1* Office de la Propriété

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CA 2960477 A1 2016/03/17

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Un organisme An agency of (12) DEMANDE DE BREVET CANADIEN
d'industrie Canada Industry Canada
CANADIAN PATENT APPLICATION
(13) A1

(86) Date de dépôt PCT/PCT Filing Date: 2015/09/11 (51) Cl.Int./Int.CI. C07D 471/04(2006.01),
A61K31/4375A61P35/00
(87) Date publication PCT/PCT Publication Date: 2016/03/17
C07D 4/75//4(2006.01)
(85) Entrée phase nationale/National Entry: 2017/03/07
(71) Demandeur/Applicant:
(86) N° demande PCT/PCT Application No.: GB 2015/052640 REDX PHARMA PLC, GB
(87) N° publication PCT/PCT Publication No.: 2016/038389 (72) Inventeurs/lnventors:
(30) Priorité/Priority: 2014/09/12 (GB1416186.3) BINGHAM, MATILDA, GB;
TESTAR, RICHARD, GB;
GIGNOUX, CAMILLE, GB
(74) Agent: BERESKIN & PARR LLP/S.E.N.C.R.L,S.R.L.

(54) Titre : COMPOSES (HETERO)AROMATIQUES BICYCLIQUES CONDENSES UTILES POUR LE TRAITEMENT DE

CANCERS
(54) Title: FUSED BICYCLIC (HETERO)AROMATIC COMPOUNDS USEFUL FOR THE TREATMENT OF CANCERS

(57) Abrégé/Abstract:
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.

Canada http://opic.gc.ca · Ottawa-Hull KIA 0C9 · http://cipo.gc.ca

OPIC-CIPO 191
O PI c CIPO
 CA 02960477 2017-03-07

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Property
Organization IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIN
International Bureau
(10) International Publication Number
(43) International Publication Date WO 2016/038389 Al
17 March 2016 (17.03.2016) WIPO I PCT

(51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every
C07D 405/14 (2006.01) A61K31/4433 (2006.01) kind of national protection available): AE, AG, AL, AM,
C07D 471/04 (2006.01) A61K 31/4439 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY,
A61K31/4375 (2006.01) A61P 35/00 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM,
DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
(21) International Application Number:
HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR,
PCT/GB2015/052640 KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG,
(22) International Filing Date: MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM,
11 September 2015 (11.09.2015) PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC,
SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN,
(25) Filing Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
(26) Publication Language: English (84) Designated States (unless otherwise indicated, for every
(30) Priority Data: kind of regional protection available): ARIPO (BW, GH,
1416186.3 12 September 2014 (12.09.2014) GB GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ,
TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU,
(71) Applicant: REDX PHARMA PLC [GB/GB]; 2nd Floor, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE,
Biohub, Mereside, Alderley Park, Alderley Edge, Cheshire DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
SK10 4TF (GB). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK,
SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
(72) Inventors: BINGHAM, Matilda; 2nd Floor, Biohub,
GW, KM, ML, MR, NE, SN, TD, TG).
Mereside, Alderly Edge, Cheshire SK10 4TF (GB). TEST-
__ AR, Richard; 2nd Floor, Biohub, Mereside, Alderly Edge, Declarations under Rule 4.17:
Cheshire SK10 4TF (GB). GIGNOUX, Camille; 2nd
— of inventorship (Rule 4.17(iv))
~~ Floor, Biohub, Mereside, Alderly Edge, Cheshire SK10
4TF (GB). Published:
(74) Agent: HGF LIMITED (LEEDS); Belgrave Hall, Bel- — with international search report (Art. 21(3))
grave Street, Leeds, West Yorkshire LS2 8DD (GB).
WO 2016/038389 Al

(54) Title: FUSED BICYCLIC (HETERO)AROMATIC COMPOUNDS USEFUL FOR THE TREATMENT OF CANCERS
(57) Abstract: 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 can­
cer, haematological tumors, lymphoma, carcinoma and leukemia.
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FUSED BICYCLIC (HETERO)AROMATIC COMPOUNDS USEFUL FOR THE TREATMENT OF CANCERS

[0001] 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
5 addition the invention contemplates processes to prepare the compounds and uses of the
compounds.

BACKGROUND

[0002] 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
10 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.

[0003] 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
15 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.

[0004] Defects in the MAPK pathway can affect the signalling within a cell and can lead to
20 uncontrolled cell growth through deviant cell division and irregular cell death. Such 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-
RApveooE can gjve rjse to uncontrolled cell growth and consequently cancer.

[0005] Thus, controlling aberrant functioning of RAF kinases by small molecule inhibition
25 presents a useful approach for the treatment of cancers.

[0006] A number of RAF inhibitors have been identified. Two such compounds are dabrafenib
and vemurafenib. 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
30 the treatment of melanoma by the US FDA. As with dabrafenib, vemurafenib is a B-RAF inhibitor,
specifically of the B-RAFV600E mutation.

[0007] 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
35 MAPK pathway. Furthermore, RAF inhibitor treatment of RAS-mutant, B-RAFWT-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
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the MAPK pathway that do not have the undesirable properties of EGFR-mediated feedback
reactivation of the MAPK pathway and MAPK pathway paradoxical activation.

[0008] A number of patents have been published describing B-RAF inhibitors. One such
publication is WO 2012/125981 which describes a compound having a structure related to
5 dabrafenib. Both compounds contain a central 5-membered heterocycle flanked by two substituted
6-membered (or higher) ring systems. In addition to WO 2012/125981, 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.

[0009] In addition to these documents fused tricyclic compounds as RAF kinase inhibitors were
10 recently disclosed in WO 2013/097224. In addition, US 2010/0197924 discloses aminotetralin
compounds with kinase inhibitory activity, specifically RAF kinase inhibitory activity and WO
2007/067444 discloses bicyclic compounds for the same purpose.

[0010] It is an aim of certain embodiments of this invention to provide new cancer treatments. In
particular, it is an aim of certain embodiments of this invention to provide compounds which have
15 comparable activity to existing cancer treatments, ideally better activity.

[0011] 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,
20 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, prostate cancer, renal cancer, sarcoma,
25 uveal melanoma and skin cancer. 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 BRAFV600E mutation. For example BRAFV800E melanoma, BRAFV600E colorectal cancer,
BRAFV800E papillary thyroid cancers, BRAFV600E low grade serous ovarian cancers, BRAFV800E
glioma, BRAFVS00E hepatobiliary cancers, BRAFV600E hairy cell leukaemia, BRAFV800E non-small cell
30 cancer, and BRAFV600E pilocytic astrocytoma.

[0012] RAF inhibitor treatment of RAS-mutant, BRAFWT-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
35 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
BRAFWT cells and which inhibit the MAPK pathway at therapeutically relevant concentrations.
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[0013] 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. Certain
embodiments also aim to reduce paradoxical activation of MAPK pathway compared to dabrafenib
5 and/or vemurafenib.

[0014] It is an aim of certain embodiments of this invention to provide compounds which exhibit
reduced cytotoxicity relative to prior art compounds and existing therapies.

[0015] 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
10 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).

[0016] Certain embodiments of the present invention satisfy some or all of the above aims.

BRIEF SUMMARY OF THE DISCLOSURE

[0017] In an aspect of the invention there is provided a compound of formula (I):

15 (l)

wherein:

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, C1-4 alkyl, C1-4 haloalkyl, Cs-e cycloalkyl, -ORA, -NRARB, SO2RA and SORA;

20 R1 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 R1 contains 1 to
4 substituents independently selected from: halo, -ORA, -NRARB, =O, -OC(O)Rc, -C(O)Rc, -
C(O)ORA, -NRAC(O)Rc, -C(O)NRARB, -SO2RC, -SORC, -NRASO2RC, -SO2NRARB, -CN, Ci-4 alkyl, Ci_
4 haloalkyl and C3-5 cycloalkyl;

25 XisN, OorS;

Y is -CR2BW or -CW;

W represents: -het1-R3 or -het2, in which het1 is a five or six membered carbocyclic ring or
heterocyclic ring, and het2 is a carbocyclic or heterocyclic ring system containing 8, 9 or 10 atoms in
a fused bicyclic ring system; and in which each of het1 and het2 may be independently unsubstituted
30 or substituted and contain 1 or 2 substituents independently selected at each occurrence from: halo,
-ORA, -CN, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, in which the aforementioned alkyl, haloalkyl and
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WO 2016/038389 PCT/GB2015/052640

cycloalkyl groups may themselves also be unsubstituted or substituted with 1 to 3 groups

independently selected from: -ORA, -CN, -NRARB;

Z is N, O, S, -CR2C, -CR2CR2D;

R2A, R2B, R2C and R2D are each independently selected at each occurrence from: H, halo, -ORA, -
5 CN, C1-4 alkyl, C1-4 haloalkyl and C3-6 cycloalkyl;

R3 is selected from substituted or unsubstituted: C1-6 alkyl, Ci-e 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 R3
contains 1 to 4 substituents independently selected from: halo, -ORA, -NRARB, -SO2RC, -SORC, -CN,
10 C1-4 alkyl, C1-4 haloalkyl, C3-e 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: -ORA, -CN, -SORC, and -NRARB;

RA and RB are each independently selected from H, Ch alkyl and C1-4 haloalkyl; and

Rc is selected from C1-4 alkyl and C1-4 haloalkyl.

15 [0018] The present invention provides pharmaceutically acceptable salts of compounds of

formula (I) and all other formulae disclosed herein.

[0019] Het1 may be a five or six membered cycloalkyl or heterocyclic ring, and het2 may be a
carbocyclic or heterocyclic ring system containing 8, 9 or 10 atoms in a fused bicyclic ring system
Preferably, het1 is a five or six membered heterocyclic ring and het2 is a heterocyclic ring system
20 containing 8, 9 or 10 atoms in a fused bicyclic ring system.

[0020] 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.

[0021] In embodiments the compound of formula (I) is a compound according to formula (la)

(la)

25 wherein A1, A2 and A3 are each independently selected from CR4 or N, and R4 is independently
selected at each occurrence from: halo, -ORA, -NRARB, =O, -CN, C1-4 alkyl, C1-4 haloalkyl and C3-6
cycloalkyl.

[0022] In preferred embodiments A is phenyl. Thus, in an embodiment, there is provided a

compound of formula (II):
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[0023] In preferred embodiments, there is provided a compound of formula (Ila):

i^YxYR2A

R<0-^Az'>Y
(Ha)

[0024] In embodiments X is O or S. Preferably, X is O.

5 [0025] In certain embodiments Z is O, CR2C or CR2CR2D. In certain embodiments Z is O and Y is

CR2BW. In certain embodiments Z is CR2CR2D and Y is CR2BW. In certain embodiments Z is CR2C
and Y is CW.

[0026] In certain embodiments X is Ο, Z is CR2CR2D and Y is CR2BW. Thus, there is provided a

compound according to formula (Illa):

[0027] In certain embodiments X is Ο, Z is CR2C and Y is CW. Thus, there is provided a

compound according to formula (I I lb):

(lllb)

[0028] In certain embodiments X is Ο, Z is O and Y is CR2BW. Thus, there is provided a

15 compound according to formula (lllc):

[0029] In certain embodiments the compound of formulae (Illa) and (lllc) may be single
enantiomers. For example, compounds of formula (Illa) may be compounds of formula (Hid) or (I I le)
and compounds of formula (lllc) may be compounds of formula (lllf) and (Illg):
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R2C R2D

(Hid)

[0030] The central bicyclic ring system of the compound of formula (Illa) is a chromane ring. The
central bicyclic ring system of the compound of formula (I lib) is a chromene ring. The central
bicyclic ring system of the compound of formula (II Ic) is a dihydrobenzodioxine ring. Each of the
5 central bicyclic ring systems are substituted with -O-R1. The atoms of each of the central bicyclic
groups are numbered as illustrated below.

The -O-R1 substituent on the chromane, chromene or dihydrobenzodioxine of formulae (Illa), (lllb)
and (IIIc) respectively may be substituted at positions 5, 6, 7, or 8. Preferably -O-R1 is substituted at
10 position 6. When -OR1 is substituted at position 6 of the chromane, chromene or
dihydrobenzodioxine of formulae (Illa), (lllb) and (lllc) respectively there is provided a compound of
formulae (IVa), (IVb) and (IVc):

[0031] In an embodiment the compounds of the invention are single enentiomers. Thus, as
15 indicated below, the compounds of the present invention may be a compound of formulae (IVd),
(IVe), (IVf) or (IVg):
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[0032] In a preferred embodiment R2A, R2B, R2C and R2D are each H. It is particularly preferred
that R2A, R2B, R2C and R2D are each H in the compounds of formulae (IVa), (IVb), (IVc), (IVd), (IVe),
(IVf) and (IVg) as appropriate.

5 [0033] R1 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, oxo-
10 tetrahydronaphthyridinyl, dihydropyrrolopyridinone (optionally a 1,3-dihydropyrrolopyridinone) and
oxo-dihydro-H-naphthyridinyl. Preferably, R1 is substituted or unsubstituted pyridyl, substituted or
unsubstituted oxo-dihydro-H-naphthyridinyl, or substituted or unsubstituted dihydropyrrolopyridinone
(optionally a 1,3-dihydropyrrolopyridinone). Further preferably, R1 is methylpyridyl or oxo-dihydro-H-
naphthyridinyl.

15 [0034] In embodiments R1 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. R1 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.
Optionally, the heterocyclic moiety contains 1,2 or 3 heteroatoms selected from N, O or S.
20 Preferably, the heterocyclic moiety contains 1 or 2 nitrogen atoms.

[0035] When R1 is substituted it is preferably substituted with halo, -ORA, -NRARB, =O, -CN, C1-4
alkyl, Ci-4 haloalkyl, -NRAC(O)Rc, -C(O)NRARB, -NRASO2RC or-S02NRARB. Preferably R1 is
substituted with -NRAC(O)RC, -C(O)NRARB, -NRASO2RC or-S02NRARB.

[0036] In preferred embodiments when R1 is substituted it is preferably substituted with fluoro,

25 chloro, -OH, -NH2, -OMe, -NHMe, -NMe2, =O, -CN, methyl, trifluoromethyl, -NHC(O)Me, -
NMeC(O)Me, -NHC(O)Et, -NMeC(O)Et, -C(O)NH2, -C(O)NHMe, -C(O)NMe2, -C(O)NHEt, -
NHSO2Me, -NMeSO2Me, -SO2NH2, -SO2NHMe, -SO2NMe2. Preferably R1 is substituted with methyl
or =O.
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[0037] R1 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,
5 dihydronappthyridinyl, tetrahydronaphthyridinyl, oxo-tetrahydronaphthyridinyl,
dihydropyrrolopyridinone (optionally a 1,3-dihydropyrrolopyridinone), and oxo-dihydro-H-
naphthyridinyl. Preferably, R1 is substituted or unsubstituted pyridyl, dihydropyrrolopyridinone
(optionally a 1,3-dihydropyrrolopyridinone) or substituted or unsubstituted oxo-dihydro-H-
naphthyridinyl. Further preferably, R1 is methylpyridyl or oxo-dihydro-H-naphthyridinyl.

10 [0038] In an embodiment, there is provided a compound of formulae (I), (II), (III) or (IV) wherein
R1 is methylpyridyl or oxo-dihydro-H-naphthyridinyl. For example, there is provided a compound of
formula (IVa) wherein R1 is methylpyridyl or oxo-dihydro-H-naphthyridinyl and R2A, R2B, R2C and R2D
are each H. Thus, in an embodiment there is provided a compound of formulae (Va) and (Vb):

15 [0039] Het1 and het2 may be substituted or unsubstituted. Het1 and het2 may not be substituted
with an oxo group, for example pyrollidinone is not a het1 group and purinone is not a het2 group
because the groups contain a substiuted oxo group. In an embodiment het2 is not purinone.

[0040] In embodiments, W represents -het1-R3 or-het2, wherein het1 is a substituted or

unsubstituted five membered carbocyclic ring or heterocyclic ring, and

20 het2 is a substituted or unsubstituted carbocyclic or heterocyclic ring system, containing 8, 9 or 10

atoms in a fused bicyclic ring system.

[0041] In embodiments, W represents -het1-R3 or-het2, wherein het1 is a substituted or

unsubstituted five membered heterocyclic ring, and

het2 is a substituted or unsubstituted heterocyclic ring system, containing 8, 9 or 10 atoms in a

25 fused bicyclic ring system.

[0042] In embodiments, W represents -het1-R3 or-het2, wherein het1 is represented by a group

selected from substituted or unsubstituted: C5-6 cycloalkyl, C6 aryl, C5-6 heterocycloalkyl orCs-e
heteroaryl, and

het2 is represented by a group selected from substituted or unsubstituted Ce-w cycloalkyl, Cw aryl,
30 Ce-ίο heterocycloalkyl or Ce-io heteroaryl.
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[0043] In embodiments, W represents -het1-R3 or-het2, wherein het1 is represented by a group

selected from substituted or unsubstituted: Cs-β cycloalkyl, Cs-β heterocycloalkyl or Cs-β heteroaryl,
and

het2 is represented by a group selected from substituted or unsubstituted Ce-w cycloalkyl, Cw aryl,
5 Cs-io heterocycloalkyl or Cs-io heteroaryl.

[0044] Het1 may be a five or six membered heterocyclic ring, and het2 may be a heterocyclic ring
system containing 8, 9 or 10 atoms in a fused bicyclic ring system

[0045] Preferably, het1 is represented by C5-6 heteroaryl and het2 is represented by Ce-io
heteroaryl. Further preferably, het1 is represented by C5 heteroaryl.

10 [0046] In any of the embodiments described herein het1 may be a five membered carbocyclic ring
or heterocyclic ring (preferably heterocyclic) which is unsubstituted or substituted and het2 may be a
9 membered carbocyclic or heterocyclic bicyclic ring system (preferably heterocyclic) which is
unsubstituted or substituted.

[0047] In embodiments het2 may be a bicyclic ring system with one of the rings of the bicyclic ring
15 system being a five membered ring. Optionally, 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 ordihydrobenzodioxine of formulae (Illa), (lllb) and (lllc) respectively.

[0048] In embodiments het1 and het2 are unsubstituted.

