USRE49361E1 - Fused bicyclic (hetero)aromatic compounds useful for the treatment of cancers - Google Patents

Fused bicyclic (hetero)aromatic compounds useful for the treatment of cancers Download PDF

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USRE49361E1
USRE49361E1 US17/102,621 US201517102621A USRE49361E US RE49361 E1 USRE49361 E1 US RE49361E1 US 201517102621 A US201517102621 A US 201517102621A US RE49361 E USRE49361 E US RE49361E
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Matilda Bingham
Richard Testar
Camille Gignoux
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Jazz Pharmaceuticals Ireland Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • This invention relates to compounds. More specifically, the invention relates to compounds useful as kinase inhibitors, for example RAF kinases such as B-RAF and C-RAF. In addition the invention contemplates processes to prepare the compounds and uses of the compounds.
  • RAF kinases such as B-RAF and C-RAF.
  • the invention contemplates processes to prepare the compounds and uses of the compounds.
  • kinases are a class of enzyme that control the transfer of phosphate groups from phosphate donors, for example ATP, to specific substrates. Protein kinases are a subset of kinases and serine/threonine-protein kinase B-RAF is one such protein kinase. Serine/threonine-protein kinase B-RAF is more commonly known as B-RAF and throughout this application these two terms will be used interchangeably.
  • B-RAF is a member of the RAF kinase family, the other members of the family being A-RAF and C-RAF.
  • Each of the RAF kinases is a serine/threonine-specific protein kinase, an enzyme that phosphorylates the hydroxyl group of serine or threonine residues within a protein.
  • the RAF kinases are involved in the mitogen-activated protein kinase (MAPK) cascade, a key pathway involved in internal cell signalling responsible for cell division, cell proliferation, programmed cell death (apoptosis), cell differentiation, and embryonic development.
  • MAPK mitogen-activated protein kinase
  • Defects in the MAPK pathway can affect the signalling within a cell and can lead to uncontrolled cell growth through deviant cell division and irregular cell death.
  • defects in the MAPK pathway can be caused by mutations to the RAF kinases or aberrant expression of the RAF kinases, as such abnormalities associated with the RAF kinases, such as the known mutation B-RAF V600E can give rise to uncontrolled cell growth and consequently cancer.
  • Dabrafenib is a B-RAF inhibitor indicated in the treatment of malignant melanoma and marketed by GlaxoSmithKline. Dabrafenib was approved for the treatment of malignant melanoma in May 2013 by the US FDA. Similarly, in August 2011 vemurafenib was approved for the treatment of melanoma by the US FDA. As with dabrafenib, vemurafenib is a B-RAF inhibitor, specifically of the B-RAF V600E mutation.
  • RAF inhibitors such as dabrafenib and vemurafenib have been approved for the treatment of unresectable and metastatic B-RAF-mutant melanoma, but these agents lack efficacy in B-RAF-mutant colorectal cancer (CRC), partly because of EGFR-mediated feedback reactivation of the MAPK pathway.
  • CRC B-RAF-mutant colorectal cancer
  • RAF inhibitor treatment of RAS-mutant, B-RAF WT -melanomas has been associated with other skin cancers, such as cutaneous squamous cell carcinoma due to MAPK pathway paradoxical activation. There is therefore a clinical need for novel agents targeting the MAPK pathway that do not have the undesirable properties of EGFR-mediated feedback reactivation of the MAPK pathway and MAPK pathway paradoxical activation.
  • B-RAF inhibitors have also been disclosed in WO 2012/016993, WO 2011/085269, WO 2011/025927, WO 2011/092088 and WO 2011/023773, for example.
  • Certain embodiments of this invention aim to provide for compounds which are suitable for the treatment of cancers which have been identified as containing a mutation of the BRAF kinase, for example human melanomas, thyroid cancer, Barret's adenocarcinoma, biliary tract carcinomas, breast cancer, cervical cancer, cholangiocarcinoma, central nervous system tumors, glioblastomas, astrocytomas, ependymomas, colorectal cancer, large intestine colon cancer, gastric cancer, carcinoma of the head and neck, hematologic cancers, leukaemia, acute lymphoblastic leukaemia, myelodysplastic syndromes, chronic myelogenous leukaemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukaemia, multiple myeloma, hepatocellular carcinoma, lung cancer, ovarian cancer, pancreatic cancer, pituitary adenoma
  • Certain embodiments of this invention aim to provide for compounds which are suitable for the treatment of cancers which have been identified as containing the BRAF V600E mutation.
  • BRAF V600E melanoma BRAF V600 E colorectal cancer, BRAF V600E papillary thyroid cancers, BRAF V600E low grade serous ovarian cancers, BRAF V600E glioma, BRAF V600E hepatobiliary cancers, BRAF V600E hairy cell leukaemia, BRAF V600E non-small cell cancer, and BRAF V600E pilocytic astrocytoma.
  • BRAF WT -melanomas has been associated with other skin cancers, such as cutaneous squamous cell carcinoma due to MAPK pathway paradoxical activation. There is therefore a clinical need for novel agents targeting the MAPK pathway that do not have these undesirable properties.
  • Certain embodiments of this invention aim to provide compounds which show reduced side effects. For example, certain embodiments of this invention aim to provide for compounds which show reduced paradoxical activation of the MAPK pathway in BRAF WT cells and which inhibit the MAPK pathway at therapeutically relevant concentrations.
  • Certain embodiments of this invention aim to provide for compounds which show sustained MAPK pathway inhibition over 24 hours in cell lines known to undergo reactivation of the MAPK pathway following treatment with the RAF inhibitors dabrafenib and vemurafenib. Especiallymbodiments also aim to reduce paradoxical activation of MAPK pathway compared to dabrafenib and/or vemurafenib.
  • Another aim of certain embodiments of this invention is to provide compounds having a convenient pharmacokinetic profile and a suitable duration of action following dosing.
  • a further aim of certain embodiments of this invention is to provide compounds in which the metabolised fragment or fragments of the drug after absorption are GRAS (Generally Regarded As Safe).
  • A is a phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or thiophenyl ring which is substituted or unsubstituted, and when substituted A contains 1 to 3 substituents independently selected from: halo, ⁇ O, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, —OR A , —NR A R B , SO 2 R A and SOR A ; 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: halo, —OR A , —NR A R B , ⁇ O, —OC(O)R C , —C(O)R C ,
  • R 2A , R 2B , R 2C and R 2D are each independently selected at each occurrence from: H, halo, —OR A , —CN, C 1-4 alkyl, C 1-4 haloalkyl and C 3-6 cycloalkyl;
  • R 3 is selected from 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: 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 may themselves also be unsubstituted or substituted with 1 to 3 groups independently selected from: —OR A , —CN, —SOR C , and —NR A R B ; R A and R
  • the present invention provides pharmaceutically acceptable salts of compounds of formula (I) and all other formulae disclosed herein.
