IP Library › Granted Patent US 7,928,227

Granted Patent B2

US 7,928,227 · App. 10/788,405 · Granted Apr 19, 2011

2-oxo-1,3,5-perhydrotriazapine derivatives useful in the treatment of hyper-proliferative, angiogenesis, and inflammatory disorders

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Patent No.: US 7,928,227
App. No.: 10/788,405
Granted: Apr 19, 2011
Kind: B2

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Abstract

This invention relates to novel diaryl ureas, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for treating hyper-proliferative and angiogenesis disorders, as a sole agent or in combination with cytotoxic therapies.

Claims (201)

1. A compound of formula I,

or a pharmaceutically acceptable salt thereof,

wherein A is

(i) phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of R 1 , OR 1 , NR 1 R 2 , S(O) p R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 2 , NR 1 C(O)OR 2 , halogen, cyano, and nitro;

(ii) naphthyl, optionally substituted with 1-3 substituents independently selected from the group consisting of R 1 , OR 1 , NR 1 R 2 , S(O) p R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 2 , NR 1 C(O)OR 2 , 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 R 1 , OR 1 , NR 1 R 2 , S(O) p R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 2 , NR 1 C(O)OR 2 , halogen, cyano, and nitro;

(iv) 8 to 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 R 1 , OR 1 , NR 1 R 2 , S(O) p R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 2 , NR 1 C(O)OR 2 , halogen, cyano, and nitro; or

(v) a group of the formula

optionally substituted with 1-4 substituents independently selected from the group consisting of R 1 , OR 1 , NR 1 R 2 , S(O) p R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 2 , NR 1 C(O)OR 2 , halogen, cyano, and nitro

B is (i) phenyl or naphthyl, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl up to perhalo, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy up to per haloalkoxy, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, cyano, and nitro; and A is additionally C 3 to C 6 linear or branched alkyl;

L is a bridging group selected from the group consisting of:

(a) —(CH 2 ) m —O—(CH 2 ) l —,

(d) —(CH 2 ) m —NR 3 —(CH 2 ) l —,

(e) —(CH 2 ) m —NR 3 C(O)—(CH 2 ) l —,

(f) —(CH 2 ) m —S—(CH 2 ) l —,

(g) —(CH 2 ) m —C(O)NR 3 —(CH 2 ) l —,

(h) —(CH 2 ) m —CF 2 —(CH 2 ) l —,

(i) —(CH 2 ) m —CCl 2 —(CH 2 ) l —,

(j) —(CH 2 ) m —CHF—(CH 2 ) l —, and

(k) —(CH 2 ) m —CH(OH)—(CH 2 ) l —;

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

M is

(i) phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of R 4 , OR 4 , NR 4 R 5 , S(O) q R 4 , SO 2 NR 4 R 5 , C(O)NR 4 R 5 , C(NR 4 )R 5 , NR 4 SO 2 R 5 , C(O)R 4 , C(O)OR 4 , NR 4 C(O)R 5 , NR 4 C(O)OR 5 , halogen, cyano, and nitro;

(ii) naphthyl, optionally substituted with 1-3 substituents independently selected from the group consisting of R 4 , OR 4 , NR 4 R 5 , S(O) q R 4 , SO 2 NR 4 R 5 , C(O)NR 4 R 5 , C(NR 4 )R 5 , NR 4 SO 2 R 5 , C(O)R 4 , C(O)OR 4 , NR 4 C(O)R 5 , NR 4 C(O)OR 5 , 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 R 4 , OR 4 , NR 4 R 5 , S(O) q R 4 , SO 2 NR 4 R 5 , C(O)NR 4 R 5 , C(NR 4 )R 5 , NR 4 SO 2 R 5 , C(O)R 4 , C(O)OR 4 , NR 4 C(O)R 5 , NR 4 C(O)OR 5 , halogen, cyano, nitro and oxides;

