IP Library › Granted Patent US 10,322,130

Granted Patent B2

US 10,322,130 · App. 15/677,614 · Granted Jun 18, 2019

Substituted chromenones as modulators of protein kinases

Inventors: Dhanapalan Nagarathnam (Bethany, CT); Swaroop K. Vakkalanka (La Chaux-de-Fonds, CH); Meyyappan Muthuppalaniappan (Hyderabad, IN); Srikant Viswanadha (Hyderabad, IN); Govindarajulu Babu (Hyderabad, IN); Prashant K. Bhavar (Hyderabad, IN)

Assignee: RHIZEN PHARMACEUTICALS SA

A61K31/519 A61K31/185 A61K31/52 A61K31/5355 A61K31/5377 A61K45/06 C07D311/22 C07D311/36 C07D405/06 C07D473/18 C07D473/34 C07D473/40 C07D487/04 Y02A50/422

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Quick Facts

Patent No.: US 10,322,130
App. No.: 15/677,614
Granted: Jun 18, 2019
Kind: B2

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Abstract

The present invention provides PI3K protein kinase modulators of formula wherein R, Cy 1 , R 1 , R 2 , L 1 and Cy 2 are as defined herein. The present invention also relates to methods of preparing compounds of formula (I) to pharmaceutical compositions containing them and to methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them.

Claims (236)

1. A compound of formula (I)

or a pharmaceutically acceptable salt, N-oxide or tautomer thereof,

wherein:

each occurrence of R is independently selected from hydroxy, halogen, carboxy, 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, —COOR x , —C(O)R x , —C(S)R x , —C(O)NR x R y , —C(O)ONR x R y , —NR x R y , —NR x CONR x R y , —N(R x )SOR x , —N(R x )SO 2 R y , —(═N—N(R x )R y ), —NR x C(O)OR y , —NR x R y , —NR x C(O)R y —, —NR x C(S)R y —NR x C(S)NR x R y , —SONR x R y —, —SO 2 NR x R y —, —OR x , —OR x C(O)NR x R y , —OR x C(O)OR x —, —OC(O)R x , —OC(O)NR x R y , —R x NR y C(O)R z , —R x OR y , —R x C(O)OR y , —R x C(O)NR x R y , —R x C(O)R y , —R x OC(O)R y , —SR x , —SOR x , —SO 2 R x , or —ONO 2 , wherein R x , R y and R z in each of the above groups is 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 heterocyclyl, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or (i) any two of R x and R y may be joined to form a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NR z or S, or (ii) any two of R x and R y join to form (═O), (—S) or (═NR f ) (wherein R f is hydrogen or substituted or unsubstituted alkyl);

R 1 and R 2 may be the same or different and are independently selected from hydrogen, halogen, and substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, and substituted or unsubstituted heterocyclyl, or both R 1 and R 2 directly bound to a common atom, may be joined to form (═O);

Cy 1 is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

Cy 2 is selected from a substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

L 1 is absent or selected from —(CR a R b ) q —, —O—, —S(═O) q —, —NR a — or —C(═Y)—;

each occurrence of R a and R b may be the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C 1-6 )alkyl, —NR c R d (wherein R c and R d are independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C 1-6 )alkyl, or (C 1-6 )alkoxy) and —OR c (wherein R c is substituted or unsubstituted (C 1-6 )alkyl) or when R a and R b are directly bound to a common atom, they may be joined to form (═O) or form a substituted or unsubstituted, saturated or unsaturated 3-10 member ring (including the common atom to which R a and R b are directly bound), which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NR d (wherein R d is hydrogen or substituted or unsubstituted (C 1-6 )alkyl) or S;

Y is selected from O, S, and NR a ; and

q is 0, 1 or 2;

wherein the term “substituted” refers to substitution by any one or more of the following substituents, which may be the same or different, and are independently selected from hydroxy, halogen, cyano, A alkyl, alkoxy, fluorinated alkoxy, heteroaryl, heterocyclyl, alkylheterocyclyl, —NH 2 , —NH(alkyl), N(alkyl) 2 , —NHC(O)(alkyl), —S(alkyl), —SO 2 NH 2 , —SO 2 NH(alkyl), —SO 2 N(alkyl) 2 , —SO 2 NH(cycloalkyl), —SO 2 N(cycloalkyl) 2 , —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , —O-heterocyclyl, —O-heterocyclyl-alkylaryl, —SO 2 NH(cycloalkyl), and —CO 2 (alkyl).

