US 10,851,096 B2Granted

Aryl and heteroaryl amides for use as anti-proliferative, anti-thrombotic, and anti-viral agents

AssigneesRutgers, The State University of New Jersey, The Curators of the University of Missouri

InventorsWilliam J. Welsh, Raymond Birge, Vladyslav Kholodovych, Youyi Peng, Thomas Walter Comollo, Stanley G. Kimani, Kamlendra Singh

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Abstract

Certain compounds of formula I: I and salts including pharmaceutically acceptable salts thereof are disclosed. Also disclosed are pharmaceutical compositions comprising a compound of formula I, processes for preparing compounds of formula I, intermediates useful for preparing compounds of formula I and therapeutic methods using a compound of formula I.

Claims18

Dependent claims

A compound of formula I:

wherein:
(a) X1 is N or CRa1, X2 is N or CRa2, X3 is N or CRa3, X4 is N or CRa4, wherein:
(i) no more than two of X1, X2, X3, or X4 is N;
(ii) each Ra1, Ra2, Ra3, and Ra4 is independently hydrogen, halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, —O(C1-C4)alkyl, or —O(C1-C4)haloalkyl;
(b) Y is S, S(═O), S(═O)2, or O;
(c) Z is a 5-membered heteroaryl or 6-membered heteroaryl, wherein any 5-membered heteroaryl or 6-membered heteroaryl of Z is optionally substituted with one or more halogen, NO2, CN, —OH, (C1-C4)alkyl, (C1-C4)haloalkyl, —O(C1-C4)alkyl, or —O(C1-C4)haloalkyl;
(d) R1 is hydrogen or (C1-C4)alkyl, R2 is hydrogen or (C1-C4)alkyl and L is absent;
(e) each R3 is independently hydrogen or (C1-C4)alkyl;
(f) each R4 is independently hydrogen or (C1-C4)alkyl;
(g) M is an aryl or a 5-10-membered heteroaryl, wherein any aryl or 5-10-membered heteroaryl of M is optionally substituted with one or more halogen, NO2, CN, —OH, (C1-C4)alkyl, (C1-C4)haloalkyl, —O(C1-C4)alkyl, or —O(C1-C4)haloalkyl;
or a salt thereof;
provided the compound is not
2-[[(2-methyl-4-thiazolyl)methyl]thio]-N-[2-[[3-(trifluoromethyl)-2-pyridinyl]amino]ethyl]-benzamide;
N-[2-[(2-cyano-3-fluorophenyl)amino]ethyl]-2-[(3-thienylmethyl)thio]-benzamide;
N-[2-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]amino]ethyl]-2-[[(2-methyl-4-thiazolyl)methyl]thio]-benzamide;
2-[[(3-methyl-5-isoxazolyl)methyl]thio]-N-[2-[[2-nitro-4-(trifluoromethyl)phenyl]amino]ethyl]-benzamide;
N-[2-[(3-cyano-2-pyridinyl)amino]ethyl]-2-[(2-thienylmethyl)thio]-benzamide;
2-[[(5-methyl-3-isoxazolyl)methyl]thio]-N-[2-[(2- nitrophenyl)amino]ethyl]-3-pyridinecarboxamide;
N-[2-[(3,5-dichloro-2-pyridinyl)amino]ethyl]-2-[[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]thio]-benzamide;
2-[[(2-methyl-4-thiazolyl)methyl]thio]-N-[2-[(4-nitrophenyl)amino]ethyl]-benzamide;
N-[2-(2-benzothiazolylamino)ethyl]-2-[(2-thienylmethyl)thio]-benzamide;
N-[2-[(3-cyano-2-pyridinyl)amino]ethyl]-2-[(4-thiazolylmethyl)thio]-benzamide;
2-[[(3-methyl-5-isoxazolyl)methyl]thio]-N-[2-[(6-methyl-3-pyridazinyl)amino]ethyl]-benzamide;
2-[[(3,5-dimethyl-4-isoxazolyl)methyl]thio]-N-[2-[[3-(trifluoromethyl)-2-pyridinyl]amino]ethyl]-3-pyridinecarboxamide;
2-[[(3-methyl-5-isoxazolyl)methyl]thio]-N-[2-[(2-nitrophenyl)amino]ethyl]-benzamide;
N-[2-[(2-nitrophenyl)amino]ethyl]-2-[(3-thienylmethyl)thio]-benzamide;
2-[[(3,5-dimethyl-4-isoxazolyl)methyl]thio]-N-[1-methyl-2-(methylphenylamino)ethyl]-3-pyridinecarboxamide;
N-[2-[(2-cyano-3-fluorophenyl)amino]ethyl]-2-[[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]thio]-benzamide;
