ES2365687T3 - THIAZOLIOPIRIMIDINAS AND ITS USE AS INHIBITORS OF PHOSFATIDYLINOSITOL-3-QUINASA. - Google Patents

Abstract

Compound which is a thiazolopyrimidine of formula (I): in which: W represents a thiazole ring, R 1 and R 2 form, together with the N atom to which they are attached, a group with the following formula (IIa): wherein A is selected from: (a) a saturated nitrogen heterocyclic ring of 4 to 7 elements that includes 0 or 1 additional heteroatom selected from N, S and O, the unsubstituted or substituted ring being found, (b) a 4 to 7 elements saturated nitrogen heterocyclic ring that includes 0 or 1 additional heteroatom selected from N, S and O, the fused ring being found with a second ring selected from a saturated 4 to 7 elements nitrogen heterocyclic ring as it has been defined above, an unsaturated heterocyclic ring of 5 to 12 elements, a saturated oxygenated heterocyclic ring of 5 to 7 elements, a saturated carbocyclic ring of 3 to 12 elements and an unsaturated carbocyclic ring of 5 to 12 elements, forming a heteropolyclic ring system, the unsubstituted or substituted heteropolyclic ring system being found, (c) a saturated nitrogen heterocyclic ring of 4 to 7 elements that includes 0 or 1 additional heteroatom selected from N, S and O and which It also comprises joining two constituent atoms of the ring, a bridgehead group selected from - (CR'2) n- and - (CR'2) rO- (CR'2) s-, in which each R 'is , independently, H or C1-C6 alkyl, n is 1, 2 or 3, r is 0 or 1 and s is 0 or 1, the remaining ring positions being unsubstituted or substituted, and (d) a group of formula (IIb) : wherein the B ring is a saturated nitrogen heterocyclic ring of 4 to 7 elements that includes 0 or 1 additional heteroatom selected from N, S and O, and the B 'ring is a saturated carbocyclic ring of 3 elements, a saturated oxygenated heterocyclic ring of 5 to 7 elements or a saturated nitrogen heterocyclic ring or from 4 to 7 elements as defined above, each of B and B 'being unsubstituted or substituted, or one of R 1 and R 2 is C 1 -C 6 alkyl and the other of R 1 and R 2 is selected from a saturated carbocyclic group of 3 to 12 elements that is unsubstituted or substituted, an unsaturated carbocyclic group of 5 to 12 elements that is unsubstituted or substituted, an unsaturated hectocyclic group of 5 to 12 elements that is found unsubstituted or substituted, a saturated heterocyclic group of 4 to 12 elements that is unsubstituted or substituted, and a C1-C6 alkyl group that is substituted with a group selected from a saturated carbocyclic group of 3 to 12 elements that is found unsubstituted or substituted, an unsaturated carbocyclic group of 5 to 12 elements that is unsubstituted or substituted, an unsaturated heterocyclic group of 5 to 12 elements that is unsubstituted or substituted, and a g unsaturated heterocyclic rump of 4 to 12 elements that is unsubstituted or substituted. m is 0, 1 or 2, R 3 is H or C1-C6 alkyl, and R 4 is an indole group that is unsubstituted or substituted, or a pharmaceutically acceptable salt thereof.

Description

5 Field of the invention

The present invention relates to indolyl-thiazolipyrimidine compounds and their use as inhibitors of phosphatidylinositol-3-kinase (PI3K).

10 Background of the invention

Phosphatidylinositol (hereinafter abbreviated "PI") is one of several phospholipids present in cell membranes. In recent years it has become clear that IP plays an important role in the transduction of intracellular signals. At the end of the 1980s, it was found that a PI3 kinase (PI3K) was a

15 enzyme that phosphorylated position 3 of the inositol ring of phosphatidylinositol (D. Whitman et al. Nature 332: 664, 1988).

Originally, PI3K was considered to be a single enzyme, but it has now been clarified that a plurality of subtypes are present in PI3K. Each subtype presents its own activity regulation mechanism. Three main classes of PI3Ks have been identified based on their substrate specificity in vitro (B. 20 Vanhaesebroeck, Trend in Biol. Sci. 22: 267, 1997). The substrates of class I PI3Ks are PI, PI 4-phosphate (PI4P) and PI 4,5-bisphosphate ((4,5) P2 from PI). Class I PI3Ks are further divided into two groups, class Ia and class Ib, in terms of their activation mechanism. Class Ia PI3Ks include the subtypes of PI3K p110α, p110β and p110δ, which transmit signals from the tyrosine kinase coupled receptors. Class Ib of PI3K includes a subtype p110γ activated by a receptor coupled to protein G. The PI and the (4) P of PI are

25 known as substrates of class II PI3Ks. Class II PI3Ks include the subtypes of PI3K C2α, C2β and C2γ, which are characterized in that they contain C2 domains at the C-terminal end. The substrate of class II PI3Ks is only the PI.

In the PI3K subtypes, the class Ia subtype has been the most extensively investigated to date. The three subtypes

30 of class Ia are heterodimers of a catalytic subunit of 110 kDa and regulatory subunits of 85 or 55 kDa. Regulatory subunits contain SH2 domains and bind to phosphorylated tyrosine residues by growth factor receptors with tyrosine kinase activity or by oncogenic products, thereby inducing the PI3K activity of the p110 catalytic subunit that phosphorylates its lipid substrate. In this way, subtypes of class Ia are considered to be associated with cell proliferation and

35 carcinogenesis, and immune disorders and conditions that involve inflammation.

WO Patent No. 01/083456 describes a series of condensed heteroaryl derivatives that exhibit activity as PI3K inhibitors and that suppress the growth of cancer cells.

Other PI3K inhibitors are disclosed in WO Patents 2006/046031, US 2002/151544 and WO 2006/114606.

Summary Description of the Invention

45 It has now been found that a series of new thiazolopyrimidine compounds exhibit activity as PI3K inhibitors. The compounds show selectivity for the subtype p110δ of PI3 kinase, compared to the other two classes, class Ia and class Ib, of PI3Ks. In accordance with the foregoing, the present invention provides

50 in which: W represents a thiazole ring, R1 and R2 form, together with the N atom to which they are attached, a group with the following formula (IIa):

image 1

2

image2

in which A is selected from:

(a) a saturated nitrogen heterocyclic ring of 4 to 7 elements including 0 or 1 additional heteroatom 5 selected from N, S and O, the ring being unsubstituted or substituted,

(b)

 a saturated nitrogen heterocyclic ring of 4 to 7 elements that includes 0 or 1 additional heteroatom selected from N, S and O, the fused ring being found with a second ring selected from the saturated nitrogen heterocyclic rings of 4 to 7 elements indicated above, an unsaturated heterocyclic ring of 5 to 12 elements, a saturated oxygenated heterocyclic ring of 5 to 7 elements, a saturated carbocyclic ring of 3 to 12 elements and an unsaturated carbocyclic ring of 5 to 12 elements, forming a heteropolyclic ring system, the heteropolyclic ring system unsubstituted or substituted,

(C)

 a saturated nitrogen heterocyclic ring of 4 to 7 elements that includes 0 or 1 additional heteroatom selected from N, S and O and also comprises joining two constituent atoms of the ring, a bridgehead group selected from - (CR'2 ) n- and - (CR'2) rO- (CR'2) s-, in which each R 'is, independently,

15 H or C1-C6 alkyl, n is 1, 2 or 3, r is 0 or 1 and s is 0 or 1, the remaining ring positions being unsubstituted or substituted, and

(d) a group of formula (IIb):

image2

wherein ring B is a saturated nitrogen heterocyclic ring of 4 to 7 elements that includes 0 or 1 additional heteroatom selected from N, S and O, and ring B 'is a saturated carbocyclic ring of 3 to 12 elements, a saturated oxygenated heterocyclic ring of 5 to 7 elements or a saturated nitrogen heterocyclic ring of 4 to 7 elements as defined above, each of B and B 'being unsubstituted

or replaced,

25 or one of R1 and R2 is C1-C6 alkyl and the other of R1 and R2 is selected from a saturated carbocyclic group of 3 to 12 elements that is unsubstituted or substituted, an unsaturated carbocyclic group of 5 to 12 elements that are unsubstituted or substituted, an unsaturated heterocyclic group of 5 to 12 elements that is unsubstituted or substituted, a saturated heterocyclic group of 4 to 12 elements that is unsubstituted or substituted, and a C1-C6 alkyl group that is substituted with a group selected from a saturated carbocyclic group of 3 to 12 elements that is unsubstituted or substituted, an unsaturated carbocyclic group of 5 to 12 elements that is unsubstituted or substituted, an unsaturated heterocyclic group of 5 to 12 elements that are unsubstituted or substituted, and a saturated heterocyclic group of 4 to 12 elements that is unsubstituted or substituted,

35 m is 0, 1 or 2, R3 is H or C1-C6 alkyl, and R4 is an indole group which is unsubstituted or substituted,

or a pharmaceutically acceptable salt thereof.

Detailed description of the invention

As used herein, the term "fused" indicates that two rings have joined together with a common bond between two adjacent ring atoms. The term "spiro-fused" indicates that two rings are joined by a single common carbon atom. The expression "bridgehead" refers to a link group, of

45 one or more atoms in length, which connects two atoms of non-contiguous rings. In each of these three cases the result is a polycyclic structure (typically bicyclic).

In the event that any group, ring, substituent or fraction defined herein is substituted, it is typically substituted with Z or R5, as defined below.

A C1-C6 alkyl group is linear or branched. A C1-C6 alkyl group is typically a C1-C4 alkyl group, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl or tert-butyl group. A C1-C6 alkyl group is unsubstituted or substituted, typically with one or more Z or R5 groups as defined below. Is typically

3

a C1-C4 alkyl, for example methyl, ethyl, i-propyl, n-propyl, t-butyl, s-butyl or n-butyl.

Z is selected from H, unsubstituted C1-C6 alkyl, halo, -OR, -SR, - (C (R6) 2) qR, -CH2OR, -CF3, - (halo) -C1C6 alkyl, - (C ( R6) 2) qO- (halo) -C1-C6 alkyl, -CO2R, - (C (R6) 2) qCO2R, - (C (R6) 2) qCOR, CF2OH, CH (CF3) OH, C (CF3) OH, (CH2) qOR, - (C (R6) 2) qOR, - (CH2) NR2, - (C (R6) 2) qNR2, -C (O) N (R) 2, - (C (R6) 2) qCONR2, -NR2, - (C (R6) 2) qNR2, (C (R6) 2) qNRC (O) R, - (C (R6) 2) qNRC (O) OR, -S (O) pR , -S (O) pN (R) 2, - (C (R6) 2) qS (O) pN (R) 2, -OC (O) R, - (C (R6) 2) qOC (O) R , OC (O) N (R) 2, - (C (R6) 2) qOC (O) N (R) 2, -NRS (O) pR, - (C (R6) 2) qNRS (O) pR, - (C (R6) 2) qNRS (O) pR, NRC (O) N (R) 2, (C (R6) 2) qNRC (O) N (R) 2, CN, -NO2, = O, a saturated carbocyclic ring of 3 to 12 elements that is unsubstituted or substituted, an unsaturated carbocyclic ring of 5 to 12 elements that is unsubstituted or substituted, an unsaturated heterocyclic group of 5 to 12 elements that is unsubstituted or substituted and a saturated heterocyclic group of 4 to 12 elements that is substituted or unsubstituted, in which each R is independently selected from among H, C1-C6 alkyl, C3-C10 cycloalkyl and an aryl or heteroaryl group of 5 to 12 elements, the unsubstituted or substituted group being found, or in the case where two R groups are attached to an atom of N together with the N atom form a saturated nitrogen heterocyclic ring of 4 to 7 elements, p is 1 or 2 and q is 0, 1 or 2.

R5 is selected from C1-C6 alkoxy, OR6, SR6, S (O) pR6, nitro, CN, halogen, -C (O) R6, -CO2R6, -C (O) N (R6) 2 and N (R6 ) 2R6, each of which is the same or different if more than one is present in a given substituent, and is selected from H, C1-C6 alkyl and C3-C10 cycloalkyl, and p is 1 or 2 .

A halogen or halo group is F, Cl, Br or I. Preferably it is F, Cl or Br. A halogen substituted C1-C6 alkyl group may be indicated by the term "C1-C6 haloalkyl", which means that an alkyl group in which is substituted one or more hydrogens by halo. A C1-C6 haloalkyl group preferably contains one, two or three halo groups. A preferred example of this type of group is trifluoromethyl.

A C1-C6 alkoxy group is linear or branched. It is typically a C1-C4 alkoxy group, for example a methoxy, ethoxy, propoxy, i-propoxy, n-propoxy, n-butoxy, sec-butoxy or tert-butoxy group. A C1-C6 alkoxy group is unsubstituted or substituted, typically with one or more Z or R5 groups as defined above.

A C3-C10 cycloalkyl group may be, for example, a C3-C8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Typically it is C3-C6 cycloalkyl. A C3-C10 cycloalkyl group is unsubstituted or substituted, typically with one or more Z or R5 groups as defined above.

A saturated nitrogen heterocyclic ring of 4 to 7 elements typically contains a nitrogen atom and an additional atom of N, O or S, or no additional heteroatom. It can be, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine or homopiperazine.

A saturated nitrogen heterocyclic ring of 4 to 7 elements as defined above is unsubstituted or substituted in one or more annular carbon atoms and / or any additional N atoms present in the ring. Examples of suitable substituents include one or more Z or R5 groups as defined above, and a C1-C6 alkyl group that is unsubstituted or substituted with a Z or R5 group as defined above.

Among the specific examples of a saturated nitrogen heterocyclic ring of 4 to 7 elements found

image3

4

image2

A saturated oxygenated heterocyclic ring of 5 to 7 elements contains at least one atom of O and 0, 1 or 2, typically 0 or 1, additional heteroatoms selected from O, N and S. For example it is tetrahydrofuran, tetrahydropyran, oxetane or morpholine

A saturated carbocyclic group of 3 to 12 elements is a carbocyclic ring of 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 elements contains only saturated bonds. It is a fused monocyclic or bicyclic ring system. For example it is a saturated carbocyclic ring of 3 to 7 elements. Examples include cyclopropane,

10 cyclobutane, cyclopentane, cyclohexane and cycloheptane, and bicyclic ring systems in which two of said rings are fused together. Specific examples of a saturated carbocyclic group of 3 to 12 elements include the following structures:

image2

An unsaturated carbocyclic group of 5 to 12 elements is a carbocyclic ring of 5, 6, 7, 8, 9, 10, 11 or 12

5

elements that contain at least one unsaturated link. It is a fused monocyclic or bicyclic ring system. The group is non-aromatic or aromatic, for example aryl. Thus, in one embodiment, an unsaturated carbocyclic group of 5 to 12 elements is an aryl group of 5 to 12 elements. Examples of an unsaturated carbocyclic group of 5 to 12 elements include benzene, naphthalene, indane, indene and tetrahydronaphthalene rings, or phenyl, naphthyl, indanyl, indenyl and tetrahydronaphthyl groups. The group is unsubstituted or substituted, typically with one or more Z or R5 groups as defined above. Specific examples of an unsaturated carbocyclic group of 5 to 12 elements include the following structure:

image2

An aryl group is an aromatic carbocyclic group of 5 to 12 elements. It is monocyclic or bicyclic. Between the

Examples include phenyl and naphthyl groups. The group is unsubstituted or substituted, for example with a group Z or R5 as defined above. Specific examples of an aryl group include the following structures:

image2

15 An unsaturated heterocyclic group of 5 to 12 elements is a heterocyclic ring of 5, 6, 7, 8, 9, 10, 11 or 12 elements containing at least one unsaturated bond and at least one heteroatom selected from O, N and S. It is a fused monocyclic or bicyclic ring system. The group is non-aromatic or aromatic, for example heteroaryl. Thus, in one embodiment, an unsaturated heterocyclic group of 5 to 12 elements is a heteroaryl group of 5 to 12 elements. The unsaturated heterocyclic group of 5 to 12 elements may be, for example,

20 furan, thiophene, pyrrole, pyrrolopyrazine, pyrrolopyrimidine, pyrrolopyridine, pyrrolopyridazine, indole, isoindole, pyrazole, pirazolopirazina, pyrrolopyrimidine, pyrrolopyridine, pyrrolopyridazine, indole, isoindole, pyrazole, pirazolopirazina, pyrazolopyrimidine, pyrazolopyridine, pirazolopiridazina, imidazole, imidazopyrazine, imidazopyrimidine, imidazopyridine , imidazopyridazine, benzimidazole, benzodioxol, benzodioxine, benzoxazol, benzothiophene, benzothiazole, benzofuran, indolizinyl, isoxazole, oxazole, oxadiazole, thiazole, isothiazole, thiadiazole, dihydroimidazole, dihydroimidazole, dihydroimidazole

Dihydrodioxynopyridine, dihydropyrrolopyridine, dihydrofurannopyridine, dioxolopyridine, pyridine, quinoline, isoquinoline, purine, quinoxaline, tetrahydrobenzofuran, tetrahydroquinoline, tetrahydroisoquinoline, 5,6,7,8-tetrahydro] imidazo [1,5, 8,8 -tetrahydro-imidazo [1,2-a] pyrazine, thienopyrazine, pyrimidine, pyridazine, pyrazine, triazine, triazole or tetrazole. The group is unsubstituted or substituted, typically with one or more Z or R5 groups as defined above. Among the specific examples of an unsaturated heterocyclic group of 5 to 12 elements are

30 include the following structures:

image2

Heteroaryl is an aromatic heterocyclic group of 5 to 12 elements containing 1, 2, 3 or 4 heteroatoms selected from O, N and S. It is monocyclic or bicyclic. It typically contains an atom of N and 0, 1, 2 or 3

Additional heteroatoms selected from O, S and N. It may be, for example, a heteroaryl group of 5 to 7 elements. Typically, it is selected from the heteroaryl groups included in the above indicated list of unsaturated heterocyclic group options of 5 to 12 elements.

