USRE49700EActiveUtilityPatentIndex 60
Substituted nitrogen containing compounds
Est. expiryJun 1, 2037(~10.9 yrs left)· nominal 20-yr term from priority
Inventors:YADAV NAVNATH DNYANOBABHIDE RAJEEV SBORA RAJESH ONKARDASGUNAGA PRASHANTHAPANDA MANORANJANPRIESTLEY ELDON SCOTTRICHTER JEREMY
C07D 405/14C07D 413/14C07D 417/14C07D 487/04A61P 9/00A61P 9/04A61P 9/12A61K 31/506A61P 13/12C07D 471/04A61K 31/454A61K 31/4439A61K 31/496A61K 31/5377A61K 31/501A61K 31/444
60
PatentIndex Score
0
Cited by
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References
61
Claims
Abstract
Disclosed are compounds of Formula (I)or a salt thereof,wherein R1 is:each W is independently NR1b or O; Z is a bond or CHR1d; and R1, R2, Rd, R3a, R3b, L1, B, V, Y, and n are defined herein. Also disclosed are methods of using such compounds as inhibitors of ROMK, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating cardiovascular diseases.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A compound having the structure of Formula (I)
or a salt thereof, wherein:
R 1 is:
each W is independently NR 1b or O;
Z is a bond or CHR 1d ;
X is independently N or CR 1a , wherein X is N at only 0, 1, or 2 positions;
each R 1a is independently H, F, Cl, —OH, —CN, C 1-3 alkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, or C 1-3 fluoroalkoxy;
each R 1b is independently H, C 1-3 alkyl, C 2-3 fluoroalkyl, or C 3-6 cycloalkyl;
R 1c is independently H, deuterium, C 1-4 alkyl, C 1-4 fluoroalkyl, or C 3-6 cycloalkyl;
R 1d is H, C 1-3 alkyl, C 1-4 fluoroalkyl, or C 3-6 cycloalkyl;
Y is —C(R 6 ) 2 —, —C(R 6 ) 2 —C(R 6 ) 2 —,—C(O)—, —C(O)—C(R 6 ) 2 —, —C(R 6 ) 2 —C(O)—, or —SO 2 —;
V is —O—, —NR 4 —, —CR 5 R 5 —-, —S—, —S(O)—, —SO 2 —, or —C(O)—; wherein if V is —O—, —S—, —S(O)—, —SO 2 —, or —C(O)—, then Y is not —SO 2 —, and wherein if V is —O—, —S—, or NR 4 , then Y is not C(R 6 ) 2 , and wherein if V is —S(O)—, —SO 2 —, or C(═O)—, then Y is not —C(═O)—, —C(═O)—C(R 6 ) 2 —;
L 1 is —C(R) 2 —, —C(O)—, or —C(R) 2 —C(R) 2 —; wherein R is independently H, F, OH, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxyalkyl, or C 1-3 fluoroalkyl; wherein R is not —OH or F if it is attached to a carbon atom that is adjacent to a nitrogen atom:
Ring B is phenyl, pyridinyl, pyrimidinyl, pyrrazolyl pyrazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazinyl, oxazolyl, pyridazinyl, pyrrolidinyl, or imidazolidinyl;
R 2 is a C 6-10 aryl, or a 5 to 10 membered heterocycle ring containing 1 to 4 heteroatoms selected from N, O, and S, the heterocycle ring optionally containing an oxo substitution, the aryl or heterocycle ring are substituted with 0-3 R 2a ;
R 2a is independently OH, ═O, CN, halo, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 deuteroalkoxy, C 1-4 fluoroalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy,
C(═O)NR 4b R 4b , C(═O)C 1-4 alkyl, SO 2 R e , NR 4b SO 2 R 4b , or a 4 to 6 membered heterocycle having 1, 2, 3, or 4 heteroatoms selected from O, S, and N, the heterocycle optionally containing an oxo substitution and is substituted with 0-3 R 2b ;
R 2b is independently C 1-3 alkyl, C 1-3 fluoralkyl fluoroalkyl, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, or C 3-6 fluorocycloalkyl;
R 3a is H, halo, OH, CN, C 13 alkyl, C 1-3 hydroxyalkyl, C 1-3 fluoroalkyl, C 1-3 alkoxy, or C 3-6 cycloalkyl, wherein if V is —O—, —NR 4 —, —S—, —S(O)—, —SO 2 —, or —C(═O)—, then R 3a is not halo, and wherein if V is —O—, —NR 4 —, or —S—, then R 3a is not OH, or CN;
R 3b is H, ═O, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 fluoroalkyl, C 1-3 alkoxy, or C 3-6 cycloalkyl;
R 4 is H, C 1-3 alkyl, C 2-3 fluoroalkyl, C 2-3 hydroxyalkyl, CO 2 R 4a , C(O)R 4a , SO 2 R 4a , C(O)N(R 4b R 4b ), SO 2 N(R 4b R 4b ), or OH;
R 4a is C 1-3 alkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, C 6-10 aryl or a 4 to 10 membered heterocycle having 1, 2, 3 or 4 heteroatoms selected from O, S, and N, the aryl or heterocycle being substituted with 0-3 R 4c ;
R 4b is independently H, C 1-3 alkyl, C 2-3 fluoroalkyl, C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, C 6-10 aryl or a 4 to 10 membered heterocycle having 1, 2, 3 or 4 heteroatoms selected from O, S, and N;
alternatively, 2 R 4b s, along with the atom to which they are attached, join to form a 3 to 6 membered saturated ring containing an additional 0-2 heteroatoms selected from O, S, and N;
R 4c is independently H, F, Cl, or C 1-3 alkyl;
R 5 is independently H, F, OH, C 1-3 alkoxy, C 1-3 fluoroalkoxy, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, NR 5b R 5b , O—R 5c , or 2 R 5 s are ═O; wherein if one R 5 is F, OH or NR 5b R 5b , then the other R 5 is not OH, or NR 5b R 5b ;
