Heterocyclic kinase inhibitors
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.
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
R 502 is optionally substituted alkenyl, optionally substituted alkynyl, CN, or optionally substituted (C 3 -C 6 )cycloalkenyl.
9. A compound according to claim 8 , wherein
R 6 is optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 12 )cycloalkyl, optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, optionally substituted 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl; or
R 6 is —R 601 -R 602 wherein R 601 is attached to the —N(H)— and
R 601 is optionally substituted pyrazolyl, or optionally substituted pyridinyl;
R 602 is —N(R a ) 2 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted azetidinyl, optionally substituted morpholinyl, optionally substituted piperidinyl, or optionally substituted tetrahydropyranyl.
10. The compound according to claim 9 , wherein R 1 is H.
11. The compound according to claim 5 , wherein R 502 is optionally substituted alkenyl.
12. The compound according to claim 11 , wherein R 1 is H, R 3 is H, and R 4 is H.