  • Het 1 may be a five or six membered cycloalkyl or heterocyclic ring
  • het 2 may be a carbocyclic or heterocyclic ring system containing 8, 9 or 10 atoms in a fused bicyclic ring system
  • het 1 is a five or six membered heterocyclic ring
  • het 2 is a heterocyclic ring system containing 8, 9 or 10 atoms in a fused bicyclic ring system.
  • Ring A is fused to the ring containing X, Y and Z.
  • the two fused rings share two carbon atoms at the point of fusion, as would be understood by the person skilled in the art.
  • the compound of formula (I) is a compound according to formula (Ia)
  • a 1 , A 2 and A 3 are each independently selected from CR 4 or N, and R 4 is independently selected at each occurrence from: halo, —OR A , —NR A R B , ⁇ O, —CN, C 1-4 alkyl, C 1-4 haloalkyl and C 3-6 cycloalkyl.
  • A is phenyl.
  • X is O or S.
  • X is O.
  • Z is O, CR 2C or CR 2C R 2D . In certain embodiments Z is O and Y is CR 2B W. In certain embodiments Z is CR 2C R 2D and Y is CR 2B W. In certain embodiments Z is CR 2C and Y is CW.
  • the compound of formulae (IIIa) and (IIIc) may be single enantiomers.
  • compounds of formula (IIIa) may be compounds of formula (IId) or (IIIe) and compounds of formula (IIIc) may be compounds of formula (IIIf) and (IIIg):
  • the central bicyclic ring system of the compound of formula (IIIa) is a chromane ring.
  • the central bicyclic ring system of the compound of formula (IIIb) is a chromene ring.
  • the central bicyclic ring system of the compound of formula (IIIc) is a dihydrobenzodioxine ring.
  • Each of the central bicyclic ring systems are substituted with —O—R 1 .
  • the atoms of each of the central bicyclic groups are numbered as illustrated below.
  • —O—R 1 substituent on the chromane, chromene or dihydrobenzodioxine of formulae (IIIa), (IIIb) and (IIIc) respectively may be substituted at positions 5, 6, 7, or 8.
  • —O—R 1 is substituted at position 6.
  • —OR 1 is substituted at position 6 of the chromane, chromene or dihydrobenzodioxine of formulae (IIIa), (IIIb) and (IIIc) respectively there is provided a compound of formulae (IVa), (IVb) and (IVc):
  • the compounds of the invention are single enantiomers.
  • the compounds of the present invention may be a compound of formulae (IVd), (IVe), (IVf) or (IVg):
  • R 2A , R 2B , R 2C and R 2D are each H. It is particularly preferred that R 2A , R 2B , R 2C and R 2D are each H in the compounds of formulae (IVa), (IVb), (IVc), (IVd), (IVe), (IVf) and (IVg) as appropriate.
  • R 1 may be selected from substituted or unsubstituted: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, quinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, quinolinone-yl, tetrahydroquinolinone-yl, dihydroquinolinone-yl, isoquinolinyl, tetrahydroisoquinolinyl, dihydroisoquinolinyl, isoquinolinone-yl, tetrahydroisoquinolinone-yl, dihydroisoquinolinone-yl, napthyridinyl, oxo-napthyridinyl, dihydronappthyridinyl, tetrahydronaphthyridinyl
  • R 1 is substituted or unsubstituted pyridyl, substituted or unsubstituted oxo-dihydro-H-naphthyridinyl, or substituted or unsubstituted dihydropyrrolopyridinone (optionally a 1,3-dihydropyrrolopyridinone).
  • R 1 is methylpyridyl or oxodihydro-H-naphthyridinyl.
  • 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.
  • R 1 may be a substituted or unsubstituted heterocyclic moiety, wherein the heterocyclic moiety is a 6 membered aromatic ring or a fused bicyclic ring system that is unsaturated or aromatic containing 10 atoms.
  • the heterocyclic moiety contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • the heterocyclic moiety contains 1 or 2 nitrogen atoms.
  • R 1 When R 1 is substituted it is preferably substituted with halo, —OR A , —NR A R B , ⁇ O, —OCN, C 1-4 alkyl, C 1-4 haloalkyl, —NR A C(O)R C , —C(O)NR A R B , —NR A SO 2 R C or —SO 2 NR A R B .
  • R 1 is substituted with —NR A C (O)R C , —C(O)NR A R B , —NR A SO 2 R C or —SO 2 NR A R B .
  • R 1 when R 1 is substituted it is preferably substituted with fluoro, chloro, —OH, —NH 2 , —OMe, —NHMe, —NMe 2 , ⁇ O, —CN, methyl, trifluoromethyl, —NHC(O)Me, —NMeC(O)Me, —NHC(O)Et, —NMeC(O)Et, —C(O)NH 2 , —C(O)NHMe, —C(O)NMe 2 , —C(O)NHEt, —NHSO 2 Me, —NMeSO 2 Me, —SO 2 NH 2 , —SO 2 NHMe, —SO 2 NMe 2 .
  • R 1 is substituted with methyl or ⁇ O.
  • R 1 may be selected from substituted or unsubstituted: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, quinolinone-yl, tetrahydroquinolinone-yl, dihydroquinolinone-yl, isoquinolinyl, tetrahydroisoquinolinyl, dihydroisoquinolinyl, isoquinolinone-yl, tetrahydroisoquinolinone-yl, dihydroisoquinolinone-yl, napthyridinyl, oxo-napthyridinyl, dihydronappthyridinyl, tetrahydronaphthyridinyl, oxotetrahydronaphthyridinyl, dihydropyrrolopyri
  • R 1 is substituted or unsubstituted pyridyl, dihydropyrrolopyridinone (optionally a 1,3-dihydropyrrolopyridinone) or substituted or unsubstituted oxo-dihydro-H-naphthyridinyl. Further preferably, R 1 is methylpyridyl or oxo-dihydro-H-naphthyridinyl.
  • R 1 is methylpyridyl or oxo-dihydro-H-naphthyridinyl and R 2A , R 2B , R 2C and R 2D are each H.
  • Het 1 and het 2 may be substituted or unsubstituted. Het 1 and het 2 may not be substituted with an oxo group, for example pyrollidinone is not a het 1 group and purinone is not a het 2 group because the groups contain a substiuted oxo group. In an embodiment het 2 is not purinone.
