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Compounds suitable for use as raf kinase inhibitors
Compounds suitable for use as raf kinase inhibitors
IPC classes for russian patent Compounds suitable for use as raf kinase inhibitors (RU 2492166):
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Described are novel chiral cis-imidazolines selected from a group which includes 2-{4-[(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-acetamide, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(1,1-dioxohexahydrothiopyran-4-yl)-piperazin-1-yl]-methanone, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(3-methanesulphonylpropyl)-piperazin-1-yl]-methanone, 2-{4-[(4S,5R)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-N,N-bis-(2-methoxyethyl)-acetamide. 2-{1-[(48;5K)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperidin-4-yl}-acetamide and others described by the general structural formula (I), and pharmaceutical composition containing said compounds.
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Dipeptide prodrugs and use thereof Dipeptide prodrugs and use thereof / 2486183
Application describes prodrugs being 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)-phenyl]pyridine-3,5-dicarbonitryl derivatives, and a method for preparing them.
Method of producing substituted pyrimidin-5-yl carboxylic acids Method of producing substituted pyrimidin-5-yl carboxylic acids / 2485083
Invention relates to a method of producing substituted pyrimidin-5-yl carboxylic acids of formula I and can be used in organic chemistry. The method is realised by reacting N-substituted guanidines and hetarylamidines with ethoxymethylene derivatives of 1,3-ketoesters according to a scheme given below (where the substitutes are as defined in the claim).
Adrenergic compounds Adrenergic compounds / 2491284
Invention relates to compounds, which represent (4,5-dihydrooxazol-2-yl)-(5,6,7,8-tetrahydroquinoxylan-5-yl)-amino and (4,5-dihydrooxazol-2-yl(-(5,6,7,8-tetrahydroquinolin-5-yl)-amino or their pharmaceutically acceptable salt. Said compounds are applied in methods of intraocular pressure reduction and treatment of pain in mammals who require it.

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula 1:

or pharmaceutically acceptable salts thereof, where values of Cy1; Cy2; L1; L2, R; R1; Rx and Ry and R2 are given in claim 1.

EFFECT: compounds are suitable for use as Raf protein kinase inhibitors.

36 cl, 6 tbl

 

The text descriptions are given in facsimile form.

The compound of the formula I

or pharmaceutically acceptable salt of the compounds,
where Cy1represents phenyl or 5-6-membered aromatic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Cy represents a 5 to 14-membered saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic ring containing 0 to 4 heteroatoms, independently selected from nitrogen or oxygen, where the specified ring may be mono - or disubstituted with groups independently selected from halogen, -CF3With1-4the alkyl and 1-methylcyclopropyl;
L1represents a direct bond or linear or branched alkylenes chain With1-6;
L2represents a direct bond or linear or branched alkylenes chain With1-6while one or two methylene link in the group L2can be independently replaced by-N(R)-, -C(O)-, -C(O)N(R) -, or-N(R)C(O)-;
each group R independently represents hydrogen or an aliphatic group C1-6;
R1represents hydrogen or an aliphatic group C1-6;
each of Rxand Ryindependently selected from the following groups: -R2, -halogen, -CN, -OR2, -SR2, -N(R2)2, -CO2R2, -C(O)N(R2)2, -N(R2)C(O)R2, -N(R2)N(R2)2, -N(R2)SO2N(R2)2, -NH2CH2CH2N(CH3)2or-N(R2)SO2R2: and
each R2independently represents hydrogen or a group selected from the following groups of aliphatic C 1-6, monocyclic or bicyclic aryl rings6-10or 5-10-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring, containing from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or
two groups of R2at the same nitrogen atom together with the indicated nitrogen atom form a 5-8-membered saturated, partially unsaturated or aromatic ring containing from 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

2. The compound according to claim 1, in which each of Rxand Ryindependently selected from the following groups: R2, halogen, -OR2, -N(R2)2, -N(R2)C(O)R2, -N(R2)N(R2)2, -N(R2)SO2N(R2)2or-N(R2)SO2R2.

3. The compound according to claim 2, in which Rxrepresents hydrogen, an aliphatic group, a C1-6or halogen.

4. The compound according to claim 2, in which Ryselected from R2, -OR2or-N(R2)2.

5. The compound according to claim 4, in which Ryrepresents-NH2, -NH3, -NHCH2CH3, -N2CH2CH3, -NH(CH3)2, -NH(C3H5), -NHCH2CH2CH2OH, -N(CH2CH2)2O or-N2CH2CH2N(CH3)2 .

