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1. WO2014198647 - PRODRUG DERIVATIVES OF SUBSTITUTED TRIAZOLOPYRIDINES

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

CLAIMS

1. A compound of general formula (I) :


(I)

in which

represents a group selected from:

-C(=0)-(CH2)3-N(H)R3,

-C(=0)-(CR4R )-N(R6)R7,

-C(=0)-0-(CH2)2-N(H)R3,

-C(=0)-0-(CR4R )-0-P(=0)(OH)2,

-C(=0)-0-(CR4R5)-0-C(=0)-R8,

-C(=0)-0-(CR4R )-0-C(=0)-CH(R6)-NH-C(=0)-R9;

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

R2 re resents a group selected from:


wherein "*" indicates the point of attachment to the phenyl ring R2 is attached to;

R3 represents a group selected from:

Ci-C&-alkyl, C3-C&-cycloalkyl-,

4- to 7-membered heterocycloalkyl-;

said group being optionally substituted, one or more times, identically or differently, with a group selected from:

-OH, -NH2, -N(H)R10, -N(R10)R11, -0-P(=0)(OH)2;

R4 and R5, independently from each other, represent a group selected from a hydrogen atom and a CrC3-alkyl- group,

or

R4 and R5, together with the carbon atom to which they are attached, form a C3-C&-cycloalkyl ring;

R6 represents a hydrogen atom or a CrC3-alkyl- group;

R7 represents a hydrogen atom or a group -C(=0)R9;

R8 represents a group selected from:

Ci-C&-alkyl, C3-C&-cycloalkyl-,

4- to 7-membered heterocycloalkyl-;

said group being optionally substituted, one or more times, identically or differently, with a group selected from:

-OH, -NH2, -N(H)R10, -N(R10)R11, -0-P(=0)(OH)2;

R9 represents a group


or R9 represents a group selected from:


wherein "**" indicates the point of attachment to the carbonyl group R9 is attached to;

R10 and R11, independently from each other, represent a group selected from a hydrogen atom and a CrC3-alkyl- group, or

R10 and R11, together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring;

R12 represents a group selected from a hydrogen atom, -OH, -NR10R11, -NH-C(=NH)-NH2;

n is an integer of 0, 1 , 2, 3 or 4;

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

A compound according to claim 1 , wherein :

represents a group selected from:

-C(=0)-(CH2)3-N(H)R3,

-C(=0)-0-(CR4R )-0-C(=0)-R8,

-C(=0)-0-(CR4R )-0-C(=0)-CH(R6)-NH-C(=0)-R9

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

3. A compound according to claim 1 , wherein :

RA represents a group:

-C(=0)-0-(CR4R )-0-C(=0)-R8,

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

4. A compound according to claim 1 ,2 or 3, wherein :

R1 represents a methoxy- group,

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

5. A compound according to any one of claims 1 to 4, wherein :

R2 represents a -S(=0)2CH3 group,

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

6. A compound according to any one of claims 1 to 5, wherein :

R3 represents a CrC3-alkyl- group,

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

7. A compound according to any one of claims 1 to 6, wherein :

R4 represents a hydrogen atom or a CrC3-alkyl- group, and

R5 represents a hydrogen atom,

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

8. A compound according to any one of claims 1 to 7, wherein :

R6 represents a hydrogen atom or a methyl- group,

or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

9. A compound according to any one of claims 1 to 8, wherein :

R8 represents a group selected from:

Ci -C&-alkyl, substituted one or more times, identically or differently, with a group selected from: -NH2, -N(H)R10, -N(R10)R11,

4- to 7-membered heterocycloalkyl-, optionally substituted, one or more times, identically or differently, with a group selected from:

-NH2, -N(H)R10, -N(R10)R11,

or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

10. A compound according to any one of claims 1 to 9, wherein :

R9 re resents a group selected from:



wherein "**" indicates the point of attachment to the carbonyl group R9 is attached to,

or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

1 1 . A compound according to any one of claims 1 to 10, wherein :

R10 and R11, independently from each other, represent a group selected from a hydrogen atom and a CrC3-alkyl- group,

or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

1 2. A compound according to any one of claims 1 to 1 1 , wherein :