  • W represents -het 1 -R 3 or -het 2 , wherein het 1 is a substituted or unsubstituted five membered carbocyclic ring or heterocyclic ring, and
  • het 2 is a substituted or unsubstituted carbocyclic or heterocyclic ring system, containing 8, 9 or 10 atoms in a fused bicyclic ring system.
  • W represents -het 1 -R 3 or -het 2 , wherein het 1 is a substituted or unsubstituted five membered heterocyclic ring, and
  • het 2 is a substituted or unsubstituted heterocyclic ring system, containing 8, 9 or 10 atoms in a fused bicyclic ring system.
  • W represents -het 1 -R 3 or -het 2 , wherein het 1 is represented by a group selected from substituted or unsubstituted: C 5-6 cycloalkyl, C 6 aryl, C 5-6 heterocycloalkyl or C 5-8 heteroaryl, and
  • het 2 is represented by a group selected from substituted or unsubstituted C 8-10 cycloalkyl, C 10 aryl, C 8-10 heterocycloalkyl or C 8-10 heteroaryl.
  • W represents -het 1 -R 3 or -het 2 , wherein het 1 is represented by a group selected from substituted or unsubstituted: C 5-6 cycloalkyl, C 5-6 heterocycloalkyl or C 5-6 heteroaryl, and
  • het 2 is represented by a group selected from substituted or unsubstituted C 8-10 cycloalkyl, C 10 aryl, C 8-10 heterocycloalkyl or C 8-10 heteroaryl.
  • Het 1 may be a five or six membered heterocyclic ring
  • het 2 may be a heterocyclic ring system containing 8, 9 or 10 atoms in a fused bicyclic ring system
  • het 1 is represented by C 5-6 heteroaryl and het 2 is represented by C 8-10 heteroaryl. Further preferably, het 1 is represented by C 5 heteroaryl.
  • het 1 may be a five membered carbocyclic ring or heterocyclic ring (preferably heterocyclic) which is unsubstituted or substituted and het 2 may be a 9 membered carbocyclic or heterocyclic bicyclic ring system (preferably heterocyclic) which is unsubstituted or substituted.
  • het 2 may be a bicyclic ring system with one of the rings of the bicyclic ring system being a five membered ring.
  • the five membered ring may be bonded to the ring containing X, Y and Z, for example the five membered ring may be bonded to the chromane, chromene or dihydrobenzodioxine of formulae (IIIa), (IIIb) and (IIIc) respectively.
  • het 1 and het 2 are unsubstituted.
  • Het 1 may be represented by substituted or unsubstituted: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole and triazole
  • het 2 may be represented by substituted or unsubstituted: indoline, isoindoline, benzodioxane, benzofurane, isobenzofurane, benzothiophene, isobenzothiophene, benzodioxolane, indazole, indazoline, benzimidazole, benzimidazoline, benzthiazole, benzoisothiazole, chromane, isochromane, tetraline, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline and tetrahydroquinoxaline
  • W represents -het 1 -R 3 and het 1 is represented by substituted or unsubstituted: pyrazole, imidazole or oxadiazole.
  • W represents -het 2 and het 2 is represented by substituted or unsubstituted benzimidazole.
  • W represents -het 1 and het 2 is represented by substituted or unsubstituted benzimidazole.
  • W represents -het 2 and het 2 is represented by substituted or unsubstituted benzimidazole.
  • the compounds according to formula (I) are compounds of formulae (VIa), (VIb), (VIc), (VId) or (VIe):
  • m is selected from 0, 1 or 2; and R 5 is independently selected at each occurrence from: halo, —OR A , C 1-4 alkyl, C 1-4 haloalkyl and C 3-6 cycloalkyl.
  • the compounds according to formula (I) are compounds of formulae (VIf), (VIg), (VIh), (VIi) or (VIj):
  • m is selected from 0, 1 or 2; and R 5 is independently selected at each occurrence from: halo, —OR A , C 1-4 alkyl, C 1-4 haloalkyl and C 3-6 cycloalkyl.
  • the compounds according to formula (I) are compounds of formulae (VIk), (VIm), (VIn), (VIo) or (VIp):
  • m is selected from 0, 1 or 2; and R 5 is independently selected at each occurrence from: halo, —OR A , C 1-4 alkyl, C 1-4 haloalkyl and C 3-6 cycloalkyl.
  • R 2A , R 2B , R 2C and R 2D are each H.
  • m is 0 or 1.
  • R 5 is halo, preferably chloro.
  • m is 0 or 1 and R 5 is halo, preferably chloro.
  • compounds of formulae (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj) (VIk), (VIm), (VIn), (VIo) or (VIp), wherein R 1 is substituted or unsubstituted pyridyl or substituted or unsubstituted oxo-dihydro-H-naphthyridinyl, preferably wherein R 1 is methylpyridyl or oxo-dihydro-H-naphthyridinyl.
  • R 3 is selected from: 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.
  • R 3 may be selected from 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, benzoisothia
  • R 3 may be selected from: tert-butyl, phenyl, pyridyl, benzodioxanyl, benzofuranyl, benzodioxolanyl and thiophenyl.
  • R 3 When R 3 is substituted it may contain 1 or 2 substituents. When R 3 is substituted it may contain 1 to 4 substituents independently selected from: 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 , —CN, C 1-4 alkyl, C 1-4 haloalkyl and C 3-6 cycloalky in which the aforementionedalkyl, haloalkyl and cycloalkyl groups may themselves also be unsubstituted or substituted with 1 to 3 groups independently selected from: —OR A , —CN, —SOR C , and NR A R B I.
  • substituents independently selected from: halo, —OR A , —NR A R B
  • R 3 is substituted by 1 or 2 substituents selected from: chloro, fluoro, methyl, ethyl, —OMe, —CN, —SO 2 Me, trifluoromethyl and trifluoroethyl, in particular chloro, fluoro, methyl, ethyl, —SO 2 Me, trifluoromethyl and trifluoroethyl.
  • R A and R B are each independently selected from H, methyl, ethyl or trifluoromethyl and R C is selected from methyl, ethyl or trifluoromethyl.
  • R A and R B are H; R A and R B are methyl; or R A is H and R B is methyl.
  • R C is methyl.
  • Any compound of the invention may be a racemic mixture of two enantiomers or a single enantiomer, either the (R)- or (S)-enantiomer.
  • the compounds of the invention may also be a single enantiomer, either the (+)- or ( ⁇ )-enantiomer, as determined by the degree of rotation of plane polarized light.
  • the invention provides the following compounds.
  • the above compounds have a chiral centre. Both enantiomers of the above compounds are contemplated by the invention. The chiral centre is indicated on the compounds above with a * symbol.
