US 10,377,718 B2Granted

Apelin receptor (APJ) agonists and uses thereof

AssigneeResearch Triangle Institute

InventorsScott P. Runyon, Rangan Maitra, Sanju Narayanan, James Barnwell Thomas

Life of this patent

Estimating the term…

Abstract

This disclosure is directed to agonists of the apelin receptor (APJ) and uses of such agonists.

Claims29

Dependent claims

A compound represented by the Formula I:

or a pharmaceutically acceptable salt, a prodrug, or a salt of a prodrug thereof, wherein
R1 is represented by the formula:
each A is independently C1-8 alkoxy, C1-8 alkoxy-C5-12 aryl, halogen, or O(CH2)xCO2R7;
R7 and R8
R7 and R8 are independently optionally substituted C5-12 aryl, optionally substituted C1-8 alkyl, optionally substituted C3-8 cycloalkyl, hydroxyl, or H;
or
R7 and R8 together make an optionally substituted 3-8 member ring, which may be substituted with one or more heteroatoms selected from O, N, or S;
n is 1, 2, 3, or 4;
wherein the first A is substituted ortho to the point of attachment from the depicted pyrazole;
each x is independently 1, 2, 3, or 4;
R2 is substituted C5-12 aryl, optionally substituted C1-8 alkyl, optionally substituted C2-8 alkyl-substituted C5-12 aryl, optionally substituted C2-8 alkyl-optionally substituted C3-8 cycloalkyl, or optionally substituted C3-8 cycloalkyl;
R3 is absent;
R4 is C2-8 alkyl, C2-8 alkenyl, C3-8 cycloalkyl, C2-8 alkyl-C5-12 aryl, C1-8 alkyl-C3-8 cycloalkyl, C1-8 alkyl-5 to 7 membered heteroaryl, (CH2)xNR7R8, or C1-8 alkyl-substituted C5-12 aryl where the C5-12 aryl is substituted either meta or para from the C1-8 alkylene linker;
R5 is optionally substituted C1-8 alkyl, C5-12 aryl, C1-8 alkyl-C5-12 aryl, C1-8 alkyl-C3-8 cycloalkyl, C1-8 alkyl-5 to 7 membered heteroaryl, C3-8 cycloalkyl, (CH2)xNR7R8, (CH2)xNHCOR7, (CH2)xNHCO2R7, (CH2)xCONR7R8, (CH2)xCONR7(CH2)yCO2R9, (CH2)xCONR7(CH2)yCONR7R8, (CH2)xCONR7(CH2)yR9, (CH2)xCOR7, (CH2)xCO2R7, CHR7COR9 , CHR7CONHCHR8COR9, or CONR7R8;
R6 is H;
or R4 and R5 together make a 4-8 member ring which may be substituted with one or more heteroatoms selected from O, N, or S, and may be further substituted with one or more of C1-8 alkoxy, C1-8 alkyl, H, isoxazolyl, or hydroxyl;
R9 is C1-8 alkoxy, C1-8 alkyl, H, isoxazolyl, or hydroxyl;
each y is independently 1, 2, or 3;
and Z is ═O, where the depicted dashed line to Z is a double bond,
wherein substituted refers to substitution with one or more of C1-8 alkyl, halogen, C1-8 haloalkyl, C1-8 alkoxy, hydroxyl, carbonyl, CO2R9, C5-12 aryl, 5 to 7 membered heteroaryl, C3-8 cycloalkyl, C1-8 alkyl-C5-12 aryl, C1-8 alkyl-5 to 7 membered heteroaryl, C1-8 alkyl-C3-8 cycloalkyl, NO2, N3, NH2, N(CH3)2, SO(1-3)H, or SH.

17 more elements

A compound selected from:

(2S)-2-{[5-(2,6-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazol-3-yl]formamido}-4-methylpentanoic acid;
(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanoic acid;
(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanamide;
(3R)-3-{[5-(2,6-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanoic acid;
2-(2-cyclohexyl-2-{[5-(2,6-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazol-3-yl]formamido}acetamido)acetic acid;
2-[(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanamido]acetic acid;
(3S)-3-{[1-cyclohexyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanoic acid;
2-[(3S)-3-{[1-cyclohexyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanamido]acetic acid;
(3S)-3-({5-[2-(benzyloxy)-6-methoxyphenyl]-1-(4-fluorophenyl)-1H-pyrazol-3-yl}formamido)-5-methylhexanoic acid;
(3S)-3-{[1-(4-fluorophenyl)-5-[2-methoxy-6-(2-methoxy-2-oxoethoxy)phenyl]-1H-pyrazol-3-yl]formamido}-5-methylhexanoic acid;
2-cyclohexyl-2-{[1-cyclohexyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}acetic acid;
(3S)-3-{[1-(cyclohexylmethyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanoic acid;
methyl 2-[(3S)-3-{[1-cyclohexyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanamido]acetate;
(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2-methylpropyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanoic acid;
(3S)-3-({5-[2-(benzyloxy)-6-methoxyphenyl]-1-cyclohexyl-1H-pyrazol-3-yl}formamido)-5-methylhexanoic acid;
methyl 2[(3S)-3-({5-[2(benzyloxy)-6-methoxyphenyl]-1-cyclohexyl-1H-pyrazol-3-yl}formamido)-5-methylhexanamido]acetate;
2-[(3S)-3-({5-[2(benzyloxy)-6-methoxyphenyl]-1-cyclohexyl-1H-pyrazol-3-yl}formamido)-5-methylhexanamido]acetic acid;
methyl 2[(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanamido]acetate;
(3S)-N-benzyl-3-({5-[2-(benzyloxy)-6-methoxyphenyl]-1-cyclohexyl-1H-pyrazol-3-yl}formamido)-5-methylhexanamide;
(3S)-3-({5-[2(benzyloxy)-6-methoxyphenyl]-1-cyclohexyl-1H-pyrazol-3-yl}formamido)-N-butyl-5-methylhexanamide;
(3S)-3-({5-[2(benzyloxy)-6-methoxyphenyl]-1-cyclohexyl-1H-pyrazol-3-yl}formamido)-5-methyl-N-(1,3-oxazol-2ylmethyl)hexanamide;
(3S)-3-({5-[2(benzyloxy)-6-methoxyphenyl]-1-cyclohexyl-1H-pyrazol-3-yl}formamido)-N-[(dimethylcarbamoyl)methyl]-5-methylhexanamide;
methyl 2-[(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanamido]acetate;
ethyl 3-[(3S)-3-({5-[2(benzyloxy)-6-methoxyphenyl]-1-cyclohexyl-1H-pyrazol-3-yl}formamido)-5-methylhexanamido]propanoate;
(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-5-methyl-N-(1,3-oxazol-2ylmethyl)hexanamide;
(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-N,5-dimethylhexanamide;
(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-N-(2-hydroxyethyl)-5-methylhexanamide;
(3S)-N-butyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanamide;
(3R)-N-butyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanamide;
(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-N-hexyl-5-methylhexanamide;
(3S)-N-(cyclohexylmethyl)-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanamide;
(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-5-methyl-N-pentylhexanamide;
(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-5-methyl-N-propylhexanamide;
(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-N-ethyl-5-methylhexanamide;
(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-5-methyl-N-(propan-2yl)hexanamide;
(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-N-(4-fluorophenyl)-5-methylhexanamide;
methyl (3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanoate;
(3S)-3-{[5-(3,5-difluoro-2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanoic acid;
(3S)-N-butyl-3-{[5-(3,5-difluoro-2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanamide;
(2S)-2cyclohexyl-2-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}acetic acid;
(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-N,5-dimethyl-N-propylhexanamide;
(3S)-N-cyclopropyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanamide;
(3S)-N-cyclobutyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanamide;
2-[(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanamido]acetic acid;
(3S)-N-(carbamoylmethyl)-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanamide;
(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-5-methyl-N-[(methylcarbamoyl)methyl]hexanamide;
(3S)-3-{[1-(cyclopropylmethyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanoic acid;
(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanoic acid;
methyl 2-[(3S)-3-{[1-(cyclopropylmethyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanamido]acetate;