A saturated heterocyclic group of 4 to 12 elements is a heterocyclic ring of 4, 5, 6, 7, 8, 9, 10, 11 or 12

40 elements containing 1, 2, 3, or 4 heteroatoms selected from O, N and S. It is a fused monocyclic or bicyclic ring system. Examples of such heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, dithianyl, dithiolanyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3

45 azabicyclo [4.1.0] heptanyl and azabicyclo [2.2.2] hexanyl. Spiro groups are also included within the scope of that definition. In one embodiment, the saturated heterocyclic group of 4 to 12 elements is a saturated nitrogen heterocyclic ring of 4 to 7 elements as defined above, which is unsubstituted or substituted. The saturated heterocyclic group of 4 to 12 elements is unsubstituted or substituted, typically with one or more Z or R5 groups as defined above. Among the specific examples

Additional 50 of a saturated heterocyclic group of 4 to 12 elements (in which the heteroatom is O) include the following structures:

6

image2

Examples of a 4 to 7 element saturated nitrogen heterocyclic ring that is fused to a second ring as defined above to form a heteropolyclic ring system include a group selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine and homopiperazine, said group being fused with a second ring as defined above. The second ring is typically a saturated nitrogen heterocyclic ring of 4 to 7 elements as defined above or an unsaturated heterocyclic group of 5 to 12 elements. More typically, the second ring is a saturated nitrogenous heterocyclic ring of 5, 6 or 7 elements or an unsaturated heterocyclic ring of 5 to 7 elements. Typical examples of the second ring include azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, homopiperazine, pyrrole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrahydrofuran and tetrahydropyran. Examples of the resulting heteropolyclic system include octahydropyrrolo [1,2a] pyrazine and octahydropyrrolo [3,4-c] pyrrole. Specific examples of the heteropolyclic system include the

image4

Among the examples of a saturated nitrogen heterocyclic group of 4 to 7 elements as defined above that includes a bridgehead group - (CR'2) n- or - (CR'2) rO- (CR'2 ) s- as defined above include 3,8-diaza-bicyclo [3.2.1] octane, 2,5-diaza-bicyclo [2.2.1] heptane, 8-aza-bicyclo [3.2.1] octane , 2-aza-bicyclo [2.2.1] heptane, 3,6-diaza-bicyclo [3.1.1] heptane, 6-aza-bicyclo [3.1.1] heptane, 3,9-diazabicyclo [4.2.1] nonano and 3-oxa-7,9-diazabicyclo [3.3.1] nonane.

20 Specific examples of that group include the following structures:

7

image2

Examples of a group of formula (IIb) as defined above include groups derived from a saturated nitrogenous heterocyclic group of 4 to 7 elements as defined above that is fused spiro in any carbon atom. ring available to a saturated carbocyclic ring of 3 to 12 elements, typically a saturated carbocyclic ring of 3 to 6 elements, or a saturated nitrogen heterocyclic group of 4 to 7 elements. Examples include a group selected from azetidine, pyrrolidine, piperidine and piperazine, which is spiro-fused in an annular carbon atom with a group selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, azetidine, pyrrolidine, piperidine,

10 piperazine and tetrahydropyran.

The group of formula (IIb) can be, for example, a group derived from 3,9-diazaspiro [5.5] undecano, 2,7-diazaspiro [3.5] nonano, 2,8-diazaspiro [4.5] dean or 2.7 -diazaspiro [4.4] nonano. Specific examples of a group of formula (IIb) include the following structures:

fifteen

image2

8

image2

R4 is an indolyl group that is unsubstituted or substituted. The indolyl group can be attached to a thiazolopyrimidine core through any available ring position. It can be, for example, an indole-4-yl, indole-5-yl, indole-6-yl or indole-7-yl group. It is typically an indole-4-yl or indole-6-yl group, more typically an indole-4-yl group.

In case it is substituted, the indolyl can be substituted in one or more available ring positions. It typically carries a substituent in the benzene fraction of the indole group. For example, an indole-4yl group is typically substituted at the 5, 6 or 7 position, more typically at the 5 or 6 position. An indole-5-yl group is typically substituted at the 4, 6 or 7 position, more typically. in position 4 or 6. An indole-6-yl group is typically substituted in position 4, 5 or 7, more typically in position 4 or 5. An indole-7-yl group is typically substituted in position 4, 5 or 6, more typically in the 5 or 6 position.

In the event that the indolyl group is substituted, it can be substituted with a group Z or R5 as defined above. In a typical embodiment, the indolyl group is substituted with a group selected from R, -OR, -SR, -S (O) pR, CH2OR, -C (O) R, -CO2R, CF3, CF2OH, CH ( CF3) OH, C (CF3) 2OH, - (CH2) qOR, (CH2) qNR2, -C (O) N (R) 2, -NR2, -N (R) C (O) R, -S (O ) pN (R) 2, -OC (O) R, OC (O) N (R) 2, -N (R) S (O) pR, -NRC (O) N (R) 2, CN, halo, -NO2 and a 5-element heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from O, N and S, wherein R, p and q are as defined above in the definition of Z. In another embodiment Typically, the indolyl group is substituted with a group selected from C1-C6 alkyl, CN, halo, -C (O) NR2, C1-C6 haloalkyl, such as CF3, NO2, OR, SR, NR2, C (O ) R, SOR, SO2R, SO2NR2, NRC (O) R, CO2R and a 5-element heteroaryl group as defined above. In another more typical embodiment, the indolyl group is substituted with a group selected from CN, halo, -C (O) NR2, C1-C6 haloalkyl such as CF3, -SO2R, -SO2NR2 and a 5-element heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from O, N and S. In the aforementioned embodiments, R is typically H or C1-C6 alkyl.

Typically the substituent in the indolyl group is an electron acceptor group. In the event that the substituent Be a 5-element heteroaryl group, may be, for example, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole or thiadiazole.

In one embodiment, a substituted indole group is a substituted indole-4-yl group in the 5 or 6 position, particularly in

9

position 6, with CN, halo, -C (O) NH2, -CF3, -SO2Me, -SO2NMe or a 5-element heteroaryl group as defined above. Typically, the indole-4-yl group is substituted in the 5 or 6 position with halo, in particular with F. More typically, the indole-4-yl group is substituted in the 6-position with halo, in particular with F .

5 The parameter m in formula (I) is 0, 1 or 2. Typically m is 1 or 2. More typically m is 1.

In formula (I), a saturated heterocyclic group of 4 to 12 elements in the definitions of R1 and R2 may be a saturated heterocyclic ring of 4 to 7 elements that includes 0 or 1 additional heteroatom selected from N, S

10 and O. An unsaturated heterocyclic group of 5 to 12 elements in the definitions of R1 and R2 may be a heteroaryl group of 5 to 12 elements. An unsaturated carbocyclic group of 5 to 12 elements in the definitions of R1 and R2 may be an aryl group of 5 to 12 elements.

wherein: W represents a thiazole ring, R1 and R2 form, together with the N atom to which they are attached, a group with the following formula (IIa):

image5

image2

20 in which A is selected from:

(to)

 a saturated nitrogen heterocyclic ring of 4 to 7 elements that includes 0 or 1 additional heteroatom selected from N, S and O, the ring being unsubstituted or substituted,

(b)

 a saturated nitrogenous heterocyclic ring of 4 to 7 elements including 0 or 1 additional heteroatom

25 selected from N, S and O, the fused ring being found with a second ring selected from a saturated nitrogen heterocyclic ring of 4 to 7 elements as defined above, an unsaturated heterocyclic ring of 5 to 12 elements, a ring saturated oxygenated heterocyclic of 5 to 7 elements, a saturated carbocyclic ring of 3 to 12 elements and an unsaturated carbocyclic ring of 5 to 12 elements, forming a heteropolyclic ring system, the unsubstituted heteropolyclic ring system being found or

30 replaced,

(c) a saturated nitrogen heterocyclic ring of 4 to 7 elements that includes 0 or 1 additional heteroatom selected from N, S and O and further comprising joining two constituent atoms of the ring, a bridgehead group selected from - ( CR'2) n- and - (CR'2) rO- (CR'2) s-, in which each R 'is, independently, H or C1-C6 alkyl, n is 1, 2 or 3, r is 0 or 1 and s is 0 or 1, with the remaining ring positions found not

35 substituted or substituted, and

(d) a group of formula (IIb): elements, a saturated oxygenated heterocyclic ring of 5 to 7 elements or a saturated nitrogen heterocyclic ring of 4 to 7 elements as defined above, each being of B and B 'no replaced

image2

or replaced,

5 or one of R1 and R2 is C1-C6 alkyl and the other is a saturated nitrogen heterocyclic ring of 4 to 7 elements as defined above, or a C1-C6 alkyl group that is substituted with a heterocyclic ring group saturated nitrogen from 4 to 7 elements as defined above, m is 0, 1 or 2, R3 is H

or C1-C6 alkyl, and R4 is an indole group that is unsubstituted or substituted, or a pharmaceutically acceptable salt thereof.

10 The thiazole W ring in formula (I) adopts one of the two available regiochemical orientations. Thus, in one embodiment the thiazolopyrimidine is of the following formula (Ia):

image2

Wherein R1, R2, R3, R4 and m are as defined above for formula (I). In a second embodiment, the thiazolopyrimidine is of the following formula (Ib):

image6

Specific examples of compounds of the invention include the compounds listed in the Table below:

Table 1 (continued)

Compound No.

Structure Name

one

5- (6-Fluoro-1H-indole-4-yl) -2- (hexahydropyrrolo [3,4-c] pyrrol-2-ylmethyl) -7-morpholin-4-ylthiazolo [4,5-d] pyrimidine

2

image2 5- (6-Fluoro-1H-indole-4-yl) -2- (hexahydropyrrolo [3,4-c] pyrrol-2-ylmethyl) -7-morpholin-4-ylthiazolo [5,4-d] pyrimidine

3

image2 2- (2,7-Diaza-spiro [3.5] non-2-ylmethyl) -5- (1H-indol4-yl) -7-morpholin-4-yl-thiazolo [5,4-d] pyrimidine

4

image2 2- (2,7-Diaza-spiro [3.5] non-2-ylmethyl) -5- (6-fluoro1H-indole-4-yl) -7-morpholin-4-yl-thiazolo [5,4d] pyrimidine

5

image2 2- (2,7-Diaza-spiro [3.5] non-2-ylmethyl) -5- (5-fluoro1H-indole-4-yl) -7-morpholin-4-yl-thiazolo [5,4d] pyrimidine

Compound No.

Structure Name

6

image2 2- (3,8-Diaza-bicyclo [3.2.1] oct-3-ylmethyl) -5- (1H-indol4-yl) -7-morpholin-4-yl-thiazolo [5,4-d] pyrimidine

7

image2 2- (4-Azetidin-1-yl-piperidin-1-ylmethyl) -5- (1H-indole-4il) -7-morpholin-4-yl-thiazolo [5,4-d] pyrimidine

8

2 - [(S) -1- (Hexahydro-pyrrolo [1.2-a] pyrazin-2-yl) methyl] 5- (1H-indol-4-yl) -7-morpholin-4-yl-thiazolo [5, 4d] pyrimidine

9

image2 2- (3,5-Dimethyl-piperazin-1-ylmethyl) -5- (1H-indol-4-yl) 7-morpholin-4-yl-thiazolo [5,4-d] pyrimidine

10

image2 Format 2- (2,7-diaza-spiro [3.5] non-2-ilmethyl) -5 (6-fluoro-1H-indole-4-yl) -7-morpholin-4-yl-thiazolo [4,5d ] pyrimidine

Compound No.

Structure Name

eleven

image2 5- (1H-indole-4-yl) -7-morpholin-4-yl-2- (4-morpholin-4-ylpiperidin-1-ylmethyl) -thiazolo [4,5-d] pyrimidine

12

2- (3,3-Dimethylpiperazin-1-ylmethyl) -5- (5-fluoro-1Hindole-4-yl) -7-morpholin-4-yl-thiazolo [4,5-d] pyrimidine

13

image2 5- (5-Fluoro-1H-indole-4-yl) -7-morpholin-4-yl-2- (4morpholin-4-ylpiperidin-1-ylmethyl) -thiazolo [4,5d] pyrimidine

14

image2 5- (1H-indole-4-yl) -7-morpholin-4-yl-2- (4-morpholin-4-ylpiperidin-1-ylmethyl) -thiazolo [4,5-d] pyrimidine

fifteen

5- (5-Fluoro-1H-indole-4-yl) -2 - [(S) -1- (hexahydropyrrolo [1,2-a] pyrazin-2-yl) methyl] -7-morpholin-4-ylthiazolo [4,5-d] pyrimidine

Compound No.

Structure Name

16

2- (4-Azetidin-1-ylpiperidin-1-ylmethyl) -5- (5-fluoro-1Hindol-4-yl) -7-morpholin-4-yl-thiazolo [4,5-d] pyrimidine

17

2- (4-Azetidin-1-ylpiperidin-1-ylmethyl) -5- (1H-indole-4il) -7-morpholin-4-ylthiazolo [4,5-d] pyrimidine

18

2- (4-Cyclopropylmethylpiperazin-1-ylmethyl) -5- (5-fluoro1H-indole-4-yl) -7-morpholin-4-yl-thiazolo [4,5-d] pyrimidine

19

{1- [5- (5-Fluoro-1H-indol-4-yl) -7-morpholin-4-thiazolo [4,5-d] pyrimidin-2-ylmethyl] piperidine-4-yl} dimethylamine

twenty

{1- [5- (1H-Indol-4-yl) -7-morpholin-4-ylthiazolo [4,5d] pyrimidin-2-ylmethyl] piperidin-4-yl} dimethylamine

Compound No.

Structure Name

twenty-one

image2 {2- [5- (5-Fluoro-1H-indole-4-yl) -7-morpholin-4-thiazolo [4,5-d] pyrimidin-2-ylmethyl] -piperazin-1-yl} isobutyramide

22

image2 2- (4-Azetidin-1-ylpiperidin-1-ylmethyl) -5- (5-fluoro1H-indol-4-yl) -7-morpholin-4-yl-thiazolo [5,4d] pyrimidine

2. 3

5- (S-Fluoro-1H-indole-4-yl) -7-morpholin-4-yl-2piperazin-1-ylmethylthiazolo [5,4-d] pyrimidine

24

image2 2- (4-Cyclopropylpiperazin-1-ylmethyl) -5- (5-fluoro1H-indole-4-yl) -7-morpholin-4-ylthiazolo [5,4d] pyrimidine

25

image2 2- {4- [5- (1H-Indol-4-yl) -7-morpholin-4-ylthiazolo [5,4d] pyrimidin-2-ylmethyl] piperazin-1-yl} isobutyramide

Compound No.

Structure Name

26

image2 2- {4- [5- (5-Fluoro-1H-Indol-4-yl) -7-morpholin-4-thiazolo [5,4-d] pyrimidin-2-ylmethyl] piperazin-1-yl} isobutyramide

27

{1- [5- (1H-Indol-4-yl) -7-morpholin-4-ylthiazolo [5,4d] pyrimidin-2-ylmethyl] piperidin-4-yl} dimethylamine

28

5- (1H-indole-4-yl) -7-morpholin-4-yl-2- (4-morpholin-4-ylpiperidin-1-ylmethyl) -thiazolo [5,4-d] pyrimidine

29

5- (5-Fluoro-1H-indole-4-yl) -7-morpholin-4-yl-2- (4morpholin-4-ylpiperidin-1-ylmethyl) thiazolo [5,4d] pyrimidine

and pharmaceutically acceptable salts thereof.

A suitable synthetic strategy for producing a thiazolopyrimidine of formula (I) uses the carboxaldehyde precursor of formula (III):

image2

in which W is as defined above. Starting from this precursor, the synthesis comprises carrying out, in any order, a reductive amination and a cross coupling reaction (Suzuki type) mediated by palladium.

In this way a compound of the invention can be produced by a method comprising treating

a compound of formula (III):

wherein W is as defined above, with an amine of formula NHR image2 1aR2a in which R1a and R2a are as defined above for R1 and R2 or R1a and R2a are as defined above for R1 and R2, in which an atom of N is present and protected with a group amine protector, in the presence of a suitable reducing agent, treating the resulting compound of formula (IV):

image2

10 in which W, R1a and R2a are as defined above, with a boronic acid or ester thereof of formula R4B (OR15) 2, in which R4 is as defined above and each R15 is H or C1-C6 alkyl or the two OR15 groups together, together with the boron atom to which they are attached, a boronate pinacholate ester group, in the presence of a Pd catalyst and, in the event that R1a and / or R2a include an amine protective group, the removal of the protective group. Any suitable amine protecting groups may be used in

R1a and / or R2a, for example a butoxycarbonyl group (BOC).

A compound of formula (I) can also be produced by a method comprising treating a compound of formula (III):

image2

twenty

wherein W is as defined above, with a boronic acid or ester thereof of formula R4B (OR15) 2 in which R4 is as defined above and each R15 is H or C1-C6 alkyl, or the two OR15 groups form, together with the boron atom to which they are attached, a pinacolato ester group

Boronate, in the presence of a Pd catalyst, treating the resulting compound of formula (V): in which W and R4 are as defined above, with an amine of formula NHR1aR2a in which R1a and R2a are as defined above, in the presence of a suitable reducing agent and, in the case that R1a

image2

5 and / or R2a include an amine protecting group, the removal of the protecting group. In the present embodiment of the process, the N atom of the indole group R4 can, if necessary, be protected before treating the compound of formula (V) with the amine of formula NHR1aR2a, for example as discussed further below and as It is shown in Scheme 5, below: In this case, the indole protecting group is removed at a later stage.

10 Both the reductive amination stage and the Pd-mediated cross-coupling stage take place under conventional conditions. The palladium catalyst can be any of those typically used for cross couplings of the Suzuki type, such as PdCl2 (PPh3) 2. The reducing agent in the amination step is typically a borohydride, for example NaBH (OAc) 3, NaBH4 or NaCNBH3, in particular NaBH (OAc) 3.

A compound of formula (III) can also be produced as defined above by a

image7

20 in which W is as defined above under suitable conditions. The oxidation can be carried out, for example, using SeO2 in dioxane.

A compound of formula (III) can also be produced as defined above by a

25

wherein W is as defined above, with a deprotonating agent and then with dimethylformamide at -78 ° C increasing to room temperature. A suitable deprotonating agent is a lithiating agent, for example alkyl lithium, such as n-butyllithium in the presence of trimethylethylenediamine in THF at -78 ° C.

A compound of formula (VI) or (VII) can also be produced as defined above by a method comprising treating a compound of formula (VIII):

image8

image2

5 wherein W is as defined above and R '' is H or CH3 with a chlorinating agent followed by morpholine in a suitable solvent, for example methanol at room temperature. A suitable chlorinating agent is POCl3 in PhNMe2. This reaction is conveniently carried out at about 100 ° C.

A compound of formula (VIII) can be prepared by known methods or analogously to methods

10 known. For example, included in the formula (VIII) are compounds that have the following formulas (VIIIa) and (VIIIb):

image2

These can be prepared, respectively, as shown in the following schemes 1 and 2, in which they are present as synthetic intermediates.