  • the compounds of the invention have the (R)-configuration at the stereocentre.
  • the compounds of the invention have the (S)-configuration at the stereocentre.
  • a compound of formula (I) is for use in the treatment of a condition which is modulated by RAF kinases, for example B-RAF or C-RAF.
  • RAF kinases for example B-RAF or C-RAF.
  • conditions that are modulated by RAF kinases, optionally B-RAF or C-RAF are conditions that would be treated by the inhibition of RAF kinases, optionally B-RAF or C-RAF, using a compound of the present invention.
  • a compound of formula (I) may be for use in the treatment of a condition treatable by the inhibition of RAF kinases, optionally B-RAF or C-RAF.
  • RAF kinase inhibition is relevant for the treatment of many different diseases associated with the abnormal activity of the MAPK pathway.
  • condition treatable by the inhibition of RAF kinases for example B-RAF or C-RAF, may be selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma and leukemia.
  • Specific cancers, sarcomas, melanomas, skin cancers, haematological tumors, lymphomas, carcinomas and leukemia treatable by the inhibition of RAF kinases may be selected from: 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 myelogen
  • RAF kinases inhibition for example B-RAF or C-RAF, may also be relevant to the treatment of cardio-facio cutaneous syndrome and polycystic kidney disease.
  • a compound of formula (I) is for use in the treatment of a condition which is modulated by a mutant RAF kinase, for example B-RAF V600E .
  • a condition which is modulated by a mutant RAF kinase for example B-RAF V600E .
  • conditions that are modulated by mutant RAF kinases, optionally B-RAF V600E are conditions that would be treated by the inhibition of mutant RAF kinases, optionally B-RAF V600E , using a compound of the present invention.
  • a compound of formula (I) may be for use in the treatment of a condition treatable by the inhibition of mutant RAF kinases, optionally B-RAF V600E .
  • the condition treatable by the inhibition of mutant RAF kinases may be selected from: BRAF V600E melanoma, BRAF V600E colorectal cancer, BRAF V600E papillary thyroid cancers, BRAF V600E low grade serous ovarian cancers, BRAF V600E glioma, BRAF V600E hepatobiliary cancers, BRAF V600E hairy cell leukaemia, BRAF V600E non-small cell cancer, and BRAF V600E pilocytic astrocytoma.
  • the conditions treatable by the inhibition of RAF kinases may be selected from melanoma, non-small cell cancer, colorectal cancer, ovarian cancer, thyroid cancer, breast cancer and cholangiocarcinoma.
  • the condition treatable by the inhibition of RAF kinases for example B-RAF or C-RAF, may be colorectal cancer or melanoma.
  • the invention contemplates methods of treating the above mentioned conditions and contemplates compounds of the invention for use in a method of treatment of the above mentioned conditions
  • a compound of the invention may be for use in the treatment of a condition selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma and leukemia.
  • Specific cancers, sarcomas, melanomas, skin cancers, haematological tumors, lymphomas, carcinomas and leukemia may be selected from: 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;
  • a compound of the invention may be for use in the treatment of a condition selected from: melanoma, non-small cell cancer, colorectal cancer, ovarian cancer, thyroid cancer, breast cancer and cholangiocarcinoma.
  • the compound of the invention may be for use in the treatment of colorectal cancer or melanoma.
  • a method of treatment of a condition which is modulated by RAF kinases comprising administering a therapeutic amount of a compound of the invention, to a patient in need thereof.
  • the method of treatment may be a method of treating a condition treatable by the inhibition of RAF kinases, e.g. B-RAF or C-RAF. These conditions are described above in relation to conditions treatable by the inhibition of RAF kinases.
  • a method of treatment of a condition selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma and leukemia wherein the method comprises administering a therapeutic amount of a compound of the invention, to a patient in need thereof.
  • Specific cancers, sarcomas, melanomas, skin cancers, haematological tumors, lymphomas, carcinomas and leukemia may be selected from: 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; hairy cell leukaemia; Ho
  • the method may be for treating a condition selected from: melanoma, non-small cell cancer, colorectal cancer, ovarian cancer, thyroid cancer, breast cancer and cholangiocarcinoma, wherein the method comprises administering a therapeutic amount of a compound of the invention to a patient in need thereof.
  • method may be for treating colorectal cancer or melanoma.
  • composition comprising a compound of the invention and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition may be a combination product comprising an additional pharmaceutically active agent.
  • the additional pharmaceutically active agent may be an anti-tumor agent described below.
  • a compound of formula (I) in the manufacture of a medicament for the treatment of a condition which is modulated by RAF kinases, e.g. B-RAF or C-RAF.
  • the condition may be any of the conditions mentioned above.
  • the RAF kinases may be B-RAF or C-RAF. In any of the aspects or embodiments of the invention the B-RAF kinase may be the B-RAF V600E mutant.
  • the compounds of the invention may be utilised in the treatment of a condition which is modulated by B-RAF and/or C-RAF.
  • the compounds of the invention may be utilised in the treatment of conditions treatable by the inhibition of B-RAF and/or C-RAF.
  • the compounds of the invention may be utilised in the treatment of a condition which is modulated by B-RAF V600E .
  • the compounds of the invention may be utilised in the treatment of conditions treatable by the inhibition of B-RAF V600E .
  • B-RAF V600E is a mutant form of wild type B-RAF which is believed to play a role in aberrant MAPK pathway signalling, giving rise to uncontrolled cell growth.
  • FIG. 1 is a graph showing reduced paradoxical activation of MAPK pathway for a compound of the invention (Example 3).
  • halo refers to one of the halogens, group 17 of the periodic table.
  • the term refers to fluorine, chlorine, bromine and iodine.
  • the term refers to fluorine or chlorine.
  • C 1-6 alkyl refers to a linear or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.
  • Alkylene groups may likewise be linear or branched and may have two places of attachment to the remainder of the molecule. Furthermore, an alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph.
  • the alkyl and alkylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C 1-6 alkoxy.
  • C 1-6 alkoxy refers to an alkyl group which is attached to a molecule via oxygen. This includes moieties where the alkyl part may be linear or branched and may contain 1, 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Therefore, the alkoxy group may be methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • the alkyl part of the alkoxy group may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C 1-6 alkoxy.
  • C 1-6 haloalkyl refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromine and iodine.
  • the halogen atom may be present at any position on the hydrocarbon chain.
  • C 1-6 haloalkyl may refer to chloromethyl, flouromethyl, trifluoromethyl, chloroethyl e.g. 1-chloromethyl and 2-chloroethyl, trichloroethyl e.g. 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g.