R 5b is independently H, C 1-3 alkyl, C 3-6 cycloalkyl, C(O)R a , SO 2 R a , or C(O)NR b R b ; alternatively, 2 R 5b s, along with the atom to which they are attached, join to form a 3 to 6 membered saturated ring containing 0-2 heteroatoms selected from O, S, or N;
R 5c is independently H, C 1-3 alkyl, C 3-6 cycloalkyl, or C(O)NR b R b ;
R 6 is independently H, OH, F, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1-3 hydroxydeuteroalkyl, C 1-3 alkoxyalkyl, or C 1-3 fluoroalkoxyalkyl, or NR 6b R 6b ; wherein if one R 6 on one carbon atom is F, OH or NR 6b R 6b , then the other R 6 on the same carbon atom is not OH or NR 6b R 6b ;
R 6b is independently H, C 1-3 alkyl, C 3-6 cycloalkyl, C(O)R a , SO 2 R a , or C(O)NR b R b ; alternatively, 2 R 6 s along with the same atom to which they are attached can form a 3 to 6 membered saturated ring containing 0-2 heteroatoms selected from O, S, and N;
R a is independently H, C 1-3 alkyl, C 2-3 fluoroalkyl, C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, C 6-10 aryl or a 4 to 10 membered heterocycle having 1, 2, 3, or 4 heteroatoms selected from O, S, and N;
R b is independently H, C 1-3 alkyl, C 2-3 fluoroalkyl, C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, C 6-10 aryl or a 4 to 10 membered heterocycle having 1, 2, 3 or 4 heteroatoms selected from O, S, and N;
alternatively, 2 R b 's along with the atom to which they are attached, join to form a 3 to 6 membered saturated ring, containing 0-2 heteroatoms selected from O, S, and N;
each R d is independently H, F, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-3 alkoxy, C 1-3 fluoroalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, halo, OH, ═O, CN, OCF 3 , OCHF 2 , CHF 2 CF 3 , or C(O)NR e R e ;
each R e is independently H, C 1-3 alkyl, C 2-3 fluoroalkyl, C 3-6 cycloalkyl, C 2-3 hydroxyalkyl, C 2-3 alkoxyalkyl, C 6-10 aryl, or a 5 to 10 membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from O, S, and N;
alternatively, 2 R e s along with the atom to which they are attached, join to form a 3 to 6 membered saturated ring, containing 0-2 heteroatoms selected from O, S, or N; and
n is 0, 1, or 2.
2. A compound of claim 1 , or salt thereof, wherein:
R 1 is:
each R 1a is independently selected from F, Cl, C 1-3 alkyl, C 1-3 fluoroalkyl, and C 3-6 cycloalkyl;
R 1c is independently H, deuterium, C 1-2 alkyl, or C 3-6 cycloalkyl; and
n is zero, 1, or 2.
3. A compound of claim 2 , or salt thereof, wherein:
R 2 is phenyl, pyridinyl, indolyl, indazolyl, benzo[d]oxazol-onyl, pyrazolo[4,3-b]pyridinyl, pyridin-2-onyl, pyrazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-b]pyridazinyl, pyrazinyl, pyrazolo[1,5-a]pyrimidinyl, thiazolyl, thiophenyl, 1,2,3-triazolyl, benzo[d][1,2,3]triazolyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[d]imidazolyl, imidazolyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrrolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, tetrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyridazinyl, pyrimidinyl, or benzo[d]oxazol-2-onyl, triazolyl, oxadiazolyl, or pyrrolopyridinyl, each being substituted with 0-3 R 2a .
4. A compound of claim 3 , or salt thereof, wherein:
Ring B is pyridinyl, pyrimidinyl, pyrrazolyl pyrazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, pyrazinyl, oxazolyl, or pyridazinyl.
5. A compound of claim 4 , or salt thereof, wherein:
V is —O—, —CR 5 R 5 —, or —C(═O)—;
wherein if V is —O—, or NR 4 , then Y is not C(R 6 ) 2 ;
Y is —C(R 6 ) 2 —, —C(R 6 ) 2 —C(R 6 ) 2 —, —C(═O)—, —C(═O)—C(R 6 ) 2 —, or —C(R 6 ) 2 —C(O)—; and
L 1 is —C(R) 2 —, —C(O)—, or —CH 2 —C(R) 2 —; wherein R is independently from hydrogen, F, OH, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxyalkyl, or C 1-3 fluoroalkyl.
6. A compound of claim 5 , or salt thereof, wherein:
R 2 is phenyl, pyridinyl, indolyl, indazolyl, benzo[d]oxazol-2(3H)-onyl, pyrazolo[4,3-b]pyridinyl, pyridin-2(1H)-onyl, pyrazolyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-b]pyridazinyl, pyrazinyl, pyrazolo[1,5-a]pyrimidinyl, thiophenyl, [1,2,4]triazolo[4,3-b]pyridazinyl, or pyrazolo[1,5-a]pyrimidinyl, or benzo[d]oxazol-2(3H )-only, each being substituted with 0-3 R 2a ; and
R 2a is OH, ═O, CN, halo, C 1-4 alkyl, SO 2 C 1-4 SO 2 C 1-3 alkyl, or oxazolidin-2-one substituted with 0-1 R 2b ;
R 2b is C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-3 alkoxy, or C 1-3 fluoroalkoxy.
7. A compound of claim 6 , or salt thereof, wherein:
R 1 is
R 1a is independently H or —CH 3 .
8. The compound according to claim 7 , or salt thereof, wherein:
Ring B is pyridinyl, triazolyl, thiazolyl, oxadiazolyl, imidazolyl, or pyrrazolyl pyrazolyl; and
R 2 is phenyl, pyridinyl, pyrimidinyl, benzo[d]oxazol-2(3H)-onyl, imidazolyl, pyrazolyl, triazolyl, or oxadiazolyl, each being substituted with 0-3 R 2a .
