 is as defined hereinbefore for a compound of the formula (I), and R3 is as defined hereinbefore for a compound of the formula (IIA), with a compound of the formula (VIB) as defined hereinbefore.

In one aspect of the invention, a compound of the formula (XXIII) can be prepared by reacting a compound of the formula (XXII):

wherein X is as defined hereinbefore for a compound of the formula (IV), Y is as defined hereinbefore for a compound of the formula (VI) and R2 is as defined hereinbefore for a compound of the formula (I), with an alkoxide anion source.

The present invention encompasses all combinations of embodiments and aspects that are described herein.

Detailed description of the invention

The present invention is described in terms known and appreciated by those skilled in the art. For ease of reference, certain terms are defined below. The fact that some terms are defined, however, should not be considered indicative that the defined terms are used inconsistently with the ordinary meaning nor, alternatively, that any undefined term is undefined or not used with

The usual and accepted meaning. Instead, it is believed that all terms used herein describe the invention such that a person of ordinary experience can appreciate the scope of the present invention. The following definitions are intended to clarify, but not limit, the terms that are defined.

References to "alkyl" include references to both straight chain and branched chain aliphatic isomers of the corresponding alkyl, which suitably contains up to eight carbon atoms, for example up to four carbon atoms or up to three carbon atoms. Such references to "alkyl" are also applicable when an alkyl group is part of another group, for example an alkylamino or alkoxy group. Examples of such alkyl groups and groups containing alkyl groups are C 1-4 alkyl, (C 1-6 alkyl) amino, C 1-8 alkoxy, (C 3-7 cycloalkyl) (C 1-6 alkyl) amino, (C 3-7 cycloalkyl) ) C1-6 alkoxy, and (C1-3 alkoxy) C2-3 alkoxy.

References to "heterocycle" or "heterocyclyl" refer to monocyclic saturated heterocyclic aliphatic rings containing 5 or 6 carbon atoms, and a heteroatom, which is an oxygen heteroatom. Examples of said heterocyclic rings are tetrahydrofuranyl and tetrahydropyranyl. fifteen

References to "cycloalkyl" refer to monocyclic alkyl groups containing between three and seven carbon atoms, for example three carbon atoms, or five carbon atoms, or six carbon atoms. Examples of such cycloalkyl groups are cyclopropyl, cyclopentyl and cyclohexyl.

References to "halogen" refer to iodine, bromine, chlorine or fluorine, usually bromine or chlorine.

It should be understood that the references below to compounds of the invention mean a compound of the formula (I) in the form of the free base, or in the form of a salt, or in the form of a solvate.

It will be appreciated from the foregoing that within the scope of the invention all solvates, hydrates, complexes, isomers and polymorphic forms of the compounds of the formula (I) and their salts and solvates are included.

Salts of the compounds of the formula (I) include pharmaceutically acceptable salts and salts that may not be pharmaceutically acceptable but may be useful in the preparation of compounds of the formula (I) and their pharmaceutically acceptable salts. The salts may be derived from certain inorganic or organic acids, or certain inorganic or organic bases.

The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of the formula (I).

Examples of salts that are pharmaceutically acceptable salts. Salts 35

Pharmaceutically acceptable include acid addition salts and base addition salts. For a review of suitable salts see Berge et al., J. Pharm. Sci., 66: 1-19 (1977).

Examples of pharmaceutically acceptable acid addition salts of a compound of the formula (I) include salts hydrobromide, hydrochloride, sulfate, p-toluenesulfonate, methanesulfonate, naphthalenesulfonate, and phenylsulfonate. 5

Examples of pharmaceutically acceptable base salts include alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium.

The salts can be formed using techniques well known in the art, for example by precipitation from solution followed by filtration, or by evaporation of the solvent.

Usually, a pharmaceutically acceptable acid addition salt may be formed by reacting a compound of the formula (I) with a suitable strong acid (such as hydrobromic, hydrochloric, sulfuric, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid), optionally in a suitable solvent such as an organic solvent, providing the salt that is usually isolated for example by crystallization and filtration.

It will be appreciated that many organic compounds may complex with solvents in which they are reacted or from which they precipitate or crystallize. These complexes are known as "solvates." For example, a complex with water is known as "hydrate." Solvents with high boiling points and / or solvents with a high propensity to form hydrogen bonds such as water, ethanol, isopropyl alcohol, and N-methyl pyrrolidinone can be used to form solvates. Solvates of the compounds of the formula (I) are within the scope of the invention. As used herein, the term "solvate" encompasses solvates of both a free base compound and any salt thereof.

Certain compounds of the invention may contain chiral atoms and / or multiple bonds, and therefore may exist in one or more stereoisomeric forms. The present invention encompasses all stereoisomers of the compounds of the invention, including geometric isomers and optical isomers, either in the form of individual stereoisomers 30 or in the form of mixtures thereof including racemic modifications. Any stereoisomer may contain less than 10% by weight, for example less than 5% by weight, or less than 0.5% by weight, of any other stereoisomer. For example, any optical isomer may contain less than 10% by weight, for example less than 5% by weight, or less than 0.5% by weight, of its opposite. 35

As used herein, the terms "Isomer 1" and "Isomer 2" and "Diastereoisomer 1" and "Diastereoisomer 2" refer to the first and second isomer or diastereoisomer in eluting respectively when separations are performed using the conditions Chromatographs specified in the relevant text. It will be appreciated that the elution order may change depending on the particular chromatographic conditions used.

Certain compounds of the invention may exist in tautomeric forms. It will be understood that the present invention encompasses all tautomers of the compounds of the invention either in the form of individual tautomers or mixtures thereof.

The compounds of the invention may be in crystalline or amorphous form. In addition, some of the crystalline forms of the compounds of the invention may exist in the form of polymorphs, all of which are included within the scope of the present invention. Of particular interest are the most thermodynamically stable form or forms of the compounds of the invention.

Examples of disease states in which the compounds of the formula (I) and the pharmaceutically acceptable salts or solvates thereof have potentially beneficial effects include infectious diseases, cancer, allergic diseases and other inflammatory conditions. The compounds of the formula (I) and the pharmaceutically acceptable salts or solvates thereof are also of potential use as vaccine adjuvants. twenty

The compounds of the formula (I) and the pharmaceutically acceptable salts or solvates thereof can therefore be useful in the treatment of various disorders, in particular in the treatment of infectious diseases that include, but are not limited to, those caused by hepatitis viruses (for example hepatitis B virus, hepatitis C virus), human immunodeficiency virus, papillomavirus, herpesvirus, respiratory viruses (for example influenza virus, syncytial virus, rhinovirus, metapneumovirus, parainfluenzavirus, SARS ), and West Nile virus. The compounds of the formula (I) and pharmaceutically acceptable salts or solvates thereof may also be useful in the treatment of microbial infections caused, for example, by bacteria, fungi or protozoa. These include, but are not limited to, tuberculosis, bacterial pneumonia, aspergillosis, histoplasmosis, candidiasis, pneumocytosis, leprosy, chlamydia, cryptococcal disease, cryptosporidosis, toxoplasmosis, leishmania, malaria, and trypanosomiasis.

As potent modulators of the immune response, the compounds of the formula (I) and the pharmaceutically acceptable salts or solvates thereof can therefore be useful in the treatment of inflammation, which includes but not limited to diseases.

inflammatory or allergic such as asthma, allergic rhinitis, pulmonary hypersensitivity diseases, eosinophilic pneumonitis, delayed type hypersensitivity, atherosclerosis, pancreatitis, gastritis, osteoarthritis, psoriasis, sarcoidosis, pulmonary fibrosis, dysneic syndrome, bronchiolitis, chronic obstructive pulmonary disease, sinusitis, cystic fibrosis and dermatitis.

The compounds of the formula (I) and pharmaceutically acceptable salts or solvates thereof 5 may also be useful in the treatment of autoimmune diseases that include but are not limited to rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, Sjögren's disease, spondylitis ankylosing, scleroderma, diabetes, graft rejection, which includes graft versus host disease, inflammatory bowel diseases that include, but are not limited to, 10 Crohn's disease and ulcerative colitis.

The compounds of the formula (I) and the pharmaceutically acceptable salts or solvates thereof may also be useful in the treatment of various cancers, in particular in the treatment of cancers known to respond to immunotherapy and include, but not limitation, renal cell carcinoma, lung cancer, breast cancer, colorectal cancer, bladder cancer, melanoma, leukemia, lymphomas and ovarian cancer.

Those skilled in the art will appreciate that references herein to treatment or therapy extend to prophylaxis as well as to the treatment of established conditions.

As mentioned herein, the compounds of the formula (I) and the pharmaceutically acceptable salts or solvates thereof may be useful as therapeutic agents.

As indicated, the present invention includes a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic agent. 25

A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, is therefore also provided for use in the treatment of infectious diseases, cancer, allergic diseases and other inflammatory conditions.

A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, is therefore also provided for use as a vaccine adjuvant. 30

A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, is also therefore provided for use in the treatment of allergic rhinitis.

A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, is also therefore provided for use in the treatment of asthma.

The use of a compound of the formula (I), or a salt or solvate is also provided.

pharmaceutically acceptable thereof, for the manufacture of a medicament for the treatment of infectious diseases, cancer, allergic diseases and other inflammatory conditions.

The present invention also includes a method for the treatment of infectious diseases, cancer, allergic diseases and other inflammatory conditions, a method comprising administering an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof. .

The use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, is also provided for the manufacture of a medicament for the treatment of allergic rhinitis. 10

The present invention also includes a method for the treatment of allergic rhinitis, a method comprising administering an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof.

 The use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of asthma is also provided.

The present invention also includes a process for the treatment of asthma, a method comprising administering an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof.

The compounds according to the invention, and their pharmaceutically acceptable salts and solvates, can be formulated for administration in any convenient form.

The compounds according to the invention, and their pharmaceutically acceptable salts and solvates, for example, can be formulated for oral, topical, inhaled, intranasal, buccal, parenteral (eg intravenous, subcutaneous, intradermal, or intramuscular) or rectal administration. In one aspect, the compounds of the formula (I), and their pharmaceutically acceptable salts and solvates, are formulated for oral administration. In a further aspect, the compounds of the formula (I), and their pharmaceutically acceptable salts and solvates, are formulated for topical administration, for example intranasal administration.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, gum arabic, gelatin, sorbitol, tragacanth, starch mucilage, cellulose or polyvinylpyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, corn starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycolate; or wetting agents such as sodium lauryl sulfate. The tablets may be 35

coated according to procedures well known in the art.

The oral liquid preparations may be in the form, for example, of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they may be presented in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan monooleate or gum arabic; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or 10 preservatives, for example, methyl or propyl p-hydroxybenzoates or sorbic acid. The preparations may also contain buffer salts, flavoring agents, colorants and / or sweeteners (eg, mannitol) as appropriate.

Formulations for intranasal administration include aqueous formulations that are administered to the nose by drops or by a pressurized pump. Suitable formulations contain water as diluent or vehicle for this purpose. Aqueous formulations for administration to the lung or nose can be provided with conventional excipients such as buffering agents, tonicity modifying agents and the like. Aqueous formulations can also be administered to the nose or to other regions of the airways by nebulization. twenty

Formulations for inhaled administration include aqueous, organic or aqueous / organic mixtures, dry or crystalline powder formulations administered to the respiratory tract by a pressurized pump or inhaler. Suitable formulations contain water as a diluent or vehicle for this purpose and can be provided with conventional excipients such as buffering agents, tonicity modifying agents and the like. Aqueous formulations can also be administered to the nose and other regions of the airways by nebulization. Such formulations may be aqueous solutions or suspensions or aerosols administered from pressurized containers, such as a metered dose inhaler, using a suitable propellant. Aerosol compositions suitable for inhalation may be a suspension or a solution and may contain a compound of the formula (I) or a salt or solvate thereof and a suitable propellant such as a fluorocarbon or chlorofluorocarbon containing hydrogen or mixtures thereof. , in particular hydrofluoroalkanes, especially 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. The aerosol composition may optionally contain additional formulation excipients well known in the

techniques such as surfactants for example oleic acid, lecithin or an oligolactic acid or derivative thereof for example as described in WO 94/21229 and WO 98/34596 (Minnesota Mining and Manufacturing Company) and co-solvents for example ethanol.

Ointments, creams and gels, for example, can be formulated with an aqueous or oily base by adding thickening and / or gelling agents and / or solvents. Such bases in that way, for example, may include water and / or an oil such as liquid paraffin or a vegetable oil such as peanut oil or castor oil, or a solvent such as polyethylene glycol. Thickening and gelling agents that can be used according to the nature of the base include soft paraffin, aluminum stearate, ketostearyl alcohol, polyethylene glycols, wool fat, beeswax, carboxypolymethylene and cellulose derivatives and / or glyceryl monostearate and / or non-ionic emulsifying agents.

Lotions may be formulated with an aqueous or oily base and will generally also contain one or more emulsifying agents, stabilizing agents, emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.

Powders for external application can be formed with the aid of any powdered base, for example, talc, lactose or starch. The drops may be formulated with an aqueous or non-aqueous base which also comprises one or more dispersing agents, solubilizing agents, suspending agents or preservatives.

The compounds according to the invention and the pharmaceutically acceptable salts or solvates thereof can be formulated, for example, for transdermal administration by patching or other devices (for example gas pressure devices) that administer the active component to the skin.

For oral administration, the compositions may be in the form of tablets or tablets formulated in a conventional manner.

The compounds and pharmaceutically acceptable salts or solvates thereof can also be formulated in the form of suppositories, for example with conventional suppository bases such as cocoa butter or other glycerides.

The compounds according to the invention or the pharmaceutically acceptable salts or solvates thereof can also be formulated for parenteral administration by embolate injection or continuous infusion and can be presented in single-dose form, for example in the form of ampoules, vials, infusions of little volume or syringes previously loaded or in multi-dose containers with an added preservative. The compositions may take forms such as solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles, and may contain formulating agents such as antioxidants, buffers, antimicrobial agents and / or tonicity adjusting agents. Of 35

Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, for example sterile pyrogen free water, before use. The dry solid presentation can be prepared by loading a sterile powder aseptically into individual sterile containers or by loading a sterile solution sterically into each container and lyophilizing.

The compounds according to the invention or pharmaceutically acceptable salts or solvates thereof can also be formulated with vaccines as adjuvants to modulate their activity. Such formulations may contain antibody (s) or antibody fragment (s) or an antigenic component that includes but is not limited to live or attenuated protein, DNA, bacteria and / or viruses or thyroid particles, together with one or more components with adjuvant activity that includes but not limited to aluminum salts, emulsions of oil and water, heat shock proteins, lipid A preparations and derivatives, glycolipids, other TLR agonists such as CpG DNA or similar agents, cytokines such as GM- CSF or IL-12 or similar agents.

The compounds of the present invention or the pharmaceutically acceptable salts or solvates thereof can be used alone or in combination with other therapeutic agents. The compound (s) of the present invention or the pharmaceutically acceptable salts or solvates thereof and the other pharmaceutically active agent (s) can be administered together or separately and, when administered by separately, administration can occur simultaneously or sequentially in any order. The amounts of the compound (s) of the present invention and the pharmaceutically acceptable salts or solvates thereof and the other pharmaceutically active agent (s) and the relative administration times will be selected. so that the desired combined therapeutic effect can be achieved. The combined administration of a compound of the present invention and the pharmaceutically acceptable salts or solvates thereof with other treatment agents can be combined by concomitant administration in a unit pharmaceutical composition that includes both compounds, or in separate pharmaceutical compositions that includes each One of the compounds. Alternatively, the combination can be administered sequentially in which one treatment agent is administered first and the other second or vice versa. Said sequential administration may be close in time or remote in time. 30

The present invention can be used in combination with one or more agents useful in the prevention or treatment of viral infections. Examples of such agents include: polymerase inhibitors such as those described in WO 2004/037818-A1, as well as those described in WO 2004/037818 and WO 2006/045613; JTK-003, JTK-019, NM-283, HCV-796, R-803, R1728, R1626, as well as those that

are described in WO 2006/018725, WO 2004/074270, WO 2003/095441, US2005 / 0176701, WO 2006/020082, WO 2005/080388, WO 2004/064925, WO 2004/065367, WO 2003/007945, WO 02/04425, WO 2005/014543, WO 2003/000254, EP 1065213, WO 01/47883, WO 2002/057287, WO 2002/057245 and similar agents; replication inhibitors such as acyclovir, famciclovir, ganciclovir, cidofovir, lamivudine and similar agents; protease inhibitors such as HIV protease inhibitors saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, atazanavir, tipranavir, palinavir, lasinavir, and HCV protease inhibitors BILN2061, VX-950, SCH503034; and similar agents; nucleoside and nucleotide reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavidin, adefovir, adefovir 10 dipivoxil, fozivudine, todoxyl, emtricitabine, alovudine, amdoxovir, elvucitabine, and similar agents; non-nucleoside reverse transcriptase inhibitors (which include an agent that has antioxidant activity such as immunocal, oltipraz, etc.) such as nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, TMC-278, TMC-125, etravirine, and similar agents; entry inhibitors such as enfuvirtide (T-20), T-1249, PRO-542, 15 PRO-140, TNX-355, BMS-806, 5-Helix and similar agents; integrase inhibitors such as L-870,180 and similar agents; germination inhibitors such as PA-344 and PA-457, and similar agents; Chemokine receptor inhibitors such as vicriviroc (Sch-C), Sch-D, TAK779, Maraviroc (UK-427,857), TAK449, as well as those described in WO 02/74769, WO 2004/054974, WO 2004/055012, WO 2004/055010, WO 20 2004/055016, WO 2004/055011, and WO 2004/054581, and similar agents; neuraminidase inhibitors such as zanamivir, oseltamivir, peramivir and similar agents; ion channel blockers such as amantadine or rimantadine and similar agents; and interfering and non-coding RNA oligonucleotides such as ISIS-14803 and similar agents; antiviral agents of undetermined mechanism of action, for example those described in WO 2005/105761, WO 2003/085375, and WO 2006/122011, and similar agents. The present invention can also be used in combination with another or other agents that may be useful in the prevention or treatment of viral infections for example immunotherapies (for example with interferon or other cytokines / chemokines, cytokine / chemokine receptor modulators, agonists or 30 cytokine antagonists and similar agents); and therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs and similar agents.

The scope of the combinations of compounds of the present invention and the pharmaceutically acceptable salts or solvates thereof with antiviral agents is not limited to those mentioned above, but in principle includes any combination with any

Pharmaceutical composition useful for the treatment of viral disease. As indicated, in said combinations the compounds of the present invention and the pharmaceutically acceptable salts or solvates thereof and other antiviral agents can be administered separately or together. In addition, an agent may be prior, concurrent or subsequent to the administration of the other agent (s). 5

The compounds of the present invention and the pharmaceutically acceptable salts or solvates thereof can be used in combination with another or other agents that may be useful in the prevention or treatment of allergic disease, inflammatory disease, autoimmune disease or the like, for example; immunotherapy with antigens, antihistamines, steroids, non-steroidal anti-inflammatory agents, bronchodilators (for example 10 beta 2 agonists, adrenergic agonists, anticholinergic agents, theophylline), methotrexate, leukotriene modulators and similar agents; treatment with monoclonal antibodies such as anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents; receptor therapies for example entanercept and similar agents; non-specific immunotherapies with antigens (for example with interferon or other cytokines / chemokines, cytokine / chemokine receptor modulators, cytokine agonists or antagonists, TLR agonists and similar agents).

The compounds of the present invention and pharmaceutically acceptable salts or solvates thereof may be used in combination with another or other agents that may be useful in the prevention or treatment of cancer, for example chemotherapeutic agents such as alkylating agents, inhibitors of topoisomerases, antimetabolites, antimitotic agents, kinase inhibitors and similar agents; treatment with monoclonal antibodies such as trastuzumab, gemtuzumab and other similar agents; immunotherapies (for example with interferon or other cytokines / chemokines, cytokine / chemokine receptor modulators, cytokine agonists or antagonists, TLR agonists and similar agents) and hormonal therapy such as tamoxifen, goserelin and similar agents.

The pharmaceutical compositions according to the invention can also be used alone or in combination with at least one other therapeutic agent from other therapeutic areas, for example gastrointestinal disease. The compositions according to the invention can also be used in combination with gene replacement therapy. 30

The invention includes a combination comprising at least one compound of the formula (I), or (a) pharmaceutically acceptable salt (s) or solvate (s) thereof, together with at least one other therapeutically active agent.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus, the formulations.

Pharmaceuticals comprising a combination as defined above together with at least one pharmaceutically acceptable diluent or carrier thereof represent a further aspect of the invention.

A therapeutically effective amount of a compound of the present invention or pharmaceutically acceptable salts or solvates thereof will depend on a number of 5 factors. For example, the species, age and weight of the recipient, the precise condition that requires treatment and its severity, the nature of the formulation, and the route of administration are all factors to consider. The therapeutically effective amount should finally be according to the judgment of the attending physician. Regardless, an effective amount of a compound of the present invention for the treatment of humans suffering from a medical condition should generally be in the range of 0.01 to 100 mg / kg of body weight of the recipient (mammal) per day. More usually the effective amount should be in the range of 0.1 to 10 mg / kg of body weight per day. Thus, for an adult mammal of 70 kg an example of a real amount per day would usually be 7 to 700 mg. This amount can be administered in a single dose per day or in a number (such as two, three, four, five or 15 more) of sub-doses per day so that the total daily dose is the same. An effective amount of a pharmaceutically acceptable salt or solvate of a compound of the formula (I) can be determined as a proportion of the effective amount of the compound of the present invention per se. Similar doses should be appropriate for the treatment of the other conditions referred to herein. twenty

The compounds of the formula (I) and the pharmaceutically acceptable salts or solvates thereof can also be administered with any appropriate frequency for example 1-7 times a week week. The precise dosage will, of course, depend on factors such as the therapeutic indication, the age and condition of the patient and the particular route of administration chosen. 25

Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Said unit may contain, as a non-limiting example, 0.5 mg to 1 g of a compound of the formula (I) or pharmaceutically acceptable salts or solvates thereof, depending on the condition being treated, the route of administration, and the age, weight and condition of the patient. The preferred single dose formulations are those containing a daily dose or sub-dose, as cited herein, or an appropriate fraction thereof, of an active ingredient. Such pharmaceutical formulations can be prepared by any of the procedures well known in the pharmaceutical art.

In this way a pharmaceutical composition is also provided comprising a

compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, and optionally one or more pharmaceutically acceptable diluents or carriers.

A process for preparing said pharmaceutical composition is also provided comprising mixing a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, with one or more pharmaceutically acceptable diluents or carriers.

Throughout the following description and claims, unless the context dictates otherwise, the word "understand", and its variations such as "comprises" and "comprising", will be understood to imply the inclusion of a mentioned integer or stage or group of integers but not excluding any other integer or stage or group of integers or stages.

The compounds of the formula (I) and their salts and solvates can be prepared according to the methodology described below, which constitutes a further aspect of the present invention.

Accordingly, a process is provided for the preparation of a compound of the formula (I), a process comprising deprotection of a compound of the formula (IIA):

wherein R1 and R2 are as defined hereinbefore for a compound of the formula (I) and R3 is C1-6 alkyl, and thereafter, if necessary, carrying out one or more of The following optional stages:

(i). converting a compound of the formula (I) into another compound of the formula (I);

(ii). Prepare a salt or solvate of the compound so formed.

For example, a compound of the formula (IIA) is dissolved in a suitable solvent, for example methanol, and treated with a solution of a suitable mineral acid in a suitable solvent, for example 4 N hydrogen chloride in 1.4 -dioxane. The reaction is stirred at a suitable temperature, for example room temperature, for a suitable period of time, for example 4-18 hours, and the solvent is removed under reduced pressure to provide a material which is then suspended in water. A sufficient amount of a suitable alcohol can be added, for example methanol, can until a solution is obtained. A suitable aqueous base is added, for example 2 N sodium hydroxide solution,

to bring the mixture to pH 7, and the solution can be concentrated until a suspension is formed. The solid is then filtered and washed with water before drying to provide a compound of the formula (I). Alternatively, the reaction mixture can be neutralized without first removing the solvent, and the resulting product was recovered by filtration before or after removing a proportion of the solvent. 5

 A compound of the formula (IIA) can be prepared by reacting a compound of the formula (II):

wherein R1 is as defined hereinbefore for a compound of the formula (I) and R3 is as defined hereinbefore for a compound of the formula (IIA), with a compound of formula (IIB):

R2-L (IIB)

wherein R2 is as defined hereinbefore for a compound of the formula (I) and L is a suitable leaving group, for example an alkylsulfonyloxy group such as a methanesulfonyloxy group or a halogen atom, such as bromine. fifteen

For example, the trifluoroacetate salt of a compound of the formula (II) is heated at a suitable temperature, for example 60 ° C, for a suitable period of time, for example 1 hour, with anhydrous potassium carbonate in a suitable dry solvent, for Dry DMF example, and allowed to cool to room temperature before adding a compound of the formula (IIB). The reaction may be stirred at room temperature for a suitable period of time, for example 20-40 hours, and may be heated if necessary for a suitable period of time, for example 1-2 hours, at a suitable temperature, for example up to 90 ° C. The reaction mixture is poured into water and extracted into a suitable solvent, for example ethyl acetate. The solvent extracts are dried, evaporated to dryness under reduced pressure, and purified. It will be appreciated that the reaction times and reaction temperatures necessary to carry out the reaction of a compound of the formula (II) with a compound of the formula (IIB) providing a compound of the formula (IIA) will vary depending on the precise nature of the individual reagents that are used, for example the reaction times and reaction temperatures should be chosen to ensure that a compound of the formula (IIA) is obtained, but that N-alkylation is minimized or avoided at 30 position 7.

A compound of the formula (II) can be used in the form of a salt, for example the salt

trifluoroacetate. This salt is produced from the deprotection of a compound of the formula (III), for example, with trifluoroacetic acid, as described hereinbelow.

Alternatively, a compound of the formula (I) can be prepared by reacting a compound of the formula (II) as defined hereinbefore, usually in the form of a salt, for example the trifluoroacetate salt, with a compound of the formula (IIB) as defined hereinbefore, without isolating the intermediate compound (IIA).

For example, to the trifluoroacetate salt of a compound of the formula (II) in a suitable solvent, for example dry N, N-dimethyl formamide (DMF), a suitable base is added, for example anhydrous potassium carbonate. The mixture is heated to a suitable temperature, for example 60 ° C, for a suitable period of time, for example 1 hour, and cooled to room temperature. A compound of the formula (IIB) is then added and the reaction mixture is heated to a suitable temperature, for example 50 ° C, for a suitable period of time, for example 12-18 hours. The reaction is quenched with water and extracted with a suitable solvent, for example ethyl acetate. The organic phase is separated and dried. The evaporation of the organic phase and the purification of the oil thus formed provides a product that is then dissolved in a suitable solvent, for example methanol, treated with a solution of a suitable mineral acid in a suitable solvent, for example hydrogen chloride 4 N in 1,4-dioxane, and stir overnight at room temperature. The reaction mixture is evaporated to dryness under reduced pressure to provide a compound of the formula (I), which can be purified. It will be appreciated that the reaction times and reaction temperatures necessary to achieve the reaction of a trifluoroacetate salt of a compound of the formula (II) with a compound of the formula (IIB) providing a compound of the formula (IIA) will vary depending of the precise nature of the individual reagents that are used, for example reaction times and reaction temperatures should be chosen to ensure that a compound of the formula (IIA) is obtained, but that N-alkylation is minimized or avoided to position 7.

A compound of the formula (II) can be prepared by reacting a compound of formula (III):

wherein R1 is as defined hereinbefore for a compound of the formula (I), P is a protective group, usually a tetrahydro-2H-pyran-2-yl group, and R3 is as it is defined hereinbefore for a compound of the formula (IIA), with a suitable deprotection agent, for example trifluoroacetic acid (the use of trifluoroacetic acid causes the formation of a compound of the formula (II) in the form of a trifluoroacetate salt).

For example, to a solution of a compound of the formula (III) in a suitable solvent, for example dry methanol, a suitable deprotection agent, for example trifluoroacetic acid, is added. The mixture is stirred at a suitable temperature, for example room temperature, for 24-48 hours. The reaction mixture is concentrated to a suspension before diluting with a suitable solvent, for example ethyl acetate. The suspension is filtered and washed with a small volume of solvent, for example ethyl acetate, until the filtrate is colorless. The remaining solid is dried with air and then under vacuum providing, in the case where trifluoroacetic acid is used as the deprotection agent, the trifluoroacetate salt of a compound of the formula (II). The filtrate obtained above can be concentrated to provide a thick suspension which is then diluted with a small volume of solvent, for example ethyl acetate, and then filtered and dried to provide a second crop of the trifluoroacetate salt of a compound of formula (II ).

Alternatively, the reaction mixture can be concentrated under reduced pressure to provide a solid, which can then be crushed in the presence of a suitable solvent, for example diethyl ether.

A compound of the formula (IIB) in which L is a halogen atom can be prepared by reacting a compound of the formula (IX):

R2-OG (IX) 25

wherein R2 is as defined hereinbefore for a compound of the formula (I) and OG is a leaving group, for example an alkanesulfonate group such as a methanesulfonate group, with an anhydrous alkali metal halide such as anhydrous lithium bromide.

For example, a compound of the formula (IX) and a suitable halogenating agent, for example anhydrous lithium bromide, in a suitable solvent, for example, acetone, are refluxed by stirring for a suitable period of time, for example Three hours. After allowing the solvent to cool, it is removed under reduced pressure, the residue is treated with water, and extracted with a suitable solvent, for example dichloromethane. The combined solvent extracts are washed, dried and the solvent is removed under reduced pressure.

providing a compound of the formula (IIB).

A compound of the formula (IX), or a compound of the formula (IIB) in which L is an alkylsulfonyl group, can be prepared by reacting a compound of formula (X):

R2-OH (X)

wherein R2 is as defined hereinbefore for a compound of the formula (I), with a suitable activating agent, for example an alkylsufonyl halide such as methanesufonyl chloride.

For example, to an ice-cold stirring solution of a compound of the formula (X) and a suitable base, for example triethylamine, in a suitable dry solvent, for example dry dichloromethane, an activating agent is added dropwise suitable, for example methane sulfonyl chloride. The mixture is allowed to slowly warm to room temperature for a suitable period of time, for example 16 hours, then washed with saturated sodium hydrogen carbonate. The aqueous phase is extracted again with a suitable organic solvent, for example dichloromethane, and the organic extracts are washed, dried and the solvent is removed under reduced pressure to provide a compound of the formula (IX). fifteen

A compound of the formula (X) can be prepared by reacting a compound of the formula (XI):

Het- (CH2) (n-1) -COO (C1-6 alkyl) (XI)

wherein Het and n are as defined hereinbefore for a compound of the formula (I) with a suitable reducing agent, such as lithium hydride and aluminum.

For example, a stirring solution of a compound of the formula (XI) in a suitable dry solvent, for example dry tetrahydrofuran, is cooled, for example using an ice bath, and a solution of lithium aluminum hydride is added in a suitable solvent, for example dry tetrahydrofuran, dropwise in a suitable atmosphere, for example a nitrogen atmosphere, at a suitable temperature, for example less than 15 ° C. The reaction is allowed to warm to room temperature and, after a suitable period of time, for example 3 hours, it is cooled again using, for example, an ice bath, and a suitable base is added, for example 5 N sodium hydroxide while maintaining a suitable temperature, for example less than 10 ° C. A suitable organic solvent is then added, for example diethyl ether, and the resulting solid is filtered and washed with more organic solvent, for example diethyl ether. The combined filtrates are then evaporated to provide a compound of the formula (X).

A compound of the formula (X) in which Het is 3-tetrahydropyranyl and n is an integer having a value of 2 can be prepared by reacting the compound of the compound.

formula (XII):

Het- (CH2) -CHO (XII)

wherein Het is 3-tetrahydropyranyl, with a suitable reducing agent, for example sodium borohydride.

For example, a suspension of a suitable reducing agent, for example sodium borohydride, in a suitable solvent, for example ethanol, is cooled, for example using an ice bath, and a solution of the compound of the formula (XII) is added in a suitable solvent, for example ethanol dropwise by stirring for a suitable period of time, for example 10 minutes. After a suitable period of time, for example 15 minutes, the ice bath is removed and after an additional period of time, for example 3 hours, the mixture is heated to a suitable temperature, for example 50 ° C for a period of adequate time, for example 1 hour. After cooling, the solvent is evaporated and the residue is treated with water and extracted with a suitable organic solvent, for example dichloromethane. The combined extracts were washed, dried and evaporated to provide the compound of the formula (X) in which Het is 3-tetrahydropyranyl and n is an integer that has a value of 2.

The compound of the formula (XII) can be prepared by reacting a compound of the formula (XIII):

Het-CH = CH (O-C1-6 alkyl) º (XIII)

wherein Het is 3-tetrahydropyranyl, with a suitable mineral acid, for example hydrochloric acid.

For example, to a stirring solution of a compound of the formula (XIII) in a suitable solvent, for example tetrahydrofuran, a suitable mineral acid is added, for example 2 N hydrochloric acid. After a suitable period of time, for example 1 hour, the mixture is diluted with water and extracted with a suitable organic solvent, for example ether. The organic extract is then washed, dried and evaporated to provide the compound of the formula (XII).

A compound of the formula (XIII) can be prepared by reacting the compound of the formula (XIV):

Het-CHO (XIV) 30

wherein Het is 3-tetrahydropyranyl, with a compound of the formula (XV):

C1-6 alkoxy- (CH2) -P + (Ph) 3 Cl- (XV)

For example, a suspension of a compound of the formula (XV) in a suitable dry solvent, for example dry tetrahydrofuran, is cooled to a suitable temperature, for example less than 40 ° C using, for example, a cooling bath containing a mixture of 35

carbonic ice and acetone, and a solution of a suitable strong base, for example potassium tert-butoxide in a suitable dry solvent, for example dry tetrahydrofuran, is added dropwise by stirring under a suitable atmosphere, for example a nitrogen atmosphere. After a suitable period of time, for example, 45 minutes, the mixture is further cooled to less than 65 ° C using, for example, a cooling bath containing a mixture of carbonic ice and acetone, and a solution of the compound of Formula (XIV) in a suitable dry solvent, for example dry tetrahydrofuran dropwise. The cooling bath is removed and the reaction mixture is allowed to warm to room temperature. The reaction mixture is then stirred for an additional period of time, for example 30 minutes, and then quenched by pouring on ice. The mixture is then extracted with a suitable solvent, for example ether, and the combined extracts are washed, dried and evaporated to provide a crude compound of the formula (XIII), which can be purified by, for example, chromatography. .

The compound of the formula (XIV) can be prepared by hydrogenation of the compound of the formula (XVI):

For example, the compound of the formula (XVI) in a suitable solvent, for example ethanol, is treated with 10% palladium on carbon catalyst in a suitable atmosphere, for example a nitrogen atmosphere, then hydrogenated at temperature and pressure environments for a suitable period of time, for example 30 minutes. The catalyst is removed by filtration and the filtrate is evaporated to provide the compound of the formula (XIV).

The compound of the formula (XVI) can be prepared from acrolein.

For example, concentrated hydrochloric acid is added to water followed by acrolein and a suitable solvent, for example toluene. The stirring mixture is heated at reflux at 75 ° C for a suitable period of time, for example 1 hour when the reflux is gradually moderated. After allowing to cool, a suitable base, for example potassium carbonate, is added until the mixture is basified and the mixture is extracted with a suitable organic solvent, for example diethyl ether. The organic extracts are washed with brine, dried and evaporated to provide a crude product. The compound of the formula (XVI) is obtained from the crude mixture by distillation.

A compound of the formula (III) can be prepared by reacting a compound of the formula (IV):

wherein R1 is as defined hereinbefore for a compound of the formula (I), P is as defined hereinbefore for a compound of the formula (III), and X is a halogen atom, for example bromine, with an alkali metal alkoxide, for example sodium methoxide. 5

For example, a compound of the formula (IV) is heated to a suitable temperature, for example at reflux temperature just below the reflux temperature, with an alcohol solution of an alkali metal alkoxide, for example 25% of sodium methoxide in methanol, in a suitable solvent, for example methanol, for a suitable period of time, for example 2-8 hours. The reaction mixture is concentrated under reduced pressure and fractionated between suitable aqueous and non-aqueous phases, for example ethyl acetate and saturated ammonium chloride solution. The organic phase is separated and the aqueous phase is repeatedly extracted in ethyl acetate. The combined organic phases are washed, dried and then subjected to reduced pressure to provide a compound of the formula (III).

A compound of the formula (IV) can be prepared by reacting a compound 15 of the formula (V):

wherein R1 is as defined hereinbefore for a compound of the formula (I) and P is as defined hereinbefore for a compound of the formula (III), with an agent of suitable halogenation, for example N-bromosuccinimide.

For example, a compound of the formula (V) is dissolved in a suitable solvent, for example chloroform, and cooled to a suitable temperature, for example 0 ° C. To this solution is added N-bromosuccinimide in portions, while maintaining a suitable temperature, for example less than 3 ° C. The resulting mixture is stirred at a suitable temperature, for example 2-3 ° C, for a suitable period of time, for example 30 minutes, before being allowed to warm to room temperature and then stirred

for an additional period of time, for example 6 hours. The reaction mixture is then washed with water. The organic phase is dried / separated using hydrophobic porous glass and evaporated to provide a crude compound of the formula (IV), which can be purified.

A compound of the formula (V), wherein R 1 is C 1-8 alkoxy, (C 3-7 cycloalkyl) C 1-6 alkoxy, (C 1-6 alkoxy) C 1-6 alkoxy, or Hetb-C 1-3 alkoxy, may be prepared by reacting a compound of the formula (VI):

wherein P is as defined hereinbefore for a compound of the formula (III) and Y is a halogen atom, for example chlorine, with a compound of the formula (VIA):

R1-H (VIA)

wherein R1 is C1-8 alkoxy, (C3-7 cycloalkyl) C1-6 alkoxy, (C1-6 alkoxy) C1-6 alkoxy, or Hetb-C1-3 alkoxy, in the presence of a strong base of suitable potency, for example sodium metal, sodium hydride, or sodium tert-butoxide.

For example, a strong base, for example sodium tert-butoxide, is added in 15 portions to a compound of the formula (VIA), for example butan-1-ol. The mixture is stirred until it becomes homogeneous before adding a compound of the formula (VI) to the solution. The reaction mixture is then heated to a suitable temperature, for example 100 ° C, for a suitable period of time, for example 12-18 hours. The reaction mixture is subjected to reduced pressure by removing as much of a compound of the formula (VIA) 20 as possible before fractionating between a suitable organic solvent, for example diethyl ether and water. The organic phase is separated and the aqueous phase can be reextracted with more organic solvent. The combined organic phases are dried over a suitable drying agent, for example anhydrous magnesium sulfate. The drying agent is removed by filtration and the filtrate is evaporated under reduced pressure to provide a compound of the formula (V) in which R1 is C1-6 alkoxy, which can then be reacted, for example, by azeotroping with toluene and subjected under reduced pressure.

A compound of the formula (V), wherein R 1 is (C 1-8 alkyl) amino or (C 3-7 cycloalkyl) amino (C 1-6 alkyl) amino can be prepared by reacting a compound of the formula (VI) such as defined hereinbefore, with a compound of the formula 30 (VIB):

R1-H (VIB)

wherein R 1 is (C 1-6 alkyl) amino or (C 3-7 cycloalkyl) C 1-6 amino.

For example, a solution of a compound of the formula (VI) in a suitable dry solvent, for example dry ethylene glycol, at a suitable temperature, for example room temperature, and in a suitable atmosphere, for example a nitrogen atmosphere, is add a compound of the formula (VIB). The reaction is heated to a suitable temperature, for example 120 ° C, for a suitable period of time, for example 12-18 hours. The reaction is cooled to room temperature, diluted with a suitable solvent, for example ethyl acetate, and washed with water. The organic phase is dried over a suitable drying agent, for example anhydrous magnesium sulfate, filtered and concentrated in vacuo to provide a compound of the formula (V) in which R 1 is (C 1-6 alkyl) amino.

A compound of the formula (VI) can be prepared by reacting a compound of the formula (VII):

wherein P is as defined hereinbefore for a compound of the formula (III), Y is as defined hereinbefore for a compound of the formula (VI), and Z it is a halogen atom, for example chlorine, with an alcoholic ammonia solution.

For example, a compound of the formula (VII) is heated with 2M solution of ammonia in a suitable alcohol, for example, isopropyl alcohol, at a suitable temperature, for example 50 ° C, for a suitable period of time, for example 5 hours. After standing at room temperature for a suitable period of time, for example 12-18 hours, an additional amount of the alcoholic ammonia is added to dissociate the resulting cake and the reaction mixture is heated for a suitable additional period of time, for example 9 hours, until the reaction is complete. Water is added to the reaction mixture and the solid product is filtered off. The solid is then washed, for example with a mixture of isopropyl alcohol and water, and then air dried with suction providing a first crop. The filtrate can be filtered again after standing for 12-18 hours providing a second crop and then the crops are dried under vacuum.

A compound of the formula (VII) can be prepared from a compound of the formula (VIII):

wherein Y is as defined hereinbefore for a compound of the formula (VI) and Z is as defined hereinbefore for a compound of the formula (VII), by reaction with a suitable protective reagent, for example 3,4-dihydro-2H-pyran. 5

For example, a suitable solvent is added to a compound of the formula (VIII), for example ethyl acetate, followed by p-toluenesulfonic acid. The mixture is heated to a suitable temperature, for example 50 ° C, and then 3,4-dihydro-2H-pyran is added. The reaction mixture is then heated to a suitable temperature, for example 50 ° C, for a suitable period of time, for example 4 hours. The reaction mixture is then evaporated in vacuo to provide a compound of the formula (VII).

The present invention includes a process for the preparation of a compound of the formula (I), a process comprising the hydrolysis of a compound of the formula (XXI):

 fifteen

wherein R1 and R2 are as defined hereinbefore for a compound of the formula (I) and X is as defined hereinbefore for a compound of the formula (IV).

For example, to a solution of a compound of the formula (XXI) in a suitable solvent, for example dry n-butanol, a suitable concentrated mineral acid is added, for example concentrated hydrochloric acid at a suitable temperature, for example room temperature . The reaction is then heated to a suitable temperature, for example 80-120 ° C for a suitable period of time, for example 0.5-8 hours. Then the volume of the reaction mixture is reduced, for example by concentration in vacuo, water is added and the mixture is neutralized by the addition of a suitable aqueous base, for example sodium hydroxide solution. The product is then isolated and purified by conventional means, for example the product can be isolated by filtration and purified

by chromatography

A compound of the formula (XXI) can be prepared by halogenation of a compound of the formula (XX):

wherein R1 and R2 are as defined hereinbefore for a compound of the formula (I).

When R 1 is (C 1-8 alkyl) amino or (C 3-7 cycloalkyl) (C 1-6 alkyl) amino, the halogenation of a compound of the formula (XX) can be carried out, for example, as follows:

To a solution of a compound of the formula (XX) in a suitable dry solvent, for example dry chloroform, at a suitable temperature, for example room temperature 10 N-bromosuccinimide is added. The reaction mixture is stirred at a suitable temperature, for example room temperature, for a suitable period of time, for example one hour. The reaction mixture is then diluted with a suitable solvent, for example dichloromethane, and washed with water. The organic phase is then dried, for example by passing through a hydrophobic frit, and concentrated. fifteen

When R 1 is C 1-8 alkoxy, (C 3-7 cycloalkyl) C 1-6 alkoxy, (C 1-3 alkoxy) C 2-3 alkoxy, or Hetb-C 1-3 alkoxy, the halogenation of a compound of the formula (XX) can undertake, for example, as follows:

A compound of the formula (XX) is dissolved in glacial acetic acid before adding sodium acetate. The mixture is then cooled to a suitable temperature, for example in an ice bath, and bromine is gradually added. The reaction mixture is heated to a suitable temperature, for example room temperature, before heating to a suitable temperature, for example in a heating device set at a temperature of 60-80 ° C for a suitable period of time, for example 3- 6 hours. The reaction mixture is quenched with sodium thiosulfate solution and then the pH is adjusted to 6-7 by the addition of a suitable base, for example aqueous sodium hydroxide solution. The mixture is then extracted in a suitable organic solvent, for example ethyl acetate, the organic phase is separated, dried and the solvent is removed.

A compound of the formula (XX), wherein R 1 is C 1-8 alkoxy, (C 3-7 cycloalkyl) C 1-6 alkoxy, (C 1-6 alkoxy) C 1-6 alkoxy, or Hetb-C 1-3 alkoxy can be prepared by reaction of a compound 30 of the formula (XIX):

wherein Y is as defined hereinbefore for a compound of the formula (VI) and R2 is as defined hereinbefore for a compound of the formula (I), with a compound of the formula (VIA) as defined hereinbefore. 5

For example, a compound of the formula (XIX) is added to a suspension of a compound of the formula (VIA) and a strong base, for example sodium tert-butoxide. The reaction mixture is then heated, for example in a microwave oven, for a suitable period of time, for example 20-45 minutes at a suitable temperature, for example 90-120 ° C. The reaction mixture is then diluted with a suitable solvent, for example ethyl acetate, and washed with water. The organic phase is separated and dried, for example by passing through a hydrophobic frit, and concentrated. The compound of the formula (XX) can be isolated by conventional means, for example crushing followed by filtration.

A compound of the formula (XX), wherein R 1 is (C 1-8 alkyl) amino, (C 3-7 cycloalkyl) (C 1-6 alkyl) amino, can be prepared by reacting a compound of the formula (XIX) with a compound of the formula (VIB) as defined hereinbefore.

For example, a solution of a compound of the formula (XIX) in a suitable solvent, for example cyclohexylamine, is heated, for example in a microwave oven, at a suitable temperature, for example 150-180 ° C, for a period of time suitable, for example, five minutes. The crude reaction mixture is then purified by, for example chromatography.

A compound of the formula (XIX) can be prepared by reacting a compound of the formula (XVIII):

 25

wherein Y is as defined hereinbefore for a compound of the formula (VI), Z is as defined hereinbefore.

document for a compound of the formula (VII), and R2 is as defined hereinbefore for a compound of the formula (I), with ammonia.

For example, a compound of the formula (XVIII) (which may contain residual triphenylphosphine oxide as an impurity from the synthesis of a compound of the formula (XVIII), is heated with an alcoholic ammonia solution, for example 2M ammonia in 5 isopropyl alcohol, at a suitable temperature, for example 40-60 ° C, for a suitable period of time, for example 12-18 hours, the reaction mixture is then evaporated to dryness and the product is purified by recrystallization from a suitable solvent, for example methanol.

A compound of the formula (XIX) can also be prepared by reacting a compound of the formula (XVII):

wherein Y is as defined hereinbefore for a compound of the formula (VI), with a compound of the formula (IIB) as defined hereinbefore. fifteen

For example, to a suspension of a compound of the formula (XVII) and a suitable base, for example potassium carbonate, in a suitable solvent, for example N, N-dimethylformamide, a compound of the formula (IIB) is added. The mixture is stirred at a suitable temperature, for example 80-100 ° C, for a suitable period of time, for example 12-18 hours. The reaction mixture is then taken in a suitable solvent, for example a mixture of chloroform and isopropyl alcohol and extracted with water. The organic phase is then separated, dried for example by passing through a hydrophobic frit, and concentrated.

A compound of the formula (XVIII) can be prepared by reacting a compound of the formula (VIII) as defined hereinbefore with a compound of the formula R2-OH, wherein R2 is as it is defined hereinbefore for a compound of the formula (I).

For example, a mixture of a compound of the formula (VIII) and a compound of the formula R2-OH is dissolved in a suitable dry solvent, for example dry tetrahydrofuran. To this solution is added triphenylphosphine, followed by diisopropyl azodicarboxylate (drop by drop). The temperature of the reaction mixture is kept below about

45 ° C by cooling, for example with an ice water bath. The reaction mixture is then stirred for a suitable period of time, for example 12-18 hours, at a suitable temperature, for example room temperature, quenched with water, and extracted into a suitable organic solvent, for example ethyl acetate. . The organic phase is separated, washed with water, and then dried for example by passing through a hydrophobic frit, and concentrated under reduced pressure. The crude product can be purified by conventional means, for example chromatography.

A compound of the formula (XVII) can be prepared by reacting a compound of the formula (VIII) as defined hereinbefore with ammonia. 10

For example, a mixture of a compound of the formula (VIII) and ammonia solution in a suitable solvent, for example isopropyl alcohol, is stirred and heated to a suitable temperature, for example 100-140 ° C in an autoclave for a period. of adequate time, for example 12-18 hours. The reaction is then cooled and concentrated to provide a compound of the formula (XVII). fifteen

The present invention includes a synthesis process for a compound of the formula (I), wherein R 1 is (C 1-8 alkyl) amino or (C 3-7 cycloalkyl) (C 1-6 alkyl) amino, which can be prepared by reaction of a compound of the formula (XXIII):

wherein Y is as defined hereinbefore for a compound of the formula (VI), R2 is as defined hereinbefore for a compound of the formula (I), and R3 it is as defined hereinbefore for a compound of the formula (IIA), with a compound of the formula (VIB) as defined hereinbefore.

For example, a mixture of a compound of the formula (XXIII) and a compound of the formula (VIB) is heated, for example in a microwave oven, to a suitable temperature, for example 150-190 ° C for a period of time suitable, for example 10-20 minutes. The reaction mixture is then concentrated to provide a crude product that is purified by conventional means, for example chromatography.

A compound of the formula (XXIII) can be prepared by reacting a compound of the formula (XXII):

wherein X is as defined hereinbefore for a compound of the formula (IV), Y is as defined hereinbefore for a compound of the formula (VI) and R2 is such as defined hereinbefore for a compound of the formula (I), with an alkoxide anion source.

For example, to a solution of a compound of the formula (XXII) in a suitable solvent, for example dry methanol, a suitable base is added, for example aqueous sodium hydroxide solution and the mixture is stirred at reflux for a period of time. suitable, for example 15-45 minutes. The reaction mixture is cooled to a suitable temperature, for example room temperature, and concentrated. The obtained residue is triturated with water and extracted with a suitable solvent, for example ethyl acetate. The organic phase is separated, washed, dried, filtered and concentrated to provide a solid product that can be purified by conventional means, for example chromatography.

A compound of the formula (XXII) can be prepared by reacting a compound of the formula (XIX) as defined hereinbefore, with a halogenating agent.

For example, to a solution of a compound of the formula (XIX) in a suitable dry solvent, for example chloroform, at a suitable temperature, for example room temperature, a suitable halogenating agent is added, for example N-bromosuccinimide. The reaction mixture is stirred at a suitable temperature, for example 50-70 ° C for a suitable period of time, for example 5-7 hours. The reaction mixture is cooled, for example at room temperature, taken in a suitable solvent, for example dichloromethane, and washed with water. The organic phase is then dried, for example, passing through a hydrophobic frit, and concentrated. 25

Abbreviations

The following list provides definitions of certain abbreviations as used herein. It will be appreciated that the list is not exhaustive, but the meaning of the abbreviations that are not included below will be readily apparent to those skilled in the art. 30

DCM Dichloromethane

DME 1,2-Dimethoxyethane

DMF N, N-Dimethylformamide

EtOAc Ethyl Acetate

Et2O Diethyl Ether

h 5 hours

HCl Hydrochloric Acid

HPLC High Resolution Liquid Chromatography

ISCO Companion Automated flash chromatography equipment with fraction analysis by UV absorption available from Presearch Limited, Basingstoke, Hants., RG24 8PZ, UK 10

MDAP HPLC HPLC reverse phase on a C18 column using a gradient solution with two solvents with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95: 5 v / v) containing formic acid (0.05%) as eluents, and analysis of the fractions by electrospray mass spectroscopy. fifteen

MeOH Methanol

Min. Minutes

NBS N-Bromosuccinimide

Distillation Removal of solvent under reduced pressure

TBME Terc-Butyl Methyl Ether 20

TFA Trifluoroacetic Acid

iPr iso-propyl

t-Bu tert-butyl

Ms Mesilo

Ac Acetyl 25

n-Bu n-Butyl

Ph phenyl

The synthesis procedures described above are summarized in Scheme 1.

Scheme 1 30

The reaction conditions for each of the synthesis steps of Scheme 1 are provided below:

A Dihydropyran / paratoluenesulfonic acid, for example 50 ° C for 4 hours.

B Ammonia / iPrOH, for example 50 ° C for 5 hours, then room temperature for 12-18 hours, then 50 ° C for 9 hours; or 60 ° C for 4 hours.

C For X = NH: -RANH2 / ethylene glycol for example 120 ° C for 12-18 hours.

 For X = O: -RAOH / KOtBu / dimethoxyethane for example 93-110 ° C for 12-18 hours. 10

 RAOH / KOtBu or NaH for example 50 ° C for 72 hours; or 12-18 hours, then 72 hours, or 80-90 ° C for 2-4 hours, or 100 ° C for 12-18 hours.

D NBS in CH2Cl2 or CHCl3 for example 0-20 ° C for 10 minutes at 6.5 hours, or room temperature for 0.25-2 hours.

E NaOMe / MeOH for example reflux 1–18 hours or 60 ° C for 12–48 hours. 5

F TFA / MeOH for example room temperature for 18-65 hours.

G K2CO3 / DMF then R2L where L = halogen - Width for example 60 ° C for 1-1.5 hours, thereafter;

 a) 50 ° C for 2-18 hours, or;

 b) 60 ° C for 2-16 hours, or; 10

 c) 50 ° C for 12-18 hours, then 70 ° C for 8 hours, or;

 d) room temperature for 39 hours after 50 ° C for 2 hours, or

 e) 50 ° C for 12-18 hours after 70 ° C for 8 hours, or;

 f) 50 ° C for 12-18 hours, then 90 ° C for 2 hours.

 fifteen

or where L = OMs for example 60 ° C for 1-1.5 hours later;

 a) 90 ° C for 2-3.5 hours, or;

 b) 50 ° C 5 hours, room temperature 16 hours, LiBr at 90 ° C for 8 hours, or;

 c) 60 ° C for 3-16 hours.

H HCl / 1,4-dioxane for example room temperature for 1-18 hours. twenty

I Ammonia / iPrOH for example 120 ° C for 12-18 hours.

J K2CO3 / DMF then R2L where L = halogen, for example 90 ° C for 12-18 hours.

K X = O: R1OH / KOtBu for example 30 minutes. At 105 ° C in a microwave oven.

 X = NH: R1NH2 for example 170 ° C in microwave oven for 2-5 minutes. 25

L X = O: Br2 / AcOH for example ice bath - room temperature after 70 ° C for 4 hours.

 X = NH: NBS in CHCl3 for example room temperature for 40 minutes - 1 hour.

M R2OH / PPh3 / diisopropyl azodicarboxylate for example room temperature -43 30 ° C

N Ammonia / iPrOH for example 50 ° C for 12-18 hours.

Or NBS in CHCl3 for example 60 ° C for 6 hours.

P NaOH MeOH for example reflux 0.5 hours.

Pure Q R1NH2 for example 170 ° C in microwave oven for 10-15 minutes. 35

 R1NH2 / ethylene glycol for example 170 ° C in a microwave oven for 2 x 30 minutes. Then 180 ° C in microwave oven for 30 minutes.

R c. HCl conc / nBuOH for example 100 ° C for 0.5-6 hours.

The compounds of the formulas (VIA), (VIB), (VIII), (X), (XI), (XII), (XIII), (XIV), XV), (XVI), and acrolein are commercially available and they can be obtained, for example, in 5 Sigma-Aldrich, United Kingdom; TCI Europe, Belgium; ABCR GmbH & Co. KG, Germany; PharmaCore Inc., USA UU .; Chemical Block Ltd., Russia; Lancaster Synthesis (Alfa Aesar), United Kingdom, or can be prepared by analogy with known procedures, for example those described in standard reference texts of synthetic methodology such as J. March, Advanced Organic Chemistry, 4th Edition (1992), Wiley Interscience, or Comprehensive 10 Organic Synthesis (Trost BM and Fleming I., (Eds.), Pergamon Press, 1991), each of which is hereby incorporated by reference in regard to such procedures.

Examples of other protecting groups that can be used in the synthetic pathways described herein and the means for their removal can be found in TW Greene "Protective Groups in Organic Synthesis", 3rd edition, J. Wiley and Sons, 1999, 15 which is hereby incorporated by reference as regards such procedures.

For any of the reactions or procedures described hereinbefore, conventional heating and cooling procedures may be employed, for example oil baths with temperature regulation or heating blocks with temperature regulation and ice baths and salt or baths of carbonic ice and acetone 20 respectively. Conventional isolation procedures can be used, for example extraction from or in aqueous or non-aqueous solvents. Conventional methods of drying organic solvents, solutions, or extracts, such as stirring with magnesium sulfate, or sodium sulfate, or passing through a hydrophobic frit can be employed. Conventional purification procedures can be used, for example crystallization and chromatography, for example silica chromatography or reverse phase chromatography, as necessary. Crystallization can be performed using conventional solvents such as methanol, ethanol, or butanol, or aqueous mixtures thereof. It will be appreciated that temperatures at specific reaction times can usually be determined by reaction control techniques, for example thin layer chromatography and LCMS.

When appropriate, individual isomeric forms of the compounds of formula (I) can be prepared as individual isomers using conventional methods such as fractional crystallization of diastereoisomeric derivatives or chiral high resolution liquid chromatography (chiral HPLC). 35

The absolute stereochemistry of the compounds can be determined using conventional procedures, such as X-ray crystallography.

The invention is illustrated by reference, but is by no means limited, by the following Examples.

Experimental Details 5

The experimental details of the CLEM systems A and B as referred to herein are as follows:

System A

Column: 3.3cm x 4.6mm ID, 3 µm ABZ + PLUS by Supelco

Flow rate: 3 ml / minute. 10

Injection volume: 5 µl

Temp: room temperature

UV detection range: 215 to 330 nm

Solvents: A: 0.1% formic acid + 10 mM ammonium acetate

  B: 95% acetonitrile + 0.05% formic acid 15

Gradient:

 Time (min.)

 A% B%

 0

 100

 0

 0.7

 100 0

 4.2

 0 100

 5.3

 0 100

 5.5

 100 0

System B

Column: 50 mm x 2.1 mm ID, 1.7 µm Acquity UPLC BEH C18

Flow rate: 1 ml / minute. twenty

Injection volume: 0.5 µl

Temp: 40 ° C

UV detection range: 220 to 330nm

Solvents: A: 0.1% formic acid + 10 mM ammonium acetate

  B: 95% acetonitrile + 0.05% formic acid 25

Gradient:

 Time (min.)

 A% B%

 0

 97 3

 0.7

 97 3

 4.2

 0 100

 5.3

 0 100

 5.5

 97 3

For Intermediates 219-292 and Examples 61-141, chromatographic purification was performed as detailed below.

Chromatographic purification was usually performed using previously packaged silica gel cartridges. The Flashmaster II is an automated 5-use ultra-fast chromatography system, available from Argonaut Technologies Ltd, which uses normal, disposable solid phase extraction (SPE) cartridges (2 g to 100 g). It provides a mixture of quaternary solvents in line to allow gradient procedures. The samples are aligned using the multifunctional free access program that handles solvents, flow rates, gradient profile and collection conditions. The system is provided with a Knauer variable wavelength UV detector and two Gilson FC204 fraction collectors that allow automated peak cutting, collection and tracking.

For Intermediates 219-292 and Examples 61-141, NMR spectra have been recorded as detailed below.

The 1 H NMR spectra were recorded with CDCl3 or DMSO-d6 on a Bruker DPX 400 or Bruker Avance DRX or Varian Unity 400 spectrometer, all operating at 400 MHz. The internal standard used was either tetramethylsilane or protonated solvent residual at 7.25 ppm for CDCl3 or 2.50 ppm for DMSO-d6.

 For Intermediates 219-292, a mass-directed self-preparation was carried out under the conditions detailed below. twenty

Mass-directed self-healing HPLC was performed on an XBridge C18 column (100 mm x 19 mm ID 5 μm inside diameter) at room temperature. The solvents that were used were:

A = 10 mM aqueous ammonium bicarbonate adjusted to pH 10 with ammonia solution.

B = acetonitrile. 25

A flow rate of 20 ml / minute was used. A typical gradient was:

 Time (min.)

 A% B%

 0

 70 30

 one

 70 30

 10

 15 85

 eleven

 1 99

 fifteen

 1 99

UV detection was a signal averaged from a wavelength of 210 nm to 350 nm and mass spectra were recorded on a mass spectrometer using alternating electrospray ionization between positive and negative mode.

Examples 5

Intermediate 1: 2,6-Dichloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine

To 2,6-dichloropurine (25.0 g) was added ethyl acetate (260 ml), followed by p-toluenesulfonic acid (0.253 g). The mixture was heated to 50 ° C and then 3,4-dihydro-2H-pyran (16.8 g) was added. The reaction mixture was then heated at 50 ° C for 4 hours. The reaction mixture 10 was evaporated in vacuo to give the title compound as a yellow solid (36.9 g).

