ES2825974T3 - Process for the preparation of optically pure and optionally substituted 2- (1-hydroxy-alkyl) -chromen-4-one derivatives and their use in the preparation of pharmaceutical products - Google Patents

Abstract

A process for the preparation of a compound of formula (IA) or a salt thereof, the process (a) comprising reacting a compound of formula (6) with a compound of formula (A) to obtain a compound of formula (7a ) (b) deprotecting the compound formed in step (a) to obtain a compound of formula (IA); and (c) optionally converting the compound of formula (IA) into a salt thereof, wherein each occurrence of R is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted alkoxy or unsubstituted, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, heterocycliclakyl substituted, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -COORX, -C (O) RX, -C (S) RX, -C (O) NRxRy, -C (O) ONRxRy, - NRxRy, -NRxCONRxRy, -N (RX) SORX, -N (Rx) SO2Ry, - (= NN (Rx) Ry), -NRxC (O) ORy, -NRxC (O) Ry -, - NRxC (S) Ry, -NRxC (S) NRxRy, -SONRxRy, -SO2NRxRy, -ORX, -ORxC (O) NRxRy, -ORXC (O) ORX, - OC (O) RX, -OC (O) NRxRy, -RxNRyC (O) Rz, -RxORy, -RxC (O) ORy, -RxC (O) NRxRy, -RxC (O) Ry, - RxOC (O) Ry, -SRX, -SORX, -SO2RX, and -ONO2, wherein each occurrence of Rx, Ry, and Rz is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted alkynyl, or unsubstituted, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, a substituted heterocyclic ring or unsubstituted, a substituted or unsubstituted heterocyclylalkyl ring, or a substituted or unsubstituted amino, or (i) any two of Rx and Ry, when attached to a common atom, join to form a substituted 3-14 membered ring or unsubstituted, saturated, or unsaturated, which may optionally include heteroatoms that e can be the same or different and they are selected from O, NRZ or S, or (ii) any two of Rx and Ry, when attached to a common atom, join to form an oxo (= O), uncle ( = S) or imino (= NRf) (where Rf is hydrogen or substituted or unsubstituted alkyl); R1 is substituted or unsubstituted C1-6 alkyl; Cy1 is a monocyclic or bicyclic group selected from substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Pg is a protecting group; and n is an integer that is selected from 0, 1, 2, 3, or 4.

Description

DESCRIPTION

Process for the preparation of optically pure and optionally substituted 2- (1-hydroxy-alkyl) -chromen-4-one derivatives and their use in the preparation of pharmaceutical products

Priority

The present application claims the benefit of Indian Provisional Patent Application No. 1737 / CHE / 2012 dated May 4, 2012 and US Provisional Patent Application No. 61 / 671,956 dated July 16 2012.

Field of the invention

The present invention relates to compounds useful as pharmaceutical intermediates, to processes for the preparation of intermediates, to intermediates used in the processes, and to the use of intermediates in the preparation of pharmaceutical compounds. In particular, the present invention encompasses the enantiomerically pure and optionally substituted 2- (1-hydroxy-alkyl) -chromen-4-one derivatives, the processes for preparing the alcohol derivatives and their use in the preparation of pharmaceutical compounds.

Background of the invention

International Publication No. WO 2011/055215, International Publication No. WO 2012/151525 A1, US Publication No. 2011/0118257, US Publication No. 2012/0289496 , Indian Provisional Patent Applications No. 1542 / CHE / 2011 dated May 4, 2011 and No. 81 / CHE / 2012 dated January 9, 2012 generally disclose 2,34H-chromene compounds. 4-disubstituted one as PI3K inhibitors useful for the treatment, prevention and / or amelioration of kinase-mediated diseases or disorders. Summary of the invention

The present inventors have developed an improved process for the preparation of optionally substituted derivatives of 2- (1-hydroxy-alkyl) -chromen-4-one (including 6-substituted compounds of 2- (1-hydroxy-alkyl) 4H-chromen -4-one) that can be used for the preparation of 2,34H-chromen-4-disubstituted-one compounds. The process is particularly useful for the preparation of optionally substituted enantiomerically pure derivatives 2- (1-hydroxy-alkyl) -chromen-4-one. The process is enantioselective and suitable for large-scale production, features high throughput, uses non-hazardous reagents and results in less waste.

The present invention provides processes for the preparation of a compound of formula (IA)

(a) reacting a compound of formula (6) with a compound of formula (A)

to obtain a compound of formula (7a)

(b) deprotecting the compound formed in step (a) to obtain a compound of formula (IA); and (c) optionally converting the compound of formula (IA) into a salt thereof,

in which

each occurrence of R is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, heteroaryl, substituted or unsubstituted heteroaryl or unsubstituted, -COORX, -C (O) RX, -C (S) RX, -C (O) NRxRy, -C (O) ONRxRy, -NRxRy, -NRxCONRxRy, -N (RX) SORX, -N (Rx) SO2Ry, - (= NN (Rx) Ry), -NRxC (O) ORy, -NRxC (O) Ry-, -NRxC (S) Ry, -NRxC (S) NRxRy, -SONRxRy, -SO2NRxRy, -ORX, -ORxC (O) NRxRy, -ORXC (O) ORX, -OC (O) RX, -OC (O) NRxRy, -RxNRyC (O) Rz, -RxORy, -RxC (O) ORy, -RxC (O) NRxRy, -RxC (O) Ry, -RxOC (O) Ry , -SRX, -SORX, -SO2RX and -ONO2, wherein each occurrence of Rx, Ry and Rz is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl substituted, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring substituted, a substituted or unsubstituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or (i) any two of Rx and Ry, when attached to a common atom, join to form a substituted or unsubstituted 3-14 membered ring substituted, saturated or unsaturated, which may optionally include heteroatoms which may be the same or different and which are selected from O, NRZ or S, or (ii) any two of Rx and Ry, when bonded to a common atom, bond to form an oxo (= O), thio (= S), or imino (= NRf) (where Rf is hydrogen or substituted or unsubstituted alkyl);

R1 is substituted or unsubstituted C1-6 alkyl;

Cy1 is a group (eg, a monocyclic or bicyclic group) that is selected from substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

Pg is a protecting group; Y

n is an integer that is selected from 0, 1,2, 3, or 4.

In one embodiment, the compound is not selected from:

or a salt of it.

Further preferred is a compound of formula (IA) wherein R is alkyl (eg, C1-C4 alkyl such as methyl or ethyl) or halogen.

Further preferred is a compound of formula (IA) wherein R is chloro, fluoro or methyl.

Further preferred is a compound of formula (IA), wherein Cy1 is a monocyclic group selected from substituted or unsubstituted aryl.

Further preferred is a compound of formula (IA), wherein Cy1 is selected from

Further preferred is a compound of formula (IA) wherein R1 is methyl or ethyl.

Further preferred is a compound of formula (IA) wherein n is 1.

In yet another embodiment, it is a compound that is selected from:

1. (R) -6-fluoro-3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one,

2. (R) -2- (1-hydroxyethyl) -5-methyl-3-phenyl-4H-chromen-4-one,

3. (R) -6-fluoro-2- (1-hydroxyethyl) -3-phenyl-4H-chromen-4-one,

4. (R) -2- (1-hydroxyethyl) -3-phenyl-4H-chromen-4-one,

5. (R) -3- (3-fluorophenyl) -2- (1-hydroxypropyl) -4H-chromen-4-one,

6. (R) -3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one,

7. (S) -3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one.

Table 1

One embodiment is a process for the preparation of a compound of formula (IA) that includes

(a) treating a compound of formula (6) in which R, n and Cy1 are as defined above with a compound of formula (A) in which R1 is as defined above and Pg is a protecting group (such as benzyl)

Y

(b) deprotecting the compound formed in step (a) to obtain a compound of formula (IA) and optionally converting it to its salt.

In yet another embodiment, the reaction of the compound of formula (6) with the compound of formula A is carried out in the presence of a suitable coupling reagent such as HATU (2- (7-Aza-1H-benzotriazole-hexafluorophosphate) 1-yl) -1,1,3,3-tetramethyluronium), HBTU (O-Benzotriazol-N, N, N ', N'-tetramethyl-uronium-hexafluoro-phosphate), TBTU (O- tetrafluoroborate (Benzotriazole- 1-yl) -N, N, N ', N'-tetramethyl uronium), COMU (Morpholino, 4 - [[[(1-cyano-2-ethoxy-2-oxoethylidene) amino] oxayl] (dimethylamino) methylene] -hexafluorophosphate), TOTU ((O - [(Ethoxycarbonyl) cyanomethyleneamino] -N, N, N ', N'-tetramethyluronium tetrafluoroborate), HCTU ((2- (6-Chloro-1H-benzotriazol-1-yl ) -1,1,3,3-tetramethylaminium), TCTU (O- (6-Chloro-1-hydrocibenzotriazoM-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate), TATU (O- (7 tetrafluoroborate) -Azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyl uronium), TSTU (O- (N-Succinimidyl) -1,1,3,3-tetramethyluranium tetrafluoroborate), TDBTU (N tetrafluoroborate , N, N ', N'-Tetramethyl-O- (3 , 4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl) uranium), any other suitable coupling reagent, or any combination of any of the aforementioned.

It is further preferred where the reaction of the compound of formula (6) with the compound of formula A is carried out in the presence of HATU, HBTU, TBTU or COMU.

It is further preferred where the reaction of the compound of formula (6) with the compound of formula A is carried out in the presence of HATU.

Another embodiment is a process for the preparation of a compound of formula (IB)

wherein all variables are as defined above and the process includes the steps of (a) reacting a compound of formula (6) with a compound of formula (B)

to obtain a compound of formula (7b)

Y

(b) deprotecting the compound formed in step (a) to obtain a compound of formula (IB); and (c) optionally converting the compound of formula (IB) into a salt thereof.

In one embodiment, the compound is not selected from:

or a salt of it.

Further preferred is a compound of formula (IB) wherein R is alkyl (eg, C1-C4 alkyl such as methyl or ethyl) or halogen.

Further preferred is a compound of formula (IB) wherein R is chloro, fluoro or methyl.

Further preferred is a compound of formula (IB), wherein Cy1 is a monocyclic group selected from substituted or unsubstituted aryl.

Further preferred is a compound of formula (IB), wherein Cy1 is selected from

Further preferred is a compound of formula (IB) wherein R1 is methyl or ethyl.

Further preferred is a compound of formula (IB) wherein n is 1.

