RU2011103189A

RU2011103189A - OXINDOL DERIVATIVES

Info

Publication number: RU2011103189A
Application number: RU2011103189/04A
Authority: RU
Inventors: Мустафа ХАДДАХ (US); Мустафа ХАДДАХ; Джонни Ясуо НАГАСАВА (US); Джонни Ясуо НАГАСАВА
Original assignee: Силин Фармасьютикалз, Инк. (Us); Силин Фармасьютикалз, Инк.
Priority date: 2008-06-30
Filing date: 2009-06-30
Publication date: 2012-08-10

Abstract

1. Соединение формулы (I) !! где R1 выбирают из H, алкила, замещенного алкила, -SO2NR2 и -C(=O)R; ! R2 выбирают из H, D, алкила и замещенного алкила; ! Y1 представляет собой O или S; ! Y2 представляет собой O, S или NR1; ! каждый X1, X2 и X3 выбирают независимо из галогена, CN, CF3, NO2, алкила, замещенного алкила, OR и NR2, COR, CONR, SOqR, NSOqR, NRCONR и NRC(O)OR; ! m, n и p, каждый независимо, равны 0, 1 или 2; ! W1, W2 и W3 представляют собой каждый независимо C или N, где каждый C замещен H или X3 или Ar, при условии, что или W2 или W3 является точкой присоединения для Ar; ! Ar представляет собой 5-10-членную ароматическую или гетероароматическую группу, которая необязательно замещена (X2)n; ! A выбирают из группы, состоящей из CH2Q, -O-Z, -NRZ, SOqZ, SOqNRZ, NRSOqZ, NR-C(O)Z, NRC(O)-OZ, NRC(O)-NRZ, OC(O)NRZ, -C(=O)OZ и -C(=O)NRZ, ! где Z представляет собой H, алкил, замещенный алкил, гетероциклил, замещенный гетероциклил, арил или замещенный арил, ! и Q представляет собой OZ или NRZ; ! R при каждом появлении выбирают независимо из группы, состоящей из H, алкила или замещенного алкила, и два R в NR2 могут замыкаться в цикл с образованием 5-7-членного цикла, который может быть замещенным и может необязательно содержать в качестве члена цикла один дополнительный гетероатом, выбранный из N, O и S, ! и R и Z, когда присутствуют оба у A или Q, могут необязательно замыкаться в цикл с образованием 5-7-членного цикла, который может быть замещенным и может включать в качестве члена цикла дополнительный O, N или S; и ! каждый q равен независимо 0, 1 или 2; ! или его фармацевтически приемлемая соль. ! 2. Соединение по п.1, где Y1 представляет собой O. ! 3. Соединение по п.1, где R1 представляет собой H или Me. ! 4. Соединение по п.1, где R2 представляет собой H, D, Me, Et, циклопропил, изопропил или CH2OH. 1. The compound of formula (I) !! where R1 is selected from H, alkyl, substituted alkyl, —SO2NR2, and —C (= O) R; ! R2 is selected from H, D, alkyl, and substituted alkyl; ! Y1 represents O or S; ! Y2 represents O, S or NR1; ! each X1, X2 and X3 are independently selected from halogen, CN, CF3, NO2, alkyl, substituted alkyl, OR and NR2, COR, CONR, SOqR, NSOqR, NRCONR and NRC (O) OR; ! m, n and p, each independently, are 0, 1 or 2; ! W1, W2 and W3 are each independently C or N, where each C is substituted with H or X3 or Ar, provided that either W2 or W3 is an attachment point for Ar; ! Ar is a 5-10 membered aromatic or heteroaromatic group which is optionally substituted with (X2) n; ! A is selected from the group consisting of CH2Q, -OZ, -NRZ, SOqZ, SOqNRZ, NRSOqZ, NR-C (O) Z, NRC (O) -OZ, NRC (O) -NRZ, OC (O) NRZ, - C (= O) OZ and -C (= O) NRZ,! where Z is H, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, aryl or substituted aryl,! and Q represents OZ or NRZ; ! R at each occurrence is independently selected from the group consisting of H, alkyl or substituted alkyl, and two R in NR2 may be closed in a cycle to form a 5-7 membered ring, which may be substituted and may optionally contain one additional member of the cycle heteroatom selected from N, O and S,! and R and Z, when both are present on A or Q, may optionally be locked into a cycle to form a 5-7 membered cycle, which may be substituted and may include additional O, N or S as a member of the cycle; and! each q is independently 0, 1, or 2; ! or a pharmaceutically acceptable salt thereof. ! 2. The compound according to claim 1, where Y1 is O.! 3. The compound according to claim 1, where R1 represents H or Me. ! 4. The compound according to claim 1, where R2 is H, D, Me, Et, cyclopropyl, isopropyl or CH2OH.

Claims

1. The compound of formula (I)

where R ^{1 is} selected from H, alkyl, substituted alkyl, —SO ₂ NR ₂ and —C (= O) R;

R ² selected from H, D, alkyl and substituted alkyl;

Y ¹ represents O or S;

Y ² represents O, S or NR ¹ ;

each X ¹ , X ² and X ³ are independently selected from halogen, CN, CF ₃ , NO ₂ , alkyl, substituted alkyl, OR and NR ₂ , COR, CONR, SO _q R, NSO _q R, NRCONR and NRC (O) OR;

m, n and p, each independently, are 0, 1 or 2;

W ¹ , W ² and W ³ are each independently C or N, where each C is substituted with H or X ³ or Ar, provided that either W ² or W ³ is an attachment point for Ar;

Ar is a 5-10 membered aromatic or heteroaromatic group which is optionally substituted with (X ² ) _n ;

A is selected from the group consisting of CH ₂ Q, -OZ, -NRZ, SO _q Z, SO _q NRZ, NRSO _q Z, NR-C (O) Z, NRC (O) -OZ, NRC (O) -NRZ , OC (O) NRZ, -C (= O) OZ and -C (= O) NRZ,

where Z represents H, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, aryl or substituted aryl,

and Q represents OZ or NRZ;

R at each occurrence is independently selected from the group consisting of H, alkyl or substituted alkyl, and two R in NR ₂ may be closed in a loop to form a 5-7 membered ring, which may be substituted and may optionally contain one as a member of the cycle additional heteroatom selected from N, O and S,

and R and Z, when both are present on A or Q, may optionally be locked into a cycle to form a 5-7 membered cycle, which may be substituted and may include additional O, N or S as a member of the cycle; and

each q is independently 0, 1, or 2;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, where Y ¹ represents O.

