Autotaxin inhibitors

Patent metadata

Field	Value
Publication number	US-9409895-B2
Application number	US-201313833460-A
Country	US
Kind code	B2
Filing date	Mar 15, 2013
Priority date	Dec 19, 2012
Publication date	Aug 9, 2016
Grant date	Aug 9, 2016

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 (I)

or a pharmaceutically acceptable salt thereof, wherein
A is selected from

Y 1 is —(CR 2b R 2c ) m — or —CH═CH—;
X is selected from —C(═O)—, —N(R 3 )—C(═O)— and —C(═O)—N(R 3 )—;
Y 2 is —(CR 4a R 4b ) n —;
m is selected from 0, 1, 2, 3, 4 and 5;
n is selected from 0, 1, 2, 3, 4 and 5;
wherein when Y 1 is —(CR 2b R 2c ) m — the sum of m and n is not less than 2 and no more than 5; or
A-Y 1 —X— is

L is selected from

W is CH or N;
Z is selected from CH 2 , O and NR 5c ;
Y 3 is selected from —O—(CR 6a R 6b )—, —(CR 6c R 6d )—O—, —CH═CH—, —CR 6e R 6f —CR 6g R 6h —, and —O—(CR 6i R 6j —CR 6k R 6l )—;
R 1a , R 1b , R 1c , R 1d and R 1e are defined according to any one of
(a) R 1b is halogen; R 1d is halogen, CN, C 1-4 haloalkyl or C 1-4 haloalkoxy; and R 1a , R 1c and R 1e are H;
(b) R 1b is halogen; R 1d is halogen, CN, C 1-4 haloalkyl or C 1-4 haloalkoxy; R 1c is halogen; and R 1a and R 1e are H;
(c) R 1b is C 1-4 alkyl; R 1d is C 1-4 alkyl, C 1-4 haloalkoxy or CN; R 1a , R 1c and R 1e are H;
(d) R 1b is CN; R 1d is C 1-4 haloalkyl or C 1-4 haloalkoxy; and R 1a , R 1c and R 1e are H;
(e) R 1b is C 1-4 haloalkyl or C 1-4 haloalkoxy; and R 1a , R 1c and R 1e are H; and R 1d is H or CN;
(f) R 1a is halogen; R 1c is halogen, CN, C 1-4 haloalkyl or C 1-4 haloalkoxy; and R 1b , R 1d and R 1e are H;
(g) R 1c is halogen, CN, C 1-4 haloalkyl or C 1-4 haloalkoxy; and R 1a , R 1b and R 1e are H; and R 1d is halogen, CN, C 1-4 haloalkyl, C 1-4 haloalkoxy, or H;
R 2a , R 2b , R 2c , R 3 , R 4a , R 4b , R 4c , R 4d , R 5a , R 5b , R 5c , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , R 6i , R 6j , R 6k and R 6l are independently selected from H and C 1-4 alkyl.

2. The compound or salt according to claim 1 , wherein R 1a , R 1b , R 1c , R 1d and R 1e are defined according to any one of
(a) R 1b is fluoro, chloro or bromo; R 1d is fluoro, chloro, bromo, CN, methyl, trifluoromethyl or trifluoromethoxy; and R 1a , R 1c and R 1e are H;
(c) R 1b is methyl; R 1d is methyl, trfluoromethyl, trifluoromethoxy or CN; R 1a , R 1c and R 1e are H;
(f) R 1a is fluoro, chloro or bromo; R 1c is fluoro, chloro, bromo, CN, methyl, trifluoromethyl or trifluoromethoxy; and R 1b , R 1d and R 1e are H; and
(g) R 1c is fluoro, chloro, bromo, CN, methyl, trifluoromethyl or trifluoromethoxy; and R 1a , R 1b and R 1e are H; and R 1d is fluoro, chloro, bromo, CN, methyl, trifluoromethyl, trifluoromethoxy, or H.

3. The compound or salt according to claim 1 , wherein Y 3 is
—O—(CR 6a R 6b ))— or —(CR 6c R 6d )—O—.

4. The compound or salt according to claim 1 , wherein X is selected from —N(R 3 )—C(═O)— and —C(═O)—N(R 3 )—.

5. The compound or salt according to claim 1 , wherein the compound is of formula (II)

6. The compound or salt according to claim 1 , wherein —Y 1 —X—Y 2 — is selected from

7. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. A pharmaceutical combination comprising a therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and one or more therapeutically active co-agent.