  • C 2-6 alkenyl refers to a branched or linear hydrocarbon chain containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms.
  • the double bond(s) may be present as the E or Z isomer.
  • the double bond may be at any possible position of the hydrocarbon chain.
  • the “C 2-6 alkenyl” may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.
  • C 2-6 alkynyl refers to a branched or linear hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5 or 6 carbon atoms.
  • the triple bond may be at any possible position of the hydrocarbon chain.
  • the “C 2-6 alkynyl” may be ethynyl, propynyl, butynyl, pentynyl and hexynyl.
  • C 1-6 heteroalkyl refers to a branched or linear hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatom selected from N, O and S positioned between any carbon in the chain or at an end of the chain.
  • the hydrocarbon chain may contain one or two heteroatoms.
  • the C 1-6 heteroalkyl may be bonded to the rest of the molecule through a carbon or a heteroatom.
  • the “C 1-6 heteroalkyl” may be C 1-6 N-alkyl, C 1-6 N,N-alkyl, or C 1-6 O-alkyl.
  • Carbocyclic refers to a saturated or unsaturated carbon containing ring system.
  • a “carbocyclic” system may be monocyclic or a fused polycyclic ring system, for example, bicyclic or tricyclic.
  • a “carbocyclic” moiety may contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system.
  • Carbocyclic encompasses cycloalkyl moieties, cycloalkenyl moieties, aryl ring systems and fused ring systems including an aromatic portion.
  • heterocyclic refers to a saturated or unsaturated ring system containing at least one heteroatom selected from N, O or S.
  • a “heterocyclic” system may contain 1, 2, 3 or 4 heteroatoms, for example 1 or 2.
  • a “heterocyclic” system may be monocyclic or a fused polycyclic ring system, for example, bicyclic or tricyclic.
  • a “heterocyclic” moiety may contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system.
  • “Heterocyclic” encompasses heterocycloalkyl moieties, heterocycloalkenyl moieties and heteroaromatic moieties.
  • the heterocyclic group may be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.
  • C 3-8 cycloalkyl refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms.
  • the “C 3-8 cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • C 3-8 cycloalkenyl refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms that is not aromatic.
  • the ring may contain more than one double bond provided that the ring system is not aromatic.
  • the “C 3-8 cycloalkyl” may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.
  • C 3-8 heterocycloalkyl refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example there may be 1, 2 or 3 heteroatoms, optionally 1 or 2.
  • the “C 3-8 heterocycloalkyl” may be bonded to the rest of the molecule through any carbon atom or heteroatom.
  • the “C 3-8 heterocycloalkyl” may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring.
  • the “C 3-8 heterocycloalkyl” may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine,isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.
  • C 3-8 heterocycloalkenyl refers to an unsaturated hydrocarbon ring system, that is not aromatic, containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example there may be 1, 2 or 3 heteroatoms, optionally 1 or 2.
  • the “C 3-8 heterocycloalkenyl” may be bonded to the rest of the molecule through any carbon atom or heteroatom.
  • the “C 3-8 heterocycloalkenyl” may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring.
  • the “C 3-8 heterocycloalkyl” may be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline.
  • aromatic when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n+2 electrons in a conjugated ⁇ system within the ring or ring system where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • aryl refers to an aromatic hydrocarbon ring system.
  • the ring system has 4n+2 electrons in a conjugated ⁇ system within a ring where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • the “aryl” may be phenyl and naphthyl.
  • the aryl system itself may be substituted with other groups.
  • heteroaryl refers to an aromatic hydrocarbon ring system with at least one heteroatom within a single ring or within a fused ring system, selected from O, N and S.
  • the ring or ring system has 4n+2 electrons in a conjugated ⁇ system where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • the “heteroaryl” may be imidazole, thiene, furane, thianthrene, pyrrol, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.
  • alkaryl refers to an aryl group, as defined above, bonded to a C 1-4 alkyl, where the C 1-4 alkyl group provides attachment to the remainder of the molecule.
  • alkheteroaryl refers to a heteroaryl group, as defined above, bonded to a C 1-4 alkyl, where the alkyl group provides attachment to the remainder of the molecule.
  • halogen herein includes reference to F, Cl, Br and I. Halogen may be Cl. Halogen may be F.
  • a bond terminating in a “ ” represents that the bond is connected to another atom that is not shown in the structure.
  • a bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be connected to any of the atoms in the ring structure where allowed by valency.
  • a moiety may be substituted at any point on the moiety where chemically possible and consistent with atomic valency requirements.
  • the moiety may be substituted by one or more substituents, e.g. 1, 2, 3 or 4 substituents; optionally there are 1 or 2 substituents on a group. Where there are two or more substituents, the substituents may be the same or different.
  • the substituent(s) may be selected from: OH, NHR 9 , amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, C(O)H, acyl, acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, nitro, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl or alkaryl.
  • the substituent may be ⁇ O.
  • the moiety is substituted with two or more substituents and two of the substituents are adjacent the adjacent substituents may form a C 4-8 ring along with the atoms of the moiety on which the substituents are substituted, wherein the C 4-8 ring is a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7, or 8 carbon atoms or a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7, or 8 carbon atoms and 1, 2 or 3 heteroatoms.
  • ortho, meta and para substitution are well understood terms in the art.
  • “ortho” substitution is a substitution pattern where adjacent carbons possess a substituent, whether a simple group, for example the fluoro group in the example below, or other portions of the molecule, as indicated by the bond ending in “ ”
  • Metal substitution is a substitution pattern where two substituents are on carbons one carbon removed from each other, i.e with a single carbon atom between the substituted carbons. In other words there is a substituent on the second atom away from the atom with another substituent.
  • substituents are on carbons one carbon removed from each other, i.e with a single carbon atom between the substituted carbons. In other words there is a substituent on the second atom away from the atom with another substituent.
  • the groups below are meta substituted.
  • “Para” substitution is a substitution pattern where two substituents are on carbons two carbons removed from each other, i.e with two carbon atoms between the substituted carbons. In other words there is a substituent on the third atom away from the atom with another substituent.
  • the groups below are para substituted.
  • acyl is meant an organic radical derived from, for example, an organic acid by the removal of the hydroxyl group, e.g. a radical having the formula R—C(O)—, where R may be selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or C 1-3 alkyl.
  • R may be selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or C 1-3 alkyl.
  • acyl is alkyl-carbonyl.
  • Examples of acyl groups include, but are not limited to, formyl, acetyl, propionyl and butyryl. A particular acyl group is acetyl.
  • a compound also encompasses pharmaceutically acceptable salts, solvates and stereoisomers thereof.
