Bicyclic-fused heteroaryl or aryl compounds

Patent metadata

Field	Value
Publication number	US-9879022-B2
Application number	US-201615232892-A
Country	US
Kind code	B2
Filing date	Aug 10, 2016
Priority date	Apr 4, 2014
Publication date	Jan 30, 2018
Grant date	Jan 30, 2018

Abstract

Compounds, tautomers and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula Ia,

as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

First claim

We claim:

1. A compound of Formula IIc, IId, IIe, IIf or IIg,

wherein
R 1 is C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; —(CR 3a R 3b ) m -(3- to 7-membered cycloalkyl); or —(CR 3a R3 b ) m -(3- to 7-membered heterocycloalkyl) having one to three heteroatoms; wherein said alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted with one to five halogen, deuterium, —OR 5 , —SR 5 , —NR 11a R 11b , cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or —C 1 -C 6 alkoxy;
R 2 is —(CR 3a R3 b ) m -(3- to 10-membered heterocycloalkyl) having one to three heteroatoms, wherein said heterocycloalkyl is optionally substituted at a carbon atom with one to five R 4 and wherein, if the heteroatom is N, said N is optionally substituted with R 4′ ;
R 3a and R 3b are each independently hydrogen or C 1 -C 3 alkyl;
R 4 for each occurrence is independently and optionally halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, oxo, —OR 5 , —SR 5 , —S(O)R 9 , —S(O) 2 R9, —C(O)R 10 , —(CR 3a R 3b ) n -(3- to 7-membered cycloalkyl) or —(CR 3a R 3b ) n -(4- to 7-membered heterocycloalkyl) wherein said alkyl, cycloalkyl and heterocycloalkyl are each optionally and independently substituted with one to five deuterium, halogen, —OR 5 , —SR 5 , —NR 11a R 11b , cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl C 1 -C 6 alkoxy or NR 11a R 11b ; or two R 4 taken together with the respective carbons to which each are bonded form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one to three halogen, deuterium, —OR 5 , —SR 5 , —NR 11a R 11b , cyano or C 1 -C 6 alkyl or C 1 -C 6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with halogen, deuterium, —OR 5 , —NR 11a R 11b , or cyano; and wherein, if a heteroatom on said heterocycloalkyl is N, said N is optionally substituted with R 4′ ;
R 4′ is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —S(O)R 9 , —S(O) 2 R 9 , —C(O)R 10 , C(O)(CH 2 ) t CN; wherein said alkyl is optionally substituted with NH 2 , cyano or halogen —(CR 3a R 3b ) n -(3- to 7-membered cycloalkyl), —(CR 3a R 3b ) n -(4- to 10-membered heterocycloalkyl), wherein said alkyl, alkenyl, cycloalkyl, or heterocycloalkyl is each optionally and independently substituted with one to five deuterium, halogen, OH, cyano or C 1 -C 6 alkoxy; or R 4 and R 4′ taken together with the respective atoms to which each are bonded form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one to three halogen, deuterium, —OR 5 , —SR 5 , —NR 11a R 11b , cyano, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with halogen, deuterium, —OR 5 , —SR 5 , —NR 11a R 11b or cyano;
R 5 is hydrogen or C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with halogen;
R 6 is —C(O)NHR 7 or cyano;
R 7 is hydrogen or C 1 -C 6 alkyl;
R 8 is independently hydrogen, halogen, cyano, —NR 11a R 11b , C 1 -C 6 alkyl, 5- to 6-membered heteroaryl or 5- to 6-membered aryl, wherein said alkyl or heteroaryl or aryl is optionally substituted with one to three halogen, —NR 11a R 11b , C 1 -C 3 alkyl or oxo;
R 8 is hydrogen, deuterium, halogen, cyano, —OR 5 , or NR 11a NR 11 b;
R 9 is —(CR 3a R 3b ) p —(C 1 -C 3 alkyl), —(CR 3a R 3b ) p —(4- to 6-membered cycloalkyl), —(CR 3a R 3b ) p —(4- to 6-membered heterocycloalkyl) or —(CR 3a R 3b ) p —(C 5 -C 9 aryl), wherein said alkyl, cycloalkyl, heterocycloalkyl or aryl is each optionally substituted with fluoro or C 1 -C 3 alkyl;
R 10 is C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with fluoro or cyano;
R 11a and R 11b are each independently hydrogen or C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with OH;
m is independently 0, 1 or 2;
n is independently 0 or 1;
p is independently 0 or 1; and
t is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt of said compound or a tautomer of said compound or said salt.

