US 2019/0169160 A1Published application

Ire1 small molecule inhibitors

AssigneeQuentis Therapeutics, Inc.

InventorsJoseph P. VACCA, Dansu LI, Sarah BETTIGOLE

Life of this patent

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Abstract

Provided herein are small molecule inhibitors for the targeting or IRE1 protein family members. Binding may be direct or indirect. Further provided herein are methods of using IRE1 small molecule inhibitors for use in treating or ameliorating cancer in a subject. Moreover, IRE1 small molecule inhibitors described herein are for the treatment of cancer, where the cancer is a solid or hematologic cancer.

Claims55

Dependent claims

A compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof:

wherein,
each Z is independently N or CR1, provided that at least one Z is N;
each R1 is independently H, halogen, —CN, —OR8, —SR8, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R8)2, —NR8S(═O)2R9, —C(═O)R9, —OC(═O)R9, —C(═O)OR8, —OC(═O)OR9, —N(R8)2, —OC(═O)N(R8)2, —NR8C(═O)R9, —NR8C(═O)OR9, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R3 is —CN, —OR8, —SR8, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted —O—C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted —O—C3-C6cycloalkyl, optionally substituted C3-C6heterocycloalkyl, optionally substituted —O—C3-C6heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R4 is halogen, —CN, —OR8, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, or optionally substituted C1-C4heteroalkyl;
each R5 is independently H, halogen, —CN, —OR8, —SR8, —N(R8)2, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R2 is independently H, halogen, —CN, —OR8, —SR8, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R8)2, —NR8S(═O)2R9, —C(═O)R9, —OC(═O)R9, —C(═O)OR8, —OC(═O)OR9, —N(R8)2, —OC(═O)N(R8)2, —NR8C(═O)R9, —NR8C(═O)OR9, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R6 is H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cycloalkylalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R7 is optionally substituted C3-C6cycloalkylalkyl or R7 is methyl, ethyl, —CH2CF3, —CH2-cyclopropyl, or —CH2CH2OCH3;
each R8 is independently H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or two R8 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;
each R9 is independently optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
RA1 and RA2 are each independently H, halogen, —OR9, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, or optionally substituted aryl;
provided that both RA1 and RA2 are not H;
n is 0, 1, 2, 3, or 4;
and
q is 0, 1, 2, 3, or 4.

14 more elements

A compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof:

wherein,
each Z is independently N or CR1, provided that at least one Z is N;
each R1 is independently H, halogen, —CN, —OR8, —SR8, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R8)2, —NR8S(═O)2R9, —C(═O)R9, —OC(═O)R9, —C(═O)OR8, —OC(═O)OR9, —N(R8)2, —OC(═O)N(R8)2, —NR8C(═O)R9, —NR8C(═O)OR9, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R3 is —CN, —OR8, —SR8, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted —O—C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted —O—C3-C6cycloalkyl, optionally substituted C3-C6heterocycloalkyl, optionally substituted —O—C3-C6heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R4 is halogen, —CN, —OR8, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, or optionally substituted C1-C4heteroalkyl;
each R5 is independently H, halogen, —CN, —OR8, —SR8, —N(R8)2, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R2 is independently H, halogen, —CN, —OR8, —SR8, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R8)2, —NR8S(═O)2R9, —C(═O)R9, —OC(═O)R9, —C(═O)OR8, —OC(═O)OR9, —N(R8)2, —OC(═O)N(R8)2, —NR8C(═O)R9, —NR8C(═O)OR9, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R6 is H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cycloalkylalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R7 is optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cycloalkylalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or R6 and R7 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;
each R8 is independently H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or two R8 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;
each R9 is independently optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
RA1 and RA2 are each independently H, halogen, —OR9, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, or optionally substituted aryl;
provided that both RA1 and RA2 are not H;
n is 0, 1, 2, 3, or 4;
and
q is 0, 1, 2, 3, or 4.

15 more elements

A compound, or a pharmaceutically acceptable salt, or solvate thereof, selected from:

N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-methylpyrimidin-2-yl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyrazin-2-yl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)phenyl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyridin-2-yl)-2-chlorobenzenesulfonamide;
N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyridin-3-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-1H-pyrazol-3-yl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-hydroxyquinazolin-6-yl)-3-methylphenyl)-2-chloro-N-methylbenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-methylphenyl)-2-chloro-N-methylbenzenesulfonamide;
N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyridazin-3-yl)-2-chlorobenzenesulfonamide;
N-(2-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyrimidin-5-yl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-ethylphenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-methoxyquinazolin-6-yl)-3-methylphenyl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-methylthiazol-2-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyrimidin-2-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-isopropylquinazolin-6-yl)-1-methyl-1H-pyrazol-3-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)thiazol-2-yl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluoro-5-methoxyphenyl)-2-chlorobenzenesulfonamide;
N-(1-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-1H-pyrazol-4-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)isoxazol-3-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-methoxyquinazolin-6-yl)-1-methyl-1H-pyrazol-3-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-methoxypyrimidin-2-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-propylquinazolin-6-yl)-1-methyl-1H-pyrazol-3-yl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-3-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)pyridazin-3-yl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-5-fluoropyridin-3-yl)-2-chlorobenzenesulfonamide;
N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-fluoropyridin-3-yl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-2,5-difluorophenyl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-3-fluoropyridin-2-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoropyridin-2-yl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-2,3-difluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(3-(((1r,4r)-4-aminocyclohexyl)amino)isoquinolin-7-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
(S)-2-amino-N-((1r,4S)-4-((6-(4-((2-chlorophenyl)sulfonamido)-3-fluorophenyl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)-3-methylbutanamide;
N-((1r,4r)-4-((6-(4-((2-chlorophenyl)sulfonamido)-3-fluorophenyl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)acetamide;
2-chloro-N-(4-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-2-fluorophenyl)benzenesulfonamide;
2-chloro-N-(6-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)pyridazin-3-yl)benzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-3,5-difluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2,6-difluorophenyl)-2-chlorobenzenesulfonamide;
2-chloro-N-(6-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)pyridazin-3-yl)benzenesulfonamide;
N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-methoxypyridazin-3-yl)-2-chlorobenzenesulfonamide;
N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-methoxypyridazin-3-yl)-2-chlorobenzenesulfonamide;
N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-methylpyridazin-3-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-4-methylpyrimidin-2-yl)-2-chlorobenzenesulfonamide;
2-chloro-N-(4-(2-(((1r,4r)-4-(dimethyl amino)cyclohexyl)amino)-8-ethyl quinazolin-6-yl)-2-fluorophenyl)benzenesulfonamide;
N-(4-(2-(((1R,3R,4 S)-4-amino-3-methylcyclohexyl)amino)-8-ethyl quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethyl quinazolin-6-yl)-2-fluoro-3-methylphenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1R,3 S)-3-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
(S)-2-chloro-N-(4-(8-ethyl-2-(piperidin-3-ylamino)quinazolin-6-yl)-2-fluorophenyl)benzenesulfonamide;
N-(4-(2-(((1R,3R,4R)-4-amino-3-methylcyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1R,3 S)-3-aminocyclohexyl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
(S)-2-chloro-N-(2-fluoro-4-(2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)benzenesulfonamide;
N-(4-(2-(((1R,3R)-3-aminocyclopentyl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1R,3R)-3-aminocyclopentyl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1R,3 S)-3-aminocyclopentyl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1R,3 S)-3-aminocyclopentyl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-((4-aminobicyclo[2.2.2]octan-1-yl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((2r,5r)-5-aminooctahydropentalen-2-yl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((2r,5r)-5-aminooctahydropentalen-2-yl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((2s,5 s)-5-aminooctahydropentalen-2-yl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((2s, 5 s)-5-aminooctahydropentalen-2-yl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-((4-aminobicyclo[2.2.1]heptan-1-yl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-((4-aminobicyclo[2.2.2]octan-1-yl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
2-chloro-N-(4-(8-ethyl-2-(((1r,4r)-4-(pyrrolidin-1-yl)cyclohexyl)amino)quinazolin-6-yl)-2-fluorophenyl)benzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-1,3,4-thiadiazol-2-yl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-7-methylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide;
N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-methoxypyridin-3-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyrazin-2-yl)-2-chlorobenzenesulfonamide;
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoropyridin-2-yl)benzenesulfonamide;
N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-ethylpyridazin-3-yl)-2-chlorobenzenesulfonamide;
and
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyrazin-2-yl)-2-chlorobenzenesulfonamide.

72 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/184,916Filed 8 Nov 2018
Priority: 10 Nov 2017
Published: 6 Jun 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07D 401/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings
A61P 35/00
Antineoplastic agents
C07D 217/22
Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems: with hetero atoms or with carbon atoms having three…
C07D 239/84
With hetero atoms directly attached in position 2: nitrogen atoms

Family

Application62/584,575Us provisional application · filed 10 Nov 2017
Application62/678,723Us provisional application · filed 31 May 2018
US 10,745,379 B2Related patent
US 2019/0169160 A1This patent

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

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Abstract

A compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof:

wherein,
each Z is independently N or CR1, provided that at least one Z is N;
each R1 is independently H, halogen, —CN, —OR8, —SR8, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R8)2, —NR8S(═O)2R9, —C(═O)R9, —OC(═O)R9, —C(═O)OR8, —OC(═O)OR9, —N(R8)2, —OC(═O)N(R8)2, —NR8C(═O)R9, —NR8C(═O)OR9, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R3 is —CN, —OR8, —SR8, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted —O—C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted —O—C3-C6cycloalkyl, optionally substituted C3-C6heterocycloalkyl, optionally substituted —O—C3-C6heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R4 is halogen, —CN, —OR8, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, or optionally substituted C1-C4heteroalkyl;
each R5 is independently H, halogen, —CN, —OR8, —SR8, —N(R8)2, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R2 is independently H, halogen, —CN, —OR8, —SR8, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R8)2, —NR8S(═O)2R9, —C(═O)R9, —OC(═O)R9, —C(═O)OR8, —OC(═O)OR9, —N(R8)2, —OC(═O)N(R8)2, —NR8C(═O)R9, —NR8C(═O)OR9, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R6 is H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cycloalkylalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R7 is optionally substituted C3-C6cycloalkylalkyl or R7 is methyl, ethyl, —CH2CF3, —CH2-cyclopropyl, or —CH2CH2OCH3;
each R8 is independently H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or two R8 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;
each R9 is independently optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
RA1 and RA2 are each independently H, halogen, —OR9, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, or optionally substituted aryl;
provided that both RA1 and RA2 are not H;
n is 0, 1, 2, 3, or 4;
and
q is 0, 1, 2, 3, or 4.

14 more elements

Facts

Application

16/184,916Filed 8 Nov 2018

Priority

10 Nov 2017

Published

6 Jun 2019

Term ends

Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07D 401/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings
A61P 35/00
Antineoplastic agents
C07D 217/22
Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems: with hetero atoms or with carbon atoms having three…
C07D 239/84
With hetero atoms directly attached in position 2: nitrogen atoms