1H NMR (CDCl3): 8.35 (1H, s), 5.77 (1H, dd), 4.20 (1H, m), 3.79 (1H, m), 2.20-1.65 (6H, m).

Intermediate 2: 2-Chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine 15

2,6-Dichloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (36.9 g) was heated with 2M ammonia in isopropanol (250 ml) at 50 ° C for 5 hours. After standing at room temperature overnight, an additional amount of 2M ammonia in isopropanol (100 ml) was added to decompose the resulting cake and the reaction mixture was heated for another 9 hours until the reaction was complete. Water (70 ml) was added to the reaction mixture and the yellow solid was filtered off. The solid was washed with isopropyl alcohol: water (5: 1 (v / v), 60 ml) and then air dried with suction to provide a first crop. The filtrate was filtered again after standing overnight to isolate the precipitate and both solids were dried under vacuum. The first crop was pure, with very minor impurities from the second crop material (wide isolated signal at 3.5 ppm that is not observed in the first crop) but otherwise it was identical. Solid of the first crop (28.4 g), solid of the second crop (3.42 g).

1H NMR (CDCl3): 8.01 (1H, s), 5.98 (2H, wide s), 5.70 (1H, dd), 4.16 (1H, m), 3.78 (1H, m), 2.15-1.60 (6H, m superimposed).

Intermediate 2 (alternative procedure): 2-Chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

 5

To a solution of 2,6-dichloropurine (25 g) in dry ethyl acetate (200 ml) was added p-toluenesulfonic acid monohydrate (235 mg). The reaction was heated to 50 ° C and 3,4-dihydro-2H-pyran (18.1 ml) was added at one time. The reaction was allowed to stir at 50 ° C for 1 hour and the solvent was removed under reduced pressure. This provided a yellow solid. A suspension of this solid (~ 36 g) in 2.0 M ammonia in isopropanol (460 ml) was heated under a nitrogen atmosphere at 60 ° C for 4 hours with a condenser attached. The reaction was poured into water (50 ml) and allowed to cool overnight. The precipitate was filtered and dried on a rotary evaporator (60 ° C) for 30 minutes to provide the title compound as an off-white solid (31 g, 93%, 2 steps).

MS calculated for (C10H12ClN5O) + = 254, 256 15

MS found (electrospray): (M) + = 254, 256 (3: 1)

1H NMR ((CD3) 2SO): δ 8.43 (1H, s), 7.82 (2H, s), 5.55 (1H, dd), 4.00 (1H, m), 3.69 (1H, m), 2.21 (1H , m), 1.95 (2H, m), 1.74 (1H, m), 1.56 (2H, m).

Intermediate 3: 2- (Butoxy) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

To butan-1-ol (76 ml) was added portionwise sodium tert-butoxide (15.2 g) (Note: the reaction mixture is heated). The above was stirred until it became homogeneous (~ 15 minutes) before adding 2-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (10.0 g) to the resulting light yellow solution. The reaction mixture was then heated at 100 ° C, overnight. The reaction mixture was evaporated under reduced pressure to remove as much butan-1-ol as possible before fractionating between diethyl ether and water. The diethyl ether phase was separated and the aqueous one was further extracted with diethyl ether. Organic phases

combined, dried over magnesium sulfate (anhydrous). The magnesium sulfate was removed by filtration and the filtrate was evaporated under reduced pressure to provide a viscous brown oil that was azeotroped with toluene (3 times) and subjected to high vacuum overnight, transferred to a new flask with dichloromethane and evaporated under reduced pressure, subjected to high vacuum to provide the title compound as a brown crystal (9.45 g). 5

1H NMR (CDCl3): 7.85 (1H, s), 5.92 (2H, wide s), 5.64 (1H, d), 4.32 (2H, t), 4.14 (1H, m), 3.75 (1H, m), 2.10-1.95 (3H, overlapping m), 1.81-1.58 (5H, overlapping m), 1.50 (2H, m), 0 , 97 (3H, t).

Intermediate 4: 8-Bromo-2-butoxy-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

 10

2-Butoxy-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (9.45 g) was dissolved in chloroform (50 ml) and cooled to 0 ° C (ice bath) . To this solution was added in portions N-bromosuccinimide (6.07 g) keeping the temperature below 3 ° C. This provided a dark green solution, stirred at 2.5 ° C for 30 minutes before allowing to warm to room temperature and then stirring for 6 hours. The reaction mixture was then washed with water (100 ml, twice). The organic phase was dried / separated using a hydrophobic frit and evaporated to provide a dark brown gum that was purified by silica chromatography (120 g) (ISCO) using a gradient elution of 0–50% ethyl acetate: cyclohexane providing the title compound as a light yellow solid (8.37 g). twenty

1H NMR (CDCl3): 5.61 (1H, dd), 5.49 (2H, broad s), 4.32 (2H, m), 4.17 (1H, m), 3.71 (1H, m), 3.04 (1H, m), 2.11 (1H, broad d), 1.89-1.45 (6H, m superimposed), 1.50 (2H, m), 0.97 (3H , t).

Intermediate 5: 2-Butoxy-8-methoxy-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

 25

8-Bromo-2-butoxy-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (8.37 g) was refluxed with 25% sodium methoxide in methanol (14, 4 ml) and methanol (65 ml) for 4.5 hours. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and

saturated solution of ammonium chloride. The organic phase was separated and the extraction was repeated in ethyl acetate. The organic phases were combined and washed with brine (twice). The organic phase was passed through a hydrophobic frit after separating the aqueous phase and evaporated to provide a light brown gum that was subjected to high vacuum providing a foam (7.52 g) that collapsed to form a gum (7.34 g) at ambient pressure and solidified overnight providing the title compound as an amorphous yellow solid.

MS calculated for (C15H23N5O3) + = 321

MS found (electrospray): (M + H) + = 322

1H NMR (CDCl3): 5.50 (1H, dd), 5.17 (2H, broad s), 4.29 (2H, t), 4.12 (3H, s and 1H, m), 10 3, 70 (1H, m), 2.77 (1H, m), 2.05 (1H, m), 1.82-1.63 (6H, m superimposed), 1.50 (2H, m), 0, 97 (3H, t).

Intermediate 6: 2-Butoxy-8-methoxy-9H-purin-6-amine, trifluoroacetate salt

 fifteen

To a solution of 2-butoxy-8-methoxy-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (7.34 g) in methanol (100 ml) was added trifluoroacetic acid ( 10 ml) The mixture was stirred at room temperature over the weekend to provide a suspension. The reaction mixture was concentrated to a small volume (thick suspension) before diluting with ethyl acetate (50 ml). The resulting suspension was filtered and washed with a small volume of ethyl acetate until the filtrate was colorless. The remaining solid was dried by air and then under vacuum to give the title compound as a solid (6.20 g). The filtrate obtained above was concentrated to provide a suspension that was diluted with a small volume of ethyl acetate (10 ml) and then filtered and dried as before. This second crop was isolated as a white solid (0.276 g). Both crops were identical by NMR.

MS calculated for (C10H15N5O2) + = 237

MS found (electrospray): (M + H) + = 238

1H NMR (CD3OD): 4.47 (2H, t), 4.15 (3H, s), 1.80 (2H, m), 1.50 (2H, m), 0.99 (3H, t ) (no exchangeable protons of NH2, NH and COOH were observed). 30

Intermediate 7: 2-Butoxy-8-methoxy-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine

2-Butoxy-8-methoxy-9H-purin-6-amine salt trifluoroacetate (0.5 g) was heated at 60 ° C for 1 hour with anhydrous potassium carbonate (0.79 g) in dry DMF (10 ml) and was allowed to cool to room temperature before adding 4- (bromomethyl) tetrahydro-2H-pyran (0.26 g). The reaction was stirred at room temperature for 39 hours and heated for 2 hours at 50 ° C. The reaction was poured into water and extracted into ethyl acetate (twice). The combined ethyl acetate extracts were dried through a hydrophobic frit, evaporated under reduced pressure to dryness and first purified by silica chromatography (ISCO) (40 g) eluting with 0–100% ethyl acetate: cyclohexane then 0–20% methanol: ethyl acetate and then by reverse phase chromatography (43 g, C-18) (ISCO) eluting with 20–10 60% acetonitrile (0.05% formic acid): water ( 0.1% formic acid) providing the title compound as a white solid.

MS calculated for (C16H25N5O3) + = 335

MS found (electrospray): (M + H) + = 336

1H NMR (CD3OD): 4.29 (2H, t), 4.13 (3H, s), 3.92 (2H, m), 3.81 (2H, dd), 3.36 (2H, 15 m), 2.12 (1H, m), 1.74 (2H, m), 1.52-1.47 (4H, m), 1.37 (2H, m), 0.98 (3H, t ) (NH2 exchanged).

Intermediate 8: 2-Butoxy-8-methoxy-9- (tetrahydro-2H-pyran-2-ylmethyl) -9H-purin-6-amine

2-Butoxy-8-methoxy-9H-purin-6-amine salt trifluoroacetate (0.20 g) was heated with anhydrous potassium carbonate (0.315 g) in dry DMF (5 ml) at 60 ° C for 1 hour and cooled at room temperature. 2- (Bromomethyl) tetrahydro-2H-pyran (73 µl) was added and the reaction mixture was heated at 50 ° C, overnight. The reaction mixture was quenched in water (50 ml) and extracted into ethyl acetate (25 ml, 3 times). The combined organic phases were separated and passed through a hydrophobic frit to dry, then evaporated under reduced pressure to dryness and the pale yellow gum (145 mg), which became a white solid when triturated with methanol, purified by MDAP to provide the title compound (6 mg)

(~ 85% purity).

MS calculated for (C16H25N5O3) + = 335

MS found (electrospray): (M + H) + = 336.

Intermediate 9: N2-Butyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-2,6-diamine

 5

To a solution of 2-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (10 g) in dry ethylene glycol (50 ml) at room temperature and under nitrogen atmosphere was added n-butylamine (16 ml) at one time. The reaction was heated at 120 ° C overnight. The reaction was cooled to room temperature, diluted with ethyl acetate (150 ml) and washed with water (2 x 50 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. This gave the title compound as a viscous green oil (10.2 g) that was used in the next step without further purification.

MS calculated for (C14H22N6O) + = 290

MS found (electrospray): (M + H) + = 291

1H NMR ((CD3) 2SO): δ 7.8 (1H, s), 6.6 (2H, s), 6.2 (1H, t), 5.4 (1H, dd), 4.0 (1H, m), 15 3.6 (1H, m), 3.2 (2H, m), 2.2 (1H, m), 1.9 (1H, m), 1.8 (1H, m ), 1.7 (1H, m), 1.5 (2H, m), 1.4 (2H, m), 1.3 (2H, m), 0.9 (3H, t).

Intermediate 10: N2-butyl-8-methoxy-9H-purin-2,6-diamine trifluoroacetic acid salt

To a solution of crude N2-butyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-2,6-diamine 20 (~ 10.2 g) in dry chloroform (100 ml) at temperature N-bromosuccinimide (6.3 g) was added portionwise over 5 minutes. The dark solution was allowed to stir at room temperature for 30 minutes. The reaction mixture was washed with water (20 ml). The organic phase was passed through a hydrophobic frit and concentrated in vacuo. This provided a beige solid that was dissolved in dry methanol (100 ml) and at room temperature under a nitrogen atmosphere a solution of sodium methoxide (25% by weight in methanol, 24 ml) was added at one time. The reaction was heated at 65 ° C, with a condenser attached, overnight. The reaction was cooled and concentrated in vacuo. The resulting orange residue was taken in ethyl acetate (150 ml) and poured into saturated aqueous ammonium chloride (50 ml). The organic phase was separated and

washed further with water (50 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. To this material in dry methanol (70 ml) at room temperature was added trifluoroacetic acid (7 ml) at one time. The reaction was stirred for 30 hours and concentrated in vacuo to provide a dark brown solid. This was taken in diethyl ether (20 ml) and triturated. The solid was filtered to give the title compound as a beige solid 5 (3.3 g, 35%, 4 steps).

MS calculated for (C10H16N6O) + = 236

MS found (electrospray): (M + H) + = 237

1H NMR ((CD3) 2SO): δ 13.3-12.3 (1H, broad m), 8.6-7.3 (2H, m), 4.05 (3H, s), 3.28 (2H, m), 1.52 (2H , m), 1.33 (2H, m), 0.89 (3H, t) (the remaining interchangeable protons are not clearly observed).

Intermediate 11: N2-Butyl-8-methoxy-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-2,6-diamine

To a solution of trifluoroacetic acid salt of N2-butyl-8-methoxy-9H-purin-2,6-diamine (500 mg) in dry N, N-dimethylformamide (8 ml) at room temperature and under nitrogen atmosphere potassium carbonate (1.17 g) was added at one time. The reaction was stirred at 60 ° C for 1.5 hours and then cooled to room temperature. 4- (Bromomethyl) tetrahydro-2H-pyran (0.3 ml) was added at one time and the reaction was heated at 50 ° C overnight. The reaction was diluted with ethyl acetate (20 ml) and washed with water (10 ml). The organic phase was separated and concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (10-45%) to provide the compound of title in the form of a viscous yellow oil (315 mg, clean at 90%).

MS calculated for (C16H26N6O2) + = 334

MS found (electrospray): (M + H) + = 335 25

1H NMR ((CD3) 2SO): δ 6.29 (2H, s), 6.17 (1H, t), 4.00 (3H, s), 3.81 (2H, m), 3.66 (2H, d), 3.20 (4H, 2xm), 2.01 (1H, m), 1.47 (2H, m), 1.40 (2H, m), 1.31 (2H, m) , 1.22 (2H, m), 0.89 (3H, t).

Intermediate 11, alternative procedure: N2-Butyl-8- (methoxy) -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-2,6-diamine

A mixture of N2-butyl-8- (methoxy) -3H-purin-2,6-diamine trifluoroacetate (12.89 g) and anhydrous potassium carbonate (20.58 g) in anhydrous DMF (175 ml) was heated to 60 ° C (external) for 1.5 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature before adding tetrahydro-2H-pyran-4-ylmethyl methanesulfonate (7.571 g) and then the reaction was heated at 90 ° C for 2.5 hours. The reaction mixture was examined by LCMS and showed that the reaction was incomplete so that the reaction temperature was reduced to 50 ° C (external) and the reaction mixture was heated overnight under a nitrogen atmosphere.

The reaction mixture was then partitioned between water (300 ml) and ethyl acetate (300 ml). The organic phase was separated and the aqueous phase was reextracted with more ethyl acetate (300 ml). The organic extracts were combined and washed with brine (500 ml). The organic phase was dried by passing through a hydrophobic frit (after separating the brine phase). The organic phase was evaporated under reduced pressure to provide a crude brown mobile oil (16.01 g) which solidified to give a wet solid (for 2 days). This material in batches of ~ 3 g was purified using reverse phase chromatography {ISCO [column (C18) 330 g] (20-60% acetonitrile: water)}. The appropriate pure fractions of all purifications were combined and evaporated under reduced pressure to provide the clean title compound as a light tan roasted solid (5.1530 g).

MS calculated for (C16H26N6O2) + = 334 20

MS found (electrospray): (M + H) + = 335

1H NMR (CDCl3): 6.95 (2H, wide s), 6.52 (1H, wide s), 4.10 (3H, s), 4.01-3.92 (2H, m), 3 , 80-3.73 (2H, m), 3.44-3.29 (4H, m superimposed), 2.14-2.00 (1H, m), 1.65-1.34 (8H, m superimposed), 0.98-0.91 (3H, m).

Remark: contains residual formic acid. 25

Intermediate 12: N2-Butyl-8-methoxy-9- (tetrahydro-2H-pyran-2-ylmethyl) -9H-purin-2,6-diamine

To a solution of trifluoroacetic acid salt of N2-butyl-8-methoxy-9H-purin-2,6-diamine (400 mg) in dry N, N-dimethylformamide (6 ml) at room temperature and under a nitrogen atmosphere, added potassium carbonate (630 mg) at one time. The reaction was stirred at 60 ° C for 1.5 hours and then cooled to 50 ° C. 2- (Bromomethyl) tetrahydro-2H-pyran (175 µl) was added at one time and the reaction was heated at 50 ° C overnight and then at 90 ° C for 2.5 hours. The reaction was diluted with ethyl acetate (20 ml) and washed with water (10 ml). The organic phase was separated and concentrated in vacuo. The product was half purified by MDAP to provide a mixture of the title compound and an isomer. This mixture was taken without further purification.

MS calculated for (C16H26N6O2) + = 334 10

MS found (electrospray): (M + H) + = 335.

Intermediate 13: 3- (Bromomethyl) tetrahydro-2H-pyran

To tetrahydro-2H-pyran-3-ylmethanol (1 g) in dry dichloromethane (28 ml) at 0 ° C and under a nitrogen atmosphere, triethylamine (2.7 ml) was added at one time, followed by methanesufonyl chloride (15 0.87 ml) drop by drop for 1 minute. The reaction was allowed to warm to room temperature and was left at this temperature overnight. The reaction mixture was diluted with dichloromethane (20 ml) and washed with saturated aqueous sodium bicarbonate (20 ml). The organic phase was passed through a hydrophobic frit to dry and concentrated in vacuo to provide a yellow oil. To this oil in dry acetone (40 ml) and at room temperature, lithium bromide (3 g) was added at once. The reaction was heated at reflux for 1 hour. The reaction was allowed to cool to room temperature and taken in dichloromethane (60 ml) and washed with water (20 ml). The organic phase was passed through a hydrophobic frit to dry and concentrated in vacuo. The product was purified by silica chromatography (40 g) (ISCO) using a gradient elution of 0–50% cyclohexane: ethyl acetate to give the title compound as a yellow oil (340 mg).

1H NMR (CDCl3): δ 3.99 (2H, m), 3.84 (1H, m), 3.41 (1H, m), 3.35-3.21 (2H, m), 2, 05-1.90 (2H, m), 1.71-1.59 (2H, m), 1.38 (1H, m).

Intermediate 14: N2-Butyl-8-methoxy-9- (tetrahydro-2H-pyran-3-ylmethyl) -9H-purin-2,6-diamine

To a salt solution of the N2-butyl-8-methoxy-9H-purin-2,6-diamine acid (100 mg) in dry N, N-dimethylformamide (1 ml) at room temperature and under a nitrogen atmosphere carbonate was added potassium (158 mg) at one time. The reaction was stirred at 60 ° C for 1.5 hours and then cooled to 50 ° C. A solution of 3- (bromomethyl) tetrahydro-2H-pyran (56 5 mg) in dry N, N-dimethylformamide (0.3 ml) was added at one time and the reaction was heated at 50 ° C for 16 hours. The reaction was diluted with ethyl acetate (15 ml) and washed with water (5 ml). The organic phase was separated, dried over magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (20-60%) to provide the compound of title in the form of a yellow oil (45 mg).

MS calculated for (C16H26N6O2) + = 334

MS found (electrospray): (M + H) + = 335.

Intermediate 15: 3- (Bromomethyl) tetrahydrofuran 15

To tetrahydrofuran-3-ylmethanol (1 g) in dry dichloromethane (30 ml) at 0 ° C and under a nitrogen atmosphere, triethylamine (2.7 ml) was added at one time, followed by methanesufonyl chloride (1 ml) drop a drop for 3 minutes. The reaction was stirred at 0 ° C until the ice in the bath melted and then left at room temperature overnight. The reaction mixture was washed with saturated aqueous sodium bicarbonate (10 ml). The organic phase was passed through a hydrophobic frit to dry and concentrated in vacuo to provide a yellow oil (1.7 g). To this oil in dry acetone (50 ml) and at room temperature was added lithium bromide (3.3 g) at one time. The reaction was heated at reflux for 20 hours. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was taken in dichloromethane (50 ml) and washed with water (25 ml). The organic phase was passed through a hydrophobic frit to dry and concentrated in vacuo. The product was purified by silica chromatography (40 g) (ISCO) using a gradient elution of 0–50% cyclohexane: ethyl acetate to provide the

title compound in the form of a colorless oil (890 mg).

1H NMR ((CD3) 2SO): δ 3.81-3.73 (2H, m), 3.66 (1H, m), 3.54 (2H, m), 3.42 (1H, m), 2.61 (1H, m), 2 , 02 (1H, m), 1.60 (1H, m).

Intermediate 16: 2-Butoxy-8-methoxy-9- (tetrahydrofuran-3-ylmethyl) -9H-purin-6-amine

 5

2-Butoxy-8-methoxy-9H-purin-6-amine salt trifluoroacetate (0.20 g) was dissolved in anhydrous N, N-dimethylformamide (5 ml) treated with anhydrous potassium carbonate (0.315 g), heated to 60 ° C for 1 hour and then cooled to room temperature. To the above was added 3- (bromomethyl) tetrahydrofuran (0.103 g) and the reaction mixture was heated at 50 ° C, overnight. The reaction mixture was quenched with water (25 ml) and extracted into ethyl acetate (3 times, 100 ml of total combined volume). The combined organic phase was separated and passed through a hydrophobic frit to dry. The organic phase was evaporated under reduced pressure to provide a gum that was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent. (20-60%) providing the title compound as a white solid (97 mg).

MS calculated for (C15H23N5O3) + = 321

MS found (electrospray): (M + H) + = 322

1H NMR (CDCl3): 5.39 (2H, s), 4.24 (2H, t), 4.08 (3H, s), 3.96-3.85 (3H, m20 superimposed), 3 , 71 (2H, m), 3.60 (1H, m), 2.81 (1H, m), 1.93 (1H, m), 1.76-1.63 (3H, m superimposed), 1 , 46 (2H, m), 0.93 (3H, t).

Intermediate 16, alternative procedure: 2- (Butyloxy) -8- (methyloxy) -9- (tetrahydro-3-furanylmethyl) -9H-purin-6-amine

 25

A solution of 2-butoxy-8-methoxy-9H-purin-6-amine salt trifluoroacetate (4.5 g),

tetrahydro-3-furanylmethyl methanesulfonate (2.77 g) and potassium carbonate (5.31 g) in dimethyl sulfoxide (45 ml) was stirred and heated at 60 ° C for 1.5 hours, followed by heating at 90 ° C for 2.5 hours The reaction was allowed to cool and the mixture was diluted with water and brine, and stirred with ethyl acetate. The insoluble solid present was filtered (209 mg of product) and the organic phase separated. The aqueous phase was extracted four more times with ethyl acetate. The combined organic phases were washed with water and then brine. The organic phase was dried by passing through a hydrophobic frit and concentrated in vacuo to provide a light brown solid (4.18 g). This was recrystallized from acetonitrile (25 ml) to provide the product (2.28 g). This was further purified by dissolving in dichloromethane and washing with 1M hydrochloric acid, brine and saturated sodium hydrogen carbonate. The organic phase was dried through a hydrophobic frit and concentrated in vacuo to provide the product as a cream-colored solid (2.03 g).

MS calculated for (C15H23N5O3) + = 321

MS found (electrospray): (M + H) + = 322

1H NMR (CDCl3): δ 5.32 (2H, broad s), 4.27 (2H, t), 4.12 (3H, s), 4.00-3.88 (3H, m), 15 3.76 (2H, m), 3.63 (1H, m), 2.85 (1H, m), 1.97 (1H, m), 1.81-1.66 (3H, m), 1 , 49 (2H, m), 0.96 (3H, t).

Intermediate 17: 2-Butoxy-8-methoxy-9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -9H-purin-6-amine

2-Butoxy-8-methoxy-9H-purin-6-amine salt trifluoroacetate (0.2 g) in anhydrous N, N-dimethylformamide (5 ml) was treated with anhydrous potassium carbonate (0.315 g) and then heated to 60 ° C for 1 hour. Upon cooling to room temperature, 4- (2-bromoethyl) tetrahydro-2H-pyran (0.110 g) was added thereto and the reaction was heated at 50 ° C, overnight. The reaction mixture was quenched with water (5 ml) and extracted into ethyl acetate (3 times, 100 ml of total combined volume). The combined organic phases were combined and passed through a hydrophobic frit to dry. The organic phase was evaporated under reduced pressure to provide a gum that was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent. 20-60%) providing the title compound as a white solid (111 mg). 30

MS calculated for (C17H27N5O3) + = 349

MS found (electrospray): (M + H) + = 350

1H NMR (CDCl3): 5.20 (2H, s), 4.24 (2H, t), 4.10 (3H, s), 3.94 (4H, m superimposed), 3.31 (2H, m), 1.78-1.65 (6H, m superimposed), 1.52-1.39 (3H, m superimposed), 1.30 (2H, m), 0.95 (3H, t). 5

Intermediate 18: 2-Butoxy-8-methoxy-9- (tetrahydro-2H-pyran-3-ylmethyl) -9H-purin-6-amine

2-Butoxy-8-methoxy-9H-purin-6-amine salt trifluoroacetate (0.2 g) in dry N, N-dimethylformamide (5 ml) was heated at 60 ° C with anhydrous potassium carbonate (0.315 g) for 1 hour and allowed to cool to room temperature before adding 3- (bromomethyl) tetrahydro-2H-pyran (0.121 10 g). The reaction mixture was heated at 50 ° C, overnight. The reaction mixture was quenched with water (20 ml) and extracted into ethyl acetate (3 times, 75 ml of combined volume). The organic phase was separated, combined and passed through a hydrophobic frit to dry. The organic phase was evaporated under reduced pressure to provide a yellow oil that was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (20-60%) providing the title compound as a white solid (105.4 mg).

MS calc. for (C16H25N5O3) + = 335

MS found (electrospray): (M + H) + = 336

1H NMR (CDCl3): 5.14 (2H, s), 4.26 (2H, t), 4.10 (3H, s), 3.88-3.72 (4H, m20 superimposed), 3 , 42 (1H, m), 3.27 (1H, dd), 2.18 (1H, m), 1.80-1.63 (4H, overlapping m), 1.61-1.42 (3H, m superimposed), 1.33-1.18 (1H, m), 0.95 (3H, t).

Intermediate 19: 2- (Tetrahydrofuran-2-yl) ethanol

A stirring solution of ethyl tetrahydrofuran-2-ylacetate (2.5 g) in dry THF (25 ml) was cooled (ice bath) and 1 M aluminum lithium hydride in tetrahydrofuran was added dropwise in atmosphere of nitrogen at less than 15 ° C. The reaction was allowed to warm to room temperature and after 3 h it was cooled again (ice bath) and 5 N sodium hydroxide (5.5 ml) was added with caution at less than 10 ° C. Then diethyl ether (50 ml) was added and after 10 minutes the resulting solid was filtered and washed well with ether. The filtered 30

combined they were evaporated to give the title compound as a clear oil, in a yield of 1.9 g.

1H NMR (CDCl3): δ 4.03 (1H, m), 3.91 (1H, m), 3.79 (2H, m), 3.74 (1H, m), 2.82 (1H, s), 2.03 (1H, m), 1.98-1.84 (2H, m), 1.84-1.70 (2H, m), 1.63-1.50 (1H, m) .

Intermediate 20: 2- (tetrahydrofuran-2-yl) ethyl methanesulfonate 5

To an ice-cold stirring solution of 2- (tetrahydrofuran-2-yl) ethanol (1.9 g) and triethylamine (4.4 ml) in dry dichloromethane (30 ml) was added dropwise over 5 minutes. methanesufonyl (1.59 ml). The mixture was allowed to slowly warm to room temperature for 16 h, then washed with saturated sodium hydrogen carbonate. The aqueous phase 10 was extracted again with dichloromethane and the combined extracts were washed with brine, dried through a phase separation cartridge and evaporated under reduced pressure to give the title compound as a light brown oil, with a yield of 3.1 g.

1H NMR (CDCl3): δ 4.36 (2H, t), 3.96 (1H, m), 3.86 (1H, m), 3.74 (1H, m), 3.02 (3H, 15 s), 2.01-1.84 (4H, m), 1.58-1.40 (2H, m).

Intermediate 21: 2- (2-Bromoethyl) tetrahydrofuran

2- (tetrahydrofuran-2-yl) ethyl methanesulfonate (3.1 g) and anhydrous lithium bromide (6.57 g) in acetone (50 ml) were refluxed with stirring for 3 h. After allowing to cool, the solvent was evaporated under reduced pressure and the residue was treated with water and extracted three times with dichloromethane. The combined extracts were washed with saturated sodium hydrogen carbonate, dried by passing through a phase separation cartridge and evaporated under reduced pressure to give the title compound as an orange oil, in a yield of 1.99 g. 25

1H NMR (CDCl3): δ 3.98 (1H, m), 3.85 (1H, m), 3.74 (1H, m), 3.50 (2H, m), 2.12-1, 96 (3H, m), 1.96-1.85 (2H, m), 1.54-1.43 (1H, m).

Intermediate 22: 2-Butoxy-8-methoxy-9- [2- (tetrahydrofuran-2-yl) ethyl] -9H-purin-6-amine

A stirring mixture of 2-butoxy-8-methoxy-1H-purin-6-amine salt trifluoroacetate (200 30

mg) and potassium carbonate (236 mg) in dry N, N-dimethylformamide (2 ml) was heated by stirring at 60 ° C for 1 h. 2- (2-Bromoethyl) tetrahydrofuran (122 mg) was added and the stirred mixture was heated at 50 ° C for 4 h. After allowing to cool, water was added and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with water and then brine, dried by passing through a phase separation cartridge and evaporated under reduced pressure to provide a brown oil. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (20-60%) and the appropriate fractions were combined. and evaporated to remove acetonitrile. The remaining aqueous mixture was basified with saturated sodium hydrogen carbonate, extracted three times with dichloromethane and the combined extracts dried by passing through a phase separation cartridge then evaporated to give the title compound as a clear oil, with a yield of 122 mg).

MS calc. for (C16H25N5O3) + = 335

MS found (electrospray): (M + H) + = 336 15

1H NMR (CDCl3): δ 5.10 (2H, s), 4.28 (2H, m), 4.12 (3H, s), 4.04 (2H, m), 3.85 (2H, m), 3.71 (1H, m), 1.98 (3H, m), 1.88 (2H, m), 1.77 (2H, m), 1.51 (3H, m), 0, 97 (3H, t).

Intermediate 23: N2-Butyl-8-methoxy-9- [2- (tetrahydrofuran-2-yl) ethyl] -9H-purin-2,6-diamine

A stirring mixture of N2-butyl-8-methoxy-9H-purin-20 2,6-diamine trifluoroacetic acid salt (200 mg) and potassium carbonate (236 mg) in dry N, N-dimethylformamide (2 ml) It was heated by stirring at 60 ° C for 1 h. 2- (2-Bromoethyl) tetrahydrofuran (122 mg) was added and the stirred mixture was heated at 50 ° C for 4 h. After allowing to cool, water was added and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with water and then with brine, dried by passing through a 25 phase separation cartridge and evaporated under reduced pressure to provide a brown oil. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (20-60%) and the appropriate fractions were combined. and evaporated to remove acetonitrile. The remaining aqueous mixture was basified with saturated sodium hydrogen carbonate, extracted three times with dichloromethane and the combined extracts dried by passing through a cartridge of

phase separation, then evaporated to provide the title compound, in a yield of 107 mg.

MS calc. for (C16H26N6O2) + = 334

MS found (electrospray): (M + H) + = 335

1H NMR (CDCl3): δ 4.90 (2H, s), 4.58 (1H, broad t), 4.09 (3H, s), 3.98 (2H, m), 3.86 5 (2H, m), 3.72 (1H, m), 3.38 (2H, m), 1.99 (3H, m), 1.88 (2H, m), 1.57 (2H, m), 1.52-1.36 ( 3H, m), 0.95 (3H, t).

Intermediate 24: 5,6-Dihydro-2H-pyran-3-carbaldehyde

Concentrated hydrochloric acid (5.5 ml) was added to water (28 ml) followed by acrolein 10 (33.8 ml) and toluene (15 ml). The stirring mixture was heated at reflux at 75 ° C for 1 h when the reflux was gradually decreased. After allowing to cool, potassium carbonate was added until it became basic and the mixture was extracted twice with ether. The combined extracts were washed with brine, dried (Na2SO4) and evaporated to a brown oil. Distillation at a pressure of 6 mbar gave the product as a pale yellow mobile liquid, eg 76-9 ° C, in a yield of 4 g (14%).

1H NMR (CDCl3): δ 9.42 (1H, s), 6.94 (1H, m), 4.35 (2H, m), 3.82 (2H, m), 2.46 (2H, m).

Intermediate 25: Tetrahydro-2H-pyran-3-carbaldehyde

 twenty

5,6-Dihydro-2H-pyran-3-carbaldehyde (2.98 g) in ethanol (70 ml) was treated with 10% palladium on carbon catalyst under nitrogen atmosphere, then hydrogenated at ambient temperature and pressure for 30 minutes. The catalyst was removed by filtration through Celite and the filtrate was evaporated, then evaporated again from toluene to provide the product as an oil, in a yield of 2.58 g. 25

1H NMR (CDCl3): δ 9.72 (1H, s), 3.98 (1H, m), 3.82 (1H, m), 3.73 (1H, m), 3.58 (1H, m), 2.49 (1H, m), 1.95 (1H, m), 1.87 (1H, m), 1.70 (1H, m), 1.61 (1H, m).

Intermediate 26: 3 - [(E, Z) -2- (Methoxy) ethenyl] tetrahydro-2H-pyran

A suspension of methoxymethyltriphenylphosphonium chloride (15.5 g) in dry THF (40 ml) was

cooled to -40 ° C and a solution of potassium tert-butoxide (5.08 g) in dry THF (40 ml) was added dropwise while stirring under a nitrogen atmosphere. After 45 minutes the mixture was cooled further to -65 ° C and a solution of tetrahydro-2H-pyran-3-carbaldehyde (2.58 g) in dry THF (15 ml) was added dropwise. The cooling bath was removed and after allowing to warm to room temperature the reaction was stirred for another 30 minutes. The mixture was then quenched on ice, extracted three times with ether and the combined extracts washed with brine, dried (Na2SO4) and evaporated, then evaporated again with toluene. The crude product was purified by flash chromatography (silica, 0-20% ethyl acetate-cyclohexane) to give the title compound as a colorless oil, in a yield of 2.22 g (69%). 10

1H NMR (CDCl3): δ 6.36 + 5.89 (1H, m), 4.53 + 4.12 (1H, m), 3.88 (1H, m), 3.78 (1H, m ), 3.58 + 3.51 (3H, s), 3.34 (1H, m), 3.10 (1H, m), 2.73 + 2.20 (1H, m), 1.84 ( 1H, m), 1.63 (2H, m), 1.30 (1H, m).

Intermediate 27: Tetrahydro-2H-pyran-3-ilacetaldehyde

 fifteen

To a stirring solution of 3- [2- (methoxy) ethenyl] tetrahydro-2H-pyran (2.22 g) in THF (15 ml) was added 2N hydrochloric acid (15 ml). After 1 h the mixture was diluted with water and extracted three times with ether. The combined extracts were washed with brine, dried (Na2SO4) and evaporated to give the title product as a pale yellow oil, in a yield of 1.79 g. twenty

1H NMR (CDCl3): δ 9.77 (1H, s), 3.85 (2H, m), 3.43 (1H, m), 3.17 (1H, m), 2.34 (2H, m), 2.23 (1H, m), 1.90 (1H, m), 1.64 (2H, m), 1.27 (1H, m).

Intermediate 28: 2- (Tetrahydro-2H-pyran-3-yl) ethanol

A suspension of sodium borohydride (554 mg) in ethanol (20 ml) was cooled (ice bath) and a solution of tetrahydro-2H-pyran-3-ylacetaldehyde (1.88 g) in ethanol (8 ml) was added. ) drop by drop stirring for 10 minutes. After 15 minutes the ice bath was removed and after another 3 h the mixture was heated at 50 ° C for 1 h. After cooling the solvent was evaporated and the residue was treated with water and extracted three times with dichloromethane. The combined extracts were washed with dilute brine, dried through a hydrophobic frit and evaporated to give the title product as an oil. Another batch of product was obtained by acidifying the aqueous solution with 2N hydrochloric acid, saturating with sodium chloride and extracting three times with dichloromethane. These extracts are

They were treated as before and the batches were combined providing a total yield of 1.54 g (81%).

1H NMR (CDCl3): δ 3.88 (2H, m), 3.70 (2H, m), 3.38 (1H, m), 3.11 (1H, t), 1.89 (1H, m), 1.76 (1H, m), 1.61 (1H, m), 1.45 (2H, m), 1.22 (2H, m). OH not visible.

Intermediate 29: 2- (tetrahydro-2H-pyran-3-yl) ethyl methanesulfonate 5

A solution of 2- (tetrahydro-2H-pyran-3-yl) ethanol (1.54 g) and triethylamine (3.3 ml) in dichloromethane (25 ml) was cooled (ice bath) and methanesufonyl chloride was added (1.19 ml) dropwise by stirring for 5 minutes. The reaction slowly warmed to room temperature while the ice bath melted. After 16 hours the mixture was washed with saturated aqueous sodium hydrogen carbonate, the aqueous phase was extracted twice with dichloromethane and the combined extracts were washed with diluted brine, dried by passing through a hydrophobic frit and evaporated to provide the compound of the title in the form of a brown oil, with a yield of 2.38 g.

1H NMR (CDCl3): δ 4.27 (2H, t), 3.86 (2H, m), 3.41 (1H, m), 3.14 (1H, m), 3.02 (3H, 15 s), 1.91 (1H, m), 1.8 (1H, m), 1.71 (1H, m), 1.63 (3H, m), 1.23 (1H, m).

Intermediate 30: 2-Butoxy-8-methoxy-9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -9H-purin-6-amine

A stirring mixture of 2-butoxy-8-methoxy-9H-purin-6-amine salt trifluoroacetate (200 mg) and potassium carbonate (236 mg) in dry N, N-dimethylformamide (2 ml) was heated by stirring to 20 60 ºC for 1 h. 2- (Tetrahydro-2H-pyran-3-yl) ethyl methanesulfonate (142 mg) was added and the stirred mixture was heated at 60 ° C for 3 h. Water was added and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with water and then with brine, dried by passing through a phase separation cartridge and evaporated under reduced pressure to provide a brown oil. This was purified by C18 reverse phase chromatography using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (20-70%) and the appropriate fractions were combined and evaporated. to remove acetonitrile. The remaining aqueous mixture was basified with saturated sodium hydrogen carbonate, extracted three times with dichloromethane and the combined extracts dried by passing through a phase separation cartridge, then evaporated to give the title compound as a brown oil, with a yield of

108 mg

MS calc. for (C17H27N5O3) + = 349

MS found (electrospray): (M + H) + = 350

1H NMR (CDCl3): δ 5.10 (2H, s), 4.28 (2H, t), 4.12 (3H, s), 3.96 (2H, t), 3.87 (2H, m), 3.38 (1H, m), 3.12 (1H, m), 1.96 (1H, m), 1.77 (2H, m), 1.71-1.44 (6H, m ), 1.21 (2H, m), 0.97 5 (3H, t).

Intermediate 31: N2-Butyl-8-methoxy-9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -9H-purin-2,6-diamine

A stirring mixture of trifluoroacetic acid salt of N2-butyl-8-methoxy-9H-purin-2,6-diamine (200 mg) and potassium carbonate (236 mg) in dry N, N-dimethylformamide (2 ml) is 10 heated by stirring at 60 ° C for 1 h. 2- (Tetrahydro-2H-pyran-3-yl) ethyl methanesulfonate (142 mg) was added and the stirred mixture was heated at 60 ° C for 3 h. Water was added and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with water and then with brine, dried by passing through a phase separation cartridge and evaporated under reduced pressure to provide a brown oil. This was purified by C18 reverse phase chromatography using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (20-60%) and the appropriate fractions were combined and evaporated. to remove acetonitrile. The remaining aqueous mixture was basified with saturated sodium hydrogen carbonate, extracted three times with dichloromethane and the combined extracts dried by passing through a phase separation cartridge 20 then evaporated to give the title compound as a brown solid, with a yield of 138 mg.

MS calc. for (C17H28N6O2) + = 348

MS found (electrospray): (M + H) + = 349

1H NMR (CDCl3): δ 4.89 (2H, wide s), 4.57 (1H, wide t), 4.08 (3H, s), 3.88 (4H, m), 25 3.36 (3H, m), 3.12 (1H, m), 1.97 (1H, m), 1.68-1.52 (7H, m), 1.40 (2H, m), 1.20 ( 1H, m), 0.94 (3H, t).

Intermediate 32: 2- (Tetrahydro-2H-pyran-4-yl) ethanol

To a frozen solution of lithium aluminum hydride (12.6 ml, 2.3 M solution in tetrahydrofuran) in dry tetrahydrofuran (20 ml) and under a nitrogen atmosphere, a solution of tetrahydro-2H-pyran-4- was added ethyl ilacetate (5 g) in dry tetrahydrofuran dropwise over 10 minutes. After the addition, the reaction was heated to reflux, overnight. The reaction was cooled and diluted with diethyl ether (100 ml). A 5M aqueous solution of 5-sodium hydroxide (~ 10 ml) was added with caution to the reaction mixture until effervescence ended. The white precipitate that formed was removed by filtration. The resulting filtrate was dried over potassium carbonate, filtered and concentrated in vacuo. This gave the title compound as a colorless oil (3.3 g).

MS calc. for (C7H14O2) + = 130 10

MS found (electrospray): (M + H) + = 131

 1H NMR (DMSO): 4.35 (1H, t), 3.80 (2H, m), 3.43 (2H, m), 3.25 (2H, m), 1.60 (1H, m ), 1.54 (2H, m), 1.35 (2H, m), 1.13 (2H, m).

Intermediate 33: 2- (tetrahydro-2H-pyran-4-yl) ethyl methanesulfonate

 fifteen

At 2- (tetrahydro-2H-pyran-4-yl) ethanol (3.3 g) in dry dichloromethane (100 ml) at 0 ° C and under nitrogen atmosphere triethylamine (4.6 ml) was added, followed by methanesufonyl (2.6 ml) drop by drop for 5 minutes. The reaction was stirred until the bath ice melted and left overnight at room temperature. The reaction was washed with saturated aqueous sodium bicarbonate (40 ml). The organic phase was dried by passing through a hydrophobic frit and concentrated in vacuo to give the title compound as a yellow oil (5.4 g).

1H NMR (DMSO): 4.24 (2H, t), 3.82 (2H, m), 3.80 (3H, s), 3.27 (2H, m), 2.50 (5H, m ), 1.60 (2H, m).

Intermediate 34: 4- (2-Bromoethyl) tetrahydro-2H-pyran 25

To 2- (tetrahydro-2H-pyran-4-yl) ethyl methanesulfonate (5.4 g) in dry acetone at room temperature, lithium bromide (9 g) was added at one time. The reaction was heated at reflux for 4 hours, under a nitrogen atmosphere. The reaction was cooled to room temperature and concentrated in vacuo. The residue was taken in dichloromethane (100 ml) and washed with water (50 ml). The organic phase was dried by passing through a hydrophobic frit, and concentrated in vacuo. The product was purified by silica chromatography (40 g) (ISCO) using a gradient elution of 0–50% cyclohexane: ethyl acetate to give the title compound as a colorless oil (3.5 g).

1H NMR (DMSO): 3.82 (2H, m), 3.56 (2H, t), 3.26 (2H, m), 1.75 (2H, m), 1.65 (1H, m ), 1.57 (2H, m), 1.16 (2H, m). 10

Intermediate 35: 2 - [(2,2-Dimethylpentyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

To a suspension of 2-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (500 mg) and 2,2-dimethylpentanol (3.8 ml) at 50 ° C was added sodium hydride (396 mg, 60% dispersion) in portions. Other portions of 2,2-dimethylpentanol 15 (1.5 ml) were added to the resulting viscous foam. The reaction was stirred at 50 ° C for 72 h. The reaction mixture was then cooled with caution, quenched with water (10 ml) and extracted with EtOAc (3 x 25 ml). The organic phases were combined, washed with brine (30 ml), dried over MgSO4, filtered and concentrated in vacuo to provide a yellow oil. This was azeotroped with toluene (x 3) and the resulting viscous yellow oil was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (30-80%) providing the title compound as a brown solid (372 mg).

MS calc. for (C17H27N5O2) + = 333

MS found (electrospray): (M + H) + = 334 25

Intermediate 36: 8-Bromo-2 - [(2,2-dimethylpentyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

A 2 - [(2,2-dimethylpentyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (372 mg) in dry chloroform (4.05 ml) at 0 ° C NBS (209 mg) was added in a single portion. The reaction was heated to room temperature and stirred for 5 h. The mixture was taken in DCM (20 ml) and washed with water (30 ml). The organic phases were separated and dried using a hydrophobic frit then concentrated in vacuo to provide the title compound as a green / brown viscous foam (475 mg).

MS calc. for (C17H26BrN5O2) + = 411/413

MS found (electrospray): (M + H) + = 412/414

1H NMR ((CD3) 2SO): δ 7.48 (2H, broad s), 5.52 (1H, dd), 4.08-3.89 (3H, m), 3.70 (1H, m), 2.97-2.83 (1H , m), 2.04-1.94 (1H, m), 1.89-1.51 (4H, m), 1.35-1.21 (4H, m), 0.99-0.91 10 (6H, s), 0.90-0.84 (3H, m).

Intermediate 37: 2 - [(2,2-Dimethylpentyl) oxy] -8-methoxy-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

To a solution of 8-bromo-2 - [(2,2-dimethylpentyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-15 6-amine (475 mg) in dry MeOH (3.92 ml) a solution of sodium methoxide (0.649 ml, 30% by weight in MeOH) was added. The reaction mixture was stirred at reflux for 5 h. The reaction was cooled and concentrated in vacuo to provide an orange residue. The residue was taken in saturated ammonium chloride solution (25 ml) and extracted with EtOAc (25 ml). The organic phase was separated and washed with water (15 ml). The organic phases were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as an orange solid (323 mg).

MS calc. for (C18H29N5O3) + = 363

MS found (electrospray): (M + H) + = 364

1H NMR ((CD3) 2SO): δ 6.85 (2H, s), 5.37 (1H, dd), 4.05 (3H, s), 4.02-3.83 (3H, m), 3.63-3.54 (1H , m), 2.72-2.58 (1H, m), 1.97-1.91 (1H, m), 1.77-1.46 (4H, m), 1.31-1.23 (4H, m), 0.93 (6H, s), 0.89-0.83 (3H, m).

Intermediate 38: Trifluoroacetic acid salt of 2 - [(2,2-dimethylpentyl) oxy] -8-methoxy-9H-purin-6-amine

To a solution of 2 - [(2,2-dimethylpentyl) oxy] -8-methoxy-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (323 mg) in dry MeOH ( 3.23 ml) TFA (0.323 ml) was added and the reaction was stirred at room temperature for 48 h. The reaction was concentrated in vacuo to provide a yellow residue. The residue was triturated with Et2O and filtered to give the title compound 5 as an off-white solid (252 mg).

MS calc. for (C13H21N5O2) + = 279

MS found (electrospray): (M + H) + = 280

Intermediate 39: 2 - [(2,2-Dimethylpentyl) oxy] -8-methoxy-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine 10

To a solution of trifluoroacetic acid salt of 2 - [(2,2-dimethylpentyl) oxy] -8-methoxy-9H-purin-6-amine (252 mg) in dry DMF (3.97 ml) was added potassium carbonate (356 mg). The mixture was stirred at 60 ° C for 90 minutes. The reaction was cooled and 4- (bromomethyl) tetrahydro-2H-pyran (127 mg) was added. The mixture was stirred at 50 ° C for 6 h. Reaction 15 was cooled and taken in EtOAc (40 ml). The mixture was washed with water (2 x 20 ml) and the organic phases were separated, dried over MgSO4 and concentrated in vacuo to provide a viscous oil. The crude material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (30-80%) to provide the compound of title in the form of an off-white solid 20 (116 mg).

MS calc. for (C19H31N5O3) + = 377

MS found (electrospray): (M + H) + = 378

Intermediate 40: N2-Pentyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-2,6-diamine

To a solution of 2-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (500 mg) in dry ethylene glycol (2.3 ml) was added 1-pentylamine (689 mg ). The solution was stirred at reflux (120 ° C) overnight. The reaction was cooled, taken in EtOAc (30 ml) and washed with water (2 x 20 ml). The organic phases were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a viscous brown oil (561 mg).

MS calc. for (C15H24N6O) + = 304

MS found (electrospray): (M + H) + = 305

1H NMR ((CD3) 2SO): δ 7.85 (1H, s), 6.62 (2H, s), 6.22 (1H, t), 5.40 (1H, dd), 4.01-3.95 (1H, m), 3 , 63-3.55 (1H, m), 3.26-3.19 (2H, m), 2.25-2.13 (1H, m), 1.95 (1H, m), 1.85 (1H, 10 m), 1.66 (1H, m), 1.60-1.15 (8H, m), 0.87 (3H, m). Evidence of additional protons 0.8-1.6 - fat or hydrocarbon fragments.

Intermediate 41: 8-Bromo-N2-pentyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-2,6-diamine

A solution of N2-pentyl-9- (tetrahydro-2H-piran-2-yl) -9H-purin-2,6-diamine (543 mg) in dry chloroform (4.6 ml) was cooled to 0 ° C and NBS (334 mg) was added. The mixture was stirred at room temperature for 10 minutes. The reaction was taken in DCM (30 ml) and washed with water (30 ml). The organic phases were separated, dried using a hydrophobic frit and concentrated in vacuo to give the title compound as a viscous brown residue (627 mg) which was used crude in the next step. twenty

MS calc. for (C15H23BrN6O) + = 382/384

MS found (electrospray): (M + H) + = 383/385

Intermediate 42: 8-Methoxy-N2-pentyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-2,6-diamine

To a solution of 8-bromo-N2-pentyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-2,6-diamine (607 mg) in dry MeOH (4.75 ml) was added a solution of sodium methoxide (0.906 ml, 30% by weight in MeOH) and the mixture was stirred at 60 ° C for 48 h. The reaction was concentrated in vacuo. The residue was taken in EtOAc (25 ml) and washed with saturated ammonium chloride (25 ml). The organic phases were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a viscous red / brown oil (520 mg) which was used crude in the next step.

MS calc. for (C16H26N6O2) + = 334

MS found (electrospray): (M + H) + = 335 10

Intermediate 43: 8-Methoxy-N2-pentyl-9H-purin-2,6-diamine trifluoroacetic acid salt

To a solution of 8-methoxy-N2-pentyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-2,6-diamine (520 mg) in dry MeOH (5.2 ml) was added TFA (0.52 ml) and the mixture was stirred at room temperature for 48 h. The reaction was concentrated in vacuo to provide an orange residue that was triturated with Et2O and filtered to give the title compound as an off-white solid (223 mg).

MS calc. for (C11H18N6O) + = 250

MS found (electrospray): (M + H) + = 251

1H NMR ((CD3) 2SO): δ 13.02-12.15 (1H, broad d), 8.33-7.18 (2H, broad m), 4.04 20 (3H, s), 3.32-3.17 (2H, m) , 1.59-1.47 (2H, m), 1.38-1.20 (4H, m), 0.88 (3H, t), an exchangeable proton is not observed.

Intermediate 44: 8-Methoxy-N2-pentyl-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-2,6-diamine

To a salt solution of 8-methoxy-N2-pentyl-9H-purin-2,6-diamine trifluoroacetic acid (223 mg) in dry DMF (3.85 ml) was added potassium carbonate (339 mg) at 60 ° C and the mixture was stirred for 90 minutes. The mixture was cooled to room temperature and 4- (bromomethyl) tetrahydro-2H-pyran (121 mg) was added in one portion. The reaction was stirred at 50 ° C overnight and then cooled and taken in EtOAc (20 ml). The organic phases were washed with water (2 x 10 ml), separated, dried over MgSO4, filtered and concentrated in vacuo to give an off-white solid. The crude material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (20-60%) to provide the compound of title in the form of an off-white solid (140 mg).

MS calc. for (C17H28N6O2) + = 348

MS found (electrospray): (M + H) + = 349

Intermediate 45: 2 - [(3-Methylbutyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

 fifteen

To 3-methyl-1-butanol (1.03 ml) in DME (5 ml) was added sodium tert-butoxide (912 mg) in portions for 5 minutes with stirring. The mixture was stirred at room temperature until it became homogeneous. 2-Chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (600 mg) was added followed by DME (4.6 ml). The reaction was heated at 110 ° C overnight. The reaction was allowed to cool, taken in water (20 ml) and washed with EtOAc (2 x 20 ml). The organic phases were extracted with brine, separated, dried over MgSO4, filtered and concentrated in vacuo to provide a viscous yellow oil. The crude material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (30-80%) to provide the compound of title in the form of a yellow residue (266 mg). 25

MS calc. for (C15H23N5O2) + = 305

MS found (electrospray): (M + H) + = 306

Intermediate 46: 8-Bromo-2 - [(3-methylbutyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

To a solution of 2 - [(3-methylbutyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (266 mg) in dry chloroform (3.15 ml) at At 0 ° C NBS (163 mg) was added. The reaction was heated to room temperature and stirred for 5 h. The reaction was taken in DCM (20 ml) and extracted with water (20 ml). The organic phases were separated, dried using a hydrophobic frit and concentrated in vacuo to give the title compound as a green / brown solid (314 mg).

MS calc. for (C15H22BrN5O2) + = 383/385

MS found (electrospray): (M + H) + = 384/386

1H NMR ((CD3) 2SO): δ 7.38 (2H, broad s), 5.49 (1H, dd), 4.24 (2H, t), 4.03 (1H, d), 10 3.68-3.57 (1H, m) , 3.03-2.90 (1H, m), 2.03-1.50 (8H, m), 0.92 (6H, d).

Intermediate 47: 2 - [(3-Methylbutyl) oxy] -8-methoxy-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

To a solution of 8-bromo-2 - [(3-methylbutyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (314 mg) was added a solution of methoxide sodium (0.460 ml, 30% by weight in MeOH) 15 and the mixture was stirred at reflux for 4 h. The reaction was allowed to cool and concentrated in vacuo to provide an orange residue. The residue was taken in EtOAc (20 ml) and extracted with saturated ammonium chloride solution (20 ml), followed by water (20 ml). The organic phases were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a light orange solid (210 mg). twenty

MS calc. for (C16H25N5O3) + = 335

MS found (electrospray): (M + H) + = 336

1H NMR ((CD3) 2SO): δ 6.81 (2H, wide s), 5.34 (1H, dd), 4.26-4.15 (2H, m), 4.05 (3H, s), 3.96 (1H, d), 3.61-3.52 (1H, m), 2.77-2.66 (1H, m), 1.98-1.90 (1H, m), 1.79-1.46 (7H, m ), 0.92 (6H, d). 25

Intermediate 48: Trifluoroacetic acid salt of 2 - [(3-methylbutyl) oxy] -8-methoxy-9H-purin-6-amine

To a solution of 2 - [(3-methylbutyl) oxy] -8-methoxy-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (210 mg) in dry MeOH (2, 1 ml) TFA (0.21 ml) was added and the mixture was stirred at room temperature for 24 h. The reaction was concentrated in vacuo to provide a yellow residue that was triturated with Et2O (15 ml) and filtered under reduced pressure to give the title compound as an off-white solid (143 mg).

MS calc. for (C11H17N5O2) + = 251

MS found (electrospray): (M + H) + = 252

1H NMR ((CD3) 2SO): δ 7.90 (1H, wide), 4.38-4.30 (2H, m), 4.05 (3H, s), 1.79-1.68 (1H, m), 1.65-1, 56 (2H, m), 0.93 (6H, d) no two exchangeable protons were observed. 10

Intermediate 49: 2 - [(3-Methylbutyl) oxy] -8- (methoxy) -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine

To a solution of trifluoroacetic acid salt of 2 - [(3-methylbutyl) oxy] -8-methoxy-9H-purin-6-amine (143 mg) in dry DMF (2.42 ml) was added potassium carbonate (217 mg) and mixture 15 was stirred at 60 ° C for 90 minutes. The reaction was cooled and 4- (bromomethyl) tetrahydro-2H-pyran (77 mg) was added. The reaction was stirred at 50 ° C overnight and cooled to room temperature. The mixture was taken in EtOAc (30 ml) and extracted with water (2 x 15 ml). The organic phases were separated, dried over MgSO4 and concentrated in vacuo to provide a viscous yellow oil. The crude material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (20-60%) to provide the compound. of the title in the form of a transparent viscous oil (52 mg).

MS calc. for (C17H27N5O3) + = 349

MS found (electrospray): (M + H) + = 350 25

Intermediate 50: 2 - [(2-Methylbutyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

To sodium 2-methyl-1-butanol (0.855 ml) in DME (4 ml) was added tert-butoxide (760 mg). The mixture was stirred at room temperature until it became homogeneous. 2-Chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (500 mg) was added followed by DME (4 ml). The reaction was heated at 110 ° C overnight. The mixture was cooled and concentrated in vacuo to give a yellow residue. The residue was taken in water (30 ml) and extracted with EtOAc (2 x 30 ml). The organic phases were separated and washed with brine (30 ml). The organic phases were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a yellow / brown residue. This material was taken to the next stage without further purification. 10

MS calc. for (C15H23N5O2) + = 305

MS found (electrospray): (M + H) + = 306

Intermediate 51: 8-Bromo-2 - [(2-methylbutyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

A solution of 2 - [(2-methylbutyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (245-15 mg) in dry chloroform (2.9 ml) is cooled to 0 ° C and NBS (150 mg) was added providing a green / brown solution. The reaction mixture was stirred at room temperature for 6 h. The mixture was taken in DCM (20 ml) and washed with water (20 80 ml). The organic phases were separated, dried by passing through a hydrophobic frit and concentrated in vacuo to give the title compound as a green solid (292 mg). twenty

MS calc. for (C15H22BrN5O2) + = 383/385

MS found (electrospray): (M + H) + = 384/386

1H NMR ((CD3) 2SO): δ 7.39 (2H, width), 5.50 (1H, dd), 4.15-4.07 (1H, m), 4.06-3.95 (2H, m), 3.70-3, 57 (1H, m), 3.02-2.88 (1H, m), 2.03-1.40 (7H, m), 1.27-1.13 (1H, m), 0.99- 0.84 (6H, m). 25

Intermediate 52: 2 - [(2-Methylbutyl) oxy] -8-methoxy-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

To a solution of 8-bromo-2 - [(2-methylbutyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (284 mg) in dry MeOH (2, 54 ml) a solution of sodium methoxide (0.416 ml, 30% by weight in MeOH) was added and the mixture was stirred at reflux for 1 h. The reaction was allowed to cool and concentrated in vacuo. The resulting residue was dissolved in EtOAc (15 ml) and poured into saturated ammonium chloride solution (15 ml). The organic phases were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as an orange foam (199 mg).

MS calc. for (C16H25N5O3) + = 335 10

MS found (electrospray): (M + H) + = 336

1H NMR ((CD3) 2SO): δ 6.87 (2H, s), 5.35 (1H, dd), 4.13-3.91 (6H, m), 3.66-3.50 (1H, m), 2.77-2, 62 (1H, m), 1.98-1.42 (7H, m), 1.26-1.13 (1H, m), 0.98-0.85 (6H, m).

Intermediate 53: Trifluoroacetic acid salt of 2 - [(2-methylbutyl) oxy] -8- (methoxy) -9H-purin-6-amine 15

To a solution of 2 - [(2-methylbutyl) oxy] -8-methoxy-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (199 mg) in dry MeOH (1, 99 ml) TFA (0.199 ml) was added. The mixture was stirred at room temperature for 24 h. The reaction was concentrated in vacuo to provide a yellow residue. The residue was triturated with Et2O and filtered to give the title compound 20 as an off-white solid (111 mg).

MS calc. for (C11H17N5O2) + = 251

MS found (electrospray): (M + H) + = 252

1H NMR ((CD3) 2SO): δ 8.01-7.46 (2H, width), 4.20-4.00 (6H, m), 1.88-1.73 (1H, m), 1.54-1.40 (1H, m ), 1.28-1.12 (1H, m), 0.99-0.84 (6H, m). 25

Intermediate 54: 2 - [(2-Methylbutyl) oxy] -8-methoxy-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine

To a solution of 2 - [(2-methylbutyl) oxy] -8-methoxy-9H-purin-6-amine (109 mg) in dry DMF (1.86 ml) was added potassium carbonate (165 mg) and the mixture stirred at 60 ° C for 90 minutes. The mixture was cooled to room temperature and 4- (bromomethyl) tetrahydro-2H-pyran (59 mg) was added. The reaction was stirred at 50 ° C overnight and cooled to room temperature. The mixture was taken in EtOAc (15 ml) and washed with water (2 x 10 ml). The organic phases were separated, dried over MgSO4, filtered and concentrated in vacuo to provide a yellow viscous oil. The material was purified by C18 10 reverse phase chromatography (ISCO) using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (20-60%) to provide the title compound. in the form of a yellow oil (41 mg).