2. The compound of claim 1 , wherein the compound has the formula (IA-1), formula (IA-II), formula (IA-III), formula (IA-IV), formula (IA-V), formula (IA-Ia), formula (IA-IIa), formula (IA-IIIa), formula (IA-Ib) or formula (IA-IIb):

or a pharmaceutically acceptable salt, N-oxide or tautomer thereof,

wherein:

R is selected from halogen, hydroxy, substituted or unsubstituted alkoxy, cyano, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl, and substituted or unsubstituted heterocyclyl;

R 1 and R 2 may be the same or different and are independently selected from hydrogen, halogen, and substituted or unsubstituted C 1-6 alkyl, or both R 1 and R 2 directly bound to a common atom, may be joined to form (═O);

Cy 1 is a monocyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

X is CR 3 ;

each occurrence of R′ and R″ is independently selected from hydrogen, hydroxy, halogen, carboxy, cyano, nitro, 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 cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted guanidine, —COOR x , —C(O)R x , —C(S)R x , —C(O)NR x R y , —C(O)ONR x R y , —NR y R z , —NR x CONR y R z , —N(R x )SOR y , —N(R x )SO 2 R y , —(═N—N(R x )R y ), —NR x C(O)OR y , —NR x R y , —NR x C(O)R y —, —NR x C(S)R y —NR x C(S)NR y R z , —SONR x R y —, —SO 2 NR x R y —, —OR x , —OR x C(O)NR y R z , —OR x C(O)OR y —, —OC(O)R x , —OC(O)NR x R y , —R x NR y C(O)R z , —R x OR y , —R x C(O)OR y , —R x C(O)NR y R z , —R x C(O)R x , —R x OC(O)R y , —SR x , —SOR x , —SO 2 R x , or —ONO 2 , or both the R′ and R″ together with the nitrogen atom may be joined to form a substituted or unsubstituted, saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NR f (wherein R f is hydrogen or substituted or unsubstituted alkyl) or S;

each occurrence of R x , R y and R z in each of the above groups are 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 heterocyclyl, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or any two of R x , R y and R z may be joined to form a substituted or unsubstituted, saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NR f or S (wherein R f is hydrogen or substituted or unsubstituted alkyl);

each occurrence of R a is independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C 1-6 )alkyl, —NR c R d (wherein R c and R d are independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C 1-6 )alkyl, or (C 1-6 )alkoxy) and —OR c (wherein R c is substituted or unsubstituted (C 1-6 )alkyl); and

q is 0, 1 or 2.

3. The compound of claim 1 , wherein each occurrence of R is independently selected from halogen, cyano, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl, and substituted or unsubstituted heterocyclyl.

4. The compound of claim 3 , wherein each occurrence of R is independently selected from fluoro, methyl, methoxy and morpholinyl.

5. The compound of claim 1 , wherein Cy 1 is selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

6. The compound of claim 1 , wherein Cy 1 is selected from

7. The compound of claim 1 , wherein R 1 and R 2 are independently selected from hydrogen and substituted or unsubstituted C 1-6 alkyl.

8. The compound of claim 1 , wherein L 1 is absent, or selected from S(═O) q — or —NR a —.

9. The compound of claim 8 , wherein q is 0, L 1 is absent or L 1 is —NH—.

10. The compound of claim 1 , wherein Cy 2 is selected from substituted or unsubstituted heterocyclyl and substituted or unsubstituted heteroaryl.