[0049] Het1 may be represented by substituted or unsubstituted: pyrrole, furan, thiophene,

20 pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole and triazole,
and het2 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
25 tetrahydroquinoxaline. Preferably, het1 is represented by substituted or unsubstituted: pyrazole,
imidazole or oxadiazole and het2 is represented by substituted or unsubstituted benzimidazole.

[0050] In an embodiment there are provided compounds wherein W represents -het1-R3 and
het1 is represented by substituted or unsubstituted: pyrazole, imidazole or oxadiazole. In an
alternative embodiment there are provided compounds wherein W represents -het2 and het2 is
30 represented by substituted or unsubstituted benzimidazole.

[0051] In an embodiment there are provided compounds of formulae (Illa), (lllb) and (lllc),
wherein W represents -het1-R3 and het1 is represented by substituted or unsubstituted: pyrazole,
imidazole or oxadiazole. In an alternative embodiment there are provided compounds of formulae
(Illa), (lllb) and (lllc), wherein W represents -het2 and het2 is represented by substituted or
35 unsubstituted benzimidazole.

[0052] In an embodiment there are provided compounds of formulae (IVa), (IVb) and (IVc),
wherein W represents -het1-R3 and het1 is represented by substituted or unsubstituted: pyrazole,
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10

imidazole or oxadiazole. In an alternative embodiment there are provided compounds of formulae

(IVa), (IVb) and (IVc), wherein W represents -het2 and het2 is represented by substituted or
unsubstituted benzimidazole.

[0053] In an embodiment the compounds according to formula (I) are compounds of formulae
5 (Via), (Vlb), (Vic), (Vid) or (Vie):

wherein

m is selected from 0, 1 or 2; and

R5 is independently selected at each occurrence from: halo, -ORA, C1-4 alkyl, C1-4 haloalkyl and C3-6
10 cycloalkyl.

[0054] In an embodiment the compounds according to formula (I) are compounds of formulae
(Vlf), (Vlg), (Vlh), (Vli) or(Vlj):
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wherein

m is selected from 0, 1 or 2; and

R5 is independently selected at each occurrence from: halo, -ORA, C1-4 alkyl, C1-4 haloalkyl and C3-6
5 cycloalkyl.

[0055] In an embodiment the compounds according to formula (I) are compounds of formulae
(Vlk), (Vim), (Vln), (Vlo) or (VIp):
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wherein

m is selected from 0, 1 or 2; and

R5 is independently selected at each occurrence from: halo, -ORA, C1-4 alkyl, C1-4 haloalkyl and C3-e
5 cycloalkyl.

[0056] In an embodiment there is provided compounds of formulae (Via), (Vlb), (Vic), (Vid), (Vie),
(Vlf), (Vlg), (Vlh), (Vli), (Vlj) (Vlk), (Vim), (Vln), (Vlo) or(Vlp).

[0057] In a preferred embodiment of the compounds of (Via), (Vlb), (Vic), (Vid), (Vie), (Vlf), (Vlg),
(Vlh), (Vli), (Vlj) (Vlk), (Vim), (Vln), (Vlo) or (VIp), R2A, R2B, R2C and R2D (as appropriate) are each H.

10 [0058] In an embodiment m is 0 or 1. In an embodiment R5 is halo, preferably chloro. In a

preferred embodiment m is 0 or 1 and R5 is halo, preferably chloro.

[0059] In an embodiment, there are provided compounds of formulae (Via), (Vlb), (Vic), (Vid),
(Vie), (Vlf), (Vlg), (Vlh), (Vli), (Vlj) (Vlk), (Vim), (Vln), (Vlo) or (VIp), wherein R1 is substituted or
unsubstituted pyridyl or substituted or unsubstituted oxo-dihydro-H-naphthyridinyl, preferably
15 wherein R1 is methylpyridyl or oxo-dihydro-H-naphthyridinyl.

[0060] In embodiments R3 is selected from: Ci-e 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.

20 [0061] R3 may be selected from a substituted or unsubstituted: /so-propyl, fert-butyl, phenyl,

pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl,
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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,
5 tetrahydroisoquinolinyl and tetrahydroquinoxalinyl.

[0062] Preferably, R3 may be selected from: tert-butyl. phenyl, pyridyl, benzodioxanyl,

benzofuranyl, benzodioxolanyl and thiophenyl.

[0063] When R3 is substituted it may contain 1 or 2 substituents. When R3 is substituted it may

contain 1 to 4 substituents independently selected from: halo, -ORA, -NRARB, =O, -OC(O)Rc, -
10 C(O)RC, -C(O)ORA, -NRAC(O)RC, -C(O)NRARB, -SO2RC, -SORC, -CN, Ci-4 alkyl, Ci-4 haloalkyl and
C3-6 cycloalky in which the aforementioned alkyl, haloalkyl and cycloalkyl groups may themselves
also be unsubstituted or substituted with 1 to 3 groups independently selected from: -ORA, -CN, -
SORC, and -NRARBI.

[0064] In embodiments R3 is substituted by 1 or 2 substituents selected from: chloro, fluoro,

15 methyl, ethyl, -OMe, -CN, -SO2Me, trifluoromethyl and trifluoroethyl, in particular chloro, fluoro,
methyl, ethyl, -SOzMe, trifluoromethyl and trifluoroethyl.

[0065] In embodiments RA and RB are each independently selected from H, methyl, ethyl or
trifluoromethyl and Rc is selected from methyl, ethyl or trifluoromethyl. Preferably, RA and RB are H;
RA and RB are methyl; or RA is H and RB is methyl. Preferably, Rc is methyl.

20 [0066] 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.

[0067] In particular, the invention provides the following compounds.

25
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[0068] Some of 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
5 above with a * symbol. In one embodiment the compounds of the invention have the (R)-
configuration at the stereocentre. In an alternative embodiment the compounds of the invention
have the (S)-configuration at the stereocentre.

[0069] In another aspect of the invention there is provided a compound of formula (I) for use as a
medicament.

10 [0070] In another aspect 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. Usually 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
15 of RAF kinases, optionally B-RAF or C-RAF.

[0071] RAF kinase inhibition is relevant for the treatment of many different diseases associated
with the abnormal activity of the MAPK pathway. In embodiments the 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
20 cancers, sarcomas, melanomas, skin cancers, haematological tumors, lymphomas, carcinomas and
leukemia treatable by the inhibition of RAF kinases, for example B-RAF or C-RAF, 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
25 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 lymphoma; megakaryoblastic leukemia;
30 multiple myeloma; erythroleukemia; hepatocellular carcinoma; lung cancer; small cell lung cancer;
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non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary
adenoma; prostate cancer; renal cancer; metastatic melanoma; uveal melanoma; and papilliary
thyroid cancers.

[0072] RAF kinases inhibition, for example B-RAF or C-RAF, may also be relevant to the
5 treatment of cardio-facio cutaneous syndrome and polycystic kidney disease.

[0073] In another aspect 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-RAFV60DE. Usually conditions that are
modulated by mutant RAF kinases, optionally B-RAFV800E, are conditions that would be treated by
the inhibition of mutant RAF kinases, optionally B-RAFV600E, using a compound of the present
10 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-RAFV600E. In embodiments the condition treatable by
the inhibition of mutant RAF kinases, for example B-RAFV600E, may be selected from: BRAFV600E
melanoma, BRAFV800E colorectal cancer, BRAFV800E papillary thyroid cancers, BRAFV800E low grade
serous ovarian cancers, BRAFV600E glioma, BRAFV800E hepatobiliary cancers, BRAFV800E hairy cell
15 leukaemia, BRAFV600E non-small cell cancer, and BRAFV600E pilocytic astrocytoma.

[0074] In an embodiment the conditions treatable by the inhibition of RAF kinases, 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. In particular, the condition
treatable by the inhibition of RAF kinases, for example B-RAF or C-RAF, may be colorectal cancer
20 or melanoma.

[0075] 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

[0076] In an aspect of the invention, a compound of the invention may be for use in the treatment
25 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 that may be treated by the
compound of the invention may be selected from: Barret’s adenocarcinoma; biliary tract
carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors;
30 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);
35 myelodysplastic syndromes; chronic myelogenous leukemia; hairy cell leukaemia; 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; uveal melanoma; and papilliary thyroid cancers.
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[0077] In an embodiment 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. In particular, the compound of the invention
may be for use in the treatment of colorectal cancer or melanoma.

5 [0078] In an aspect of the invention there is provided a method of treatment of a condition which
is modulated by RAF kinases, wherein the method comprises administering a therapeutic amount of
a compound of the invention, to a patient in need thereof.

[0079] 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
10 conditions treatable by the inhibition of RAF kinases.

[0080] In an aspect of the invention there is provided 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,
15 skin cancers, haematological tumors, lymphomas, carcinomas and leukemia that may be treated by
the method of treatment 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
20 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 lymphoma; megakaryoblastic leukemia; multiple myeloma; erythroleukemia;
25 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; uveal melanoma; and papilliary thyroid cancers.

[0081] In an embodiment the method may be for treating a condition selected from: melanoma,
non-small cell cancer, colorectal cancer, ovarian cancer, thyroid cancer, breast cancer and
30 cholangiocarcinoma, wherein the method comprises administering a therapeutic amount of a
compound of the invention to a patient in need thereof. In particular, method may be for treating
colorectal cancer or melanoma.

[0082] In another aspect of the invention there is provided a pharmaceutical composition,

wherein the composition comprises a compound of the invention and one or more pharmaceutically
35 acceptable excipients.

[0083] In an embodiment 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.
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[0084] In an aspect of the invention there is provided a use of 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 orC-RAF. The condition may be any of the conditions mentioned above.

[0085] In any of the aspects or embodiments of the invention the RAF kinases may be B-RAF or
5 C-RAF. In any of the aspects or embodiments of the invention the B-RAF kinase may be the B-RAF
V600E mutant. Thus, the compounds of the invention may be utilised in the treatment of a condition
which is modulated by B-RAF and/or C-RAF. Similarly, the compounds of the invention may be
utilised in the treatment of conditions treatable by the inhibition of B-RAF and/or C-RAF.
Furthermore, the compounds of the invention may be utilised in the treatment of a condition which is
10 modulated by B-RAFV60°. In addition compounds of the invention may be utilised in the treatment of
conditionstreatable by the inhibition of B-RAFV600E. B-RAFV600E 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.

[0086] In an aspect of the invention there is provided a use of a compound of the invention for
15 preventing cutaneous squamous cell carcinoma during the treatment of melanomas.

BRIEF DESCRIPTION OF THE DRAWINGS

[0087] Embodiments of the invention are further described hereinafter with reference to the
accompanying drawings, in which:

Figure 1 is a graph showing reduced paradoxical activation of MAPK pathway for a

20 compound of the invention (Example 3).

DETAILED DESCRIPTION

[0088] Given below are definitions of terms used in this application. Any term not defined herein
takes the normal meaning as the skilled person would understand the term.

[0089] The term “halo” refers to one of the halogens, group 17 of the periodic table. In particular
25 the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or
chlorine.

[0090] The term “Ci-e 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, /so-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
30 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, Ci-e alkoxy.

35 [0091] The term “Ci-s 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
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or 6 carbon atoms, for example methyl, ethyl, n-propyl, /so-propyl, n-butyl, sec-butyl, tert-butyl, n-
pentyl and n-hexyl. Therefore, the alkoxy group may be methoxy, ethoxy, n-propoxy, /so-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
5 below. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine,
OH, Ci-6 alkoxy.

[0092] The term “Ci-β 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. For example, Ci-e
10 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. 1-
fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g. 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl,
chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl.

[0093] The term “C2-6 alkenyl” refers to a branched or linear hydrocarbon chain containing at least
15 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. For
example, the “C2-6 alkenyl” may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl,
hexenyl and hexadienyl.

[0094] The term “C2-6 alkynyl” refers to a branched or linear hydrocarbon chain containing at least
20 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. For example, the “C2-6 alkynyl” may be ethynyl, propynyl, butynyl,
pentynyl and hexynyl.

[0095] The term “C1-6 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
25 between any carbon in the chain or at an end of the chain. For example, the hydrocarbon chain may
contain one or two heteroatoms. The Ci-β heteroalkyl may be bonded to the rest of the molecule
through a carbon or a heteroatom. For example, the “Ci-β heteroalkyl” may be Ci-e /V-alkyl,
C1-6 N,/V-alkyl, or C1-6 O-alkyl.

[0096] The term “carbocyclic” refers to a saturated or unsaturated carbon containing ring system.
30 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.

35 [0097] The term “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
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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. For example, the heterocyclic group may be: oxirane,
5 aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine,
oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine,
piperazine, and tetrahydropyran.

[0098] The term “C3-8 cycloalkyl” refers to a saturated hydrocarbon ring system containing 3, 4, 5,
6, 7 or 8 carbon atoms. For example, the “C3-8 cycloalkyl” may be cyclopropyl, cyclobutyl,
10 cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0099] The term “C3-8 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. For example, the “C3-8 cycloalkyl” may be
cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly,
15 cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.

[00100] The term “C3-8 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
5. For example there may be 1,2 or 3 heteroatoms, optionally 1 or 2. The “C3-8 heterocycloalkyl”
may be bonded to the rest of the molecule through any carbon atom or heteroatom. The “C3-8

20 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. For example, the “C3-8 heterocycloalkyl" may be
oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide,
pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine,
thiomorpholine, piperazine, and tetrahydro pyran.

25 [00101] The term “C3-8 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 “C3-8 heterocycloalkenyl” may be bonded to the rest of the molecule through any carbon atom
or heteroatom. The “C3-8 heterocycloalkenyl” may have one or more, e g. one or two, bonds to the
30 rest of the molecule: these bonds may be through any of the atoms in the ring. For example, the
“C3-8 heterocycloalkyl” may be tetrahydro pyridine, dihydropyran, dihydrofuran, pyrroline.

[00102] The term “aromatic” when applied to a substituent as a whole means a single ring or
polycyclic ring system with 4n + 2 electrons in a conjugated π system within the ring or ring system
where all atoms contributing to the conjugated π system are in the same plane.

35 [00103] The term “aryl” refers to an aromatic hydrocarbon ring system. The ring system has 4n +2
electrons in a conjugated π system within a ring where all atoms contributing to the conjugated π
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system are in the same plane. For example, the “aryl” may be phenyl and naphthyl. The aryl system
itself may be substituted with other groups.

[00104] The term “heteroaryl” refers to an aromatic hydrocarbon ring system with at least one
heteroatom within a single ring orwithin a fused ring system, selected from Ο, N and S. The ring or
5 ring system has 4n +2 electrons in a conjugated π system where all atoms contributing to the
conjugated π system are in the same plane. For example, the “heteroaryl" may be imidazole,
thiene, furane, thianthrene, pyrrol, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and
indole.

[00105] The term “alkaryl” refers to an aryl group, as defined above, bonded to a Ci-4 alkyl, where
10 the Ci-4 alkyl group provides attachment to the remainder of the molecule.

[00106] The term “alkheteroaryl" refers to a heteroaryl group, as defined above, bonded to a
C1-4 alkyl, where the alkyl group provides attachment to the remainder of the molecule.

[00107] The term “halogen” herein includes reference to F, Cl, Br and I. Halogen may be Cl.
Halogen may be F.

15 [00108] 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.

[00109] Where a moiety is substituted, it may be substituted at any point on the moiety where
20 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, NHR9, amidino, guanidino,
hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, C(O)H, acyl, acyloxy, carboxy,
25 sulfo, sulfamoyl, carbamoyl, cyano, azo, nitro, halo, Ci-β alkyl, Ci-s alkoxy, Ci-β haloalkyl, C3-8
cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl or alkaryl. Where the group to be substituted is
an alkyl group the substituent may be =O. Where the moiety is substituted with two or more
substituents and two of the substituents are adjacent the adjacent substituents may form a C4-8 ring
along with the atoms of the moiety on which the substituents are substituted, wherein the C48 ring is
30 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.

[00110] Substituents are only present at positions where they are chemically possible, the person
skilled in the art being able to decide (either experimentally or theoretically) without inappropriate
effort which substitutions are chemically possible and which are not.
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[00111] Ortho, meta and para substitution are well understood terms in the art. For the absence of
doubt, “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 “ ”,

5 H

[00112] “Meta” 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.
For example the groups below are meta substituted.

10 H

[00113] “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.
For example the groups below are para substituted.

15

[00114] By “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, Ci-6 alkyl, C3-8 cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or C1-3 alkyl. In one
embodiment acyl is alkyl-carbonyl. Examples of acyl groups include, but are not limited to, formyl,
20 acetyl, propionyl and butyryl. A particular acyl group is acetyl.

[00115] Throughout the description the disclosure of a compound also encompasses

pharmaceutically acceptable salts, solvates and stereoisomers thereof. Where a compound has a
stereocentre, both (/?) and (S) stereoisomers are contemplated by the invention, equally mixtures of
stereoisomers or a racemic mixture are completed by the present application. Where a compound
25 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
30 the enantiomeric excess may be any of those disclosed above. Where the compound is a single
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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%

[00116] In embodiments where there is a single enantiomer of the compounds of the invention, the
5 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). In
embodiments where there is a mixture of enantiomers of the compounds of the invention, the
compounds of the invention may be a racemic mixture or any other mixture of enantiomers, for
10 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).

[00117] The invention contemplates pharmaceutically acceptable salts of the compounds of

15 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.

[00118] 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,
20 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, succinate, tartrate,
25 tosylate and trifluoroacetate salts.

[00119] 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. For a review
30 on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl
and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[00120] Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or
more of three methods:

(i) by reacting the compound of formula (I) with the desired acid or base;
35 (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the
compound of formula (I) or by ring-opening a suitable cyclic precursor, for example, a lactone or
lactam, using the desired acid or base; or
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(iii) by converting one salt of the compound of formula (I) to another by reaction with an
appropriate acid or base or by means of a suitable ion exchange column.

[00121] All three reactions are typically carried out in solution. The resulting salt may precipitate
out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of
5 ionisation in the resulting salt may vary from completely ionised to almost non-ionised.

[00122] The compounds of the invention may exist in both unsolvated and solvated forms. The
term '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. The term 'hydrate' is employed when said solvent is water.

10 [00123] Included within the scope of the invention are 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. Also included are 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.
15 For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

[00124] Hereinafter all references to compounds of any formula include references to salts,
solvates and complexes thereof and to solvates and complexes of salts thereof.

[00125] 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
20 optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled
compounds of the invention.