MS calc. for (C17H27N5O3) + = 349

MS found (electrospray): (M + H) + = 350 15

Intermediate 55: 2 - [(1-Methylbutyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

To 2-pentanol (3.65 ml) sodium tert-butoxide (760 mg) was added portionwise for 5 minutes. The mixture was stirred at room temperature until it became homogeneous. 2-Chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (500 mg) was added and the reaction was heated at 20 50 ° C overnight, then for another 72 h. The reaction mixture was cooled and quenched with water (10 ml) and extracted with EtOAc (3 x 25 ml). The organic phases were combined, washed with brine (30 ml), dried over MgSO4, filtered and concentrated in vacuo to give the crude title compound as a viscous yellow oil. In another flask, a suspension of 2-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine 25 (500 mg) and 2-pentanol (3.8 ml) was heated to 50 ° C. Sodium hydride (396 mg, 60% dispersion) was added

portionwise and the reaction was stirred at 50 ° C for 72 h. The reaction was cooled and quenched with water (10 ml) and extracted with EtOAc (3 x 25 ml). The combined organic phases were washed with brine (30 ml), dried over MgSO4, filtered and concentrated in vacuo to afford the crude title compound as a yellow oil. The two crude reaction products were combined and purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (20- 60%) providing the title compound as a brown oil (382 mg).

MS calc. for (C15H23N5O2) + = 305

MS found (electrospray): (M + H) + = 306 10

Intermediate 56: 8-Bromo-2 - [(1-methylbutyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

To a solution of 2 - [(1-methylbutyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (382 mg) in dry chloroform (4.52 ml) at At 0 ° C NBS (234 mg) was added in a single portion. The reaction was heated to room temperature and stirred for 5 h. The reaction mixture was taken in DCM (20 ml) and washed with water (30 ml). The organic phases were separated, dried by passing through a hydrophobic frit and concentrated in vacuo to provide a green / brown foam (493 mg).

MS calc. for (C15H22BrN5O2) + = 383/385

MS found (electrospray): (M + H) + = 384/386 20

1H NMR ((CD3) 2SO): δ 7.44 (2H, width), 5.48 (1H, dd), 5.09-4.98 (1H, m), 4.07-3.98 (1H, m), 3.68-3, 57 (1H, m), 3.02-2.88 (1H, m), 2.03-1.91 (1H, m), 1.87-1.79 (1H, m), 1.74- 1.45 (5H, m), 1.44-1.20 (5H, m), 0.95-0.85 (3H, m).

Intermediate 57: 2 - [(1-Methylbutyl) oxy] -8-methoxy-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

 25

To a solution of 8-bromo-2 - [(1-methylbutyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-

Amine (493 mg) in dry MeOH (4.37 ml) was added a solution of sodium methoxide (0.722 ml, 30% by weight in MeOH) and the mixture was stirred at reflux for 6 h. Another portion of sodium methoxide solution (0.120 ml, 30% by weight in MeOH) was added and the reaction continued for 90 minutes. The reaction was cooled and concentrated in vacuo to provide an orange residue. The residue was taken in saturated ammonium chloride (25 ml) and washed with EtOAc (25 ml). The organic phases were separated and washed with water (15 ml). The organic phases were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as an orange foam (313 mg).

MS calc. for (C16H25N5O3) + = 335

MS found (electrospray): (M + H) + = 336 10

1H NMR ((CD3) 2SO): δ 6.78 (2H, s), 5.33 (1H, d), 5.07-4.96 (1H, m), 4.09-3.92 (4H, m), 3.62-3, 49 (1H, m), 2.80-2.64 (1H, m), 1.97-1.88 (1H, m), 1.77-1.43 (6H, m), 1.42- 1.19 (5H, m), 0.95-0.84 (3H, m).

Intermediate 58: Trifluoroacetic acid salt of 2 - [(1-methylbutyl) oxy] -8-methoxy-9H-purin-6-amine 15

To a solution of 2 - [(1-methylbutyl) oxy] -8-methoxy-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (313 mg) in dry MeOH (3, 13 ml) TFA (0.313 ml) was added and the mixture was stirred at room temperature for 48 h. The reaction mixture was concentrated in vacuo to provide a yellow residue that was triturated with Et2O and filtered to give the title compound as an off-white solid (218 mg).

MS calc. for (C11H17N5O2) + = 251

MS found (electrospray): (M + H) + = 252

1H NMR ((CD3) 2SO): δ 8.12 (2H, width), 5.20-5.09 (1H, m), 4.05 (3H, s), 1.74-1.52 (2H, m), 1.45-1, 27 (5H, m), 0.94-0.85 (3H, m), an exchangeable proton is not observed. 25

Intermediate 59: 2 - [(1-Methylbutyl) oxy] -8-methoxy-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine

To a salt solution of trifluoroacetic acid of 2 - [(1-methylbutyl) oxy] -8-methoxy-9H-purin-6-amine (218 mg) in dry DMF (3.71 ml) was added potassium carbonate (330 mg) The mixture was stirred at 60 ° C for 90 minutes. The reaction was cooled and 4- (bromomethyl) tetrahydro-2H-pyran (118 mg) was added. The reaction was stirred at 50 ° C for 6 h and cooled to room temperature. The mixture was taken in EtOAc (40 ml) and washed with water (2 x 20 ml). The organic phases were separated, dried over MgSO4 and concentrated in vacuo to provide a viscous yellow oil. The material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (20-60%) to provide the title compound in form of a transparent oil (92 mg). 10

MS calc. for (C17H27N5O3) + = 349

MS found (electrospray): (M + H) + = 350

Intermediate 60: 2-Chloro-1H-purin-6-amine

 fifteen

A mixture of 2,6-dichloro-1H-purine (5 g) and ammonia solution (79.2 ml, 2 M in (isopropanol) was stirred and heated at 120 ° C in an autoclave overnight. cooled and concentrated in vacuo to provide the title compound as a whitish solid with quantitative yield.

MS calc. for (C5H4ClN5) + = 169/171 20

MS found (electrospray): (M + H) + = 170/172

1H NMR ((CD3) 2SO): δ 8.14 (1H, s), 7.66 (2H, s), an exchangeable proton is not observed.

Intermediate 61: 2-Chloro-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine

 25

To a suspension of 2-chloro-1H-purin-6-amine (1.57 g) and potassium carbonate (2.57 g) in DMF (55 ml) was added 4- (bromomethyl) tetrahydro-2H-pyran (2 , 0 g) in one serving. The mixture was stirred at 90 ° C overnight. The reaction mixture was taken in chloroform / isopropanol (3: 1, 100 ml) and extracted with water (100 ml). The organic phases were separated and the aqueous one was extracted.

with chloroform / isopropanol (3: 1, 2 x 50 ml). The organic phases were combined, dried by passing through a hydrophobic frit and concentrated in vacuo to give the title compound as an off-white solid (1.30 g, 52%).

MS calc. for (C11H14ClN5O) + = 267/269

MS found (electrospray): (M + H) + = 268/270 5

1H NMR ((CD3) 2SO): δ 8.13 (1H, s), 7.73 (2H, wide s), 4.00 (2H, d), 3.81 (2H, dd), 3.28-3.17 (2H, m), 2.14-1.99 (1H, m), 1.43-1.33 (2H, m), 1.33-1.17 (2H, m).

Intermediate 62: 8-Bromo-2-chloro-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine

To a solution of 2-chloro-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine (1.30 g) in 10 dry chloroform (32 ml) at room temperature was added NBS ( 2.16 g). The reaction was stirred at 60 ° C for 6 h. The mixture was cooled, taken in DCM (50 ml) and washed with water (50 ml). The organic phases were passed through a hydrophobic frit and concentrated in vacuo to give the title compound as a brown solid (1.36 g).

MS calc. for (C11H13BrClN5O) + = 345/347/349 15

MS found (electrospray): (M + H) + = 346/348/350

1H NMR ((CD3) 2SO): δ 7.91 (2H, width), 4.04-3.94 (1H, m), 3.82 (2H, dd), 3.31-3.15 (2H, m), 2.19-2, 01 (1H, m), 1.48-1.15 (5H, m).

Intermediate 63: 2-Chloro-8-methoxy-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine

 twenty

To a solution of 8-bromo-2-chloro-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine (1.36 g) in dry MeOH (27.5 ml) was added 1 M solution of sodium hydroxide (27.5 ml) and the mixture was stirred at reflux for 30 minutes. The reaction was cooled to room temperature and concentrated in vacuo. The obtained residue was triturated with water (60 ml) and extracted with EtOAc (120 ml). The organic phase was washed with brine (60 ml), dried over MgSO4, filtered and concentrated in vacuo to give a pink / white solid. The material was taken in MeOH / DMSO (1: 1) and a precipitate settled in the solution. The solid was removed by filtration and the filtrate

It was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (10-45%). The filtered solid was combined with the material obtained from purification to provide the title compound (192 mg).

MS calc. for (C12H16ClN5O2) + = 297/299 5

MS found (electrospray): (M + H) + = 298/300

1H NMR ((CD3) 2SO): δ 7.45-7.28 (2H, m), 4.10 (3H, s), 3.87-3.73 (3H, m), 3.22 (3H, t), 2.07-1, 93 (1H, m), 1.46-1.36 (2H, m), 1.33-1.14 (2H, m).

Intermediate 64: 2 - [(2-Cyclopropylethyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

 10

To a mixture of 2-cyclopropyletanol (3.45 g) in DME (20 ml) was added sodium tert-butoxide (3.86 g) gradually. The reaction was stirred under a nitrogen atmosphere for 30 minutes, then 2-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (2.54 g) and DME (20 ml) The reaction was heated at reflux (110 ° C) overnight, then for another 8 h. The reaction was quenched in water (100 ml) and extracted with EtOAc (2 x 100 ml). The organic phases were combined and washed with brine (100 ml) and dried using a hydrophobic frit. The resulting oil was azeotroped with toluene (x 2) to provide a gum. This was triturated with Et2O (CO2 and acetone bath cooled) until the title compound was obtained as a yellow powder (1,579 g) that was subjected to high vacuum for 24 h.

MS calc. for (C15H21N5O2) + = 303 20

MS found (electrospray): (M + H) + = 304

1H NMR (CDCl3): δ 7.85 (1H, s), 5.64 (1H, dd), 5.51 (2H, width), 4.39 (2H, dt), 4.19-4.11 (1H, m), 3 , 80-3.71 (1H, m), 2.13-1.94 (3H, m), 1.83-1.59 (5H, m), 0.94-0.82 (1H, m) , 0.53-0.43 (2H, m), 0.16-0.09 (2H, m).

Intermediate 65: 8-Bromo-2 - [(2-cyclopropylethyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-25 amine

2 - [(2-Cyclopropylethyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (1,579 g) is

dissolved in chloroform (15 ml) and cooled in an ice bath at 1 ° C. NBS (1.02 g) was added gradually, keeping the reaction temperature below 2 ° C. The reaction was stirred for 30 minutes (cooling in an ice bath) before allowing to warm to room temperature. The reaction was then stirred for 6 h. Chloroform (50 ml) was added and the mixture was fractionated with water (50 ml) and separated using a hydrophobic frit. The organic phases were evaporated under reduced pressure to give the title compound as a brown foam (1.867 g).

MS calc. for (C15H20BrN5O2) + = 381/383

MS found (electrospray): (M + H) + = 382/384

1H NMR (CDCl3): δ5.62 (1H, dd), 5.45 (2H, wide), 4.44-4.34 (2H, m), 4.22-4.14 10 (1H , m), 3.72 (1H, dt), 3.11-2.99 (1H, m), 2.16-2.07 (1H, m), 1.90-1.58 (6H, m ), 0.93-0.82 (1H, m), 0.53-0.46 (2H, m), 0.16-0.10 (2H, m).

Intermediate 66: 2 - [(2-Cyclopropylethyl) oxy] -8-methoxy-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

 fifteen

A solution of 8-bromo-2 - [(2-cyclopropylethyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (1,867 g) in dry MeOH (14 ml) It was treated with sodium methoxide solution (3.1 ml, 25% by weight in MeOH) and heated at reflux for 5 h. The reaction was concentrated under reduced pressure before fractionating between EtOAc (100 ml) and ammonium chloride (100 ml). The organic phases were separated and the aqueous one was reextracted with EtOAc (100 ml). The combined organic phases were washed with brine (100 ml), separated and dried using a hydrophobic frit. The organic phases were evaporated under reduced pressure to give the title compound as a brown foam (845 mg).

MS calc. for (C16H23N5O3) + = 333

MS found (electrospray): (M + H) + = 334 25

1H NMR (CDCl3): δ 5.51 (1H, dd), 5.13 (2H, wide), 4.36 (2H, t), 4.13 (3H, t), 3.70 (1H, dt), 2.84-2 , 72 (1H, m), 2.10-2.01 (1H, m), 1.82-1.53 (7H, m), 0.93-0.82 (1H, m), 0.52 -0.45 (2H, m), 0.16-0.09 (2H, m).

Intermediate 67: Trifluoroacetic acid salt of 2 - [(2-Cyclopropylethyl) oxy] -8-methoxy-9H-purin-6-amine

2 - [(2-Cyclopropylethyl) oxy] -8-methoxy-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (845 mg) was dissolved in MeOH (10 ml) and was added TFA (1 ml). The reaction was stirred for a weekend of 5 weeks and evaporated to dryness under reduced pressure to provide a brown solid. EtOAc was added and the solid was filtered off and washed with more EtOAc (a total of 15 ml of EtOAc was used). The solid was then washed with Et2O (5 ml) and air dried with suction to give the title compound as an off-white solid (937 mg).

MS calc. for (C11H15N5O2) + = 249 10

MS found (electrospray): (M + H) + = 250

1H NMR (CDCl3): δ 7.91 (2H, width), 4.24 (2H, t), 3.93 (3H, s), 1.53-1.45 (2H, m), 0.71-0.60 (1H, m), 0.34-0.27 (2H, m), 0.02--0.04 (2H, m), no exchangeable proton is observed, traces of ammonium ion present.

Intermediate 68: Tetrahydro-3-furanylmethyl methanesulfonate 15

To triethylamine (68 ml) was added in a single portion to tetrahydro-3-furanmethanol (25 g) in dry DMC (250 ml) at 0 ° C under a nitrogen atmosphere. Methanesufonyl chloride (24.7 ml) was added dropwise over 15 minutes. The reaction was heated to room temperature and left for a weekend. The mixture was taken in DCM (50 ml) and washed with saturated sodium bicarbonate solution (100 ml). The organic phases were dried using a hydrophobic frit and concentrated in vacuo to give the title compound as a brown oil with quantitative yield.

1H NMR ((CD3) 2SO): δ 4.19-4.08 (2H, m), 3.77-3.69 (2H, m), 3.66-3.59 (1H, m), 3.46 (1H, dd), 3, 19 (3H, s), 2.64-2.53 (1H, m), 2.03-1.92 (1H, m), 1.63-1.53 (1H, m). 25

Intermediate 69: 2 - [(2-Cyclopropylethyl) oxy] -8-methoxy-9- (tetrahydro-3-furanylmethyl) -9H-purin-6-amine

To a salt solution of trifluoroacetic acid of 2 - [(2-cyclopropylethyl) oxy] -8-methoxy-9H-purin-6-amine (300 mg) in dry DMF (5 ml) was added anhydrous potassium carbonate (457 mg ) and the mixture was heated at 60 ° C for 1.5 h. The reaction was cooled to room temperature and tetrahydro-3-furanylmethyl methanesulfonate (164 mg) was added. The reaction was heated at 90 ° C for 3.5 h and then quenched in water (50 ml) and extracted with EtOAc (3 x 50 ml). The organic phases were separated, dried by passing through a hydrophobic frit and evaporated under reduced pressure to provide a vitreous solid. The material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (20-60%) to provide the title compound. (103.8 mg).

MS calc. for (C16H23N5O3) + = 333

MS found (electrospray): (M + H) + = 334 15

1H NMR (CDCl3): δ 5.37 (2H, width), 4.22 (2H, t), 4.00 (3H, s), 3.89-3.77 (3H, m), 3.69-3.61 (2H, m), 3.52 (1H, dd), 2.80-2.67 (1H, m), 1.91-1.81 (1H, m), 1.65-1.53 (3H, m) , 0.80-0.69 (1H, m), 0.39-0.32 (2H, m), 0.02--0.04 (2H, m).

Intermediate 70: 2 - [(E / Z) -2-methoxyetenyl] tetrahydro-2H-pyran

 twenty

A solution of oxalyl chloride (5.33 ml) in DCM (30 ml) was cooled to -60 ° C and a solution of DMSO (7.4 ml) in DCM (100 ml) was added dropwise while stirring, maintaining the temperature between -55 ºC and -60 ºC. After 20 minutes tetrahydro-2H-pyran-2-ylmethanol (6 g) was added dropwise. After 30 minutes, triethylamine (36 ml) was added dropwise and after another 30 minutes the mixture was allowed to warm to room temperature. After 25 minutes the mixture was treated with water, the mixture was stirred and the phases separated. The aqueous phase was extracted with DCM (x 2) and the combined extracts were washed with dilute brine, dried using a hydrophobic frit and evaporated to give a pale oil (3.8 g). The material was purified by normal phase chromatography (ISCO) using cyclohexane / EtOAc

as eluent (0-40%) providing a clear oil (780 mg). A suspension of (methoxymethyl) triphenylphosphonium chloride (4.69 g) in dry THF was cooled to -40 ° C and a solution of potassium tert-butoxide (1.54 g) in dry THF was added dropwise with stirring. After 45 minutes, the reaction was cooled to -65 ° C and the clear oil (780 mg, prepared above) in dry THF was added dropwise, keeping the temperature between -60 ° C and -65 ° C. The mixture was allowed to warm to room temperature and after another 30 minutes it was quenched with ice / water. The mixture was extracted with Et2O (x 3) and the combined extracts were washed with brine, dried over sodium sulfate, evaporated in vacuo, then evaporated again in vacuo with toluene to provide crude material (3.71 g). The material was purified by normal phase chromatography (ISCO) using cyclohexane / EtOAc as eluent (0-10-20%) to give the title compound as a clear oil (581 mg).

1H NMR (CDCl3): δ 6.58 + 5.91 (1H d + d), 4.81 + 4.45 (1H, dd + dd), 4.31-4.23 + 3.76-3.69 + 3.52-3 , 44 (2H, m + m + m), 4.04-3.95 (1H, m), 3.61 + 3.56 (3H, s + s), 1.89-1.77 (1H, m), 1.67-1 / 32 (5H, m), mixture of isomers in a proportion approx. from 60:40.

Intermediate 71: Tetrahydro-2H-pyran-2-ilacetaldehyde 15

To a solution of 2 - [(E / Z) -2- (methoxy) ethenyl] tetrahydro-2H-pyran (581 mg) in THF (4 ml) was added 2N HCl (4 ml) with stirring. After 2 h the mixture was diluted with water and extracted with DCM (x 3). The combined organic phases were washed with dilute brine, dried through a hydrophobic frit and evaporated to give the title compound as a clear oil (528 mg).

1H NMR (CDCl3): δ 9.80 (1H, t), 4.01-3.93 (1H, m), 3.88-3.79 (1H, m), 3.51-3.43 (1H, m), 2, 63-2.54 (1H, m), 2.50-2.42 (1H, m), 1.91-1.80 (1H, m), 1.68-1.48 (4H, m), 1.44-1.31 (1H, m).

Intermediate 72: 2- (Tetrahydro-2H-pyran-2-yl) ethanol 25

To a stirred solution of tetrahydro-2H-pyran-2-ylacetaldehyde (528 mg) in ethanol (5 ml) was added sodium borohydride in granules (156 mg). The mixture was heated at 50 ° C for 2 h under nitrogen atmosphere. After cooling, the solvent was evaporated and the residue was treated with brine. The mixture was acidified by the careful addition of 2N HCl 30 and this mixture was extracted with DCM (x 3). The combined organic phases were washed with brine, dried using a hydrophobic frit and evaporated to provide the

title compound in the form of a transparent oil (465 mg).

1H NMR (CDCl3): δ 4.02-3.93 (1H, m), 3.83-3.73 (2H, m), 3.57-3.38 (2H, m), 2.83-2.74 (1H, m ), 1.88-1.32 (7H, m), the hydroxyl proton was not observed.

Intermediate 73: 2- (tetrahydro-2H-pyran-2-yl) ethyl methanesulfonate

 5

2- (Tetrahydro-2H-pyran-2-yl) ethanol (465 mg) was dissolved in dry DMC (10 ml) and triethylamine (996 mg) was added. The stirring solution was cooled in an ice bath under a nitrogen atmosphere and methanesufonyl chloride (359 mg) was added dropwise over 5 minutes. The reaction was allowed to warm to room temperature while the ice bath was melting and left for 16 h. The mixture was then stirred with saturated sodium bicarbonate solution and the aqueous phase was extracted with DCM (x 2). The combined organic extracts were washed with brine, dried using a hydrophobic frit and evaporated to give the title compound as a brown oil (718 mg).

1H NMR (CDCl3): δ 4.43-4.27 (2H, m), 4.00-3.92 (1H, m), 3.47-3.35 (2H, m), 3.01 (3H, s), 1, 93-1.78 (3H, m), 1.64-1.44 (4H, m), 1.37-1.24 (1H, m). fifteen

Intermediate 74: 2-Butyloxy-8-methoxy-9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -9H-purin-6-amine

A mixture of 2-butoxy-8-methoxy-9H-purin-6-amine salt trifluoroacetate (200 mg) and potassium carbonate (236 mg) in dry DMF (2 ml) was heated at 60 ° C with stirring for 1 h. 2- (tetrahydro-2H-pyran-2-yl) ethyl methanesulfonate (142 mg) was added and the reaction continued for 16 h at 60 ° C. The mixture was quenched with water and extracted with EtOAc (x 3). The combined organic phases were washed with water and brine, dried using a hydrophobic frit and evaporated to provide crude material (540 mg). The material was purified by normal phase chromatography (ISCO) using 0-20% methanol / EtOAc as eluent to give the title compound as a white solid (88 mg). 25

MS calc. for (C17H27N5O3) + = 349

MS found (electrospray): (M + H) + = 350

1H NMR (CDCl3): δ 5.12 (2H, s), 4.29 (2H, t), 4.12 (3H, s), 4.05 (2H, dt), 3.99-3.92 (1H, m), 3 , 36 (1H, dt), 3.27-3.19 (1H, m), 1.88 (2H, quartet), 1.84-1.66 (5H, m), 1.63-1.37 (4H, m), 1.36-1.23 (1H, m), 0.97 (3H, t). 30

Intermediate 75: (2,2-Dimethyltetrahydro-2H-pyran-4-yl) methanol

A solution of 2,2-dimethyltetrahydro-2H-pyran-4-carbaldehyde (2.5 g) in ethanol (30 ml) was cooled (ice bath) and sodium borohydride (665 mg) was added with stirring. The ice bath was removed and the mixture was allowed to warm to room temperature. After 2 h the reaction was heated at 50 ° C for 1 h, then allowed to cool to room temperature. The solvent was evaporated and the residue was treated with brine, acidified and extracted into DCM (x 3). The combined organic phases were dried through a hydrophobic frit and evaporated to provide a clear oil (2.54 g).

1H NMR (CDCl3): δ 3.87-3.62 (2H, m), 3.47 (2H, d), 1.99-1.87 (1H, m), 1.67-1.55 (3H, 10 m), 1 , 28-1.06 (8H, m).

 Intermediate 76: (2,2-dimethyltetrahydro-2H-pyran-4-yl) methyl methanesulfonate

(2,2-Dimethyltetrahydro-2H-pyran-4-yl) methanol (2.54 g) was dissolved in dry DMC (40 ml) and triethylamine (4.9 ml) was added with stirring. The solution was cooled (ice bath) under a nitrogen atmosphere and methanesufonyl chloride (1.77 ml) was added dropwise over 5 minutes. The mixture was allowed to slowly warm to room temperature while the ice bath was melting and left for 16 h. The mixture was stirred with saturated sodium bicarbonate solution and the aqueous phase was extracted with DCM (x 2). The combined organic phases were washed with brine, dried using a hydrophobic frit and evaporated to give the title compound (3.93 g).

1H NMR (CDCl3): δ 4.03 (2H, d), 3.82-3.75 (1H, m), 3.68 (1H, dt), 3.02 (3H, s), 2.25-2.12 (1H, m), 1.70-1.55 (3H, m), 1.33-1.13 (7H, m).

Intermediate 77: 4- (Bromomethyl) -2,2-dimethyltetrahydro-2H-pyran

 25

A mixture of (2,2-dimethyltetrahydro-2H-pyran-4-yl) methyl methanesulfonate (1.5 g) and

Anhydrous lithium bromide (2.72 g) in acetone (40 ml) was refluxed under a nitrogen atmosphere for 4 h. The reaction was allowed to cool and the solvent was evaporated. The residue was treated with saturated sodium bicarbonate solution and extracted with DCM (x 3). The combined organic phases were washed with dilute brine, dried by passing through a hydrophobic frit and evaporated to give the title compound as a brown oil (1.23 g).

1H NMR (CDCl3): δ 3.82-3.75 (1H, m), 3.71-3.62 (1H, m), 3.26 (2H, d), 2.11-1.98 (1H, m), 1, 80-1.66 (2H, m), 1.29-1.08 (8H, m).

Intermediate 78: 2-Butyloxy-9 - [(2,2-dimethyltetrahydro-2H-pyran-4-yl) methyl] -8-methoxy-9H-purin-6-amine 10

A mixture of 2-butoxy-8-methoxy-9H-purin-6-amine salt trifluoroacetate (223 mg) and potassium carbonate (264 mg) in dry DMF (2 ml) was heated at 60 ° C under a nitrogen atmosphere while stirring for 1 h. 4- (Bromomethyl) -2,2-dimethyltetrahydro-2H-pyran (158 mg) was added and the reaction was stirred for 16 h at 60 ° C. The mixture was quenched with water and extracted with EtOAc (x 3). The combined organic phases were washed with water and brine, dried using a hydrophobic frit and evaporated to provide a brown oil. The crude material was purified by normal phase chromatography (ISCO) using 5-20% methanol / EtOAc as eluent to give a pale oil (181 mg). The material was purified again by normal phase chromatography (ISCO) using 0-15% methanol / EtOAc 20 as eluent to give the title compound (161 mg).

MS calc. for (C18H29N5O3) + = 363

MS found (electrospray): (M + H) + = 364

Intermediate 79: N2-Butyl-9 - [(2,2-dimethyltetrahydro-2H-pyran-4-yl) methyl] -8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid

A mixture of N2-Butyl-8-methoxy-9H-purin-2,6-diamin acid (200 mg) and potassium carbonate (236 mg) salt in dry DMF (2 ml) was heated at 60 ° C under a nitrogen atmosphere

stirring for 1 h. 2-Dimethyltetrahydro-2H-pyran-4-yl) methyl methanesulfonate (152 mg) was added and stirring was continued for 5 h at 50 ° C. The reaction was cooled to room temperature and stirred for 16 h. Lithium bromide (50 mg) was added and heating continued for 5 h at 50 ° C, then 8 h at 90 ° C. The mixture was quenched with water and extracted with EtOAc (x 3). The combined organic phases were washed with water and brine, dried using a hydrophobic frit and evaporated to provide crude material (210 mg). This was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (20-60%) to provide the title compound (75 mg)

MS calc. for (C18H30N6O2) + = 362 10

MS found (electrospray): (M + H) + = 363

1H NMR (CDCl3): δ 4.92 (2H, width), 4.60 (1H, t), 4.09 (3H, s), 3.79-3.68 (3H, m), 3.65-3.55 (1H, m), 3.43-3.33 (2H, m), 2.36-2.23 (1H, m), 1.62-1.53 (2H, m), 1.51-1.13 ( 12H, m), 0.99-0.91 (3H, m).

Intermediate 80: 3 - [(E / Z) -2-methoxyetenyl] tetrahydrofuran 15

A suspension of (methoxymethyl) triphenylphosphonium chloride (13.71 g) in dry THF (40 ml) was cooled to -40 ° C and a solution of potassium tert-butoxide (4.94 g) in dry THF (40 ml) was added ) drop by drop stirring. After 45 minutes the reaction was cooled to -65 ° C. Meanwhile, a solution of tetrahydro-3-furancarbaldehyde (8 ml, 50% in water) was treated with brine to provide a cloudy suspension. This was extracted with Et2O (x 3), and the combined organic phases were dried over sodium sulfate and the solution was added dropwise to the reaction at -60 ° C to -65 ° C. The mixture was then allowed to warm to room temperature. After 30 minutes the mixture was poured into water and extracted with Et2O (x 3). The combined extracts were washed with brine, dried over sodium sulfate and evaporated under reduced pressure to provide an oil. This was dissolved in a small amount of DCM and loaded into an ISCO silica cartridge, and the solvent was removed under reduced pressure. The crude material was purified by normal phase chromatography (ISCO) using 0-20% EtOAc / cyclohexane as eluent to afford the title compound (460 mg).

1H NMR (CDCl3): δ 6.37 (0.75H, d), 5.92 (0.25H, d), 4.67 (0.75H, dd), 4.32 (0.25H, 30 dd), 3.97-3 , 85 (2H, m), 3.84-3.75 (1H, m), 3.60 (0.75H, s), 3.52 (2.25H, s), 3.38-3.31 (1H, m), 3.28-3.19 (0.25H, m), 2.81-2.69 (0.75H, m), 2.16-2.03 (1H, m), 1 , 71-1.58 (1H, m), mixture of isomers in a proportion of approx. 1: 3

Intermediate 81: 2- (Tetrahydro-3-furanyl) ethanol

3 - [(E / Z) -2-methoxyetenyl] tetrahydrofuran (460 mg) was treated with ethanol (2 ml) and 2 N HCl (2 ml), and the clear solution was stirred for 4 h. The solution was heated at 50 ° C for 1 h, then left at room temperature for 16 h. The acid was neutralized by adding a 2 N solution of sodium hydroxide (2 ml) and diluted with ethanol (3 ml). Sodium borohydride (136 mg) was added while stirring. After 3 h the solvent was removed by evaporating under reduced pressure and the residue was treated with brine and cautiously acidified with 2N HCl. The mixture was extracted with DCM (x 3), washed with brine, dried using a frit. hydrophobic and evaporated to a clear oil (200 mg). The aqueous phases were combined, saturated with solid NaCl, extracted with DCM (x 3), dried using a hydrophobic frit and evaporated to provide a second crop of material (100 mg). This was combined with the first crop of clear oil (200 mg), and purified by normal phase chromatography (ISCO) using 0-20% MeOH / EtOAc as eluent to afford the title compound (230 mg). fifteen

1H NMR (CDCl3): δ 3.98-3.83 (2H, m), 3.82-3.64 (3H, m), 3.42-3.35 (1H, m), 2.39-2.27 (1H, m ), 2.14-2.03 (1H, m), 1.72-1.64 (2H, m), 1.58-1.51 (1H, m), the hydroxyl proton was not observed.

Intermediate 82: 2- (Tetrahydro-3-furanyl) ethyl methanesulfonate

 twenty

2- (tetrahydro-3-furanyl) ethanol (230 mg) was dissolved in dry DMC (5 ml) and triethylamine (0.552 ml) was added. The stirring solution was cooled (ice bath) under a nitrogen atmosphere and methanesufonyl chloride (0.199 ml) was added dropwise over 5 minutes. The mixture was allowed to slowly warm to room temperature while the ice bath was melting and left for 16 h. The mixture was stirred with saturated sodium bicarbonate solution and the aqueous phase was extracted with DCM (x 2). The combined organic phases were washed with brine, dried using a hydrophobic frit and evaporated to give the title compound (364 mg).

1H NMR (CDCl3): δ 4.32-4.22 (2H, m), 3.98-3.73 (4H, m), 3.44-3.37 (1H, m), 3.03 (3H, s), 2, 40-2.30 (1H, m), 2.18-2.06 (1H, m), 1.95-1.79 (2H, m). 30

Intermediate 83: 3- (2-Bromoethyl) tetrahydrofuran

A mixture of 2- (tetrahydro-3-furanyl) ethyl methanesulfonate (364 mg) and anhydrous lithium bromide (780 mg) was refluxed with stirring in acetone (10 ml) under a nitrogen atmosphere for 4 h. The mixture was allowed to cool and the solvent was evaporated. The residue was treated with saturated sodium bicarbonate solution and extracted with DCM (x 3). The combined organic phases were washed with dilute brine, dried using a hydrophobic frit and evaporated to give the title compound (308 mg).

1H NMR (CDCl3): δ 3.97-3.84 (2H, m), 3.81-3.74 (1H, m), 3.46-3.36 (3H, m), 2.47-2.36 (1H, m ), 2.16-2.06 (1H, m), 2.01-1.92 (2H, m), 1.56-1.49 (1H, m).

Intermediate 84: 2-Butyloxy-8-methoxy-9- [2- (tetrahydro-3-furanyl) ethyl] -9H-purin-6-amine

 10

A mixture of 2-butoxy-8-methoxy-9H-purin-6-amine salt trifluoroacetate (200 mg) and potassium carbonate (236 mg) in dry DMF (2 ml) was heated at 60 ° C with stirring for 1 h. 3- (2-Bromoethyl) tetrahydrofuran (123 mg) was added and the reaction continued for 2 h. The mixture was quenched with water and extracted with EtOAc (x 3). The combined organic phases were washed with water and brine, dried using a hydrophobic frit and evaporated to provide an oil (265 mg). The crude material was purified by normal phase chromatography (ISCO) using 0-15% MeOH / EtOAc as eluent to afford the title compound (102 mg).

MS calc. for (C16H25N5O3) + = 335

MS found (electrospray): (M + H) + = 336 20

1H NMR (CDCl3): δ 5.15 (2H, width), 4.32-4.24 (2H, m), 4.12 (3H, s), 3.99-3.94 (2H, m), 3.93-3, 82 (2H, m), 3.77-3.69 (1H, m), 3.39 (1H, dd), 2.19-2.06 (2H, m), 1.90-1.72 ( 4H, m), 1.59-1.45 (3H, m), 0.97 (3H, t).

Intermediate 85: Tetrahydro-2H-pyran-3-ylmethyl methanesulfonate

 25

To tetrahydro-2H-pyran-3-ylmethanol (4.92 g) in dry dichloromethane (140 ml) at 0 ° C and under a nitrogen atmosphere, anhydrous triethylamine (13.6 ml) was added at one time, followed by mesyl (4.3 ml) drop by drop for 5 minutes. The reaction was allowed to warm to room temperature and stirred at this temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate (50 ml). The organic phase was separated, passed through a hydrophobic frit to dry and concentrated in vacuo to provide a red oil (8.8 g).

1H NMR (CDCl3): δ 4.18-4.08 (2H, m), 3.94-3.88 (1H, m), 3.81 (1H, m), 3.51-3.43 (1H, m), 3, 37-3.31 (1H, m), 3.01 (3H, s), 2.07 (1H, m), 1.85 (1H, m), 1.72-1.56 (2H, m) , 1.47-1.36 (1H, m).

Intermediate 86: Tetrahydro-2H-pyran-4-ylmethyl methanesulfonate

 5

To tetrahydro-2H-pyran-4-ylmethanol (6.2 g) in dry dichloromethane (226.3 ml) at 0 ° C and under a nitrogen atmosphere, triethylamine (18.1 ml) was added, followed by mesyl chloride ( 5.4 ml). The reaction was allowed to warm to room temperature and was left at this temperature overnight. The reaction mixture was washed with saturated aqueous sodium bicarbonate (200 ml). The organic phase was separated, passed through a hydrophobic frit to dry and concentrated under vacuum to provide a lumpy light brown solid (10.17 g).

 1 H NMR (DMSO): δ 4.06 (2H, d), 3.85 (2H, m), 3.35-3.25 (1H, m), 3.17 (3H, s), 2.50 (1H, m), 2 , 00-1.87 (1H, m), 1.58 (2H, m), 1.32-1.20 (2H, m).

Intermediate 87: N2-Butyl-8- (methoxy) -9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -9H-purin-2,6-diamine

A mixture of trifluoroacetic acid salt of N2-butyl-8-methoxy-9H-purin-2,6-diamine (200 mg) and potassium carbonate (236 mg) in dry DMF (2 ml) was heated at 60 ° C while stirring during 1 hour. 2- (tetrahydro-2H-pyran-2-yl) ethyl methanesulfonate (142 mg) was added and the reaction continued for 3 h at 60 ° C. The mixture was quenched with water and extracted with EtOAc 20 (x 3). The combined organic phases were washed with water and brine, dried using a hydrophobic frit and evaporated to provide crude material (250 mg). The material was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (20-60%) and the appropriate fractions were combined and evaporated to remove acetonitrile. The remaining aqueous mixture was basified with saturated sodium hydrogen carbonate, extracted three times with dichloromethane and the combined extracts dried through a phase separation cartridge, then evaporated to provide 75 mg of material that was recrystallized from ether. / naphtha providing the title compound in the form of a

solid, 54 mg

1H NMR (CDCl3): δ 4.92 (2H, s), 4.59 (1H, m), 4.10 (3H, s), 3.99 (3H, m), 3.38 (3H, m), 3.25 (1H , m), 1.93-1.37 (11H, m), 1.37-1.23 (1H, m), 0.96 (3H, t).

Intermediate 88: N2-Butyl-8- (methoxy) -9- [2- (tetrahydro-3-furanyl) ethyl] -9H-purin-2,6-diamine

 5

A mixture of trifluoroacetic acid N2-butyl-8-methoxy-9H-purin-2,6-diamine acid salt (200 mg) and potassium carbonate (236 mg) in dry DMF (2 ml) was heated at 60 ° C while stirring for 1 h. 3- (2-Bromoethyl) tetrahydrofuran, Intermediate 83 (123 mg) was added and the reaction continued for 2 h at 60 ° C. The mixture was quenched with water and extracted with EtOAc (x 3). The combined organic phases were washed with water and brine, dried using a hydrophobic frit and evaporated to an oil (261 mg). This material was purified by flash chromatography (silica, 5-20% methanol: ethyl acetate) and the appropriate fractions were combined and evaporated to give the title compound, in a yield of 181 mg.

MS calc. for (C16H26N6O2) + = 334 15

MS found (electrospray): (M + H) + = 335

1H NMR (CDCl3): δ 4.96 (2H, s), 4.60 (1H, broad t), 4.10 (3H, s), 3.88 (4H, m), 3.73 (1H, m), 3.38 ( 3H, m), 2.12 (1H, m), 1.85 (3H, m), 1.57 (3H, m), 1.41 (2H, m), 0.95 (3H, t).

Intermediate 89 and Intermediate 90: 2-Butoxy-8-methoxy-9- (tetrahydrofuran-3-ylmethyl) -9H-purin-6-amine, enantiomers

2-Butoxy-8-methoxy-9- (tetrahydrofuran-3-ylmethyl) -9H-purin-6-amine (0.5 g) was separated into their respective enantiomers using a 1 ”x 25 cm Chiralpak AD column, eluting with heptane: IPA 90:10. The fractions containing the fastest eluting material were combined and evaporated to a solid to provide isomer 1, Intermediate 89, 176 mg. 25

MS calc. for (C15H23N5O3) + = 321

MS found (electrospray): (M + H) + = 322

1H NMR (CDCl3): 5.20 (2H, s), 4.28 (2H, t), 4.13 (3H, s), 4.01-3.89 (3H, m superimposed), 3, 77 (2H, m), 3.64 (1H, m), 2.85 (1H, m), 1.97 (1H, m), 1.81-1.67 (3H, m

superimposed), 1.50 (2H, m), 0.96 (3H, t).

Fractions containing the slowest eluting material were combined and evaporated to a solid to provide isomer 2, Intermediate 90, 178 mg.

MS calc. for (C15H23N5O3) + = 321

MS found (electrospray): (M + H) + = 322 5

1H NMR (CDCl3): 5.15 (2H, s), 4.27 (2H, t), 4.13 (3H, s), 4.01-3.89 (3H, m superimposed), 3, 77 (2H, m), 3.64 (1H, m), 2.85 (1H, m), 1.97 (1H, m), 1.81-1.67 (3H, m superimposed), 1, 50 (2H, m), 0.96 (3H, t).

Intermediate 89, alternative procedure: 2- (Butyloxy) -8- (methyloxy) -9- (tetrahydro-3-furanylmethyl) -9H-purin-6-amine (Isomer 1) 10

A stirring mixture of trifluoroacetic acid salt of N2-butyl-8-methoxy-9H-purin-2,6-diamine (3.25 g) and potassium carbonate (3.83 g) in dry N, N-dimethylformamide ( 30 ml) was heated by stirring at 60 ° C for 1 h. Tetrahydro-3-furanylmethyl methanesulfonate (2 g, Isomer 1) was added and the stirred mixture was heated at 90 ° C for 3 h. The solvent was evaporated, water was added and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with water and then with brine, dried by passing through a hydrophobic frit and evaporated under reduced pressure to provide an orange solid. This was purified by C18 reverse phase chromatography using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (20-60%) and the appropriate fractions were combined and evaporated. providing the title compound as a light orange solid, with a yield of 1.56 g.

MS calc. for (C15H23N5O3) + = 321

MS found (electrospray): (M + H) + = 322

Intermediate 90, alternative procedure: 2- (Butyloxy) -8- (methoxy) -9- (tetrahydro-3-25 furanylmethyl) -9H-purin-6-amine (Isomer 2)

A stirring mixture of trifluoroacetic acid salt of N2-butyl-8-methoxy-9H-purin-2,6-diamine (3.25 g) and potassium carbonate (3.83 g) in dry N, N-dimethylformamide ( 30 ml) was heated by stirring at 60 ° C for 1 h. Tetrahydro-3-furanylmethyl methanesulfonate was added

(2 g, Isomer 2) and the stirring mixture was heated at 90 ° C for 3 h. The solvent was evaporated, water was added and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with water and then with brine, dried by passing through a hydrophobic frit and evaporated under reduced pressure to provide an orange solid. This was purified by C18 reverse phase chromatography using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (20-60%) and the appropriate fractions were combined and evaporated. providing the title compound as a light orange solid, with a yield of 2.2 g.

MS calc. for (C15H23N5O3) + = 321

MS found (electrospray): (M + H) + = 322 10

Intermediate 91: 2 - {[2- (Ethyloxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

To a stirring solution of potassium t-butoxide (9.3 g, 82.8 mmol) in 1-ethoxy-2-ethanol (70 ml) was added 2-chloro-9- (tetrahydro-2H-pyran-2- il) -9H-purin-6-amine (7 g, 27.6 mmol). The mixture was heated at 80-90 ° C for 2 h. Then most of the solvent was removed by evaporation under reduced pressure. The residue was partitioned between water and dichloromethane. The dichloromethane phase was separated, concentrated to provide a light brown solid, which was washed with petroleum ether, dried under vacuum (7.8 g, 92%).

 1H NMR (CDCl3): 7.86 (1H, s), 6.0-5.8 (2H, wide s), 5.61 (1H, d), 4.49 (2H, m), 4, 3-4.1 (1H, m), 3.80 (2H, t), 3.8-3.7 (1H, m), 3.60 (2H, t), 2.15-1.9 ( 3H, m), 1.85-1.55 (3H, m), 1.23 20 (3H, t). Impurity peaks at 3.75, 3.55, 1.2, 0.85.

Intermediate 92: 8-Bromo-2 - {[2- (ethyloxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

To a stirring solution of 2 - {[2- (ethyloxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-25 6-amine (7.8 g, 25, 4 mmol) in dichloromethane (100 ml) and NBS (5 g, 27.9 mmol) was added with stirring. After 2 h, the solvent was removed. The product was purified through a

silica column using petroleum ether: 2: 1 ethyl acetate as eluent, which was a light yellow solid (7.8 g, 79.6%).

1H NMR (CDCl3): 5.9-5.7 (2H, broad s), 5.57 (1H, d), 4.55-4.4 (2H, m), 4.2-4.1 (1H, m), 3.78 (2H, t), 3.75-3.6 (1H, m), 3.58 (2H, q), 2.9-3.1 (1H, m), 2.15-2.0 (1H, m), 1.9-1.5 (4H, m), 1.21 (3H, t). 5

Intermediate 93: 2 - {[2- (Ethyloxy) ethyl] oxy} -8- (methyloxy) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

Sodium (1.25 g, 54.4 mmol) was dissolved in methanol (40 ml). After 10 minutes, 8-bromo-2 - {[2- (ethyloxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (7 g, 18 mmol) stirring. The mixture was heated at reflux for 2 h. The solvent was removed. The residue on a silica column using DCM: MeOH 100: 1 as eluent to provide the product as a yellow solid (4.78 g, 78.4%).

1H NMR (CD3OD): 5.6-5.5 (1H, m), 4.55-4.4 (2H, m), 4.18 (3H, s), 4.15-4.05 ( 1H, m), 3.9-3.8 (2H, 2xm), 3.8-3.7 (1H, m), 3.7-3.6 (2H, q), 2.9-2, 75 (1H, m), 2.15-2.05 (1H, m), 1.9-1.55 (4H, m), 1.25 (3H, t). No exchangeable protons were observed.

Intermediate 94: 2 - {[2- (ethyloxy) ethyl] oxy} -8- (methyloxy) -1H-purin-6-amine trifluoroacetic acid salt

2 - {[2- (Ethyloxy) ethyl] oxy} -8- (methyloxy) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (4.78 g, 20 14, 2 mmol) was dissolved in MeOH (30 ml) and TFA (7.5 ml) was added with stirring at 0 ° C. The mixture was allowed to stand at room temperature for 1 day. A white solid formed. The solid was filtered off and washed with ethyl acetate and dried in vacuo. This provided product (4 g, 80.5%).

1H NMR (CD3OD): 4.6-4.55 (2H, m), 4.15 (3H, s), 3.85-3.75 (2H, m), 3.37 (2H, q) , 1.18 (3H, d). No exchangeable protons were observed.

Intermediate 95: 2- (2-Ethoxyethoxy) -8-methoxy-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine

To a solution of trifluoroacetic acid salt of 2- [2- (ethyloxy) ethyl] oxy-8- (methoxy) -9H-purin-6-amine (500 mg) in dry N, N-dimethylformamide (4.5 ml ) at room temperature and under 5 nitrogen atmosphere potassium carbonate (0.75 g) was added at one time. The reaction was stirred at 60 ° C for 1.5 hours. Tetrahydro-2H-pyran-4-ylmethyl methanesulfonate (0.29 g) was added in one portion and the reaction was heated at 90 ° C for 3 hours. The reaction was cooled to room temperature and then diluted with ethyl acetate (20 ml) and washed with water (15 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (10-45%) to provide the compound of title in the form of a white solid (240 mg).

MS calc. for (C16H25N5O4) + = 351 15

MS found (electrospray): (M + H) + = 352

1H NMR ((CD3) 2SO): δ 6.81 (2H, s), 4.27 (2H, m), 4.05 (3H, s), 3.81 (2H, m), 3.73 (2H, d), 3.64 (2H , m), 3.48 (2H, q), 3.22 (2H, m), 2.01 (1H, m), 1.41 (2H, m), 1.23 (2H, m), 1 , 12 (3H, t).

Intermediate 96: 2 - {[2- (Ethyloxy) ethyl] oxy} -8- (methoxy) -9- (tetrahydro-2H-pyran-3-ylmethyl) -9H-purin-20 6-amine

To a solution of trifluoroacetic acid salt of 2 - {[2- (ethyloxy) ethyl] oxy} -8- (methoxy) -9H-purin-6-amine (500 mg) in dry N, N-dimethylformamide (6, 0 ml) at room temperature and under nitrogen atmosphere potassium carbonate (0.75 g) was added at one time. The reaction was stirred 25 at 60 ° C for 1.5 hours. A solution of tetrahydro-2H-pyran methanesulfonate was added

3-ylmethyl (0.29 g) in dry N, N-dimethylformamide (1.0 ml) at one time and the reaction was heated at 90 ° C for 2 hours. The reaction was cooled to room temperature and then diluted with ethyl acetate (20 ml) and washed with water (10 ml). The organic phase was concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (10-60%) to provide the compound of title in the form of a transparent viscous oil that crystallizes at room temperature (245 mg).

MS calc. for (C16H25N5O4) + = 351

MS found (electrospray): (M + H) + = 352

Intermediate 97: 2 - {[1-Methyl-2- (methoxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine 10

To a stirring solution of potassium t-butoxide (9.3 g, 82.8 mmol) in 1-methoxy-2-propanol (70 ml) was added 2-chloro-9- (tetrahydro-2H-pyran-2- il) -9H-purin-6-amine (7 g, 27.6 mmol). The mixture was heated at 80-90 ° C for 4 h. Then most of the solvent was removed by evaporation under reduced pressure. The residue was partitioned between water and dichloromethane. The dichloromethane phase was separated, concentrated to give a brown oil (7.2 g, 84.7%).

1H NMR (CDCl3): 7.84 (1H, s), 5.8-5.55 (2H, wide s + 1H, m), 5.45-5.3 (1H, m), 4.2 -4.05 (1H, m), 3.8-3.6 (2H, 2xm), 3.5-3.42 (1H, m), 3.40 (3H, s), 2.1-1 , 9 (3H, m), 1.8-1.55 (3H, m), 1.35 (3H, dd). Impurity peaks at 5.05, 3.38, 1.21, 1.12. twenty

Intermediate 98: 8-Bromo-2 - {[1-methyl-2- (methoxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

To a stirring solution of 2 - {[1-methyl-2- (methoxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (7.2 g , 23.4 mmol) in dichloromethane (100 ml) NBS (4.6 g, 25.8 mmol) was added. After 4 h, the solvent was removed. The product was purified on a silica column using petroleum ether: 2: 1 ethyl acetate as eluent. This provided the product.

(7.3 g, 81.1%).

1H NMR (CDCl3): 5.9-5.65 (2H, broad s), 5.65-5.55 (1H, m), 5.4-5.2 (1H, m), 4.2 -4.05 (1H, m), 3.8-3.6 (2H, m), 3.55-3.42 (1H, m), 3.40 (3H, 2xs), 2.9-3 , 1 (1H, m), 2.15-2.0 (1H, m), 1.9-1.5 (4H, m), 1.37 (3H, dd).

Intermediate 99: 2 - {[1-Methyl-2- (methoxy) ethyl] oxy} -8- (methoxy) -9- (tetrahydro-2H-pyran-2-yl) -9H-5 purine-6-amine

Sodium (1.16 g, 50.5 mmol) was dissolved in methanol (40 ml) and 8-bromo-2 - {[1-methyl-2- (methoxy) ethyl] oxy} -9- (tetrahydro- 2H-piran-2-yl) -9H-purin-6-amine (6.5 g, 16.8 mmol) with stirring. The mixture was heated at reflux for 2 h. The solvent was removed by evaporation. The residue was purified on a silica column using DCM: MeOH 150: 1 as eluent. This provided product (4.7 g, 82.9%).

1H NMR (CD3OD): 5.6-5.5 (1H, m), 5.4-5.3 (1H, m), 4.20 (3H, s), 4.2-4.1 ( 1H, m), 3.8-3.6 (2H, 2xm), 3.6-3.5 (1H, m), 3.45 (3H, 2xs), 2.95-2.8 (1H, m), 2.2-2.05 (1H, m), 1.9-1.6 (4H, m), 1.40 (3H, dd). No exchangeable protons were observed. fifteen

Intermediate 100: Trifluoroacetic acid salt of 2 - {[1-methyl-2- (methoxy) ethyl] oxy} -8- (methoxy) -9H-purin-6-amine

TFA (7.5 ml) was added to a solution of 2 - {[1-methyl-2- (methoxy) ethyl] oxy} -8- (methoxy) -9- (tetrahydro-2H-piran-2-yl) -9H-purin-6-amine (4.7 g, 13.9 mmol) in MeOH (30 ml) with stirring. The mixture was allowed to stand at room temperature for 1 day. A white solid formed which was removed by filtration and washed with ethyl acetate. This provided the product (3.7 g, 76.1%)

1H NMR (CD3OD): 5.55-5.4 (1H, m), 4.16 (3H, s), 3.7-3.55 (2H, m), 3.39 (3H, s) , 1.40 (3H, d). No exchangeable protons were observed. 25

Intermediate 101: 2 - {[1-Methyl-2- (methoxy) ethyl] oxy} -8- (methoxy) -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine

To a solution of trifluoroacetic acid salt of 2 - {[1-methyl-2- (methoxy) ethyl] oxy} -8- (methoxy) -9H-purin-6-amine (500 mg) in N, N-dimethylformamide Dry (4.5 ml) at room temperature and under nitrogen atmosphere potassium carbonate (0.75 g) was added at one time. The reaction was stirred at 60 ° C for 1.5 hours. Tetrahydro-2H-pyran-5-4-ylmethyl methanesulfonate (0.29 g) was added at one time and the reaction was heated at 90 ° C for 3 hours. The reaction was cooled to room temperature and then diluted with ethyl acetate (20 ml) and washed with water (15 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (10-45%) to provide the compound of title in the form of a transparent viscous oil (260 mg).

MS calc. for (C16H25N5O4) + = 351

MS found (electrospray): (M + H) + = 352.

1H NMR ((CD3) 2SO): δ 6.77 (2H, s), 5.16 (1H, m), 4.05 (3H, s), 3.81 (2H, m), 3.72 15 (2H, d), 3.48 ( 2H, m), 3.28 (3H, s), 3.22 (2H, m), 2.01 (1H, m), 1.41 (2H, m), 1.24 (2H, m), 1.21 (3H, d).

Intermediate 102: 2 - {[1-Methyl-2- (methyloxy) ethyl] oxy} -8- (methoxy) -9- (tetrahydro-2H-pyran-3-ylmethyl) -9H-purin-6-amine

 twenty

To a solution of trifluoroacetic acid salt of 2 - {[1-methyl-2- (methoxy) ethyl] oxy} -8- (methoxy) -9H-purin-6-amine (500 mg) in N, N-dimethylformamide Dry (6.0 ml) at room temperature and under nitrogen atmosphere potassium carbonate (0.75 g) was added at one time. The reaction was stirred at 60 ° C for 1.5 hours. A solution of tetrahydro-2H-pyran-3-ylmethyl methanesulfonate (0.29 g) in dry N, N-dimethylformamide (1.0 ml) was added at one time and the reaction was heated at 90 ° C for 2 hours . The reaction was cooled to room temperature and then diluted with ethyl acetate (20 ml) and washed with water (10 ml). The organic phase is

concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (10-60%) to provide the title compound. in the form of a transparent viscous oil (300 mg).

MS calc. for (C16H25N5O4) + = 351 5

MS found (electrospray): (M + H) + = 352

Intermediate 103: (2-Cyclopropylethyl) amine

To a 1.0 M solution of lithium aluminum hydride in diethyl ether (40 ml) at 0 ° C concentrated sulfuric acid (1.09 ml) was added dropwise over 12 minutes. The reaction was heated to room temperature and stirred for 1 hour. A solution of cyclopropylacetonitrile (1.06 g) in diethyl ether (5 ml) was added dropwise to the reaction for 10 minutes. The reaction was heated at reflux for 2 hours, cooled to 0 ° C and quenched with the slow addition of water. A solution of sodium hydroxide (2 g) in water (18 ml) was added and the organic phase was decanted from the resulting white precipitate. The precipitate was rinsed with diethyl ether (2x20 ml). The combined organic phases were concentrated in vacuo (30 ° C, 300 mbar) to provide the title compound as a colorless oil (1.10 g).

1H NMR ((CD3) 2SO): δ 2.58 (2H, t), 1.23 (2H, q), 0.68 (1H, m), 0.36 (2H, m), -0.01 (2H, m). The protons of NH2 are not observed.

Intermediate 104: Cyclopentylmethylamine 20

To a 1.0 M solution of lithium aluminum hydride in dry diethyl ether (27 ml) at room temperature was added a solution of cyclopentanecarbonitrile (2 g) in dry diethyl ether (10 ml) dropwise over 10 minutes. The purple solution was stirred at room temperature for 24 hours. The resulting pink solution was cooled to 0 ° C and 5.0 M sodium hydroxide solution (10 ml) was slowly added until effervescence ceased. The reaction was filtered from the white precipitate that had formed. The filtrate was dried over magnesium sulfate, filtered and concentrated in vacuo (room temperature, 200 mbar) to provide the title compound as a clear oil (1.6 g).

1H NMR ((CD3) 2SO): δ 2.63 (2H, d), 1.92 (1H, m), 1.77 (2H, m), 1.57 (4H, m), 1.18-30 (2H, m). The protons of NH2 are not observed.

Intermediate 105: 8-Bromo-N2- (cyclopentylmethyl) -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-

2,6-diamine

A solution of 2-chloro-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine (150 mg) in cyclopentylamine (276 mg) was heated in the microwave at 170 ° C for two minutes. The reaction mixture was concentrated in vacuo. To the resulting yellow residue in dry chloroform (2.5 ml) at room temperature, NBS (120 mg) was added once. The reaction was stirred at room temperature for 10 minutes. More NBS (150 mg) was added and the reaction was stirred for a further 30 minutes at room temperature. The reaction was concentrated in vacuo and the product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (20- 60%) providing the title compound as a white solid (40 mg).

MS calc. for (C17H25BrN6O) + = 409/410

MS found (electrospray): (M + H) + = 410/411

Intermediate 106: N2- (Cyclohexylmethyl) -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-2,6-15 diamine

A solution of 2-chloro-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine (150 mg) in cyclohexylamine (363 ul) was heated in the microwave at 170 ° C for five minutes. The crude reaction mixture was subjected to C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (20-60%) providing a white solid (98 mg).

MS calc. for (C18H28N6O) + = 344

MS found (electrospray): (M + H) + = 345

1H NMR ((CD3) 2SO): δ 7.64 (1H, s), 6.54 (2H, s), 6.20 (1H, m), 3.84 (4H, m), 3.21 25 (2H, m), 3.08 ( 2H, m), 2.09 (1H, m), 1.78-1.52 (6H, m), 1.40 (2H, m), 1.30-1.10 (5H, m), 0 , 89

(2H, m).

Intermediate 107: 8-Bromo-N2- (cyclohexylmethyl) -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-2,6-diamine

To a solution of N2- (cyclohexylmethyl) -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-2,6-5 diamine (90 mg) in dry chloroform (1 ml) at room temperature was added NBS (46 mg) at one time. The dark brown reaction was stirred at room temperature for 1 hour. The reaction was diluted with DCM (15 ml) and washed with water (5 ml). The organic phases were passed through a hydrophobic frit and concentrated in vacuo.

MS calc. for (C18H27BrN6O) + = 422/424 10

MS found (electrospray): (M + H) + = 423/425

Intermediate 108: Tetrahydro-2H-pyran-4-ylmethanol

Tetrahydro-2H-methyl pyran carboxylate (SC / 143233, Aldrich) (5.0 g) in dry THF (10 ml) was added dropwise to a cold solution of 1 M lithium aluminum hydride in THF (32 15 ml), keeping the temperature below 10 ° C. Upon completion of the addition, the exothermic process was allowed to finish before allowing the reaction mixture to warm to room temperature. The reaction was then stirred for 2 hours. The reaction was quenched with water (2 ml) which was added with great caution and cooling, followed by 2 N sodium hydroxide (2 ml). Water (100 ml) was then added to the resulting suspension and then extracted with dichloromethane (100 ml, 3 times). The organic phase was separated, combined and dried by passing through a hydrophobic frit. The organic phase was evaporated under reduced pressure to provide colorless mobile oil which was then subjected to high vacuum for 30 minutes at room temperature. This gave the title compound as a colorless mobile oil (2.4367 g). 25

1H NMR (CDCl3): 4.04-3.96 (2H, m), 3.54-3.47 (2H, m), 3.46-3.36 (2H, m), 1.82 - 1.61 (3H, m), 1.57-1.50 (1H, m), 1.40-1.27 (2H, m)

Intermediate 109: 2,6-Dichloro-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purine

A mixture of tetrahydro-2H-pyran-4-ylmethanol (2.44 g) and 2,6-dichloropurine (1.97 g) was dissolved in dry THF (25 ml). To this solution was added triphenylphosphine (5.51 g), followed by diisopropyl azodicarboxylate (4.14 ml) added dropwise. The reaction temperature was maintained at less than 43 ° C (it was necessary to cool slightly with a water bath). The reaction was stirred overnight at room temperature before quenching with water (100 ml) and extracted into ethyl acetate (50 ml, twice). The separated and combined organic phase was then washed with water (100 ml). The organic phase was separated and then dried by passing through a hydrophobic frit before evaporation under reduced pressure to provide a light yellow viscous oil. The material was partially purified by silica chromatography (ISCO) 10 using 0-100% ethyl acetate: cyclohexane. The desired product eluted in two peaks. Peak 1 eluted at 70% ethyl acetate: cyclohexane. Peak 2 eluted with 100% ethyl acetate.

NMR (CD3OD) showed that both batches were identical except that the second peak contained a marginally higher amount of triphenylphosphine oxide as an impurity.