11. The compound of claim 1 , in L 1 -Cy 2 is selected from formula a, formula b, formula c, formula d, formula e, formula f, formula a 1 , formula b 1 , formula c 1 , formula f 1 , formula a 2 , formula b 2 , formula c 2 or formula f 2 :

wherein:

X is CR 3 ; and

each occurrence of R 3 is independently selected from hydrogen, hydroxy, halogen, carboxy, 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 cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted guanidine, —COOR x , C(O)R x , —C(S)R x , —C(O)NR x R y , —C(O)ONR x R y , —NR y R z , —NR x CONR y R z , —N(R x )SOR y , —N(R x )SO 2 R y , —(═N—N(R x )R y ), —NR x C(O)OR y , —NR x R y , —NR x C(O)R y —, —NR x C(S)R y —NR x C(S)NR y R z , —SONR x R y —, —SO 2 NR x R y —, —OR x , —OR x C(O)NR y R z , —OR x C(O)OR y —, —OC(O)R x , —OC(O)NR x R y , —R x NR y C(O)R z , —R x OR y , —R x C(O)OR y , —R x C(O)NR y R z , —R x C(O)R x , —R x OC(O)R y , —SR x , —SOR x , —SO 2 R x , or —ONO 2 , wherein R x , R y and R z in each of the above groups is 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 heterocyclylalkyl ring, or substituted or unsubstituted amino, or any two of R x , R y and R z may be joined to form a substituted or unsubstituted, saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NR f or S (wherein R f is hydrogen or substituted or unsubstituted alkyl);

each occurrence of R′ and R″ is independently selected from hydrogen, hydroxy, halogen, carboxy, cyano, nitro, 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 cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted guanidine, —COOR x , —C(O)R x , —C(S)R x , —C(O)NR x R y , —C(O)ONR x R y , —NR y R z , —NR x CONR y R z , —N(R x )SOR y , —N(R x )SO 2 R y , —(═N—N(R x )R y ), —NR x C(O)OR y , —NR x R y , —NR x C(O)R y —, —NR x C(S)R y —NR x C(S)NR y R z , —SONR x R y —, —SO 2 NR x R y —, —OR x , —OR x C(O)NR y R z , —OR x C(O)OR y —, —OC(O)R x , —OC(O)NR x R y , —R x NR y C(O)R z , —R x OR y , —R x C(O)OR y , —R x C(O)NR y R z , —R x C(O)R x , —ROC(O)R y , —SR x , —SOR x , —SO 2 R x , or —ONO 2 , or both the R′ and R″ together with the nitrogen atom may be joined to form a substituted or unsubstituted, saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NR f (wherein R f is hydrogen or substituted or unsubstituted alkyl) or S;

wherein R x , R y and R z in each of the above groups is 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 heterocyclyl, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or any two of R x , R y and R z may be joined to form a substituted or unsubstituted, saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NR f or S (wherein R f is hydrogen or substituted or unsubstituted alkyl); and

q is 0, 1 or 2.

12. The compound of claim 11 , wherein R 3 is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

13. The compound of claim 12 , wherein R 3 is independently selected from

wherein:

each occurrence of X is independently CR 4 or N;

X 1 is O, S, or NR 4 ; and

each occurrence of R 4 is independently selected from hydrogen, hydroxy, halogen, carboxy, 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 cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted guanidine, —COOR x , —C(O)R x , —C(S)R x , —C(O)NR x R y , —C(O)ONR x R y , —NR y R z , —NR x CONR y R z , —N(R x )SOR y , —N(R)SO 2 R y , —(═N—N(R x )R y ), —NR x C(O)OR y , —NR x R y , —NR x C(O)R y —, —NR x C(S)R y —NR x C(S)NR y R z , —SONR x R y —, —SO 2 NR x R y —, —OR x , —OR x C(O)NR y R z , —OR x C(O)OR y —, —OC(O)R x , —OC(O)NR x R y , —R x NR y C(O)R z , —R x OR y , —R x C(O)OR y , —R x C(O)NR y R z , —R x C(O)R x , —R x OC(O)R y , —SR x , —SOR x , —SO 2 R x , or —ONO 2 , wherein R x , R y and R z 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 or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or any two of R x , R y and R z may be joined to form a substituted or unsubstituted, saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NR f (wherein R f is hydrogen or substituted or unsubstituted alkyl) or S.