  • a compound has a stereocentre
  • both (R) and (S) stereoisomers are contemplated by the invention, equally mixtures of stereoisomers ora racemic mixture are completed by the present application.
  • a compound of the invention has two or more stereocentres any combination of (R) and (S) stereoisomers is contemplated.
  • the combination of (R) and (S) stereoisomers may result in a diastereomeric mixture or a single diastereoisomer.
  • the compounds of the invention may be present as a single stereoisomer or may be mixtures of stereoisomers, for example racemic mixtures and other enantiomeric mixtures, and diasteroemeric mixtures. Where the mixture is a mixture of enantiomers the enantiomeric excess may be any of those disclosed above. Where the compound is a single stereoisomer the compounds may still contain other diasteroisomers or enantiomers as impurities. Hence a single stereoisomer does not necessarily have an enantiomeric excess (e.e.) or diastereomeric excess (d.e.) of 100% but could have an e.e. or d.e. of about at least 85%
  • the compounds of the invention may have an enantiomeric purity of at least about 90% enantiomeric excess (ee), at least about 95% enantiomeric excess (ee), at least about 98% enantiomeric excess (ee), at least about 99% enantiomeric excess (ee), or 100% enantiomeric excess (ee).
  • the compounds of the invention may be a racemic mixture or any other mixture of enantiomers, for example the compounds of the invention may have an enantiomeric purity of at least about 50% enantiomeric excess (ee), at least about 60% enantiomeric excess (ee), at least about 70% enantiomeric excess (ee), at least about 80% enantiomeric excess (ee), at least about 90% enantiomeric excess (ee), or at least about 95% enantiomeric excess (ee).
  • the invention contemplates pharmaceutically acceptable salts of the compounds of formula (I). These may include the acid addition and base salts of the compounds. These may be acid addition and base salts of the compounds. In addition the invention contemplates solvates of the compounds. These may be hydrates or other solvated forms of the compound.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 1,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.
  • suitable salts see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
  • compositions of formula (I) may be prepared by one or more of three methods:
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • solvate is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • hydrate is employed when said solvent is water.
  • complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts.
  • the resulting complexes may be ionised, partially ionised, or non-ionised.
  • references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
  • the compounds of the invention include compounds of a number of formula as herein defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of the invention.
  • the compounds of the present invention may exist as a mixture of enantiomers depending on the synthetic procedure used.
  • the enantiomers can be separated by conventional techniques known in the art.
  • the invention covers individual enantiomers as well as mixtures thereof.
  • any compatible protecting radical can be used.
  • methods of protection and deprotection such as those described by T. W. GREENE (Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used.
  • the compounds of the present invention as well as intermediates for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatography.
  • the method of treatment or the compound for use in the treatment of cancer, sarcoma, melanoma, skin cancer, haematologicaltumors, lymphoma, carcinoma and leukemia as defined hereinbefore may be applied as a sole therapy or be a combination therapy with an additional active agent.
  • the method of treatment or the compound for use in the treatment of cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma and leukemia may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti-tumor agents:
  • antiproliferative/antineoplastic drugs and combinations thereof such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, bendamustin, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, and hydroxyurea); antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine
  • Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within a therapeutically effective dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • a pharmaceutical product comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof as defined hereinbefore and an additional active agent.
  • the additional active agent may be an anti-tumour agent as defined hereinbefore for the combination treatment of a condition modulated by a RAF kinase, for example B-RAF or C-RAF.
  • a method of treatment a condition modulated by a RAF kinase for example B-RAF or C-RAF comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable saltthereof simultaneously, sequentially or separately with an additional anti-tumor agent, as defined hereinbefore, to a patient in need thereof.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for use simultaneously, sequentially or separately with an additional anti-tumour agent as defined hereinbefore, in the treatment of a condition modulated by a RAF kinase, for example B-RAF or C-RAF.
  • the compound of formula (I) in combination with an anti-tumor agent as hereinbefore described.
  • the compound of formula (I) may be used simultaneously, sequentially or separately with the additional anti-tumor agent
  • the use may be in a single combination product comprising the compound of formula (I) and the anti-tumor agent.
  • a method of providing a combination product comprising providing a compound of formula (I) simultaneously, sequentially or separately with an anti-tumor agent, as defined hereinbefore.
  • the method may comprise combining the compound of formula (I) and the anti-tumor agent in a single dosage form.
  • the method may comprise providing the anti-tumor agent as separate dosage forms.
  • a method of providing a combination product comprising providing a compound of formula (I) simultaneously, sequentially or separately with an anti-tumor agent, as defined hereinbefore.
  • the method may comprise combining the compound of formula (I) and the anti-tumor agent in a single dosage form.
  • the method may comprise providing the anti-tumor agent as separate dosage forms.
  • the condition modulated by a RAF kinase for example B-RAF or C-RAF, described above may be cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma and leukemia.
  • condition modulated by a RAF kinase may be selected from: 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; hairy cell leukaemia; Hodgkin's lymphoma; non-Hodgkin's lymph
  • condition modulated by a RAF kinase for example B-RAF or C-RAF, may be selected from: melanoma, non-small cell cancer, colorectal cancer, ovarian cancer, thyroid cancer, breast cancer and cholangiocarcinoma.
  • Compounds of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous.
  • compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight (m/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • a compound of the invention, or pharmaceutically acceptable salt thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutically acceptable adjuvant diluent or carrier.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceuticals—The Science of Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 1988.
  • the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99% w (percent by weight) compounds of the invention, more preferably from 0.05 to 80% w compounds of the invention, still more preferably from 0.10 to 70% w compounds of the invention, and even more preferably from 0.10 to 50% w compounds of the invention, all percentages by weight being based on total composition.
  • compositions may be administered topically (e.g. to the skin) in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.
  • parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.
  • the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.
  • an adjuvant or a carrier for example, lactose, saccharose, sorbitol, mannitol
  • a starch for example, potato starch, corn starch or amylopectin
  • a cellulose derivative for example, gelatine or polyvinylpyrrolidone
  • a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax
  • the cores may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets.
  • liquid or semi-solid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquidpreparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • the compounds of the invention may be administered as a sterile aqueous or oily solution.
  • the size of the dose for therapeutic purposes of compounds of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
  • Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient.
  • the standard duration of treatment with compounds of the invention is expected to vary between one and seven days for most clinical indications. It may be necessary to extend the duration of treatment beyond seven days in instances of recurrent infections or infections associated with tissues or implanted materials to which there is poor blood supply including bones/joints, respiratory tract, endocardium, and dental tissues.