Peak 1:

1H NMR (CD3OD): 8.56 (1H, s), 4.24-4.20 (2H, m), 3.96-3.90 (2H, m), 3.42-3.33 ( 2H, m), 2.30-2.17 (1H, m), 1.55-1.34 (5H, m superimposed).

[7.69-7.52 (15H, m superimposed) - triphenylphosphine oxide impurity]. The title compound 20: triphenylphosphine oxide impurity (1: 0.92).

Peak 2:

1H NMR (CD3OD): 8.56 (1H, s), 4.24-4.20 (2H, m), 3.96-3.90 (2H, m), 3.42-3.33 ( 2H, m), 2.30-2.17 (1H, m), 1.55-1.34 (5H, m superimposed).

[7.69-7.52 (15H, m superimposed) - triphenylphosphine oxide impurity]. The title compound 25: triphenylphosphine oxide impurity (1: 0.54).

Both lots were combined to provide the title compound (3.0833 g, crude) and triphenylphosphine as EM calc impurity. for (C11H12Cl2N4O) + = 286, 288, 290

MS found (electrospray): (M + H) + = 287, 289, 291

Intermediate 110: 2-Chloro-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine 30

2,6-Dichloro-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purine (3.08 g, containing triphenylphosphine oxide) was heated with 2M ammonia in IPA (50 ml) at 50 ° C , all night. The reaction mixture was then evaporated to dryness to provide a yellow solid. This material (3.2089 g) was recrystallized using methanol (50 ml) and after cooling the resulting solid was filtered and washed with methanol (5 ml) to provide the title compound (1.5554 g). The filtrate was evaporated and recrystallized from methanol (25 ml) and after cooling the resulting solid was filtered to provide a second crop (0.2324 g) and was consistent with the first batch by NMR and LCMS.

1H NMR (CD3OD): 8.06 (1H, s), 4.10-4.05 (2H, m), 3.96-3.88 (2H, m), 3.41-3.32 ( 2H, 10 m), 2.23-2.10 (1H, m), 1.53-1.45 (2H, m), 1.43-1.30 (2H, m) (NH2 exchanged).

MS calc. for (C11H14ClN5O) + = 267, 269

MS found (electrospray): (M + H) + = 268, 270

Intermediate 111: 2 - [(2-Methylpropyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine

 fifteen

2-Chloro-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine (0.20 g) was added to a suspension of 2-methyl-1-propanol (2 ml) and tert -sodium peroxide (0.288 g). The mixture was heated in a microwave for 30 minutes at 105 ° C. The reaction mixture was washed with water after diluting with ethyl acetate (50 ml). The organic phase was separated and dried by passing through a hydrophobic frit before removing volatile substances by evaporating under reduced pressure to provide a pink solid. This material was triturated with diethyl ether and filtered to give the title compound as a pink solid (91.1 mg).

1H NMR ((CD3) 2SO): 7.89 (1H, s), 7.14 (2H, wide s), 4.02-3.90 (4H, m), 3.85-3.76 ( 2H, m), 3.31-3.13 (2H, m), 2.15-1.92 (2H, m slightly overlapping), 1.43-1.35 (2H, m), 1.29- 1.16 (2H, m), 1.00-0.92 (6H, m). 25

MS calc. for (C15H23N5O2) + = 305

MS found (electrospray): (M + H) + = 306

Intermediate 112: 8-Bromo-2 - [(2-methylpropyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine

2 - [(2-Methylpropyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine (88 mg) was dissolved in glacial acetic acid (1.5 ml) before of adding sodium acetate (355 110 mg). The above was then cooled in an ice bath before adding bromine (0.2 ml) gradually. The reaction mixture was heated at room temperature before heating at 70 ° C (external temperature) for 4 hours. The reaction mixture was quenched with 10% (w / v) solution of sodium thiosulfate (giving a light yellow color without further changes) and then the pH was adjusted to 6-7 by the addition of 2M sodium hydroxide. then it was extracted in ethyl acetate (20 ml, 3 times). The organic phase was separated, combined and dried by passing through a hydrophobic frit. The organic phase was evaporated under reduced pressure and then azeotroped with toluene to give the title compound as a light yellow solid (0.10 g). This material was then used in the next stage without purification.

1H NMR (CD3OD): 4.11-4.07 (2H, m), 4.05-4.01 (2H, m), 3.96-3.86 (2H, m), 3.40- 3.25 (2H, m) (slightly blurred by residual protons of CHD2OD), 2.29-2.16 (1H, m), 2.14-2.00 (1H, m), 1.55-1 , 37 (4H, m), 1.06-0.90 (6H, m) (NH2 exchanged).

MS calc. for (C15H22BrN5O2) + = 383, 385

MS found (electrospray): (M + H) + = 384, 386 20

Intermediate 113: 2 - [(2-Cyclopropylethyl) oxy] -8- (methyloxy) -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine

Salt of 2 - [(2-cyclopropylethyl) oxy] -8-methoxy-9H-purin-6-amine trifluoroacetic acid (0.30 g) was heated with potassium carbonate (anhydrous, 0.46 g) in anhydrous DMF ( 5 ml) at 60 ° C for 1 hour. The reaction was cooled to room temperature before adding 4- (bromomethyl) tetrahydro-

2H-pyran (0.16 g) in anhydrous DMF (1 ml). The reaction mixture was then heated at 50 ° C overnight. The reaction was quenched in water (50 ml) and extracted with ethyl acetate (50 ml, 3 times). The organic phase was combined and washed with brine (50 ml). The organic phase was separated and dried by passing through a hydrophobic frit before evaporating under reduced pressure to provide oil.) This material was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (20-60%). This material was purified by reverse phase chromatography (20-60% acetonitrile: water). This gave the title compound as a white solid (0.1279 g).

1H NMR (CDCl3): 5.14 (2H, broad s), 4.39-4.32 (2H, m), 4.12 (3H, m), 4.00-3.92 (2H, 10 m), 3.85-3.79 (2H, m), 2.19-2.07 (1H, m), 1.80-1.62 (represents 2H, m [underlying water]), 1.54 -1.34 (4H, m), 0.91-0.81 (1H, m), 0.91-0.81 (2H, m), 0.50-0.08 (2H, m), 0 , 14-0.08 (2H, m).

MS calc. for (C17H25N5O3) + = 347

MS found (electrospray): (M + H) + = 348

Intermediate 114: 2 - [(Cyclohexylmethyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine 15

Cyclohexylmethanol (4.5784 g) was diluted with 1,2-dimethoxyethane (+ 99%) (20 ml) before adding sodium tert-butoxide (3.853 g) gradually by stirring under a nitrogen atmosphere. An exothermic reaction was observed by adding sodium tert-butoxide. 2-Chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (2.5428 g) was added and the resulting mixture was heated at reflux 20 to 93 ° C (internal). An additional amount of 1,2-dimethoxyethane (+ 99%) (20 ml) was added to aid dissolution and heated at reflux overnight. The reaction mixture was dissolved in water (100 ml) and extracted with ethyl acetate (100 ml, twice). The combined organic extracts were washed with brine (100 ml) before separating the organic phase and dried by passing through a hydrophobic frit. Volatile substances were evaporated under reduced pressure and then azeotroped with toluene (50 ml, twice) to provide a mobile amber oil. This material was purified by silica chromatography (ISCO) eluting with 0-100% ethyl acetate: cyclohexane). This provided the title compound after vacuuming in the form of a light yellow foam (1.0364 g) (94% purity by LCMS, 6% 2-chloro-9- (tetrahydro-2H-pyran-2- il) -9H-purin-6-amine) and was used in the next step without further purification.

1H NMR (CDCl3): 7.85 (1H, s), 5.69-5.61 (1H, m), 5.45 (2H, wide s), 4.20-4.07 (3H, m superimposed), 3.82-3.72 (1H, m), 2.14-1.59 (12H, m superimposed), 1.36-1.01 (5H, m superimposed).

MS calc. for (C17H25N5O2) + = 331

MS found (electrospray): (M + H) + = 332 5

Intermediate 115: 8-Bromo-2 - [(cyclohexylmethyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

2 - [(Cyclohexylmethyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (1.0364 g) was dissolved in chloroform (20 ml) and cooled to 0 ° C before adding N-bromosuccinimide 112 10 (0.5852 g) gradually (the reaction temperature did not exceed 1.9 ° C during the addition of N-bromosuccinimide). The reaction mixture was stirred at ~ 2 ° C for 15 minutes before heating to room temperature at which it was stirred for 6 hours (under nitrogen atmosphere). Water (100 ml) was added to the reaction mixture and stirred rapidly before separating the organic phase using a hydrophobic frit. The organic phase was evaporated under reduced pressure to provide a dark brown oil. This material was purified by chromatography on silica eluting with 0-50% ethyl acetate: cyclohexane to give the title compound as a light yellow solid (0.8200 g).

1H NMR (CDCl3): 5.64-5.58 (1H, m), 5.50-5.37 (2H, wide s), 4.20-4.06 (3H, overlapping m), 3, 75-3.66 (1H, m), 3.09-2.97 (1H, m), 2.15-2.06 (1H, m), 1.93-1.57 (10H, m 20 superimposed ), 1.35-1.01 (5H, m superimposed).

MS calc. for (C17H24BrN5O2) + = 409, 411

MS found (electrospray): (M + H) + = 410, 412

Intermediate 116: 2 - [(Cyclohexylmethyl) oxy] -8- (methoxy) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

8-Bromo-2 - [(cyclohexylmethyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (0.8151 g)

It was refluxed with 30% sodium methoxide (w / v) in methanol (1.1 ml), diluted with anhydrous methanol (6.0 ml). The suspension was refluxed (external 70 ° C) overnight. The reaction was partitioned between ethyl acetate (50 ml) and saturated aqueous ammonium chloride solution (50 ml). The organic phase was separated and the aqueous phase was reextracted with ethyl acetate (50 ml). The organic phases were combined and washed with brine (50 ml) and separated before drying by passing through a hydrophobic frit. Evaporation under reduced pressure gave the crude title compound as foam (0.7132 g) which was used without purification.

NMR (CDCl3) consistent but mixing more than one compound.

MS calc. for (C18H27N5O3) + = 361 observed with other parent ions (for example 10 404)

MS found (electrospray): (M + H) + = 362

Intermediate 117: 2 - [(Cyclohexylmethyl) oxy] -8- (methyloxy) -9H-purin-6-amine salt trifluoroacetate

2 - [(Cyclohexylmethyl) oxy] -8-methoxy-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (0.7132 g, crude 15) was dissolved in methanol (5 ml) To this solution was added pure trifluoroacetic acid (0.5 ml). The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and the residue was triturated with ethyl acetate (50 ml). The resulting white solid was filtered, washed using diethyl ether (10 ml) and then dried with suction. This gave the clean title compound as a white solid (0.2799 20 g).

1H NMR (CD3OD): 4.29-4.24 (2H, m), 4.14 (3H, s), 1.89-1.66 (6H, m superimposed), 1.39-1.03 (5H, m superimposed) [NH2 and NH of N-9 are interchanged].

MS calc. for (C13H19N5O2) + = 277

MS found (electrospray): (M + H) + = 278 25

Intermediate 118: 2 - [(Cyclohexylmethyl) oxy] -8- (methoxy) -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine

2 - [(Cyclohexylmethyl) oxy] -8- (methoxy) -9H-purin-6-amine salt trifluoroacetate (0.28 g) was heated with anhydrous potassium carbonate (0.3957 g) in anhydrous DMF (5 ml) in nitrogen atmosphere for 1 hour at 60 ° C (external). The reaction mixture was cooled to room temperature before adding 4- (bromomethyl) tetrahydro-2H-pyran (0.14 g) in anhydrous DMF (1 ml). 5 The reaction mixture was heated at 50 ° C, overnight. The reaction mixture was quenched in water (20 ml) and extracted into ethyl acetate (20 ml, 3 times). The organic phases were separated, combined and then washed with brine (20 ml). The organic phase was separated and then dried by passing through a hydrophobic frit. Evaporation under reduced pressure gave pale yellow oil that solidified on standing. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (30-80%) to provide the title compound. in the form of a white solid (0.1777 g).

1H NMR (CDCl3): 5.11 (2H, s), 4.11 (3H, s), 4.10-4.06 (2H, m), 3.99-3.91 (2H, m) , 3.85-3.79 (2H, m), 3.38-3.29 (2H, m), 2.19-2.06 (1H, m), 1.94-1.63 (represents 5H , water 15 superimposed), 1.54-1.00 (10H, m superimposed).

MS calc. for (C19H29N5O3) + = 375

MS found (electrospray): (M + H) + = 376

Intermediate 119: 2 - {[2- (Methoxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (Procedure A) 20

2-Methoxyethanol (3.2 ml) was diluted with 1,2-dimethoxyethane (20 ml). To this, sodium tert-butoxide (3.9 g) was added gradually and the reaction mixture was stirred under a nitrogen atmosphere until it became homogeneous. Then 2-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (2.5376 g) was added to the reaction mixture, followed by 1,2-dimethoxyethane (20 ml ). The reaction mixture was then heated to reflux (110 ° C, external) overnight. The

The reaction was quenched with water (100 ml) and extracted with ethyl acetate (100 ml, twice). The combined organic phases were then washed with brine (100 ml). The organic phase was then dried by passing through a hydrophobic frit and then evaporated under reduced pressure (followed by azeotropization with toluene (100 ml, twice)). This provided an amber oil that under high vacuum provided a gummy foam. This material was triturated with diethyl ether (cooling) until this gave the title compound, a light yellow solid.

1H NMR (CDCl3): 7.86 (1H, s), 5.66-5.59 (1H, m), 5.47 (2H, wide s), 4.54-4.46 (2H, m ), 4.19-4.10 (1H, m), 3.80-3.65 (3H, m superimposed), 3.43 (3H, s), 2.13-1.93 (3H, m superimposed ), 1.81-1.58 (represents 3H, m superimposed, [water superimposed]). 10

MS calc. for (C13H19N5O3) + = 293

MS found (electrospray): (M + H) + = 294

Intermediate 119: 2 - {[2- (Methoxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (Procedure B)

 fifteen

Potassium tert-butoxide (46.5 g, 475 mmol) was added to 2-methoxyethanol (200 ml) in 20 minutes at room temperature, then 2-chloro-9- (tetrahydro-2H-pyran-2-yl) was added -9H-purin-6-amine (30 g) and the resulting mixture was heated at 80-90 ° C for approximately 3 h. After evaporating most of the solvent, 100 ml of water was added to the residue, stirred for 1 h at 0 ° C, filtered and dried. This provided product (30 g, 87%) that was almost 20 identical to that of Intermediate 119, procedure A.

1H NMR (CDCl3): 7.84 (1H, s), 5.66-5.59 (1H, m), 4.48 (2H, t), 4.18-4.08 (1H, m) , 3.80-3.65 (3H, m superimposed), 3.43 (3H, s), 2.1-1.85 (3H, m), 1.80-1.55 (3H, m).

 Intermediate 120: 8-Bromo-2 - {[2- (methoxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

2 - {[2- (Methoxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (1.61 g) dissolved

in chloroform (20 ml) and cooled to 0 ° C. To this solution was then added N-bromosuccinimide (1.02 g) gradually, keeping the temperature at ~ 2 ° C. The reaction was stirred at 2 ° C for approximately 15 minutes before allowing to warm to room temperature. The reaction mixture was then stirred under a nitrogen atmosphere for 5 hours. The reaction mixture was quenched with water (100 ml) and stirred rapidly before separating the organic phase using a hydrophobic frit. The organic phase was evaporated under reduced pressure to provide a dark brown gum. This material was purified by silica chromatography (ISCO) eluting initially with 0-70% ethyl acetate: cyclohexane keeping the isocratic at 70% ethyl acetate; cyclohexane until it eluted a minor impurity. Then the gradient from 70% to 95% ethyl acetate: cyclohexane was returned. This gave the title compound as a white solid (1.4489 g).

1H NMR (CDCl3): 5.65-5.56 (1H, m) 5.44 (2H, broad s), 4.52-4.43 (2H, m), 4.20-4.12 ( 1H, m), 3.79-3.65 (3H, m superimposed), 3.43 (3H, s), 3.09-2.96 (1H, m), 2.14-2.03 (1H , m), 1.89-1.56 (represents 4H, m superimposed, [underlying water]).

MS calc. for (C13H18BrN5O3) + = 371, 373 15

MS found (electrospray): (M + H) + = 372, 374

Intermediate 121: 8- (Methoxy) -2 - {[2- (methyloxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

8-Bromo-2 - {[2- (methoxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (1,4489 g) was suspended in methanol dry (11.5 ml) and then treated with 25% (w / v) sodium methoxide in methanol (2.5 ml). The reaction mixture was heated to reflux (65 ° C, external) from which a solution was obtained. After 4 hours the reaction mixture was concentrated under reduced pressure and saturated aqueous ammonium chloride (100 ml) was added. This was then extracted with ethyl acetate (100 ml, twice). The organic phases were separated, combined and washed with brine (100 ml). The organic phase was separated and then dried by passing through a hydrophobic frit. This was then evaporated under reduced pressure to provide the title compound as a white solid (1.2032 g) after being subjected to high vacuum overnight.

1H NMR (CDCl3): 5.53-5.45 (1H, m), 5.16 (2H, broad s), 4.50-4.40 (2H, m), 4.16-4.40 30 (1H, m) superimposed 4.12 (3H, s), 3.80-3.62 (3H, m superimposed), 3.43 (3H, s), 2.83-2.69 (1H,

m), 2.05-1.99 (1H, m), 1.82-1.51 (4H, m superimposed).

MS calc. for (C14H21N5O4) + = 323

MS found (electrospray): (M + H) + = 324

Intermediate 122: 8- (Methoxy) -2 - {[2- (methoxy) ethyl] oxy} -9H-purin-6-amine salt trifluoroacetate

 5

8- (Methoxy) -2 - {[2- (methyloxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (1.2032 g) was dissolved in methanol (10 ml) which was treated with pure trifluoroacetic acid (1 ml) and then stirred for 2 days. The reaction mixture was evaporated under reduced pressure and the resulting solid was suspended in ethyl acetate (25 ml) before filtering to give the title compound (1.1310 g) as a white solid. 10

1H NMR ((CD3) 2SO): 7.50 (2H, broad s), 4.42-4.34 (2H, m), 4.04 (3H, s) 3.67-3.61 (2H , m), 3.30 (3H, s) (the proton of N9 is not observed).

MS calc. for (C9H13N5O3) + = 239

MS found (electrospray): (M + H) + = 240

Intermediate 123: 8- (Methoxy) -2 - {[2- (methyloxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-15 purin-6-amine

8- (Methoxy) -2 - {[2- (methoxy) ethyl] oxy} -9H-purin-6-amine salt trifluoroacetate (0.30 g) was heated with anhydrous potassium carbonate (0.4698 g) in anhydrous DMF (5 ml) at 60 ° C for 1 hour. The reaction mixture was cooled to room temperature before adding 4- (bromomethyl) tetrahydro-2H-pyran (0.1669 g) in anhydrous DMF (1 ml). The reaction mixture was then stirred overnight at 50 ° C. The reaction mixture was quenched in water (20 ml) and extracted into ethyl acetate (20 ml, 3 times). The combined combined organic phases were then washed with brine (20 ml). The separated organic phase was dried by passing through a hydrophobic frit before evaporating under reduced pressure to provide a pale yellow oil that solidified on standing. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (10-45%) to provide the title compound in form of a white solid (0.1454

g).

1H NMR (CDCl3): 5.12 (2H, broad s), 4.47-4.41 (2H, m), 4.12 (3H, s), 4.00-3.91 (2H, m ), 3.85-3.73 (4H, m partially overlaid), 3.43 (3H, s), 3.38-3.28 (2H, m), 2.18-2.06 (1H, m ), 1.53-1.33 (4H, m superimposed).

MS calc. for (C15H23N5O4) + = 337 5

MS found (electrospray): (M + H) + = 338

Intermediate 124: 8- (Methoxy) -2 - {[2- (methyloxy) ethyl] oxy} -9- (tetrahydro-3-furanylmethyl) -9H-purin-6-amine

8- (Methoxy) -2 - {[2- (methoxy) ethyl] oxy} -9H-purin-6-amine trifluoroacetate salt (0.30 g) was dissolved in dry DMF (5 ml). To this was added anhydrous potassium carbonate (0.47 g) and then heated at 60 ° C for 1.5 hours. The reaction mixture was cooled to room temperature and tetrahydro-3-furanylmethyl methanesulfonate (0.168 g) was added. The reaction mixture was then heated at 90 ° C for 3.5 hours. The reaction mixture was then quenched in water (100 ml) and extracted into ethyl acetate (50 ml, 3 times). The organic phase was separated and dried by passing through a hydrophobic frit and then evaporated under reduced pressure to provide a vitreous solid. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (10-45%). This gave the title compound as a white solid (0.1233 g). twenty

1H NMR (CDCl3): 5.46 (2H, broad s), 4.48-4.39 (2H, m), 4.12 (3H, s), 4.01-3.87 (3H, m superimposed), 3.79-3.70 (4H, m superimposed), 3.65-3.59 (1H, m), 3.43 (3H, s), 2.91-2.78 (1H, m ), 2.02-1.90 (1H, m), 1.76-1.64 (1H, m).

MS calc. for (C14H21N5O4) + = 323

MS found (electrospray): (M + H) + = 324 25

Intermediate 125: 2 - [(Tetrahydro-2-furanylmethyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

Tetrahydrofurfuryl alcohol (4.09 g) was diluted with 1,2-dimethoxyethane (20 ml). To this solution was added sodium tert-butoxide (3.84 g) gradually. The resulting reaction mixture was stirred until it became homogeneous (orange solution) before adding 2-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (2.53 g) . The reaction mixture was then heated at 110 ° C (external) overnight under a nitrogen atmosphere. The reaction mixture was quenched with water (100 ml) and extracted with ethyl acetate (100 ml, 3 times). The organic phase was separated, combined and then dried by passing through a hydrophobic frit. This was evaporated under reduced pressure and the resulting material was then purified by silica chromatography eluting with 0 -100% ethyl acetate: cyclohexane followed by methanol. A fault was detected in the ISCO pump while it was eluting with methanol, this route previously carried ethyl acetate and it is unknown if the fault existed while eluting with ethyl acetate: cyclohexane. The appropriate fractions were evaporated to give the title compound as a solid (1.7258 g). This material was used in the next step without further purification. fifteen

1H NMR (CDCl3): 7.87 (1H, m), 6.69 (2H, broad m), 5.68-5.54 (1H, m), 4.45-4.36 (1H, m ), 4.35-4.21 (2H, m superimposed), 4.17-4.08 (1H, m), 3.98-3.89 (1H, m), 3.85-3.68 ( 2H, m superimposed), 2.15-1.55 (10H, m superimposed).

Intermediate 126: 8-Bromo-2 - [(tetrahydro-2-furanylmethyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

2 - [(Tetrahydro-2-furanylmethyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (1.7202 g) was dissolved in chloroform (15 ml) and cooled to ~ 1 ° C before adding N-bromosuccinimide (1,056 g) keeping the reaction temperature below 2 ° C. The reaction mixture was then stirred at ~ 1 ° C for 30 minutes before allowing to warm to room temperature after 25 which the reaction mixture was stirred for 3 hours. The reaction mixture then rested.

overnight at room temperature before fractionating in water (50 ml) and the organic phase was separated using a hydrophobic frit. The organic phase was evaporated under reduced pressure to provide a brown gum that was purified using silica chromatography (ISCO) eluting with 0 -100% ethyl acetate: cyclohexane. This gave the title compound as a white foamy solid (1.3748 g). 5

1H NMR (CDCl3): 5.63-5.56 (1H, m), 5.43 (2H, broad s), 4.45-4.36 (1H, m), 4.34-4.10 (3H, m superimposed), 4.98-3.89 (1H, m), 3.85-3.77 (1H, m), 3.74-3.66 (1H, m), 3.09- 2.97 (1H, m), 2.15-1.56 (represents 9H [superimposed water])

MS calc. for (C15H20BrN5O3) + = 397, 399

MS found (electrospray): (M + H) + = 398, 400 10

Intermediate 127: 8- (Methoxy) -2 - [(tetrahydro-2-furanylmethyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

8-Bromo-2 - [(tetrahydro-2-furanylmethyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (1.3748 g) was dissolved in methanol (10 , 2 ml) and treated with 25% (w / v) sodium methoxide in methanol (2.2 ml). This was refluxed under a nitrogen atmosphere for 3.5 hours. The reaction mixture was evaporated under reduced pressure to dryness and saturated ammonium chloride solution (100 ml) was added. This was then extracted with ethyl acetate (100 ml, 3 times). The organic phases were combined and washed with brine (100 ml) and then dried by passing through a hydrophobic frit after separating the aqueous phase. The organic phase 20 was evaporated under reduced pressure to provide the title compound as a white foam (1.1614 g) and was used in the next step without requiring purification.

1H NMR (CDCl3): 5.52-5.46 (1H, m), 5.15 (2H, broad s), 4.43-4.36 (1H, m), 4.33-4.26 (1H, m), 4.23-4.17 (1H, m), 4.16-4.09 (1H, m superimposed 4.13 (3H, s)), 3.97-3.90 (1H , m), 3.84-3.76 (1H, m), 3.73-3.65 (1H, m), 2.83-2.71 (1H, m), 2.13-1.53 (represents 9H, m 25 superimposed [water superimposed]).

MS calc. for (C16H23N5O4) + = 349

MS found (electrospray): (M + H) + = 350

Intermediate 128: 8- (Methoxy) -2 - [(tetrahydro-2-furanylmethyl) oxy] -9H-purin-6-amine salt trifluoroacetate 30

8- (Methoxy) -2 - [(tetrahydro-2-furanylmethyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (1.1614 g) was dissolved in methanol (20 ml) and treated with pure trifluoroacetic acid (2 ml). The reaction mixture was stirred for 24 hours to provide a white suspension. The reaction mixture was then evaporated to dryness under reduced pressure. The resulting white solid 5 was suspended using ethyl acetate (10 ml) and then isolated by filtration, washing with ethyl acetate (2 ml). The solid was air dried with suction and then further dried under vacuum at 50 ° C. This gave the title compound as a white solid (1.0602 g).

1H NMR ((CD3) 2SO): 7.76 (2H, wide s), 4.35-4.11 (3H, overlapping m), 4.05 (3H, s), 10 3.82-3, 73 (1H, m), 3.73-3.63 (1H, m), 2.05-1.77 (3H, m superimposed), 1.70-1.59 (1H, m) (NH of N -9 not obvious from the spectrum - indicates an extremely wide signal at 12.7 ppm (but could be an FT artifact)).

MS calc. for (C11H15N5O3) + = 265

MS found (electrospray): (M + H) + = 266 15

Intermediate 129: 8- (Methoxy) -2 - [(tetrahydro-2-furanylmethyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine

8- (Methoxy) -2 - [(tetrahydro-2-furanylmethyl) oxy] -9H-purin-6-amine salt trifluoroacetate (0.30 g) was dissolved in dry DMF (5 ml). To this solution was added anhydrous potassium carbonate (0.4376 20 g) and then the reaction mixture was heated at 60 ° C under a nitrogen atmosphere for 1 hour. The reaction mixture was then cooled to room temperature before adding tetrahydro-2H-pyran-4-ylmethyl methanesulfonate (0.1690 g) and then the resulting reaction mixture was heated at 90 ° C for 2.5 hours. The reaction mixture was cooled and then quenched with water (50 ml), followed by extraction in ethyl acetate (50 ml, 3 times). After separating, the organic phases were combined and dried by passing through a hydrophobic frit. Evaporation under reduced pressure provided mobile oil which was then

purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (10-45%). This gave the title compound as a white solid (0.1560 g).

1H NMR (CDCl3): 5.17 (2H, broad s), 4.40-4.26 (2H, near m), 4.23-4.17 (1H, m), 4.11 (3H, s), 3.99-3.89 (3H, m superimposed), 3.84-3.76 (3H, m superimposed), 3.37-3.29 (2H, m), 5 2.18-1 , 66 (represents 5H [underlying water peak]), 1.52-1.33 (4H, m superimposed).

MS calc. for (C17H25N5O4) + = 363

MS found (electrospray): (M + H) + = 364

Intermediate 130: (2E) -3- (5,6-Dihydro-2H-pyran-3-yl) -2-ethyl propenoate

 10

At 5,6-dihydro-2H-pyran-3-carbaldehyde (5.0 g) in dry dichloromethane (150 ml) at 0 ° C, carbetoxymethylene triphenylphosphorane (15.53 g) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was diluted with dichloromethane (150 ml) and washed with water (150 ml) and a saturated aqueous brine solution (150 ml). The organic phase was dried by passing through a hydrophobic frit and concentrated in vacuo to provide a yellow oil. The product was purified by silica chromatography (120 g) (ISCO) using a gradient elution of 0-10% cyclohexane: ethyl acetate to give the title compound as a clear oil (5.59 g).

1H NMR (CDCl3): δ 7.27 (1H, t), 6.33 (1H, m), 5.67 (1H, d), 4.35 (2H, m), 4.26 (2H, q), 3.84 (2H , t), 2.39 (2H, m), 1.35 (3H, t). twenty

Intermediate 131: 3- (Tetrahydro-2H-pyran-3-yl) ethyl propanoate

A solution of ethyl (2E) -3- (5,6-dihydro-2H-pyran-3-yl) -2-propenoate (3 g) and palladium on carbon (170 mg, 10%, wet) in acetate Ethyl (75 ml) was hydrogenated at atmospheric pressure and room temperature. Hydrogen uptake (~ 825 ml) was completed after 30 minutes. The catalyst was filtered through celite and the filtrate was concentrated in vacuo to provide a pale yellow oil (2.90 g).

The above was repeated in exactly the same way with a second batch. A solution of ethyl (2E) -3- (5,6-dihydro-2H-pyran-3-yl) -2-ethyl propenoate (2.59 g) and palladium on was therefore hydrogenated at atmospheric pressure and room temperature carbon (147mg, 10% wet) in 30

ethyl acetate (65 ml). Hydrogen uptake (~ 715 ml) was completed after 15 minutes. The catalyst was filtered through celite and the filtrate was concentrated in vacuo to provide a pale yellow oil that was combined with that of the first batch (5.34 g). This was purified by silica chromatography (120 g) (ISCO) using a gradient elution of 0-10% cyclohexane: ethyl acetate to give the title compound as a clear oil (4.61 g).

1H NMR (CDCl3): δ 4.13 (2H, q), 3.86 (2H, m), 3.35 (1H, m), 3.06 (1H, m), 2.31 (2H, m), 1.87 (1H , m), 1.64-1.41 (5H, m), 1.26 (3H, t), 1.15 (1H, m).

Intermediate 132: 3- (Tetrahydro-2H-pyran-3-yl) -1-propanol

 10

To a stirring solution of lithium aluminum hydride (24.8 ml, 1.0 M in diethyl ether) in dry diethyl ether (77 ml) at 0 ° C was added a solution of 3- (tetrahydro-2H-pyran- Ethyl 3-yl) propanoate (4.61 g) in dry diethyl ether (77 ml) dropwise over 20 minutes. After 15 minutes at 0 ° C the reaction mixture was heated to room temperature and stirred for another nine hours. The reaction was quenched by the dropwise addition of water for a period of one hour, while cooling on ice. The resulting solids were filtered from the mixture and washed with diethyl ether. The organic phase was removed by decantation from the aqueous phase, dried over magnesium sulfate, filtered and concentrated in vacuo to provide a clear oil (3.33 g). The product was purified by silica chromatography (40 g) (ISCO) using a gradient elution of 0–50% of cyclohexane: ethyl acetate to give the title compound as a clear oil (2.64 g).

1H NMR (CDCl3): δ 3.87 (2H, m), 3.64 (2H, m), 3.35 (1H, m), 3.05 (1H, m), 1.88 (1H, m), 1.66-1 , 51 (5H, m), 1.39 (1H, t), 1.31-1.08 (3H, m).

Intermediate 133: 3- (tetrahydro-2H-pyran-3-yl) propyl methanesulfonate

To a solution of 3- (tetrahydro-2H-pyran-3-yl) -1-propanol (2.64 g) in dry dichloromethane (78 ml) at 0 ° C was added triethylamine (6.21 ml) followed by mesyl (1.85 ml). The reaction mixture was allowed to warm to room temperature while the ice was melting and allowed to stir for three hours. The reaction mixture was washed with sodium hydrogen carbonate. The organic phase 30 was separated, dried by passing through a hydrophobic frit and concentrated in vacuo,

providing a yellow oil (4.42 g). The product was purified by silica chromatography (80 g) (ISCO) using a gradient elution of 0–50% cyclohexane: ethyl acetate to provide the title compound as a clear oil (3.79 g).

1H NMR (CDCl3): δ 4.22 (2H, t), 3.86 (2H, m), 3.36 (1H, m), 3.07 (1H, m), 3.01 (3H, s), 1.87 (1H , m), 1.82-1.69 (2H, m), 1.65-1.54 (3H, m), 1.36-1.10 (3H, m). 5

Intermediate 134: N2-Butyl-8- (methoxy) -9- [3- (tetrahydro-2H-pyran-3-yl) propyl] -9H-purin-2,6-diamine

To a salt solution of the trifluoroacetic acid of N2-butyl-8-methoxy-9H-purin-2,6-diamine (300 mg) in dry N, N-dimethylformamide (5.3 ml) was added potassium carbonate (474 10 mg) The reaction was stirred at 60 ° C for ninety minutes. The reaction was cooled and 3- (tetrahydro-2H-pyran-3-yl) propyl methanesulfonate (209 mg) was added and the reaction was heated at 90 ° C for three hours. The reaction was cooled, diluted with ethyl acetate and washed with water (2x). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to provide a yellow oil. The product was purified by C18 reverse phase chromatography (43 g) (ISCO) using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (30-80%) to provide the title compound as a yellow oily residue (198 mg).

MS calc. for (C18H30N6O2) + = 362

MS found (electrospray): (M + H) + = 363 20

 1 H NMR (DMSO): δ 6.23 (2H, s), 6.01 (1H, t), 3.99 (3H, s), 3.77-3.67 (4H, m), 3.26-3.15 (3H, m), 2.91 (1H, m), 1.76 (1H, m), 1.71-1.60 (2H, m), 1.54-1.40 (5H, m), 1.36 -1.26 (2H, m), 1.16-0.96 (3H, m), 0.88 (3H, m).

Intermediate 135: 9- (Tetrahydro-2H-pyran-2-yl) -2 - [(tetrahydro-2H-piran-2-ylmethoxy] -9H-purin-6-amine 25

Tetrahydropyran-2-methanol (from Aldrich) (4.66 g) was diluted with 1,2-dimethoxyethane (20 ml). Gradually, sodium tert-butoxide (3.85 g) was added to the above and stirred until it became homogeneous (orange solution). 2-Chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (2.54 g) was added thereto and then heated to reflux (110 ° C, external), all the night and in 5 atmosphere of nitrogen. The reaction mixture was quenched in water (100 ml) and extracted using ethyl acetate (100 ml, 3 times). The organic phase was separated and then passed through a hydrophobic frit. Evaporation under reduced pressure provided a gum that was then purified by ISCO (120 g, SiO2) eluting with 0-50% methanol: DCM to provide the title compound as a light yellow foam (2.1732 g). 10

MS calc. for (C16H23N5O3) + = 333

MS found (electrospray): (M + H) + = 334

1H NMR (CDCl3): 7.85 (1H, s), 5.66-5.49 (superimposed 1H, m and 2H, broad s), 4.41-4.34 (1H, m), 4.25 -4.19 (1H, m), 4.18-4.11 (1H, m), 4.06-4.00 (1H, m), 3.78-3.69 (2H, m), 3 , 54-3.45 (1H, m), 2.12-1.83 (4H, m superimposed), 1.83-1.36 (8H, m superimposed). fifteen

Intermediate 136: 8-Bromo-9- (tetrahydro-2H-piran-2-yl) -2 - [(tetrahydro-2H-piran-2-ylmethoxy] -9H-purin-6-amine

To a solution of 9- (tetrahydro-2H-piran-2-yl) -2 - [(tetrahydro-2H-piran-2-ylmethoxy] -9H-purin-6-amine (2.17 g) in dry chloroform ( 23.5 ml), cooled to 0 ° C, N-20 bromosuccinimide (1.22 g) was added.The reaction was allowed to return to room temperature and stirred for 4 hours.The reaction was diluted with DCM (50 ml) and washed with water (50 ml) and then brine (50 ml). The organic phase was separated, dried through a hydrophobic frit, and concentrated in vacuo. This gave the title product as a solid. sparkling brown (2.76 g) .25

MS calculated for (C16H22BrN5O3) + = 412, 413

MS found (electrospray): (M + H) + = 413, 414

Intermediate 137: 8- (Methoxy) -9- (tetrahydro-2H-pyran-2-yl) -2 - [(tetrahydro-2H-pyran-2-ylmethoxy] -9H-purin-6-amine

To a solution of 8-bromo-9- (tetrahydro-2H-piran-2-yl) -2 - [(tetrahydro-2H-pyran-2-ylmethoxy] -9H-purin-6-amine (2.76 g) in dry methanol (22.6 ml) at room temperature, sodium methoxide (4.6 ml, 25% by weight in methanol) was added.The reaction was heated at reflux for 4 hours.The reaction was cooled and concentrated to vacuum providing an orange residue This was taken in ammonium chloride solution (100 ml) and extracted with ethyl acetate (100 ml) The organic phase was separated and washed with water (50 ml). dried over magnesium sulfate, filtered and concentrated in vacuo This gave the title compound as an orange foamy solid (2.06 g).

MS calculated for (C17H25N5O4) + = 363

MS found (electrospray): (M + H) + = 364

Intermediate 138: 8- (Methoxy) -2 - [(tetrahydro-2H-pyran-2-ylmethoxy] -9H-purin-6-amine salt trifluoroacetate 15

To a solution of 8- (methoxy) -9- (tetrahydro-2H-pyran-2-yl) -2 - [(tetrahydro-2H-pyran-2-ylmethoxy] -9H-purin-6-amine (2.06 g) in dry methanol (20.6 ml) trifluoroacetic acid (2.06 ml) was added.The reaction was stirred at room temperature for 24 hours.The reaction mixture was concentrated in vacuo and the resulting residue was triturated in diethyl ether This produced an off-white solid after filtration (1.59 g).

MS calculated for (C12H17N5O3) + = 279

MS found (electrospray): (M + H) + = 280

Intermediate 139: 8- (Methoxy) -9- (tetrahydro-2H-pyran-4-ylmethyl) -2 - [(tetrahydro-2H-pyran-2-ylmethoxy] -9H-purin-6-amine 25

To a solution of 8- (methoxy) -2 - [(tetrahydro-2H-pyran-2-ylmethoxy] -9H-purin-6-amine salt trifluoroacetate (1.59 g) in dry N, N-dimethylformamide (25 ml ) potassium carbonate (2.24 g) was added.The reaction was stirred at 60 ° C for 1.5 hours.The reaction was cooled and tetrahydro-2H-pyran-4-ylmethyl methanesulfonate (866 mg) was added. It was stirred at 90 ° C. for 5 hours. The reaction was cooled and taken in ethyl acetate and washed twice with water. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to provide a yellow solid The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (20-50%) to provide the title compound in the form of an off-white solid (704 mg).

MS calculated for (C18H27N5O4) + = 377

MS found (electrospray): (M + H) + = 378

Intermediate 140: 2 - ({2 - [(1-Methylethyl) oxy] ethyl} oxy) -8- (methoxy) -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine 15

To a solution of 2 - ({2 - [(1-methyl ethyl) oxy] ethyl} oxy) -8- (methoxy) -9H-purin-6-amine salt trifluoroacetate (400 mg) in dry N, N-dimethylformamide ( 6.4 ml) potassium carbonate (579 mg) was added. The reaction was stirred at 60 ° C for 1.5 hours. The reaction was cooled and tetrahydro-2H-pyran-4-ylmethyl methanesulfonate (224 mg) was added. The reaction was stirred at 90 ° C for 4 hours. The reaction was cooled and taken in ethyl acetate and washed twice with water. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to provide a yellow oil (432 mg). The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (20-50%) to provide the compound of the title in the form of a transparent viscous oil (166 mg).

MS calculated for (C17H27N5O4) + = 365

MS found (electrospray): (M + H) + = 366

Intermediate 141: 5- {4 - [(Phenylmethyl) oxy] -1-buten-1-yl} -3,6-dihydro-2H-pyran

To a suspension of (3-benzyloxypropyl) triphenylphosphonium bromide (9.90 g) in dry tetrahydrofuran (30.5 ml) at -15 ° C was added butyl lithium (8.06 ml, 2.5 M in hexanes) drop by drop providing a dark orange solution. The reaction temperature was increased to 0 ° C and stirring was continued for 30 minutes. A solution of 5,6-dihydro-2H-pyran-3-carbaldehyde (2.26 g) in dry tetrahydrofuran (3 ml) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was filtered through celite and washed with diethyl ether. The filtrate was concentrated in vacuo to give an orange oil. The product was purified by silica chromatography using a gradient elution of 0-25% ethyl acetate / cyclohexane to give the title compound as a colorless oil (2.04 g).

1 H NMR (CDCl 3): mixture of cis and trans δ 7.40-7.27 (5H, m), 6.02 (0.60H, d), 5.76 15 (1.36H, m), 5 , 49-5.37 (1H, m), 4.53 (2H, m), 4.29 (1.23H), 4.22 (0.74H, m), 3.77 (2H, t), 3.51 (2H, m), 2.52 (0.78H, m), 2.40 (1.29H, m), 2.24 (2H, m).

Intermediate 142: 4- (Tetrahydro-2H-pyran-3-yl) -1-butanol

A solution of 5- {4 - [(phenylmethyl) oxy] -1-buten-1-yl} -3,6-dihydro-2H-pyran (2.03 g) and 10% 20 palladium on carbon (88 mg ) in ethyl acetate (83 ml) was hydrogenated at atmospheric pressure and room temperature. Hydrogen uptake (~ 500 ml) was completed after 15 hours. The catalyst was filtered through celite and the filtrate was concentrated in vacuo to give a colorless oil. 1 H NMR analysis showed that the benzyl group was present in most of the compound. Hydrogenation continued under the same conditions for another 24 hours with additional hydrogen uptake of ~ 300 ml. The catalyst was filtered through celite and the filtrate was concentrated in vacuo to give the title compound as a colorless oil (1.21 g).

1H NMR (CDCl3): δ 3.86 (2H, m), 3.63 (2H, t), 3.34 (1H, m), 3.04 (1H, t), 1.86 (1H, m), 1.75 (1H, s), 1.66-1.47 (5H, m), 1.45-1.27 (2H, m), 1.26-1.06 (3H, m) . 30

Intermediate 143: 4- (tetrahydro-2H-pyran-3-yl) butyl methanesulfonate

A solution of 4- (tetrahydro-2H-pyran-3-yl) -1-butanol (1.20 g) in dry dichloromethane (30.3 ml), cooled to 0 ° C, triethylamine (2.43 ml) was added ) and methanesufonyl chloride (0.77 ml) providing a yellow solution. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate (25 ml). The organic phase was separated, dried by passing through a hydrophobic frit and concentrated in vacuo to provide a yellow oil (1.80 g). The product was purified by silica chromatography using a gradient elution of 0-40% ethyl acetate / cyclohexane to give the title compound as a yellow oil (1.58 g).

1H NMR (CDCl3): δ 4.23 (2H, t), 3.86 (2H, m), 3.35 (1H, m), 3.05 (1H, m), 3.01 (3H, s), 1.86 (1H, m), 1.79-1.67 (2H, m), 1.64-1.52 (3H, m), 1.47-1.34 (2H, m) , 1.28-1.05 (3H, m).

Intermediate 144: N2-butyl-8- (methoxy) -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -9H-purin-2,6-diamine

To a solution of N2-butyl-8- (methoxy) -9H-purin-2,6-diamine (250 mg) in dry N, N-dimethylformamide (4.46 ml) at room temperature was added potassium carbonate (395 mg ). The reaction mixture was stirred at 60 ° C for 90 min. The reaction was cooled to room temperature and 4- (tetrahydro-2H-pyran-3-yl) butyl methanesulfonate (186-20 mg) was added and the reaction was stirred at 90 ° C for 2 hours. The reaction mixture was taken in ethyl acetate (50 ml) and washed with water (2 x 50 ml). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to provide an orange oil (366 mg). The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (30-70%) to provide the compound of title in the form of an orange gum (172 mg).

MS calculated for (C19H32N6O2) + = 376

MS found (electrospray): (M + H) + = 377

Intermediate 145: N2- (2-Cyclopropylethyl) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-2,6-diamine

To a suspension of 2-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (3.49 g) in 5 ethylene glycol (17 ml) at room temperature was added cyclopropylethylamine (4 , 69 g). The reaction mixture was heated at 120 ° C with reflux condenser overnight, producing a yellow / brown solution. The reaction was allowed to cool, taken in ethyl acetate (100 ml) and washed with water (2 x 100 ml). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to provide a dark brown gum (4.17 g). 10

MS calculated for (C15H22N6O) + = 302

MS found (electrospray): (M + H) + = 303

Intermediate 146: 8-Bromo-N2- (2-cyclopropylethyl) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-2,6-diamine

 fifteen

To a solution of N2- (2-cyclopropylethyl) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-2,6-diamine (4.17 g) in chloroform (46.0 ml) at At 0 ° C, N-bromosuccinimide (2.58 g) was added to provide a dark green suspension. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was taken in dichloromethane (100 ml) and washed with water (1x100 ml). The organic phase was separated, dried by passing through a hydrophobic frit and concentrated under vacuum to provide a green gum (5.50 g, 80% purity).

MS calculated for (C15H21BrN6O) + = 380, 382

MS found (electrospray): (M + H) + = 381, 383

Intermediate 147: N2- (2-Cyclopropylethyl) -8- (methoxy) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-2,6-diamine

To a solution of 8-bromo-N2- (2-cyclopropylethyl) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-2,6-diamine (5.50 g) in methanol (48, 1 ml) at room temperature sodium methoxide (9.9 ml, 25% by weight in methanol) was added providing a brown solution. The reaction mixture was stirred at reflux for 24 hours. The reaction was allowed to cool before adding 5 ammonium chloride solution (100 ml) and extracting with ethyl acetate (150 ml). The organic phase was separated and washed with water (100 ml). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to give a brown solid (3.79 g). The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (20-60%) to provide the compound of title in the form of a brown gum (3.3 g, 79% purity).

MS calculated for (C16H24N6O2) + = 332

MS found (electrospray): (M + H) + = 333

Intermediate 148: N2- (2-cyclopropylethyl) -8- (methoxy) -9H-purin-2,6-diamine trifluoroacetate

 fifteen

To a solution of N2- (2-cyclopropylethyl) -8- (methoxy) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-2,6-diamine (3.30 g) in methanol ( 33.0 ml) at room temperature trifluoroacetic acid (3.30 ml) was added providing an orange solution. The reaction mixture was stirred at room temperature for 70 hours. The reaction mixture was concentrated in vacuo to provide a yellow solid which was then triturated in diethyl ether (100 ml) and filtered under vacuum to give an off-white solid (2.4 g).

MS calculated for (C11H16N6O) + = 248

MS found (electrospray): (M + H) + = 249

Intermediate 149: N2- (2-Cyclopropylethyl) -8- (methoxy) -9- (tetrahydro-3-furanylmethyl) -9H-purin-2,6-diamine

To a solution of trifluoroacetate of N2- (2-cyclopropylethyl) -8- (methoxy) -9H-purin-2,6-diamine (400 mg) in N, N-dimethylformamide (6.90 ml) at room temperature was added potassium carbonate (610 mg) and the reaction mixture was stirred at 60 ° C for 90 minutes. The reaction was cooled to room temperature and tetrahydro-3-5 furanylmethyl methanesulfonate (219 mg) was added, stirring was continued at 50 ° C for 20 h. The reaction temperature was increased to 90 ° C and stirring was continued. The reaction was cooled and taken in ethyl acetate (50 ml) and washed with water (2x50 ml). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange oil. The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (10-45%) to provide the compound of title in the form of a yellow oil (209 mg, 84% purity).

MS calculated for (C16H24N6O2) + = 332

MS found (electrospray): (M + H) + = 333 15

Intermediate 150: N2- (2-Cyclopropylethyl) -8- (methyloxy) -9- (tetrahydro-2H-pyran-3-ylmethyl) -9H-purin-2,6-diamine

To a solution of trifluoroacetate of N2- (2-cyclopropylethyl) -8- (methoxy) -9H-purin-2,6-diamine (400 mg) in N, N-dimethylformamide (6.90 ml) at room temperature was added 20 potassium carbonate (610 mg) and the reaction was stirred at 60 ° C for 90 minutes. The reaction mixture was cooled to room temperature and tetrahydro-2H-pyran-3-ylmethyl methanesulfonate (236 mg) was added. Stirring was continued at 50 ° C for 20 hours. The reaction temperature was increased to 90 ° C and stirring was continued. The reaction was cooled and taken in ethyl acetate (50 ml) and washed with water (2x50 ml). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange oil. He

product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (10-50%) to provide the title compound in form of a colorless oil (198 mg, 88% purity).

MS calculated for (C17H26N6O2) + = 346 5

MS found (electrospray): (M + H) + = 347

Intermediate 151: 8-Bromo-2 - ({2 - [(1-methyl ethyl) oxy] ethyl} oxy) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

2-Chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (5 g, 20 mmol) was added to a stirring solution of potassium tert-butoxide in 2 - [( 1-methyl ethyl oxy] ethanol (50 ml). The mixture was heated at 80-90 ° C for 4 h. The alcohol was removed under reduced pressure. The residue was added to ethyl acetate and washed with water three times, dried, filtered and concentrated to give the crude product. This product was semi-purified by silica gel chromatography eluting with 1: 1 ethyl acetate: petroleum ether to provide material (3.3 g). 15 This and similarly prepared material was used in the next step. To this material (6.8 g, 21.2 mmol) in DCM was added NBS (4.15 g, 23.3mmol). It was stirred for 16 h at room temperature and washed twice with aqueous sodium bicarbonate. The crude product was purified through silica gel eluting with 1: 2 ethyl acetate: petroleum ether to give the title compound (5.6 g). twenty

1H NMR (CDCl3): 6.15-5.95 (2H, broad s), 5.52 (1H, m), 4.38 (2H, m), 4.15-4.0 (1H, m ), 3.73 (2H, t), 3.7-3.55 (2H, m), 3.05-2.85 (1H, m), 2.1-1.95 (1H, m), 1.85-1.45 (4H, m superimposed), 1.12 (6H, d).

Intermediate 152: 2 - ({2 - [(1-Methylethyl) oxy] ethyl} oxy) -8- (methoxy) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine 25

To methanol (120 ml) was added sodium (0.966 g). When the metal dissolved, 8-

Bromo-2 - ({2 - [(1-methylethyl) oxy] ethyl} oxy) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (5.69 g, 21, 2 mmol), heated to reflux and the solution was stirred for 16 h, cooled to room temperature. The solvent was removed. It was extracted with ethyl acetate after adding water, dried and concentrated to provide the crude product that was purified through silica gel eluting with 2: 1 ethyl acetate: petroleum ether to provide the title compound (4.8 5 g)

1H NMR (CDCl3): 5.47 (1H, m), 5.33 (2H, wide s), 4.41 (2H, m), 4.2-4.0 (4H, wide s), 3 , 76 (2H, m), 3.7-3.55 (2H, m), 2.85-2.65 (1H, m), 2.1-1.9 (1H, m), 1.85 -1.45 (4H, m superimposed), 1.17 (6H, d).

Intermediate 153: 2 - ({2 - [(1-Methylethyl) oxy] ethyl} oxy) trifluoroacetate -8- (methoxy) -9H-purin-6-10 amine

A 2 - ({2 - [(1-methylethyl) oxy] ethyl} oxy) -8- (methoxy) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (4, 5 g, 14 mmol) in methanol (30 ml) trifluoroacetic acid (8 ml) was added, stirred for 10 minutes and kept at room temperature for 2 days. It was filtered to provide the crude product that was purified by preparative hplc (Gilson GX-281 instrument with a 5.0 µm YMC C18 column (250 x 20 mm) eluting with water containing TFA (0.1%): acetonitrile at 30-60% This gave the title compound 2.1 g.

1H NMR (CD3OD): 4.55 (2H, m), 4.13 (3H, s), 3.78 (2H, t), 3.67 (1H, m), 1.14 (6H, d ). No exchangeable protons were observed. twenty

Intermediate 154: Tetrahydro-3-Furancarbonyl Chloride

To tetrahydro-3-furanecarboxylic acid (24.3 g) in anhydrous dichloromethane (299 ml) at room temperature and under nitrogen atmosphere oxalyl chloride (27.5 ml) was added dropwise over 10 minutes followed by a few drops of DMF. The reaction was allowed to stir overnight. The reaction was concentrated in vacuo to provide an orange oil (28 g).

1H NMR (CDCl3): δ 4.11 (1H, dd), 4.01 (1H, m), 3.93 (1H, m), 3.84 (1H, m), 3.57 (1H, m), 2.34 (1H , m), 2.23 (1H, m).

Intermediate 155 (diastereoisomer 1) and Intermediate 156 (diastereoisomer 2): (4R) -4- (Phenylmethyl) -3 - [(3S) -tetrahydro-3-furanylcarbonyl] -1,3-oxazolidin-2-one and (4R ) -4- (phenylmethyl) -3-30

[(3S) -tetrahydro-3-furanylcarbonyl] -1,3-oxazolidin-2-one

To a solution of (4R) -4- (phenylmethyl) -1,3-oxazolidin-2-one (31 g) in anhydrous tetrahydrofuran (583 ml) at -78 ° C and under a nitrogen atmosphere, n-butyl- was added lithium (115 ml) drop by drop for 30 minutes keeping the internal temperature below -65 ° C. Reaction 5 was stirred at -78 ° C for 25 minutes and then a solution of tetrahydro-3-furancarbonyl chloride (28.2 g) in anhydrous tetrahydrofuran (20 ml) was added dropwise over 20 minutes keeping the temperature below from -65 ° C. After the addition, the reaction was heated for 30 minutes at room temperature. The reaction was quenched with saturated aqueous ammonium chloride (50 ml) and then concentrated in vacuo. The residue was taken in dichloromethane (400 ml) and washed with brine (2 x 50 ml). The organic phase was dried through a hydrophobic frit and concentrated in vacuo. The product was purified by silica chromatography (1.5 kg) (ISCO) using a gradient elution of 2% ethyl acetate: dichloromethane. This provided 15 g of the product that moved faster (Diastereoisomer 1 semi-pure) and 15 g of the product that moved slower (Diastereoisomer 15 2 semi-pure). Approximately 20 g of mixed fractions were also collected. The semi-pure diastereoisomer 1 was crystallized from cyclohexane / 5% ethyl acetate. The crystals were collected by suction filtration and dried on a rotary evaporator at 50 ° C for 15 minutes. 1 H NMR indicated the presence of the other diastereoisomer. The product was further purified by silica chromatography (~ 800 g, toluene / 5% diethyl ether) to provide diastereoisomer 1 as a white solid (6.85 g, 98.4: 1.56 by chiral HPLC) . The semi-pure diastereoisomer 2 was recrystallized from cyclohexane / 5% ethyl acetate. The crystals were collected by suction filtration and dried on a rotary evaporator at 50 ° C for 15 minutes. 1 H NMR indicated the presence of the other diastereoisomer. The product was purified by silica chromatography (~ 800 g, toluene / 5% diethyl ether) to provide a white solid (96: 4 by chiral HPLC). This was recrystallized from cyclohexane / 15% ethyl acetate to provide diastereoisomer 2 as white crystals (6.2 g, 96.4: 3.6 by chiral HPLC).

The mixed fractions (~ 20 g) were purified by ISCO silica chromatography (1.5 kg) (ISCO) using a gradient elution of 5% TBME / toluene to provide 30

semi-pure diastereoisomer 1, in the form of a transparent oil that crystallized (7.3 g, 95.2: 4.80 by chiral HPLC) and semi-pure diastereoisomer 2 in the form of a transparent oil that crystallized (6.7 g, 96.1 : 3.80 by chiral HPLC). The two solid batches of diastereoisomer 1 were combined and recrystallized from cyclohexane: ethyl acetate, 5: 1. The crystals were filtered. This recrystallization procedure was repeated 3 times 5 providing diastereoisomer 1 (10.7 g, 98.5: 1.5 by chiral HPLC).

The two solid batches of diastereoisomer 1 were combined and recrystallized from cyclohexane: ethyl acetate, 5: 1. The crystals were filtered. This recrystallization procedure was repeated 3 times to provide diastereoisomer 2 (9.6 g, 99.5: 0.5 by chiral HPLC). 10

Intermediate 155 (diastereoisomer 1)

1H NMR (CDCl3): δ 7.43-7.31 (3H, m), 7.29-7.23 (2H, m), 4.75 (1H, m), 4.33-4.25 (2H, m), 4, 23-4.12 (2H, m), 4.07-4.00 (2H, m), 3.90 (1H, m), 3.33 (1H, dd), 2.86 (1H, dd) , 2.39 (1H, m), 2.19 (1H, m).

Intermediate 156 (diastereoisomer 2) 15

1H NMR (CDCl3): δ 7.43-7.31 (3H, m), 7.29-7.23 (2H, m), 4.74 (1H, m), 4.32-4.19 (3H, m), 4, 10-4.03 (2H, m), 4.00 (1H, m), 3.90 (1H, m), 3.36 (1H, dd), 2.84 (1H, dd), 2.31 (2H, m).

Intermediate 155 and Intermediate 156, alternative procedure: (4R) -4- (Phenylmethyl) -3 - [(3S) -tetrahydro-3-furanylcarbonyl] -1,3-oxazolidin-2-one and (4R) -4- ( phenylmethyl) -3 - [(3R) -tetrahydro-3-20 furanylcarbonyl] -1,3-oxazolidin-2-one

To tetrahydro-3-furoic acid (13 g) in dry toluene (90 ml) at room temperature and under a nitrogen atmosphere, (4R) -4- (phenylmethyl) -1,3-oxazolidin-2-one (10 g) at one time followed by dry triethylamine (31.5 ml) at one time. The reaction was heated to 80 ° C and pivaloyl chloride (13.9 ml) was added dropwise to the clear solution for five minutes after which the reaction became cloudy and viscous. The reaction was heated at 115 ° C overnight. The reaction was cooled to room temperature and diluted with ethyl acetate (150 ml). This mixture was washed with 2M HCl (50 ml), water (50 ml) and a saturated aqueous solution of sodium hydrogen carbonate (50 ml). The organic phase was dried over magnesium sulfate, dried.

filtered and concentrated in vacuo to provide a brown viscous oil. The product was purified by silica chromatography (~ 750 g) using a gradient elution of toluene / 10% diethyl ether to provide 4.6 g of the fastest moving product (Diastereoisomer 1, 99.5: 0.5 by Chiral HPLC) and 4.3 g of the product that moved slower (Diastereoisomer 2, 91.8: 8.2 by chiral HPLC). 5

1H NMR (CDCl3): As for the first procedure.

Intermediate 157: Tetrahydro-3-furanylmethanol (Isomer 1)

To a solution of (4R) -4- (phenylmethyl) -3- [tetrahydro-3-furanylcarbonyl] -1,3-oxazolidin-2-one, Diastereoisomer 1 (4.6 g) in diethyl ether (320 ml, quality AR) and water (0.33 ml), at 0 ° C, lithium borohydride (9.2 ml, 2M solution in tetrahydrofuran) was added dropwise over 5 minutes, keeping the temperature between 0-5 ° C. The reaction was allowed to stir for 30 minutes at this temperature and then heated at room temperature for 3 hours. A white precipitate formed during the reaction. Then 2M sodium hydroxide (8.4 ml) was added dropwise. The reaction became clear and stirred for 20 minutes at room temperature. The organic phase was decanted, dried over MgSO4, filtered through celite and concentrated in vacuo. The product was purified by silica chromatography (120 g) (ISCO) using a gradient elution of cyclohexane: ethyl acetate, 0-70%, to give the title compound as a clear oil (1.3 g).

1H NMR (CDCl3): δ 3.90-3.81 (2H, m), 3.74 (1H, m), 3.67-3.55 (3H, m), 2.47 (1H, m), 20 2.03 (1H , m), 1.64 (1H, m). No exchangeable protons were observed.

