Pyridine, quinoline, and isoquinoline N-oxides as kinase inhibitors

• US 7,678,811 B2
• Filed: 07/10/2007
• Issued: 03/16/2010
• Est. Priority Date: 02/11/2002
• Status: Active Grant

• Current Assignee: Bayer Healthcare LLC (Bayer AG)
• Original Assignee: Bayer Healthcare LLC (Bayer AG)
• Inventors: Riedl, Bernd, Dumas, Jacques, Scott, William J.
• Primary Examiner(s): Davis; Zinna N
• Application Number:
  US11/775,457
• Publication Number:
  US 20070265315A1
• Time in Patent Office: 980 Days
• Field of Search: None
• US Class Current: 514/307
• 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—

(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 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;

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,

N(C₁-C₅ alkyl)(C₁-C₅ alkyl);

N(C₁-C₅ alkyl)(phenyl);

N(C₁-₅ alkyl)(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);

CO(phenyl);

CO(pyridinyl);

COO(C₁-C₆alkyl);

COO(phenyl);

COO(pyridinyl);

COOH;

CONH₂;

CONH(C₁-C₆ alkyl);

CONH(phenyl);

CONH(pyridinyl);

CON(C₁-C₆alkyl);

CON(phenyl);

CON(pyridinyl);

NHCO(C₁-C₅ alkyl);

NHCO(phenyl);

NHCO(pyridinyl); and

N(C₁-C₅ alkyl)CO(C₁-C₅ alkyl).

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);

NH(phenyl);

NH(pyridinyl);

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.

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:

methylethyl, methyipropyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, propoxy, butyoxy, pentoxy, methyl sulfonyl, trifluoromethyl sulfonyl, Cl, Br, F, cyano, nitro, hydroxy, amino, methylamino, dimethylamino, ethylamino and diethylamino.

12. 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.

15. 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.

16. 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.

17. 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.

13. 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;

14. A compound as in claim 13 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.