Benzylidene-1,3-dihydro-indol-2-one derivatives a receptor tyrosine kinase inhibitors, particularly of Raf kinases

• US 6,268,391 B1
• Filed: 04/07/2000
• Issued: 07/31/2001
• Est. Priority Date: 08/06/1997
• Status: Expired due to Fees

• Current Assignee: Glaxo Wellcome Incorporated (GSK plc)
• Original Assignee: Glaxo Wellcome Incorporated (GSK plc)
• Inventors: Peel, Michael Robert, Jung, David Kendall, Dickerson, Scott Howard, Harris, Philip Anthony, Veal, James Marvin, Lackey, Karen Elizabeth, Hunter, Robert Neil III, McNutt, Robert Walton Jr.
• Primary Examiner(s): AULAKH, CHARANJIT
• Application Number:
  US09/446,586
• Time in Patent Office: 480 Days
• Field of Search: 514/418, 514/379, 514/381, 514/366, 514/365, 514/339, 514/292, 548/486, 548/151, 548/181, 548/235, 548/252, 548/433, 548/466, 546/84, 546/277.7
• US Class Current: 514/418
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 209/34 in position 2
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

Compounds of general formula (I) wherein: R¹ is H or optionally joined with R² to form a fused ring selected from the group consisting of five to ten membered aryl, heteroaryl or heterocyclyl rings, R² and R³ are independently H, HET, aryl, C_1-12 aliphatic, CN, NO₂, halogen, R¹⁰, —OR¹⁰, —SR¹⁰, —S(O)R¹⁰, —SO₂R¹⁰, —NR¹⁰R¹¹, —NR¹¹R¹², —NR¹²COR¹¹, —NR¹²CO₂R¹¹, —NR¹²CONR¹¹R¹², —NO¹²SO₂R¹¹, —NR¹²C(NR ¹²)NHR¹¹, —COR¹¹, —CO₂R¹¹, —CONR¹²R¹¹, —SO₂NR¹²R¹¹, —OCONR¹²R¹¹, C(NR¹²)NR¹²R¹¹, R⁶ and R⁷ are independently halogen, CN, NO₂, —CONR¹⁰R¹¹, —SO₂NR¹⁰R¹¹, —NR¹⁰R¹¹, or —OR¹¹, where R¹⁰ and R¹¹ are as defined below; R⁸ is OH, NHSO₂R¹² or NHCOCF₃; and their use in therapy, especially in the treatment of disorders mediated by cRaf1 kinase.

Claims

1. A compound of formula (I)

wherein

R¹ is H or is optionally joined with R² to form a fused ring selected from the group consisting of five to ten membered aryl, heteroaryl or heterocyclyl rings, said heteroaryl or said heterocyclyl rings having one to three heteroatoms where zero to three of said heteroatoms are N and zero to 1 of said heteroatoms are O or S and where said fused ring is optionally substituted by one to three of R⁹, where R² and R⁹ are as defined below;

R² and R³ are independently H, HET, aryl, C_1-12 aliphatic, CN, NO₂, halogen, R¹⁰, —

OR¹⁰, —

SR¹⁰, —

S(O)R¹⁰, —

SO₂R¹⁰, —

NR¹⁰R¹¹, —

NR¹¹R¹², —

NR¹²COR¹¹, —

NR¹²CO₂R¹¹, —

NR¹²CONR¹¹R¹², —

NR¹²SO₂R¹¹, —

NR¹²C(NR¹²)NHR¹¹, —

COR¹¹, —

CO₂R¹¹, —

CONR¹²R¹¹, —

SO₂NR¹²R¹¹, —

OCONR¹²R¹¹, C(NR¹²)NR¹²R¹¹ where said C_1-12 aliphatic optionally bears one or two insertions of one to two groups selected from C(O), O, S, S(O), SO₂ or NR¹²;

with said HET, aryl or C_1-12 aliphatic being optionally substituted by one to three of R¹⁰; and

where R² is optionally joined with R³ to form a fused ring selected from the group consisting of five to ten membered aryl, heteroaryl or heterocyclyl rings, said heteroaryl or said heterocyclyl rings having zero to three heteroatoms where zero to three of said heteroatoms are N and zero to one of said heteroatoms are O or S and where said fused ring is optionally substituted by one to three of R⁹;

where HET, R⁹, R¹⁰, R¹¹ and R¹² are as defined below;

or R² and R³ are independently —

R¹²NH₂, —

R¹²-halogen, —

COR¹¹NR¹²R¹¹, —

C(NH)R¹¹, where R¹¹ is as defined below, and R¹² is H, C_1-6 aliphatic, NO₂, C_1-6 alkoxy, halogen, aryl or HET, said C_1-6 aliphatic optionally substituted by one to three of halogen or OH, where HET is as defined below;

