Substituted benzoxazoles and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9493429-B2
Application number	US-201414772726-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

The invention provides compounds having the general formula (I): and pharmaceutically acceptable salts thereof, wherein the variables RA, subscript n, ring A, X 2 , L, subscript m, X 1 , R 1 , R 2 , R 3 , R 4 , and R N have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.

First claim

We claim:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 3-12 carbocycle, C-linked C 2-11 heterocycle or —NR 1A R 1B , wherein R 1A and R 1B are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 alkoxy, (6-10 membered aryl)-(X R1 ) 0-1 —, and 5-10 membered heteroaryl)-(X R1 ) 0-1 —, and wherein R 1A and R 1B are optionally combined to form a 3 to 8 membered heterocyclic ring optionally comprising 1 additional heteroatoms selected from N, O and S as ring vertex and optionally fused thereto is a benzene or pyridine ring; X R1 is selected from the group consisting of C 1-4 alkylene, C 1-4 heteroalkylene, C 2-4 alkenylene, and C 2-4 alkynylene; and wherein the aliphatic and aromatic portions of R 1 are optionally substituted with from 1 to 5 R R1 substituents selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, oxo (═O), F, Cl, Br, I, —OH, —CN, —NO 2 , —(X 1R ) 0-1 —NR R1a R R1b , —(X 1R ) 0-1 OR R1a , —(X 1R ) 0-1 SR R1a , —(X 1R ) 0-1 N(R R1a )C(═O)OR R1c , —(X 1R ) 0-1 OC(═O)N(R R1a )(R R1b ), —(X 1R ) 0-1 N(R R1a )C(═O)N(R R1a )(R R1b ), —(X 1R ) 0-1 C(═O)N(R R1a )(R R1b ), —(X 1R ) 0-1 N(R R1a )C(═O)R R1b , —(X 1R ) 0-1 C(═O)OR R1a , —(X 1R ) 0-1 OC(═O)R R1a , —(X 1R ) 0-1 —P(═O)(OR R1a )(R R1b ), —(X 1R ) 0-1 S(O) 1-2 R R1c , —(X 1R ) 0-1 S(O) 1-2 N(R R1a )(R R1b ), —(X 1R ) 0-1 N(R R1a )S(O) 1-2 N(R R1a )(R R1b ) and —(X 1R ) 0-1 N(R R1a )S(O) 1-2 (R R1c ), wherein X 1R is selected from the group consisting of C 1-4 alkylene, C 1-4 heteroalkylene, C 2-4 alkenylene and C 2-4 alkynylene; wherein R R1a and R R1b are independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 carbocycle, phenyl, benzyl, C 5-6 heteroaryl and C 2-7 heterocycle; R R1c is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 carbocycle, phenyl, benzyl, C 5-6 heteroaryl and C 2-7 heterocycle;
R N is hydrogen, C 1-4 alkyl or C 1-4 haloalkyl;
R 2 and R 3 are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8 alkyl, C 1-8 haloalkyl and C 1-8 alkoxy;
R 4 is selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 3-8 carbocycle, C 2-7 heterocycle, 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 R 5 substituents selected from F, Cl, Br, I, —CN, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 alkoxy;
L is a linker selected from the group consisting of C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, and C 1-4 heteroalkylene, wherein L is optionally substituted with from 1 to 3 R L substituents selected from the group consisting of ═O, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 acyl;
the subscript m represents the integer 0 or 1;
X 1 and X 2 are each independently selected from the group consisting of absent, —O—, —S(O)—, —S(O) 2 — and —N(R X )— wherein R x is H, C 1-8 alkyl, C 1-8 acyl or —S(O) 2 (C 1-8 alkyl), and wherein if the subscript m is 0 then one of X 1 or X 2 is absent;
the subscript n is an integer from 0 to 5;
A is selected from the group consisting of hydrogen, C 3 -C 20 carbocycle, C 3 -C 20 heterocycle, aryl, and heteroaryl, wherein if A is hydrogen then the subscript n is 0; and
R A is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, F, Cl, Br, I, —OH, —CN, —NO 2 , carbocycle, heterocycle, heteroaryl, —(X RA ) 0-1 NR A1 R A2 , —(X RA ) 0-1 OR A1 , —(X RA ) 0-1 SR A1 , —(X RA ) 0-1 N(R A1 )C(═O)OR A3 , —(X RA ) 0-1 OC(═O)N(R A1 )(R A2 ), —(X RA ) 0-1 N(R A1 )C(═O)N(R A1 )(R A2 ), —(X RA ) 0-1 C(═O)N(R A1 )(R A2 ), —(X RA ) 0-1 N(X RA )C(═O)R A2 , —(X RA ) 0-1 C(═O)OR A1 , —(X RA ) 0-1 OC(═O)R A1 , —P(═O)(OR A1 )(OR A2 ), —(X RA ) 0-1 S(O) 1-2 R A3 , —(X RA ) 0-1 S(O) 1-2 N(R A1 )(R A2 ), —(X RA ) 0-1 N(R A1 )S(O) 1-2 N(R A1 )(R A2 ) and —(X RA ) 0-1 N(R A1 )S(O) 1-2 (R A3 ), wherein X RA is selected from the group consisting of C 1-4 alkylene, C 1-4 heteroalkylene, C 2-4 alkenylene and C 2-4 alkynylene; wherein R A1 and R A2 are independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 carbocycle, tetrahydronaphthalene, phenyl, benzyl, C 5-6 heteroaryl and C 2-7 heterocycle; R A3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 carbocycle, tetrahydronaphthalene, phenyl, benzyl, C 5-6 heteroaryl and C 2-7 heterocycle; and wherein the aliphatic and aromatic portions of a R A substitutent is optionally substituted with from 1 to 5 R RA substitutents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , ═O, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 (halo)alkyl-C(═O)—, C 1-4 (halo)alkyl-S(O) 0-2 —, C 1-4 (halo)alkyl-C(═O)N(H)—, C 1-4 (halo)alkyl-N(H)—C(═O)—, ((halo)alkyl) 2 N—C(═O)—, C 1-4 (halo)alkyl-OC(═O)N(H)—, C 1-4 (halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl) 2 N—C(═O)O—, C 1-4 alkylamino, C 1-4 dialkylamino, C 3-6 carbocycle, C 3-6 cycloalkoxy, C 2-5 heterocycloalkoxy and tetrahydronaphthalene.