(iv) 8 to 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 R 4 , OR 4 , NR 4 R 5 , S(O) q R 4 , SO 2 NR 4 R 5 , C(O)NR 4 R 5 , C(NR 4 )R 5 , NR 4 SO 2 R 5 , C(O)R 4 , C(O)OR 4 , NR 4 C(O)R 5 , NR 4 C(O)OR 5 , halogen, cyano, nitro and oxides;

(v) saturated and partially saturated C 3 -C 7 monocyclic carbocyclic moiety optionally substituted with 1-3 substituents independently selected from the group consisting of R 4 , OR 4 , NR 4 R 5 , S(O) q R 4 , SO 2 NR 4 R 5 , C(O)NR 4 R 5 , C(NR 4 )R 5 , NR 4 SO 2 R 5 , C(O)R 4 , C(O)OR 4 , NR 4 C(O)R 5 , NR 4 C(O)OR 5 , halogen, cyano, and nitro;

(vi) saturated and partially saturated C 5 -C 12 bicyclic carbocyclic moiety, optionally substituted with 1-3 substituents independently selected from the group consisting of R 4 , OR 4 , NR 4 R 5 , S(O) q R 4 , SO 2 NR 4 R 5 , C(O)NR 4 R 5 , C(NR 4 )R 5 , NR 4 SO 2 R 5 , C(O)R 4 , C(O)OR 4 , NR 4 C(O)R 5 , NR 4 C(O)OR 5 , halogen, cyano, and nitro;

(vii) saturated and partially saturated 5 to 7 membered monocyclic heterocyclic moiety, 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 R 4 , OR 4 , NR 4 R 5 , S(O) q R 4 , SO 2 NR 4 R 5 , C(O)NR 4 R 5 , C(NR 4 )R 5 , NR 4 SO 2 R 5 , C(O)R 4 , C(O)OR 4 , NR 4 C(O)R 5 , NR 4 C(O)OR 5 , halogen, cyano, nitro and oxides (e.g. ═O, —O − or —OH); or

(viii) saturated and partially saturated 7 to 12 membered bicyclic heterocyclic moiety, 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 R 4 , OR 4 , NR 4 R 5 , S(O) q R 4 , SO 2 NR 4 R 5 , C(O)NR 4 R 5 , C(NR 4 )R 5 , NR 4 SO 2 R 5 , C(O)R 4 , C(O)OR 4 , NR 4 C(O)R 5 , NR 4 C(O)OR 5 , halogen, cyano, nitro and oxides; and

each R 1 , R 2 , R 3 , R 4 , R 5 and Q is, independently,

(a) hydrogen,

(b) C 1 -C 5 linear, branched, or cyclic alkyl, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, up to perhalo substituted C 1 -C 5 linear or branched alkyl, C 1 -C 3 alkoxy, hydroxy, carboxy, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, cyano, and nitro;

(c) phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, up to perhalo substituted C 1 -C 5 linear or branched alkyl, C 1 -C 3 alkoxy, hydroxy, carboxy, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, cyano, and nitro;

(d) 5-6 membered monocyclic 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, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, up to perhalo substituted C 1 -C 5 linear or branched alkyl, C 1 -C 3 alkoxy, hydroxy, carboxy, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, cyano, and nitro;

(e) C 1 -C 3 alkyl-phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, up to perhalo substituted C 1 -C 5 linear or branched alkyl, C 1 -C 3 alkoxy, hydroxy, carboxy, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, cyano, and nitro;

(f) C 1 -C 3 heteroaryl-alkyl having 1-4 heteroatoms selected from the group consisting of O, N and S, wherein said heteroaryl group is a 5-6 membered monocyclic heteroaryl or a 8-10 membered bicyclic heteroaryl, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, up to perhalo substituted C 1 -C 5 linear or branched alkyl, C 1 -C 3 alkoxy, hydroxy, carboxy, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, cyano, and nitro; or

(g) up to per-halo substituted C 1 -C 5 linear, branched or cyclic alkyl and when not perhalo substituted, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, up to perhalo substituted C 1 -C 5 linear or branched alkyl, C 1 -C 3 alkoxy, hydroxy, carboxy, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, cyano, and nitro.