6. The compound according to claim 4, in which Ryrepresents an aliphatic group1-6.

7. The connection according to claim 6, in which Ryrepresents a group selected from C2-6alkenylphenol or2-6alkenylphenol group.

8. The compound according to claim 4, in which Ryis a 5-10-membered saturated monocyclic or bicyclic ring, containing from 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

9. The connection of claim 8, in which Ryrepresents a group chosen from:
(a) a 5-6-membered saturated monocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
(b) a 5-6-membered aromatic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
(c) an 8-10 membered saturated, partially unsaturated or aromatic bicyclic ring containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

10. The connection of claim 8, in which Ryrepresents a group selected from phenyl, octahydrate, citicapital, thiacyclohexane, pyrrolidinyl, piperidinyl, piperazinil, tetrahydrothiopyran, tetrahydrothiophene, dithiolane, tetrahydrofuranyl, tetrahydropyranyl, dioxane, dioxane, morpholine oxathiolane, imidazolidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiophenyl, furanyl, thiazolyl, isothiazoline, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, piratininga, pyridazinyl, triazinyl, tetrazine, tetrahydropyridine, benzofuranyl, tianeptine, pyrrolidinyl, indolyl, chinoline, izochinolina, benzimidazolyl, imidazopyridine, purinol, indazole, pyrrolopyridine, cinnoline, heatline, phthalazine, naphthyridine or khinoksalinona.

11. The compound according to claim 1, in which R1represents hydrogen, a L1represents a linear or branched alkylenes chain C1-4.

12. Connection by claim 11, in which L1represents a branched alkylenes chain With1-4.

13. The compound according to claim 1, in which Cy1represents a 5-membered aromatic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

14. The connection 13, in which Cy1represents pyrrolidino, pyrazolidine, imidazolidine, triazoline, tetrazolyl, tiffaniejoy, fornillo, thiazolidine, isothiazolinone, thiadiazolidine, oxazolidinyl, isoxazolyl or oxadiazolyl group.

15. The compound according to claim 1, in which L2represents a direct bond and a is linear or branched alkylenes chain With 1-4while one or two methylene link in the group L2substituted with-N(R)- or-C(O)N(R).

16. The connection indicated in paragraph 15, in which L2represents-C(O)N(R).

17. Connection P16, where L2represents-C(O)N(H)-.

18. The compound according to claim 1, in which Cy2represents a group chosen from:
(a) a 5-membered saturated, partially unsaturated or aromatic monocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen or oxygen;
(b) phenyl or 6-membered saturated, partially unsaturated or aromatic monocyclic ring containing 1 to 4 nitrogen atoms; or
(c) a 5-10 membered saturated, partially unsaturated or aromatic bicyclic ring containing 1 to 4 nitrogen atoms;
where the specified cyclic Deputy may be mono - or disubstituted with groups independently selected from halogen, -CF3With1-4the alkyl and 1-methylcyclopropyl.

19. Connection p in which Cy2represents a group chosen from:
(a) a 5-membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from nitrogen or oxygen;
(b) phenyl or 6-membered heteroaryl ring containing 1 to 3 nitrogen atoms; or
(c) 5,6-condensed bicyclic heteroaryl cycle containing the t 1 to 4 nitrogen atoms,
where the specified cyclic Deputy may be mono - or disubstituted with groups independently selected from halogen, -CF3With1-4the alkyl and 1-methylcyclopropyl.

20. The connection according to claim 19, in which Cy2represents a group selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazine, pyrrolidinyl, indolyl, chinoline, izochinolina, benzimidazolyl, imidazopyridine, indazole, purine, cinnoline, hypotonia, phthalazine, natricinae, khinoksalinona, tianeptine or benzofuranyl;
where the specified cyclic Deputy may be mono - or disubstituted with groups independently selected from halogen, -CF3With1-4the alkyl and 1-methylcyclopropyl.

21. The compound according to claim 1, characterized in that the said compound is a compound of formula II

or pharmaceutically acceptable salt of the compounds.

22. Connection item 21, characterized in that the said compound is a compound of formula II-a or II-b

23. Connection p.22, in which Cy1represents a 5-membered heteroaryl ring, with the holding from 1 to 3 heteroatoms, independently selected from nitrogen, oxygen or sulfur.