2. The compound of claim 1 , wherein the compound has the formula

3. The compound of claim 1 wherein R 4 is F, Cl, Br, I, —CN, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, or C 3-8 carbocycle.

4. The compound of claim 1 wherein R 4 is Cl or C 3-8 cyclopropyl.

5. The compound of claim 1 wherein R 1 is C 1-8 alkyl or C 3-12 carbocycle, wherein the aliphatic portions of R 1 are optionally substituted with from 1 to 5 R R1 substituents.

6. The compound of claim 5 wherein R 1 is methyl, cyclopropyl, or 2-methoxyethyl.

7. The compound of claim 1 wherein R 1 is selected from the group consisting of: —NH(CH 3 ), —N(CH 3 ) 2 ,

8. The compound of claim 1 wherein X 1 is —O— or —N(H)—; X 2 is absent; the subscript m is 1; and -(L)- is an optionally substituted group selected from the group consisting of C 1-4 alkylene, C 2-4 alkenylene or C 2-4 alkynylene.

9. The compound of claim 1 wherein A is an optionally substituted ring selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, adamantane, bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[4.1.1]octane, bicyclo[3.3.1]nonane and 1,2,3,4-tetrahydro-1,4-methanonaphthalene, 1,2,3,4-tetrahydroisoquinoline, cubane, spiro[2,5]octane, tetrahydronaphthalene and chromane.

10. The compound of claim 9 , wherein ring A is an optionally substituted ring selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, adamantane, cubane, bicyclo[2.2.2]octane, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, spiro[2,5]octane, tetrahydronaphthalene and chromane.

11. The compound of claim 1 wherein ring A is selected from the group consisting of

12. The compound of claim 1 wherein ring A is an optionally substituted ring selected

Assignees

• Genentech Inc
• Xenon Pharmaceuticals Inc

Inventors

• Chen Chien-An
• Chowdhury Sultan
• Dehnhardt Christoph Martin
• Sun Shaoyi

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/06

  Antiarrhythmics · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title