HRP20201687T1

HRP20201687T1 - Process for preparation of optically pure and optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives and their use in preparing pharmaceuticals

Info

Publication number: HRP20201687T1
Application number: HRP20201687TT
Authority: HR
Inventors: Jayaraman Venkat Raman; Swaroop Kumar Venkata Satya VAKKALANKA
Original assignee: Rhizen Pharmaceuticals S.A.
Priority date: 2012-05-04
Filing date: 2020-10-19
Publication date: 2020-12-25
Also published as: DK2844647T3; LT2844647T; HUE051029T2; ES2825974T3; PT2844647T

Claims

1. Procedure for preparing the compound of formula (IA) [image] or its salts, that procedure contains (a) reaction of compound of formula (6) with compound of formula (A) [image] to obtain the compound of formula (7a) [image] (b) deprotection of the compound formed in step (a) to give a compound of formula (IA); and (c) optionally converting a compound of formula (IA) into its salt, whereby each occurrence of R 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 heterocyclylalkyl, 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, -(=N-N(Rx)Ry), - NRxC(O)ORy, -NRxC(O)Ry-, -NRxC(S)Ry, - NRxC(S)NRxRy, -SONRxRy, -SO2NRxRy, -ORx, -ORxC(O)NRxRy, - OR xC(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 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 or unsubstituted heterocyclylalkyl ring , or substituted or unsubstituted amino, or (i) any two of Rx and Ry, when linked by a common atom, are joined to form a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may will arbitrarily include heteroatoms which may be the same or different are selected from O, NRz or S, or (ii) any two of Rx and Ry, when linked to a common atom, are joined to form oxo (=O), thio (=S) or imino (=NRf) (wherein Rf is hydrogen or substituted or unsubstituted alkyl); R 1 is substituted or unsubstituted C 1-6 alkyl; Cy1 is a monocyclic or bicyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Pg is a protecting group; and n is an integer selected from 0, 1, 2, 3, or 4.

2. The process according to patent claim 1, wherein the compound of formula (6) is obtained with the help of the process which contains (a) converting the compound of formula (1) [image] where Pg is a protecting group, in the compound of formula (2) [image] (b) converting the compound of formula (2) into the compound of formula (3) [image] (c) converting the compound of formula (3) into the compound of formula (5) [image] wherein R, n, Cy1 and Pg are as defined in claim 1; and (d) deprotection of a compound of formula (5) to give a compound of formula (6) [image]

3. The process according to any of claims 1 and 2, wherein the compound of formula (IA) has the formula (IA-I) [image] and that procedure contains (a) converting the compound of formula (1a) [image] to the compound of formula (2a) [image] wherein Pg is a protecting group; (b) converting the compound of formula (2a) into the compound of formula (3a) [image] (c) converting the compound of formula (3a) into the compound of formula (5a) [image] (d) deprotection of a compound of formula (5a) to give a compound of formula (6a) [image] (e) reaction of the compound of formula (6a) with the compound of formula (A) [image] to obtain the compound of formula (7aa) [image] (f) deprotection of a compound of formula (7aa) to give a compound of formula (IA-1); and (g) optionally converting a compound of formula (IA-1) into a salt thereof.

4. The process according to any of claims 1 and 2, wherein the compound of formula (IA) has the formula (IA-II) [image] and that procedure contains (a) converting the compound of formula (1b) [image] where Pg is a protecting group, in the compound of formula (2b) [image] (b) converting the compound of formula (2b) into the compound of formula (3b) [image] (c) converting the compound of formula (3b) into the compound of formula (5b) [image] (d) deprotection of the compound of formula (5b) to give the compound of formula (6b) [image] (e) reaction of the compound of formula (6b) with the compound of formula (A) [image] to obtain the compound of formula (7ab) [image] and (f) deprotection of a compound of formula (7ab) to give a compound of formula (IA-II); and (g) optionally converting a compound of formula (IA-II) into a salt thereof.

