Autotaxin inhibitors

Patent metadata

Field	Value
Publication number	US-2016184318-A1
Application number	US-201414906161-A
Country	US
Kind code	A1
Filing date	Jul 16, 2014
Priority date	Jul 18, 2013
Publication date	Jun 30, 2016
Grant date	—

Abstract

The present invention relates to novel compounds that are autotaxin inhibitors, processes for their preparation, pharmaceutical compositions and medicaments containing them and to their use in diseases and disorders mediated by autotaxin.

First claim

1 . A compound according to formula (I)

or a pharmaceutically acceptable salt thereof, wherein
A is selected from the group consisting of

R 1 is selected from the group consisting of H and C 1-4 alkyl;
R 1a is C 1-4 alkyl;
R 2 is halogen, —CF 3 , —CF 2 H, —OCF 3 , —OCF 2 H, —OCH 3 , —CH 3 or CN, and R 3 , R 4 and R 5 are H;
or
R 3 is halogen and R 2 , R 4 and R 5 are H; or
R 4 is halogen and R 2 , R 3 and R 5 are H; or
R 2 is halogen, —CF 3 , —CF 2 H, —OCF 3 , —OCF 2 H, —OCH 3 , —CH 3 or CN, R 3 is halogen and R 4 and R 5 are H;
Y is selected from the group consisting of —CH═CH—, —CH 2 —CH 2 —, —O—CH 2 —, —CH 2 —O—, —C(CH 3 )═CH— and —C═C(CH 3 )—;
B is a 4 to 8 membered nitrogen-containing heterocyclic ring or a bridged 4 to 8 membered nitrogen-containing heterocyclic ring system which 4 to 8 membered nitrogen-containing heterocyclic ring or bridged 4 to 8 membered nitrogen-containing heterocyclic ring system is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of Q;
Q is selected from the group consisting of
(i) —(CR Ba R Bb ) n -5 or 6 membered heteroaryl or —(CR Ba R Bb ) n1 —O—(CR Ba R Bb ) n -5 or 6 membered heteroaryl which heteroaryl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of X;
(ii) —(CR Ba R Bb ) n -phenyl or —(CR Ba R Bb ) n1 —O—(CR Ba R Bb ) n -phenyl which phenyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of X;
(iii) —(CR Ba R Bb ) n -9 to 10 membered fused bicyclic ring system or —(CR Ba R Bb ) n1 —O—(CR Ba R Bb ) n -9 to 10 membered fused bicyclic ring system which 9 to 10 membered fused bicyclic ring system is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of X;
(iv) —(CR Ba R Bb ) n -5 or 6 membered heterocyclyl or —(CR Ba R Bb ) n1 —O—(CR Ba R Bb ) n -5 or 6 membered heterocyclyl which heterocyclyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of X;
(v) C 1-4 alkyl;
(vi) C 1-4 alkoxy;
(vii) C 1-4 alkoxy C 1-4 alkyl;
(viii) C 1-4 haloalkyl;
(ix) hydroxy C 1-4 alkyl;
(x) —(CR Ba R Bb ) n C 3-6 cycloalkyl;
(xi) —(CR Ba R Bb ) n —C(═O)R Bc or —(CR Ba R Bb ) n1 —O—(CR Ba R Bb ) n —C(═O)R Bc ;
(xii) —(CR Ba R Bb ) n- C(═O)OR Be or —(CR Ba R Bb ) n1 —O—(CR Ba R Bb ) n —C(═O)OR Be ;
(xiii) —(CR Ba R Bb ) n NR Bd —C(═O)RB or —(CR Ba R Bb ) n1 —O—(CR Ba R Bb ) n NR Bd —C(═O)R Bc ;
(xiv) —(CR Ba R Bb ) n NR Bd —C(═O)ORB or —(CR Ba R Bb ) n1 —O—(CR Ba R Bb ) n —NR Bd —C(═O)OR Bc ;
(xv) —(CR Ba R Bb ) n —C(═O)NR Bc R Bd or —(CR Ba R Bb ) n1 —O—(CR Ba R Bb ) n —C(═O)NR Bc R Bd ;
(xvi) —(CR Ba R Bb ) n —NR Bd R Be or —(CR Ba R Bb ) n1 —O—(CR Ba R Bb ) n —NR Bd R Be ;
(xvii) —(CR Ba R Bb ) n —NR Bd —S(O) 2 —R Bf ;
(xviii) —(CR Ba R Bb ) n —S(O) 2 —NR Bd R Be or —(CR Ba R Bb ) n1 —O—(CR Ba R Bb ) n —S(O) 2 —NR Bd R Be ;
(xix) —(CR Ba R Bb ) n —S(O) 2 —R Bf ;
(xx) halogen;
(xxi) OH;
(xxii) oxo; and
(xxiii) CN;
R Ba , R Bb , R Xa , R Xb are independently selected from the group consisting of H, OH, C 1-4 alkyl and C 1-4 alkoxy;
R Bc , R Be and R Bf are independently selected from the group consisting of H, C 1-4 alkyl, —(CR Ba R Bb ) n1 —C 3-6 cycloalkyl, —(CR Ba R Bb ) n1 —C 3-6 cycloalkenyl, hydroxyC 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyC 1-4 alkyl, OH, —(CR Ba R Bb ) n1 -5 or 6 membered heteroaryl, —(CR Ba R Bb ) n1 -phenyl and —(CR Ba R Bb ) n1 -5 or 6 membered heterocyclyl, wherein the C 3-6 cycloalkyl, heteroaryl, phenyl and heterocyclyl are unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of X;
R Bd is selected from the group consisting of H and C 1-4 alkyl; or
R Bc and R Bd or R Bd and R Be together with the nitrogen atom to which they are attached form a 5 to 6 membered heterocyclyl which heterocyclyl is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of X;
X is independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, hydroxyC 1-4 alkyl, C 1-4 alkoxyC 1-4 alkyl, —(CR Xa R Xb ) q —C 3-6 cycloalkyl, —(CR Ba R Bb ) n1 —C 3-6 cycloalkenyl, halogen, CN, —(CR Xa R Xb ) q -5 or 6 membered heterocyclyl, —(CR Xa R Xb ) q -5 or 6 membered heteroaryl, —(CR Xa R Bb ) q -phenyl, oxo, OH, —(CR Xa R Xb ) q —C(═O)R Xc , —(CR Xa R Xb ) q —C(═O)OR Xc , —(CR Xa R Xb ) q —NR Xd R Xe and —(CR Xa R Xb ) q —C(═O)NR Xd R Xe ; wherein the C 3-6 cycloalkyl, heteroaryl, phenyl and heterocyclyl are unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, —(CR Xa R Xb ) q —C 3-6 cycloalkyl, hydroxyC 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyC 1-4 alkyl, halogen and OH;
R Xc , R Xd and R Xe are independently selected from the group consisting of H, C 1-4 alkyl, —(CR Xa R Xb ) q —C 3-6 cycloalkyl, hydroxyC 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyC 1-4 alkyl, OH—(CR Xa R Xb ) q1 -5 or 6 membered heterocyclyl and —(CR Xa R Xb ) q1 -5 or 6 membered heteroaryl; wherein the C 3-6 cycloalkyl, heterocyclyl and heteroaryl are unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, —(CR Xa R Xb ) q1 —C 3-6 cycloalkyl, C 1-4 haloalkyl, hydroxyC 1-4 alkyl, C 1-4 alkoxyC 1-4 alkyl, halogen and OH; or
R Xd and R Xe together with the nitrogen atom to which they are attached form a 5 to 6 membered heterocyclyl which heterocyclyl is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, —(CR Xa R Xb ) q —C 3-6 cycloalkyl, hydroxyC 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyC 1-4 alkyl, halogen and OH;
n and n1 are independently selected from the group consisting of 0, 1, 2, 3, 4 and 5;
q and q1 are independently selected from the group consisting of 0, 1 and 2;
with the proviso that the compound is not 2-[4-chloro-2-(1H-tetrazol-5-ylmethyl)-phenoxy]-1-[(cis)-3-(4-fluoro-phenoxy)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethanone.