2. A compound of formula I,

or a pharmaceutically acceptable salt thereof,

wherein B is

(i) phenyl or naphthyl, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl up to perhalo, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy up to per haloalkoxy, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, cyano, and nitro;

A is a 5-10 membered cyclic moiety which is optionally substituted with 1-4 substituents independently selected from the group consisting of R 1 , OR 1 , NR 1 R 2 , S(O) p R 1 , SO 2 NR 1 R 2 , C(O)NR 1 R 2 , C(NR 1 )R 2 , NR 1 SO 2 R 2 , C(O)R 1 , C(O)OR 1 , NR 1 C(O)R 2 , NR 1 C(O)OR 2 , cyano, and nitro, and A is additionally C 3 to C 6 linear or branched alkyl;

L is a bridging group selected from the group consisting of:

(a) —(CH 2 ) m —O—(CH 2 ) l —,

(b) —(CH 2 ) m —(CH 2 ) l —,

(d) —(CH 2 ) m —NR 3 —(CH 2 ) l —,

(e) —(CH 2 ) m —NR 3 C(O)—(CH 2 ) l —,

(f) —(CH 2 ) m —S—(CH 2 ) l —,

(g) —(CH 2 ) m —C(O)NR 3 —(CH 2 ) l —,

(h) —(CH 2 ) m —CF 2 —(CH 2 ) l —,

(i) —(CH 2 ) m —CCl 2 —(CH 2 ) l —,

(j) —(CH 2 ) m —CHF—(CH 2 ) l —,

(k) —(CH 2 ) m —CH(OH)—(CH 2 ) l —;

(l) —(CH 2 ) m —C≡C—(CH 2 ) l ; and

(m);

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

M is

(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 R 4 , OR 4 , NR 4 R 5 , S(O) q R 4 , SO 2 NR 4 R 5 , C(O)NR 4 R 5 , C(NR 4 )R 5 , NR 4 SO 2 R 5 , C(O)R 4 , C(O)OR 4 , NR 4 C(O)R 5 , NR 4 C(O)OR 5 , halogen, cyano, nitro and oxides;

(iv) 8 to 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 R 4 , OR 4 , NR 4 R 5 , S(O) q R 4 , SO 2 NR 4 R 5 , C(O)NR 4 R 5 , C(NR 4 )R 5 , NR 4 SO 2 R 5 , C(O)R 4 , C(O)OR 4 , NR 4 C(O)R 5 , NR 4 C(O)OR 5 , halogen, cyano, nitro and oxides;

each R1, R 2 , R 3 , R 4 , R 5 and Q is, independently,

(a) hydrogen,

3. A compound as in claim 2 wherein B is phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 3 alkoxy, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, cyano, and nitro.

4. A compound as in claim 1 , wherein M is optionally substituted pyridine, quinoline, morpholine, indazole, isoquinoline, pyrimidine, or benzimidazole.

5. A compound as in claim 1 , wherein A is optionally substituted furyl, thienyl, thiadiazolyl, pyrrolyl, pyrazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, quinolyl, indazolyl, benzimidazolyl, phenyl, tetrahydro-4H-benzo [1,3]dioxinyl or naphthyl.

6. A compound as in claim 1 , wherein A is optionally substituted furyl, thienyl, thiadiazolyl, pyrrolyl, pyrazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, indazolyl, benzimidazolyl, phenyl, tetrahydro-4H-benzo [1,3]dioxinyl or naphthyl, and B is optionally substituted phenyl, naphthyl, quinolyl, or pyridyl.