N-[2-[ethyl(2-methylphenyl)amino]ethyl]-2-[[(5-methyl-3-isoxazolyl)methyl]thio]-3-pyridinecarboxamide;
2-[[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]thio]-N-[2-[(2-nitrophenyl)amino]ethyl]-benzamide;
2-[[(2-methyl-4-thiazolyl)methyl]thio]-N-[2-(2-pyrazinylamino)ethyl]-benzamide;
N-[2-[ethyl(2-methylphenyl)amino]ethyl]-2-[[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]thio]-benzamide;
N-[1-methyl-2-(methylphenylamino)ethyl]-2-[(2-thienylmethyl)thio]-benzamide;
2-[[(3,5-dimethyl-4-isoxazolyl)methyl]thio]-N-[2-[ethyl(2-methylphenyl)amino]ethyl]-3-pyridinecarboxamide;
2-[[(5-methyl-3-isoxazolyl)methyl]thio]-N-[2-(methylphenylamino)propyl]-3-pyridinecarboxamide;
2-[[(2-methyl-4-thiazolyl)methyl]thio]-N-[2-(4-quinazolinylamino)ethyl]-benzamide;
2-[[(3,5-dimethyl-4-isoxazolyl)methyl]thio]-N-[2-(2-pyrimidinylamino)ethyl]-benzamide;
2-[[(3,5-dimethyl-4-isoxazolyl)methyl]thio]-N-[2- [[2-nitro-4-(trifluoromethyl)phenyl]amino]ethyl]-3-pyridinecarboxamide;
N-[2-(methylphenylamino)propyl]-2-[(4-thiazolylmethyl)thio]-benzamide;
N-[2-[(3,5-dichloro-2-pyridinyl)amino]ethyl]-2-[(4-thiazolylmethyl)thio]-benzamide;
N-[2-[ethyl(3-methylphenyl)amino]ethyl]-2-[[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]thio]-benzamide;
2-[[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]thio]-N-[2-[(4-nitrophenyl)amino]ethyl]-benzamide;
N-[2-[(2-cyano-3-fluorophenyl)amino]ethyl]-2-[[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]thio]-benzamide;
2-[[(3,5-dimethyl-4-isoxazolyl)methyl]thio]-N-[2-[(5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)amino]ethyl]-benzamide;
N-[2-(methylphenylamino)propyl]-2-[(2-thienylmethyl)thio]-benzamide;
2-[[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]thio]-N-[2-[(2-nitrophenyl)amino]ethyl]-benzamide;
2-[[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]thio]-N-[2-(methylphenylamino)propyl]-benzamide;
2-[[(3-methyl-5-isoxazolyl)methyl]thio]-N-[2-[(4-nitrophenyl)amino]ethyl]-benzamide;
N-[2-[(2-cyano-3-fluorophenyl)amino]ethyl]-2-[[(3,5-dimethyl-4-isoxazolyl)methyl]thio]—3-pyridinecarboxamide;
2-[[(2-methyl-4-thiazolyl)methyl]thio]-N-[2-[(2-nitrophenyl)amino]ethyl]-benzamide;
N-[2-[(3-cyano-2-pyridinyl)amino]ethyl]-2-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-benzamide;
2-[(3,5-dimethyl-4-isoxazolyl)methoxy]-N-[2-[(4-nitrophenyl)amino]ethyl]-benzamide;
2-[(3,5-dimethyl-4-isoxazolyl)methoxy]-N-[2-[ethyl(2-methylphenyl)amino]ethyl]-benzamide;
2-[(3,5-dimethyl-4-isoxazolyl)methoxy]-N-[2-[ethyl(3-methylphenyl)amino]ethyl]-benzamide;
N-[2-[(3-cyano-2-pyridinyl)amino]ethyl]-2-[(3,5-dimethyl-4-isoxazolyl)methoxy]-benzamide;
N-[2-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]amino]ethyl]-2-[(3,5-dimethyl-4-isoxazolyl)methoxy]-benzamide;
N-[2-(methylphenylamino)ethyl]-2-(4-thiazolylmethoxy)- benzamide;
N-[2-(methylphenylamino)propyl]-2-(4-thiazolylmethoxy)- benzamide
2-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-N-[2-[(2-nitrophenyl)amino]ethyl] benzamide;
2-[(3,5-dimethyl-4-isoxazolyl)methoxy]-N-[2-(2-pyrimidinylamino)ethyl]-benzamide;
2-[(3,5-dimethyl-4-isoxazolyl)methoxy]-N-[1-methyl-2-(methylphenylamino)ethyl]-benzamide;
2-[(3,5-dimethyl-4-isoxazolyl)methoxy]-N-[2-[(6-methyl-3-pyridazinyl)amino]ethyl]-benzamide;
or
2-[(2-methyl-4-thiazolyl)methoxy]-N-[2-[[2-nitro-4-(trifluoromethyl)phenyl]amino]ethyl]-benzamide;
or a salt thereof.

