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US 2014/0371203 A1Published application
Thieno- and furo - pyrimidines and pyridines, useful as potassium channel inhibitors
AssigneeXention Limited
InventorsDavid Madge, Fiona Chan, Derek Edward John, Simon D. Edwards, Richard Blunt, Basil Hartzoulakis, Lindsay Brown
Life of this patent
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Abstract
The present invention provides compounds of formula (I): (Formula (I); wherein A, R1, R2, R3I, V, X, and Z are defined herein, which are potassium channel inhibitors. The invention further provides pharmaceutical compositions comprising the compounds of formula (I) and their use in therapy, in particular in treatment of diseases or conditions that are mediated by Kir3.1 and/or Kir3.4 or any heteromultimers thereof, or that require inhibition of Kir3.1 and/or Kir3.4 or any heteromultimers thereof.
Claims25
A compound of formula (i)
- or a pharmaceutically acceptable derivative thereof, wherein:
- A is O or S;
- X is N or CR3II;
- V is N or CR3III;
- Z is N or CR3IV;
- wherein one or two of V, X and Z are N;
- R1 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
- R2 is selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally substituted alkoxy, —NR4R5, —NR6C(O)R7, —NR6S(O)2R7, —S(O)2NR4R5, —CONR4R5, —CO2R7, optionally substituted oxazolinyl, —SR14, —S(O)R4 and —S(O)2R14;
- R3I is selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkoxy, —NR6C(O)R7, —NR6S(O)2R7, —S(O)2NR4R5, —CONR4R5, —CO2R7, —NR8R9, —C≡C-J, optionally substituted cycloalkyl-J and —(NRaRb)-J;
- Each of R3II, R3III, and R3IV is independently selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkoxy, optionally substituted heterocycloalkylalkyl, —NR6C(O)R7, —NR6S(O)2R7, —S(O)2NR4R5, —CONR4R5, optionally substituted -alkylene-CONR4R5, —CO2R7, —NR10R11, —C≡C-J, optionally substituted cycloalkyl-J and (NRcRd)-J,
- provided that R3I is —C≡C-J, optionally substituted cycloalkyl-J or —(NRaRb)-J, and/or at least one of R3II, R3III, and R3IV is present as —C≡C-J, optionally substituted cycloalkyl-J or —(NRcRd)— J;
- wherein Ra and Rb are linked to form an optionally substituted 4 to 7 membered heterocycloalkyl ring, which is optionally bridged by a bond, optionally substituted C1-2alkylene, —NR6—, —O—, or —S(O)z—, wherein the optionally bridged, optionally substituted heterocycloalkyl ring is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydro-1,3-oxazinyl, hexahydropyrimidinyl, 1,4-thiazanyl, azepanyl, 1,4-oxaazepanyl, and 1,4-thieazepanyl;
- wherein Rc and Rd are linked to form an optionally substituted 4 to 7 membered heterocycloalkyl ring, which is optionally bridged by a bond, optionally substituted C1-2alkylene, —NR6—, —O—, or —S(O)z—;
- J is selected from H and —(CR12R13)q-L-M-W,
- wherein
- q is 0, 1 or 2;
- L is —O— or —N(G)-;
- and
- G is selected from hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl;
- M is —(CR2R13)t;
- t is 0, 1, 2 or 3;
- W is selected from the group consisting of optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and —NR8R9,
- wherein when W is optionally substituted cycloalkyl it may optionally be bridged by a bond or optionally substituted C1-2alkylene, and
- wherein when W is optionally substituted heterocycloalkyl it may optionally be bridged by a bond, optionally substituted C1-2alkylene, —NR6—, —O—, or —S(O)z—;
