IP Library › Granted Patent US 9,145,393

Granted Patent B2

US 9,145,393 · App. 14/603,937 · Granted Sep 29, 2015

Arylpyridinone ITK inhibitors for treating inflammation and cancer

Inventors: Eric Jon Jacobsen (Chesterfield, MO); James Robert Blinn (O'Fallon, MO)

Assignee: Confluence Life Sciences, Inc.

C07D401/14 A61K31/444 A61K31/4427 A61K31/4545 A61K31/497 A61K31/506 A61K31/5377 A61K45/06 C07D401/12 C07D405/14

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Quick Facts

Patent No.: US 9,145,393
App. No.: 14/603,937
Granted: Sep 29, 2015
Kind: B2

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Abstract

Disclosed herein are arylpyridinone compounds and compositions useful in the treatment of ITK mediated diseases, such as inflammation, having the structure of Formula (I): wherein Ar, R 2 , R 4 , R 5 , n and X are as defined in the detailed description. Methods of inhibition of ITK activity in a human or animal subject are also provided.

Claims (177)

1. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, of Formula (I):

wherein:

Ar is chosen from aryl and heteroaryl, wherein Ar may be optionally substituted with one or more R 6 substituents;

R 2 is chosen from hydrogen, halo and C 1-4 alkyl;

R 3 is chosen from hydrogen, halo and C 1-4 alkyl;

R 4 is chosen from cyano, C(O)CH 2 R 2 , C(O)CF 3 , C(O)CH═CH 2 , C(O)CR 7 ═CH 2 , C(O)CH═CHR 7 , C(O)CR 7 ═CHR 7 , C(O)CH═CR 7 R 7 , C(O)CH═CHCH 2 R 8 , C(O)CH═CHC(O)CH 2 R 8 , C(O)C(CN)═CH 2 , C(O)(C(O)NH 2 )C═CH 2 , S(O) 2 CH═CH 2 , (CH 2 ) m CR 7 ═CR 9 C(O)Me, (CH 2 ) m CR 7 ═CR 9 C(O)NH 2 , (CH 2 ) m CR 7 ═CR 9 C(O)NHR 7 , (CH 2 ) m CR 7 CR 9 C(O)N(R 7 ) 2 , and (CH 2 ) m CR 7 ═CR 9 CN;

R 5 is chosen from hydrogen, —(CH 2 ) n C 3-7 cycloalkyl, and C 1-4 alkyl;

each R 6 is independently chosen from hydrogen, C 1-4 alkyl, —(CH 2 ) n C 3-7 cycloalkyl, OC 1-4 alkyl, C 1-4 alkylamino, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , cyano, C(O)NH 2 , C(O)NHR 5 , C(O)N(R 5 ) 2 , C(O)C 1-4 alkyl, trifluoromethyl, halo, —(CH 2 ) n C 3-7 cycloalkyl, C(O)NHaryl, and C(O)NHheteroaryl, wherein aryl and heteroaryl may be optionally substituted with one or more R 9 ;

each R 7 is independently chosen from hydrogen, CN, C 1-4 alkyl, C 3-7 cycloalkyl, C 3-7 heterocycle, aryl, and heteroaryl wherein aryl and heteroaryl may be optionally substituted with one or more R 9 ;

R 8 is chosen from hydrogen, C 1-4 alkyl, C 1-4 alkylaryl, C 1-4 alkyl-O-aryl, C 1-4 alkylheteroarylaryl, C 3-7 cycloalkyl, C 3-7 heterocycle, OH, OC 1-4 alkyl, C 1-4 alkylOC 1-4 alkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , heterocycle, aryl and heteroaryl, wherein each aryl and heteroaryl may be optionally substituted with one or more R 9 ;

R 9 is chosen from hydrogen, C 1-4 alkyl, CN, CF 3 , C(O)Me, C(O)NH 2 , and aryl;

X is chosen from N and CR 3 ;

m is chosen from 1, 2 and 3; and

n is chosen from 0, 1, 2, and 3.

