Autotaxin inhibitors

Patent metadata

Field	Value
Publication number	US-10183025-B2
Application number	US-201715673155-A
Country	US
Kind code	B2
Filing date	Aug 9, 2017
Priority date	Jul 18, 2013
Publication date	Jan 22, 2019
Grant date	Jan 22, 2019

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

The invention claimed is:

1. A compound of formula (Ia)

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;
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 )—;
A′ is CR 6 ;
R 6 is selected from H, OH and C 1-4 alkoxy;
Z is selected from the group consisting of —(CR 7a R 7b ) m —;
R 7a and R 7b is independently selected from H, OH, C 1-4 alkyl and C 1-4 alkoxy;
R 8 is selected from H and C 1-4 alkyl;
m is selected from the group consisting of 0 and 1;
E is selected from the group consisting of
(i) oxadiazolyl;
(ii) pyrazolyl;
(iii) oxazolyl;
(iv) isoxazolyl;
(v) pyridinyl;
(vi) thiazolyl;
(vii) triazolyl;
(viii) pyrimidinyl;
(ix) tetrazolyl;
(x) pyrazinyl; and
(xi) furanyl;
wherein each ring is unsubstituted or substituted with 1 to 3 substituents independently 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, 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 Xb ) 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 Xa and R Xb are independently selected from the group consisting of H, OH, C 1-4 alkyl and C 1-4 alkoxy;
R Xc , R Xd and R Xe are independently selected from the group consisting of H, C 1-4 alkyl, —(CR Xa R Xb ) q1 —C 3-6 cycloalkyl, hydroxyC 1-4 alkyl, C 1-4 haloalkyl C 1-4 alkoxyC 1-4 alkyl, OH and —(CR Xa R Xb ) q1 -5 or 6 membered heterocyclyl; wherein the C 3-6 cycloalkyl 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 ) 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 ) q1 —C 3-6 cycloalkyl, hydroxyC 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyC 1-4 alkyl, halogen and OH;
q and q1 are selected from the group consisting of 0, 1 and 2.

2. A compound according to claim 1 selected from the group consisting of
(E)-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-3-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenyl)prop-2-en-1-one;
(E)-1-(4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidin-1-yl)-3-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethoxy)phenyl)prop-2-en-1-one;
(E)-1-(4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidin-1-yl)-3-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenyl)prop-2-en-1-one;
(E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-(4-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one;
(E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one;
(E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-(5-methyl-1H-1,2,4-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one;
(E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-(5-methyl-1H-tetrazol-1-yl)piperidin-1-yl)prop-2-en-1-one;
(E)-3-(4-chloro-2-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)phenyl)-1-(4-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)piperidin-1-yl)prop-2-en-1-one;
(E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-hydroxy-4-((4-(morpholine-4-carbonyl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)prop-2-en-1-one;
(E)-1-((1-(3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)acryloyl)-4-hydroxypiperidin-4-yl)methyl)-N,N-dimethyl-1H-pyrazole-4-carboxamide;
(E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-hydroxy-4-((4-(piperidine-1-carbonyl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)prop-2-en-1-one;
(E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-(5-methyl-2H-tetrazol-2-yl)piperidin-1-yl)prop-2-en-1-one;
(E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-hydroxy-4-((4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)prop-2-en-1-one;
(E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidin-1-yl)prop-2-en-1-one;
(E)-3-(4-chloro-2-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)phenyl)-1-(4-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)piperidin-1-yl)prop-2-en-1-one;
(E)-1-(4-(2H-1,2,3-triazol-2-yl)piperidin-1-yl)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)prop-2-en-1-one;
(E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-(5-methyloxazol-2-yl)piperidin-1-yl)prop-2-en-1-one;
(E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-(4-methyl-2H-1,2,3-triazol-2-yl)piperidin-1-yl)prop-2-en-1-one;
(E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-(2-methyloxazol-4-yl)piperidin-1-yl)prop-2-en-1-one;
(E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-(4-methyl-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one;
(E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-((5-methyloxazol-2-yl)methyl)piperidin-1-yl)prop-2-en-1-one;
(E)-ethyl 1-((1-(3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)acryloyl)-4-hydroxypiperidin-4-yl)methyl)-1H-pyrazole-4-carboxylate;
(E)-1-((1-(3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)acryloyl)-4-hydroxypiperidin-4-yl)methyl)-1H-pyrazole-4-carboxylic acid;
1-(4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidin-1-yl)-2-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenoxy)ethanone;
(E)-1-(4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidin-1-yl)-3-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenyl)prop-2-en-1-one;
(E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-1-yl)but-2-en-1-one;
1-(4-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-3-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenyl)propan-1-one;
(E)-3-(4-fluoro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)piperidin-1-yl)prop-2-en-1-one;
(E)-3-(4-chloro-2-((5-methyloxazol-2-yl)methyl)phenyl)-1-(4-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)piperidin-1-yl)prop-2-en-1-one;
4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)benzyl 4-(5-methyl-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate;
4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)benzyl 4-(5-methyloxazol-2-yl)piperidine-1-carboxylate;
(E)-1-(4-((1H-pyrazol-1-yl)methyl)piperidin-1-yl)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)prop-2-en-1-one;
(E)-3-(4-(difluoromethyl)-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-(5-methyl-1,3,4-oxadiazol-

Assignees

• Novartis Ag

Inventors

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

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · 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

• A61P3/00

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

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title