Fused bicyclic (hetero)aromatic compounds useful for the treatment of cancers
This invention relates to novel compounds. The compounds of the invention are kinase inhibitors. Specifically, the compounds of the invention are useful as inhibitors of Raf kinases, e.g., B-Raf and C-Raf. The invention also contemplates the use of the compounds for treating conditions treatable by the inhibition of Raf kinases, for example, cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, and leukemia.
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof;
wherein:
the bond between Y and Z is a single bond or a double bond;
A is a phenyl ring;
R 1 is a substituted or unsubstituted heterocyclic moiety which either contains 5 or 6 atoms in a single ring or 8, 9, 10 or 11 atoms in a fused bicyclic ring system, when substituted R 1 contains 1 to 4 substituents independently selected from the group consisting of halo, —OR A , —NR A R B , ═O, —OC(O)R C , —C(O) R C , —C(O)OR A , —NR A C(O)R C , —C(O)NR A R B , —SO 2 R C , —SOR C , —NR A SO 2 R C , —SO 2 NR A R B , —CN, C 1-4 alkyl, C 1-4 haloalkyl and C 3-6 cycloalkyl;
X is O;
Y is —CHW and the bond between Y and Z is a single bond; or Y is —CW and the bond between Y and Z is a double bond;
W represents -het 1 -R 3 or -het 2 , in which het 1 is an optionally further substituted five or six membered cycloalkyl ring or heterocyclic ring, and het 2 is a carbocyclic or heterocyclic ring system containing 8, 9 or 10 atoms in a fused bicyclic ring system; in which het 2 is unsubstituted or substituted; and het 1 , when further substituted, and het 2 when substituted contain 1 or 2 substituents independently selected at each occurrence from halo, —OR A , —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, in which the aforementioned alkyl, haloalkyl and cycloalkyl groups are themselves unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of —OR A , —CN, and —NR A R B ;
Z is O, or —CH 2 and the bond between Y and Z is a single bond: or Z is —CH and the bond between Y and Z is a double bond;
R 2A is selected from the group consisting of H, halo, —OR A , —CN, C 1-4 alkyl, C 1-4 haloalkyl and C 3-6 cycloalkyl;
R 3 is selected from the group consisting of substituted or unsubstituted: C 1-6 alkyl, C 1-6 haloalkyl, a carbocyclic moiety or a heterocyclic moiety, wherein the carbocyclic moiety and heterocyclic moiety either contain 5 or 6 atoms in a single ring or 8, 9 or 10 atoms in a fused bicyclic ring system, and when substituted R 3 contains 1 to 4 substituents independently selected from the group consisting of halo, —OR A , —NR A R B , —SO 2 R C , —SOR C , CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl in which the aforementioned alkyl, haloalkyl and cycloalkyl groups are themselves unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of —OR A , —CN, —SOR C and —NR A R B ;
R A and R B are each independently selected from the group consisting of H, C 1-4 alkyl and C 1-4 haloalkyl; and
R C is selected from the group consisting of C 1-4 alkyl and C 1-4 haloalkyl.
2. The compound of claim 1 , wherein Z is O; and Y is —CHW.
3. The compound of claim 1 , wherein Z is —CH 2 ; and Y is —CHW.
4. The compound of claim 1 , wherein Z is —CH; and Y is —CW.
5. The compound of claim 1 , wherein R 1 is a substituted or unsubstituted heterocyclic moiety which either contains 6 atoms in a single ring or 10 atoms in a fused bicyclic ring system.
6. The compound of claim 1 , wherein R 1 is selected from the group consisting of substituted or unsubstituted: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, quinolinone-yl, tetrahydroquinolinone-yl, dihydroquinolinone-yl, isoquinolinyl, tetrahydroisoquinolinyl, dihydroisoquinolinyl, isoquinolinoneyl, tetrahydroisoquinolinone-yl, dihydroisoquinolinone-yl, napthyridinyl, oxo-napthyridinyl, dihydronappthyridinyl, tetrahydronaphthyridinyl, oxo-tetrahydronaphthyridinyl, and oxo-dihydro-H-naphthyridinyl.
7. The compound of claim 6 , wherein R 1 is substituted or unsubstituted pyridyl or substituted or unsubstituted oxodihydro-H-naphthyridinyl.
8. The compound of claim 1 , wherein
W represents -het 1 -R 3 or -het 2 , wherein het 1 is represented by a group selected from the group consisting of substituted or unsubstituted: C 5-6 cycloalkyl, C 5-6 heterocycloalkyl and C 5-6 heteroaryl, and
het 2 is represented by a group selected from the group consisting of substituted or unsubstituted: C 8-10 cycloalkyl, C 10 aryl, C 8-10 heterocycloalkyl and C 8-10 heteroaryl.
9. The compound of claim 1 , wherein het 1 is represented by substituted or unsubstituted: pyrazole, imidazole or oxadiazole; and het 2 is represented by substituted or unsubstituted benzimidazole.
10. The compound of claim 1 , wherein R 3 is selected from the group consisting of C 1-6 alkyl, a substituted or unsubstituted carbocyclic moiety or a substituted or unsubstituted heterocyclic moiety, wherein the carbocyclic moiety and heterocyclic moiety either contain 5 or 6 atoms in a single aromatic ring or 8, 9 or 10 atoms in a fused bicyclic ring system, wherein one ring of the bicyclic ring system is aromatic.