7. A compound as in claim 2 , wherein B is optionally substituted by one or more of methyl, trifluoromethyl, ethyl, n-propyl, n-butyl, n-pentyl, i-propyl, t-butyl, methoxy, ethoxy, propoxy, cyano, nitro, hydroxy, amino, methylamino, dimethylamino, ethylamino or diethylamino.

8. A compound as in claim 1 , wherein A is optionally substituted by one or more of methyl, trifluoromethyl, ethyl, n-propyl, n-butyl, n-pentyl, isopropyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, 4-methyl-phenyl, methoxy, ethoxy, propoxy, Cl, Br, F, cyano, nitro, hydroxy, amino, methylamino, dimethylamino, ethylamino or diethylamino.

9. A compound as in claim 1 , where L is —O— and M is optionally substituted morpholine, pyridine, quinoline, isoquinoline, benzimidazole, indazole, or pyrimidine.

10. A compound as in claim 1 , wherein

A is optionally substituted phenyl or tetrahydro-4H-benzo[1,3]dioxinyl,

B is phenyl or naphthyl,

L is —O—,

and M is optionally substituted pyridine, quinoline, isoquinoline, benzimidazole, indazole, or pyrimidine.

11. A compound as in claim 1 , wherein

A is optionally substituted pyrazolyl,

B is phenyl or naphthyl,

L is —(CH 2 ) m —O—(CH 2 ) l —, and M is morpholine.

12. A compound as in claim 1 ,

wherein A is 2-(4-methyl-phenyl)-5-tert-butyl-2H-pyrazole-3-yl, B is naphthyl, L is —O—(CH 2 ) 2 — and M is morpholine.

13. A compound as in claim 1 , wherein A is 3-trifluoromethyl-4-chloro-phenyl, B is phenyl, L is —O— and M is 2-methylcarbamoyl -pyridine-4-yl.

14. A compound which is:

1-(4-chloro-3(trifluoromethyl)phenyl)-3-(4-(2-(N-methylcarbamoyl)-4-(pyridyloxy)phenyl)-2-oxo-(1,3,5-perhydrotriazapine)

4-{3-fluoro-4-[5-methyl-2-oxo-3-(2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxin-6-yl) -[1,3,5]triazinan-1-yl]-phenoxy}-pyridine-2-carbonitrile or

4-{3-fluoro-4-[5-methyl-2-oxo-3-(2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxin-6-yl) -[1,3,5]triazinan-1-yl]-phenoxy}-pyridine-2-carboxylic acid methylamide.

15. The compound which is 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)-2-oxo-(1,3,5-perhydrotriazapine).

16. A pharmaceutical composition with an effective amount Of one or more compounds of claim 1 and a physiologically acceptable carrier.

17. A method for treating the following condition in humans and/or other mammals: rheumatoid arthritis

comprising administering to a human or other mammal in need thereof a compound of claim claim 1 .

18. A method for treating rheumatoid arthritis, comprising administering the compound 1-(5-tert-butyl-2-(4-methyl-phenyl)-2H-pyrazole-3-yl)-3-[4-(2-morpholinylethoxy)naphthalene-1-yl])-2-oxo-(1,3,5-perhydrotriazapine).

19. A compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein

A of formula I is phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of R 1 , OR 1 , NR 1 R 2 , S(O) p R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 2 , NR 1 C(O)OR 2 , halogen, cyano, and nitro;

B is phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl up to perhalo, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy up to per haloalkoxy, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, cyano, and nitro;

L is —O— or —S—,

M is phenyl, pyridine, quinoline, morpholine, indazole, isoquinoline, pyrimidine, or benzimidazole, optionally substituted with 1-3 substituents independently selected from the group consisting of R 4 , OR 4 , NR 4 R 5 , S(O) q R 4 , SO 2 NR 4 R 5 , C(O)NR 4 R 5 , C(NR 4 )R 5 , NR 4 SO 2 R 5 , C(O)R 4 , C(O)OR 4 , NR 4 C(O)R 5 , NR 4 C(O)OR 5 , halogen, cyano, and nitro;

each R 1 , R 2 , R 4 , R 5 and Q is independently selected from the group consisting of:

(a) hydrogen,

(b) C 1 -C 5 linear, branched, or cyclic alkyl,

(d) C 1 -C 5 linear or branched alkoxy substituted —C 1 -C 5 linear or branched alkyl,

(e) phenyl,

(f) pyridinyl

(g) C 1 -C 3 alkyl-phenyl,

(h) C 1 -C 3 alkyl-pyridinyl or

(i) up to per-halo substituted C 1 -C 5 linear, branched or cyclic alkyl and the variables p and q are integers independently selected from 0, 1, or 2.

20. A compound of claim 19 wherein, M is phenyl or pyridine.

21. A compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein

A of formula I is pyridinyl, optionally substituted with 1-3 substituents independently selected from the group consisting of R 1 , OR, NRR 2 , S(O) p R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 2 , NR 1 C(O)OR 2 , halogen, cyano, and nitro;

L is —O— or —S—,

M is phenyl, pyridine, quinoline, morpholine, indazole, isoquinoline, pyrimidine, or benzimidazole, optionally substituted with 1-3 substituents which independently are R 4 , OR, NRR 5 , S(O) q R 4 , SO 2 NR 4 R 5 , C(O)NR 4 R 5 , C(NR 4 )R 5 , NR 4 SO 2 R 5 , C(O)R 4 , C(O)OR 4 , NR 4 C(O)R 5 , NR 4 C(O)OR 5 , halogen, cyano, or nitro;

each R 1 , R 2 , R 4 , R 5 and Q is independently:

(a) hydrogen,

(b) C 1 -C 5 linear, branched, or cyclic alkyl,

(d) C 1 -C 5 linear or branched alkoxy substituted —C 1 -C 5 linear or branched alkyl,

(e) phenyl,

(f) pyridinyl

(g) C 1 -C 3 alkyl-phenyl,

(h) C 1 -C 3 alkyl-pyridinyl or

(i) up to per-halo substituted C 1 -C 5 linear, branched or cyclic alkyl, each R is independently:

(b) C 1 -C 5 linear, branched, or cyclic alkyl,

(d) C 1 -C 5 linear or branched alkoxy substituted —C 1 -C 5 linear or branched alkyl,

(e) phenyl,

(f) pyridinyl

(g) C 1 -C 3 alkyl-phenyl,

(h) C 1 -C 3 alkyl-pyridinyl or

(i) up to per-halo substituted C 1 -C 5 linear, branched or cyclic alkyl, and the variables p and q are integers independently selected from 0, 1, or 2.

22. A compound of claim 21 wherein M is phenyl or pyridine.

23. A compound of formula I,

or a pharmaceutically acceptable salt thereof,

wherein

A of formula I is pyrazole, optionally substituted with 1-3 substituents independently selected from the group consisting of R 1 , OR 1 , NR 1 R 2 , S(O) p R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 2 , NR 1 C(O)OR 2 , halogen, cyano, and nitro;

B is phenyl or naphthyl, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl up to perhalo, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy up to per haloalkoxy, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, cyano, and nitro;

L is —O—or —S—,

M is phenyl, pyridine, quinoline, morpholine, indazole, isoquinoline, pyrimidine, or benzimidazole, optionally substituted with 1-3 substituents which independently are R 4 , OR 4 , NR 4 R 5 , S(O) q R 4 , SO 2 NR 4 R 5 , C(O)NR 4 R 5 , C(NR 4 )R 5 , NR 4 SO 2 R 5 , C(O)R 4 , C(O)OR 4 , NR 4 C(O)R 5 , NR 4 C(O)OR 5 , halogen, cyano, or nitro;

each R 1 , R 2 , R 4 , R 5 and Q is independently:

(a) hydrogen,

(b) C 1 -C 5 linear, branched, or cyclic alkyl,

(d) C 1 -C 5 linear or branched alkoxy substituted —C 1 -C 5 linear or branched alkyl,

(e) phenyl,

(f) pyridinyl

(g) C 1 -C 3 alkyl-phenyl,

(h) C 1 -C 3 alkyl-pyridinyl or

(i) up to per-halo substituted C 1 -C 5 linear, branched or cyclic alkyl and the variables p and q are integers independently selected from 0, 1, or 2.

