US 10,745,377 B2Granted

Piperidine or piperazine linked imidazole and triazole derivatives and methods of use

AssigneeMerck Sharp & Dohme Corp.

InventorsCraig A. Coburn, Milana M. Maletic, Yunfu Luo, Zhiqi Qi, Tingting Yu, Richard Soll

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Abstract

The present invention relates to piperidine or piperazine linked imidazole and triazole derivatives, compositions comprising said compounds, alone or in combination with other drugs, and methods of using the compounds for improving the pharmacokinetics of a drug. The compounds of the invention are useful in human and veterinary medicine for inhibiting CYP3A4 and for improving the pharmacokinetics of a therapeutic compound that is metabolized by CYP3A4.

Claims8

Dependent claims

A compound having the formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
n is 1;
W is —N═ or —CH═;
X is —N(R3)—;
R1 is selected from —(C1-C6 alkylene)-aryl, —(C1-C6 alkylene)-(5 or 6-membered heteroaryl), —(C1-C6 alkylene)-O-aryl, —(C1-C6 alkylene)-O-(5 or 6-membered heteroaryl) and C3-C6 cycloalkyl, wherein any aryl, heteroaryl or C3-C6 cycloalkyl group can be optionally substituted with up to four R9 groups, which can be the same or different, and wherein said C3-C6 cycloalkyl group can be fused to a benzene ring and said fused benzene ring can be optionally substituted with up to four R9 groups, which can be the same or different;
one occurrence of R2 is H and the other occurrence of R2 is C1-C6 alkyl;
R3 is selected from Y, —O—Y, —C(O)—Y, —(C1-C6 alkylene)-Y, —(C1-C6 alkylene)-C(O)—Y, —(C1-C6 alkylene)-C(O)—O—Y and —(C1-C6 alkylene)-O—Y, wherein each Y is independently selected from:
(1) C1-C4 alkyl,
(2) C1-C4 haloalkyl,
(3) C1-C4 hydroxyalkyl,
(4) C3-C6 cyclohaloalkyl,
(5) C3-C6 cycloalkyl,
(6) phenyl, wherein said phenyl group can be optionally substituted with up to four R7 groups,
(7) 5 or 6-membered heteroaryl, wherein said 5 or 6-membered heteroaryl group can be optionally substituted with up to four R7 groups, and
(8) 5 or 6-membered monocyclic heterocycloalkyl or 9 or 10-membered bicyclic heterocycloalkyl, wherein said 5 or 6-membered monocyclic heterocycloalkyl group can optionally form a spirocycle with a C3-C6 cycloalkyl group or another 5 or 6-membered monocyclic heterocycloalkyl group, and wherein said 5 or 6-membered monocyclic heterocycloalkyl group and said 9 or 10-membered bicyclic heterocycloalkyl group can be optionally substituted on one or more ring carbon atoms with up to four R7 groups, which can be the same or different, and wherein a ring carbon atom of a 5 or 6-membered monocyclic heterocycloalkyl group may be functionalized as a carbonyl group;
R5 is selected from H, C1-C6 alkyl, phenyl, —C(O)N(R8)2 and —C(O)—Z, wherein Z is selected from piperidinyl, piperazinyl and morhoplinyl and wherein said Z is optionally substituted with 1 to 3 halo groups, and phenyl is optionally substituted with —N(R8)2,
R6 is H;
each occurrence of R7 and each occurrence of R9 are is independently selected from C1-C6 alkyl, phenyl, benzyl, 5 or 6-membered heteroaryl, —CH2-(5 or 6-membered heteroaryl), 5 or 6-membered heterocycloalkyl, —CH2-(5 or 6-membered heterocycloalkyl), C1-C6 hydroxyalkyl, C1-C6 haloalkyl, halo, —CN, —N(R8)2, —(C1-C6 alkylene)-N(R8)2, —OR8, —C(O)OR8, —SR8, —S(O)2R8, —C(O)N(R8)2, —(C1-C6 alkylene)-C(O)OR8, —(C1-C6 alkylene)-SR8, —(C1-C6 alkylene)-S(O)2R8 and (C1-C6 alkylene)-C(O)N(R8)2, wherein said phenyl, 5 or 6-membered heteroaryl and 5 or 6-membered heterocycloalkyl groups can be optionally substituted with one to three groups selected from C1-C6 alkyl, halo, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, halo, —CN, —N(R8)2 and —OR8;
and
each occurrence of R8 is independently H, C1-C6 alkyl or benzyl optionally substituted with one or two methoxy groups.