2. A compound of claim 1 , wherein:

Ar is chosen from aryl and heteroaryl, wherein Ar may be optionally substituted with one or more R 6 substituents;

R 2 is chosen from hydrogen, halo and C 1-4 alkyl;

R 3 is chosen from hydrogen, halo and C 1-4 alkyl;

R 4 is chosen from cyano, C(O)CH═CH 2 , C(O)CR 7 ═CH 2 , C(O)CH═CHR 7 , C(O)CR 7 ═CHR 7 , C(O)CH═CR 7 R 7 , C(O)CH═CHCH 2 R 8 , C(O)C(CN)═CH 2 , (CH 2 ) m CR 7 ═CR 9 C(O)Me, (CH 2 ) m CR 7 ═CR 9 C(O)NH 2 , (CH 2 ) m CR 7 ═CR 9 C(O)NHR 7 , (CH 2 ) m CR 7 ═CR 9 C(O)N(R 7 ) 2 , and (CH 2 ) m CR 7 ═CR 9 CN;

R 5 is chosen from hydrogen, —(CH 2 ) n C 3-7 cycloalkyl, and C 1-4 alkyl;

each R 6 is independently chosen from hydrogen, C 1-4 alkyl, OC 1-4 alkyl, C 1-4 alkylamino, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , cyano, C(O)NHR 5 , C(O)C 1-4 alkyl, —(CH 2 ) n C 3-7 cycloalkyl, wherein aryl and heteroaryl may be optionally substituted with one or more R 9 ;

each R 7 is independently chosen from hydrogen, CN, C 1-4 alkyl, and C 3-7 cycloalkyl;

R 8 is chosen from hydrogen, C 1-4 alkyl, C 1-4 alkylaryl, C 3-7 cycloalkyl, OC 1-4 alkyl, C 1-4 alkylOC 1-4 alkyl, NH 2 , NHC 1-4 alkyl, and N(C 1-4 alkyl) 2 ;

R 9 is chosen from hydrogen, C 1-4 alkyl, CN, and CF 3 ;

X is chosen from N or CR 3 ;

m is chosen from 1, and 2; and

n is chosen from 0, 1, and 2.

3. A compound of claim 1 , wherein:

Ar is chosen from aryl and heteroaryl, wherein Ar may be optionally substituted with one or more R 6 substituents;

R 2 is hydrogen;

R 3 is hydrogen;

R 4 is chosen from, C(O)CH═CH 2 , C(O)CR 7 ═CH 2 , C(O)CH═CHR 7 , C(O)CH═CHCH 2 R 8 , C(O)C(CN)═CH 2 , (CH 2 ) m CR 7 ═CR 9 C(O)Me, (CH 2 ) m CR 7 ═CR 9 C(O)NH 2 , and (CH 2 ) m CR 7 ═CR 9 C(O)NHR 7 ;

R 5 is chosen from hydrogen, —(CH 2 ) n C 3-7 cycloalkyl, and C 1-4 alkyl;

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

each R 7 is independently chosen from hydrogen, CN, and C 1-4 alkyl;

R 8 is chosen from hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl, OC 1-4 alkyl, NH 2 , NHC 1-4 alkyl, and N(C 1-4 alkyl) 2 ;

R 9 is chosen from hydrogen, C 1-4 alkyl, and CF 3 ;

X is CR 3 ;

m is 1; and

n is chosen from 0, 1, and 2.

4. A compound of claim 1 , wherein the compound has formula (II):

wherein:

Ar is chosen from aryl and heteroaryl, wherein Ar may be optionally substituted with one or more R 6 substituents;

R 2 is chosen from hydrogen, halo and C 1-4 alkyl;

R 3 is chosen from hydrogen, halo and C 1-4 alkyl;

R 5 is chosen from hydrogen, —(CH 2 ) n C 3-7 cycloalkyl, and C 1-4 alkyl;

R 9 is chosen from hydrogen, C 1-4 alkyl, CN, CF 3 , C(O)Me, C(O)NH 2 , and aryl;

X is chosen from N and CR 3 ; and

m is chosen from 1, 2 and 3.