62 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/311,136Filed 16 Jun 2017 · us provisional application
Priority: 20 Jun 2016
Published: US 2019/0127361 A12 May 2019
Granted: 1 Dec 2020
Term ends: Not estimatedThe source records don’t support an estimate.

Classification18 codes

C07D 417/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61K 31/42
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: oxazoles
A61K 31/496
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: non-condensed piperazines…
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Family

Application62/352,499Us provisional application · filed 20 Jun 2016
US 2019/0127361 A1Pre-grant publication · published 2 May 2019
US 10,851,096 B2This patent

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

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Abstract

A compound of formula I:

wherein:
(a) X1 is N or CRa1, X2 is N or CRa2, X3 is N or CRa3, X4 is N or CRa4, wherein:
(i) no more than two of X1, X2, X3, or X4 is N;
(ii) each Ra1, Ra2, Ra3, and Ra4 is independently hydrogen, halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, —O(C1-C4)alkyl, or —O(C1-C4)haloalkyl;
(b) Y is S, S(═O), S(═O)2, or O;
(c) Z is a 5-membered heteroaryl or 6-membered heteroaryl, wherein any 5-membered heteroaryl or 6-membered heteroaryl of Z is optionally substituted with one or more halogen, NO2, CN, —OH, (C1-C4)alkyl, (C1-C4)haloalkyl, —O(C1-C4)alkyl, or —O(C1-C4)haloalkyl;
(d) R1 is hydrogen or (C1-C4)alkyl, R2 is hydrogen or (C1-C4)alkyl and L is absent;
(e) each R3 is independently hydrogen or (C1-C4)alkyl;
(f) each R4 is independently hydrogen or (C1-C4)alkyl;
(g) M is an aryl or a 5-10-membered heteroaryl, wherein any aryl or 5-10-membered heteroaryl of M is optionally substituted with one or more halogen, NO2, CN, —OH, (C1-C4)alkyl, (C1-C4)haloalkyl, —O(C1-C4)alkyl, or —O(C1-C4)haloalkyl;
or a salt thereof;
provided the compound is not
2-[[(2-methyl-4-thiazolyl)methyl]thio]-N-[2-[[3-(trifluoromethyl)-2-pyridinyl]amino]ethyl]-benzamide;
N-[2-[(2-cyano-3-fluorophenyl)amino]ethyl]-2-[(3-thienylmethyl)thio]-benzamide;
N-[2-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]amino]ethyl]-2-[[(2-methyl-4-thiazolyl)methyl]thio]-benzamide;
2-[[(3-methyl-5-isoxazolyl)methyl]thio]-N-[2-[[2-nitro-4-(trifluoromethyl)phenyl]amino]ethyl]-benzamide;
N-[2-[(3-cyano-2-pyridinyl)amino]ethyl]-2-[(2-thienylmethyl)thio]-benzamide;
