PYRIDINE, QUINOLINE, AND ISOQUINOLINE N-OXIDES AS KINASE INHIBITORS

• US 20070265315A1
• Filed: 07/10/2007
• Published: 11/15/2007
• Est. Priority Date: 02/11/2002
• Status: Active Grant

• Current Assignee: Bayer Healthcare LLC (Bayer AG)
• Original Assignee: Bayer Healthcare LLC (Bayer AG)
• Inventors: Dumas, Jacques, Riedl, Bernd, Scott, William
• Granted Patent: US 7,678,811 B2
• Time in Patent Office: Days
• US Class Current: 514/350
• 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 35/00 Antineoplastic agents
• CPC Class Codes: C07D 213/89 with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 215/60 N-oxides
• CPC Class Codes: C07D 217/08 with a hetero atom directly attached to the ring nitrogen atom

Abstract

This invention relates to urea compounds containing a pyridine, quinoline, or isoquinoline functionality which is oxidized at the nitrogen heteroatom and which are useful in the treatment of (i) raf mediated diseases, for example, cancer, (ii) p38 mediated diseases such as inflammation and osteoporosis, and (iii) VEGF mediated diseases such as angogenesis disorders.

Claims

1. A compound of formula (I) or a salt, prodrug or isolated stereoisomer thereof

M-L-B—

NH—

C(O)—

NH-A  

 

I

wherein A is selected from the group consisting of;

(i) phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of R¹, OR¹, NR¹R², S(O)_qR¹, SO₂NR¹R², NR¹SO₂R², COR¹, COOR¹, CONR¹R², NR¹C(O)R² halogen, cyano, and nitro;

(ii) naphthyl, optionally substituted with 1-3 substituents independently selected from the group consisting of R¹, OR¹, NR¹R², S(O)_qR¹, SO₂NR¹R², NR¹SO₂R², COR¹, COOR¹, CONR¹R², NR¹C(O)R², halogen, cyano, and nitro;

(iii) 5 and 6 membered monocyclic heteroaryl, having 1-3 heteroatoms independently selected from the group consisting of O, N and S, optionally substituted with 1-3 substituents independently selected from the group consisting of R¹, OR¹, NR¹R², S(O)_qR¹, SO₂NR¹R², NR¹SO₂R², COR¹, COOR¹, CONR¹R², NR¹COR², halogen, cyano, and nitro; and

(iv) 8-10 membered bicyclic heteroaryl, having 1-6 heteroatoms independently selected from the group consisting of O, N and S, optionally substituted with 1-3 substituents independently selected from the group consisting of R¹, OR¹, NR¹R², S(O)_qR¹, SO₂NR¹R², NR¹SO₂R², COR¹, COOR¹, CONR¹R², NR¹COR², halogen, cyano, and nitro;

B is selected from the group consisting of;

(i) phenylene, optionally substituted with 1-3 substituents independently selected from the group consisting of C₁-C₅ linear or branched alkyl, C₁-C₅ linear or branched haloalkyl, C₁-C₃ alkoxy, hydroxy, amino, C₁-C₃ alkylamino, C₁-C₃ dialkylamino, halogen, cyano, and nitro;

(ii) naphthylene, optionally substituted with 1-3 substituents independently selected from the group consisting of C₁-C₅ linear or branched alkyl, C₁-C₅ linear or branched haloalkyl, C₁-C₃ alkoxy, hydroxy, amino, C₁-C₃ alkylamino, C₁-C₃ dialkylamino, halogen, cyano, and nitro;

(iii) 5 and 6 membered monocyclic heteroaryl-ene, having 1-3 heteroatoms independently selected from the group consisting of O, N and S, optionally substituted with 1-3 substituents independently selected from the group consisting of C₁-C₅ linear or branched alkyl, C₁-C₅ linear or branched haloalkyl, C₁-C₃ alkoxy, hydroxy, amino, C₁-C₃ alkylamino, C₁-C₃ dialkylamino, halogen, cyano, and nitro; and