R⁴ is H, halogen, NO₂ or CN;

R⁵ is H or C_1-12 aliphatic optionally substituted by one to three of halo, hydroxyl, or aryl;

R⁶ and R⁷ are independently bromo or chloro;

R⁸ is OH;

each R⁹is independently halogen, C_1-12 aliphatic, CN, —

NO₂, R¹⁰, —

OR¹¹, —

SR¹¹, —

S(O)R¹⁰, —

SO₂R¹⁰, —

NR¹⁰R¹¹, —

N¹¹R¹², —

NR¹²COR¹¹, —

NR¹²CO₂R¹¹, —

NR¹²CONR¹¹R¹², —

NR¹²SO₂R¹¹, —

NR¹²C(NR¹²)NHR¹¹, —

CO₂R¹¹, —

CONR¹²R¹¹, —

SO₂NR¹²R¹¹, —

OCONR¹²R¹¹ or C(NR¹²)NR¹²R¹¹, where R¹⁰, R¹¹ and R¹² are as defined below;

each R¹⁰ is independently H, halogen, C_1-12 aliphatic, aryl or HET, where said C_1-12 aliphatic optionally bears an inserted one to two groups selected from O, S, S(O), SO₂ or NR¹², where said C_1-12 aliphatic, aryl or HET is optionally substituted by one to three of halo, another HET, aryl, CN, —

SR¹², —

OR¹², —

N(R²)₂, —

S(O)R¹², —

SO₂R¹², SO₂N(R¹²)₂, —

NR¹²COR¹², —

NR¹²CO₂R¹², —

NR¹²CON(R¹²)₂, —

NR¹²(NR¹²)NHR¹², —

CO₂R¹², —

CON(R¹²)₂, —

NR¹²SO₂R¹², —

OCON(R¹²)₂, where HET and R¹² are as defined below;

or each R¹⁰ is independently C_1-6 aliphatic, aryl or HET optionally substituted by one to three of NO₂, R¹², —

R¹²N(R¹²)₂ or trifluoro, where R¹² is H, C_1-6 aliphatic, NO₂, C_1-6 alkoxy, halogen, aryl or HET, said C_1-6 aliphatic optionally substituted by one to three of halogen or OH, where HET is as defined below;

or each R¹⁰ is oxo, cyano or amino;

or each R⁹ is —

COR¹⁰, where R¹⁰ is H, C_1-6 aliphatic or amino;

R¹¹ is H or R¹⁰;

R¹² is H, C_1-12 aliphatic or HET, said C_1-12 aliphatic optionally substituted by one to three of halogen or OH where HET is as defined below;

or R¹² is NO₂, C_1-6 alkoxy, halogen or aryl;

HET is a five to ten-membered saturated or unsaturated heterocyclic ring selected from the group consisting of benzofuran, benzoxazole, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, indole, indazole, morpholine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxiadiazine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine, quinoline, quinazoline, tetrahydrofuran, tetrazine, tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thianaphthalene, thiopyran, triazine, and triazole;

or R¹² is (R¹¹)₂N—

C_1-6 aliphatic, where R¹¹ is H, C_1-6 aliphatic, hydroxy-C_1-6 aliphatic, phenyl, phenyl-C, aliphatic or HET, where HET is oxazole, pyridine, tetrazole or thiazole; and

and the pharmaceutically acceptable salts or solvates thereof.

