Prodrug derivatives of substituted triazolopyridines

Patent metadata

Field	Value
Publication number	US-9586958-B2
Application number	US-201414897951-A
Country	US
Kind code	B2
Filing date	Jun 6, 2014
Priority date	Jun 11, 2013
Publication date	Mar 7, 2017
Grant date	Mar 7, 2017

Abstract

The present invention relates to prodrug derivatives of Mps-1 kinase inhibitors, processes for their preparation, and their use for the treatment and/or prophylaxis of diseases.

First claim

The invention claimed is:

1. A compound of formula (I):

in which:
R A represents a group selected from:
—C(═O)—(CH 2 ) 3 —N(H)R 3 ,
—C(═O)—(CR 4 R 5 )—N(R 6 )R 7 ,
—C(═O)—O—(CH 2 ) 2 —N(H)R 3 ,
—C(═O)—O—(CR 4 R 5 )—O—P(═O)(OH) 2 ,
—C(═O)—O—(CR 4 R 5 )—O—C(═O)—R 8 , and
—C(═O)—O—(CR 4 R 5 )—O—C(═O)—CH(R 6 )—NH—C(═O)—R 9 ;

R 1 represents a group selected from methoxy- and 2,2,2-trifluoroethoxy-;
R 2 represents a group selected from:

 wherein “*” indicates the point of attachment to the phenyl ring R 2 is attached to;
R 3 represents a group selected from:
C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl-, and
4- to 7-membered heterocycloalkyl-;
said group being optionally substituted, one or more times, identically or differently, with a group selected from:
—OH, —NH 2 , —N(H)R 10 , —N(R 10 )R 11 , and —O—P(═O)(OH) 2 ;

R 4 and R 5 , independently from each other, represent a group selected from a hydrogen atom and a C 1 -C 3 -alkyl- group,
or
R 4 and R 5 , together with the carbon atom to which they are attached, form a C 3 -C 6 -cycloalkyl ring;
R 6 represents a hydrogen atom or a C 1 -C 3 -alkyl- group;
R 7 represents a hydrogen atom or a group —C(═O )R 9 ;
R 8 represents a group selected from:
C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl-, and
4- to 7-membered heterocycloalkyl-;
said group being optionally substituted, one or more times, identically or differently, with a group selected from:
—OH, —NH 2 , —N(H)R 10 , —N(R 10 )R 11 , and —O—P(═O)(OH) 2 ;

R 9 represents a group

 or R 9 represents a group selected from:

 wherein “**” indicates the point of attachment to the carbonyl group R 9 is attached to;
R 10 and R 11 , independently from each other, represent a group selected from a hydrogen atom and a C 1 -C 3 -alkyl- group, or
R 10 and R 11 , together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring;
R 12 represents a group selected from a hydrogen atom, —OH, —NR 10 R 11 , and —NH—C(═NH)—NH 2 ;
n is an integer of 0, 1, 2, 3 or 4;
or a tautomer or a salt thereof, or a mixture of same.

2. A compound according to claim 1 , wherein:
R A represents a group selected from:
—C(═O)—(CH 2 ) 3 —N(H)R 3 ,
—C(═O)—O—(CR 4 R 5 )—O—C(═O)—R 8 , and
—C(═O)—O—(CR 4 R 5 )—O—C(═O)—CH(R 6 )—NH—C(═O)—R 9 ,

or a tautomer or a salt thereof, or a mixture of same.

3. A compound according to claim 1 , wherein:
R A represents a group:
—C(═O)—O—(CR 4 R 5 )—O—C(═O)—R 8 ,

or a tautomer or a salt thereof, or a mixture of same.

4. A compound according to claim 1 , wherein:
R 1 represents a methoxy- group,
or a tautomer or a salt thereof, or a mixture of same.

5. A compound according to claim 1 , wherein:
R 2 represents a —S(═O) 2 CH 3 group,
or a tautomer or a salt thereof, or a mixture of same.

6. A compound according to claim 1 , wherein:
R 3 represents a C 1 -C 3 -alkyl- group,
or a tautomer or a salt thereof, or a mixture of same.