18 more elements

A compound selected from the following:

(R)-2-(4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole;
(R)-4-(1-(5-((4-(benzo[d]oxazol-2-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;
4-(1-(5-((4-(benzo[d]oxazol-2-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)cyclopropyl)benzonitrile;
2-(4-((1-(2-isopropoxyethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole;
2-(4-((1-(3-methylbutan-2-yl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole;
(R)-4-(1-(5-((4-(7-fluorobenzo[d]oxazol-2-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;
(R)-4-(1-(5-((4-(7-methylbenzo[d]oxazol-2-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;
(R)-4-(1-(5-((4-(6-fluorobenzo[d]oxazol-2-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;
(R)-4-(1-(5-((4-(6,7-difluorobenzo[d]oxazol-2-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;
2-(4-((1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole;
2-(4-((1-(2-(pyridin-2-yl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole;
2-(4-((1-(1-(4-(methylsulfonyl)phenyl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole;
6,7-difluoro-2-(4-((1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole;
2-(4-((1-(3,3,3-trifluoro-2-methylpropyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole;
2-(4-((1-(4-fluorophenethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole;
(R)-4-(1-(5-((4-(6-methoxybenzo[d]thiazol-2-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;
(R)-4-(1-(5-((4-(1H-benzo[d]imidazol-2-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;
(R)-5-(ethylsulfonyl)-2-(4-((1-(1-(4-fluorophenyl)propan-2-yl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)thiazole;
(R)-5-(2-(ethylsulfonyl)ethyl)-2-(4-((1-(1-(4-fluorophenyl)propan-2-yl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)thiazole;
(R)-2-(4-((1-(1-(4-chlorophenyl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)-5-(2-(ethylsulfonyl)ethyl)thiazole;
(R)-2-(4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)-5-(2-(ethylsulfonyl)ethyl)thiazole;
N-(tert-butyl)-4-((1-((R)-1-(4-cyanophenyl)ethyl)-1H-imidazol-5-yl)methyl)-1-phenylpiperazine-2-carboxamide;
4-((1R)-1-(5-((4-phenyl-3-(piperidine-1-carbonyl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;
4-((1R)-1-(5-((3-(morpholine-4-carbonyl)-4-phenylpiperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;
4-((1R)-1-(5-((3-(4,4-difluoropiperidine-1-carbonyl)-4-phenylpiperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;
((S)-4-((1-((R)-1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-1-phenylpiperazin-2-yl)(piperidin-1-yl)methanone;
(4-((1-((R)-1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-2-phenylpiperazin-1-yl)(5-methylisoxazol-3-yl)methanone;
(4-((1-((R)-1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-2-phenylpiperazin-1-yl)(phenyl)methanone;
1-(4-((1-((R)-1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-2-phenylpiperazin-1-yl)ethanone;
(4-((1-((R)-1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-2-phenylpiperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(4-((1-((R)-1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-2-phenylpiperazin-1-yl)(pyridin-2-yl)methanone;
(4-((1-((R)-1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-2,6-dimethylpiperazin-1-yl)(1-methylcyclopropyl)methanone;
(2-(tert-butyl)-4-((1-((R)-1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)(phenyl)methanone;
(2,6-dimethyl-4-((1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)(1-methylcyclopropyl)methanone;
(2-(4-(dimethylamino)phenyl)-4-((1-((R)-1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)(1-methylcyclopropyl)methanone;
4-((1R)-1-(5-((4-(3,3-difluorocyclobutanecarbonyl)-3,5-dimethylpiperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;
(4-((1-(1-(4′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)(phenyl)methanone;
1-(4-((1-(1-(4′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)ethanone;
(R)-1-benzyl-4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-2-one;
(R)-1-(2-((1H-1,2,4-triazol-1-yl)methyl)benzyl)-4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-2-one;
(R)-4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)piperazin-2-one;
(R)-4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-1-((5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)methyl)piperazin-2-one;
(R)-1-((2-((2,4-dimethoxybenzyl)amino)thiazol-5-yl)methyl)-4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-2-one;
(R)-1-((2-(dimethylamino)thiazol-5-yl)methyl)-4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-2-one;
(R)-4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-1-((2-(methylamino)thiazol-5-yl)methyl)piperazin-2-one;
(R)-4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-1-((2-morpholinothiazol-5-yl)methyl)piperazin-2-one;
(R)-4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-1-((2-(4-methylpiperazin-1-yl)thiazol-5-yl)methyl)piperazin-2-one;
ethyl 2-(4-((1-(1-(4′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)acetate;
2-(4-((1-(1-(4′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)ethanol;
and
1-((1-(1-(4′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-1H-imidazol-5-yl)methyl)-4-(2-methoxyethyl)piperazine;
or a pharmaceutically acceptable salt thereof.