2. A compound of formula (I) as claimed in claim 1 wherein

R² and R³ are independently H, HET, aryl, C_1-12 aliphatic, CN, NO₂, halogen, R¹⁰, — OR¹⁰, —

SR¹⁰, —

S(O)R¹⁰, —

SO₂R¹⁰, —

NR¹⁰R¹¹, —

NR¹¹R¹², —

NR¹²COR¹¹, —

NR¹²CO₂R¹¹, —

NR¹²CONR¹¹R¹², —

NR¹²SO₂R¹¹, —

NR¹²C(NR¹²)NHR¹¹, —

COR¹¹, —

CO₂R¹¹, —

CONR¹²R¹¹, —

SO₂NR¹²R¹¹, —

OCONR¹²R¹¹, C(NR¹²)NR¹²R¹¹ where said C_1-12 aliphatic optionally bears one or two insertions of one to two groups selected from C(O), O, S, S(O), SO₂ or NR¹²;

with said HET, aryl or C_1-12 aliphatic being optionally substituted by one to three of R¹⁰; and

where R² is optionally joined with R³ to form a fused ring selected from the group consisting of five to ten membered aryl, heteroaryl or heterocyclyl rings, said heteroaryl or said heterocyclyl rings having zero to three heteroatoms where zero to three of said heteroatoms are N and zero to one of said heteroatoms are O or S and where said fused ring is optionally substituted by one to three of R⁹;

where HET, R⁹, R¹⁰, R¹¹ and R¹² are as defined below;

each R¹⁰ is independently H, halogen, C_1-12 aliphatic, aryl or HET, where said C_1-12 aliphatic optionally bears an inserted one to two groups selected from O, S, S(O), SO₂ or NR¹², where said C_1-12 aliphatic, aryl or HET is optionally substituted by one to three of halo, another HET, aryl, CN, —

SR¹², —

OR¹², —

N(R¹²)₂, —

S(O)R¹², —

SO₂R¹², —

SO₂N(R¹²)₂, —

NR¹²COR¹², —

NR¹²CO₂R¹², —

NR¹²CON(R¹²)₂, —

NR¹²(NR¹²)NHR¹², —

CO₂R¹², —

CON(R¹²)₂, —

NR¹²SO₂R¹², —

OCON(R¹²)₂, where HET and R¹² are as defined below;

R¹² is H, C_1-12 aliphatic or HET, said C_1-12 aliphatic optionally substituted by one to three of halogen or OH where HET is as defined below; and

HET, R¹, R⁴, R⁵, R⁶, R⁷, R⁸ R⁹ and R¹¹ are as defined in claim 1;

and the pharmaceutically acceptable salts or solvates thereof.

3. A compound of formula (I) as claimed in claim 2 wherein

R¹ is H or is optionally joined with R² to form a fused ring selected from the group as defined for HET below, and where said fused ring is optionally substituted by one to three of R⁹, where R² and R⁹ are as defined below;

R² and R³ are independently H, HET, aryl, C_1-6 aliphatic, CN, NO₂, halogen, R¹⁰, —

OR¹⁰, —

SR¹⁰, —

S(O)R¹⁰, —

SO₂R¹⁰, —

NR¹⁰R¹¹, —

NR¹¹R¹², —

NR¹²COR¹¹, —

NR¹²CO₂R¹¹, —

NR¹²CONR¹¹R¹², —

NR¹²SO₂R¹¹, —

NR¹²C(NR¹²)NHR<sup>11 , —

COR11</sup>, —

CO₂R¹¹, —

CONR¹²R¹¹, —

SO₂NR¹²R¹¹, —

OCONR¹²R¹¹, C(NR¹²)NR¹²R¹¹ where said C_1-6 aliphatic optionally bears one or two insertions of one to two groups selected from C(O), O, S, S(O), SO₂ or NR¹²;

with said HET, aryl or C_1-6 aliphatic being optionally substituted by one to three of R¹⁰; and

where R² is optionally joined with R³ to form a fused ring selected from the group as defined for HET below and where said fused ring is optionally substituted by one to three of R⁹, where HET, R⁹, R¹⁰, R¹¹ and R¹² are as defined below;