An additional compound of formula (VIII) has the formula (VIIIc) below:

image2

Said compound can be prepared as described in the literature, for example in M. Sekiya, Y. Osaki Chem. Pharm. Bull. 13: 1319-1325, 1965; S.J. Childress, R.L. McKee, J. Am. Chem. Soc. 73: 3862-3864, 1952, and US Patent No. 2933498.

An alternative synthetic strategy for producing a thiazolopyrimidine of formula (I) involves joining the R4 group to the

25 thiazolopyrimidine nucleus by Suzuki coupling and then protect the N atom from the indole of the R4 group, prior to the introduction of the -CHO fraction that is subjected to reductive amination. The process comprises oxidizing a compound of formula (IX):

image2

wherein W is as defined above and R4a is a group R4 as defined above in which the N atom of the indole is protected, under suitable conditions. The N atom of the indole is protected with any suitable protecting group, for example a toluenesulfonyl group. Oxidation can take away

5

wherein W and R4a are as defined above. The compound of formula (X) is then subjected to reductive amination by treatment with an NHR1aR2a compound as defined above. Subsequently, any protective group is removed. This strategy is illustrated in scheme 5, below.

The thiazolopyrimidines of formula (I) can be converted into pharmaceutically acceptable salts, and the salts can be converted into the free compound, by conventional methods. Pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, and salts of organic acids such as acetic acid, oxalic acid, malic acid, methanesulfonic acid, acid

Trifluoroacetic acid, benzoic acid, citric acid and tartaric acid. In the case of compounds of the invention bearing a free carboxy substituent, the salts include both the above-mentioned acid addition salts such as sodium, potassium, calcium or ammonium salts. The latter are prepared by treatment of the free thiazolopyrimidine of formula (I), or an acid addition salt thereof, with the corresponding metal base or ammonium.

It has been found in biological tests that the compounds of the present invention are inhibitors of PI3 kinase. The compounds are selective for the isoform p110δ, which is a class of a PI3 kinase of class Ia, with respect to other PI3 kinases of class Ia. Thus, they are selective for the p110δ isoform with respect to both the p110α isoform and the p110β isoform. In particular, they are selective for p110δ with respect to p110β. The compounds are also selective for the p110δ isoform with respect to p110γ, which is a class Ib kinase.

The selectivity shown by the compounds of the invention for p110δ with respect to other PI3 kinase isoforms is of at least factor 2. Typically the selectivity is of factor 5 or 10 or 20 or 50, increasing to 100 or higher in many cases. In this way, the compounds can be selective with a factor of 2, 5, 10, 20, 50 or 100 for p110δ with respect to p110β. It can also be selective with a factor of 2, 5, 10, 20, 50 or 100 for

30 p110δ with respect to p110α or p110γ.

A compound of the present invention can be used as a PI3 kinase inhibitor, in particular of a class Ia PI3 kinase. Accordingly, a compound of the present invention can be used to treat a disease or disorder that appears as a consequence of cell growth, function or behavior.

Abnormal associated with the PI3 kinase, in particular the PI3 kinase of isoform p110δ. Examples of such diseases and disorders are discussed in Drees et al., Expert Opin. Ther. Patents 14 (5): 703-732, 2004. These include proliferative disorders such as cancer, immune disorders, cardiovascular diseases, viral infections, inflammation, metabolism / endocrine disorders and neurological disorders. Examples of metabolic / endocrine disorders include diabetes and obesity. Among the examples of cancers with

Those that can be used in the present compounds in a treatment include leukemia, brain tumors, renal cancer, gastric cancer and cancer of the skin, bladder, breast, uterus, lung, colon, prostate, ovary and pancreas.

image9

A compound of the present invention can be used as a PI3 kinase inhibitor. A human or animal patient suffering from a disease or disorder that appears as a result of abnormal cell growth, function or behavior associated with the PI3 kinase, in particular the PI3 kinase of isoform p110δ, such as an immune disorder, a cardiovascular disease, a Viral infection, inflammation, a metabolic / endocrine disorder or a neurological disorder can be treated in this way, using a method comprising the administration in said patient of a compound of the present invention as defined above. A human or animal patient suffering from cancer can also be treated using a method comprising the administration therein of a compound of the present invention as defined above. The patient's condition can, in this way, be improved or relieved.

A compound of the present invention can be administered in a variety of dosage forms, for example orally, such as in the form of tablets, capsules, sugar-coated tablets or a film, liquid solutions or suspensions, or parenterally, for example intramuscularly, intravenously or subcutaneously. Therefore, the compound can be provided by injection or infusion.

The dose depends on a variety of factors, including the age, weight and condition of the patient and the route of administration. Daily doses may vary within wide limits and will be adjusted to the individual requirements in each particular case. However, typically the dose adopted for each route of administration in the event that a compound is administered alone in adult humans is between 0.0001 and 50 mg / kg, more commonly between 0.001 and 10 mg / kg. body weight, for example between 0.01 and 1 mg / kg. Said dose may be administered, for example, 1 to 5 times a day. For intravenous injection an adequate daily dose is between 0.0001 and 1 mg / kg of body weight, preferably between 0.0001 and 0.1 mg / kg of body weight. A daily dose may be administered as a single dose or according to a divided dose schedule.

A compound of the invention is formulated for use as a pharmaceutical or veterinary composition which also comprises a pharmaceutically or veterinarily acceptable carrier or diluent. The compositions are typically prepared according to conventional methods and are administered in a pharmaceutically or veterinarily suitable form. The compound can be administered in any conventional form, for example as follows:

A) Orally, for example in the form of tablets, coated tablets, dragees, troches, tablets, aqueous or oily suspensions, liquid solutions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the preparation of pharmaceutical compositions and said compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives in order to provide pharmaceutically elegant and edible preparations.

The tablets contain the active ingredient mixed with pharmaceutically acceptable non-toxic excipients that are suitable for the preparation of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, dextrose, sucrose, cellulose, corn starch, potato starch, calcium phosphate or sodium phosphate; granulating agents and disintegrants, for example corn starch, alginic acid, alginates or sodium starch glycolate; binding agents, for example starch, gelatin or acacia; lubricating agents, for example silica, magnesium or calcium stearate, stearic acid or talc; effervescent mixtures; pigments, sweeteners, wetting agents such as lecithin, polysorbates or lauryl sulfate. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thus provide sustained action for a longer period of time. For example, a temporary delay material such as glycerol monostearate or distearate can be used. Such preparations can be manufactured in a known manner, for example by means of mixing, granulating, tableting or coating processes with sugar or film.

Formulations for oral use may also be presented in the form of hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules, in the that the active ingredient is present without modification, or mixed with water or an oily medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active mixing materials with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; dispersing or wetting agents may be naturally occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxyethanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides , for example polyoxyethylene sorbitan monooleate.

Such aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents such as sucrose or saccharin.

The oily suspension can be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.

Sweetening agents, such as those indicated above, and flavoring agents, may be added to provide an edible oral preparation. Such compositions can be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in the mixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. The suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients may also be present, for example sweetening, flavoring and coloring agents.

The pharmaceutical compositions of the invention can also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be gums of natural origin, for example acacia gum or tragacanth gum, phosphatides of natural origin, for example soy lecithin, and partial esters or esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters and ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs can be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. In particular, a syrup for diabetic patients may contain as carriers only products, for example sorbitol, that are not metabolized to form glucose or that are only metabolized into glucose in a very small amount.

Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

B) Parenterally, subcutaneously, or intravenously, or intramuscularly, or intrasternally, or by infusion techniques, in the form of sterile injectable aqueous or oleaginous suspensions. This suspension can be formulated according to the known technique using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation can also be a solution

or sterile injectable suspension in a nontoxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol. Suitable vehicles and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvent or suspension medium. For this purpose, any mild fixed oil, including synthetic monoglycerides or diglycerides, can be used. In addition, fatty acids such as oleic acid are useful in the preparation of injectables. C) By inhalation, in the form of aerosols or solutions for nebulizers. D) Rectally, in the form of suppositories prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum, releasing the drug. Such materials are cocoa butter and polyethylene glycols. E) Topically, in the form of creams, ointments, jellies, eye drops, solutions or suspensions.

The invention is further described in the following Examples:

EXAMPLES

General synthetic procedure

The following general schemes 1 to 6 illustrate routes to obtain compounds of formula (I). Schemes 7 and 8 illustrate routes to obtain intermediates used in the synthesis of compounds of formula (I).

image2

image2

image2

image2

image2

General experimental data:

NMR spectroscopy

NMR spectra were obtained on a Varian Unity Inova 400 spectrometer with a reverse detection probe

5 for triple resonance 5 mm operating at 400 MHz or on a Bruker Avance DRX 400 spectrometer with a 5 mm TXI triple resonance reverse detection probe or on a Bruker Avance DPX 300 spectrometer with a standard 5 mm double frequency probe operating at 300 MHz. Offsets are given in ppm relative to tetramethylsilane.

10 Purification by column chromatography

Compounds purified by column chromatography were purified using silica gel or an Isolute® cartridge or a Redisep® cartridge, eluting with gradients of 100-0 to 0-100% cyclohexane / EtOAc, or 100-0 to 0100% of pentane / EtOAc, or 100-0 to 70-30% DCM / MeOH (with or without the addition of 0.1% NH3). The expression

"Silica gel" refers to silica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (for example Fluka 60 silica gel), and an applied nitrogen pressure of up to 10 p.s.i. for accelerated elution of the column. In the case of the use of thin layer chromatography (TLC), it refers to silica gel TLC using plates, typically a 3x6 cm column of silica gel in aluminum foil plates with a fluorescent indicator (254 nm) ( for example Fluka 60778).

twenty

Purification by preparative HPLC:

Compounds purified by preparative HPLC were purified using a reverse phase C18 column

(i.d. 100 x 22.5 mm, Genesis column with particle size of 7 mm, UV detection at 230 or 254 nm,

25 flow rate: 5 to 15 ml / minute) or a phenyl-hexyl column (id 250 x 21.2 mm, Gemini column with particle size of 5 mm, UV detection at 230 or 254 nm, flow rate: 5 a 20 ml / minute), eluting with gradients of 100-0% to 0-100% water / acetonitrile or water / MeOH containing 0.1% TFA or water / acetonitrile containing 0.1% formic acid. The free base was released by division between EtOAc and a saturated sodium bicarbonate solution. The organic layer was dried (MgSO4) and concentrated in vacuo. Alternatively, the free base was released

30 by passing it through an Isolate® SCX-2 cartridge, eluting with NH3 in methanol.

Microwave assisted reactions:

Microwave experiments were carried out using a Personal Chemistry Smith synthesizer or a Biotage 35 InitiationTM, which uses a single mode resonator and dynamic field adjustment, providing both reproducibility and control. Temperatures between 40ºC and 250ºC and pressures up to 20 bar can be reached.

All commercial solvents and reagents were used without modification. Reagents / reactants not commercially available were prepared following procedures described in the literature.

40 Abbreviations used in the experimental section: iPrOH = isopropanol

here

= aqueous

BOC

= t-Butoxycarbonyl

bs

= wide singlet (NMR)

Cs2CO3

= cesium carbonate

d

= double (NMR)

DCM

= dichloromethane

DIPEA

= diisopropylethylamine

 Dma

= dimethylacetamide

DMAP

= dimethylaminopyridine

 DMF

dimethylformamide

DMSO

= dimethylsulfoxide

eq.

= equivalent

EtOAc

= ethyl acetate

EtOH

= ethanol

h

= one or more hours

 HEY YOU

= O- (7-azabenzotriazol-1-yl) -N, N, N ’, N’-tetramethyluronium hexafluorophosphate

 HCl

= hydrochloric acid

H2O

= water

image10

LCMS = liquid chromatography-mass spectrometry

M = molar

m = multiplet (NMR)

MeOH = methanol

mg = milligram

MgSO4 = magnesium sulfate

min = one or more minutes

ml = milliliter

Na2CO3 = sodium carbonate

NaHCO3 = sodium hydrogen carbonate

NaOH = sodium hydroxide

Na2SO4 = sodium sulfate

NMR = nuclear magnetic resonance

q = quartet (NMR)

Rt = retention time

RT = room temperature

sat = saturated

t = triplet (NMR)

TBAF = tetrabutylammonium fluoride

TBS = t-butyldimethylsilyl

TFA = trifluoroacetic acid

THF = tetrahydrofuran

TLC = thin layer chromatography

Xanftos = 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene

Reference example 1: Formation of boronate ester

5 The boronate ester product of the final stage of the above-mentioned schemes 1 to 4, of the

as follows: to a solution of halide (1 eq.) and bis (pinacolato) diboro (1.3 eq.) in DMSO KOAc (3

eq.) and [1,1'-bis (diphenylphosphine) ferrocene] -dichloropaladium (0.05 eq.). The mixture was heated to 90 ° C until complete

reaction. The reaction mixture was partitioned between EtOAc and H2O. The organic layer was washed successively with H2O and

Hypersaline solution, dried over Na2SO4 and evaporated to dryness. Then, the resulting residue 10 was purified by column chromatography.

Reference Example 2: Suzuki Coupling

image2

image2

The following methods were used for Suzuki coupling reactions illustrated in Schemes A and B above.

Method A

A mixture of the appropriate 5-chlorothiazolopyrimidine (1 eq.), Na2CO3 (2 eq.), The appropriate indole boronate ester (1.5 eq.) And bis (triphenylphosphine) palladium (II) chloride (0.1 eq. .) in acetonitrile / water (2: 1) was heated at 140 ° C for 20 to 50 minutes in a microwave reactor. The resulting mixture was diluted with water and then extracted with ethyl acetate. The pooled organic extracts were dried (Na2SO4), filtered and concentrated in vacuo and then purified by HPLC or column chromatography to provide the desired product. Alternatively, the reaction mixture was loaded into an Isolate® SCX-2 cartridge, washed with MeOH and then eluted with 2M NH3 in MeOH. Then, the resulting residue was purified by preparative HPLC or column chromatography to provide the desired product.

Method B

A mixture of the appropriate 5-chlorothiazolopyrimidine (1 eq.), Cs2CO3 (1.5 eq.), The appropriate indole boronate ester (1.2 eq.) And tetracis (triphenylphosphine) palladium (0.05 eq.) In Dioxane / water (3: 1) was heated at 125 ° C for 10 to 30 minutes in a microwave reactor. The resulting mixture was diluted with water and then extracted with ethyl acetate. The pooled organic extracts were dried (MgSO4), filtered and concentrated in vacuo and then purified by HPLC or column chromatography to provide the desired product. Alternatively, the reaction mixture was loaded into an Isolate® SCX-2 cartridge, washed with MeOH and then eluted with 2M NH3 in MeOH. Then, the resulting residue was purified by preparative HPLC or column chromatography to provide the desired product.

Method C

A mixture of the appropriate 5-chlorothiazolopyrimidine (1 eq.), Cs2CO3 (1.5 eq.), The appropriate indole-boronic acid (1.2 eq.) And tetracis (triphenylphosphine) palladium (0.05 eq.) In Dioxane / water (3: 1) was heated at 125 ° C for 10 to 30 minutes in a microwave reactor. The resulting mixture was diluted with water and then extracted with ethyl acetate. The pooled organic extracts were dried (MgSO4), filtered and concentrated in vacuo and then purified by preparative HPLC or column chromatography to provide the desired product. Alternatively, the reaction mixture was loaded into an Isolate® SCX-2 cartridge, washed with MeOH and then eluted with 2M NH3 in MeOH. Then, the resulting residue was purified by preparative HPLC or column chromatography to provide the desired product.

Method D

A mixture of the appropriate 5-chlorothiazolopyrimidine (1 eq.), Cs2CO3 (1.5 eq.), The appropriate indole-boronic acid (1.2 eq.) And tetracis (triphenylphosphine) palladium (0.05 eq.) In Acetonitrile / water (3: 1) was heated at a temperature between 125 ° C and 140 ° C for 10 to 30 minutes in a microwave reactor. The resulting mixture was diluted with water and then extracted with ethyl acetate. The pooled organic extracts were dried (MgSO4), filtered and concentrated in vacuo and then purified by preparative HPLC or column chromatography to provide the desired product. Alternatively, the reaction mixture was loaded into an Isolate® SCX2 cartridge, washed with MeOH and then eluted with 2M NH3 in MeOH. Then, the resulting residue was purified by preparative HPLC or column chromatography to provide the desired product.

Method E

A mixture of the appropriate 5-chlorothiazolopyrimidine (1 eq.), Cs2CO3 (1.5 eq.), The appropriate indole boronate ester (1.2 eq.) And tetracis (triphenylphosphine) palladium (0.05 eq.) In Acetonitrile / water (3: 1) was heated at 140 ° C for 10 to 30 minutes in a microwave reactor. The resulting mixture was diluted with water and then extracted with acetate.

5 ethyl. The pooled organic extracts were dried (MgSO4), filtered and concentrated in vacuo and then purified by HPLC or column chromatography to provide the desired product. Alternatively, the reaction mixture was loaded into an Isolate® SCX-2 cartridge, washed with MeOH and then eluted with 2M NH3 in MeOH. Then, the resulting residue was purified by preparative HPLC or column chromatography to provide the desired product.

10

F method

A mixture of the appropriate 5-chlorothiazolopyrimidine (1 eq.), Na2CO3 (1.5 eq.), The appropriate indole boronate ester (1.2 eq.) And tetracis (triphenylphosphine) palladium (0.1 eq.) In Acetonitrile / water (2: 1) was heated at 140 ° C for 10 to 30 minutes in a microwave reactor. The resulting mixture was diluted with water and then extracted with ethyl acetate. The pooled organic extracts were dried (MgSO4), filtered and concentrated in vacuo and then purified by preparative HPLC or column chromatography to provide the desired product. Alternatively, the reaction mixture was loaded into an Isolate® SCX-2 cartridge, washed with MeOH and then eluted with 2M NH3 in MeOH. Then, the resulting residue was purified by preparative HPLC or

20 column chromatography, providing the desired product.

G method

A mixture of the appropriate 5-chlorothiazolopyrimidine (1 eq.), Na2CO3 (1.5 eq.), The appropriate indole-boronic acid

25 (1.2 eq.) And tetracis (triphenylphosphine) palladium (0.1 eq.) In acetonitrile / water (2: 1) was heated at 140 ° C for 10 to 30 minutes in a microwave reactor. The resulting mixture was diluted with water and then extracted with ethyl acetate. The pooled organic extracts were dried (MgSO4), filtered and concentrated in vacuo and then purified by preparative HPLC or column chromatography to provide the desired product. Alternatively, the reaction mixture was loaded into an Isolate® SCX-2 cartridge, washed with MeOH and then

30 eluted with 2M NH3 in MeOH. Then, the resulting residue was purified by preparative HPLC or column chromatography to provide the desired product.

