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US 10,851,108 B2Granted
Substituted bicyclic heterocyclic compounds
AssigneeBristol-Myers Squibb Company
InventorsPrashantha Gunaga, Jeremy Richter, Navnath Dnyanoba Yadav, Manoranjan Panda, Sreenivasulu Godesi
Life of this patent
Estimating the term…
Abstract
Disclosed are compounds of Formula (I), or a salt thereof, wherein: X is CR4 or N; Y is CR4 or N, provided that Y is N only if X is N; R1 is Formulae (A) or (B); each W is independently NR1b or O; Z is a bond or CHR1d; and R1, R2, R3, R4, L1, R1a, R1b, R1c, 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.
Claims14
A compound having the structure of Formula (I)
- or a salt thereof, wherein:
- X is CR4 or N;
- Y is CR4 or N, provided that Y is N only if X is N;
- R1 is:
- each W is independently NR1b or O;
- Z is a bond or CHR1d;
- each R1a is independently H, F, Cl, —OH, C1-3 alkyl, C1-3 fluoroalkyl, C3-6 cycloalkyl, C1-3 alkoxy, or C1-3 fluoroalkoxy;
- each R1b is independently H, C1-3 alkyl, C1-3 fluoroalkyl, aryl, or heteroaryl;
- R1c is H, C1-4 alkyl, or C3-6 cycloalkyl;
- R1d is H, C1-3 alkyl, C3-6 cycloalkyl, or C1-3 alkoxy;
- n is zero, 1, 2, or 3;
- L1 is a bond, —CHRb—, or —CHRaCHRb—;
- Ra is H, halo, —OH, C1-4 alkyl, C1-3 fluoroalkyl, C1-3 hydroxyalkyl, C3-6 cycloalkyl, C1-3 alkoxy, or C1-3 fluoroalkoxy;
- Rb is H, C1-4 alkyl, C1-3 fluoroalkyl, C1-3 hydroxyalkyl, C3-6 cycloalkyl, C1-3 alkoxy, or C1-3 fluoroalkoxy;
- R2 is R2a or -L2-R2b;
- L2 is —NRa— or —NRcCH2—;
- Rc is H, C1-3 alkyl, C1-3 fluoroalkyl, C3-6 cycloalkyl, or (C1-3 alkoxy)-(C1-3 alkylenyl);
- R2a is a nitrogen-linked heterocyclyl selected from imidazolyl, indolinyl, morpholinyl, piperidinyl, pyrazolyl, pyrrolidinyl, pyrrolyl, triazolyl, 1,2,3,4-tetrahydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,7-naphthyridinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3-triazolo[4,5-b]pyridinyl, benzo[d][1,2,3]triazolyl, benzo[d]imidazolyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, indazolyl, indolyl, pyrazolo[3,4-b] pyrazinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-b] pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-d]pyrimidinyl, pyrrolo[2,3-b] pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, 2,3-dihydro-pyrrolo[2,3-b]pyridinyl, 2,3-dihydro-pyrrolo[2,3-c]pyridinyl, 2,3-dihydro-pyrrolo[3,2-b]pyridinyl, 2,3-dihydro-pyrrolo[3,2-c]pyridinyl, 3,4-dihydro-benzo[b][1,4]oxazinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, 5,6,7,8-tetrahydropyrido[3,2-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl, pyrrolo[3,2-c] pyridazinyl, pyrrolo[3,2-d]pyrimidinyl, 6,7-dihydro-pyrrolo[3,2-d]pyrimidinyl, and purinyl, wherein each of said heterocyclyl is substituted with zero to 4 Rd;
- R2b is phenyl or a carbon-linked heterocyclyl selected from pyrrolyl, furan, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c]isothiazolyl, benzo[c]isoxazolyl, benzo[d]imidazolyl, benzo[d]isothiazolyl, benzo[d]isoxazolyl, benzo[d]oxazol-2(3H)-onyl, benzo[d]oxazolyl, benzo[d]thiazolyl, indazolyl, indolyl, isobenzofuran-1(3H)-onyl, isochroman-l-only, pyrazolo[1,5-a]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, and pyrrolo[3,2-c]pyridinyl;
- wherein each of said phenyl and said heterocyclyl is substituted with zero to 4 Rd;
- each R3 is independently H, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C3-6 cycloalkyl, (C1-3 alkoxy)-(C1-3 alkylenyl), —C(O)ORe, or —C(O)NReRe;
- each R4 is independently H, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C3-6 cycloalkyl, (C1-3 alkoxy)-(C1-3 alkylenyl), aryl, heteroaryl, —CO2H, —CO2Re, —CONHRe, —CONReRe, or —NR4aR4a, wherein each of said cycloalkyl, aryl, and said heteroaryl is substituted with zero to 3 Rd;
- each R4a is independently H, C1-3 alkyl, C1-3 fluoroalkyl, C3-6 cycloalkyl, aryl, or heteroaryl, wherein each of said cycloalkyl, aryl, and said heteroaryl is substituted with zero to 3 Rd;
- or two R4a along with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl;
- each Rd is independently F, Cl, —OH, —CN, C1-3 alkyl, C1-3 fluoroalkyl, C3-6 cycloalkyl, C1-3 alkoxy, C1-3 fluoroalkoxy, —C(O)ORe, —C(O)NReRe, —OC(O)NReRe, —NHC(O)ORe, —NReC(O)ORe, —S(O)2Re, or tetrazolyl;
- and
- each Re is independently H, C1-3 alkyl, C1-3 fluoroalkyl, C3-6 cycloalkyl, aryl, or heteroaryl;
- or two Re along with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl.