R⁵ is H or C_1-6 aliphatic optionally substituted by one to three of halo, OH, or aryl;

each R⁹ is independently halo, C_1-6 aliphatic, CN, —

NO₂, R¹⁰, —

OR¹¹, —

SR¹¹, —

S(O)R¹⁰, —

SO₂R¹⁰, —

NR¹⁰R¹¹, —

N¹¹R¹², —

NR¹²COR¹¹, —

NR¹²CO₂R¹¹,

—

NR¹²CONR¹¹R¹², —

NR¹²SO₂R¹¹, —

NR¹²C(NR¹²)NHR¹¹, —

CO₂R¹¹, —

CONR¹²R¹¹, —

SO₂NR¹²R¹¹, —

OCONR¹²R¹¹ or C(NR¹²)NR¹²R¹¹, where R¹⁰, R¹¹ and R¹² are as defined below;

each R¹⁰ is independently H, halogen, C_1-6 aliphatic, aryl or HET, where said C_1-6 aliphatic optionally bears an inserted one to two groups selected from O, S, S(O), SO₂ or NR¹², where said C_1-6 aliphatic, aryl or HET is optionally substituted by one to three of halo, another HET, aryl, CN, —

SR¹², —

OR¹², —

N(R¹²)₂, —

S(O)R¹², —

SO₂R¹², —

SO₂N(R¹²)₂, —

NR¹²COR¹², —

NR¹²CO₂R¹², —

NR¹²CON(R¹²)₂, —

NR¹²(NR¹²)NHR¹², —

CO₂R¹², —

CON(R¹²)₂, —

NR¹²SO₂R¹², —

OCON(R¹²)₂, where HET and R¹² are as defined below;

R¹² is H, C_1-6 aliphatic or HET, said C_1-6 aliphatic optionally substituted by one to three of halogen or OH where HET is as defined below; and

HET, R⁴, R⁶, R⁷, R³ and R¹¹ are as defined in claim 1;

and the pharmaceutically acceptable salts or solvates thereof.

4. A compound of formula (I) as claimed in claim 1 wherein

R¹ is H or is optionally joined with R² to form a fused ring selected from the group consisting of fused pyridine, fused triazole, fused thiazole or fused amino-substituted thiazole;

or R¹ and R² comprise a fused ring which is methyl substituted fused pyridine.

HET is a five or six-membered saturated or unsaturated heteroaryl ring selected from the group consisting of dioxin, dioxane dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, imidazopyridinyl, morpholine, oxazole, oxadiazoie, oxathiazole, oxathiazolidine, oxazine, oxiadiazine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine, tetrahydrofuran, tetrazine, thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thiopyran, thioxotriazine, triazine, and triazole;

R², R³, R¹⁰ and R¹² are as defined in claim 1;

R⁴, R⁶, R⁷, R⁸ and R¹¹ are as defined in claim 1; and

R⁵ and R⁹ are as defined in claim 3;

and the pharmaceutically acceptable salts or solvates thereof.

5. A compound of formula (I) as claimed in claim 1 wherein

R¹ is H or is optionally joined with R² to form a fused ring selected from the group consisting of five to six membered heteroaryl rings, said heteroaryl ring having one to two heteroatoms where zero to two of said heteroatoms are N and zero to two of said heteroatoms are O or S and where said fused ring is optionally substituted by one to three of R⁹, where R² and R⁹ are as defined below;

R² and R³ are independently H, HET, phenyl, C_1-6 aliphatic, —

NR¹⁰R¹¹, —

COR¹¹, —

CO₂R¹¹, —

CONR¹²R¹¹, —

SO₂NR¹²R¹¹, with said HET, phenyl or C_1-6 aliphatic being optionally substituted by R¹⁰; and

where R² is optionally joined with R³ to form a fused five membered heterocyclyl ring, said heterocyclyl ring having zero to 1 heteroatoms where said heteroatom is N and zero to 1 heteroatoms where said heteroatoms are O or S and where said fused ring is optionally substituted by R⁹, where HET, R⁹, R¹⁰, R¹¹ and R¹² are as defined below;

R⁴ is H;

R⁵ is H;

R⁶, R⁷ and R⁸ are as defined in claim 1;

R⁹ is C_1-6 aliphatic or —

COR¹⁰, where R¹⁰ is as defined below;

R¹⁰ is H, C_1-6 aliphatic or amino;

R¹¹ is H, C_1-6 aliphatic, hydroxy-C_1-6 aliphatic, phenyl, phenyl-C_1-6 aliphatic or HET;

R¹² is H, C_1-6 aliphatic, hydroxy-C_1-6 aliphatic or (R¹¹)₂N—

C_1-6 aliphatic; and

HET is a heterocyclic ring selected from the group consisting of oxazole, pyridine, tetrazole and thiazole;

and the pharmaceutically acceptable salts or solvates thereof.

