WO2017100819A1

WO2017100819A1 - Modular syntheses of discoipyrrole type alkaloids and analogues

Info

Publication number: WO2017100819A1
Application number: PCT/AU2016/000397
Authority: WO
Inventors: Martin Gerhardt Banwell; Yiwen Zhang
Original assignee: The Australian National University
Priority date: 2015-12-14
Filing date: 2016-12-13
Publication date: 2017-06-22

Abstract

The present invention relates to methods for preparing a variety of discoipyrrole compounds and analogues using an oxidative cyclisation reaction as one of the steps. The present invention also relates to novel discoipyrrole analogues, pharmaceutical compositions comprising these compounds, and to their use in therapy, in particular in the treatment of disease states or conditions mediated by the discoidin domain receptor 2 (DDR2).

Description

MODULAR SYNTHESES OF DISCOIPYRROLE TYPE ALKALOIDS AND

ANALOGUES

Technical Field

[0001] The present invention relates to methods for preparing a variety of discoipyrrole compounds and analogues using an oxidative cyclisation reaction as one of the steps. The present invention also relates to novel discoipyrrole analogues, pharmaceutical compositions comprising these compounds, and to their use in therapy, in particular in the treatment of disease states or conditions mediated by the discoidin domain receptor 2 (DDR2).

Background

[0002] Recently, MacMillan and co-workers reported the isolation, using a functional signature-based ontology (FUSION) map approach, of four new alkaloids from the marine-derived Bacillus hunanensis strain SNA-048 (Y. Hu, et al, J. Am. Chem. Soc, 2013, 135, 13387; M. B. Potts, et al, Sci. Signaling, 2013, 6 (297), ra90). Using a range of relatively conventional spectroscopic techniques they assigned structures 1-4 (Figure 1) to these compounds and named them discoipyrroles A-D, respectively. Each of these was isolated as the racemate and the structure of the first (viz. 1) was confirmed by single- crystal X-ray analysis of the bis-/7-bromobenzoate derivate of the (-)-enantiomer obtained using chiral-phase HPLC techniques.

1 (R = OH, discoipyrrole A) 3 (discoipyrrole C) 4 (discoipyrrole D)

2 (R = H, discoipyrrole B)

Figure 1: Discoipyrroles A-D

[0003] Discoipyrroles 1, 2 and 4 are the first examples of natural products that embody a 3H-benzo[d]pvrrole[l ,3]oxazine-3,5-dione core. All four compounds proved to be particularly strong inhibitors of the discoidin domain receptor 2 or DDR2-dependent migration of BR5 fibroblasts (Y. Hu, et al, J. Am. Chem. Soc, 2013, 135, 13387). They also show selective cytotoxicity towards DDR2 mutant lung cancer cell lines (IC₅₀ 120- 400 nM). As such, these natural products and their analogues could provide important new tools for interrogating the DDR2 signaling pathway, one that has been implicated in various cancers (C. E. Ford, et al, Br. J. Cancer, 2007, 96, 808; K. Zhang, et al, Nature Cell Biol, 2013, 15, 677; B. Poudel, et al, Acta Biochim. Biophys. S «.,doi: 10. 1093/abbs/gmv005), fibroblast migration and proliferation (W. Vogel, et al, Mol. Cell., 1997, 1 , 13; A. Shrivastava, et al, Mol. Cell, 1997, I, 25) as well as obstructive diseases of blood vessels (L. Xu, et al, Arth. Rheum., 2010, 62, 2736).

[0004] The biogenesis of the racemic discoipyrroles is believed to be nonenzymic in nature and involves, in the case of compound 1 for example, oxidative coupling of 2- hydroxy- l -(/7-hydroxyphenyl)-5-methylhexan-3-one and />-hydroxybenzaldehyde with the resulting 1 ,3,4-trione engaging in successive inter- then intra-molecular condensation reactions with the amine and carboxylic acid residues, respectively, of anthranilic acid (Y. Hu, et al, J. Am. Chem. Soc, 2013, 135, 13387; D. A. Colosimo et al, . Am. Chem. Soc, 2016, 138, 2383;). Various feeding experiments have served to support such proposals and by mixing the three reaction partners just mentioned in dimethyl sulfoxide containing 1% trifluoroacetic acid at 50 °C then modest amounts of discoipyrrole A were obtained as an admixture with a number of side-products (Y. Hu, et al, J. Am. Chem. Soc, 2013, 135, 13387). A variation on this theme has been employed by May and co-workers in the total synthesis of the dimethyl ether of discoipyrrole D (4) (J-L. Shih, et al, Angew. Chem. Int. Ed., doi.org/10.1002/anie201503528).

[0005] The fascinating origins, structures and biological activities of the discoipyrroles together with the potential for "tuned" analogues to serve as molecular probes of the DDR2 cellular signaling process makes these compounds attractive and important synthetic targets.

[0006] There is a need for a synthetic route that provides a modular approach to the synthesis of both the discoipyrroles A-D as well as a variety of discoipyrrole analogues.

Summary

[0007] The present invention provides a process for the preparation of compounds of general Formula (I), via oxidati ve cyclisation of compounds of Formula (II).

comprising the step of oxidative cyclization of a compound of Formula (II)

wherein m is 0 or 1 ; n is 0 or 1 ;

W is O, S, NH or CH₂;

Z is O, S or NH;

R is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted amino, optionally substituted alkylthio, optionally substituted C_1-6alkoxy, optionally substituted C3.₇cycloalkyl, optionally substituted Qwheterocycloalkyl, and C_{1 -6}haloalkyl;

R^A1"A6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted Ci-ealkyl, Ci-ehaloalkyl, Ci_ ₆alkyloxy, optionally substituted C^^cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, - C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶; or when m is 1 ,

(i) R and R may optionally together form a bond and R and R^A4 are as defined above or together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R²; or

(ii) R^A2 and R^A3 together with the carbon atoms to which they are attached form a saturated or unsaturated carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R ; or

(iii) R^A1R^A2C-CR^A3R^A4 forms an aryl or heteroaryl group, wherein the aryl or heteroaryl groups are optionally substituted by one or more R^~; or when m and n are both 1 ,

(i) R^A4 and R^A5 may optionally together form a bond and R^A3 and

_RA6

are as defined above or together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R²: or (ii) R^M and R^A5 together with the carbon atoms to which they are attached form a saturated or unsaturated carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R²; or

(iii) R^A3R^A4C-CR^A5R^A6 forms an aryl or heteroaryl group, wherein the aryl or heteroaryl groups are optionally substituted by one or more R^"; each R is independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, C_1-6haloalkyl, C_1-6alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

X is selected from the group consisting of hydrogen, C_1-6alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, cycloalkyl,

heterocycloalkyl, aryl, and heteroaryl is optionally substituted by one or more R⁴;

Y is selected from the group consisting of hydrogen, C_1-6alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, cycloalkyl,

heterocycloalkyl, aryl, and heteroaryl is optionally substituted by one or more R⁵; or

X and Y, together with the carbon atoms to which they are attached form an optionally substituted aryl or heteroaryl group; wherein each aryl or heteroaryl group is optionally substituted by one or more R⁴;

R³ is hydrogen or C_1-6alkyl;

4 5

R" and R^J are each independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, C_1-6alkyloxy, optionally substituted C3.₇cycloa.kyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and - NR⁷C(0)R⁶; or 4 5

when two R or R substituents are attached to adjacent carbon atoms on the respective aryl or heteroaryl groups, they are joined to form a methylenedioxy, -CH₂-0-CH₂-, group;

R⁶ is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted C_3-7cycloalkyl and optionally substituted Ci_-6haloalkyl;

7 8

R' and R° are independently selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl and optionally substituted C_3- ₇cycloalkyl; or

7 8

R and R when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members.

[0010] A second aspect of the invention provides for a compound of Formula (I) as defined in the first aspect of the invention, prepared according to the first aspect of the invention.

[0011] A third aspect of the invention provides for a compound of Formula (I)

wherein m i s 0 or 1 ; n is 0 or 1 :

W is O, S, NH or CH₂; Z is O, S or NH;

R is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted amino, optionally substituted Ci_ 6alkyloxy, optionally substituted alkylthio, optionally substituted C_3-7cycloalkyl, optionally substituted C_3-7heterocycloalkyl, and C_1-6haloalkyl;

RA1-A6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted d^alkyl, C_1-6haloalkyl, Ci_ ₆alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaiyl, -CN, - C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶; or wh en m i s 1 ,

(i) R^A2 and R^{' 3} may optionally together form a bond and R^A1 and

_RA4

are as defined above or together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R²; or

(ii) R^A2 and R^A3 together with the carbon atoms to which they are attached form a saturated or unsaturated carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R²; or

(iii) R^A1R^A2C-CR^A3R^A4 forms an aryl or heteroaryl group, wherein the aryl or heteroaryl groups are optionally substituted by one or more R^"; or when m and n are both 1 ,

(i) R^A4 and R^A5 may optionally together form a bond and R^A3 and R^A6 are as defined above or together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R²; or

(ii) R^A4 and R^A5 together with the carbon atoms to which they are attached fonn a saturated or unsaturated carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R ; or

(iii) R^A R^A4C-CR^A5R^A6 forms an aryl or heteroaryl group, wherein the aryl or heteroaryl groups are optionally substituted by one or more R^"; each R² is independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, C_1-6haloalkyl, Ci-ealkyloxy, optionally substituted Cwcycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

heterocycloalkyl, aryl, and heteroaryl is optionally substituted by one or more R ;

X and Y, together with the carbon atoms to which they are attached fonn an optionally substituted aryl or heteroaryl group; wherein each aryl or heteroaryl group is optionally substituted by one or more R ;

R⁴ and R⁵ are each independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, Ci^alkyloxy, optionally substituted C₃.₇cycloalkyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and - NR⁷C(0)R⁶; or

4 5

when two R or R substituents are attached to adjacent carbon atoms on the respective aryl or heteroaryl groups, they are joined to form a methyl enedioxy, -CH₂-0-CH₂-, group;

R⁶ is selected from the group consisting of hydrogen, optionally substituted Ci-ealkyl, optionally substituted Cwcycloalkyl and optionally substituted Ci^haloalkyl;

7 8

R and R when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members; with the proviso that the compound is not discoipyrrole A, discoipyrrole B or discoipyrrole D. A fourth aspect of the invention provides for a compound of Formula (II)

wherein m is 0 or 1 ; n is 0 or 1 ; W is O, S, NH or CH₂;

Z is O, S or NH;

R is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted amino, optionally substituted alkylthio, optionally substituted Ci_f,alkoxy, optionally substituted C3_₇cycloalkyl, optionally substituted C_.wheterocycloalkyl, and C_1-6haloalkyl; A^1"A6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted Ci_-6alkyl, C_1-6haloalkyl, Ci_ ₆alkyloxy, optionally substituted C _-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, - C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶; or when m is 1 ,

(i) R^A2 and R^A3 may optionally together form a bond and R^A1 and R^A4 are as defined above or together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R²; or

(iii) R^A1R^A2C-CR^A3R^A4 forms an aryl or heteroaryl group, wherein the aryl or heteroaryl groups are optionally substituted by one or more R^"; or when m and n are both 1 , (i) R^A4 and R^A5 may optionally together form a bond and R^A3 and

_RA6

(ii) R^A4 and R^A5 together with the carbon atoms to which they are attached form a saturated or unsaturated carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R ; or

(iii) R^A3R^A4C-CR^A5R^A6 forms an aryl or heteroaryl group, wherein the aryl or heteroaryl groups are optionally substituted by one or more R^"; each R² is independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, C_1-6haloalkyl, C^alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

X is selected from the group consisting of hydrogen, Ci_-6alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, cycloalkyl,

X and Y, together with the carbon atoms to which they are attached form an optionally substituted aryl or heteroaryl group; wherein each aryl or heteroaryl group is optionally substituted by one or more R⁴; R³ is hydrogen or C_1-6alkyl;

R⁴ and R⁵ are each independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, Ci^alkyloxy, optionally substituted C₃-₇cycloalkyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and - NR⁷C(0)R⁶; or

4 5

when two R or R substituents are attached to adjacent carbon atoms on the respective aryl or heteroaryl groups, they are joined to form a methylenedioxy, -CH2-O-CH2-, group;

R⁶ is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted C_3-7cycloalkyl and optionally substituted C_1-6haloalkyl;

R 7 and R 8 are independently selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl and optionally substituted C_3- ₇cycloalkyl; or

7 8

[0013] A fifth aspect of the invention provides for a compound selected from the group consisting of:

a compound of Formula (Illb):

(Illb) wherein 1 ^

U¹ and IT are independently selected from Br, I, CF₃S0₃- and CF3CF2CF2CF2SO3-;

-CHO or -C(0)R⁹

R⁹ is selected from the group consisting of optionally substituted C_1-6alkyl, optionally substituted C3_-7cycloalkyl and optionally substituted C^haloalkyl;

R R³ and p are as defined herein; a compound of Formula (IVb):

OR^{1 1}

(IVb) wherein

R¹⁰ and Rⁿ are each independently H or C_1-6alkyl; or

R¹⁰ and R^{1 1}, together with the oxygen atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by one or more Ci_-3alkyl; R⁴ and q are as defined herein; a compound of Formula (Vb): C0₂R³

(Vb) a compound of Formula (VIb):

wherein

R^s and r are as defined herein: and a compound of Formula (Vllb):

(Vllb)

[0014] A sixth aspect of the invention provides for a pharmaceutical composition comprising a compound prepared by the process of the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a compound of the second, third, fourth or fifth aspects of the invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, carrier or diluent. [0015] A seventh aspect of the invention provides for a method for the treatment of a disease state or condition mediated by the discoidin domain receptor 2 (DDR2), comprising administering to a subject in need thereof a therapeutically effective amount of a compound prepared by the process of the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a compound of the second, third, fourth or fifth aspects of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the sixth aspect of the invention.

[0016] An eighth aspect of the invention provides for use of a compound prepared by the process of the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a compound of the second, third, fourth or fifth aspects of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease state or condition mediated by the discoidin domain receptor 2 (DDR2).

[0017] A ninth aspect of the invention provides for a compound prepared by the process of the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a compound of the second, third, fourth or fifth aspects of the invention, or a pharmaceutically acceptable salt thereof for use in the treatment of a disease state or condition mediated by the discoidin domain receptor 2 (DDR2).

[0018] In one embodiment of the methods and uses of the present invention, the disease state or condition is selected from the group consisting of cancer, osteoarthritis, fibrosis, rheumatoid arthritis, osteoporosis, cartilage injury, chronoidal neovascularization and liver cirrhosis.

Definitions

[0019] The following are some definitions that may be helpful in understanding the description of the present invention. These are intended as general definitions and should in no way limit the scope of the present invention to those terms alone, but are put forth for a better understanding of the following description.

[0020] Unless the context requires otherwise or specifically stated to the contrary, integers, steps, or elements of the invention recited herein as singular integers, steps or elements clearly encompass both singular and plural forms of the recited integers, steps or elements. [0021 ] Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated step or element or integer or group of steps or elements or integers, but not the exclusion of any other step or element or integer or group of elements or integers. Thus, in the context of this specification, the term "comprising" means "including principally, but not necessarily solely".

[0022] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features.

[0023] As used herein, the term "alkyl" includes within its meaning monovalent ("alkyl") and divalent ("alkylene") straight chain or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms, e.g., 1, 2, 3, 4, 5 or 6 carbon atoms. The straight chain or branched alkyl group is attached at any available point to produce a stable compound. For example, the term alkyl includes, but is not limited to, methyl, ethyl, 1 -propyl, isopropyl, 1 -butyl, 2-butyl, isobutyl, tert-butyl, amyl, 1,2-dimethylpropyl, 1 , 1 -dimethylpropyl, pentyl, isopentyl, hexyl, 4-methylpentyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 1 ,2,2-trimethylpropyl,

1 , 1 ,2-trimethylpropyl, and the like.

[0024] The term "alkoxy" or "alkyloxy" as used herein refers to straight chain or branched alkyloxy (i.e, O-alkyl) groups, wherein alkyl is as defined above. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy.