5. Procedure for obtaining the compound of formula (IB) [image] or its salts, that procedure contains (a) reaction of compound of formula (6) with compound of formula (B) [image] to obtain the compound of formula (7b) [image] and (b) deprotecting the compound created in step (a) to give a compound of formula (IB); and (c) optionally converting a compound of formula (IB) into a salt thereof; whereby 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 heterocyclylalkyl, 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, -(=N-N(Rx)Ry), -NRxC(O)ORy, -NRxC(O)Ry-, -NRxC(S)Ry, -NRxC(S)NRxRy, -SONRxRy, -SO2NRxRy, -ORx, -ORxC(O)NRxRy, - O RxC(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 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 or unsubstituted heterocyclylalkyl ring , or substituted or unsubstituted amino, or (i) any two of Rx and Ry, when linked by a common atom, are joined to form a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which m may optionally include heteroatoms which may be the same or different and selected from the group consisting of O, NRz or S, or (ii) any two Rx and Ry, when linked to a common atom, are joined to form oxo (=O), thio (=S) or imino (=NRf) (wherein Rf is hydrogen or substituted or unsubstituted alkyl); R 1 is substituted or unsubstituted C 1-6 alkyl; Cy1 is a monocyclic or bicyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Pg is a protecting group; and n is 0, 1, 2, 3 or 4.

6. Process according to patent claim 5, wherein the compound of formula (6) is obtained by the process containing (a) converting the compound of formula (1) [image] to the compound of formula (2) [image] wherein Pg is a protecting group; (b) converting the compound of formula (2) into the compound of formula (3) [image] (c) converting the compound of formula (3) into the compound of formula (5) [image] and (d) deprotection of a compound of formula (5) to give a compound of formula (6) [image]

7. The process according to any of claims 5 and 6, wherein the compound of formula (IB) has the formula (IB-I) [image] and that procedure contains (a) Reaction of compound of formula (6a) with compound of formula (B) [image] to obtain the compound of formula (7ba) [image] (b) deprotection of a compound of formula (7ba) to give a compound of formula (IB-I); and (c) optionally converting a compound of formula (IB-I) into a salt thereof.

8. The process according to any of claims 5 and 6, wherein the compound of formula (IB) has the formula (IB-II) [image] and that procedure contains (a) reaction of compound of formula (6b) with compound of formula (B) [image] to obtain a compound of formula (7bb) [image] (b) deprotection of a compound of formula (7bb) to give a compound of formula (IB-II); and (c) optionally converting a compound of formula (IB-II) into a salt thereof.

9. The 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.

10. The process according to any one of claims 1, 5, 7 and 8, wherein the deprotection reaction from step (b) is performed using aluminum chloride, boron tribromide, or their combination, or by hydrogenation.

11. Process for obtaining PI3K inhibitor of formula (I) [image] or its tautomer, its N oxide, or its pharmaceutically acceptable salt, wherein R, n, Cy1, and R1 are as described in claim 1; Cy2 is selected from 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- and -C(=Y)-; at each occurrence 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 (wherein Rc and Rd are independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C1-6)alkyl, or (C1-6)alkoxy) and -ORc (wherein Rc is substituted or unsubstituted (C1-6)alkyl) or wherein Ra and Rb are directly linked to a common atom , they may be joined to form an oxo group (=O) or to form a substituted or unsubstituted, saturated or unsaturated 3-10 membered ring (including the common atom to which Ra and Rb are directly attached), which may optionally include one or more heteroatoms which may be the same or different or selected from O, NRd (wherein Rd is hydrogen or substituted or unsubstituted (C1-6)alkyl) or S; Y is selected from O, S, and NRa; and q is 0, 1 or 2, that procedure contains (a) treating a compound of formula (IA) with Cy2-H to give a compound of formula (I) or a tautomer thereof; and (b) optionally converting a compound of formula (I) into its N-oxide, or a pharmaceutically acceptable salt thereof.

12. Process for obtaining PI3K inhibitor of formula (I) [image] or its tautomer, its N-oxide, or its pharmaceutically acceptable salt, wherein R, n, Cy1, and R11 are defined as described in claim 1; Cy2 is selected from 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)-; at each occurrence, Ra and Rb can be the same or different and are independently protected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C1-6)alkyl, -NRcRd (wherein Rc and Rd are independently hydrogen, halogen, hydroxy, cyano , substituted or unsubstituted (C1-6)alkyl, or (C1-6)alkoxy) and -ORc (wherein Rc is substituted or unsubstituted (C1-6)alkyl) or wherein Ra and Rb are directly linked to a common atom, they may be joined to form an oxo group (=O) or to form a substituted or unsubstituted, saturated or unsaturated 3-10 membered ring (including the common atom to which Ra and Rb are directly attached), which may optionally include one or multiple heteroatoms which may be the same or different or selected from O, NRd (wherein Rd is hydrogen or substituted or unsubstituted (C1-6)alkyl) or S; Y is selected from O, S, and NRa; and q is 0, 1 or 2, the procedure contains (a) Reaction of a compound of formula (IA) with phosphorus hydride or mesyl hydride in the presence of a base to give a compound of formula (8a) [image] wherein X 1 is halogen or -O-Mesyl; (b) reacting a compound of formula (8a) with Cy2-H in the presence of a base to give a compound of formula (I) or a tautomer thereof; and (c) optionally, converting a compound of formula (I) into its N-oxide, or a pharmaceutically acceptable salt thereof.