(iv) 8-10 membered bicyclic heteroaryl-ene, having 1-6 heteroatoms independently selected from the group consisting of O, N and S, optionally substituted with 1-3 substituents independently selected from the group consisting of C₁-C₅ linear or branched alkyl, C₁-C₅ linear or branched haloalkyl, C₁-C₃ alkoxy, hydroxy, amino, C₁-C₃ alkylamino, C₁-C₃ dialkylamino, halogen, cyano, and nitro;

L is selected from the group consisting of;

(a) —

(CH₂)_m—

O—

(CH₂)_l—

,

(b) —

(CH₂)_m—

(CH₂)_l—

,

(c) —

(CH₂)_m—

C(O)—

(CH₂)_l—

,

(d) —

(CH₂)_m—

NR^3a—

(CH₂)_l—

,

(e) —

(CH₂)_m—

NR^3aC(O)—

(CH₂)_l—

,

(f) —

(CH₂)_m—

S—

(CH₂)_l—

,

(g) —

(CH₂)_m—

C(O)NR^3a—

(CH₂)_l—

,

(h) —

(CH₂)_m—

CF₂—

(CH₂)_l—

,

(i) —

(CH₂)_m—

CCl₂—

(CH)_l—

,

(j) —

(CH₂)_m—

CHF—

(CH₂)_l—

,

(k) —

(CH₂)_m—

CR^3a(OH)—

(CH₂)_l—

;

(l) —

(CH₂)_m—

C≡

C—

(CH₂)_l—

;

(m) —

(CH₂)_m—

C═

C—

(CH₂)_l—

;

(n) a single bond; and

(o) —

(CH₂)_m—

CR^3aR^3b(CH₂)_l—

;

wherein m and 1 are integers independently selected from 0-4;

M is selected from the group consisting of

(a) pyridine-1-oxide substituted 1 to 3 times by a substituent selected from the group consisting of —

C(O)NR⁴R⁵, —

C(NR⁴)R⁵, —

C(O)R⁴, —

SO₂R⁴, and —

SO₂NR⁴R⁵;

which is optionally additionally substituted by Z_r;

(b) quinoline-1-oxide, which is optionally substituted by Z_n; and

(c) isoquinoline-1-oxide, which is optionally substituted by Z_n;

wherein r is 0-2, n is 0-3, and each Z is independently selected from the group consisting of R⁴, halogen, cyano, —

CO₂R⁴, —

C(O)R⁴, —

C(O)NR⁴R⁵, —

NO₂, —

OR⁴—

, —

NR⁴R⁵, —

NR⁴C(O)OR⁵, —

NR⁴C(O)R⁵, —

S(O)_pR⁴, and —

SO₂NR⁴R⁵

wherein each R¹, R², R⁴ and R⁵ is independently selected from the group consisting of;

(a) hydrogen,

(b) C₁-C₅ linear, branched, or cyclic alkyl,

(c) phenyl,

(d) 5-6 membered monocyclic heteroaryl heteroaryl having 1-4 heteroatoms selected from the group consisting of O, N and S or 8-10 membered bicyclic heteroaryl having 1-6 heteroatoms selected from the group consisting of O, N and S,

(e) C₁-C₃ alkyl-phenyl,

(f) C₁-C₃ alkyl heteroaryl having 1-4 heteroatoms selected from the group consisting of O, N and S, said heteroaryl including 5-6 membered monocyclic and 8-10 membered bicyclic heteroaryl, and

(g) up to per-halo substituted C₁-C₅ linear or branched alkyl; and

wherein each R¹, R², R⁴ and R⁵, when not hydrogen or perhalo substituted C₁-C₅ linear or branched alkyl, are optionally substituted with 1-3 substituents independently selected from the group consisting of C₁-C₅ linear or branched alkyl, up to perhalo substituted C₁-C₅ linear or branched alkyl, C₁-C₃ alkoxy, hydroxy, amino, C₁-C₃ alkylamino, C₁-C₆ dialkylamino, halogen, cyano, and nitro;

wherein each R^3a and R^3b is hydrogen or C₁-C₅ linear or branched alkyl;

and p and q are integers each independently selected from 0, 1, or 2

subject to the proviso that formula I does not include compounds of formula II;

wherein,

Y is OR¹ or NHR²,

Hal is chlorine or bromine,

R¹ is H or C₁-C₆ alkyl

R² is H, OH, CH₃ or CH₂OH,

X¹ to X⁷ are each, independently, H, OH or O(CO)C₁-C₄ alkyl.

