US 8,933,236 B2Granted

N-substituted benzamides and methods of use thereof

AssigneesXenon Pharmaceuticals Inc., Genentech, Inc.

InventorsSultan Chowdhury, Christoph Martin Dehnhardt, Thilo Focken, Michael Edward Grimwood, Ivan William Hemeon, Qi Jia, Daniel Ortwine, Brian Safina, Shaoyi Sun, Daniel P. Sutherlin, Alla Yurevna Zenova

Life of this patent

Estimating the term…

Abstract

The invention provides novel compounds having the general formula: and pharmaceutically acceptable salts thereof, wherein the variables RA, subscript n, ring A, X2, L, subscript m, X1, B, R1, R2, R3, R4, R5 and RN have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.

Claims32

Dependent claims

A compound selected from a compound of Formula I:

and pharmaceutically acceptable salts thereof, wherein in Formula I:
R1 is C1-8 alkyl, C1-8 haloalkyl, C1-8 alkoxy, C3-12 cycloalkyl, C-linked C2-11 heterocycloalkyl, heteroaryl, or —NR1AR1B, wherein R1A and R1B are each independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkoxy, (6-10 membered aryl)-(XR1)0-1—, (5-10 membered heteroaryl)-(XR1)0-1—, and wherein R1A and R1B are optionally combined to form a 3 to 8 membered heterocyclic ring optionally comprising 1 additional heteroatom selected from N, O and S as ring vertex and optionally fused thereto is a benzene or pyridine ring;
XR1 is selected from the group consisting of C1-4 alkylene, C1-4 heteroalkylene, C2-4 alkenylene, C2-4 alkynylene;
and wherein the aliphatic and aromatic portions of R1 are optionally substituted with from 1 to 5 RR1 substituents selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, F, Cl, Br, I, —OH, —CN, —NO2, ═O, —(X1R)0-1NRR1aRR1b, —(X1R)0-1ORR1a, —(X1R)0-1SRR1a, —(X1R)0-1N(RR1a)C(═O)ORR1c, —(X1R)0-1OC(═O)N(RR1a)(RR1b), —(X1R)0-1N(RR1a)C(═O)N(RR1a)(RR1b), (X1R)0-1C(═O)N(RR1a)(RR1b), —(X1R)0-1N(RR1a)C(═O)RR1b, —(X1R)0-1C(═O)ORR1a, —(X1R)0-1OC(═O)RR1a, —(X1R)0-1—P(═O)(ORR1a)(ORR1b), —(X1R)0-1S(O)1-2RR1c, —(X1R)0-1S(O)1-2N(RR1a)(RR1b), —(X1R)0-1N(RR1a)S(O)1-2N(RR1a)(RR1b) and —(X1R)0-1N(RR1a)S(O)1-2(RR1c), wherein X1R is selected from the group consisting of C1-4 alkylene, C1-4 heteroalkylene, C2-4 alkenylene and C2-4 alkynylene;
wherein RR1a and RR1b are independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-8 cycloalkyl, phenyl, benzyl, heteroaryl, and C2-7 heterocycloalkyl;
RR1c is selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-8 cycloalkyl, phenyl, benzyl, heteroaryl, and C2-7 heterocycloalkyl;
RN is hydrogen, C1-4 alkyl or C1-4 haloalkyl;
B is C or N;
R2, R3 and R4 are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, C1-8 alkyl, C1-8 haloalkyl and C1-8 alkoxy, and R3 is absent when B is nitrogen;
R5 is selected from the group consisting of H, F, Cl, Br, I, —CN, C1-8 alkyl, C1-8 haloalkyl, C1-8 alkoxy, C3-8 cycloalkyl, C2-7 heterocycloalkyl, phenyl and 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl is further optionally substituted with from 1 to 3 R5 substituents selected from F, Cl, Br, I, —CN, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkoxy;
L is a linker selected from the group consisting of C1-4 alkylene, C2-4 alkenylene, C2-4 alkynylene, and C1-4 heteroalkylene, wherein L is optionally substituted with from 1 to 3 RL substituents selected from the group consisting of ═O, C1-4 alkyl, C1-4 haloalkyl and C1-4 acyl;
the subscript m represents the integer 0 or 1;
X1 and X2 are each independently selected from the group consisting of absent, —O—, —S(O)—, —S(O)2— and —N(RX)— wherein Rx is H, C1-8 alkyl, C1-8 acyl or —S(O)2(C1-8 alkyl), and wherein if the subscript m is 0 then one of X1 or X2 is absent;
and
A-(RA)n is selected from the group consisting of:

