Heterocyclic kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10280184-B2
Application number	US-201515304131-A
Country	US
Kind code	B2
Filing date	Apr 16, 2015
Priority date	Apr 17, 2014
Publication date	May 7, 2019
Grant date	May 7, 2019

Abstract

The invention provides compounds of Formula (I) pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variable are defined herein. The compounds of the invention are useful for treating immunological and oncological conditions.

First claim

What is claimed:

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein
U is CR 1 ;
X is N;
Y is CR 3 ;
Z is CR 4 ;
R 1 is independently H or deuterium;
R 3 is H, deuterium or optionally substituted (C 1 -C 3 )alkyl;
R 4 is H or deuterium;
R 5 is —R 501 -L-R 502 , wherein
R 501 is a bond, —O—, —OCH 2 —, or optionally substituted (C 1 -C 3 )alkylene,
L is —C(═O)—, —CH 2 N(H)C(═O)—, —N(H)C(═O)—, or —N(H)S(O) 2 —; or
L is a bond and R 502 is —CN; or
L is -L 1 -L 2 , wherein L 1 is attached to R 501 , wherein
L 1 is optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted saturated or partially saturated heterocyclyl, or optionally substituted saturated or partially saturated (C 3 -C 7 )cycloalkyl and L 2 is a bond, —CH 2 N(R a )—, —CH 2 N(R a )C(O)—, —N(R a )C(O)—, —N(R a )S(O) 2 — or —N(R a )—; or
L 1 is a saturated or partially saturated heterocyclyl containing one or more heteroatoms wherein at least one heteroatom is nitrogen and L 2 is a bond, —C(═O)—, or —S(O) 2 —;

R 502 is optionally substituted alkenyl, optionally substituted alkynyl, CN, or optionally substituted (C 3 -C 6 )cycloalkenyl;

R 6 is optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 12 )cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; or
R 6 is —R 601 -R 602 , wherein R 601 is attached to the —N(H)— and
R 601 is optionally substituted heteroaryl;
R 602 is —N(R a ) 2 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, or optionally substituted heterocyclyl; and
R a is independently H or optionally substituted (C 1 -C 6 )alkyl.

2. The compound according to claim 1 , wherein
U is CR 1 ;
X is N;
Y is CR 3 ;
Z is CR 4 ;
R 1 is independently H or deuterium;
R 3 is H, deuterium or optionally substituted (C 1 -C 3 )alkyl;
R 4 is H or deuterium;
R 5 is —R 501 -L-R 502 , wherein
R 501 is a bond, —O—, —OCH 2 —, or optionally substituted (C 1 -C 3 )alkylene,
L is —C(═O)—, —CH 2 N(H)C(═O)—, —N(H)C(═O)—, or —N(H)S(O) 2 —; or
L is a bond and R 502 is —CN; or
L is -L 1 -L 2 , wherein L 1 is attached to R 501 , wherein
L 1 is optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted saturated or partially saturated heterocyclyl, or optionally substituted saturated or partially saturated (C 3 -C 6 )cycloalkyl and L 2 is —CH 2 N(R a )—, —CH 2 N(R a )C(O)—, —N(R a )C(O)—, —N(R a )S(O) 2 — or —N(R a )—; or
L 1 is a saturated or partially saturated heterocyclyl containing one or more heteroatoms wherein at least one heteroatom is nitrogen and L 2 is a bond, —C(═O)—, or —S(O) 2 —;

R 502 is optionally substituted alkenyl, optionally substituted alkynyl, CN, or optionally substituted (C 3 -C 6 )cycloalkenyl;

R 6 is optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 12 )cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and
R a is independently H or optionally substituted (C 1 -C 6 )alkyl.

3. The compound of claim 2 , wherein
L is —C(═O)—, —CH 2 N(H)C(═O)—, or —N(H)C(═O)—; and R 502 is —CH═CH 2 or —C≡CH; or
L is a bond and R 502 is —CN; or
L is -L 1 -L 2 , wherein L 1 is attached to R 501 , wherein
L 1 is optionally substituted phenyl, optionally substituted heteroaryl or optionally substituted saturated or partially saturated (C 3 -C 6 )cycloalkyl and L 2 is —CH 2 N(R a )—, —CH 2 N(R a )C(O)—, —N(R a )C(O)—, —N(R a )S(O) 2 — or —N(R a )—; or
L 1 is azepanyl, azetidinyl, morpholinyl, oxazepanyl, piperidinyl, or pyrrolidinyl, and L 2 is a bond, —C(═O)—, or —S(O) 2 —.