7. A compound according to claim 1 , wherein:
R 4 represents a hydrogen atom or a C 1 -C 3 -alkyl- group, and
R 5 represents a hydrogen atom,
or a tautomer or a salt thereof, or a mixture of same.

8. A compound according to claim 1 , wherein:
R 6 represents a hydrogen atom or a methyl- group,
or a tautomer or a salt thereof, or a mixture of same.

9. A compound according to claim 1 , wherein:
R 8 represents a group selected from:
C 1 -C 6 -alkyl, substituted one or more times, identically or differently, with a group selected from: —NH 2 , —N(H)R 10 , and —N(R 10 )R 11 , and
4- to 7-membered heterocycloalkyl-, optionally substituted, one or more times, identically or differently, with a group selected from: —NH 2 , —N(H)R 10 , and —N(R 10 )R 11 ,

or a tautomer or a salt thereof, or a mixture of same.

10. A compound according to claim 1 , wherein:
R 9 represents a group selected from:

wherein “**” indicates the point of attachment to the carbonyl group R 9 is attached to,
or a tautomer or a salt thereof, or a mixture of same.

11. A compound according to claim 1 , wherein:
R 10 and R 11 , independently from each other, represent a group selected from a hydrogen atom and a C 1 -C 3 -alkyl-group,
or a tautomer or a salt thereof, or a mixture of same.

12. A compound according to claim 1 , wherein:
R 12 represents a group —NR 10 R 11 ,
or a tautomer or a salt thereof, or a mixture of same.

13. A compound according to claim 1 , which is selected from the group consisting of:
({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1,2,4]triazolo[1,5-α]pyridin-2-yl][2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)methyl piperidine-4-carboxylate trifluoroacetate,
({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1,2,4]triazolo[1,5-α]pyridin-2-yl][2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)methyl L-valinate hydrochloride,
({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1,2,4]triazolo[1,5-α]pyridin-2-yl][2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)methyl L-leucinate hydrochloride,
({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1,2,4]triazolo[1,5-α]pyridin-2-yl][2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)methyl N-methyl-L-valinate hydrochloride,
({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1,2,4]triazolo[1,5-α]pyridin-2-yl][2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)methyl 3-methyl-L-valinate hydrochloride,
(phosphonooxy)methyl [6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1,2,4]triazolo[1,5-α]pyridin-2-yl][2-methoxy-4-(methylsulfonyl)phenyl]carbamate,
({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1,2,4]triazolo[1,5-α]pyridin-2-yl][2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)methyl 3-methyl-L-isovalinate hydrochloride,
({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1,2,4]triazolo[1,5-α]pyridin-2-yl][2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)methyl 3-amino-2,2-dimethylpropanoate trifluoroacetate,
({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1,2,4]triazolo[1,5-α]pyridin-2-yl][2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)methyl L-lysyl-L-valinate dihydrochloride,
(1RS)-1-({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1,2,4]triazolo[1,5-α]pyridin-2-yl][2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)ethyl L-lysyl-L-valinate dihydrochloride (mixture of 2 epimers),
({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1,2,4]triazolo[1,5-α]pyridin-2-yl][2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)methyl L-valyl-L-valinate hydrochloride,
(1RS)-1-({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1,2,4]triazolo[1,5-α]pyridin-2-yl][2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)ethyl L-valyl-L-valinate hydrochloride (mixture of 2 epimers),
(1RS)-1-({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1,2,4]triazolo[1,5-α]pyridin-2-yl][2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)ethyl L-valinate hydrochloride (mixture of 2 epimers),
(1RS)-1-({[6-(4-{[(2R)-2-(4-fluorophenyl)

Assignees

• Bayer Pharma AG

Inventors

• Schulze Volker
• Lerchen Hans-Georg
• Bierer Donald
• Wengner Antje Margret
• Siemeister Gerhard
• Lienau Philip
• Krenz Ursula
• Kosemund Dirk
• Stöckigt Detlef
• Brüning Michael
• Lücking Ulrich
• Terebesi Ildikó

Classifications

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K5/06086

  with the first amino acid being basic · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title