Biheteroaryl compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-RE47848-E
Application number	US-201815902746-A
Country	US
Kind code	E1
Filing date	Feb 22, 2018
Priority date	May 1, 2013
Publication date	Feb 11, 2020
Grant date	Feb 11, 2020

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. Compounds A compound of formula (I)

or salts a pharmaceutically acceptable salt thereof wherein
R 1 , R 2 and R 3 are each independently H, F, Cl, Br, I, CN, C 1-6 alkyl or C 1-6 haloalkyl;
X 1 is N or 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, —I, CN, -(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, -(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)-, ═O and —C(═O)—, and L 2 is selected from the group consisting of —O—, —N(H)—, —N(C 1-6 alkyl)-, —S—, ═O —C(═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, 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, 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 ) -(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 substitutents 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. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein either A or Cy is a polycyclic carbocycle or polycyclic heterocycle.

3. A compound according to claim 1 , wherein X 1 is N.

4. A compound according to claim 1 , wherein X 1 is C—R 4 .

5. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, 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.

6. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, 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.

7. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, 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, monofluoromethyl difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl and cyclopentyl.

8. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of (L 2 ) 0-1 -phenyl -(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 -pyrroly

Assignees

• Genentech Inc

Inventors

• Estrada Anthony
• Olivero Alan G
• Patel Snahel
• Siu Michael
• Lyssikatos Joseph
• Huestis Malcolm
• Kellar Terry

Classifications

• 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

• A61P39/02

  Antidotes · CPC title

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title