Intermediate 157, alternative procedure: Tetrahydro-3-furanylmethanol (Isomer 1)

2 - {[(tetrahydro-3-furanylmethyl) oxy] carbonyl} benzoic acid (isomer 2.65 g) was dissolved in THF (25 ml) and 4 N sodium hydroxide (10.94 ml) was added. The mixture was refluxed with vigorous stirring for 2 h, then allowed to cool. After 16 h a few ml of brine were added and the mixture was extracted 3 times with ethyl acetate, and the combined extracts were washed with brine, dried by passing through a hydrophobic frit and evaporated at a pressure of> 10 mbar, with a water bath at 40 ° C providing the title compound as a milky oil, with a yield of 1.3 g. 30

1H NMR (CDCl3): δ 3.91-3.81 (2H, m), 3.79-3.71 (1H, m), 3.68-3.55 (3H, m), 2.53-

2.42 (1H, m), 2.09-1.99 (1H, m), 1.68-1.60 (1H, m). No exchangeable protons were observed.

Intermediate 158: Tetrahydro-3-furanylmethanol (Isomer 2)

To a solution of (4R) -4- (phenylmethyl) -3- [tetrahydro-3-furanylcarbonyl] -1,3-oxazolidin-2-one, Diastereoisomer 2 (4.3 g) in diethyl ether (310 ml, quality AR) and water (0.31 ml), at 0 ° C, lithium borohydride (8.6 ml, 2M solution in tetrahydrofuran) was added dropwise over 5 minutes, keeping the temperature between 0-5 ° C. The reaction was allowed to stir for 30 minutes at this temperature and then heated at room temperature for 3 hours. Then 2M sodium hydroxide (7.6 ml) was added for 5 minutes and the reaction was stirred for 20 minutes at room temperature. The organic phase was decanted, dried over 10 MgSO4, filtered and concentrated in vacuo. The product was purified by silica chromatography (120 g) (ISCO) using a gradient elution of cyclohexane: ethyl acetate, 0-100%, to give the title compound as a clear oil (1.4 g).

1H NMR (CDCl3): δ 3.90-3.81 (2H, m), 3.74 (1H, m), 3.67-3.55 (3H, m), 2.47 (1H, m), 2.03 (1H, m), 1.64 (1H, m). No exchangeable protons are observed. fifteen

Intermediate 158, alternative procedure: Tetrahydro-3-furanylmethanol (Isomer 2)

2 - {[(tetrahydro-3-furanylmethyl) oxy] carbonyl} benzoic acid (isomer 1, 4.89 g) was dissolved in THF (30 ml) and 4 N sodium hydroxide (14.7 ml) was added. The mixture was refluxed with vigorous stirring for 2 h, then allowed to cool. After 16 h, a few 20 ml of brine was added and the mixture was extracted 3 times with DCM. The combined extracts were dried by passing through a hydrophobic frit and evaporated at a pressure of> 10, in a water bath at 40 ° C to provide the title compound as a pink oil, with a yield of 1.77 g.

1H NMR (CDCl3): δ 3.89-3.82 (2H, m), 3.77-3.71 (1H, m), 3.67-3.56 (3H, m), 2.52-25 2.42 (1H, m), 2.07-1.99 (1H, m), 1.68-1.61 (1H, m). No exchangeable protons were observed.

Intermediate 159: Tetrahydro-3-furanylmethyl methanesulfonate (Isomer 1)

To tetrahydro-3-furanylmethanol, Isomer 1 (1.3 g) in dry dichloromethane (40 ml) at 0 ° C and under a nitrogen atmosphere, triethylamine (4.09 ml) was added followed by methanesufonyl chloride (1.29 ml ). The reaction was stirred at room temperature overnight. The orange solution was diluted with dichloromethane (80 ml) and washed with saturated aqueous sodium bicarbonate (40 ml). The organic phase was separated, dried through a hydrophobic frit and concentrated in vacuo to give the title compound as a yellow oil (2.2 g).

1H NMR ((CD3) 2SO): δ 4.13 (2H, m), 3.77-3.68 (1H, m), 3.62 (1H, m), 3.46 (1H, m), 3.19 (3H, s), 2 , 58 (1H, m), 1.97 (1H, m), 1.57 (1H, m).

Intermediate 160: Tetrahydro-3-furanylmethyl methanesulfonate (Isomer 2) 10

A (3S) -tetrahydro-3-furanylmethanol, Isomer 2 (1.4 g) in dry dichloromethane (40 ml) at 0 ° C and under a nitrogen atmosphere, triethylamine (3.83 ml) was added followed by methanesufonyl chloride ( 1.39 ml). The reaction was stirred at room temperature overnight. The orange solution was diluted with dichloromethane (50 ml) and washed with saturated aqueous sodium bicarbonate (20 ml). The organic phase was separated, dried through a hydrophobic frit and concentrated in vacuo to give the title compound as an orange oil (2.6 g).

1H NMR ((CD3) 2SO): δ 4.13 (2H, m), 3.77-3.68 (1H, m), 3.62 (1H, m), 3.46 (1H, m), 3.19 (3H, s), 2 , 58 (1H, m), 1.97 (1H, m), 1.57 (1H, m).

Intermediate 161: N2-Butyl-8- (methoxy) -9- [tetrahydro-3-furanylmethyl] -9H-purin-2,6-diamine 20 (Isomer 1)

To a salt solution of the trifluoroacetic acid salt of N2-butyl-8-methoxy-9H-purin-2,6-diamine (3.89 g) in dry N, N-dimethylformamide (46 ml) at room temperature was added potassium carbonate (6.14 g) at one time. The reaction was heated at 60 ° C, under a nitrogen atmosphere, for 1.5 hours. A solution of tetrahydro-3-furanylmethyl methanesulfonate, Isomer 1 (2.2 g) in dry N, N-dimethylformamide (2 ml) was added by means of a Pasteur pipette and the reaction was heated at 70 ° C for 16 hours. The reaction was cooled to temperature.

ambient, diluted with ethyl acetate (100 ml) and washed with brine (20 ml). The organic phase was concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (10-50%) to provide the title compound as a transparent viscous oil (2.79 g). 5

MS calculated for (C15H24N6O2) + = 320

MS found (electrospray): (M + H) + = 321

Intermediate 162: N2-Butyl-8- (methoxy) -9- [tetrahydro-3-furanylmethyl] -9H-purin-2,6-diamine (Isomer 2)

 10

To a salt solution of the trifluoroacetic acid of N2-butyl-8-methoxy-9H-purin-2,6-diamine (4.60 g) in dry N, N-dimethylformamide (55 ml) at room temperature was added potassium carbonate (7.25 g) at one time. The reaction was heated at 60 ° C for 1.5 hours. A solution of tetrahydro-3-furanylmethyl methanesulfonate, Isomer 2 (2.6 g) in dry N, N-dimethylformamide (3 ml) was added by means of a Pasteur pipette and the reaction was heated at 15 70 ° C for 16 hours . The reaction was cooled to room temperature, diluted with ethyl acetate (100 ml) and washed with brine (20 ml). The organic phase was concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (10-60%) to provide the title compound as a transparent viscous oil (3 g). twenty

MS calculated for (C15H24N6O2) + = 320

MS found (electrospray): (M + H) + = 321

Intermediate 163: 2 - {[(tetrahydro-3-furanylmethyl) oxy] carbonyl} benzoic acid

A mixture of phthalic anhydride (7.41 g) and tetrahydro-3-furanmethanol was heated by stirring 25 to 130 ° C under a nitrogen atmosphere. After 1.5 h, the clear liquid was allowed to cool, treated with water and extracted with EtOAc (x 3). The combined organic phases were dried by passing through a hydrophobic frit and evaporated to a transparent oil that crystallized on crushing with naphtha. The solid was filtered, washed and dried, with a yield of 11.93 g.

MS calculated for (C13H14O5) + = 250

MS found (electrospray): (M + H) + = 251

Intermediate 164 and Intermediate 165: 2 - {[(tetrahydro-3-furanylmethyl) oxy] carbonyl} benzoic acid, (Isomers 1 and 2)

 5

2 - {[(tetrahydro-3-furanylmethyl) oxy] carbonyl} benzoic acid (11.93 g) was separated in 250 mg portions by chiral HPLC using a 5 cm x 20 cm Chiralpak AD column, eluting with heptane: ethanol containing 0.1% trifluoroacetic acid (80:20). The mixed fractions were evaporated and separated again as described above. Fractions containing the material eluting before pure were combined and evaporated to provide a white solid, yielding 4.89 g, Isomer 1, Intermediate 164.

1H NMR (CDCl3): 7.99 (1H, broad s), 7.93-7.86 (1H, m), 7.74-7.65 (1H, m), 7.65-7.53 (2H, m superimposed), 4.44-4.34 (1H, m), 4.29-4.18 (1H, m), 4.00-3.88 (2H, m), 3.85- 3.67 (2H, m superimposed), 2.81-2.66 (1H, m), 2.17-2.05 (1H, m), 1.80-1.68 (1H, m). fifteen

Fractions containing the material that eluted more slowly were treated similarly to provide a white solid, in a yield of 3.65 g, Isomer 2, Intermediate 165.

1H NMR (CDCl3): 7.92-7.84 (1H, m), 7.74-7.66 (1H, m), 7.63-7.52 (2H, m superimposed), 7.38 (1H, wide s), 4.43-4.33 (1H, m), 4.27-4.17 (1H, m), 3.98-3.87 (2H, m), 20 3.83 -3.65 (2H, m), 2.79-2.65 (1H, m), 2.16-2.03 (1H, m), 1.78-1.65 (1H, m).

Intermediate 166: 2 - [(2-Cyclopropylethyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

To a stirring solution of sodium tert-butoxide (13.45 g) in DME (80 ml) was added dropwise under a nitrogen atmosphere a solution of 2-cyclopropyletanol (12.1 g) in DME (40 ml) for 5 minutes. After 30 minutes 2-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (11.84 g) was added and the stirred mixture was heated under reflux for 20 h. After cooling the mixture was treated with water and extracted twice with ethyl acetate. The combined extracts were washed with water and then with brine, dried by passing through

a hydrophobic frit and evaporated to a brown oil. This was re-evaporated twice from toluene then purified on a silica column using an ISCO Companion, eluting with methanol: ethyl acetate (0-12%) to provide the title compound. Yield of 6.53 g.

MS calculated for (C15H21N5O2) + = 303 5

MS found (electrospray): (M + H) + = 304

Intermediate 167: 8-Bromo-2 - [(2-cyclopropylethyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

To an ice-cold stirring solution of 2 - [(2-cyclopropylethyl) oxy] -9- (tetrahydro-10 2H-pyran-2-yl) -9H-purin-6-amine (6.53 g) in chloroform (75 ml), N-bromosuccinimide (4.02 g) was added. The reaction mixture was allowed to warm to room temperature and after 16 h it was treated with water and extracted twice with DCM. The combined extracts were washed with diluted sodium metabisulfite and then with diluted brine, dried through a hydrophobic frit and evaporated to give the title compound as an orange foam, yielding 7.96 g.

MS calculated for (C15H20BrN5O2) + = 381, 383

MS found (electrospray): (M + H) + = 382, 384

Intermediate 168: 2 - [(2-Cyclopropylethyl) oxy] -8- (methoxy) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

An agitated suspension of 8-bromo-2 - [(2-cyclopropylethyl) oxy] -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (7.96 g) in methanol ( 80 ml) was treated with 25% by weight of sodium methoxide in methanol (14.29 ml) and heated under reflux under a nitrogen atmosphere for 3.5 h. After allowing to cool for 16 h the solvent was evaporated and the residue was treated with saturated ammonium chloride 25 and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried by passing through a hydrophobic frit and evaporated to give the title compound as a brown solid, in a yield of

6.49 g.

MS calculated for (C16H23N5O3) + = 333

MS found (electrospray): (M + H) + = 334

Intermediate 169: 2 - [(2-Cyclopropylethyl) oxy] -8- (methoxy) -1H-purin-6-amine salt trifluoroacetate

 5

2 - [(2-Cyclopropylethyl) oxy] -8- (methoxy) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (6.49 g) was treated with methanol (65 ml) and the resulting suspension was stirred and cooled on ice while TFA (6.5 ml) was added. The mixture was allowed to warm to room temperature and after 72 h the solvents were evaporated and the remaining orange solid was triturated with cold ethyl acetate (50 ml), filtered, washed and dried in vacuo to provide the title compound. , with a yield of 4.78 g.

MS calculated for (C11H15N5O2) + = 249

MS found (electrospray): (M + H) + = 250

A second crop was obtained by evaporation of the filtrate and trituration of the residue with ether, in a yield of 0.99 g. Slightly less pure than the first 15 harvest.

Intermediate 170: 2 - [(2-Cyclopropylethyl) oxy] -8- (methoxy) -9- (tetrahydro-3-furanylmethyl) -9H-purin-6-amine (Isomer 1)

A stirring mixture of trifluoroacetic acid salt of 2 - [(2-cyclopropylethyl) oxy] -8-20 (methoxy) -1H-purin-6-amine (2.89 g), potassium carbonate (4.41 g) and dry DMF (32 ml) was heated at 60 ° C under a nitrogen atmosphere for 90 minutes. Then tetrahydro-3-furanylmethyl methanesulfonate (1,869 g, isomer 1) was added and stirring was continued at 70 ° C for 1 h, then at 90 ° C for 2 h. The solvent was evaporated and the residue was treated with water and extracted three times with ethyl acetate. The combined extracts were washed with water and then with brine, dried by passing through a hydrophobic frit and evaporated to a brown oil. This was purified on a C18 360 g column using water (+ 0.1% formic acid) / acetonitrile (+ 0.05% formic acid). The appropriate fractions were combined and evaporated, with a yield of 814 mg.

MS calculated for (C16H23N5O3) + = 333

MS found (electrospray): (M + H) + = 334

Intermediate 171: 2 - [(2-Cyclopropylethyl) oxy] -8- (methoxy) -9- [tetrahydro-3-furanylmethyl] -9H-purin-6-amine (Isomer 2)

 5

To a solution of trifluoroacetic acid salt of 2 - [(2-cyclopropylethyl) oxy] -8- (methoxy) -1H-purin-6-amine (2.89 g) in dry N, N-dimethylformamide (32 ml) under nitrogen atmosphere and at room temperature, potassium carbonate (4.41 g) was added at one time. The reaction was heated to 60 ° C and stirred for 90 minutes. Then a solution of tetrahydro-3-furanylmethyl methanesulfonate, Isomer 2 (1,869 g) in dry DMF (3 ml) was added gradually using a pipette. The reaction was heated to 70 ° C and allowed to stir overnight. According to the CLEM, there was still 22% of the initial material left, therefore the temperature was increased to 90 ° C and stirred for another 3 hours at this temperature. The reaction was cooled and diluted with ethyl acetate (100 ml) and washed with water (50 ml) and brine (50 ml). The organic phase was concentrated in vacuo to provide an orange oil. The product was purified by C18 reverse phase chromatography using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (10-60%) to provide the title compound as an orange viscous oil (1.45 g).

MS calculated for (C16H23N5O3) + = 333

MS found (electrospray): (M + H) + = 334 20

Intermediate 172: N2-Butyl-8- (methoxy) -9- (tetrahydro-3-furanylmethyl) -9H-purin-2,6-diamine

Salt of the trifluoroacetic acid of N2-butyl-8- (methoxy) -3H-purin-2,6-diamine (0.25 g) and anhydrous potassium carbonate (0.395 g) in anhydrous DMF (3 ml) was heated for 1 hour at 60 ° C (external) under a nitrogen atmosphere, before allowing to cool to room temperature. To the reaction mixture was then added 3- (bromomethyl) tetrahydrofuran (0.236 g) and the reaction mixture was heated under a nitrogen atmosphere at 50 ° C (external) for 18.5 hours. Mix

The reaction was then diluted with water (15 ml) and extracted with diethyl ether (15 ml, 3 times). The organic phases were combined and dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was evaporated under reduced pressure to provide an oil. This oil was triturated with cyclohexane and some diethyl ether to provide a solid. The cyclohexane and diethyl ether were evaporated under reduced pressure to give a white solid. The solid (0.2606 g) was dissolved in hot ethanol (2 ml). To this solution was then added water (8 ml) and the resulting suspension was heated to reflux (93 ° C, external) to provide a solution. The solution was then allowed to cool slowly (without removing the flask from the reaction block and turning off the heating block). This provided a solid gum on cooling than when a white solid was ultrasonic. This solid was isolated by suction filtration and then dried under vacuum at 50 ° C, overnight. This gave the title compound (0.1043 g) as a white solid.

MS calculated for (C15H24N6O2) + = 320

MS found (electrospray): (M + H) + = 321

1H NMR (CDCl3): δ 4.94 (2H, wide s), 4.64-4.55 (1H, m), 4.1 (3H, s), 3.98-3.82 (3H, 15m), 3.81- 3.72 (2H, m), 3.68-3.62 (1H, m), 3.37 (2H, q), 2.89-2.76 (1H, m), 2.02-1, 91 (1H, m), 1.79-1.68 (1H, m), 1.62-1.52 (2H, m), 1.48-1.36 (2H, m), 0.95 ( 3H, t).

Intermediate 172, alternative procedure: N2-Butyl-8- (methoxy) -9- (tetrahydro-3-furanylmethyl) -9H-purin-2,6-diamine

 twenty

Salt of the trifluoroacetic acid of N2-butyl-8- (methoxy) -3H-purin-2,6-diamine (0.25 g) and anhydrous potassium carbonate (0.395 g) in anhydrous DMF (3 ml) was heated under an atmosphere of nitrogen at 60 ° C (external) for 1 hour. After allowing the reaction mixture to cool to room temperature, tetrahydro-2-furanylmethyl methanesulfonate (0.257 g) was added and the reaction mixture was heated at 70 ° C (external) for 18.5 hours under a nitrogen atmosphere. The reaction mixture [N2420-15-D3] was diluted with water (15 ml) and extracted with diethyl ether (15 ml, 3 times). The organic phases were combined and dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was evaporated under reduced pressure to provide an oily gum. This material was then triturated with cyclohexane and diethyl ether by scratching until a light yellow solid was obtained. Cyclohexane and diethyl ether 30

it was removed by evaporation under reduced pressure to provide a light yellow solid (0.2123 g). This was dissolved in hot ethanol (2 ml). Water (8 ml) was added to this solution to provide an oily suspension which was then heated to reflux (90 ° C, external) to provide a solution. The solution was then allowed to cool slowly (without removing the flask from the reaction block and turning off the heating block). Upon cooling to room temperature, the resulting gum was sonicated and scraped to provide a solid. This solid was filtered off with suction and the resulting filter cake was washed with water (2 ml). The resulting white solid was then air dried with suction before further drying under vacuum at 50 ° C at constant weight to provide the title compound as a slightly off-white solid (0.109 g). 10

MS calculated for (C15H24N6O2) + = 320

MS found (electrospray): (M + H) + = 321

1H NMR (CDCl3): δ 4.93 (2H, wide s), 4.64-4.53 (1H, m), 4.1 (3H, s), 3.98-3.82 (3H, m), 3.81-3 , 71 (2H, m), 3.69-3.61 (1H, m), 3.37 (2H, q), 2.89-2.76 (1H, m), 2.03-1.91 (1H, m), 1.79-1.68 (1H, m), 1.63-1.51 (2H, m), 1.48-1.36 (2H, m), 0.95 (3H , t). fifteen

Intermediate 173: 2 - [(3S) -Tetrahydro-3-furanyl] ethanol

1 M borane and tetrahydrofuran complex in THF (50 ml, 50.0 mmol) was added dropwise over an hour to a stirring solution of (3R) -tetrahydro-3-furanylacetic acid (2.4 g, 18 , 44 mmol) (J. Med Chem., 1993, 36, 2300) in dry THF (35 ml), cooled to -5 ° C under a nitrogen atmosphere. The reaction mixture was heated to room temperature and allowed to stir under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to -5 ° C and methanol (15 ml) was added dropwise, keeping the temperature below 5 ° C. The solution was concentrated in vacuo and the residue was dissolved in DCM and purified by silica chromatography (100 g) using a dichloromethane: ethyl acetate 25 gradient (0-100% gradient for 40 minutes). The desired fractions were combined and concentrated in vacuo to give the title compound as a colorless oil (1.4 g).

1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 -1.52 (m, 3 H) 1.91 -2.01 (m, 1 H) 2.11 -2.24 (m, 1 H) 3.17 -3.23 (m, 1 H) 3.35 -3.46 (m, 2 H) 3.56 -3.63 (m, 1 H) 3.66 -3.72 (m, 2 H 30 excess) 3.75 -3, 80 (m, 2 H excess) OH is not observed.

Intermediate 174: (3R) -3- (2-Bromoethyl) tetrahydrofuran

A solution of triphenylphosphine (6.32 g, 24.11 mmol) in dry dichloromethane (10 ml) was added dropwise over 30 minutes to a stirring solution of 2 - [(3S) -tetrahydro-3-furanyl] ethanol (1.4 g, 12.05 mmol) and carbon tetrabromide (7.99 g, 24.11 mmol) in dry dichloromethane (20 ml) at -2 ° C under a nitrogen atmosphere. The reaction mixture was heated to room temperature and allowed to stir under a nitrogen atmosphere for 20 hours. The reaction mixture was filtered over celite and the white solid was washed with ether and DCM. The orange filtrate was concentrated in vacuo. The residue was dissolved in DCM and purified by silica chromatography (100 g) using a gradient of cyclohexane: ethyl acetate (gradient of 0-25% for 40 minutes). The desired fractions were combined and concentrated in vacuo to give the title compound as a colorless oil (1.4 g).

1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 -1.54 (m, 1 H) 1.84 -1.91 (m, 2 H) 1.94 -2.03 (m, 1 H) 2.23 -2.31 (m, 1 H) 3.24 -3.28 (m, 1 H) 3.49 -3.56 (m, 2 H) 3.58 -3.65 (m, 1 H) 3.68 -3.74 ( m, 1 H) 3.75 -3.80 (m, 1 H) [α] = - 9.01 (c = 1 in EtOAc, 20 ° C)

Intermediate 175: 2 - [(3R) -Tetrahydro-3-furanyl] ethanol 15

A solution of (3S) -tetrahydro-3-furanylacetic acid (1.8 g, 13.83 mmol) (J. Med Chem., 1993, 36, 2300) in dry THF (35 ml) was stirred and cooled to -5 ° C under nitrogen atmosphere. Lithium aluminum hydride, 1 M in ether (20.75 ml, 20.75 mmol) was added keeping the temperature below 0 ° C. The reaction mixture was then heated to room temperature and allowed to stir under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to -5 ° C and more lithium aluminum hydride, 1 M in ether (20.75 ml, 20.75 mmol) was added, keeping the temperature below 0 ° C. The reaction mixture was heated again to room temperature and allowed to stir under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to -5 ° C and quenched with saturated aqueous NH4Cl solution (15 ml) which was added dropwise keeping the temperature below 5 ° C. Then, ether (100 ml) was added. The mixture was filtered and the white solid obtained was washed with ether (50 ml) and saturated aqueous NH4Cl solution (50 ml). The filtrate phases were separated and the organic phase was dried by passing through a hydrophobic frit and concentrated in vacuo. He

White solid was then washed with saturated aqueous NH4Cl solution (50 ml) and EtOAc (50 ml). The filtrate phases were separated and the organic phase dried and concentrated in vacuo. The aqueous phases were combined and extracted with EtOAc (4 x 100 ml). All organic extracts were combined, dried using a hydrophobic frit and concentrated in vacuo to give the title compound as a colorless oil (1 g). 5

1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 -1.52 (m, 3 H) 1.92 -2.02 (m, 1 H) 2.11 -2.24 (m, 1 H) 3.17 -3.23 (m, 1 H) 3.34 -3.47 (m, 2 H) 3.55 -3.64 (m, 1 H) 3.65 -3.73 (m, 1 H) 3.74 -3.81 ( m, 1 H) 4.35 -4.41 (m, 1 H)

Intermediate 176: (3S) -3- (2-Bromoethyl) tetrahydrofuran

 10

Prepared similarly to Intermediate 174 from 2 - [(3R) -tetrahydro-3-furanyl] ethanol.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 -1.54 (m, 1 H) 1.84 -1.91 (m, 2 H) 1.94 -2.03 (m, 1 H) 2.21 -2.33 (m, 1 H) 3.24 -3.28 (m, 1 H) 3.50 -3.57 (m, 2 H) 3.58 -3.65 (m, 1 H) 3.68 -3.75 ( m, 1 H) 3.77 (dd, J = 8.28, 7.28 Hz, 1 H) [α] = + 9.01 (c = 1 in EtOAc, 20 ° C). fifteen

Intermediate 177: 3- (tetrahydro-3-furanyl) propanoic acid

A solution of (2E) -3- (3-furanyl) -2-propenoic acid (4.75 g, 34.4 mmol) and 10% palladium on carbon (0.366 g, 3.44 mmol) in ethyl acetate (100 ml) was hydrogenated at atmospheric pressure and room temperature for 72 hours. Hydrogen uptake ~ 1.4 l 20 (expected 2.4 l). The catalyst was filtered through Celite and concentrated in vacuo to provide a brown oil. 1 H NMR analysis showed that part of the material still contained the furan ring. Hydrogenation was continued under the same conditions with a new catalyst for another 24 hours with an additional 400 ml hydrogen uptake. The catalyst was filtered through Celite and the filtrate was concentrated in vacuo to give the title compound as a colorless oil (4.73 g).

1H NMR (400 MHz, DMSO-d6) δ ppm 1.37 -1.48 (m, 1 H) 1.50 -1.63 (m, 2 H) 1.90 -2.01 (m, 1 H) 2.04 -2.17 (m, 1 H) 2.17 -2.29 (m, 2 H) 3.18 -3.25 (m, 1 H) 3.56 -3.65 (m, 1 H)

3.67 -3.79 (m, 2 H) 12.00 (wide s, 1 H)

Intermediate 178: 3- (Tetrahydro-3-furanyl) -1-propanol

To a solution of 3- (tetrahydro-3-furanyl) propanoic acid (1 g, 6.94 mmol) in dry THF (20 ml) at 0 ° C was added a 1 M solution of boron complex and THF (21.16 ml, 21.16 147 5 mmol) in THF drop by drop for 2 minutes. The mixture was stirred at 0 ° C for 1 hour then allowed to warm to room temperature and stirred for 18 h. The reaction mixture was cautiously quenched with methanol (~ 20 ml) and the solvent was removed in vacuo. The residue was redissolved in methanol and concentrated in vacuo four times to give the title compound as a colorless oil (3.37 g).

 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 -1.50 (m, 5 H) 1.90 -2.01 (m, 1 H) 2.09 (spt, J = 7.28 Hz, 1 H) 3.13 -3.22 (m, 1 H) 3.34 -3.43 (m, 2 H) 3.56 -3.65 (m, 1 H) 3.66 -3.74 (m, 1 H) 3.74 -3 , 81 (m, 1 H) 4.33 (wide s, 1 H)

Intermediate 179: 3- (3-Bromopropyl) tetrahydrofuran

 fifteen

3- (Tetrahydro-3-furanyl) -1-propanol (1 g, 7.68 mmol) was dissolved in DMF (10 ml) and carbon tetrabromide (5.09 g, 15.36 mmol) was added. The solution turned yellow. The solution was cooled to 0 ° C and triphenylphosphine (4.03 g, 15.36 mmol) was added dropwise as a solution in DMF (20 ml) (~ 30 minutes, the temperature was maintained <2 ° C throughout the weather). The reaction mixture was stirred at 0 ° C for 1 hour before gradually allowing to warm to room temperature and stirred for another 2 hours. The solvent was removed in vacuo. An attempt was made to crush the resulting brown oil with DCM or cyclohexane but it did not work. The solvent was removed and the oil was diluted with DCM and purified by silica chromatography (100 g) using 0-25% ethyl acetate-cyclohexane for 40 minutes using a Flashmaster II. The appropriate fractions were combined and dried to provide the title compound as a yellow oil (0.676 g).

1H NMR (400 MHz, DMSO-d6) δ ppm 1.37 -1.49 (m, 5 H, excess) 1.74 -1.88 (m, 2 H) 1.93 -2.02 (m, J = 12.20, 7.58, 7 , 58, 4.77 Hz, 1 H) 2.13 (spt, J = 7.36 Hz, 1 H) 3.18 -3.24 (m, 1 H)

3.50 -3.56 (m, 1 H) 3.57 -3.65 (m, 1 H) 3.67 -3.74 (m, 1 H) 3.75 -3.81 (m, 1 H).

Intermediate 180: 3 - {(1E / Z) -4 - [(Phenylmethyl) oxy] -1-buten-1-yl} furan

To a suspension of (3-benzyloxypropyl) triphenylphosphonium bromide (25.6 g, 52.0 mmol) in dry THF (60 ml) at -15 ° C was added butyl lithium (32.5 ml, 1.6 M in hexanes) drop by drop 5 providing a solution. A solution of 3-furancarbaldehyde (5 g, 52.0 mmol) in THF (20 ml) was added dropwise to form a dark orange / red solution. The reaction mixture was stirred at -10 ° C for 30 minutes before adding 3-furancarbaldehyde (5 g, 52.0 mmol) dropwise in the form of a solution in tetrahydrofuran (20 ml) to provide a brown solution. The reaction mixture was then allowed to warm to room temperature and stirred overnight. A brown precipitate formed so that the reaction mixture was filtered through Celite and washed with diethyl ether. The filtrate was concentrated in vacuo to provide a dark orange oil that was loaded into DCM and purified in two batches by silica chromatography (100 g) using a gradient of 0-25% ethyl acetate and cyclohexane for 40 minutes using a Flashmaster. II. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a pale yellow oil (6.11 g).

LCMS (Procedure B): tRET = 1.31 minutes; MH + 229

Intermediate 181: 4- (Tetrahydro-3-furanyl) -1-butanol

A solution of 3- {4 - [(phenylmethyl) oxy] -1-buten-1-yl} furan (6.11 g, 26.8 mmol) and 10% of 20 palladium on carbon (0.285 g, 2.68 mmol) in ethyl acetate (150 ml) and acetic acid (15 ml) was hydrogenated at atmospheric pressure and room temperature for 24 hours. The catalyst was filtered through Celite and the filtrate was concentrated in vacuo. 1 H NMR showed that no reduction had occurred, so that the reaction mixture was hydrogenated under the same conditions for another 72 hours. The catalyst was filtered through Celite and the filtrate was concentrated in vacuo, 1 H NMR showed the double bond had been reduced but that the ring

Benzyl and Furan were still intact. The residue was hydrogenated under the same conditions for another 2 days. The catalyst was filtered through Celite and the filtrate was concentrated in vacuo.

A portion of the material (500 mg) was dissolved in ethyl acetate (5 ml) and hydrogenated using a Thales H cube (settings: room temperature, 20 bar, flow rate of 1 ml / minute) using 10% palladium on carbon as catalyst. The resulting solution was concentrated, 1 H NMR showed that no changes had occurred.

All batches of the material were combined, loaded into dichloromethane and purified on silica (100 g) using a gradient of 0-25% ethyl acetate-cyclohexane for 40 minutes using a Flashmaster II. The appropriate fractions were combined and evaporated in vacuo, a solution of the residue (3.42 g, 14.9 mmol) and 10% palladium on 10 carbon (684 mg) in ethyl acetate (100 ml) was hydrogenated under pressure. atmospheric and room temperature for 24 hours. The catalyst was filtered through Celite and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (2.22 g).

1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 -1.47 (m, 7 H) 1.88 -2.01 (m, 1 H) 2.01 -15 2.15 (m, 1 H) 3.13 -3.22 (m , 1 H) 3.33 -3.42 (m, 2 H) 3.60 (q, J = 7.78 Hz, 1 H) 3.65 -3.81 (m, 2 H) 4.30 - 4.36 (m, 1 H)

Intermediate 182: 3- (4-Bromobutyl) tetrahydrofuran

Prepared similarly to Intermediate 174 from 4- (tetrahydro-3-furanyl) -1-20 butanol.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 -1.46 (m, 8 H) 1.76 -1.85 (m, 2 H) 1.92 -2.01 (m, 1 H) 2.05 -2.15 (m, 1 H) 3.16 -3.22 (m, 1 H) 3.50 -3.55 (m, 2 H) 3.57 -3.64 (m, 1 H) 3.67 -3.74 ( m, 1 H) 3.74 -3.80 (m, 1 H)

Intermediate 183: 2- (2-Bromoethyl) tetrahydro-2H-pyran 25

A solution of triphenylphosphine (1.93 g, 7.37 mmol) in DCM (10 ml) was added dropwise to a solution of Intermediate 72 (0.80 g, 6.15 mmol) and carbon tetrabromide (2853 mg , 8.60 mmol) in DCM (40ml) at 0 ° C under a nitrogen atmosphere. The solution was stirred at 0 ° C for 15 minutes, cyclohexane (30 ml) was added and the mixture was evaporated gently to remove DCM. 30

The resulting cyclohexane solution was decanted from the gummy precipitate directly into a silica cartridge (50 g) (previously moistened with cyclohexane) and eluted with cyclohexane -DCM 1: 1 to give the title compound as a colorless oil ( 0.68 g).

1H NMR (400 MHz, CDCl3) ppm 1.23 -1.35 (m, 1 H) 1.48 -1.62 (m, 4 H) 1.80 -1.96 5 (m, 2 H) 1.98 -2.08 (m, 1 H) 3.39 -3.58 (m, 4 H) 3.93 -4.00 (m, 1 H)

Intermediate 184: 2- (3-Bromopropyl) tetrahydro-2H-pyran

Prepared similarly to Intermediate 174 from 3- (tetrahydro-2H-pyran-2-yl) -1-propanol (WO 2007/70201). 10

1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 -1.21 (m, 1 H) 1.36 -1.57 (m, 8 H excess) 1.70 -1.95 (m, 3 H) 3.17 -3.32 (m , 2 H) 3.43 -3.57 (m, 2 H) 3.49 -3.56 (m, 2 H) 3.80 -3.87 (m, 1 H).

Intermediate 185: 2- (4-Bromobutyl) tetrahydro-2H-pyran

 fifteen

Prepared similarly to Intermediate 174 from 4- (tetrahydro-2H-pyran-2-yl) -1-butanol (J. Am. Chem. Soc, 2005, 127, 12180).

1H NMR (400 MHz, CDCl3) δ ppm 1.20 -1.32 (m, 1 H) 1.37 -1.64 (m, 11 H excess) 1.78 -1.93 (m, 2 H) 3.20 -3.28 (m , 1 H) 3.38 -3.46 (m, 3 H) 3.94 -4.00 (m, 1 H)

Intermediate 186: 2- (Tetrahydro-2H-pyran-3-yl) ethanol 20

A solution of lithium aluminum hydride in Et2O (4.16 ml, 4.16 mmol) was added dropwise to a solution of tetrahydro-2H-pyran-3-ylacetic acid (Tet. Lett. 2003, 44, 6355 ) (0.6 g, 4.16 mmol) in THF (5 ml) at room temperature under a nitrogen atmosphere. The mixture was stirred for 1 hour and treated very slowly dropwise with water (1 ml). After quenching the reaction, aqueous sodium hydroxide (2 N, 1 ml) was added and the mixture was stirred for 5 minutes. The suspension was filtered through Hyflo and evaporated to give the title compound as a colorless oil (0.3 g).

1H NMR (400 MHz, CDCl3) δ ppm 1.12 -1.94 (m, 9 H excess) 3.06 -3.15 (m, 1 H)

3.33 -3.42 (m, 1 H) 3.63 -3.72 (m, 2 H) 3.83 -3.91 (m, 2 H)

Intermediate 187: 3- (2-Bromoethyl) tetrahydro-2H-pyran

A solution of triphenylphosphine (725 mg, 2.77 mmol) in DCM (4 ml) was added dropwise by cooling with a water bath to a solution of 2- (tetrahydro-2H-pyran-3-yl) ethanol (300 mg , 5,304 mmol) and carbon tetrabromide (917 mg, 2.77 mmol) in DCM (6 ml). The solution was stirred at room temperature for 2 hours and evaporated on florisyl and applied to a silica cartridge (20 g) previously moistened with cyclohexane. Elution with cyclohexane and DCM (3: 1) provided the title compound as a colorless oil (0.42 g).

1H NMR (400 MHz, CDCl3) δ ppm 1.13 -1.26 (m, 1 H) 1.59 -1.94 (m, 6 H) 3.08 -3.16 10 (m, 1 H) 3.35 -3.48 (m , 3 H) 3.82 -3.91 (m, 2 H)

Intermediate 188: 3- (3-Bromopropyl) tetrahydro-2H-pyran

Prepared similarly to Intermediate 174 from 3- (tetrahydro-2H-pyran-3-yl) -1-propanol. fifteen

1H NMR (400 MHz, CDCl3) δ ppm 1.09 -1.40 (m, 5 H excess) 1.56 -1.67 (m, 3 H excess) 1.81 -1.92 (m, 4 H) 3.02 -3.11 ( m, 1 H) 3.32 -3.45 (m, 3 H) 3.82 -3.92 (m, 2 H)

Intermediate 189: 3- (4-Bromobutyl) tetrahydro-2H-pyran

Prepared similarly to Intermediate 174 from 4- (tetrahydro-2H-pyran-3-yl) -1-20 butanol.

1H NMR (400 MHz, CDCl3) δ ppm 1.05 -1.30 (m, 3 H) 1.36 -1.65 (m, 8 H excess) 1.79 -1.92 (m, 3 H) 2.99 -3.10 (m , 1 H) 3.30 -3.46 (m, 3 H) 3.81 -3.92 (m, 2 H)

Intermediate 190: 4- (3-Bromopropyl) tetrahydro-2H-pyran

 25

Prepared similarly to Intermediate 174 from 3- (tetrahydro-2H-pyran-4-yl) -1-

propanol

1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 -1.19 (m, 2 H) 1.25 -1.36 (m, 2 H) 1.41 -1.60 (m, 3 H) 1.75 -1.86 (m, 2 H) 3.20 -3.34 (m, 2 H) 3.47 -3.56 (m, 2 H) 3.76 -3.85 (m, 2 H)

Intermediate 191: 4 - {(1E / Z) -4 - [(Phenylmethyl) oxy] -1-buten-1-yl} tetrahydro-2H-pyran

 5

To a suspension of (3-benzyloxy-propyl) triphenyl-phosphonium bromide (21.57 g, 43.8 mmol) in dry THF (67 ml) at -15 ° C was added 1.6 M Buli in hexanes (27, 4 ml, 43.8 mmol) drop by drop for one hour providing a dark orange solution. The reaction was raised to 0 ° C and stirring was continued for 30 minutes. A solution of tetrahydro-2H-pyran-4-carbaldehyde (5 g, 43.8 mmol) in dry THF (7 ml) was added dropwise at 0 ° C for 15 minutes. The reaction mixture was stirred at room temperature for 20 hours. This was filtered through pre-packed celite (10 g) and washed with diethyl ether. The filtrate was concentrated in vacuo to give orange oil. The raw material was distributed in two batches and each was pre-absorbed on silica and purified by silica chromatography (50 g) using a gradient of 0-25% ethyl acetate and cyclohexane for 60 minutes using Flashmaster II. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a colorless oil (4.509 g).

1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 -1.35 (m, 2 H) 1.40 (s, 5 H excess) 2.29 -2.36 (m, 1 H) 3.27 -3.37 (m, 2 H) 3.39 -3.46 (m, 2 H) 3.74 -3.84 (m, 2 H) 4.46 (s, 2 H) 5.21 -5.46 (m, 2 H) 7, 22-7.42 (m, 5 H) 20

Intermediate 192: 4- (Tetrahydro-2H-pyran-4-yl) -1-butanol

A solution of 4 - {(1E) -4 - [(phenylmethyl) oxy] -1-buten-1-yl} tetrahydro-2H-pyran (4.5059 g, 18.29 mmol) and palladium on carbon (0.195 g , 0.183 mmol) in ethyl acetate (140 ml) was hydrogenated at atmospheric pressure and room temperature. This was allowed to stir overnight in 25 hydrogen. The mixture was then filtered through previously packaged celite (10 g) to remove palladium and washed with ether (~ 30 ml). The organic phase was concentrated in vacuo, 1 H NMR of the resulting oil was performed showing that the benzyl group and double bonds were still present. A solution of the material and palladium on carbon (0.3 g) was hydrogenated in

ethyl acetate (140 ml) at atmospheric pressure and room temperature. This was allowed to stir overnight in a hydrogen atmosphere. The mixture was then passed through previously packaged celite (10 g) to remove palladium and washed with ether (~ 30 ml). The filtrate of the organic phase was concentrated in vacuo to give the title compound as a colorless oil (2.27 g).

 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80 -0.92 (m, 1 H) 1.01 -1.60 (m, 10 H) 3.17 -3.42 (m, 4 H) 3.74 -3.87 (m, 2 H) 4.32 (s, 0.6 H)

Intermediate 193: 4- (4-Bromobutyl) tetrahydro-2H-pyran

Prepared similarly to Intermediate 174 from 4- (tetrahydro-2H-pyran-4-yl) -1-10 butanol.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 -1.27 (m, 4 H) 1.33 -1.60 (m, 5 H) 1.72 -1.84 (m, 2 H) 3.20 -3.33 (m, 2 H) 3.49 -3.57 (m, 2 H) 3.77 -3.86 (m, 2 H)

Intermediate 194: 2,2-Dimethyl-4 - [(E) -2- (methyloxy) ethenyl] tetrahydro-2H-pyran

 fifteen

To a stirring suspension of [(methyloxy) methyl] (triphenyl) phosphonium chloride (24.1 g, 70.3 mmol) in dry THF (70 ml) at -40 ° C under nitrogen atmosphere was added potassium t-butoxide , 1 M solution in THF, (70 ml, 70.0 mmol) dropwise over 30 minutes. After stirring for 40 minutes, the mixture was cooled to -70 ° C and a solution of 2,2-dimethyltetrahydro-2H-pyran-4-carbaldehyde (2.5 g, 17.58 mmol) in dry THF (10 ml) drop by drop 20 for 10 minutes. The mixture was stirred at this temperature for 10 minutes and the cooling bath was removed. The mixture was stirred for another 30 minutes at room temperature then quenched by pouring on ice. The aqueous phase was extracted with Et2O (3 x 100 ml), the organic extracts were combined and washed with saturated NaCl solution (100 ml), dried (Na2SO4) filtered and evaporated to dryness to provide an amber oil (19 g). 2 g of the crude product were loaded into diethyl ether and purified on 50 g of silica using 0-25% ethyl acetate-cyclohexane for 40 minutes using Flashmaster II. The fractions were controlled by staining in an iodine tank and the appropriate fractions were combined and evaporated in vacuo to provide the necessary product as a colorless oil.

The bulk of the crude mixture was then purified in the same way: 30 cyclohexane was added followed by ether to the residue, the mixture was filtered and the filtrate was purified on 2 x silica.

100 g using a gradient of 0-25% ethyl acetate-cyclohexane for 40 minutes in a Flashmaster II. Appropriate fractions were identified by iodine staining and combined and evaporated in vacuo. This was combined with the product obtained from the first small-scale purification to provide the title compound as a colorless liquid (2.96 g). 5

1H NMR (400 MHz, CDCl3) δ ppm 1.17 -1.25 (m, 8 H excess) 1.25 -1.39 (m, 2 H) 1.48 -1.59 (m, 2 H) 2.22 -2.34 (m , 0.6 H) 2.76 -2.88 (m, 0.3 H) 3.50 (s, 2 H) 3.58 (s, 1 H) 3.62 -3.77 (m, 2 H) 4.14 (dd, J = 8.53, 6.27 Hz, 0.3 H) 4.61 (dd, J = 12.67, 7.65 Hz, 0.6 H) 5.82 ( dd, J = 6.27, 1.00 Hz, 0.3 H) 6.32 (d, J = 12.80 Hz, 0.6 H)

Intermediate 195: (2,2-Dimethyltetrahydro-2H-pyran-4-yl) acetaldehyde 10

To a stirring solution of 2,2-dimethyl-4 - [(E) -2- (methyloxy) ethenyl] tetrahydro-2H-pyran (2.93 g, 17.21 mmol) in THF (15 ml) was added 2N HCl (15 ml, 30.0 mmol) and the mixture was stirred at 20 ° C. After 1 hour the mixture was extracted with diethyl ether (3 x 25 ml); The combined ether extracts were dried (Na2SO4), filtered and evaporated in vacuo (at 50 mbar and water bath at 15 ° C) to provide the title compound as a pale yellow oil (2.56 g).

1H NMR (400 MHz, CDCl3) δ ppm 1.19 -1.29 (m, 9 H excess) 1.53 -1.65 (m, 4 H) 1.83 -1.88 (m, 1 H) 2.25 -2.38 (m , 2 H) 3.65 -3.77 (m, 2 H) 9.77 -9.79 (m, 1 H)

Intermediate 196: 2- (2,2-Dimethyltetrahydro-2H-pyran-4-yl) ethanol 20

A stirring suspension of sodium borohydride (0.620 g, 16.39 mmol) in dry ethanol (20 ml) was cooled to 0 ° C (ice bath) under a nitrogen atmosphere and a solution of (2,2-dimethyltetrahydro- 2H-pyran-4-yl) acetaldehyde (2.56 g, 16.39 mmol) in ethanol (20 ml) dropwise over a period of 20 minutes. The mixture was then stirred cold for a further 25 hours, then allowed to warm to room temperature and stirred for 72 hours. The solvent was removed by evaporation and the residual oil was poured on ice and extracted with DCM (3 x 30 ml). The organic extracts were combined and dried by passing through a hydrophobic frit and evaporated in vacuo to provide a colorless oil containing the title compound. 30

1H NMR (400 MHz, CDCl3) δ ppm 1.04 -1.27 (m, 11 H excess) 1.43 -1.64 (m, 5 H excess) 1.77 -1.93 (m, 1 H) 3.44 -3.55 ( m, 1 H) 3.59 -3.77 (m, 4 H)

Intermediate 197: 4- (2-Bromoethyl) -2,2-dimethyltetrahydro-2H-pyran

Prepared similarly to Intermediate 174 from 2- (2,2-dimethyltetrahydro-2H-5 pyran-4-yl) ethanol.

1H NMR (400 MHz, CDCl3) δ ppm 1.04 -1.12 (m, 1 H) 1.14 -1.20 (m, 1 H) 1.20 -1.25 (m, 6 H) 1.54 -1.64 (m, 6 H excess) 1.71 -1.83 (m, 2 H) 1.87 -2.01 (m, 1 H) 3.42-3.49 (m, 2 H) 3.62 -3.80 (m, 1 H)

Intermediate 198: (4E / Z) -2,2-dimethyl-4- {3 - [(phenylmethyl) oxy] propyliden} -tetrahydro-2H-pyran

To a stirring suspension of triphenyl {3 - [(phenylmethyl) oxy] propyl} phosphonium bromide (23.00 g, 46.8 mmol) in THF (60 ml) at -15 ° C under a nitrogen atmosphere was added n- butyllithium, 1.6 M in hexane (29.3 ml, 46.8 mmol) dropwise over 30 minutes. The orange / red solution was stirred at -10 ° C for 30 minutes. A solution of 2,2-dimethyltetrahydro-4H-pyran-15 4-one (6 g, 46.8 mmol) in THF (10 ml) was added dropwise at -10 ° C for 25 minutes. The reaction mixture was then stirred at -10 ° C for 15 minutes and then allowed to warm gradually to room temperature while stirring under a nitrogen atmosphere for 20 hours. 10 ml of ether was added and the suspension was filtered on Celite. The Celite was washed with ether (2 x 40 ml). The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica (2 x 100 g) using a gradient of cyclohexane: 0-> 25% ethyl acetate for 40 minutes in a Flashmaster II. The fractions were analyzed by TLC (revealed by immersion in permanganate). The desired fractions were combined and concentrated in vacuo to give the title compound as a colorless oil (5.98 g).

1H NMR (400 MHz, DMSO-d6) δ ppm 1.97 -2.01 (m, 1 H) 2.01 -2.14 (m, 3 H) 2.19 -25 2.33 (m, 2 H) 3.36 -3.44 (m , 2 H) 3.48-3.58 (m, 2 H) 4.45 (s, 2 H) 5.09-5.19 (m, 0.6H) 5.26-5.33 (m, 0.4 H) 7.22 -7.38 (m, 5 H)

Intermediate 199: 3- (2,2-Dimethyltetrahydro-2H-pyran-4-yl) -1-propanol

A solution of 2,2-dimethyl-4- {3 - [(phenylmethyl) oxy] propyliden} tetrahydro-2H-pyran (5.98 g, 22.97 mmol) in ethyl acetate (70 ml) was hydrogenated on palladium 10% on activated carbon (0.733 g, 0.689 mmol) at atmospheric pressure and room temperature. After 16 5 hours, the mixture was filtered under vacuum through Celite, washed with EtOAc (2 x 50 ml) and the filtrate was evaporated to dryness to give a yellow mobile oil. 1 H NMR showed that most of the benzyl group had hydrogenated but the double bond was still present. The residue was dissolved in ethyl acetate (70 ml) and hydrogenated with 10% palladium on activated carbon (1.1 g) at atmospheric pressure and room temperature. After 16 hours, the mixture was filtered under vacuum through Celite, washed thoroughly with EtOAc (2 x 50 ml) and the filtrate was evaporated to dryness to provide a yellowish mobile oil. The residue was purified by silica chromatography (100 g) using a gradient of cyclohexane: 0-> 50% ethyl acetate for 40 minutes in a Flashmaster II. The desired fractions (analyzed with a permanganate dip) were combined and concentrated in vacuo to give the title compound as a pale yellow oil (2.17 g).

1H NMR (400 MHz, CDCl3) δ ppm 1.01 -1.31 (m, 12 H excess) 1.50 -1.74 (m, 6 H excess) 3.59 -3.69 (m, 3 H) 3.70 -3.78 ( m, 1 H)

Intermediate 200: 4- (3-Bromopropyl) -2,2-dimethyltetrahydro-2H-pyran

 twenty

Prepared similarly to Intermediate 174 from 4- (3-bromopropyl) -2,2-dimethyltetrahydro-2H-pyran.

1H NMR (400 MHz, CDCl3) δ ppm 0.98 -1.27 (m, 9 H excess) 1.27 -1.37 (m, 2 H) 1.45 -1.71 (m, 3 H) 1.79 -1.91 (m , 2 H) 3.31 -3.43 (m, 4 H) 3.56 -3.66 (m, 2 H) 3.67 -3.75 (m, 2 H) 25

Intermediate 201: 2,2-Dimethyl-4 - {(1E) -4 - [(phenylmethyl) oxy] -1-buten-1-yl} tetrahydro-2H-pyran

To a stirring suspension of triphenyl {3 - [(phenylmethyl) oxy] propyl} phosphonium bromide (20.74 g, 42.2 mmol) in THF (60 ml) at -15 ° C under a nitrogen atmosphere was added n- butyl lithium, 1.6 M in hexane (26.4 ml, 42.2 mmol) dropwise over 30 minutes. The orange / red solution was stirred at -10 ° C for 30 minutes. A solution of 2,2-dimethyltetrahydro-2H-pyran-5 4-carbaldehyde (6 g, 42.2 mmol) in THF (10 ml) was added dropwise at -10 ° C for 25 minutes. The reaction mixture was then stirred at -10 ° C for 15 minutes and then gradually allowed to warm to room temperature while stirring under a nitrogen atmosphere for 16 hours. Ether (10 ml) was added and the suspension was filtered with Celite. The Celite was washed with ether (2 x 40 ml). The filtrate was concentrated in vacuo. The residue was purified by silica chromatography (2 x 100 g) using a gradient of cyclohexane: 0-> 25% ethyl acetate for 40 minutes in a Flashmaster II. The fractions were analyzed by TLC (revealed by immersion in permanganate). The desired fractions were combined and concentrated in vacuo to give the title compound as a colorless oil (7.46 g). fifteen

1H NMR (400 MHz, DMSO-d6) δ ppm 1.01 -1.20 (m, 8 H) 1.31 -1.40 (m, 2 H) 2.27 -2.36 (m, 2 H) 2.59 -2.72 (m, 1 H) 3.39 -3.47 (m, 2 H) 3.51 -3.58 (m, 2 H) 4.42 -4.48 (m, 2 H) 5.13 -5.42 ( m, 2 H) 7.23-7.38 (m, 5 H)

Intermediate 202: 4- (2,2-Dimethyltetrahydro-2H-pyran-4-yl) -1-butanol

 twenty

A solution of 2,2-dimethyl-4- {4 - [(phenylmethyl) oxy] -1-buten-1-yl} tetrahydro-2H-pyran (7.46 g, 27.2 mmol) in ethyl acetate ( 70 ml) was hydrogenated with 10% palladium on activated carbon (1,447 g, 1,359 mmol) at atmospheric pressure and room temperature. After 16 hours, the mixture was filtered under vacuum through Celite, washed thoroughly with EtOAc (2 x 50 ml) and the filtrate was evaporated to dryness to provide a yellowish mobile oil (4.8 g). The residue was purified by silica chromatography (70 g) using a gradient of cyclohexane: 0-> 50% ethyl acetate for 40 minutes using a Flashmaster II. The desired fractions (analyzed by permanganate immersion) were combined and

concentrated in vacuo to provide the title compound as a yellow oil (1.675 g).

 158 1H NMR (400 MHz, CDCl3) δ ppm 1.00 -1.29 (m, 10 H) 1.33 -1.44 (m, 2 H) 1.50 -1.71 (m, 5 H) 3.62 -3.68 (m, 3 H) 3.70 -3.76 (m, 1 H)

Intermediate 203: 4- (4-Bromobutyl) -2,2-dimethyltetrahydro-2H-pyran 5

Prepared similarly to Intermediate 174 from 4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) -1-butanol.

1H NMR (400 MHz, CDCl3) δ ppm 1.00 -1.29 (m, 10 H) 1.39 -1.71 (m, 5 H) 1.79 -1.90 (m, 2 H) 3.37 -3.47 (m, 2 H) 3.59 -3.78 (m, 2 H) 10

Intermediate 204: 2 - {[(1R) -1-Methylbutyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

Sodium t-butoxide (27.3 g, 284 mmol) was added in portions at (R) -2-pentanol (140 ml) at room temperature, the mixture was stirred until it became homogeneous. 2-Chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (18.0 g, 71.0 mmol) was added and the reaction mixture was heated at 50 ° C for 160 hours The reaction was cooled to room temperature and partitioned between ethyl acetate (500 ml) and water (500 ml). The organic phase was washed with saturated sodium chloride solution (100 ml), dried (MgSO4), filtered and evaporated. The residue was triturated with ether and the solid material was filtered. The precipitate was washed again with ether and the filtrates were combined and evaporated. The crude material (approximately 10 g) was dissolved in 20 DMSO: methanol (1: 1) and purified on a reverse phase column (330 g) (C18) using a gradient of 25-65% acetonitrile (+ 0 , 1% TFA) -water (+ 0.1% TFA) with 8 column volumes, the fractions were immediately neutralized with saturated aqueous sodium carbonate solution. The appropriate fractions were combined and partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The organic phase was dried (MgSO4), filtered and evaporated to give the title compound as a light cream foam (5.05 g).

LCMS (Procedure A): tRET = 2.95 minutes; MH + 306

Intermediate 205: 8-Bromo-2 - {[(1R) -1-methylbutyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

2 - {[(1R) -1-methylbutyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (5.05 g, 16.54 mmol) was dissolved in chloroform (30 ml) and cooled to 0 ° C. To this solution was added N-bromosuccinimide (3.24 g, 18.19 mmol) in portions keeping the temperature below 2 ° C. This provided a dark green solution that was stirred at 0 ° C for 30 minutes before allowing to warm to room temperature and stir for 6 hours. The reaction mixture was washed with water (2 x 50 ml) and the phases were separated using hydrophobic porous glass. The organic phase 10 was concentrated to provide a dark brown gum that was dissolved in dichloromethane and purified by silica chromatography (100 g) using a gradient of 0-50% ethyl acetate-cyclohexane for 60 minutes in a Flashmaster II. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow foam (5.23 g). fifteen

LCMS (Procedure B): tRET = 1.21 minutes; MH + 384/386

Intermediate 206: 2 - {[(1R) -1-Methylbutyl] oxy} -8- (methyloxy) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

8-Bromo-2 - {[(1R) -1-methylbutyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (5.23 g, 20 13.61 mmol) was heated to reflux with 25% sodium methoxide in methanol (8.8 ml, 13.61 mmol) and methanol (40 ml) for 4 hours. The reaction mixture was concentrated under reduced pressure and partitioned between saturated ammonium chloride (100 ml) and dichloromethane (100 ml). The aqueous was washed with more dichloromethane (100 ml) and the combined organic phases were passed through a hydrophobic frit and concentrated to give the title compound as a light yellow foam (4.80 g).

LCMS (Procedure B): tRET = 1.14 minutes; MH + 336

Intermediate 207: 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine trifluoroacetate

To a solution of 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -9- (tetrahydro-2H-pyran-2-yl) -9H-5 purin-6-amine (4, 8 g, 14.31 mmol) in methanol (100 ml) trifluoroacetic acid (8 ml, 104 mmol) was added. The reaction mixture was stirred at room temperature for 72 hours. The solvent was removed in vacuo to provide a light yellow solid that was suspended in ethyl acetate (30 ml). The precipitate was filtered off and washed with more ethyl acetate until the filtrate was colorless. The remaining solid was dried by air and then under vacuum to provide the title compound as a cream solid (3.85 g).

LCMS (Procedure B): tRET = 0.82 minutes; MH + 252

Intermediate 208: 2 - {[(1S) -1-Methylbutyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

Prepared similarly to Intermediate 204 using (2S) -pentanol. fifteen

LCMS (Procedure A): tRET = 2.95 minutes; MH + 306

Intermediate 209: 8-Bromo-2 - {[(1S) -1-methylbutyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

Prepared similarly to Intermediate 205 from 2 - {[(1S) -1-Methylbutyl] oxy} -9-20

(tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine.

LCMS (Procedure A): tRET = 3.30 minutes; MH + 384/386

Intermediate 210: 2 - {[(1S) -1-Methylbutyl] oxy} -8- (methyloxy) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine

 5

Prepared similarly to Intermediate 206 from 8-Bromo-2 - {[(1S) -1-methylbutyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine .

LCMS (Procedure A): tRET = 3.08 minutes; MH + 336

Intermediate 211: 2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine trifluoroacetate 10

Prepared similarly to Intermediate 207 from 2 - {[(1S) -1-Methylbutyl] oxy} -8- (methyloxy) -9- (tetrahydro-2H-piran-2-yl) -9H-purin-6 -amine.

LCMS (Procedure A): tRET = 2.31 minutes; MH + 252

Intermediate 212: N2-Butyl-8- (methyloxy) -9- [3- (tetrahydro-2-furanyl) propyl] -9H-purin-2,6-15 diamine

Prepared similarly to Intermediate 216 from trifluoroacetate N2-butyl-8- (methyloxy) -3H-purin-2,6-diamine and 2- (3-bromopropyl) tetrahydrofuran.

LCMS (Procedure A): tRET = 2.53 minutes; MH + = 349 20

Intermediate 213: N2-Butyl-8- (methyloxy) -9- [4- (tetrahydro-2-furanyl) butyl] -9H-purin-2,6-diamine

2- (Butyloxy) -8- (methyloxy) -1H-purin-6-amine trifluoroacetate (120 mg, 0.342 mmol) was heated with potassium carbonate (189 mg, 1.366 mmol) in dry DMF (5 mL) at 60 ° C for 1 hour and then cooled to room temperature. 2- (4-Bromobutyl) tetrahydrofuran (82 mg, 0.394 mmol) was added and the reaction mixture was heated at 50 ° C under nitrogen atmosphere 5 for 16 hours and then partitioned between water (2 ml) and DCM (5 ml ). The aqueous phase was extracted again with DCM (2 x 5ml) and the combined organic phases were dried by passing through a hydrophobic frit and evaporated to dryness using a nitrogen blow evaporation unit. The residue was dissolved in methanol (0.6 ml) and purified by mass directed self-preparation. Fractions containing product were combined and evaporated to dryness in a nitrogen blow-off evaporation apparatus to provide the title compound (76 mg).

LCMS (Procedure B): tRET = 1.20 minutes; MH + = 363

Intermediate 214: N2-Butyl-8- (methyloxy) -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -9H-purin-2,6-diamine

Prepared similarly to Intermediate 215 from N2-butyl-8- (methyloxy) -3H-purin-2,6-diamine trifluoroacetate and (3R) -3- (2-bromoethyl) tetrahydrofuran.

LCMS (Procedure B): tRET = 1.07 minutes; MH + = 335

Intermediate 215: N2-Butyl-8- (methyloxy) -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -9H-purin-2,6-20 diamine

N2-Butyl-8- (methyloxy) -3H-purin-2,6-diamine (157 mg, 0.447 mmol) was heated in dry DMF (3 mL) with potassium carbonate (232 mg, 1.675 mmol) at 60 ° C for a hour. (3S) -3- (2-Bromoethyl) tetrahydrofuran (100 mg, 0.588 mmol) in dry DMF (2 ml) was added and the mixture was stirred and heated at 60 ° C under a nitrogen atmosphere for 4 hours. The mixture was cooled to

room temperature, it was quenched in water (40 ml) and extracted with ethyl acetate (3 x 25 ml). The organic extracts were combined, dried by passing through a hydrophobic frit and concentrated in vacuo. The residue was dissolved in 1: 1 MeOH: DMSO and purified by mass directed self-preparation. The desired fractions were combined and concentrated using a nitrogen blow evaporation unit to provide the title compound 5 as a white solid (119 mg).