49 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/036,268Filed 7 Nov 2014
Priority: WO PCT/CN2013/08692312 Nov 2013
Published: US 2016/0297792 A113 Oct 2016
Granted: 18 Aug 2020
Term ends: Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
A61K 31/4178
1,3-Diazoles: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
A61K 31/454
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
A61K 31/4545
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine

Family

US 2016/0297792 A1Pre-grant publication · published 13 Oct 2016
US 10,745,377 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound having the formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
n is 1;
W is —N═ or —CH═;
X is —N(R3)—;
R1 is selected from —(C1-C6 alkylene)-aryl, —(C1-C6 alkylene)-(5 or 6-membered heteroaryl), —(C1-C6 alkylene)-O-aryl, —(C1-C6 alkylene)-O-(5 or 6-membered heteroaryl) and C3-C6 cycloalkyl, wherein any aryl, heteroaryl or C3-C6 cycloalkyl group can be optionally substituted with up to four R9 groups, which can be the same or different, and wherein said C3-C6 cycloalkyl group can be fused to a benzene ring and said fused benzene ring can be optionally substituted with up to four R9 groups, which can be the same or different;
one occurrence of R2 is H and the other occurrence of R2 is C1-C6 alkyl;
R3 is selected from Y, —O—Y, —C(O)—Y, —(C1-C6 alkylene)-Y, —(C1-C6 alkylene)-C(O)—Y, —(C1-C6 alkylene)-C(O)—O—Y and —(C1-C6 alkylene)-O—Y, wherein each Y is independently selected from:
(1) C1-C4 alkyl,
(2) C1-C4 haloalkyl,
(3) C1-C4 hydroxyalkyl,
(4) C3-C6 cyclohaloalkyl,
(5) C3-C6 cycloalkyl,
(6) phenyl, wherein said phenyl group can be optionally substituted with up to four R7 groups,
(7) 5 or 6-membered heteroaryl, wherein said 5 or 6-membered heteroaryl group can be optionally substituted with up to four R7 groups, and
(8) 5 or 6-membered monocyclic heterocycloalkyl or 9 or 10-membered bicyclic heterocycloalkyl, wherein said 5 or 6-membered monocyclic heterocycloalkyl group can optionally form a spirocycle with a C3-C6 cycloalkyl group or another 5 or 6-membered monocyclic heterocycloalkyl group, and wherein said 5 or 6-membered monocyclic heterocycloalkyl group and said 9 or 10-membered bicyclic heterocycloalkyl group can be optionally substituted on one or more ring carbon atoms with up to four R7 groups, which can be the same or different, and wherein a ring carbon atom of a 5 or 6-membered monocyclic heterocycloalkyl group may be functionalized as a carbonyl group;
R5 is selected from H, C1-C6 alkyl, phenyl, —C(O)N(R8)2 and —C(O)—Z, wherein Z is selected from piperidinyl, piperazinyl and morhoplinyl and wherein said Z is optionally substituted with 1 to 3 halo groups, and phenyl is optionally substituted with —N(R8)2,
R6 is H;
each occurrence of R7 and each occurrence of R9 are is independently selected from C1-C6 alkyl, phenyl, benzyl, 5 or 6-membered heteroaryl, —CH2-(5 or 6-membered heteroaryl), 5 or 6-membered heterocycloalkyl, —CH2-(5 or 6-membered heterocycloalkyl), C1-C6 hydroxyalkyl, C1-C6 haloalkyl, halo, —CN, —N(R8)2, —(C1-C6 alkylene)-N(R8)2, —OR8, —C(O)OR8, —SR8, —S(O)2R8, —C(O)N(R8)2, —(C1-C6 alkylene)-C(O)OR8, —(C1-C6 alkylene)-SR8, —(C1-C6 alkylene)-S(O)2R8 and (C1-C6 alkylene)-C(O)N(R8)2, wherein said phenyl, 5 or 6-membered heteroaryl and 5 or 6-membered heterocycloalkyl groups can be optionally substituted with one to three groups selected from C1-C6 alkyl, halo, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, halo, —CN, —N(R8)2 and —OR8;
and
each occurrence of R8 is independently H, C1-C6 alkyl or benzyl optionally substituted with one or two methoxy groups.

18 more elements

Facts

Application

15/036,268Filed 7 Nov 2014

Priority

WO PCT/CN2013/08692312 Nov 2013

Published

US 2016/0297792 A113 Oct 2016

Granted

18 Aug 2020

Term ends

Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
A61K 31/4178
1,3-Diazoles: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
A61K 31/454
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
A61K 31/4545
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine