Biheteroaryl compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-10028954-B2
Application number	US-201615041375-A
Country	US
Kind code	B2
Filing date	Feb 11, 2016
Priority date	Apr 30, 2013
Publication date	Jul 24, 2018
Grant date	Jul 24, 2018

Abstract

The present invention provides for compounds of Formula I and embodiments and salts thereof for the treatment of diseases (e.g., neurodegenerative diseases). R 1 , R 2 , R 3 , X 1 , X 2 , A and Cy variable in Formula all have the meaning as defined herein.

First claim

The invention claimed is:

1. A method for decreasing the progression of a neurodegenerative disease or condition in a human suffering therefrom, wherein said neurodegenerative disease or condition is selected from the group consisting of: Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS); and glaucoma;
wherein said method comprises administering to said patient a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein
R 1 , R 2 and R 3 are each independently H, F, Cl, Br, I, C 1-6 alkyl or C 1-6 haloalkyl;
X 1 is C—R 4 , wherein R 4 is selected from the group consisting of —F, —Cl, —Br, I, -(L 1 ) 0-1 -C 1-6 alkyl, -(L 1 ) 0-1 -C 1-6 haloalkyl, -(L 1 ) 0-1 -C 1-6 heteroalkyl, -(L 2 ) 0-1 -C 3-8 cycloalkyl, -(L 2 ) 0-1 -3 to 7 membered heterocycloalkyl, -(L 2 ) 0-1 -6-10 membered aryl and -(L 2 ) 0-1 -5-10 membered heteroaryl, wherein L 1 is selected from the group consisting of —O—, —N(H)—, —S—, —N(C 1-6 alkyl)- and ═O, and L 2 is selected from the group consisting of —O—, —N(H)—, —N(C 1-6 alkyl)-, —S—, ═O, C 1-4 alkylene, C 1-4 alkenylene, C 1-4 alkynylene, C 1-4 alkoxylene, C 1-4 aminoalkylene, C 1-4 thioalkylene and C 1-4 heteroalkylene, and wherein R 4 is optionally substituted on carbon atoms and heteroatoms with R R4 substituents selected from the group consisting of F, Cl, Br, I, C 1-6 alkyl, C 1-6 haloalkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 dialkylamino, C 1-6 alkylthio, ═O, —NH 2 , —CN, —NO 2 and —SF 5 ;
X 2 is N;
A is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 dialkylamino, 3 to 12 membered cycloalkyl and 3 to 12 membered heterocycloalkyl, wherein A is optionally substituted with 1-5 R A substituents selected from the group consisting of F, Cl, Br, I, —OH, —CN, —NO 2 , —SF 5 , C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 heteroalkyl, -(L A ) 0-1 -3-8 membered cycloalkyl, -(L A ) 0-1 -3-8 membered heterocycloalkyl, -(L A ) 0-1 -5 to 6 membered heteroaryl, -(L A ) 0-1 -C 6 aryl, -(L A ) 0-1 -NR R1a R R1b , -(L A ) 0-1 -OR R1a , -(L A ) 0-1 —SR R1a , -(L A ) 0-1 —N(R R1a )C(═Y 1 )OR R1c , -(L A ) 0-1 -OC(═O)N(R R1a )(R R1b ), -(L A ) 0-1 -N(R R1a )C(═O)N(R R1a )(R R1b ), -(L A ) 0-1 -C(═O)N(R R1a )(R R1b ), -(L A ) 0-1 —N(R R1a )C(═O)R R1b , -(L A ) 0-1 -C(═O)OR R1a , -(L A ) 0-1 -OC(═O)R R1a , -(L A ) 0-1 -P(═O)(OR R1a )(OR R1b ), -(L A ) 0-1 -S(O) 1-2 R R1c , -(L A ) 0-1 -S(O) 1-2 N(R R1a )(R R1b ), -(L A ) 0-1 -N(R R1a )S(O) 1-2 N(R R1a )(R R1b ) and -(L A ) 0-1 -N(R R1a )S(O) 1-2 (R R1c ), wherein L A is selected from the group consisting of C 1-4 alkylene, C 1-4 heteroalkylene, C 1-4 alkoxylene, C 1-4 aminoalkylene, C 1-4 thioalkylene, 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, 3-8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 8 membered heterocycloalkyl; R R1c is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, 3 to 8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 7 membered heterocycloalkyl, and wherein R A is optionally substituted on carbon atoms and heteroatoms with R RA substituents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , ═O, —SF 5 , 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-N(H)S(O) 0-2 —, C 1-4 (halo)alkyl-S(O) 0-2 N(H)—, (halo)alkyl-N(H)—S(O) 0-2 N(H)—, 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 alkylthio, C 1-4 alkylamino and C 1-4 dialkylamino; and
Cy is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, 3 to 12 membered cycloalkyl and 3 to 12 membered heterocycloalkyl, wherein Cy is optionally substituted on carbon or heteroatoms with R Cy substituents selected from the group consisting of F, Cl, Br, I, —OH, —CN, —NO 2 , —SF 5 , C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 heteroalkyl, -(L Cy ) 0-1 -3-8 membered cycloalkyl, -(L Cy ) 0-1 -3-8 membered heterocycloalkyl, -(L Cy ) 0-1 -5 to 6 membered heteroaryl, -(L Cy ) 0-1 -phenyl, -(L Cy ) 0-1 -NR RCa R RCb , -(L Cy ) 0-1 -OR RCa , -(L Cy ) 0-1 -SR RCa , -(L Cy ) 0-1 -N(R RCa )C(═Y 1 )OR RCc , -(L Cy ) 0-1 -OC(═O)N(R RCa )(R RCb ), -(L Cy ) 0-1 -N(R RCa )C(═O)N(R RCa )(R RCb ), -(L Cy ) 0-1 -C(═O)N(R RCa )(R RCb ), -(L Cy ) 0-1 -N(R RCa )C(═O)R RCb , -(L Cy ) 0-1 -C(═O)OR RCa , -(L Cy ) 0-1 -OC(═O)R RCa , -(L Cy ) 0-1 -P(═O)(OR RCa )(OR RCb ), -(L Cy ) 0-1 -S(O) 1-2 R RCc , -(L Cy ) 0-1 -S(O) 1-2 N(R RCa )(R RCb ), -(L Cy ) 0-1 -N(R RCa )S(O) 1-2 N(R RCa )(R RCb ) and -(L Cy ) 0-1 -N(R RCa )S(O) 1-2 (R RCc ), wherein L Cy is selected from the group consisting of C 1-4 alkylene, C 1-4 heteroalkylene, C 1-4 alkoxylene, C 1-4 aminoalkylene, C 1-4 thioalkylene, C 2-4 alkenylene, and C 2-4 alkynylene; wherein R Rca and R Rcb are independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, 3-8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 8 membered heterocycloalkyl; R RCc is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, 3 to 8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 7 membered heterocycloalkyl, and wherein R Cy is optionally substituted on carbon atoms and heteroatoms with from 1 to 5 R RCy substituents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , ═O, —SF 5 , 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-N(H)S(O) 0-2 —, C 1-4 (halo)alkyl-S(O) 0-2 N(H)—, (halo)alkyl-N(H)—S(O) 0-2 N(H)—, 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 alkylthio, C 1-4 alkylamino and C 1-4 dialkylamino.