14. The compound of claim 12 , wherein R 3 is independently selected from

15. The compound of claim 1 , wherein L 1 -Cy 2 is selected from

16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or a pharmaceutically acceptable salt, N-oxide or tautomer thereof.

17. The pharmaceutical composition of claim 16 , wherein the composition further comprises one or more additional therapeutic agents selected from the group consisting of an anti-cancer agent, an anti-inflammatory agent, an immunosuppressive agent, a steroid, a non-steroidal anti-inflammatory agent, an antihistamine, an analgesic, or a mixture thereof.

18. A method of inhibiting a catalytic activity of a phophoinositol 3-kinase present in a cell, comprising contacting the cell with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, N-oxide or tautomer thereof.

19. The method of claim 18 , wherein the inhibition occurs in the cell of a subject suffering from a disease or disorder selected from the group consisting of cancer, a bone disorder, an inflammatory disease, an immune disease, a nervous system disease, a metabolic disease, a respiratory disease, thrombosis, and a cardiac disease.

20. A method of treating asthma in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, N-oxide or tautomer thereof.

21. A method of treating chronic obstructive pulmonary disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, N-oxide or tautomer thereof.

22. A compound of formula (IA-III), formula (IA-Ia), formula (IA-IIa), formula (IA-IIIa), formula (IA-Ib) or formula (IA-IIb):

or a pharmaceutically acceptable salt, N-oxide or tautomer thereof;

wherein:

R is selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkoxy, cyano, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl, and substituted or unsubstituted heterocyclyl;

X is CR 3 ;

R′ and R″ together with the nitrogen atom may be joined to form a substituted or unsubstituted, saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NR f (wherein R f is hydrogen or substituted or unsubstituted alkyl) or S;

q is 0, 1 or 2,

wherein the term “substituted’ refers to substitution by any one or more of the following substituents which may be the same or different, and are independently selected from hydroxy, halogen, cyano, alkyl, alkoxy, fluorinated alkoxy, heroroaryl, heterocyclyl, alkylheterocyclyl, —NH 2 , —NH(alkyl), N(alkyl) 2 , —NHC(O)(alkyl), —S(alkyl), —SO 2 NH 2 , —SO 2 NH(alkyl), —SO 2 N(alkyl) 2 , —SO 2 NH(cycloalkyl), —SO 2 N(cycloalkyl) 2 , —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , —O-heterocyclyl, —O-heterocyclyl-alkylaryl, —SO 2 NH(cycloalkyl), and —CO 2 (alkyl).

23. A compound of formula (IA-VI):

or a pharmaceutically acceptable salt thereof,

wherein:

each occurrence of R is independently selected from hydroxy, halogen, —OR a , cyano, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl, and substituted or unsubstituted heterocyclyl;

X is CR 3 ;

each occurrence of R′ and R″ is independently selected from hydrogen, hydroxy, halogen, carboxy, cyano, nitro, 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 cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted guanidine, —COOR x , —C(O)R x , —C(S)R x , —C(O)NR x R y , —C(O)ONR x R y , —NR y R z , —NR x CONR y R z , —N(R x )SOR y , —N(R x )SO 2 R y , —(═N—N(R x )R y ), —NR x C(O)OR y , —NR x R y , —NR x C(O)R y —, —NR x C(S)R y —NR x C(S)NR y R z , —SONR x R y —, —SO 2 NR x R y —, —OR x , —OR x C(O)NR y R z , —OR x C(O)OR y —, —OC(O)R x , —OC(O)NR x R y , —R x NR y C(O)R z , —R x OR y , —R x C(O)OR y , —R x C(O)NR y R z , —R x C(O)R x , —R x OC(O)R y , —SR x , —SOR x , —SO 2 R x , or —ONO 2 , or both R′ and R″ together with the nitrogen atom may be joined to form a substituted or unsubstituted, saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NR f (wherein R f is hydrogen or substituted or unsubstituted alkyl) or S;