Reference Example 3

Deprotection of t-butoxycarbonyl

To a DCM solution of the protected BIA protected thiazolopyrimidine was added TFA and the resulting solution was stirred at room temperature for 30 to 180 minutes. The resulting mixture was diluted with water, neutralized with saturated aqueous NaHCO3 solution and then extracted with DCM. The pooled organic extracts were dried (MgSO4 or Na2SO4), filtered and concentrated in vacuo and then purified by HPLC

Preparative or column chromatography, providing the desired product. Alternatively, the reaction mixture was loaded into an Isolate® SCX-2 cartridge, washed with MeOH and then eluted with 2M NH3 in MeOH. Then, the resulting residue was purified by preparative HPLC or column chromatography to provide the desired product.

45 Reference Example 4 Deprotection of TBS:

To a THF solution of the relevant TBS-protected 1H-indole-4-yl-thiazolopyrimidine was added TBAF and the resulting solution was stirred at room temperature for 30 minutes and then concentrated in vacuo. Alternatively, the

The resulting solution was diluted with hypersaline solution and then extracted with DCM. The pooled organic extracts were dried (MgSO4 or Na2SO4), filtered and concentrated in vacuo. In either case, the resulting residue was purified by preparative HPLC or column chromatography to provide the desired product.

Reference Example 5 5-Amino-2-methyl-thiazol-4-carboxylic acid ethyl ester

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To a solution of ethyl acetylamino-cyanoacetic acid ethyl ester (27.2 g, 0.160 mol) in anhydrous toluene (300 ml),

Lawesson reagent (32.0 g, 0.079 mol) was added and the resulting mixture was heated under reflux for 18 hours. The resulting yellow suspension was partitioned between an aqueous solution of HCl (1 M) and tert-butyl methyl ether. The layers were separated and the organic layer was extracted with an aqueous solution of HCl (1 M). The pooled organic layers were basified to pH 10 with an aqueous solution of NaOH (2 M) and then extracted with EtOAc.

The organic layer was isolated, dried (Na2SO4) and concentrated in vacuo to give the title compound as a pale yellow solid (17.0 g, 57%). [M + H] + 187.0

Reference Example 6 2-Methyl-5-ureido-thiazol-4-carboxylic acid ethyl ester

10

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To a solution of ethyl ester of 5-amino-2-methyl-thiazol-4-carboxylic acid (15.0 g, 0.081 mol) in DCM (550 ml) was added chlorosulfonyl isocyanate (8.92 ml, 0.102 mol ) drop by drop at -78 ° C. The dense suspension was allowed to warm to room temperature and stirred for 45 minutes. The resulting precipitate was collected

15 by filtration and dried under vacuum. The resulting white solid was suspended in an aqueous HCl solution (6 M, 400 ml) and heated at 90 ° C for 1 hour. The resulting solution was cooled to 0 ° C and the pH was adjusted to 5 with an aqueous solution of NaOH (6 M). The resulting precipitate was collected by filtration and dried under vacuum at 60 ° C for 36 hours to provide the title compound (16.4 g, 89%). [M + H] + 230.0

Reference Example 7 2-Methyl-4H-thiazolo [5,4-d] pyrimidin-5,7-dione

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To a suspension of 2-methyl-5-ureido-thiazol-4-carboxylic acid ethyl ester (21.0 g, 0.079 moles9 in iPrOH (300 ml)

An aqueous solution of NaOH (3 M, 26 ml, 0.078 mol) was added at 80 ° C. The dense white suspension was heated at 80 ° C for 45 minutes, then diluted with H2O and cooled to 0 ° C. The reaction mixture was acidified to pH 3 and the precipitate was collected by filtration. The white solid was washed with H2O and dried under vacuum at 60 ° C for 17 hours to provide the title compound as a white solid (12.3 g, 83%). 1 H NMR (DMSO-D6, 300 MHz): δ 2.56 (s, 3 H).

30

Reference Example 8 5,7-Dichloro-2-methyl-thiazolo [5,4-d] pyrimidine

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To a mixture of 2-methyl-4H-thiazolo [5,4-d] pyrimidin-5,7-dione (7.5 g, 0.041 mol) in N, N-dimethylaniline (3.7 ml, 0.029 mol) phosphorus oxychloride (38.0 ml, 0.410 mol) was added and the mixture was heated at 130 ° C for 4 hours. The resulting black solution was cooled to room temperature, then gently cooled with crushed ice and H2O, before extracting it with EtOAc. The organic layer was isolated, dried (MgSO4) and concentrated in vacuo,

40 providing a yellow solid. The solid was dissolved in DCM, then washed with an aqueous NaHCO3 solution followed by hypersaline solution, dried (Na2SO4) and concentrated in vacuo to give the title compound as a pale yellow solid (4.90 g, 54%) 1 H NMR (CDCl 3, 300 MHz): δ 2.95 (s, 3 H).

Reference Example 9 5-Chloro-2-methyl-7-morpholin-4-yl-thiazolo [5,4-d] pyrimidine

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To a solution of 5,7-dichloro-2-methyl-thiazolo [5,4-d] pyrimidine (4.1 g, 18.72 mmol) in MeOH (100 ml) was added morpholine (3.26 ml, 37.44 mmol) at 0 ° C and the mixture was stirred at 0 ° C for 30 minutes. The resulting precipitate was collected by filtration and dried in vacuo at 40 ° C to give the title compound as a cream solid (4.42 g, 89%). 1 H NMR (CDCl 3, 300 MHz): δ 2.74 (s, 3 H), 3.80-3.86 (m, 4 H) and 4.35 (m, 4 H).

10

Reference Example 10 5- (1H-Indol-4-yl) -2-methyl-7-morpholin-4-yl-thiazolo [5,4-d] pyrimidine

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Prepared by the Suzuki coupling method of Reference Example 2, using 5-chloro-2-methyl-7morpholin-4-yl-thiazolo [5,4-d] pyrimidine. The title compound was obtained as a white solid (130 mg, 50%). [M + H] + 352.9

Reference Example 11 20 4-Hydroxy-2-methyl-thiazol-5-carboxylic acid ethyl ester

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To a solution of thioacetamide (17.2 g, 0.229 mol) in toluene (130 ml) was added diethyl bromomalonate (55.0

25 g, 0.230 mol) and the mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, filtered through Celite and then concentrated in vacuo. The resulting solid was triturated with hexane to give the title compound as a yellow solid (11.0 g, 26%). 1 H NMR (CDCl 3, 400 MHz): δ 1.36 (t, J = 7.1 Hz, 3 H), 2.67 (s, 3 H) and 4.35 (q, J = 7.1 Hz, 2 H).

Reference Example 12 2-Methyl-4- (Toluen-4-Sulfonyloxy) -thiazole-5-carboxylic acid ethyl ester

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To a solution of ethyl ester of 4-hydroxy-2-methyl-thiazol-5-carboxylic acid (5.0 g, 26.74 mmol) in chloroform (80 ml) was added p-toluenesulfonyl chloride (5, 61 g, 29.41 mmol) and triethylamine (4.84 ml, 34.76 mmol) at 0 ° C. The reaction mixture was allowed to warm to room temperature for 4 hours and then diluted with DCM and H2O. The organic layer was separated, washed with H2O and saturated hypersaline solution, then dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography, providing the

The title compound in the form of a pale brown solid (8.1 g, 89%).

1 H NMR (CDCl 3, 400 MHz): δ 1.34 (t, J = 7.1 Hz, 3 H), 2.47 (s, 3 H), 2.64 (s, 3 H), 4.30 (q, J = 7.1 Hz, 2 H), 7.37 (d, J = 8.1 Hz, 2 H) and 7.94 (d, J = 8.1 Hz, 2 H).

Reference Example 13 4-Benzylamino-2-methyl-thiazol-5-carboxylic acid ethyl ester

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To a solution of 2-methyl-4- (toluene-4-sulfonyloxy) -thiazole-5-carboxylic acid ethyl ester (2.0 g, 5.865 mmol) in 1,4-dioxane (50 ml) was added benzylamine (1 , 92 ml, 17.6 mmol) and the mixture was heated at 120 ° C for 6 hours. The

The reaction mixture was cooled to room temperature and partitioned between EtOAc and an aqueous solution of HCl (1 M). The organic layer was isolated, washed with saturated hypersaline solution, then dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography to provide the title compound as a yellow solid (0.80 g, 49%). 1 H NMR (CDCl 3, 300 MHz): δ 1.31 (t, J = 7.1 Hz, 3 H), 2.60 (s, 3 H), 4.24 (q, J = 7.1 Hz, 2 H), 4.76 (d, J = 6.1 Hz, 2

15 H), 7.07 (bs, 1 H) and 7.21-7.38 (m, 5 H).

Reference Example 14 4-Benzyl-2-methyl-4H-thiazolo [4,5] pyrimidin-5,7-dione

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twenty

To a solution of ethyl ester of 4-benzylamino-2-methyl-thiazol-5-carboxylic acid (0.40 g, 1.45 mol) in DCM (10 ml) was added chlorosulfonyl isocyanate (140 ml, 1, 59 mmol) drop by drop at -78 ° C. The mixture was allowed to warm to room temperature and stirred for 30 minutes. The resulting solution was concentrated in vacuo 25 and then dissolved in acetone (5 ml), before adding H2O (2 ml) dropwise. The mixture was stirred at room temperature for 30 minutes and then concentrated in vacuo. The resulting oil was divided between EtOAc and H2O. The organic layer was isolated, washed with hypersaline solution, dried (MgSO4) and concentrated in vacuo to afford 4- (1-benzyl-ureido) -2-methyl-thiazole-5-carboxylic acid ethyl ester as of a pale brown oil. To a solution of 4- (1-benzyl-ureido) -2-methyl-thiazol-5-carboxylic acid ethyl ester in MeOH (10 ml) was added a solution of

30 sodium methoxide in MeOH (25% w / w, 1.33 ml, 5.80 mmol) and the mixture was stirred at room temperature for 18 hours. The crude reaction mixture was concentrated in vacuo and partitioned between EtOAc and an aqueous solution of HCl (1 M). The organic layer was isolated, washed with saturated hypersaline solution, then dried (MgSO4) and concentrated in vacuo. The resulting residue was triturated with EtOAc to provide the title compound as a pale yellow solid (0.25 g, 63%).

1 H NMR (DMSO-D6, 300 MHz): δ 2.76 (s, 3 H), 5.25 (s, 2 H), 7.19-7.40 (m, 5 H) and 11.71 (s , 1 HOUR).

Reference Example 15

2-Methyl-4H-thiazolo [4,5-d] pyrimidin-5,7-dione

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40

Method A

To a solution of 4-benzyl-2-methyl-4H-thiazolo [4,5-d] pyrimidin-5,7-dione (3.80 g, 13.87 mmol) in xylene (40 ml) was added tribromide of boron (5.34 ml, 55.47 mmol) dropwise at 120 ° C. The reaction mixture was heated to 170 ° C.

45 for 1 hour, then cooled to 0 ° C, before slowly adding MeOH (30 ml). The resulting precipitate was collected by filtration, washed with MeOH followed by H2O and then dried under vacuum at 80 ° C to give the title compound as a white solid (2.3 g, 91%).

1 H NMR (DMSO-D6, 400 MHz): δ 2.73 (s, 3 H).

Method B

To a solution of 6-benzyl-2-methyl-4H-thiazolo [4,5-d] pyrimidin-5,7-dione (6 g, 22 mmol) in xylene (120 ml) was added boron tribromide (8 , 3 ml, 88 mmol) dropwise at 120 ° C. The reaction mixture was heated at 170 ° C for 1 hour, then cooled to 0 ° C, before slowly adding MeOH (30 ml). The resulting precipitate was collected by filtration, washed with MeOH followed by H2O and then dried in vacuo at 50 ° C to give the title compound as a white solid (4.0 g, 100%).

1 H NMR (DMSO, 400 MHz): δ 2.73 (s, 3 H).

Reference Example 16

5,7-Dichloro-2-methyl-thiazolo [4,5-d] pyrimidine

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Prepared using the method used in the preparation of 5,7-dichloro-2-methyl-thiazolo [5,4-d] pyrimidine using 2-methyl-4H-thiazolo [4,5-d] pyrimidine-5,7 -diona instead of 2-methyl-4H-thiazolo [5,4-d] pyrimidin-5,7-dione. The title compound was obtained as a white solid (140 mg, 28%). 1 H NMR (DMSO-D6, 400 MHz): δ 2.97 (s, 3 H). twenty

Reference Example 17 5-Chloro-2-methyl-7-morpholin-4-yl-thiazolo [4,5-d] pyrimidine

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To a solution of 5,7-dichloro-2-methyl-thiazolo [4,5-d] pyrimidine (92 mg, 0.42 mmol) in MeOH (3 ml) morpholine (81 ml, 0.93 mmol) was added ) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc and H2O. The organic layer was isolated, washed with hypersaline solution, then dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography to provide the title compound as a creamy solid (102 mg, 90%).

1 H NMR (400 MHz, CDCl3): δ 2.85 (s, 3 H), 3.80-3.86 (m, 4 H) and 3.88-3.94 (m, 4 H).

Reference Example 18

5-Chloro-7-morpholin-4-yl-thiazolo [4,5-d] pyrimidin-2-carbaldehyde

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35

To a solution of 5-chloro-2-methyl-7-morpholin-4-yl-thiazolo [4,5-d] pyrimidine (102 mg, 0.38 mmol) in 1,4-dioxane (5 ml) was added Selenium dioxide (51 mg, 0.46 mmol) and the solution was heated at 105 ° C for 6 hours. The reaction mixture was cooled to room temperature and partitioned between DCM and hypersaline solution. The layer was isolated

Organic and then dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography to give the title compound as an orange solid (53 mg, 49%). 1H NMR (DMSO-D6, 400 MHz): δ 3.73-3.78 (m, 4 H), 3.85-3.96 (m, 4 H) and 10.12 (s, 1 H).

Reference Example 19 5- (5-Chloro-7-morpholin-4-yl-thiazolo [4,5-d] pyrimidin-2-ylmethyl) -hexahydro-pyrrolo [3,4c] pyrrole acid tert-butyl ester -2-carboxylic

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To a solution of 5-chloro-7-morpholin-4-yl-thiazolo [4,5-d] pyrimidin-2-carbaldehyde (25 mg, 0.088 mmol) in 1,2-dichloroethane (1 ml) was added tert-butyl -hexahydro-pyrrolo [3,4-c] pyrrole-2-carboxylic acid ester (21 mg, 0.10 mmol). The mixture was stirred at room temperature for 5 minutes before adding sodium triacetoxyborohydride (28 mg, 0.135 mmol). The resulting solution was stirred at room temperature for 1 hour. The crude reaction mixture was partitioned between DCM and hypersaline solution. The organic layer was isolated and then dried (MgSO4) and

10 was concentrated in vacuo. The resulting residue was purified by column chromatography, to give the title compound as a white solid (26 mg, 61%). 1H NMR (400 MHz, CDCl3): δ 1.55 (s, 9 H), 2.70-2.83 (m, 4 H), 2.88 (s, 2 H), 3.30 (s, 2 H), 3.63 (s, 2 H), 3.82-3.87 (m, 4 H), 3.93-4.01 (m, 4 H) and 4.05-4.177 (m, 2 H).

Reference example 20 1- (tert-Butyl-dimethyl-silanyl) -5-fluoro-1H-indole

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To a solution of 5-fluoro-1H-indole (30.0 g, 0.222 mol) in anhydrous THF (250 ml) was added sodium hydride (60% suspension in mineral oil, 10.22 g, 0.255 mol) per parts and keeping the solution at 0 ° C. The reaction mixture was stirred at 0 ° C for 20 minutes and then a solution of tert-butyl-chloro-dimethyl-silane (40.15 g, 0.266 mol) in anhydrous THF (20 ml) was added and the solution was stirred at temperature ambient for 25 hours. The reaction mixture was poured into H2O and the layers were separated. The aqueous layer was extracted with EtOAc and the layers

The pooled organics were dried (MgSO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, cyclohexane: DCM 100% to 50:50), to give the title compound as a colorless oil (41.2 g, 74%). 1H NMR (400 MHz, CDCl3): δ 0.60 (s, 6 H), 0.94 (s, 9 H), 6.58 (dd, J = 3.2, 1.0 Hz, 1 H) , 6.87-6.93 (m, 1 H), 7.23 (d, J = 3.2 Hz, 1 H), 7.24-7.29 (m, 1 H) and 7.41 ( m, 1 H).

30

Reference Example 21 1- [1- (tert-Butyl-dimethyl-silanyl) 5-fluoro-1H-indol-4-yl] boronic acid

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To a solution of 1- (tert-butyl-dimethyl-silanyl) -5-fluoro-1H-indole (30.0 g, 0.12 mol) in anhydrous THF (1,000 ml) was added N, N, N ' , N'-tetramethylethylenediamine (36.6 ml, 0.241 mol) and a solution of s-butyllithium (1.4 M in cyclohexane, 172 ml, 0.241 mmol) at -78 ° C. The resulting mixture was stirred at -78 ° C for 2 hours and then triisopropyl borate (37.5 ml, 162.7 mmol) was added dropwise. The resulting solution was stirred at -78 ° C for 40 minutes and then allowed to warm to -20 ° C. An aqueous solution of HCl (2.4 M, 250 ml) was added

40 and the resulting mixture was poured into H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The pooled organic layers were dried (MgSO4) and concentrated in vacuo. The resulting yellow solid was then crystallized from DCM and cyclohexane to provide the title compound as a white solid (25.0 g,

71%). 1H NMR (400 MHz, CD3OD): δ 0.62 (s, 6 H), 0.92 (s, 9 H), 6.51 (d, J = 3.2 Hz, 1 H), 6.79 -6.90 (m, 1 H), 7.30-7.36 (m, 1 H) and 7.54 (dd, J = 9.0, 4.6 Hz, 1 H).

Reference Example 22 5-Fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborollan-2-yl) -1H-indole

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Stage 1

A solution of 5-fluoroindole (5 g, 37.0 mmol) in DMF (40 ml) was treated at 0 ° C with trifluoroacetic anhydride (6.1 ml, 42.6 mmol). After 30 minutes, the reaction was poured into water and the resulting precipitate was collected by filtration, washed with water and then dried under vacuum. Then, the serum was dissolved in 10% aqueous NaOH (200 ml) and heated under reflux for 1 hour. The reaction mixture was cooled to room temperature,

15 washed with DCM and acidified with aqueous HCl. The resulting white precipitate was collected by filtration, washed with water, introduced into DCM, washed with water, dried (MgSO4) and evaporated in vacuo. The resulting material (5 g, 75%) was dissolved in methanol (80 ml) and treated with concentrated sulfuric acid (2 ml) and then heated under reflux overnight. The reaction was cooled and the resulting precipitate was collected, washed with water and concentrated in vacuo to provide 5-fluoro-1H-indole-3-carboxylic acid methyl ester as a colored solid.