5. A compound of claim 4 , wherein:

Ar is chosen from aryl and heteroaryl, wherein Ar may be optionally substituted with one or more R 6 substituents;

R 2 is chosen from hydrogen, halo and C 1-4 alkyl;

R 3 is chosen from hydrogen, halo and C 1-4 alkyl;

R 5 is chosen from hydrogen, —(CH 2 ) n C 3-7 cycloalkyl, and C 1-4 alkyl;

each R 7 is independently chosen from hydrogen, CN, C 1-4 alkyl, and C 3-7 cycloalkyl;

R 8 is chosen from hydrogen, C 1-4 alkyl, C 1-4 alkylaryl, C 3-7 cycloalkyl, OC 1-4 alkyl, C 1-4 alkylOC 1-4 alkyl, NH 2 , NHC 1-4 alkyl, and N(C 1-4 alkyl) 2 ;

R 9 is chosen from hydrogen, C 1-4 alkyl, CN, and CF 3 ;

X is chosen from N and CR 3 ; and

m is chosen from 1 and 2.

6. A compound of claim 4 , wherein:

Ar is chosen from aryl and heteroaryl, wherein Ar may be optionally substituted with one or more R 6 substituents;

R 2 is hydrogen;

R 3 is hydrogen;

R 5 is chosen from hydrogen, —(CH 2 ) n C 3-7 cycloalkyl, and C 1-4 alkyl;

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

each R 7 is independently chosen from hydrogen, CN, and C 1-4 alkyl;

R 8 is chosen from hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl, OC 1-4 alkyl, NH 2 , NHC 1-4 alkyl, and N(C 1-4 alkyl) 2 ;

R 9 is chosen from hydrogen, C 1-4 alkyl, and CF 3 ;

X is CR 3 ; and

m is 1.

7. A compound of claim 1 , wherein the compound has formula (III):

wherein:

Ar is chosen from aryl and heteroaryl, wherein Ar may be optionally substituted with one or more R 6 substituents;

R 2 is chosen from hydrogen, halo and C 1-4 alkyl;

R 3 is chosen from hydrogen, halo and C 1-4 alkyl;

R 5 is chosen from hydrogen, —(CH 2 ) n C 3-7 cycloalkyl, and C 1-4 alkyl;

R 9 is chosen from hydrogen, C 1-4 alkyl, CN, CF 3 , C(O)Me, C(O)NH 2 , and aryl; and

m is chosen from 1, 2 and 3.

8. A compound of claim 7 , wherein:

Ar is chosen from aryl and heteroaryl, wherein Ar may be optionally substituted with one or more R 6 substituents;

R 2 is chosen from hydrogen, halo and C 1-4 alkyl;

R 3 is chosen from hydrogen, halo and C 1-4 alkyl;

R 5 is chosen from hydrogen, —(CH 2 ) n C 3-7 cycloalkyl, and C 1-4 alkyl;

each R 7 is independently chosen from hydrogen, CN, C 1-4 alkyl, and C 3-7 cycloalkyl;

R 8 is chosen from hydrogen, C 1-4 alkyl, C 1-4 alkylaryl, C 3-7 cycloalkyl, OC 1-4 alkyl, C 1-4 alkylOC 1-4 alkyl, NH 2 , NHC 1-4 alkyl, and N(C 1-4 alkyl) 2 ;

R 9 is chosen from hydrogen, C 1-4 alkyl, CN, and CF 3 ; and

m is chosen from 1 and 2.

9. A compound of claim 7 , wherein:

Ar is chosen from aryl and heteroaryl, wherein Ar may be optionally substituted with one or more R 6 substituents;

R 2 is hydrogen;

R 3 is hydrogen;

R 5 is chosen from hydrogen, —(CH 2 ) n C 3-7 cycloalkyl, and C 1-4 alkyl;

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

each R 7 is independently chosen from hydrogen, CN, and C 1-4 alkyl;

R 8 is chosen from hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl, OC 1-4 alkyl, NH 2 , NHC 1-4 alkyl, and N(C 1-4 alkyl) 2 ;

R 9 is chosen from hydrogen, C 1-4 alkyl, and CF 3 ; and

m is 1.

