Imidazopyridazines useful as inhibitors of the PAR-2 signaling pathway

Patent metadata

Field	Value
Publication number	US-10030024-B2
Application number	US-201615081076-A
Country	US
Kind code	B2
Filing date	Mar 25, 2016
Priority date	Sep 25, 2013
Publication date	Jul 24, 2018
Grant date	Jul 24, 2018

Abstract

The present invention relates to compounds useful as inhibitors of the PAR-2 signaling pathway. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of GPCRs in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such GPCRs; and the comparative evaluation of new inhibitors of the PAR-2 signaling pathway. The compounds of this invention have formula I:

wherein the variables are as defined herein.

First claim

The invention claimed is:

1. A compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein
A is

wherein
n is 1 or 2;
Z is —O—, —CH 2 —, or —NX—;
X is R 5 , —C(O)R 5 , or —S(O) 2 R 5 ;
J is CN; oxo; a C 1-6 aliphatic wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with —O—, —NR—, —S— or —C(O)—; or a 3-7 membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein said J is optionally and independently substituted with 1-3 occurrences of halo or C 1-4 alkyl, wherein up to one methylene unit of said C 1-4 alkyl is optionally and independently replaced with —O—, —NR—, or —S—;
or two J groups on the same or different atom(s), together with the atom(s) to which they are bound, form a 3-6 membered saturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein said 3-6 membered ring is optionally substituted with one occurrence of oxo;
p is 0-4;

R 5 is —(V) b —Y; wherein
V is C 1-6 aliphatic wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with —O—, —NR—, —S— or —C(O)—; wherein V is optionally and independently substituted with 1-3 occurrences of halo or C 1-6 alkyl, wherein up to three methylene units of said C 1-6 alkyl are optionally and independently replaced with —O—, —NR—, —S—, or C(O);
Y is H; CN; a 3-7 membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur; or a 6-10 membered saturated, partially unsaturated, or aromatic bicyclic ring having 0-6 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein Y is optionally substituted with 1-4 occurrences of J Y ;
J Y is oxo, halo, CN, —OP(═O)(OR) 2 , phenyl, or C 1-6 aliphatic, wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with O, NR, S, or C(O), wherein said C 1-6 aliphatic optionally and independently substituted with 1-3 occurrences of halo or OR;
b is independently 0 or 1; and

R 4 is H; halo; CN; C 1-6 aliphatic wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with —O—, —NR—, —S— or —C(O)—; a 3-7 membered saturated, partially saturated, or aromatic monocyclic ring having 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur; or a 6-10 membered saturated, partially unsaturated, or aromatic bicyclic ring having 0-6 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein said R 4 is optionally and independently substituted with 1-3 occurrences of oxo, halo, or C 1-6 aliphatic wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with O, NR, S or C(O); and
each R independently is H or C 1-4 alkyl.

2. The compound of claim 1 , wherein:
J is CN; oxo; a C 1-6 aliphatic wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with —O—, —NR—, —S— or —C(O)—; or a 3-7 membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein said J is optionally and independently substituted with 1-2 occurrences of halo or C 1-4 alkyl, wherein up to one methylene unit of said C 1-4 alkyl is optionally and independently replaced with —O—, —NR—, or —S—;
or two J groups on the same or different atom(s), together with the atom(s) to which they are bound, form a 3-6 membered saturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein said 3-6 membered ring is optionally substituted with one occurrence of oxo; and
R 5 is —(V) b —Y; wherein
V is C 1-6 aliphatic wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with —O—, —NR—, —S— or —C(O)—; wherein V is optionally substituted with 1-3 occurrences of halo or C 1-4 alkyl, wherein up to two methylene units of said C 1-4 alkyl are optionally replaced with —O—, —NR—, —S—, or C(O);
Y is H, a 3-7 membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur; or a 6-10 membered saturated, partially unsaturated, or aromatic bicyclic ring having 0-6 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein Y is optionally substituted with 1-4 occurrences of J Y ; and
J Y is oxo, halo, phenyl, or C 1-6 aliphatic, wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with O, NR, S, or C(O); and

R 4 is halo; CN; C 1-6 aliphatic wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with —O—, —NR—, —S— or —C(O)—; a 3-7 membered saturated, partially saturated, or aromatic monocyclic ring having 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur; or a 6-10 membered saturated, partially unsaturated, or aromatic bicyclic ring having 0-6 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein said R 4 is optionally and independently substituted with 1-3 occurrences of oxo, halo, or C 1-6 aliphatic wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with O, NR, S or C(O); and
R is H or C 1-4 alkyl.

3. The compound of claim 1 , wherein J is oxo, CN, halo, —OH, —O(C 1-6 alkyl), —NHC(═O)O(C 1-6 alkyl), —C(═O)NR, —C(═O)O(C 1-6 alkyl), or C 1-4 alkyl optionally substituted with 1-3 occurrences of halo.

4. The compound of claim 1 , wherein A is

wherein
Z 1 is —O—, —CH 2 —, or —NX—; wherein X is X 1 ;
Z 2 is —CH 2 — or —NX—; wherein X is X 2 ;
X 1 is R 5 , —C(O)R 5 , or —S(O) 2 R 5 ;
X 2 is R 5 ;
J A is C 1-4 alkyl;
J B is C 1-4 alkyl;
or J A and J B , together with the carbon atom to which they are bound, form a 3-6 membered saturated monocyclic ring having 0-1 heteroatom selected from oxygen, nitrogen, or sulfur; and
J C is methyl; and
J D is methyl.

5. The compound of claim 4 , wherein:
R 5 is —(V) b —Y;
V is C 1-6 aliphatic wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with —O—, —NR—, —S— or —C(O)—; wherein V is optionally and independently substituted with halo, C 1-4 alkyl, OH, NH 2 , or —NRC(O)C 1-4 alkyl;
Y is H or a 3-7 membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein Y is optionally substituted with 1-4 occurrences of J Y ; and
J Y is oxo, halo, phenyl, or C 1-6 aliphatic, wherein up to three carbon units of said C 1-6 aliphatic can each be optionally and independently replaced with O, NR, S or C(O), and wherein said C 1-6 aliphatic is optionally substituted with 1-3 occurrences of halo.

6. The compound of claim 1 , wherein R 4 is H, C 1-4 aliphatic, or a 3-7 membered saturated, partially saturated, or aromatic monocyclic ring having 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein said C 1-4 aliphatic is optionally substituted with 1-3 occurrences of halo, —OH, or —O(C 1-4 alkyl), and wherein said monocyclic ring is optionally substituted with 1-3 occurrences of halo, C 1-4 alkyl, —

Assignees

• Vertex Pharma

Inventors

• Farmer Luc J
• Fournier Pierre-Andre
• Lessard Stephanie
• Liu Bingcan
• St-Onge Miguel
• Sturino Claudio
• Szychowski Janek
• Yannopoulos Constantin
• Vallee Frederic
• Lacoste Jean-Eric
• Martel Julien
• Bubenik Monica
• Ramtohul Yeeman
• Sayegh Camil Elie

Classifications

• A61P43/00

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

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

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