- alternatively, when L=-N(G)-, L, G, M and W may be linked to form an optionally substituted heterocycloalkyl, an optionally substituted hetercycloalkenyl, or an optionally substituted heteroaryl;
- z is 0, 1 or 2;
- R4 and R5 are, at each instance, independently selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted cycloalkyl, or are linked to form an optionally substituted heterocycloalkyl;
- R6 and R7 are, at each instance, independently selected from H and optionally substituted alkyl, or are linked to form an optionally substituted heterocycloalkyl;
- R6 and R9 are, at each instance, independently selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted cycloalkyl;
- R10 and R11 are, at each instance, independently selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted cycloalkyl;
- R12 and R13 are, at each instance, independently selected from H, hydroxy, and optionally substituted alkyl, or may be linked to form an optionally substituted cycloalkyl ring, or may together form ═O;
- and
- R14 is optionally substituted alkyl,
- wherein the optional substituents are independently selected from halo, trihalomethyl, trihaloethyl, trihalomethoxy, trihaloethoxy, —OH, —NO2, —CN, —CO2H, —CO2C1-6alkyl, —SO3H, —SOC1-6alkyl, —SO2C1-6alkyl, —NHSO2C1-6alkyl, —NC1-6alkylSO2C1-6alkyl, —SO2NH2, —SO2NHC1-6alkyl, —SO2N(C1-6alkyl)2, —NHSO2NH2, —NHSO2NHC1-6alkyl, —NHSO2N(C1-6alkyl)2, —NC1-6alkylSO2NH2, —NC1-6alkylSO2NHC1-6alkyl, —NC1-6alkylSO2N(C1-6alkyl)2, —C(═O)H, —C(═O)C1-6alkyl, —NHC(═O)C1-6alkyl, —NC1-16alkylC(═O)C1-6alkyl, C1-6alkylenedioxy, ═O, —N(C1-6alkyl)2, —C(═O)NH2, —C(═O)NHC1-6alkyl, —C(═O)N(C1-6alkyl)2, —NHC(═O)NH2, —NHC(═O)NHC1-6alkyl, —NHC(═O)N(C1-6alkyl)2, —NC1-6alkylC(═O)NH2, —NC1-6alkylC(═O)NHC1-6alkyl, —NC1-6alkylC(═O)N(C1-6alkyl)2, —C(═NH)NH2, —C(═NH)NHC1-6alkyl, —C(═NH)N(C1-6alkyl)2, —C(═NC1-6alkyl)NH2, —C(═NC1-6alkyl)NHC1-6alkyl, —C(═NC1-6alkyl)N(C1-6alkyl)2, —C1-6alkyl, —C3-6cycloalkyl, —C3-6heterocycloalkyl, 2-imidazolidinon-3-yl, 1-C1-6alkyl-2-imidazolidinon-3-yl, C1-6alkylC3-6heterocycloalkyl, aryl, haloaryl, C1-6alkoxyaryl, —C1-6alkylene-NHSO2C1-6alkyl, —C1-6alkylene-NC1-6alkylSO2C1-6alkyl, —C1-6alkylene-SO2NH2, —C1-6alkylene-SO2NHC1-6alkyl, —C1-6alkylene-SO2N(C1-6alkyl)2, —ZtH, —Zt—C1-6alkyl, —C1-6alkylene-ZtH, —Zt—C3-6cycloalkyl, or —C(═O)NHC1-6alkylene-ZtH wherein Zt is independently O, S, NH or N(C1-6alkyl),
- wherein said compound is not:
- 2-Benzyl-5-methyl-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbonitrile,
- [1-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester,
- [1-(6-methyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester,
- {1-[5-(4-bromo-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester,
- [1-(5-p-tolyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester,
- [1-(5-methyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester,
- 1-(5-phenyl-thieno[2,3-d]pyrimidine-4-yl)-piperidin-4-ylamine,
- 1-(6-methyl-5-phenyl-thieno[2,3-d]pyrimidine-4-yl)-piperidin-4-ylamine,
- 1-(5-(4-bromo-phenyl)-thieno[2,3-d]pyrimidine-4-yl)-piperidin-4-ylamine,
- 1-(5-p-tolyl-thieno[2,3-d]pyrimidine-4-yl)-piperidin-4-ylamine,
- 1-(5-methyl-thieno[2,3-d]pyrimidine-4-yl)-piperidin-4-ylamine,
- 1-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-one,
- 1-[5-(4-bromo-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-piperidin-4-one,
- 1-(5-p-tolyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-one,