[0025] The term "cycloalkyl" as used herein includes within its meaning monovalent ("cycloalkyl") and divalent ("cycloalkylene") saturated, monocyclic, bicyclic, polycyclic or fused analogs. In the context of the present disclosure the cycloalkyl group may have from 3 to 10 carbon atoms. A fused analog of a cycloalkyl means a monocyclic ring fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl and fused analogs thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like. [0026] The term "aryl" or variants such as "arylene" as used herein refers to monovalent ("aryl") and divalent ("arylene") single, polynuclear, conjugated and fused analogs of aromatic hydrocarbons having from 6 to 10 carbon atoms. A fused analog of aryl means an aryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion. Examples of aryl and fused analogs thereof include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1,3-benzodioxole, 1 ,4-benzodioxanyl, and the like. A "substituted aryl" is an aryl that is independently substituted, with one or more, preferably 1, 2 or 3 substituents, attached at any available atom to produce a stable compound.

[0027] The term "alkylaiyl" as used herein, includes within its meaning monovalent ("aryl") and divalent ("arylene"), single, polynuclear, conjugated and fused aromatic hydrocarbon radicals attached to divalent, saturated, straight or branched chain alkylene radicals. Examples of alkylaryl groups include benzyl.

[0028] The term "heteroaryl" and variants such as "heteroaromatic group" or "heteroarylene" as used herein, includes within its meaning monovalent ("heteroaryl") and divalent ("heteroarylene"), single, polynuclear, conjugated and fused heteroaromatic radicals having from 5 to 10 atoms, wherein 1 to 4 ring atoms, or 1 to 2 ring atoms are heteroatoms independently selected from O, N, NH and S. Heteroaryl is also intended to include oxidized S or N, such as sulfmyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable compound is produced. The heteiOaromatic group may be C_4-9 heteroaromatic. A fused analog of heteroaryl means a heteroaryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion. Examples of heteroaryl groups and fused analogs thereof include pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, triazinyl, thienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 2,2'-bipyridyl, phenanthrolinyl, quinolinyl, isoquinolinyl, imidazolinyl, thiazolinyl, pyrrolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, and the like. "Nitrogen containing heteroaryl" refers to heteroaryl wherein any heteroatoms are N. A "substituted heteroaryl" is a heteroaryl that is independently substituted, with one or more, preferably 1 , 2 or 3 substituents, attached at any available atom to produce a stable compound. [0029] The term "heterocyclyl" and variants such as "heterocycloalkyl" as used herein, includes within its meaning monovalent ("heterocyclyl") and divalent ("heterocyclylene"), saturated, monocyclic, bicyclic, polycyclic or fused hydrocarbon radicals having from 3 to 10 ring atoms, wherein from 1 to 5, or from 1 to 3, ring atoms are heteroatoms independently selected from O, N, NH, or S, in which the point of attachment may be carbon or nitrogen. A fused analog of heterocyclyl means a monocyclic heterocycle fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion. The heterocyclyl group may be C_3-9 heterocyclyl. The heterocycloalkyl group may be C_3-6 heterocyclyl. The heterocyclyl group may be C_3-5 heterocyclyl. Examples of heterocyclyl groups and fused analogs thereof include aziridinyl, pyrrolidinyl, thiazolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, quinuclidinyl, azetidinyl, morpholinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, and the like. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4- pyridones attached through the nitrogen or N-substituted uracils.

[0030| The term "amino" as used herein refers to groups of the form -NR^aR^b wherein R^a and R^b are individually selected from hydrogen, optionally substituted (Ci_-4)alkyl, optionally substituted (C_2-4)alkenyl, optionally substituted (C_2-4)alkynyl, optionally substituted (C6-io)aryl and optionally substituted aralkyl groups, such as benzyl. The amino group may be a primary, secondary or tertiary amino group.

[0031] The term "halogen" or variants such as "halide" or "halo" as used herein refers to fluorine, chlorine, bromine and iodine.

[0032] The term "heteroatom" or variants such as "hetero-" or "heterogroup" as used herein refers to O, N, NH and S,

[0033] In general, "substituted" refers to an organic group as defined herein (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Thus, a substituted group will be substituted with one or more substituents, unless otherwise specified. In some embodiments, a substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents.

[0034] The term "optionally substituted" as used herein means the group to which this tenn refers may be unsubstituted, or may be substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, halo, haloalkyl, haloalkynyl, hydroxyl, hydroxyalkyl, alkoxy, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, N0₂, NH(alkyl), N(alkyl)₂, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroheterocyclyl, alkylamino, dialkylamino, alkenylamine, alkynylamino, acyl, alkenoyl, alkynoyl, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, heterocycloxy, heterocycloamino, haloheterocycloalkyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio, phosphorus-containing groups such as phosphono and phosphinyl, aryl, heteroaryl, alkylaryl, aralkyl, alkylheteroaiyl, cyano, cyanate, isocyanate, C0₂H, C0₂alkyl, C(0)NH₂, -C(0)NH(alkyl), and -C(0)N(alkyl)₂. Preferred substituents include halogen, Ci-C₆alkyl, C₂-C₆alkenyl, C Cehaloalkyl, Ci-Cealkoxy, hydroxy(C_1-6)alkyl, C₃-C₆cycloalkyl, C(0)H, C(0)OH, NHC(0)H, NHC(0)C]-C₄alkyl, C(0)Ci-C₄alkyl, NH₂, NHCi-C₄alkyl, N(Ci-C₄alkyl)₂, N0₂, OH and CN. Particularly preferred substituents include C_1-3alkyl, C_1- alkoxy, halogen, OH, hydroxy(C_1-3)alkyl (e.g. CH₂OH), C(0)Ci-C₄alkyl (e.g. C(0)CH₃), and C_1-3haloalkyl (e.g. CF₃, CH₂CF₃).

[0035] The present invention includes within its scope all stereoisomeric and isomeric forms of the compounds disclosed herein, including all diastereomeric isomers, racemates, enantiomers and mixtures thereof. It is also understood that the compounds described by Formula I may be present as E and Z isomers, also known as cis and trans isomers. Thus, the present disclosure should be understood to include, for example, E, Z, cis, trans, (R), (S), (L), (D), (+), and/or (-) forms of the compounds, as appropriate in each case. Where a structure has no specific stereoisomerism indicated, it should be understood that any and all possible isomers are encompassed. Compounds of the present invention embrace all conformational isomers. Compounds of the present invention may also exist in one or more tautomeric forms, including both single tautomers and mixtures of tautomers. Also included in the scope of the present invention are all polymorphs and crystal forms of the compounds disclosed herein.

[0036] The present invention includes within its scope isotopes of different atoms. Any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Thus, the present disclosure should be understood to include deuterium and tritium isotopes of hydrogen.

[0037] All references cited in this application are specifically incorporated by cross- reference in their entirety. Reference to any such documents should not be construed as an admission that the document forms part of the common general knowledge or is prior art.

[0038] In the context of this specification the term "administering" and variations of that term including "administer" and "administration", includes contacting, applying, delivering or providing a compound or composition of the invention to an organism, or a surface by any appropriate means. In the context of this specification, the term "treatment", refers to any and all uses which remedy a disease state or symptoms, prevent the establishment of disease, or otherwise prevent, hinder, retard, or reverse the progression of disease or other undesirable symptoms in any way whatsoever.

[0039] In the context of this specification the term "effective amount" includes within its meaning a sufficient but non-toxic amount of a compound or composition of the invention to provide a desired effect. Thus, the term "therapeutically effective amount" includes within its meaning a sufficient but non-toxic amount of a compound or composition of the invention to provide the desired therapeutic effect. The exact amount required will vary from subject to subject depending on factors such as the species being treated, the sex, age and general condition of the subject, the severity of the condition being treated, the particular agent being administered, the mode of administration, and so forth. Thus, it is not possible to specify an exact "effective amount". However, for any given case, an appropriate "effective amount" may be determined by one of ordinary skill in the art using only routine experimentation.

Detailed Description

[0040] The present invention provides a process for the preparation of a compound of Formula (I):

(I) comprising the step of oxidative cyclization of a compound of Formula (II)

(Π) wherein m is 0 or 1 ; n is 0 or 1 ;

W is O, S, NH or CH₂; Z is O, S or NH;

R¹ is selected from the group consisting of hydrogen, optionally substituted Ci_-6alkyl, optionally substituted amino, optionally substituted alkylthio, optionally substituted Ci_-6alkoxy, optionally substituted C_3-7cycloalkyl, optionally substituted C_.wheterocycloalkyl, and C_{1 -6}haloalkyl;

R^A1"A6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted Ci_-6alkyl, C_1-6haloalkyl, C_\. 6alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, - C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶; or when m is 1 ,

(i) R^A2 and R^{' 3} may optionally together form a bond and R^A1 and

_RA4

(iii) R^A1R^A2C-CR^A3R^A4 forms an aryl or heteroaryl group, wherein the aryl or heteroaryl groups are optionally substituted by one or more R²; or when m and n are both 1 ,

(i) R^A4 and R^A5 may optionally together form a bond and R^A3 and

_RA6

(ii) R^A4 and R^A5 together with the carbon atoms to which they are attached form a saturated or unsaturated carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R²; or

(iii) R^A3R^A4C-CR^A5R^A6 forms an aryl or heteroaryl group, wherein the aryl or heteroaryl groups are optionally substituted by one or more R ; each R² is independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, C_{1 -6}haloalkyl, Ci_-6alkyloxy, optionally substituted C3-₇cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

X is selected from the group consisting of hydrogen, Ci-ealkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, cycloalkyl,

R³ is hydrogen or C_{1 -6}alkyl;

R" and R^J are each independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_{1 -6}alkyl, Ci^alkyloxy, optionally substituted C3-₇cyc.oa.kyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and - NR⁷C(0)R⁶; or when two or R^' substituents are attached to adjacent carbon atoms on the respective aryl or heteroaryl groups, they are joined to form a methylenedioxy, -CH₂-0-CH₂-, group;

R⁶ is selected from the group consisting of hydrogen, optionally substituted Ci- alkyl, optionally substituted Q^cycloalkyl and optionally substituted C_1-6haloalkyl; 7 8

R and R° are independently selected from the group consisting of hydrogen, optionally substituted Ci^alkyl and optionally substituted C - ₇cycloalkyl; or

7 8

[0041] In one embodiment of compounds of the present invention m is 0 or 1. In another embodiment of compounds of the present invention m is 0. In another embodiment of compounds of the present invention m is 1.

[0042] In one embodiment of compounds of the present invention n is 0 or 1. In another embodiment of compounds of the present invention n is 0. In another embodiment of compounds of the present inventi on n is 1.

[0043] In one embodiment of compounds of present invention m and n are both 0. In another embodiment of compounds of the present invention m is 1 and n is 0. In a further embodiment of compounds of the present invention m is 0 and n is 1. In a still further embodiment of compounds of the present invention m and n are both 1.

[0044] In one embodiment of compounds of present invention W is O, S, NH or CH₂. In another embodiment of compounds of the present invention W is O, S or NH. In a further embodiment of compounds of the invention W is O or S. In another embodiment of compounds of the present invention, W is O.

[0045] In one embodiment of compounds of the present invention Z is O, S or NH. In another embodiment of compounds of the invention Z is O or S. In a further embodiment of compounds of the present invention, Z is O.

[0046] In one embodiment of compounds of the present invention W is O and Z is O. In another embodiment of compounds of the present invention W is S and Z is O. In a further embodiment of compounds of the present invention W is O and Z is NH.

[0047] In one embodiment of compounds of the present invention R¹ is selected from the group consisting of hydrogen, optionally substituted Ci^alkyl, optionally substituted amino, optionally substituted alkylthio, optionally substituted C^alkoxy, optionally substituted C_3-7cycloalkyl, optionally substituted C_3-7heterocycloalkyl, and C_1-6haloalkyl. In another embodiment of compounds of the present invention R¹ is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted Q. ₆alkoxy, and C_1-6haloalkyl. In a further embodiment of compounds of the present invention R¹ is selected from the group consisting of hydrogen and optionally substituted C_1-6alkyl. In another embodiment of compounds of the invention R¹ is hydrogen or iso- butyl. In a further embodiment of compounds of the present invention R¹ is /s -butyl.

[0048] In one embodiment of compounds of the present invention R^A1~A6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted C_1-6alkyl, C_1-6haloalkyl, C_1-6alkyloxy, optionally substituted C - ₇cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶. In another embodiment of compounds of the present invention R^a1~A6 _are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted C_1-6alkyl, Cj. ₆haloalkyl, C_1-6alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In a further embodiment of compounds of the present invention R^A1~A6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted C_1-6alkyl, C_1-6haloalkyl and Ci_ ₆alkyloxy. In another embodiment of compounds of the present invention R^A1~A6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, and optionally substituted C_1-6alkyl. In a further embodiment of compounds of the present invention R^{A1 ~A6} are each independently hydrogen or C_1-6alkyl. In another embodiment of compounds of the present invention R^A1~A6 are each hydrogen.

[0049] In one embodiment of compounds of the present invention, m is 1 and R^ and R^A3 may optionally together form a bond and R^A1 and R^A4 are as defined above or together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R^". In another embodiment of compounds of the present invention, m is 1 and R^A2 and R^A3 may optionally together form a bond and R^A1 and R^A4 are as defined above. In a further embodiment of compounds of the present invention, m is 1 and R^A2 and R^A3 may optionally together form a bond and R^A1 and R^A4 together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic group. wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R².

[0050] In one embodiment of compounds of the present invention m is 1 and R' and R^A3 together with the carbon atoms to which they are attached form a saturated or unsaturated carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R . In another embodiment of compounds of the present invention m is 1 and R^' and R' ^' together with the carbon atoms to which they are attached fonn a saturated or unsaturated carbocyclic group, wherein the carbocyclic group is optionally substituted by one or more R . In a further embodiment of compounds of the present invention m is 1 and R ² and R^A3 together with the carbon atoms to which they are attached fonn a saturated or unsaturated heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more R .

[0051] In one embodiment of compounds of the present invention m is 1 and R^A1R^A2C- CRA R^A4 f_{orms an ar}y _or heteroaryl group, wherein the aryl or heteroaryl groups are optionally substituted by one or more R^". In another embodiment of compounds of the present invention m is 1 and R' R⁷ C-CR' R' forms an aiyl group, wherein the aryl group is optionally substituted by one or more R^". In a further embodiment of compounds of the present invention m is 1 and R^A1R^A2C-CR^A3R^A4 forms a heteroaryl group, wherein the heteroaryl group is optionally substituted by one or more R^". In another embodiment of the compounds of the present invention m is 1 and R^A1 R^A2C- CR^A3R^A4 forms a phenyl group, wherein the phenyl group is optionally substituted by one or more R^". In a further embodiment of compounds of the present invention m is 1 and

_RA1_RA2_C__{C R}A3_RA4 _{& pheny}j

[0052] In one embodiment of compounds of the present invention, m and n are both 1 and R and R'" may optionally together form a bond and R^{' '} and R^{^} ' are as defined above or together with the carbon atoms to which they are attached fonn a carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R^". In another embodiment of compounds of the present invention, m is 1 and R^A4 and R^A3 may optionally together form a bond and R^A' and R^A6 are as defined above. In a further embodiment of compounds of the present invention, m is 1 and R^A4 and R^A5 may optionally together fonn a bond and R^A3 and R^A6 together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R².

[0053] In one embodiment of compounds of the present invention m and n are both 1 and R^A4 and R^A5 together with the carbon atoms to which they are attached form a saturated or unsaturated carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R². In another embodiment of compounds of the present invention m is 1 and R^A4 and R^A5 together with the carbon atoms to which they are attached form a saturated or unsaturated carbocyclic group, wherein the carbocyclic group is optionally substituted by one or more R . In a further embodiment of compounds of the present invention m is 1 and R^A4 and R^A5 together with the carbon atoms to which they are attached form a saturated or unsaturated heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more R .

[0054] In one embodiment of compounds of the present invention m and n are both 1 and R^A3R^A4C-CR^A5R^A6 forms an aryl or heteroaryl group, wherein the aryl or heteroaryl groups are optionally substituted by one or more R . In another embodiment of compounds of the present invention m and n are both land R^A3R^A4C-CR^A5R^A6 forms an aryl group, wherein the aryl group is optionally substituted by one or more R^~. In a further embodiment of compounds of the present invention m and n are both 1 and R^A3R^A4C-CR^A5R^A6 forms a heteroaryl group, wherein the heteroaryl group is optionally substituted by one or more R . In another embodiment of the compounds of the present invention m and n are both 1 and R^R^A4C-CR^A3R^A0 forms a phenyl group, wherein the phenyl group is optionally substituted by one or more R . In a further embodiment of compounds of the present invention m and n are both 1 and R^A3R^A4C-CR^A5R^A6 forms a phenyl group.

[0055] In one embodiment of the compounds of the present invention each R^" is independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci.ealkyl, C_1-6haloalkyl, Ci^alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, - CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶. In another embodiment of the compounds of the present invention each R² is independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, C_1-6haloalkyl, Cj. ₆alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, and optionally substituted alkylheteroaryl. In a further embodiment of compounds of the present invention each R is independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci_-6alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, and optionally substituted alkylheteroaryl. In another embodiment of compounds of the present invention each R² is independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci_-6alkyl, and optionally substituted alkylheteroaryl. In a further embodiment of compounds of the present invention each R^" is an optionally substituted alkylheteroaryl.

[0056] In one embodiment of compounds of the present invention X is selected from the group consisting of hydrogen, C_1-6alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted by one or more R . In another embodiment of compounds of the present invention X is selected from the group consisting of hydrogen, Ci_-6alkyl, cycloalkyl and heterocycloalkyl; wherein each alkyl and cycloalkyl is optionally substituted by one or more R . In a further embodiment of compounds of the present invention X is selected from the group consisting of aryl, and heteroaryl; wherein each aryl and heteroaryl is optionally substituted by one or more R . In another embodiment of compounds of the present invention X is selected from the group consisting of hydrogen and aryl optionally substituted by one or more R . In a further embodiment of compounds of the present invention X is phenyl optionally substituted by one or more R .

[0057] In one embodiment of compounds of the present inventi on Y is selected from the group consisting of hydrogen, Ci- alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted by one or more R⁵. In another embodiment of compounds of the present invention Y is selected from the group consisting of hydrogen, Ci_-6alkyl, cycloalkyl and heterocycloalkyl; wherein each alkyl and cycloalkyl is optionally substituted by one or more R⁵. In a further embodiment of compounds of the present invention Y is selected from the group consisting of aryl, and heteroaryl; wherein each aryl and heteroaryl is optionally substituted by one or more R⁵. In another embodiment of compounds of the present invention Y is selected from the group consisting of hydrogen and aryl optionally substituted by one or more R⁵. In a further embodiment of compounds of the present invention Y is phenyl optionally substituted by one or more R⁵.

[0058] In one embodiment of compounds of the present invention X and Y, together with the carbon atoms to which they are attached form an optionally substituted aryl or heteroaryl group; wherein each aryl or heteroaryl group is optionally substituted by one or more R⁴. In another embodiment of compounds of the present invention X and Y, together with the carbon atoms to which they are attached form an aryl group optionally substituted by one or more R . In a further embodiment of compounds of the present invention X and Y, together with the carbon atoms to which they are attached form an heteroaryl group optionally substituted by one or more R⁴. In another embodiment of compounds of the present invention X and Y, together with the carbon atoms to which they are attached form a phenyl group optionally substituted by one or more R⁴.

[0059] In one embodiment of compounds of the present invention R is hydrogen or C_\. ₆alkyl. In another embodiment of compounds of the present invention R is hydrogen. In a further embodiment of compounds of the present invention R is C_{1 -6}alkyl.

[0060] In one embodiment of compounds of the present invention R⁴ and R⁵ are each independently selected from the group consisting of halogen, hydroxyl, optionally

7 8 substituted C_1-6alkyl, C_1-6alkyloxy, optionally substituted C_3-7cycloalkyl, -CN, -NR R , - C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶. In another embodiment of compounds of the

4 ^

present invention R and R^" are each independently selected from the group consisting of

7 8 6 halogen, hydroxyl, optionally substituted Ci_-6alkyl, C_{1 -6}alkyloxy, -NR R , and -C(0)OR . In a further embodiment of compounds of the present invention R⁴ and R⁵ are each independently selected from the group consisting of halogen, hydroxyl, C_1-6alkyl and C{. ₆alkyloxy. In another embodiment of compounds of the present invention R⁴ and R⁵ are each independently selected from the group consisting of hydroxyl and Ci_6alkyloxy.

4 5

[0061] In one embodiment of compounds of the present invention two R or R substituents are attached to adjacent carbon atoms on the respective aryl or heteroaryl groups, and are joined to form a methylenedioxy, -CH₂-0-CH₂-, group. In another

4 5

embodiment of compounds of the present invention two R or R substituents are attach ed to adjacent carbon atoms on the respective phenyl groups, and are joined to form a methylenedioxy, -CH₂-0-CH₂-, group. [0062] In one embodiment of compounds of the present invention R⁶ is selected from the group consisting of hydrogen, optionally substituted C_1- alkyl, optionally substituted C_3-7cycloalkyl and optionally substituted C_1-6haloalkyl. In another embodiment of compounds of the present invention R⁶ is hydrogen. In a further embodiment of compounds of the present invention R⁶ is optionally substituted Ci_-6alkyl or optionally substituted C _-7cycloalkyl. In a still further embodiment of compounds of the present invention R⁶ is hydrogen or optionally substituted C_1-6alkyl. In another embodiment of compounds of the present invention R⁶ is optionally substituted C_1- alkyl. In a further embodiment of compounds of the present invention R⁶ is methyl or ethyl. In another embodiment of compounds of the present invention R⁶ is selected from the group consisting of hydrogen, methyl and ethyl.

[0063] In one embodiment of compounds of the present invention R 7 and R 8 are independently selected from the group consisting of hydrogen, optionally substituted Ci_ ₆alkyl and optionally substituted C_3-7cycloalkyl. In another embodiment of compounds of the present invention R 7 and R 8 are independently selected from the group consisting of hydrogen and optionally substituted C_1-6alkyl. In another embodiment of compounds of the present invention R 7 and R 8 are hydrogen. In a further embodiment of compounds of

7 8

the present invention R and R are optionally substituted C_1-6alkyl. In another embodiment of compounds of the present invention R 7 and R 8 are both methyl. In a

7 8

further embodiment of compounds of the present invention R and R are independently selected from the group consisting of hydrogen and optionally substituted C_3-7cycloalkyl.

In another embodiment of compounds of the present invention R 7 is hydrogen and R 8 is optionally substituted C_1- alkyl. In one embodiment of compounds of the present invention R 7 is hydrogen and R 8 is methyl.

[0064] In one embodiment of compounds of the present invention R 7 and R 8 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having

7 8 from 0 to 2 additional heteroatoms as ring members. In another embodiment R and R when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members. In a further embodiment R

Q

and R when attached to the same nitrogen atom are combined to form a 3- to 7- membered ring having 1 additional heteroatom as ring members. In another embodiment

7 8

R and R when attached to the same nitrogen atom are combined to form a 3- to 7- membered ring having 0 additional heteroatoms as ring members. [0065] In one embodiment the present invention also relates to a process for preparing a compound of Formula (la)

(la) comprising the step of oxidative cyclization of a compound of Fonnula (lla)

(lla) wherein p is 0, 1, 2, 3 or 4; W is O, S, NH or CH₂; Z is O, S or H;

R¹ is selected from the group consisting of hydrogen, optionally substituted Ci- alkyl, optionally substituted amino, optionally substituted Ci_ ealkyloxy, optionally substituted alkylthio, optionally substituted C_3-7cycloalkyl, optionally substituted C _-7heterocycloalkyl, and C_1-6haloalkyl; each R² is independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, C_1-6haloalkyl, Ci_-6alkyloxy, optionally substituted C3-₇cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

X and Y, together with the carbon atoms to which they are attached, form an optionally substituted aryl or heteroaryl group; wherein each aryl or heteroaryl group is optionally substituted by one or more R ;

R³ is hydrogen or C_1-6alkyl;

R" and R^J are each independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci-ealkyl, Ci-ealkyloxy, optionally substituted C_3-7cycloalkyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and - NR⁷C(0)R⁶; or

4 5

R⁶ is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted C_3-7cycloalkyl and optionally substituted Ci-ehaloalkyl;

7 8

R' and R° are independently selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl and optionally substituted C - ₇cycloalkyl; or 7 8

[0066] In another embodiment the present invention relates to a process for preparing a compound of Formula (lb)

(lb)

comprising the step of oxidative cychzation of a compound of Formula (lib)

wherein p is 0, 1, 2, 3 or 4; q is O, 1 , 2, 3 or 4; r is 0, 1 , 2, 3 or 4;

R is selected from the group consisting of hydrogen, optionally substituted Ci- alkyl, optionally substituted amino, optionally substituted Ci. ₆alkyloxy, optionally substituted alkylthio, optionally substituted C_3-7cycloalkyl, optionally substituted Cs^heterocycloalkyl, and C_1-6haloalkyl; each R² is independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci_-6alkyl, C_1-6haloalkyl, C_1-6alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

R³ is hydrogen or C_1-6alkyl;

R⁴ and R⁵ are each independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, Ci ^alkyloxy, optionally substituted C₃-₇cycloalkyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and - NR⁷C(0)R⁶; or

4 5

when two R or two R substituents are attached to adjacent carbon atoms on the respective phenyl rings, they are joined to form a methyl enedioxy, -CH₂- O-CH2-, group;

R 7 and R 8 are independently selected from the group consisting of hydrogen, optionally substituted Ci_-6alkyl and optionally substituted C - ₇cycloalkyl; or

7 8

[0067| In a further embodiment the present invention relates to a process for preparing a compound of Formula (Ic)

(Ic) comprising the step of oxidative cyclisation of a compound of Formula (lie)

(lie) wherein p is 0, 1, 2, 3 or 4; s is 0, 1, 2, 3 or 4;

W is O, S, NH or CH₂;

Z is O, S or NH; 1 is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted amino, optionally substituted Cj. 6alkyloxy, optionally substituted alkylthio, optionally substituted C_3-7cycloalkyl, optionally substituted C_3-7heterocycloalkyl, and C_1-6haloalkyl; each R² is independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, C_1-6haloalkyl, C_1-6alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaiyl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

R³ is hydrogen or C_1-6alkyl; each R is independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci_₆alkyl, Ci_₆alkyloxy, optionally substituted Cs_ ycycloalkyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

7 8

R' and R° are independently selected from the group consisting of hydrogen, optionally substituted Ci-ealkyl and optionally substituted C_3- ₇cycloalkyl; or

7 8

[0068] The oxidative cyclisation reactions of compounds of Formula (II), Formula (Ha), Formula (lib) and Formula (lie) to prepare compounds of Formula (I), Formula (la), Formula (lb) and Formula (Ic) respectively can be carried out by any suitable means known to those skilled in the art. Suitable methods are described below, however, any other method which will affect the desired cyclisation also forms part of the present invention. It is to be understood that the groups W, X, Y, Z, R^]-Rⁿ and R^A1-R^A6 are such that they do not interfere with the cyclisation process.

[0069] The oxidative cyclisation may be performed using a variety of reagents, for example organic peroxides including but not limited to /er/-butyl hydroperoxide or meta- chloroperbenzoic acid; any of the above peroxides optionally combined with a transition metal catalyst such as Ti(OiPr)₄ or VO(acac)₂; dioxiranes such as dimethyldioxirane; inorganic oxidants including hydrogen peroxide, oxone, sodium hypochlorite; high oxidation state transition metal complexes such as chromium (VI) salts, osmium tetroxide or MoOs-based systems. The cyclisation may be performed by a halogenating reagent such as Λ-bromosuccinimide, pyridinium tribromide or a halogen such as bromine in conjunction with oxygen or air. The cyclisation may result in a racemic or enantioenriched product. Any reagent may be used in conjunction with a chiral ligand or auxiliary. A suitable ligand or auxiliary may be derived from an enantiopure amino acid or sugar. In one embodiment the oxidative cyclisation is performed using a MoOs-based system. In one embodiment the cyclisation is performed by oxoperoxymolybdenum(pyridine)(hexamethylphosphoric triamide) (MoOPH).

[0070] In one embodiment of the process of the present invention the compound of Formula (lib) is prepared by coupling of a compound of Formula (Illb)

(Illb) wherein and U^" are independently selected from Br, I, CF₃S0₃- and

CF₃CF₂CF₂CF₂S0₃-;

-CHO or -C(0)R⁹

R⁹ is selected from the group consisting of optionally substituted Ci_-6alkyl, optionally substituted C_3-7cycloalkyl and optionally substituted C_1-6haloalkyl;

R , R^J and p are as defined herein; with a compound of Formula (IVb) OR

(IVb) wherein

R¹⁰ and R^{1 1} are each independently H or C_1-6alkyl; or

R¹⁰ and R¹¹, together with the oxygen atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by one or more C_1-3alkyl;

R⁴ and q are as defined herein; to form a compound of Formula (Vb)

followed by coupling of a compound of Formula (VIb)

(VIb) wherein

R⁵ and r are as defined herein; with the compound of Formula (Vb) to form a compound of Formula (Vllb)

(Vllb) followed by conversion of the compound of Formula (Vllb) to a compound of Formula (lib).

[0071 ] In one embodiment of compounds of the present invention U and U^" are independently selected from Br, I, CF₃SO₃- and CF₃CF₂CF₂CF₂SO₃-. In another

1 2

embodiment of compounds of the present invention U and U are independently selected from the group consisting of Br or I. In another embodiment of compounds of the present

1 2

invention U and U are independently selected from CF₃SO₃- and CF₃CF₂CF₂CF₂SO₃-.

In a further embodiment of compounds of the present invention U 1 and U 2 are both Br. In another embodiment of compounds of the present invention U¹ and U² are both I. In a

1 2

further embodiment of compounds of the present invention one of U and U is Br and the other is I.

[0072] In one embodiment of compounds of the present invention V is -CHO or - C(0)R⁹. In another embodiment of compounds of the present invention V is -CHO. In a further embodiment of compounds of the present invention V is -C(0)R⁹.

[0073] In one embodiment of compounds of the present invention R⁹ is selected from the group consisting of optionally substituted Ci^alkyl, optionally substituted C_3- ₇cycloalkyl and optionally substituted C_1-6haloalkyl. In another embodiment of compounds of the present invention R⁹ is selected from the group consisting of optionally substituted C_1-6alkyl, optionally substituted C_3-7cycloalkyl. In a further embodiment of compounds of the present invention R⁹ is C_1-6alkyl. In another embodiment of compounds of the present invention R⁹ is methyl or ethyl. [0074] In one embodiment of compounds of the present invention R¹⁰ and R^{1 1} are each independently H or Ci_-6alkyl. In another embodiment of compounds of the present invention R¹⁰ and R¹¹ are both hydrogen. In a further embodiment of compounds of the present invention R¹⁰ and R¹¹ are both C_1- alkyl.

[0075] In one embodiment of compounds of the present invention R¹⁰ and R¹ ', together with the oxygen atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by one or more C_1- alkyl.

[0076] Suitable coupling conditions for the reaction between the compound of Formula (Illb) and the compound of Formula (IVb) and for the coupling between the compound of Formula (Vb) and Formula (VIb) comprise providing a catalytic or stoichiometric amount of a transition metal which acts as a catalyst. In one embodiment the coupling between the compound of Formula (Illb) and the compound of Formula (IVb) and the coupling between the compound of Formula (Vb) and Formula (VIb) is a palladium catalyzed reaction and in particular a Pd(0) catalyzed reaction. Pd(0) may be generated in situ by the reduction of Pd(II) or any transition metal species may be reduced or oxidized to a suitable catalytically active oxidation state in situ. Pd(0) or any catalytically active transition metal species may be introduced directly in to the reaction. A ligand which coordinates to the metallic species may be provided, examples of suitable ligands are triphenylphosphine, other phosphines such as l,2-bis(diphenylphosphino)ethane, acetate, nitrile or chloride. In one embodiment the process further provides providing a base for regeneration of the Pd(0) catalyst. Suitable bases for regenerating Pd(0) from Pd(II), which is formed duing the coupling reaction include, but are not limited to; alkylamines, such as triethylamine and diisopropylethylamine; acetates such as sodium acetate and potassium acetate; carbonates such as potassium carbonate, sodium carbonate, silver carbonate; and hydroxides such as sodium and potassium hydroxide.

[0077] The compounds of Formula (IVb) and Formula (VIb) may be the same or different. The compounds of Formula (IVb) and Formula (VIb) may be boronic acids or boronic esters, including but not limited to, pinacol boronate esters and boronate esters formed from ethylene glycol and 1 ,3 -propanediol. In one embodiment of the present invention, when the compounds of Formula (IVb) and Formula (VIb) are the same, a compound of Formula (Vllb) may be made in a single coupling directly from a compound of Formula (Illb). In one embodiment of the present invention the coupling of a compound of Formula (Illb) to prepare a compound of Formula (Vllb) in a single step involves reaction of a compound of Formula (Mb) with greater than or equal to 2 equivalents of a compound of Formula (IVb).

1 ^

[0078] In one embodiment of the present invention, when U and U^" are the same, the coupling between the compound of Formula (Mb) and Formula (IVb) occurs in a regioselective manner to provide a compound of Formula (Vb). In one embodiment of the present invention the reaction of a compound of Formula (Mb) to prepare a compound of Formula (Vb) involves reaction of a compound of Formula (Mb) with about 1 to 1 .2 equivalents of a compound of Formula (IVb).

[0079] Although the above process depicts the coupling between boronic acids and esters with aryl halides, triflates and nonaflates, it is to be understood that coupling reactions mediated by other transition metals such as Fe, Cu, Cr or Ni or other oxidation states of Pd may also be suitable through the choice of appropriate coupling partners and reaction conditions. The most appropriate conditions for the coupling reaction will be selected based on the identity of the coupling partners. One of the coupling partners, for example, may be another organometallic species such as an organotin, organozinc or organomagnesium species, in any relevant oxidation state.

[0080] In one embodiment of the processes of the present invention the compound of Formula (VMb) can be converted to a compound of Fonnula (lib) through a Wittig reaction with an appropriate ylid. For example, when R¹ is an sobutyl group, as in the discoipyrrole compounds A-D, a Wittig olefination reaction using the ylid obtained by treating /^'s -propyltriphenylphosponium iodide with potassium tert-butoxide would install an ivo-butene substituent. Subjecting this /so-butene compound to a standard hydrogenation reaction provides the .v -butylsubstituted compounds of Formula (lib). Depending on the identity of R¹ , a person skilled in the art would understand that there are a number of transformations to convert a compound of Formula (VMb) to a Formula (lib).

[0081 ] A person skilled in the art will appreciate the compounds of Formula (Mb) can be readily prepared using methods and materials known in the art. In one embodiment of compounds of the present invention a compound of Formula (Mb) can be prepared through coupling of a suitably substituted or unsubstituted pyrrole with and aryl or heteroaryl halide. When V is CHO, the aldehyde functionality can be incorporated to the product so generated by subjecting the compound to standard Vilsmeier-Hack reaction conditions using N./V-dimethylforraamide (DMF) and POCI₃. The introduction of the substituents U and U^" can be achieved by a number of means. For example, when U and U^" are bromide these substituents can be introduced by reaction with N-

1 ^

bromosuccinimide (NBS). Alternatively, when U and U^" are iodide these substituents can be introduced by reaction with iodine and silver triflate.

[0082] A person skilled in the art will appreciate that in order to access compounds of Formula (lie), a suitably substituted or unsubstituted indole would be employed instead of the pyrrole.

[0083] In one embodiment the present invention also provides for a compound of Formula (I)

(I) wherein m is 0 or 1 ; n is 0 or 1 ;

W is O, S, NH or CH₂; Z is O, S or NH;

R¹ is selected from the group consisting of hydrogen, optionally substituted Ci-ealkyl, optionally substituted amino, optionally substituted Ci. 6alkyloxy, optionally substituted alkylthio, optionally substituted Ci-vcycloalkyl, optionally substituted C3-₇heterocycloalkyl, and Ci.₆haloalkyl;

R.A1-A6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted Ci_-6alkyl,

Q. ₆alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, - C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶; or when m is 1 ,

(i) R^A2 and R^A3 may optionally together form a bond and R^A1 and R^M are as defined above or together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R²; or

(iii) R^{A I} R^A:(^'-(^'R ^{A i}R^{A 1} forms an aryl or heteroaryl group, wherein the aryl or heteroaryl groups are optionally substituted by one or more R^"; or when m and n are both 1 ,

(ii) R^A4 and R^A5 together with the carbon atoms to which they are attached form a saturated or unsaturated carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R ; or (iii) R^A3R^A4C-CR^A5R^A6 forms an aryl or heteroaryl group, wherein the aryl or heteroaryl groups are optionally substituted by one or more R^~; each R² is independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci-ealkyl, Ci-ehaloalkyl, Ci^alkyloxy, optionally substituted C^cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

Y is selected from the group consisting of hydrogen, Ci^alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, cycloalkyl,

X and Y, together with the carbon atoms to which they are attached form an optionally substituted aryl or heteroaryl group; wherein each aryl or heteroaryl group is optionally substituted by one or more R ;

R" and R^J are each independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci-ealkyl, Ci^alkyloxy, optionally substituted C_3-7cycloalkyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and - NR⁷C(0)R⁶; or

4 5

when two R or two R substituents are attached to adjacent carbon atoms on the respective phenyl rings, they are joined to form a methyl enedioxy, -CH₂- 0-CH₂-, group; R⁶ is selected from the group consisting of hydrogen, optionally substituted Ci_-6alkyl, optionally substituted C3_-7cycloalkyl and optionally substituted Ci-ehaloalkyl;

7 8

R and R when attached to the same nitrogen atom are combined to fonn a

3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members; with the proviso that the compound is not discoipyrrole A, discoipyrrole B or discoipyrrole D.

[0084] In another embodiment the present invention provides for a compound of Formula (la)

(la) wherein p is 0, 1, 2, 3 or 4;

W is O, S, NH or CH₂;

Z is O, S or NH;

R is selected from the group consisting of hydrogen, optionally substituted Ci_-6alkyl, optionally substituted amino, optionally substituted Ci_ ₆alkyloxy, optionally substituted alkylthio, optionally substituted C_3-7cycloalkyl, optionally substituted C _-7heterocycloalkyl, and C_{1 -6}haloalkyl; each R^" is independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci_-6alkyl, C_{1 -6}haloalkyl, C_1-6alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

R" and R^J are each independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_{1 -6}alkyl, C_{1 -6}alkyloxy, optionally substituted C3.₇cycloa.kyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and - NR⁷C(0)R⁶; or

4 5

when two R or R substituents are attached to adjacent carbon atoms on the respective aryl or heteroaryl groups, they are joined to form a methyl enedioxy, -CH₂-O-CH₂-, group; R⁶ is selected from the group consisting of hydrogen, optionally substituted Ci_-6alkyl, optionally substituted C3.₇cycloalkyl and optionally substituted Ci-ehaloalkyl;

7 8

R and R when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members, with the proviso that the compound is not discoipyrrole A, discoipyrrole B or discoipyrrole D.

[0085] In one embodiment the present invention also provides for a compound of Formula (lb)

p is 0, 1, 2, 3 or 4 q is O, 1, 2, 3 or 4 r is 0, 1, 2, 3 or 4;

R is selected from the group consisting of hydrogen, optionally substituted Ci_-6alkyl, optionally substituted amino, optionally substituted Ci_ ₆alkyloxy, optionally substituted alkylthio, optionally substituted C_3-7cycloalkyl, optionally substituted C _-7heterocycloalkyl, and C_1-6haloalkyl; each R^" is independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci_-6alkyl, C_1-6haloalkyl, C_1-6alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

R" and R^J are each independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci.ealkyl, C_1-6alkyloxy, optionally substituted C_3-7cycloalkyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and - NR⁷C(0)R⁶; or

4 5

7 8

R and R when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members; with the proviso that the compound is not discoipyrrole A, discoipyrrole B or discoipyrrole D.

[0086] In one embodiment the present invention also provides for a compound of Formula (Ic)

wherein p is 0, 1, 2, 3 or 4; s is 0, 1, 2, 3 or 4; W is O, S, NH or CH₂; Z is O, S or NH;

R¹ is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted amino, optionally substituted Ci_ 6alkyloxy, optionally substituted alkylthio, optionally substituted C_3-7c-ycloalkyl, optionally substituted C_3-7heterocycloalkyl, and C_1-6haloalkyl; each R^" is independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, C_1-6haloalkyl, C_1-6alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶; each R⁴ is independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci_-6alkyl, C_1-6alkyloxy, optionally substituted C_3- vcycloalkyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶; R⁶ is selected from the group consisting of hydrogen, optionally substituted Ci_-6alkyl, optionally substituted C3.₇cycloalkyl and optionally substituted Ci-ehaloalkyl;

7 8

[0087] In one embodiment the present invention also provides for a compound of Formula (II)

wherein m is 0 or 1 ; n is 0 or 1 ;

W is O, S, NH or CH₂;

Z is O, S or NH;

R is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted amino, optionally substituted alkylthio, optionally substituted Ci_-6alkoxy, optionally substituted C_3-7cycloalkyl, optionally substituted C_3-7heterocycloalkyl, and C_1-6haloalkyl; R^A1"A6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted Ci_-6alkyl,

Cu ₆alkyloxy, optionally substituted C3-₇cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, - C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶; or when m is 1 ,

(i) R^A4 and R^A5 may optionally together form a bond and R^A3 and

_RA6

(iii) R^A3R^A4C-CR^A5R^A6 forms an aryl or heteroaryl group, wherein the aryl or heteroaryl groups are optionally substituted by one or more R~; each R^" is independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci_-6alkyl, C_1-6haloalkyl, Ci^alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

Y is selected from the group consisting of hydrogen, C _1-6alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, cycloalkyl,

R³ is hydrogen or C_1-6alkyl;

R" and R^J are each independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci-ealkyl, Ci-ealkyloxy, optionally substituted C_3-7cycloalkyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and - NR⁷C(0)R⁶; or 4 5

7 8

[0088] In one embodiment the present invention also provides for a compound of Formula ( I la)

(Ila) wherein p is 0, 1, 2, 3 or 4; W is O, S, NH or CH₂; Z is O, S or NH;

R¹ is selected from the group consisting of hydrogen, optionally substituted Ci_-6alkyl, optionally substituted amino, optionally substituted Cj. ₆alkyloxy, optionally substituted alkylthio, optionally substituted C_3-7cycloalkyl, optionally substituted C _-7heterocycloalkyl, and C_1-6haloalkyl; each R² is independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci_-6alkyl, C_1-6haloalkyl, C_1-6alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

R³ is hydrogen or C_1-6alkyl;

R⁴ and R⁵ are each independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl,

optionally substituted C_3-7cycloalkyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and - NR⁷C(0)R⁶; or

4 5

when two R or R substituents are attached to adjacent carbon atoms on the respective aryl or heteroaiyl groups, they are joined to form a methylenedioxy, -CH₂-0-CH₂-, group; R⁶ is selected from the group consisting of hydrogen, optionally substituted Ci_-6alkyl, optionally substituted C3.₇cycloalkyl and optionally substituted Ci-ehaloalkyl;

7 8

[0089] In one embodiment the present invention also provides for a compound of Formula (lib)

wherein p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; r is 0, 1 , 2, 3 or 4;

R¹ is selected from the group consisting of hydrogen, optionally substituted Ci- alkyl, optionally substituted amino, optionally substituted Ci. 6alkyloxy, optionally substituted alkylthio, optionally substituted C_3-7cycloalkyl, optionally substituted C _-7heterocycloalkyl, and C_1-6haloalkyl; each R² is independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, C_1-6haloalkyl, Ci_-6alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

R³ is hydrogen or C_1-6alkyl;

optionally substituted C₃.₇cycloalkyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and - NR⁷C(0)R⁶; or when two R⁴ or two R⁵ substituents are attached to adjacent carbon atoms on the respective phenyl rings, they are joined to form a methyl enedioxy, -CH₂- 0-CH₂-, group;

R⁶ is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted C_3-7cycloalkyl and optionally substituted Ci^haloalkyl;

R 7 and R 8 are independently selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl and optionally substituted C - ₇cycloalkyl; or

7 8

[0090] In one embodiment the present invention also provides for a compound of Formula (lie)

wherein p is 0, 1, 2, 3 or 4; s is 0, 1, 2, 3 or 4;

W is O, S, NH or CH₂;

Z is O, S or NH;

R¹ is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted amino, optionally substituted Ci_ 6alkyloxy, optionally substituted alkylthio, optionally substituted C _-7cycloalkyl, optionally substituted C3_-7heterocycloalkyl, and C_1-6haloalkyl; each R² is independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, C_1-6haloalkyl, Ci_-6alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaiyl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

R³ is hydrogen or C_1- alkyl; each R⁴ is independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci_-6alkyl, C_1-6alkyloxy, optionally substituted C_3- vcycloalkyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶; R⁶ is selected from the group consisting of hydrogen, optionally substituted Ci_-6alkyl, optionally substituted C3_-7cycloalkyl and optionally substituted Ci-ehaloalkyl;

7 8

R and R when attached to the same nitrogen atom are combined to form a

3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members.

[0091 ] In one embodiment of the present invention, the compounds of Formula (II), Fonnula (Ila), Formula (lib) and Formula (lie) may act as prodrugs and be converted in vivo into compounds of Formula (I), Formula (la), Formula (lb) and Formula (Ic) respectively. In a further embodiment the compounds of Formula (II), Formula (Ila), Fonnula (lib) and Formula (lie) may have therapeutic activity in their own right.

[0092] In one embodiment the present invention also provides for a compound selected from the group consisting of:

a compound of Formula (Illb):

(nib) wherein

1 ^

U' and IT are independently selected from Br, I, CF3SO3- and

CF3CF2CF2CF2SO3-;

-CHO or -C(0)R⁹ R⁹ is selected from the group consisting of optionally substituted C_1-6alkyl, optionally substituted C _-7cycloalkyl and optionally substituted Ci^haloalkyl; and p are as defined herein; a compound of Formula (IVb):

OR 11

(IVb) wherein

R¹⁰ and Rⁿ are each independently H or C_1-6alkyl; or

R¹⁰ and R¹¹, together with the oxygen atoms to which they are attached, fonn a 5 to 7 membered ring, optionally substituted by one or more C_1-3alkyl;

R⁴ and q are as defined herein;

a compound of Formula (VIb):

(VIb) wherein

R and r are as defined herein: and a compound of Formula (Vllb):

(Vllb)

[0093] In one embodiment the compounds of Fomiula (Illb), Formula (Vb), and Formula (Vllb) may have therapeutic activity in their own right.

[0094] In one embodiment the present invention provides for a compound selected from the compounds set forth in Table 1.

Table 1

Synthesis of Compounds of Formula (I) and (II)

[0095] Compounds of formula (I) can be readily prepared by those skilled in the art using methods and materials known in the art and with reference to standard textbooks, such as such as "Advanced Organic Chemistry" by Jerry March (third edition, 1985, John Wiley and Sons) or "Comprehensive Organic Transformations" by Richard C. Larock (1989, VCH Publishers).

[0096] Compounds of formula (I) may be synthesised as described below. The following schemes provide an overview of representative non-limiting embodiments of the invention. Those skilled in the art will recognize that analogues of compounds of formula (I), including different isomeric forms, also may be prepared from the analogous starting materials.

[0097] As illustrated in Scheme 1, pyrrole (5) was crossed coupled with methyl o- iodobenzoate (6) using conditions very similar to those reported by Buchwald (J. C. Antilla, et al, J. Org. Chem., 2004, 69, 5578; R. A. Altmann and S. L. Buchwald, Nature Protocols, 2007, 2, 2474) and thereby affording the anticipated and previously reported product 7 (S. J. Hwang, et al, J. Am. Chem. Soc, 2008, 130, 16158) (99%). Subjection of the latter compound to a standard Vilsmeier-Haack formylation reaction using N,N- dimethylfomiamide (DMF) and POCl₃ afforded aldehyde 8 (G. V. Mokrov, et al, Heterocycles, 2008, 75, 2713) (58%) that could be dibrominated with N- bromosuccinimide (NBS) and so delivering the dihalogenated product 9 in 99% yield.

[0098] Two-fold Suzuki-Miyaura cross coupling of this last compound with boronic acid 10 then gave the 1 ,2,3-triarylated pyrrole-2- carboxaldehyde 11 (86%) that was itself subject to a Wittig olefination reaction using the ylid obtained by treating iso- propyltriphenylphosphonium iodide with potassium /er/-butoxide. The /so-butene 12 (85%o) so-formed was subjected to hydrogenation at atmospheric pressures using palladium on carbon as catalyst and the targeted C5-«o-buylated and triaryl-substituted pyrrole 13 thereby obtained in 95% yield.

Scheme 1 [0099] The ester 13 was saponified (Scheme 2) using potassium hydroxide and after work up with aqueous HC1 the corresponding carboxylic acid 14 was obtained in 99% yield. When a solution of compound 14 in dichloromethane was treated, at 20 °C for 16 h, with freshly prepared oxoperoxymolybdenum(pyridine)(hexamethyl-phosphoric triamide) (MoOPH) (E. Vedejs and S. Larsen, Org. Synth., 1985, 64, 127) then the desired 3H-benzo[<J]pyrrole[l,3]oxazine-3,5-dione 15 was obtained in 55% yield after chromatographic purification.

[00100] A second substrate, bis-phenol 16, used to examine the scope of the oxidative cyclisation process was obtained in 90% yield through the boron tribromide-mediated demethylation of compound 14. On treatment with MoOPH in dichloromethane compound 16 was converted into discoipyrrole (1) (56%), the derived spectral data for which proved an excellent match with those reported for the natural product.

BBr₃, CH₂C½,

-78 to 20 "C

16 h, 90%

16

Scheme 2

[00101] Regioselective Suzuki -Miyaura arylation reactions of the dibromopyrrole 9 are possible. When dibromopyrrole compound 9 was cross coupled with 1.2 molar equivalents of boronic acid 10 then the diarylated pyrrole 17 was obtained and immediately engaged in a second cross-coupling reaction with phenylboronic acid (18) to give the triarylated pyrrole 19 in 77% yield (Scheme 3). [00102] Compound 19 was converted into olefin 20 (70%) using the same ylid as employed previously and the double bond associated with the latter hydrogenated under conventional conditions and thus affording the so-butyl substituted pyrrole 21 in 95% yield. Saponification of the last compound then gave, after acidic work-up, the benzoic acid 22 (99%), the structure of which was confirmed by single-crystal X-ray analysis. When treated with boron tribromide aryl methyl ether 22 was cleaved to give the phenol 23 (82%)) that upon reaction with MoOPH in dichloromethane afforded lactone 2 in 55% yield. The structure of compound 2 was confirmed by single-crystal X-ray analysis. Furthermore, the derived NMR and IR spectral data were in excellent agreement with those reported for discoipyrrole B.

BBr,, CH₂C1₂,

78 to 20 °C

16 h, 82%

23

Scheme 3 [00103] Completely regioselective cross-coupling of the dibrominated pyrrole 9 can be accomplished under the illustrated conditions and thus affording the differentially triarylated pyrroles 25 and 29.

[00104 J As shown in Scheme 4, compound 25 can be accessed by the following steps. Dibromopyrrole compound 9 was cross coupled with 1.2 molar equivalents of phenylboronic acid 18 then the diarylated pyrrole 24 was obtained and immediately engaged in a second cross-coupling reaction with boronic acid 10 to give the triarylated pyrrole 25 in 60% yield.

Scheme 4

[00105] As shown in Scheme 5, compound 29 was accessed by cross coupling of dibromopyrrole 9 with 1.2 molar equivalents of boronic acid 26 then the diarylated pyrrole 27 was obtained and immediately engaged in a second cross-coupling reaction with boronic acid 28 to give the triarylated pyrrole 29 in 54% yield.

Scheme 5 [00106] Scheme 6, like Scheme 5, demonstrates that the illustrated Suzuki -Miyaura cross-coupling reactions can deliver highly oxygenated systems with cross coupling of dibromopyiTole 9 with boronic acid 28 to give the triarylated pyrrole 30 in 71 % yield.

Scheme 6

[00107] The reaction sequence shown in Scheme 7 demonstrates that an indole- containing, rather than a pyrrole-containing, oxidative cyclisation substrate, can engage in the pivotal oxidation cyclisation reaction.

[00108] Coupling of indole 31 with 1 -bromo-Aro-butene 32 afforded compound 33 that can be N-arylated using methyl o-iodobenzoate (6) and thus affording the disubstituted pyrrole 34. Saponification of this last compound then delivers, after acidic work -up, the corresponding acid 35 that upon exposure to MoOPH affords the novel discoipyrrole analogue 36.

Scheme 7

[00109] In one embodiment of the process of the present invention, Compound 4, discoipyrrole D, could be synthesised according to the procedure outlined in Scheme 8.

Scheme 8 [00110] Further analogues of Formula (I) can be accessed according to the reaction sequence outlined in Scheme 9, in which an unexpected regioselectivity was observed in the Suzuki-Miyaura cross-coupling reaction of compound 51 with compound 10 to afford compound 52.

Scheme 9

[00111 ] Further compounds that have been prepared according to analogous procedures to those detailed above and described in the Examples below include those compounds set forth in Table 2.

able 2

[00112] In one embodiment the present invention provides for a compound selected from the compounds set forth in Table 2.

Therapeutic uses and formulations

[00113] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, together with a pharmaceutically acceptable excipient, carrier or diluent. In one embodiment the compound of formula (1) is prepared by oxidative cyclisation of a compound of formula (II).

[00114] The present invention also relates to the use of compounds of formula (1) in therapy, in particular, for the treatment of a disease state or condition mediated by the discoidin domain receptor 2 (DDR2).

[00115] Accordingly, a further aspect of the invention is directed to a method for the treatment of a disease state or condition mediated by the discoidin domain receptor 2 (DDR2), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In one embodiment the compound of Formula (I) is prepared according to the process of the present invention by oxidative cyclisation of a compound of Formula (II).

[00116] In one embodiment of the methods of the present invention the disease state or condition is selected from the group consisting of cancer, osteoarthritis, fibrosis, rheumatoid arthritis, osteoporosis, cartilage injury, choroidal neovascularization and liver cirrhosis. In one embodiment of the methods of the present invention the cancer is a lymphoma, a sarcoma or carcinoma. In another embodiment of the methods of the present invention the cancer is of the lung, breast or ovary. In a further embodiment of the methods of the present invention the cancer is non-small-cell lung cancer or squamous cell carcinoma of the lung. In a further embodiment of the methods of the present invention the fibrosis is of the lung, liver or kidney.

[00117] In one embodiment of the methods of the present invention the subject is selected from the group consisting of humans, pets and livestock. In another embodiment of the methods of the present invention the subject is a human. Pharmaceutical and/or Therapeutic Formulations

[00118] In accordance with the present invention, when used for the treatment or prevention of a disease state or condition mediated by the discoidin domain receptor 2 (DDR2), compound(s) of the invention may be administered alone. Alternatively, the compounds may be administered as a pharmaceutical or veterinarial, formulation which comprises at least one compound according to the invention. The compound(s) may also be present as suitable salts, including pharmaceutically acceptable salts.

[00119] By pharmaceutically acceptable salt it is meant those salts which, within the scope of sound medical judgement, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art and include acid addition and base salts. Hemisalts of acids and bases may also be formed.

[00120] For compounds of formula (I) having a basic site, suitable pharmaceutically acceptable salts may be acid addition salts. For example, suitable pharmaceutically acceptable salts of such compounds may be prepared by mixing a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, phosphoric acid, acetic acid, oxalic acid, carbonic acid, tartaric acid, or citric acid with the compounds of the invention.

[00121] S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, (56: 1-19. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, asparate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Suitable base salts are formed from bases that 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. Representative alkali or alkaline earth metal salts include sodium, lithium potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, triethanolamine and the like.

[00122] Pharmaceutically acceptable salts of compounds of formula I may be prepared by methods known to those skilled in the art, including for example:

(i) by reacting the compound of formula I with the desired acid or base;

(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

(iii) by converting one salt of the compound of formula 1 to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

[00123] The above reactions (i)-(iii) 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 ionisation in the resulting salt may vary from completely ionised to almost non-ionised.

[00124] Thus, for instance, suitable pharmaceutically acceptable salts of compounds according to the present invention may be prepared by mixing a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, phosphoric acid, acetic acid, oxalic acid, carbonic acid, tartaric acid, or citric acid with the compounds of the invention. Suitable pharmaceutically acceptable salts of the compounds of the present invention therefore include acid addition salts.

[00125] 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 the solvent is water. [00126] In accordance with the present invention, the compounds of the invention may be used in combination with other known treatments or antibacterial agents, including antibiotics. Suitable agents are listed, for example, in the Merck Index, An Encyclopaedia of Chemicals, Drugs and Biologicals, 12^th Ed., 1996, the entire contents of which are incorporated herein by reference.

Modes of Administration

[00127] Convenient modes of administration include injection (subcutaneous, intravenous, etc.), oral administration, inhalation, transdermal application, topical creams or gels or powders, or rectal administration. Depending on the route of administration, the formulation and/or compound may be coated with a material to protect the compound from the action of enzymes, acids and other natural conditions which may inactivate the therapeutic activity of the compound. The compound may also be administered parenterally or intraperitoneally.

[00128] Dispersions of the compounds according to the invention may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, pharmaceutical preparations may contain a preservative to prevent the growth of microorganisms.

[00129] Pharmaceutical compositions suitable for injection include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Ideally, the composition is stable under the conditions of manufacture and storage and may include a preservative to stabilise the composition against the contaminating action of microorganisms such as bacteria and fungi.

[00130] In one embodiment of the invention, the compound(s) of the invention may be administered orally, for example, with an inert diluent or an assimilable edible carrier. The compound(s) and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into an individual's diet. For oral therapeutic administration, the compound(s) may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Suitably, such compositions and preparations may contain at least 1 % by weight of active compound. The percentage of the compound(s) of formula (I) in pharmaceutical compositions and preparations may, of course, be varied and, for example, may conveniently range from about 2% to about 90%, about 5% to about 80%, about 10% to about 75%, about 15% to about 65%; about 20% to about 60%, about 25% to about 50%, about 30% to about 45%, or about 35% to about 45%, of the weight of the dosage unit. The amount of compound in therapeutically useful compositions is such that a suitable dosage will be obtained.

[00131 ] The language "pharmaceutically acceptable carrier" is intended to include solvents, dispersion media, coatings, anti-bacterial and anti-fungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the compound, use thereof in the therapeutic compositions and methods of treatment and prophylaxis is contemplated. Supplementary active compounds may also be incorporated into the compositions according to the present invention. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. "Dosage unit form" as used herein refers to physically discrete units suited as unitary dosages for the individual to be treated; each unit containing a predetermined quantity of compound(s) is calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The compound(s) may be formulated for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in an acceptable dosage unit. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.

[00132] In one embodiment, the carrier may be an orally administrable carrier.

[00133] Another form of a pharmaceutical composition is a dosage form formulated as enterically coated granules, tablets or capsules suitable for oral administration.

[00134] Also included in the scope of this invention are delayed release formulations.

[00135] Compounds of formula (I) according to the invention may also be administered in the form of a "prodrug". A prodrug is an inactive form of a compound which is transformed in vivo to the active form. Suitable prodrugs include esters, phosphonate esters etc, of the active fonn of the compound. [00136] In one embodiment, the compound may be administered by injection. In the case of injectable solutions, the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by including various anti-bacterial and/or anti-fungal agents. Suitable agents are well known to those skilled in the art and include, for example, parabens, chlorobutanol, phenol, benzyl alcohol, ascorbic acid, thimerosal, and the like. In many cases, it may be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminium monostearate and gelatin.

[00137] Sterile injectable solutions can be prepared by incorporating the analogue in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilisation. Generally, dispersions are prepared by incorporating the analogue into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.

[00138] Tablets, troches, pills, capsules and the like can also contain the following: a binder such as gum gragacanth, acacia, corn starch or gelatin; excipients such as di calcium phosphate; a disintegrating agent such as com starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier. Various other materials can be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules can be coated with shellac, sugar or both. A syrup or elixir can contain the analogue, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the analogue can be incorporated into sustained-release preparations and formulations. [00139] Preferably, the pharmaceutical composition may further include a suitable buffer to minimise acid hydrolysis. Suitable buffer agent agents are well known to those skilled in the art and include, but are not limited to, phosphates, citrates, carbonates and mixtures thereof.

[00140] Single or multiple administrations of the pharmaceutical compositions according to the invention may be carried out. One skilled in the art would be able, by routine experimentation, to determine effective, non-toxic dosage levels of the compound and/or composition of the invention and an administration pattern which would be suitable for treating the diseases and/or infections to which the compounds and compositions are applicable.

[00141] Further, it will be apparent to one of ordinary skill in the art that the optimal course of treatment, such as the number of doses of the compound or composition of the invention given per day for a defined number of days, can be ascertained using convention course of treatment determination tests.

[00142] Generally, an effecti ve dosage per 24 hours may be in the range of about 0.0001 mg to about 1000 mg per kg body weight; suitably, about 0.001 mg to about 750 mg per kg body weight; about 0.01 mg to about 500 mg per kg body weight; about 0.1 mg to about 500 mg per kg body weight; about 0.1 mg to about 250 mg per kg body weight; or about 1.0 mg to about 250 mg per kg body weight. More suitably, an effective dosage per 24 hours may be in the range of about 1.0 mg to about 200 mg per kg body weight; about 1.0 mg to about 100 mg per kg body weight; about 1.0 mg to about 50 mg per kg body weight; about 1.0 mg to about 25 mg per kg body weight; about 5.0 mg to about 50 mg per kg body weight; about 5.0 mg to about 20 mg per kg body weight; or about 5.0 mg to about 15 mg per kg body weight.

[00143] Alternatively, an effective dosage may be up to about 500mg/m\ For example, generally, an effective dosage is expected to be in the range of about 25 to about

1 1 ")

500mg/m^~, about 25 to about 350mg/m^", about 25 to about 300mg/m^", about 25 to about

^ 2 2

250mg/m^", about 50 to about 250mg/m , and about 75 to about 150mg/m .

[00144] In another embodiment, a compound of Formula (I) may be administered in an amount in the range from about 100 to about 1000 mg per day, for example, about 200 rag to about 750 mg per day, about 250 to about 500 mg per day, about 250 to about 300 rag per day, or about 270 mg to about 280 rag per day.

[00145] Compounds in accordance with the present invention may be administered as part of a therapeutic regimen with other drugs. It may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition. Accordingly, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound of formula (I) according to the present invention, may be combined in the form of a kit suitable for co-administration of the compositions.

[00146] The invention will now be described in more detail, by way of illustration only, with respect to the following examples. The examples are intended to serve to illustrate this invention and should not be construed as limiting the generality of the disclosure of the description throughout this specification.

Examples

General Experimental Protocols

1 1

[00147] Unless otherwise specified, proton ( H) and carbon ( ^~ C) NMR spectra were recorded at room temperature in base-filtered CDC1₃ on a Bruker spectrometer operating at 400 MHz for proton and 100 MHz for carbon nuclei. For 1H NMR spectra, signals arising from the residual protio-forms of the solvent were used as the internal standards. ^]H NMR data are recorded as follows: chemical shift (δ) [multiplicity, coupling constants ) J (Hz), relative integral] where multiplicity is defined as: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet or combinations of the above. The signal due to residual CHCI₃ appearing at δκ 7.26 and the central resonance of the CDCI₃ "triplet" appearing at 5c 77.0 were used to reference Ή and ¹ C NMR spectra, respectively. The signal due to residual CH₂C1₂ appearing at 5H 5.30 and the central resonance of the CD₂C1₂ "multiplet" appearing at 5c 53.5 were used to reference Ή and

13

^' C NMR spectra, respectively. Infrared spectra (v_max) were recorded on a Perkin-Elmer 1800 Series FTIR Spectrometer. Samples were analyzed as thin films on KBr plates. Low-resolution ESI mass spectra were recorded on a single quadrupole liquid chromatograph-mass spectrometer, while high-resolution measurements were conducted on a time-of- flight instrument. Low- and high-resolution EI mass spectra were recorded on a magnetic-sector machine. Melting points were measured on an Optimelt automated melting point system and are uncorrected. Analytical thin layer chromatography (TLC) was performed on aluminum-backed 0.2 mm thick silica gel 60 F₂₅₄ plates as supplied by Merck. Eluted plates were visualized using a 254 nm UV lamp and/or by treatment with a suitable dip followed by heating. These dips included phosphomolybdic acid : eerie sulfate : sulfuric acid (cone.) : water (37.5 g : 7.5 g : 37.5 g : 720 mL) or potassium permanganate : potassium carbonate : 5% sodium hydroxide aqueous solution : water (3 g : 20 g: 5 mL : 300 mL). Flash chromatographic separations were carried out following protocols defined by Still et al. (W. C. Still, et al, J. Org. Chem., 1978, 43, 2923) with silica gel 60 (40-63 μιη) as the stationary phase and using the A - or HPLC-grade solvents indicated. Starting materials and reagents were generally available from the Sigma-Aldrich, Merck, TCI, Strem or Lancaster Chemical Companies and were used as supplied. Drying agents and other inorganic salts were purchased from the AJAX, BDH or Unilab Chemical Companies. Tetrahydrofuran (THF), diethyl ether, methanol and dichloromethane were dried using a Glass Contour solvent purification system that is based upon a technology originally described by Grubbs et al (A. B. Pangborn, et al, Organometallics, 1996, 15, 1518). Where necessary, reactions were performed under an nitrogen atmosphere.

Specific Chemical Transformations

Example 1 - Compound 7

7

[00148] A magnetically stirred and degassed mixture of compound 5 (1.66 mL, 24 mmol), compound 6 (3 mL, 20 mmol), Cul (380 mg, 2mmol), 1 ,10-phenanthroline (720 mg, 4 mmol) and K₃P0₄ (9.1 g, 42 mmol) in anhydrous 1,4-dioxane (20 mL) was heated at reflux under a nitrogen atmosphere for 16 h. The cooled reaction mixture was then passed through a pad of silica. The filtrate was concentrated under reduced pressure, and the residue was subjected to flash chromatography (silica, 30: 1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (R = 0.7 in 4: 1 v/v hexane/ethyl acetate), compound 7 (3.98 g, 99%) as a colorless syrup.

¹H NMR (400 MHz, CDC1₃) δ 7.69 (m, 1 H), 7.43 (m, 1H), 7.30-7.26 (complex m, 2H),

6.72-6.70 (complex m, 2H), 6.22-6.20 (complex m, 2H), 3.60 (s, 1H).

¹³C NMR (100 MHz, CDC1₃) δ 167.4, 140.3, 132.2, 130.5, 127.9, 127.0, 126.6, 121.9,

109.7, 52.4.

IR (KBr) v_max 2950, 1724, 1603, 1502, 1453, 1333, 1296, 1265, 1243, 1 126, 1085, 1071 , 924, 825, 764, 728, 626 cm^"1.

MS (ESI, +ve): m/z 202 ( | I I | \ 52%), 224 ([M+Na] ' , 23).

HRMS Found: (M+H)⁺, 202.0872. Ci₂HuN0₂ requires (M+H)\ 202.0868.

Example 2 - Compound 8

8

[00149] A magnetically stirred solution of anhydrous DMF (10 mL) maintained at 0 °C under a nitrogen atmosphere was treated with POCI₃ (2.19 mL, 23.74 mmol), and the ensuing orange mixture was stirred at 0 °C for 45 min before being treated with a solution of compound 7 (3.98 g, 19.79 mmol) in anhydrous THF (20 mL). The resulting mixture was stirred at 20 °C for 3 h and then quenched with ice (50 g). The mixture was neutralised using NaHC0₃ to pH 7, and then extracted with Et₂0 (3x80 mL). The combined organic phases were washed with brine (200 mL) before being dried (Na₂S0₄), filtered, and then concentrated under reduced pressure, and the residue was subjected to flash chromatography (silica, 6: 1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (R/ = 0.6 in 2: 1 v/v hexane/ethyl acetate), compound 8 (2.66 g, 59%) as a colorless syrup.

1H NMR (400 MHz, CDCI₃) δ 9.47 (s, 1H), 8.03 (dd, J = 7.7 and 1.7 Hz, 1H), 7.59 (td, J = 7.7 and 1.7 Hz, 1H), 7.51 (td, J = 7.6 and 1.3 Hz, 1H), 7.32 (dd, J = 7.8 and 1.3 Hz, 1 H), 7.10 (dd, J = 4.0 and 1.7 Hz, 1 H), 6.96 (m, 1H), 6.41 (dd, J = 4.0 and 2.5 Hz, l H), 3.66 (s, 3H). "C NMR (100 MHz, CDC1₃) δ 178.6, 165.3, 139.2, 133.3, 132.6, 131.5, 131.0, 128.9, 128.8, 128.5, 122.9, 1 10.6, 52.3.

IR (KBr) i¾_iax 2951, 1729, 1667, 1601 , 1528, 1497, 1468, 1413, 1365, 1295, 1262, 1080, 783 cm^"1.

MS (ESI, +ve): m/z 252 ([M+Naf, 100%).

HRMS Found: (M i l ) , 230.0819. C,₃HiiN0₃ requires (M+H)\ 230.0817.

Example 3 - Compound 9

9

[00150] A magnetically stirred solution of compound 8 (643 mg, 2.8 mmol) in dry THF (15 mL) maintained at -78 °C under a nitrogen atmosphere was treated with NBS (1.05 g, 5.8 mmol). The resulting pale yellow mixture was left to warm to 20 °C over 16 h and was then treated with Na₂S0₃ (700 mg, 5.8 mmol) at 0 °C. The suspension was stirred at 0 °C for 30 min and was then passed through a pad of (^'elite ' . The filtrate was concentrated under reduced pressure, and the residue was subjected to flash chromatography (silica, 8: 1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (R/ = 0.5 in 2: 1 v/v hexane/ethyl acetate), compound 9 (1.06 g, 99%) as a pale yellow oil.

lH NMR (400 MHz, CDCI₃) δ 9.24 (s, 1H), 8.15(m, 1H), 7.68(m, lH), 7.62 (m, l H), 7.29 (m, 1H), 7.14 (s, l H), 3.71 (s, 3H).

¹³C NMR (100 MHz, CDCI₃) δ 177.0, 164.3, 137.3, 134.1 , 133.2, 131.6, 130.0, 129.9, 128.4, 122.9, 1 17.5, 101.5, 52.44.

IR (KBr) v_max 3441 , 1726, 1674, 1495, 1397, 1296, 1269, 1092, 969, 815, 700 cm^"1.

MS (ESI, +ve): m/z 408 ([M+Naf, 48%), 386 (| \M I | . 13).

HRMS Found: (M+Naf, 407.8847. ¾Η₉ΒΓ₂ΝΌ₃ requires (M+Naf, 407.8847. Example 4 - Compound 11

11

[00151 ] A magnetically stirred and degassed mixture of compound 9 (639 mg, 1.63 mmol), compound 10 (1.28 g, 8.14 mmol), Pd(PPh₃)₄ (188 mg, 0.16 mmol) and Na₂C0₃ (1.04 g, 9.78 mmol) in 1,2-DME/H₂0 (28 mL of a 6: 1 v/v mixture) was heated to 85 °C under a nitrogen atmosphere for 20 h. The cooled reaction mixture was passed through a pad of Celite*. The filtrate was concentrated under reduced pressure, and the residue was subjected to flash chromatography (silica, 3: 1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (R/= 0.2 in 2: 1 v/v hexane/ethyl acetate), compound 11 (618 mg, 86%) as a pale yellow foam.

1H NMR (400 MHz, CDC1₃) δ 9.47 (s, 1 H), 7.92 (dd, J = 7.8 and 1.8 Hz, l H), 7.48 (m, 1H), 7.40 (m, l H), 7.32 (s, l H), 7.26 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.9 Hz, 2H), 6.67 (d, J = 8.8 Hz, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 3.70 (s, 3H).

¹³C NMR (100 MHz, CDCI₃) δ 178.6, 165.3, 159.4, 158.2, 139.6, 137.9, 132.8, 132.3, 132.0, 130.9, 130.8, 129.6, 129.2, 128.6, 127.2, 125.1 , 122.6, 1 13.8, 1 13.7, 55.2, 55.1 , 52.3.

IR ( Br) v_max 2952, 2836, 1727, 1664, 1610, 1513, 1460, 1292, 1249, 1 178, 1031, 825, 792 cm^"1.

MS (ESI, +ve): m/z 464 ([M+Na] ' , 100%), 442 (| \M I | . 38).

HRMS Found: (M i l ) . 442.1664. C27H23NO5 requires (M+H) , 442.1654. Example 5 - Compound 12

12

[00152] A magnetically stirred suspension of -PrPPh₃I (871 mg, 1.98 mmol) in anhydrous THF (10 mL) maintained at 0 °C under a nitrogen atmosphere was treated with /-BuOK (1.6 mL of a l .O M solution in THF, 1.61 mmol), and the ensuing red suspension was stirred at 0 °C for 30 min before being cooled to -78 °C. Then a solution of compound 11 (545 mg, 1.24 mmol) in anhydrous THF (8 mL) was added, and the resulting orange mixture was stirred at 0 °C for 1 h before being treated, successively, with NH₄CI (10 mL of a saturated aqueous solution) and water (20 mL) and then extracted with DCM (3x30 mL). The combined organic phases were washed with brine (100 mL) before being dried (Na₂S0₄), filtered, and then concentrated under reduced pressure, and the residue was subjected to flash chromatography (silica, 8: 1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (R/ = 0.7 in 2: 1 v/v hexane/ethyl acetate), compound 12 (488 mg, 85%) as a pale yellow foam.

¹H NMR (400 MHz, CDCI3) δ 7.84 (dd, J = 7.8 and 1.7 Hz, 1 H), 7.47 (td, J = 7.7 and 1.7 Hz, l H), 7.37 (td, J = 7.6 and 1.3 Hz, 1H), 7.29-7.21 (complex m, 3H), 6.99 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.67 (d, J = 8.8 Hz, 2H) , 6.55 (s, 1 H), 5.62 (s, lH), 3.79 (s, 3H), 3.73 (s, 3H), 3.68 (s, 3H), 2.05 (s, 3H), 1.81 (s, 3H).

¹³C NMR (100 MHz, CDCI₃) δ 166.2, 158.3, 157.4, 138.5, 134.4, 132.2, 132.1, 132.0, 131.3, 130.8, 130.6, 129.6, 129.4, 129.0, 127.7, 125.2, 122.4, 1 14.8, 1 13.6, 1 13.4, 108.9, 55.2, 55.0, 52.2, 27.0, 20.3.

IR (KBr) v_max 2934, 1730, 1516, 1456, 1289, 1246, 1 178, 1033, 833, 775 cm^"1.

MS (ESI, +ve): m/z 490 (| M · \^'a | . 100%), 467 (| M I I | . 77).

HRMS Found: (M i l ) . 468.2174. C30H29NO4 requires (M i l ) . 468.2175. Example 6 - Compound 13

13

[00153] A magnetically stirred solution of compound 12 (233 mg, 0.5 mmol) in dry THF (20 mL) was treated with palladium on carbon (53 mg, 0.05 mmol), and the ensuing black suspension was stirred at 20 °C under a hydrogen atmosphere for 16 h before being passed through a pad of Celite*. The filtrate was concentrated under reduced pressure, and the residue was subjected to flash chromatography (silica, 8:1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (R/= 0.4 in 4:1 v/v hexane/ethyl acetate), compound 13 (222 mg, 95%) as a pale yellow foam.

1H NMR (400 MHz, CDC1₃) δ 7.85 (m, IH), 7.53 (m, lH), 7.41-7.33 (complex m, 2H), 7.26 (m, 2H), 6.97 (m, 2H), 6.8 l(m, 2H), 6.67 (m, 2H), 6.34 (d, J= 6.4 Hz, 1H), 3.79 (d, J= 7.0 Hz, 3H), 3.73 (d,J= 7.3 Hz, 3H), 3.70 (d,J= 7.2 Hz, 3H), 2.32 (m, 2H), 1.79 (m, 1H), 1.03-0.90 (complex m, 6H).

¹ C NMR (100 MHz, CDCI₃) δ 166.0, 158.2, 157.2, 138.8, 133.6, 132.2, 132.0, 131.2, 130.8, 130.6, 129.6, 128.8, 127.8, 125.5, 121.5, 113.5, 113.3, 107.3, 55.1, 54.9, 52.2, 36.3,27.7, 22.7, 22.7.

IR(KBr) v_max2952, 1732, 1721, 1517, 1492, 1456, 1291, 1246, 1177, 1033, 832 cm^"1.

MS (ESI, +ve): m/z 492 ([M+Naf, 100%), 469 ([M+Hf, 71).

HRMS Found: (M il) .470.2332. C₃₀H₃₁NO₄ requires (M+H)\ 470.2331. Example 7 - Compound 14

14

[00154] A magnetically stirred solution of compound 13 (105 mg, 0.22 mmol) in TH F/H₂0/MeOH (20 mL of a 1:1:2 v/v/v mixture) was treated with KOH (123 mg, 2.2 mmol) and benzyltriethylammonium chloride (Cat.), and the ensuing mixture was heated at reflux for 16 h. The cooled reaction mixture was concentrated under reduced pressure, and the residue was acidified, using HCl (2 M aqueous solution), to pH 1. The suspension thus formed was diluted with brine (50 mL) and the extracted with ethyl acetate (3x50 mL). The combined organic phases were dried (Na₂S0₄), filtered, and the concentrated under reduced pressure. The residue was subjected to flash chromatography (silica, 50:1 v/v DCM/MeOH elution). Concentration of the appropriate fractions (Rf = 0.3 in 50:1 v/v DCM/MeOH) gave a yellow oil that upon recrystallization (hexane/DCM) afforded compound 14 (TOO mg, 99%) as a yellow, crystalline solid.

1H NMR (400 MHz, CDC1₃) δ 7.88 (dd, J= 7.8 and 1.6 Hz, 1H), 7.53 (td,J= 7.6 and 1.6 Hz, 1H), 7.36 (td, J= 7.7 and 1.2 Hz, 1H), 7.26 (d, J= 7.5 Hz, lH), 7.13 (d, J= 8.7 Hz, 2H), 6.87 (d, J= 8.7 Hz, 2H), 6.73 (d, J= 8.7 Hz, 2H), 6.52 (d, J= 8.7 Hz, 2H), 6.23 (s, lH), 3.76 (s, 3H), 3.64 (s, 3H), 2.28 (dd, J= 15.1 and 7.0 Hz, lH), 2.18 (dd, J= 15.1 and 7.3 Hz, 1H), 1.67 (m, lH), 0.86 (d, J= 6.5 Hz, 3H), 0.84 (d, J= 6.5 Hz, 3H).

1 C NMR (100 MHz, CDCI₃) δ 169.8, 158.3, 157.3, 139.5, 133.5, 133.0, 132.5, 131.6, 131.6, 129.7, 129.6, 129.3, 129.0, 128.0, 125.5, 122.0, 113.6, 113.5, 107.7, 55.3, 55.1, 36.4, 27.8,22.8,22.7.

IR (KBr) v_max3068, 2954, 1698, 1601, 1517, 1463, 1288, 1246, 1177, 1033, 834, 778 cm^" 1

MS (ESI, +ve): m/z 456 (|M II|\ 100%), 478 (|M · \^'a| .28).