2. A compound as in claim 1 wherein A and B of formula I, are each independently:

a substituted or unsubstituted phenyl group, a substituted or unsubstituted a naphthyl group, a substituted or unsubstituted monocyclic heteroaryl group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-triazinyl, 4triazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,3-triazol-3-yl, 1,2,3-triazol-5-yl, 1-tetrazolyl, 5-tetrazolyl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,3,4-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 3-pyridazinyl-, 4-pyridazinyl, 2-pyrazinyl and 3-pyrazinyl or

a substituted or unsubstituted bicyclic heteroaryl group selected from the group consisting of 2-, 3-, 4-, 5-, 6- and 7-benzofuryl, 2-, 3-, 4-, 5-, 6- and 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- and 7-indolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-isoindolyl, 1-, 2-, 4- and 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- and 7-indazolyl (benzopyrazolyl), 2-, 4-, 5-, 6- and 7-benzoxazolyl, 3-, 4-, 5- 6- and 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- and 7-benzothiazolyl, 2-, 4-, 5-, 6- and 7-benzisothiazolyl, 2-, 4-, 5-, 6- and 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- and 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, and 2-, 4-, 5-, 6-, 7- and 8-quinazolinyl.

3. A compound as in claim 1 wherein A of formula I is

a substituted or unsubstituted phenyl group,

a substituted or unsubstituted a naphthyl group,

a substituted or unsubstituted monocyclic heteroaryl group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-triazinyl, 4-triazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,3-triazol-3-yl, 1,2,3-triazol-5-yl, 1-tetrazolyl, 5-tetrazolyl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,3,4-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 3-pyridazinyl-, 4-pyridazinyl, 2-pyrazinyl and 3-pyrazinyl or

a substituted or unsubstituted bicyclic heteroaryl group selected from the group consisting of 2-, 3-, 4-, 5-, 6- and 7-benzofuryl, 2-, 3-, 4-, 5-, 6- and 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- and 7-indolyl, 1-, 2-, 4- and 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- and 7-indazolyl (benzopyrazolyl), 2-, 4-, 5-, 6- and 7-benzoxazolyl, 3-, 4-, 5- 6- and 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- and 7-benzothiazolyl, 2-, 4-, 5-, 6- and 7-benzisothiazolyl, 2-, 4-, 5-, 6- and 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- and 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, and 2-, 4-, 5-, 6-, 7- and 8-quinazolinyl and B of formula I is

a substituted or unsubstituted phenyl group,

a substituted or unsubstituted monocyclic heteroaryl group selected from the group consisting of 2- furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-triazinyl, 4-triazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,3-triazol-3-yl, 1,2,3-triazol-5-yl, 1-tetrazolyl, 5-tetrazolyl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,3,4-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 3-pyridazinyl-, 4-pyridazinyl, 2-pyrazinyl and 3-pyrazinyl or

a substituted or unsubstituted bicyclic heteroaryl group selected from the group consisting of 2-, 3-, 4-, 5-, 6- and 7-benzofuryl, 2-, 3-, 4-, 5-, 6- and 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- and 7-indolyl, 1-, 2-, 4- and 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- and 7-indazolyl (benzopyrazolyl), 2-, 4-, 5-, 6- and 7-benzoxazolyl, 3-, 4-, 5- 6- and 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- and 7-benzothiazolyl, 2-, 4-, 5-, 6- and 7-benzisothiazolyl, 2-, 4-, 5-, 6- and 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- and 8-quinolinyl7 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, and 2-, 4-, 5-, 6-, 7- and 8-quinazolinyl.