- 1-(6-methyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-one,
- 2-{1-[5-(4-bromo-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-piperidin-4-ylamino}-cyclohexanol,
- 2-{1-(5-p-tolyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamino}-cyclohexanol,
- 2-{1-(6-methyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamino}-cyclohexanol,
- 1-benzyloxy-3-[1-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamino]-propan-2-ol,
- 2-[1-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamino]-cyclohexanol,
- 5-methoxy-2-{[1-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamino]methyl}-phenol,
- bis -(2-fluoro-benzyl)-[1-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-amine,
- 2-fluoro-6-{[1-(6-methyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamino]methyl}-phenol,
- 2-({1-[5-(4-bromo-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-piperidin-4-ylamino}methyl)-6-fluoro-phenol,
- 2-fluoro-6-{[1-(5-p-tolyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamino]methyl}-phenol (3-Benzyloxy-2-hydroxy-propyl)-[1-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-ammonium;
- chloride,
- 4-{4-[2-(4-Fluoro-phenoxymethyl-morpholin-4-yl]-piperidin-1-yl}-5-phenyl-thieno[2,3-d]pyrimidine,
- 4-{4-[2-(Benzo[1,3]dioxol-5-yloxymethyl)-morpholin-4-yl]-piperidin-1-yl}-5-phenyl-thieno[2,3-d]pyrimidine, or
- 6-(Benzo[1,3]dioxol-5-yloxymethyl)-4-[1-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-morpholin-3-one.
61 more elements
The compound of 1, wherein q is 0 or 1.
A method for the treatment of a disease or condition that is mediated by Kir3.1 and/or Kir3.4 or any heteromultimers thereof, or that requires inhibition of Kir3.1 and/or Kir3.4 or any heteromultimers thereof, comprising administering to a subject an effective amount of at least one compound of formula (i)
- or a pharmaceutically acceptable derivative thereof, wherein:
- A is O or S;
- X is N or CR3II;
- V is N or CR3II;
- Z is N or CR3IV;
- wherein one or two of V, X and Z are N;
- R1 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
- R2 is selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally substituted alkoxy, —NR4R5, —NR6C(O)R7, —NR6S(O)2R7, —S(O)2NR4R5, —CONR4R5, —CO2R7, optionally substituted oxazolinyl, —SR4, —S(O)R14 and —S(O)2R14;
- R3I is selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkoxy, —NR6C(O)R7, —NR6S(O)2R7, —S(O)2NR4R5, —CONR4R5, —CO2R7, —NR8R9, —C≡C-J, optionally substituted cycloalkyl-J and —(NRaRb)-J;
- Each of R3II, R3III, and R3IV is independently selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkoxy, optionally substituted heterocycloalkylalkyl, —NR6C(O)R7, —NRS(O)2R7, —S(O)2NR4R5, —CONR4R5, optionally substituted -alkylene-CONR4R5, —CO2R7, —NR10R11. —C≡C-J, optionally substituted cycloalkyl-J and —(NRcRd)-J,
- provided that R3I is —C≡C-J, optionally substituted cycloalkyl-J or —(NRcRd)-J, and/or at least one of R311, R3II, and R3IV is present as —C≡C-J, optionally substituted cycloalkyl-J, or —(NRcRd)-J;
- wherein Ra and Rb are linked to form an optionally substituted 4 to 7 membered heterocycloalkyl ring, which is optionally bridged by a bond, optionally substituted C1,2alkylene, —NR6—, —O—, or —S(O)z—, wherein the optionally bridged, optionally substituted heterocycloalkyl ring is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydro-1,3-oxazinyl, hexahydropyrimidinyl, 1,4-thiazanyl, azepanyl, 1,4-oxaazepanyl, and 1,4-thieazepanyl;