2 . (canceled)

3 . (canceled)

4 . A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein
A is selected from the group consisting of

R 1 is selected from the group consisting of H and C 1-4 alkyl;
R 1a is C 1-4 alkyl;
R 2 is halogen, —CF 3 , —CF 2 H, —OCF 3 , —OCF 2 H, —OCH 3 , —CH 3 or CN, and R 3 , R 4 and R 5 are H;
or
R 3 is halogen and R 2 , R 4 and R 5 are H; or
R 4 is halogen and R 2 , R 3 and R 5 are H; or
R 2 is halogen, —CF 3 , —CF 2 H, —OCF 3 , —OCF 2 H, —OCH 3 , —CH 3 or CN, R 3 is halogen and R 4 and R 5 are H;
Y is selected from the group consisting of —CH═CH—, —CH 2 —CH 2 —, —O—CH 2 —, —CH 2 —O—, —C(CH 3 )═CH— and —C═C(CH 3 )—;
B is selected from the group consisting of

wherein
(1.1) R B11 , R B12 , R B13 and R B14 are H; R

Assignees

• Beattie David
• Baettig Urs
• Legrand Darren Mark
• Lister Andrew Stuart
• Mckenna Jeffrey
• Pearce David William
• Sandham Ddavid Andrew
• Steward Oliver Ross
• Thomson Christopher
• Novartis Ag

Inventors

• Beattie David
• Baettig Urs
• Legrand Darren Mark
• Lister Andrew Stuart
• Mckenna Jeffrey
• Pearce David William
• Sandham Ddavid Andrew
• Steward Oliver Ross
• Thomson Christopher

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P29/00

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

• A61P13/12

  of the kidneys · CPC title