9. The compound according to claim 8 , or salt thereof, wherein:
V is —O—, —NR 4 —, or —CR 5 R 5 —;
Y is —C(R 6 ) 2 —C(R 6 ) 2 — or —C(R 6 ) 2 —;
L 1 is —C(R) 2 —; wherein R is independently hydrogen, F, OH, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxyalkyl, or C 1-3 fluoroalkyl; and
R 6 is independently H, C 1-3 -alkyl, C 1-3 -fluoroalkyl, or C 3-6 -cycloalkyl.
10. A compound of claim 1 , or salt thereof, wherein the compound is selected from
(R)-4-methyl-6-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-3-methyl-5-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)pyridin-2-yl)benzo[d]oxazol-2(3H)-one;
5-(4-((4,4-difluoro-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-pyrazol-1-yl)-3-methylbenzo[d] oxazol-2(3H)-one;
6-(4-((4,4-difluoro-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile;
(R)-6-(5-methoxy-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile;
(R)-4-methyl-5-(4-((1-(2-methylthiazol-5-yl)-1H-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran-1(3H)-one;
(R)-4-cyclopropyl-6-(4-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-4-methyl-6-(4-((5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxooxazolidin-3-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-4-methyl-6-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxomorpholino)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-4-methoxy-6 (4 (2 (2 (4 methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)ethyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-4-methoxy-6-(4-(2-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)ethyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-6-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1,3,4-oxadiazol-2-yl)nicotinonitrile;
(R)-4-methyl-6-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)nicotinonitrile;
(R)-4-methoxy-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)nicotinonitrile;
(R)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxopiperazin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-4-methyl-5-(4-((6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)methyl)morpholin-2-yl)isobenzofuran-1(3H)-one;
(R)-4-methoxy-5′-((5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxooxazolidin-3-yl)methyl)-[2,2′-bipyridine]-5-carbonitrile;
6-(4-(1-hydroxy-2-((R)-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)ethyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile (Diastereomer-I & II);
(R)-3-methyl-5-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)thiazol-2-yl)benzo[d]oxazol-2(3H)-one;
(R)-3-methyl-5-(5-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholine-4-carbonyl)thiazol-2-yl)benzo[d]oxazol-2(3H)-one;
(R)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)thiazol-2-yl)-1H-imidazole-4-carbonitrile;
(R)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile;
(R)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)nicotinonitrile;
Methyl-(R)-4-((1-(5-cyano-4-methylpyridin-2-yl)-1H-pyrazol-4-yl)methyl)-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate;
(S)-4-methyl-6-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-3-methyl-5-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)benzo[d]oxazol-2(3H)-one;
(R)-6-(5-methoxy-4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile;
(R)-4-methoxy-6-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-imidazol-1-yl)nicotinonitrile;
(R)-6-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-imidazol-1-yl)nicotinonitrile;
(R)-3-methyl-5-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-imidazol-1-yl)benzo[d]oxazol-2(3H)-one;
(R)-4-methyl-6-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1,3,4-oxadiazol-2-yl)nicotinonitrile;
(R)-4-methyl-6 (4 (2 (2 (4 methyl-1-oxo-1,3-isobenzofuran-5-yl)morpholino)ethyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-4-methyl-6-(4-(2-(2-(4-methyl-1-oxo-1,3-isobenzofuran-5-yl)morpholino)ethyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-4-methoxy-6-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)thiazol-2-yl)nicotinonitrile;
(R)-4-methyl-6-(5-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholine-4-carbonyl)thiazol-2-yl)nicotinonitrile;
(R)-4-methoxy-6-(5-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholine-4-carbonyl)thiazol-2-yl)nicotinonitrile;
(R)-4-methoxy-5′-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-[2,2′-bipyridine]-5-carbonitrile;
(R)-4-methyl-5-(4-((2-(4-methyl-1H-imidazol-1-yl)thiazol-5-yl)methyl)morpholin-2-yl)isobenzofuran-1(3H)-one;
(R)-1-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)pyridin-2-yl)-1H-imidazole-4-carbonitrile;
(R)-4-methyl-5-(4-((1-(thiophen-3-yl)-1H-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran-1(3H)-one;
(R)-4-methyl-5-(4-((1-(pyrazin-2-yl)-1H-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran-1(3H)-one;
(R)-4-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)benzonitrile;
(R)-4-methyl-5-(4-((1-(6-methylpyrazin-2-yl)-1H-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran-1(3H)-one;
(R)-5-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1- yl)nicotinonitrile;
(R)-3-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)benzonitrile;
(R)-4-methyl-5-(4-((1-(pyridin-4-yl)-1H-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran-1(3H)-one;
(R)-4-methyl-5-(4-((1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran-1(3H)-one;
(R)-2-methyl-4-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)benzonitrile;
(R)-3-methyl-4-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)benzonitrile;
(R)-5-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)picolinonitrile;
(R)-2-methoxy-4-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)benzonitrile;
(R)-4-methyl-5-(4-((1-(pyrazolo[1,5-a]pyrimidin-5-yl)-1H-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran-1(3H)-one;
(R)-3-methoxy-4-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)benzonitrile;
(R)-4-methyl-6-(3-methyl-4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-4-methyl-6-(3-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
(S)-4-methyl-6-(4-(3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-5-(5-methoxy-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-3-methylbenzo[d]oxazol-2(3H)-one;
(R)-7-fluoro-3-methyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)benzo[d]oxazol-2(3H)-one;
(R)-7-methoxy-3-methyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)benzo[d]oxazol-2(3H)-one;
(R)-3,7-dimethyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)benzo[d]oxazol-2(3H)-one;