4. The compound of claim 3 , wherein R 6 is optionally substituted (C 1 -C 6 )alkyl, optionally substituted phenyl, optionally substituted bicyclo[1.1.1]pentanyl, optionally substituted 1,2,4 oxadiazolyl, optionally substituted pyrazolyl, optionally substituted pyridazinyl, optionally substituted pyridinyl, 4,5-dihydro-1H-benzo[b]azepin-2(3H)-one, 3,4-dihydroquinolin-2(1H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, or 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl.

5. The compound of claim 4 , wherein R 6 is optionally substituted with one or more substituents independently selected from (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, optionally substituted imidazolidinone, and morpholinyl.

6. The compound of claim 5 , wherein -L-R 502 forms —CN, —CH 2 N(H)C(═O)CH═CH 2 , —C(═O)CH═CH 2 , or —N(H)C(═O)CH═CH 2 .

7. The compound according to claim 1 , wherein the compound is
1-(3-(8-((1-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)pyrrolidin-1-yl)prop-2-en-1-one;
8-((6-(1-acryloylpyrrolidin-3-yl)-[1,2,4]triazolo[15-a]pyridin-8-yl)amino)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one;
1-(3-(8-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)pyrrolidin-1-yl)prop-2-en-1-one;
1-(3-(8-((1-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)piperidin-1-yl)prop-2-en-1-one;
1-(3-(8-((6-morpholinopyridazin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)piperidin-1-yl)prop-2-en-1-one;
1-(3-(8-((5-morpholinopyridin-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)piperidin-1-yl)prop-2-en-1-one;
1-(3-(8-((6-morpholinopyridin-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)piperidin-1-yl)prop-2-en-1-one;
1-(3-(8-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-(8-((1-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)pyrrolidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(8-((1-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)pyrrolidin-1-yl)prop-2-en-1-one;
1-(3-(8-((3-isopropyl-1,2,4-oxadiazol-5-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)piperidin-1-yl)prop-2-en-1-one;
N-((1R,3S)-3-(8-((1-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)cyclohexyl)acrylamide;
1-(3-(8-((3-methyl-1,2,4-oxadiazol-5-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)piperidin-1-yl)prop-2-en-1-one;
N-((1S,3S)-3-(8-((1-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)cyclohexyl)cyanamide;
3-(8-((1-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)piperidine-1-carbonitrile;
3-(8-((1-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)pyrrolidine-1-carbonitrile;
N-((1R,3S)-3-(8-((1-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazol[1,5-a]pyridin-6-yl)cyclopentyl) acrylamide;
N-((1S)-3-(8-((1-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)cyclopentyl) acrylamide;
3-(8-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)piperidine-1-carbonitrile;
(S)-1-(3-(8-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)pyrrolidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(8-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)pyrrolidin-1-yl)prop-2-en-1-one;
(S)-1-(3-(8-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)piperidin-1-yl)prop-2-en-1-one; or
(R)-1-(3-(8-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)piperidin-1-yl)prop-2-en-1-one.

8. The compound according to claim 1 , wherein
R 5 is —R 501 -L-R 502 , wherein
R 501 is a bond;
L is -L 1 -L 2 , wherein L 1 is attached to R 501 , wherein
L 1 is optionally substituted saturated or partially saturated (C 3 -C 7 )cycloalkyl and L 2 is a bond, —CH 2 N(R a )C(O)—, or —N(R a )C(O)—; and

Assignees

• Abbvie Inc

Inventors

• Friedman Michael M
• Cox Philip
• Frank Kristine E
• Hoemann Michael Z
• OSUMA Augustine
• Wilson Noel S
• Xu Xiangdong
• Cusack Kevin
• Huntley Raymond
• Herold J Martin

Classifications

• A61P43/00

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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P35/02

  specific for leukemia · CPC title