[00126] Before purification, 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. Thus the invention covers individual enantiomers as well
25 as mixtures thereof.

[00127] For some of the steps of the process of preparation of the compounds of formula (I), it
may be necessary to protect potential reactive functions that are not wished to react, and to cleave
said protecting groups in consequence. In such a case, any compatible protecting radical can be
used. In particular methods of protection and deprotection such as those described by T.W.
30 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. All of the above
reactions and the preparations of novel starting materials used in the preceding methods are
conventional and appropriate reagents and reaction conditions fortheir performance or preparation
as well as procedures for isolating the desired products will be well-known to those skilled in the art
35 with reference to literature precedents and the examples and preparations hereto.
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[00128] Also, 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.

[00129] The method of treatment or the compound for use in the treatment of cancer, sarcoma,
5 melanoma, skin cancer, haematological tumors, lymphoma, carcinoma and leukemia as defined
hereinbefore may be applied as a sole therapy or be a combination therapy with an additional active
agent.

[00130] 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,
10 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:

(i) 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
15 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, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase
20 inhibitors); proteasome inhibitors, for example carfilzomib and bortezomib; interferon therapy; and
topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide,
amsacrine, topotecan, mitoxantrone and camptothecin);

(ii) cytostatic agents such as antiestrogens (for example tamoxifen, fulvestrant, toremifene,
raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide,
25 nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin,
leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for

example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such

as finasteride;

(iii) anti-invasion agents, for example dasatinib and bosutinib (SKI-606), and metalloproteinase
30 inhibitors, inhibitors of urokinase plasminogen activator receptor function or antibodies to
Heparanase;

(iv) inhibitors of growth factor function: for example such inhibitors include growth factor
antibodies and growth factor receptor antibodies, for example the anti-erbB2 antibody trastuzumab
[Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine
35 kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR
family tyrosine kinase inhibitors such as gefitinib, erlotinib and 6-acrylamido-/V-(3-chloro-4-
fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase
inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin
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growth factor family; modulators of protein regulators of cell apoptosis (for example Bcl-2 inhibitors);
inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (AMN107);
inhibitors of serine/threonine kinases (for example Ras/RAF signalling inhibitors such as farnesyl
transferase inhibitors, for example sorafenib, tipifarnib and lonafarnib), inhibitors of cell signalling
5 through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3
kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor, kinase inhibitors; aurora kinase inhibitors
and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;

(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth
factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab
10 (Avastin™); thalidomide; lenalidomide; and for example, a VEGF receptor tyrosine kinase inhibitor
such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib;

(vi) gene therapy approaches, including for example approaches to replace aberrant genes such
as aberrant p53 or aberrant BRCA1 or BRCA2;

(vii) immunotherapy approaches, including for example antibody therapy such as alemtuzumab,
15 rituximab, ibritumomab tiuxetan (Zevalin®) and ofatumumab; interferons such as interferon a;
interleukins such as IL-2 (aldesleukin); interleukin inhibitors for example IRAK4 inhibitors; cancer
vaccines including prophylactic and treatment vaccines such as HPV vaccines, for example
Gardasil, Cervarix, Oncophage and Sipuleucel-T (Provenge); toll-like receptor modulators for
example TLR-7 orTLR-9 agonists; and PD-1 antagonists, PDL-1 antagonists, and IDO-1
20 antagonists; and

(viii) cytotoxic agents for example fludaribine (fludara), cladribine, pentostatin (Nipent™);

(ix) steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for

example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone,
beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone
25 sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate,
clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide,
desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone
isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone
acetonide, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate,
30 fluocortolone pivalate, fluoromethoIone, fluprednidene, fluprednidene acetate, flurandrenolone,
fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate,
hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone
valerate, icomethasone, icomethasone enbutate, meprednisone, methylprednisolone, mometasone
paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone,
35 tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their
respective pharmaceutically acceptable derivatives. A combination of steroids may be used, for
example a combination of two or more steroids mentioned in this paragraph;

(x) targeted therapies, for example PI3Kd inhibitors, for example idelalisib and perifosine.
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[00131] Such combination treatment may be achieved byway 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.

5 [00132] According to a further aspect of the invention there is provided a pharmaceutical

product comprising a compound of formula (I), ora 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.

10 [00133] According to a further aspect of the invention there is provided 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 salt
thereof simultaneously, sequentially or separately with an additional anti-tumor agent, as defined
hereinbefore, to a patient in need thereof.

15 [00134] According to a further aspect of the invention there is provided 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.

[00135] According to another aspect of the invention there is provided a use of the compound of
20 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.

[00136] According to a further aspect there is provided a method of providing a combination

25 product, wherein the method comprises 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.
Alternatively the method may comprise providing the anti-tumor agent as separate dosage forms.

[00137] According to a further aspect there is provided a method of providing a combination

30 product, wherein the method comprises 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.
Alternatively the method may comprise providing the anti-tumor agent as separate dosage forms.

[00138] The condition modulated by a RAF kinase, for example B-RAF or C-RAF, described
35 above may be cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma,
carcinoma and leukemia. More specifically the condition modulated by a RAF kinase, for example
B-RAF or C-RAF, may be selected from: Barret’s adenocarcinoma; biliary tract carcinomas; breast
cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors; primary CNS tumors;
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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
5 lymphoblastic leukemia; acute myelogenous leukemia (AML); myelodysplastic syndromes; chronic
myelogenous leukemia; hairy cell leukaemia; 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
10 papilliary thyroid cancers. In particular, the 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 .

[00139] Compounds of the invention may exist in a single crystal form or in a mixture of crystal
forms or they may be amorphous. Thus, compounds of the invention intended for pharmaceutical
15 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.

[00140] For the above-mentioned compounds of the invention the dosage administered will, of
20 course, vary with the compound employed, the mode of administration, the treatment desired and
the disorder indicated. For example, if the compound of the invention is administered orally, then
the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per
kilogram body weight (qg/kg) to 100 milligrams per kilogram body weight (mg/kg).

[00141] A compound of the invention, or pharmaceutically acceptable salt thereof, may be used on
25 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. Conventional procedures for the selection
and preparation of suitable pharmaceutical formulations are described in, for example,
"Pharmaceuticals - The Science of Dosage Form Designs", Μ. E. Aulton, Churchill Livingstone,
30 1988.

[00142] Depending on the mode of administration of the compounds of the invention, the
pharmaceutical composition which is used to administer the compounds of the invention will
preferably comprise from 0.05 to 99 %w (per cent 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
35 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.

[00143] The pharmaceutical compositions may be administered topically (e.g. to the skin) in the
form, e.g., ofcreams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral
administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral
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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.

[00144] For oral administration the compounds of the invention may be admixed with an adjuvant
5 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. If coated tablets
are required, the cores, prepared as described above, may be coated with a concentrated sugar
10 solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic
solvent.

[00145] For the preparation of soft gelatine capsules, the compounds of the invention may be
admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may
15 contain granules of the compound using eitherthe above-mentioned excipients fortablets. Also
liquid or semisolid 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. Optionally such liquid preparations may
20 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.

[00146] For intravenous (parenteral) administration the compounds of the invention may be
administered as a sterile aqueous or oily solution.

25 [00147] 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.

[00148] 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
30 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.

35 [00149] EXAMPLES AND SYNTHESIS

[00150] Solvents, reagents and starting materials were purchased from commercial vendors and
used as received unless otherwise described. All reactions were performed at room temperature
unless otherwise stated. Reactions heated in a microwave used a Biotage® Initiator Sixty.
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Compound identity and purity confirmations were performed by LCMS UV using a Waters Acquity
SQ Detector 2 (ACQ-SQD2#LCA081). The diode array detector wavelength was 254nM and the
LCMS was in positive and negative electrospray mode (m/z: 150-800). A 2pL aliquot was injected
onto a guard column (0.2pm x2 mm filters) and UPLC column (C18, 50 x2.1 mm, < 2pm) in
5 sequence maintained at 40 °C. The samples were eluted at a flow rate of 0.6mL/min with a mobile
phase system composed of A (0.1% (v/v) Formic Acid in Water) and B (0.1% (v/v) Formic Acid in
Acetonitrile) according to the gradients outlined in Table 1 below. Retention times RT are reported
in minutes.

Table 1
10

Long Short
Time (min) %A %B Time (min) %A %B
0 95 5 0 95 5
1.1 95 5 0.3 95 5
6.1 5 95 2 5 95
7 5 95 2.6 95 5
7.5 95 5 3 95 5
8 95 5

[00151]

[00152] Chiral column conditions as follows:

15 Table 2

Instrument Agilent 1100 HPLC-DAD

Column Chiralcel OZ-RH,
4.6 x 150 mm, 5 μΜ
Analysis wavelength (nm) 254 nm
Flow Rate (mL/min) 1.10 mL/min
Mobile Phase A 20 mM Ammonium bicarbonate (pH 9.0)
Mobile Phase B Acetonitrile
Standard diluent 1 mL Acetonitrile
Sample diluent 1 mL Methanol

Isocratic conditions Time %A % B

(min)
0 40 60
20 40 60

[00153] NMR was also used to characterise final compounds. NMR spectra were obtained on a
Bruker AVIII 400 Nanobay with 5mm BBFO probe.

20 [00154] Compound purification was performed by flash column chromatography on silica using a
Biotage® Isolera One or by preparative LCMS. LCMS purification was performed using a Waters
3100 Mass detector in positive and negative electrospray mode (m/z: 150-800) with a Waters 2489
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UV/Vis detector. Samples were eluted at a flow rate of 20mL/min on a XBridgeTM prep C18 5μΜ
OBD 19x100mm column with a mobile phase system composed of A (0.1% (v/v) Formic Acid in
Water) and B (0.1% (v/v) Formic Acid in Acetonitrile) according to the gradient outlined in Table 2
below.

5 Table 3

Time (min) %A %B

0 70 30

1.5 70 30

11.7 5 95

13.7 5 95

14 70 30

15 70 30

[00155] Chemical names were generated using mol2nam - Structure to Name Conversion by
OpenEye Scientific Software. Starting materials were purchased from commercial sources or
synthesised according to literature procedures.

10 [00156] Abbreviations: DCM - Dichloromethane; EtOAc - Ethyl acetate; MeOH - methanol; DMF
- Dimethylacetamide; Hept - Heptane; pet. Ether - 40/60 petroluem ether; Et2O - Diethyl ether;
‘BuOH - tert butanol; hr(s)- hour or hours; sat - saturated; NaH - sodium hydride 60% in mineral
oil; NaHCO3 - sodium hydrogen carbonate; CS2CO3 - Cesium carbonate; Brine - saturated
aqueous sodium chloride solution; Na2SO4 - anhydrous sodium sulphate; NH4OAc - ammonium
15 acetate; Sat aq NH4CI - saturated aqueous ammonium chloride; AcOH - acetic acid; HCI - 1N
aqueous hydrochloric acid; TFA - trifluoroacetic acid; SCX-2 - strong cationic resin; NEt3 -
triethylamine; DIPEA - Diisopropylethylamine.; MW - microwave irradiation; HATU - 1-
[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] pyridinium 3-oxid hexafluorophosphate;
DMP - Dess-Martin Periodinane; CDCI3 - deuterated chloroform; MeOD4 - deuterated Methanol;
20 de-DMSO - deuterated dimethylsulfoxide; Na - sodium; ‘Bu - tert butyl.

[00157] Preparation of intermediates useful in the synthesis of compounds of the invention.

[00158] Intermediate 1: 5-fluoro-3,4-dihydro-1H-1,8-naphthyridin-2-one (prepared according to

J. Med. Chem. 2011,54, 1836-1846.)

25 [00159] Intermediate 2: 6-hydroxychromane-3-carboxylic acid

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[00160] Step 1.

[00161] To a solution of 2,5-dihydroxybenzaldehyde (5.33 g, 38.59 mmol) and pyridinium p-

toluenesulfonate (0.97 g, 3.86 mmol) in DCM (165 mL) was added 3,4-dihydro-2H-pyran (3.8 mL,
5 41.68 mmol) dropwise. The reaction was stirred for 18 hrs, diluted with DCM (150 mL), washed sat.
aq. NaHCCh (250 mL)/brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The
aqueous layer was extracted with EtOAc (400 mL), dried (Na2SO4), filtered and concentrated in
vacuo. The combined organic residues were purified by flash column chromatography (0-10%
EtOAc/Hept) to provide 2-hydroxy-5-tetrahydropyran-2-yloxy-benzaldehyde (8.17 g, 95% yield) as a
10 yellow solid.
LCMS (ES+, Short): RT 1.66 min, m/z 223.2 [M+H]+
Ή NMR (400MHz, CDCb) δ: 10.69 (1H, s), 9.84 (1H, d, J=0.5 Hz), 7.28-7.24 (2H, m), 6.94-6.90
(1H, m), 5.34 (1H, t, J=3.3 Hz), 3.95-3.87 (1H, m), 3.66-3.59 (1H, m), 2.04-1.93 (1H, m), 1.90-1.83
(2H, m), 1.76-1.60 (3H, m).

15 [00162] Step 2:

To a solution of 2-hydroxy-5-tetrahydropyran-2-yloxy-benzaldehyde (4.0 g, 18 mmol) in DMF (60

mL) was added K2CO3 (2.49 g, 18 mmol) and tert-butyl acrylate (3.95 mL, 27 mmol). The mixture
was heated at 100 °C for 1 hr, then slowly raising the temperature from 100 °C to 135 °C (over 2
hrs) and maintained at 135 °C for 18 hrs. The reaction was cooled, concentrated in vacuo and the
20 residue was partitioned between DCM (300 mL) and water (250 mL). The aqueous layer was
extracted with DCM (250 mL), EtOAc (250 mL) and the combined organic layers were dried
(Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column
chromatography (0-10% EtOAc/Hept) to provide tert-butyl 6-tetrahydropyran-2-yloxy-2H-chromene-
3-
carboxylate (2.13 g, 36% yield) as a yellow solid.
25 LCMS (ES+, Short) RT 2.21 min. m/z 277.2 [M+H-'Buf
Ή NMR (400MHz, CDCb) δ: 7.31 (1H, br s), 6.94 (1H, dd, J=2.8, 8.6 Hz), 6.89 (1H, d, J=2.8 Hz),
6.79 (1H, d, J=8.7 Hz), 5.31 (1H, t, J=3.2 Hz), 4.93-4.89 (2H, m), 3.98-3.89 (1H, m), 3.66-3.58 (1H,
m), 2.05-1.95 (1H, m), 1.90-1.83 (2H, m), 1.73-1.60 (3H, m), 1.55 (9H, s).

[00163] Step 3

30 A solution of tert-butyl 6-tetrahydropyran-2-yloxy-2H-chromene-3-carboxylate (2.15 g, 6.47 mmol) in

MeOH (180 mL) was hydrogenated on the H Cube (10%Pd/C cartridge) for 26 hrs. The solution
was concentrated in vacuo to provide crude tert-butyl 6-tetrahydropyran-2-yloxychromane-3-
carboxylate (2.01 g, 93% yield) as a pale yellow oil.

LCMS (ES+, Short) RT2.10 min, m/z 357.3 [M+Na]+

35 [00164] Step 4:
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To a solution of tert-butyl 6-tetrahydropyran-2-yloxychromane-3-carboxylate (2.01 g, 6.01 mmol) in

MeOH (30 mL) was added pyridinium p-toluenesulfonate (194 mg, 0.77 mmol) and the mixture was
stirred for 18 hrs. The reaction was concentrated in vacuo, partitioned between EtOAc (150 mL) and
water (50 mL), washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The
5 residue was purified by flash column chromatography (0-30% EtOAc/Hept) to provide tert-butyl 6-
hydroxychromane-3-carboxylate (1.48 g, 98% yield) as an off white solid.
LCMS (ES+, Short) RT 1.63 min, m/z 273.2 [M+Na]+
Ή NMR (400MHz, CDCb) δ: 6.71 (1H, d, J=8.5 Hz), 6.63-6.57 (2H, m), 4.52 (1H, s), 4.40 - 4.34
(1H, m), 4.07-4.00 (1H, m), 3.06-2.87 (3H, m), 1.48 (9H, s).

10 [00165] Step 5:

To a solution of tert-butyl 6-hydroxychromane-3-carboxylate (1.48 g, 5.91 mmol) in DCM (20mL)

was added TFA (10 mL, 130.68 mmol) and the mixture stirred for 18hrs. Further TFA (10 mL,
130.68 mmol) was added and the reaction stirred for 72 hrs. The reaction was concentrated in
vacuo to provide 6-hydroxychromane-3-carboxylic acid (1.267 g, 110% yield) as an off white solid.
15 LCMS (ES; Short) RT 1.03 min, m/z 193.1 [M-H]’

Ή NMR (400MHz, CDsOD) δ: 6.61-6.56 (1H, m), 6.53-6.49 (2H, m), 4.33-4.25 (1H, m), 4.10-4.03
(1H, m), 2.99-2.88 (3H, m).

[00166] Intermediate 3: 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-

carboxylic acid

OH

20 O

A mixture of 5-fluoro-3,4-dihydro-1H-1,8-naphthyridin-2-one (500.mg, 3.01 mmol), 6-

hydroxychromane-3-carboxylic acid (642.8 mg, 3.31 mmol) and Cs2CO3 (2.94 g, 9.03 mmol) in DMF
(15 mL) was split into 2 MW vials and irradiated at 150 °C for 1 hr. The combined reactions were
diluted with water (100 mL), stirred for 10 mins, pH adjusted to ~ 3 and the precipitate was filtered
25 and dried. The precipitate was purified by SCX-2 and flash column chromatography (1-10%
MeOH/DCM) to provide intermediate 3 [6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-
yl)oxy]chromane-3-carboxylic acid] (335 mg, 33% yield) as a light brown solid.
LCMS (ES+, Short) RT 1.25 min, m/z 341.3 [M+H]+

[00167] Intermediate 4: 6-hydroxy-2H-chromene-3-carboxylic acid

.OH
HO
30 O

[00168] Step 1
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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).

LCMS (ES; Short) RT 1.73 min, m/z 247.2 [M-H]’

5 Ή NMR (400MHz, DMSO) δ: 9.17 (1H, s), 7.34-7.31 (1H, m), 6.73-6.71 (1H, m), 6.70-6.67 (2H, m),
4.67 (2H, d, J=1.4 Hz), 1.49 (9H, s).