methyl 2-[(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanamido]acetate;
(3S)-N-cyclopentyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanamide;
methyl 2-[(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-propyl-1H-pyrazol-3-yl]formamido}-5-methylhexanamido]acetate;
methyl 2-[(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2,2dimethylpropyl)-1H-pyrazol-3-yl]formamido}-5-methylhexanamido]acetate;
methyl 2-[(2S)-2-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-4-methylpentanamido]acetate;
methyl 2-[(2S)-2-{[1-cyclohexyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-4-methylpentanamido]acetate;
ethyl 3-[(2S)-2-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-4-methylpentanamido]propanoate;
methyl 2-[(2S)-3-cyclohexyl-2-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}propanamido]acetate;
(2S)-3-cyclohexyl-2-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}propanoic acid;
methyl 2-[(2S)-2-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-3-phenylpropanamido]acetate;
methyl 2-[(2S)-2-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}hexanamido]acetate;
methyl 2-[(2S)-2-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-4-phenylbutanamido]acetate;
(3S)-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}pentanoic acid;
methyl 2-[(3S)-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}pentanamido]acetate;
methyl 2-[(2S)-3-cyclohexyl-2-{[5-(2,5-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}propanamido]acetate;
methyl 2-[(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-N,5-dimethylhexanamido]acetate;
methyl 2-[(2S)-2-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-N,4-dimethylpentanamido]acetate;
2-[(3S)-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}pentanamido]acetic acid;
(2S)-2-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-4-phenyl-N-propylbutanamide;
5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-N-[(2S)-1-oxo-4-phenyl-1-(pyrrolidin-1-yl)butan-2yl]-1H-pyrazole-3-carboxamide;
methyl 2-[(2S)-2-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-N-methyl-4-phenylbutanamido]acetate;
(2S)-2-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-N-(2-methoxyethyl)-4-phenylbutanamide;
(3S)-N-cyclobutyl-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}pentanamide;
(3S)-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}pentanamide;
(3S)-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-N-(2hydroxybutyl)pentanamide;
(2S)-2-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-N-(2-hydroxybutyl)-4-phenylbutanamide;
(2S)-2-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-N-(2-oxobutyl)-4-phenylbutanamide;
(3S)-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-N-(2oxobutyl)pentanamide;
methyl 2-[(3S)-3-{1-[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]-N-methylformamido}-5-methylhexanamido]acetate;
(3S)-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-N-(2methoxyethyl)pentanamide;
methyl 2-[(3S)-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-N-methylpentanamido]acetate;
(2S)-N-cyclobutyl-2-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-4-phenylbutanamide;
methyl 2-[(3S)-6-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}hexanamido]acetate;
(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-N-(2-hydroxybutyl)-5-(piperidin-1-yl)pentanamide;
(3S)-N-cyclobutyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-5-(piperidin-1yl)pentanamide;
(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-N-(2-methoxyethyl)-5-(piperidin-1-yl)pentanamide;
(3S)-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-5-(piperidin-1-yl)pentanoic acid;
(3S)-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-(piperidin-1yl)pentanoic acid;
(3S)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}-5-(piperidin-1yl)pentanamide;
(2S)-4-cyclohexyl-2-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-N-(2methoxyethyl)-N-methylbutanamide;
(3R)-3-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazol-3-yl]formamido}propanoic acid;
methyl 2(3-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazol-3-yl]formamido}propanamido)acetate;
(3S)-5-cyclohexyl-3-{[5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazol-3-yl]formamido}-N-[(2R)-2hydroxybutyl]pentanamide;
(3R)-N-cyclobutyl-3-{[1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]formamido}pent-4-enamide;
or
N-[2S)-4-cyclohexyl-1-(1H-1,2,3,4-tetrazol-5-yl)butan-2yl]-5-(2,6-dimethoxyphenyl)-1-(2methylpropyl)-1H-pyrazole-3-carboxamide,
or a pharmaceutically acceptable salt, prodrug, or salt of a prodrug thereof.