12 more elements

A compound selected from:

Structure
Name
4-((adamantan-1-ylmethoxy)-2,5- difluoro-N- (methylsulfonyl)benzamide
4-(adamantan-1-ylmethoxy)-5- chloro-2-fluoro-N- (methylsulfonyl)benzamide
5-chloro-4-(((1S,2S,5S)-6,6- dimethylbicyclo[3.1.1]heptan-2- yl)methoxy)-2-fluoro-N- (methylsulfonyl)benzamide
4-(adamantan-2-yloxy)-5-chloro-2- fluoro-N-(methylsulfonyl)benzamide
5-chloro-2-fluoro-N- (methylsulfonyl)-4-(((1R,2R,3R,5S)- 2,6,6-trimethylbicyclo[3.1.1]heptan- 3-yl)oxy)benzamide
4-(2-(adamantan-1-yl)ethoxy)-5- chloro-2-fluoro-N- (methylsulfonyl)benzamide
5-chloro-2-fluoro-N- (methylsulfonyl)-4-(((1S,2R,4S)- 1,7,7-trimethylbicyclo[2.2.1]heptan- 2-yl)oxy)benzamide
5-chloro-2-fluoro-N- (methylsulfonyl)-4-((exo-1,7,7- trimethylbicyclo[2.2.1]heptan-2- yl)oxy)benzamide
5-chloro-2-fluoro-N- (methylsulfonyl)-4-(((1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]heptan- 3-yl)oxy)benzamide
5-chloro-2-fluoro-4-((3- fluoroadamantan-1-yl)methoxy)-N- (methylsulfonyl)benzamide
4-(((3s,5s,7s)-adamantan-1- ylamino)methyl)-3-chloro-N- (methylsulfonyl)benzamide
4-((-adamantan-1-ylmethyl)amino)- 5-chloro-2-fluoro-N- (methylsulfonyl)benzamide
4-(adamantan-1-ylmethoxy)-3- chloro-N-(methylsulfonyl)benzamide
4-(2-(adamantan-1-yl)ethoxy)-3- chloro-N-(methylsulfonyl)benzamide
6-(adamantan-1-ylmethoxy)-5- chloro-N-methanesulfonylpyridine- 3-carboxamide
5-chloro-4-((-3,5- dimethyladamantan-1-yl)methoxy)- 2-fluoro-N- (methylsulfonyl)benzamide
3-chloro-4-(((1r,3s,5R,7S)-3- hydroxyadamantan-1-yl)methoxy)- N-(methylsulfonyl)benzamide
5-chloro-2-fluoro-N- (methylsulfonyl)-4-(((1R,2S,4R)- 1,7,7-trimethylbicyclo[2.2.1]heptan- 2-yl)oxy)benzamide
4-(adamantan-1-ylmethoxy)-5- chloro-N-(N,N-dimethylsulfamoyl)- 2-fluorobenzamide
N1-((3s,5s,7s)-adamantan-1-yl)-2- chloro-5-fluoro-N4- (methylsulfonyl)terephthalamide
5-chloro-2-fluoro-4-((3- hydroxyadamantan-1-yl)methoxy)-N- (methylsulfonyl)benzamide
4-(1-(adamantan-1-yl)ethoxy)-5- chloro-2-fluoro-N- (methylsulfonyl)benzamide
4-(adamantan-2-yloxy)-5-chloro-N- (N,N-dimethylsulfamoyl)-2- fluorobenzamide
5-chloro-4-(((1S,2S,5S)-6,6- dimethylbicyclo[3.1.1]heptan-2- yl)methoxy)-N-(N,N- dimethylsulfamoyl)-2- fluorobenzamide
4-(((3s,5s,7s)-adamantan-1- yl(methyl)amino)methyl)-3-chloro- N-(methylsulfonyl)benzamide
N1-((3s,5s,7s)-adamantan-1-yl)-2- chloro-5-fluoro-N1-methyl-N4- (methylsulfonyl)terephthalamide
5-chloro-2-fluoro-4-((3- methoxyadamantan-1-yl)methoxy)- N-(methylsulfonyl)benzamide
5-chloro-2-fluoro-N- (methylsulfonyl)-4-((4- pentylbicyclo[2.2.2]octan-1- yl)methoxy)benzamide