Still another embodiment is a process for the preparation of a compound of formula (IA)

wherein all variables are as defined above and the procedure includes the steps of (a) converting a compound of formula (1)

where R and n are as defined above and Pg is a protecting group in a compound of formula (2)

(b) converting the compound of formula (2) into a compound of formula (3)

(c) converting the compound of formula (3) into a compound of formula (5)

in which

(d) deprotecting the compound of formula (5) to give a compound of formula (6)

(e) reacting the compound of formula (6) with a compound of formula (A)

(f) deprotecting the compound of formula (7a) to give the desired compound of formula (IA); Y

(g) optionally converting the compound of formula (IA) to a salt of the compound.

The compound of Formula (1) can be converted to a compound of Formula (2) by treating the compound of formula (1) with hydroxylamine or a salt thereof (such as NH2OH ^ HCl) in the presence of a base. The compound of Formula (3) can be obtained by treating the compound of formula (2) with N, N'-carbonyldiimidazole (CDI). The compound of Formula (3) can be converted to a compound of Formula (5) by treating the compound of formula (3) with a Grignard reagent of formula (4a)

Cy1-CH2-MgX 4a

where X is halogen and Cy1 is as defined above.

Still another embodiment is a process for the preparation of a compound of formula (IB)

wherein all variables are as defined above and the process includes the steps of (a) converting a compound of formula (1)

in a compound of formula (2)

wherein R and n are as defined above and Pg is a protecting group (for example, by reacting the compound of formula (1) with hydroxylamine or a salt thereof (such as NH2OH ^ HCl) in the presence of a base );

(b) converting the compound of formula (2) into a compound of formula (3)

(for example, by treating the compound of formula (2) with N, N -carbonyldiimidazole (CDI)); (c) converting the compound of formula (3) into a compound of formula (5)

wherein R, n, Cy1 and Pg are as described above (for example, by treating the compound of formula (3) with a Grignard reagent of formula (4a)

Cy1-CH2-MgX 4a

wherein X is halogen and Cy1 is as defined above);

(d) deprotecting the compound of formula (5) to give a compound of formula (6)

(e) reacting the compound of formula (6) with a compound of formula (B)

to give a compound of formula (7b)

(f) deprotecting the compound of formula (7b) to give the desired compound of formula (IB) in which all variables (R, R1, n and Cy1) are as described above in relation to Formula (IA); Y

(g) optionally converting the compound of formula (IB) to a salt of the compound.

In yet another embodiment, the reaction of the compound of formula (6) with the compound of formula B is carried out in the presence of a suitable coupling reagent such as HATU (2- (7-Aza-1H-benzotriazole-hexafluorophosphate) 1-yl) -1,1,3,3-tetramethyluronium), HBTU (O-Benzotriazol-N, N, N ', N'-tetramethyl-uronium-hexafluoro-phosphate), TBTU (O- tetrafluoroborate (Benzotriazole- 1-yl) -N, N, N ', N'-tetramethyl uronium), COMU (Morpholino, 4 - [[[(1-cyano-2-ethoxy-2-oxoethylidene) amino] oxayl] (dimethylamino) methylene] -hexafluorophosphate), TOTU ((O - [(Ethoxycarbonyl) cyanomethyleneamino] -N, N, N ', N'-tetramethyluronium tetrafluoroborate), HCTU ((2- (6-Chloro-1H-benzotriazol-1-yl ) -1,1,3,3-tetramethyluronium), TCTU (O- (6-Chloro-1-hydrocybenzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate), TATU (O- tetrafluoroborate (7-Azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyl uronium), TSTU (O- (N-Succinimidyl) -1,1,3,3-tetramethyluranium tetrafluoroborate), TDBTU (tetrafluoroborate of N, N, N ', N'-Tetramethyl-O- (3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl) uranium), any other suitable coupling reagent, or any combination of any of the aforementioned.

It is further preferred wherein the reaction of the compound of formula (6) with the compound of formula B is carried out in the presence of HATU, HBTU, TBTU or COMU.

It is further preferred wherein the reaction of the compound of formula (6) with the compound of formula B is carried out in the presence of HATU.

Still another embodiment is a process for the inversion of a compound of formula (IA) to provide a compound of formula (IB)

comprising the stage of

(a) reacting the compound of formula (IA) with R'-COOH (where R 'is selected from substituted or unsubstituted alkyl or substituted or unsubstituted aryl) to provide a compound of formula IA-2.

(b) treating the compound of formula (IA-2) with a suitable base in a polar solvent to provide a compound of formula (IB).

Still another embodiment is a process for the inversion of a compound of formula (IB) to provide a compound of formula (IA)

comprising the stage of:

(a) reacting the compound of formula (IB) with R'-COOH (where R 'is selected from substituted or unsubstituted alkyl or substituted or unsubstituted aryl) to provide a compound of formula IB-2

(b) treating the compound of formula (IB-2) with a suitable base in a polar solvent to provide a compound of formula (IA).

It is further preferred where R 'is 4-chlorophenyl.

It is further preferred where the base is selected from inorganic bases, such as K2CO3, Na2CO3 or CsCO3 and the polar solvent used is a suitable alcohol selected from methanol or ethanol.

Still another embodiment is a process for the preparation of a compound of formula (IA-1)

in which all the variables are as defined above and the procedure comprises the steps of:

(a) converting a compound of formula (1a)

in a compound of formula (2a)

wherein R and n are as defined above and Pg is a protecting group (for example, by reacting a compound of formula (1a) with hydroxylamine or a salt thereof (such as NH2OH ^ HCl) in the presence of a base);

(b) converting a compound of formula (2a) into a compound of formula (3a)

(eg, by treating the compound of formula (2a) with N, N -carbonyldiimidazole (CDI)); (c) converting a compound of formula (3a) into a compound of formula (5a)

(for example by treating the compound of formula (3a) with a Grignard reagent of formula (4a)

Cy1-CH2-MgX 4a

wherein X is halogen and Cy1 is as described above);

(d) deprotecting the compound of formula (5a) to give a compound of formula (6a)

(e) reacting the compound of formula (6a) with a compound of formula (A)

(f) deprotecting the compound of formula (7aa) to give the desired compound of formula (IA-1) in which all variables (R, R1, n and Cy1) are as described above in relation to Formula (IA ); Y

(g) optionally converting the compound of formula (IA-I) into a salt of the compound.

Still another embodiment is a process for the preparation of a compound of formula (IA-II)

in which all the variables are as defined above and the procedures comprise the stage of

(a) convert a compound of formula (1b)

wherein R is as defined above and Pg is a protecting group, in a compound of formula (2b)

(for example, by treating a compound of formula (1a) with hydroxylamine or a salt thereof (such as NH2OH ^ HCl) in the presence of a base);

(b) converting a compound of formula (2b) into a compound of formula (3b)

(for example, by treating the compound of formula (2b) with N, N'-carbonyldiimidazole (CDI)); (c) converting the compound of formula (3b) into a compound of formula (5b)

(for example, treating a compound of formula (3b) with a Grignard reagent of formula (4a)

Cy1-CH2-MgX 4a

wherein X is halogen and Cy1 is as described above);

(d) deprotecting the compound of formula (5b) to give a compound of formula (6b)

(e) reacting the compound of formula (6b) with a compound of formula (A)

Y

(f) deprotecting the compound of formula (7ab) to give the desired compound of formula (IA-II) in which all variables (R, R1, n and Cy1) are as described above in relation to Formula (IA ); Y

(g) optionally converting the compound of formula (IA-II) into a salt of the compound.

Still another embodiment is a process for the preparation of a compound of formula (IB-I)

in which all the variables are as defined above and the procedure comprises the steps of:

(a) reacting the compound of formula (6a) with a compound of formula (B)

to give a compound of formula (7ba)

(b) deprotecting the compound of formula (7ba) to give the desired compound of formula (IB-I) in which all variables (R, R1, n and Cy1) are as described above in relation to Formula (IA ); Y

(c) optionally converting the compound of formula (IB-I) into a salt of the compound.

Still another embodiment is a process for the preparation of a compound of formula (IB-II)

in which all variables are as defined above and the procedure comprises the steps of

(a) reacting the compound of formula (6b) with a compound of formula (B)

to give a compound of formula

(b) deprotect the compound of formula (7bb) to give the desired compound of formula (IB-II) in which all variables (R, R1, n and Cy1) are as described above in relation to Formula (IA ); Y

(c) optionally converting the compound of formula (IB-II) into a salt of the compound.

Still another embodiment is a compound of formula (IA) or (IB)

or a salt thereof, in which the variables R, n, Cy1 and R1 are defined the same as above.

In one embodiment, the compound of formula (IA) or (IB) exhibits an enantiomeric excess (EE) of at least 75%, 90%, 95%, 97% or 98%.

Still another embodiment is the use of the compound of formula (IA) or any other intermediate described herein for the preparation of the PI3K inhibitors of formula (I)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof or pharmaceutically acceptable salt thereof, wherein

the variables R, n, Cy1 and R1 are defined as before;

Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

L1 is absent or selected from - (CRaRb) q-, -O-, -S (= O) q-, -NRa- or -C (= Y) -;

each occurrence of Ra and Rb may be the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (1-6C) alkyl, -NRcRd (where Rc and Rd are independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C1-6) alkyl or (C1-6) alkoxy) and -ORC (where Rc is substituted or unsubstituted (C1-6) alkyl) or when Ra and Rb are attached directly to a common atom can join to form an oxo group (= O) or form a 3-10 membered substituted or unsubstituted, saturated or unsaturated ring (which includes the common atom to which Ra and Rb are directly attached ), which optionally may include one or more heteroatoms which may be the same or different and are selected from O, NRd (where Rd is hydrogen or substituted or unsubstituted (1-6C) alkyl) or S;

Y is selected from O, S, and NRa; Y

q is 0, 1, or 2.

The compound of formula (I) can be prepared by

(a) the treatment of the compound of formula (IA)

with Cy2-H (for example, by a Mitsunobu reaction) to give the desired compound of formula (I) or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. same, in which

R, R1, n and Cy1 are as described above in relation to Formula (IA),

Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Y

L1 is absent, and

(b) optionally, the conversion of the compound of formula (I) to a salt of the compound.

The compound of formula (I) can also be prepared by

(a) the treatment of the compound of formula (IA)

with a phosphorous halide or mesyl chloride (or other mesyl halide) in the presence of a base to give a compound of formula (8a)

wherein X1 is halogen or -O-Mesyl (i.e. -O-SO2CH3), and

(b) reacting the compound of formula (8a) with Cy2-H in the presence of a base to give the desired compound of formula (I) or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug of the same, in which

R, R1, n and Cy1 are as described above in relation to Formula (IA);

Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Y

Li is absent, and

(c) optionally, the conversion of the compound of formula (I) to a salt of the compound.