2. The method of claim 1 , wherein either A or Cy is a polycyclic carbocycle or polycyclic heterocycle.

3. The method of claim 1 , wherein R 4 is selected from the group consisting of —F, —Cl, —CN, -(L 2 ) 0-1 -C 3-8 cycloalkyl, -(L 2 ) 0-1 -3 to 7 membered heterocycloalkyl, -(L 1 ) 0-1 -C 1-6 alkyl, -(L 1 ) 0-1 -C 1-6 haloalkyl, -(L 1 ) 0-1 -C 1-6 heteroalkyl, -(L 2 ) 0-1 -6-10 membered aryl and -(L 2 ) 0-1 -5-10 membered heteroaryl, and is optionally substituted.

4. The method of claim 1 , wherein R 4 is selected from the group consisting of —F, —Cl, C 3-8 cycloalkyl, 3 to 7 membered heterocycloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, —(O)—C 3-8 cycloalkyl, —(O)-3 to 7 membered heterocycloalkyl, —(O)—C 1-6 alkyl and —(O)—C 1-6 haloalkyl, and is optionally substituted.

5. The method of claim 1 , wherein R 4 is selected from the group consisting of methoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, methyl, monofluoromethyh difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl and cyclopentyl.

6. The method of claim 1 , wherein R 4 is selected from the group consisting of (L 2 ) 0-1 -phenyl, -(L 2 ) 0-1 -pyridyl, -(L 2 ) 0-1 -pyrimidinyl, -(L 2 ) 0-1 -pyrazinyl, -(L 2 ) 0-1 -pyridazinyl, -(L 2 ) 0-1 -pyrrolyl, -(L 2 ) 0-1 -pyrazolyl, -(L 2 ) 0-1 -imidazolyl, -(L 2 ) 0-1 -thienyl, -(L 2 ) 0-1 -thiazolyl, -(L 2 ) 0-1 -thiadiazolyl, -(L 2 ) 0-1 -triazoloyl, -(L 2 ) 0-1 -oxazolyl, -(L 2 ) 0-1 -oxadiazol

Assignees

• Genentech Inc

Inventors

• Estrada Anthony
• Olivero Alan G
• Patel Snahel
• Siu Michael
• Lyssikatos Joseph

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P39/02

  Antidotes · 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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P31/18

  for HIV · CPC title