LCMS (Procedure B): tRET = 1.00 minutes; MH + = 335

Intermediate 216: N2-Butyl-8- (methyloxy) -9- [3- (tetrahydro-3-furanyl) propyl] -9H-purin-2,6-diamine

 10

N2-Butyl-8- (methyloxy) -3H-purin-2,6-diamine trifluoroacetate (150 mg, 0.428 mmol) was heated in dry DMF (2.5 ml) at 60 ° C for 1 hour with potassium carbonate (237 mg, 1,713 mmol). The reaction mixture was cooled to room temperature and 3- (3-bromopropyl) tetrahydrofuran (99 mg, 0.514 mmol) was added. The mixture was then heated at 50 ° C overnight. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate 15 (3 x 25 ml). The combined organic phases were separated and then dried by passing through a hydrophobic frit and evaporated to dryness. The residue was dissolved in MeOH: 1: 1 DMSO (2.8 ml) and purified by mass-directed self-preparation. Fractions containing product were evaporated in a stream of nitrogen in a blow evaporation apparatus to provide the title compound as a clear gum (84 mg).

LCMS (Procedure B): tRET = 1.14 minutes; MH + = 349

Intermediate 217: N2-Butyl-8- (methyloxy) -9- [4- (tetrahydro-3-furanyl) butyl] -9H-purin-2,6-diamine

Prepared similarly to Intermediate 216 from N2-butyl-8-25 (methyloxy) -3H-purin-2,6-diamine trifluoroacetate and 3- (4-bromobutyl) tetrahydrofuran.

LCMS (Procedure B): tRET = 1.05 minutes; MH + = 363

Intermediate 218: N2-Butyl-8- (methyloxy) -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -9H-purin-2,6-

diamine

Prepared similarly to Intermediate 216 from N2-butyl-8- (methyloxy) -3H-purin-2,6-diamine trifluoroacetate and 2- (3-bromopropyl) tetrahydro-2H-pyran.

LCMS (Procedure B): tRET = 1.16 minutes; MH + = 363 5

Intermediate 219: N2-Butyl-8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -9H-purin-2,6-diamine

Prepared similarly to Intermediate 220 from N2-butyl-8- (methyloxy) -3H-purin-2,6-diamine trifluoroacetate and 2- (4-bromobutyl) tetrahydro-2H-pyran. 10

LCMS (Procedure B): tRET = 1.50 minutes; MH + = 377

Intermediate 220: N2-Butyl-8- (methyloxy) -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -9H-purin-2,6-diamine

A mixture of N2-butyl-8- (methyloxy) -3H-purin-2,6-diamine (150 mg, 0.429 mmol) and potassium carbonate (237 mg, 1.718 mmol) in dry DMF (5 ml) was stirred at 60 ° C for 1 hour under nitrogen atmosphere and then cooled to room temperature. 4- (3-Bromopropyl) tetrahydro-2H-pyran (0.087 ml, 0.515 mmol) was added and the mixture was stirred at 50 ° C overnight. The mixture was cooled and partitioned between ethyl acetate: DCM 1: 1 (10 ml) and water (10 ml). The organic phase was separated using a hydrophobic frit and evaporated in a stream of nitrogen using a blow evaporation apparatus. The residue was dissolved in methanol: DCM 1: 1 (2.8 ml) and purified by mass directed self-preparation. Fractions containing product were evaporated in a stream of nitrogen to give the title compound as a white solid (93.13 mg).

LCMS (Procedure B): tRET = 1.27 minutes; MH + = 363 165 25

Intermediate 221: N2-Butyl-8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -9H-purin-2,6-

diamine

Prepared in a similar way to Intermediate 220 from N2-butyl-8- (methyloxy) -3H-purin-2,6-diamine trifluoroacetate and 4- (4-bromobutyl) tetrahydro-2H-pyran.

LCMS (Procedure B): tRET = 1.38 minutes; MH + = 377 5

Intermediate 222: N2-Butyl-9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -8- (methyloxy) -9H-purin-2,6-diamine

A mixture of N2-butyl-8- (methyloxy) -3H-purin-2,6-diamine trifluoroacetate (0.2 g, 0.571 mmol) and anhydrous potassium carbonate (0.316 g, 2.284 mmol) in DMF (2, 5 ml) was heated at 10 50 ° C for 1 hour. The mixture was cooled to room temperature and 4- (2-bromoethyl) -2,2-dimethyltetrahydro-2H-pyran (0.152 g, 0.685 mmol) was added and the mixture was heated at 50 ° C for 18 hours. The mixture was quenched with water (2 ml) and then extracted with DCM (2 x 5 ml). The DCM was separated through a hydrophobic frit and evaporated by blowing in a stream of nitrogen. DMSO: MeOH (1: 1) was added to the residue and the resulting precipitate was collected by filtration, washed with methanol and dried in vacuo to afford the title compound as a white solid (136 mg).

LCMS (Procedure A): tRET = 2.65 minutes; MH + = 377

Intermediate 223: N2-Butyl-9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -8- (methyloxy) -9H-purin-2,6-diamine

A mixture of N2-butyl-8- (methyloxy) -3H-purin-2,6-diamine trifluoroacetate (149 mg, 0.425 mmol) and potassium carbonate (294 mg, 2.126 mmol) in DMF (2 ml) was stirred and It was heated at 60 ° C under a nitrogen atmosphere for one hour. 4- (3-Bromopropyl) -2,2-dimethyltetrahydro-2H-pyran (125 mg, 0.532 mmol) in dry DMF (1 ml) was added and the mixture was heated at 25 ° C under a nitrogen atmosphere for another 2, 5 hours. The reaction mixture was cooled to

room temperature, it was quenched in water (10 ml) and extracted with DCM: EtOAc (1: 1, 2 x 20 ml). The organic extracts were combined, dried by passing through a hydrophobic frit and concentrated in vacuo. The residue was purified by mass directed self-preparation. Fractions containing product were combined and evaporated to provide the title compound (40 mg). 5

LCMS (Procedure A): tRET = 2.81 minutes; MH + = 391

Intermediate 224: N2-Butyl-9- [4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) butyl] -8- (methyloxy) -9H-purin-2,6-diamine

Prepared in a similar way to Intermediate 223 from N2-butyl-8-10 (methyloxy) -3H-purin-2,6-diamine and 4- (4-bromobutyl) -2,2-dimethyltetrahydro-2H-pyran trifluoroacetate but performing the alkylation for 1.5 hours at 60 ° C.

LCMS (Procedure A): tRET = 2.95 minutes; MH + = 405

Intermediate 225: 2- (Butyloxy) -8- (methyloxy) -9- [3- (tetrahydro-2-furanyl) propyl] -9H-purin-6-amine

Prepared similarly to Intermediate 216 from 2- (butyloxy) -8- (methyloxy) -1H-purin-6-amine and 2- (3-bromopropyl) tetrahydrofuran trifluoroacetate.

LCMS (Procedure A): tRET = 2.96 minutes; MH + = 350

Intermediate 226: 2- (Butyloxy) -8- (methyloxy) -9- [4- (tetrahydro-2-furanyl) butyl] -9H-purin-6-amine

Prepared similarly to Intermediate 213 from 2- (butyloxy) -8- (methyloxy) -1H-purin-6-amine and 2- (4-bromobutyl) tetrahydrofuran trifluoroacetate.

LCMS (Procedure B): tRET = 1.14 minutes; MH + = 364

Intermediate 227: 2- (Butyloxy) -8- (methyloxy) -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -9H-purin-6-25

amine

Prepared similarly to Intermediate 215 from 2- (butyloxy) -8- (methyloxy) -1H-purin-6-amine trifluoroacetate and (3R) -3- (2-bromoethyl) tetrahydrofuran.

LCMS (Procedure B): tRET = 0.99 minutes; MH + = 336 5

Intermediate 228: 2- (Butyloxy) -8- (methyloxy) -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -9H-purin-6-amine

Prepared similarly to Intermediate 215 from 2- (butyloxy) -8- (methyloxy) -1H-purin-6-amine trifluoroacetate and (3S) -3- (2-bromoethyl) tetrahydrofuran. 10

LCMS (Procedure B): tRET = 0.99 minutes; MH + = 336

Intermediate 229: 2- (Butyloxy) -8- (methyloxy) -9- [3- (tetrahydro-3-furanyl) propyl] -9H-purin-6-amine

Prepared similarly to Intermediate 216 from 2- (butyloxy) -15 8- (methyloxy) -1H-purin-6-amine and 3- (3-bromopropyl) tetrahydrofuran trifluoroacetate.

LCMS (Procedure B): tRET = 1.04 minutes; MH + = 350

Intermediate 230: 2- (Butyloxy) -8- (methyloxy) -9- [4- (tetrahydro-3-furanyl) butyl] -9H-purin-6-amine

Prepared similarly to Intermediate 216 from 2- (butyloxy) -20 8- (methyloxy) -1H-purin-6-amine and 3- (4-bromobutyl) tetrahydrofuran trifluoroacetate.

LCMS (Procedure B): tRET = 1.11 minutes; MH + = 364

Intermediate 231: 2- (Butyloxy) -8- (methyloxy) -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -9H-purin-6-

amine

Prepared similarly to Intermediate 216 from 2- (butyloxy) -8- (methyloxy) -1H-purin-6-amine and 2- (3-bromopropyl) tetrahydro-2H-pyran trifluoroacetate.

LCMS (Procedure B): tRET = 1.19 minutes; MH + = 364 5

Intermediate 232: 2- (Butyloxy) -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -9H-purin-6-amine

Prepared similarly to Intermediate 216 from 2- (butyloxy) -8- (methyloxy) -1H-purin-6-amine and 2- (4-bromobutyl) tetrahydro-2H-pyran trifluoroacetate. 10

LCMS (Procedure B): tRET = 1.25 minutes; MH + = 378

Intermediate 233: 2- (Butyloxy) -8- (methyloxy) -9- [3- (tetrahydro-2H-pyran-3-yl) propyl] -9H-purin-6-amine

Prepared similarly to Intermediate 213 from 2- (butyloxy) -15-8- (methyloxy) -1H-purin-6-amine and 3- (3-bromopropyl) tetrahydro-2H-pyran trifluoroacetate.

LCMS (Procedure B): tRET = 1.13 minutes; MH + = 364

Intermediate 234: 2- (Butyloxy) -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -9H-purin-6-amine

 twenty

Prepared similarly to Intermediate 243 from 2- (butyloxy) -8- (methyloxy) -1H-purin-6-amine and 3- (4-bromobutyl) tetrahydro-2H-pyran trifluoroacetate.

LCMS (Procedure A): tRET = 3.27 minutes; MH + = 378

Intermediate 235: 2- (Butyloxy) -8- (methyloxy) -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -9H-purin-6-amine

Prepared similarly to Intermediate 216 from 2- (butyloxy) -5-8- (methyloxy) -1H-purin-6-amine and 4- (3-bromobutyl) tetrahydro-2H-pyran trifluoroacetate.

LCMS (Procedure B): tRET = 1.11 minutes; MH + = 364

Intermediate 236: 2- (Butyloxy) -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -9H-purin-6-amine

 10

Prepared similarly to Intermediate 216 from 2- (butyloxy) -8- (methyloxy) -1H-purin-6-amine and 4- (4-bromobutyl) tetrahydro-2H-pyran trifluoroacetate.

LCMS (Procedure B): tRET = 1.18 minutes; MH + = 378

Intermediate 237: 2- (Butyloxy) -9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -8- (methyloxy) -9H-purin-6-amine

A mixture of 2- (butyloxy) -8- (methyloxy) -1H-purin-6-amine trifluoroacetate (0.2 g, 0.569 mmol) and anhydrous potassium carbonate (0.315 g, 2.277 mmol) in DMF was heated to 60 ºC for 1 hour. The mixture was cooled to room temperature and 4- (2-bromoethyl) -2,2-dimethyltetrahydro-2H-pyran (0.151 g, 0.683 mmol) was added and the mixture was heated at 50 ° C for 18 hours. The mixture was quenched with water (2 ml) and extracted with DCM (2 x 5 ml). The DCM was separated through a hydrophobic frit and evaporated by blowing in a stream of nitrogen. The addition of DMSO: MeOH (1: 1) provided a precipitate that was collected by filtration, washed with methanol and dried in vacuo to afford the title compound (29 mg).

LCMS (Procedure A): tRET = 3.10 minutes; MH + = 378 25

Evaporation of the filtrate to dryness and trituration of the residue with DMSO: MeOH

(1: 1, 0.5 ml) provided a second batch of material (101 mg).

LCMS (Procedure A): tRET = 3.10 minutes; MH + = 378

Intermediate 238: 2- (Butyloxy) -9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -8- (methyloxy) -9H-purin-6-amine

 5

Prepared similarly to Intermediate 224 from 2- (butyloxy) -8- (methyloxy) -1H-purin-6-amine and 4- (3-bromopropyl) -2,2-dimethyltetrahydro-2H-pyran trifluoroacetate.

LCMS (Procedure A): tRET = 3.25 minutes; MH + = 392

Intermediate 239: 2- (Butyloxy) -9- [4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) butyl] -8- (methyloxy) -9H-purin-6-amine 10

Prepared similarly to Intermediate 224 from 2- (butyloxy) -8- (methyloxy) -1H-purin-6-amine and 4- (4-bromobutyl) -2,2-dimethyltetrahydro-2H-pyran trifluoroacetate but performing the alkylation for 1.5 hours at 60 ° C.

LCMS (Procedure A): tRET = 3.43 minutes; MH + = 406 15

Intermediate 240: 2 - [(2-Cyclopropylethyl) oxy] -8- (methyloxy) -9- [2- (tetrahydro-2-furanyl) ethyl] -9H-purin-6-amine

Prepared similarly to Intermediate 213 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -1H-purin-6-amine trifluoroacetate and 2- (2-bromoethyl) tetrahydrofuran. twenty

LCMS (Procedure B): tRET = 1.05 minutes; MH + = 348

Intermediate 241: 2 - [(2-Cyclopropylethyl) oxy] -8- (methyloxy) -9- [3- (tetrahydro-2-furanyl) propyl] -9H-purin-6-amine

Prepared similarly to Intermediate 216 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -1 H -purin-6-amine trifluoroacetate and 2- (3-bromopropyl) tetrahydrofuran.

LCMS (Procedure A): tRET = 2.98 minutes; MH + = 362

Intermediate 242: 2 - [(2-Cyclopropylethyl) oxy] -8- (methyloxy) -9- [4- (tetrahydro-2-furanyl) butyl] -9H-5 purine-6-amine

Prepared similarly to Intermediate 213 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -1H-purin-6-amine trifluoroacetate and 2- (4-bromobutyl) tetrahydrofuran.

LCMS (Procedure B): tRET = 1.15 minutes; MH + = 376 10

Intermediate 243: 2 - [(2-Cyclopropylethyl) oxy] -8- (methyloxy) -9- [2- (tetrahydro-3-furanyl) ethyl] -9H-purin-6-amine

A mixture of trifluoroacetate of 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -1 H -purin-6-amine (0.16 g, 0.450 mmol) and anhydrous potassium carbonate (0.243 g, 1,762 mmol) in DMF (2.5 ml) was heated at 50 ° C for 1 hour. The mixture was cooled to room temperature and 3- (2-bromoethyl) tetrahydrofuran (0.095 g, 0.528 mmol) was added and the mixture was heated at 50 ° C for 18 hours. The mixture was quenched with water (2 ml) and extracted with DCM (2 x 5 ml). The DCM was separated through a hydrophobic frit and evaporated by blowing in a stream of nitrogen. The sample was dissolved in MeOH: 1: 1 DMSO (3 x 0.5 ml) and purified by mass directed self-preparation. Fractions containing product were evaporated in a stream of nitrogen in a blow evaporation apparatus to provide the title compound as a white solid (98 mg).

LCMS (Procedure A): tRET = 2.80 minutes; MH + = 348

Intermediate 244: 2 - [(2-Cyclopropylethyl) oxy] -8- (methyloxy) -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -25 9H-purin-6-amine

Prepared similarly to Intermediate 215 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -1H-purin-6-amine trifluoroacetate and (3R) -3- (2-bromoethyl) tetrahydrofuran.

LCMS (Procedure B): tRET = 1.00 minutes; MH + = 348

Intermediate 245: 2 - [(2-Cyclopropylethyl) oxy] -8- (methyloxy) -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -5 9H-purin-6-amine

Prepared similarly to Intermediate 215 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -1 H -purin-6-amine trifluoroacetate and (3 S) -3- (2-bromoethyl) tetrahydrofuran.

LCMS (Procedure A): tRET = 2.80 minutes; MH + = 348 10

Intermediate 246: 2 - [(2-Cyclopropylethyl) oxy] -8- (methyloxy) -9- [3- (tetrahydro-3-furanyl) propyl] -9H-purin-6-amine

Prepared similarly to Intermediate 216 from trifluoroacetate of 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -1H-purin-6-amine and 3- (3-bromopropyl) tetrahydrofuran. fifteen

LCMS (Procedure B): tRET = 1.04 minutes; MH + = 362

Intermediate 247: 2 - [(2-Cyclopropylethyl) oxy] -8- (methyloxy) -9- [4- (tetrahydro-3-furanyl) butyl] -9H-purin-6-amine

Prepared similarly to Intermediate 216 from trifluoroacetate of 2 - [(2-20 cyclopropylethyl) oxy] -8- (methyloxy) -1H-purin-6-amine and 3- (4-bromobutyl) tetrahydrofuran.

LCMS (Procedure B): tRET = 1.11 minutes; MH + = 376

Intermediate 248: 2 - [(2-Cyclopropylethyl) oxy] -8- (methyloxy) -9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -9H-purin-6-amine

Prepared similarly to Intermediate 216 from trifluoroacetate of 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -1H-purin-6-amine and 2- (2-bromoethyl) tetrahydro-2H-pyran.

LCMS (Procedure A): tRET = 3.12 minutes; MH + = 362

Intermediate 249: 2 - [(2-Cyclopropylethyl) oxy] -8- (methyloxy) -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -5 9H-purin-6-amine

Prepared similarly to Intermediate 216 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -1H-purin-6-amine trifluoroacetate and 2- (3-bromopropyl) tetrahydro-2H-pyran.

LCMS (Procedure B): tRET = 1.18 minutes; MH + = 376 10

Intermediate 250: 2 - [(2-Cyclopropylethyl) oxy] -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -9H-purin-6-amine

Prepared similarly to Intermediate 213 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -1H-purin-6-amine and 2- (4-bromobutyl) tetrahydro-2H trifluoroacetate -pyran. fifteen

LCMS (Procedure A): tRET = 3.27 minutes; MH + = 390

Intermediate 251: 2 - [(2-Cyclopropylethyl) oxy] -8- (methyloxy) -9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -9H-purin-6-amine

Prepared similarly to Intermediate 216 from trifluoroacetate of 2 - [(2-20 cyclopropylethyl) oxy] -8- (methyloxy) -1H-purin-6-amine and 3- (2-bromoethyl) tetrahydro-2H-pyran .

LCMS (Procedure A): tRET = 2.99 minutes; MH + = 362

Intermediate 252: 2 - [(2-Cyclopropylethyl) oxy] -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -

9H-purin-6-amine

Prepared similarly to Intermediate 243 from trifluoroacetate of 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -1H-purin-6-amine and 3- (4-bromobutyl) tetrahydro-2H-pyran.

LCMS (Procedure A): tRET = 3.28 minutes; MH + = 390 5

Intermediate 253: 2 - [(2-Cyclopropylethyl) oxy] -8- (methyloxy) -9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -9H-purin-6-amine

Prepared similarly to Intermediate 215 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -1H-purin-6-amine trifluoroacetate and 4- (2-bromoethyl) tetrahydro-2H-pyran. 10

LCMS (Procedure B): tRET = 1.04 minutes; MH + = 362

Intermediate 254: 2 - [(2-Cyclopropylethyl) oxy] -8- (methyloxy) -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -9H-purin-6-amine

Prepared similarly to Intermediate 220 from 2 - [(2-15 cyclopropylethyl) oxy] -8- (methyloxy) -1H-purin-6-amine trifluoroacetate and 4- (3-bromopropyl) tetrahydro-2H-pyran .

LCMS (Procedure B): tRET = 1.12 minutes; MH + = 376

Intermediate 255: 2 - [(2-Cyclopropylethyl) oxy] -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -9H-purin-6-amine

 twenty

Prepared similarly to Intermediate 220 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -1H-purin-6-amine trifluoroacetate and 4- (4-bromobutyl) tetrahydro-2H-pyran.

LCMS (Procedure B): tRET = 1.19 minutes; MH + = 390

Intermediate 256: 2 - [(2-Cyclopropylethyl) oxy] -9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -8- (methyloxy) -9H-purin-6-amine

Prepared similarly to Intermediate 216 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -1H-purin-6-amine and 4- (2-bromoethyl) -2,2-dimethyltetrahydro trifluoroacetate -2H-5 pyrano.

LCMS (Procedure A): tRET = 3.12 minutes; MH + = 390

Intermediate 257: 2 - [(2-Cyclopropylethyl) oxy] -9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -8- (methyloxy) -9H-purin-6-amine

 10

Prepared similarly to Intermediate 223 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -1H-purin-6-amine trifluoroacetate and 4- (3-bromopropyl) -2,2-dimethyltetrahydro -2H-pyrano.

LCMS (Procedure A): tRET = 3.26 minutes; MH + = 404

Intermediate 258: 2 - [(2-Cyclopropylethyl) oxy] -9- [4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) butyl] -8-15 (methyloxy) -9H-purin-6- amine

Prepared similarly to Intermediate 223 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -1H-purin-6-amine and 4- (4-bromobutyl) -2,2-dimethyltetrahydro trifluoroacetate -2H-pyrano but performing alkylation for 1.5 hours at 60 ° C. twenty

LCMS (Procedure A): tRET = 3.43 minutes; MH + = 418

Intermediate 259: 2 - {[(1S) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [2- (tetrahydro-2-furanyl) ethyl] -9H-purin-6-amine

Prepared similarly to Intermediate 243 from 2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -1 H -purin-6-amine and 2- (2-bromoethyl) tetrahydrofuran trifluoroacetate.

LCMS (Procedure A): tRET = 3.07 minutes; MH + = 350

Intermediate 260: 2 - {[(1S) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [3- (tetrahydro-2-furanyl) propyl] -9H-5 purin-6-amine

Prepared similarly to Intermediate 215 from 2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 2- (3-bromopropyl) tetrahydrofuran trifluoroacetate but performing the alkylation for 1 hour at 60 ° C. 10

LCMS (Procedure A): tRET = 3.00 minutes; MH + = 364

Intermediate 261: 2 - {[(1S) -1-Methylbutyl] oxy} -8- (methyloxy) -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -9H-purin-6-amine

Prepared similarly to Intermediate 216 from 2 - {[(1S) -1-15 methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine trifluoroacetate and (3R) -3- (2 -bromoethyl) tetrahydrofuran.

LCMS (Procedure A): tRET = 2.81 minutes; MH + = 350

Intermediate 262: 2 - {[(1S) -1-Methylbutyl] oxy} -8- (methyloxy) -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -9H-purin-6-amine

 twenty

Prepared similarly to Intermediate 215 from 2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine trifluoroacetate and (3S) -3- (2- bromoethyl) tetrahydrofuran but performing alkylation for 1 hour at 60 ° C.

LCMS (Procedure A): tRET = 2.96 minutes; MH + = 350 178

Intermediate 263: 2 - {[(1S) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [3- (tetrahydro-3-furanyl) propyl] -9H-purin-6-amine

Prepared similarly to Intermediate 220 from 2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 3- (3-bromopropyl) tetrahydrofuran trifluoroacetate. 5

LCMS (Procedure B): tRET = 1.13 minutes; MH + = 364

Intermediate 264: 2 - {[(1S) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [4- (tetrahydro-3-furanyl) butyl] -9H-purin-6-amine

Prepared similarly to Intermediate 220 from 2 - {[(1S) -1-10 methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 3- (4-bromobutyl) tetrahydrofuran trifluoroacetate .

LCMS (Procedure B): tRET = 1.19 minutes; MH + = 378

Intermediate 265: 2 - {[(1S) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -9H-purin-6-amine

 fifteen

Prepared similarly to Intermediate 243 from 2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 2- (2-bromoethyl) tetrahydro- trifluoroacetate 2H-pyrano.

LCMS (Procedure A): tRET = 3.27 minutes; MH + = 364

Intermediate 266: 2 - {[(1S) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -9H-purin-6-amine twenty

Prepared similarly to Intermediate 220 from 2 - {[(1S) -1- trifluoroacetate

methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 2- (3-bromopropyl) tetrahydro-2H-pyran.

LCMS (Procedure B): tRET = 1.26 minutes; MH + = 378

Intermediate 267: 2 - {[(1S) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -9H-purin-6-amine

 5

Prepared similarly to Intermediate 213 from 2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine trifluoroacetate and 2- (4-bromobutyl) tetrahydro- 2H-pyrano.

LCMS (Procedure A): tRET = 3.33 minutes; MH + = 392

Intermediate 268: 2 - {[(1S) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -9H-purin-6-amine 10

Prepared similarly to Intermediate 243 from 2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 3- (2-bromoethyl) tetrahydro- trifluoroacetate 2H-pyrano.

LCMS (Procedure A): tRET = 3.13 minutes; MH + = 364

Intermediate 269: 2 - {[(1S) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -15 9H-purin-6- amine

Prepared similarly to Intermediate 243 from trifluoroacetate of 2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 3- (4-bromobutyl) tetrahydro- 2H-pyrano.

LCMS (Procedure A): tRET = 3.42 minutes; MH + = 392 20

Intermediate 270: 2 - {[(1S) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -9H-purin-6-amine

Prepared similarly to Intermediate 215 from 2 - {[(1S) -1- trifluoroacetate

methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 4- (2-bromoethyl) tetrahydro-2H-pyran but performing alkylation for 1 hour at 60 ° C.

LCMS (Procedure A): tRET = 2.97 minutes; MH + = 364

Intermediate 271: 2 - {[(1S) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -9H-purin-6-amine 5

Prepared similarly to Intermediate 216 from trifluoroacetate of 2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 4- (3-bromopropyl) tetrahydro- 2H-pyrano.

LCMS (Procedure B): tRET = 1.19 minutes; MH + = 378

Intermediate 272: 2 - {[(1S) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -10 9H-purin-6- amine

Prepared similarly to Intermediate 216 from trifluoroacetate of 2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 4- (4-bromobutyl) tetrahydro- 2H-pyrano.

LCMS (Procedure B): tRET = 1.26 minutes; MH + = 392 15

Intermediate 273: 9- [2- (2,2-Dimethyltetrahydro-2H-pyran-4-yl) ethyl] -2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -9H-purin -6-amine

Prepared similarly to Intermediate 243 from 2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 4- (2-bromoethyl) -2 trifluoroacetate , 2-dimethyltetrahydro-2H-pyran. twenty

LCMS (Procedure A): tRET = 3.26 minutes; MH + = 392

Intermediate 274: 9- [3- (2,2-Dimethyltetrahydro-2H-pyran-4-yl) propyl] -2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -9H-purin -6-amine

Prepared similarly to Intermediate 215 from 2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 4- (3-bromopropyl) -2 trifluoroacetate , 2-dimethyltetrahydro-2H-pyran but performing alkylation for 1 hour at 60 ° C.

LCMS (Procedure A): tRET = 3.37 minutes; MH + = 406 5

Intermediate 275: 9- [4- (2,2-Dimethyltetrahydro-2H-pyran-4-yl) butyl] -2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -9H-purin -6-amine

Prepared similarly to Intermediate 215 from 2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 4- (4-bromobutyl) -2 trifluoroacetate , 2-dimethyltetrahydro-2H-pyran 10 but performing alkylation for 1 hour at 60 ° C.

LCMS (Procedure A): tRET = 3.44 minutes; MH + = 420

Intermediate 276: 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -9- [2- (tetrahydro-2-furanyl) ethyl] -9H-purin-6-amine

 fifteen

Prepared similarly to Intermediate 290 from 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 2- (2-bromoethyl) tetrahydrofuran trifluoroacetate.

LCMS (Procedure B): tRET = 1.11 minutes; MH + = 350

Intermediate 277: 2 - {[(1R) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [3- (tetrahydro-2-furanyl) propyl] -9H-purin-6-amine

Prepared similarly to Intermediate 223 from 2 - {[(1R) -1- trifluoroacetate

methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 2- (3-bromopropyl) tetrahydrofuran but performing alkylation for 1 hour at 60 ° C.

LCMS (Procedure A): tRET = 3.00 minutes; MH + = 364

Intermediate 278: 2 - {[(1R) -1-Methylbutyl] oxy} -8- (methyloxy) -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -9H-purin-6-amine 5

Prepared similarly to Intermediate 216 from 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine trifluoroacetate and (3R) -3- (2- bromoethyl) tetrahydrofuran.

LCMS (Procedure A): tRET = 2.81 minutes; MH + = 350

Intermediate 279: 2 - {[(1R) -1-Methylbutyl] oxy} -8- (methyloxy) -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -10 9H-purin-6- amine

Prepared similarly to Intermediate 223 from trifluoroacetate 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and (3S) -3- (2-bromoethyl ) tetrahydrofuran but performing alkylation for 1 hour at 60 ° C. fifteen

LCMS (Procedure A): tRET = 2.81 minutes; MH + = 350

Intermediate 280: 2 - {[(1R) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [3- (tetrahydro-3-furanyl) propyl] -9H-purin-6-amine

Prepared similarly to Intermediate 216 from 2 - {[(1R) -1-20 methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 3- (3-bromopropyl) tetrahydrofuran trifluoroacetate .

LCMS (Procedure B): tRET = 1.09 minutes; MH + = 364

Intermediate 281: 2 - {[(1R) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [4- (tetrahydro-3-furanyl) butyl] -9H-purin-6-amine

Prepared similarly to Intermediate 216 from trifluoroacetate of 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 3- (4-bromobutyl) tetrahydrofuran.

LCMS (Procedure B): tRET = 1.16 minutes; MH + = 378

Intermediate 282: 2 - {[(1R) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -5 9H-purin-6- amine

Prepared similarly to Intermediate 213 from 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 2- (2-bromoethyl) tetrahydro- trifluoroacetate 2H-pyrano.

LCMS (Procedure B): tRET = 1.21 minutes; MH + = 364 10

Intermediate 283: 2 - {[(1R) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -9H-purin-6-amine

Prepared similarly to Intermediate 216 from trifluoroacetate 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 2- (3-bromopropyl) tetrahydro-2H -pyran. fifteen

LCMS (Procedure B): tRET = 1.25 minutes; MH + = 378

Intermediate 284: 2 - {[(1R) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -9H-purin-6-amine

Prepared in a similar way to Intermediate 213 from 2 - {[(1R) -1-20 methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 2- (4-bromobutyl) tetrahydro trifluoroacetate -2H-pyrano.

LCMS (Procedure A): tRET = 3.33 minutes; MH + = 392?

Intermediate 285: 2 - {[(1R) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -

9H-purin-6-amine

Prepared similarly to Intermediate 213 from 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 3- (2-bromoethyl) tetrahydro- trifluoroacetate 2H-pyrano.

LCMS (Procedure B): tRET = 1.13 minutes; MH + = 364 5

Intermediate 286: 2 - {[(1R) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -9H-purin-6-amine

Prepared similarly to Intermediate 213 from trifluoroacetate of 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 3- (4-bromobutyl) tetrahydro- 2H-pyrano. 10

LCMS (Procedure B): tRET = 1.26 minutes; MH + = 392

Intermediate 287: 2 - {[(1R) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -9H-purin-6-amine

Prepared similarly to Intermediate 223 from trifluoroacetate of 2 - {[(1R) -1-15 methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 4- (2-bromoethyl) tetrahydro -2H-pyrano but performing alkylation for 1 hour at 60 ° C.

LCMS (Procedure A): tRET = 2.94 minutes; MH + = 364

Intermediate 288: 2 - {[(1R) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -9H-purin-6-amine twenty

Prepared similarly to Intermediate 216 from 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 4- (3-bromopropyl) tetrahydro- trifluoroacetate 2H-pyrano.

LCMS (Procedure B): tRET = 1.16 minutes; MH + = 378

Intermediate 289: 2 - {[(1R) -1-Methylbutyl] oxy} -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -9H-purin-6-amine

Prepared similarly to Intermediate 216 from trifluoroacetate 2 - {[(1R) -1-5 methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 4- (4-bromobutyl) tetrahydro- 2H-pyrano.

LCMS (Procedure B): tRET = 1.24 minutes; MH + = 392

Intermediate 290: 9- [2- (2,2-Dimethyltetrahydro-2H-pyran-4-yl) ethyl] -2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -9H-purin -6-amine

 10

2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine trifluoroacetate (100 mg, 0.274 mmol) was heated with potassium carbonate (37.8 mg, 0.274 mmol ) in dry DMF (2 ml) at 60 ° C under a nitrogen atmosphere for 1 hour and then cooled to room temperature. 4- (2-Bromoethyl) -2,2-dimethyltetrahydro-2H-pyran (72.6 mg, 0.328 mmol) was added and the reaction mixture was heated at 50 ° C for 16 hours. LCMS indicated that the reaction was incomplete and more 4- (2-bromoethyl) -2,2-dimethyltetrahydro-2H-pyran (35 mg) was added, and the reaction was stirred at 50 ° C for another 5 hours and then fractioned between water (2 ml) and DCM (5 ml). The aqueous phase was extracted again with DCM (2 x 5 ml). The combined organic phases were combined and dried by passing through a hydrophobic frit and then evaporated to dryness using a nitrogen blow evaporation unit. The residue was dissolved in methanol (0.6 ml) and purified by mass directed self-preparation. Evaporation of the fractions containing product in a stream of nitrogen in a blow evaporation apparatus provided the title compound as a white solid (92 mg).

LCMS (Procedure B): tRET = 1.19 minutes; MH + = 392 25

Intermediate 291: 9- [3- (2,2-Dimethyltetrahydro-2H-pyran-4-yl) propyl] -2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -9H-purin -6-amine

Prepared similarly to Intermediate 223 from 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 4- (3-bromopropyl) -2 trifluoroacetate , 2-dimethyltetrahydro-2H-pyran but performing alkylation for 1 hour at 60 ° C.

LCMS (Procedure A): tRET = 3.27 minutes; MH + = 406 5

Intermediate 292: 9- [4- (2,2-Dimethyltetrahydro-2H-pyran-4-yl) butyl] -2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -9H-purin -6-amine

Prepared similarly to Intermediate 223 from 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -1H-purin-6-amine and 4- (4-bromobutyl) -2 trifluoroacetate , 2-dimethyltetrahydro-2H-pyran 10 but performing alkylation for 1 hour at 60 ° C.

LCMS (Procedure A): tRET = 3.44 minutes; MH + = 420

Example 1: 6-Amino-2-butoxy-9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one

2-Butoxy-8-methoxy-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine (0.22 g) was dissolved in methanol (10 ml) and treated with 4 N hydrogen in 1,4-dioxane (1 ml). The reaction was stirred at room temperature 16 hours and evaporated under reduced pressure to provide a solid that was suspended in water (2 ml) before adding sufficient methanol until a solution was obtained. 2N sodium hydroxide solution was added to bring to pH 7, and the solution was concentrated until a suspension formed. The white solid was filtered and washed with water (2 20 ml, twice to complete the transfer and washing). This was dried with suction and then under vacuum at 50 ° C to give the title compound as a white solid (0.189 g).

MS calculated for (C15H23N5O3) + = 321

MS found (electrospray): (M + H) + = 322

1H NMR ((CD3) 2SO): 9.86 (1H, s), 6.41 (2H, s), 4.14 (2H, t), 3.81 (2H, m), 3.55 ( 2H, 25

d), 3.22 (2H, m), 2.03 (1H, m), 1.64 (2H, m), 1.49-1.33 (4H, overlapping m), 1.22 (2H, m), 0.92 (3H, t).

Example 2: 6-Amino-2-butoxy-9- (tetrahydro-2H-pyran-2-ylmethyl) -7,9-dihydro-8H-purin-8-one

2-Butoxy-8-methoxy-9- (tetrahydro-2H-pyran-2-ylmethyl) -9H-purin-6-amine (6 mg, ~ 85% of 5 purity) was dissolved in methanol (1 ml), se treated with 4 N hydrogen chloride in 1,4-dioxane (0.5 ml) and stirred for 5 hours at room temperature. The mixture was evaporated under reduced pressure to dryness to provide the title compound (77.8: 10.8 by LCMS) as a colorless gum (8 mg).

MS calculated for (C15H23N5O3) + = 321 10

MS found (electrospray): (M + H) + = 322

1H NMR (CD3OD): 4.54 (2H, t), 4.06-3.65 (5H, m superimposed), 1.87-1.83 (3H, m superimposed), 1.69 (1H, d), 1.52 (4H, m superimposed), 1.35 (2H, m), 1.01 (3H, t) (NH2 & NH protons exchanged).

Example 3: 6-Amino-2-butoxy-9- (tetrahydrofuran-2-ylmethyl) -7,9-dihydro-8H-purin-8-one

To the 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (0.20 g) in dry DMF (5 ml) was added anhydrous potassium carbonate (0.315 g). This was heated at 60 ° C for 1 hour and then cooled to room temperature. Tetrahydrofurfuryl bromide (65 µl) was added and the reaction mixture was then heated at 50 ° C overnight. The reaction was quenched with water 20 and extracted with ethyl acetate (twice). The organic phase was separated, combined and dried by passing through a hydrophobic frit. Evaporation of the organic phase and the purification of the oil thus formed by silica chromatography (40 g) (ISCO) eluting with 0–100% ethyl acetate: cyclohexane and then 0–10% methanol: ethyl acetate and then Methanol provided a gum. This gum was dissolved in methanol (5 ml) and treated with 4N hydrogen chloride in 1,4-dioxane (1 ml) and stirred overnight at room temperature. The reaction mixture was evaporated under reduced pressure to dryness to provide a gum (~ 44

mg) which was purified by MDAP to provide the title compound (slower isomer by LCMS) as a white solid (15.2 mg).

MS calculated for (C14H21N5O3) + = 307

MS found (electrospray): (M + H) + = 308

1H NMR (CD3OD): 4.36 (1H, m), 4.27 (2H, t), 3.90 (2H, m), 3.75 (2H, d), 2.00 (2H, 5 m), 1.90 (1H, m), 1.73 (3H, m superimposed), 1.48 (2H, m), 0.98 (3H, t) (NH2 and NH exchanged).

Example 4: 6-Amino-2-butylamino-9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one

 10

To a solution of N2-butyl-8-methoxy-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-2,6-diamine (310 mg) in dry methanol (30 ml) at room temperature and In a nitrogen atmosphere, 4.0 M hydrogen chloride in 1,4-dioxane (5.5 ml) was added at one time. The reaction was allowed to stir at room temperature for 16 hours. The reaction was neutralized by the addition of 2.0 M solution of sodium hydroxide and concentrated in vacuo. The residue was taken in water (10 15 ml) and the solid was filtered and dried on the rotary evaporator (60 ° C) for 30 minutes. This provided the title compound as a solid (170 mg).

MS calculated for (C15H24N6O2) + = 320

MS found (electrospray): (M + H) + = 321

1H NMR ((CD3) 2SO): δ 9.82 (1H, s), 6.16 (1H, t), 6.09 (2H, s), 3.81 (2H, m), 3.50 (2H, 20 d), 3.21 ( 2H, m), 3.16 (2H, m), 2.03 (1H, m), 1.44 (4H, m), 1.29 (2H, m), 1.22 (2H, m), 0.88 (3H, t).

Example 4, alternative procedure: 6-Amino-2- (butylamino) -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one

 25

N2-Butyl-8- (methoxy) -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-2,6-diamine (5.16 g) was dissolved in methanol (50 ml) to provide a solution orange. To this solution afterwards

4N hydrogen chloride in 1,4-dioxane (5 ml) was added. The resulting orange solution was stirred at room temperature (~ 22 ° C) for ~ 17 hours. The reaction mixture was examined by LCMS and it showed that the reaction was not complete. Other aliquots of 4N hydrogen chloride in 1,4-dioxane (5 ml) were then added to the reaction mixture and the reaction mixture was stirred for another 5.25 hours. Examination of the reaction mixture by LCMS showed that the reaction was almost complete with a small amount of the N2-butyl-8- (methoxy) -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H- Purin-2,6-diamine remaining. The reaction was evaporated under reduced pressure to provide a clear tan solid to avoid unwanted reaction / decomposition since the reaction was left unattended over the weekend. To summarize the experiment, the material was re-dissolved in 10 methanol (50 ml) to provide an orange solution to which 4N hydrogen chloride in 1,4-dioxane (5 ml) was then added. The reaction mixture was then stirred at room temperature (~ 20 ° C) for 1.6 hours after which it was found that the reaction was completed by LCMS.

The reaction mixture was then evaporated under reduced pressure to provide a clear tan solid. The material was suspended in a mixture of water (10 ml) and methanol (60 ml) and then subjected to ultrasound providing a finely fractionated suspension before adding a 2M solution of sodium hydroxide gradually to neutralize (when the suspension began to thicken another volume of water (10 ml) was added).

The resulting suspension was filtered with suction and the filter cake was washed with water (30-20 ml) before air drying with suction to give an off-white solid. The filtrate was evaporated with suction to provide a clear tan solid that was suspended in water (10 ml) and isolated by suction filtration. This solid was then washed with water: methanol (10 ml, 1: 1 v / v) to provide a clear tan solid which was air dried with suction providing (~ 0.3 g). The combined solids were then dried in vacuo (50 ° C) overnight until a fluid off-white solid (4.69 g) was obtained.

This material (4.69 g) was added to a round bottom flask (250 ml) equipped with a magnetic stir bar. To the round bottom flask was then added absolute ethanol (94 ml). The resulting suspension was gently heated by stirring until the solid dissolved. Then water (94 ml) was added and a precipitate formed. The resulting suspension 30 was then heated (round bottom flask now equipped with a reflux condenser) (external, 95 ° C) until the solid dissolved again. Heating was continued for 5 minutes, before removing the heat source and allowed to cool while stirring. The resulting solid was then isolated by filtration and washed using absolute ethanol: water (50 ml, 1: 1 v / v). The resulting filter cake was then air dried with suction before drying at 35

constant weight under vacuum (50 ° C) for ~ 24 hours, this provided the title compound as an off-white solid (3.57 g).

MS calculated for (C15H24N6O2) + = 320

MS found (electrospray): (M + H) + = 321

1H NMR ((CD3) 2SO): 10.56 (1H, s), 7.77 (3H, wide s), 3.87-3.78 (2H, m), 3.61-3.53 5 (2H, m), 3.34-3.26 (2H, m), 3.26-3.18 (2H, m), 2.09-1.94 (1H, m), 1.59-1 , 44 (4H, m superimposed), 1.40-1.29 (2H, m), 1.29-1.14 (2H, m), 0.95-0.87 (3H, m).

Example 5: 6-Amino-2-butylamino-9- (tetrahydro-2H-pyran-2-ylmethyl) -7,9-dihydro-8H-purin-8-one

 10

To a solution of N2-butyl-8-methoxy-9- (tetrahydro-2H-pyran-2-ylmethyl) -9H-purin-2,6-diamine in dry methanol (5 ml) at room temperature and under a nitrogen atmosphere 4.0 M hydrogen chloride in 1,4-dioxane (1.5 ml) was added at one time. The reaction was allowed to stir at room temperature overnight. The reaction was concentrated in vacuo and the product was purified by MDAP. This gave the title compound 6 mg (slower in MDAP). fifteen

MS calculated for (C15H24N6O2) + = 320

MS found (electrospray): (M + H) + = 321

1H NMR ((CD3) 2SO): δ 10.71 (1H, s), 7.91 (3H, wide s), 3.79-3.85 (1H, m), 3.71-3.78 (1H, m), 3.62-3 , 71 (1H, m), 3.54-3.60 (1H, m), 3.26-3.38 (2H, m), 3.19-3.27 (1H, m), 1.70 -1.80 (1H, m), 1.53-1.59 (1H, m), 1.49-1.54 (2H, m), 1.43 (3H, s), 1.29-1 , 39 (2H, m), 1.12-1.25, 20 (1H, m), 0.90 (3H, t).

Example 6: 6-Amino-2-butylamino-9- (tetrahydrofuran-2-ylmethyl) -7,9-dihydro-8H-purin-8-one

To a solution of trifluoroacetic acid salt of N2-butyl-8-methoxy-9H-purin-2,6-diamine (400 mg) in dry N, N-dimethylformamide (6 ml) at room temperature and under nitrogen atmosphere potassium carbonate (630 mg) was added at one time. The reaction was stirred at 60 ° C

for 1.5 hours and then cooled to 40 ° C. 2- (Bromomethyl) tetrahydrofuran (156 µl) was added at one time and the reaction was heated at 50 ° C overnight and then at 90 ° C for 2 hours. The reaction was diluted with ethyl acetate (20 ml) and washed with water (10 ml). The organic phase was separated and concentrated in vacuo. The product was half purified by MDAP to provide a mixture. To this mixture, in dry methanol (5 ml) at room temperature and 5 under nitrogen atmosphere, 4.0 M hydrogen chloride in 1,4-dioxane (1.5 ml) was added at one time. The reaction was allowed to stir at room temperature overnight. The reaction was concentrated in vacuo and the product was purified by MDAP (slower isomer). This gave the title compound as a white solid (15 mg).

MS calculated for (C14H22N6O2) + = 306 10

MS found (electrospray): (M + H) + = 307

1H NMR ((CD3) 2SO): δ 10.69 (1H, s), 7.82 (3H, wide s), 4.18 (1H, m), 3.67-3.79 (2H, m), 3.56-3.64 (2H , m), 3.28 (2H, s), 1.76-1.92 (3H, m), 1.65 (1H, m), 1.52 (2H, m), 1.32 (2H, m), 0.88 (3H, t).

Example 7: 6-Amino-2-butylamino-9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-15 8-one

To a solution of trifluoroacetic acid salt of N2-butyl-8-methoxy-9H-purin-2,6-diamine (100 mg) in dry N, N-dimethylformamide (1 ml) at room temperature and under a nitrogen atmosphere, added potassium carbonate (158 mg) at one time. The reaction was stirred at 60 ° C for 1.5 hours and then cooled to 50 ° C. A solution of 4- (2-bromoethyl) tetrahydro-2H-pyran (60 mg) in dry N, N-dimethylformamide (0.5 ml) was added at one time and the reaction was heated at 50 ° C overnight. The reaction was diluted with ethyl acetate (15 ml) and washed with water (5 ml). The organic phase was separated and concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (20-60%) to provide a yellow viscous oil (47mg) which was dissolved in dry methanol (4 ml) at room temperature and under nitrogen atmosphere 4.0 M hydrogen chloride in 1,4-dioxane (0.8 ml) was added at one time. The reaction was allowed to stir at room temperature overnight. The reaction was neutralized by the addition of 2.0 M solution of sodium hydroxide and concentrated in vacuo. The residue is 30

taken in water (5 ml) and the solid was filtered and dried in vacuo (60 ° C) for 30 minutes. This gave the title compound as a beige solid (23 mg).

MS calculated for (C16H26N6O2) + = 334

MS found (electrospray): (M + H) + = 335

1H NMR ((CD3) 2SO): δ 9.78 (1H, s), 6.08-6.21 (3H, wide s), 3.80 (2H, m), 3.65 (2H, 5 t), 3.21 (2H, m) , 3.16 (2H, m), 1.66 (2H, m), 1.57 (2H, m), 1.36-1.49 (3H, m), 1.29 (2H, m), 1.13 (2H, m), 0.88 (3H, t).

Example 8: 6-Amino-2-butylamino-9- (tetrahydrofuran-3-ylmethyl) -7,9-dihydro-8H-purin-8-one

To a solution of trifluoroacetic acid salt of N2-butyl-8-methoxy-9H-purin-2,6-10 diamine (100 mg) in dry N, N-dimethylformamide (1 ml) at room temperature and under a nitrogen atmosphere potassium carbonate (158 mg) was added at one time. The reaction was stirred at 60 ° C for 1.5 hours and then cooled to 50 ° C. A solution of 3- (bromomethyl) tetrahydrofuran (52 mg) in dry N, N-dimethylformamide (0.5 ml) was added at one time and the reaction was heated at 50 ° C overnight. The reaction was diluted with ethyl acetate (15 ml) and washed with water (5 ml). The organic phase was separated and concentrated in vacuo. The product was half purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (10-45%) to provide a yellow oil. (32mg) which was dissolved in dry methanol (3 ml) at room temperature and under nitrogen atmosphere 4.0 M hydrogen chloride in 1,4-dioxane (0.6 ml) was added at one time. The reaction was allowed to stir at room temperature overnight. The reaction was neutralized by the addition of 2.0 M solution of sodium hydroxide and concentrated in vacuo. The residue was taken in water (5 ml) and the solid was filtered and dried in vacuo (60 ° C) for 15 minutes. This gave the title compound as a white solid (20 mg). 25

MS calculated for (C14H22N6O2) + = 306

MS found (electrospray): (M + H) + = 307

1H NMR ((CD3) 2SO): δ 9.73 (1H, s), 6.17 (1H, m), 6.04 (1H, m), 3.74 (2H, m), 3.56-3.64 (4H, m), 3 , 53 (1H, m), 3.16 (2H, m), 2.69 (1H, m), 1.85 (1H, m), 1.64 (1H, m), 1.46 (2H, m), 1.29 (2H, m), 0.87 (3H, t). 30

Example 8, alternative procedure: 6-Amino-2- (butylamino) -9- (tetrahydro-3-

furanylmethyl) -7,9-dihydro-8H-purin-8-one

N2-Butyl-8- (methoxy) -9- (tetrahydro-3-furanylmethyl) -9H-purin-2,6-diamine (98 mg) was dissolved in methanol (2 ml). To the resulting solution was added 4 N hydrogen chloride in 1,4-dioxane (0.5 ml). The reaction mixture was then stirred at room temperature until it was completed (controlled by LCMS) for 2.5 hours. The reaction mixture was then evaporated under reduced pressure to provide an oil. To this oil was added water (2 ml) and methanol (2 ml). The resulting solution was then neutralized using 2M sodium hydroxide solution. More water (5 ml) was added when the product precipitated (pH 4-5). The white solid was isolated by filtration with suction and then washed with water (5 ml). The filter cake 10 was then air dried with suction to provide (68 mg) which was dissolved in ethanol (2 ml). Water (2 ml) was added to this solution to provide a precipitate. The resulting suspension was heated (90 ° C, external) to reflux to provide a solution. The resulting solution was refluxed for a few minutes before being allowed to cool to room temperature to provide a white filamentous solid. This solid was isolated by filtration with suction and the residues were transferred using water (8 ml). The filter cake was air dried with suction and then dried under vacuum at 50 ° C for 4 hours to provide a white solid that was then transferred to a vial and dried further at 50 ° C (16 hours) to provide 55 mg of the compound of the title in the form of a white solid.

MS calculated for (C14H22N6O2) + = 306 20

MS found (electrospray): (M + H) + = 307

1H NMR ((CD3) 2SO): δ 9.55 (1H, wide s), 6.11-6.19 (1H, m), 5.95 (2H, wide s), 3.80-3.70 (1H, m), 3.66- 3.56 (4H, m), 3.56-3.49 (1H, m), 3.16 (2H, q), 2.76-2.63 (1H, m), 1.91-1, 80 (1H, m), 1.69-1.59 (1H, m), 1.52-1.41 (2H, m), 1.36-1.22 (2H, m), 0.88 ( 3H, t).

Example 9: 6-Amino-2-butylamino-9- (tetrahydro-2H-pyran-3-ylmethyl) -7,9-dihydro-8H-purin-8-25 one

To a solution of N2-butyl-8-methoxy-9- (tetrahydro-2H-pyran-3-ylmethyl) -9H-purin-2,6-diamine (45 mg) in dry methanol (3 ml) at room temperature and In a nitrogen atmosphere, 4.0 M hydrogen chloride in 1,4-dioxane (0.7 ml) was added at one time. The reaction was allowed to stir at room temperature for 3 hours. The reaction was neutralized by the addition of 2.0 M sodium hydroxide solution and concentrated in vacuo. The residue was taken in water (5 ml) and the solid was filtered and dried in vacuo (60 ° C) for 30 minutes. This provided the title compound as a solid (25 mg).

MS calculated for (C15H24N6O2) + = 320

MS found (electrospray): (M + H) + = 321 10

1H NMR ((CD3) 2SO): δ 9.59 (1H, s), 6.17 (1H, t), 5.90 (2H, t), 3.65 (2H, m), 3.42-3.67 (2H, m), 3 , 31 (1H, m), 3.10-3.20 (3H, m), 2.14 (1H, m), 1.64 (2H, m), 1.36-1.50 (3H, m ), 1.30 (2H, m), 1.22 (1H, m), 0.88 (3H, t).

Example 10: 6-Amino-2-butoxy-9- (tetrahydrofuran-3-ylmethyl) -7,9-dihydro-8H-purin-8-one

 fifteen

2-Butoxy-8-methoxy-9- (tetrahydrofuran-3-ylmethyl) -9H-purin-6-amine (97 mg) was dissolved in methanol (2 ml) and treated with 4 N hydrogen chloride in 1.4 -dioxane (1 ml). The reaction mixture was stirred for 4 hours. The reaction was evaporated under reduced pressure to dryness. Water (2 ml) and methanol (15 ml) were added to the residue and then neutralized by the addition of 2 N sodium hydroxide solution. The above was evaporated under reduced pressure almost to dryness 20 (a small amount of water remained) and the solid thus obtained was filtered (the solid was transferred and washed with water (2ml, 3 times)). The solid was dried with suction before further drying under vacuum (50 ° C) for 2 hours. This gave the title compound as a white solid (62 mg).

MS calculated for (C14H21N5O3) + = 307 25

MS found (electrospray): (M + H) + = 308

1H NMR ((CD3) 2SO): 9.88 (1H, s), 6.42 (2H, s), 4.13 (2H, t), 3.75 (1H, m), 3.65- 3.56 (4H, m superimposed), 3.51 (1H, m), 2.68 (1H, m), 1.87 (1H, m), 1.66-1.57 (3H, m superimposed) , 1.38 (2H, m), 0.90 (3H, t).

Example 11: 6-Amino-2-butoxy-9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-8-one

2-Butoxy-8-methoxy-9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -9H-purin-6-amine (0.11 g) was dissolved in methanol (2 ml) and was treated with 4 N hydrogen chloride in 1,4-dioxane (1 ml). The reaction mixture was stirred for 4 hours and evaporated under reduced pressure to dryness. Water (2 ml) and methanol (15 ml) were added to the residue and then neutralized by the addition of 2 N sodium hydroxide solution. The above was evaporated under reduced pressure almost to dryness (a small amount of water remained) and the solid thus obtained was filtered (the solid was transferred and washed with water (3 ml)). The solid was dried with suction before further drying under vacuum to give the title compound as a white solid (82 mg).

MS calculated for (C16H25N5O3) + = 335 15

MS found (electrospray): (M + H) + = 336

1H NMR ((CD3) 2SO): 9.84 (1H, s), 6.40 (2H, s), 4.13 (2H, t), 3.79 (2H, dd), 3.70 ( 2H, d), 3.21 (2H, t), 1.70-1.53 (6H, m superimposed), 1.46-1.32 (3H, m superimposed), 1.14 (2H, m) , 0.91 (3H, t).

Example 12: 6-Amino-2-butoxy-9- (tetrahydro-2H-pyran-3-ylmethyl) -7,9-dihydro-8H-purin-8-20 one

2-Butoxy-8-methoxy-9- (tetrahydro-2H-pyran-3-ylmethyl) -9H-purin-6-amine (105 mg) was dissolved in methanol (2 ml) and treated with 4 N hydrogen chloride in 1,4-dioxane (1 ml). The reaction mixture was stirred for 4 hours and evaporated under reduced pressure to dryness. Water 25 was added

(2 ml) and methanol (15 ml) to the residue and then neutralized by the addition of 2 N sodium hydroxide solution. The above was evaporated under reduced pressure almost to dryness (a small amount of water remained) and the solid thus obtained was filtered off with suction (transferred and washed with water (2 ml, 3 times)). The solid was dried with suction before further drying under vacuum to give the title compound as a white solid (71.5 mg).

MS calculated for (C15H23N5O3) + = 321

MS found (electrospray): (M + H) + = 322

1H NMR ((CD3) 2SO): 9.85 (1H, s), 6.40 (2H, s), 4.13 (2H, t), 3.65 (2H, m), 3.54 ( 2H, m), 3.32 (1H, m), 3.15 (1H, dd), 2.02 (1H, m), 1.69-1.56 (4H, m superimposed), 1.45- 1.32 (3H, overlapping m 10), 1.21 (1H, m), 0.91 (3H, t).

Example 13: 6-Amino-2-butoxy-9- [2- (tetrahydrofuran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one

2-Butoxy-8-methoxy-9- [2- (tetrahydrofuran-2-yl) ethyl] -9H-purin-6-amine (122 mg) was dissolved in methanol (2 ml) and 4 N hydrogen chloride was added in dioxane (1 ml). After 4 h, the reaction mixture was basified with 2N sodium hydroxide (2.2 ml) then the organic solvents were evaporated under reduced pressure. A few drops of 2N hydrochloric acid were added and the pH was adjusted again to 7-8 with saturated sodium hydrogen carbonate. The resulting solid was filtered, washed and dried to give the title compound as a solid, in a yield of 65mg. twenty

MS calculated for (C15H23N5O3) + = 321

MS found (electrospray): (M + H) + = 322

1H NMR ((CD3) 2SO): δ 9.83 (1H, s), 6.39 (2H, s), 4.14 (2H, t), 3.72 (4H, m), 3.56 (1H, m), 1.96 (1H , m), 1.80 (4H, m), 1.64 (2H, m), 1.38 (3H, m), 1.91 (3H, t).

25 mg of this enantiomer mixture was resolved by chiral HPLC on a Chiralpak AS column of 2 x 25 cm eluted with heptane: ethanol 7: 3 with a flow rate of 15 ml / minute for 30 minutes to give Example 13 Isomer 1 (9 , 9 mg) and Example 13 Isomer 2 (10.8 mg).

Example 13 Isomer 1: analytical chiral HPLC (Chiralpak AS column 25 x 0.46 cm, heptane: ethanol 7: 3 eluting at 1 ml / minute, 30 minute cycle): tRET = 10.8 minutes. 30

LCMS (Procedure A): tRET = 2.78 minutes; MH + = 322

Example 13 Isomer 2: analytical chiral HPLC (Chiralpak AS column 25 x 0.46 cm, heptane: ethanol 7: 3 eluting at 1 ml / minute, 30 minute cycle): tRET = 15.8 minutes.

LCMS (Procedure A): tRET = 2.78 minutes; MH + = 322

Example 14: 6-Amino-2-butylamino-9- [2- (tetrahydrofuran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one

N2-Butyl-8-methoxy-9- [2- (tetrahydrofuran-2-yl) ethyl] -9H-purin-2,6-diamine (107 mg) was dissolved in methanol (2 ml) and hydrogen chloride was added 4 N in dioxane (1 ml). After 4 h the solvents were evaporated under reduced pressure and the residue was taken in water and made basic with 2 N sodium hydroxide. A few drops of 2 N hydrochloric acid were added and the pH was adjusted to 7-8 by adding saturated sodium hydrogen carbonate. The resulting solid was filtered, washed and dried to give the title compound as a solid, in a yield of 101 mg.

MS calculated for (C15H24N6O2) + = 320

MS found (electrospray): (M + H) + = 321 15

1H NMR ((CD3) 2SO): δ 9.51 (1H, s), 6.17 (1H, m), 5.94 (2H, s), 3.77-3.53 (5H, m), 3.16 (2H, m), 1 , 96 (1H, m), 1.80 (4H, m), 1.51-1.24 (5H, m), 0.88 (3H, t).

Example 15: 6-Amino-2-butoxy-9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin-8-one

 twenty

2-Butoxy-8-methoxy-9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -9H-purin-6-amine (108 mg) was dissolved in methanol (2 ml) and chloride was added of 4 N hydrogen in dioxane (1 ml). After 16 h, the reaction mixture was evaporated under reduced pressure, quenched with water, then saturated sodium hydrogen carbonate was added, and a solid precipitated. This was filtered, washed with water and dried. The solid was treated with hot methanol and filtered after allowing to cool to provide 66 mg of the title compound.