Still another provided embodiment is the use of the compound of formula (IA) for the preparation of the PI3K inhibitors of formula (I)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, wherein

R, R1, n and Cy1 are as described above in relation to Formula (IA);

Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Y

L1 is NH.

The compound of formula (I) can be prepared by

(a) the treatment of the compound of formula (IA)

with a phosphorous halide or mesyl chloride (or other mesyl halide) in the presence of a base to give a compound of formula (8a)

wherein X1 is halogen or -O-Mesyl;

(b) converting the compound of formula (8a) to give a compound of formula (9a)

(for example, by treating the compound of formula (8a) with sodium azide);

(c) converting the compound of formula (9a) to give a compound of formula (10a)

(for example, by treating the compound of formula (8a) with triphenylphosphine);

(d) coupling the compound of formula (10a) with a compound of formula Cy2-Lg, in which Lg is a leaving group, in the presence of a base to give the desired compound of formula (II); Y

(e) optionally, the conversion of the compound of formula (II) to a salt of the compound.

Still another embodiment is the use of the compound of formula (IB) or any other intermediate described herein, for the preparation of the PI3K inhibitors of formula (III)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof or pharmaceutically acceptable salt thereof, wherein

the variables R, n, Cy1 and R1 are defined as before;

Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

L1 is absent or selected from - (CRaRb) q-, -O-, -S (= O) q-, -NRa- or -C (= Y) -;

each occurrence of Ra and Rb may be the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (1-6C) alkyl, -NRcRd (where Rc and Rd are independently hydrogen , halogen, hydroxy, cyano, substituted or unsubstituted (1-6C) alkyl or (1-6C) alkoxy) and -ORC (where Rc is substituted or unsubstituted (1-6C) alkyl) or when Ra and Rb are attached directly to a common atom can join to form an oxo group (= O) or form a 3-10 membered substituted or unsubstituted, saturated or unsaturated ring (which includes the common atom to which Ra and Rb are directly attached ), which optionally may include one or more heteroatoms which may be the same or different and are selected from O, NRd (where Rd is hydrogen or substituted or unsubstituted (1-6C) alkyl) or S;

Y is selected from O, S, and NRa; Y

q is 0, 1, or 2.

The compound of formula (III) can be prepared by:

(a) the treatment of the compound of formula (IB)

with Cy2-H (for example, by a Mitsunobu reaction) to give the desired compound of formula (III) or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. same, in which

R, R1, n and Cy1 are as described above in relation to Formula (IB);

Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Y

L1 is absent, and

(b) optionally, the conversion of the compound of formula (III) to a salt of the compound.

The compound of formula (III) can also be prepared by:

(a) the treatment of the compound of formula (IB)

with a phosphorous halide or mesyl chloride (or other mesyl halide) in the presence of a base to give a compound of formula (8b)

wherein X1 is halogen or -O-Mesyl (i.e. -O-SO2CH3), and

(b) reacting the compound of formula (8b) with Cy2-H in the presence of a base to give the desired compound of formula (III) or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof or pharmaceutically acceptable salt thereof, wherein R, R1, n and Cy1 are as described above in connection with Formula (IB);

Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Y

L1 is absent, and

(c) optionally, the conversion of the compound of formula (III) to a salt of the compound.

Still another embodiment provided is the use of the compound of formula (IB) for the preparation of PI3K inhibitors of formula (III)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof or pharmaceutically acceptable salt thereof, wherein

R, R1, n and Cy1 are as described above in relation to Formula (IB);

Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Y

L1 is NH.

The compound of formula (III) can be prepared by

(a) the treatment of the compound of formula (IB)

with a phosphorous halide or mesyl chloride (or other mesyl halide) in the presence of a base to give a compound of formula (8b)

wherein X1 is halogen or -O-Mesyl;

(b) converting the compound of formula (8b) to give a compound of formula (9b)

(for example, by treating the compound of formula (8b) with sodium azide);

(c) converting the compound of formula (9b) to give a compound of formula (10b)

(for example, by treating the compound of formula (8b) with triphenylphosphine);

(d) coupling the compound of formula (10b) with a compound of formula Cy2-Lg, in which Lg is a leaving group, in the presence of a base to give the desired compound of formula (IV); Y

(e) optionally, the conversion of the compound of formula (IV) to a salt of the compound.

In a preferred embodiment, the coupling reaction of the compound of formula 6 with the compound of formula A or B is carried out in the presence of N - [(dimethylamino) -1H-1,2,3- hexafluorophosphate N-oxide triazolo- [4,5-b] pyridin-1-ylmethylene] -N-methylmethanaminium (HATU).

Protecting groups, such as those in the compounds of formulas 7a, 7b, 7aa, 7ab, 7ba and 7bb, can be removed by the use of suitable deprotection agents, such as aluminum chloride, boron tribromide, or any combination of the that precede. Optionally, deprotection can be carried out by other suitable deprotection agents including the use of hydrogenation for deprotection.

Still another embodiment is a composition (eg, a pharmaceutical composition) comprising (a) a PI3K inhibitor of formula (I) or a salt thereof and (b) a compound of formula (IA) or (IB) or a Get out of these. In one embodiment, the composition comprises at least about 99.5% by weight of the PI3K inhibitor and the compound of formula (IA) or (IB) in an amount of up to 0.5% by weight, based on the total of components (a) and (b). In another embodiment, the composition includes the compound of formula (IA) or (IB) in an amount of up to 0.2% or 0.1% by weight. The pharmaceutical composition can be, for example, a tablet or a capsule.

Detailed description of the invention

As used herein, the following definitions apply unless otherwise indicated. Furthermore, many of the groups defined herein can be optionally substituted. The listing of substituents in the definition is by way of example and should not be construed as limiting the substituents that are defined elsewhere in the specification.

The term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and bound to the remainder of the molecule via a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).

The term "alkenyl" refers to an aliphatic hydrocarbon group that contains a carbon-carbon double bond and can be a straight or branched chain having from 2 to about 10 carbon atoms, for example, ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.

The term "alkynyl" refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond and having between 2 and up to 12 carbon atoms (radicals having between 2 and up to 10 carbon atoms) eg ethynyl, propynyl and butynyl.

The term "alkoxy" describes an alkyl, cycloalkyl or cycloalkylalkyl group as defined above, attached through an oxygen bond to the rest of the molecule. The term "substituted alkoxy" refers to an alkoxy group, in which the alkyl constituent is substituted (ie, -O- (substituted alkyl)) wherein the term "substituted alkyl" is the same as defined above for "I rent". For example, "alkoxy" refers to the group -O-alkyl that includes 1 to 8 carbon atoms of a linear, branched, cyclic configuration and combinations thereof, attached to the backbone via an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy.

The term "cycloalkyl" denotes a mono or multicyclic non-aromatic ring system of 3 to about 12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of cycloalkyl groups Multicyclic include perhydronaphthyl, adamantyl, and norbornyl groups, bridged cyclic groups, and spirobicyclic groups, eg, spiro (4,4) non-2-yl.

The term "cycloalkylalkyl" refers to a radical containing cyclic rings containing from 3 to about 8 carbon atoms directly attached to an alkyl group and which are then attached to the backbone at any carbon of the alkyl group, which gives as a result the creation of a stable structure such as cyclopropylmethyl, cyclobutylethyl and cyclopentylethyl.

The term "cycloalkenyl" refers to radicals containing cyclic rings containing from 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl. The term "cycloalkenylalkyl" refers to a "cycloalkenyl" group directly attached to an alkyl group and then attached to the backbone at any carbon in the alkyl group, resulting in the creation of a stable structure.

The term "aryl" refers to aromatic radicals having 6 to 20 carbon atoms such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.

The term "arylalkyl" refers to an aryl group as defined above, directly attached to an alkyl group as defined above, for example, -CH2C6H5 and -C2H5C6H5.

The term "heterocyclic ring" refers to a 3- to 15-membered non-aromatic ring radical consisting of carbon atoms and at least one heteroatom selected from nitrogen, phosphorus, oxygen, and sulfur. For the purposes of the present invention, the heterocyclic ring radical may be a mono, bi, tri, or tetracyclic ring system which may include fused, bridged, or spiro ring systems, and the nitrogen, phosphorous, carbon, oxygen, or Sulfur in the heterocyclic ring radical can optionally be oxidized to various oxidation states. Furthermore, the nitrogen atom can be optionally quaternized. The heterocyclic ring radical can be attached to the backbone at any hetero atom or carbon atom resulting in the creation of a stable structure.

The term "heterocyclyl" refers to a heterocyclic ring radical as defined above. The heterocyclyl ring radical can be attached to the backbone at any heteroatom or carbon atom resulting in the creation of a stable structure.

The term "heterocyclylalkyl" refers to a heterocyclic ring radical as defined above directly attached to an alkyl group. The heterocyclylalkyl radical can be attached to the backbone at the carbon atom in the alkyl group resulting in the creation of a stable structure. Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl [1,3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxydynopyrrolyl, 2-oxydynopyrrolyl, 2-oxydinopyrrolyl, 2-oxydinopyrrolyl , oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1-oxo-thiomorpholinyl.

The term "heteroaryl" refers to an optionally substituted 5- to 14-membered aromatic ring having one or more heteroatoms selected from N, O, and S as ring atoms. Heteroaryl can be a mono, bi, or tricyclic ring system. Examples of such "heterocyclic ring" or "heteroaryl" radicals include, but are not limited to, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl. , azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl , 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyrrolidinyl, pyridazinyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, isothiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl , isoindolinyl, octahydroindolyl, octahydroisoind lyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulphone, dioxaphospholanyl, oxadiazolyl, chromanyl echromanyl. The heteroaryl ring radical can be attached to the backbone at any heteroatom or carbon atom, resulting in the creation of a stable structure. The term "substituted heteroaryl" also includes ring systems substituted with one or more oxide substituents, such as pyridinyl N-oxides.

The term "heteroarylalkyl" refers to a heteroaryl ring radical as defined above directly attached to an alkyl group. The heteroarylalkyl radical can be attached to the backbone at any carbon atom of the alkyl group resulting in the creation of a stable structure. The term "cyclic ring" refers to a cyclic ring containing 3 to 10 carbon atoms.

The term "substituted", unless otherwise specified, refers to a substitution with any of or any combination of the following substituents, which may be the same or different, and which are independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (= O), thio (= S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted arylalkyl or unsubstituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, heterocyclic substituted ring , substituted or unsubstituted guanidine, -COORX, -C (O) RX, -C (S) RX, -C (O) NRxRy, -C (O) ONRxRy, -NRxCONRy Rz, -N (Rx) SORy, -N (Rx) SO2Ry, - (= NN (Rx) Ry), -NRxC (O) ORy, -NRxRy, -NRxC (O) Ry-, -NRxC (S) Ry -NRxC (S) NRyRz, -SONRxRy-, -SO2NRxRy-, -ORX, -ORxC (O) NRyRz, -ORxC (O) ORy-, -OC (O) RX, -OC (O) NRxRy, -RxNRyC ( O) Rz, -RxORy, -RxC (O) ORy, -RxC (O) NRyRz, -RXC (O) RX, -RxOC (O) Ry, -SRX, -SORX, -SO2RX and -ONO2, where Rx, Ry and Rz in each of the above groups can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl substituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring or substituted heterocyclylalkyl ring, or Any two of Rx, Ry, and Rz can join together to form a sub ring 3-10 membered saturated or unsaturated substituted or unsubstituted which may optionally include heteroatoms which may be the same or different and which are selected from O, NRX (for example, Rx may be hydrogen or Cia alkyl) ^or S. The substitution or combination The substituents envisioned by this invention are preferably those that result in the formation of a stable or chemically viable compound. The term "stable" as used herein refers to the structure or compounds that are not substantially altered when subjected to conditions to allow their production, detection, and preferably their recovery, purification, and incorporation into a pharmaceutical composition. Substituents on the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" cannot be "substituted alkenyl".

The term "halo", "halide" or, alternatively, "halogen" means fluoro, chloro, bromo or iodo. The terms "haloalkyl", "haloalkenyl", "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluoro.

The term "protecting group" or "Pg" refers to a substituent that is used to block or protect a particular functionality. Other functional groups on the compound can remain reactive. For example, an "amino protecting group" is a substituent attached to an amino group that blocks or protects the functionality of the amino in the compound. Suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent on a hydroxy group that blocks or protects the functionality of the hydroxy. Suitable hydroxy protecting groups include, but are not limited to, acetyl and silyl. A "carboxy protecting group" refers to a substituent on a carboxy group that blocks or protects the functionality of the carboxy. Suitable carboxy protecting groups include, but are not limited to, -CH2CH2SO2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, -2- (p-toluenesulfonyl) ethyl, 2- (pnitrophenylsulfenyl) ethyl, 2 - (diphenylphosphino) -ethyl and nitroethyl. For a general description of protecting groups and their use, see TW Greene, Protective Groups in Organic Synthesis , John Wiley & Sons, New York, 1991.

Some of the compounds described herein contain one or more asymmetric centers and therefore can produce enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) - or (S) -. The chemical entities, pharmaceutical compositions, and methods herein are intended to include all such possible isomers including racemic mixtures, optically pure forms, and mixtures of intermediates. For example, the non-limiting example of non-limiting intermediate mixtures includes a mixture of isomers in a ratio of 10:90, 13:87, 17:83, 20:80, or 22:78. The optically active (R) - and (S) - isomers can be prepared with chiral synthons or chiral reagents, or they can be resolved by conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both the E and Z geometric isomers.

The term "tautomers" refers to compounds that are characterized by relatively easy interconversion of isomeric forms at equilibrium. The present invention is intended to encompass such isomers. "Tautomers" are structurally different isomers that are interconverted by tautomerism. "Tautomerism" is a form of isomerization and includes prototropic or proton displacement tautomerism, which is considered a subset of acid-base chemistry. "Prototropic tautomerism" or "proton displacement tautomerism" involves the migration of a proton accompanied by changes in the bond order, often exchanging a single bond with an adjacent double bond. In cases where tautomerism is possible (for example, in solution), a chemical equilibrium of tautomers can be achieved. An example of tautomerism is keto-enol tautomerism. A specific example of ketoenolic tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. A specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers.

A "leaving atom or group" is any group or atom that, under reaction conditions, cleaves from the starting material and thus promotes the reaction at a specific site. Suitable examples of such groups, unless otherwise specified, are halogen atoms and mesyloxy, p-nitrobenzenesulfonyloxy and tosyloxy groups.

The term "prodrug" refers to a compound that is a precursor (eg, an inactive precursor) of a compound, converted to its active form in the body by normal metabolic processes. The design of prodrugs is generally discussed in Hardma, et al. (Eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics , 9th ed., Pp. 11-16 (1996). A detailed discussion in Higuchi, et to the., Prodrugs as Novel Delivery Systems (Prodrugs as Management Systems Novedosos), Volume 14, ASCD Symposium Series, and in Roche (ed.), Bioreversible Carriers in Drug Design (Bearers bioreversible is provided in Drug Design), American Pharmaceutical Association and Pergamon Press (1987). By way of illustration, prodrugs can be converted to a pharmacologically active form through hydrolysis of, for example, an ester or amide bond, such that a functional group of the resulting product is introduced or exposed. Prodrugs can be designed to react with an endogenous compound to form a water soluble conjugate that further improves the pharmacological properties of the compound, eg, increased circulatory half-life. Alternatively, the prodrugs can be designed to undergo covalent modification at a functional group with, for example, glucuronic acid, sulfate, glutathione, amino acids, or acetate. The resulting conjugate can be inactivated and secreted in the urine, or it can become more potent than the parent compound. High molecular weight conjugates can also be excreted into the bile, subjected to enzymatic cleavage, and re-circulated, thus effectively increasing the biological half-life of the originally administered compound.

The term "ester" refers to a compound that is formed by reaction between an acid and an alcohol with elimination of water. An ester can be represented by the general formula RCOOR '.

These prodrugs and esters are intended to be covered by the scope of the present invention.

Furthermore, the present invention also includes compounds that differ only in the presence of one or more isotopically enriched atoms, for example, replacement of hydrogen with deuterium or tritium or replacement of a carbon with enriched 13C or 14C carbon.

The compounds of the present invention may also contain unnatural ratios of atomic isotopes at one or more of the atoms that make up such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine 125 (125l) or carbon 14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are within the scope of the present invention.

The pharmaceutically acceptable salts that form part of the present invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn and Mn; salts of organic bases such as N.N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine and thiamine; chiral bases such as alkylphenylamine, glycinol, and phenyl glycinol; natural amino acid salts such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, omitin, lysine, arginine, and serine; quaternary ammonium salts of the compounds of the invention with alkyl halides, alkyl sulfates such as Mel and (Me) 2SO4; non-natural amino acids such as D-isomers or substituted amino acids; guanidine and substituted guanidine in which the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts and aluminum salts. Salts can include acid addition salts, where appropriate, which are sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulfonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates and ketoglutarates.

Representative processes of the present invention include those specified below. The present invention should not be construed to be limited by these.

Experimental phase

The examples and preparations provided below further illustrate and exemplify the methods of preparing the compounds of the invention. It will be understood that the scope of the present invention is in no way limited to the scope of the following examples and preparations. In the following examples, molecules with a single chiral center, unless otherwise stated, exist as a racemic mixture. Those molecules with two or more chiral centers, unless stated otherwise, exist as a racemic mixture of diastereomers. Simple enantiomers / diastereomers can be obtained by procedures known to those skilled in the art.

Example 1

(R) -6-fluoro-3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one

Step 1: (R) -2- (1- (benzyloxy) ethyl) -6-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one : HATU (33.7 g, 88.63 mmol) and (R) -benzyloxypropionic acid (9.58 g, 53.17 mmol) to 1- (5-fluoro-2-hydroxyphenyl) -2- (3-fluorophenyl) ethanone (11 g, 44.31 mmol) in dichloromethane (110 ml) and stirred for ~ 10 min. Triethylamine (67 ml, 478 mmol) is added dropwise and stirred at room temperature (RT) for 24 hours. The reaction mixture was quenched with water and extracted with dichloromethane (2 x 250 ml). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to provide the title compound as an off-white solid (10.9 g, 63%). 1H-NMR (8 ppm, CDCI3, 400 MHz): 7.85 (dd, J = 8.1.3.0 Hz, 1H), 7.58 (dd, J = 9.1.4.1 Hz, 1H), 7.47-7.39 (m, 1H), 7.39-7.34 (m, 1H), 7.28-7.20 (m, 3H), 7.20-7.14 ( m, 2H), 7.16-7.14 (m, 1H), 6.99-7.89 (m, 2H), 4.50-4.31 (m, 3H), 1.56 (d, J = 6.4 Hz, 3H). Mass: 392.9 (M +).

Step 2: (R) -6-fluoro-3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one : Anhydrous aluminum chloride (5.35 g, 40.03 mmol) in parts a (R) -2- (1- (benzyloxy) ethyl) -6-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one (10.5 g, 26.69 mmol) in dichloromethane (110 ml) cooled to 0 ° C, stirred for 1 hour and then at RT for 2 hours. The reaction mixture was quenched with dilute aqueous HCl (10 ml), extracted with dichloromethane (2 x 50 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to provide the title compound as an off-white solid (6.5 g, 81%). 1H-NMR (8 ppm, CDCI3, 400 MHz): 7.86 (dd, J = 8.3, 3.0 Hz, 1H), 7.56 (dd, J = 9.2, 4.2 Hz, 1H), 7.45 (m, 2H), 7.12-6.99 (m, 3H), 4.76 (q, J = 6.6 Hz, 1H), 1.55 (d, J = 6 , 6Hz, 3H). Mass: 303.2 (M + 1). Purity: 99.78%. [a] 25D 0.287 (c = 1, CHCl3). Enantiomeric excess: 97.74%, enriched in the isomer that ultimately eluted (retention time: 10.93 minutes as determined by HPLC on a Chiralpak AD-H column.

Example 2

(R) -2- (1-hydroxyethyl) -5-methyl-3-phenyl-4H-chromen-4-one

Step 1: (R) -2- (1- (benzyloxy) ethyl) -5-methyl-3-phenyl-4H-chromen-4-one : Add R (+) - benzyloxypropionic acid (0.382 g, 2.12 mmol) and HATU (2.01 g, 5.30 mmol) to 1- (2-hydroxy-6-methylphenyl) -2-phenylethanone (0.400 g, 1.76 mmol) in dichloromethane (4 ml), followed by triethylamine (2.6 ml, 19.08 mmol). After 20 hours at room temperature, the reaction mixture was quenched with water, extracted with ethyl acetate, dried over sodium sulfate, and concentrated. The crude product was subjected to column chromatography with ethyl acetate: petroleum ether to provide the title compound as an off-white solid (0.080 g, 12%). 1H-NMR (8 ppm, CDCI3, 400 MHz): 7.55 (t, J = 8.1 Hz, 1H), 7.43-7.13 (m, 12H), 4.47 (m, 2H) , 4.30 (d, J = 11.8 Hz, 1H), 2.84 (s, 3H), 1.54 (d, J = 6.5 Hz, 3H). Mass: 370.9 (M +).

