IP Library › Granted Patent US 9,499,551
Granted Patent B2
US 9,499,551 · App. 14/604,016 · Granted Nov 22, 2016

Substituted pyrrolo[2,3-b]pyridines for treating cancer or inflammatory diseases

Inventors: Eric Jon Jacobsen (Chesterfield, MO); James Robert Blinn (O'Fallon, MO); John Robert Springer (Wentzville, MO); Susan L. Hockerman (Kirkwood, MO)
Assignee: Confluence Life Sciences, Inc.
C07D487/04C07D471/04
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Quick Facts
Patent No.
US 9,499,551
App. No.
14/604,016
Granted
Nov 22, 2016
Kind
B2
Abstract

Disclosed herein are substituted pyrrolopyridine and pyrrolopyrazine compounds and compositions useful in the treatment of TAK mediated diseases, such as cancer, having the structure of Formula (I): wherein R 1 , R 2 , R 3 , and R 4 are as defined in the detailed description. Methods of modulation of TAK activity in a human or animal subject are also provided, providing therapeutic benefit to subjects with disease conditions, especially cancer.

Claims (85)

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is chosen from C 2-6 alkyl, OC 3-7 cycloalkyl, C 1-4 alkylamino, N(R 4 ) 2 , NH(CH 2 ) n C 3-7 cycloalkyl, CN, C(O)N(R 4 ) 2 , C(O)C 1-4 alkyl, C(O)aryl, C(O)heteroaryl, CH 2 aryl, CHFaryl, CH 2 heteroaryl, CHFheteroaryl, heterocyclyl, aryl and heteroaryl; wherein each alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group of R 1 may be optionally substituted with one or more R 5 substituents;

R 2 is chosen from hydrogen, fluoro, C 1-6 alkyl, C(O)R 4 , CN, C(O)NH 2 , and C(O)NHCH 3 ;

R 3 is chosen from C(O)R 4 , CN, C(O)NH 2 , C(O)NHCH 3 , C(O)alkyl, C(O)C 1-6 alkylN(R 4 ) 2 , and C(O)C 1-6 alkylOR 4 ; or when R 2 is C(O)R 4 , C(O)NH 2 , C(O)NHCH 3 , or CN, then R 3 is chosen from hydrogen, fluoro, and CH 3 ;

each R 4 is independently chosen from hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;

wherein each R 4 together with the atoms to which they are attached optionally form a heterocycloalkyl or heteroaryl ring, which may be optionally substituted with one or more R 5 substituents;

each R 5 is independently chosen from C 1-6 alkyl, (CH 2 ) n C 3-7 cycloalkyl, OH, OC 1-6 alkyl, OCF 3 , O-aryl, O-heteroaryl, CH 2 aryl, CH 2 heteroaryl, CH(OH)aryl, CH(OH)heteroaryl, O(CH 2 ) n C 3-6 cycloalkyl, C 1-4 alkylamino, NHC 3-7 cycloalkyl, N(R 4 ) 2 , NHC(O)alkyl, NHC(O)aryl, NHC(O)heteroaryl, CN, C(O)N(R 4 ) 2 , C(O)OC 1-6 alkyl, C(O)O-aryl, C(O)O-heteroaryl, C(O)C 1-6 alkyl, C(O)CF 3 , C(O)C 3-7 cycloalkyl, C(O)aryl, C(O)heteroaryl, C(O)heterocyclyl, trifluoromethyl, halo, S(O) 2 CH 3 , S(O)CH 3 , SCH 3 , aryl, and heteroaryl; wherein each alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl of R 5 may be optionally substituted with one or more R 6 ;

each R 6 is independently chosen from halo, C 1-6 alkyl, C 3-6 cycloalkyl, CF 3 , OH, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 2 F, O(CH 2 ) n CF 3 , and CN;

R 7 is chosen from hydrogen, C 1-6 alkyl, OC 1-6 alkyl, OC 3-7 cycloalkyl, C 1-4 alkylamino, NHC 1-6 alkyl, NHC 3-7 alkyl, CN, trifluoromethyl, halo, aryl and heteroaryl; wherein alkyl, aryl or heteroaryl groups of R 7 may be optionally substituted with one or more R 5 substituents;

X is CR 7 ;

Y is chosen from a bond, CH 2 , CHF, C(O), and NHC(O); and

n is chosen from 0, 1, and 2.