2-[[(5-methyl-3-isoxazolyl)methyl]thio]-N-[2-[(2- nitrophenyl)amino]ethyl]-3-pyridinecarboxamide;
N-[2-[(3,5-dichloro-2-pyridinyl)amino]ethyl]-2-[[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]thio]-benzamide;
2-[[(2-methyl-4-thiazolyl)methyl]thio]-N-[2-[(4-nitrophenyl)amino]ethyl]-benzamide;
N-[2-(2-benzothiazolylamino)ethyl]-2-[(2-thienylmethyl)thio]-benzamide;
N-[2-[(3-cyano-2-pyridinyl)amino]ethyl]-2-[(4-thiazolylmethyl)thio]-benzamide;
2-[[(3-methyl-5-isoxazolyl)methyl]thio]-N-[2-[(6-methyl-3-pyridazinyl)amino]ethyl]-benzamide;
2-[[(3,5-dimethyl-4-isoxazolyl)methyl]thio]-N-[2-[[3-(trifluoromethyl)-2-pyridinyl]amino]ethyl]-3-pyridinecarboxamide;
2-[[(3-methyl-5-isoxazolyl)methyl]thio]-N-[2-[(2-nitrophenyl)amino]ethyl]-benzamide;
N-[2-[(2-nitrophenyl)amino]ethyl]-2-[(3-thienylmethyl)thio]-benzamide;
2-[[(3,5-dimethyl-4-isoxazolyl)methyl]thio]-N-[1-methyl-2-(methylphenylamino)ethyl]-3-pyridinecarboxamide;
N-[2-[(2-cyano-3-fluorophenyl)amino]ethyl]-2-[[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]thio]-benzamide;
N-[2-[ethyl(2-methylphenyl)amino]ethyl]-2-[[(5-methyl-3-isoxazolyl)methyl]thio]-3-pyridinecarboxamide;
2-[[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]thio]-N-[2-[(2-nitrophenyl)amino]ethyl]-benzamide;
2-[[(2-methyl-4-thiazolyl)methyl]thio]-N-[2-(2-pyrazinylamino)ethyl]-benzamide;
N-[2-[ethyl(2-methylphenyl)amino]ethyl]-2-[[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]thio]-benzamide;
N-[1-methyl-2-(methylphenylamino)ethyl]-2-[(2-thienylmethyl)thio]-benzamide;
2-[[(3,5-dimethyl-4-isoxazolyl)methyl]thio]-N-[2-[ethyl(2-methylphenyl)amino]ethyl]-3-pyridinecarboxamide;
2-[[(5-methyl-3-isoxazolyl)methyl]thio]-N-[2-(methylphenylamino)propyl]-3-pyridinecarboxamide;
2-[[(2-methyl-4-thiazolyl)methyl]thio]-N-[2-(4-quinazolinylamino)ethyl]-benzamide;
2-[[(3,5-dimethyl-4-isoxazolyl)methyl]thio]-N-[2-(2-pyrimidinylamino)ethyl]-benzamide;
2-[[(3,5-dimethyl-4-isoxazolyl)methyl]thio]-N-[2- [[2-nitro-4-(trifluoromethyl)phenyl]amino]ethyl]-3-pyridinecarboxamide;
N-[2-(methylphenylamino)propyl]-2-[(4-thiazolylmethyl)thio]-benzamide;
N-[2-[(3,5-dichloro-2-pyridinyl)amino]ethyl]-2-[(4-thiazolylmethyl)thio]-benzamide;
N-[2-[ethyl(3-methylphenyl)amino]ethyl]-2-[[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]thio]-benzamide;
2-[[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]thio]-N-[2-[(4-nitrophenyl)amino]ethyl]-benzamide;
N-[2-[(2-cyano-3-fluorophenyl)amino]ethyl]-2-[[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]thio]-benzamide;