Step 2: (R) -2- (1-hydroxyethyl) -5-methyl-3-phenyl-4H-chromen-4-one : Slowly add boron tribromide (0.78 ml, 1M in dichloromethane, 4.58 mmol) a (R) -2- (1- (benzyloxy) ethyl) -5-methyl-3-phenyl-4H-chromen-4-one (0.850 g, 2.29 mmol) in dichloromethane (8.0 ml) at -78 ° C and held for 4 hours. The reaction mass was quenched at -78 ° C with 2N HCl (50 mL), extracted with ethyl acetate, dried over sodium sulfate, and concentrated. The crude product was subjected to column chromatography with ethyl acetate: petroleum ether to provide the title compound as a pale yellow liquid (0.200 g, 31%). 1H-NMR (8 ppm, CDCI3, 400 MHz): 7.54 (t, J = 8.0 Hz, 1H), 7.46-7.26 (m, 6H), 7.13 (d, J = 7.4Hz, 1H), 4.71 (q, J = 6.6Hz, 1H), 2.83 (s, 3H), 1.53 (d, J = 6.6Hz, 3H). Mass: 280.8 (M +).

Example 3

(R) -6-fluoro-2- (1-hydroxyethyl) -3-phenyl-4H-chromen-4-one

Step 1: (R) -2- (1- (benzyloxy) ethyl) -6-fluoro-3-phenyl-4H-chromen-4-one : HATU (6.60 g, 17.36 mmol) and acid are added R - (+) 2-benzyloxypropionic (1.87 g, 10.42 mmol) to 1- (5-fluoro-2-hydroxyphenyl) -2-phenylethanone (2.00 g, 8.68 mmol) in dichloromethane (15 ml) and stirred for 10 minutes. Triethylamine (13.0 ml, 93.7 mmol) is added dropwise and stirred at RT for 24 hours. The reaction mixture was quenched with water, extracted with dichloromethane, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to provide the title compound as a yellow solid (0.634 g, 19%). 1H-NMR (8 ppm, CDCI3, 400 MHz): 7.87 (dd, J = 8.2, 3.1 Hz, 1H), 7.59 (dd, J = 9.1.4.1 Hz, 1H), 7.45-7.37 (m, 4H), 7.25-7.15 (m, 7H), 4.53 (q, J = 6.5 Hz, 1H), 4.43 (d , J = 11.8 Hz, 1H), 4.33 (d, J = 11.7 Hz, 1H), 1.56 (d, J = 6.5 Hz, 3H). Mass: 375.0 (M +).

Step 2: (R) -6-fluoro-2- (1-hydroxyethyl) -3-phenyl-4H-chromen-4-one : Aluminum chloride (0.330 g, 2.52 mmol) is added in parts to (R ) -2- (1- (benzyloxy) ethyl) -6-fluoro-3-phenyl-4H-chromen-4-one (0.63 g, 1.68 mmol) in dichloromethane (6 ml) cooled to 0 ° C and stirred at RT for 6 hours. The reaction mixture was quenched with 2N HCl solution, extracted with dichloromethane, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to provide the title compound as a yellow solid (0.348 g, 73%). 1H-NMR (8 ppm, CDCI3, 400 MHz): 7.83 (m, 1H), 7.76 (m, 2H), 7.46 (m, 3H), 7.30 (m, 2H), 5 , 60 (d, J = 4.9Hz, 1H), 4.53 (m, 1H), 1.38 (d, J = 6.5Hz, 3H). Mass: 285.2 (M ++ 1). Purity: 86.82%. [a] 25D -1.18 (c = 1, CHCl3). Enantiomeric excess: 97.8%, enriched in the isomer that ultimately eluted (retention time: 11.39 minutes) as determined by HPLC on a Chiralpak AD-H column.

Example 4

(R) -2- (1-hydroxyethyl) -3-phenyl-4H-chromen-4-one

Step 1: (R) -2- (1- (benzyloxy) ethyl) -3-phenyl-4H-chromen-4-one : The title compound was obtained as a yellow solid (1.50 g, 37%) by the procedure described for Step 1 of Example 3 starting from 1- (2-hydroxyphenyl) -2-phenylethanone (2.40 g, 11.30 mmol), dichloromethane (30 ml), HATU (8.60 g, 22 , 60 mmol), R - (+) 2-benzyloxypropionic acid (2.44 g, 13.56 mmol) and triethylamine (17.0 ml, 122.11 mmol), and was used as such in the next step.

Step 2: (R) -2- (1-Hydroxyethyl) -3-phenyl-4H-chromen-4-one : The title compound was obtained as a yellow solid (0.650 g, 58%) by the procedure described for Step 2 of Example 3 starting from (R) -2- (1- (benzyloxy) ethyl) -3-phenyl-4H-chromen-4-one (1.50 g, 4.20 mmol) in dichloromethane (15 ml ) cooled to 0 ° C and aluminum chloride (0.843 g, 6.30 mmol). 1H-NMR (8 ppm, CDCI3, 400 MHz): 8.24 (dd, J = 7.9, 1.5 Hz, 1H), 7.72 (m, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.46-7.37 (m, 4H), 7.29 (m, 2H), 4.79 (q, J = 6.6 Hz, 1H), 1.55 ( d, J = 6.6 Hz, 3H). Mass: 267.0 (M +). Purity: 98.28%. [a] 25D 6.53 (c = 1, CHCl3). Enantiomeric excess: 92.2%, enriched in the isomer which ultimately eluted (retention time: 10.38 minutes) as determined by HPLC on a Chiralpak AD-H column.

Example 5

(R) -3- (3-fluorophenyl) -2- (1-hydroxypropyl) -4H-chromen-4-one

Step 1: (R) -2- (1- (benzyloxy) propyl) -3- (3-fluorophenyl) -4H-chromen-4-one : The title compound was obtained as a yellow solid (1.65 g, 45%) by the procedure described for Step 1 of Example 3 from 2- (3-fluorophenyl) -1- (2-hydroxyphenyl) ethanone (2.15 g, 9.36 mmol), dichloromethane (20 ml) , HATU (4.27 g, 11.23 mmol), R - (+) 2-benzyloxybutyric acid (2.00 g, 10.29 mmol) and triethylamine (14.0 ml, 101.1 mmol). 1H-NMR (8 ppm, CDCI3, 400 MHz): 8.24 (dd, J = 7.9, 1.5 Hz, 1H), 7.74 (dt, J = 7.1, 1.7 Hz, 1H), 7.58 (dd, J = 8.3, 0.4 Hz, 1H), 7.44-7.06 (m, 10H), 4.51 (d, J = 7.8 Hz, 1H ), 4.34 (d, J = 7.8 Hz, 1H), 4.25 (dd, J = 7.8, 6.2 Hz, 1H), 2.17-1.90 (m, 2H) , 0.95 (t, J = 7.5 Hz, 3H). Mass: 389.0 (M +).

Step 2: (R) -3- (3-fluorophenyl) -2- (1-hydroxypropyl) -4H-chromen-4-one : The title compound was obtained as a yellow solid (0.552 g, 48%) by means of Procedure described for Step 2 of Example 3 starting from (R) -2- (1- (benzyloxy) propyl) -3- (3-fluorophenyl) -4H-chromen-4-one (1.50 g, 3, 86 mmol) in dichloromethane (15 ml) cooled to 0 ° C and aluminum chloride (1.00 g, 7.72 mmol). 1H-NMR (8 ppm, CDCI3, 400 MHz): 8.24 (dd, J = 8.0, 1.6 Hz, 1H), 7.72 (m, 1H), 7.52 (dd, J = 8.4, 0.5 Hz, 1H), 7.44 (m, 2H), 7.12-7.01 (m, 3H), 4.49 (t, J = 7.0 Hz, 1H), 1.94 (m, 2H), 0.93 (t, J = 7.5 Hz, 3H). Mass: (299.0 (M +). Purity: 96.93%. [A] 25D -14.73 (c = 1, CHCl3). Enantiomeric excess: 85.92%, enriched in the fast-eluting isomer (time retention time: 8.57 minutes) as determined by HPLC on a Chiralpak AS-3R column.

Example 6

(R) -3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one

Step 1: (R) -2- (1- (benzyloxy) ethyl) -3- (3-fluorophenyl) -4H-chromen-4-one : HATU (33.0 g, 86.86 mmol) and acid are added R - (+) 2-benzyloxypropionic (9.39 g, 52.12 mmol) to 2- (3-fluorophenyl) -1- (2-hydroxyphenyl) ethanone (10.0 g, 43.43 mmol) in dichloromethane ( 75 ml) and stirred for 10 minutes. Triethylamine (65.4 ml, 0.469 mol) is added dropwise and stirred at RT for 24 hours. The reaction mixture was quenched with water, extracted with dichloromethane, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to provide the title compound as an off-white solid (9.0 g, 55%). 1H-NMR (8 ppm, CDCI3, 400 MHz): 8.23 (dd, J = 7.9, 1.2 Hz, 1H), 7.74-7.70 (m, 1H), 7.58 ( d, J = 8.3 Hz, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.37 (q, J = 7.2 Hz, 1H), 7.29-7, 15 (m, 5H), 7.09 (dt, J = 8.6, 1.7 Hz, 1H), 7.00-6.90 (m, 2H), 4.51-4.35 (m, 3H), 1.57 (d, J = 6.4 Hz, 3H).

Step 2: (R) -3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one : Add boron tribromide (1M in dichloromethane, 36.5 ml, 0.145 mmol) drop dropwise to (R) -2- (1- (benzyloxy) ethyl) -3- (3-fluorophenyl) -4H-chromen-4-one (5.0 g, 13.35 mmol) in dichloromethane (50 ml) cooled to -78 ° C and stirred for 1 hour. The reaction mixture was quenched with 2N HCl solution, extracted with dichloromethane, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to provide (R) -3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one as an off-white solid (3.05g, 80%).

1H-NMR (8 ppm, CDCI3, 400 MHz): 8.24 (dd, J = 7.9, 1.5 Hz, 1H), 7.73 (m, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.44 (m, 2H), 7.13-7.01 (m, 3H), 4.71 (q, J = 6.6 Hz, 1H), 1.56 ( d, J = 6.5 Hz, 3H). Mass: 284.9 (M +). Purity: 99.73%. [a] 25D -0.605 (c = 1, CHCl3). Enantiomeric excess: 95.2%, enriched in the isomer that ultimately eluted (retention time: 10.19 minutes) as determined by HPLC on a Chiralpak AD-H column.