3. The compound according to claim 1, where R ¹ represents H or Me.

4. The compound according to claim 1, where R ² represents H, D, Me, Et, cyclopropyl, isopropyl or CH ₂ OH.

5. The compound according to claim 1, where W ¹ and W ² are each independently CH or CMe.

6. The compound according to claim 1, where m is 1, and X ¹ represents a halogen.

7. The compound according to claim 1, where W ³ is the point of attachment for Ar.

8. The compound according to claim 1, where W ² is the point of attachment for Ar.

9. The compound according to claim 1, where Ar represents phenyl or pyridyl, each of which may be substituted.

10. The compound according to claim 9, where Ar is substituted, in addition to A, by another group selected from halogen, amino, alkyl and hydroxyl.

11. The compound according to claim 1, where A is —NR-C (O) Z or —C (= O) NRZ, where R is H or Me, or where R and Z may optionally be looped to form 5 -7 member cycle, which may be substituted and may include an additional heteroatom O, N or S. as a member of the cycle

12. The compound according to claim 11, where Z is a group of the formula - (CH ₂ ) _r Z ', where r is 0, 1, 2, 3 or 4, and Z' is —NR ¹ R ² or 5-6 a membered heteroaryl or heterocyclic group containing at least one N as a member of the ring, and which is optionally substituted.

13. The compound according to claim 1, which is a compound of formula (II)

where A, R ¹ , R ² , X ¹ , X ² , X ³ , m, n and p have the meanings indicated for formula (I),

and each of Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ is independently C or N, provided that no more than two of Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ are N, and where each C represents CH or CX ² or is an attachment point for A;

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13, wherein A is —C (═O) —NRZ or —NRC (O) Z, where R is H or Me, or where R and Z may optionally ring to form 5- 7 of the member cycle, which may be substituted and may include an additional heteroatom O, N or S. as a member of the cycle

15. The compound of claim 13, wherein m is 1 and X ¹ is halogen.

16. The compound according to item 13, where Z ³ represent CA.

17. The compound according to item 13, where Z ⁴ represent CA.

18. The compound according to claim 1, which is a compound of formula (III)

where X ¹ represents Cl or F, and m is 0 or 1;

X ² represents halogen, NH ₂ , OH or CH ₂ OH, and n is 0 or 1;

X ³ represents Me, and p is 0 or 1;

R ² represents H, D, Me, Et, cyclopropyl, isopropyl or CH ₂ OH;

one of Z ³ and Z ⁴ represents CH, and the other of Z ³ and Z ⁴ represents CA;

Z ⁵ represents N or CH, or Z ⁵ may represent CX if n is 1;

R ¹ represents H or —C (O) R;

A represents COOH, OH, CH ₂ OH, NH ₂ , CONH ₂ , -SO ₂ NH ₂ , -NHSO ₂ CF ₃ , tetrazole or a group of the formula-L-Az, where L is a linker selected from the group consisting of -NR-, -C (O) -, -O-, -NRC (O) -, -C (O) NR-, -NRSO ₂ -, -SO ₂ NR-, -NRC (O) - (CH ₂ ) _r - and -C (O) NR- (CH ₂ ) _r -, where each r is independently 1-3;

each R is independently H, alkyl or substituted alkyl; and

Az is a 5-7 membered nitrogen-containing heterocyclic or heteroaryl group;

or a pharmaceutically acceptable salt thereof.

19. The compound of formula (IIIa)

where m is equal to 1, and X ¹ represents Cl or F;

X ^{2 is} selected from H, Cl, OH, OMe, NH ₂ , NHMe, Me, and F;

R ² represents H, D or Me; and

R represents H, Me, Et or isopropyl;

or a pharmaceutically acceptable salt thereof.

20. The compound of formula (IV)

R ² selected from H, D, alkyl and substituted alkyl;

R ^{3 is} selected from H, D, F, OH, alkyl, and substituted alkyl;

Y ¹ represents O or S;

Y ² represents O, S or NR ¹ ;

m, n and p, each independently, are 0, 1 or 2;

and Q represents OZ or NRZ;

and R and Z, when both are present at A or Q, may optionally be locked into a cycle to form a 5-7 membered ring, which may be substituted and may include an additional O, N or S heteroatom as a member of the cycle; and

each q is, independently, 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 1 in a mixture with at least one pharmaceutically acceptable excipient.

22. A method of treating cancer, comprising administering to a subject in need of cancer treatment an effective amount of a compound of formula (I) according to claim 1.

23. The method of claim 22, wherein the cancer is selected from the group consisting of colon cancer, pancreatic cancer, prostate cancer, and leukemia.

24. The method according to item 23, where the leukemia is acute myeloid leukemia (AML).

25. The method according to paragraph 24, where the leukemia is a refractory AML or where AML is associated with mutated Flt3.

26. A method of treating inflammation, comprising administering to a subject in need of such treatment an effective amount of a compound of formula (I) according to claim 1.