HRMS Found: (M+H)⁺, 456.2175. C₂₉H₂₉N0₄ requires (M+H)⁺, 456.2175.

m.p. = 145- 146 °C. Example 8 - Compound 15

15

[00155] A magnetically stirred solution of compound 14 (73 mg, 0.16 mmol) in MeOH/DCM (8 mL of a 1:1 v/v mixture) under a nitrogen atmosphere was treated with MoOPH (165 mg, 0.48 mmol), and the ensuing yellow mixture was stirred in dark for 16 h before being passed through a pad of Celite*. The filtrate was washed with H₂0 (2x50 mL), brine (100 mL) before being dried (Na₂S0₄), filtered, and then concentrated under reduced pressure. The residue was subjected to flash chromatography (silica, 5:1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (R/ = 0.7 in 1:1 v/v hexane/ethyl acetate), compound 15 (41 mg, 55%) as a yellow oil.

1H N R (400 MHz, CDC1₃) δ 8.07 (dd,J= 7.8 and 1.6 Hz, 1H), 7.30 (td,J= 8.0 and 1.7 Hz, 1H), 7.19 (td, J = 7.6 and 1.1 Hz, 1H), 7.12 (d,J=8.2 Hz, 2H), 7.08 (d, J =8.9 Hz, 2H), 6.93 (d,J= 9.0 Hz, 2H), 6.74 (d,J= 8.8 Hz, 2H), 6.32 (d,J= 8.2 Hz, lH), 2.34 (dd, J= 14.0 and 5.9 Hz, l H), 1.97 (dd, J= 14.0 and 6.9 Hz, l H), 1.77 (m, 1H), 0.94 (d, J = 6.6 Hz, 3H), 0.82 (d, J= 6.7 Hz, 3H).

¹³C NMR (100 MHz, CDC1₃) S 194.3, 168.6, 161.9, 161.3, 158.6, 137.5, 134.6, 131.0, 130.4, 130.2, 124.9, 122.0, 121.7, 121.4, 118.3, 115.2, 114.7, 113.8, 91.3, 55.5, 55.3, 42.0, 24.1,24.0, 23.1.

IR(KBr) v_max2958, 2918, 1740, 1700, 1609, 1484,1385, 1252, 1175, 1021, 753 cm^"1.

MS (ESI, +ve): m/z 470 (|M II|\ 100%), 492 (|M · \^'a| .8).

HRMS Found: (M+Na)^', 492.1792. C₂₉H₂₇N0₅ requires (M+Na)⁺, 492.1787. Example 9 - Compound 16

16

[00156] A magnetically stirred solution of compound 14 (502 mg, 1.1 mmol) in dry DCM (40 mL) maintained at -78 °C under a nitrogen atmosphere was treated with BBr₃ (11 mL of a 1.0 M solution in DCM, 11 mmol), the ensuing red mixture was left to warm to 20 °C over 16 h before being treated, successively, with ice (100 g) and brine (100 mL) and then extracted with ethyl acetate (3x100 mL). The combined organic phases were dried (Na₂S0₄), filtered, and then concentrated under reduced pressure. The residue was subjected to flash chromatography (silica, 20:1 v/v DCM/MeOH elution) to afford, after concentration of the appropriate fractions (R/= 0.1 in 20:1 v/v DCM/MeOH), compound 16 (422 mg, 90%) as a yellow foam.

¹H NMR (400 MHz, CD₃OD) δ 7.84 (dd, J = 7.8 and 1.7 Hz, 1H), 7.46 (td, J = 7.6 and 1.7 Hz, 1H), 7.36 (td,J= 7.6 and 1.3 Hz, 1H), 7.14 (dd,J= 7.8 and 1.3 Hz, 1H), 7.03 (d, J= 8.6 Hz, 2H), 6.86 (d, J= 8.6 Hz, 2H), 6.59 (d, J= 8.6 Hz, 2H), 6.50 (d, J= 8.6 Hz, 2H), 6.15 (s, 1H), 2.29 (dd,J= 15.1 and 7.3 Hz, lH), 2.19 (dd,J= 15.0 and 7.1 Hz, lH), 1.63 (m, 1H), 0.84 (t, J= 6.6 Hz, 6H).

¹ C NMR (100 MHz, CD₃OD) δ 169.0, 157.1, 155.6, 140.3, 134.2, 133.7, 133.0, 132.8, 132.5, 131.7, 130.9, 130.1, 129.7, 128.8, 126.1, 122.6, 115.7, 115.6, 108.0, 37.5, 28.9, 23.1,22.9.

IR(KBr)v_max 3338, 2954, 1699, 1601, 1518, 1493, 1365, 1227, 1171, 1100, 834 cm^"1.

MS (ESI, +ve): m/z 428 (| II| .100%), 450 (|M · Na| .53).

HRMS Found: (M il) , 428.1866. C₂₇H₂₅N0₄ requires (M+H)\ 428.1862.

[00157] A magnetically stirred solution of compound 16 (243 mg, 0.57 mmol) in MeOH/DCM (20 mL of a 1 : 1 v/v mixture) under a nitrogen atmosphere was treated with MoOPH (543 mg, 1.25 mmol), and the ensuing yellow mixture was stirred in dark for 16 h before being passed through a pad of Celite*. The filtrate was washed with H₂0 (2x80 mL), brine (150 mL) before being dried (Na₂S0₄), filtered, and then concentrated under reduced pressure. The residue was subjected to flash chromatography (silica, 3:1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (R/ = 0.4 in 1:1 v/v hexane/ethyl acetate), compound 1 (140 mg, 56%) as a yellow amorphous solid.

1H NMR (400 MHz, CD₃OD) δ 8.03 (dd, J = 7.9 and 1.6 Hz, 1 H), 7.43 (td, J = 7.9 and 1.6 Hz, 1H), 7.27 (td, J = 7.7 and 1.0 Hz, lH), 7.08 (d, J= 8.2 Hz, 2H), 6.96 (d, J= 8.7 Hz, 2H), 6.85 (d, J= 8.6 Hz, 2H), 6.63 (d, J= 8.7 Hz, 2H), 6.47 (d, J= 8.2 Hz, 1H), 2.21 (dd,J= 14.0 and 6.1 Hz, lH), 1.99 (dd,J= 14.0 and 6.5 Hz, 1H), 1.76 (m, lH), 0.95 (d,J = 6.7 Hz, 3H), 0.84 (d, J= 6.7 Hz, 3H).

¹³C NMR (100 MHz, CD₃OD) δ 196.5, 172.1, 163.3, 161.1, 157.7, 138.7, 136.0, 131.6, 131.5, 126.2, 123.5, 121.7, 121.0, 119.2, 116.9, 116.4, 115.9, 92.5,43.0, 25.2, 24.2, 23.5. IR(KBr) v_max3352, 2962, 1735, 1709, 1673, 1608, 1559, 1522, 1483, 1385, 1272, 1235, 1172, 1071, 1022, 835, 754 cm^"1.

MS (ESI, +ve): m/z 442 (|\MI|\ 100%), 464 ([M+Na] ^', 24).

HRMS Found: (M+Na)^", 464.1477. C₂7H₂₃N0₅ requires (M+Na) ^T , 464.1474. Example 11 - Compound 19

19

[00158] A magnetically stirred and degassed mixture of compound 9 (4.56 g, 1 1.79 mmol), compound 10 (2.01 g, 12.97 mmol), Pd(PPh )₄ (1.36 g, 1.18 mmol) and Na₂C0₃ (10 g, 94.32 mmol) in 1,2-DME/H₂0 (120 mL of a 5: 1 v/v mixture) was heated to 85 °C under a nitrogen atmosphere for 4 h before being treated with compound 18 (2.85 g, 23.58 mmol), Pd(PPh₃)₄ (680 mg, 0.59 mmol) and Na₂C0₃ (5 g, 47.16 mmol). The resulting mixture was stirred at 85 °C for 16 h. The cooled reaction mixture was passed through a pad of ( elite \ The filtrate was concentrated under reduced pressure, and the residue was subjected to flash chromatography (silica, 4: 1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (R/ = 0.5 in 2: 1 v/v hexane/ethyl acetate), compound 19 (3.74 g, 77%) as a pale yellow foam.

1H NMR (400 MHz, CDC1₃) δ 9.51 (s, 1H), 7.95 (dd, J = 7.8 and 1.7 Hz, 1H), 7.51 (td, J = 7.6 and 1.7 Hz, 1H), 7.43 (td, J = 7.7 and 1.3 Hz, 1 H), 7.38 (s, 1 H), 7.28-7.26 (complex m, 5H), 7.23-7.18 (complex m, 1H), 6.97 (d, J = 8.6 Hz, 2H), 6.68 (d, J = 8.7 Hz, 2H), 3.74 (s, 3H), 3.72 (s, 3H).

¹³C NMR (100 MHz, CDC1₃) δ 178.7, 165.3, 159.5, 140.0, 137.9, 134.8, 132.9, 132.4, 132.0, 131.0, 130.8, 129.6, 128.7, 128.4, 128.1, 126.3, 125.4, 122.5, 122.0, 1 13.8, 55.1 , 52.4.

IR (KBr) vmax 2951 , 2838, 1727, 1664, 1603, 1496, 1462, 1427, 1293, 1252, 1 177, 1 156,

1092, 1030, 912, 848, 766, 735, 700 cm^"1.

MS (ESI, +ve): m/z 434 (| M · \^'a | . 100%), 412 (| \M I | . 26).

HRMS Found: (M+Na)⁺, 434.1368. C₂₆H₂₁N0₄ requires (M a) . 434.1368. Example 12 - Compound 20

20

[00159] A magnetically stirred suspension of /-PrPPhVI (6.41 g, 14.54 mmol) in anhydrous THF (30 mL) maintained at 0 °C under a nitrogen atmosphere was treated with -BuOK (13.64 mL of a 1.0 M solution in THF, 13.64 mmol), and the ensuing red suspension was stirred at 0 °C for 30 min before being cooled to -78 °C. Then a solution of compound 19 (3.74 g, 9.09 mmol) in anhydrous THF (50 mL) was added, and the resulting orange mixture was stirred at 0 °C for 1 h before being treated, successively, with NH₄CI (30 mL of a saturated aqueous solution) and water (50 mL) and then extracted with DCM (3x 100 mL). The combined organic phases were washed with brine ( 100 mL) before being dried (Na₂S0₄), filtered, and then concentrated under reduced pressure, and the residue was subjected to flash chromatography (silica, 15: 1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (Rf = 0.7 in 2: 1 v/v hexane/ethyl acetate), compound 20 (2.79 g, 70%) as a pale yellow foam. 1H NMR (400 MHz, CDCI₃) δ 7.82 (m, 1H), 7.46 (m, I H), 7.36 (m, l H), 7.31 -7.28 (complex m, 2H), 7.24-7.19 (complex m, 3H), 7.1 1 (m, IH), 6.94 (d, J = 8.1 Hz, 2H), 6.64 (d, J = 8.1 Hz, 2H), 6.54 (s, I H), 5.57 (s, IH), 3.72 (s, 3H), 3.64 (s, 3H), 2.01 (s, 3H), 1 .77 (s, 3H).

¹³C NMR (100 MHz, CDCI₃) S 166.2, 158.5, 138.5, 136.8, 134.7, 132.4, 132.2, 132.1 , 131 .4, 130.9, 130.7, 130.3, 128.1 , 128.1 , 127.8, 125.2, 125.1 , 122.8, 1 14.8, 1 13.5, 109.0, 55.1 , 52.3, 27.0, 20.4.

IR (KBr) v_max 2950, 1729, 1600, 1520, 1493, 1455, 1366, 1292, 1248, 1 178, 1 127, 1090, 1033, 832, 762, 698 cm^"1.

MS (ESI, +ve): m/z 438 ( | M I I | \ 100%), 460 · \'a | . 19).

HRMS Found: (M+H)⁺, 438.2069. C29H27NO3 requires (M+H)\ 438.2069. Example 13 - Compound 21

21

[00160] A magnetically stirred solution of compound 20 (2.79 g, 6.39 mmol) in dry THF (80 mL) was treated with palladium on carbon (677 mg, 0.64 mmol), and the ensuing black suspension was stirred at 20 °C under a hydrogen atmosphere for 16 h before being passed through a pad of Celite*. The filtrate was concentrated under reduced pressure, and the residue was subjected to flash chromatography (silica, 10:1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions {R/= 0.6 in 4:1 v/v hexane/ethyl acetate), compound 21 (2.65 g, 95%) as a pale yellow foam.

1H NMR (400 MHz, CDC1₃) δ 7.83 (dd, J= 7.8 and 1.6 Hz, 1H), 7.52 (td,J= 7.6 and 1.6 Hz, lH), 7.39 (td, J = 7.6 and 1.3 Hz, lH), 7.32-7.27 (complex m, 3H), 7.21 (m, 2H), 7.10 (m, 1H), 6.93 (d,J=8.8Hz, 2H), 6.64 (d,J=8.8Hz, 2H), 6.33 (s, 1H), 3.73 (s, 3H), 3.67 (s, 3H), 2.31 (dd, J= 15.2 and 6.9 Hz, lH), 2.22 (dd, J= 15.2 and 7.2 Hz, 1H), 1.75 (m, 1H), 0.91 (d,J= 6.6 Hz, 3H), 0.91 (d,J= 6.6 Hz, 3H).

¹³C NMR (100 MHz, CDC1 ) δ 166.2, 158.4, 138.8, 137.1, 133.9, 132.3, 132.2, 131.4, 131.0, 130.7, 130.3, 128.1, 128.0, 127.9, 125.5, 124.9, 122.0, 113.4, 107.4, 55.1, 52.4, 36.4,27.8,22.8,22.8.

IR(KBr) v_max2952, 1733, 1722, 1600, 1528, 1508, 1493, 1455, 1291, 1247, 1175, 1127, 1088, 1033, 840, 760, 698 cm^"1.

MS (ESI, +ve): m/z 440 (|\MI| .100%), 462 (|\l \^'a|\ 33).

HRMS Found: (M il) .440.2224. C₂₉H₂₉N0 requires (M il) .440.2226. Example 14 - Compound 22

22

[00161] A magnetically stirred solution of compound 21 (2.65 g, 6.04 mmol) in THF/H₂0/MeOH (120 mL of a 1:1:2 v/v/v mixture) was treated with KOH (1.7 g, 30.18 mmol) and benzyltriethylammonium chloride (Cat.), and the ensuing mixture was heated at reflux for 16 h. The cooled reaction mixture was concentrated under reduced pressure, and the residue was acidified, using HCl (2 M aqueous solution), to pH 1. The suspension thus fonned was diluted with brine (100 mL) and the extracted with ethyl acetate (3*100 mL). The combined organic phases were dried (Na₂S0₄), filtered, and the concentrated under reduced pressure. The residue was subjected to flash chromatography (silica, 50:1 v/v DCM/MeOH elution). Concentration of the appropriate fractions (R/= 0.3 in 50:1 v/v DCM/MeOH) gave a yellow oil that upon recrystallization (hexane/DCM) afforded compound 22 (2.59 g, 99%) as a yellow, crystalline solid.

1H NMR (400 MHz, CDC1₃) δ 7.88 (dd, J = 7.8, 1.6 Hz, 1H), 7.54 (td, J= 7.7 and 1.7 Hz, 1H), 7.37 (td, J =1.6 and 1.2 Hz, IH), 7.30 (dd, J= 7.8 and 1.2 Hz, IH), 7.23-7.14 (complex m, 4H), 7.08 (m, lH), 6.88 (d, J= 8.7 Hz, 2H), 6.51 (d, J= 8.8 Hz, 2H), 6.28 (s, IH), 3.63 (s, 3H), 2.29 (dd, J= 15.1 and 6.9 Hz, IH), 2.21 (dd, J= 15.1 and 7.3 Hz, 1H), 1.68 (m, IH), 0.86 (t, J= 6.7 Hz, 6H).

¹³C NMR (100 MHz, CDC1₃) δ 170.5, 158.3, 139.5, 137.0, 133.6, 133.0, 132.5, 131.6, 131.6, 130.2, 129.3, 128.1, 128.0, 128.0, 125.4, 124.9, 122.2, 113.5, 107.8, 55.1, 36.4, 27.8,22.8,22.7.