20 peach (4.5 g, 83%).

Stage 2

A solution of thallium tris (trifluoroacetate) (8.45 g, 15.6 mmol) in TFA (35 ml) was added to a solution of methyl

5-Fluoro-1H-indole-3-carboxylic acid ester (2 g, 10.4 mmol) in TFA (10 ml) at room temperature and stirred for 2 hours. The reaction mixture was evaporated in vacuo and the resulting residue was suspended in water (25 ml) before being treated with a solution of potassium iodide (5.2 g, 31.3 mmol) in water (50 ml). The reaction mixture was treated with dichloromethane (100 ml) and methanol (5 ml) and the resulting precipitate was removed by filtration through Celite. The organic layer was separated, washed successively with sodium thiosulfate solution and solution

Hypersaline, then dried (MgSO4) and evaporated in vacuo. The resulting material was dissolved in methanol (60 ml) and treated with 40% aqueous NaOH solution (60 ml) and then refluxed for 2 hours. The reaction mixture was cooled to room temperature and extracted with DCM / MeOH (95: 5 ratio). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, pentane: EtOAc 75:25), to provide 5-fluoro-4-iodo-1H-indole as a pale brown solid (1.05

35 g, 39%). ΔH NMR (300 MHz, CDCl3) 6.49-6.52 (m, 1H), 6.95 (apparent dt, J = 0.4, 8.6, 1H), 7.26-7.33 (m , 2H) and 8.35 (S, 1H).

Stage 3

A solution of 5-fluoro-4-iodo-1H-indole (1.28 g, 4.90 mmol) in dioxane (5 ml) was treated with triethylamine (1.0 ml, 7.18 mmol), acetate palladium (22.0 mg, 0.098 mmol) and bis (cyclohexyl) phosphino-2-biphenyl (137 mg, 0.40 mmol) and then heated to 80 ° C. A solution of pinacolborane (1 M in THF, 13.0 ml, 13.0 mmol) was added by syringe. After 30 minutes, the reaction mixture was cooled to room temperature, then diluted with water (50 ml) and DCM (50 ml). The resulting mixture was passed through a phase separation cartridge and the organic layer

45 was concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, pentane: EtOAc 75:25), to give the title compound as a brown solid (1.06 g, 83%). [M + H] + 262.1

Reference Example 23 50 1-Bromo-5-fluoro-2-methyl-3-nitro-benzene

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To a solution of 4-fluoro-2-nitrotoluene (10.0 g, 64.4 mmol) in trifluoroacetic acid (40 ml) was added concentrated sulfuric acid (12.5 ml) followed by N-bromosuccinimide (17.2 g , 96.6 mmol) and the reaction mixture was stirred at room temperature for 16 hours. Then, the reaction mixture was poured onto ice and water and stirred for 15 minutes. Then, the product was extracted in EtOAc and the organic layer was washed with solution

5 Hypersaline, dried (MgSO4) and concentrated in vacuo to give the title compound as a pale oil that crystallized on standing (11.76 g, 77%). ΔH NMR (300 MHz, CDCl3) 2.59 (s, 3H), 7.50 (dd, J = 2.8, 7.6, 1H) and 7.58 (dd, J = 2.9, 7, 4, 1H).

Reference example 24 10 4-Bromo-6-fluoro-1H-indole

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To a solution of 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (7.49 g, 31.8 mmol) in dioxane (40 ml) DMFDMA (21.0 ml, 158 mmol) and pyrrolidine was added (2.6 ml, 31.1 mmol). The reaction mixture was heated at 100 ° C for 3 hours. The mixture was cooled to room temperature and concentrated in vacuo to provide 1- [2- (2-bromo-4-fluoro-6nitrophenyl) -1-methylvinyl] -pyrrolidine as a dark red residue. To a suspension of pyrrolidine (10.0 g, 31.7 mmol) and Raney® nickel (suspension in H2O, 15 ml) in MeOH: THF (1: 1, 150 ml) was added hydrazine monohydrate (2.3 ml, 47.4 mmol) at 0 ° C and the mixture was stirred at room temperature for 5 hours. Then, the reaction mixture was filtered through Celite and the filter cake was washed with EtOAc. The filtrate was concentrated to

The mixture was vacuum and the resulting residue was purified by column chromatography (silica gel, pentane: EtOAc 75:25), to give the title compound as a pale oil (2.57 g, 37%). ΔH NMR (300 MHz, CDCl3) 6.57 (apparent t, J = 2.7, 1H), 7.04 (dd, J = 2.1, 9.1, 1H), 7.12 (dd, J = 2.1, 9.1, 1H), 7,207.25 (m, 1H) and 8.25 (s, 1H).

25 Reference Example 25 6-Fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborollan-2-yl) -1H-indole

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To a solution of 4-bromo-6-fluoro-1H-indole (6.0 g, 25.53 mmol) and bis (pinacolato) diboro (9.7 g, 38.19 mmol) in

Anhydrous DMSO (120 ml) KOAc (7.5 g, 76.41 mmol) and [1,1'-bis (diphenylphosphine) ferrocene] -dichloropaladium (1.0 g, 1.22 mmol) were added. The mixture was heated at 80 ° C for 18 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc and H2O. The organic layer was washed successively with H2O and hypersaline solution, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, pentane: EtOAc 75:25), to give the title compound as a white solid (4.6 g, 61%).

ΔH NMR (300 MHz, CDCl3) 1.39 (s, 12H), 7.02 (m, 1H), 7.14-7.19 (m, 1H), 7.20-7.26 (m, 1H), 7.38 (dd, J = 2.4, 9.9, 1H) and 8.16 (s, 1H).

Reference Example 26

2- (5-Chloro-7-morpholin-4-yl-thiazolo [5,4-d] pyrimidin-2-yl) -1-phenyl-ethanol

40

image2

To a solution of 5-chloro-2-methyl-7-morpholin-4-yl-thiazolo [5,4-d] pyrimidine (1.33 g, 4.91 mmol) and N, N, N ', N' tetramethylethylenediamine (0.74 ml, 5.40 mmol) in anhydrous THF (50 ml) was added a solution of n-BuLi (2.5 M in hexanes, 2.4 ml, 6.0 mmol) dropwise at - 78 ° C. The reaction mixture was stirred for 15 minutes, and then a solution of benzaldehyde (0.65 ml, 6.29 mmol) in anhydrous THF (5 ml) was quickly added. The mixture was stirred at -78 ° C for 15 minutes, then allowed to warm to room temperature and partitioned between EtOAc and H2O. The organic layer was isolated, washed with hypersaline solution and then dried (Na2SO4) and concentrated

under vacuum The resulting residue was purified by column chromatography, to give the title compound as a yellow solid (1.20 g, 66%). [M + H] + 377.0

Reference Example 27 5-Chloro-7-morpholin-4-yl-thiazolo [5,4-d] pyrimidin-2-carbaldehyde

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To a suspension of 2- (5-chloro-7-morpholin-4-yl-thiazolo [5,4-d] pyrimidin-2-yl) -1-phenyl-ethanol (1.1 g, 2.9 mmol) in toluene (25 ml) p-toluenesulfonic acid (0.11 g, 0.58 mmol) was added and the resulting solution was stirred at 120 ° C for 24 hours. The reaction mixture was concentrated in vacuo to provide 5-chloro-7-morpholin-4-yl-2-styrylthiazolo [5,4-d] pyrimidine as a crude yellow solid that was used without purification. To a suspension of 5-chloro-7-morpholin-4-yl-2-styryl-thiazolo [5,4-d] pyrimidine (2.9 mmol) in THF (9 ml), acetonitrile (9 ml) and H2O (3 ml ) Ruthenium (III) chloride (18 mg, 0.081 mmol) and periodic acid (1.3 g, 5.80 mmol) were added. The resulting solution was stirred at room temperature for 2 hours and then partitioned between EtOAc and an aqueous solution.

15 of sodium thiosulfate. The aqueous phase was isolated and extracted with EtOAc. The pooled organic layers were washed with hypersaline solution, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography to give the title compound as a yellow solid (0.34 g, 42%). 1 H NMR (400 MHz, CDCl 3): δ 3.83-3.88 (m, 4 H), 4.06-4.15 (m, 2 H), 4.72 (m, 2 H) and 9, 95 (s, 1 H).

Reference example 28 tert-Butyl-acid ester (5-Chloro-7-morpholin-4-yl-thiazolo [5,4-d] pyrimidin-2-ylmethyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-carboxylic

image2

To a solution of 5-chloro-7-morpholin-4-yl-thiazolo [5,4-d] pyrimidin-2-carbaldehyde (57 mg, 0.020 mmol) in 1,2-dichloroethane (2 ml) was added tert-butyl -hexahydro-pyrrolo [3,4-c] pyrrole-2-carboxylic acid ester (46 mg, 0.22 mmol). The mixture was stirred at room temperature for 5 minutes before adding sodium triacetoxyborohydride (64 mg, 0.30 mmol). The resulting solution was stirred at room temperature for 1 hour. The crude reaction mixture was partitioned between DCM and hypersaline solution. The organic layer was isolated and then dried (MgSO4) and

30 was concentrated in vacuo. The resulting residue was purified by column chromatography to give the title compound as a white solid (83 mg, 86%). 1 H NMR (400 MHz, CDCl 3): δ 1.45 (s, 9 H), 1.55 (m, 2 H), 2.61 (m, 2 H), 2.75-2.87 (m, 4 H), 3.23 (m, 2 H), 3.57 (s, 2 H), 3.80 (t, J = 4.8 Hz, 4 H), 3.91 (m, 2 H) and 4.31 (m, 2 H).

Reference Example 29 2- (5-Chloro-7-morpholin-4-yl-thiazolo [5,4-d] pyrimidin-2-ylmethyl) -2,7-diaza-spiro [3 , 5] nonan7-carboxylic

image2

5 Prepared according to the method used in the preparation of 5- (5-chloro-7-morpholin-4-ylthiazolo [5,4-d] pyrimidin-2-ylmethyl) -hexahydro-pyrrolo [3] tert-butyl ester , 4-c] pyrrol-2-carboxylic acid using 2,7-diaza-spiro [3.5] nonane-7-carboxylic acid tert-butyl ester hydrochloride instead of hexahydro-pyrrolo acid tert-butyl ester [3 , 4-c] pyrrol-2-carboxylic. The title compound was obtained as a white solid (70 mg, 71%).

10 [M + H] + 495.3

Reference example 30terc-Butyl ester of 3- (5-chloro-7-morpholin-4-yl-thiazolo [5,4-d] pyrimidin-2-ylmethyl) -3,8-diaza-bibyclo [3, 2] octane 8-carboxylic

fifteen

image2

Prepared according to the method used in the preparation of 5- (5-chloro-7-morpholin-4-ylthiazolo [5,4-d] pyrimidin-2-ylmethyl) -hexahydro-pyrrolo [3, tert-butyl ester] 4-c] pyrrol-2-carboxylic acid using 3,8diaza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester instead of hexahydro-pyrrolo acid tert-butyl ester [3,4- c] pyrrole-2-carboxylic.

The title compound was obtained as a white solid (91 mg, 95%). 1H NMR (400 MHz, CDCl3): δ 1.47 (s, 9 H), 1.90 (m, 2 H), 1.93-2.00 (m, 2 H), 2.54 (bs, 2 H), 2.74 (dd, J = 10.6, 2.6 Hz, 2 H), 3.79 (s, 2 H), 3.82 (m, 4 H) and 4.12-4 , 43 (m, 6 H).

Reference Example 31 25 2- (4-Azetidin-1-yl-piperidin-1-ylmethyl) -5-chloro-7-morpholin-4-yl-thiazolo [5,4-d] pyrimidine

image2

Prepared according to the method used in the preparation of 5- (5-chloro-7-morpholin-4-yl-tert-butyl ester)

Thiazolo [5,4-d] pyrimidin -2-ylmethyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-carboxylic acid using 4-azetidin-1-yl-piperidine instead of tert-butyl ester of hexahydro-pyrrolo [3,4-c] pyrrole-2-carboxylic acid. The title compound was obtained as a creamy solid (54 mg, 66%). [M + H] + 409.3

Reference Example 32 5-Chloro-2 - [(S) -1- (hexahydro-pyrrolo [1,2-a] pyrazin-2-yl) methyl] -7-morpholin-4-yl-thiazolo [5.4 -d] pyrimidine

image2

Prepared according to the method used in the preparation of 5- (5-chloro-7-morpholin-4-yl-tert-butyl ester)

5 thiazolo [5,4-d] pyrimidin-2-ylmethyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-carboxylic acid using (S) -octahydro-pyrrolo [1,2a] pyrazine instead of tert- butyl ester of hexahydro-pyrrolo [3,4-c] pyrrol-2-carboxylic acid. The title compound was obtained as a white solid (34 mg, 43%). [M + H] + 395.3

10 Reference Example 33 8- (5-Chloro-7-morpholin-4-yl-thiazolo [5,4-d] pyrimidin-2-ylmethyl) -2,8-diaza-spiro [3-tert-Butyl ester 4.5] decane-2 carboxylic

image2

Prepared according to the method used in the preparation of 5- (5-chloro-7-morpholin-4-ylthiazolo [5,4-d] pyrimidin -2-ylmethyl) -hexahydro-pyrrolo [3-tert-butyl ester of acid [3] , 4-c] pyrrol-2-carboxylic acid using 2,8-diaza-spiro [4.5] decan-2-carboxylic acid tert-butyl ester instead of hexahydro-pyrrolo [3,4-c] pyrrole-2-carboxylic acid. The title compound was obtained as a white solid (81 mg, 80%).

20 [M + H] + 509.3

Reference Example 34 5-Chloro-2- (cis-3,5-dimethyl-piperazin-1-ylmethyl) -7-morpholin-4-yl-thiazolo [5,4-d] pyrimidine

Prepared according to the method used in the preparation of 5- (5-chloro-7-morpholin-4-ylthiazolo [5,4-d] pyrimidin-2-ylmethyl) -hexahydro-pyrrolo [3] tert-butyl ester , 4-c] pyrrole-2-carboxylic acid using cis-2,6-dimethyl-piperazine instead of tert-butyl ester of hexahydro-pyrrolo [3,4-c] pyrrol-2-carboxylic acid. The title compound was obtained as a pale yellow solid (32 mg, 42%). 30 [M + H] + 383.3

image2

Reference Example 35 2- tert-Butyl ester of 2- (5-chloro-7-morpholin-4-yl-thiazolo [4,5-d] pyrimidin-2-ylmethyl) -2,7-diaza-spiro [3 , 5] nonan7-carboxylic

image2

5 Prepared according to the method used in the preparation of 5- (5-chloro-7-morpholin-4-ylthiazolo [4,5-d] pyrimidin-2-ylmethyl) -hexahydro-pyrrolo [3-tert-butyl ester] , 4-c] pyrrol-2-carboxylic acid using 2,7diaza-spiro [3.5] nonan-7-carboxylic acid tert-butyl ester instead of hexahydro-pyrrolo [3,4-c tert-butyl ester] ] pyrrole-2-carboxylic. The title compound was obtained as a white solid (46.4 mg, 72%). 1H NMR (400 MHz, CDCl3): δ 1.43 (s, 9 H), 1.73 (t, J = 5.3 Hz, 4 H), 3.08-3.35 (m, 4 H) , 3.27-3.37 (m, 4 H), 3.78-3.84

10 (m, 4 H), 3.90-3.95 (m, 5 H) and 4.07 (d, J = 9.0 Hz, 2 H).

Reference Example 36 5-Chloro-7-morpholin-4-yl-2- (4-morpholin-4-yl-piperidin-1-ylmethyl) -thiazolo [4,5-d] pyrimidine

image2

fifteen

Prepared according to the method used in the preparation of tert-butyl ester of 5- (5-chloro-7-morpholin-4-ylthiazolo [4,5-d] pyrimidin-2-ylmethyl) -hexahydro-pyrrolo [3, 4-c] pyrrol-2-carboxylic acid using 4-piperidin-4-yl-morpholine instead of tert-butyl ester of hexahydro-pyrrolo [3,4-c] pyrrol-2-carboxylic acid. The title compound was obtained as

20 a creamy solid (28 mg, 80%). 1 H NMR (CDCl 3, 400 MHz): δ 1.63 (q, J = 12.3 Hz, 2 H), 1.92 (d, J = 12.3 Hz, 2 H), 2.24 (m, 1 H), 2.34 (t, J = 11.5 Hz, 2 H), 2.60 (m, 4 H), 3.04 (d, J = 11.5 Hz, 2 H), 3, 76 (t, J = 4.4 Hz, 4 H), 3.81-3.86 (m, 4 H) and 3.92-3.98 (m, 6 H).

Reference Example 37 25 2-Methyl-4- (trifluoromethanesulfonyloxy) thiazole-5-carboxylic acid ethyl ester

image2

To a solution of ethyl ester of 4-hydroxy-2-methylthiazol-5-carboxylic acid (1.87 g, 10 mmol) in DCM (50 ml) at 78 ° C under an atmosphere of N2 was added triethylamine (2.08 ml , 15 mmol), followed by the dropwise addition of

30 trifluoromethanesulfonic anhydride (1.85 ml, 11 mmol). The resulting mixture was stirred at -78 ° C for 1 hour and then heated to room temperature. The solvent was removed in vacuo and the resulting residue was purified by column chromatography to give the title compound as a yellow oil (2.86 g, 90%). [M + H] + 320.0

Reference Example 38 6-Benzyl-2-methyl-4H-thiazolo [4,5-d] pyrimidin-5,7-dione

image2

To a solution of 2-methyl-4- (trifluoromethanesulfonyloxy) thiazole-5-carboxylic acid ethyl ester (6.38 g, 20 mmol) in

Dioxane (80 ml) under an atmosphere of N2 was added cesium carbonate (13.0 g, 40 mmol), benzylurea (3.3 g, 22 mmol), Xantfos (0.58 g, 1 mmol) and tris ( dibenzylidenacetone) dipaladium (0) (0.46 g, 0.5 mmol). The resulting mixture was stirred at 60 ° C for 18 hours, cooled to room temperature, then poured into water (500 ml) and stirred for 15 minutes. The resulting mixture was filtered, the filtrate was collected and its volume was reduced in vacuo to approximately one third. The resulting precipitate was collected by filtration, washed with ether and dried.