25 more elements
A compound having the structure of Formula (I)
- or a salt thereof, wherein:
- X is CR4 or N;
- Y is CR4 or N, provided that Y is N only if X is N;
- R1 is:
- each W is independently NR1b or O;
- Z is a bond or CHR1d;
- each R1a is independently H, F, Cl, —OH, C1-3 alkyl, C1-3 fluoroalkyl, C3-6 cycloalkyl, C1-3 alkoxy, or C1-3 fluoroalkoxy;
- each R1b is independently H, C1-3 alkyl, C1-3 fluoroalkyl, aryl, or heteroaryl;
- R1c is H, C1-4 alkyl, or C3-6 cycloalkyl;
- R1d is H, C1-3 alkyl, C3-6 cycloalkyl, or C1-3 alkoxy;
- n is zero, 1, 2, or 3;
- L1 is a bond, —CHRb—, or —CHRaCHRb—;
- Ra is H, halo, —OH, C1-4 alkyl, C1-3 fluoroalkyl, C1-3 hydroxyalkyl, C3-6 cycloalkyl, C1-3 alkoxy, or C1-3 fluoroalkoxy;
- Rb is H, C1-4 alkyl, C1-3 fluoroalkyl, C1-3 hydroxyalkyl, C3-6 cycloalkyl, C1-3 alkoxy, or C1-3 fluoroalkoxy;
- R2 is R2a or -L2-R2b;
- L2 is —NRa— or —NRcCH2—;
- Rc is H, C1-3 alkyl, C1-3 fluoroalkyl, C3-6 cycloalkyl, or (C1-3 alkoxy)-(C1-3 alkylenyl);
- R2a is a nitrogen-linked heterocyclyl selected from imidazolyl, indolinyl, morpholinyl, piperidinyl, pyrazolyl, pyrrolidinyl, pyrrolyl, triazolyl, 1,2,3,4-tetrahydro-1,5-naphthyridinyl, 1,2,3,4-tetrahydro-1,7-naphthyridinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3-triazolo[4,5-b]pyridinyl, benzo[d][1,2,3]triazolyl, benzo[d]imidazolyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, indazolyl, indolyl, pyrazolo[3,4-b] pyrazinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-b] pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-d]pyrimidinyl, pyrrolo[2,3-b] pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, 2,3-dihydro-pyrrolo[2,3-b]pyridinyl, 2,3-dihydro-pyrrolo[2,3-c]pyridinyl, 2,3-dihydro-pyrrolo[3,2-b]pyridinyl, 2,3-dihydro-pyrrolo[3,2-c]pyridinyl, 3,4-dihydro-benzo[b][1,4]oxazinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, 5,6,7,8-tetrahydropyrido[3,2-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl, pyrrolo[3,2-c] pyridazinyl, pyrrolo[3,2-d]pyrimidinyl, 6,7-dihydro-pyrrolo[3,2-d]pyrimidinyl, and purinyl, wherein each of said heterocyclyl is substituted with zero to 4 Rd;
- R2b is phenyl or a carbon-linked heterocyclyl selected from pyrrolyl, furan, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c]isothiazolyl, benzo[c]isoxazolyl, benzo[d]imidazolyl, benzo[d]isothiazolyl, benzo[d]isoxazolyl, benzo[d]oxazol-2(3H)-onyl, benzo[d]oxazolyl, benzo[d]thiazolyl, indazolyl, indolyl, isobenzofuran-1(3H)-onyl, isochroman-l-only, pyrazolo[1,5-a]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, and pyrrolo[3,2-c]pyridinyl;
- wherein each of said phenyl and said heterocyclyl is substituted with zero to 4 Rd;
- each R3 is independently H, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C3-6 cycloalkyl, (C1-3 alkoxy)-(C1-3 alkylenyl), —C(O)ORe, or —C(O)NReRe;
- each R4 is independently H, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C3-6 cycloalkyl, (C1-3 alkoxy)-(C1-3 alkylenyl), aryl, heteroaryl, —CO2H, —CO2Re, —CONHRe, —CONReRe, or —NR4aR4a, wherein each of said cycloalkyl, aryl, and said heteroaryl is substituted with zero to 3 Rd;
- each R4a is independently H, C1-3 alkyl, C1-3 fluoroalkyl, C3-6 cycloalkyl, aryl, or heteroaryl, wherein each of said cycloalkyl, aryl, and said heteroaryl is substituted with zero to 3 Rd;
- or two R4a along with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl;
- each Rd is independently F, Cl, —OH, —CN, C1-3 alkyl, C1-3 fluoroalkyl, C3-6 cycloalkyl, C1-3 alkoxy, C1-3 fluoroalkoxy, —C(O)ORe, —C(O)NReRe, —OC(O)NReRe, —NHC(O)ORe, —NReC(O)ORe, or —S(O)2Re;
- and
- each Re is independently H, C1-3 alkyl, C1-3 fluoroalkyl, C3-6 cycloalkyl, aryl, or heteroaryl;
- or two Re along with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl.
25 more elements
Dependencies are inferred from the claim text.