2. The compound of claim 1 , wherein the compound has formula (II)

wherein:

R 1 is chosen from C 2-6 alkyl, OC 3-7 cycloalkyl, C 1-4 alkylamino, N(R 4 ) 2 , CN, C(O)N(R 4 ) 2 , C(O)C 1-4 alkyl, C(O)aryl, C(O)heteroaryl, CH 2 aryl, CHFaryl, CH 2 heteroaryl, CHFheteroaryl, aryl and heteroaryl;

wherein each alkyl, aryl or heteroaryl group of R 1 may be optionally substituted with one or more R 5 substituents;

R 2 is chosen from hydrogen, fluoro, C 1-6 alkyl, C(O)R 4 , CN, C(O)NH 2 , and C(O)NHCH 3 ;

R 3 is chosen from C(O)R 4 , CN, C(O)NH 2 , C(O)NHCH 3 , C(O)alkyl, C(O)C 1-6 alkylN(R 4 ) 2 , and C(O)C 1-6 alkylOR 4 ; or when R 2 is C(O)R 4 , C(O)NH 2 , C(O)NHCH 3 , or CN, then R 3 is chosen from hydrogen, fluoro and CH 3 ;

each R 4 is independently chosen from hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;

wherein each R 4 together with the atoms to which they are attached optionally form a heterocycloalkyl or heteroaryl ring, which may be optionally substituted with one or more R 5 substituents;

each R 5 is independently chosen from C 1-4 alkyl, OH, OC 1-6 alkyl, CH 2 aryl, CH 2 heteroaryl, O(CH 2 ) n C 3-6 cycloalkyl, C 1-4 alkylamino, NHC 3-7 cycloalkyl, N(R 4 ) 2 , NHC(O)alkyl, NHC(O)aryl, NHC(O)heteroaryl, CN, C(O)N(R 4 ) 2 , C(O)OC 1-6 alkyl, C(O)C 1-6 alkyl, C(O)C 3-7 cycloalkyl, C(O)aryl, C(O)heteroaryl, C(O)heterocyclyl, trifluoromethyl, halo, S(O) 2 CH 3 , S(O)CH 3 , SCH 3 , aryl, and heteroaryl; wherein each alkyl, aryl, heteroaryl or heterocyclyl of R 5 may be optionally substituted with one or more R 6 ;

each R 6 is independently chosen from halo, C 1-4 alkyl, C 3-6 cycloalkyl, CF 3 , OH, OCH 3 and CN;

R 7 is chosen from hydrogen, C 1-6 alkyl, OC 1-6 alkyl, OC 3-7 cycloalkyl, C 1-4 alkylamino, NHC 1-6 alkyl, NHC 3-7 alkyl, CN, trifluoromethyl, halo, aryl and heteroaryl; wherein alkyl, aryl or heteroaryl groups of R 7 may be optionally substituted with one or more R 5 substituents;

Y is chosen from a bond, CH 2 , CHF, C(O), and NHC(O);

and n is chosen from 0, 1, and 2.

3. The compound of claim 2 , wherein the compound has formula (III):

wherein:

R 1 is chosen from C 2-6 alkyl, OC 3-7 cycloalkyl, C 1-4 alkylamino, N(R 4 ) 2 , CN, C(O)N(R 4 ) 2 , C(O)C 1-4 alkyl, C(O)aryl, C(O)heteroaryl, CH 2 aryl, CHFaryl, CH 2 heteroaryl, CHFheteroaryl, aryl and heteroaryl;

wherein each alkyl, aryl or heteroaryl group of R 1 may be optionally substituted with one or more R 5 substituents;

R 2 is chosen from hydrogen, fluoro, C 1-6 alkyl, C(O)R 4 , CN, C(O)NH 2 , and C(O)NHCH 3 ;