5-chloro-4-(((1R,2s,3S,5s,7s)-5- chloroadamantan-2-yl)oxy)-2-fluoro- N-(methylsulfonyl)benzamide
5-chloro-4-(((1R,2r,3S,5s,7s)-5- chloroadamantan-2-yl)oxy)-2-fluoro- N-(methylsulfonyl)benzamide
6-(1-adamantylmethoxy)-5- cyclopropyl-N-methylsulfonyl- pyridine-3-carboxamide
4-(2-adamantyloxymethyl)-5- cyclopropyl-2-fluoro-N- methylsulfonylbenzamide
4-(1-adamantylmethoxy)-5-ethyl-2- fluoro-N-methylsulfonylbenzamide
4-(1-adamantylmethoxy)-N- (azetidin-1-ylsulfonyl)-5-ethyl-2- fluoro-benzamide
4-(1-adamantylmethoxy)-5- cyclopropyl-2-fluoro-N-(3- hydroxyazetidin-1-yl)sulfonyl- benzamide
4-(1-adamantylmethoxy)-5- cyclopropyl-2-fluoro-N-(2- hydroxyethylsulfonyl)benzamide
4-(1-adamantylmethoxy)-5- cyclopropyl-2-fluoro-N-(2- methoxyethylsulfonyl)benzamide
4-(1-adamantylmethoxy)-3- cyclobutyl-N- methylsulfonylbenzamide
4-(2-adamantyloxymethyl)-5-chloro- 2-fluoro-N- methylsulfonylbenzamide
4-(1-adamantylmethoxy)-N- (azetidin-1-ylsulfonyl)-3- (trifluoromethyl)-benzamide
5-chloro-4-[[(1R,2R,5R)-6,6- dimethylnorpinan-2-yl]methoxy]-2- fluoro-N-methylsulfonylbenzamide
4-(2-adamantylmethoxy)-3- cyclopropyl-N-methylsulfonyl- benzamide
4-(1-adamantylmethoxy)-5-chloro-2- methoxy-N- methylsulfonylbenzamide
4-(1-adamantylmethoxy)-5- cyclopropyl-2-fluoro-N- methylsulfonylbenzamide
4-(1-adamantylmethoxy)-3-bromo- N-methylsulfonylbenzamide
4-(1-adamantylmethoxy)-N- methylsulfonyl-3- (trifluoromethyl)benzamide
4-(1-adamantylmethoxy)-5- cyclopropyl-2-fluoro-N- (methylsulfamoyl)benzamide
4-(1-adamantylmethoxy)-N- (azetidin-1-ylsulfonyl)-5- cyclopropyl-2-fluoro-benzamide
4-(1-adamantylmethoxy)-5-chloro-2- fluoro-N-(2-hydroxyethylsulfonyl)- benzamide
4-(1-adamantylmethoxy)-2,5- dichloro-N- methylsulfonylbenzamide
4-(1-adamantylmethoxy)-5-chloro-2- fluoro-N- (methylsulfamoyl)benzamide
4-(1-adamantylmethoxy)-N- (azetidin-1-ylsulfonyl)-5-chloro-2- fluoro-benzamide
4-(1-adamantylmethoxy)-5-chloro-2- fluoro-N-(1-methylimidazol-4- yl)sulfonylbenzamide
4-(1-adamantylmethoxy)-5-chloro-2- fluoro-N-(2-methoxyethylsulfonyl)- benzamide
4-(1-adamantylmethoxy)-5-chloro-2- fluoro-N-(1H-imidazol-4- ylsulfonyl)benzamide
4-(1-adamantylmethoxy)-5-chloro-2- fluoro-N-morpholinosulfonyl- benzamide
5-chloro-2-fluoro-N-methylsulfonyl- 4-[[3-(5-methyltetrazol-2-yl)-1- adamantyl]methoxy]benzamide
5-chloro-N-(dimethylsulfamoyl)-2- fluoro-4-[(1-pentyl-4-bicyclo[2.2.2]- octanyl)methoxy]benzamide
5-chloro-4-[(3-chloro-1- adamantyl)methoxy]-N- (dimethylsulfamoyl)-2-fluoro- benzamide
4-(1-adamantylmethoxy)-3- cyclopropyl-N-(dimethylsulfamoyl)- benzamide