  • NMR NMR was also used to characterise final compounds. NMR spectra were obtained on a Bruker AVIII 400 Nanobay with 5 mm BBFO probe.
  • Tert-butyl 6-hydroxy-2H-chromene-3-carboxylate was prepared using the material tert-butyl 6-tetrahydropyran-2-yloxy-2H-chromene-3-carboxylate (Intermediate 2, step 2) following the synthetic procedure for tert-butyl 6-hydroxychromane-3-carboxylate (Intermediate 2, step 4).
  • 6-Hydroxy-2H-chromene-3-carboxylic acid was prepared using the material tert-butyl 6-hydroxy-2H-chromene-3-carboxylate following the synthetic procedure for 6-hydroxychromane-3-carboxylic acid (Intermediate 2, step 5).
  • Example 3 Chiral purification of Example 3 provided two enantiomrs 3A and 3B:
  • Example 8 5-[3-[5-(2-chlorophenyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2 -one
  • the brown oil was dissolved in AcOH (3 mL), NH 4 OAc (1.81 g, 23.51 mmol) was added and the mixture heated in a sealed vial at 140° C. for 18 hrs. The mixture was added to sat. aq. NaHCO 3 (100 mL) and EtOAc (50 mL) and stirred until neutralised. The mixture was diluted with EtOAc (50 mL) and the combined organic layers were washed with brine (50 mL). The combined aqueous layers were extracted with EtOAc (50 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated in vacuo.
  • the yellow oil was dissolved in AcOH (6 mL), NH 4 OAc (3.62 g, 47.01 mmol) was added and the mixture heated in a sealed tube at 140° C. for 3 hrs. The mixture was diluted with sat. aq. NaHCO 3 (250 mL) and EtOAc (50 mL) and stirred till neutralised. The biphasic mixture was diluted with EtOAc (100 mL). The organic layer was washed with brine (100 mL) and the combined aqueous layers were extracted with EtOAc (100 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated invacuo.
  • the yellow oil was dissolved in AcOH (6 mL), NH 4 OAc (3.62 g, 47.01 mmol) was added and the mixture heated in a sealed tube at 140° C. for 1.5 hrs, cooled and stirred for a further 90 hrs.
  • the mixture was diluted with sat. aq. NaHCO 3 (150 mL), EtOAc (50 mL) and stirred till neutralised.
  • the mixture was diluted with further EtOAc (50 ml).
  • the organic layer was washed with brine (100 mL) and the combined aqueous layers were extracted with EtOAc (100 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered, concentrated in vacuo.
  • Example 17 5-[3-(3-phenyl-1,2,4-oxadiazol-5-yl) chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one
  • Trimethyl-[2-[[4-phenyl-2-[(3S)-6-tetrahydropyran-2-yloxy-2,3-dihydro-1,4-benzodioxin-3-yl]imidazol-1-yl]methoxy]ethyl]silane 739 mg, 1.45 mmol was dissolved in MeOH (5 mL), loaded onto a pre-wetted 5 g SCX cartridge and washed with methanol (3 ⁇ 15 mL), 1 N NH 3 /MeOH (3 ⁇ 15 mL), and product fractions were concentrated in vacuo. The residue was purified by column chromatography (0-25% EtOAc/pet.
  • the Invitrogen LanthaScreenTM Eu binding assay involves the binding of an Alexa-Fluor® 647-labelled, ATP-competitive kinase tracer to the kinase of interest.
  • a Europium-labelled anti-tag antibody also binds to the kinase of interest. Simultaneous binding of the tracer and the antibody brings them into close proximity and upon excitation at 340 nm, triggers fluorescence resonance energy transfer (FRET) between the Europium donor fluorophore on the antibody and the Alexa Fluor® 647 acceptor on the tracer.
  • FRET fluorescence resonance energy transfer
  • DMSO dimethyl sulfoxide
  • Each well in a 96-well OptiplateTM contains 30 ⁇ l of final volume per sample, including 10 ⁇ l compound at 3 ⁇ the desired concentration, providing 10 ⁇ M at the final maximum concentration, 10 ⁇ l of kinase/antibody mixture at 3 ⁇ the desired concentration of RAF recombinant kinases and antibody providing 5 nM final concentration of B-RAF V600E kinase (Invitrogen PV3849) and 3 nM final concentration of C-RAF Y340D/Y341D kinase (Invitrogen PV3805) and 2 nM final concentration of Eu-anti-GST antibody (PV5594), and 10 ⁇ l of 3 ⁇ the desired concentration of kinase tracer 178 (Invitrogen PV5593) providing final concentrations of 20 nM tracer for B-RAF V600E kinase and 6 nM tracer for C-RAF kinase.
  • the plates are incubated for 5 hours at room temperature
  • IC 50 value is defined as the concentration of compound which decreased the level of FRET signal measured at 665 nm by 50%.
  • the results of the in vitro biological binding affinity study of the compounds of the invention are given in Table 3 below.
  • the compounds all show binding affinity against B-RAF V600E mutant and C-RAF.
  • the table shows the B-RAF V600E and C-RAF inhibition activity of compounds of the invention categorised based on the IC 50 values, the categories being “+”, “++” and “+++”.
  • the category “+” refers to compounds with an IC 50 value of greater than 100 nM.
  • the category “++” refers to compounds with an IC 50 value of 4 nM to 100 nM.
  • the category “+++” refers to compounds with an IC 50 value of less than 4 nM.
  • the human WiDr colorectal cell line endogenously expresses the B-RAF V600E mutation, which leads to constitutive activation of the MAP kinase pathway and phosphorylation of ERK in the absence of ligands.
  • To determine whether compounds inhibit constitutive ERK phosphorylation in WiDr cells they are tested using AlphaScreen® SureFire® technology (Perkin Elmer ERK1/2 p-T202/Y204 assay kit TGRES10K).
  • WiDr cells (ATCC CRL-218TM) are counted, centrifuged and resuspended in growth media (Minimum essential medium containing 1 g/L D-glucose and 2 mM L-glutamine (Gibco 31095), 10% fetal bovine serum (VWR S061)).
  • growth media Minimum essential medium containing 1 g/L D-glucose and 2 mM L-glutamine (Gibco 31095), 10% fetal bovine serum (VWR S061).
  • the cells are plated, 200 ⁇ l in each well of 96-well culture dish (Corning 3585) to a final cell density of 80,000 cells per well and incubated at 37° C. in 5% CO 2 overnight.
  • DMSO dimethyl sulfoxide
  • lysis buffer containing phosphatase inhibitors for 10 minutes at room temperature.