(R)-3-methyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)benzo[d]oxazol-2(3H)-one;
(R)-4-methoxy-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-3-methyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)benzo[d]oxazol-2(3H)-one;
(R)-6-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)nicotinonitrile;
(R)-4-methoxy-5′-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-[2,2′-bipyridine]-5-carbonitrile;
(R)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)-1H-pyrazole-4-carbonitrile;
(R)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)-1H-imidazole-4-carbonitrile;
(R)-4-methyl-5-(4-((6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)methyl)piperazin-2-yl)isobenzofuran-1(3H)-one;
(R)-4-methyl-5-(4-((6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)methyl)piperazin-2-yl)isobenzofuran-1(3H)-one;
(R)-6-(4-((4-acetyl-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile;
(R)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-4-methyl-6-(4-((4-methyl-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-3-methyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxopiperazin-1-yl)methyl)-1H-pyrazol-1-yl)benzo[d]oxazol-2(3H)-one;
(R)-3-methyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxopiperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)benzo[d]oxazol-2(3H)-one;
(R)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxopiperazin-1-yl)methyl)pyridine-2-yl)-1H-1,2,4-triazole-3-carbonitrile;
(R)-4-methoxy-5′-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxopiperazin-1-yl)methyl)-2,2′-bipyridine-5-carbonitrile;
(R)-6-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-((6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)methyl)piperazin-2-one;
(R)-6-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-((6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)methyl)piperazin-2-one;
(R)-4-methyl-6-(4-((4-methyl-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxopiperazin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-4-methoxy-6-(4-((5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxooxazolidin-3-yl)methyl)-1H-imidazol-1-yl)nicotinonitrile;
(R)-6-(5-methoxy-4-((5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxooxazolidin-3-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile;
(R)-3-methyl-5-(4-((5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxooxazolidin-3-yl)methyl)-1H-pyrazol-1-yl)benzo[d]oxazol-2(3H)-one;
6-(4-(((3R,5R)-3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile;
6-(4-((3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)-4-methylnicotinonitrile;
4-methyl-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile;
6-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-4-methylnicotinonitrile;
2,4-dimethyl-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile;
4-methoxy-2-methyl-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)nicotinonitrile;
6-(4-((3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile, (Enantiomer-III);
6-(4-((3-(hydroxymethyl)-5-(4-methyl-1 oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-4-methylnicotinonitrile, (Enantiomer-III);
6-(4-((3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methoxynicotinonitrile, (Enantiomer-III);
6-(4-((3-(hydroxymethyl-d2)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile, (Enantiomer-I);
1-(5-(((3R,5R)-3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)-3-methyl-1H-pyrazole-4-carbonitrile;
6-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-pyrazol-1-yl)-2,4-dimethylnicotinonitrile;
2-methoxy-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
5-((2R,6S)-4-((2-(4,5-dimethyl-1H-imidazol-1-yl)pyrimidin-5-yl)methyl)-6-methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one;
4,6-dimethyl-2-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)pyrimidine-5-carbonitrile;
4-methyl-2-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)pyrimidine-5-carbonitrile;
4-methoxy-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)nicotinonitrile;
4-methyl-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)nicotinonitrile;
4-methoxy-2-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)pyrimidine-5-carbonitrile;
4-methyl-2-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)pyrimidine-5-carbonitrile;
2-methoxy-4-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)benzonitrile;
4-methyl-5-((2R,6S)-6-methyl-4-((1-(2-methylpyridin-4-yl)-1H-pyrazol-4-yl)methyl)piperazin-2-yl)isobenzofuran-1(3H)-one;
4-methoxy-2-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)pyrimidine-5-carbonitrile;
2-(4-(((3R,5R)-3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)-4-methylpyrimidine-5-carbonitrile;
4-methyl-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
4-methyl-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)nicotinonitrile;
4-methoxy-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile;
3-methyl-1-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrimidin-2-yl)-1H-pyrazole-4-carbonitrile;
5-(4-(((3R,5R)-3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)-3-methylbenzo[d]oxazol-2(3H)-one;
6-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile;
6-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)-4-methoxynicotinonitrile;
6-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methoxynicotinonitrile;
4,4-methyl-6-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)thiazol-2-yl)nicotinonitrile;
6-(4-((4-hydroxy-4-methyl-3-(4-methyl-1-oxo-1,3-dihydroisob enzofuran-5-yl)piperidin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile;
4-methyl-6-(4-((2-methyl-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
6-(4-((4-hydroxy-3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile;
4-methyl-6-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2-oxooxazol-3(2H)-yl)nicotinonitrile;
(R)-4-methyl-6-(4-((4-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxoimidazolidin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-4-methyl-6-(4-((4-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
2-methyl-6-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)pyridazin-3(2H)-one;
4-methyl-6-(4-(1-((R)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)ethyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile (Dia-I:Ena-I);
4-methyl-6-(4-(1-((R)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)ethyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile (Dia-II:Ena-I);
4-methyl-6-(3-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-1,2,4-triazol-1-yl)nicotinonitrile;
6-(4-((2-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile (Dia-I:Ena-I);