[00169] Step 2

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
10 (Intermediate 2, step 5).

LCMS (ES-, Short) RT 1.13 min. m/z 191.2 [M-H]’

[00170] Intermediate 5: 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]-2H-chromene-3-

carboxylic acid

15 [00171] 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]-2H-chromene-3-carboxylic acid

(Intermediate 5) was prepared using the material 5-fluoro-3,4-dihydro-1 H-1,8-naphthyridin-2-one
(Intermediate 1) and 6-hydroxy-2H-chromene-3-carboxylic acid (Intermediate 4) following the
synthetic procedure for 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic
acid (Intermediate 3)

20 LCMS (ES+, Short) RT 1.31 min, m/z 339.1 [M+H]+

Ή NMR (400MHz, de-DMSO) δ: 12.90 (1H, brs), 10.49 (1H, s), 7.97 (1H, d, J= 5.8 Hz), 7.47-7.43
(1H, m), 7.21 (1H, d, J= 2.9 Hz), 7.09-7.05 (1H, m), 6.94 (1H, d, J=8.8 Hz), 6.29 (1H, d, J=5.8 Hz),
4.94 (2H, d, J=1.4 Hz), 2.96-2.90 (2H, m), 2.57-2.51 (2H, m).

[00172] Examples:

25 [00173] Example 1: 5-(3-(1 H-benzimidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-1 H-1,8-

naphthyridin-2-one

To a mixture of o-phenylenediamine (20.27 mg, 0.19 mmol), 6-[(7-oxo-6,8-dihydro-5H-1,8-

naphthyridin-4-yl)oxy]chromane-3-carboxylic acid (58 mg, 0.17 mmol) and DIPEA (0.12 mL, 0.66
30 mmol) in DMF (2 mL) was added HATU (73.21 mg, 0.19 mmol). The mixture was stirred for 20 hrs,
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diluted with EtOAc (40 mL), washed brine (2 X 30 mL), dried (Na2SO4), filtered and concentrated in
vacuo.
The residue was dissolved in AcOH (2 mL), heated at 80 °C for 4 hrs and concentrated in vacuo.
The residue was diluted with sat. aq. Na2CO3 (30 mL), extracted with EtOAc (75, 50 mL) and the
5 combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was
purified by flash column chromatography (0-6% MeOH/DCM) to provide 5-(3-(1 H-benzimidazol-2-
yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one (40 mg, 57% yield) as an off white solid.

LCMS: (ES+, Long): RT2.11 min, m/z 413.3 [M+H]+

1H NMR shows a mixture of confirmers:

10 Ή NMR (400 MHz, de-DMSO) δ: 12.61 (1H, brs), 10.47 (1H, s), 7.97 (1H, d, J=5.9 Hz), 7.57-7.50
(2H, m), 7.26-7.14 (2H, m), 7.03 (1H, d, J=2.6 Hz), 6.94 (0.2H, d, J=2.7 Hz), 6.92 (0.8H, d, J=2.7
Hz), 6.90 (0.8H, S), 6.88 (0.2H, s), 6.28 (1H, d, J=5.8 Hz), 4.64-4.56 (1H,m), 4.33-4.26 (1H, m),
3.64-3.55 (1H, m), 3.27-3.18 (2H, m), 2.97-2.90 (2H, m), 2.57-2.52 (2H, m).

[00174] Example 2: 5-[3-(7-chloro-1H-benzimidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-

15 1,8-
naphthyridin-2-one

,o.
Cl

To a solution of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic acid (50

mg, 0.15 mmol) and 3-chlorobenzene-1,2-diamine (22 mg, 0.15 mmol) in DMF (2 mL) was added
DIPEA (0.1 mL, 0.5700mmol) and HATU (62.56 mg, 0.16 mmol) . The mixture was stirred for 24
20 hrs, diluted with water (15 mL) and extracted with EtOAc (60, 30 mL). The combined organic layers
were washed with brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo.
The residue was dissolved in AcOH (3 mL), heated at 80 °C for 20 hrs, cooled and concentrated in
vacuo. The residue was diluted with sat. aq. Na2CO3 (30 mL), extracted with EtOAc (75, 50 mL) and
the combined organic layers were washed with brine (30 mL), dried (Na2SO4), filtered and
25 concentrated in vacuo. The residue was purified by flash column chromatography (0-5% and 2-5%
MeOH/DCM) and prep HPLC to provide 5-[3-(7-chloro-1 H-benzimidazol-2-yl)chroman-6-yl]oxy-3,4-
dihydro-1H-1,8-naphthyridin-2-one (22.9 mg, 35% yield) as an off white solid.
LCMS (ES+, Long): RT 3.26 min, m/z 447.0, 449.0 [M+H]+

1H NMR shows a mixture of confirmers:

30 Ή NMR (400 MHz, d6-DMSO) δ: 12.82 (1H, brs), 10.47 (1H, s), 7.97 (1H, d, J=5.8 Hz), 7.54-7.44
(2H, m), 7.24 (1H, d, J=7.4 Hz), 7.17 (1H, t, J=7.8 Hz), 7.05 (1H, d, J=2.4 Hz), 6.95 (0.2H, d, J= 2.6
Hz), 6.93 (0.8H, d, J=2.6 Hz), 6.92 (0.8H, s), 6.89 (0.2H, s), 6.28 (1H, d, J=5.8 Hz), 4.65-4.57 (1H,
m), 4.29 (0.5H, d, J= 9.7 Hz), 4.27 (0.5H, 9.6 Hz), 3.68-3.57 (1H, m), 3.27-3.12 (1H, m), 2.94 (2H, t,
J=7.7 Hz), 2.57-2.53 (2H, m).
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[00175] Example 3: 5-[3-(4-phenyl-1H-imidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-

naphthyridin-2-one]

To a solution of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic acid (80

5 mg, 0.24 mmol) in DMF (2 mL) was added K2CO3 (97.48 mg, 0.71 mmol) and 2-
bromoacetophenone (93.59 mg, 0.47 mmol). The reaction was stirred for 30 mins, diluted with
water (30 mL) and extracted with EtOAc (2 X 50 mL). The combined organic layers were washed
with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by
flash column chromatography (0-5%MeOH/DCM) to provide a yellow solid (66 mg).
10 The residue as dissolved in AcOH (1 mL) and added to a solution of NH4OAC (181.22 mg,
2.35mmol) in AcOH (1 mL). The mixture was heated at 120 °C in a sealed vial for 72 hrs, cooled
and concentrated in vacuo. The residue was diluted with sat. aq. NaHCO3 (30 mL) and extracted
with EtOAc (2 X 50 mL). The combined organic layers were washed with brine (30 mL), dried
(Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column
15 chromatography (0-5% and 2-5% MeOH/DCM) to provide 5-[3-(4-phenyl-1H-imidazol-2-yl)chroman-
6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one (20.2 mg, 20% yield) as an orange solid.
LCMS: (ES+, Long): RT2.65 min, m/z 439.2 [M+H]+

1H NMR shows a mixture of confirmers:

Ή NMR (400MHz, de-DMSO) δ: 12.31 (0.2H, s), 12.09 (0.8H, s), 10.46 (1H, s), 7.96 (1H, d, J=5.8
20 Hz), 7.77-7.73 (1.6H, m), 7.66-7.62 (0.4H, m), 7.60 (0.8H, d, J=2.0 Hz), 7.43-7.38 (0.5H, m), 7.36-
7.30 (1.5H, m), 7.28 (0.2H, d, J=1.6 Hz), 7.26-7.21 (0.3H, m), 7.19-7.13 (0.7H, m), 7.03-6.99 (1H,
m), 6.93 (0.2H, d, J=2.7 Hz), 6.91 (0.8H, d, J=2.6 Hz), 6.90 (0.8H, s), 6.88 (0.2H, s), 6.27 (1H, d,
J=5.8 Hz), 4.55-4.48 (1H, m), 4.17-4.09 (1H, m), 3.45-3.35 (1H, m), 3.30-3.20 (1H, m), 3.17-3.07
(1H, m), 2.97-2.90 (2H, m), 2.57-2.52 (2H, m).

25

[00176] Chiral purification of Example 3 provided two enantiomers 3A and 3B:

[00177] Analytical separation method:

Instrument: Thar analytical SFC

Column: ChiraCel OJ-H, 250x4.6mm
30 Mobile phase: A for CO2 and B for MeOH (0.05%DEA)
Gradient: B 50%
Flow rate: 2.0mL/min
Back pressure: 100bar
Column temperature: 35°C
35 Wavelength: 220nm
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[00178] Preparative separation method

Instrument: MGH preparative SFC

Column: ChiraCel OJ-H, 250x30mml.D.
Mobile phase: A for CO2 and B for MEOH
5 Gradient: B 50%
Flow rate: 50mL/min
Back pressure: 100bar
Column temperature: 38°C
Wavelength: 220nm
10 Cycletime: ~7.0min

[00179] Example 3A:

[00180] Light tan solid (45.7 mg)

LCMS: (ES+, final purity): RT 2.67 min, m/z 439.2 [M+H]+
15 Chiral ee of enantiomer - 99.5% [RT - 7.26 mins]

[00181] Example 3B:

[00182] Off white solid (48.1 mg)

LCMS: (ES+, final purity): RT 2.69 min, m/z 439.2 [M+H]+
Chiral ee of enantiomer - 99.7% [RT - 8.46 mins]

20 [00183] Example 4: 5-[3-[4-(4-pyridyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-

naphthyridin-2-one

To a mixture of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic acid

(80.mg, 0.24 mmol) and K2CO3 (0.04 mL, 0.47 mmol) in DMF (1 mL) was added a mixture of 4-
25 (bromoacetyl)pyridine hydrobromide (0.07 mL, 0.47 mmol) and NEt3 (0.07mL, 0.47 mmol) in DMF (1
mL). The mixture was stirred for 30 mins, diluted with water (30 mL) and extracted with EtOAc (2 X
50 mL). The combined organic layers were washed with brine (30 mL), dried (Na2SO4), filtered and
concentrated in vacuo. The combined aqueous layers were extracted with EtOAc (100 mL) and the
organic layer was dried (Na2SO4), filtered and concentrated in vacuo.
30 The combined residues were dissolved in AcOH (2.5 mL), NI-kOAc (2.23 g, 28.93 mmol) was added
and the reaction heated in a sealed vial at 130 °C for 68 hrs. The reaction was cooled, concentrated
in vacuo, added to sat. aq. NaHCO3 (70 mL) and extracted with EtOAc (2 X 70 mL). The combined
organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by
flash column chromatography (0-10% and 5-10% MeOH/DCM) to provide 5-[3-[4-(4-pyridyl)-1 H-
35 imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one (25 mg, 22% yield) as a
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yellow powder.
LCMS (ES+, Long): RT 2.40 min, m/z 440.1 [M+H]+.

1H NMR shows a mixture of confirmers:

Ή NMR (400MHz, de-DMSO) δ 12.37 (1H, s), 10.47 (1H, s), 8.51-8.46 (2H, m), 7.96 (1H,d,J=5.8
5 Hz), 7.90 (1H,s), 7.71-7.67 (2H,m), 7.02 (1H,d,J=2.7 Hz), 6.94 (0.2H, d, J=2.7 Hz), 2.92 (0.8H, d,
J=2.7 Hz), 6.90 (0.8H, s), 6.88 (02H, s), 6.27 (1H, d, J=5.8 Hz), 4.54-4.49 (1H, m), 4.15 (1H, t,
J=10.2 Hz), 3.47-3.37 (1H, m), 3.27-3.20 (1H, m), 3.18-3.09 (1H, m), 2.94 (2H, t, J=7.7 Hz), 2.57-
2.52 (2H, m).

10 [00184] Example 5: 5-[3-(4-tert-butyl-1H-imidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-

naphthyridin-2-one

.0

To a solution of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic acid (80

mg, 0.24 mmol) in DMF (2 mL) was added K2CO3 (64.97 mg, 0.47 mmol) and 1-bromo-3,3-
15 dimethylbutan-2-one (0.06 mL, 0.47 mmol). The reaction was stirred for 30 mins, diluted with water
(30 mL), extracted with EtOAc (2 X 50 mL) and the combined organic layers were washed with
brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo to provide a brown solid (101 mg).
The residue was dissolved in AcOH (3 mL), NH4OAc (2.23 g, 28.93 mmol) was added and the
reaction heated in a sealed tube at 130 °C for 120 hrs. The mixture was cooled, concentrated in
20 vacuo. The residue was slowly added dropwise to sat. aq. NaHCO3 (50 mL) and extracted with
EtOAc (2 X 100 mL). The combined organic layers were washed with brine (30 mL), dried
(Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column
chromatography (0-5% MeOH/DCM) and SCX-2. The residue was dissolved in EtOAc (50 mL),
washed with sat. aq. NaHCO3 (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The
25 residue was purified by flash column chromatography (0-5% MeOH/DCM) provided 5-[3-(4-tert-
butyl-1H-imidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one (10 mg, 10% yield)
as an off white solid.

LCMS (ES+, Long): RT 2.57 min, m/z 419.2 [M+H]+

1H NMR shows a mixture of confirmers:

30 Ή NMR (400 MHz, de-DMSO) δ: 11.62 (0.5H, s), 11.55 (0.5H, s), 10.46 (1H, s), 7.96 (1H, dd, J=1.7,
5.8 Hz), 7.00-6.97 (1H, m), 6.92 (0.2H, d, J=2.8 Hz), 6.90 (0.8H, d, J=2.6 Hz), 6.89 (0.8H, s), 6.86
(0.2H, s), 6.73 (0.5H, d, J=1.9 Hz), 6.46 (0.5H, d, J=1.8 Hz), 6.26 (1H, dd, J= 0.9, 5.8 Hz), 4.48-4.40
(1H, m), 4.07-3.97 (1H, td,J=3.8, 4.0 Hz), 3.32-3.24 (1H, m), 3.20-3.10 (1H, m), 3.08-2.99 (1H, m),
2.93 (2H, t, J=7.7 Hz), 2.57-2.53 (2H, m), 1.27 (5H, s), 1.19 (4H, s).
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[00185] Example 6: 5-[3-[4-(3-thienyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-

naphthyridin-2-one

To a solution of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic acid (80

5 mg, 0.24 mmol) in DMF (2 mL) was added K2CO3 (64.97 mg, 0.47 mmol) and 3-
(bromoacetyl)thiophene (0.07 mL, 0.47 mmol). The reaction was stirred for 30 mins, diluted with
water (30 mL) and extracted with EtOAc (2 X 50 mL). The combined organic layers were washed
with brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo to provide a brown solid (106
mg).
10 The solid was dissolved in AcOH (3 mL), NFUOAc (2.23 g, 28.93 mmol) was added and the reaction
heated in a sealed tube at 130 °C for 72 hrs. The mixture was cooled, concentrated in vacuo, the
residue dissolved in EtOAc (50 mL) and washed with sat. aq. NaHCO3 (2 X 50 mL) and water (50
mL). The combined aqueous phases were extracted with EtOAc (50 mL) and the combined organic
layers were dried (NazSOfi, filtered and concentrated in vacuo. The residue was purified by flash
15 column chromatography (0-5% MeOH/DCM) and prep HPLC to provide 5-[3-[4-(3-thienyl)-1H-
imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one (9.3 mg, 9% yield) as an off
white solid.
LCMS (ES+, Long) RT2.59 min, m/z 445.1 [M+H]+

1H NMR shows a mixture of confirmers:

20 Ή NMR (400MHz, de-DMSO) δ: 12.33 (0.3H, brs), 12.05 (0.7H, brs), 10.47 (1H, s), 7.96 (1H, d, J
= 5.8 Hz), 7.60-7.38 (4H, m), 7.01 (1 H, d, J = 2.4 Hz), 6.93 (0.2H, d, J=2.5 Hz), 6.91 (0.8H, d, J =
2.6 Hz), 6.90 (0.8H, s), 6.89 (0.2H, s), 6.27 (1H, d, J=5.8 Hz), 4.53-4.63 (1H, m), 4.11 (1H, t, J =
10.3 Hz), 3.43-3.35 (1H, m), 3.28-3.18 (1H, m), 3.14-3.06 (1H, m), 2.94 (2H, t, J = 7.7 Hz), 2.57-
2.53 (2H, m).

25 [00186] Example 7: 5-[3-[4-(2-thienyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-

naphthyridin-2-one

To a solution of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic acid (80

mg, 0.24 mmol) in DMF (2 mL) was added K2CO3 (64.97 mg, 0.47 mmol) and 2-bromo-1-(2-
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thienyl)ethanone (0.07 mL, 0.47 mmol). The reaction was stirred for 30 mins, diluted with water (30
mL) and extracted with EtOAc (2 X 50 mL). The combined organic layers were washed with brine
(30 mL), dried (NazSOfl, filtered and concentrated in vacuo to provide a brown solid (159 mg).
The solid was dissolved in AcOH (3 mL), NHUOAc (2.23 g, 28.93 mmol) was added and the reaction
5 heated in a sealed tube at 130 °C for 72 hours. The mixture was cooled, concentrated in vacuo and
the residue dissolved in EtOAc (50 mL). The organic layerwas washed with sat. aq. NaHCOe (2 X
50 mL) and water (50 mL). The combined aqueous phases were extracted with EtOAc (50 mL) and
the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue
was purified by flash column chromatography (0-5% MeOH/DCM) and prep HPLC to provide 5-[3-
10 [4-(2-thienyl)-1 H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one (22.6 mg,
22% yield) as an off white solid.
LCMS (ES+, Long): RT 2.65 min, m/z 445.1 [M+H]+

1H NMR shows a mixture of confirmers:

Ή NMR (400MHz, de-DMSO) δ: 12.16 (1H, s), 10.46 (1H, s), 7.96 (1H, d, J = 5.8 Hz), 7.46 (1H, s),
15 7.31 (1H, d, J = 4.4 Hz), 7.22 (1H, d, J = 3.0 Hz), 7.02 (2H, m), 6.93 (0.2H, d, J=2.7Hz), 6.91 (0.8H,
d, J = 2.7 Hz), 6.90 (0.8H, s), 6.87 (0.2H, s), 6.27 (1H, d, J=5.8Hz), 4.52-4.44 (1H, m), 4.11 (1H, t, J
= 10.3Hz), 3.43-3.35 (1H, m), 3.26-3.17 (1H, m), 3.14-3.06 (1H, m), 2.93 (2H, t, J = 7.7Hz), 2.57-
2.53 (2H, m).