4-(1-adamantyloxymethyl)-5-chloro- 2-fluoro-N- methylsulfonylbenzamide
4-(1-adamantylmethoxy)-3- cyclopropyl-N-methylsulfonyl- benzamide
5-chloro-N-(dimethylsulfamoyl)-2- fluoro-4-[(3-fluoro-1- adamantyl)methoxy]benzamide
5-chloro-4-[(4,4-difluoro-1- adamantyl)methoxy]-N- (dimethylsulfamoyl)-2-fluoro- benzamide
5-chloro-2-fluoro-N-methylsulfonyl- 4-[[4-(trifluoromethyl)cyclohexyl]- methoxy]benzamide
5-chloro-4-[[(1S,2S,5S)-6,6- dimethylnorpinan-2-yl]methoxy]-2- fluoro-N-sulfamoylbenzamide
5-chloro-4-[[(1S,2R,5S)-6,6- dimethylnorpinan-2-yl]methoxy]-N- (dimethylsulfamoyl)-2-fluoro- benzamide
4-(2-adamantylmethoxy)-5-chloro- N-(dimethylsulfamoyl)-2-fluoro- benzamide
5-chloro-4-[(3-chloro-1- adamantyl)methoxy]-2-fluoro-N- methylsulfonylbenzamide
5-chloro-2-fluoro-N-methylsulfonyl- 4-[[4-(trifluoromethyl)cyclohexyl]- methoxy]benzamide
5-chloro-4-[[(1S,2R,5S)-6,6- dimethylnorpinan-2-yl]methoxy]-2- fluoro-N-methylsulfonylbenzamide
4-(1-adamantylmethoxy)-3-(2- methoxy-3-pyridyl)-N- methylsulfonyl-benzamide
4-(2-adamantylmethoxy)-5-chloro-2- fluoro-N-methylsulfonylbenzamide
5-chloro-2-fluoro-N-methylsulfonyl- 4-[(1-pentyl-4- bicyclo[2.2.2]octanyl)- methoxy]benzamide
5-chloro-2-fluoro-N-methylsulfonyl- 4-[(1R,2R,4S)-1,3,3- trimethylnorbornan-2- yl]oxybenzamide
5-chloro-4-(3,3- dimethylcyclohexoxy)-2-fluoro-N- methylsulfonylbenzamide
5-chloro-N-(dimethylsulfamoyl)-2- fluoro-4-[(1S,2R,4S)-1,7,7- trimethylnorbornan-2-yl]oxy- benzamide
5-chloro-2-fluoro-N-methylsulfonyl- 4-[4-(trifluoromethyl)cyclohexoxy]- benzamide
5-chloro-2-fluoro-N-methylsulfonyl- 4-[4-(trifluoromethyl)cyclohexoxy]- benzamide
5-chloro-4-[(5-chloro-2- adamantyl)oxy]-N- (dimethylsulfamoyl)-2-fluoro- benzamide
5-chloro-4-[(5-chloro-2- adamantyl)oxy]-N- (dimethylsulfamoyl)-2-fluoro- benzamide
5-chloro-N-(dimethylsulfamoyl)-2- fluoro-4-[4-(trifluoromethyl)- cyclohexoxy]benzamide
5-chloro-N-(dimethylsulfamoyl)-2- fluoro-4-[4-(trifluoromethyl)- cyclohexoxy]benzamide
4-[2-(1-adamantyl)ethoxy]-5-chloro- N-(dimethylsulfamoyl)-2-fluoro- benzamide
4-(1-adamantylmethoxy)-5-chloro- N-cyclopropylsulfonyl-2-fluoro- benzamide
4-(1-adamantylmethoxy)-5- cyclopropyl-2-fluoro-N-[(3S)-3- hydroxypyrrolidin-1-yl]sulfonyl- benzamide
4-(1-adamantylmethoxy)-5- cyclopropyl-N-cyclopropylsulfonyl- 2-fluorobenzamide
4-(1-adamantylmethoxy)-5-chloro-2- fluoro-N-[(3S)-3-hydroxypyrrolidin- 1-yl]sulfonylbenzamide
4-(1-adamantylmethoxy)-5- cyclopropyl-2-fluoro-N-(3- fluoroazetidin-1-yl)sulfonyl- benzamide
4-(1-adamantylmethoxy)-5-chloro-2- fluoro-N-(3-fluoroazetidin-1- yl)sulfonylbenzamide
