IP Library › Granted Patent US 10,596,184

Granted Patent B2

US 10,596,184 · App. 16/022,031 · Granted Mar 24, 2020

Aza-heteroaryl compounds as PI3K-gamma inhibitors

Inventors: Ge Zou (Greenville, DE); Andrew P. Combs (Kennett Square, PA)

Assignee: Incyte Corporation

A61K31/675 A61K31/423 A61K31/437 A61K31/4439 A61K31/4545 A61K31/4709 A61K31/495 A61K31/506 A61K31/5377 C07D401/14 C07D413/04 C07D413/14 C07D417/14 C07D471/04

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 10,596,184
App. No.: 16/022,031
Granted: Mar 24, 2020
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention provides aza-heteroaryl derivatives of Formula I: and pharmaceutically acceptable salts thereof, wherein X, Y, Z, A, W, R 4 , R 5 , and R 6 are defined herein, that inhibit the activity of phosphoinositide 3-kinases-gamma (PI3Kγ) and are useful in the treatment of diseases related to the activity of PI3Kγ including, for example, autoimmune diseases, cancer, cardiovascular diseases, and neurodegenerative diseases.

Claims (108)

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is N or CR 1 ;

Y is N or CR 2 ;

Z is N or CR 3 ;

R 1 , R 2 , and R 3 are each independently selected from H, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, Cy 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2 or 3 independently selected R 10 groups; or

alternatively, R 1 and R 2 , taken together with the carbon atoms to which they are attached, form a phenyl, C 3-6 cycloalkyl, or a 5-6-membered heteroaryl ring, which is optionally substituted by 1, 2, or 3 independently selected R 11 groups; or

alternatively, R 2 and R 3 , taken together with the carbon atoms to which they are attached, form a phenyl or a 5-6-membered heteroaryl ring, which is optionally substituted by 1, 2, or 3 independently selected R 11 groups;

A is CR 7 ═CR 8 ;

R 4 , R 5 , and R 6 are each independently selected from H, OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

R 7 and R 8 are independently selected from H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, OH, C 1-6 alkoxy, and C 1-6 haloalkoxy;

W is halo or Cy;

Cy is a phenyl ring, a piperazine ring, a pyridine ring, or a pyrimidine ring, each of which is optionally substituted by 1 or 2 substituents independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, Cy 1 , —(C 1-2 alkylene)-Cy 1 , CN, OR a , P(O)R a R b , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O) 2 R b , and S(O) 2 NR c R d ;

each R 10 is independently selected from halo, CN, NO 2 , Cy 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ;

each R 11 is independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R c2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2 or 3 independently selected R 12 groups;

each R 12 is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

each R a , R c , and R d is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, Cy 1 , and —(C 1-4 alkylene)-Cy 1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 independently selected R g groups;

each R b is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, Cy 1 , and —(C 1-4 alkylene)-Cy 1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 independently selected R g groups; or

alternatively, any R c and R d attached to the same N atom, together with the N atom to which they are attached, form a 4-6 membered heterocycloalkyl group or a 5-6 membered heteroaryl group, each optionally substituted with 1, 2, or 3 independently selected R g groups;

each R a1 , R c1 , and R d1 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, and Cy 3 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2 or 3 independently selected R 12 groups;

each R b1 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, and Cy 3 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2 or 3 independently selected R 12 groups; or

alternatively, any R c1 and R d1 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 independently selected R 12 groups;

each R a2 , R c2 , and R d2 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-4 haloalkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2 or 3 independently selected R 12 groups;

each R b2 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-4 haloalkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2 or 3 independently selected R 12 groups; or

alternatively, any R c2 and R d2 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 independently selected R 12 groups;

each Cy 1 is independently selected from phenyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl, and 4-6 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R g groups;

each Cy 2 is independently selected from phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl; wherein said phenyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl, and 4-6 membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 independently selected R 11 groups;

each Cy 3 is independently selected from phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl; wherein said phenyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl, and 4-6 membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 independently selected C 1-4 alkylene-R 12 or R 12 groups; and

each R g is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

X is N or CR 1 ;

Y is N or CR 2 ;

