IP Library › Granted Patent US 9,751,888
Granted Patent B2
US 9,751,888 · App. 15/026,947 · Granted Sep 5, 2017

Heterocyclic compounds and uses thereof

Inventors: Alfredo C. Castro (Woburn, MA); Catherine A. Evans (Somerville, MA); Somarajannair Janardanannair (Woburn, MA); Andre Lescarbeau (Somerville, MA); Tao Liu (Ashland, MA); Martin R. Tremblay (Melrose, MA)
Assignee: Infinity Pharmaceuticals, Inc.
C07D487/04C07D401/12C07D401/14C07D403/12C07D405/12
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Quick Facts
Patent No.
US 9,751,888
App. No.
15/026,947
Granted
Sep 5, 2017
Kind
B2
Abstract

Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.

Claims (78)

1. A compound of Formula (I′):

or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable form thereof, wherein

B is (C 1 -C 4 )alkylene-R 18 ;

R 3 is alkyl, cycloalkyl, heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo, cyano, aryl, heteroaryl, hydroxyl, or nitro;

each R 5 is independently hydrogen, alkyl or halogen;

R 8 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl or nitro;

R 9 is hydrogen, alkyl, cycloalkyl, heterocyclyl, or heteroalkyl;

W d is heterocyclyl, aryl, cycloalkyl, or heteroaryl, each of which is substituted with one or more R 10 , R 11 , R 12 , or R 13 ;

R 10 , R 11 , R 12 , and R 13 are each independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ together with the nitrogen to which they are attached form a cyclic moiety;

R 18 is aryl, heteroaryl, alkynyl, —OR 19 , —NHS(O) 2 R 20 ,—NR 20 C(O)OR 21 , —NR 20 C(O)R 21 , —NR 20 C(O)NR 21 R 22 , —NR 20 R 21 , —S(O) 2 R 20 , or —S(O) 2 NR 20 R 21 ;

R 19 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R 20 is hydrogen, amino, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R 21 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and

R 22 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or when R 21 and R 22 are attached to one nitrogen, the R 21 and R 22 together with the nitrogen to which they are attached form a 3- to 7-membered heterocyclyl ring;

wherein aryl contains 6 to 14 ring carbon atoms;

wherein heteroaryl contains 5 to 18 ring atoms and contains 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, phosphorous, and sulfur;

wherein heterocyclyl contains 3 to 18 ring atoms and contains at least one ring heteroatom selected from nitrogen, oxygen, phosphorous, and sulfur; and

wherein the compound is not one of the following compounds:

2. The compound of claim 1 , wherein the compound is a compound of Formula (I):

or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable form thereof.

3. The compound of claim 2 , wherein R 3 is halogen.

4. The compound of claim 2 , wherein W d is

5. The compound of claim 2 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

6. A compound of Formula (I):

or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable form thereof, wherein

B is hydrogen, alkyl, amino, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted with 0, 1, 2, 3, or 4 occurrence(s) of R 2 ;

each R 2 is independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, or carbonate;

R 3 is (i) —(CH 2 ) n —C(═R 23 )—R 24 , wherein R 23 is O or N—R 25 , wherein R 25 is OH; and R 24 is (C 1 -C 3 )alkyl; or (ii) —(CH 2 ) n —R 26 or —O—(CH 2 ) n —R 26 , wherein R 26 is

n is 0, 1, 2, 3, or 4;

R 8 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl or nitro;

R 9 is hydrogen, alkyl, cycloalkyl, heterocyclyl, or heteroalkyl;

W d is heterocyclyl, aryl, cycloalkyl, or heteroaryl, each of which is substituted with one or more R 10 , R 11 , R 12 , or R 13 ; and

R 10 , R 11 , R 12 , and R 13 are each independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ together with the nitrogen to which they are attached form a cyclic moiety;

wherein aryl contains 6 to 14 ring carbon atoms;

wherein heteroaryl contains 5 to 18 ring atoms and contains 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, phosphorous, and sulfur;

wherein heterocyclyl contains 3 to 18 ring atoms and contains at least one ring heteroatom selected from nitrogen, oxygen, phosphorous, and sulfur; and

wherein the compound is not one of the following compounds:

7. The compound of claim 6 , wherein W d is

8. The compound of claim 6 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

9. A compound of Formula (I):

or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable form thereof, wherein

B is hydrogen, alkyl, amino, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted with 0, 1, 2, 3, or 4 occurrence(s) of R 2 ;

each R 2 is independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, or carbonate;

R 3 is alkyl, cycloalkyl, heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, alkylsulfonyl, halo, cyano, aryl, heteroaryl, hydroxyl, or nitro;

R 8 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl or nitro;

R 9 is hydrogen, alkyl, cycloalkyl, heterocyclyl, or heteroalkyl;

W d is

wherein aryl contains 6 to 14 ring carbon atoms;

wherein heteroaryl contains 5 to 18 ring atoms and contains 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, phosphorous, and sulfur;

wherein heterocyclyl contains 3 to 18 ring atoms and contains at least one ring heteroatom selected from nitrogen, oxygen, phosphorous, and sulfur; and

wherein when W d is

then B is not a group selected from an alkyl, a unsubstituted cyclopropyl, a unsubstituted cyclohexyl, a unsubstituted phenyl, and a phenyl substituted with one or two fluoro.

10. The compound of claim 9 , wherein R 3 is halogen or alkoxy optionally substituted with one or more halo.

11. The compound of claim 9 , wherein W d is

12. The compound of claim 9 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

13. A compound of Formula (II-A):

or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable form thereof, wherein

B is alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted with 0, 1, 2, 3, or 4 occurrence(s) of R 2 , provided that when B is heteroalkyl, heterocyclyl, or heteroaryl, none of the heteroatoms contained therein can be the point of attachment to the quinazolione ring;

each R 2 is independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, or carbonate;

R 3 is hydrogen, halogen, alkyl, alkoxyl, cycloalkyl, heterocyclyl, aryl, 5-membered heteroaryl, CN, or amino;

each R 5 is independently hydrogen, alkyl or halogen, provided that when R 3 is hydrogen, at least one of R 5 is alkyl or halogen;

R 9 is alkyl, cycloalkyl, heterocyclyl, or heteroalkyl;

W d is heterocyclyl or heteroaryl, each of which is substituted with one or more R 10 , R 11 , R 12 , or R 13 , provided that when B is alkyl, W d cannot be thiophene; and

R 10 , R 11 , R 12 , and R 13 are each independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ together with the nitrogen to which they are attached form a cyclic moiety;

wherein aryl contains 6 to 14 ring carbon atoms;

wherein heteroaryl contains 5 to 18 ring atoms and contains 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, phosphorous, and sulfur;

wherein heterocyclyl contains 3 to 18 ring atoms and contains at least one ring heteroatom selected from nitrogen, oxygen, phosphorous, and sulfur; and

with the proviso that the compound is not:

14. The compound of claim 13 , wherein W d is

15. The compound of claim 13 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound of claim 2 , and a pharmaceutically acceptable excipient, diluent, or carrier.

17. A pharmaceutical composition comprising a compound of claim 6 , and a pharmaceutically acceptable excipient, diluent, or carrier.

18. A pharmaceutical composition comprising a compound of claim 9 , and a pharmaceutically acceptable excipient, diluent, or carrier.

19. A pharmaceutical composition comprising a compound of claim 13 , and a pharmaceutically acceptable excipient, diluent, or carrier.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 21, 2024
From: INFINITY PHARMACEUTICALS, INC.
To: TWELVE THERAPEUTICS, INC.
Reel/Frame 069193/0925 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 25, 2016
From: CASTRO, ALFREDO C.; EVANS, CATHERINE A.; JANARDANANNAIR, SOMARAJANNAIR; LESCARBEAU, ANDRE; LIU, TAO; TREMBLAY, MARTIN R.
To: INFINITY PHARMACEUTICALS, INC.
Reel/Frame 039825/0304 →
Continuity (2)
Provisional Application 61887243 · Oct 4, 2013
Related Publication 20160222016A1 · Aug 4, 2016