6-(4-((2-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile (Dia-I:Ena-II);
6-(5-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)thiazol-2-yl)-4-methylnicotinonitrile;
5-((2R,6S)-4-((1-(2-methoxypyridin-4-yl)-1H-imidazol-4-yl)methyl)-6-methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one;
5-((2R,6S)-4-((1-(2-(difluoromethyl)pyridin-4-yl)-1H-pyrazol-4-yl)methyl)-6-methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one;
4-methyl-5-((2R,6S)-6-methyl-4-((1-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4-yl)methyl)piperazin-2-yl)isobenzofuran-1(3H)-one;
1-(difluoromethyl)-4-(4-(((3 S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)pyridin-2(1H)-one;
1-(difluoromethyl)-4-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)pyridin-2(1H)-one;
1-(5-(((3R,5R)-3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin--yl)methyl)pyridin-2-yl)-3-methyl-1H-pyrazole-4-carbonitrile;
1-(difluoromethyl)-4-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)pyridin-2(1H)-one;
6-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)oxazol-2-yl)-4-methylnicotinonitrile;
4-methyl-6-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)oxazol-2-yl)nicotinonitrile;
5-((2R,6S)-4-((1-(6-(difluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)methyl)-6-methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one;
(R)-3,4-dimethyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)benzo[d]oxazol-2(3H)-one;
(R)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)-1H-pyrazole-3-carbonitrile;
(R)-4-ethoxy-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;
(R)-5-(4-((2-(2,4-dimethyl-1H-imidazol-1-yl)pyrimidin-5-yl)methyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one;
(R)-4-isopropoxy-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-4-methyl-5-(4-((4-methyl-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)methyl)piperazin-2-yl)isobenzofuran-1(3H)-one;
(R)-4-methyl-5-(4-((2-methyl-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)methyl)piperazin-2-yl)isobenzofuran-1(3H)-one;
(R)-4,6′-dimethoxy-5′-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-[2,2′-bipyridine]-5-carbonitrile;
(R)-5-(4-((5-fluoro-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)methyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one;
(R)-4-methyl-6-(3-methyl-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-4-methyl-6-(5-methyl-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-4-methyl-5-(4-((6-(4-methyl-1H-imidazol-1-yl)-4-(trifluoromethyl)pyridin-3-yl)methyl)piperazin-2-yl)isobenzofuran-1(3H)-one;
(R)-5-(4-((2-(4,5-dimethyl-1H-imidazol-1-yl)pyrimidin-5-yl)methyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one;
(R)-5-(4-((4-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)methyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one;
(R)-5-(4-((2-(5-(difluoromethyl)-4-methyl-1H-imidazol-1-yl)pyrimidin-5-yl)methyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one;
4,6-dimethyl-2-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)pyrimidine-5-carbonitrile;
3-(3-methyl-5-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)phenyl)oxazolidin-2-one;
(R)-4-methyl-5-(4-((6-(4-methyl-1H-imidazol-1-yl)pyridazin-3-yl)methyl)piperazin-2-yl)isobenzofuran-1(3H)-one;
4-methoxy-6-(3-(((R)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)nicotinonitrile (Diastereomer-I);
4-methoxy-6-(3-(((R)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)nicotinonitrile (Diastereomer-II);
4-methyl-6-(3-(((R)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)nicotinonitrile (Diastereomer-I);
4-methyl-6-(3-(((R)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)nicotinonitrile (Diastereomer-II);
4-methyl-6-(4-(((R)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2-oxopyrrolidin-1-yl)nicotinonitrile (Diastereomer-II);
4-methoxy-6-(4-(((R)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2-oxopyrrolidin-1-yl)nicotinonitrile (Diastereomer-I);
4-methyl-6-(5-(((R)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2-oxooxazolidin-3-yl)nicotinonitrile (Diastereomer-II);
4-methyl-5-((2R,6S)-6-methyl-4-((1-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-4-yl)methyl)piperazin-2-yl)isobenzofuran-1(3H)-one;
4-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-imidazol-1-yl)-2-methoxybenzonitrile;
6-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-imidazol-1-yl)-4-methylnicotinonitrile;
4-methyl-2-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)pyrimidine-5-carbonitrile; -yl)isobenzofuran-1(3H)-one;
4-methoxy-2-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)pyrimidine-5-carbonitrile;
4-methoxy-2-(2-methyl-4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)pyrimidine-5-carbonitrile;
(R)-4-methoxy-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile;
(R)-4-methyl-6-(4-methyl-5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile;
4-methoxy-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2-oxopyrrolidin-1-yl)nicotinonitrile (Diastereomer-I);
6-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methoxynicotinonitrile;
6-(3-isopropyl-4-((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methoxynicotinonitrile;
3-methyl-4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1-(2-methylpyrimidin-4-yl)-1,3-dihydro-2H-imidazol-2-one;
3-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-[2,4′-bipyridin]-2′-yl)oxazolidin-2-one;
6-(4-((3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-5-methyl-2H-1,2,3-triazol-2-yl)-4-methylnicotinonitrile (Enantiomer-I);
4-methyl-6-(5-methyl-4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)nicotinonitrile;
(R)-4-methyl-5-(4-((1-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran-1(3H)-one;
4-methyl-5-((2R,6S)-6-methyl-4-((1-(p-tolyl)-1H-imidazol-4-yl)methyl)piperazin-2-yl)isobenzofuran-1(3H)-one;
4-methyl-5-((2R,6S)-6-methyl-4-((1-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)methyl)piperazin-2-yl)isobenzofuran-1(3H)-one;
4-methyl-5-((2R,6S)-6-methyl-4-((1-(6-methylpyridin-3-yl)-1H-imidazol-4-yl)methyl)piperazin-2-yl)isobenzofuran-1(3H)-one;
5-((2R,6S)-4-((1-(2,6-dimethylpyridin-4-yl)-1H-imidazol-4-yl)methyl)-6-methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one;
5-((2R,6S)-4-((1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-imidazol-4-yl)methyl)-6-methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one;
(R)-4-methyl-6-(2-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrimidin-5-yl)nicotinonitrile;