10 under vacuum, providing the title compound as a white solid (3.9 g, 72%). [M + H] + 274.1

Reference Example 39 4- (5-Chloro-7-morpholin-4-ylthiazolo [4,5-d] pyrimidin-2-ylmethyl) -2,2-dimethylpiperazin-115 carboxylic acid tert-Butyl ester

image2

Prepared according to the method used in the preparation of tert-butyl ester of 5- (5-chloro-7-morpholin-4-ylthiazolo [4,5-d] pyrimidin-2-ylmethyl) -hexahydro-pyrrolo [3, 4-c] pyrrol-2-carboxylic acid using tert-butyl ester of 2,2-dimethylpiperazin-1-carboxylic acid instead of tert-butyl ester of hexahydro-pyrrolo [3,4-c] pyrrole-2-carboxylic acid. He

The title compound was obtained as a yellow solid (100 mg, 38%). [M + H] + 483.2

Reference Example 40 5-Chloro-7-morpholin-4-yl-2- (4-morpholin-4-yl-piperidin-1-ylmethyl) -thiazolo [4,5-d] pyrimidine

25

image2

Prepared according to the method used in the preparation of tert-butyl ester of 5- (5-chloro-7-morpholin-4-ylthiazolo [4,5-d] pyrimidin-2-ylmethyl) -hexahydro-pyrrolo [3, 4-c] pyrrol-2-carboxylic acid using 4-piperidin-4-yl-morpholine instead of tert-butyl ester of hexahydro-pyrrolo [3,4-c] pyrrol-2-carboxylic acid. The title compound was obtained as

30 a yellow solid (220 mg, 39%). [M + H] + 439.2

Reference Example 41 5-Chloro-2 - [(S) -1- (hexahydro-pyrrolo [1,2-a] pyrazin-2-yl) methyl] -7-morpholin-4-ylthiazolo [4,5-d ] pyrimidine

image2

Prepared according to the method used in the preparation of 5- (5-chloro-7-morpholin-4-yl-tert-butyl ester)

5 thiazolo [4,5-d] pyrimidin -2-ylmethyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-carboxylic acid using (S) -octahydro-pyrrolo [1,2-a] pyrazine instead of tert-butyl ester of hexahydro-pyrrolo [3,4-c] pyrrol-2-carboxylic acid. The title compound was obtained as an orange solid (131 mg, 46%). , [M + H] + 395.4

10

Reference Example 42 4-Azetidin-1-yl-piperidine

image2

To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.75 g, 8.88 mmol) in dichloroethane (80

15 ml) azetidine (0.6 g, 10.53 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (3.9 g, 18.44 mmol) was added and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was partitioned between water and DCM and the layers were separated. The organic layer was further extracted with DCM and the pooled organic layers were concentrated in vacuo. The resulting white semi-solid was suspended in DCM and a saturated aqueous solution of NaHCO3 was added. The layers mixed

Evenly, the organic layer was isolated and the aqueous layer was further extracted with DCM. The pooled organic layers were washed with hypersaline solution, dried (Na2SO4) and concentrated in vacuo to provide 4-azetidine-1-yl-piperidine-1-carboxylic acid tert-butyl ester as a white solid (2, 0 g, 95%). BOC deprotection of 4-azetidin-1-yl-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 1.67 mmol) using TFA: DCM (1: 4) provided the title compound as of yellow oil (185 mg, 79%).

ΔH NMR (400 MHz, CDCl3) 1.04-1.16 (m, 2 H), 1.68 (d, J = 12.8 Hz, 2 H), 1.98-2.08 (m, 3 H), 2.55 (td, J = 12.1, 2.6 Hz, 2 H), 3.06 (dt, J = 12.8, 3.6 Hz, 2 H) and 3.15 ( t, J = 6.9 Hz, 4 H).

Reference Example 43

2- (4-Azetidin-1-ylpiperidin-1-ylmethyl) -5-chloro-7-morpholin-4-ylthiazolo [4,5-d] pyrimidine

30

image2

Prepared according to the method used in the preparation of 5- (5-chloro-7-morpholin-4-ylthiazolo [4,5-d] pyrimidine acid tert-butyl ester

35 -2-ylmethyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-carboxylic acid using 4-azetidin-1-yl-piperidine instead of tert-butyl ester of hexahydro-pyrrolo acid [3,4- c] pyrrole-2-carboxylic. The title compound was obtained as a yellow solid (97 mg, 33%). [M + H] + 409.3 (35Cl) and 411.3 (37Cl)

Reference Example 44 5-Chloro-2- (4-cyclopropylmethylpiperazin-1-ylmethyl) -7-morpholin-4-ylthiazolo [4,5-d] pyrimidine

image2

5 Prepared according to the method used in the preparation of 5- (5-chloro-7-morpholin-4-ylthiazolo [4,5-d] pyrimidin-2-ylmethyl) -hexahydro-pyrrolo [3-tert-butyl ester] , 4-c] pyrrol-2-carboxylic acid using 1-cyclopropylmethylpiperazine instead of tert-butyl ester of hexahydro-pyrrolo [3,4-c] pyrrol-2-carboxylic acid. The title compound was obtained as a yellow solid (170 mg, 58%). [M + H] + 409.5

10

Reference Example 45

[1- (5-Chloro-7-morpholin-4-ylthiazolo [4,5-d] pyrimidin-2-ylmethyl) -piperidin-4-yl] dimethylamine

image2

Prepared according to the method used in the preparation of 5- (5-chloro-7-morpholin-4-ylthiazolo [4,5-d] pyrimidin-2-ylmethyl) -hexahydro-pyrrolo [3-tert-butyl ester] , 4-c] pyrrol-2-carboxylic acid using dimethylpiperidin-4-ylamine instead of tert-butyl ester of hexahydro-pyrrolo [3,4-c] pyrrol-2-carboxylic acid. The title compound was obtained as an orange solid (244 mg, 40%). [M + H] + 397.2 (35Cl) and 399.2 (37Cl)

twenty

Reference Example 46

2- [4- (5-Chloro-7-morpholin-4-ylthiazolo [4,5-d] pyrimidin-2-ylmethyl) -piperazin-1-yl] -isobutyramide

image2

To a solution of tert-butyl-1-piperazinecarboxylate (15.0 g) in dichloromethane (150 ml) and methanol (150 ml) at 0 ° C was added hydrochloric acid (40 ml, 2M solution in diethyl ether). The mixture was stirred at room temperature for 1.5 hours and reduced in vacuo to provide tert-butyl-1-piperazinecarboxylate hydrochloride (17.9 g).

To a solution of tert-butyl-1-piperazinecarboxylate hydrochloride (17.9 g) in water (200 ml) at room temperature

30 sodium cyanide (3.94 g) was added. Then, a solution of acetone (5.9 ml) in water (20 ml) was added dropwise and stirred at room temperature for 48 hours. The mixture was partitioned between ethyl acetate and water. The pooled organic layers were washed with hypersaline solution, separated, dried (MgSO4) and reduced in vacuo to afford 4- (cyano-dimethyl-methyl) -piperazin-1-carboxylic acid tert-butyl ester (17, 5 g)

To a solution of 4- (cyano-dimethyl-methyl) -piperazin-1-carboxylic acid tert-butyl ester (960 mg) in methyl sulfoxide (20 ml) at 0 ° C was added potassium carbonate (104 mg). Next, hydrogen peroxide (2.0 ml, 27.5% solution by weight in water) was added dropwise. The resulting mixture was heated at 40 overnight. Water was added to the cooled mixture and the precipitated solid was filtered and dried, yielding 4- (1-carbamoyl-2-methyl-ethyl) -piperazin-1-carboxylic acid tert-butyl ester (677 mg). The BOC group was removed using HCl in ether under standard conditions, providing 2-piperazin-1-yl-isobutyramide dihydrochloride (600 mg).

The title compounds were prepared following the method used in the preparation of 5- (5-chloro-7-morpholin-4-yl-thiazolo [4,5-d] pyrimidin-2-ylmethyl acid tert-butyl ester] ) -hexahydro-pyrrolo [3,4-c] pyrrol-2-carboxylic acid using 2piperazin-1-yl-isobutyramide instead of tert-butyl ester of hexahydro-pyrrolo [3,4-c] pyrrole-2-carboxylic acid . The title compound was obtained as an off-white solid (71 mg, 36%). [M + H] + 440.2

10

Reference Example 47

2- (4-Azetidin-1-ylpiperidin-1-ylmethyl) -5-chloro-7-morpholin-4-ylthiazolo [5,4-d] pyrimidine

image2

To a solution of 5-chloro-7-morpholin-4-ylthiazolo [5,4-d] pyrimidin-2-carbaldehyde (308 mg, 1.08 mmol) in DCE (8 ml) was added 4-azetidine-1 -ilpiperidine (166 mg, 1.19 mmol). The resulting mixture was stirred at room temperature for 10 minutes and then triacetoxyborohydride (297 mg, 1.40 mmol) was added and stirring was continued for 18 hours. The reaction mixture was loaded into an Isolute® SCX-2 cartridge, washed with MeOH and then eluted with 2M NH3 in MeOH and concentrated in vacuo to give the title compound as a solid.

20 off-white (263 mg, 60%). [M + H] + 409.2

Reference example 48 tert-Butyl ester of 4- (5-chloro-7-morpholin-4-ylthiazolo [5,4-d] pyrimidin-2-ylmethyl) -piperazin-1-carboxylic acid

Prepared according to the method used in the preparation of 2- (4-azetidin-1-ylpiperidin-1-ylmethyl) -5-chloro-7-morpholin-4-thiazolo [5,4-d] pyrimidine using tert-butyl ester of Piperazin-1-carboxylic acid instead of 4-azetidine-1 -piperidine. The title compound was obtained as a white solid (129 mg, 81%).

image2

30 [M + H] + 455.2

Reference Example 49 5-Chloro-2- (4-cyclopropylpiperazin-1-ylmethyl) -7-morpholin-4-ylthiazolo [5,4-d] pyrimidine

image2

ilthiazolo [5,4-d] pyrimidine using 1-cyclopropylpiperazine instead of 4-azetidin-1-ylpiperidine. The title compound was obtained as a white solid (117 mg, 56%). [M + H] + 395.5

Reference Example 50 2- [4- (5-Chloro-7-morpholin-4-ylthiazolo [5,4-d] pyrimidin-2-ylmethyl) piperazin-1-yl] -isobutyramide

image2

Prepared according to the method used in the preparation of 2- (4-azetidin-1-ylpiperidin-1-ylmethyl) -5-chloro-7-morpholin-4

10 ilthiazolo [5,4-d] pyrimidine using 2-piperazin-1-ylisobutyramide instead of 4-azetidin-1-ylpiperidine. The title compound was obtained as a white solid (70 mg, 46%). [M + H] + 440.3

Reference example 51 [1- (5-Chloro-7-morpholin-4-ylthiazolo [5,4-d] pyrimidin-2-ylmethyl) -piperidin-4-yl] dimethylamine

image2

Prepared according to the method used in the preparation of 2- (4-azetidin-1-ylpiperidin-1-ylmethyl) -5-chloro-7-morpholin-4-thiazolo [5,4-d] pyrimidine using dimethylpiperidine-4-ylamine instead of 4-azetidin-1-ylpiperidine. The compound of

20 titer was obtained as a pale yellow solid (101 mg, 72%). [M + H] + 397.4

Reference Example 52 5-Chloro-7-morpholin-4-yl-2- (4-morpholin-4-ylpiperidin-1-ylmethyl) -thiazolo [5,4-d] pyrimidine

Prepared according to the method used in the preparation of 2- (4-azetidin-1-ylpiperidin-1-ylmethyl) -5-chloro-7-morpholin-4-thiazolo [5,4-d] pyrimidine using 4-piperidine-1- ilmorpholine instead of 4-azetidin-1-ylpiperidine. The title compound was obtained as a white solid (104 mg, 67%).

image2

30 [M + H] + 397.4

Example 1 5- (6-Fluoro-1H-indol-4-yl) -2- (hexahydro-pyrrolo [3,4-c] pyrrol-2-ylmethyl) -7-morpholin-4-yl-thiazolo [4, 5-d] pyrimidine

image2

This compound was produced using Suzuki coupling method B described in Reference Example 2,

5 above, followed by deprotection of BOC using TFA: DCM (1: 1). The title compound was obtained as a pale yellow film (2.0 mg, 16%). [M + H] + 480.2 1H NMR (400 MHz, CH3OH-d4): δ 2.63 (dd, J = 9.6, 5.6 Hz, 2 H), 3.01 (d, J = 9.6 Hz, 2 H), 3.06 (m, 2 H), 3.20 (dd, J = 11.8, 4.3 Hz, 2 H), 3.45-3.54 (m, 2 H), 3.89 (t, J = 4.8 Hz, 4 H), 4.07 (t, J = 4.8 Hz, 4 H), 4.18 (s, 2 H), 7, 24 (dd, J = 11.3, 2.4, 1 H), 7.35 (d, J = 3.2 Hz, 1 H), 7.44 (dd, J = 3.2, 1 Hz, 1 H) and 7.88 (dd, J = 11.3, 2.4 Hz, 1 H).

10

Example 2 5- (6-Fluoro-1H-indol-4-yl) -2- (hexahydro-pyrrolo [3,4-c] pyrrol-2-ylmethyl) -7-morpholin-4-yl-thiazolo [5, 4-d] pyrimidine

image2

Prepared by using Suzuki coupling method B of Reference Example 2 (Scheme B), followed by deprotection of BOC using TFA: DCM (1: 2) according to Reference Example 3. The title compound was obtained. in the form of an off-white solid (2.0 mg, 16%). [M + H] + 480.13 RMN 1H (400 MHz, CH3OH-d4): δ 2.57 (dd, J = 9.6, 5.3 Hz, 2 H), 2.98 (d, J = 9 , 6 Hz, 2 H), 2.99-3.06 (m, 2 H), 3.13 (dd, J = 11.7, 5.3 Hz, 2 H), 3.57 (dd, J = 11.7, 7.2 Hz, 2 H), 3.87 (t, J = 4.7 Hz, 4 H), 4.06 (s, 2 H), 4.45

20 (t, J = 4.7 Hz, 4 H), 7.22 (dd, J = 10.6, 2.4 Hz, 1 H), 7.30 (dd, J = 3.2, 0, 9 Hz, 1 H), 7.34 (d, J = 3.2 Hz, 1 H) and 7.77 (dd, J = 10.6, 2.4 Hz, 1 H).

Example 3 2- (2,7-Diaza-spiro [3.5] non-2-ylmethyl) -5- (1 H -indol-4-yl) -7-morpholin-4-yl-thiazolo [5,4-d] pyrimidine

Prepared by using the Suzuki coupling method B of Example 2 (scheme B), followed by deprotection of BOC using TFA: DCM (1: 2) according to Reference Example 3. The title compound was obtained as of an off-white solid (15 mg, 29%).

image2

30 [M + H] + 476.3 1 H NMR (CDCl 3, 400 MHz): δδ 1.74-1.79 (m, 4 H), 2.79 (t, J = 5.3 Hz, 4 H), 3.21 (s, 4 H), 3.88-3.94 (m, 4 H), 3.99 (s, 2 H), 4.45 (m, 4 H), 7.30 (t, J = 7.7 Hz, 1 H), 7.33 (t, J = 2.7 Hz, 1 H), 7.49-7.53 (m, 2 H), 8.18 (dd, J = 7.7, 1.0 Hz, 1 H) and 8.30 (bs, 1 H).

Example 4 2- (2,7-Diaza-spiro [3.5] non-2-ylmethyl) -5- (6-fluoro-1H-indol-4-yl) -7-morpholin-4-yl-thiazolo [5, 4-d] pyrimidine

image2

Prepared by using the Suzuki coupling method B of Example 2 (scheme B), followed by

5 the deprotection of BOC using TFA: DCM (1: 2) according to Reference Example 3. The title compound was obtained as a pale gray solid (20 mg, 58%). [M + H] + 494.3 1H NMR (CDCl3, 400 MHz): δ 1.77 (t, J = 5.4 Hz, 4 H), 2.79 (t, J = 5.4 Hz, 4 H), 3.21 (s, 4 H), 3.90 (t, J = 4.6 Hz, 4 H), 3.99 (s, 2 H), 4.45 (t, J = 4, 6 Hz, 4 H), 7.18 (dd, J = 8.8, 2.5 Hz, 1 H), 7.31 (t, J = 2.5 Hz, 1 H), 7.51 (m , 1 H), 7.95 (m,

10 1 H) and 8.27 (bs, 1 H).

Example 52- (2,7-Diaza-spiro [3.5] non-2-ylmethyl) -5- (5-fluoro-1H-indole-4-yl) -7-morpholin-4-yl-thiazolo [5.4 -d] pyrimidine

image2

Prepared by using Suzuki coupling method B of Reference Example 2 (scheme B), followed by deprotection of BOC using TFA: DCM (1: 2) according to Reference Example 3 and deprotection of TBDMS using TBAF : THF (1: 10) according to Reference Example 4. The title compound was obtained as solid ogris (49 mg, 55%). 20 [M + H] + 494.3 1H NMR (CDCl3, 400 MHz): δ 1.75 (t, J = 5.3 Hz, 4 H), 2.78 (t, J = 5.3 Hz, 4 H), 3.20 (s, 4 H), 3.86 (m, 4 H), 4.00 (s, 2 H), 4.42 (m, 4 H), 6.93 (bs, 1 H), 7.04 (dd, J = 11.0, 8.8 Hz, 1 H), 7.28 (m, 1 H), 7.37 (dd, J = 8.8, 3.8 Hz, 1 H) and 8.32 (bs, 1 H).

Example 6 2- (3,8-Diaza-bicyclo [3.2.1] oct-3-ylmethyl) -5- (1H-indole-4-yl) -7-morpholin-4-yl-thiazolo [5.4 -d] pyrimidine

image2

Prepared by using Suzuki coupling method B of Reference Example 2 (scheme

30 B), followed by deprotection of BOC using TFA: DCM (1: 2) according to Reference Example 3. The title compound was obtained as a white solid (3.0 mg, 7%). [M + H] + 462.2 1H NMR (CD3OD, 400 MHz): δ 2.03-2.08 (m, 2 H), 2.27-2.33 (m, 2 H), 2.73 (d, J = 12.5 Hz, 2 H), 3.03 (dd, J = 12.5, 2.7 Hz, 2 H), 3.83-3.88 (m, 4 H), 4 , 02 (m, 4 H), 4.45 (m, 4 H), 7.20 (t, J = 7.8 Hz, 1 H), 7.27 (dd, J = 3.2, 0, 9 Hz, 1 H),

7.35 (d, J = 3.2 Hz, 1 H), 7.52 (apparent dt, J = 7.8, 0.9 Hz, 1 H) and 7.98 (dd, J = 7, 8, 0.9 Hz, 1 H).