R 3 is chosen from C(O)R 4 , CN, C(O)NH 2 , C(O)NHCH 3 , C(O)alkyl, C(O) C1-6 alkylN(R 4 ) 2 , and C(O)C 1-6 alkylOR 4 ; or when R 2 is C(O)R 4 , C(O)NH 2 , C(O)NHCH 3 , or CN, then R 3 is chosen from hydrogen, fluoro and CH 3 ;

each R 4 is independently chosen from hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;

wherein each R 4 together with the atoms to which they are attached optionally form a heterocycloalkyl or heteroaryl ring, which may be optionally substituted with one or more R 5 substituents;

each R 5 is independently chosen from C 1-4 alkyl, OH, OC 1-6 alkyl, CH 2 aryl, CH 2 heteroaryl, O(CH 2 ) n C 3-6 cycloalkyl, C 1-4 alkylamino, NHC 3-7 cycloalkyl, N(R 4 ) 2 , NHC(O)alkyl, NHC(O)aryl, NHC(O)heteroaryl, CN, C(O)N(R 4 ) 2 , C(O)OC 1-6 alkyl, C(O)C 1-6 alkyl, C(O)C 3-7 cycloalkyl, C(O)aryl, C(O)heteroaryl, C(O)heterocyclyl, trifluoromethyl, halo, S(O) 2 CH 3 , S(O)CH 3 , SCH 3 , aryl, and heteroaryl; wherein each alkyl, aryl, heteroaryl or heterocyclyl of R 5 may be optionally substituted with one or more R 6 ;

each R 6 is independently chosen from halo, C 1-4 alkyl, C 3-6 cycloalkyl, CF 3 , OH, OCH 3 , and CN;

R 7 is chosen from hydrogen, C 1-6 alkyl, OC 1-6 alkyl, OC 3-7 cycloalkyl, C 1-4 alkylamino, NHC 1-6 alkyl, NHC 3-7 alkyl, CN, trifluoromethyl, halo, aryl and heteroaryl, wherein alkyl, aryl or heteroaryl groups of R 7 may be optionally substituted with one or more R 5 substituents;

wherein alkyl, aryl or heteroaryl groups of R 7 may be optionally substituted with one or more R 5 substituents; and

n is chosen from 0, 1, and 2.

4. The compound of claim 3 , wherein:

R 1 is chosen from C 2-6 alkyl, OC 3-7 cycloalkyl, C 1-4 alkylamino, NH 2 , NHC 1-6 alkyl, N(C 1-4 alkyl) 2 , CN, aryl and heteroaryl; wherein each alkyl, aryl or heteroaryl group of R 1 may be optionally substituted with one or more R 5 substituents;

R 2 is chosen from hydrogen, fluoro, alkyl, C(O)R 4 , CN, C(O)NH 2 , and C(O)NHCH 3 ;

R 3 is chosen from C(O)R 4 , CN, C(O)NH 2 , C(O)NHCH 3 , C(O)alkyl, C(O)C 1-6 alkylN(R 4 ) 2 , C(O)C 1-6 alkylOR 4 ; or when R 2 is C(O)R 4 , C(O)NH 2 , C(O)NHCH 3 , or CN, R 3 is chosen from hydrogen, fluoro and CH 3 ;

each R 4 is independently chosen from hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;

wherein each R 4 together with the atoms to which they are attached optionally form a heterocycloalkyl or heteroaryl ring, which may be optionally substituted with one or more R 5 substituents;

each R 5 is independently chosen from C 1-4 alkyl, OH, OC 1-6 alkyl, CH 2 aryl, CH 2 heteroaryl, O(CH 2 ) n C 3-6 cycloalkyl, C 1-4 alkylamino, NHC 3-7 cycloalkyl, N(R 4 ) 2 , NHC(O)alkyl, NHC(O)aryl, NHC(O)heteroaryl, CN, C(O)N(R 4 ) 2 , C(O)OC 1-6 alkyl, C(O)C 1-6 alkyl, C(O)C 3-7 cycloalkyl, C(O)aryl, C(O)heteroaryl, C(O)heterocyclyl, trifluoromethyl, halo, CN, S(O) 2 CH 3 , S(O)CH 3 , SCH 3 , aryl, and heteroaryl; wherein each alkyl, aryl, heteroaryl or heterocyclyl of R 5 may be optionally substituted with one or more R 6 ;

each R 6 is independently chosen from halo, C 1-4 alkyl, C 3-6 cycloalkyl, CF 3 , OH, OCH 3 and CN;