24. A compound selected from the following compounds:




























































































































































































































































































































































































































or pharmaceutically acceptable salts of such compounds.

25. A method of inhibiting the activity of Raf kinase in a patient or in a biological sample, comprising the introduction of a specified patient connection according to claim 1 or the pharmaceutical compositions of the compounds or the conversion of a specified biological sample into contact with a compound according to claim 1 or a pharmaceutical composition of the compounds.

26. A method of treating or reducing the severity of the violation, mediated Raf, a mammal suffering from or to such breach, and the breach is selected from proliferative disorders, cardiac abnormalities, neurodegenerative disorders, autoimmune disorders, conditions associated with organ transplantation, inflammatory disorders, and immunologically mediated disorders, viral diseases or lesions of the bones, with the specified method includes the step of introducing a specified patient connection according to claim 1 or pharmaceutical composition based on the specified connection.

27. The method according to p in which the breach is selected from melanoma, leukemia, colon cancer, breast cancer, cancer of jeludochno-intestinal tract, ovarian cancer, lung cancer, brain cancer, larynx cancer, cervical cancer, kidney cancer, cancer of the lymphatic system, cancer of the genitourinary tract (including bladder cancer and prostate cancer), gastric cancer, bone cancer, lymphoma, melanoma, glioma, papillary thyroid cancer, neuroblastoma, and pancreatic cancer.

28. The method of obtaining the compounds of formula II-a'

or pharmaceutically acceptable salts of the compounds,
where Cy1is a 5-6-membered aromatic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Cy2represents a 5-10 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring containing 0 to 4 heteroatoms, independently selected from nitrogen or oxygen, where the specified ring may be mono - or disubstituted with groups independently selected from halogen, -CF3With1-4the alkyl and 1-methylcyclopropyl;
each of the groups Rxand Ryindependently selected from R2, -halogen, -CN, -OR2, -SR2, -N(R2)2, -CO2R2, -C(O)N(R2)2, -N(R2)C(O)R2, -N(R2)N(R2)2, -N(R2)SO2N(R2)2or-N(R2)SO2R2;
each group R2n is dependent represents hydrogen or the group selected from the following groups: aliphatic group C1-6, monocyclic or bicyclic aryl rings6-10or 5-10-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring, containing from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two groups R2at the same nitrogen atom together with the indicated nitrogen atom form a 5-8-membered saturated, partially unsaturated or aromatic ring containing from 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, comprising the stage of the reaction of a combination of compounds of formula II-viii

with a compound of formula II-vii

with the formation of the compounds of formula II-a'.

29. The method according to p, in which the compound of formula II-vii are obtained from the compounds of formula II-vi-b

where a' represents a suitable chiral anion,
including the stage of processing the compounds of formula II-vi-b with a suitable base to form compounds of formula II-vii.

30. The method according to clause 29, in which the compound of formula II-vi-b are obtained from the compounds of formula II-v

includes the following stages:
(a) treating the compounds of formula II-v chiral agent with the formation with the organisations of the formula II-vi-a

and
(b) separating the received diastereomers using appropriate physical methods
obtaining the compounds of formula II-vi-b.

31. The method according to item 30, in which the compound of formula II-v

obtained from the compounds of formula II-iv

including phase transformations Aksenovo fragment of formula II-iv in the amino group of the formula II-v.

32. The method according to p, in which the compound of formula II-iv are obtained from the compounds of formula II-iii

including the stage of processing the compounds of formula II with hydroxylamine to form compounds of formula II-iv.

33. The method according to p, in which the compound of formula II is obtained by implementation of a combination of compounds of formula II-i

with a compound of formula II-ii

34. A compound selected from

and

35. The compound of formula II-iv

in which Cy1is a 5-6-membered saturated, partially unsaturated or aromatic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
Cy2represents a 5-10 membered saturated, partially n is saturated or aromatic monosilicide or bicyclic ring, containing 0 to 4 heteroatoms, independently selected from nitrogen or oxygen, where the specified ring may be mono - or disubstituted with groups independently selected from halogen, -CF3With1-4the alkyl and 1-methylcyclopropyl.

36. The compound according to claim 1 the following formula:

or its pharmaceutically acceptable salt.

 
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