Example 7

Step 1: (S) -1- (3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl 4-chlorobenzoate: Add 4-chlorobenzoic acid (1.10 g, 2, 15 mmol) and triphenylphosphine (2.70 g, 10.55 mmol) to a solution of Example 6 (2.00 g, 7.03 mmol) in THF (20 ml) and heated to 45 ° C, followed by diisopropylazodicarboxylate (2.0 ml, 10.55 mmol). The mixture was refluxed for 1 hour, concentrated, and the residue was purified by column chromatography with ethyl acetate: petroleum ether to obtain the title compound as an off-white solid (2.35 g, 79%) which was used in the next step without purification.

Step 2: (S) -3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one : Potassium carbonate (0.384 g, 2.77 mmol) is added at 0 ° C to (R) -11- (3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl 4-chlorobenzoate (2.35 g, 5.55 mmol) in methanol (20 ml). After 30 minutes, the methanol was concentrated, quenched with 2N HCl, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to provide (S) -3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one as a yellow solid pale (1.15 g, 73%). Enantiomeric excess: 95.2%, enriched in the fast-eluting isomer (retention time: 8.75 minutes) as determined by HPLC on a Chiralpak AD-H column.

In order to fully understand the invention and to demonstrate its various embodiments, certain detailed examples illustrating the utility and / or performance of the present invention are provided below.

Illustrative example 1

(R) -2- (1- (4-amino-3- (3-fluoro-4-morpholinophenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3 - (3-fluorophenyl) -4H-chromen-4-one

The present example is also described in Example 59 of WO 2012/151525. Tris (4-methoxyphenyl) phosphine (0.134 g, 0.381 mmol) and diisopropylazodicarboxylate (0.07 ml, 0.381 mmol) are added to a solution of 3- (3-fluoro-4-morpholinophenyl) -1H-pyrazolo [3,4 -d] pyrimidin-4-amine (0.080 g, 0.254 mmol) in THF (2 ml) and stirred at room temperature (RT) for 10 minutes. (-) - 5-fluoro-3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one (0.077 g, 0.254 mmol) is added to this mixture and stirred for 12 hours. The reaction mixture is diluted in water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The crude product is purified by column chromatography with methanol: dichloromethane to provide the title compound as an off-white solid. MP: 242-245 ° C. Enantiomeric excess: 96.21% Mass: 599.1 (M ++ 1).

Illustrative example 2

(+) - 2- (1- (9H-purin-6-ylamino) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one

The present example is also described in Example 68 of WO 2012/151525. The title compound is obtained as an off-white solid by a procedure similar to that described in Illustrative Example 1 from tert-butyl 9-trityl-9H-purin-6-ylcarbamate (0.235 g, 0.494 mmol), (-) -5-fluoro-3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one (0.150 g, 0.494 mmol), triphenylphosphine (0.194 g, 0.741 mmol), THF (8 mL) and diisopropylazodicarboxylate (0.15 ml, 0.749 mmol), followed by cleavage of the intermediate with trifluoroacetic acid (1.8 ml) and dichloromethane (5 ml). MP: 194-197 ° C. Enantiomeric excess: 99.62%. [a] 25D 142.00 (c = 1, CHCl3). Mass: 420.1 (M + 1).

Illustrative example 3

(+) 2- (1- (4-amino-3- (4-isopropoxy-3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one

The present example is also described in Example 114 of WO 2012/151525. The title compound is obtained as an off-white solid by a procedure similar to that described in Illustrative Example 1 from 3- (4-isopropoxy-3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4- amine (0.150 g, 0.529 mmol), (-) - 5-fluoro-3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one (0.145 g, 0.481 mmol), tris- 4- methoxyphenylphosphine (0.254 g, 0.721 mmol), THF (3 ml) and diisopropylazodicarboxylate (0.14 ml, 0.721 mmol). MP: 217-220 ° C. 1H-NMR (8 ppm, CDCI3, 400 MHz): 58.22 (s, 1H), 7.61 (dt, J = 8.4, 5.4 Hz, 1H), 7.43 (m, 2H) , 7.29 (m, 2H), 7.05-6.97 (m, 4H), 6.92 (d, J = 9.4 Hz, 1H), 6.07 (q, J = 7.1 Hz, 1H), 5.42 (s, 2H), 4.63 (quintet, J = 6.0 Hz, 1H), 2.28 (s, 3H), 1.97 (d, J = 7.1 Hz, 3H), 1.39 (d, J = 6.0 Hz, 6H). Enantiomeric excess: 100% as determined by HPLC on a Chiralpak AD-H column, enriched with the fast-eluting isomer (retention time = 9.36 minutes) [a] 25D 176.04 (c = 1, CHCl3) .

Illustrative example 4

(-) 2- (1- (4-amino-3- (4-isopropoxy-3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one

The present example is also described in Example 115 of WO 2012/151525. The title compound is obtained as an off-white solid by a procedure similar to that described in Illustrative Example 1 from 3- (4-isopropoxy-3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4- amine (0.128 g, 0.453 mmol), (+) - 5-fluoro-3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one (0.125 g, 0.412 mmol), tris-4-methoxytriphenylphosphine (0.217 g, 0.618 mmol) , THF (3 ml) and diisopropylazodicarboxylate (0.12 ml, 0.618 mmol). MP: 221-224 ° C. 1H-NMR (8 ppm, CDCI3, 400 MHz): 58.22 (s, 1H), 7.61 (dt, J = 8.4, 5.5 Hz, 1H), 7.43 (m, 2H) , 7.29 (m, 2H), 7.05-6.95 (m, 4H), 6.92 (d, J = 9.5 Hz, 1H), 6.05 (q, J = 7.1 Hz, 1H), 5.40 (s, 2H), 4.62 (quintet, J = 6.0 Hz, 1H), 2.28 (s, 3H), 1.99 (d, J = 7.2 Hz, 3H), 1.39 (d, J = 6.0 Hz, 6H). Enantiomeric excess: 99.6% as determined by HPLC on a Chiralpak AD-H column, enriched with the isomer that ultimately eluted (retention time = 11.43 minutes) [a] 25D -183.59 (c = 1, CHCI3).

(S) / (R) -2- (1-aminoethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one

The present example is also described in Intermediate 141-143 of WO 2012/151525.

Step 1 : (S) / (R) -1- (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl methanesulfonate: Add methanesulfonyl chloride (0.400 ml , 5.27 mmol) to a cold solution of (+) - 5-fluoro-3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one (0.800 g, 2.63 mmol ) in dichloromethane (16 ml) and triethylamine (1.10 ml, 7.91 mmol) with stirring and at room temperature for 2 hours. The reaction mass is quenched with water, extracted with dichloromethane, dried over sodium sulfate and concentrated to obtain the title compound as a brown solid which is used as such in the subsequent step.

Step 2 : (S) / (R) -2- (1-azidoethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one: Sodium azide (0.306 g, 4, 72 mmol) to a methanesulfonate solution of (S) / (R) -1- (5-fluoro-3- (3-fluorophenyl) -4-oxo-4H-chromen-2-yl) ethyl (0.900 g, 2 , 36 mmol) in DMF (18 ml) and heated to 60 ° C. After 2 hours, the reaction mass is quenched with water, extracted with dichloromethane, dried over sodium sulfate, and concentrated. The crude product is analyzed by column chromatography with ethyl acetate: petroleum ether to obtain the title compound as a brown liquid which is used as such in the next step.

Step 3 : (S) / (R) -2- (1-aminoethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one: Add triphenylphosphine (0.455 g, 1.73 mmol ) to a solution of (S) / (R) -2- (1-azidoethyl) -5-fluoro-3- (3-fluorophenN) -4H-chromen-4-one (0.600 g, 1.82 mmol) in THF (2.4 ml) and water (1.2 ml), and stirred at room temperature for 14 hours. The reaction mass is quenched with water, extracted with ethyl acetate, dried over sodium sulfate, and concentrated. Column chromatography is performed on the crude product with methanol: dichloromethane to obtain the title compound as a brown liquid.

Illustrative example 6

(S) / (R) -5-fluoro-2- (1- (2-fluoro-9H-purin-6-iIamino) ethyl) -3- (3-fluorophenyl-1) -4H-chromen-4-one

The present example is also described in Example 136 of WO 2012/151525. Tert-butanol (1.5 ml), N, N-diisopropylethylamine (0.25 ml, 1.46 mmol) and 6-chloro-2-fluoro-9H-purine (0.102 g, 0.663 mmol) are added to a solution of (S) / (R) -2- (1-aminoethyl) -5-fluoro-3- (3-fluorophenyl) -4H-chromen-4-one (0.22 g, 0.730 mmol) and heated under reflux for 248 h. The reaction mixture is concentrated, quenched with water, extracted with ethyl acetate, dried over sodium sulfate, and concentrated. The crude product is purified by column chromatography with methanol: ethyl acetate to provide the title compound as a brown solid. MP: 183-186 ° C. Mass: 437.9 (M +). Enantiomeric excess: 33% as determined by HPLC on a Chiralpak AD-H column, enriched with the fast-eluting isomer (retention time = 7.21 minutes).

Illustrative example 7

(S) -2- (1- (9H-purin-6-ylamino) ethyl) -6-bromo-3-phenyl-4H-chromen-4-one

The present example is also described in Example 24 of WO 2011/055215. N, N-diisopropylethylamine (0.2 ml, 1.162 mmol) and 6-bromopurine (0.087 g, 0.435 mmol) are added to a solution of (S) -2- (1-aminoethyl) -6-bromo-3-phenyl -4H-chromen-4-one (0.20 g, 0.581 mmol) in tert-butanol (6 ml) and refluxed for 24 hours. The reaction mixture is concentrated, diluted with water, extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The crude product is purified by column chromatography with methanol: ethyl acetate to provide the title compound as a yellow solid. MP: 151-154 ° C. 1H-NMR (8 ppm, DMSO-Ds, 400 MHz): 512.94 (s, 1H), 8.09 (br s, 3H), 7.94 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 8.7Hz, 1H), 7.42 (m, 6H), 5.22 (br t, 1H), 1.82 (d, J = 6.4Hz, 3H). Mass: 463.99 (M + 1).