[00187] Example 8: 5-[3-[5-(2-chlorophenyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-

20 1 H-1,8-naphthyridin-2-one

,o

o
To a solution of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic acid (70
mg, 0.21 mmol) in DMF (2 mL) was added K2CO3 (56.86 mg, 0.41 mmol) and 2-bromo-1-(2-
chlorophenyl)ethanone (59.9 uL, 0.41 mmol) . The reaction was stirred for 2 hrs, diluted with water
25 (20 mL) and extracted with EtOAc (50 mL). The organic layerwas washed with water (30 mL), brine
(20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash
column chromatography (0-5% MeOH/DCM) to provide a solid.

The solid was dissolved in AcOH (3 mL) and NH4OAC (1.58 g, 20.57 mmol) was added. The mixture
was heated in a seal vial at 140 °C for 24 hrs, cooled and added to sat. aq. NaHCOe (250
30 mL)/EtOAc (50 mL). The mixture was stirred for 1 hr, diluted with EtOAc (100 mL) and the
combined organic layers were washed with brine (100 mL). The combined aqueous layers were
extracted with EtOAc (100 mL) and the combined organic layers were dried (Na2SO4), filtered and
concentrated in vacuo. The residue was purified by flash column chromatography (0-5%
MeOH/DCM) and prep HPLC to provide 5-[3-[5-(2-chlorophenyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-
35 3,4-
dihydro-1H-1,8-naphthyridin-2-one (14.1 mg, 14% yield) as an off white solid.
LCMS: (ES+, Long): RT 2.88 min, m/z 473.1,475.1 [M+H]+
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1H NMR shows a mixture of confirmers:

Ή NMR (400 MHz, d6-DMSO) δ: 12.34 (0.2 H, s), 12.28 (0.8H, s), 10.46 (1H, s), 8.13-8.08 (1H,
m), 7.95 (1H, d, J = 6.0 Hz), 7.74 (1H, s), 7.47-7.42 (1H, m), 7.38-7.32 (1H, m), 7.24-7.18 (1H,
m), 7.02 - 6.99 (1H, m), 6.93 (0.2H, d, J = 2.7 Hz), 6.91 (0.8H, d, J = 2.6 Hz), 6.90 (0.8H, s), 6.87
5 (0.2H, s), 6.27 (1 H, d, J = 5.8 Hz), 4.55 - 4.49 (1H, m), 4.15 (1 H, t, J = 10.2 Hz), 3.48 - 3.37 (1H, m),
3.29 - 3.21 (1H, m), 3.18-3.08 (1H, m), 2.93 (2H, t, J = 7.7 Hz), 2.56-2.52 (2H, m).

[00188] Example 9: 5-[3-[5-(3-chlorophenyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-

1H-1,8-naphthyridin-2-one

o
10 To a solution of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic acid (70
mg, 0.21 mmol) in DMF (2 mL) was added K2CO3 (56.86 mg, 0.41 mmol) and 2-bromo-1-(3-
chlorophenyl)ethanone (96.06 mg, 0.41 mmol). The reaction was stirred for 3 days and further 2-
bromo-1-(3-chlorophenyl)ethanone (96.06 mg, 0.41 mmol) and K2CO3 (56.86 mg, 0.41 mmol) were
added. The mixture was stirred for 24 hrs, diluted with water (50 mL) and extracted with EtOAc (2 X
15 50 mL). The organic layers were washed with brine (50 mL). The combined aqueous layers were
extracted with EtOAc (50 mL) and the combined organic layers were dried (Na2SO4), filtered and
concentrated in vacuo to provide a solid.
The solid was dissolved in AcOH (3 mL) and NH4OAC (1.59 g, 20.57 mmol) was added. The mixture
was heated in a sealed vial at 140 °C for 24 hrs. The mixture was added to sat. aq. NaHCOe (250
20 mL) and extracted with EtOAc (200 mL). The organic layer was washed with brine (2 X 100 mL),
dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column
chromatogrpahy (0-5% MeOH/DCM) to provide 5-[3-[5-(3-chlorophenyl)-1H-imidazol-2-yl]chroman-
6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one (10.1 mg, 10% yield) as a brown solid.

LCMS (ES+, Long): RT 3.04 min, m/z 473.1,475.1 [M+ H]+

25 1H NMR shows a mixture of confirmers:

Ή NMR (400 MHz, de-DMSO) δ: 12.40 (0.2H, s),12.31 (0.8H, s), 10.46 (1H, s), 7.96 (1H, d, J = 5.8
Hz), 7.80 (0.8H, t, J = 1.8 Hz), 7.76 - 7.69 (2.2H, m), 7.36 (1 H, t, J = 7.9 Hz), 7.23-7.19 (1H, m),
7.03 - 7.00 (1H, m), 6.94 (0.2H, d , J=2.6 Hz) 6.91 (0.8H, d, J = 2.6 Hz), 6.89 (0.7H, s), 6.88 (0.3H,
s), 6.27 (1 H, d, J = 5.8 Hz), 4.54 - 4.48 (1 H,m), 4.14 (1 H, t, J = 10.2 Hz), 3.44 - 3.36 (1H, m), 3.29 -
30 3.20 (1H, m), 3.16 - 3.08 (1H, m), 2.93 (2H, t, J = 7.7 Hz), 2.57 - 2.52 (2H, m).

[00189] Example 10: 5-[3-[4-(benzofuran-3-yl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-

dihydro-1 H-1,8-naphthyridin-2-one
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To a solution of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic acid (70

mg, 0.21 mmol) and K2CO3 (56.85 mg, 0.41 mmol) in DMF (2 mL) was added 1-(benzofuran-3-yl)-2-
bromo-ethanone (98.35 mg, 0.41 mmol). The reaction was stirred for 1.5 hrs, diluted with water (10
5 mL) and extracted with EtOAc (80 mL). The organic layerwas washed with water (30 mL), brine (30
mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column
chromatography (0-5% MeOH/DCM) to provide a beige solid (104 mg).
The solid was dissolved in AcOH (4 mL), NI-UOAc (1.49 g, 19.27 mmol) was added and the mixture
heated at 140 "C in a sealed vial for 18 hrs. The reaction was cooled, added to water (40 mL), pH
10 adjusted to 8-9 and extracted with EtOAc (2 X 150 mL). The combined organic layers were dried
(Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column
chromatography (0-10% MeOH/DCM) and prep HPLC to provide 5-[3-[4-(benzofuran-3-yl)-1 H-
imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one (6 mg, 6% yield) as an off
white solid.
15 LCMS (ES+, Long): RT 2.98 min, m/z 479.2 [M+H]+

1H NMR shows a mixture of confirmers:

Ή NMR (400MHz, de-DMSO) δ: 12.42 (0.2H, brs), 12.21 (0.8H, brs), 10.47 (1H, s), 8.25 (0.2H, br
s), 8.18 (0.8H, s), 8.11-8.04 (1H, m), 7.96 (1H, d, J=5.8 Hz), 7.58-7.56 (2H, m), 7.44-7.28 (2H, m),
7.03 (1H, d, J=2.4 Hz), 6.94 (0.2H, d, J=2.9 Hz), 6.92 (0.8H, d, J=2.6 Hz), 6.91 (0.8H, s), 6.89
20 (0.2H, s), 6.28 (1H, d, J=5.8 Hz), 4.57-4.50 (1H, m), 4.16 (1H, t, J=10.3 Hz), 3.48-3.39 (1H, m),
3.30-3.23 (1H, m), 3.19-3.10 (1H, m), 2.94 (2H, t, J=7.7 Hz), 2.58-2.52 (2H, m).

[00190] Example 11: 5-[3-[5-(3-pyridyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-

1,8-
naphthyridin-2-one

.0

25 To a mixture of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic acid (80

mg, 0.24 mmol) in DMF (2 mL) was added K2CO3 (64.99 mg, 0.47 mmol) and 2-bromo-1-(3-
pyridyl)ethanone hydrobromide (132.1 mg, 0.47 mmol). The reaction was 1 hr, diluted with water
(20 mL) and extracted with EtOAc (50 mL). The organic layerwas washed with water (30 mL) and
brine (50 mL). The combined aqueous layers were extracted with EtOAc (50 mL). The combined
30 organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified
using flash column chromatography (0-5% MeOH/DCM) to provide a dark brown oil (100mg).
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The brown oil was dissolved in AcOH (3 mL), NHUOAc (1.82 g, 23.51 mmol) was added and the
miture heated in a sealed vial at 140 °C for 18 hrs. The mixture was added to sat. aq. NaHCO3 (250
mL) and EtOAc (50 mL) and stirred for 1 hr. The mixture was diluted with EtOAc (100 mL). The
organic layer was washed with brine (100 mL) and the combined aqueous layers were extracted
5 with EtOAc (100 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in
vacuo and the resiude was purified by prep HPLC to provide 5-[3-[5-(3-pyridyl)-1H-imidazol-2-
yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one (7 mg, 7% yield) as an off white solid.
LCMS (ES+, Long): RT 2.40 min, m/z 440.1 [M+H]+

1H NMR shows a mixture of confirmers:

10 Ή NMR (400 MHz, de-DMSO) δ: 12.26 (1H, s), 10.46 (1H, s), 8.97 (1H, s), 8.40-8.35 (1H, m), 8.10
- 8.04 (1H, m), 7.96 (1H, d, J=5.8 Hz), 7.75 (1H, s), 7.38 - 7.33 (1H, m), 7.04 - 7.00 (1H, m), 6.94
(0.2H, d, J=2.6 Hz), 6.92 (0.8H, d, J=2.6 Hz), 6.90 (0.8H, s), 6.88 (0.2H, s), 6.27 (1H, d, J=5.8 Hz),
4.55-4.48 (1H, m), 4.15 (1H, t, J=10.3 Hz), 3.47 - 3.38 (1H, m), 3.29 - 3.21 (1H, m), 3.18-3.10 (1H,
m), 2.94 (2H, t, J=7.7 Hz), 2.57-2.52 (2H, m).

15

[00191] Example 12: 5-[3-[5-(4-methylsulfonylphenyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-

dihydro-1
3,4- H-1,8-naphthyridin-2-one

To a stirred mixture of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic

20 acid (80 mg, 0.24 mmol) in DMF (2 mL) was added K2CO3 (64.99mg, 0.47 mmol) and 4-
Methylsulfonyl alpha-bromoacetophenone (130.31 mg, 0.47 mmol). The reaction was stirred for 1
hr, diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was washed
with water (30 mL) and brine (50 mL). The combined aqueous layers were extracted with EtOAc (50
mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to
25 provide a dark orange solid (1 OOmg).

The orange solid was dissolved in AcOH (3 mL), NH4OAc (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. NaHCO3
(250 mL) and EtOAc (50 mL) and stirred until neutralised. Further EtOAc (100 mL) was added and
the organic layer was washed with brine (100 mL). The combined aqueous layers were extracted
30 with EtOAc (100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated
in vacuo. The residue was purified using flash column chromatography (0-5% MeOH/DCM and 0-
5% MeOH/DCM) and prep HPLC to provide 5-[3-[5-(4-methylsulfonylphenyl)-1H-imidazol-2-
yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one (26.8mg, 22% yield) as a pale yellow
solid.

35 LCMS (ES+, Long): RT 2.62 min, m/z 517.1 [M+H]+

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1H NMR shows a mixture of confirmers:

Ή NMR (400 MHz, d6-DMSO) δ: 12.35 (1H, s), 10.46 (1H, s), 8.02-7.95 (3H, m), 7.90-7.84 (3H,
m), 7.04-7.00 (1H, m), 6.95-6.87 (2H, m), 6.27 (1H, d, J=5.8 Hz), 4.56-4.49 (1H, m), 4.15 (1H,
t, J=10.2 Hz), 3.48-3.38 (1H, m), 3.28-3.21 (1H, m), 3.20 (3H, s), 3.18-3.09 (1H, m), 2.94 (2H,
5 t, J=7.7 Hz), 2.57 - 2.52 (2H, m).

[00192] Example 13: 5-[3-[5-(4-fluorophenyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-

1H-1,8-naphthyridin-2-one

To a solution of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic acid (80

10 mg, 0.24 mmol) in DMF (2 mL) was added K2CO3 (64.99 mg, 0.47 mmol) and p-fluorophenacyl
bromide (102.05 mg, 0.47 mmol). The reaction was stirred for 1 hr, diluted with water (20 mL) and
extracted with EtOAc (50ml). The organic layer was washed with water (30 mL) and brine (50 mL).
The combined aqueous layers were extracted with EtOAc (50 mL). The combined organic layers
were combined dried (Na2SO4), filtered, concentrated in vacuo and purified by flash column
15 chromatography (0-5% MeOH/DCM) to provide a dark brown oil.
The brown oil was dissolved in AcOH (3 mL), NH4OAC (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. NaHCO3
(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
20 layers were extracted with EtOAc (50 mL). The combined organic layers were dried (Na2SO4),
filtered and concentrated in vacuo. The residue was purifed by flash column chromatography (0-5%
MeOH/DCM) and prep HPLC to provide 5-[3-[5-(4-fluorophenyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-
3,4-
dihydro-1H-1,8-naphthyridin-2-one (7.7mg, 7% yield) as an off white solid.
LCMS: (ES+, Long): RT 2.76min, m/z 457.2 [M+H]+

25 1H NMR shows a mixture of confirmers:

Ή NMR (400 MHz, d6-DMSO) δ: 12.33 (0.2H, s), 12.11 (0.8H, s), 10.46 (1H, s), 7.96 (1H, d, J=5.8
Hz), 7.81 - 7.74 (1,7H, m), 7.70 - 7.64 (0.3H, m), 7.58 (0.8H, s), 7.29 - 7.23 (0.5H, m), 7.20 - 7.12
(1,7H, m), 7.03 - 6.99 (1H, m), 6.94 (0.2H, d, J=2.6 Hz), 6.91 (0.8H, d, J=2.6 Hz), 6.90 (0.8H, s),
6.88 (0.2H, s), 6.27 (1H, d, J=5.8 Hz), 4.54-4.48 (1H, m), 4.13 (1H, t, J=10.3 Hz), 3.45- 3.36 (1H,
30 m), 3.29-3.19 (1H, m), 3.16-3.07 (1H, m), 2.94 (2H, t, J=7.7 Hz), 2.57-2.53 (2H, m).

[00193] Example 14 : 5-[3-[5-(1,3-benzodioxol-5-yl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-

dihydro-1 H-1,8-naphthyridin-2-one
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0'

[00194] To a mixture of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic

acid (160 mg, 0.47 mmol) in DMF (4 mL) was added K2CO3 (129.95mg, 0.94 mmol) and 1-(1,3-
benzodioxol-5-yl)-2-bromoethanone (228.53 mg, 0.94 mmol) . The reaction was stirred for 2 hrs,
5 diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was washed with
water (30 mL) and brine (50 mL). The combined aqueous layers were extracted with EtOAc (50
mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and residue
was purified by flash column chromatography (0-5% MeOH/DCM) to provide a yellow oil.
The yellow oil was dissolved in AcOH (6 mL), NFLOAc (3.62 g, 47.01 mmol) was added and the
10 mixture heated in a sealed tube at 140 °C for 3 hrs. The mixture was diluted with sat. aq. NaHCOe
(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 (Na2SO4),
filtered and concentrated invacuo. The residue was purified using flash column chromatography (0-
15 5% DCM/MeOH) and HPLC prep to provide 5-[3-[5-(1,3-benzodioxol-5-yl)-1 H-imidazol-2-
yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one (13.8mg, 6% yield) as an off white solid.

LCMS (ES+, Long): RT2.71 min, m/z 483.2 [M+H]+

1H NMR shows a mixture of confirmers:
Ή NMR (400 MHz, de-DMSO) δ: 12.19 (0.2H, s), 12.02 (0.8H, s), 10.45 (1H, s), 7.95 (1H, d, J=5.9
20 Hz), 7.50-7.45 (1H, m), 7.30-7.10 (2H, m), 7.01 -6.98 (1H, m), 6.94-6.84 (3H, m), 6.26 (1H, d,
J=5.7 Hz), 6.05 - 5.96 (2H, m), 4.52 - 4.46 (1H, m), 4.11 (1H, t, J=10.2 Hz), 3.41 - 3.34 (1H, m),
3.27 - 3.18 (1H, m), 3.13-3.05 (1H, m), 2.93 (2H, t, J=7.7 Hz), 2.57-2.52 (2H, m).

[00195] Example 15 : 5-[3-[5-(2,3-dihydro-1,4-benzodioxin-6-yl)-1H-imidazol-2-yl]chroman-6-

25 yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one

o
[00196] To a solution of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic
acid (160 mg, 0.47 mmol) in DMF (4 mL) was added K2CO3 (129.95 mg, 0.94 mmol) and 3,4-
(Ethylenedioxy)phenacyl bromide (168 mg, 0.65 mmol). The reaction was stirred for 1 hr, diluted
30 with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was washed with water (30
mL) and brine (50 mL). The combined aqueous layers were extracted with EtOAc (50 mL). The
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combined organic layers were dried (Na2SO4), filtered, concentrated invacuo and residue purifed by
flash column chromatography (0-5% MeOH/DCM) to provide a yellow oil.

The yellow oil was dissolved in AcOH (6 mL), NhLOAc (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
5 mixture was diluted with sat. aq. NaHCCh (150 mL), EtOAc (50 mL) and stirred till neutralised. The
mixture was diluted with further EtOAc (50ml). 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 (Na2SO4), filtered, concentrated in vacuo. The residue was purified by flash
column chromatography (0-5% DCM/MeOH) and prep HPLC to provide 5-[3-[5-(2,3-dihydro-1,4-
10 benzodioxin-6-yl)-1 H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one (21.6
mg, 9% yield) as an off white solid
LCMS: (ES+, Long): RT2.73 min, m/z 497.1 [M+H]+
1H NMR shows a mixture of confirmers:
Ή NMR (400 MHz, de-DMSO) δ: 12.02 (1H, s), 10.47 (1H, s), 7.96 (1H, d, J=5.8 Hz), 7.42 (1H, s),
15 7.24 - 7.15 (2H, m), 7.02-6.98 (1H, m), 6.93 (0.2H, d, J=2.7 Hz), 6.91 (0.8H, d, J=2.7 Hz), 6.89
(0.8H, s), 6.88 (0.2H, s), 6.82 (1H, d, J=8.5 Hz), 6.27 (1H, d, J=5.8 Hz), 4.53 - 4.46 (1H, m), 4.24
(4H, s), 4.12 (1H, t, J=10.3 Hz), 3.42-3.34 (1H, m), 3.27-3.18 (1H, m), 3.15-3.06 (1H, m), 2.93
(2H, t, J=7.7 Hz), 2.57-2.52 (2H, m).