24. A compound of claim 23 wherein M is phenyl or pyridine.

25. A compound of formula I,

or a pharmaceutically acceptable salt thereof,

wherein

A is phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of R 1 , OR 1 and halogen;

L is —O—or —S—:

M is pyridinyl, optionally with 1-3 substituents independently selected from the group consisting R 4 , OR 4 , NR 4 R 5 , S(O) q R 4 , SO 2 NR 4 R 5 , C(O)NR 4 R 5 , C(NR 4 )R 5 , NR 4 SO 2 R 5 , C(O)R 4 , C(O)OR 4 , NR 4 C(O)R 5 , NR 4 C(O)OR 5 , halogen, cyano, nitro and oxides;

each R 4 , R 5 and Q is independently :

(a) hydrogen,

(b) C 1 -C 5 linear, branched, or cyclic alkyl,

(d) C 1 -C 5 linear or branched alkoxy substituted —C 1 -C 5 linear or branched alkyl,

(e) phenyl,

(f) pyridinyl,

(g) C 1 -C 3 alkyl-phenyl,

(h) C 1 -C 3 alkyl-pyridinyl or

(i) up to per-halo substituted C 1 -C 5 linear, branched or cyclic alkyl and the variables p and q are integers independently selected from 0, 1, or 2.

26. A compound of formula I,

or a pharmaceutically acceptable salt thereof,

wherein

A is of the formula X:

where A is optionally substituted with 1-4 substituents independently selected from the group consisting of R 1 , OR 1 , NR 1 R 2 , S(O) p R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C(O)R 2 , NR 1 C(O)OR 2 , halogen, cyano, and nitro,

L is —O—or —S—:

M is:

(ii) pyridinyl optionally with 1-3 substituents independently selected from the group consisting R 4 , OR 4 , NR 4 R 5 , S(O) q R 4 , SO 2 NR 4 R 5 , C(O)NR 4 R 5 , C(NR 4 )R 5 , NR 4 SO 2 R 5 , C(O)R 4 , C(O)OR 4 , NR 4 C(O)R 5 , NR 4 C(O)OR 5 , halogen, cyano, nitro and oxides;

where R 4 , R 5 and Q are independently:

(a) hydrogen,

(b) C 1 -C 5 linear, branched, or cyclic alkyl,

(d) C 1 -C 5 linear or branched alkoxy substituted —C 1 -C 5 linear or branched alkyl,

(e) phenyl,

(f) up to per-halo substituted C 1 -C 5 linear, branched or cyclic alkyl, and the variables p and q are integers independently selected from 0, 1, or 2.

27. A pharmaceutical composition with an effective amount of one or more compounds of claim 2 and a physiologically acceptable carrier.

28. A pharmaceutical composition with an effective amount of one or more compounds of claim 19 and a physiologically acceptable carrier.

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 27, 2009

From: BAYER PHARMACEUTICALS CORPORATION

To: BAYER HEALTHCARE LLC

Reel/Frame 023031/0963 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 26, 2008

From: BAYER PHARMACEUTICALS CORPORATION

To: BAYER HEALTHCARE LLC

Reel/Frame 021893/0640 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 19, 2004

From: BOYER, STEPHEN; DUMAS, JACQUES; PHILLIPS, BARTON; SCOTT, WILLIAM J.; SMITH, ROGER A.; CHEN, JIANQING; JONES, BENJAMIN; WANG, GAN

To: BAYER PHARMACEUTICAL CORPORATION

Reel/Frame 015898/0826 →