4. A compound as in claim 1 wherein

A of formula I is a substituted or unsubstituted group selected from the group consisting of phenyl, naphthyl, furyl, isoindolyl, oxadiazolyl, oxazolyl, isooxazolyl, indolyl, indazolyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrazolyl, thiadiazolyl, thiazolyl and thienyl,

B of formula I is a substituted or unsubstituted group selected from the group consisting of phenylene, naphthylene, thienylene, furylene, pyridine-ene, quinoline-ene, isoquinoline-ene and indole-ene,

L is selected from the group consisting of —

CH₂O—

, —

OCH₂—

, —

O—

, a single bond, —

CH₂—

, —

NH—

, —

N(CH₃)—

, —

N(CH₃)CH₂—

, —

NC₂H₄—

, —

C(O)—

, —

NHCH₂—

, —

N(CH₃)C(O)—

, —

NHC(O)—

, —

CH₂N(Cl₃)—

, —

C(O)NH—

, —

CH₂S—

, —

SCH₂—

, —

S—

, —

C(O)NCH₃—

, —

CH₂C(O)N(CH₃)—

, —

C(O)N(CH₃)CH₂—

, —

CF₂—

, —

CCl₂—

, —

CHF— and

—

CH(OH)—

, and M is defined as in claim 1.

5. A compound as in claim 1 wherein

A of formula I is a substituted or unsubstituted group selected from the group consisting of phenyl, naphthyl, furyl, isoindolyl, oxadiazolyl, oxazolyl, isoxazolyl, indolyl, indazolyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrazolyl, thiadiazolyl, thiazolyl and thienyl,

B of formula I is a substituted or unsubstituted group selected from the group consisting of phenylene, thienylene, furylene, pyridine-ene, quinoline-ene, isoquinoline-ene and indole-ene,

L is selected from the group consisting of —

CH₂O—

, —

OCH₂—

, —

O—

, a single bond, —

CH₂—

, —

NH—

, —

N(CH₃)—

, —

N(CH₃)CH₂—

, —

NC₂H₄—

, —

C(O)—

, —

NHCH₂—

, —

N(CH₃)C(O)—

, —

NHC(O)—

, —

CH₂N(CH₃)—

, —

C(O)NH—

, —

CH₂S—

, —

SCH₂—

, —

S—

, —

C(O)NCH₃—

, —

CH₂C(O)N(CH₃)—

, —

C(O)N(CH₃)CH₂—

, —

CF₂—

, —

CCl₂—

, —

CHF— and

—

CH(OH)—

, and M is defined as in claim 1.

6. A compound as in claim 4 wherein

A of formula I is a substituted group and the substituents are selected from the group consisting of methyl, trifluoromethyl, ethyl, n-propyl, n-butyl, n-pentyl, i-propyl, t-butyl, methylethyl, methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, propoxy, butyoxy, pentoxy, methyl sulfonyl, trifluoromethyl sulfonyl, Cl, Br, F, cyano, nitro, hydroxy, amino, methylamino, dimethylamino, ethylamino and diethylamino.

7. A compound as in claim 1 wherein

A of formula I is a substituted or unsubstituted group selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazolyl, quinolinyl, isoquinolinyl, isoindolyl, pyrrolyl, indazolyl, thienyl, furyl and isoxazolyl and

B of formula I is a substituted or unsubstituted group selected from the group consisting of phenylene, naphthylene, thienylene, furylene, pyridine-ene, quinoline-ene, isoquinoline-ene and indole-ene.

8. A compound as in claim 1 wherein

A of formula I is a substituted or unsubstituted group selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazolyl, quinolinyl, isoquinolinyl, isoindolyl, pyrrolyl, indazolyl, thienyl, furyl and isoxazolyl and

B of formula I is a substituted or unsubstituted group selected from the group consisting of phenylene, thienylene, furylene, pyridine-ene, isoquinoline-ene and indole-ene.

9. A compound as in claim 1 wherein

A of formula I is a substituted or unsubstituted group selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazolyl, quinolinyl, isoquinolinyl, isoindolyl, pyrrolyl, indazolyl, thienyl, furyl and isoxazolyl and

B of formula I is a substituted or unsubstituted group selected from the group consisting of phenylene and pyridine-ene.