Example 7 2- (4-Azetidin-1-yl-piperidin-1-ylmethyl) -5- (1H-indole-4-yl) -7-morpholin-4-yl-thiazolo [5,4-d] pyrimidine

image2

Prepared by using the Suzuki coupling method B of Example 2 (scheme B), followed by

5 the deprotection of BOC using TFA: DCM (1: 2) according to Reference Example 3. The title compound was obtained as an off-white solid (15 mg, 24%). [M + H] + 490.3 RMN 1H (400 MHz, CD3OD): δ 1.15-1.29 (m, 2 H), 1.67 (d, J = 12.1 Hz, 2 H), 1 , 92-2.00 (m, 2 H), 2.23 (t, J = 11.30 Hz, 2 H), 2.86 (d, J = 11.0 Hz, 2 H), 3.21 (m, 3 H), 3.80 (m, 4 H), 3.88 (s, 2 H), 4.34 (m, 4 H), 7.19 (apparent t, J = 7.8 Hz , 1 H), 7.33 (s, 1 H), 7.45 (t, J = 2.7 Hz, 1 H), 7.53 (d, J = 7.8 Hz, 1 H), 8 , 09 (d, J = 7.8 Hz, 1 H) and

10 11.25 (bs, 1 H).

Example 8 2 - [(S) -1- (Hexahydro-pyrrolo [1.2-a] pyrazin-2-yl) methyl] -5- (1H-indole-4-yl) -7-morpholin-4-yl-thiazolo [5,4-d] pyrimidine

image2

15 Prepared by using Suzuki coupling method B of Reference Example 2 (scheme B). The title compound was obtained as a pale yellow solid (34 mg, 83%). [M + H] + 476.2 1H NMR (CDCl3, 400 MHz): δ 1.46 (m, 1 H), 1.60 (m, 1 H), 1.67-1.93 (m, 3 H), 2.13-2.29 (m, 2 H), 2.41 (m, 1 H), 2.55 20 (m, 1 H), 2.96 (d, J = 10.9 Hz , 1 H), 3.01-3.14 (m, 3 H), 3.86-3.94 (m, 6 H), 4.44 (t, J = 4.6 Hz, 4 H), 7.28-7.33 (m, 2 H), 7.47-7.52 (m, 2 H), 8.17 (dd, J = 7.5, 1.0 Hz, 1 H) and 8 , 29 (bs, 1 H).

Example 9 2- (3,5-Dimethyl-piperazin-1-ylmethyl) -5- (1H-indol-4-yl) -7-morpholin-4-yl-thiazolo [5,4-d] pyrimidine

25 Prepared by using the Suzuki coupling method of Reference Example 2 (scheme B). The title compound was obtained as a beige solid (24 mg, 62%). [M + H] + 464.3

image2

1 H NMR (CDCl3, 400 MHz): δ 1.05 (d, J = 6.4 Hz, 6 H), 1.86 (t, J = 10.5 Hz, 2 H), 2.86-2 , 92 (m, 2 H), 2.96-3.06 (m, 2 H), 3.84 (s, 2 H), 3.89 (t, J = 4.6 Hz, 4 H), 4.44 (t, J = 4.6 Hz, 4 H), 7.26-7.33 (m, 2 H), 7.47-7.52 (m, 2 H), 8.17 (dd , J = 7.7, 0.9 Hz, 1 H) and 8.29 (bs, 1 H).

Example 10 Format of 2- (2,7-diaza-spiro [3.5] non-2-ilmethyl) -5- (6-fluoro-1H-indol-4-yl) -7-morpholin-4-yl-thiazolo [ 4,5-d] pyrimidine

image2

5 Prepared by using Suzuki coupling method B of Reference Example 2 (Scheme A), followed by deprotection of BOC using TFA: DCM (2: 3) according to Reference Example 3. The format salt of the title compound in the form of a creamy solid (2.6 mg, 12%). [M + H] + 494.2 1H NMR (CD3OD, 400 MHz): δ 2.02 (t, J = 5.6 Hz, 4 H), 3.08-3.14 (m, 4 H), 3.37 (s, 4 H), 3.89 (t, J = 4.7 Hz, 4 H),

10 4.07 (t, J = 4.7 Hz, 4 H), 4.19 (s, 2 H), 7.23 (ddd, J = 10.0, 2.4, 0.9 Hz, 1 H), 7.34 (d, J = 3.2 Hz, 1 H), 7.42 (dd, J = 3.2, 0.9 Hz, 1 H), 7.86 (dd, J = 10 , 0, 2.4 Hz, 1 H) and 8.54 (bs, 1 H).

Example 11 5- (1H-Indol-4-yl) -7-morpholin-4-yl-2- (4-morpholin-4-yl-piperidin-1-ylmethyl) -thiazolo [4,5-d] pyrimidine

fifteen

image2

Prepared by using Suzuki coupling method B of Reference Example 2 (scheme TO). The title compound was obtained as a brown glass (10 mg, 20%). [M + H] + 520.2 NMR 1H (400 MHz, DMSO-d6): δ 1.41-1.54 (m, 2 H), 1.81 (d, J = 12.3 Hz, 2 H) , 2.11-2.22 (m, 1 H),

20 2.23-2.36 (m, 2 H), 2.44-2.49 (m, 4H), 3.02 (d, J = 11.2 Hz, 2 H), 3.57 (t , J = 4.3 Hz, 4 H), 3.82 (t, J = 4.6 Hz, 4 H), 3.98 (t, J = 4.6 Hz, 4 H), 4.01 ( s, 2 H), 7.21 (t, J = 7.8 Hz, 1 H), 7.42-7.48 (m, 2 H), 7.54 (d, J = 8.0 Hz, 1 H), 8.14 (dd, J = 7.8, 1.0 Hz, 1 H) and 11.25 (bs, 1 H).

Example 12 2- (3,3-Dimethylpiperazin-1-ylmethyl) -5- (5-fluoro-1H-indole-4-yl) -7-morpholin-4-yl-thiazolo [4,5-d] pyrimidine

image2

Prepared using Suzuki coupling method C, followed by TBS and BOC. The title compound was obtained as a yellow solid (13 mg, 22%). [M + H] + 482.1

1 H NMR (DMSO, 400 MHz): δ 1.16 (s, 6 H), 2.31-2.38 (m, 2 H), 2.57 (m, 2 H), 2.87-2 , 94 (m, 2 H), 3.74-3.80 (m, 4 H), 3.92 (m, 4 H), 3.98 (s, 2 H), 6.73 (m, 1 H), 7.07 (dd, J = 11.4, 8.8 Hz, 1 H), 7.45 (m, 1 H), 7.48 (dd, J = 8.9, 4.0 Hz , 1 H) and 11.28 (s, 1 H).

Example 13 5- (5-Fluoro-1H-indol-4-yl) -7-morpholin-4-yl-2- (4-morpholin-4-ylpiperidin-1-ylmethyl) thiazolo [4,5-d] pyrimidine

image2

Prepared by using Suzuki coupling method G. The title compound was obtained in

5 form of a pale yellow solid (101 mg, 76%). [M + H] + 538.1 1 H NMR (DMSO, 400 MHz): δ 1.42-1.55 (m, 2 H), 1.80 (d, J = 11.8 Hz, 2 H), 2.17 (tt, J = 11.1, 3.6 Hz, 1 H), 2.22-2.31 (m, 2 H), 2.44-2.49 (m, 4 H), 3 , 02 (d, J = 11.6 Hz, 2 H), 3.58 (m, 4 H), 3.77 (m, 4 H), 3.92 (m, 4 H), 4.01 ( s, 2 H), 6.73 (m, 1 H), 7.02 (dd, J = 11.0, 8.9 Hz, 1 H), 7.43-7.50 (m, 2 H) and 11.27 (bs, 1 H).

10

Example 14 5- (1H-indole-4-yl) -7-morpholin-4-yl-2- (4-morpholin-4-ylpiperidin-1-ylmethyl) thiazolo [4,5-d] pyrimidine

image2

15 Prepared by using Suzuki coupling method F. The title compound was obtained as an off-white solid (55 mg, 43%). [M + H] + 520.2 1H NMR (CDCl3, 400 MHz): δ 1.63 (m, 2 H), 1.91 (d, J = 11.8 Hz, 2 H), 2.17- 2.28 (m, 1 H), 2.29-2.39 (m, 2 H), 2,532.65 (m, 4 H), 3.09 (d, J = 11.1 Hz, 2 H) , 3.72-3.78 (m, 4 H), 3.89-3.95 (m, 4 H), 4.00 (s, 2 H), 4.03-4.08 (m, 4 H),

20 7.27-7.35 (m, 2 H), 7.51 (d, J = 8.2 Hz, 1 H), 7.68 (m, 1 H), 8.32 (bs, 1 H ) and 8.36 (m, 1 H).

Example 15 5- (5-Fluoro-1H-indol-4-yl) -2 - [(S) -1- (hexahydro-pyrrolo [1,2-a] pyrazin-2-yl) methyl] -7-morpholin -4-ilthiazolo [4,5d] pyrimidine

25 Prepared by using Suzuki coupling method G. The title compound was obtained as an orange solid (41 mg, 25%). [M + H] + 494.1

image2

1 H NMR (CDCl3, 400 MHz): δ 1.38-1.51 (m, 1 H), 1.71-1.93 (m, 3 H), 2.15-2.28 (m, 3 H), 2.37-2.46 (m, 1 H), 2.60 (td, J = 10.9, 3.0 Hz, 1 H), 2.95-3.16 (m, 4 H ), 3.84-3.90 (m, 4 H), 4.00-4.05 (m, 4 H), 4.08 (d, J = 5.5 Hz, 2 H), 7.04 (dd, J = 10.9, 8.7 Hz, 1 H), 7.09-7.11 (m, 1 H), 7.28 (t, J = 2.9 Hz, 1 H), 7 , 35-7.40 (m, 1 H) and 8.30 (bs, 1 H).

Example 16 2- (4-Azetidin-1-ylpiperidin-1-ylmethyl) -5- (5-fluoro-1H-indol-4-yl) -7-morpholin-4-ylthiazolo [4,5-d] pyrimidine

image2

Prepared by using Suzuki coupling method G. The title compound was obtained in

5 form of a yellow solid (8 mg, 7%). [M + H] + 508.16 1H NMR (CDCl3, 400 MHz): δ 1.37-1.49 (m, 2 H), 1.71-1.79 (m, 2 H), 2.00 -2.11 (m, 3 H), 2.37 (td, J = 11.5, 2.3 Hz, 2 H), 2.94-3.01 (m, 2 H), 3.20 ( t, J = 6.9 Hz, 4 H), 3.87 (m, 4 H), 4.01 (m, 6 H), 7.04 (dd, J = 11.2, 8.9 Hz, 1 H), 7.09 (m, 1 H), 7.27 (m, 1 H), 7.34-7.39 (m, 1 H) and 8.31 (bs, 1 H).

10

Example 17 2- (4-Azetidin-1-ylpiperidin-1-ylmethyl) -5- (1H-indole-4-yl) -7-morpholin-4-ylthiazolo [4,5-d] pyrimidine

image2

15 Prepared by using Suzuki coupling method E. The title compound was obtained as a yellow solid (48 mg, 52%). [M + H] + 490.1 1H NMR (CDCl3, 400 MHz): δ 1.37-1.49 (m, 2 H), 1.71-1.79 (m, 2 H), 2.01 -2.12 (m, 3 H), 2.37 (td, J = 11.3, 2.3 Hz, 2H), 2.94-3.01 (m, 2 H), 3.16-3 , 24 (m, 4 H), 3.89-3.94 (m, 4 H), 4.00 (s, 2 H), 4.03-4.07 (m, 4 H), 7.28 -7.34 (m, 2 H),

20 7.51 (bd, J = 8.0 Hz, 1 H), 7.69 (m, 1 H), 8.31 (bs, 1 H) and 8.36 (m, 1 H).

Example 18 2- (4-Cyclopropylmethylpiperazin-1-ylmethyl) -5- (5-fluoro-1H-indol-4-yl) -7-morpholin-4-yl-thiazolo [4,5-d] pyrimidine

image2

25 Prepared by using Suzuki coupling method G by deprotection of TBS. The title compound was obtained as a yellow solid (74 mg, 35%). [M + H] + 508.1 1H NMR (CDCl3, 400 MHz): δ 0.14 (q, J = 5.0 Hz, 2 H), 0.51-0.58 (m, 2 H), 0.84-0.95 (m, 1 H), 2.33 (d, J = 5.7 Hz, 2 30 H), 2.58-2.84 (m, 8 H), 3.84- 3.90 (m, 4 H), 4.00-4.05 (m, 6 H), 7.04 (dd, J = 11.2, 8.7 Hz, 1 H), 7.10 (m , 1 H), 7.28 (m, 1 H), 7.38 (m, 1 H) and 8.31 (bs, 1 H).

Example 19 {1- [5- (5-Fluoro-1H-indol-4-yl) -7-morpholin-4-ylthiazolo [4,5-d] pyrimidin-2-ylmethyl] piperidin-4-yl} dimethylamine

image2

Prepared by using Suzuki coupling method D. The title compound was obtained in

5 form of an orange solid (67 mg, 45%). [M + H] + 496.1 1H NMR (CDCl3, 400 MHz): δ 1.56-1.71 (m, 4 H), 1.85-1.93 (m, 2 H), 2.13 -2.22 (m, 1 H), 2.32 (s, 6 H), 3.04-3.12 (m, 2 H), 3.87 (m, 4 H), 4.02 (m , 6 H), 7.04 (dd, J = 11.1, 8.9 Hz, 1 H), 7.10 (m, 1 H), 7.28 (m, 1 H), 7.38 ( ddd, J = 8.7, 3.9, 0.9 Hz, 1 H) and 8.31 (bs, 1 H).

10

Example 20 {1- [5- (1H-Indol-4-yl) -7-morpholin-4-ylthiazolo [4,5-d] pyrimidin-2-ylmethyl] piperidin-4-yl} dimethylamine

image2

15 Prepared by using Suzuki coupling method E. The title compound was obtained as an orange solid (123 mg, 70%). [M + H] + 478.1 1H NMR (CDCl3, 400 MHz): δ 1.58-1.72 (m, 4 H), 1.86-1.93 (m, 2 H), 2.15 -2.24 (m, 1 H), 2.33 (s, 6 H), 3.04-3.12 (m, 2H), 3.89-3.95 (m, 4 H), 4, 01 (s, 2 H), 4.03-4.09 (m, 4 H), 7.28-7.34 (m, 2 H), 7.52 (m, 1 H), 7.68 ( m, 1 H), 8.32 (bs, 1

20 H) and 8.36 (dd, J = 7.4, 0.9 Hz, 1 H).

Example 21 {2- {4- (5-Fluoro-1H-indol-4-yl) -7-morpholin-4-ylthiazolo [4,5-d] pyrimidin-2-ylmethyl] -piperazin-1-yl} - isobutyramide

image2

25 Prepared by using Suzuki coupling method G. The title compound was obtained as an orange solid (7 mg, 12%). [M + H] + 539.3 1 H NMR (DMSO, 400 MHz): δ 1.10 (s, 6 H), 2.49-2.54 (m, 4 H, hidden), 2.66-2 , 71 (m, 4 H), 3.76-3.79 (m, 4 H), 3.9030 3.93 (m, 4 H), 4.03 (s, 2 H), 6.72 ( m, 1 H), 6.96 (d, J = 2.5 Hz, 1 H), 7.02 (dd, J = 11.5, 9.0 Hz, 1 H), 7.10 (d, J = 2.5 Hz, 1 H), 7.45 (t, J 2.7 Hz, 1 H), 7.48 (ddd, J = 8.5, 4.1, 1.0 Hz, 1 H ) and 11.27 (s, 1 H).

Example 22 2- (4-Azetidin-1-ylpiperidin-1-ylmethyl) -5- (5-fluoro-1H-indol-4-yl) -7-morpholin-4-ylthiazolo [5,4-d] pyrimidine

image2

Prepared by using Suzuki coupling method G. The title compound was obtained in

5 form an off-white solid (69 mg, 43%). [M + H] + 508.2 1H NMR (CDCl3, 400 MHz): δ 1.35-1.45 (m, 2 H), 1.67-1.74 (m, 2 H), 2.00 -2.10 (m, 3 H), 2.28 (td, J = 11.1.2.5 Hz, 2 H), 2.95 (dt, J = 12.1.3.8 Hz, 2 H), 3.19 (t, J = 7.0 Hz, 4 H), 3.84-3.87 (m, 6 H), 4.39-4.44 (m, 4 H), 6, 92-6.94 (m, 1 H), 7.04 (dd, J = 11.1, 8.9 Hz, 1 H), 7.29 (t, J = 2.9 Hz, 1 H), 7.37 (dd, J = 8.9, 3.8 Hz, 1 H) and 8.34 (bs, 1 H).

10

Example 23 5- (5-Fluoro-1H-indole-4-yl) -7-morpholin-4-yl-2-piperazin-1-ylmethylthiazolo [5,4-d] pyrimidine

image2

15 Prepared by using Suzuki coupling method G followed by BOC deprotection. The title compound was obtained as a white solid (46 mg, 37%). [M + H] + 454.1 1H NMR (CDCl3, 400 MHz): δ 2.59-2.68 (m, 4 H), 2.96 (t, J = 4.9 Hz, 4 H), 3.84-3.88 (m, 6 H), 4.39-4.43 (m, 4 H), 6.91-6.94 (m, 1 H), 7.04 (dd, J = 11.1, 8.6 Hz, 1 H), 7.29 (t, J = 3.2 Hz, 1 H), 7.37 (ddd, J = 8.9, 3.5, 0.9 Hz , 1 H) and

20 8.34 (bs, 1 H).

Example 24 2- (4-Cyclopropylpiperazin-1-ylmethyl) -5- (5-fluoro-1H-indole-4-yl) -7-morpholin-4-ylthiazolo [5,4-d] pyrimidine

image2

25 Prepared by using Suzuki coupling method G. The title compound was obtained as a white solid (63 mg, 46%). [M + H] + 494.1 1H NMR (CDCl3, 400 MHz): δ 0.38-0.49 (m, 4 H), 1.64-1.70 (m, 1 H), 2.61 -2.75 (m, 8 H), 3.86 (t, J = 5.1 Hz, 4 H), 30 3.88 (s, 2 H), 4.39-4.44 (m, 4 H), 6.92-6.94 (m, 1 H), 7.04 (dd, J = 11.1, 8.6 Hz, 1H), 7.29 (t, J = 3.2 Hz, 1 H), 7.37 (ddd, J = 8.9, 3.5, 0.9 Hz, 1 H) and 8.31 (bs, 1 H).