each occurrence of R 5 is hydrogen, C 1-6 alkyl or halogen; and

p is 0, 1, 2, 3, 4 or 5,

wherein the term “substituted” refers to substitution by any one or more of the following substituents which may be the same or different, and are independently selected from hydroxy, halogen, cyano, alkyl, alkoxy, fluorinated alkoxy, heroroaryl, heterocyclyl, alkylheterocyclyl, —NH 2 , —NH(alkyl), N(alkyl) 2 , —NHC(O)(alkyl), —S(alkyl), —SO 2 NH 2 , —SO 2 NH(alkyl), —SO 2 N(alkyl) 2 , —SO 2 NH(cycloalkyl), —SO 2 N(cycloalkyl) 2 , —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , —O-heterocyclyl, —O-heterocyclyl-alkylaryl, —SO 2 NH(cycloalkyl), and —CO 2 (alkyl).

24. The compound of claim 23 , wherein each of R′ and R″ is independently selected from hydrogen and C 1-6 alkyl, or both R′ and R″, together with the nitrogen atom to which they are attached, may be joined to form a substituted or unsubstituted, saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NR f or S, wherein R f is hydrogen or substituted or unsubstituted alkyl.

25. The compound of claim 24 , wherein each of R′ and R″ is independently selected from hydrogen and methyl, or both R′ and R″, together with the nitrogen atom to which they are attached, are joined to form a saturated 6-membered ring selected from morpholin-4-yl and 4-methylpiperidin-1-yl.

26. A method of treating asthma in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 23 , or a pharmaceutically acceptable salt thereof.

27. A method of treating chronic obstructive pulmonary disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 23 , or a pharmaceutically acceptable salt thereof.

28. A compound of formula (IA-VIII):

or a pharmaceutically acceptable salt thereof,

wherein:

X is CR 3 ;

each occurrence of R 5 is hydrogen, C 1-6 alkyl or halogen; and

p is 0, 1, 2, 3, 4 or 5,

29. The compound of claim 28 , wherein each occurrence of R 3 is independently selected from hydrogen, hydroxy, halogen and NH 2 .

30. The compound of claim 29 , wherein each occurrence of R 3 is independently selected from hydrogen and fluoro.

31. A method of treating asthma in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 28 , or a pharmaceutically acceptable salt thereof.

32. A method of treating chronic obstructive pulmonary disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 28 , or a pharmaceutically acceptable salt thereof.

33. A compound selected from the group consisting of:

2-(6-Amino-9H-purin-9-yl) methyl)-3-(3-fluorophenyl)-5-methoxy-4H-chromen-4-one;

2-((4-Amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) methyl)-3-(3-fluorophenyl)-5-methoxy-4H-chromen-4-one;

2-((4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) methyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

2-((4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

(+)-2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

(−)-2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

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

2-(1-(6-amino-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

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

2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one;

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

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

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

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

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

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

2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) ethyl)-5-fluoro-3-(1H-pyrazol-4-yl)-4H-chromen-4-one;

2-(1-(4-amino-3-(3-fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

2-(1-(4-amino-3-(3-isopropyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

2-(1-(4-amino-3-(3-fluoro-4-(piperidin-4-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

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

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

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

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;

2-(1-(4-amino-3-(2-methyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

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

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

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

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

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

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

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

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

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

2-(1-(4-amino-3-(benzo[b]thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

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

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

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

2-(1-(4-amino-3-(6-isopropoxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

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

2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one 4-methylbenzenesulfonate;

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

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

2-(1-(4-amino-3-(3-fluoro-4-(oxetan-3-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

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

N-(4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)isobutyramide;

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

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;

2-(1-(4-amino-3-(4-(5,6-dihydro-4H-1,3-oxazin-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methylbenzenesulfonamide;

4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-N-isopropylbenzamide;

2-(1-(4-amino-3-(4-(5-(methylamino)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

N-(4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)methanesulfonamide;

4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isopropylbenzenesulfonamide;