10. A compound as in claim 7 wherein

A of formula I is a substituted group and the substituents are selected from the group consisting of:

NH(C₁-C₅ alkyl, phenyl or pyridinyl);

N(C₁-C₅ alkyl)(C₁-C₅ alkyl, phenyl or pyridinyl);

S(O)₂ (C₁-C₅ alkyl);

SO₂NH(C₁-C₅ alkyl);

SO₂N(C₁-C₅ alkyl)(C₁-C₅ alkyl);

NHSO₂(C₁-C₅ alkyl);

N(C₁-C₃ alkyl) SO₂(C₁-C₅ alkyl);

CO(C₁-C₆ alkyl, phenyl or pyridinyl);

COO(C₁-C₆ alkyl, phenyl or pyridinyl);

COOH;

CONH₂;

CONH(C₁-C₆ alkyl, phenyl or pyridinyl);

CON(C₁-C₆ alkyl, phenyl or pyridinyl);

NHCO(C₁-C₅ alkyl, phenyl or pyridinyl) and

N(C₁-C₅ alkyl)CO(C₁-C₅ alkyl).

11. A compound of formula I of claim 1 wherein in A, and B are one of the following combinations and M is as defined in claim 1:

A=phenyl, B=phenylene,

A=phenyl, B=pyridinyl-ene,

A=phenyl, B=isoquinolinyl-ene,

A=pyridinyl, B=phenylene,

A=pyridinyl, B=pyridinyl-ene,

A=pyridinyl, B=isoquinolinyl-ene,

A=naphthyl, B=phenylene,

A=naphthyl, B=pyridinyl-ene,

A=naphthyl, B=isoquinolinyl-ene,

A=isoquinolinyl, B=phenylene,

A=isoquinolinyl, B=pyridinyl-ene,

A=isoquinolinyl, B=isoquinolinyl-ene,

A=quinolinyl, B=phenylene,

A=quinolinyl, B=pyridinyl-ene,

A=quinolinyl, B=isoquinolinyl-ene,

A=pyrazolyl, B=phenylene,

A=pyrazolyl, B=pyridinyl-ene,

A=pyrazolyl, B=isoquinolinyl-ene,

A=isoxazolyl, B=phenylene,

A=isoxazolyl, B=pyridinyl-ene,

A=isoxazolyl, B=isoquinolinyl-ene.

A=indazolyl, B=phenylene,

A=indazolyl, B=pyridinyl-ene,

and

A=indazolyl, B=isoquinolinyl-ene.

12. A pharmaceutical composition comprising

a) one or more compounds of formula I of claim 1, or a isolated stereoisomer, a pharmaceutically acceptable salt, or a prodrug of a compound of formula (I) and

b) at least one pharmaceutically acceptable carrier.

13. A pharmaceutical composition comprising

a) one or more compounds of formula I of claim 1, or a salt, prodrug or isolated stereoisomer of a compound of formula I,

b) at least one other cytotoxic or cytostatic chemotherapeutic agent, wherein the amounts of a) and b) are jointly effective for treating a cancer, and

c) at least one pharmaceutically acceptable carrier.

36. A compound of formula I of claim 1, wherein in A, and B are one of the following combinations and M is as defined in claim 1:

A=phenyl, B=phenylene, and

A=phenyl, B=pyridinyl-ene.

37. A method for the treatment of raf-mediated tumor in humans and/or other mammals, which comprises administering a compound of formula I of claim 1 or a salt, prodrug or isolated stereoisomer thereof to a human or other mammal in need thereof.

38. A method for the treatment of p38-mediated inflammation in humans and/or other mammals, which comprises administering a compound of formula I of claim 1 or a salt, prodrug or isolated stereoisomer thereof to a human or other mammal in need thereof.

39. A method for the treatment of a disease which is mediated by the VEGF-induced signal transduction pathway that is characterized by abnormal angiogenesis or hyperpermeability processes in humans and/or other mammals, which comprises administering a compound of formula I of claim 1 or a salt, prodrug or isolated stereoisomer thereof to a human or other mammal in need thereof.

40. A kit comprising a separate dose of a compound of formula I of claim 1, or a salt, prodrug or isolated stereoisomer thereof, and a separate dose of a cytotoxic or cytostatic chemotherapeutic agent in separate containers.