Illustrative example 8

(R) -2- (1- (9H-purin-6-Namino) etN) -3- (3-fluorophenN) -4H-chromen-4-one

The present example is also described in Example 56 of WO 2011/055215. N, N-diisopropylethylamine (0.53 ml, 3.04 mmol) and 6-bromopurine (0.242 g, 1.21 mmol) are added to a solution of (R) -2- (1-amino-ethyl) 3- (3-fluoro-phenyl) -chromen-4-one (0.41 g, 1.52 mmol) in tert-butanol (7 ml) and reflux for 24 hours. The reaction mixture is concentrated, diluted with water, and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The crude product is purified by column chromatography with methanol: ethyl acetate to provide the title compound as an off-white solid. MP: 274-276 ° C. 1H-NMR (5 ppm, DMSO-Da, 400 MHz): 12.96 (s, 1H), 8.14-8.01 (m, 4H), 8.11 (s, 1H), 7.81 (dt, J = 8.5, 1.5 Hz, 1H), 7.60 (d, J = 8.4Hz, 1H), 7.49 (m, 2H), 7.25-7.19 (m , 3H), 5.18 (br m, 1H), 1.56 (d, J = 7.0Hz, 3H). Mass: 402.04 (M + 1).

Claims (26)

1. A process for the preparation of a compound of formula (IA)

or a salt of it, understanding the process (a) reacting a compound of formula (6) with a compound of formula (A)

to obtain a compound of formula (7a)

(b) deprotecting the compound formed in step (a) to obtain a compound of formula (IA); and (c) optionally converting the compound of formula (IA) into a salt thereof, in which each occurrence of R is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, heteroaryl, substituted or unsubstituted heteroaryl or unsubstituted, -COORX, -C (O) RX, -C (S) RX, -C (O) NRxRy, -C (O) ONRxRy, -NRxRy, -NRxCONRxRy, -N (RX) SORX, -N (Rx) SO2Ry, - (= NN (Rx) Ry), -NRxC (O) ORy, -NRxC (O) Ry-, -NRxC (S) Ry, -NRxC (S) NRxRy, -SONRxRy, -SO2NRxRy, -ORX, -ORxC (O) NRxRy, -ORXC (O) ORX, -OC (O) RX, -OC (O) NRxRy, -RxNRyC (O) Rz, -RxORy, -RxC (O) ORy, -RxC (O) NRxRy, -RxC (O) Ry, -RxOC (O) Ry , -SRX, -SORX, -SO2RX and -ONO2, wherein each occurrence of Rx, Ry and Rz is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl substituted, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring substituted, a substituted or unsubstituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or (i) any two of Rx and Ry, when attached to a common atom, join to form a substituted or unsubstituted 3-14 membered ring substituted, saturated or unsaturated, which may optionally include heteroatoms which may be the same or different and which are selected from O, NRZ or S, or (ii) any two of Rx and Ry, when bonded to a common atom, bond to form an oxo (= O), thio (= S), or imino (= NRf) (where Rf is hydrogen or substituted or unsubstituted alkyl); R1 is substituted or unsubstituted C1-6 alkyl; Cy1 is a monocyclic or bicyclic group selected from substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted heteroaryl or not substituted; Pg is a protecting group; Y n is an integer that is selected from 0, 1, 2, 3, or 4. 2. The process according to claim 1, wherein the compound of formula (6) is prepared by a process comprising (a) converting a compound of formula (1)

in which Pg is a protecting group, in a compound of formula (2)

(b) converting the compound of formula (2) into a compound of formula (3)

(c) converting the compound of formula (3) into a compound of formula (5)

wherein R, n, Cy1 and Pg are as defined in claim 1; Y (d) deprotecting the compound of formula (5) to obtain a compound of formula (6)

3. The process according to any one of claims 1 and 2, wherein the compound of formula (IA) has the formula (IA-I)

and the process comprises (a) converting a compound of formula (1a)

in a compound of formula (2a)

where Pg is a protecting group; (b) converting a compound of formula (2a) into a compound of formula (3a)

(c) converting a compound of formula (3a) into a compound of formula (5a)

(d) deprotecting the compound of formula (5a) to obtain a compound of formula (6a)

(e) reacting the compound of formula (6a) with a compound of formula (A)

to obtain a compound of formula (7aa)

(f) deprotecting the compound of formula (7aa) to obtain the compound of formula (IA-1); and (g) optionally converting the compound of formula (IA-1) into a salt thereof. 4. The process according to any one of claims 1 and 2, wherein the compound of formula (IA) has the formula (IA-II) and the process comprises (a) converting a compound to formula

in which Pg is a protecting group, to a compound of formula (2b)

(b) converting a compound of formula (2b) into a compound of formula (3b)

(c) converting the compound of formula (3b) into a compound of formula (5b)

(d) deprotect the compound of formula (5b) to obtain a compound of formula (6b)

(e) reacting the compound of formula (6b) with a compound of formula (A)

to obtain a compound of formula (7ab)

Y (f) deprotecting the compound of formula (7ab) to obtain the compound of formula (IA-II); and (g) optionally converting the compound of formula (IA-II) into a salt thereof. 5. A process for the preparation of a compound of formula (IB)

or a salt of it, understanding the process (a) reacting a compound of formula (6) with a compound of formula (B)

to obtain a compound of formula (7b)

Y (b) deprotecting the compound formed in step (a) to obtain a compound of formula (IB); and (c) optionally converting the compound of formula (IB) into a salt thereof; in which each occurrence of R is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, heteroaryl, substituted or unsubstituted heteroaryl or unsubstituted, -COORX, -C (O) RX, -C (S) RX, -C (O) NRxRy, -C (O) ONRxRy, -NRxRy, -NRxCONRxRy, -N (RX) SORX, -N (Rx) SO2Ry, - (= NN (Rx) Ry), -NRxC (O) ORy, -NRxC (O) Ry-, -NRxC (S) Ry, -NRxC (S) NRxRy, -SONRxRy, -SO2NRxRy, -ORX, -ORxC (O) NRxRy, -ORXC (O) ORX, -OC (O) RX, -OC (O) NRxRy, -RxNRyC (O) Rz, -RxORy, -RxC (O) ORy, -RxC (O) NRxRy, -RxC (O) Ry, -RxOC (O) Ry , -SRX, -SORX, -SO2RX and -ONO2, wherein each occurrence of Rx, Ry and Rz is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl substituted, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring substituted, a substituted or unsubstituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or (i) any two of Rx and Ry, when attached to a common atom, join to form a substituted or unsubstituted 3-14 membered ring substituted, saturated or unsaturated, which may optionally include heteroatoms which may be the same or different and which are selected from O, NRZ or S, or (ii) any two of Rx and Ry, when bonded to a common atom, bond to form an oxo (= O), thio (= S), or imino (= NRf) (where Rf is hydrogen or substituted or unsubstituted alkyl); R1 is substituted or unsubstituted C1-6 alkyl; Cy1 is a monocyclic or bicyclic group selected from substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Pg is a protecting group; Y n is an integer that is selected from 0, 1, 2, 3, or 4. 6. The process according to claim 5, wherein the compound of formula (6) is prepared by a process comprising (a) converting a compound of formula (1)

in a compound of formula (2)

where Pg is a protecting group; (b) converting the compound of formula (2) into a compound of formula (3)

(c) converting the compound of formula (3) into a compound of formula (5)

Y (d) deprotecting the compound of formula (5) to obtain a compound of formula (6)

7. The process according to any one of claims 5 and 6, wherein the compound of formula (IB) has the formula (IB-I)

and the process comprises (a) reacting the compound of formula (6a) with a compound of formula (B)

to obtain a compound of formula (7ba)

(b) deprotecting the compound of formula (7ba) to obtain the compound of formula (IB-I); and (c) optionally converting the compound of formula (IB-I) into a salt thereof. 8. A process according to any one of claims 5 and 6, wherein the compound of formula (IB) has the formula (IB-II)

and the process comprises (a) reacting the compound of formula (6b) with a compound of formula (B)

to obtain a compound of formula (7bb)

(b) deprotecting the compound of formula (7bb) to obtain the compound of formula (IB-II); and (c) optionally converting the compound of formula (IB-II) into a salt thereof. 9. A process according to any one of claims 1, 5, 7 and 8, wherein the reaction in step (a) is carried out in the presence of HATU, HBTU, TBTU, COMU, TOTU, HCTU, TCTU, TATU, TSTU or TDBTU. A process according to any one of claims 1, 5, 7 and 8, wherein the deprotection reaction of step (b) is carried out using aluminum chloride, boron tribromide or a combination thereof, or by hydrogenation. 11. A process for the preparation of a PI3K inhibitor of formula (I)

or a tautomer thereof, N-oxide thereof, or pharmaceutically acceptable salt thereof, wherein R, n, Cy1 and R1 are defined as in claim 1; Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; L1 is absent or selected from - (CRaRb) q-, -O-, -S (= O) q-, -NRa- or -C (= Y) -; each occurrence of Ra and Rb may be the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C1_6) alkyl, -NRcRd (where Rc and Rd are independently hydrogen, halogen , hydroxy, cyano, substituted or unsubstituted (1-6C) alkyl or (1-6C) alkoxy) and -ORC (where Rc is substituted or unsubstituted (1-6C) alkyl) or when Ra and Rb are directly attached to A common atom can join to form an oxo group (= O) or form a 3-10 membered substituted or unsubstituted, saturated or unsaturated ring (which includes the common atom to which Ra and Rb are directly attached), which optionally may include one or more heteroatoms which may be the same or different and are selected from O, NRd (where Rd is hydrogen or substituted or unsubstituted (1-6C) alkyl) or S; Y is selected from O, S, and NRa; Y q is 0, 1 or 2, understanding the process (a) treating the compound of formula (IA) with Cy2-H to obtain the compound of formula (I) or a tautomer thereof; Y (b) optionally converting the compound of formula (I) into an N-oxide thereof, or a pharmaceutically acceptable salt thereof. 12. A process for the preparation of a PI3K inhibitor of formula (I)

or a tautomer thereof, N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R, n, Cy1 and R1 are defined as in claim 1; Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; L1 is absent, - (CRaRb) q-, -O-, -S (= O) q-, -NRa- or -C (= Y) -; each occurrence of Ra and Rb may be the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C1_6) alkyl, -NRcRd (where Rc and Rd are independently hydrogen, halogen , hydroxy, cyano, substituted or unsubstituted (1-6C) alkyl or (1-6C) alkoxy) and -ORC (where Rc is substituted or unsubstituted (1-6C) alkyl) or when Ra and Rb are attached directly to a common atom they can join to form an oxo group (= O) or form a 3-10 membered substituted or unsubstituted, saturated or unsaturated ring (which includes the common atom to which Ra and Rb are directly attached), which optionally may include one or more heteroatoms which may be the same or different and are selected from O, NRd (where Rd is hydrogen or substituted or unsubstituted (1-6C) alkyl) or S; Y is selected from O, S, and NRa; Y q is 0, 1 or 2, understanding the process (a) reacting the compound of formula (IA) with a phosphorous halide or mesyl halide in the presence of a base to obtain a compound of formula (8a)