R 7 is chosen from hydrogen, C 1-6 alkyl, OC 1-6 alkyl, OC 3-7 cycloalkyl, C 1-4 alkylamino, NHC 1-6 alkyl, NHC 3-7 alkyl, CN, trifluoromethyl, halo, aryl and heteroaryl, wherein alkyl, aryl or heteroaryl groups of R 7 may be optionally substituted with one or more R 5 substituents; and

n is chosen from 0, 1, and 2.

5. The compound of claim 4 , wherein:

R 1 is chosen from OC 3-7 cycloalkyl, NHC 1-6 alkyl, CN, aryl and heteroaryl; wherein each alkyl, aryl or heteroaryl group of R 1 may be optionally substituted with one or more R 5 substituents;

R 2 is chosen from hydrogen, fluoro, alkyl, C(O)R 4 , CN, C(O)NH 2 , and C(O)NHCH 3 ;

R 3 is chosen from C(O)R 4 , CN, C(O)NH 2 , C(O)alkyl, C(O)C 1-6 alkylOR 4 ; or when R 2 is C(O)R 4 , C(O)NH 2 , C(O)NHCH 3 , or CN, R 3 is chosen from hydrogen, fluoro and CH 3 ;

each R 4 is independently chosen from hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;

wherein each R 4 together with the atoms to which they are attached optionally form a heterocycloalkyl or heteroaryl ring, which may be optionally substituted with one or more R 5 substituents;

each R 5 is independently chosen from C 1-4 alkyl, OH, OC 1-6 alkyl, O(CH 2 ) n C 3-6 cycloalkyl, C 1-4 alkylamino, NHC 1-6 alkyl, NHC 3-7 cycloalkyl N(C 1-4 alkyl) 2 , NHC(O)alkyl, CN, trifluoromethyl, halo, aryl, and heteroaryl, wherein alkyl, aryl or heteroaryl groups of R 5 may be optionally substituted with R 6 ;

each R 6 is independently chosen from halo, CF 3 , OCH 3 , and CN;

R 7 is chosen from hydrogen, OC 1-6 alkyl, OC 3-7 cycloalkyl, NHC 1-6 alkyl, NHC 3-7 alkyl CN, trifluoromethyl, halo, aryl and heteroaryl wherein alkyl, aryl or heteroaryl groups of R 7 may be optionally substituted with one or more R 5 substituents; and

n is chosen from 0 and 1.

6. The compound of claim 1 , wherein:

R 1 is chosen from OC 3-7 cycloalkyl, C 1-4 alkylamino, N(R 4 ) 2 , NH(CH 2 ) n C 3-7 cycloalkyl, C(O)N(R 4 ) 2 , C(O)aryl, C(O)heteroaryl, CH 2 aryl, CH 2 heteroaryl, heterocyclyl, aryl and heteroaryl; wherein each alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group of R 1 may be optionally substituted with one or more R 5 substituents;

R 2 is chosen from hydrogen, fluoro, C(O)R 4 , CN, C(O)NH 2 , and C(O)NHCH 3 ;

R 3 is chosen from C(O)R 4 , CN, C(O)NH 2 , C(O)NHCH 3 , and C(O)alkyl; or when R 2 is C(O)R 4 , C(O)NH 2 , C(O)NHCH 3 , or CN, then R 3 is chosen from hydrogen and CH 3 ;

each R 4 is independently chosen from hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;

wherein each R 4 together with the atoms to which they are attached optionally form a heterocycloalkyl or heteroaryl ring, which may be optionally substituted with one or more R 5 substituents;

each R 5 is independently chosen from C 1-6 alkyl, (CH 2 ) n C 3-7 cycloalkyl, OH, OC 1-6 alkyl, O-aryl, O(CH 2 ) n C 3-6 cycloalkyl, C 1-4 alkylamino, NHC 3-7 cycloalkyl, N(R 4 ) 2 , NHC(O)alkyl, CN, C(O)N(R 4 ) 2 , C(O)C 1-4 alkyl, C(O)OC 1-6 alkyl, C(O)O-aryl, C(O)O-heteroaryl, C(O)CF 3 , C(O)aryl, C(O)heteroaryl, C(O)heterocyclyl, trifluoromethyl, halo, S(O) 2 CH 3 , aryl, and heteroaryl; wherein each alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl of R 5 may be optionally substituted with one or more R 6 ;

each R 6 is independently chosen from halo, C 1-6 alkyl, C 3-6 cycloalkyl, CF 3 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 2 F, O(CH 2 ) n CF 3 , and CN;