14-35. -35. (canceled)

41. A compound of formula (I) or a salt, or isolated stereoisomer thereof

M-L-B—

NH—

C(O)—

NH-A  

 

I

wherein A is selected from the group consisting of;

(i) phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of R¹, OR¹, NR¹R², S(O)_qR¹, SO₂NR¹R², NR¹SO₂R², COR¹, COOR¹, CONR¹R², NR¹C(O)R², halogen, cyano, and nitro;

(ii) naphthyl, optionally substituted with 1-3 substituents independently selected from the group consisting of R¹, OR¹, NR¹R², S(O)_qR¹, SO₂NR¹R², NR¹SO₂R², COR¹, COOR¹, CONR¹R², NR¹C(O)R², halogen, cyano, and nitro;

(iii) 5 and 6 membered monocyclic heteroaryl, having 1-3 heteroatoms independently selected from the group consisting of O, N and S, optionally substituted with 1-3 substituents independently selected from the group consisting of R¹, OR¹, NR¹R², S(O)_qR¹, SO₂NR¹R², NR¹SO₂R², COR¹, COOR¹, CONR¹R², NR¹COR², halogen, cyano, and nitro; and

(iv) 8-10 membered bicyclic heteroaryl, having 1-6 heteroatoms independently selected from the group consisting of O, N and S, optionally substituted with 1-3 substituents independently selected from the group consisting of R¹, OR¹, NR¹R², S(O)_qR¹, SO₂NR¹R², NR¹SO₂R², COR¹, COOR¹, CONR¹R², NR¹COR², halogen, cyano, and nitro;

B is selected from the group consisting of;

(i) phenylene, optionally substituted with 1-3 substituents independently selected from the group consisting of C₁-C₅ linear or branched alkyl, C₁-C₅ linear or branched haloalkyl, C₁-C₃ alkoxy, hydroxy, amino, C₁-C₃ alkylamino, C₁-C₃ dialkylamino, halogen, cyano, and nitro;

(ii) naphthylene, optionally substituted with 1-3 substituents independently selected from the group consisting of C₁-C₅ linear or branched alkyl, C₁-C₅ linear or branched haloalkyl, C₁-C₃ alkoxy, hydroxy, amino, C₁-C₃ alkylamino, C₁-C₃ dialkylamino, halogen, cyano, and nitro;

(iii) 5 and 6 membered monocyclic heteroaryl-ene, having 1-3 heteroatoms independently selected from the group consisting of O, N and S, optionally substituted with 1-3 substituents independently selected from the group consisting of C₁-C₅ linear or branched alkyl, C₁-C₅ linear or branched haloalkyl, C₁-C₃ alkoxy, hydroxy, amino, C₁-C₃ alkylamino, C₁-C₃ dialkylamino, halogen, cyano, and nitro; and

(iv) 8-10 membered bicyclic heteroaryl-ene, having 1-6 heteroatoms independently selected from the group consisting of O, N and S, optionally substituted with 1-3 substituents independently selected from the group consisting of C₁-C₅ linear or branched alkyl, C₁-C₅ linear or branched haloalkyl, C₁-C₃ alkoxy, hydroxy, amino, C₁-C₃ alkylamino, C₁-C₃ dialkylamino, halogen, cyano, and nitro;

L is selected from the group consisting of;

(a) —

(CH₂)_m—

O—

(CH₂)_l—

,

(b) —

(CH₂)_m—

(CH₂)_l—

,

(c) —

(CH₂)_m—

C(O)—

(CH₂)_l—

,

(d) —

(CH₂)_m—

NR^3a—

(CH₂)_l—

,

(e) —

(CH₂)_m—

NR^3aC(O)—

(CH₂)_l—

,

(f) —

(CH₂)_m—

S—

(CH₂)_l—

,

(g) —

(CH₂)_m—

C(O)NR^3a—

(CH₂)_l—

,

(h) —

(CH₂)_m—

CF₂—

(CH₂)_l—

,

(i) —

(CH₂)_m—

CCl₂—

(CH₂)_l—

,

(j) —

(CH₂)_m—

CHF—

(CH₂)_l—

,

(k) —

(CH₂)_m—

CR^3a(OH)—

(CH₂)_l—

;

(l) —

(CH₂)_m—

C≡

C—

(CH₂)_l—

;

(m) —

(CH₂)_m—

C═

C—

(CH₂)_l—

;