- wherein Rc and Rd are linked to form an optionally substituted 4 to 7 membered heterocycloalkyl ring, which is optionally bridged by a bond, optionally substituted C1-2alkylene, —NR6—, —O—, or —S(O)z—;
- J is selected from H and —(CR12R13)q-L-M-W,
- wherein
- q is 0, 1 or 2;
- L is —O— or —N(G)-;
- and
- G is selected from hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl;
- M is —(CR12R13)t—;
- t is 0, 1, 2 or 3;
- W is selected from the group consisting of optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and —NR8R9,
- wherein when W is optionally substituted cycloalkyl it may optionally be bridged by a bond or optionally substituted C1-2alkylene, and
- wherein when W is optionally substituted heterocycloalkyl it may optionally be bridged by a bond, optionally substituted C1-2alkylene, —NR6—, —O—, or —S(O)z—;
- alternatively, when L=-N(G)-, L, G, M and W may be linked to form an optionally substituted heterocycloalkyl, an optionally substituted hetercycloalkenyl, or an optionally substituted heteroaryl;
- z is 0, 1 or 2;
- R4 and R5 are, at each instance, independently selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted cycloalkyl, or are linked to form an optionally substituted heterocycloalkyl;
- R6 and R7 are, at each instance, independently selected from H and optionally substituted alkyl, or are linked to form an optionally substituted heterocycloalkyl;
- R8 and R9 are, at each instance, independently selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted cycloalkyl;
- R10 and R11 are, at each instance, independently selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted cycloalkyl;
- R12 and R13 are, at each instance, independently selected from H, hydroxy, and optionally substituted alkyl, or may be linked to form an optionally substituted cycloalkyl ring, or may together form ═O;
- and
- R14 is optionally substituted alkyl,
- wherein the optional substituents are independently selected from halo, trihalomethyl, trihaloethyl, trihalomethoxy, trihaloethoxy, —OH, —NO2, —CN, —CO2H, —CO2C1-6alkyl, —SO3H, —SOC1-6alkyl, —SO2C1-6alkyl, —NHSO2C1-6alkyl, —NC1-6alkylSO2C1-6alkyl, —SO2NH2, —SO2NHC1-6alkyl, —SO2N(C1-6alkyl)2, —NHSO2NH2, —NHSO2NHC1-6alkyl, —NHSO2N(C1-6alkyl)2, —NC1-6alkylSO2NH2, —NC1-6alkylSO2NHC1-16alkyl, —NC1-6alkylSO2N(C1-6alkyl)2, —C(═O)H, —C(═O)C1-6alkyl, —NHC(═O)C1-6alkyl, —NC1-6alkylC(═O)C1-6alkyl, C1-6alkylenedioxy, ═O, —N(C1-6alkyl)2, —C(═O)NH2, —C(═O)NHC1-6alkyl, —C(═O)N(C1-6alkyl)2, —NHC(═O)NH2, —NHC(═O)NHC1-6alkyl, —NHC(═O)N(C1-6alkyl)2, —NC1-6alkylC(═O)NH2, —NC1-6alkylC(═O)NHC1-6alkyl, —NC1-6alkylC(═O)N(C1-6alkyl)2, —C(═NH)NH2, —C(═NH)NHC1-6alkyl, —C(═NH)N(C1-6alkyl)2, —C(═NC1-6alkyl)NH2, —C(═NC1-6alkyl)NHC1-6alkyl, —C(═NC1-6alkyl)N(C1-6alkyl)2, —C1-16alkyl, —C3-6cycloalkyl, —C3-6heterocycloalkyl, 2-imidazolidinon-3-yl, 1-C1-6alkyl-2-imidazolidinon-3-yl, C1-6alkylC3-6heterocycloalkyl, aryl, haloaryl, C1-6alkoxyaryl, —C1-6alkylene-NHSO2C1-6alkyl, —C1-6alkylene-NC1-6alkylSO2C1-6alkyl, —C1-6alkylene-SO2NH2, —C1-6alkylene-SO2NHC1-6alkyl, —C1-6alkylene-SO2N(C1-6alkyl)2, —ZtH, —Zt—C1-6alkyl, —C1-6alkylene-ZtH, —Zt—C3-6cycloalkyl, or —C(═O)NHC1-6alkylene-ZtH wherein Zt is independently O, S, NH or N(C1-6alkyl),
- or a composition comprising at least one compound of formula (i) and, optionally, one or more pharmaceutically acceptable excipients.
32 more elements
Dependencies are inferred from the claim text.