9. The compound of claim 1 , selected from the group consisting of:
3,5-dichlorobenzyl 4-(2-(3-hydroxy-N-methylisoxazole-5-carboxamido)ethyl)piperidine-1-carboxylate;
3,5-dichlorobenzyl 4-(2-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)(methyl)amino)ethyl)piperidine-1-carboxylate;
3,5-dichlorobenzyl 4-(2-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)ethyl)piperidine-1-carboxylate;
3,5-dichlorobenzyl 4-(2-((2-hydroxy-3,4-dioxocyclobut-1-en-1-yl)amino)ethyl)piperidine-1-carboxylate;
3,5-dichlorobenzyl 4-((3-(3-hydroxyisoxazol-5-yl)propanamido)methyl)-2-methylpiperidine-1-carboxylate;
3,5-dichlorobenzyl 4-(2-(N-methyl-2-(1H-1,2,3-triazol-4-yl)acetamido)ethyl)piperidine-1-carboxylate;
3,5-dichlorobenzyl 4-(2-(2-(1H-1,2,3-triazol-4-yl)acetamido)ethyl)piperidine-1-carboxylate;
(E)-3,5-dichlorobenzyl 4-(3-(1H-imidazol-4-yl)acrylamido)piperidine-1-carboxylate;
3,5-dichlorobenzyl 2-(2-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)ethyl)morpholine-4-carboxylate;
3,5-dichlorobenzyl 2-(2-(2-oxo-2,3-dihydrooxazole-5-carboxamido)ethyl)morpholine-4-carboxylate;
3,5-dichlorobenzyl 2-(2-(N-methyl-2-oxo-2,3-dihydrooxazole-5-carboxamido)ethyl)morpholine-4-carboxylate;
3,5-dichlorobenzyl 2-(2-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)(methyl)amino)ethyl)morpholine-4-carboxylate;
3,5-dichlorobenzyl 4-(2-(N-methyl-2-oxo-2,3-dihydrothiazole-5-carboxamido)ethyl)piperidine-1-carboxylate;
3,5-dichlorobenzyl 4-(4-(1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate;
3,5-dichlorobenzyl 4-(N-methyl-4-(1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate;
3,5-dichlorobenzyl 4-(3-(1H-1,2,3-triazol-4-yl)propanamido)piperidine-1-carboxylate;
3,5-dichlorobenzyl 4-(5-(1H-1,2,3-triazol-4-yl)pentanamido)piperidine-1-carboxylate;
3,5-dichlorobenzyl 4-(2-(2-oxo-2,3-dihydrooxazole-5-carboxamido)ethyl)piperidine-1-carboxylate;
3,5-dichlorobenzyl 4-(2-(3-(3-hydroxyisoxazol-5-yl)propanamido)ethyl)piperidine-1-carboxylate;
3,5-dichlorobenzyl 4-(3-(3-hydroxyisoxazol-5-yl)propanamido)piperidine-1-carboxylate;
3,5-dichlorobenzyl 4-(2-(N-methyl-2-oxo-2,3-dihydrooxazole-4-carboxamido)ethyl)piperidine-1-carboxylate;
3,5-dichlorobenzyl 4-(3-(N-methyl-2-oxo-2,3-dihydrooxazole-5-carboxamido)propyl)piperazine-1-carboxylate;
3,5-dichlorobenzyl 4-(2-(2-oxo-2,3-dihydrooxazole-5-carboxamido)ethyl)piperazine-1-carboxylate;
(E)-N-(2-(1-(3-(3,5-dichlorophenyl)acryloyl)piperidin-4-yl)ethyl)-N-methyl-2-oxo-2,3-dihydrooxazole-5-carboxamide;
(E)-N-(2-(1-(3-(3,5-dichlorophenyl)acryloyl)piperidin-4-yl)ethyl)-2-oxo-2,3-dihydrooxazole-5-carboxamide;
3,5-dichlorobenzyl 4-(2-(N-methyl-2-oxo-2,3-dihydrooxazole-5-carboxamido)ethyl)piperidine-1-carboxylate;
3,5-dichlorobenzyl 4-(3-(3-hydroxyisoxazol-5-yl)propanamido)methyl)piperidine-1-carboxylate;
3,5-dichlorobenzyl 4-(3-(1H-1,2,3-triazole-4-carboxamido)propyl)piperazine-1-carboxylate;
3,5-dichlorobenzyl 4-(2-(N-methyl-1H-1,2,3-triazole-4-carboxamido)ethyl)piperidine-1-carboxylate;
3-Chloro-5-cyanobenzyl 4-(2-(N-methyl-1H-1,2,3-triazole-4-carboxamido)ethyl)piperidine-1-carboxylate;
3-Chloro-5-fluorobenzyl 4-(4-(1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate;
(E)-N-(1-(3-(3,5-Dichlorophenyl)acryloyl)piperidin-4-yl)-4-(1H-1,2,3-triazol-4-yl)butanamide;
(E)-N-(1-(3-(2,4-Dichlorophenyl)acryloyl)piperidin-4-yl)-4-(1H-1,2,3-triazol-4-yl)butanamide;
3,5-Dichlorobenzyl 4-((4-(1H-1,2,3-triazol-5-yl)butanamido)methyl)piperidine-1-carboxylate;
N-(1-(3-(3,5-Dichlorophenyl)propanoyl)piperidin-4-yl)-4-(1H-1,2,3-triazol-4-yl)butanamide;
N-(1-(3-(2,4-Dichlorophenyl)propano

Assignees

• Legrand Darren Mark
• Furminger Vikki
• Thomson Christopher
• Hughes Owen Rhys
• Stanley Emily
• Novartis Ag

Inventors

• Legrand Darren Mark
• Furminger Vikki
• Thomson Christopher
• Hughes Owen Rhys
• Stanley Emily

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D295/185

  from aliphatic carboxylic acids · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D249/08

  1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles · CPC title