(b) reacting the compound of formula (8a) with Cy2-H in the presence of a base to obtain the compound of formula (I) or a tautomer thereof; Y (c) optionally, converting the compound of formula (I) into an N-oxide thereof, or a pharmaceutically acceptable salt thereof. 13. A process for the preparation of a PI3K inhibitor of formula (I)

or a tautomer thereof, N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R, n, Cy1 and R1 are as defined in claim 1; Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Y L1 is NH; understanding the process (a) reacting the compound of formula (IA)

with a phosphorous halide or mesyl halide in the presence of a base to obtain a compound of formula (8a)

wherein X1 is halogen or -O-Mesyl; (b) converting the compound of formula (8a) to obtain a compound of formula (9a)

(c) converting the compound of formula (9a) to obtain a compound of formula (10a)

(d) coupling the compound of formula (10a) with a compound of formula Cy2-Lg, in which Lg is a leaving group, in the presence of a base to obtain the compound of formula (I) or a tautomer thereof; Y (e) optionally converting the compound of formula (II) into an N-oxide thereof, or a pharmaceutically acceptable salt thereof. 14. A process for the preparation of a PI3K inhibitor of formula (III)

or a tautomer thereof, N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R, n, Cy1 and R1 are defined as in claim 1; Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; L1 is absent or selected from - (CRaRb) q-, -O-, -S (= O) q-, -NRa- or -C (= Y) -; each occurrence of Ra and Rb may be the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C1_6) alkyl, -NRcRd (where Rc and Rd are independently hydrogen, halogen , hydroxy, cyano, substituted or unsubstituted (1-6C) alkyl or (1-6C) alkoxy) and -ORC (where Rc is substituted or unsubstituted (1-6C) alkyl) or when Ra and Rb are directly attached to A common atom can join to form an oxo group (= O) or form a 3-10 membered substituted or unsubstituted, saturated or unsaturated ring (which includes the common atom to which Ra and Rb are directly attached), which optionally may include one or more heteroatoms which may be the same or different and are selected from O, NRd (where Rd is hydrogen or substituted or unsubstituted (1-6C) alkyl) or S; Y is selected from O, S, and NRa; Y q is 0, 1 or 2, understanding the process (a) reacting the compound of formula (IB)

with Cy2-H to obtain the compound of formula (III) or a tautomer thereof; Y (b) optionally converting the compound of formula (III) into an N-oxide thereof, or a pharmaceutically acceptable salt thereof. 15. A process for the preparation of a PI3K inhibitor of formula (III)

or a tautomer thereof, N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R, n, Cy1 and R1 are defined as in claim 1; Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; L1 is absent or selected from - (CRaRb) q-, -O-, -S (= O) q-, -NRa- or -C (= Y) -; each occurrence of Ra and Rb may be the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C1_6) alkyl, -NRcRd (where Rc and Rd are independently hydrogen, halogen , hydroxy, cyano, substituted or unsubstituted (1-6C) alkyl or (1-6C) alkoxy) and -ORC (where Rc is substituted or unsubstituted (1-6C) alkyl) or when Ra and Rb are attached directly to a common atom they can join to form an oxo group (= O) or form a 3-10 membered substituted or unsubstituted, saturated or unsaturated ring (which includes the common atom to which Ra and Rb are directly attached), which optionally may include one or more heteroatoms which may be the same or different and are selected from O, NRd (where Rd is hydrogen or substituted or unsubstituted (1-6C) alkyl) or S; Y is selected from O, S, and NRa; Y q is 0, 1 or 2, understanding the process (a) treating the compound of formula (IB)

with a phosphorous halide or mesyl halide in the presence of a base to obtain a compound of formula (8b)

(b) reacting the compound of formula (8b) with Cy2-H in the presence of a base to obtain the compound of formula (III) or a tautomer thereof; Y (c) optionally converting the compound of formula (III) into an N-oxide thereof or a pharmaceutically acceptable salt thereof. 16. A process for the preparation of a PI3K inhibitor of formula (III)

or a tautomer thereof, N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R, n, Cy1 and R1 are as defined in claim 1; Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Y Li is NH; understanding the process (a) reacting the compound of formula (IB)

with a phosphorous halide or mesyl halide in the presence of a base to obtain a compound of formula (8b)

(b) converting the compound of formula (8b) to obtain a compound of formula (9b)

(c) converting the compound of formula (9b) to obtain a compound of formula (10b)

(d) coupling the compound of formula (10b) with a compound of formula Cy2-Lg, in which Lg is a leaving group, in the presence of a base to obtain the compound of formula (IV); Y (e) optionally converting the compound of formula (IV) into a salt thereof. 17. A process for the inversion of a compound of formula (IA) to obtain a compound of formula (IB)

wherein R, R1, Cy1 and n are as defined in claim 1; understanding the process (a) reacting the compound of formula (IA) with R'-COOH (where R 'is selected from substituted or unsubstituted alkyl or substituted or unsubstituted aryl) to obtain a compound of formula IA-2

Y (b) converting the compound of formula (IA-2) to obtain a compound of formula (IB). 18. A process for the inversion of a compound of formula (IB) to obtain a compound of formula (IA)

wherein R, R1, Cy1 and n are as defined in claim 1; understanding the process (a) reacting the compound of formula (IB) with R'-COOH (where R 'is selected from substituted or unsubstituted alkyl or aryl) to obtain a compound of formula IB-2

Y (b) converting the compound of formula (IB-2) to obtain a compound of formula (IA). 19. A process according to any one of claims 17 and 18, wherein R 'is 4-Chlorophenyl. 20. A compound of formula (IA) or (IB)

or a salt of it, in which each occurrence of R is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, heteroaryl, substituted or unsubstituted heteroaryl or unsubstituted, -COORX, -C (O) RX, -C (S) RX, -C (O) NRxRy, -C (O) ONRxRy, -NRxRy, -NRxCONRxRy, -N (RX) SORX, -N (Rx) SO2Ry, - (= NN (Rx) Ry), -NRxC (O) ORy, -NRxC (O) Ry-, -NRxC (S) Ry, -NRxC (S) NRxRy, -SONRxRy, -SO2NRxRy, -ORX, -ORxC (O) NRxRy, -ORXC (O) ORX, -OC (O) RX, -OC (O) NRxRy, -RxNRyC (O) Rz, -RxORy, -RxC (O) ORy, -RxC (O) NRxRy, -RxC (O) Ry, -RxOC (O) Ry , -SRX, -SORX, -SO2RX and -ONO2, wherein each occurrence of Rx, Ry and Rz is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl substituted, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring substituted, a substituted or unsubstituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or (i) any two of Rx and Ry, when attached to a common atom, join to form a substituted or unsubstituted 3-14 membered ring substituted, saturated or unsaturated, which may optionally include heteroatoms which may be the same or different and which are selected from O, NRZ or S, or (ii) any two of Rx and Ry, when bonded to a common atom, bond to form an oxo (= O), thio (= S), or imino (= NRf) (where Rf is hydrogen or substituted or unsubstituted alkyl); R1 is substituted or unsubstituted C1-6 alkyl; Cy1 is a monocyclic or bicyclic group selected from substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Pg is a protecting group; Y n is an integer that is selected from 0, 1,2, 3 or 4, wherein the compound is not selected from

or a salt of it. 21. A compound of claim 20, wherein R is alkyl or halogen, Cy1 is a monocyclic group selected from substituted or unsubstituted aryl; Y n is 1. 22. A compound according to any one of claims 20 and 21, wherein R is chloro, fluoro or methyl; Cy1 is selected from

Y R1 is methyl or ethyl. 23. A compound according to claim 20, wherein the compound of formula (IA) or (IB) has an enantiomeric excess of at least 75%, 90%, 95%, 97% or 98%. 24. A compound selected from (R) -6-fluoro-3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one, (R) -2- (1-hydroxyethyl) -5-methyl-3-phenyl-4H-chromen-4-one, (R) -6-fluoro-2- (1-hydroxyethyl) -3-phenyl-4H-chromen-4-one, (R) -2- (1-hydroxyethyl) -3-phenyl-4H-chromen-4-one, (R) -3- (3-fluorophenyl) -2- (1-hydroxypropyl) -4H-chromen-4-one, (R) -3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one, (S) -3- (3-fluorophenyl) -2- (1-hydroxyethyl) -4H-chromen-4-one. and you get out of them. 25. A composition comprising (i) (a) a compound of formula (IA) or (IB)

or a salt of it, and (b) a PI3K inhibitor of formula (I)

or a tautomer thereof, N-oxide thereof, or a pharmaceutically acceptable salt thereof, or (ii) (a) a compound of formula (IA) or (IB)

or a salt of it, and (b) a PI3K inhibitor of formula (III)

or a tautomer thereof, N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R, n, Cy1 and R1 are defined as in claim 1; Cy2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Li is absent or selected from - (CRaRb) q-, -O-, -S (= O) q-, -NRa- or -C (= Y) -; each occurrence of Ra and Rb may be the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (Ci_6) alkyl, -NRcRd (where Rc and Rd are independently hydrogen, halogen , hydroxy, cyano, substituted or unsubstituted (Ci-6) alkyl or (Ci-6) alkoxy) and -ORC (where Rc is substituted or unsubstituted (Ci_6) alkyl) or when Ra and Rb are directly attached to A common atom can join to form an oxo group (= O) or form a 3-10 membered substituted or unsubstituted, saturated or unsaturated ring (which includes the common atom to which Ra and Rb are directly attached), which optionally may include one or more heteroatoms which may be the same or different and are selected from O, NRd (where Rd is hydrogen or substituted or unsubstituted (1-6C) alkyl) or S; Y is selected from O, S, and NRa; Y q is 0, 1 or 2, wherein the compound of formula (IA) or (IB) is present in composition (i) or composition (ii) is in an amount of up to 0.5% by weight, based on the total of the components (a) and (b) in composition. 26. The composition of claim 25, wherein the compound of formula (IA) or (IB) is present in the composition (i) or composition (ii) is in an amount up to 0.2% by weight , based on the total of components (a) and (b) in the composition.