10. A compound according to claim 1 , which is a compound selected from the group consisting of:

5-((1-(2-chloroacetyl)azetidin-3-yl)amino)-[3,4′-bipyridin]-6(1H)-one;

5-((1-acryloylazetidin-3-yl)amino)-[3,4′-bipyridin]-6(1H)-one;

(E)-5-((1-(but-2-enoyl)azetidin-3-yl)amino)-[3,4′-bipyridin]-6(1H)-one;

5-((1-acryloylazetidin-3-yl)amino)-2′-methyl-[3,4′-bipyridin]-6(1H)-one;

3-((1-acryloylazetidin-3-yl)amino)-5-(6-methoxypyrazin-2-yl)pyridin-2(1H)-one;

5-((1-acryloylazetidin-3-yl)amino)-2′-(methylamino)-[3,4′-bipyridin]-6(1H)-one;

3-((1-acryloylazetidin-3-yl)amino)-5-(2-(methylamino)pyrimidin-4-yl)pyridin-2(1H)-one;

3-((1-acryloylazetidin-3-yl)amino)-5-(6-(methylamino)pyrazin-2-yl)pyridin-2(1H)-one;

(E)-N-methyl-4-oxo-4-(3-((6-oxo-1,6-dihydro-[3,4′-bipyridin]-5-yl)amino)azetidin-1-yl)but-2-enamide; and

(E)-5-((1-(4-(methylamino)but-2-enoyl)azetidin-3-yl)amino)-[3,4′-bipyridin]-6(1H)-one.

11. A compound of claim 7 , wherein:

Ar is phenyl, 3-methoxyphenyl, 3-aminomethylphenyl, 4-pyridine, 3-methyl-4-pyridyl, 3-aminomethyl-4-pyridinyl, 3-aminomethyl-2,4-pyrimidinyl, 3-methoxy-2,5-pyrazinyl, 3-methylamino-2,5-pyrazinyl, wherein Ar may be optionally substituted with one or more R 6 substituents;

R 2 is independently chosen from hydrogen, halo and C 1-4 alkyl;

R 4 is independently chosen from cyano, C(O)CH 2 R 2 , C(O)CF 3 , C(O)CH═CH 2 , C(O)CR 7 ═CH 2 , C(O)CH═CHR 7 , C(O)CR 7 ═CHR 7 , C(O)CH═CR 7 R 7 , C(O)CH═CHCH 2 R 8 , C(O)CH═CHCOR 8 , C(O)CH═CHC(O)CH 2 R 8 , C(O)C(CN)═CH 2 , CO(C(O)NH 2 )C═CH 2 , S(O) 2 CH═CH 2 , (CH 2 ) m CR 7 ═CR 9 C(O)Me, (CH 2 ) m CR 7 ═CR 9 C(O)NH 2 , (CH 2 ) m CR 7 ═CR 9 C(O)NHR 7 , (CH 2 ) m CR 7 ═CR 9 C(O)N(R 7 ) 2 , and (CH 2 ) m CR 7 ═CR 9 CN;

R 5 is chosen from hydrogen, —(CH 2 ) n C 3-7 cycloalkyl, and C 1-4 alkyl;

each R 6 is independently chosen from hydrogen, C 1-4 alkyl, OC 1-4 alkyl, —(CH 2 ) n C 3-7 cycloalkyl, C 1-4 alkylamino, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , cyano, C(O)NH 2 , C(O)NHR 5 , C(O)N(R 5 ) 2 , C(O)C 1-4 alkyl, trifluoromethyl, halo, C(O)NHaryl, and C(O)NHheteroaryl wherein aryl and heteroaryl may be optionally substituted with one or more R 9 ;

R 8 is chosen from hydrogen, C 1-4 alkyl, C 1-4 alkylaryl, C 1-4 alkylheteroarylaryl, C 3-7 cycloalkyl, C 3-7 heterocycle, OH, OC 1-4 alkyl, C 1-4 alkylOC 1-4 alkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , heterocycle, aryl and heteroaryl wherein aryl and heteroaryl may be optionally substituted with one or more R 9 ;

R 9 is chosen from hydrogen, C 1-4 alkyl, CN, CF 3 , C(O)Me, C(O)NH 2 , and aryl; and

m is chosen from 1, 2 and 3.

12. A compound of claim 7 , wherein:

Ar is 4-pyridine, 3-methyl-4-pyridyl, 3-aminomethyl-4-pyridinyl, 3-aminomethyl-2,4-pyrimidinyl, 3-methoxy-2,5-pyrazinyl, 3-methylamino-2,5-pyrazinyl;

R 2 is independently chosen from hydrogen, halo and C 1-4 alkyl;

R 5 is chosen from hydrogen, —(CH 2 ) n C 3-7 cycloalkyl, and C 1-4 alkyl;

R 9 is chosen from hydrogen, C 1-4 alkyl, CN, CF 3 , C(O)Me, C(O)NH 2 , and aryl; and

m is chosen from 1, 2 and 3.