  • Cell lysates are transferred to a 96-well OptiplateTM (Perkin Elmer 6005569) and incubated with anti-mouse IgG acceptor beads, a biotinylated anti-ERK1/2 rabbit antibody recognising both phosphorylated and non-phosphorylated ERK1/2, a mouse antibody targeted to the Thr202/Tyr204 epitope and recognising phosphorylated ERK proteins only, and streptavidin-coated donor beads.
  • the biotinylated antibody binds to the streptavidin-coated donor beads and the phopsho-ERK1/2 antibody binds to the acceptor beads. Plates are read on an EnVision reader (Perkin Elmer) and excitation of the beads at 680 nm with a laser induces the release of singlet oxygen molecules from the donor beads that triggers energy transfer to the acceptor beads in close proximity, producing a signal that can be measured at 570 nm. Both antibodies bind to phosphorylated ERK proteins, bringing the donor and acceptor beads into close proximity.
  • IC 50 value is defined as the concentration of compound which decreased the level of phosphorylated ERK proteins by 50%.
  • the results of WiDr AlphaScreen SureFire pERK1/2 cellular assay are given in Table 6 below.
  • the compounds tested all showed activity within a cell.
  • the activity of the compounds of the invention has been categorised based on the IC 50 values, the categories being “+”, “++” and “+++”
  • the category “+” refers to compounds with an IC 50 value of greater than 300 nM.
  • the category “++” refers to compounds with an IC 50 value of 70 nM to 300 nM.
  • the category “+++” refers to compounds with an IC 50 value of less than 70 nM.
  • IC 50 (nM) ample Name 1 hr 24 hrs 3 5-[3-(4-phenyl-1H-imidazol-2-yl)chroman- 100 671 6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin- 2-one] 3A Enantiomer 1 of 5-[3-(4-phenyl-1H- 32 562 imidazol-2-yl)chroman-6-yl]oxy-3,4- dihydro-1H-1,8-naphthyridin-2-one] 3B Enantiomer 2 of 5-[3-(4-phenyl-1H- 115 416 imidazol-2-yl)chroman-6-yl]oxy-3,4- dihydro-1H-1,8-naphthyridin-2-one]
  • the human A375 malignant melanoma cell line endogenously expresses the B-RAF V600E mutation, which leads to constitutive activation of the MAP kinase pathway and phosphorylation of ERK in the absence of ligands.
  • To determine whether compounds inhibit constitutive ERK phosphorylation in A375 cells they are tested using AlphaScreen® SureFire® technology (Perkin Elmer ERK1/2 p-T202/Y204 assay kit TGRES10K).
  • A375 cells (ATCC CRL-1619) are counted, centrifuged and resuspended in growth media (Dulbecco's modified Eagle's medium containing 4.5 g/L D-glucose (Gibco 41965), 10% fetal bovine serum (VWR S061) and 4 mM L-glutamine (Sigma G7513)).
  • the cells are plated, 200 ⁇ l in each well of 96-well culture dish (Corning 3585) to a final cell density of 60,000 cells per well and incubated at 37° C. in 5% CO 2 overnight.
  • DMSO dimethyl sulfoxide
  • Cell lysates are transferred to a 96-well OptiplateTM (Perkin Elmer 6005569) and incubated with anti-mouse IgG acceptor beads, a biotinylated anti-ERK1/2 rabbit antibody recognising both phosphorylated and non-phosphorylated ERK1/2, a mouse antibody targeted to the Thr202/Tyr204 epitope and recognising phosphorylated ERK proteins only, and streptavidin-coated donor beads.
  • the biotinylated antibody binds to the streptavidin-coated donor beads and the phopsho-ERK1/2 antibody binds to the acceptor beads.
  • Plates are read on an EnVision reader (Perkin Elmer) and excitation of the beads at 680 nm with a laser induces the release of singlet oxygen molecules from the donor beads that trigger energy transfer to the acceptor beads in close proximity, producing a signal that can be measured at 570 nm. Both antibodies bind to phosphorylated ERK proteins, bringing the donor and acceptor beads into close proximity.
  • IC 50 value is defined as the concentration of compound which decreased the level of phosphorylated ERK proteins by 50%.
  • the results of AlphaScreen SureFire pERK1/2 cellular assay are given in Table 8 below.
  • the compounds tested all showed activity within a cell.
  • the activity of the compounds of the invention has been categorised based on the IC 50 values, the categories being “+”, “++” and “+++”
  • the category “+” refers to compounds with an IC 50 value of greater than 300 nM.
  • the category “++” refers to compounds with an IC 50 value of 70 nM to 300 nM.
  • the category “+++” refers to compounds with an IC 50 value of less than 70 nM.
  • the human IPC-298 melanoma cell line endogenously expresses the NRAS Q61L mutation leading to constitutive activation of the MAPK pathway and phosphorylation of ERK via C-RAF in the absence of ligands.
  • IPC-298 cells (DSMZ ACC-251) are counted, centrifuged and resuspended in growth medium (RPMI 1640 containing 2 g/L D-glucose (Gibco 31870), 10% fetal bovine serum (VWR S061) and 2 mM L-glutamine (Sigma G7513).
  • the cells are plated, 100 uL in each well of 96 well culture dish (Corning 3585) to a final cell density of 40,000 cells per well and incubated at 37° C. in 5% CO 2 overnight.
  • lysis buffer containing phosphatase inhibitors for 10 minutes at room temperature with gentle shaking.
  • Cell lysates are transferred to a 96-well OptiplateTM (Perkin Elmer 6005569) and incubated with anti-mouse IgG acceptor beads, a biotinylated anti-ERK1/2 rabbit antibody recognising both phosphorylated and non-phosphorylated ERK1/2, a mouse antibody targeted to the Thr202/Tyr204 epitope and recognising phosphorylated ERK proteins only, and streptavidin-coated donor beads.
  • the biotinylated antibody binds to the streptavidin-coated donor beads and the phopsho-ERK1/2 antibody binds to the acceptor beads. Plates are read on an EnVision reader (Perkin Elmer) and excitation of the beads at 680 nm with a laser induces the release of singlet oxygen molecules from the donor beads that triggers energy transfer to the acceptor beads in close proximity, producing a signal that can be measured at 570 nm. Both antibodies bind to phosphorylated ERK proteins, bringing the donor and acceptor beads into close proximity.
  • Activation of ERK phosphorylation is expressed as a percentage of activation relative to the reference compound, Dabrafenib.
  • Example 3 (5-[3-(4-phenyl-1H-imidazol-2-yl)chroman-6-yl]oxy-3,4 -dihydro-1H-1,8-naphthyridin-2 -one]) shows reduced paradoxical activation of MAPK pathway in comparison to Dabrafenib.

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