(R)-2,4-dimethyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile;
(R)-3-(2-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)pyridin-4-yl)oxazolidin-2-one;
(R)-2,4-dimethyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)nicotinonitrile;
(R)-4-methoxy-2-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)nicotinonitrile;
(R)-4-methoxy-2-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile;
(R)-2-methoxy-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)nicotinonitrile;
6-(4-((3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)-4-methoxynicotinonitrile (Enantiomer-I);
4-methyl-6-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)nicotinonitrile;
4-methoxy-6-(4-(2-((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)ethyl)-1H-pyrazol-1-yl)nicotinonitrile;
6-(5-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)isoxazol-3-yl)-4-methylnicotinonitrile;
5-((2R,6S)-4-((1-(4-methoxy-1,3,5-triazin-2-yl)-1H-pyrazol-4-yl)methyl)-6-methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one;
6-(4-(((3R,5R)-3-(hydroxymethyl)-4-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile;
6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-4-(trifluoromethyl)nicotinonitrile;
4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile (Enantiomer-I);
(R)-2-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)isonicotinonitrile;
6-(4-((3-hydroxy-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile (Enantiomer-IV);
6-(4-((3-methoxy-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile (Enantiomer-II);
(R)-5-(4-((2-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyrimidin-5-yl)methyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one;
3-methyl-2-(4-((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)isonicotinonitrile;
6-(4-((3-fluoro-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-4-methylnicotinonitrile (Enantiomer-I);
6-(4-((3-(1-hydroxyethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methoxynicotinonitrile (Enantiomer-I);
6-(4-((3-(difluoromethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile (Enantiomer-I);
4-methyl-5-((2R,6S)-6-methyl-4-((1-(5-methylpyrazin-2-yl)-1H-pyrazol-4-yl)methyl)piperazin-2-yl)isobenzofuran-1(3H)-one;
5-((2R,6S)-4-((1-(6-methoxypyrimidin-4-yl)-1H-pyrazol-4-yl)methyl)-6-methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one;
5-((2R,6S)-4-((1-(2-methoxypyrimidin-5-yl)-1H-pyrazol-4-yl)methyl)-6-methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one;
4-methyl-5-((2R,6S)-6-methyl-4-((1-(2-methylpyrimidin-5-yl)-1H-pyrazol-4-yl)methyl)piperazin-2-yl)isobenzofuran-1(3H)-one;
4-methyl-6-(3-(((3 S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)isoxazol-5-yl)nicotinonitrile;
6-(4-((3-hydroxy-4-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)pyrrolidin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile (Diastereomer-I: Enantiomer-I);
6-(4-((3-fluoro-4-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)pyrrolidin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile (Diastereomer-I: Enantiomer-II);
6-(4-((3-(2-hydroxypropan-2-yl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile (Enantiomer-I);
4-methyl-6-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)isoxazol-3-yl)nicotinonitrile;
(R)-4-methyl-5-(4-((2-(4-methyl-1H-imidazol-1-yl)pyrimidin-5-yl)methyl)piperazin-2-yl)isobenzofuran-1(3H)-one;
(R)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrimidin-2-yl)-1H-imidazole-4-carbonitrile;
(R)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrimidin-2-yl)-1H-1,2,4-triazole-3-carbonitrile;
(R)-3-cyclopropyl-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrimidin-2-yl)-1H-pyrazole-4-carbonitrile;
(R)-3-(difluoromethoxy)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)-1H-pyrazole-4-carbonitrile;
(R)-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-4-morpholinonicotinonitrile;
(R)-3-methyl-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrimidin-2-yl)-1H-pyrazole-4-carbonitrile;
(R)-4-methyl-5-(4-((6-(4-methyl-1H-1,2,3-triazol-1-yl)pyridin-3-yl)methyl)piperazin-2-yl)isobenzofuran-1(3H)-one;
(R)-3-methoxy-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)-1H-pyrazole-4-carbonitrile;
(R)-4-methyl-5-(4-((2-(4-methyl-1H-imidazol-1-yl)pyrimidin-5-yl)methyl)morpholin-2-yl)isobenzofuran-1(3H)-one;
(R)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)-1H-1,2,3-triazole-4-carbonitrile;
(R)-3-ethyl-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)-1H-pyrazole-4-carbonitrile;
(R)-3-methoxy-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrimidin-2-yl)-1H-pyrazole-4-carbonitrile;
(R)-3-ethyl-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrimidin-2-yl)-1H-pyrazole-4-carbonitrile;
(R)-3-(difluoromethyl)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrimidin-2-yl)-1H-pyrazole-4-carbonitrile;
(R)-4-methyl-2-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)pyrimidine-5-carbonitrile;
(R)-2-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-5-(pyrrolidin-1-yl)isonicotinonitrile;
4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-oxopiperidin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
(R)-6-(3-(difluoromethyl)-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile;
(R)-5-(4-((2-(1H-1,2,4-triazol-1-yl)pyrimidin-5-yl)methyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one;
(R)-5-(4-((6-(4 (difluoromethyl)-1H-imidazol-1-yl)pyridin-3-yl)methyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one;
(R)-4-methyl-5-(4-((2-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-5-yl)methyl)piperazin-2-yl)isobenzofuran-1(3H)-one;
(R)-6-(3-cyclopropyl-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile;
1′-methyl-5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-[2,3′-bipyridin]-6′(1′H)-one;
(R)-4-methyl-6-(4-((3-(1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile;
4-methyl-6-(4-(((6R)-2-methyl-6-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)nicotinonitrile (Diastereomer-I);
(R)-3-methyl-1-(6-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-3-yl)-1H-pyrazole-4-carbonitrile;
(R)-4-methyl-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)-1H-pyrazole-3-carbonitrile;
(R)-4-methyl-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrimidin-2-yl)-1H-pyrazole-3-carbonitrile;
4-methyl-6-(4-((2-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile (Enantiomer-II);
6-(3-(difluoromethyl)-4-(((3R,4R)-4-hydroxy-3-(4-methyl -1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile;
6-(4-(((3S,5R)-4-hydroxy-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)-4-methylnicotinonitrile;