6. A compound of formula (I) as claimed in claim 1 wherein R¹ is H;

R² and R³ are independently H, HET, phenyl, C_1-6 aliphatic, cyano, halogen, —

COR¹¹, or —

CONR¹²R¹¹, with said HET, phenyl or C_1-6 aliphatic being optionally substituted by R¹⁰, where HET, R¹⁰, R¹¹ and R¹² are as defined below;

R⁴ is H;

R⁵ is H;

R⁶, R⁷ and R⁸ are as defined in claim 1;

R¹⁰ is H, C_1-6 aliphatic, oxo or cyano;

R¹¹ is H, C_1-6 aliphatic, trihalo-C_1-6 aliphatic, phenyl or nitro-substituted phenyl;

R¹² is H, C_1-6 aliphatic, hydroxy-C_1-6 aliphatic; and

HET is thiophene or pyridine;

and the pharmaceutically acceptable salts or solvates thereof.

7. A compound as claimed in claim 1, selected from the group consisting of

8. A compound as claimed in claim 1, selected from the group consisting of:

9. A compound as claimed in claim 1, selected from the group consisting of:

10. A compound as claimed in claim 1, selected from the group consisting of:

12. A compound as claimed in claim 1, wherein said compound is in the E geometric isomer form.

13. A compound as claimed in claim 1, wherein said compound is in the Z geometric isomer form.

14. A compound as claimed in claim 1, wherein said compound is a mixture of the Z geometric isomer form and the E geometric isomer form.

15. A compound as claimed in claim 1, having a chiral carbon atom and which compound is dextrorotatory.

16. A compound as claimed in claim 1, having a chiral carbon atom and which compound is levorotatory.

17. A compound as claimed in claim 1, having a chiral carbon atom and which is a mixture of dextrorotatory and levorotatory.

18. A prodrug of a compound as claimed in claim 1 which is a biohydrolyzable ester, biohydrolyzable amide, biohydrolyzable carbamate, biohydrolyzable carbonate or biohydrolyzable ureide, said biohydrolyzable functionality being linked to the OH group representing R⁸ in the compound of formula (I).

19. A prodrug as claimed in claim 18 wherein said OH group is conjugated with a carbamoyl conjugate to yield a biohydrolyzable carbamate wherein said carbamoyl conjugate is selected from the group consisting of diethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N,N,-bis(2-hydroxyethyl)aminocarbonyl, hydroxyethyloxyethylaminocarbonyl, 4-morpholinocarbonyl and 4-methyl-i-piperazinylcarbonyl.

20. A prodrug as claimed in claim 19 selected from

21. A prodrug as claimed in claim 18 wherein said OH group is conjugated with a carbonate conjugate to yield a biohydrolyzable carbonate wherein said carbonyl conjugate is selected from the group consisting of phenylmethyloxycarbonyl, ethyloxycarbonyl, isobutyloxycarbonyl, and pyridinemethyloxycarbonyl.

22. A prodrug as claimed in claim 18 wherein said OH group is conjugated with an ester conjugate to yield a biohydrolyzable ester wherein said ester conjugate is t-butylcarbonyloxymethyl.

23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound as claimed in claim 1.

24. A process for the preparation of a compound of formula (I) as claimed in claim 1, which process comprises the reaction of a compound of formula (II)

wherein R⁵, R⁶, R⁷ and R⁸ are as defined in claim 1, with a compound of formula (III)

wherein R¹, R², R³ and R⁴ are as defined in claim 1.

25. A method of treating a disease mediated by cRaf1 kinase, said method comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound as claimed in claim 1.

26. A method of inhibiting tumor growth, comprising the step of administering to a patient in need thereof a pharmacologically effective amount of a compound as claimed in claim 1.

11. The compound 3-(3,5-Dibromo-4-hydroxy-benzylidene)-5-pyrid-3-yl-1,3-dihydro-indol-2-one;

and pharmaceutically acceptable salts and solates thereof.