MS calculated for (C16H25N5O3) + = 335

MS found (electrospray): (M + H) + = 336

1H NMR ((CD3) 2SO): δ 9.85 (1H, s), 6.40 (2H, wide s), 4.15 (2H, t), 3.79 (1H, m), 3.68 (3H, m), 3.25 ( 1H, m), 2.99 (1H, m), 1.87 (1H, m), 1.64 (2H, m), 1.58-1.34 (7H, m), 1.14 (1H , m), 0.91 (3H, t).

Example 16: 6-Amino-2-butylamino-9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin-8-one

N2-Butyl-8-methoxy-9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -9H-purin-2,6-diamine (138 mg) was dissolved in methanol (2 ml) and was added 4 N hydrogen chloride in dioxane (1 ml). After 4 h the reaction mixture was evaporated under reduced pressure, quenched with water then basified with saturated sodium hydrogen carbonate. The resulting solid was filtered, washed and dried to give the title compound, in a yield of 105 mg.

MS calculated for (C16H26N6O2) + = 334

MS found (electrospray): (M + H) + = 335

1H NMR ((CD3) 2SO): δ 9.52 (1H, s), 6.14 (1H, t), 5.94 (2H, wide s), 3.78 (1H, m), 3.71 (1H, m), 3.62 ( 2H, m), 3.24 (1H, m), 3.16 (2H, m), 2.98 (1H, m), 1.87 (1H, m), 1.57-1.36 (15 7H, m), 1.29 (2H, m), 1.12 (1H, m), 0.88 (3H, t).

A sample of this mixture of enantiomers was resolved by chiral HPLC on a Chiralpak AS column of 2 x 25 cm eluted with heptane: ethanol 85: 15 with a flow rate of 15 ml / minute for 60 minutes providing Example 16 Isomer 1 (7, 6 mg) and Example 16 Isomer 2 (7.5 mg). twenty

Example 16 Isomer 1: analytical chiral HPLC (Chiralpak AS column 25 x 0.46 cm, heptane: ethanol 85:15 eluting at 1 ml / minute, 40 minute cycle): tRET = 24.2 minutes.

LCMS (Procedure A): tRET = 2.51 minutes; MH + = 335

Example 16 Isomer 2: analytical chiral HPLC (Chiralpak AS column 25 x 0.46 cm, heptane: ethanol 85:15 eluting at 1 ml / minute, 40 minute cycle): tRET = 29.0 minutes. 25

LCMS (Procedure A): tRET = 2.51 minutes; MH + = 335

Example 17: 6-Amino-2 - [(2,2-dimethylpentyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one

To a solution of 2 - [(2,2-dimethylpentyl) oxy] -8-methoxy-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine (116 mg) in dry MeOH ( 14.5 ml) 4 N HCl in 1,4-dioxane (2.48 ml) was added. The mixture was stirred at room temperature for 3 h. The reaction was neutralized to pH 7 with 2M sodium hydroxide solution and concentrated in vacuo to give an off-white solid. The solid was triturated with water (30 ml) and filtered under reduced pressure to give the title compound as an off-white solid (76 mg).

MS calculated for (C18H29N5O3) + = 363

MS found (electrospray): (M + H) + = 364

1H NMR ((CD3) 2SO): δ 9.86 (1H, s), 6.42 (2H, s), 3.87 (2H, s), 3.81 (2H, wide d), 10 3.60-3.52 (2H, m) , 3.29-3.15 (2H, m), 2.10-1.96 (1H, m), 1.50-1.40 (2H, m), 1.31-1.16 (6H, m), 0.96-0.81 (9H, m).

Example 18: 6-Amino-2- (pentylamino) -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one

 fifteen

To a solution of 8-methoxy-N2-pentyl-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-2,6-diamine (140 mg) in dry MeOH (15.7 ml) was added 4 N HCl in 1,4-dioxane (2.65 ml). The reaction mixture was stirred at room temperature for 3 h and then neutralized with 2M sodium hydroxide solution. The mixture was concentrated in vacuo and the residue was taken in water (20 ml). The mixture was filtered under reduced pressure to give the title compound (95-20 mg) as an off-white solid.

MS calculated for (C16H26N6O2) + = 334

MS found (electrospray): (M + H) + = 335

1H NMR ((CD3) 2SO): δ 9.55 (1H, s), 6.19 (1H, s), 5.96 (2H, s), 3.81 (2H, d), 3.50 (2H, d), 3.27-3 , 07 (4H, m), 2.10-1.96 (1H, m), 1.55-1.37 (4H, m), 1.35-1.13 (6H, m), 0.92 -0.79 (3H, 25 m).

Example 19: 6-Amino-2 - [(3-methylbutyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-

purin-8-one

To a solution of 2 - [(3-methylbutyl) oxy] -8-methoxy-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine (52 mg) in dry MeOH (5, 7 ml) 4 N HCl in 1,4-dioxane (0.971 ml) was added and the reaction mixture was stirred at room temperature for 3 h. The reaction was neutralized at 5 pH 7 with 2M sodium hydroxide solution and concentrated in vacuo to provide a white solid. The solid was washed with water (20 ml) and filtered under reduced pressure to give the title compound as an off-white solid (31 mg).

MS calculated for (C16H25N5O3) + = 335

MS found (electrospray): (M + H) + = 336 10

1H NMR ((CD3) 2SO): δ 9.86 (1H, s), 6.40 (2H, s), 4.18 (2H, t), 3.81 (2H, dd), 3.55 (2H, t), 3.22 (2H , t), 2.09-1.95 (1H, m), 1.78-1.64 (1H, m), 1.61-1.51 (2H, m), 1.49-1.40 (2H, m), 1.29-1.15 (2H, m), 0.91 (6H, d).

Example 20: 6-Amino-2 - [(2-methylbutyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one

To a solution of 2 - [(2-methylbutyl) oxy] -8-methoxy-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine (41 mg) in dry MeOH (4, 5 ml) 4 N HCl in 1,4-dioxane (0.766 ml) was added and the reaction mixture was stirred at room temperature for 3 h. The reaction was neutralized with 2M sodium hydroxide solution and concentrated in vacuo. The resulting white residue was taken in water (20 ml) and filtered under reduced pressure to give the title compound as an off-white solid (20 mg).

MS calculated for (C16H25N5O3) + = 335

MS found (electrospray): (M + H) + = 336

1H NMR ((CD3) 2SO): δ 9.88 (1H, width), 6.41 (2H, s), 4.08-4.00 (1H, m), 3.97-3.90 25 (1H, m), 3.85-3 , 76 (2H, m), 3.56 (2H, d), 3.22 (2H, t), 2.10-1.95 (1H, m), 1.82-1.68 (1H, m ),

1.50-1.39 (3H, m), 1.29-1.12 (3H, m), 0.97-0.84 (6H, m).

Example 21: 6-Amino-2 - [(1-methylbutyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one

 To a solution of 2 - [(1-methylbutyl) oxy] -8-methoxy-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-5 purin-6-amine (92 mg) in dry MeOH (9 , 9 ml) 4 N HCl in 1,4-dioxane (1.7 ml) was added and the reaction mixture was stirred at room temperature for 3 h. The reaction was neutralized to pH 7 with 2M sodium hydroxide solution and concentrated in vacuo to provide an off-white solid. The solid was triturated with water (30 ml) and filtered under reduced pressure to give the title compound as an off-white solid (55 mg). 10

MS calculated for (C16H25N5O3) + = 335

MS found (electrospray): (M + H) + = 336

1H NMR ((CD3) 2SO): δ 9.84 (1H, s), 6.36 (2H, s), 5.04-4.94 (1H, m), 3.86-3.76 (2H, m), 3.53 (2H, d), 3.21 (2H, t), 2.08-1.96 (1H, m), 1.68-1.55 (1H, m), 1.53-1.14 (10H, m) , 0.92-0.83 (3H, m). fifteen

Example 22: 6-Amino-2 - [(2-methylbutyl) amino] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one

 A mixture of 2-chloro-8-methoxy-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine (40 mg) in 2-methyl-1-butylamine (117 mg) was heated in a microwave at 170 ° C for 15-20 minutes. The mixture was concentrated in vacuo to provide a green oily residue that was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent. -60%) providing the title compound as an off-white solid (9 mg).

MS calculated for (C16H26N6O2) + = 334 25

MS found (electrospray): (M + H) + = 335

1H NMR ((CD3) 2SO): δ 9.60 (1H, wide), 6.18 (1H, t), 5.95 (2H, wide), 3.86-3.77

(2H, m), 3.50 (2H, d), 3.27-3.09 (3H, m), 3.00-2.89 (1H, m), 2.11-1.98 (1H , m), 1.67-1.55 (1H, m), 1.49-1.33 (3H, m), 1.28-1.02 (3H, m), 0.91-0.80 (6H, m).

 Example 23: 6-amino-2 - [(3-methylbutyl) amino] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one

 5

 A mixture of 2-chloro-8-methoxy-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine (45 mg) in 3-methyl-1-butylamine (0.234 ml) was heated in a microwave at 170 ° C for 10 minutes. The mixture was concentrated in vacuo to provide a green oily residue. This was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid) and acetonitrile (0.05% formic acid) as eluent (20-60%) to provide the title compound in form of a white solid (10 mg).

MS calculated for (C16H26N6O2) + = 334

MS found (electrospray): (M + H) + = 335

1H NMR ((CD3) 2SO): δ 9.61 (1H, s), 6.12 (1H, t), 5.97 (2H, s), 3.86-3.77 (2H, m), 3.50 (2H, d), 3 , 27-3.14 (4H, m), 2.13-1.95 (1H, m), 1.68-1.12 (7H, m), 0.96-0.79 (6H, m) . fifteen

Example 24: 6-Amino-2 - [(1-methylbutyl) amino] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one

 To a solution of 2-chloro-8-methoxy-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine (40 mg) in ethylene glycol (1.5 ml) was added 2-aminopentane (0.16 ml) and the mixture was heated in a microwave at 170 ° C for 2 x 30 minutes. Another portion of 2-aminopentane (0.08 ml) was added and the reaction was heated in a microwave at 180 ° C for 30 minutes. The mixture was taken in EtOAc (15 ml) and washed with water (3 x 15 ml). The organic phases were separated, dried over MgSO4, filtered and concentrated in vacuo to provide a brown residue. This was taken in DCM and concentrated in a vacuum oven to provide the title compound as a brown solid (18 mg).

MS calculated for (C16H26N6O2) + = 334

MS found (electrospray): (M + H) + = 335

1H NMR ((CD3) 2SO): δ 9.56 (1H, wide), 5.93 (2H, s), 5.88 (1H, d), 3.85-3.76 (2H, m), 3.50 (2H, d), 3 , 26-3.14 (2H, m), 2.09-1.97 (1H, m), 1.54-1.12 (9H, m), 1.05 (3H, d), 0.91 -0.82 (3H, m).

Example 25: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-5 purin-8-one

 To a solution of 2 - [(2-cyclopropylethyl) oxy] -8-methoxy-9- (tetrahydro-3-furanylmethyl) -9H-purin-6-amine (103.8 mg) in methanol (5 ml) was added 4N HCl in 1,4-dioxane (2 ml) and the reaction mixture was stirred at room temperature for 4 h. The reaction was evaporated under reduced pressure to provide a gum. Water (3 ml) was added to provide a white solid. The mixture was adjusted to pH 7 by adding a 2 N solution of sodium hydroxide and the white solid was filtered off with suction, then washed with a few drops of MeOH. The material was air dried with suction, then in a vacuum oven (50 ° C) to provide the title compound as a white solid (77 mg). fifteen

MS calculated for (C15H21N5O3) + = 319

MS found (electrospray): (M + H) + = 320

1H NMR ((CD3) 2SO): δ 9.89 (1H, s), 6.44 (2H, s), 4.19 (2H t), 3.80-3.72 (1H, m), 3.69-3.56 (4H, m ), 3.55-3.49 (1H, m), 2.75-2.63 (1H, m), 1.94-1.82 (1H, m), 1.68-1.53 (3H , m), 0.83-0.72 (1H, m), 0.47-0.37 (2H, m), 0.13-0.06 (2H, m). twenty

Example 26: 6-Amino-2-butyloxy-9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one

A solution of 2-butyloxy-8-methoxy-9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -9H-purin-6-amine (88 mg) in methanol (2 ml) was treated with 4 N HCl in 1,4-dioxane (1 ml) for 1 h. Reaction 25 was evaporated and the residue was treated with water, then made basic with saturated sodium bicarbonate solution. The resulting white solid was filtered, washed with water and dried to give the title compound (78.1 mg).

MS calculated for (C16H25N5O3) + = 335

MS found (electrospray): (M + H) + = 336

1H NMR ((CD3) 2SO): δ 9.80 (1H, s), 6.37 (2H, s), 4.14 (2H, t), 3.87-3.62 (3H, m), 3.30-3.16 (2H, m), 1.80-1.50 (6H, m), 1.48-1.31 (5H, m), 1.23-1.10 (1H, m), 0.91 (3H, t) .

24 mg of this enantiomer mixture was resolved by chiral HPLC on a Chiralpak AD column of 2 x 25 cm eluting with heptane: ethanol 90:10 with a flow rate of 15 ml / minute for 40 minutes to give Example 26 Isomer 1 (12 , 2 mg) and Example 26 Isomer 2 (9.4 mg).

Example 26 Isomer 1: analytical chiral HPLC (Chiralpak AD column 25 x 0.46 cm, heptane: ethanol 90:10 eluting at 1 ml / minute, 30 minute cycle): tRET = 12.3 minutes. 10

LCMS (Procedure A): tRET = 2.97 minutes; MH + = 336

Example 26 Isomer 2: analytical chiral HPLC (Chiralpak AD column 25 x 0.46 cm, heptane: ethanol 90: 10 eluting at 1 ml / minute, 30 minute cycle): tRET = 15.4 minutes.

LCMS (Procedure A): tRET = 2.97 minutes; MH + = 336

Example 27: 6-Amino-2-butyloxy-9 - [(2,2-dimethyltetrahydro-2H-pyran-4-yl) methyl] -7,9-dihydro-15 8H-purin-8-one

A solution of 2-butyloxy-9 - [(2,2-dimethyltetrahydro-2H-pyran-4-yl) methyl] -8-methoxy-9H-purin-6-amine (161 mg) in methanol (1 ml) is treated with 4 N HCl in 1,4-dioxane (0.5 ml) for 1 h. The reaction was evaporated and the residue was treated with water, then made basic with saturated sodium bicarbonate solution. The resulting solid was filtered, washed with water and dried to give the title compound (122 mg).

MS calculated for (C17H27N5O3) + = 349

MS found (electrospray): (M + H) + = 350

1H NMR ((CD3) 2SO): δ 9.85 (1H, s), 6.40 (2H, s), 4.21-4.10 (2H, m), 3.62-3.42 (4H, 25 m), 2.27-2 , 14 (1H, m), 1.69-1.59 (2H, m), 1.46-1.33 (4H, m), 1.14-0.98 (8H, m), 0.95 -0.88 (3H, m).

A sample of this mixture of enantiomers was resolved by chiral HPLC on a Chiralpak AS column of 2 x 25 cm eluting with heptane: ethanol 95: 5 with a flow rate of 15 ml / minute for 60 minutes providing Example 27 Isomer 1 (9, 07 mg) and Example 30 27 Isomer 2 (7.7 mg).

Example 27 Isomer 1: analytical chiral HPLC (Chiralpak AS column 25 x 0.46 cm, heptane: ethanol 95: 5 eluting at 1 ml / minute, 40 minute cycle): tRET = 18.6 minutes.

LCMS (Procedure A): tRET = 2.81 minutes; MH + = 350

Example 27 Isomer 2: analytical chiral HPLC (Chiralpak AS column 25 x 0.46 cm, heptane: ethanol 95: 5 eluting at 1 ml / minute, 40 minute cycle): tRET = 23.5 minutes. 5

LCMS (Procedure A): tRET = 2.81 minutes; MH + = 350

Example 28: 6-Amino-2- (butylamino) -9 - [(2,2-dimethyltetrahydro-2H-pyran-4-yl) methyl] -7,9-dihydro-8H-purin-8-one

A solution of N2-butyl-9 - [(2,2-dimethyltetrahydro-2H-pyran-4-yl) methyl] -8-methoxy-9H-purin-10 2,6-diamine (73 mg) in MeOH (2 ml) was treated with 4 N HCl in 1,4-dioxane (1 ml) and stirred for 4 h. The reaction was evaporated and the residue was treated with water, then made basic with saturated sodium bicarbonate solution. The resulting solid was filtered, washed with water and dried. The solid was precipitated again from ether / naphtha to give the title compound (37 mg). fifteen

MS calculated for (C17H28N6O2) + = 348

MS found (electrospray): (M + H) + = 349

1H NMR ((CD3) 2SO): δ 9.54 (1H, s), 6.17 (1H, wide t), 5.95 (2H, wide), 3.62-3.54 (1H, m), 3.52-3.39 (3H , m), 3.23-3.12 (2H, m), 2.29-2.14 (1H, m), 1.52-1.37 (4H, m), 1.36-1.23 (2H, m), 1.14-0.95 (8H, m), 0.92-0.83 (3H, m). twenty

Example 29: 6-Amino-2-butyloxy-9- [2- (tetrahydro-3-furanyl) ethyl] -7,9-dihydro-8H-purin-8-one

A solution of 2-butyloxy-8-methoxy-9- [2- (tetrahydro-3-furanyl) ethyl] -9H-purin-6-amine (102 mg) in methanol (1 ml) was treated with 4N HCl in 1,4-dioxane (0.5 ml) for 1.5 h. The reaction was evaporated and the residue was treated with water, then made basic with saturated sodium bicarbonate solution. The resulting solid was filtered, washed with water and dried to give the title compound (65 mg).

MS calculated for (C15H23N5O3) + = 321

MS found (electrospray): (M + H) + = 322

1H NMR ((CD3) 2SO): δ 9.86 (1H, s), 6.41 (2H, s), 4.19-4.09 (2H, m), 3.83-3.53 (5H, m), 3.25-3, 17 (1H, m), 2.12-1.94 (2H, m), 1.77-1.58 (4H, m), 1.51-1.31 (3H, m), 0.91 ( 3H, t).

Example 30: 6-Amino-2- (butylamino) -9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one

A solution of N2-butyl-8- (methoxy) -9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -9H-purin-2,6-diamine (54 mg) in methanol (1 ml ) was treated with 4 N HCl in dioxin (0.5 ml) and rested for 1.5 h. The solvents were evaporated under reduced pressure and the residue was treated with water and made basic with saturated aqueous sodium bicarbonate. The precipitated material was filtered, washed with water and dried to give the title compound as a solid, in a yield of 22.5 mg.

MS calculated for (C16H26N6O2) + = 334

MS found (electrospray): (M + H) + = 335

1H NMR ((CD3) 2SO): δ 9.49 (1H, s), 6.14 (1H, m), 5.93 (2H, m), 3.83 (1H, m), 3.78-15 3.58 (2H, m), 3.34-3.12 (4H, m), 1.79-1.10 (12H, m), 0.87 (3H, t).

Example 31: 6-Amino-2- (butylamino) -9- [2- (tetrahydro-3-furanyl) ethyl] -7,9-dihydro-8H-purin-8-one

A solution of N2-butyl-8- (methoxy) -9- [2- (tetrahydro-3-furanyl) ethyl] -9H-purin-2,6-diamine 20 (181 mg) in methanol (1 ml) was treated with 4 N HCl in 1,4-dioxane (0.5 ml) for 1.5 h. The reaction was evaporated and the residue was treated with water, then made basic with saturated sodium bicarbonate solution. The resulting solid was filtered, washed with water and dried to give the title compound (111 mg).

MS calculated for (C15H24N6O2) + = 320 25

MS found (electrospray): (M + H) + = 321

1H NMR ((CD3) 2SO): δ 9.54 (1H, s), 6.17 (1H, broad t), 5.97 (2H, s), 3.79 (1H, m), 3.74-3.54 (4H, m), 3.18 (3H, m), 2.02 (2H, m), 1.70 (2H, m), 1.45 (3H, m), 1.28 (2H, m), 0.87 (3H , t).

Example 32: 6-Amino-2- (butyloxy) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one, 30

Isomer 1

Example 32 (Isomer 1):

2-Butoxy-8-methoxy-9- (tetrahydrofuran-3-ylmethyl) -9H-purin-6-amine (isomer 1, 176 mg) was suspended in methanol (2 ml) and 4 N HCl in dioxane (1 ml) The resulting clear solution 5 was evaporated under reduced pressure and the residue was treated with water and basified with saturated aqueous sodium bicarbonate. The solid obtained was filtered, washed with water and dried to give the title compound yield 145 mg.

MS calculated for (C14H21N5O3) + = 307

MS found (electrospray): (M + H) + = 308 10

1H NMR ((CD3) 2SO): 9.88 (1H, s), 6.43 (2H, s), 4.14 (2H, t), 3.76 (1H, m), 3.68- 3.57 (4H, m), 3.52 (1H, m), 2.69 (1H, m), 1.88 (1H, m), 1.64 (3H, m), 1.38 (2H , m), 0.92 (3H, t).

Example 32, alternative procedure: 6-Amino-2- (butyloxy) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one (Isomer 1)

 fifteen

2- (Butyloxy) -8- (methoxy) -9- (tetrahydro-3-furanylmethyl) -9H-purin-6-amine (Isomer 1.54 g) was suspended in methanol (20 ml) and HCl was added 4 N in dioxane (4 ml) with stirring, providing a clear solution. After 6.5 h, the solvents were evaporated at reduced volume and stirring water was added, followed by neutralization with saturated sodium bicarbonate. The resulting off-white solid was filtered, washed with water and dried, with a yield of 1.26 g. This material was added portionwise to boiling methanol (130 ml), adding another 20 ml of methanol. The suspension was filtered, and the solid was treated with boiling methanol (20 ml) and added to the filtrate. This was boiled again, then allowed to cool while stirring and a white solid crystallized. This was filtered, washed with methanol and dried, yielding the title compound yield 932 mg. 25

MS calculated for (C14H21N5O3) + = 307

MS found (electrospray): (M + H) + = 308

1H NMR ((CD3) 2SO): δ 9.89 (1H, s), 6.43 (2H, s), 4.14 (2H, m), 3.81-3.72 (1H, m),

3.70-3.55 (4H, m), 3.55-3.48 (1H, m), 2.75-2.64 (1H, m), 1.94-1.83 (1H, m ), 1.70-1.58 (3H, m), 1.45-1.33 (2H, m), 0.96-0.88 (3H, q).

Example 33: 6-Amino-2- (butyloxy) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one, Isomer 2:

2-Butoxy-8-methoxy-9- (tetrahydrofuran-3-ylmethyl) -9H-purin-6-amine (Isomer 2, 178 mg) was suspended in methanol (2 ml) and 4 N HCl in dioxane was added ( 1 ml) The resulting clear solution was evaporated under reduced pressure and the residue was treated with water and basified with saturated aqueous sodium bicarbonate. The solid obtained was filtered, washed with water and dried to give the title compound (isomer 2), in a yield of 72 mg (low due to mechanical losses). 10

MS calculated for (C14H21N5O3) + = 307

MS found (electrospray): (M + H) + = 308

1H NMR ((CD3) 2SO): 9.88 (1H, s), 6.42 (2H, s), 4.15 (2H, t), 3.76 (1H, m), 3.68- 3.57 (4H, m), 3.52 (1H, m), 2.69 (1H, m), 1.88 (1H, m), 1.64 (3H, m), 1.38 (2H , m), 0.92 (3H, t).

Example 33, alternative procedure: 6-Amino-2- (butyloxy) -9- (tetrahydro-3-furanylmethyl) -15 7,9-dihydro-8H-purin-8-one (Isomer 2)

2- (Butyloxy) -8- (methoxy) -9- (tetrahydro-3-furanylmethyl) -9H-purin-6-amine (Isomer 2, 1.96 g) was suspended in methanol (20 ml) and HCl was added 4 N in dioxane (10 ml) with stirring providing a clear solution. After 1.5 h, the solvents were evaporated at reduced volume and water was added with stirring, followed by neutralization with saturated sodium bicarbonate. The resulting off-white solid was filtered, washed with water and dried, in a yield of 1.73 g. Initial attempts to recrystallize from methanol or ethanol were unsuccessful. The recovered material was dissolved in glacial acetic acid (10 ml) by heating but immediately precipitated by adding water (10 ml). The addition in addition to acetic acid (4 25 ml) and heating provided a clear solution, from which the product crystallized upon cooling. The solid was filtered, washed and dried, with a yield of 1.06 g (Harvest 1). A second crop was obtained from the filtrate upon standing, with a yield of 460 mg, which was dissolved in sodium hydroxide and precipitated by the addition of acetic acid and then the recovered solid was heated in methanol (20 ml) with more additions. of methanol (15 ml) to the boiling mixture providing a cloudy solution, which was allowed to cool. The resulting solid was removed by filtration, with a yield of 257 mg. This is

combined with the first batch of solid (Harvest 1) and added in portions to boiling methanol (130 ml) to provide a slightly cloudy solution. Upon cooling with stirring, a white solid crystallized which was removed by filtration, washed with methanol and dried, yielding the title compound yield 1.02 g.

MS calculated for (C14H21N5O3) + = 307 5

MS found (electrospray): (M + H) + = 308

1H NMR ((CD3) 2SO): δ 9.89 (1H, s), 6.43 (2H, s), 4.15 (2H, m), 3.81-3.72 (1H, m), 3.70-3.55 (4H, m), 3.55-3.48 (1H, m), 2.75-2.64 (1H, m), 1.94-1.83 (1H, m), 1.70-1.58 ( 3H, m), 1.45-1.33 (2H, m), 0.96-0.88 (3H, q).

Example 34: 6-Amino-2 - {[2- (ethyloxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-10 8H-purin-8-one

To a solution of 2- (2-ethoxyethoxy) -8-methoxy-9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine (240 mg) in dry methanol (10 ml) at temperature At room temperature and under nitrogen atmosphere, 4.0 M hydrogen chloride in 1,4-dioxane (4.0 ml) was added. The reaction was allowed to stir at room temperature for 3 hours. The reaction was neutralized by the addition of 2.0 M solution of sodium hydroxide and concentrated in vacuo. The residue was taken in water (15 ml) and the solid was filtered and washed with water (2x5 ml). The solid was dried in vacuo (60 ° C) for 30 minutes. This gave the title compound as an off-white solid (129 mg).

MS calculated for (C15H23N5O4) + = 337 20

MS found (electrospray): (M + H) + = 338

1H NMR ((CD3) 2SO): δ 9.92 (1H, s), 6.44 (2H, s), 4.25 (2H, s), 3.81 (2H, m), 3.63 (2H, m), 3.55 (2H , d), 3.47 (2H, q), 3.22 (2H, m), 2.03 (1H, m), 1.45 (2H, m), 1.22 (2H, m), 1 , 12 (3H, t).

Example 35: 6-Amino-2 - {[1-methyl-2- (methoxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-4-ylmethyl) -7.9-25 dihydro-8H-purin- 8-one

To a solution of 2 - {[1-methyl-2- (methoxy) ethyl] oxy} -8- (methoxy) -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine ( 260 mg) in dry methanol (10 ml) at room temperature and under nitrogen atmosphere 4.0 M hydrogen chloride in 1,4-dioxane (4.0 ml) was added. The reaction was allowed to stir at room temperature for 3 hours. The reaction was neutralized by the addition of 2.0 M sodium hydroxide solution and concentrated in vacuo. The residue was taken in water (15 ml) and the solid was filtered and washed with water (2x5 ml). The solid was dried in vacuo (60 ° C) for 30 minutes. This gave the title compound as an off-white solid (70 mg).

MS calculated for (C15H23N5O4) + = 337 10

MS found (electrospray): (M + H) + = 338

1H NMR ((CD3) 2SO): δ 9.89 (1H, s), 6.41 (2H, wide s), 5.13 (1H, m), 3.81 (2H, m), 3.55 (2H, d), 3.43 ( 2H, m), 3.27 (3H, s), 3.22 (2H, m), 2.02 (1H, m), 1.46 (2H, m), 1.24 (2H, m), 1.21 (3H, d).

Example 36: 6-Amino-2 - {[2- (ethyloxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-3-ylmethyl) -7,9-dihydro-15 8H-purin-8-one

To a solution of 2- (2-ethoxyethoxy) -8-methoxy-9- (tetrahydro-2H-pyran-3-ylmethyl) -9H-purin-6-amine (245 mg) in dry methanol (10 ml) at temperature At room temperature and under nitrogen atmosphere, 4.0 M hydrogen chloride in 1,4-dioxane (4.0 ml) was added. The reaction was allowed to stir at room temperature for 1 hour. The reaction was concentrated in vacuo and the resulting residue was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (10- 45%) providing a white solid. This was taken in water (15 ml) and neutralized by the addition of 2.0 M solution of sodium hydroxide. The solid was filtered and dried on the rotary evaporator (60 25

ºC) for 30 minutes (90 mg).

MS calculated for (C15H23N5O4) + = 337

MS found (electrospray): (M + H) + = 338

1H NMR ((CD3) 2SO): δ 9.90 (1H, s), 6.45 (2H, s), 4.25 (2H, m), 3.70-3.61 (5H, m), 3.55 (1H, m), 3 , 47 (2H, q), 3.30 (1H, m), 3.16 (1H, m), 2.03 (1H, m), 1.64 (2H, m), 1.40 (1H, m), 5 1.22 (1H, m), 1.11 (3H, t).

Example 37: 6-Amino-2 - {[1-methyl-2- (methoxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-3-ylmethyl) -7,9-dihydro-8H-purin-8 -ona

To a solution of 2 - {[1-methyl-2- (methoxy) ethyl] oxy} -8- (methyloxy) -9- (tetrahydro-2H-pyran-3-10 ylmethyl) -9H-purin-6-amine (290 mg) in dry methanol (12 ml) at room temperature and under nitrogen atmosphere 4.0 M hydrogen chloride in 1,4-dioxane (5.0 ml) was added. The reaction was allowed to stir at room temperature for 1 hour. The reaction was concentrated in vacuo and the resulting residue was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (10 -45%) providing a white solid. This was taken in water (15 ml) and neutralized by the addition of 2.0 M solution of sodium hydroxide. The solid was filtered and dried on the rotary evaporator (60 ° C) for 30 minutes (50 mg).

MS calculated for (C15H23N5O4) + = 337

MS found (electrospray): (M + H) + = 338 20

1H NMR ((CD3) 2SO): δ 9.90 (1H, s), 6.43 (2H, s), 5.12 (1H, m), 3.66 (2H, m), 3.55 (2H, m), 3.47 (1H , m), 3.38 (1H, m), 3.30 (1H, m), 3.27 (3H, s), 3.16 (1H, m), 2.02 (1H, m), 1 , 63 (2H, m), 1.40 (1H, m), 1.23 (1H, m), 1.20 (3H, t).

Example 38: 6-Amino-2 - [(cyclohexylmethyl) amino] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one

To a solution of 8-bromo-N2- (cyclohexylmethyl) -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-2,6-diamine (110 mg) in dry n-butanol (1.5 ml) 37% hydrochloric acid (1.5 ml) was added at room temperature. The reaction was heated at 100 ° C for six hours. The reaction was concentrated in vacuo, taken in water (5 ml) and neutralized by the addition of 2.0 M solution of sodium hydroxide. The resulting white precipitate was filtered. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (20-60%) to provide a white solid ( 20 mg)

MS calculated for (C18H28N6O2) + = 360

MS found (electrospray): (M + H) + = 361 10

1H NMR ((CD3) 2SO): δ 9.59 (1H, s), 6.21 (1H, s), 5.97 (2H, s), 3.81 (2H, m), 3.51 (2H, d), 3.21 (2H , m), 3.01 (2H, m), 2.04 (1H, m), 1.74-1.54 (5H, m), 1.52 (1H, m), 1.44 (2H, m), 1.28-1.04 (5H, m), 0.84 (2H, m).

Example 39: 6-Amino-2 - [(cyclopentylmethyl) amino] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one

To a solution of 8-bromo-N2- (cyclopentylmethyl) -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-2,6-diamine (40 mg) in dry n-butanol (0.5 ml) 37% hydrochloric acid (1.5 ml) was added at one time and at room temperature. The reaction was heated at 100 ° C for thirty minutes. The reaction was concentrated in vacuo and the product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) -acetonitrile (containing 0.05% formic acid) as eluent (20- 60%) providing the title compound as a white solid (10 mg).

MS calculated for (C17H26N6O2) + = 346

MS found (electrospray): (M + H) + = 347 25

1H NMR ((CD3) 2SO): δ 9.55 (1H, s), 6.19 (1H, s), 5.95 (2H, s), 3.81 (2H, m), 3.50 (2H, d), 3.21 (2H , m), 3.10 (2H, t), 2.13 (1H, m), 2.04 (1H, m), 1.69-1.59 (2H, m), 1.59-1, 50 (2H, m), 1.50-1.40 (4H, m), 1.21 (4H, m).

Example 40: 6-Amino-2 - [(2-cyclopropylethyl) amino] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one

To a solution of 2-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (550 mg) in dry ethylene glycol (27 ml) at room temperature was added 2-cyclopropylethylamine (740 mg) The reaction was heated at 120 ° C overnight. The reaction was cooled to room temperature, diluted with ethyl acetate (70 ml) and washed with water (3 x 20 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. This provided a viscous brown oil (580 mg) that was used in the next stage without further purification. To a solution of this oil (580 mg) in dry chloroform (6.5 ml) at room temperature was added NBS (320 mg) and the reaction was stirred for 15 minutes. The reaction was diluted with DCM (20 ml) and washed with water (10 ml). The organic phases were passed through a hydrophobic frit and concentrated in vacuo. This provided a light brown oil that was dissolved in dry methanol (5 ml) and at room temperature a solution of sodium methoxide (25% by weight in methanol, 1.3 ml) was added. The reaction was heated at 60 ° C, with a condenser attached, overnight. The reaction was cooled and concentrated in vacuo. The resulting orange residue was taken in ethyl acetate (30 ml) and washed with saturated aqueous ammonium chloride (20 ml). The organic phase was separated and washed further with water (2x15 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. To this material in dry methanol (3.5 ml) at room temperature was added trifluoroacetic acid (0.35 ml) at one time. The reaction was stirred at room temperature for 16 hours and concentrated in vacuo. This was taken in diethyl ether and triturated to provide a brown solid (227 mg). To a solution of this solid (160 mg) in 20 N, dry N-dimethylformamide (1.5 ml) at room temperature and under a nitrogen atmosphere was added potassium carbonate (240 mg). The reaction was stirred at 60 ° C for 1.5 hours and then cooled to 50 ° C. 4- (bromomethyl) tetrahydro-2H-pyran (59 µl) was added and the reaction was heated at 50 ° C overnight. An additional amount of 4- (bromomethyl) tetrahydro-2H-pyran (29 µl) was added and the reaction was heated at 70 ° C for 8 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (20 ml) and washed with water (5 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo to provide a brown oil. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (20-60%). The resulting clear viscous oil (50 mg) was dissolved in dry methanol (1.8 ml) at room temperature and under a nitrogen atmosphere. To this was added hydrogen chloride 4.0

M in 1,4-dioxane (0.8 ml). The reaction was allowed to stir at room temperature for 3 hours. The reaction was neutralized by the addition of saturated NaHCO3 solution and concentrated in vacuo. The white residue was taken in water (15 ml) and the solid was filtered. The solid was dried in vacuo (60 ° C) for 30 minutes. This gave the title compound as a beige solid (33 mg). 5

MS calculated for (C16H24N6O2) + = 332

MS found (electrospray): (M + H) + = 333

1H NMR ((CD3) 2SO): δ 9.55 (1H, s), 6.16 (1H, s), 5.97 (2H, s), 3.81 (2H, m), 3.50 (2H, d), 3.21 (4H , m), 2.03 (1H, m), 1.40 (4H, m), 1.21 (2H, m), 0.69 (1H, m), 0.38 (2H, m), 0 , 03 (2H, m). 10

Example 41 and Example 42: Isomers of 6-Amino-2- (butylamino) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one

The enantiomers of 6-amino-2- (butylamino) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one were separated by chiral chromatography (Chiralpak AS) using heptane-IPA 15 (containing 0.15% triethylamine) as eluent (20%). Thus racemic 6-amino-2- (butylamino) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one (700 mg) provided both enantiomers in the form of yellow liquids / orange. These were triturated with water (15 ml) to provide whitish whites, which were filtered and dried on a rotary evaporator (60 ° C) for 15 minutes. This provided Enantiomer 1 (163 mg) and Enantiomer 2 (145 mg), both containing some triethylamine. These were further purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (10-45%) to provide isomer 1 ( 40 mg) in the form of a white solid and isomer 2 (55 mg) in the form of a white solid. 25

Example 41 (Isomer 1):

MS calculated for (C14H22N6O2) + = 306

MS found (electrospray): (M + H) + = 307

1H NMR ((CD3) 2SO): δ 9.67 (1H, s), 6.43 (1H, m), 6.21 (1H, m), 3.75 (2H, m), 3.61 (4H, m), 3.53 (1H , m), 3.18 (2H, m), 2.68 (1H, m), 1.86 (1H, m), 1.64 (1H, m), 1.47 (2H, m), 1 , 30 (2H, m), 0.88 (3H, t).

Example 42 (Isomer 2):

MS calculated for (C14H22N6O2) + = 306

MS found (electrospray): (M + H) + = 307

1H NMR ((CD3) 2SO): δ 9.69 (1H, s), 6.44 (1H, m), 6.22 (1H, m), 3.75 (2H, m), 3.61 (4H, m), 3.52 (1H , m), 3.18 (2H, m), 2.68 (1H, m), 1.86 (1H, m), 1.64 (1H, m), 1.47 (2H, m), 1 , 30 5 (2H, m), 0.88 (3H, t).

Example 41 alternative procedure: 6-Amino-2- (butylamino) -9- [tetrahydro-3-furanylmethyl] -7,9-dihydro-8H-purin-8-one, Isomer 1

To a solution of N2-butyl-8- (methoxy) -9- [tetrahydro-3-furanylmethyl] -9H-purin-2,6-diamine, 10 Isomer 1 (2.79 g) in dry methanol (100 ml) at room temperature and under nitrogen atmosphere 4.0 M hydrochloric acid in 1,4-dioxane (28 ml) was added. The reaction was allowed to stir at room temperature for 2 hours. The reaction was neutralized by the addition of 2.0 M sodium hydroxide solution and concentrated in vacuo to provide an off-white residue. The residue was taken in water (30 ml) and the solid was filtered and washed with water (15 ml). The beige solid was dried on a rotary evaporator (60 ° C) for 30 minutes. This was crystallized from water / ethanol (1: 1, 35 ml) to provide a white solid (1.3 g). This was only partially crystalline. Recrystallization of this compound with water / ethanol (1: 1, 80 ml) provided an off-white solid that was dried on the rotary evaporator (60 ° C) for 1 hour (1.2 g, 100% e.e.).

MS calculated for (C14H22N6O2) + = 306 20

MS found (electrospray): (M + H) + = 307

1H NMR ((CD3) 2SO): δ 9.57 (1H, s), 6.18 (1H, m), 5.97 (2H, m), 3.75 (1H, m), 3.64-3.56 (4H, m), 3 , 52 (1H, m), 3.16 (2H, m), 2.69 (1H, m), 1.86 (1H, m), 1.64 (1H, m), 1.46 (2H, m), 1.29 (2H, m), 0.88 (3H, t).

Example 42 alternative procedure: 6-Amino-2- (butylamino) -9- [tetrahydro-3-25 furanylmethyl] -7,9-dihydro-8H-purin-8-one, Isomer 2

To a solution of N2-butyl-8- (methoxy) -9- [tetrahydro-3-furanylmethyl] -9H-purin-2,6-diamine, Isomer 2 (3 g) in dry methanol (100 ml) at room temperature and under nitrogen atmosphere 4.0 M hydrochloric acid in 1,4-dioxane (30 ml) was added. The reaction was allowed to stir at room temperature for 2 hours. The reaction was neutralized by the addition of 2.0 M solution of sodium hydroxide and concentrated in vacuo to give an off-white residue. The residue was taken in water (30 ml) and the solid was filtered and washed with water (15 ml). The beige solid was dried on a rotary evaporator (60 ° C) for 30 minutes. This was recrystallized from water / ethanol (1: 1, 40 ml) to provide a white solid (1.5 g). This was only partially crystalline. Recrystallization of this compound with water / ethanol (1: 1, 80 ml) provided an off-white solid that was dried on the rotary evaporator (60 ° C) for 1 hour (1.3 g). 10 This was only partially crystalline. Recrystallization of this compound was repeated with water / ethanol (1: 1, 80 ml) which provided an off-white solid that was dried on the rotary evaporator (60 ° C) for 1 hour (1.3 g, 91% e.e.).

MS calculated for (C14H22N6O2) + = 306

MS found (electrospray): (M + H) + = 307 15

1H NMR ((CD3) 2SO): δ 9.57 (1H, s), 6.19 (1H, m), 5.97 (2H, m), 3.75 (1H, m), 3.67-3.48 (5H, m), 3 , 16 (2H, m), 2.68 (1H, m), 1.85 (1H, m), 1.64 (1H, m), 1.46 (2H, m), 1.29 (2H, m), 0.87 (3H, t).

Example 43: 6-Amino-2 - [(2-methylpropyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one

8-Bromo-2 - [(2-methylpropyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine (100 mg) in n-butanol (2 ml) was subjected at reflux with concentrated hydrochloric acid (2 ml) at 100 ° C (external temperature) for 3 hours. The reaction mixture was evaporated under reduced pressure to dryness. A small volume of water and an equivalent volume of methanol were then added to the reaction mixture, providing a suspension that was then neutralized by the addition of 2M sodium hydroxide (from pH ~ 3 to 7). This was then evaporated under reduced pressure to provide a beige solid that was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent ( 20-60%). This gave the title compound (13 mg) as a white solid.

1H NMR ((CD3) 2SO): 9.95 (1H, s), 6.50 (2H, wide s), 3.96-3.92 (2H, m), 3.85-3.78 ( 2H, m), 3.57-3.55 (2H, m, [superimposed by water]), 3.27-3.18 (2H, m), 2.09-1.92 (2H, m) , 1.50-1.42 (2H, m), 1.29-1.15 (2H, m), 0.98-0.92 (6H, m).

MS calculated for (C15H23N5O3) + = 321

MS found (electrospray): (M + H) + = 322 5

Example 44: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one

2 - [(2-Cyclopropylethyl) oxy] -8- (methoxy) -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine (0.1259 g) was dissolved in methanol (5 ml) and 4N hydrogen chloride in 1,4-dioxane (2-10 ml) was added. The reaction was stirred at room temperature for 4 hours. The reaction mixture was evaporated under reduced pressure to provide a solid which was then suspended in water (1 ml) and a small amount of methanol (2-3 ml). This was then neutralized (at pH 7) by the addition of 2N sodium hydroxide. The suspension was evaporated almost to dryness under reduced pressure and then the solid was suspended in water (3 ml). The solid was filtered off with suction and washed with a few drops of methanol before air drying with suction. This material was then dried under constant weight under vacuum at 50 ° C to provide the title compound (94 mg).

1H NMR ((CD3) 2SO): 9.87 (1H, s), 6.42 (2H, s), 4.25-4.16 (2H, m), 3.86-3.78 (2H , m), 3.59-3.53 (2H, m), 3.27-3.18 (2H, m) 2.09-1.96 (1H, m), 1.61-1.53 ( 2H, m) 1.50-1.41 (2H, m), 20 1.29-1.14 (2H, m), 0.82-0.72 (1H, m), 0.45-0, 39 (2H, m) 0.13-0.07 (2H, m).

CLEM HE101125-2 MS calculated for (C16H23N5O3) + = 333

MS found (electrospray): (M + H) + = 334

Example 45: 6-Amino-2 - [(cyclohexylmethyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one

2 - [(Cyclohexylmethyl) oxy] -8- (methoxy) -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine (RS105369-181A2) (0.1657 g) was dissolved in methanol (5 ml) and then 4 N hydrogen chloride in 1,4-dioxane (2 ml) was added. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then evaporated under reduced pressure to provide a solid which was then suspended in water (1 ml) and methanol (~ 2-3 ml) before being neutralized (at pH 7) by the addition of 2 N sodium hydroxide. The resulting mixture was evaporated almost to dryness before being suspended in water (3 ml) and the solid was filtered off with suction. This solid was then washed with a few drops of methanol and then air dried with suction before finally drying under constant weight under vacuum at 50 ° C. This gave the title compound as a white solid (134 mg). 10

1H NMR ((CD3) 2SO): 9.86 (1H, s), 6.41 (2H, s), 3.99-3.93 (2H, m), 3.85-3.78 (2H , m), 3.59-3.52 (2H, m), 3.27-3.18 (2H, m), 2.09-1.96 (1H, m), 1.79-1.60 (6H, m superimposed), 1.50-1.41 (2H, m), 1.29-1.09 (5H, m superimposed), 1.06-0.93 (2H, m).

MS calculated for (C18H27N5O3) + = 361

MS found (electrospray): (M + H) + = 362 15

Example 46: 6-Amino-2 - {[2- (methoxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one

8- (Methoxy) -2 - {[2- (methoxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine (0.1434 g) was dissolved in methanol (5 ml) and treated with 4 N hydrogen chloride in 1,4-dioxane 20 (2 ml). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated under reduced pressure to provide a solid, which was suspended in water (1 ml) and methanol (2-3 ml) before adding 2 N sodium hydroxide to neutralize (at pH 7). After evaporating the suspension almost to dryness under reduced pressure, the solid was suspended in water (3 ml) and filtered with suction and then washed with a few drops of methanol. This solid 25 was dried under constant weight under vacuum at 50 ° C after initially drying in air with suction. This provided the title compound as a white solid (94 mg).

1H NMR ((CD3) 2SO): 9.89 (1H, s), 6.44 (2H, wide s), 4.30-4.22 (2H, m) 3.86-3.77 (2H , m), 3.65-3.87 (4H, m superimposed), 3.29 (3H, s), 3.27-3.17 (2H, m), 2.10-1.96 (1H, m), 1.50-1.40 (2H, m), 1.29-1.15 (2H, m). 30

MS calculated for (C14H21N5O4) + = 323

MS found (electrospray): (M + H) + = 324

Example 47: 6-Amino-2 - {[2- (methoxy) ethyl] oxy} -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one

 5

8- (Methoxy) -2 - {[2- (methoxy) ethyl] oxy} -9- (tetrahydro-3-furanylmethyl) -9H-purin-6-amine (0.1233 g) was dissolved in methanol (5 ml ). To this solution was added 4N hydrogen dioxane (2 ml), stirred at room temperature for 4 hours. The reaction mixture was evaporated under reduced pressure to provide a gum. Water (3 ml) was added to this material to provide a solution, which was then neutralized (at pH 7) using 2 N sodium hydroxide. This provided a white solid that was filtered with suction and then washed with a few drops of methanol. . The solid was then air dried with suction before drying under vacuum at 50 ° C for 2 hours. This gave the title compound as a white solid (86 mg).

1H NMR ((CD3) 2SO): 9.92 (1H, s), 6.46 (2H, s), 4.29-4.23 (2H, m), 3.80-3.72 (1H , m), 3.69-3.56 (6H, m superimposed), 3.55-3.48 (1H, m), 3.28 (3H, s), 2.75-2.63 (1H, m), 1.94-1.83 (1H, m), 1.68-1.58 (1H, m).

MS calculated for (C13H19N5O4) + = 309

MS found (electrospray): (M + H) + = 310

Example 48: 6-Amino-2 - [(tetrahydro-2-furanylmethyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one

8- (Methoxy) -2 - [(tetrahydro-2-furanylmethyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine (0.1500 g) was dissolved in methanol (10 ml). To this solution was added 4 N hydrogen chloride in 1,4-dioxane (2 ml). The reaction mixture was stirred for 5 hours at room temperature. The reaction mixture was evaporated under reduced pressure and then water (3 ml) and methanol (3 ml) was added to the residue to provide a finely suspended suspension.

fractional This was neutralized (at pH 7) by the addition of 2N sodium hydroxide and then evaporated under reduced pressure to dryness. Water (3 ml) was then added to the residue and the resulting white solid suspension was isolated by suction filtration. The solid was washed with methanol (1 ml) and then air dried with suction. The solid was then further dried under constant weight under vacuum at 50 ° C (~ 1 hour). This gave the title compound as a white solid (0.1130 g)

1H NMR ((CD3) 2SO): 9.88 (1H, s), 6.44 (2H, s), 4.15-4.06 (3H, overlapping m + s), 3.86-3, 73 (3H, m superimposed), 3.69-3.62 (1H, m), 3.59-3.53 (2H, m), 3.28-3.15 (2H, m), 2.10 -1.76 (4H, m), 1.67-1.56 (1H, m), 1.50-1.41 (2H, m), 1.29-1.16 (2H, m).

MS calculated for (C16H23N5O4) + = 349 10

MS found (electrospray): (M + H) + = 350

Example 49: 6-Amino-2- (butyloxy) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one hydrochloride salt

To 6-Amino-2- (propyloxy) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one (52.6 mg) an excess of hydrogen chloride was added 4 N in 1,4-dioxane (1 ml). The resulting solution was evaporated under reduced pressure (after 5 minutes) to provide a colorless gum containing some crystals. To this material was added diethyl ether to triturate 1,4-dioxane, providing a solid solid on scraping. Then, evaporation to dryness under reduced pressure for 2 hours (water bath at 50 ° C, minimum vacuum ~ 38 mbar) gave the title compound (61 mg) a fluid off-white solid.

1H NMR ((CD3) 2SO): 10.37 (1H, s), 6.88 (1H, very wide s), 5.46 (represents 1H, very wide s [seems to interfere with a peak of water from the DMSO]), 4.26-4.19 (2H, m), 3.80-3.72 (1H, m), 3.71-3.56 (4H, m superimposed), 3.54-3, 48 (1H, m), 2.74-2.63 (1H, m), 1.94-1.84 (1H, m), 1.71-1.59 (3H, overlapping m), 1.46 -1.34 (2H, m), 0.96-0.88 (3H, m). 25

MS calculated for (C14H21N5O3) + = 307

MS found (electrospray): (M + H) + = 308

Elemental analysis

 Calculated (%)

 Found (%) Average found (%)

 C

 48.91 C 48.60 48.46 C 48.53

 H

 6.45 H 6.29 6.30 H 6.30

 N

 20.37 N 19.90 19.77 N 19.84

 Cl

 10.31 Cl 10.48 10.0 * Cl 10.24

Sample weight <3 mg

Example 50: 6-Amino-2- (butylamino) -9- [3- (tetrahydro-2H-pyran-3-yl) propyl] -7,9-dihydro-8H-purin-8-one

To a solution of N2-butyl-8- (methoxy) -9- [3- (tetrahydro-2H-pyran-3-yl) propyl] -9H-purin-2,6-5 diamine (198 mg) in dry methanol (20.8 ml) 4.0 M hydrochloric acid in 1,4-dioxane (3.6 ml) was added at one time. The reaction was allowed to stir at room temperature for 4 hours. The reaction was neutralized by the addition of 2.0 M solution of sodium hydroxide and concentrated in vacuo to provide an off-white solid. Water was added to this solid, triturated, and the solid was filtered under vacuum until it dried. This gave the title compound 10 as an off-white solid (151 mg).

MS calculated for (C17H28N6O2) + = 348

MS found (electrospray): (M + H) + = 349

 1 H NMR (DMSO): δ 9.52 (1H, s), 6.15 (1H, s), 5.94 (2H, s), 3.71 (2H, m), 3.58 (2H, m), 3.27-3 , 12 (3H, m), 2.91 (1H, m), 1.77 (1H, m), 1.69-1.55 (2H, m), 1.54-1.39 (5H, m ), 1.35-15 1.22 (2H, m), 1.16-0.99 (3H, m), 0.88 (3H, m).

Example 51: 6-Amino-9- (tetrahydro-2H-pyran-4-ylmethyl) -2 - [(tetrahydro-2H-pyran-2-ylmethoxy] -7,9-dihydro-8H-purin-8-one

To a solution of 8- (methoxy) -9- (tetrahydro-2H-pyran-4-ylmethyl) -2 - [(tetrahydro-2H-pyran-2-ylmethoxy] -9H-purin-6-amine (704 mg) in dry methanol (71 ml) 4.0 M hydrogen chloride in 1,4-dioxane (12.2 ml) was added.The reaction was allowed to stir at room temperature for 6 hours.The reaction was neutralized by adding solution 2.0 M sodium hydroxide and concentrated in vacuo to provide an off-white residue.The residue was triturated in water, and the solid was filtered to give a brown solid (588 mg) The product was purified by C18 reverse phase chromatography. using water (containing 0.1% formic acid) and acetonitrile (containing 0.05% formic acid) as eluent (10-45%) to provide the title compound as a white solid (145 mg).

MS calculated for (C17H25N5O4) + = 363 10

MS found (electrospray): (M + H) + = 364

1H NMR ((CD3) 2SO): δ 9.88 (1H, s), 6.43 (2H, s), 4.07 (2H, d), 3.87 (1H, m), 3.81 (2H, m), 3.57 (1H , m), 3.55 (2H, d), 3.36 (1H, m), 3.22 (2H, m), 2.02 (1H, m), 1.79 (1H, m), 1 , 60 (1H, m), 1.51-1.41 (5H, m), 1.31-1.15 (3H, m).

Example 52: 6-Amino-2 - ({2 - [(1-methyl ethyl) oxy] ethyl} oxy) -9- (tetrahydro-2H-pyran-4-ylmethyl) -7.9-15 dihydro-8H-purin -8-one

To a solution of 2 - ({2 - [(1-methyl ethyl) oxy] ethyl} oxy) -8- (methoxy) -9- (tetrahydro-2H-pyran-4-ylmethyl) -9H-purin-6-amine (165 mg) in dry methanol (17 ml), 4.0 M hydrogen chloride in 1,4-dioxane (2.95 ml) was added at one time. The reaction was allowed to stir at room temperature 20 for 5 hours. The reaction was neutralized by the addition of 2.0 M solution of sodium hydroxide and concentrated in vacuo to provide an off-white solid. The solid was triturated in water, and filtered under vacuum, washing with more water, providing an off-white solid (120 mg).

MS calculated for (C16H25N5O4) + = 351 25

MS found (electrospray): (M + H) + = 352

1H NMR ((CD3) 2SO): δ 9.88 (1H, s), 6.43 (2H, s), 4.22 (2H, m), 3.81 (2H, m), 3.68-3.50 (5H, m), 3 , 22 (2H, m), 2.03 (1H, m), 1.45 (2H, m), 1.22 (2H, m), 1.09 (6H, d).

Example 53: 6-Amino-2- (butylamino) -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -7,9-dihydro-8H-purin-8-one

To a solution of N2-butyl-8- (methoxy) -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -9H-purin-2,6-diamine (172 mg) in methanol (15 , 2ml) at room temperature 4.0 M hydrogen chloride in 1,4-dioxane (2.86 ml, 11.42 mmol) was added to provide a colorless solution. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was neutralized with 2M NaOH and concentrated in vacuo to give a white solid. This solid was triturated in water and filtered under vacuum to give an off-white solid (85 mg).

MS calculated for (C18H30N6O2) + = 362

MS found (electrospray): (M + H) + = 363

1H NMR ((CD3) 2SO): δ 9.51 (1H, s), 6.14 (1H, m), 5.94 (2H, s), 3.70 (2H, m), 3.59 10 (2H, m), 3.26- 3.11 (3H, m), 2.90 (1H, m), 1.74 (1H, m), 1.60 (2H, m), 1.54-1.35 (5H, m), 1 , 35-0.96 (7H, m), 0.88 (3H, t).

Example 54: 6-Amino-2 - [(2-cyclopropylethyl) amino] -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one

 fifteen

To a solution of N2- (2-cyclopropylethyl) -8- (methoxy) -9- (tetrahydro-3-furanylmethyl) -9H-purin-2,6-diamine (209 mg) in methanol (21 ml) at room temperature 4.0 M hydrogen chloride in 1,4-dioxane (3.93 ml) was added to provide a colorless solution. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralized with 2M NaOH and concentrated in vacuo. The resulting solid was taken in water (50 ml) and filtered off to provide a white solid. This solid was recrystallized from ethanol: water (1: 1) and filtered to provide an off-white crystalline solid (105 mg).

MS calculated for (C15H22N6O2) + = 318

MS found (electrospray): (M + H) + = 319

1H NMR ((CD3) 2SO): δ 9.57 (1H, s), 6.17 (1H, m), 5.98 (2H, s), 3.75 (1H, m), 3.65-25

3.55 (4H, m), 3.53 (1H, m), 3.22 (2H, m), 2.69 (1H, m), 1.85 (1H, m), 1.64 (1H , m), 1.38 (2H, m), 0.68 (1H, m), 0.38 (2H, m), 0.02 (2H, m).

 Example 55: 6-Amino-2 - [(2-cyclopropylethyl) amino] -9- (tetrahydro-2H-pyran-3-ylmethyl) -7,9-dihydro-8H-purin-8-one

 5

To a solution of N2- (2-cyclopropylethyl) -8- (methoxy) -9- (tetrahydro-2H-pyran-3-ylmethyl) -9H-purin-2,6-diamine (198 mg) in methanol (19, 1 ml) at room temperature 4.0 M hydrogen chloride in 1,4-dioxane (3.57 ml) was added to provide a colorless solution. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralized with 2M NaOH and concentrated in vacuo. The resulting solid was taken in water (50 ml) and filtered off to provide a white solid. This solid was recrystallized from ethanol: water (1: 1) and filtered to give an off-white crystalline solid (113 mg).

MS calculated for (C16H24N6O2) + = 332

MS found (electrospray): (M + H) + = 333

1H NMR ((CD3) 2SO): δ 9.55 (1H, s), 6.15 (1H, m), 5.97 (2H, s), 3.72-3.61 (2H, m), 15 3.58-3.43 (2H , m), 3.29 (1H, m), 3.22 (2H, m), 3.15 (1H, m), 2.03 (1H, m), 1.71-1.57 (2H, m), 1.39 (3H, m), 1.21 (1H, m), 0.69 (1H, m), 0.38 (2H, m), 0.03 (2H, m).

Example 56: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one (Isomer 1)

 twenty

To a stirring suspension of 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -9- (tetrahydro-3-furanylmethyl) -9H-purin-6-amine (814 mg) in methanol (3 ml) 4N HCl in dioxane (3 ml) was added. After 3 h, the solvents were evaporated and the residue was treated with water and neutralized by adding saturated sodium bicarbonate with stirring. The resulting cream-colored solid was removed by filtration, washed with water and dried. The material was suspended in 1: 1 25 ethanol: water (42 ml) but did not dissolve when boiling / stirring. The complete solution was obtained by adding another 10 ml of ethanol. More water (3 ml) was added and the clear solution was allowed to cool to room temperature with stirring. The resulting cream solid was filtered, washed

with 1: 1 ethanol: water (10 ml) and dried, with a yield of 537 mg.

MS calculated for (C15H21N5O3) + = 319

MS found (electrospray): (M + H) + = 320

1H NMR ((CD3) 2SO): δ 9.89 (1H, s), 6.43 (2H, s), 4.23-4.15 (2H, m), 3.79-3.71 (1H, m), 3.69-3, 55 (4H, m), 3.54-3.48 (1H, m), 2.76-2.63 (1H, m), 1.94-1.82 (1H, m), 1.68- 1.51 (3H, 5 m), 0.83-0.71 (1H, m), 0.0.47-0.36 (2H, m), 0.14-0.04 (2H, m) .

Example 57: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- [tetrahydro-3-furanylmethyl] -7,9-dihydro-8H-purin-8-one (Isomer 2)

A 2 - [(2-Cyclopropylethyl) oxy] -8- (methoxy) -9- [tetrahydro-3-furanylmethyl] -9H-purin-6-amine, 10 Isomer 2 (1.45 g) in dry methanol (50 ml) at room temperature and under a nitrogen atmosphere, 4.0 M hydrochloric acid in 1,4-dioxane (14 ml) was added at one time. The reaction was stirred at room temperature for 4 hours. The reaction was neutralized by the addition of 2M aqueous solution of sodium hydroxide and concentrated in vacuo to provide an off-white residue. This was taken in water (40 ml) and filtered to provide a sand-colored solid. This was recrystallized from water: ethanol, 1: 1 (75 ml) to provide a beige solid (765 mg).

MS calculated for (C15H21N5O3) + = 319

MS found (electrospray): (M + H) + = 320

1H NMR ((CD3) 2SO): δ 9.79 (1H, s), 6.33 (2H, s), 4.09 (2H, t), 3.66 (1H, m), 3.58-3.47 20 (4H, m), 3.42 (1H, m), 2.60 (1H, m), 1.78 (1H, m), 1.53 (1H, m), 1.47 (2H, q), 0.67 (1H , m), 0.32 (2H, m), 0 (2H, m).