4′-methyl-4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2-oxo-2H-[1,2′-bipyridine]-5′-carbonitrile;
N-(1-((1-(5-cyano-4-methylpyridin-2-yl)-1H-pyrazol-4-yl)methyl)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-4-yl)acetamide (Diastereomer-II Enantiomer-I);
3-(6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)pyridin-2-yl)oxazolidin-2-one;
6-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methylnicotinonitrile;
3-(2-methyl-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)pyridin-4-yl)oxazolidin-2-one;
N-methyl-N-(6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)pyridin-2-yl)methanesulfonamide;
5-((2R,6S)-4-((1-(4-(1,1-dioxidoisothiazolidin-2-yl)-6-methylpyridin-2-yl)-1H-pyrazol-4-yl)methyl)-6-methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one;
1-(2-methoxypyridin-4-yl)-4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrrolidin-2-one (Diastereomer-I);
(R)-4-methoxy-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)nicotinonitrile;
6-(4-((2,2-dimethyl-6-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile (Enantiomer-II);
N-(1-((1-(5-cyano-4-methylpyridin-2-yl)-1H-pyrazol-4-yl)methyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-3-yl)acetamide (Enantiomer-I);
1-((1-(5-cyano-4-methylpyridin-2-yl)-1H-pyrazol-4-yl)methyl)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-4-ylmethylcarbamate (Enantiomer-I);
4-methyl-6-(3-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1,2,4-oxadiazol-5-yl)nicotinonitrile;
(R)-1-(5-cyano-4-methoxypyridin-2-yl)-N-methyl-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazole-3-carboxamide;
6-(4-((3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile (Diastereomer-II Enantiomer-II);
(R)-1-(5-cyano-4-methoxypyridin-2-yl)-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazole-3-carboxamide;
(R)-4-(methoxy-d3)-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)nicotinonitrile;
(R)-4-methyl-5-(4-((6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)methyl)piperazin-2-yl)isobenzofuran-1(3H)-one;
2-methyl-4-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-tetrazol-2-yl)benzonitrile;
3-methyl-4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1-(2-methylpyridin-4-yl)-1,3-dihydro-2H-imidazol-2-one;
6-(5-((3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)-4-methylnicotinonitrile (Enantiomer-I);
6-(5-((3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)isoxazol-3-yl)-4-methylnicotinonitrile (Enantiomer-I);
4-methoxy-6-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)isoxazol-3-yl)nicotinonitrile;
1-(difluoromethyl)-4-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)pyridin-2(1H)-one;
5-((2R,6S)-4-((1-(2-(difluoromethyl)pyrimidin-4-yl)-1H-imidazol-4-yl)methyl)-6-methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one;
4-(5-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-2H-tetrazol-2-yl)-2-methoxybenzonitrile;
6-(5-((3-(difluoromethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)-4-methylnicotinonitrile (Enantiomer-I);
4-methoxy-6-(3-methyl-4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2-oxoimidazolidin-1-yl)nicotinonitrile (Diastereomer-I);
1-(2-methoxypyridin-4-yl)-3-methyl-4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1,3-dihydro-2H-imidazol-2-one;
1-(2-(difluoromethyl)pyridin-4-yl)-3-methyl-4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1,3-dihydro-2H-imidazol-2-one; and
4-methoxy-6-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl-3,3-d2)piperazin-1-yl)methyl)isoxazol-3-yl)nicotinonitrile.
11. A pharmaceutical composition comprising one or more compounds according to claim 1 , or a salt thereof; and a pharmaceutically acceptable carrier or diluent.
12. A pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a compound as defined in claim 1 , or pharmaceutically acceptable salt, alone or in combination with another therapeutic agent.
13. A method for the treatment of a cardiovascular disease, which comprises administering to a patient having said disease a therapeutically affective amount of a compound of claim 1 , or pharmaceutically acceptable salt thereof.
14. The method of claim 13 , wherein the cardiovascular disease is selected from hypertension, coronary heart disease, stroke, heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, acute-decompensated heart failure, post-operative volume overload, idiopathic edema, pulmonary hypertension, pulmonary arterial hypertension, cardiac insufficiency, nephrotic syndrome, and acute kidney insufficiency.
15. A method for promoting diuresis or natriuresis, which comprises administering to a patient in need thereof a therapeutically affective amount of a compound of claim 1 , or pharmaceutically acceptable salt thereof.
16. A compound of claim 5 , or salt thereof, wherein:
R 2 is phenyl, pyridinyl, indolyl, indazolyl, benzo[d]oxazol-2(3H)-onyl, pyrazolo[4,3-b]pyridinyl, pyridin-2(1H)-onyl, pyrazolyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-b]pyridazinyl, pyrazinyl, pyrazolo[1,5-a]pyrimidinyl, thiophenyl, [1,2,4]triazolo[4,3-b]pyridazinyl, or pyrazolo[1,5-a]pyrimidinyl, or benzo[d]oxazol-2(3H)-only, each being substituted with 0-3 R 2a ; and
R 2a is OH, ═O, CN, halo, C 1-4 alkyl, C 1-4 fluoroalkyl, C 14 alkoxy, or C 1-4 fluoroalkoxy.
17. A compound of claim 16 , or salt thereof, wherein:
R 1 is
R 1a is independently H or —CH 3 .
18. The compound according to claim 17 , or salt thereof, wherein:
Ring B is pyridinyl, triazolyl, thiazolyl, oxadiazolyl, imidazolyl, or pyrrazolyl pyrazolyl; and
R 2 is phenyl, pyridinyl, pyrimidinyl, benzo[d]oxazol-2(3H)-onyl, imidazolyl, pyrazolyl, triazolyl, or oxadiazolyl, each being substituted with 0-3 R ea R 2a .
19. The compound according to claim 18 , or salt thereof, wherein:
V is —O—, —NR 4 —, or —CR 5 R 5 —;
Y is —C(R 6 ) 2 —C(R 6 ) 2 — or —C(R 6 ) 2 —;
L 1 is —C(R) 2 —; wherein R is independently hydrogen, F, OH, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxyalkyl, or C 1-3 fluoroalkyl; and
R 6 is independently H, C 1-3 -alkyl, C 1-3 -fluoroalkyl, or C 3-6 -cycloalkyl.
20. A compound, wherein the compound is
or salt thereof.
21. A compound, wherein the compound is
22. A pharmaceutical composition comprising one or more compounds according to claim 20 , or a salt thereof; and a pharmaceutically acceptable carrier or diluent.
23. A pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a compound as defined in claim 20 , or pharmaceutically acceptable salt, alone or in combination with another therapeutic agent.