20 [00197] Example 16: 5-[[3-(4-phenyl-1H-imidazol-2-yl)-2H-chromen-6-yl]oxy]-3,4-dihydro-1H-

1,8-
naphthyridin-2-one.

To a solution of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]-2H-chromene-3-carboxylic acid

(354 mg, 1.05 mmol) in DMF (7 mL) was added K2CO3 (289.13 mg, 2.09 mmol) and 2-
25 bromoacetophenone (0.31 mL, 2.09mmol). The reaction was stirred for 30 mins at room
temperature, diluted with water (30 mL) and extracted with EtOAc (2 X 50 mL). The combined
organic layers were washed with brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo
to provide a brown solid.
The solid was dissolved in AcOH (10 mL), NH4OAC (6.45 g, 83.71 mmol) was added and the
30 reaction heated in a sealed tube at 130 °C for 16 hrs. The mixture was cooled, concentrated in
vacuo and the residue dissolved in EtOAc (50 mL). The organic layer was washed with sat. aq.
NaHCO3 (2 X 50 mL) and water (1 x 50 mL). The combined aqueous layers were extracted with
EtOAc (50 mL) and the combined organic layers were dried (Na2SO4), filtered and concentrated in
vacuo. The residue was purified by flash column chromatography (0-5% MeOH/DCM) and prep
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HPLC to provide 5-[[3-(4-phenyl-1 H-imidazol-2-yl)-2H-chromen-6-yl]oxy]-3,4-dihydro-1 H-1,8-

naphthyridin-2-one (21 mg, 5% yield) as a yellow solid.
LCMS (ES+, Long) RT 3.14 min, m/z 437.2 [M+H]+

1H NMR shows a mixture of confirmers:

5 Ή NMR (400MHz, de-DMSO) δ: 12.73 (0.8H, brs), 12.70 (0.2H, brs), 10.48 (1H, s), 7.98 (1H, d,
J=5.8 Hz), 7.86-7.75 (2H, m), 7.53-7.28 (3H, m), 7.25-7.18 (1H, m), 7.15 (1H, brs), 7.02 (1H, t,
J=1.5 Hz), 6.95 (2H, d, J=1.6 Hz), 6.33 (1H, d, J=5.8 Hz), 5.27 (1.5H, s), 5.23 (0.5H, s), 2.98-2.91
(2H, m), 2.58-2.52 (2H, m).

[00198] Example 17: 5-[3-(3-phenyl-1,2,4-oxadiazol-5-yl)chroman-6-yl]oxy-3,4-dihydro-1H-

10 1,8-
naphthyridin-2-one

[00199] To a mixture of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic

acid (62 mg, 0.18 mmol), N-Hydroxybenzenecarboximidamide (26 mg, 0.19 mmol) and DIPEA (0.05
mL, 0.27 mmol) in DMF (2 mL) was added HATU (79.66 mg, 0.21 mmol). The reaction was stirred
15 for 22 hrs, quenched with water (15 mL) and extracted with EtOAc (50 mL). The aqueous layer was
diluted with EtOAc (50 mL), filtered, diluted with further EtOAc (150 mL) and brine (50 mL),
separated and the combined organic layers were dried (Na2SO4), filtered and concentrated in
vacuo.

[00200] The residue was dissolved in pyridine (3 mL, 37.09 mmol) and heated at 100 °C in a
20 sealed vial for 20 hrs. The mixture was cooled, concentrated in vacuo and the residue was purified
by flash column chromatography (0-5% MeOH/DCM) and prep HPLC to provide 5-[3-(3-phenyl-
1,2,4-
oxadiazol-5-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one (5 mg, 6% yield) as
an off white solid.

LCMS (ES+, Long): RT 4.11 min, m/z 441.2 [M+H]+

25 1H NMR shows a mixture of confirmers:
Ή NMR (400 MHz, de-DMSO) δ: 10.47 (1H, s), 8.03-7.97 (2H, m), 7.96 (1H, d, J=5.8 Hz), 7.64-7.54
(3H, m), 7.07 (1H, d, J=2.5 Hz), 6.95 (0.3H, d, J=2.7 Hz), 6.93 (0.7H, d, J= 2.7 Hz), 6.91 (0.7H, s),
6.89 (0.3H, S), 6.26 (1H, d, J=5.8Hz), 4.63-4.56 (1H, m), 4.48-4.40 (1H, dd, J=7.4 Hz), 3.98-3.88
(1H, m), 3.40-3.25 (2H, m), 2.93 (2H, t, J=7.4, 10.9 Hz), 2.57-2.53 (2H, m).

30

[00201] Example 18: 5-[3-(5-phenyl-1H-pyrazol-3-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-

naphthyridin-2-one
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[00202] Step 1 :

To a mixture of 6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-carboxylic acid (150

mg, 0.44 mmol) and Ν,Ο-Dimethylhydroxylamine hydrochloride (64.49 mg, 0.66 mmol) in DMF (3
5 mL) was added DIPEA (0.31 mL, 1.76 mmol) and HATU (201.1 mg, 0.53 mmol) . The mixture was
stirred for 24 hrs, diluted with EtOAc (100 mL), washed with water (2 X 30 mL), brine (30 mL), dried
(Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column
chromatography (0-4% MeOH/DCM) to provide N-methoxy-N-methyl-6-[(7-oxo-6,8-dihydro-5H-1,8-
naphthyridin-4-yl)oxy]chromane-3-carboxamide (133 mg, 79% yield) as an off white foam.
10 LC-MS (ES+, Short): RT 1.37 min, m/z 384.2 [M+H]+
Ή NMR (400 MHz, CDCh) δ: 8.12 (1H, s), 7.96 (1H, d, J=6.0 Hz), 6.90-6.86 (1H, m), 6.85-6.80 (2H,
m), 6.31 (1H, d, J=5.9 Hz), 4.46-4.40 (1H, m), 4.04 (1H, t, J= 10.5 Hz), 3.76 (3H, s), 3.42-3.32 (1H,
m), 3.24 (3H, s), 3.20-3.11 (1H, m), 3.06 (2H, t, J=7.5 Hz), 2.90-2.83 (1H, m), 2.73-2.66 (2H, m).

[00203] Step 2:

15 To a solution of phenylacetylene (0.09 mL, 0.85 mmol) in THF (6 mL) at -78 °C was added dropwise
n-Butyllithium solution (0.34 mL, 0.85mmol, 2.5M in THF) and the solution stirred for 30 mins. A
solution of N-methoxy-N-methyl-6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]chromane-3-
carboxamide (130 mg, 0.34 mmol) in THF (2 mL) was added dropwise and the solution stirred for 3
hrs at -78 °C then warmed to room temperature over 1 hr. The reaction was quenched with sat. aq.
20 NH4CI (20 mL) and extracted with EtOAc (100 mL). The organic layerwas washed with brine (20
mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column
chromatography (0-5% MeOH/DCM) to provide 5-[3-(3-phenylprop-2-ynoyl)chroman-6-yl]oxy-3,4-
dihydro-1H-1,8-naphthyridin-2-one (122 mg, 61% yield) as a yellow solid.
LCMS (ES+, Short): RT 1.76 min, m/z 425.3 [M+H]+.

25 [00204] Step 3:

To a solution of 5-[3-(3-phenylprop-2-ynoyl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-
one (122 mg, 0.21 mmol) in ‘BuOH (2 mL) was added hydrazine hydrate (0.02 mL, 0.41 mmol) and
the mixture heated to 85 °C for 18 hrs. The mixture was cooled, concentrated in vacuo and purified
by flash column chromatography (0-5% MeOH/DCM) and prep HPLC to provide 5-[3-(5-phenyl-1H-
30 pyrazol-3-yl)chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthyridin-2-one (20 mg, 22% yield) as an off
white solid.

LCMS (ES+, Long): RT 3.71 min, m/z 439.2 [M+H]+

1H NMR shows a mixture of confirmers:

Ή NMR (400 MHz, de-DMSO) δ: 13.14 (0.5H, brs), 12.88 (0.5H, brs), 10.47 (1H, s), 7.96 (1H, d,
35 J=5.8 Hz), 7.82 - 7.65 (2H, m), 7.50 - 7.24 (3H, m), 6.99 (1H, d, J=2.4 Hz), 6.96 - 6.85 (2H, m), 6.70
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-6.57 (1H, m), 6.27 (1H, d, J=5.8 Hz), 4.50-4.40 (1H, m), 4.19-4.02 (1H, m), 3.40-3.30 (1H, m),
3.17 - 3.03 (2H, m), 2.93 (2H, t, J=7.7 Hz), 2.57 - 2.52 (2H, m).

[00205] Example 19: 5-[[(3S)-3-(4-phenyl-1H-imidazol-2-yl)-2,3-dihydro-1,4-benzodioxin-6-

yl]oxy]-3,4-dihydro-1 H-1,8-naphthyridin-2-one

.0.

5
[00206] Step 1 :

To a suspension of NaH (60%, 0.82 g, 20.58 mmol) in DMF (20 mL) at 0 °C was added slowly a
solution of 2-hydroxy-5-tetrahydropyran-2-yloxy-benzaldehyde (3.43 g, 15.43 mmol) in DMF (20
mL) and the mixture stirred for 1 hr. [(2R)-oxiran-2-yl]methyl 3-nitrobenzenesulfonate (4.g, 15.43
10 mmol) was added, the mixture warmed to room temperature and heated at 70 °C for 18 hrs. The
reaction was cooled and concentrated in vacuo. The residue was dissolved in DCM (200 mL),
washed with aq. 1 M HCI (100 mL), sat. aq. Na2CO3 (100 mL) and brine (50 mL). The aqueous
layers were extracted with DCM (2 x 200 mL) and the combined organic layers were dried
(Na2SÛ4), filtered and concentrated in vacuo. The residue was purified by flash column
15 chromatography (0-50% EtOAc/pet. Ether) to provide 2-[[(2R)-oxiran-2-yl]methoxy]-5-
tetrahydropyran-2-yloxy-benzaldehyde (2.06 g, 48% yield) as a yellow oil.

Ή NMR (400 MHz, CDCb) δ: 10.47 (1H, s), 7.51 (1H, d, J=3.1 Hz), 7.26-7.21 (1H, m), 6.93 (1H, d,
J=8.8 Hz), 5.35 (1H, t, J=3.3Hz), 4.34 (1H, dd, J=2.9, 11.2 Hz), 4.02 (1H, dd, J=5.7, 11.1 Hz), 3.93-
3.83 (1H, m), 3.63 - 3.56 (1H, m), 3.41 - 3.35 (1H, m), 2.93 (1H, t, J=4.5 Hz), 2.79 - 2.75 (1H, m),
20 2.03 - 1.91 (1H, m), 1.88 - 1.79 (2H, m), 1.74 - 1.50 (3H, m).

[00207] Step 2:

To a solution of 2-[[(2R)-oxiran-2-yl]methoxy]-5-tetrahydropyran-2-yloxy-benzaldehyde (2.06g,

7.39mmol) in DCM (25 mL) was added mCPBA (2.55 g, 14.79 mmol). The mixture was stirred for
18 hrs, filtered and concentrated in vacuo. The residue was dissolved in Et2O, washed with aq.
25 sodium thiosulphate, sat. aq. Na2CO3, brine, dried (Na2SO4), filtered and concentrated in vacuo to
provide crude [2-[[(2R)-oxiran-2-yl]methoxy]-5-tetrahydropyran-2-yloxy-phenyl] formate (2.08 g,
95% yield).

Ή NMR (400 MHz, CDCb) δ: 8.26 (1H, s), 6.97 - 6.89 (2H, m), 6.87 (1H, d, J= 2.6 Hz), 5.30 (1H, t,
J=3.2 Hz), 4.19 (1H, dd, J=3.3, 11.4 Hz), 3.96 (1H, dd, J=5.6, 11.2 Hz), 3.92-3.83 (1H, m), 3.63-
30 3.55 (1H, m), 3.32 - 3.26 (1H, m), 2.89 - 2.85 (1H, m), 2.70 (1H, dd, J=2.7, 4.9 Hz), 2.02-1.78 (3H,
m),1.73-1.58 (3H, m).
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[00208] Step 3:
To a solution of [2-[[(2R)-oxiran-2-yl]methoxy]-5-tetrahydropyran-2-yloxy-phenyl] formate (2.08 g,
7.07 mmol) in MeOH (42.3 mL) was added Na2CO3 (2.1 g, 19.79 mmol) and the mixture stirred for
70 hrs. The mixture was diluted with DCM and washed with water. The aqueous layer was
5 extracted with DCM and the combined organic layers were dried (Na2SO4), filtered, and
concentrated in vacuo. The residue was purified by flash column chromatography (0-50%
EtOAc/pet. Ether) to provide [(3S)-6-tetrahydropyran-2-yloxy-2,3-dihydro-1,4-benzodioxin-3-
yl]methanol (1.76 g, 94% yield) as a clear, pale yellow oil.
LC/MS: (ES+, Short): RT 1.51 min, m/z 267.0 [M+H]+
10 Ή NMR (400 MHz, CDCh) δ: 6.78 (1H, d, J= 8.9 Hz), 6.67 (1H, d, J= 3.0 Hz), 6.59 - 6.53 (1H, m),
5.29 - 5.24 (1H, m), 4.28 - 4.21 (2H, m), 4.06 (1H , dd, J=8.2, 11.9 Hz), 3.96 - 3.79 (2H, m), 3.63-
3.55 (1H, m), 2.03-1.78 (4H, m), 1.72-1.52 (4H, m).

[00209] Step 4

[(3S)-6-tetrahydropyran-2-yloxy-2,3-dihydro-1,4-benzodioxin-3-yl]methanol (500 mg, 1.88 mmol)

15 was dissolved in DCM (8 mL) and cooled to 0 °C. DMP (0.88 g, 2.07 mmol) was added and the
reaction was stirred for 3 hrs. The mixture was diluted with sat. aq. NaHCCh (10 ml_)/sat. aq.
sodium thiosulphate (10 mL) and stirred for 1 hr. The layers were separated and the aqueous layer
was extracted with DCM (15 mL), The combined organic layers were dried (Na2SC>4), filtered and
concentrated in vacuo to provide crude (3R)-6-tetrahydropyran-2-yloxy-2,3-dihydro-1,4-
20 benzodioxine-3-carbaldehyde (586 mg, 118% yield) as an orange oil.

[00210] Step 5:

A solution of phenylglyoxal hydrate (285.57 mg, 1.88 mmol) in MeOH (10 mL) was added dropwise
to a stirred suspension of crude (3R)-6-tetrahydropyran-2-yloxy-2,3-dihydro-1,4-benzodioxine-3-
carbaldehyde (496 mg, 1.88 mmol) and NH4OAC (704.54 mg, 9.14 mmol) in MeOH (8 mL). The
25 reaction mixture was stirred for 18 hrs and concentrated in vacuo. The residue was partitioned
between sat. aq. NaHCO3 (20 mL) and DCM (20 mL). The organic phase was dried (Na2SO4),
filtered and concentrated in vacuo. The residue was purified by column chromatography (0-30%
EtOAc/pet. Ether) to provide 4-phenyl-2-[(3S)-6-tetrahydropyran-2-yloxy-2,3-dihydro-1,4-
benzodioxin-3-yl]-1H-imidazole (550 mg, 77%).
30 LC/MS (ES+, Short): RT 1.57 min, m/z 379.2 [M+H]+

[00211] Step 6:

To a solution of 4-phenyl-2-[(3S)-6-tetrahydropyran-2-yloxy-2,3-dihydro-1,4-benzodioxin-3-yl]-1 H-
imidazole (550 mg, 1.45 mmol) in DMF (9.4 mL), at 0 °C, was added NaH (60%, 75.57 mg, 1.89
mmol) and the mixture stirred at this temperature for 1 hr. 2-(Trimethylsilyl)ethoxymethyl chloride
35 (257.23 uL, 1.45 mmol) was added dropwise at 0 °C and the mixture stirred for 16 hrs at room
temperature. The mixture was quenched with sat. aq. NH4CI (5 mL) and extracted with EtOAc (25
mL). The organic layer was washed with water (25 mL) and the combined aqueous layers were
extracted with EtOAc (25 mL). The combined organic layers were dried (Na2SO4), filtered and
concentrated in vacuo to provide crude trimethyl-[2-[[4-phenyl-2-[(3S)-6-tetrahydropyran-2-yloxy-
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2.3- dihydro-1,4-benzodioxin-3-yl]imidazol-1-yl]methoxy]ethyl]silane (1.30g, 176% yield) as a pale

yellow oil.
LC/MS: (ES+, Short): RT 2.36 min, m/z 509.6 [M+H]+

[00212] Step 7:

5 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 (3x15 mL), 1 N NHa/MeOH (3x15 mL), and
product fractions were concentrated in vacuo. The residue was purified by column chromatography
(0-25% EtOAc/pet. Ether) to provide (3S)-3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-
10 2.3- dihydro-1,4-benzodioxin-6-ol (260 mg, 42% yield) as a pale yellow oil.
LC/MS: (ES+, Short): RT 2.02 min, m/z 425.4 [M+H]+

Ή NMR (400 MHz, CDCh) δ: 7.78 - 7.73 (2H, m), 7.40 - 7.35 (2H, m), 7.33 (1H, s), 7.29 - 7.27
(0.5H , m), 7.25 - 7.23 (0.5H, m), 6.77 (1H, d, J=8.8Hz), 6.52 (1H, d, J=3.0 Hz), 6.40 - 6.29 (2H, m),
5.52 (1H, d, J=10.8 Hz), 5.39 - 5.32 (2H, m), 4.61 - 4.51 (2H, m), 3.59 (2H, t, J=8.3 Hz), 0.97 -0.87
15 (2H, m), 0.00 - 0.02 (9H, s).