Example 58: 6-Amino-2- (butylamino) -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one hydrated hydrochloride

 25

6-Amino-2- (butylamino) -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one (1.00

g) in a round bottom flask (100 ml) it was dissolved (with ultrasound to decompose the solid) in an excess of 4N hydrogen chloride in 1,4-dioxane (15 ml). The solution soon formed a suspension that was stirred at room temperature (21 ° C) for 30 minutes before evaporating to dryness under reduced pressure. To the resulting solid was then added diethyl ether (~ 40 ml) to provide a suspension, which was then evaporated under reduced pressure at 18 mbar (water bath, 50 ° C) to provide an off-white solid (1.11 g). This solid was transferred to a round bottom flask (250 ml) equipped with magnetic stirrer and reflux condenser. 2-butanone (111 ml) was added to the flask and the resulting suspension was heated to reflux (external heating, 95 ° C). Then 2-butanol (racemic) was added portionwise (1 ml per addition) leaving the suspension back to reflux. After the addition of 10 14 ml of 2-butanol, a light tan solution was obtained which was refluxed for a few minutes, before removing the heat source and the solution was allowed to cool while stirring for a period of 21 hours . The resulting suspension was then filtered with suction and the resulting filter cake was then washed with a minimum volume of acetone. The filter cake was initially dried with suction, before further drying under vacuum at 50 ° C until it became solvent free. This gave the title compound (Lot A) as a white solid (470 mg).

MS calculated for (C15H24N6O2) + = 320

MS found (electrospray): (M + H) + = 321

1H NMR ((CD3) 2SO): 12.20 (1H, very wide s), 10.55 (1H, s), 7.77 (2H, wide s) 20 3.87-3.77 (2H, m), 3.61-3.53 (2H, m), 3.34-3.15 (4H, m partially overlaid), 2.07-1.94 (1H, m), 1.59-1, 43 (4H, m superimposed), 1.40-1.28 (2H, m), 1.28-1.15 (2H, m), 0.97-0.85 (3H, m). No interchangeable protons were observed.

A second crop (Lot B) was isolated from the filtrate by suction filtration and the resulting filter cake was dried with suction before further drying under vacuum at 50 ° C. The resulting slightly impure product (349 mg) was washed with acetone (4 ml) and then dried under vacuum at 50 ° C (18 hours). This provided little or no change in purity. This material (338 mg) was suspended in 2-butanone (35 ml) in a round bottom flask (100 ml) equipped with magnetic stirrer and reflux condenser. The resulting suspension was heated to reflux by stirring (external heating, 95 ° C) before adding 2-butanol 30 (racemic) (4 times, 1 ml) and the resulting suspension was allowed to return to reflux. After the addition of more 2-butanol (racemic, 0.26 ml) the resulting solution was refluxed for 5 minutes before removing the heat source and the solution was allowed to cool to room temperature for 21 hours.

This provided a thick suspension that was cooled in the refrigerator at 3 ° C for 35

2.5 hours The suspension was filtered with suction and the filter cake was washed with acetone (8 ml). The filter cake was air dried with suction and then further dried under vacuum at 50 ° C until it was without solvent. This provided the title compound (Lot B) (167 mg).

MS calculated for (C15H24N6O2) + = 320 5

MS found (electrospray): (M + H) + = 321

NMR ((CD3) 2SO): consistent with Lot A.

Additional corroboradote data:

Lot A Lot B

Found% Found% 10

C: 48.36, 48.43 (48.40) C: 48.54, 48.58 (48.56)

H: 7.02, 6.99 (7.01) H: 6.95, 6.97 (6.96)

N: 22.35, 22.33 (22.34) N: 22.39, 22.35 (22.37)

Cl: 9.07, 9.19 (9.13) Cl: 9.13, 9.03 (9.08)

It fits: C15H24N6O2. HCl H2O 15

Calculated% C: 48.06, H: 7.26, N: 22.42, Cl: 9.46

Example 59: 6-Amino-2- (butylamino) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one hydrochloride salt Isomer 1

A 6-amino-2- (butylamino) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one 20 (isomer 1) (1.0 g) at room temperature and in At nitrogen atmosphere, 4.0 M hydrochloric acid in 1,4-dioxane (10.61 ml) was added and the reaction was stirred for 30 minutes. The reaction was then concentrated in vacuo and left on the rotary evaporator for 2 hours at 50 ° C. The beige solid was recrystallized overnight from 2-butanone (18 ml). The crystals were collected by suction filtration and dried under vacuum at 50 ° C for 30 minutes (850 mg). 25

MS calculated for (C14H22N6O2) + = 306

MS found (electrospray): (M + H) + = 307

1H NMR ((CD3) 2SO): δ 12.37 (1H, wide s), 10.64 (1H, wide s), 7.85 (2H, wide m), 3.75 (1H, m), 3.69-3.56 (4H, m ), 3.51 (1H, m), 3.30 (2H, m), 2.66 (1H, m), 1.90 (1H, m), 1.63 (1H, m), 1.53 (2H, m), 1.34 (2H, m), 0.90 (3H, t). An interchangeable is not observed. 30

Example 60: 6-Amino-2- (butylamino) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-

Ona salt hydrochloride Isomer 2

A 6-amino-2- (butylamino) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one (isomer 2) (1.2 g) at room temperature and in atmosphere of nitrogen 4.0 M hydrochloric acid in 1,4-dioxane (12.73 ml) was added and the reaction was stirred for 30 minutes. The reaction was then concentrated in vacuo and left on the rotary evaporator for 2 hours at 50 ° C. The beige solid was recrystallized overnight from 2-butanone (18 ml). The crystals were collected by suction filtration and dried under vacuum at 50 ° C for 30 minutes (960 mg).

 MS calculated for (C14H22N6O2) + = 306 10

MS found (electrospray): (M + H) + = 307

1H NMR ((CD3) 2SO): δ 12.36 (1H, wide s), 10.62 (1H, wide s), 7.82 (2H, wide m), 3.75 (1H, m), 3.69-3.58 (4H, m ), 3.51 (1H, m), 3.30 (2H, m), 2.66 (1H, m), 1.90 (1H, m), 1.63 (1H, m), 1.53 (2H, m), 1.34 (2H, m), 0.90 (3H, t). An interchangeable is not observed.

Example 61: 6-Amino-2- (butylamino) -9- [3- (tetrahydro-2-furanyl) propyl] -7,9-dihydro-8H-purin-15 8-one

Prepared similarly to Example 97 from N2-butyl-8- (methyloxy) -9- [3- (tetrahydro-2-furanyl) propyl] -9H-purin-2,6-diamine.

LCMS (Procedure A): tRET = 2.50 minutes; MH + = 335 20

Example 62: 6-Amino-2- (butylamino) -9- [4- (tetrahydro-2-furanyl) butyl] -7,9-dihydro-8H-purin-8-one

To a solution of N2-butyl-8- (methyloxy) -9- [4- (tetrahydro-2-furanyl) butyl] -9H-purin-2,6-diamine (75 mg, 0.207 mmol) in methanol (10 ml ) at room temperature 4M HCl was added in 25

1,4-dioxane (1,324 ml, 5.30 mmol) providing a light straw colored solution. The reaction mixture was stirred at room temperature overnight (16 hours) when LCMS showed that the reaction was not complete. The solvent was removed overnight (16 hours) using a nitrogen blow evaporation unit after which the CLEM confirmed the presence of the desired product. This crude product was loaded in 5-methanol in an SPE cartridge with 5 g of aminopropyl and eluted with methanol for 20 minutes. The appropriate fractions were combined and evaporated in a stream of nitrogen to give the title compound as a white powder (49 mg).

LCMS (Procedure B): tRET = 1.06 minutes; MH + = 349

Example 63: 6-Amino-2- (butylamino) -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-10 purin-8-one

Prepared similarly to Example 73 from N2-butyl-8- (methyloxy) -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -9H-purin-2,6-diamine.

LCMS (Procedure B): tRET = 0.94 minutes; MH + = 321 15

Example 64: 6-Amino-2- (butylamino) -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8-one

Prepared similarly to Example 73 from N2-butyl-8- (methyloxy) -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -9H-purin-2,6-diamine. twenty

LCMS (Procedure B): tRET = 0.93 minutes; MH + = 321

Example 65: 6-Amino-2- (butylamino) -9- [3- (tetrahydro-3-furanyl) propyl] -7,9-dihydro-8H-purin-8-one

Prepared similarly to Example 129 from N2-butyl-8- (methyloxy) -9- [3-25 (tetrahydro-3-furanyl) propyl] -9H-purin-2,6-diamine.

LCMS (Procedure B): tRET = 0.97 minutes; MH + = 335

Example 66: 6-Amino-2- (butylamino) -9- [4- (tetrahydro-3-furanyl) butyl] -7,9-dihydro-8H-purin-8-one

Prepared similarly to Example 129 from N2-butyl-8- (methyloxy) -9- [4-5 (tetrahydro-3-furanyl) butyl] -9H-purin-2,6-diamine.

LCMS (Procedure B): tRET = 1.02 minutes; MH + = 349

Example 67: 6-Amino-2- (butylamino) -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -7,9-dihydro-8H-purin-8-one

 10

Prepared similarly to Example 129 from N2-butyl-8- (methyloxy) -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -9H-purin-2,6-diamine.

LCMS (Procedure B): tRET = 1.02 minutes; MH + = 349

Example 68: 6-Amino-2- (butylamino) -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -7,9-dihydro-8H-purin-8-one

 Prepared similarly to Example 69 from N2-butyl-8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -9H-purin-2,6-diamine.

LCMS (Procedure B): tRET = 1.26 minutes; MH + = 363

Example 69: 6-Amino-2- (butylamino) -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-20 purin-8-one

 To a solution of N2-butyl-8- (methyloxy) -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -9H-purin-2,6-diamine (93.13 mg, 0.257 mmol ) in methanol (10 ml) 4M HCl in dioxane (1.5 ml, 6 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated in a stream of nitrogen and the residue was redissolved in methanol (5 ml) and loaded into an SPE cartridge with 5 g of aminopropyl and eluted with methanol. The eluent was evaporated in a stream of nitrogen to give the title compound (64 mg).

LCMS (Procedure B): tRET = 1.10 minutes; MH + = 349

Example 70: 6-Amino-2- (butylamino) -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8-one

 10

 Prepared similarly to Example 69 from N2-butyl-8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -9H-purin-2,6-diamine.

LCMS (Procedure B): tRET = 1.19 minutes; MH + = 363

Example 71: 6-Amino-2- (butylamino) -9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-8-one

 To a solution of N2-butyl-9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -8- (methyloxy) -9H-purin-2,6-diamine (135 mg, 0.359 mmol) in methanol (10 ml) 4M solution of HCl in dioxane (2,241 ml, 8.96 mmol) was added and the mixture was allowed to stand at 20 ° C. After 6 hours the solvent was evaporated in a stream of nitrogen. The residue was loaded into methanol in an SPE cartridge with 10 g of aminopropyl and eluted with methanol. The solvent was removed by evaporation to give the title compound (129 mg).

LCMS (Procedure A): tRET = 2.63 minutes; MH + = 363

Example 72: 6-Amino-2- (butylamino) -9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8-one

4M HCl in 1,4-dioxane (3 ml, 12.00 mmol) was added in one portion to a stirring solution of N2-butyl-9- [3- (2,2-dimethyltetrahydro-2H-pyran-4 -yl) propyl] -8- (methyloxy) -9H-purin-2,6-diamine (40 mg, 0.102 mmol) in methanol (3 ml) at room temperature and the mixture was stirred under a nitrogen atmosphere overnight. The mixture was then concentrated and the residue was dissolved in MeOH: DCM (1: 1 5 ml) and loaded into an SPE cartridge with 2 g of aminopropyl. The cartridge was washed with MeOH: DCM (1: 1, 3 column volumes) and the desired fractions were concentrated in vacuo to provide material with purity of approximately 80%. This material was dissolved in DCM: MeOH (1: 1), applied to a 2 g SCX column and eluted first with MeOH: DCM (3 column volumes) and the product was then released by 2M ammonia in methanol: DCM (1: 1, 3 column volumes). The solvent was removed to provide the title compound as a yellow solid (14 mg).

LCMS (Procedure A): tRET = 2.77 minutes; MH + = 377

Example 73: 6-Amino-2- (butylamino) -9- [4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8-one

 fifteen

4M HCl in 1,4-dioxane (3 ml, 12.00 mmol) was added in one portion to a stirring solution of N2-butyl-9- [4- (2,2-dimethyltetrahydro-2H-pyran-4 -yl) butyl] -8- (methyloxy) -9H-purin-2,6-diamine (130 mg, 0.321 mmol) in methanol (3 ml) at room temperature and the mixture was stirred under a nitrogen atmosphere overnight. The mixture was then concentrated and the residue was dissolved in MeOH: DCM (1: 1 5 ml) and loaded into an SPE cartridge with 2 g of aminopropyl. The cartridge was washed with MeOH: DCM (1: 1, 3 column volumes) and the desired fractions were concentrated in vacuo to give the title compound as a yellow solid (102 mg).

LCMS (Procedure A): tRET = 2.93 minutes; MH + = 391

Example 74: 6-Amino-2- (butyloxy) -9- [3- (tetrahydro-2-furanyl) propyl] -7,9-dihydro-8H-purin-8-25 one

 Prepared similarly to Example 97 from 2- (butyloxy) -8- (methyloxy) -9- [3- (tetrahydro-2-furanyl) propyl] -9H-purin-6-amine.

LCMS (Procedure A): tRET = 2.85 minutes; MH + = 336

Example 75: 6-Amino-2- (butyloxy) -9- [4- (tetrahydro-2-furanyl) butyl] -7,9-dihydro-8H-purin-8-one

Prepared similarly to Example 62 from 2- (butyloxy) -8- (methyloxy) -9- [4-5 (tetrahydro-2-furanyl) butyl] -9H-purin-6-amine.

LCMS (Procedure B): tRET = 1.02 minutes; MH + = 350

Example 76: 6-Amino-2- (butyloxy) -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8-one

 10

Prepared similarly to Example 73 from 2- (butyloxy) -8- (methyloxy) -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -9H-purin-6-amine.

LCMS (Procedure B): tRET = 0.90 minutes; MH + = 322

Example 77: 6-Amino-2- (butyloxy) -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8-one

Prepared similarly to Example 73 from 2- (butyloxy) -8- (methyloxy) -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -9H-purin-6-amine.

LCMS (Procedure B): tRET = 0.90 minutes; MH + = 322

Example 78: 6-Amino-2- (butyloxy) -9- [3- (tetrahydro-3-furanyl) propyl] -7,9-dihydro-8H-purin-8-20 one

To a solution of 2- (butyloxy) -8- (methyloxy) -9- [3- (tetrahydro-3-furanyl) propyl] -9H-purin-6-amine (110 mg, 0.315 mmol) in methanol (9 ml ) at room temperature 4M HCl in dioxane (1.89 ml) was added. The light yellow solution is

stirred at room temperature for 18 hours and then neutralized with 2M sodium hydroxide solution and evaporated to provide a white solid. Trituration with water and filtration provided the title compound as a cream solid (74 mg).

LCMS (Procedure B): tRET = 0.94 minutes; MH + = 336

Example 79: 6-Amino-2- (butyloxy) -9- [4- (tetrahydro-3-furanyl) butyl] -7,9-dihydro-8H-purin-8-5 one

 Prepared similarly to Example 129 from 2- (butyloxy) -8- (methyloxy) -9- [4- (tetrahydro-3-furanyl) butyl] -9H-purin-6-amine.

LCMS (Procedure B): tRET = 1.00 minutes; MH + = 350 10

Example 80: 6-Amino-2- (butyloxy) -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -7,9-dihydro-8H-purin-8-one

 Prepared similarly to Example 129 from 2- (butyloxy) -8- (methyloxy) -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -9H-purin-6-amine. fifteen

LCMS (Procedure B): tRET = 1.06 minutes; MH + = 350

Example 81: 6-Amino-2- (butyloxy) -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -7,9-dihydro-8H-purin-8-one

 Prepared similarly to Example 69 from 2- (butyloxy) -8- (methyloxy) -9- [4-20 (tetrahydro-2H-pyran-2-yl) butyl] -9H-purin-6-amine.

LCMS (Procedure B): tRET = 1.10 minutes; MH + = 364

Example 82: 6-Amino-2- (butyloxy) -9- [3- (tetrahydro-2H-pyran-3-yl) propyl] -7,9-dihydro-8H-purin-8-one

Prepared similarly to Example 62 from 2- (butyloxy) -8- (methyloxy) -9- [3- (tetrahydro-2H-pyran-3-yl) propyl] -9H-purin-6-amine.

LCMS (Procedure B): tRET = 1.01 minutes; MH + = 350

Example 83: 6-Amino-2- (butyloxy) -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -7,9-dihydro-8H-purin-5 8-one

 To a solution of 2- (butyloxy) -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -9H-purin-6-amine (135 mg, 0.358 mmol) in Methanol (10 ml) 4M HCl in dioxane (2,235 ml, 8.94 mmol) was added and the mixture was allowed to stand at 20 ° C for 18 hours. The solvent was evaporated in vacuo 10 to provide a white solid that was charged in methanol in an SPE cartridge with 10 g of aminopropyl and eluted with methanol. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (50 mg).

LCMS (Procedure A): tRET = 3.14 minutes; MH + = 364 15

Example 84: 6-Amino-2- (butyloxy) -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8-one

 Prepared similarly to Example 69 from 2- (butyloxy) -8- (methyloxy) -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -9H-purin-6-amine. twenty

LCMS (Procedure B): tRET = 0.99 minutes; MH + = 350

Example 85: 6-Amino-2- (butyloxy) -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8-one

 Prepared similarly to Example 69 from 2- (butyloxy) -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -9H-purin-6-amine.

LCMS (Procedure B): tRET = 1.05 minutes; MH + = 364

Example 86: 6-Amino-2- (butyloxy) -9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-5 8H-purin-8-one

 Prepared similarly to Example 71 from 2- (butyloxy) -9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -8- (methyloxy) -9H-purin-6 -amine.

LCMS (Procedure A): tRET = 2.99 minutes; MH + = 364 10

Example 87: 6-Amino-2- (butyloxy) -9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8-one

 Prepared similarly to Example 72 from 2- (butyloxy) -9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -8- (methyloxy) -9H-purin-6 -amine. fifteen

LCMS (Procedure A): tRET = 3.12 minutes; MH + = 378

Example 88: 6-Amino-2- (butyloxy) -9- [4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8-one

 Prepared similarly to Example 73 from 2- (butyloxy) -9- [4- (2,2-20 dimethyltetrahydro-2H-pyran-4-yl) butyl] -8- (methyloxy) -9H-purin- 6-amine

LCMS (Procedure A): tRET = 3.30 minutes; MH + = 392

Example 89: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- [2- (tetrahydro-2-furanyl) ethyl] -7,9-dihydro-

8H-purin-8-one

 To a solution of 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -9- [2- (tetrahydro-2-furanyl) ethyl] -9H-purin-6-amine (88 mg, 0.253 mmol) in methanol (10 ml) at room temperature 4M HCl in 1.4 dioxane (2.106 ml, 8.42 mmol) was added to provide a light straw colored solution. The reaction mixture was stirred at room temperature overnight (16 hours) and then loaded in methanol onto an SPE cartridge with 5 g of aminopropyl and eluted with methanol. The filtrate was evaporated in a nitrogen blow evaporation unit to give the title compound as a white solid (41 mg).

LCMS (Procedure B): tRET = 0.95 minutes; MH + = 334 10

Example 90: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- [3- (tetrahydro-2-furanyl) propyl] -7,9-dihydro-8H-purin-8-one

 Prepared similarly to Example 97 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -9- [3- (tetrahydro-2-furanyl) propyl] -9H-purin-6-amine. fifteen

LCMS (Procedure A): tRET = 2.86 minutes; MH + = 348

Example 91: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- [4- (tetrahydro-2-furanyl) butyl] -7,9-dihydro-8H-purin-8-one

 Prepared similarly to Example 62 from 2 - [(2-cyclopropylethyl) oxy] -8-20 (methyloxy) -9- [4- (tetrahydro-2-furanyl) butyl] -9H-purin-6-amine .

LCMS (Procedure B): tRET = 1.03 minutes; MH + = 362

Example 92: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- [2- (tetrahydro-3-furanyl) ethyl] -7,9-dihydro-8H-purin-8-one

 Prepared similarly to Example 71 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -9- [2- (tetrahydro-3-furanyl) ethyl] -9H-purin-6-amine.

LCMS (Procedure A): tRET = 2.72 minutes; MH + = 334

Example 93: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -7.9-5 dihydro-8H-purin-8- ona

 Prepared similarly to Example 73 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -9H-purin- 6-amine

LCMS (Procedure B): tRET = 0.90 minutes; MH + = 334 10

Example 94: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8-one

 Prepared similarly to Example 73 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -9H-purin- 6-amine fifteen

LCMS (Procedure B): tRET = 0.90 minutes; MH + = 334

Example 95: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- [3- (tetrahydro-3-furanyl) propyl] -7,9-dihydro-8H-purin-8-one

 Prepared similarly to Example 78 from 2 - [(2-cyclopropylethyl) oxy] -8-20 (methyloxy) -9- [3- (tetrahydro-3-furanyl) propyl] -9H-purin-6-amine .

LCMS (Procedure B): tRET = 0.94 minutes; MH + = 348

Example 96: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- [4- (tetrahydro-3-furanyl) butyl] -7,9-dihydro-

8H-purin-8-one

 Prepared similarly to Example 129 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -9- [4- (tetrahydro-3-furanyl) butyl] -9H-purin-6-amine.

LCMS (Procedure B): tRET = 1.00 minutes; MH + = 362 5

Example 97: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one

 To a solution of 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -9H-purin-6-amine (84, 7 mg, 0.234 mmol) in methanol (7.9 ml) at room temperature was added 4.0 M HCl in 1,4-dioxane (1.46 ml) to provide a light straw colored solution. The reaction mixture was stirred at room temperature overnight (20 hours) and then evaporated in vacuo to provide a colorless oil / gum. This material was redissolved in methanol and passed through an SPE cartridge with 5 g of aminopropyl (previously conditioned in methanol), washed thoroughly with methanol and evaporated to provide the title compound as a white solid. (58.5 mg).

LCMS (Procedure A): tRET = 3.00 minutes; MH + = 348

Example 98: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -7,9-dihydro-8H-purin-8-one

 twenty

 Prepared similarly to Example 129 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -9H-purin- 6-amine

LCMS (Procedure B): tRET = 1.06 minutes; MH + = 362

Example 99: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -7,9-dihydro-8H-purin-8-one 25

 Prepared similarly to Example 84 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -9H-purin- 6-amine

LCMS (Procedure A): tRET = 3.25 minutes; MH + = 376

Example 100: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7.9-5 dihydro-8H-purin-8- ona

 Prepared similarly to Example 97 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -9H-purin- 6-amine

LCMS (Procedure A): tRET = 2.89 minutes; MH + = 348. 10

Example 101: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -7,9-dihydro-8H-purin-8-one

 Prepared similarly to Example 84 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -9H-purin- 6-amine fifteen

LCMS (Procedure A): tRET = 3.15 minutes; MH + = 3376

Example 102: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-8-one

Prepared similarly to Example 73 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -20 9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -9H-purin -6-amine.

LCMS (Procedure B): tRET = 0.94 minutes; MH + = 348

Example 103: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8-one

 Prepared similarly to Example 69 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -9H-purin- 6-amine

LCMS (Procedure B): tRET = 0.99 minutes; MH + = 362

Example 104: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -7.9-5 dihydro-8H-purin-8- ona

 Prepared similarly to Example 69 from 2 - [(2-cyclopropylethyl) oxy] -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -9H-purin- 6-amine

LCMS (Procedure B): tRET = 1.05 minutes; MH + = 376 10

Example 105: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin -8-one

 Prepared similarly to Example 71 from 2 - [(2-cyclopropylethyl) oxy] -9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -8- (methyloxy) - 9H-purin-6-amine. fifteen

LCMS (Procedure A): tRET = 3.00 minutes; MH + = 376

Example 106: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin -8-one

 Prepared similarly to Example 72 from 2 - [(2-cyclopropylethyl) oxy] -9- [3- (2,2-20 dimethyltetrahydro-2H-pyran-4-yl) propyl] -8- (methyloxy) -9H-purin-6-amine.

LCMS (Procedure A): tRET = 3.13 minutes; MH + = 390

Example 107: 6-Amino-2 - [(2-cyclopropylethyl) oxy] -9- [4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin -8-one

 Prepared similarly to Example 73 from 2 - [(2-cyclopropylethyl) oxy] -9- [4- (2,2-5 dimethyltetrahydro-2H-pyran-4-yl) butyl] -8- (methyloxy) -9H-purin-6-amine.

LCMS (Procedure A): tRET = 3.30 minutes; MH + = 404

Example 108: 6-Amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2-furanyl) ethyl] -7,9-dihydro-8H-purin-8-one

 10

 Prepared similarly to Example 84 from 2 - {[(1 S) -1-methylbutyl] oxy} -8- (methyloxy) -9- [2- (tetrahydro-2-furanyl) ethyl] -9H-purin- 6-amine

LCMS (Procedure A): tRET = 2.91 minutes; MH + = 336

Example 109: 6-Amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [3- (tetrahydro-2-furanyl) propyl] -7,9-dihydro-8H-purin-8-one fifteen

 Prepared similarly to Example 73 from 2 - {[(1 S) -1-methylbutyl] oxy} -8- (methyloxy) -9- [3- (tetrahydro-2-furanyl) propyl] -9H-purin- 6-amine

LCMS (Procedure A): tRET = 3.01 minutes; MH + = 350

Example 110: 6-Amino-2 - {[(1S) -1-methylbutyl] oxy} -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -7.9-20 dihydro-8H- purin-8-one

 Prepared similarly to Example 97 from 2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} - 9H-purin-6-amine.

LCMS (Procedure A): tRET = 2.73 minutes; MH + = 336

Example 111: 6-Amino-2 - {[(1S) -1-methylbutyl] oxy} -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin -8-one 5

 Prepared similarly to Example 73 from 2 - {[(1 S) -1-methylbutyl] oxy} -8- (methyloxy) -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} - 9H-purin-6-amine.

LCMS (Procedure A): tRET = 2.75 minutes; MH + = 336

Example 112: 6-Amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [3- (tetrahydro-3-furanyl) propyl] -7.9-10 dihydro-8H-purin-8- ona

 Prepared similarly to Example 69 from 2 - {[(1 S) -1-methylbutyl] oxy} -8- (methyloxy) -9- [3- (tetrahydro-3-furanyl) propyl] -9H-purin- 6-amine

LCMS (Procedure B): tRET = 0.99 minutes; MH + = 350 15

Example 113: 6-Amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [4- (tetrahydro-3-furanyl) butyl] -7,9-dihydro-8H-purin-8-one

 Prepared similarly to Example 69 from 2 - {[(1 S) -1-methylbutyl] oxy} -8- (methyloxy) -9- [4- (tetrahydro-3-furanyl) butyl] -9H-purin- 6-amine twenty

LCMS (Procedure B): tRET = 1.05 minutes; MH + = 364

Example 114: 6-Amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -7,9-dihydro-8H-purin -8-one

 Prepared similarly to Example 84 from 2 - {[(1 S) -1-methylbutyl] oxy} -8- (methyloxy) -9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] - 9H-purin-6-amine.

LCMS (Procedure A): tRET = 3.03 minutes; MH + = 350

Example 115: 6-Amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -7.9-5 dihydro-8H- purin-8-one

 Prepared similarly to Example 69 from 2 - {[(1 S) -1-methylbutyl] oxy} -8- (methyloxy) -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] - 9H-purin-6-amine.

LCMS (Procedure B): tRET = 1.11 minutes; MH + = 364 10

Example 116: 6-Amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -7,9-dihydro-8H-purin -8-one

 Prepared similarly to Example 84 from 2 - {[(1 S) -1-methylbutyl] oxy} -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] - 9H-purin-6-amine. fifteen

LCMS (Procedure A): tRET = 3.29 minutes; MH + = 378

Example 117: 6-Amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin -8-one

 Prepared similarly to Example 84 from 2 - {[(1 S) -1-methylbutyl] oxy} -8-20 (methyloxy) -9- [2- (tetrahydro-2H-piran-3-yl) ethyl] -9H-purin-6-amine.

LCMS (Procedure A): tRET = 2.91 minutes; MH + = 350

Example 118: 6-Amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -7,9-dihydro-8H-purin -8-one

 Prepared similarly to Example 84 from 2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] - 9H-purin-6-amine. 5

LCMS (Procedure A): tRET = 3.17 minutes; MH + = 378

Example 119: 6-Amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin -8-one

 Prepared similarly to Example 73 from 2 - {[(1 S) -1-methylbutyl] oxy} -8-10 (methyloxy) -9- [2- (tetrahydro-2H-piran-4-yl) ethyl] -9H-purin-6-amine.

LCMS (Procedure A): tRET = 2.85 minutes; MH + = 350

Example 120: 6-Amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin -8-one

 fifteen

Prepared similarly to Example 69 from 2 - {[(1 S) -1-methylbutyl] oxy} -8- (methyloxy) -9- [3- (tetrahydro-2H-piran-4-yl) propyl] - 9H-purin-6-amine.

LCMS (Procedure B): tRET = 1.04 minutes; MH + = 364

Example 121: 6-Amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin -8-one 20

 Prepared similarly to Example 69 from 2 - {[(1 S) -1-methylbutyl] oxy} -8- (methyloxy) -9- [4- (tetrahydro-2H-piran-4-yl) butyl] - 9H-purin-6-amine.

LCMS (Procedure B): tRET = 1.10 minutes; MH + = 378

Example 122: 6-Amino-9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -2 - {[(1S) -1-methylbutyl] oxy} -7,9-dihydro -8H-purin-8-one

 Prepared similarly to Example 84 from 9- [2- (2,2-dimethyltetrahydro-2H-5 pyran-4-yl) ethyl] -2 - {[(1S) -1-methylbutyl] oxy} -8 - (methyloxy) -9H-purin-6-amine.

LCMS (Procedure A): tRET = 3.24 minutes; MH + = 378

Example 123: 6-Amino-9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -2 - {[(1S) -1-methylbutyl] oxy} -7,9-dihydro -8H-purin-8-one

 10

 Prepared similarly to Example 73 from 9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -9H-purin-6-amine.

LCMS (Procedure A): tRET = 3.15 minutes; MH + = 392

Example 124: 6-Amino-9- [4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) butyl] -2 - {[(1S) -1-methylbutyl] oxy} -7,9-dihydro -8H-purin-8-one 15

 Prepared similarly to Example 73 from 9- [4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) butyl] -2 - {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -9H-purin-6-amine.

LCMS (Procedure A): tRET = 3.32 minutes; MH + = 406

Example 125: 6-Amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2-furanyl) ethyl] -7,9-dihydro-20 8H-purin-8- ona

 To a solution of 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -9- [2- (tetrahydro-2-furanyl) ethyl] -9H-purin-6-amine (50 mg 0.133 mmol) in methanol (10 ml) at room temperature 4M HCl in 1.4 dioxane (0.894 ml, 3.58 mmol) was added to provide a light straw colored solution. The reaction mixture was stirred at 37 ° C for 3 hours, and the solvent was removed in a nitrogen evaporation unit overnight. The residue was dissolved in methanol and loaded into an SPE cartridge with 2 g of aminopropyl and eluted with methanol. The appropriate fractions were combined and dried on a nitrogen stream in a blow evaporation apparatus to provide the title compound as a white solid (26 mg).

LCMS (Procedure B): tRET = 0.99 minutes; MH + = 336 10

Example 126: 6-Amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [3- (tetrahydro-2-furanyl) propyl] -7,9-dihydro-8H-purin-8-one

 Prepared similarly to Example 73 from 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -9- [3- (tetrahydro-2-furanyl) propyl] -9H-purin- 6-amine fifteen

LCMS (Procedure A): tRET = 2.90 minutes; MH + = 350

Example 127: 6-Amino-2 - {[(1R) -1-methylbutyl] oxy} -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin -8-one

 Prepared similarly to Example 97 from 2 - {[(1R) -1-methylbutyl] oxy} -8-20 (methyloxy) -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -9H-purin-6-amine.

LCMS (Procedure A): tRET = 2.72 minutes; MH + = 336

Example 128: 6-Amino-2 - {[(1R) -1-methylbutyl] oxy} -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin -8-one

 25

 Prepared similarly to Example 73 from 2 - {[(1R) -1-methylbutyl] oxy} -8-

(methyloxy) -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -9H-purin-6-amine.

LCMS (Procedure A): tRET = 2.73 minutes; MH + = 336

Example 129: 6-Amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [3- (tetrahydro-3-furanyl) propyl] -7,9-dihydro-8H-purin-8-one

 5

 To a solution of 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -9- [3- (tetrahydro-3-furanyl) propyl] -9H-purin-6-amine (52 mg 0.133 mmol) in methanol (5 ml) at room temperature 4M HCl in dioxane (0.894 ml, 3.58 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours and concentrated in vacuo to provide a white solid. This material was dissolved in methanol and loaded into an SPE cartridge with 2 g of aminopropyl, eluting with methanol. The solvent was removed to provide the title compound as a white solid (36 mg).

LCMS (Procedure B): tRET = 0.99 minutes; MH + = 350

Example 130: 6-Amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [4- (tetrahydro-3-furanyl) butyl] -7,9-dihydro-8H-purin-8-one fifteen

 Prepared similarly to Example 129 from 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -9- [4- (tetrahydro-3-furanyl) butyl] -9H-purin- 6-amine

LCMS (Procedure B): tRET = 1.05 minutes; MH + = 364

Example 131: 6-Amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -7.9-20 dihydro-8H- purin-8-one

 Prepared similarly to Example 125 from 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] - 9H-purin-6-amine.

LCMS (Procedure B): tRET = 1.08 minutes; MH + = 350 25

Example 132: 6-Amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -7.9-

dihydro-8H-purin-8-one

 Prepared similarly to Example 129 from 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] - 9H-purin-6-amine.

LCMS (Procedure B): tRET = 1.11 minutes; MH + = 364 5

Example 133: 6-Amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -7,9-dihydro-8H-purin -8-one

 Prepared similarly to Example 84 from 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] - 9H-purin-6-amine. 10

LCMS (Procedure A): tRET = 3.26 minutes; MH + = 378 249

Example 134: 6-Amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin -8-one

 Prepared similarly to Example 125 from 2 - {[(1R) -1-methylbutyl] oxy} -8-15 (methyloxy) -9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -9H-purin-6-amine.

LCMS (Procedure B): tRET = 1.02 minutes; MH + = 350

Example 135: 6-Amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -7,9-dihydro-8H-purin -8-one

 twenty

 Prepared similarly to Example 125 from 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] - 9H-purin-6-amine.

LCMS (Procedure B): tRET = 1.13 minutes; MH + = 378

Example 136: 6-Amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin -8-one

 Prepared similarly to Example 73 from 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] - 9H-purin-6-amine. 5

LCMS (Procedure A): tRET = 2.84 minutes; MH + = 350

Example 137: 6-Amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin -8-one

Prepared similarly to Example 129 from 2 - {[(1R) -1-methylbutyl] oxy} -8-10 (methyloxy) -9- [3- (tetrahydro-2H-piran-4-yl) propyl] -9H-purin-6-amine.

LCMS (Procedure B): tRET = 1.04 minutes; MH + = 364

Example 138: 6-Amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin -8-one

 fifteen

 Prepared similarly to Example 129 from 2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -9- [4- (tetrahydro-2H-piran-4-yl) butyl] - 9H-purin-6-amine.

LCMS (Procedure B): tRET = 1.10 minutes; MH + = 378

Example 139: 6-Amino-9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -2 - {[(1R) -1-methylbutyl] oxy} -7,9-dihydro -8H-purin-8-one 20

 Prepared similarly to Example 125 from 9- [2- (2,2-dimethyltetrahydro-2H-

piran-4-yl) ethyl] -2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -9H-purin-6-amine.

LCMS (Procedure B): tRET = 1.07 minutes; MH + = 378

Example 140: 6-Amino-9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -2 - {[(1R) -1-methylbutyl] oxy} -7,9-dihydro -8H-purin-8-one

 5

 Prepared similarly to Example 73 from 9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -9H-purin-6-amine.

LCMS (Procedure A): tRET = 3.16 minutes; MH + = 392

Example 141: 6-Amino-9- [4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) butyl] -2 - {[(1R) -1-methylbutyl] oxy} -7,9-dihydro -8H-purin-8-one 10

 Prepared similarly to Example 73 from 9- [4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) butyl] -2 - {[(1R) -1-methylbutyl] oxy} -8- (methyloxy) -9H-purin-6-amine.

LCMS (Procedure A): tRET = 3.33 minutes; MH + = 406

Polymorphism 15

X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) were performed on samples of certain compounds of the invention according to the following procedures.

XRPD

X-ray powder diffraction data were obtained on a PANalytical X "Pert Pro 20 powder diffractometer, model PW3040 / 60, serial number DY1850 using an XCelerator detector. The conditions for obtaining were: radiation: Cu Kα, generator voltage: 40 kV, generator current: 45 mA, starting angle 20 º 2θ, final angle: 40 º 2θ, increment size: 0.0167 º 2θ, time per stage: 31.75 seconds. He prepared by mounting a few milligrams of the sample on a Si wafer (zero background noise), which produced a thin layer of dust.

DSC

DSC thermograms were obtained using a TA Q1000 calorimeter, serial number 1000-0126. The sample was weighed in an aluminum saucer, a saucer lid was placed

on it and folded slightly without sealing the dish. The experiment was performed using a heating rate of 10 ° C minute-1.

Representative XRPD diffractograms of certain compounds of the invention are shown in Figs. 1-7. Representative DSC thermograms of certain compounds of the invention are shown in Figs. 8-12. 5

Biological data

The compounds of the invention were analyzed for in vitro biological activity according to the following tests:

Assays for the induction of interferon from human peripheral blood mononuclear cells (PBMC) 10

Trials based on the stimulation of human peripheral blood mononuclear cells (PBMC) with test compounds were developed. After incubating the test compounds with freshly isolated PBMC, cell supernatants were tested for interferon alpha using a broad specific immunoassay for most IFNα isoforms. fifteen

Some variability was observed among donors in terms of responses to known interferon inducers, therefore resiquimod was included in these tests for normalization.

Interferon Induction "A" Assay

Preparation of compounds 20

The compounds were dissolved in DMSO. Serial dilutions of factor 3 of the compounds were prepared for each compound in growth medium (RPMI 1640 medium supplemented with 10% (v / v) fetal bovine serum (FCS), 100 U / ml penicillin G, 100 µg / ml of streptomycin, 10 mM L-glutamine and 1x non-essential amino acids) in sterile 96-well tissue culture plates. Each compound was tested in duplicate for each 25 PBMC donor.

Each trial included a positive control (resiquimod) and a negative control (culture medium). The data are expressed for each compound in terms of EC50 (calculated as the concentration of compound necessary to provide an induction at 50% of the maximum interferon alpha) and in terms of relative activity compared to an EC50 calculated 30 to recover in the Same donor and experiment.

PBMC preparation.

Blood samples were obtained from two human donors. Volumes of 25 ml of whole blood were spread over 15 ml of Histopaque in Accuspin tubes, centrifuged at 2100 rpm for 20 minutes and the band was carefully discarded between 35

plasma and histopaque. The collected cells were washed twice with PBS (centrifuged at 2100 rpm for 10 minutes) and resuspended in 10 ml of culture medium. A 1:20 dilution of the trypan blue cells was prepared and counted. The PBMCs were then diluted to provide a final concentration in each well of 2x106 cells / ml in 100 µl / well when added to the diluted compounds. 5

Cell preparations were incubated for 24 h at 37 ° C in 5% CO2. The cell medium of each well was then transferred to a 96-well filter plate and the cell-free supernatant was collected in a new 96-well plate in vacuo. These supernatants were stored at -20 ° C before analysis.

Test for interferon alfa 10

A multi-isoform immunoassay was used to quantify alpha interferon in PBMC supernatants. For the direct quantification of interferon alfa, a line of recombinant human interferon alpha 2a standards (PBL laboratories) was included in each assay.

A rabbit polyclonal antibody against human IFN-alpha (catalog number 31101, Stratech Scientific) was diluted 1: 6400 in phosphate buffered saline (PBS) and 20 µl was added to each well of a Meso-Scale Discovery plate ( MSD) GAR of 96 wells for sowing a small point. The plate was incubated for 1 h at room temperature with vigorous stirring. After three washes with PBS, 20 µl of cell supernatant was added to each well of the plate. The plate was then incubated for 1 h at room temperature with vigorous stirring. A pair of monoclonal antibodies 20 were diluted against IFN-alpha (catalog numbers 21100 and 21112, Stratech Scientific), labeled with sulfo-TAG at 1: 500 in culture medium and 20 µl was added to each well of the plate. The plate was re-incubated for 1 h at room temperature with vigorous stirring. After three washes with PBS, 150 μl of x 2 T buffer (MSD) was added to each well and the plate was then read on an MSD Sector 6000 plate reader.

IFNα concentrations in the supernatants were quantified from a line of standards constructed using recombinant IFNα 2a. The limit of detection in this assay is approximately 1 pg / ml.

Interferon Induction "B" Assay

PBMC preparation. 30

Blood samples of up to 200 ml were obtained from healthy human donors. Volumes of 25 ml of whole blood were spread over 15 ml of Ficoll gradients in Leucosep tubes, and centrifuged at 1000 g for 20 minutes. The cells in the band between the plasma and the histopaque were carefully removed and washed twice with PBS (centrifuged at 400 g for 5 minutes to collect). The final sediment was resuspended in 35

freezing medium (90% heat inactivated serum, 10% DMSO) at a cell concentration of 4x107 cells / ml. Resuspended cells were cryopreserved (frozen) then using a controlled speed freezer and stored at -140 ° C for up to 4 months.

Test for interferon alfa 5

Immediately before the test, the cryopreserved (frozen) PBMC vials were rapidly thawed in a 37 ° C water bath. A 1:10 dilution of the triptan blue cells was prepared and counted. The PBMCs were then diluted in culture medium [RPMI 1640 containing 10% fetal bovine serum (Invitrogen), penicillin + streptavidin (Gibco Cat. No. 25030-024, 1:50), 2 mM L-Glutamine, and 1000 units / ml of recombinant human IFNgamma 10 (Preprotech catalog No. 300-02)] at a density of 1x106 cells / ml, and was dispensed in 384-well transparent polypropylene Greiner plates containing 0.25 µl of DMSO or test compound dissolved in pure DMSO. The final maximum concentration of compound was usually 50 µM. The plates were incubated for 24 h at 37 ° C in 5% CO2. fifteen

A multi-isoform immunoassay was used to quantify alpha interferon in PBMC supernatants. A rabbit polyclonal antibody against human IFN-alpha (catalog number 31101, Stratech Scientific) was diluted 1: 1000 in assay buffer (RPMI 1640 containing 10% fetal bovine serum, Invitrogen) and 20 μl was added to each well of Meso-Scale Discovery (MSD) GAR plate (coated with goat antibody against rabbit) of 384 20 seed wells of a small point. The plate was incubated for 1 h at room temperature with vigorous stirring. After three washes with PBS, 20 µl of cell supernatant was added to each well of the plate. The plate was then incubated for 1 h at room temperature with vigorous stirring. A pair of monoclonal antibodies against IFN-alpha (catalog numbers 21100 and 21112, Stratech Scientific) were labeled with 25 sulfo-TAG (MSD), diluted 1: 1000 in assay buffer and 20 µl was added to each well of the license plate. The plate was further incubated for 1 h at room temperature with vigorous stirring. After three washes with PBS, 30 µl of x2 T buffer (MSD) was added to each well and the plate was read on an MSD Sector 6000 plate reader.

The data were normalized against internal controls of the 1 µM 30 (n = 16) and DMSO (n = 16) resiquimod plates. The pCE50 values were derived by adjusting a 4 parameter curve with IRLS in ActivityBase, from 11 points of test compounds diluted in series of factor 2.

Inhibition of Hepatitis C virus replication by supernatants from human peripheral blood mononuclear cells (PBMC) stimulated with 35

compounds.

An assay was established to measure antiviral activity in supernatants from human PBMCs that had previously been stimulated with compounds.

Activity tests were performed using a Huh-7 cell line stably transfected with a dicistronic replicon comprising the Con1-ET construct of HCV 5 (Pietschmann et al., 2002 J. Virol. 2002 76 (8): 4008- 21) and the firefly luciferase gene (Photinus piralis), obtained from ReBLikon GmbH, Germany.

1.5x104 cells were cultured with HCV ET replicon per well in 96-well plates overnight in 90 microliters of cell culture medium. 10 µl of factor three dilutions of the previously generated PBMC supernatants (stimulation of 10 human peripheral blood mononuclear cells (PBMC) stimulated with test compounds) were added to the ET cells. After incubation for 48 hours, the assay medium was removed and luciferase activity in cell monolayers was quantified using the Steadilite assay system (Perkin Elmer). EC50 values were calculated in terms of the concentration of the compound that gave a PBMC supernatant that was capable of inhibiting HCV replication by 50% compared to a supernatant from non-stimulated PBMC cultures.

Ovalbumin inhibition (OVA) - Induced acute pulmonary inflammation.

 Female BALB / c mice (18-20 g) were inoculated on days 0 and 14, with 10 µg of OVA adsorbed onto 2 mg of aluminum hydroxide in a volume of 0.2 ml of phosphate buffered saline (PBS) ) intraperitoneally. On days 24-26, mice were exposed intranasally to 50 µl of saline or OVA (formulated as above) under general anesthesia.

Test compounds that induced interferon at 5 mg / kg were administered orally in a vehicle consisting of 0.2% Tween 80 in saline. 25 doses were administered once a day on days 23 to 27, the initial dose being 24 hours before the first exposure. On the days of exposure, the compound or vehicle was administered to the animals one hour after the exposure. Therefore the animals received a total of 5 doses.

Dexamethasone was used as a positive control administered at 10 mg / kg orally in the same vehicle once daily on days 24 to 27, the initial dose being 1 h before the first exposure. Therefore the animals received a total of 4 doses.

The animals were sacrificed on day 28 (48 hours after the last exposure a saline solution or OVA) and a bronchoalveolar lavage (BAL) was performed with 5 x 1 ml (0.1% bovine serum albumin, 10 mM EDTA in PBS) and got together. The number of lymphocytes, macrophages, eosinophils and neutrophils of the BAL was identified by flow cytometry.

Light diffraction and quantified.

Results

In Interferon Induction Test "A", Examples 1 to 60 had an average EC50 of between 0.01 and 19 µM.

In Interferon Induction Test "B", Example 13 Isomer 1, Example 13 5 Isomer 2, Example 16 Isomer 1, Example 16 Isomer 2, Example 26 Isomer 1, Example 26 Isomer 2, Example 27 Isomer 1, Example 27 Isomer 2, and Examples 61-141 also had an average EC50 of between 0.01 and 10 µM.

Replicon test

In the previous test with replicons, Examples 1 and 4 had an average EC50 of 0.043 µM and 1.05 µM respectively.

Model of acute pulmonary inflammation induced by ovalbumin

In the previous model of acute pulmonary inflammation induced by ovalbumin, compared to controls treated with saline, Example 4 reduced the number of lymphocytes, eosinophils and neutrophils of BAL by 66%, 72% and 50% respectively. In the same experiment, dexamethasone reduced the number of lymphocytes, eosinophils and neutrophils of BAL by 87%, 92% and 68% respectively.

 In the previous model of acute pulmonary inflammation induced by ovalbumin, compared to controls treated with saline, Example 12 reduced the number of lymphocytes, eosinophils and neutrophils of BAL by 68%, 67% and 58% respectively. In the same experiment, dexamethasone reduced the number of lymphocytes, eosinophils and neutrophils of BAL by 86%, 86% and 65% respectively.

Claims (17)

1. A compound of formula (I):  in which R1 is (C1-8 alkyl) amino, C1-8 alkoxy, (C3-7 cycloalkyl) (C1-6 alkyl) amino, (C3-5 cycloalkyl7) C1-6 alkoxy, (C1-3 alkoxy) C2- alkoxy 3, or Hetb-C1-3 alkoxy; Hetb is a saturated 5- or 6-membered aliphatic heterocycle containing an oxygen atom; R2 is - (CH2) n-Het; n is an integer that has a value from 1 to 4; 10 Het is a saturated 5- or 6-membered aliphatic heterocycle containing an oxygen heteroatom, a heterocycle that may be substituted with one or two C1-4 alkyl groups; or its salts or solvates. 2. A compound according to claim 1 or a salt or solvate thereof, wherein R1 is n-butylamino, n-butoxy, (R) -1-, methyl butyloxy, (S) -2-methylbutyloxy or 2- (cyclopropyl) ethoxy. fifteen 3. A compound according to claim 1 or claim 2, or a salt or solvate thereof, wherein n is 2. 4. A compound according to claim 1 or claim 2, or a salt or solvate thereof, wherein n is 3. 5. A compound according to claim 1 or claim 2, or a salt or solvate thereof, wherein n is 4. 6. A compound according to any one of claims 1 to 5, or a salt or solvate thereof, wherein Het is tetrahydro-2H-pyran-4-yl, tetrahydrofuran-2-yl, tetrahydro-2H-pyran -3-yl, tetrahydro-2H-pyran-2-yl or tetrahydrofuran-3-yl. 7. A compound according to any one of claims 1 to 6, or a salt or solvate thereof, which is selected from the list consisting of:  6-amino-2-butoxy-9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2-butoxy-9- (tetrahydro-2H-pyran-2-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2-butoxy-9- (tetrahydrofuran-2-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2-butylamino-9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; 30 6-amino-2-butylamino-9- (tetrahydro-2H-pyran-2-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2-butylamino-9- (tetrahydrofuran-2-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2-butylamino-9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2-butylamino-9- (tetrahydrofuran-3-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2-butylamino-9- (tetrahydro-2H-pyran-3-ylmethyl) -7,9-dihydro-8H-purin-8-one; 5 6-amino-2-butoxy-9- (tetrahydrofuran-3-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2-butoxy-9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2-butoxy-9- (tetrahydro-2H-pyran-3-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2-butoxy-9- [2- (tetrahydrofuran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2-butoxy-9- [2- (tetrahydrofuran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one; 10 6-amino-2-butoxy-9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2-butylamino-9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin-8-one, Isomer 1; 6-amino-2-butoxy-9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin-8-one, Isomer 2; fifteen 6-amino-2-butoxy-9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2-butylamino-9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2-butylamino-9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin-8-one, Isomer 1 6-amino-2-butylamino-9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin-8-one, 20 Isomer 2 6-amino-2 - [(2,2-dimethylpentyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2- (pentylamino) -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(3-methylbutyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; 25 6-amino-2 - [(2-methylbutyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(1-methylbutyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(2-methylbutyl) amino] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(3-methylbutyl) amino] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-30 one; 6-amino-2 - [(1-methylbutyl) amino] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2-butyloxy-9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one; 35 6-amino-2-butyloxy-9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one, Isomer 1; 6-amino-2-butyloxy-9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one, Isomer 2 6-amino-2-butyloxy-9 - [(2,2-dimethyltetrahydro-2H-pyran-4-yl) methyl] -7,9-dihydro-8H-purin-8-5 one; 6-amino-2-butyloxy-9 - [(2,2-dimethyltetrahydro-2H-pyran-4-yl) methyl] -7,9-dihydro-8H-purin-8-one, Isomer 1; 6-amino-2-butyloxy-9 - [(2,2-dimethyltetrahydro-2H-pyran-4-yl) methyl] -7,9-dihydro-8H-purin-8-one, Isomer 2; 10 6-amino-2- (butylamino) -9 - [(2,2-dimethyltetrahydro-2H-pyran-4-yl) methyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2-butyloxy-9- [2- (tetrahydro-3-furanyl) ethyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butylamino) -9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butylamino) -9- [2- (tetrahydro-3-furanyl) ethyl] -7,9-dihydro-8H-purin-8-one; fifteen 6-amino-2- (butyloxy) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one, isomer 1; 6-amino-2- (butyloxy) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one, isomer 2; 6-amino-2 - {[2- (ethyloxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2 - {[1-methyl-2- (methoxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; twenty 6-amino-2 - {[2- (ethyloxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-3-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2 - {[1-methyl-2- (methoxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-3-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(cyclohexylmethyl) amino] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; 25 6-amino-2 - [(cyclopentylmethyl) amino] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(2-cyclopropylethyl) amino] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butylamino) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one, isomer 1; 6-amino-2- (butylamino) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one, isomer 2; 6-amino-2 - [(2-methylpropyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-35 ona; 6-amino-2 - [(cyclohexylmethyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2 - {[2- (methoxy) ethyl] oxy} -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; 5 6-amino-2 - {[2- (methoxy) ethyl] oxy} -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(tetrahydro-2-furanylmethyl) oxy] -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butylamino) -9- [3- (tetrahydro-2H-pyran-3-yl) propyl] -7,9-dihydro-8H-purin-8-one; 6-amino-9- (tetrahydro-2H-pyran-4-ylmethyl) -2 - [(tetrahydro-2H-pyran-2-ylmethoxy] -7,9-dihydro-10 8H-purin-8-one; 6-amino-2 - ({2 - [(1-methyl ethyl) oxy] ethyl} oxy) -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one ; 6-amino-2- (butylamino) -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(2-cyclopropylethyl) amino] -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-15 one; 6-amino-2 - [(2-cyclopropylethyl) amino] -9- (tetrahydro-2H-pyran-3-ylmethyl) -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one, isomer 1, and; twenty 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [tetrahydro-3-furanylmethyl] -7,9-dihydro-8H-purin-8-one, isomer 2; 6-amino-2- (butylamino) -9- [3- (tetrahydro-2-furanyl) propyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butylamino) -9- [4- (tetrahydro-2-furanyl) butyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butylamino) -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8-one; 25 6-amino-2- (butylamino) -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butylamino) -9- [3- (tetrahydro-3-furanyl) propyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butylamino) -9- [4- (tetrahydro-3-furanyl) butyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butylamino) -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butylamino) -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -7,9-dihydro-8H-purin-8-one; 30 6-amino-2- (butylamino) -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butylamino) -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butylamino) -9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butylamino) -9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-35 purin-8-one; 6-amino-2- (butylamino) -9- [4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butyloxy) -9- [3- (tetrahydro-2-furanyl) propyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butyloxy) -9- [4- (tetrahydro-2-furanyl) butyl] -7,9-dihydro-8H-purin-8-one; 5 6-amino-2- (butyloxy) -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butyloxy) -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8-one;  6-amino-2- (butyloxy) -9- [3- (tetrahydro-3-furanyl) propyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butyloxy) -9- [4- (tetrahydro-3-furanyl) butyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butyloxy) -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -7,9-dihydro-8H-purin-8-one; 10 6-amino-2- (butyloxy) -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butyloxy) -9- [3- (tetrahydro-2H-pyran-3-yl) propyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butyloxy) -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butyloxy) -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butyloxy) -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8-one; fifteen 6-amino-2- (butyloxy) -9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butyloxy) -9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butyloxy) -9- [4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8-20 one; 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [2- (tetrahydro-2-furanyl) ethyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [3- (tetrahydro-2-furanyl) propyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [4- (tetrahydro-2-furanyl) butyl] -7,9-dihydro-8H-purin-8-25 one; 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [2- (tetrahydro-3-furanyl) ethyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-30 8-one 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [3- (tetrahydro-3-furanyl) propyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [4- (tetrahydro-3-furanyl) butyl] -7,9-dihydro-8H-purin-8-one; 35 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -7,9-dihydro-8H-purin-5 8-one; 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin-8-one;  6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -7,9-dihydro-8H-purin-8-one; 10 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-15 8-one; 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-8- ona; 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8- ona; twenty 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8- ona; 6-amino-2 - {[(1 S) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2-furanyl) ethyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2 - {[(1 S) -1-methylbutyl] oxy} -9- [3- (tetrahydro-2-furanyl) propyl] -7,9-dihydro-8H-purin-8-25 one; 6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8- ona; 6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8- ona; 30 6-amino-2 - {[(1 S) -1-methylbutyl] oxy} -9- [3- (tetrahydro-3-furanyl) propyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2 - {[(1 S) -1-methylbutyl] oxy} -9- [4- (tetrahydro-3-furanyl) butyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -7,9-dihydro-8H-purin-35 8-one; 6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -7,9-dihydro-8H-purin-8- ona; 6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -7,9-dihydro-8H-purin-8- ona; 5 6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin-8- ona; 6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -7,9-dihydro-8H-purin-8- ona; 6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-10 8 -one; 6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8- ona; 6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8- ona; fifteen 6-amino-9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -2 - {[(1S) -1-methylbutyl] oxy} -7,9-dihydro-8H- purin-8-one;  6-amino-9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -2 - {[(1S) -1-methylbutyl] oxy} -7,9-dihydro-8H- purin-8-one; 6-amino-9- [4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) butyl] -2 - {[(1S) -1-methylbutyl] oxy} -7.9-20 dihydro-8H -purin-8-one; 6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2-furanyl) ethyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [3- (tetrahydro-2-furanyl) propyl] -7,9-dihydro-8H-purin-8-one; 25 6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- {2 - [(3S) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8- ona; 6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- {2 - [(3R) -tetrahydro-3-furanyl] ethyl} -7,9-dihydro-8H-purin-8- ona; 6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [3- (tetrahydro-3-furanyl) propyl] -7,9-dihydro-8H-purin-8-30 one; 6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [4- (tetrahydro-3-furanyl) butyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2H-pyran-2-yl) ethyl] -7,9-dihydro-8H-purin-8- ona; 35 6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [3- (tetrahydro-2H-pyran-2-yl) propyl] -7,9-dihydro-8H-purin-8- ona; 6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [4- (tetrahydro-2H-pyran-2-yl) butyl] -7,9-dihydro-8H-purin-8- ona; 6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2H-pyran-3-yl) ethyl] -7,9-dihydro-8H-purin-5 8 -one; 6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -7,9-dihydro-8H-purin-8- ona; 6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-8- ona; 10 6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8- ona; 6-amino-2 - {[(1R) -1-methylbutyl] oxy} -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8- ona; 6-amino-9- [2- (2,2-dimethyltetrahydro-2H-pyran-4-yl) ethyl] -2 - {[(1R) -1-methylbutyl] oxy} -7,9-dihydro-15 8H -purin-8-one; 6-amino-9- [3- (2,2-dimethyltetrahydro-2H-pyran-4-yl) propyl] -2 - {[(1R) -1-methylbutyl] oxy} -7,9-dihydro-8H- purin-8-one; 6-amino-9- [4- (2,2-dimethyltetrahydro-2H-pyran-4-yl) butyl] -2 - {[(1R) -1-methylbutyl] oxy} -7,9-dihydro-8H- purin-8-one; twenty and its salts and solvates. 8. A compound according to any one of claims 1 to 6, or a salt or solvate thereof, which is selected from the list consisting of: 6-amino-2- (butyloxy) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one; hydrochloride salt; 25  6-amino-2- (butylamino) -9- (tetrahydro-2H-pyran-4-ylmethyl) -7,9-dihydro-8H-purin-8-one, hydrochloride hydrate;  6-amino-2- (butylamino) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one; hydrochloride salt, Isomer 1, and;  6-amino-2- (butylamino) -9- (tetrahydro-3-furanylmethyl) -7,9-dihydro-8H-purin-8-one; 30 hydrochloride salt, Isomer 2. 9. A compound according to any one of claims 1 to 6, or a salt or solvate thereof, which is selected from the list consisting of: 6-amino-2- (butyloxy) -9- [4- (tetrahydro-2H-pyran-3-yl) butyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2- (butyloxy) -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8-one; 35 6-amino-2- (butyloxy) -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8-one; 6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-8- ona; 5 6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [3- (tetrahydro-2H-pyran-4-yl) propyl] -7,9-dihydro-8H-purin-8- ona; 6-amino-2 - {[(1S) -1-methylbutyl] oxy} -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8- ona; 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -7,9-dihydro-8H-purin-8-10 one; 6-amino-2 - [(2-cyclopropylethyl) oxy] -9- [4- (tetrahydro-2H-pyran-4-yl) butyl] -7,9-dihydro-8H-purin-8-one; and its salts and solvates. 10. A compound according to any one of claims 1 to 9 as a pharmaceutically acceptable salt or solvate. 11. A compound as defined in any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic agent. 12. A compound as defined in any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of infectious diseases, cancer, allergic diseases and other inflammatory conditions. 13. A compound as defined in any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, for use as a vaccine adjuvant. 25 14. Use of a compound as defined in any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of infectious diseases, cancer, allergic diseases and other conditions. inflammatory 30 15. Use of a compound as defined in any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of allergic rhinitis. 16. Use of a compound as defined in any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of asthma. 17. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, and optionally one or more pharmaceutically acceptable diluents or carriers.