13. Process for obtaining PI3K inhibitor of formula (I) [image] or its tautomer, its N-oxide, or its pharmaceutically acceptable salt, wherein R, n, Cy1, and R1 are as described in claim 1; Cy2 is selected from substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and L1 is NH; the procedure contains (a) reaction of the compound of formula (IA) [image] with phosphorus hydride or mesyl hydride in the presence of a base to give a compound of formula (8a) [image] wherein X 1 is halogen or -O-Mesyl; (b) converting the compound of formula (8a) to give the compound of formula (9a) [image] (c) converting the compound of formula (9a) to give the compound of formula (10a) [image] (d) coupling a compound of formula (10a) with a compound of formula Cy2-Lg, wherein Lg is a leaving group, in the presence of a base to give a compound of formula (I) or a tautomer thereof; and (e) optionally, converting the compound of formula (II) into its N-oxide, or a pharmaceutically acceptable salt thereof.

14. Process for obtaining PI3K inhibitor of formula (III) [image] or its tautomer, its N oxide, or its pharmaceutically acceptable salt, wherein R, n, Cy1, and R1 are as described in claim 1; Cy2 is selected from 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- and -C(=Y)-; at each occurrence 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 (wherein Rc and Rd are independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C1-6)alkyl, or (C1-6)alkoxy) and -ORc (wherein Rc is substituted or unsubstituted (C1-6)alkyl) or pyri wherein Ra and Rb are directly linked to a common atom , they may be joined to form an oxo group (=O) or to form a substituted or unsubstituted, saturated or unsaturated 3-10 membered ring (including the common atom to which Ra and Rb are directly attached), which may optionally include one or more heteroatoms which may be the same or different or selected from O, NRd (wherein Rd is hydrogen or substituted or unsubstituted (C1-6)alkyl) or S; Y is selected from O, S, and NRa; and q is 0, 1 or 2, the procedure contains (a) reaction of the compound of formula (IB) [image] with Cy2-H to give a compound of formula (III) or a tautomer thereof; and (b) optionally, converting the compound of formula (III) into its N-oxide, or a pharmaceutically acceptable salt thereof.

15. Process for obtaining PI3K inhibitor of formula (III) [image] or its tautomer, its N oxide, or its pharmaceutically acceptable salt, wherein R, n, Cy1, and R1 are described as in claim 1; Cy2 is selected from 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- and -C(=Y)-; at each occurrence 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 (wherein Rc and Rd are independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C1-6)alkyl, or (C1-6)alkoxy) and -ORc (wherein Rc is substituted or unsubstituted (C1-6)alkyl) or wherein Ra and Rb are directly linked to a common atom , they may be joined to form an oxo group (=O) or to form a substituted or unsubstituted, saturated or unsaturated 3-10 membered ring (including the common atom to which Ra and Rb are directly bonded), which may optionally include one or more heteroatoms which may be the same or different or selected from O, NRd (wherein Rd is hydrogen or substituted or unsubstituted (C1-6)alkyl) or S; Y is selected from O, S, and NRa; and q is 0, 1 or 2, the procedure contains (a) treating a compound of formula (IB) [image] with phosphorus hydride or mesyl hydride in the presence of a base to give a compound of formula (8b) [image] wherein X 1 is halogen or -O-Mesyl; (b) reaction of a compound of formula (8b) with Cy2-H in the presence of a base to give a compound of formula (III) or a tautomer thereof; and (c) optionally, converting the compound of formula (III) into its N-oxide, or a pharmaceutically acceptable salt thereof.