[00213] Step 8:

(3S)-3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2,3-dihydro-1,4-benzodioxin-6-ol
(115 mg, 0.27 mmol) , 5-fluoro-3,4-dihydro-1H-1,8-naphthyridin-2-one (45 mg, 0.27 mmol) and
CS2CO3 (220.63 mg, 0.68 mmol) in DMF (2 mL) was irradiated at 150 °C for 2 hrs. The resultant
20 was partitioned between EtOAc (50 mL) and water (50 mL). To the aqueous layer was added NH4CI
(until pH to ~ 5) and the aqueous layer was extracted with EtOAc (5 x 50 mL). The combined
organic layers were washed with brine (3 x 50 mL), dried (Na2SO4), filtered and concentrated in
vacuo. The residue was redissolved in EtOAc (100 mL), washed with brine (2 x 100 mL), dried
(Na2SO4), filtered and concentrated in vacuo to provide crude 5-[[(3S)-3-[4-phenyl-1-(2-
25 trimethylsilylethoxymethyl)imidazol-2-yl]-2,3-dihydro-1,4-benzodioxin-6-yl]oxy]-3,4-dihydro-1H-1,8-
naphthyridin-2-one (105 mg, 68 % yield) as an orange-brown solid.

LC/MS: (ES+, Short): RT 2.08 min, m/z 571.3 [M+H]+

[00214] Step 9:

To a solution of 5-[[(3S)-3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2,3-dihydro-1,4-
30 benzodioxin-6-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one (105 mg, 0.18 mmol) in EtOH (3 mL)
was added aq. 1N HCI (4 mL, 4 mmol) and the mixture stirred at 70 °C for 16 hrs. The mixture was
concentrated in vacuo. The residue was dissolved in MeOH (5 mL)/DCM (50 mL) and washed with
sat. aq. Na2CO3 (25 mL). The aqueous layer was washed with DCM (4x50 mL) and EtOAc (50
mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The
35 residue was purified by flash column chromatography (0-100% EtOAc/pet. Ether), reverse phase
flash chromatography (20-60% MeCN/water/0.1% formic acid) and SCX-2 to provide 5-[[(3S)-3-(4-
phenyl-1 H-imidazol-2-yl)-2,3-dihydro-1,4-benzodioxin-6-yl]oxy]-3,4-dihydro-1 H-1,8-naphthyridin-2-
one (4.72 mg, 5 % yield) as an off-white solid.
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LCMS (ES+, Long ): RT 3.01 min, m/z 441.1 [M+H]+

Chiral ee of enantiomer-96.8% [RT -7.70 mins]

Ή NMR (400MHz, de-DMSO) δ: 12.84 (0.2H, brs), 12.52 (0.8H, s), 10.46 (1H, m), 7.97 (1H, d, J =
5.8 Hz), 7.84-7.62 (3H, m), 7.42-7.30 (3H, m), 7.02 (2H, d, J = 8.8 Hz), 6.80 (1H, d, J = 2.9 Hz),
5 6.69 (1 H, dd, J = 8.8, 2.9 Hz) 6.29 (1 H, d, J = 5.8 Hz), 5.39 (1 H, d, J = 7.0 Hz), 4.62 (1 H, dd, J =
2.5, 11,6Hz), 4.44 (1 H, dd, J = 8.3, 11.6 Hz), 2.91 (2H, t, J = 7.7 Hz), 2.56-2.51 (2H, m).

[00215] Example 20: 5-[[(3R)-3-(4-phenyl-1H-imidazol-2-yl)-2,3-dihydro-1,4-benzodioxin-6-

yl]oxy]-3,4-dihydro-1 H-1,8-naphthyridin-2-one

10
[00216] Prepared in a similar way to Example19 using (2S)-oxiran-2-yl]methyl 3-
nitrobenzenesulfonate instead of (2R)-oxiran-2-yl]methyl 3-nitrobenzenesulfonate.

[00217] LCMS (ES+, Long): RT 3.02 min, m/z 441.1 [M+H]+

Chiral ee of enantiomer-92.8% [RT -8.98 mins]
15 Ή NMR (400MHz, de-DMSO) δ: 12.84 (0.2H, brs), 12.55 (0.8H, brs), 10.46 (1H, s), 7.97 (1H, d,
J=5.8 Hz), 7.82-7.63 (3H, m), 7.45-7.28 (3H, m), 7.02 (1 H, d, J=8.8Hz), 6.80 (1 H, d, J=2.8Hz), 6.69
(1H, dd, J=2.8, 8.8 Hz), 6.29 (1H, d, J=5.8 Hz), 5.42-5.33 (1H, m), 4.65-4.57 (1H, m), 4.48-4.39 (1H,
m), 2.91 (2H, t, J=7.7 Hz), 2.66-2.51 (2H, m).

[00218] Example 21: 2-Methyl-4-[3-(5-phenyl-1H-imidazol-2-yl)chroman-6-yl]oxy-pyridine

20
[00219] Step 1:

A mixture of 4-fluoro-2-methylpyridine (100 mg, 0.9 mmol), 6-hydroxychromane-3-carboxylic acid

(199.99 mg, 1.03 mmol) and CS2CO3 (678.01 mg, 2.08 mmol) in DMF (4 mL) was irradiated at 150
°C for 3 hrs. The mixture was cooled. To the mixture was added CS2CO3 (293.21 mg, 0.9 mmol)
25 and 2-bromoacetophenone (340 mg, 1.71 mmol). The mixture was stirred for 3 hrs, diluted with
EtOAc (120 mL), washed with water (50, 30 mL), brine (30 mL), dried (Na2SO4), filtered and
concentrated in vacuo. The residue was purified by flash column chromatography (0-100%
EtOAc/Hept) to provide phenacyl 6-[(2-methyl-4-pyridyl)oxy]chromane-3-carboxylate (239 mg, 66 %
yield) as a brown oil.
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LCMS (ES+, Short): RT 1.40 min, m/z 404.4 [M+H]+

Ή NMR (400 MHz, CDCh) δ: 8.34 (1H, d, J=5.7Hz), 7.96 - 7.91 (2H, m), 7.68 - 7.63 (1H, m), 7.56 -
7.49 (2H, m), 6.93 - 6.91 (0.2H, m), 6.90 - 6.89 (0.8H, m), 6.88 - 6.85 (1,7H ,m), 6.85 - 6.84 (0.3H
,m), 6.68 - 6.63 (2H, m), 5.45 (2H, d, J=0.9 Hz), 4.64 - 4.57 (1H, m), 4.33 - 4.25 (1H, m), 3.33 - 3.20
5 (2H, m), 3.18 - 3.10 (1H, m), 2.51 (3H, s).

[00220] Step 2:

A mixture of phenacyl 6-[(2-methyl-4-pyridyl)oxy]chromane-3-carboxylate (230 mg, 0.57 mmol) and

NH4OAC (4.39 g, 57.01 mmol) in AcOH (4 mL) was heated at 120 °C for 5 hrs. The reaction was
cooled and added slowly to sat. aq. NaHCCh (150 mL) and stirred for 1 hr. The aqueous layer was
10 extracted with EtOAc (2 X 200 mL) and the combined organic layers were dried (Na2SO4), filtered,
concentrated in vacuo. The residue was purified by flash column chromatography (0-5%
MeOH/DCM), partitoned between DCM (50 mL)/sat. aq. NaHCO3 (50 mL), the organic layer was
dried (phase separator) and concentrated in vacuo to provide 2-methyl-4-[3-(5-phenyl-1H-imidazol-
2-yl)chroman-6-yl]oxy-pyridine (29.3 mg, 13% yield) as a light tan solid.
15 LCMS: (ES+, Long): RT 2.16 min, m/z 384.0 [M+H]+.

1H NMR shows a mixture of confirmers:

Ή NMR (400 MHz, de-DMSO) δ: 12.31 (0.2H, brs), 12.10 (0.8H, brs), 8.30 (1H, d, J=5.7 Hz), 7.77
- 7.73 (1,6H, m), 7.66 - 7.62 (0.4H, m), 7.60 (0.8H, d, J=2.0 Hz), 7.43 - 7.38 (0.3H, m), 7.36 - 7.30
(1.7H, m), 7.28 (0.2H, d, J=1.4 Hz), 7.26-7.21 (0.2H, m), 7.19-7.13 (0.8H, m), 7.04 -7.00 (1H, m),
20 6.95 - 6.88 (2H, m), 6.75 (1H, d, J=2.4 Hz), 6.69 (1H, dd, J=2.4, 5.7 Hz), 4.55 - 4.49 (1H, m), 4.17 -
4.09 (1H, m), 3.45 - 3.36 (1H, m), 3.30 - 3.20 (1H, m), 3.17 - 3.07 (1H, m), 2.40 (3H, s).

[00221] Example 22: Biological data

In vitro biological evaluation of compounds of the invention was carried out following the procedure
25 detailed below. The procedure provides binding affinity data for the compounds of the invention
against B-RAFV600E and C-RAF. The binding affinity is shown in Table 4 below.

[00222] LanthaScreen™ Eu kinase binding assay

[00223] To determine whether compounds bind to RAF kinases, they are tested in a competition
binding assay. The Invitrogen LanthaScreen™ Eu binding assay involves the binding of an Alexa-
30 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. The dual emission signal produced can be measured
35 at 665 and 615 nm.

[00224] Compounds at a concentration of 3 mM are serially diluted (e.g. 10μΙ 90 pl of 100%

dimethyl sulfoxide (DMSO)) seven times in 96-well plates fora total of 8 dilution points. Each DMSO
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dilution is further diluted 1:100 in kinase buffer (e.g. 5 μΙ into 495 μΙ kinase buffer) containing 50 mM
HEPES pH 7.5, 10 mM MgCb, 1 mM EGTA, 0.01% Brij-35.

[00225] Each well in a 96-well Optiplate™ (Perkin Elmer 6005569) contains 30 μΙ of final volume
per sample, including 10 μΙ compound at 3X the desired concentration, providing 10 μΜ at the final
5 maximum concentration, 10 μΙ of kinase/antibody mixture at 3X the desired concentration of RAF
recombinant kinases and antibody providing 5 nM final concentration of B-RAFV600E 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 μΙ of 3Xthe
desired concentration of kinase tracer 178 (Invitrogen PV5593) providing final concentrations of 20
10 nM tracer for B-RAFV600E kinase and 6 nM tracer for C-RAF kinase. The plates are incubated for 5
hours at room temperature and read on an EnVision plate reader (Perkin Elmer).

[00226] All data are analysed using the GraphPad Prism software package. Inhibition of tracer
binding to the kinase of interest is assessed by determination of ICso value, which is defined as the
concentration of compound which decreased the level of FRET signal measured at 665 nm by 50%.

15 [00227] 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-RAFve00E
mutant and C-RAF. The table shows the B-RAFV600E and C-RAF inhibition activity of compounds of
the invention categorised based on the ICso values, the categories being “++” and “+++”. The
category “+” refers to compounds with an ICso value of greater than 100nM. The category “++”
20 refers to compounds with an ICso value of 4 nM to 100 nM. The category “+++” refers to compounds
with an ICso value of less than 4 nM. Compounds having a designation of “+++” are thus more
active against B-RAFV600E and/or C-RAF than compounds having a designation of “++”. Similarly,
compounds having a designation of “++” are more active against B-RAF and/or C-RAF than
compounds having a designation of “+”.

25 Table 4

Name BRAFV600E CRAF

Example binding binding
affinity affinity
5-(3-(1 H-benzimidazol-2-yl)chroman-6-yl]oxy-3, 4- +++ +++
1
dihydro-1 H-1,8-naphthyridin-2-one
5-[3-(7-chloro-1H-benzimidazol-2-yl)chroman-6- ++ ++
2
yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one
5-[3-(4-phenyl-1H-imidazol-2-yl)chroman-6-yl]oxy- +++ +++
3
3,4-dihydro-1 H-1,8-naphthyridin-2-one]
Enantiomer 1 of 5-[3-(4-phenyl-1 H-imidazol-2-
3A yl)chroman-6-yl]oxy-3,4-dihydro-1 H-1,8- +++ +++
naphthyridin-2-one]
Enantiomer 2 of 5-[3-(4-phenyl-1 H-imidazol-2-
3B yl)chroman-6-yl]oxy-3,4-dihydro-1 H-1,8- +++ +++
naphthyridin-2-one]
5-[3-[4-(4-pyridyl)-1H-imidazol-2-yl]chroman-6- +++ +++
4
yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one
5-[3-(4-tert-butyl-1H-imidazol-2-yl)chroman-6- ++ +++
5
yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one
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5-[3-[4-(3-thienyl)-1H-imidazol-2-yl]chroman-6- +++ +++

6
yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one
5-[3-[4-(2-thienyl)-1H-imidazol-2-yl]chroman-6- +++ +++
7
yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one
5-[3-[5-(2-chlorophenyl)-1H-imidazol-2-yl]chroman- +++ +++
8
6-yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one
5-[3-[5-(3-chlorophenyl)-1H-imidazol-2-yl]chroman- +++ +++
9
6-yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one
5-[3-[4-(benzofuran-3-yl)-1H-imidazol-2-yl]chroman- +++ +++
10
6-yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one
5-[3-[5-(3-pyridyl)-1H-imidazol-2-yl]chroman-6- +++ +++
11
yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one
5-[3-[5-(4-methylsulfonylphenyl)-1H-imidazol-2-
12 yl]chroman-6-yl]oxy-3,4-dihydro-1 H-1,8- + ++
naphthyridin-2-one
5-[3-[5-(4-fluorophenyl)-1H-imidazol-2-yl]chroman- +++ +++
13
6-yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one
5-[3-[5-(1,3-benzodioxol-5-yl)-1 H-imidazol-2-
14 yl]chroman-6-yl]oxy-3,4-dihydro-1 H-1,8- +++ +++
naphthyridin-2-one
5-[3-[5-(2,3-dihydro-1,4-benzodioxin-6-yl)-1 H-
15 imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1 H-1,8- ++ +++
naphthyridin-2-one
5-[[3-(4-phenyl-1H-imidazol-2-yl)-2H-chromen-6- ++ +++
16
yl]oxy]-3,4-dihydro-1 H-1,8-naphthyridin-2-one
5-[3-(3-phenyl-1,2,4-oxadiazol-5-yl)chroman-6- ++ ++
17
yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one
5-[3-(5-phenyl-1H-pyrazol-3-yl)chroman-6-yl]oxy- +++ +++
18
3,4-dihydro-1 H-1,8-naphthyridin-2-one
5-[[(3S)-3-(4-phenyl-1H-imidazol-2-yl)-2,3-dihydro-
19 1,4-benzodioxin-6-yl]oxy]-3,4-dihydro-1 H-1,8- +++ +++
naphthyridin-2-one
5-[[(3R)-3-(4-phenyl-1 H-imidazol-2-yl)-2,3-dihydro-
20 1,4-benzodioxin-6-yl]oxy]-3,4-dihydro-1 H-1,8- +++ +++
naphthyridin-2-one
2-Methyl-4-[3-(5-phenyl-1 H-imidazol-2-yl)chroman-
21 ++ ++
6-yl]oxy-pyridine

[00228] Examples of compounds of the invention with values fortheir ICso are given in Table 5
below.

Table 5

Name BRAFV600E CRAF

binding binding
Example
affinity ICSo affinity IC5o
(nM) (nM)
5-[3-(4-phenyl-1H-imidazol-2-yl)chroman-6-
3 0.8 0.6
yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one]
Enantiomer 1 of 5-[3-(4-phenyl-1H-imidazol-2-
3A yl)chroman-6-yl]oxy-3,4-dihydro-1 H-1,8- 1.5 1.0
naphthyridin-2-one]
Enantiomer 2 of 5-[3-(4-phenyl-1 H-imidazol-2-
3B yl)chroman-6-yl]oxy-3,4-dihydro-1 H-1,8- 1.4 0.8
naphthyridin-2-one]
5-[3-[4-(3-thienyl)-1H-imidazol-2-yl]chroman-6-
6 1.0 0.4
yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one
7 5-[3-[4-(2-thienyl)-1H-imidazol-2-yl]ch roman-6- 1.1 0.5
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yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one

[00229] Compounds of the invention were selected to be tested in an AlphaScreen® SureFire®

pERK1/2 assay to assess the compounds cellular activity.

[00230] WiDr AlphaScreen® SureFire® pERK1/2 cellular assay

5 [00231] The human WiDr colorectal cell line endogenously expresses the B-RAFV600E 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). On day 1, WiDr cells (ATCC CRL-218™) are counted,
10 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)). The cells are
plated, 200 μΙ 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% CO2 overnight.

[00232] On day 2, compounds at a concentration of 6 mM are serially diluted 10 μΙ into 90 μΙ of

15 100% dimethyl sulfoxide (DMSO) six times in 96-well plates for a total of 7 dilution points. Each
dilution and a DMSO control are further diluted 1:200 (e.g. 5 μΙ into 995 μΙ minimum essential
medium + 0.1% fetal bovine serum). The media is removed and 100 μΙ compound dilution or control
in minimum essential medium + 0.1% fetal bovine serum is added to triplicate wells containing cells,
providing 30 μΜ compound at the maximum concentration. The cells are treated for 1 hour or 24
20 hours at 37 °C. The treatment is then removed and the cells are incubated with lysis buffer
containing phosphatase inhibitors for 10 minutes at room temperature. Cell lysates are transferred
to a 96-well Optiplate™ (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
25 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
30 measured at 570 nm. Both antibodies bind to phosphorylated ERK proteins, bringing the donor and
acceptor beads into close proximity.

[00233] All data are analysed using the GraphPad Prism software package. Inhibition of ERK
phosphorylation is assessed by determination of IC50 value, which is defined as the concentration of
compound which decreased the level of phosphorylated ERK proteins by 50%.

35 [00234] 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 IC50 values, the categories being “+”, “++” and “+++".
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The category “+” refers to compounds with an ICso value of greater than 300 nM. The category “++”
refers to compounds with an ICso value of 70 nM to 300 nM. The category “+++” refers to
compounds with an ICso value of less than 70 nM.