5-chloro-4-[(4,4-difluoro-1- adamantyl)methoxy]-2-fluoro-N- methylsulfonylbenzamide
5-cyclopropyl-4-[(4,4-difluoro-1- adamantyl)methoxy]-2-fluoro-N- methylsulfonylbenzamide
4-(1-adamantylmethoxy)-5- cyclopropyl-2-fluoro-N-pyrrolidin-1- ylsulfonylbenzamide
4-(1-adamantylmethoxy)-5- cyclopropyl-2-fluoro-N- morpholinosulfonylbenzamide
5-cyclopropyl-2-fluoro-4-[(3-fluoro- 1-adamantyl)methoxy]-N- methylsulfonylbenzamide
5-cyclopropyl-2-fluoro-4-[(3- methoxy-1-adamantyl)methoxy]-N- methylsulfonyl-benzamide
4-(1-adamantylmethoxy)-5- cyclopropyl-N-(3,3-difluoroazetidin- 1-yl)sulfonyl-2-fluoro-benzamide
2-fluoro-4-[(3-fluoro-1- adamantyl)methoxy]-N- methylsulfonylbenzamide
4-(1-adamantylmethoxy)-2-fluoro-5- methyl-N-methylsulfonyl-benzamide
4-(1-adamantylmethoxy)-N- (azetidin-1-ylsulfonyl)-2-fluoro-5- methyl-benzamide
4-(1-adamantylmethoxy)-5- cyclopropyl-N-ethylsulfonyl-2- fluoro-benzamide
4-(1-adamantylmethoxy)-N-tert- butylsulfonyl-5-cyclopropyl-2- fluoro-benzamide
4-(1-adamantylmethoxy)-5- cyclopropyl-2-fluoro-N-(2- methoxyethylsulfamoyl)benzamide
4-(1-adamantylmethoxy)-5- cyclopropyl-2-fluoro-N-(3- hydroxypropylsulfamoyl)benzamide
4-(1-adamantylmethoxy)-5- cyclopropyl-2-fluoro-N-(3- methoxyazetidin-1-yl)sulfonyl- benzamide
Azetidine-1-sulfonic acid 5- cyclopropyl-4-(4,4-difluoro- adamantan-1-ylmethoxy)-2-fluoro- benzoylamide
Cyclopropanesulfonic acid 4- (bicyclo[4.1.0]hept-1-ylmethoxy)-5- cyclopropyl-2-fluorobenzoylamide
and the pharmaceutically acceptable salts thereof.

107 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/899,469Filed 21 May 2013 · us provisional application
Priority: WO PCT/IB2012/00132422 May 2012
Published: US 2013/0317000 A128 Nov 2013
Granted: 13 Jan 2015
Term ends: Not estimatedThe source records don’t support an estimate.

Classification74 codes

C07D 491/107
Spiro-condensed systems: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
A61K 31/18
Amides, e.g. hydroxamic acids: sulfonamides
A61K 31/397
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having four-membered rings, e.g. azetidine
A61K 31/40
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having five-membered rings with one nitrogen as the only ring hetero atom,…

Family

Application61/650,934Us provisional application · filed 23 May 2012
Application61/785,601Us provisional application · filed 14 Mar 2013
US 2013/0317000 A1Pre-grant publication · published 28 Nov 2013
US 8,933,236 B2This patent

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

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Back to results