Example 25 2- {4- [5- (1H-Indol-4-yl) -7-morpholin-4-ylthiazolo [5,4-d] pyrimidin-2-ylmethyl] piperazin-1-yl} isobutyramide

image2

Prepared by using the Suzuki coupling method F. The title compound was obtained in

5 form an off-white solid (83 mg, 47%). [M + H] + 521.2 1 H NMR (DMSO, 400 MHz): δ 1.10 (s, 6 H), 2.47-2.52 (m, 4 H), 2.62-2.67 (m, 4 H), 3.81 (t, J = 4.5 Hz, 4 H), 3.92 (s, 2H), 4.33-4.38 (m, 4 H), 6.97 (d, J = 2.8 Hz, IH), 7.08 (d, J = 2.8 Hz, 1 H), 7.20 (t, J = 7.4 Hz, 1 H), 7.34 -7.36 (m, 1 H), 7.46 (t, J = 2.8 Hz, 1 H), 7.54 (d, J = 8.1 Hz, 1 H), 8.10 (d , J = 7.4 Hz, 1 H) and 11.31 (bs, 1 H).

10

Example 26 2- {4- [5- (5-Fluoro-1H-Indol-4-yl) -7-morpholin-4-ylthiazolo [5,4-d] pyrimidin-2-ylmethyl] piperazin-1-yl} isobutyramide

image2

15 Prepared by using Suzuki coupling method G. The title compound was obtained as an off-white solid (15 mg, 17%). [M + H] + 539.3 1 H NMR (DMSO, 400 MHz): δ 1.09 (s, 6 H), 2.46-2.51 (m, 4 H), 2.60-2.67 (m, 4 H), 3.76 (t, J = 5.1 Hz, 4 H), 3.93 (s, 2 H), 4.27-4.32 (m, 4 H), 6, 69-6.71 (m, 1 H), 6.97 (d, J = 3.5 Hz, 1 H), 7.00 (dd, J = 11.1, 8.9 Hz, 1 H), 7.08 (d, J = 3.5

20 Hz, 1 H), 7.44-7.49 (m, 2 H) and 11.31 (bs, 1 H).

Example 27 {1- [5- (1H-Indol-4-yl) -7-morpholin-4-ylthiazolo [5,4-d] pyrimidin-2-ylmethyl] piperidin-4-yl} dimethylamine

25 Prepared by using Suzuki coupling method B. The title compound was obtained as a brown solid (75 mg, 62%). [M + H] + 478.2 1H NMR (400 MHz, CDCl3): δ 1.59-1.71 (m, 2 H), 1.87 (d, J = 12.6 Hz, 2 H), 2.25 (dt, J = 12.2, 1.8 Hz, 3 H), 2.35 (s, 6 30 H), 3.07 (d, J = 12.0 Hz, 2 H), 3 , 87 (s, 2 H), 3.90 (t, J = 4.3 Hz, 4 H), 4.43-4.46 (m, 4 H), 7.30 (t, J = 7, 5 Hz, 1 H), 7.34 (t, J = 2.5 Hz, 1 H), 7.50 (d, J = 8.7 Hz, 1 H), 7.51-7.53 (m , 1 H), 8.18 (d, J = 7.1 Hz, 1 H) and 8.30 (bs, 1 H).

image2

Example 28 5- (1H-indol-4-yl) -7-morpholin-4-yl-2- (4-morpholin-4-ylpiperidin-1-ylmethyl) thiazolo [5,4-d] pyrimidine

image2

Prepared by using Suzuki coupling method B. The title compound was obtained in

5 form of a brown solid (38 mg, 64%). [M + H] + 520.2 1H NMR (CDCl3, 400 MHz): δ 1.63 (qd, J = 11.3, 3.7 Hz, 2 H), 1.87 (d, J = 11, 3 Hz, 2 H), 2.18-2.29 (m, 3 H), 2,552.59 (m, 4 H), 3.07 (d, J = 11.9 Hz, 2 H), 3, 72-3.76 (m, 4 H), 3.86 (s, 2 H), 3.90 (t, J = 5.1 Hz, 4 H), 4.43-4.47 (m, 4 H), 7.30 (t, J = 8.1 Hz, 1 H), 7.34 (t, J = 2.9 Hz, 1 H), 7.49-7.53 (m, 2 H) , 8.18 (d, J = 7.6 Hz, 1 H) and 8.29 (bs, 1 H).

Example 29 5- (5-Fluoro-1H-indol-4-yl) -7-morpholin-4-yl-2- (4-morpholin-4-ylpiperidin-1-ylmethyl) thiazolo [5,4-d] pyrimidine

image2

Prepared by using Suzuki coupling method C. The title compound was obtained in

15 form of a brown solid (27 mg, 45%). [M + H] + 538.2 1H NMR (CDCl3, 400 MHz): δ 1.63 (qd, J = 11.3, 3.7 Hz, 2 H), 1.87 (d, J = 11, 3 Hz, 2 H), 2.18-2.29 (m, 3 H), 2,552.59 (m, 4 H), 3.07 (d, J = 11.9 Hz, 2 H), 3, 72-3.76 (m, 4 H), 3.84-3.87 (m, 6 H), 4.40 (m, 4 H), 6.92-6.94 (m, 1 H), 7.05 (dd, J = 11.0, 8.5 Hz, 1 H), 7.29 (t, J = 2.0 Hz, 1 H), 7.38 (dd, J = 8.4, 4.2 Hz, 1 H) and 8.24 (bs, 1 H).

twenty

Example 30 Biological tests

The compounds of the invention, prepared as described in the previous Examples, were subjected to the following biological test:

Biochemical screening of PI3K

Inhibition with a PI3K compound was determined in a radiometric assay using recombinant enzyme

30 purified and ATP at a concentration of 1 µM. All compounds were serially diluted in 100% DMSO. The kinase reaction was incubated for 1 hour at room temperature and the reaction was terminated by the addition of PBS. Next, IC50 values were determined using a dose-response curve adjustment (variable slope). All the compounds tested had an IC50 against PI3K of 50 mM or less. Typically, the IC50 against the p110δ isoform of PI3K is less than 500 nM.

35

Example 31 Tablet composition

The tablets, each weighing 0.15 g and containing 25 mg of a compound of the invention, were prepared as follows:

Composition for 10,000 tablets Compound of the invention (250 g) Lactose (800 g)

Corn Starch (415 g) Talcum powder (30 g) Magnesium Stearate (5 g)

The compound of the invention, lactose and half of the corn starch were mixed. The mixture was then forced through a sieve of 0.5 mm mesh size. Corn starch (10 g) was suspended in warm water (90 ml). The resulting paste was used to granulate the powders. The granulate was dried and divided into small fragments in a sieve of 1.4 mm mesh size. The remaining amount of starch, talc and magnesium was added, mixed thoroughly and processed to form tablets.

Example 32 Injectable formulation

[0252]

Compound of the invention 200mg

0.1 M hydrochloric acid solution or 0.1 M sodium hydroxide solution c.s. for pH 4.0 to 7.0 Sterile water c.s. for 10 ml

The compound of the invention was dissolved in most of the water (at 35 ° C-40 ° C) and the pH was adjusted to a value between 4.0 and 7.0 with hydrochloric acid or sodium hydroxide as appropriate. The batch was then flush to the final volume with water and filtered through a sterile microporous filter in a 10 ml sterile amber glass vial (type 1) and sealed with sterile closures and seals.

fifteen

Example 33 Intramuscular injection

Compound of the invention 200 mg

20 Benzyl alcohol 0.10 g Glycofurol 75 1.45 g Water for injection, c.s. for 3.00 ml

The compound of the invention was dissolved in glycofurol. Then, the benzyl alcohol was added and dissolved, 25 and water was added to 3 ml. The mixture was then filtered through a sterile microporous filter and sealed in sterile 3 ml glass vials (type 1).

Example 34 Syrup formulation

Compound of the invention 250 mg Sorbitol solution 1.50 g Glycerol 2.00 g Sodium benzoate 0.005 g

35 Flavoring 0.0125 ml Purified water, c.s. for 5.00 ml

The compound of the invention was dissolved in a mixture of glycerol and most of the purified water. TO

Then, an aqueous solution of sodium benzoate was added to the solution, followed by the addition of the sorbital solution and finally the flavoring. It was made up to the final volume with purified water and mixed uniformly.

Claims (8)

1. Compound which is a thiazolopyrimidine of formula (I): image 1 wherein: W represents a thiazole ring, R1 and R2 form, together with the N atom to which they are attached, a group with the following formula (IIa): image 1 in which A is selected from: (a) a saturated nitrogen heterocyclic ring of 4 to 7 elements including 0 or 1 additional heteroatom 10 selected from N, S and O, the ring being unsubstituted or substituted, (b) a saturated nitrogen heterocyclic ring of 4 to 7 elements that includes 0 or 1 additional heteroatom selected from N, S and O, the fused ring being found with a second ring selected from a saturated nitrogen heterocyclic ring of 4 to 7 elements as defined above, an unsaturated heterocyclic ring of 5 to 12 elements, an oxygenated heterocyclic ring 15 saturated with 5 to 7 elements, a saturated carbocyclic ring with 3 to 12 elements and an unsaturated carbocyclic ring with 5 to 12 elements, forming a heteropolyclic ring system, the unsubstituted or substituted heteropolyclic ring system being found, (c) a saturated nitrogen heterocyclic ring of 4 to 7 elements that includes 0 or 1 additional heteroatom selected from N, S and O and further comprising joining two constituent atoms of the ring, a 20 bridgehead group selected from - (CR'2) n- and - (CR'2) rO- (CR'2) s-, in which each R 'is independently H or C1-C6 alkyl , n is 1, 2 or 3, r is 0 or 1 and s is 0 or 1, the remaining annular positions being unsubstituted or substituted, and (d) a group of formula (IIb): image 1 25 in which ring B is a saturated nitrogen heterocyclic ring of 4 to 7 elements which includes 0 or 1 additional heteroatom selected from N, S and O, and ring B 'is a saturated carbocyclic ring of 3 to 12 elements, a saturated oxygenated heterocyclic ring of 5 to 7 elements or a saturated nitrogen heterocyclic ring of 4 to 7 elements as defined above, each of B and B 'being unsubstituted or substituted, 30 or one of R1 and R2 is C1-C6 alkyl and the other of R1 and R2 is selected from a saturated carbocyclic group of 3 to 12 elements that is unsubstituted or substituted, an unsaturated carbocyclic group of 5 to 12 elements which is unsubstituted or substituted, an unsaturated hetreoccyclic group of 5 to 12 elements that is unsubstituted or substituted, a group 35 saturated heterocyclic of 4 to 12 elements that is unsubstituted or substituted, and a C1-C6 alkyl group that is substituted with a group selected from a saturated carbocyclic group of 3 to 12 elements that is unsubstituted or substituted, an unsaturated carbocyclic group of 5 to 12 elements that is unsubstituted or substituted, an unsaturated heterocyclic group of 5 to 12 elements that is unsubstituted or substituted, and an unsaturated heterocyclic group of 4 to 12 5 elements that are unsubstituted or substituted. m is 0, 1 or 2, R3 is H or C1-C6 alkyl, and  R4 is an indole group that is unsubstituted or substituted, or a pharmaceutically acceptable salt thereof. image 1 Compound according to claim 1, wherein the thiazolopyrimidine is of formula (Ia): image 1 wherein R1, R2, R3, R4 and m are as defined in claim 1. 3. Compound according to claim 1, wherein the thiazolopyrimidine is of formula (Ib): image 1 Wherein R1, R2, R3, R4 and m are as defined in claim 1. 4. Compound according to any of the preceding claims, wherein R4 is an indole group which is unsubstituted or substituted with a group selected from CN, halo, -C (O) NR2, C1C6 haloalkyl, -SO2R-SO2NR2 and a 5-element heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from O, N and S, wherein R is H or C1-C6 alkyl. 20 5. Compound selected from: 5- (6-Fluoro-1H-indole-4-yl) -2- (hexahydro-pyrrolo [3,4-c] pyrrol-2-ylmethyl) -7-morpholin-4-yl-thiazolo [4,5- d] pyrimidine; 5- (6-Fluoro-1H-indole-4-yl) -2- (hexahydro-pyrrolo [3,4-c] pyrrol-2-ylmethyl) -7-morpholin-4-yl-thiazolo [5.4 d ] pyrimidine; 2- (2,7-Diaza-spiro [3.5] non-2-ylmethyl) -5- (1 H -indol-4-yl) -7-morpholin-4-yl-thiazolo [5,4-d] pyrimidine; 2- (2,7-Diaza-spiro [3.5] non-2-ylmethyl) -5- (6-fluoro-1H-indole-4-yl) -7-morpholin-4-yl-thiazolo [5,4- d] pyrimidine; 2- 2- (2,7-Diaza-spiro [3.5] non-2-ylmethyl) -5- (5-fluoro-1H-indole-4-yl) -7-morpholin-4-yl-thiazolo [5.4 -d] pyrimidine; 2- (3,8-Diaza-bicyclo [3.2.1] oct-3-ylmethyl) -5- (1H-indole-4-yl) -7-morpholin-4-yl-thiazolo [5,4-d] pyrimidine; 2- (4-Azetidin-1-yl-piperidin-1-ylmethyl) -5- (1 H -indol-4-yl) -7-morpholin-4-yl-thiazolo [5,4-d] pyrimidine; 2 - [(S) -1- (Hexahydro-pyrrolo [1,2-a] pyrazin-2-yl) methyl] -5- (1H-indole-4-yl) -7-morpholin-4-yl-thiazolo [5,4-d] pyrimidine; 2- (3,5-Dimethyl-piperazin-1-ylmethyl) -5- (1H-indol-4-yl) -7-morpholin-4-yl-thiazolo [5,4-d] pyrimidine; 30 2- (2,7-Diaza-spiro [3.5] non-2-ylmethyl) -5- (6-fluoro-1H-indole-4-yl) -7-morpholin-4-yl-thiazolo [4,5 -d] pyrimidine formate; 5- (1H-Indol-4-yl) -7-morpholin-4-yl-2- (4-morpholin-4-yl-piperidin-1-ylmethyl) -thiazolo [4,5-d] pyrimidine; 2- (3,3-Dimethylpiperazin-1-ylmethyl) -5- (5-fluoro-1H-indol-4-yl) -7-morpholin-4-ylthiazolo [4,5-d] pyrimidine; 5- (5-Fluoro-1H-indole-4-yl) -7-morpholin-4-yl-2- (4-morpholin-4-ylpiperidin-1-ylmethyl) thiazolo [4,5-d] pyrimidine; 5- (1H-Indol-4-yl) -7-morpholin-4-yl-2- (4-morpholin-4-ylpiperidin-1-ylmethyl) thiazolo [4,5-d] pyrimidine; 5- (5-Fluoro-1H-indole-4-yl) -2 - [(S) -1- (hexahydro-pyrrolo [1,2-a] pyrazin-2-yl) methyl] -7-morpholin-4 -iltiazolo [4,5d] pyrimidine; 2- (4-Azetidin-1-ylpiperidin-1-ylmethyl) -5- (5-fluoro-1H-indol-4-yl) -7-morpholin-4-ylthiazolo [4,5-d] pyrimidine; 2- (4-Azetidin-1-ylpiperidin-1-ylmethyl) -5- (1H-indol-4-yl) -7-morpholin-4-ylthiazolo [4,5-d] pyrimidine; 2- (4-Cyclopropylmethylpiperazin-1-ylmethyl) -5- (5-fluoro-1H-indol-4-yl) -7-morpholin-4-ylthiazolo [4,5-d] pyrimidine; {1- [5- (5-Fluoro-1H-indol-4-yl) -7-morpholin-4-ylthiazolo [4,5-d] pyrimidin-2-ylmethyl] piperidin-4-yl} dimethyl amine; {1- [5- (1H-Indol-4-yl) -7-morpholin-4-ylthiazolo [4,5-d] pyrimidin-2-ylmethyl] piperidin-4-yl} dimethylamine; 2- {4- [5- (5-Fluoro-1H-indol-4-yl) -7-morpholin-4-yl-thiazolo [4,5-d] pyrimidin-2-ylmethyl] -piperazin-1-yl } -isobutyramide; 2- (4-Azetidin-1-ylpiperidin-1-ylmethyl) -5- (5-fluoro-1H-indol-4-yl) -7-morpholin-4-ylthiazolo [5,4-d] pyrimidine; 5- (5-Fluoro-1H-indole-4-yl) -7-morpholin-4-yl-2-piperazin-1-ylmethylthiazolo [5,4-d] pyrimidine; 2- (4-Cyclopropylpiperazin-1-ylmethyl) -5- (5-fluoro-1H-indol-4-yl) -7-morpholin-4-ylthiazolo [5,4-d] pyrimidine; 2- {4- [5- (1H-Indol-4-yl) -7-morpholin-4-ylthiazolo [5,4-d] pyrimidin-2-ylmethyl] piperazin-1-yl isobutyramide; 2- {4- [5- (5-Fluoro-1H-indol-4-yl) -7-morpholin-4-ylthiazolo [5,4-d] pyrimidin-2-ylmethyl] piperazin-1-yl} isobutyramide; {1- [5- (1H-Indol-4-yl) -7-morpholin-4-ylthiazolo [5,4-d] pyrimidin-2-ylmethyl] piperidin-4-yl} dimethylamine; 5- (1H-Indol-4-yl) -7-morpholin-4-yl-2- (4-morpholin-4-ylpiperidin-1-ylmethyl) thiazolo [5,4-d] pyrimidine; and 5- (5-Fluoro-1H-indole-4-yl) -7-morpholin-4-yl-2- (4-morpholin-4-ylpiperidin-1-ylmethyl) thiazolo [5,4-d] pyrimidine; and pharmaceutically acceptable salts thereof.

6.

Pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as an active ingredient, a compound according to any one of claims 1 to 5.

7.

Compound according to any one of claims 1 to 5, for use in a method of medical treatment of the human or animal body by therapy.

8.

Compound according to any one of claims 1 to 5, for the treatment of a disease or disorder that appears as a result of abnormal cell growth, function or behavior associated with PI3 kinase.

9.

Use of a compound according to any one of claims 1 to 5 in the preparation of a medicament for the treatment of a disease or disorder that appears as a consequence of the abnormal cellular growth, function or behavior associated with PI3 kinase.

10.

Use according to claim 9, wherein the medicament is intended for the treatment of cancer, immune disorders, cardiovascular diseases, viral infection, inflammation, metabolic disorders / endocrine function and neurological disorders.