2-[[(3,5-dimethyl-4-isoxazolyl)methyl]thio]-N-[2-[(5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)amino]ethyl]-benzamide;
N-[2-(methylphenylamino)propyl]-2-[(2-thienylmethyl)thio]-benzamide;
2-[[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]thio]-N-[2-[(2-nitrophenyl)amino]ethyl]-benzamide;
2-[[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]thio]-N-[2-(methylphenylamino)propyl]-benzamide;
2-[[(3-methyl-5-isoxazolyl)methyl]thio]-N-[2-[(4-nitrophenyl)amino]ethyl]-benzamide;
N-[2-[(2-cyano-3-fluorophenyl)amino]ethyl]-2-[[(3,5-dimethyl-4-isoxazolyl)methyl]thio]—3-pyridinecarboxamide;
2-[[(2-methyl-4-thiazolyl)methyl]thio]-N-[2-[(2-nitrophenyl)amino]ethyl]-benzamide;
N-[2-[(3-cyano-2-pyridinyl)amino]ethyl]-2-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-benzamide;
2-[(3,5-dimethyl-4-isoxazolyl)methoxy]-N-[2-[(4-nitrophenyl)amino]ethyl]-benzamide;
2-[(3,5-dimethyl-4-isoxazolyl)methoxy]-N-[2-[ethyl(2-methylphenyl)amino]ethyl]-benzamide;
2-[(3,5-dimethyl-4-isoxazolyl)methoxy]-N-[2-[ethyl(3-methylphenyl)amino]ethyl]-benzamide;
N-[2-[(3-cyano-2-pyridinyl)amino]ethyl]-2-[(3,5-dimethyl-4-isoxazolyl)methoxy]-benzamide;
N-[2-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]amino]ethyl]-2-[(3,5-dimethyl-4-isoxazolyl)methoxy]-benzamide;
N-[2-(methylphenylamino)ethyl]-2-(4-thiazolylmethoxy)- benzamide;
N-[2-(methylphenylamino)propyl]-2-(4-thiazolylmethoxy)- benzamide
2-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-N-[2-[(2-nitrophenyl)amino]ethyl] benzamide;
2-[(3,5-dimethyl-4-isoxazolyl)methoxy]-N-[2-(2-pyrimidinylamino)ethyl]-benzamide;
2-[(3,5-dimethyl-4-isoxazolyl)methoxy]-N-[1-methyl-2-(methylphenylamino)ethyl]-benzamide;
2-[(3,5-dimethyl-4-isoxazolyl)methoxy]-N-[2-[(6-methyl-3-pyridazinyl)amino]ethyl]-benzamide;
or
2-[(2-methyl-4-thiazolyl)methoxy]-N-[2-[[2-nitro-4-(trifluoromethyl)phenyl]amino]ethyl]-benzamide;
or a salt thereof.

62 more elements

Facts

Application

16/311,136Filed 16 Jun 2017 · us provisional application

Priority

20 Jun 2016

Published

US 2019/0127361 A12 May 2019

Granted

1 Dec 2020

Term ends

Not estimatedThe source records don’t support an estimate.

Classification18 codes

C07D 417/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61K 31/42
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: oxazoles
A61K 31/496
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: non-condensed piperazines…
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors