# US 9,751,888 B2 · Heterocyclic compounds and uses thereof

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- Number: US 9,751,888 B2
- Document ID: US9751888B2
- Status: Granted
- Kind: B2
- Application number: 15/026,947
- Filed: 2014-10-03
- Published: 2016-08-04
- Granted: 2017-09-05
- Earliest claimed: 2013-10-04
- Assignees: Infinity Pharmaceuticals, Inc.
- Applicants: Infinity Pharmaceuticals, Inc.
- Inventors: Alfredo C. Castro; Catherine A. Evans; Somarajannair Janardanannair; Andre Lescarbeau; Tao Liu; Martin R. Tremblay
- Web page: https://patentgrep.com/patent/US9751888B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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

### Claim 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 (C1-C4)alkylene-R18;
R3 is alkyl, cycloalkyl, heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo, cyano, aryl, heteroaryl, hydroxyl, or nitro;
each R5 is independently hydrogen, alkyl or halogen;
R8 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl or nitro;
R9 is hydrogen, alkyl, cycloalkyl, heterocyclyl, or heteroalkyl;
Wd is heterocyclyl, aryl, cycloalkyl, or heteroaryl, each of which is substituted with one or more R10, R11, R12, or R13;
R10, R11, R12, and R13 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;
R18 is aryl, heteroaryl, alkynyl, —OR19, —NHS(O)2R20,—NR20C(O)OR21, —NR20C(O)R21, —NR20C(O)NR21R22, —NR20R21, —S(O)2R20, or —S(O)2NR20R21;
R19 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R20 is hydrogen, amino, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R21 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and
R22 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or when R21 and R22 are attached to one nitrogen, the R21 and R22 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:

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 2)

The compound of claim 2, wherein R3 is halogen.

### Claim 4 (depends on 2)

The compound of claim 2, wherein Wd is

### Claim 5 (depends on 2)

The compound of claim 2, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 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 R2;
each R2 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;
R3 is (i) —(CH2)n—C(═R23)—R24, wherein R23 is O or N—R25, wherein R25 is OH; and R24 is (C1-C3)alkyl; or (ii) —(CH2)n—R26 or —O—(CH2)n—R26, wherein R26 is
n is 0, 1, 2, 3, or 4;
R8 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl or nitro;
R9 is hydrogen, alkyl, cycloalkyl, heterocyclyl, or heteroalkyl;
Wd is heterocyclyl, aryl, cycloalkyl, or heteroaryl, each of which is substituted with one or more R10, R11, R12, or R13; and
R10, R11, R12, and R13 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:

### Claim 7 (depends on 6)

The compound of claim 6, wherein Wd is

### Claim 8 (depends on 6)

The compound of claim 6, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 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 R2;
each R2 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;
R3 is alkyl, cycloalkyl, heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, alkylsulfonyl, halo, cyano, aryl, heteroaryl, hydroxyl, or nitro;
R8 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl or nitro;
R9 is hydrogen, alkyl, cycloalkyl, heterocyclyl, or heteroalkyl;
Wd 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 Wd 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.

### Claim 10 (depends on 9)

The compound of claim 9, wherein R3 is halogen or alkoxy optionally substituted with one or more halo.

### Claim 11 (depends on 9)

The compound of claim 9, wherein Wd is

### Claim 12 (depends on 9)

The compound of claim 9, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 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 R2, 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 R2 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;
R3 is hydrogen, halogen, alkyl, alkoxyl, cycloalkyl, heterocyclyl, aryl, 5-membered heteroaryl, CN, or amino;
each R5 is independently hydrogen, alkyl or halogen, provided that when R3 is hydrogen, at least one of R5 is alkyl or halogen;
R9 is alkyl, cycloalkyl, heterocyclyl, or heteroalkyl;
Wd is heterocyclyl or heteroaryl, each of which is substituted with one or more R10, R11, R12, or R13, provided that when B is alkyl, Wd cannot be thiophene; and
R10, R11, R12, and R13 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:

### Claim 14 (depends on 13)

The compound of claim 13, wherein Wd is

### Claim 15 (depends on 13)

The compound of claim 13, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 2)

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

### Claim 17 (depends on 6)

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

### Claim 18 (depends on 9)

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

### Claim 19 (depends on 13)

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