[00235] Table 6

WiDr pERK WiDrpERK

Example Name inhibition inhibition
category 1 hr category 24 hrs
5- [3-(4-phenyl-1H-imidazol-2-yl)chroman-
3 6- yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin- ++ +
2-one]
Enantiomer 1 of 5-[3-(4-phenyl-1H-
3A imidazol-2-yl)chroman-6-yl]oxy-3,4- +++ +
dihydro-1 H-1,8-naphthyridin-2-one]
Enantiomer 2 of 5-[3-(4-phenyl-1H-
3B imidazol-2-yl)chroman-6-yl]oxy-3,4- ++ +
dihydro-1 H-1,8-naphthyridin-2-one]
5-[[(3S)-3-(4-phenyl-1H-imidazol-2-yl)-2,3-
19 dihydro-1,4-benzodioxin-6-yl]oxy]-3,4- ++ +
dihydro-1 H-1,8-naphthyridin-2-one
5-[[(3R)-3-(4-phenyl-1H-imidazol-2-yl)-2,3-
20 dihydro-1,4-benzodioxin-6-yl]oxy]-3,4- ++ +
dihydro-1 H-1,8-naphthyridin-2-one

[00236] Examples of compounds of the invention with values fortheir ICso are given in Table 7
below.

[00237] Table 7

WiDrpERK WiDrpERK
Example Name inhibition inhibition
IC50 (nM) 1 hr ICso (nM) 24 hrs
5- [3-(4-phenyl-1H-imidazol-2-yl)chroman-
3 6- yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin- 100 671
2-one]
Enantiomer 1 of 5-[3-(4-pheny I-1H-
3A imidazol-2-yl)chroman-6-yl]oxy-3,4- 32 562
dihydro-1 H-1,8-naphthyridin-2-one]
Enantiomer 2 of 5-[3-(4-phenyI-1H-
3B imidazol-2-yl)chroman-6-yl]oxy-3,4- 115 416
dihydro-1 H-1,8-naphthyridin-2-one]
10

[00238] A375 AlphaScreen SureFire pERK1/2 cellular assay

[00239] The human A375 malignant melanoma cell line endogenously expresses the B-RAFV600E
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
15 phosphorylation in A375 cells, they are tested using AlphaScreen® SureFire® technology (Perkin
Elmer ERK1/2 p-T202/Y204 assay kit TGRES10K). On day 1, A375 cells (ATCC CRL-1619) are
counted, centrifuged and resuspended in growth media (Dulbecco’s modified Eagle’s medium
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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 μΙ 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% CO2 overnight.

[00240] On day 2, compounds at a concentration of 6mM are serially diluted 10 μΙ into 90 μΙ of

5 100% dimethyl sulfoxide (DMSO) six times in 96-well plates for a total of 7 dilution points. Each
dilution and a DMSO control are further diluted 1:200 (e.g. 5μI into 995μI serum-free growth media).
The media is removed and 50 μΙ compound dilution or control in serum-free media is added to
triplicate wells containing cells, providing 30 μΜ compound at the maximum concentration. The cells
are treated for 30 minutes at room temperature. The treatment is then removed and the cells are
10 incubated with lysis buffer containing phosphatase inhibitors for 10 minutes at room temperature.
Cell lysates are transferred to a 96-well Optiplate™ (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.
15 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,
20 bringing the donor and acceptor beads into close proximity.

[00241] All data are analysed using the GraphPad Prism software package. Inhibition of ERK
phosphorylation is assessed by determination of IC50 value, which is defined as the concentration of
compound which decreased the level of phosphorylated ERK proteins by 50%.

[00242] The results of AlphaScreen SureFire pERK1/2 cellular assay are given in Table 8 below.
25 The compounds tested all showed activity within a cell. The activity of the compounds of the
invention has been categorised based on the IC50 values, the categories being “++” and “+++".
The category “+” refers to compounds with an IC50 value of greater than 300 nM. The category “++”
refers to compounds with an IC50 value of 70 nM to 300 nM. The category “+++” refers to
compounds with an IC50 value of less than 70 nM.

30 [00243] Table 8

A375 pERK
Example Name inhibition
category
5-[3-(7-chloro-1H-benzimidazol-2-yl)chroman-6-yl]oxy-3,4- ++
2
d i hydro-1 H-1,8-naphthyridin-2-one
5-[3-(4-phenyl-1H-imidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-
3 +++
1 H-1,8-naphthyridin-2-one]
Enantiomer 1 of 5-[3-(4-phenyl-1H-imidazol-2-yl)chroman-6- +++
3A
yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one]
Enantiomer 2 of 5-[3-(4-phenyl-1 H-imidazol-2-yl)chroman-6- ++
3B
yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one]
5-[3-[4-(4-pyridyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4- +
4
dihydro-1 H-1,8-naphthyridin-2-one
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5-[3-[4-(3-thienyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4- +++
6
dihydro-1 H-1,8-naphthyridin-2-one
5-[3-[4-(2-thienyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4- +++
7
dihydro-1 H-1,8-naphthyridin-2-one
5-[[3-(4-phenyl-1H-imidazol-2-yl)-2H-chromen-6-yl]oxy]-3,4- +
16
d i hydro-1 H-1,8-naphthyridin-2-one
5-[3-(5-phenyl-1H-pyrazol-3-yl)chroman-6-yl]oxy-3,4-dihydro- +
18
1 H-1,8-naphthyridin-2-one
5-[[(3S)-3-(4-phenyl-1 H-imidazol-2-yl)-2,3-dihydro-1,4- ++
19
benzodioxin-6-yl]oxy]-3,4-dihydro-1 H-1,8-naphthyridin-2-one
5-[[(3R)-3-(4-phenyl-1 H-imidazol-2-yl)-2,3-dihydro-1,4- ++
20
benzodioxin-6-yl]oxy]-3,4-dihydro-1 H-1,8-naphthyridin-2-one

[00244] Examples of compounds of the invention with values fortheir ICso are given in Table 9
below.

Table 9

A375 pERK
Example Name inhibition
IC50 (nM)
5-[3-(4-phenyl-1H-imidazol-2-yl)chroman-6-yl]oxy-3,4-dihydro-
3 9.8
1 H-1,8-naphthyridin-2-one]
Enantiomer 1 of 5-[3-(4-phenyl-1H-imidazol-2-yl)chroman-6-
3A 12.0
yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one]
Enantiomer 2 of 5-[3-(4-phenyl-1 H-imidazol-2-yl)chroman-6-
3B 112
yl]oxy-3,4-dihydro-1 H-1,8-naphthyridin-2-one]
5-[3-[4-(3-thienyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-
6 23.4
dihydro-1 H-1,8-naphthyridin-2-one
5-[[(3S)-3-(4-phenyl-1 H-imidazol-2-yl)-2,3-dihydro-1,4-
19 155
benzodioxin-6-yl]oxy]-3,4-dihydro-1 H-1,8-naphthyridin-2-one
5-[[(3R)-3-(4-phenyl-1 H-imidazol-2-yl)-2,3-dihydro-1,4-
20 282
benzodioxin-6-yl]oxy]-3,4-dihydro-1 H-1,8-naphthyridin-2-one

[00245] IPC-298 AlphaScreen SureFire pERK1/2 cellular assay

[00246] The human IPC-298 melanoma cell line endogenously expresses the NRASQ61L mutation
leading to constitutive activation of the MAPK pathway and phosphorylation of ERK via C-RAF in
the absence of ligands. To determine whether compounds inhibit C-RAF-mediated ERK activation
10 in B-RAFWT IPC-298 cells, they are tested using AlphaScreen® SureFire® technology (Perkin Elmer
ERK1/2 p-T202/Y204 assay kit TGRES10K). On day 1, IPC-298 cells (DSMZ ACC-251) are
counted, centrifuged and resuspended in growth medium (RPMI 1640 containing 2g/L D-glucose
(Gibco 31870), 10% fetal bovine serum (VWR S061) and 2mM L-glutamine (Sigma G7513). The
cells are plated, 10OuL in each well of 96 well culture dish (Corning 3585) to a final cell density of
15 40,000 cells per well and incubated at 37°C in 5% CO2 overnight.

[00247] On day 2, compounds at a concentration of 6 mM are serially diluted 5 pl into 45 pl of

100% dimethyl sulfoxide (DMSO) six times in 96-well plates for a total of 7 dilution points. Each
dilution and a DMSO control are further diluted 1:200 (e.g. 5 pl into 995 pl serum-free RPMI 1640
medium). The media is removed and 100 μΙ compound dilution or control in serum-free RPMI 1640
20 medium is added to triplicate wells containing cells, providing 30 μΜ compound at the maximum
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concentration. The cells are treated for 1 hour at 37 °C in 5% CO2. The treatment is then removed
and the cells are incubated with lysis buffer containing phosphatase inhibitors for 10 minutes at
room temperature with gentle shaking. Cell lysates are transferred to a 96-well Optiplate™ (Perkin
Elmer 6005569) and incubated with anti-mouse IgG acceptor beads, a biotinylated anti-ERK1/2
5 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
10 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.

[00248] All data are analysed using the GraphPad Prism software package. Activation of ERK
15 phosphorylation is expressed as a percentage of activation relative to the reference compound,
Dabrafenib.

[00249] A representative example of the results of IPC-298 AlphaScreen SureFire pERK1/2

cellular assay is given in Figure 1. 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
20 comparison to Dabrafenib.

[00250] In total nine compounds of the invention were tested in the IPC-298 AlphaScreen SureFire
pERK1/2 cellular assay. The compounds were examples 3, 3A, 3B, 4, 6, 7, 18, 19 and 20. Each
compound yielded similar results to that of Figure 1 and showed reduced paradoxical activity

[00251] Throughout the description and claims of this specification, the words “comprise” and
25 “contain” and variations of them mean “including but not limited to", and they are not intended to
(and do not) exclude other moieties, additives, components, integers or steps. Throughout the
description and claims of this specification, the singular encompasses the plural unless the context
otherwise requires. In particular, where the indefinite article is used, the specification is to be
understood as contemplating plurality as well as singularity, unless the context requires otherwise.

30 [00252] Features, integers, characteristics, compounds, chemical moieties or groups described in

conjunction with a particular aspect, embodiment or example of the invention are to be understood
to be applicable to any other aspect, embodiment or example described herein unless incompatible
therewith. All of the features disclosed in this specification (including any accompanying claims,
abstract and drawings), and/or all of the steps of any method or process so disclosed, may be
35 combined in any combination, except combinations where at least some of such features and/or
steps are mutually exclusive. The invention is not restricted to the details of any foregoing
embodiments. The invention extends to any novel one, or any novel combination, of the features
disclosed in this specification (including any accompanying claims, abstract and drawings), or to
any novel one, or any novel combination, of the steps of any method or process so disclosed.
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The reader's attention is directed to all papers and documents which are filed concurrently with or
previous to this specification in connection with this application and which are open to public
inspection with this specification, and the contents of all such papers and documents are
incorporated herein by reference.

5
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(I)

5 wherein:

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, =0, -CN, C1-4 alkyl, Ci-4 haloalkyl, C3-e cycloalkyl, -ORA, -NRARB, SO2RA and SORA;

R1 is a substituted or unsubstituted heterocyclic moiety which either contains 5 or 6 atoms in a

10 single ring or 8, 9, 10 or 11 atoms in a fused bicyclic ring system, when substituted R1 contains 1 to
4 substituents independently selected from: halo, -ORA, -NRARB, =O, -OC(O)Rc, -C(O)Rc, -
C(O)ORA, -NRAC(O)Rc, -C(O)NRARB, -SO2RC, -SORC, -NRASO2RC, -SO2NRARB, -CN, Ci-4 alkyl, Ci-
4 haloalkyl and C3-e cycloalkyl;

XisN, OorS;

15 Y is -CR2BWor-CW;

W represents: -het1-R3 or-het2, in which het1 is a five or six membered cycloalkyl ring or
heterocyclic ring, and het2 is a carbocyclic or heterocyclic ring system containing 8, 9 or 10 atoms in
a fused bicyclic ring system; and in which each of het1 and het2 may be independently unsubstituted
or substituted and contain 1 or 2 substituents independently selected at each occurrence from: halo,
20 -ORA, -CN, Ci-4 alkyl, C1-4 haloalkyl, C3-e 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: -ORA, -CN, -NRARB;

Z is N, O, S, -CR2C, -CR2CR2D;

R2A, R2B, R2C and R2D are each independently selected at each occurrence from: H, halo, -ORA, -
25 CN, Ci-4 alkyl, C1-4 haloalkyl and C3-s cycloalkyl;

R3 is selected from substituted or unsubstituted: Ci-β alkyl, Ci-s 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 R3
contains 1 to 4 substituents independently selected from: halo, -ORA, -NRARB, -SO2RC, -SORC, -CN,
30 C1-4 alkyl, C1-4 haloalkyl, C3-6 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: -ORA, -CN, -SORC and -NRARB;
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RA and RB are each independently selected from H, C1-4 alkyl and C1-4 haloalkyl; and

Rc is selected from C1-4 alkyl and C1-4 haloalkyl.

2. A compound of claim 1, wherein A is phenyl.

3. A compound of claim 1 or claim 2, wherein X is O or S, optionally wherein X is O.

5 4. A compound of any preceding claim, wherein Z is O and Y is CR2BW.

5. A compound of any preceding claim, wherein Z is CR2CR2D and Y is CR2BW.

6. A compound of any preceding claim, wherein Z is CR2C and Y is CW.

7. A compound of any preceding claim, wherein R1 is a substituted or unsubstituted

heterocyclic moiety which either contains 6 atoms in a single ring or 10 atoms in a fused bicyclic
10 ring system.

8. A compound of any preceding claim, wherein R1 is 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,
15 dihydroisoquinolinone-yl, napthyridinyl, oxo-napthyridinyl, dihydronappthyridinyl,
tetrahydronaphthyridinyl, oxo-tetrahydronaphthyridinyl, and oxo-dihydro-H-naphthyridinyl.

9. A compound of claim 8, wherein R1 is substituted or unsubstituted pyridyl or substituted or

unsubstituted oxo-dihydro-H-naphthyridinyl.

10. A compound of any preceding claim, wherein W represents -het1-R3 or -het2, wherein het1
20 is represented by a group selected from substituted or unsubstituted: Cs-e cycloalkyl, Cs-e
heterocycloalkyl or C5-6 heteroaryl, and

het2 is represented by a group selected from substituted or unsubstituted Ce-w cycloalkyl, Cw aryl,
Ce-io heterocycloalkyl or Ce-io heteroaryl.

11. A compound of any preceding claim, wherein het1 is represented by substituted or

25 unsubstituted: pyrazole, imidazole or oxadiazole and het2 is represented by substituted or
unsubstituted benzimidazole.

12. A compound of any preceding claim, wherein R3 is selected from: C1-6 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,
30 9 or 10 atoms in a fused bicyclic ring system, wherein one ring of the bicyclic ring system is
aromatic.

13. A compound of claim 12, wherein R3 may be selected from a substituted or unsubstituted:
/so-propyl, tert-butyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl pyrrolyl, furanyl, thiophenyl,
pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
35 indolinyl, isoindolinyl, benzodioxanyl, benzofuranyl, isobenzofuranyl, benzothiophenyl,
isobenzothiophenyl, benzodioxolanyl, indazolyl, indazolinyl, benzimidazolyl, benzimidazolinyl,
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benzthiazolyl, benzoisothiazol, chromanyl, isochromanyl, tetralinyl, quinolinyl, isoquinolinyl,

tetrahydroquinolinyl, tetrahydroisoquinolinyl and tetrahydroquinoxalinyl.

14. A compound of any preceding claim, wherein RA and RB are each independently selected
from H, methyl, ethyl or trifluoromethyl and Rc is selected from methyl, ethyl or trifluoromethyl.

5 15. A compound of claim 14, wherein RA and RB are H; RA and RB are methyl; or RA is H and RB
is methyl and Rc is methyl.

16. The compound of claim 1, wherein the compound of formula (I) is selected from:
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17. The compounds of claim 14, wherein a * symbol indicates a chiral centre and the chiral
centre has a (R)-configuration or a (S)-configuration.

18. A compound, wherein the compound is a pharmaceutically acceptable salt of a compound

10 of any preceding claim.

19. A compound of any preceding claim for use as a medicament.

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20. The compound of any or claims 1 to 18 for use in the treatment of a condition which is
modulated by Raf kinases.

21. The compound of claim 20, wherein the condition treatable by the inhibition of Raf kinases
is selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma,
5 carcinoma and leukemia.

22. The compound of claim 20 or claim 21, wherein the condition treatable by the inhibition of
RAF kinases is 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
10 (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
15 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.

23. The compound of any of claims 1 to 18 for use simultaneously, sequentially or separately
with an additional anti-tumour agent, in the treatment of cancer, sarcoma, melanoma, skin cancer,
20 haematological tumors, lymphoma, carcinoma or leukemia.

24. The compound of any of claims 1 to 18 for use in the treatment of a condition selected from:
cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma and
leukemia.

25. The compound of claim 24, wherein the condition is selected from: Barret’s
25 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;
30 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;
35 metastatic melanoma and thyroid cancers.

26. A method of treatment of a condition which is modulated by RAF kinases, wherein the
method comprises administering a therapeutic amount of a compound of any of claims 1 to 18, to a
patient in need thereof.
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27. The method of claim 26, wherein the condition treatable by the inhibition of Raf kinases is
selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma,
carcinoma and leukemia.

28. The method of claim 26 or claim 27, wherein the condition treatable by the inhibition of Raf
5 kinases is 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
10 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;
15 renal cancer; metastatic melanoma and thyroid cancers.

29. The compound of any of claims 20 to 25 and the method of any of claims 26 to 28, wherein
the condition is selected from colorectal cancer or melanoma.

30. A method of providing a combination product, wherein the method comprises providing a
compound of any of claims 1 to 18 simultaneously, sequentially or separately with an anti-tumour
20 agent.

31. A use of a compound of any of claims 1 to 18 in the manufacture of a medicament for the
treatment of a condition which is modulated by RAF kinases.

32. Use of a compound of any of claims 1 to 18 in combination with an anti-tumour agent.

33. A pharmaceutical composition, wherein the composition comprises a compound of any of

25 claims 1 to 18 and one or more pharmaceutically acceptable excipients.
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Figures

120
-·- Dabrafenib
100
♦ Example 3
80

60

40

20

-20

Figure 1