24. A method for the treatment of a cardiovascular disease, which comprises administering to a patient having said disease a therapeutically affective amount of a compound of claim 20 , or pharmaceutically acceptable salt thereof.
25. The method of claim 24 , wherein the cardiovascular disease is selected from hypertension, coronary heart disease, stroke, heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, acute-decompensated heart failure, post-operative volume overload, idiopathic edema, pulmonary hypertension, pulmonary arterial hypertension, cardiac insufficiency, nephrotic syndrome, and acute kidney insufficiency.
26. A method for promoting diuresis or natriuresis, which comprises administering to a patient in need thereof a therapeutically affective amount of a compound of claim 20 , or pharmaceutically acceptable salt thereof.
27. A compound, wherein the compound is
or salt thereof.
28. A compound, wherein the compound is
29. A pharmaceutical composition comprising one or more compounds according to claim 27 , or a salt thereof; and a pharmaceutically acceptable carrier or diluent.
30. A pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a compound as defined in claim 27 , or pharmaceutically acceptable salt, alone or in combination with another therapeutic agent.
31. A method for the treatment of a cardiovascular disease, which comprises administering to a patient having said disease a therapeutically affective amount of a compound of claim 27 , or pharmaceutically acceptable salt thereof.
32. The method of claim 31 , wherein the cardiovascular disease is selected from hypertension, coronary heart disease, stroke, heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, acute-decompensated heart failure, post-operative volume overload, idiopathic edema, pulmonary hypertension, pulmonary arterial hypertension, cardiac insufficiency, nephrotic syndrome, and acute kidney insufficiency.
33. A method for promoting diuresis or natriuresis, which comprises administering to a patient in need thereof a therapeutically affective amount of a compound of claim 27 , or pharmaceutically acceptable salt thereof.
34. A compound, wherein the compound is
or salt thereof.
35. A compound, wherein the compound is
36. A pharmaceutical composition comprising one or more compounds according to claim 34 , or a salt thereof and a pharmaceutically acceptable carrier or diluent.
37. A pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a compound as defined in claim 34 , or pharmaceutically acceptable salt, alone or in combination with another therapeutic agent.
38. A method for the treatment of a cardiovascular disease, which comprises administering to a patient having said disease a therapeutically affective amount of a compound of claim 34 , or pharmaceutically acceptable salt thereof.
39. The method of claim 38 , wherein the cardiovascular disease is selected from hypertension, coronary heart disease, stroke, heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, acute-decompensated heart failure, post-operative volume overload, idiopathic edema, pulmonary hypertension, pulmonary arterial hypertension, cardiac insufficiency, nephrotic syndrome, and acute kidney insufficiency.
40. A method for promoting diuresis or natriuresis, which comprises administering to a patient in need thereof a therapeutically affective amount of a compound of claim 34 , or pharmaceutically acceptable salt thereof.
41. A compound, wherein the compound is
or salt thereof.
42. A compound, wherein the compound is
43. A pharmaceutical composition comprising one or more compounds according to claim 41 , or a salt thereof; and a pharmaceutically acceptable carrier or diluent.
44. A pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a compound as defined in claim 41 , or pharmaceutically acceptable salt, alone or in combination with another therapeutic agent.
45. A method for the treatment of a cardiovascular disease, which comprises administering to a patient having said disease a therapeutically affective amount of a compound of claim 41 , or pharmaceutically acceptable salt thereof.
46. The method of claim 45 , wherein the cardiovascular disease is selected from hypertension, coronary heart disease, stroke, heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, acute-decompensated heart failure, post-operative volume overload, idiopathic edema, pulmonary hypertension, pulmonary arterial hypertension, cardiac insufficiency, nephrotic syndrome, and acute kidney insufficiency.
47. A method for promoting diuresis or natriuresis, which comprises administering to a patient in need thereof a therapeutically affective amount of a compound of claim 41 , or pharmaceutically acceptable salt thereof.
48. A compound, wherein the compound is
or salt thereof.
49. A compound, wherein the compound is
50. A pharmaceutical composition comprising one or more compounds according to claim 48 , or a salt thereof; and a pharmaceutically acceptable carrier or diluent.
51. A pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a compound as defined in claim 48 , or pharmaceutically acceptable salt, alone or in combination with another therapeutic agent.
52. A method for the treatment of a cardiovascular disease, which comprises administering to a patient having said disease a therapeutically affective amount of a compound of claim 48 , or pharmaceutically acceptable salt thereof.
53. The method of claim 52 , wherein the cardiovascular disease is selected from hypertension, coronary heart disease, stroke, heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, acute-decompensated heart failure, post-operative volume overload, idiopathic edema, pulmonary hypertension, pulmonary arterial hypertension, cardiac insufficiency, nephrotic syndrome, and acute kidney insufficiency.
54. A method for promoting diuresis or natriuresis, which comprises administering to a patient in need thereof a therapeutically affective amount of a compound of claim 48 , or pharmaceutically acceptable salt thereof.
55. A compound, wherein the compound is
or salt thereof.
56. A compound, wherein the compound is
57. A pharmaceutical composition comprising one or more compounds according to claim 55 , or a salt thereof; and a pharmaceutically acceptable carrier or diluent.
58. A pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a compound as defined in claim 55 , or pharmaceutically acceptable salt, alone or in combination with another therapeutic agent.
59. A method for the treatment of a cardiovascular disease, which comprises administering to a patient having said disease a therapeutically affective amount of a compound of claim 55 , or pharmaceutically acceptable salt thereof.
60. The method of claim 59 , wherein the cardiovascular disease is selected from hypertension, coronary heart disease, stroke, heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, acute-decompensated heart failure, post-operative volume overload, idiopathic edema, pulmonary hypertension, pulmonary arterial hypertension, cardiac insufficiency, nephrotic syndrome, and acute kidney insufficiency.
61. A method for promoting diuresis or natriuresis, which comprises administering to a patient in need thereof a therapeutically affective amount of a compound of claim 55 , or pharmaceutically acceptable salt thereof.Cited by (0)
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