93 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/023,510Filed 5 Jun 2015 · us provisional application
Priority: 6 Jun 2014
Published: US 2016/0207889 A121 Jul 2016
Granted: 13 Aug 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification38 codes

C07D 231/14
Having two or three double bonds between ring members or between ring members and non-ring members: with hetero atoms or with carbon atoms having…
A61K 31/415
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2-Diazoles
A61K 31/4155
1,2-Diazoles: non condensed and containing further heterocyclic rings
A61K 31/422
Oxazoles: not condensed and containing further heterocyclic rings

Family

Application62/008,688Us provisional application · filed 6 Jun 2014
US 2016/0207889 A1Pre-grant publication · published 21 Jul 2016
US 10,377,718 B2This patent

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

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A compound represented by the Formula I:

or a pharmaceutically acceptable salt, a prodrug, or a salt of a prodrug thereof, wherein
R1 is represented by the formula:
each A is independently C1-8 alkoxy, C1-8 alkoxy-C5-12 aryl, halogen, or O(CH2)xCO2R7;
R7 and R8
R7 and R8 are independently optionally substituted C5-12 aryl, optionally substituted C1-8 alkyl, optionally substituted C3-8 cycloalkyl, hydroxyl, or H;
or
R7 and R8 together make an optionally substituted 3-8 member ring, which may be substituted with one or more heteroatoms selected from O, N, or S;
n is 1, 2, 3, or 4;
wherein the first A is substituted ortho to the point of attachment from the depicted pyrazole;
each x is independently 1, 2, 3, or 4;
R2 is substituted C5-12 aryl, optionally substituted C1-8 alkyl, optionally substituted C2-8 alkyl-substituted C5-12 aryl, optionally substituted C2-8 alkyl-optionally substituted C3-8 cycloalkyl, or optionally substituted C3-8 cycloalkyl;
R3 is absent;
R4 is C2-8 alkyl, C2-8 alkenyl, C3-8 cycloalkyl, C2-8 alkyl-C5-12 aryl, C1-8 alkyl-C3-8 cycloalkyl, C1-8 alkyl-5 to 7 membered heteroaryl, (CH2)xNR7R8, or C1-8 alkyl-substituted C5-12 aryl where the C5-12 aryl is substituted either meta or para from the C1-8 alkylene linker;
R5 is optionally substituted C1-8 alkyl, C5-12 aryl, C1-8 alkyl-C5-12 aryl, C1-8 alkyl-C3-8 cycloalkyl, C1-8 alkyl-5 to 7 membered heteroaryl, C3-8 cycloalkyl, (CH2)xNR7R8, (CH2)xNHCOR7, (CH2)xNHCO2R7, (CH2)xCONR7R8, (CH2)xCONR7(CH2)yCO2R9, (CH2)xCONR7(CH2)yCONR7R8, (CH2)xCONR7(CH2)yR9, (CH2)xCOR7, (CH2)xCO2R7, CHR7COR9 , CHR7CONHCHR8COR9, or CONR7R8;
R6 is H;
or R4 and R5 together make a 4-8 member ring which may be substituted with one or more heteroatoms selected from O, N, or S, and may be further substituted with one or more of C1-8 alkoxy, C1-8 alkyl, H, isoxazolyl, or hydroxyl;
R9 is C1-8 alkoxy, C1-8 alkyl, H, isoxazolyl, or hydroxyl;
each y is independently 1, 2, or 3;
and Z is ═O, where the depicted dashed line to Z is a double bond,
wherein substituted refers to substitution with one or more of C1-8 alkyl, halogen, C1-8 haloalkyl, C1-8 alkoxy, hydroxyl, carbonyl, CO2R9, C5-12 aryl, 5 to 7 membered heteroaryl, C3-8 cycloalkyl, C1-8 alkyl-C5-12 aryl, C1-8 alkyl-5 to 7 membered heteroaryl, C1-8 alkyl-C3-8 cycloalkyl, NO2, N3, NH2, N(CH3)2, SO(1-3)H, or SH.

17 more elements

Facts

Application

15/023,510Filed 5 Jun 2015 · us provisional application

Priority

6 Jun 2014

Published

US 2016/0207889 A121 Jul 2016

Granted

13 Aug 2019

Term ends

Not estimatedThe source records don’t support an estimate.

Classification38 codes

C07D 231/14
Having two or three double bonds between ring members or between ring members and non-ring members: with hetero atoms or with carbon atoms having…
A61K 31/415
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2-Diazoles
A61K 31/4155
1,2-Diazoles: non condensed and containing further heterocyclic rings
A61K 31/422
Oxazoles: not condensed and containing further heterocyclic rings