R 7 is chosen from hydrogen, C 1-6 alkyl, and CN; wherein alkyl, aryl or heteroaryl groups of R 7 may be optionally substituted with one or more R 5 substituents;

X is CR 7 ;

Y is chosen from a bond, CH 2 , C(O), and NHC(O); and

n is chosen from 0, 1, and 2.

7. The compound of claim 6 , wherein:

R 1 is chosen from N(R 4 ) 2 , C(O)N(R 4 ) 2 , C(O)aryl, C(O)heteroaryl, heterocycle heterocyclyl, aryl and heteroaryl; wherein each alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group of R 1 may be optionally substituted with one or more R 5 substituents;

R 2 is chosen from hydrogen, C(O)R 4 , CN, C(O)NH 2 , and C(O)NHCH 3 ;

R 3 is chosen from C(O)R 4 , CN, C(O)NH 2 , C(O)NHCH 3 , and C(O)alkyl; or when R 2 is C(O)R 4 , C(O)NH 2 , C(O)NHCH 3 , or CN, then R 3 is chosen from hydrogen and CH 3 ;

each R 4 is independently chosen from hydrogen, and C 1-6 alkyl; wherein each R 4 together with the atoms to which they are attached optionally form a heterocycloalkyl or heteroaryl ring, which may be optionally substituted with one or more R 5 substituents;

each R 5 is independently chosen from C 1-6 alkyl, (CH 2 ) n C 3-7 cycloalkyl, OH, OC 1-6 alkyl, O(CH 2 ) n C 3-6 cycloalkyl, C 1-4 alkylamino, NHC 3-7 cycloalkyl, N(R 4 ) 2 , NHC(O)alkyl, CN, C(O)N(R 4 ) 2 , C(O)C 1-4 alkyl, C(O)OC 1-6 alkyl, C(O)O-aryl, C(O)O-heteroaryl, C(O)CF 3 , C(O)aryl, C(O)heteroaryl, trifluoromethyl, halo, S(O) 2 CH 3 , aryl, and heteroaryl; wherein each alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl of R 5 may be optionally substituted with one or more R 6 ;

each R 6 is independently chosen from halo, C 1-6 alkyl, C 3-6 cycloalkyl, CF 3 , OCH 3 , OCH 2 CH 3 , O(CH 2 ) n CF 3 , and CN;

R 7 is hydrogen;

X is CR 7 ;

Y is chosen from a bond, CH 2 , and C(O); and

n is chosen from 0, 1, and 2.

8. A compound selected from the group consisting of:

9. The compound of claim 8 , wherein the compound is selected from the group consisting of:

10. The compound of claim 9 , wherein the compound is selected from the group consisting of:

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 15, 2018
From: ACLARIS LIFE SCIENCES, INC.
To: ACLARIS THERAPEUTICS, INC.
Reel/Frame 046153/0695 →
MERGER Recorded Nov 16, 2017
From: CONFLUENCE LIFE SCIENCES, INC.
To: ACLARIS LIFE SCIENCES, INC.
Reel/Frame 044477/0208 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 6, 2015
From: JACOBSEN, ERIC JON; BLINN, JAMES ROBERT; SPRINGER, JOHN ROBERT; HOCKERMAN, SUSAN L
To: CONFLUENCE LIFE SCIENCES, INC.
Reel/Frame 035341/0284 →
Continuity (3)
Provisional Application 62007481 · Jun 4, 2014
Provisional Application 61931491 · Jan 24, 2014
Related Publication 20150210705A1 · Jul 30, 2015