2. The compound of claim 1 wherein
R 1 is C 1 -C 4 alkyl; C 2 -C 4 alkenyl; C 2 -C 4 alkynyl; —(CR 3a R 3b ) m -(3- to 6-membered cycloalkyl); or —(CR 3a R3 b ) m -(3- to 5-membered heterocycloalkyl) having one to three heteroatoms; wherein said alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted with one to three halogen, deuterium, —OR 5 , —SR 5 , —NR 11a R 11b , cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or —C 1 -C 6 alkoxy;
R 3a and R 3b are each independently hydrogen or C 1 -C 3 alkyl;
R 6 is —C(O)NHR 7 or cyano;
R 7 is hydrogen; and
m is independently 0 or 1;
or a pharmaceutically acceptable salt of said compound or a tautomer of said compound.

3. The compound of claim 2 wherein R 1 is fluoromethyl; difluoromethyl; trifluoromethyl; methyl, ethyl, propyl or isopropyl, each optionally substituted with one to three fluoro or deuterium; allene, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, oxetane or tetrahydrofuran, each of which is optionally substituted with fluoro or C 1 -C 3 alkyl; or a pharmaceutically acceptable salt of said compound or a tautomer of said compound or said salt.

4. The compound of claim 3 wherein the heterocycloalkyl of R 2 is selected from pyrrolidinyl, pyrrolidin-2-onyl, piperidinyl, piperidin-2-onyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, oxazolidinyl, oxazolidin-2-onyl, 1,3-oxazinan-2-onyl, imidazolidinyl, imidazolidin-2-onyl, morpholinyl, morpholin-3-onyl, thiazyl, isothiazyl, isothiazolidine-1,1-dioxidyl, 1,2-thiazinane 1,1-dioxidyl, hexahydrocyclopenta[b]pyrrol-2(1H)-onyl, octahydrocyclopenta[c]pyrrolyl, azetidinyl, hexahydro-1H-indol-2(3H)-onyl, octahydro-1H-isoindolyl, azepanyl, tetrahydrofuranyl, 1,3-dioxolanyl, oxetanyl, 4-azepanyl, 1,4-oxazepanyl, tetrahydro-2H-pyranyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, or 1,2,3,4-tetrahydroisoquinolinyl; wherein said heterocycloalkyl is optionally substituted with one to four R 4 ; or a pharmaceutically acceptable salt of said compound or a tautomer of said compound or said salt.

5. The compound of claim 4 wherein the heterocycloalkyl of R 2 is selected from

wherein said heterocycloalkyl is optionally substituted with one to four R 4 ;
or two R 4 taken together with the respective carbons to which each are bonded form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one to three F, Cl, OH, cyano, C 1 -C 3 alkyl (optionally substituted with OH, F or Cl), C 1 -C 3 fluoroalkyl or C 1 -C 6 alkoxy;
R q is independently hydrogen, deuterium or C 1 -C 3 alkyl, wherein said alkyl is optionally substituted with halogen; and
R 3a and R 3b for each occurrence are independently hydrogen or C 1 -C 3 alkyl;
R 4 for each occurrence is independently and optionally halogen; C 1 -C 3 alkyl; C 2 -C 4 alkenyl; oxo; —OR 5 ; —C(O)R 10 ; —(CR 3a R 3b ) n -(3- to 5-membered cycloalkyl); or —(CR 3a R3 b ) n -(4- to 7-membered heterocycloalkyl) wherein said alkyl, cycloalkyl or heterocycloalkyl is each optionally and independently substituted with one to five deuterium, halogen, OH, cyano, C 1 -C 6 alkoxy or —NR 11a R 11b ; or two R 4 taken together with the respective carbons to which each are bonded form a cyclopr

Assignees

• Pfizer

Inventors

• Trzupek John David
• Lee Katherine Lin
• Bunnage Mark Edward
• Han Seungil
• Hepworth David
• Lovering Frank Eldridge
• Mathias John Paul
• Papaioannou Nikolaos
• Pierce Betsy Susan
• Strohbach Joseph Walter
• Wright Stephen Wayne
• Zapf Christoph Wolfgang
• Gavrin Lori Krim
• Lee Arthur
• Anderson David Randolph
• Curran Kevin Joseph
• Dehnhardt Christoph Martin
• Saiah Eddine
• Goldberg Joel Adam
• Wang Xiaolun
• Huang Horng-Chih
• Vargas Richard
• Lowe Michael Dennis
• Patny Akshay

Classifications

• A61P43/00

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title