16. Process for obtaining PI3K inhibitor of formula (III) [image] or its tautomer, its N oxide, or its pharmaceutically acceptable salt, wherein R, n, Cy1, and R1 are as described in claim 1; Cy2 is selected from substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and L1 is NH; The procedure contains (a) reaction of the compound of formula (IB) [image] with phosphoric acid or mesyl acid in the presence of a base to give a compound of formula (8b) [image] wherein X 1 is halogen or -O-Mesyl; (b) converting the compound of formula (8b) to give the compound of formula (9b) [image] (c) converting the compound of formula (9b) to give the compound of formula (10b) [image] (d) coupling compounds of formula (10b) with a compound of formula Cy2-Lg, wherein Lg is a leaving group, in the presence of a base to give a compound of formula (IV); and (e) optionally, converting a compound of formula (IV) into a salt thereof.

17. Procedure for inverting a compound of formula (IA) to obtain a compound of formula (IB) [image] wherein R, R1, Cy1 and n are as described in claim 1; the procedure contains (a) reacting a compound of formula (IA) with R'-COOH (wherein R' is selected from substituted or unsubstituted alkyl or substituted or unsubstituted aryl) to give a compound of formula IA-2 [image] and (b) converting a compound of formula (IA-2) to give a compound of formula (IB).

18. Procedure for inverting a compound of formula (IB) to obtain a compound of formula (IA) [image] wherein R, R1, Cy1 and n are as described in claim 1; the procedure contains (a) reaction of a compound of formula (IB) with R'-COOH (wherein R' is selected from substituted or unsubstituted alkyl or aryl) to give a compound of formula IB-2 [image] and (b) converting a compound of formula (IB-2) to give a compound of formula (IA).

19. The method according to any of claims 17 and 18, wherein R' is 4-chloro phenyl.

20. Compound of formula (IA) or (IB) [image] or its salt, whereby at each occurrence 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 heterocyclylalkyl, 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, -(=N-N(Rx)Ry) , -NRxC(O)ORy, -NRxC(O)Ry-, -NRxC(S)Ry, - NRxC(S)NRxRy, -SONRxRy, -SO2NRxRy, -ORx, -ORxC(O)NRxR y, -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 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 or unsubstituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or (i) any two of Rx and Ry, when linked by a common atom, are joined to form substituted or unsubstituted, saturated or unsaturated 3-14 membered rings n, which may optionally include heteroatoms which may be the same or different and are selected from O, NRz or S, or (ii) any two of Rx and Ry, when linked to a common atom, are joined to form oxo (= O), thio (=S) or imino (=NRf) (wherein Rf is hydrogen or substituted or unsubstituted alkyl); R 1 is substituted or unsubstituted C 1-6 alkyl; Cy1 is a group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and n is an integer selected from 0, 1, 2, 3 or 4, wherein that compound is not selected from [image] or its salts.

21. Compound according to patent claim 20, wherein R is alkyl or halogen, Cy1 is a monocyclic group selected from substituted or unsubstituted aryl; and n is 1.

22. A compound according to any of claims 20 and 21, wherein R is chloro, fluoro or methyl; Cy1 is selected from [image] and R 1 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. The compound is 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 their salts.

25. Preparation containing (and) (a) a compound of formula (IA) or (IB) or its salt, i (b) PI3K inhibitor of formula (I) [image] or a tautomer thereof, an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or (ii) (a) a compound of formula (IA) or (IB) [image] or its salt, i (b) PI3K inhibitor of formula (III) [image] or a tautomer thereof, an N oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R, n, Cy1, and R1 are described as in claim 1; Cy2 is selected from substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; L1 is not present or selected from -(CRaRb)q-, -O-, -S(=O)q-, -NRa- or -C(=Y)-; at each occurrence 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 (wherein Rc and Rd are independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C1-6)alkyl, or (C1-6)alkoxy) and -ORc (wherein Rc is substituted or unsubstituted (C1-6)alkyl) or wherein Ra and Rb are directly linked to a common atom , they may be joined to form an oxo group (=O) or to form a substituted or unsubstituted, saturated or unsaturated 3-10 membered ring (including the common atom to which Ra and Rb are directly bonded), which may optionally include one or more heteroatoms which may be the same or different or selected from O, NRd (wherein Rd is hydrogen or substituted or unsubstituted (C1-6)alkyl) or S; Y is selected from O, S, and NRa; and q is 0, 1 or 2, wherein the compound of formula (IA) or (IB) is present in preparation (i) or preparation (ii) in an amount of up to 0.5% by weight, based on the total components (a) and (b) in that preparation.

26. The preparation according to patent claim 25, wherein the compound of formula (IA) or (IB) is present in preparation (i) or preparation (ii) in an amount of up to 0.2% by weight, based on the total components (a) and (b) in preparation.