Z is N or CR 3 ;

alternatively, R 1 and R 2 , taken together with the carbon atoms to which they are attached, form a phenyl or a 5-6-membered heteroaryl ring, which is optionally substituted by 1, 2, or 3 independently selected R 11 groups; or

A is CR 7 ═CR 8 ;

R 7 and R 8 are independently selected from H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, OH, C 1-6 alkoxy, and C 1-6 haloalkoxy;

W is halo or Cy;

each R 11 is independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2 or 3 independently selected R 12 groups;

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H, methyl, ethyl, cyclopropyl, phenyl, or a tetrahydrofuran ring.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H, methyl, propyl, or phenyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 , together with the carbon atoms to which they are attached, form a phenyl ring or cyclohexene group, which is optionally substituted by 1, 2, or 3 independently selected R 11 groups.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 , together with the carbon atoms to which they are attached, form a phenyl ring, which is optionally substituted by 1, 2, or 3 R 11 groups independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 , and R 6 are each H.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is Cy.

10. The compound of claim 1 , wherein Cy is a pyridine ring, which is optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, OR a , NR c R d , NR c C(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O) 2 R b , and S(O) 2 NR c R d .

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, where A is CH═CH.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

A is CH═CH;

R 1 and R 2 are each independently selected from H, OR a1 , NO 2 , CN, halo, C 1-6 alkyl, C 1-6 haloalkyl, and Cy 2 ;

R 3 is H, methyl, or ethyl;

or R 1 and R 2 , together with the carbon atoms to which they are attached, form a phenyl ring, which is optionally substituted by 1, 2, or 3 independently selected R 11 groups;

R 4 , R 5 , and R 6 are each H;

W is Br or Cy;

each Cy 2 is independently selected from phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl;

each R 11 is independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl;

each R a1 is independently selected from H, C 1-6 alkyl, and C 14 haloalkyl;

or any R c and R d together with the N atom to which they are attached form a 4-6 membered heterocycloalkyl group or a 5-6 membered heteroaryl group, each optionally substituted with 1, 2, or 3 independently selected R g groups;

each R g is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

A is CH═CH;

R 1 is H, methyl, ethyl, cyclopropyl, phenyl, or a tetrahydrofuran ring;

R 2 is H, methyl, propyl, or phenyl; or

R 1 and R 2 , together with the carbon atoms to which they are attached, form a phenyl ring or cyclohexene ring, which is optionally substituted by 1 or 2 independently selected R 11 groups;

R 3 is H;

R 4 , R 5 , and R 6 are each H;

W is Br or Cy;

each R 11 is independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl;

each R a is independently selected from H and C 1-6 alkyl; wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 independently selected R g groups;

each R c and R d is independently selected from H, C 1-6 alkyl, and Cy 1 ; wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 independently selected R g groups;

each R b is independently selected from C 1-6 alkyl and Cy 1 ; wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 independently selected R g groups;

each Cy 1 is independently selected from phenyl and 6-membered heterocycloalkyl, each optionally substituted by 1 or 2 independently selected R g groups; and

each R g is, independently, OH, C 1-6 alkyl, C 1-4 haloalkyl, halo, or carboxy.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having Formula IV:

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , wherein the compound is

2-(1H-benzo[d]imidazol-2-yl)-6-(5-methoxypyridin-3-yl)quinoline;

or a pharmaceutically acceptable salt of any of the aforementioned.

17. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. A method of inhibiting an activity of PI3Kγ kinase, comprising contacting the kinase with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

19. A compound which is 2-(1H-benzo[d]imidazol-2-yl)-6-bromobenzo[d]oxazole, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a compound of claim 19 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. A method of inhibiting an activity of PI3Kγ kinase, comprising contacting the kinase with a compound of claim 19 , or a pharmaceutically acceptable salt thereof.

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 10, 2021

From: INCYTE CORPORATION

To: INCYTE CORPORATION; INCYTE HOLDINGS CORPORATION

Reel/Frame 058815/0857 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 22, 2019

From: ZOU, GE; COMBS, ANDREW P.; BUESKING, ANDREW W.

To: INCYTE CORPORATION

Reel/Frame 048674/0123 →