4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclopropylbenzenesulfonamide;

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

(R)/(S)-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;

4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzenesulfonamide;

methyl 4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophene-2-carboxylate;

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

2-(1-(4-amino-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

methyl 4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluorobenzoate;

2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenyl-4H-chromen-4-one;

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

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

(R)/(S)-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;

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

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

2-(1-(4-amino-3-(imidazo[1,2-a]pyridin-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

tert-butyl (5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)furan-2-yl)methylcarbamate;

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

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

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

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

2-(1-(4-amino-3-(1,3-dimethyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

2-(1-(4-amino-3-(2,3-dimethyl-2H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

N-(4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)isobutyramide;

N-(4-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)acetamide;

2-(1-(4-(dimethylamino)-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;

5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;

N-(2-fluoro-4-(1-(1-(5-fluoro-3-(4-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)isobutyramide;

N-(2-fluoro-4-(1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)isobutyramide;

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

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

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

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

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

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

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

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

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

(S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one;

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

(S)-2-(1-(4-amino-3-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-phenyl-4H-chromen-4-one;

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

(+)-5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;

(−)-5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;

2-(1-(6-amino-2-fluoro-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

2-(1-(6-amino-2-fluoro-9H-purin-9-yl)ethyl)-5-fluoro-3-(4-fluorophenyl)-4H-chromen-4-one;

5-fluoro-3-(4-fluorophenyl)-2-(1-(6-morpholino-9H-purin-9-yl)ethyl)-4H-chromen-4-one;

5-fluoro-3-(4-fluorophenyl)-2-(1-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)ethyl)-4H-chromen-4-one;

2-(1-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

5-fluoro-3-(3-fluorophenyl)-2-(1-(3-(3-methyl-1H-indazol-6-yl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4H-chromen-4-one;

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

(+)-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;

(−)-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;

(S)/(R)-5-fluoro-2-(1-(3-(3-fluoro-4-isopropoxyphenyl)-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;

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

2-(1-(4-amino-3-(2-methylbenzo[d]oxazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

5-fluoro-3-(3-fluorophenyl)-2-(1-(6-morpholino-9H-purin-9-yl)ethyl)-4H-chromen-4-one;

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

2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-morpholino-3-phenyl-4H-chromen-4-one;

6-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)isoindolin-1-one;

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

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

5-fluoro-3-(3-fluorophenyl)-2-(1-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)ethyl)-4H-chromen-4-one;

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

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

N-(3-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)methanesulfonamide;

(5)-2-(1-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

(R)-2-(1-(6-(dimethylamino)-9H-purin-9-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

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

2-(1-(4-amino-3-(4-ethoxy-3-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;

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

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

(S)/(R)-5-fluoro-2-(1-(2-fluoro-9H-purin-6-ylamino)ethyl)-3-(3-fluoro phenyl)-4H-chromen-4-one;

(S)/(R)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-methyl-3-phenyl-4H-chromen-4-one; and

2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-o-tolyl-4H-chromen-4-one;

and pharmaceutically acceptable salts thereof.

34. A method of treating asthma in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 33 , and pharmaceutically acceptable salts thereof.

35. A method of treating chronic obstructive pulmonary disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 33 , and pharmaceutically acceptable salts thereof.

Assignments (2)

CHANGE OF ADDRESS Recorded Oct 6, 2021

From: RHIZEN PHARMACEUTICALS AG

To: RHIZEN PHARMACEUTICALS AG

Reel/Frame 057836/0286 →

CHANGE OF ADDRESS Recorded Mar 22, 2021

From: RHIZEN PHARMACEUTICALS SA

To: RHIZEN PHARMACEUTICALS SA

Reel/Frame 056775/0375 →

Priority Claims (2)

IN 1542/CHE/2011 · May 4, 2011 · national

IN 81/CHE/2012 · Jan 9, 2012 · national

Continuity (3)

Continuation 13464587 · May 4, 2012

Related Publication 20180110783A1 · Apr 26, 2018

Related Publication 20190105324A9 · Apr 11, 2019