13. A compound of claim 7 , wherein:

Ar is 4-pyridine, 3-methyl-4-pyridyl, 3-aminomethyl-4-pyridinyl, 3-aminomethyl-2,4-pyrimidinyl, 3-methoxy-2,5-pyrazinyl, 3-methylamino-2,5-pyrazinyl;

R 2 is hydrogen;

R 5 is hydrogen;

R 9 is chosen from hydrogen, C 1-4 alkyl, CN, CF 3 , C(O)Me, C(O)NH 2 , and aryl; and

m is chosen from 1, 2 and 3.

14. A compound of claim 7 , wherein:

Ar is 4-pyridine, 3-methyl-4-pyridyl, 3-aminomethyl-4-pyridinyl, 3-aminomethyl-2,4-pyrimidinyl, 3-methoxy-2,5-pyrazinyl, 3-methylamino-2,5-pyrazinyl;

R 2 is hydrogen;

R 4 is independently chosen from C(O)CH 2 R 2 , C(O)CF 3 , C(O)CH═CH 2 , C(O)CR 7 ═CH 2 , C(O)CH═CHR 7 , C(O)CR 7 ═CHR 7 , C(O)CH═CR 7 R 7 , C(O)CH═CHCH 2 R 8 , C(O)CH═CHCOR 8 , C(O)CH═CHC(O)CH 2 R 8 , C(O)C(CN)═CH 2 , CO(C(O)NH 2 )C═CH 2 , (CH 2 ) m CR 7 ═CR 9 C(O)Me, (CH 2 ) m CR 7 ═CR 9 C(O)NH 2 , (CH 2 ) m CR 7 ═CR 9 C(O)NHR 7 , and (CH 2 ) m CR 7 ═CR 9 CN;

R 5 is hydrogen;

R 9 is chosen from hydrogen, C 1-4 alkyl, CN, CF 3 , C(O)Me, C(O)NH 2 , and aryl; and

m is chosen from 1 and 2.

15. A compound of claim 7 , wherein:

Ar is 4-pyridine, 3-methyl-4-pyridyl, 3-aminomethyl-4-pyridinyl, 3-aminomethyl-2,4-pyrimidinyl, 3-methoxy-2,5-pyrazinyl, 3-methylamino-2,5-pyrazinyl;

R 2 is hydrogen;

R 4 is independently chosen from C(O)CH═CH 2 , C(O)CR 7 ═CH 2 , C(O)CH═CHR 7 , C(O)CR 7 ═CHR 7 , C(O)CH═CR 7 R 7 , C(O)CH═CHCH 2 R 8 , C(O)CH═CHCOR 8 , C(O)CH═CHC(O)CH 2 R 8 , C(O)C(CN)═CH 2 , CO(C(O)NH 2 )C═CH 2 , (CH 2 ) m CR 7 ═CR 9 C(O)Me, (CH 2 ) m CR 7 ═CR 9 C(O)NH 2 , (CH 2 ) m CR 7 ═CR 9 C(O)NHR 7 , and (CH 2 ) m CR 7 ═CR 9 CN;

R 5 is hydrogen;

R 9 is chosen from hydrogen, C 1-4 alkyl, CN, CF 3 , C(O)Me, C(O)NH 2 , and aryl; and

m is chosen from 1 and 2.

16. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

17. A compound according to claim 1 , which is a compound selected from the group consisting of:

(R)-5-((1-(2-chloroacetyl)piperidin-3-yl)amino)-[3,4′-bipyridin]-6(1H)-one;

(R)-5-((1-acryloylpiperidin-3-yl)amino)-[3,4′-bipyridin]-6(1H)-one; and

(R)-5-((1-acryloylpyrrolidin-3-yl)amino)-[3,4′-bipyridin]-6(1H)-one.

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

To: CONFLUENCE LIFE SCIENCES, INC.

Reel/Frame 035340/0900 →

Continuity (3)

Provisional Application 62007477 · Jun 4, 2014

Provisional Application 61931484 · Jan 24, 2014

Related Publication 20150210671A1 · Jul 30, 2015