11. The compound of claim 10 , wherein R 3 is selected from the group consisting of a substituted or unsubstituted: iso-propyl, tert-butyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, indolinyl, isoindolinyl, benzodioxanyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, benzodioxolanyl, indazolyl, indazolinyl, benzimidazolyl, benzimidazolinyl, benzthiazolyl, benzoisothiazol, chromanyl, isochromanyl, tetralinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and tetrahydroquinoxalinyl.
12. The compound of claim 1 , wherein R A and R B are each independently H, methyl, ethyl or trifluoromethyl; and R C is methyl, ethyl or trifluoromethyl.
13. The compound of claim 12 , wherein R A and R B are H; R A and R B are methyl; or R A is H and R B is methyl and R C is methyl.
14. The compound of claim 1 , wherein the compound of formula (I) is selected from the group consisting of:
15. The compound of claim 14 , wherein a * symbol indicates a chiral centre; and the chiral centre relates to a single enantiomer that has either a (R)-configuration or a (S)-configuration.
16. The compound of claim 1 , wherein the compound is a pharmaceutically acceptable salt thereof.
17. A method of treatment of a condition which is modulated by RAF kinases, wherein the condition is selected from the group consisting of cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma and leukemia, wherein the method comprises administering to a patient in need thereof a therapeutic amount of a compound of formula (I):
wherein:
the bond between Y and Z is a single bond or a double bond;
A is a phenyl ring;
R 1 is a substituted or unsubstituted heterocyclic moiety which either contains 5 or 6 atoms in a single ring or 8, 9, 10 or 11 atoms in a fused bicyclic ring system, when substituted R 1 contains 1 to 4 substituents independently selected from the group consisting of halo, —OR A , —NR A R B , ═O, —OC(O)R C , —C(O)R C , —C(O)OR A , —NR A C(O)R C , —C(O)NR A R B , —SO 2 R C , —SOR C , —NR A SO 2 R C , —SO 2 NR A R B , —CN, C 1-4 alkyl, C 1-4 haloalkyl and C 3-6 cycloalkyl;
X is O;
Y is —CHW and the bond between Y and Z is a single bond; or Y is —CW and the bond between Y and Z is a double bond;
W represents -het 1 -R 3 or -het 2 , in which het 1 is an optionally further substituted five or six membered cycloalkyl ring or heterocyclic ring, and het 2 is a carbocyclic or heterocyclic ring system containing 8, 9 or 10 atoms in a fused bicyclic ring system; in which het 2 is unsubstituted or substituted; and het 1 , when further substituted, and het 2 when substituted contain 1 or 2 substituents independently selected at each occurrence from halo, —OR A , —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, in which the aforementioned alkyl, haloalkyl and cycloalkyl groups are themselves unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of —OR A , —CN, and —NR A R B ;
Z is O, or —CH 2 and the bond between Y and Z is a single bond: or Z is —CH and the bond between Y and Z is a double bond;
R 2A is selected from the group consisting of H, halo, —OR A , —CN, C 1-4 alkyl, C 1-4 haloalkyl and C 3-6 cycloalkyl;
R 3 is selected from the group consisting of substituted or unsubstituted: C 1-6 alkyl, C 1-6 haloalkyl, a carbocyclic moiety or a heterocyclic moiety, wherein the carbocyclic moiety and heterocyclic moiety either contain 5 or 6 atoms in a single ring or 8, 9 or 10 atoms in a fused bicyclic ring system, and when substituted R 3 contains 1 to 4 substituents independently selected from the group consisting of halo, —OR A , —NR A R B , —SO 2 R C , —SOR C , —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl in which the aforementioned alkyl, haloalkyl and cycloalkyl groups are themselves unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of —OR A , —CN, —SOR C and —NR A R B ;
R A and R B are each independently selected from H, C 1-4 alkyl and C 1-4 haloalkyl; and
R C is selected from C 1-4 alkyl and C 1-4 haloalkyl.
18. The method of claim 17 , wherein the condition treatable by the inhibition of Raf kinases is the group consisting of Barret's adenocarcinoma; biliary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors; primary CNS tumors; glioblastomas, astrocytomas; glioblastoma multiforme; ependymomas; seconday CNS tumors (metastases to the central nervous system of tumors originating outside of the central nervous system); brain tumors; brain metastases; colorectal cancer; large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck; squamous cell carcinoma of the head and neck; acute lymphoblastic leukemia; acute myelogenous leukemia (AML); myelodysplastic syndromes; chronic myelogenous leukemia; Hodgkin's lymphoma; non-Hodgkin's lymphoma; megakaryoblastic leukemia; multiple myeloma; erythroleukemia; hepatocellular carcinoma; lung cancer; small cell lung cancer; non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; metastatic melanoma and thyroid cancers.
19. The method of claim 17 , wherein the condition is colorectal cancer or melanoma.
20. The method of claim 17 , further comprising administering simultaneously, sequentially or separately a therapeutic amount of an anti-tumour agent.
21. A pharmaceutical composition, wherein the composition comprises a compound of claim 1 ; and one or more pharmaceutically acceptable excipients.
22. The compound of claim 1, wherein the compound of formula (I) is
23. The compound of claim 1, wherein the compound of formula (I) is
24. The compound of claim 1, wherein the compound of formula (I) is