R12 represents a group -NR10R11,

or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

1 3. 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-a]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-a]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-a]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-a]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-a]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-a]pyridin-2-yl] [2-methoxy-4-(methylsulfonyl)phenyl]carbamate,

({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4]triazolo[1 ,5-a]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-a]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-a]pyridin-2-yl] [2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)methyl L-lysyl-L-valinate dihydrochloride,

(1 RS)-1 -({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4]triazolo[1 ,5-a]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-a]pyridin-2-yl] [2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)methyl L-valyl-L-valinate hydrochloride,

(1 RS)-1 -({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl] [2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)ethyl L-valyl-L-valinate hydrochloride (mixture of 2 epimers),

(1 RS)-1 -({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl] [2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)ethyl L-valinate hydrochloride (mixture of 2 epimers),

(1 RS)-1 -({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl] [2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)ethyl 3-methyl-L-valinate hydrochloride (mixture of 2 epimers),

(1 R or 1 S)-1 -({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl] [2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)ethyl -3-methyl-L-valinate hydrochloride (single stereoisomer A),

(1 S or 1 R)-1 -({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl] [2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)ethyl -3-methyl-L-valinate hydrochloride (single stereoisomer B),

(1 RS)-1 -({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl] [2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)ethyl-L-isoleucinate hydrochloride (mixture of 2 epimers),

(1 S or 1 R)-1 -({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl] [2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)ethyl-L-isoleucinate hydrochloride (single stereoisomer B),

(1 R or 1 S)-1 -({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl] [2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)ethyl-L-isoleucinate hydrochloride (single stereoisomer A),

N-[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4] triazolo[1 ,5-a]pyridin-2-yl]-N-[2-methoxy-4-(methylsulfonyl)phenyl]-4-(methylamino)butanamide trifluoroacetate,

N-[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4] triazolo[1 ,5-a]pyridin-2-yl]-N-[2-methoxy-4-(methylsulfonyl)phenyl]-4-(methylamino)butanamide hydrochloride,

(1 RS)-1 -({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl] [2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)-2-methylpropyl 3-methyl-L-valinate hydrochloride (mixture of 2 epimers),

(1 R or S)-1 -({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl] [2- methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)-2-methylpropyl-L-valinate hydrochloride (single stereoisomer A),

(1 S or R)-1 -({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl] [2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)-2-methylpropyl-L-valinate hydrochloride (single stereoisomer B),

(1 RS)-1 -({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl] [2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)-2-methylpropyl-L-valinate hydrochloride (mixture of 2 epimers),

(1 RS)-1 -({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl] [2-methoxy-4-(methylsulfonyl)phenyl]carbamoyl}oxy)-2-methylpropyl-2-methylalaninate hydrochloride (mixture of 2 epimers),

({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl] [4-(methylsulfonyl)-2-(2,2,2-trifluoroethoxy)phenyl]carbamoyl}oxy)methyl 3-methyl-L-valinate hydrochloride,

({[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl] [4-(methylsulfonyl)-2-(2,2,2-trifluoroethoxy)phenyl]carbamoyl}oxy)methyl L-valinate hydrochloride,

[({4-[(3-fluoroazetidin-1 -yl)carbonyl]-2-(2,2,2-trifluoroethoxy)phenyl}[6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl]carbamoyl)oxy]methyl 3-methyl-L-valinate hydrochloride,

2-(methylamino)ethyl [6-(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)[1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl] [2-methoxy-4-(methylsulfonyl)phenyl]carbamate hydrochloride,

(2R)-2-(4-fluorophenyl)-N-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl] (N-methylglycyl)amino}[1 ,2,4]triazolo[1 , 5-a]pyridin-6-yl)phenyl]propanamide trifluoroacetate;

or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

14. A compound according to any one of claims 1 to 13, or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for use in the treatment or prophylaxis of a disease.

1 5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, and a pharmaceutically acceptable diluent or carrier.

16. Use of a compound of any one of claims 1 to 13, or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of a disease.

17. Use of a compound of any one of claims 1 to 13, or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the preparation of a medicament for the prophylaxis or treatment of a disease.

18. Use according to claim 14, 16 or 17, wherein said disease is a disease of uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is mediated by Mps-1 , more particularly in which the disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is a haemotological tumour, a solid tumour and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.