Inhibitors of PI3K-delta and methods of their use and manufacture

Patent metadata

Field	Value
Publication number	US-9346807-B2
Application number	US-201113822840-A
Country	US
Kind code	B2
Filing date	Sep 14, 2011
Priority date	Sep 14, 2010
Publication date	May 24, 2016
Grant date	May 24, 2016

Abstract

The invention is directed to Compounds of Formula I: and pharmaceutically acceptable salts or solvates thereof, as well as methods of making and using the compounds.

First claim

The invention claimed is:

1. A compound of Formula I

or a stereoisomer or mixture of stereoisomers thereof, optionally as a pharmaceutically acceptable salt thereof, wherein:
R 1 is alkyl, haloalkyl, or optionally substituted cycloalkyl;

 is a 4, 5, 6, or 7-membered ring, wherein:
R 2 at each occurrence is independently halo, hydroxy, alkyl, alkoxy, hydroxyalkyl, haloalkoxy, or —C(O)O-alkyl, or two R 2 groups may be joined together with the carbons to which they are attached to form a bridged or fused bicyclic ring;
n is 0, 1, 2, or 3;
X is C or N; wherein:
when X is N:
R 3 is absent;
R 3′ is aryl or heteroaryl optionally substituted with one or two groups independently selected from heteroarylalkyloxy; alkyl substituted with arylsulfonylamino; alkyl substituted with cycloalkylcarbonylamino; or
R 3′ is —SO 2 —R a , wherein R a is optionally substituted alkyl, optionally substituted phenyl, optionally substituted phenylalkyl, or optionally substituted heteroaryl;

when X is C:
R 3 is cyano, aminoalkyl, alkoxycarbonyl, or hydroxyl, and R 3′ is a optionally substituted phenyl; or
R 3 is hydrogen and R 3′ is phenyl, alkyl substituted with 1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, optionally substituted indolyl, optionally substituted 1H-benzo[d][1,2,3]triazolyl, optionally substituted oxoindolinyl, optionally substituted benzoimidazolyl, optionally substituted pyridinyl,2-oxo-3,4-dihydroquinazolinyl, —C(O)NR b R c , wherein R b is hydrogen or alkyl; and R c is optionally substituted heteroarylalkyl; or
R 3 is hydrogen and R 3′ is a group of formula (a), (b), (c), (d), (e), or (f):

wherein:
Z 1 is O, NH, or N optionally substituted with aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl;
Z 2 is CH or N; and
A is N C—H, or C—R d ; or

R 3 and R 3′ are taken together with the carbon to which they are attached to form an optionally substituted 5 or 6 membered ring (g), (h), (i), (j), (k), or (1):

wherein: Z 3 is CH 2 or NH; Z 4 is NR f or CR f , and R f is optionally substituted phenyl; and

each R d , when present, is independently halo, alkyl, optionally substituted alkoxy, or optionally substituted heterocycloalkyl, and R e is amino or haloalkyl;

Y is absent or is alkyl, —(C═O)—, —NR x —(C═O)—, or —(C═O)NR x —, —O—(C═O)—, —(C═O)—, —NR x —(C═O)O—, or —O(C═O)NR x —, wherein R x is hydrogen or optionally substituted alkyl;
R 4 is hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl; and
when Y is —N(R x )—(C═O)—, or —(C═O)—N(R x )—, R x and R 4 can be joined together along with the atoms to which they are attached to form a 4, 5, or 6 membered ring, optionally containing 1or 2 additional heteroatoms selected from N, S, and O.

2. The compound of claim 1 , which is a compound of Formula Ia, wherein

is a 5, 6, or 7-membered ring, a compound of Formula Ib, a compound of Formula Ic, or a compound of Formula Id:

3. The compound of claim 2 , wherein R 1 is alkyl or cycloalkyl.

4. The compound of claim 3 , wherein R 1 is methyl, ethyl, or cyclopropyl.

5. The compound of claim 2 , wherein n is 0 or 1.

6. The compound of claim 2 , wherein R 2 is hydroxy, carboxy, methyl, or hydroxymethyl.

7. The compound of Formula Ic of claim 2 , wherein the compound of Formula Ic is a compound of Formula Ic-1or Ic-2 wherein R is heteroarylalkyloxy, alkyl substituted with arylsulfonyalmino, or alkyl substituted with cycloalkylcarbonylamino:

8. The compound of Formula Id of claim 2 , wherein R 3 is hydrogen, cyano, hydroxy, aminomethyl, optionally substituted alkoxy, or carboxymethyl, and R 3′ is optionally substituted phenyl, optionally substituted indolyl, optionally substituted 1H-benzo[d][1,2,3]triazolyl, optionally substituted oxoindolinyl, or optionally substituted benzoimidazolyl.

9. The compound of Formula Id of claim 2 , which is a compound of Formula Id-1, Id-2, Id-3, or Id-4:

10. The compound of Formula Id-1 or Id-2 of claim 9 , which is a compound of Formula Id-1(a), Id-1(b), or Id-2(a):

11. The compound of Formula Id-3 or Id-4 of claim 9 , which is a compound of Formula Id-3(a), Id-3(b), or Id-4(a):

12. The compound of claim 1 wherein:
R 1 is alkyl, haloalkyl, or optionally substituted cycloalkyl;

 is a 4, 5, 6, or 7-membered ring, wherein:
R 2 at each occurrence is independently halo, hydroxy, alkyl, alkoxy, hydroxyalkyl, haloalkoxy, or —C(O)O-alkyl;
n is 0, 1, or 2;
X is C or N; wherein:
when X is N:
R 3 is absent and R 3′ is phenyl optionally substituted with one or two groups independently selected from heteroarylalkyloxy; alkyl substituted with arylsulfonyalmino; alkyl substituted with cycloalkylcarbonylamino; or
R 3 is —SO 2 —R a , wherein R a is optionally substituted alkyl, optionally substituted phenyl, optionally substituted phenylalkyl, or optionally substituted heteroaryl;
when X is C:
R 3 is cyano, aminoalkyl, alkoxycarbonyl, or hydroxy and R 3′ is a optionally substituted phenyl; or
R 3 is hydrogen and R 3′ is phenyl, alkyl substituted with 1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 1H-indolyl, optionally substituted, 2-oxo-3,4-dihydroquinazolinyl, or —C(O)NR b R c , wherein R b is hydrogen or alkyl; and R c is optionally substituted heteroarylalkyl; or
R 3 is a group of formula (a), (b), (c), (d), (e), or (f):

wherein Z 1 is O or NH or N optionally substituted with aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl;
Z 2 is CH or N, and A is N or C; and
each R d , when present, is independently halo, alkyl, optionally substituted alkoxy, or optionally substituted heterocycloalkyl and R e is amino or haloalkyl; or
R 3 and R 3′ are taken together with the carbon to which they are attached to form an optionally substituted 5 or 6 membered ring (g), (h), (j), (k), or (l):

wherein: Z 3 is CH 2 or

Assignees

• Kearney Patrick
• Exelixis Inc

Inventors

• Kearney Patrick

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07D473/34 Primary

  attached in position 6, e.g. adenine · CPC title

• C07D473/04

  two oxygen atoms · CPC title