(n) a single bond; and

(o) —

(CH₂)_m—

CR^3aR^3b—

(CH₂)_l—

;

wherein m and l are integers independently selected from 0-4;

M is selected from the group consisting of;

(a) pyridine-1-oxide substituted 1 to 3 times by a substituent selected from the group consisting of —

C(O)NR⁴R⁵, —

C(NR⁴)R⁵, —

C(O)R⁴, —

SO₂R⁴, and —

SO₂NR⁴R⁵;

which is optionally additionally substituted by Z_r;

(b) quinoline-1-oxide, which is optionally substituted by Z_n; and

(c) isoquinoline-1-oxide, which is optionally substituted by Z_n;

wherein r is 0-2, n is 0-3, and each Z is independently selected from the group consisting of R⁴, halogen, cyano, —

CO₂R⁴, —

C(O)R⁴, —

C(O)NR⁴R⁵, —

NO₂, —

OR⁴—

, —

NR⁴R⁵, —

NR⁴C(O)OR⁵, —

N⁴C(O)R⁵, —

S(O)_pR⁴, and —

SO₂NR⁴R⁵

wherein each R¹, R², R⁴ and R⁵ is independently selected from the group consisting of;

(a) hydrogen,

(b) C₁-C₅ linear, branched, or cyclic alkyl,

(c) phenyl,

(d) 5-6 membered monocyclic heteroaryl heteroaryl having 1-4 heteroatoms selected from the group consisting of O, N and S or 8-10 membered bicyclic heteroaryl having 1-6 heteroatoms selected from the group consisting of O, N and S,

(e) C₁-C₃ alkyl-phenyl,

(f) C₁-C₃ alkyl heteroaryl having 1-4 heteroatoms selected from the group consisting of O, N and S, said heteroaryl including 5-6 membered monocyclic and 8-10 membered bicyclic heteroaryl, and

(g) up to per-halo substituted C₁-C₅ linear or branched alkyl; and

wherein each R¹, R², R⁴ and R⁵, when not hydrogen or perhalo substituted C₁-C₅ linear or branched alkyl, are optionally substituted with 1-3 substituents independently selected from the group consisting of C₁-C₅ linear or branched alkyl, up to perhalo substituted C₁-C₅ linear or branched alkyl, C₁-C₃ alkoxy, hydroxy, amino, C₁-C₃ alkylamino, C₁-C₆ dialkylamino, halogen, cyano, and nitro;

wherein each R^3a and R^3b is hydrogen or C₁-C₅ linear or branched alkyl;

and p and q are integers each independently selected from 0, 1, or 2

subject to the proviso that formula I does not include compounds of formula II;

wherein,

Y is OR¹ or NHR²,

Hal is chlorine or bromine,

R¹ is H or C₁-C₆ alkyl

R² is H, OH, CH₃ or CH₂OH,

X¹ to X⁷ are each, independently, H, OH or O(CO)C₁-C₄ alkyl.

42. A compound as in claim 41 wherein A and B of formula I, are each independently:

a substituted or unsubstituted phenyl group,

a substituted or unsubstituted a naphthyl group,

a substituted or unsubstituted monocyclic heteroaryl group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-triazinyl, 4-triazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,3-triazol-3-yl, 1,2,3-triazol-5-yl, 1-tetrazolyl, 5-tetrazolyl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,3,4-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 3-pyridazinyl-, 4-pyridazinyl, 2-pyrazinyl and 3-pyrazinyl or

a substituted or unsubstituted bicyclic heteroaryl group selected from the group consisting of 2-, 3-, 4-, 5-, 6- and 7-benzofuryl, 2-, 3-, 4-, 5-, 6- and 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- and 7-indolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-isoindolyl, 1-, 2-, 4- and 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- and 7-benzoxazolyl, 2-, 4-, 5- 6- and 7-benzoxazolyl, 3-, 4-, 5- 6- and 7-benzothiazolyl, 1-, 3-, 4-, 5-, 6- and 7-benzothiazolyl, 2-, 4-, 5-, 6- and 7-benzisothiazolyl, 2-, 4-, 5-, 6- and 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- and 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, and 2-, 4-, 5-, 6-, 7- and 8-quinazolinyl.