IR (KBr) v_max2953, 1700, 1600, 1528, 1508, 1492, 1462, 1287, 1247, 1175, 1106, 1033, 838, 760, 697 cm^"1.

MS (ESI, +ve): m/z 426 (|M II| .100%), 448 ([M+Na] , 40).

HRMS Found: (M il) .426.2069. C28H27NO3 requires (M il) .426.2069.

m.p. = 122- 123 °C. Example 15 - Compound 23

23

[00162] A magnetically stirred solution of compound 22 (1.04 g, 2.44 mmol) in dry DCM (40 mL) maintained at -78 °C under a nitrogen atmosphere was treated with BBr₃ (12.2 mL of a 1.0 M solution in DCM, 12.2 mmol), the ensuing red mixture was left to wann to 20 °C over 16 h before being treated, successively, with ice (100 g) and brine (100 mL) and then extracted with ethyl acetate (3x 100 mL). The combined organic phases were dried (Na₂S0₄), filtered, and then concentrated under reduced pressure. The residue was subjected to flash chromatography (silica, 50: 1 v/v DCM/MeOH elution) to afford, after concentration of the appropriate fractions (R/= 0.5 in 10: 1 v/v DCM/MeOH), compound 23 (822 mg, 82%) as a yellow foam.

1H NMR (400 MHz, CD OD) δ 7.85 (dd, J = 7.8 and 1.7 Hz, 1H), 7.47 (td, J = 7.6 and 1.6 Hz, 1H), 7.37 (td, J = 7.6 and 1.3 Hz, 1H), 7.22-7.17 (complex m, 2H), 7.16 (dd, J = 7.8 and 1.3 Hz, 1H), 7.13-7.07 (complex m, 2H), 6.99 (m, l H), 6.88 (d, J = 8.6 Hz, 2H), 6.51 (d, J = 8.6 Hz, 2H), 6.23 (s, l H), 2.31 (dd, J = 15.0 and 7.2 Hz, 1H), 2.20 (dd, J = 15.0 and 7.1 Hz, 1 H), 1.65 (m, IH), 0.85 (t, J= 6.3 Hz, 6H).

¹ C NMR (100 MHz, CD₃OD) δ 168.9, 157.3, 140.1, 138.5, 134.5, 133.7, 133.0, 132.8, 132.5, 131.8, 131.7, 128.9, 128.8, 128.5, 125.9, 125.6, 122.7, 1 15.7, 108.0, 37.5, 28.8, 23.1 , 22.9.

IR (KBr) v_max 3280, 2955, 1698, 1601 , 1529, 1509, 1494, 1461 , 1266, 1170, 1098, 841 , 760, 697 cm^"1.

MS (ESI, +ve): m/z 434 (| M · \^'a | . 100%), 412 (| M I I | . 40).

HRMS Found: (M i l ) , 412.1912. C₂₇H₂₅N0 requires (M+H)⁺, 412.1913. Example 16 - Compound 2

2

[00163] A magnetically stirred solution of compound 23 (481 mg, 1.17 mmol) in MeOH/DCM (20 mL of a 1 : 1 v/v mixture) under a nitrogen atmosphere was treated with MoOPH (1.12 g, 2.57 mmol), and the ensuing yellow mixture was stin-ed in dark for 16 h before being passed through a pad of Celite*. The filtrate was washed with H₂0 (2x80 mL), brine (150 mL) before being dried (Na₂S0₄), filtered, and then concentrated under reduced pressure. The residue was subjected to flash chromatography (silica, 6: 1 v/v hexane/ethyl acetate elution). Concentration of the appropriate fractions (R/ = 0.3 in 2: 1 v/v hexane/ethyl acetate) gave a yellow solid that upon recrystallization (CD₃OD) afforded compound 2 (273 mg, 55%) as a yellow, crystalline solid.

1H NMR (400 MHz, CD₃OD) δ 8.04 (dd, J = 7.9 and 1.6 Hz, l H), 7.42 (td, J = 7.9 and 1.6 Hz, I H), 7.27 (td, J = 7.6 and 1.1 Hz, lH), 7.21-7.1 1 (complex m, 5H), 7.08 (d, J = 8.4 Hz, 2H), 6.84 (d, J= 8.8 Hz, 2H), 6.49 (d, J= 8.2 Hz, 1 H), 2.22 (dd, J = 14.1 and 6.1 Hz, 1H), 1.99 (dd, J = 14.0 and 6.5 Hz, IH), 1.78 (m, IH), 0.95 (d, J = 6.7 Hz, 3H), 0.83 (d, J= 6.7 Hz, 3H).

¹ C NMR (100 MHz, CD₃OD) δ 195.9, 172.9, 163.2, 161.2, 138.4, 136.0, 131.7, 131.6, 130.8, 130.2, 129.0, 128.0, 126.4, 123.5, 120.7, 1 19.3, 1 17.0, 1 16.2, 92.6, 43.0, 25.1 , 24.2, 23.5.

IR (KBr) Vmax 3350, 2970, 1741 , 1703, 1603, 1516, 1483, 1386, 1278, 1233, 1 173, 1 1 1 1 ,

1070, 1021, 963, 942, 838, 754, 695 cm^"1.

MS (ESI, +ve): m/z 426 ( | M I I | . 100%), 448 ([M+Na] , 40).

HRMS Found: (M+H)⁺, 426.1696. C₂₇H₂₃N0₄ requires (M+H)⁺, 426.1705.

m.p. = 143- 144 °C. Example 17 - Compound 25

25

[0100] A magnetically stirred and degassed mixture of compound 9 (962 mg, 2.5 mmol), compound 18 (370 mg, 3 mmol), Pd(PPh₃)₄ (150 mg, 0.13 mmol) and Na₂C0₃ (1.06 g, 10 mmol) in 1,2-DME/H₂0 (18 mL of a 5: 1 v/v mixture) was heated to 85 °C under a nitrogen atmosphere for 4 h before being treated with compound 10 (784 mg, 5 mmol), Pd(PPh₃)₄ (150 mg, 0.13 mmol) and Na₂C0₃ (1.06 g, 10 mmol). The resulting mixture was stirred at 85 °C for 16 h. The cooled reaction mixture was passed through a pad of ( ^'elite \ The filtrate was concentrated under reduced pressure, and the residue was subjected to flash chromatography (silica, 4: 1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions {Rj = 0.5 in 2: 1 v/v hexane/ethyl acetate), compound 25 (616 mg, 60%) as a pale yellow foam.

1H NMR (400 MHz, CDC1₃) δ 9.51 (s, I H), 7.92 (dd, J = 7.7 and 1.3 Hz, lH), 7.48 (m,

1H), 7.41 (m, IH), 7.34 (s, 1 H), 7.26 (d, J = 7.9 Hz, 1 H), 7.21-7.1 1 (complex m, 5H),

7.07-7.02 (complex m, 2H), 6.80 (d, J = 8.4 Hz, 2H), 3.79 (s, 3H), 3.71 (s, 3H).

¹³C NMR (100 MHz, CDC1₃) δ 178.8, 165.3, 158.3, 139.5, 137.8, 133.0, 132.3, 131.8,

130.9, 130.8, 130.8, 130.6, 129.6, 129.3, 128.7, 128.3, 128.2, 127.1 , 125.3, 1 13.9, 55.3,

52.4.

IR (KBr) v_max 2951 , 2836, 1730, 1671 , 1602, 1553, 1513, 1462, 1411 , 1366, 1294, 1179,

1 156, 1092, 1030, 954, 825, 791 , 768, 734, 701 cm^"1.

MS (ESI, +ve): m/z 434 ( | M \^'a| . 100%), 412 (| \M I | . 15).

HRMS Found: (M Na) . 434.1364. C₂₆H₂jN0₄ requires (M Na) . 434.1368. Example 18 - Compound 30

30

[0101] A magnetically stirred and degassed mixture of compound 9 (770 mg, 2 mmol), compound 28 (996 mg, 6 mmol), Pd(PPh₃)₄ (230 mg, 0.2 mmol) and Na₂C0₃ (1.06 g, 10 mmol) in 1,2-DME/H₂0 (18 mL of a 5: 1 v/v mixture) was heated to 85 °C under a nitrogen atmosphere for 48 h The cooled reaction mixture was passed through a pad of Celite*. The filtrate was concentrated under reduced pressure, and the residue was subjected to flash chromatography (silica, 4: 1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (Rf = 0.3 in 2: 1 v/v hexane/ethyl acetate), compound 30 (665 mg, 71 %) as a white solid.

1H NMR (400 MHz, CDC1₃) δ 9.47 (s, l H), 7.94 (dd, .1= 7.7 and 1.7 Hz, l H), 7.51 (td, J = 7.6 and 1.7 Hz, l H), 7.43 (td, J = 7.6 and 1.2 Hz, 1 H), 7.28-7.21 (complex m, 2H), 6.79-6.70 (complex m, 3H), 6.59 (m, 1H), 6.55-6.50 (m, 2H), 5.93 (s, 2H), 5.90 (s, 2H), 3.72 (s, 3H).

¹³C NMR (100 MHz, CDCI₃) δ 178.7, 165.4, 147.7, 147.6, 147.5, 146.2, 139.2, 137.8,

132.7, 132.5, 131.0, 130.7, 129.5, 128.8, 128.7, 125.3, 125.0, 123.8, 121.8, 121.7, 1 10.8,

108.8, 108.4, 108.3, 101.3, 101.0, 77.5, 77.2, 76.8, 52.4.

IR (KBr) v_max 2982, 2793, 1721 , 1558, 1465, 1449, 1233, 1092, 1030, 91 1, 812 cm^"1.

MS (ESI, +ve): m/z 492 ( | M · \^'a | . 100%), 470 ([M+H] ^' , 20).

HRMS Found: (M+H)⁺, 470.1241. C^yH^ Oy requires (M+H)⁺, 470.1240. Example 19 - Compound 29

29

[0102] A magnetically stirred and degassed mixture of compound 9 (762 mg, 1.97 mmol), compound 26 (440 mg, 2.36 mraol), Pd(PPh )₄ (1 14 mg, 0.10 mmol) and Na₂C0 (835 mg, 7.88 mmol) in 1 ,2-DME/H₂0 (18 mL of a 5: 1 v/v mixture) was heated to 85 °C under a nitrogen atmosphere for 4 h before being treated with compound 28 (807 mg, 4.9 mmol), Pd(PPh₃)₄ (1 14 mg, 0.10 mmol) and Na₂C0₃ (835 mg, 7.88 mmol). The resulting mixture was stirred at 85 °C for 16 h. The cooled reaction mixture was passed through a pad of (^'elite ' . The filtrate was concentrated under reduced pressure, and the residue was subjected to flash chromatography (silica, 4: 1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (R/ = 0.2 in 2: 1 v/v hexane/ethyl acetate), compound 29 (516 mg, 54%) as a white solid and a mixture of retainers.

1³C NMR ( 100 MHz, CDC1₃) δ (mixture of rotamers) 179.1 , 178.7, 165.5, 165.1 , 152.9, 152.6, 148.1 , 147.7, 147.6, 146.1 , 137.7, 136.0, 134.1 , 133.1 , 132.5, 131.7, 131 .2, 130.5, 130.3, 130.2, 129.5, 129.0, 128.7, 128.5, 125.3, 125.2, 125.0, 124.8, 123.8, 123.7, 121.1 , 120.9, 1 14.0, 1 13.6, 108.4, 108.2, 108.0, 100.9, 60.5, 60.3, 56.0, 55.7, 52.4, 52.2

IR (KBr) x 1727, 1658, 1495, 1458, 1399, 1267, 1235, 1090, 1035, 933, 805, 777, 727, 708 cm^"1 _.

MS (ESI, +ve): m/- 486 ( | M I I | . 100%), 508 (| M · Na | . 10).

HRMS Found: ( M i l ) , 486.1552. C₂₈H₂₃N0₇ requires (M+H)\ 486.1553.

Example 20 - Compound 33

[0103] A magnetically stirred and degassed mixture of compound 31 (354 mg, 3.03 mmol), compound 32 (1 mL, 9.09 mmol), PdCl₂(MeCN)₂ (78 mg, 0.3 mmol), norbornene (854 mg, 9.09 mmol) and K₂C0₃ (1.25 g, 9.09 mmol) in DMA/H₂0 (15.5 mL of a 30: 1 v/v mixture) was heated to 90 °C under a nitrogen atmosphere for 60 h before being passed through a pad of silica. The filtrate was concentrated under reduced pressure, and the residue was subjected to flash chromatography (silica, 30: 1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (R/ = 0.5 in 8: 1 v/v hexane/ethyl acetate), compound 33 (394 mg, 75%) as a yellow oil.

1H NMR (400 MHz, CDC1₃) δ 7.78 (bs, 1H), 7.61 (d, J = 7.5 Hz, lH), 7.32 (d, J = 7.8 Hz, 1 H), 7.17 (m, 2H), 6.30 (s, 1H), 2.64 (d, J = 7.1 Hz, 2H), 2.02 (m, 1 H), 1.04 (d, J = 6.6 Hz, 6H).

¹ C NMR (100 MHz, CDC1₃) δ 139.0, 135.9, 129.0, 121.0, 119.8, 1 19.6, 1 10.4, 100.5, 77.5, 77.2, 76.8, 37.8, 29.0, 22.6.

IR (KBr) 3407, 2955, 1714, 1550, 1457, 1416, 1291 , 1013, 778, 748 cm^"1.

MS (ESI, +ve): m/z 174 ( | M I I | . 100%).

HRMS (EI, +ve) Found: (M)⁺, 173.1204. C12H15 requires ( M ) , 173.1204.

Example 21 - Compound 34

34

[0104] A magnetically stirred and degassed mixture of compound 33 (215 mg, 1 .24 mmol), compound 6 (390 mg, 1.49 mmol), Cul (23 mg, 0.12 mmol), Ν,Ν'- dimethylethylenediamine (21 mg, 0.24 mmol) and K₃P0₄ (631 mg, 2.98 mmol) in anhydrous 1 ,4-dioxane (2 mL) was heated at 1 10 °C in a glass sealed tube for 48 h. The cooled reaction mixture was then passed through a pad of silica. The filtrate was concentrated under reduced pressure, and the residue was subjected to flash chromatography (silica, 200: 1 v/v hexane/diethyl ether elution) to afford, after concentration of the appropriate fractions (Rf = 0.5 in 8: 1 v/v hexane/diethyl ether), compound 34 (327 mg, 86%) as a colorless oil. 1H NMR (400 MHz, CDCI₃) δ 8.09 (dd, J= 7.8 and 1.7 Hz, 1 H), 7.70 (td, J= 7.6 and 1.7 Hz, 1H), 7.62-7.52 (complex m, 2H), 7.41 (dd, J = 7.8 and 1.1 Hz, lH), 7.13-7.04 (complex m, 2H), 6.86 (d, J = 7.9 Hz, 1 H), 6.45 (s, 1 H), 3.43 (s, 3H), 2.50 (dd, J = 15.1 and 7.1 Hz, 1 H), 2.37 (dd, J = 15.1 and 7.3 Hz, 1H), 1.83 (m, 1H), 0.90 (t, J = 6.2 Hz, 6H).

¹³C NMR (100 MHz, CDCI₃) δ 166.3, 141.3, 138.8, 137.7, 133.0, 131.6, 130.9, 130.7, 128.5, 128.3, 121.1, 1 19.9, 1 19.7, 109.5, 101.2, 52.3, 36.4, 27.8, 22.7.

IR (KBr) v_max 2953, 1721, 1600, 1549, 1493, 1460, 1295, 1255, 1 127, 1087, 963, 765, 747, 71 1 cm^"1.

MS (ESI, +ve): m/z 330 ([M+Na] , 100%), 308 ([M+H] , 20).

HRMS Found: ( M i l ) . 308.1650. C₂oH₂iN0₂ requires (M i l ) . 308.1651.

Example 22 - Compo

35

[0105] A magnetically stirred solution of compound 34 (98 mg, 0.32 mmol) in MeOH/H₂0 ( 15 mL of a 2: 1 v/v mixture) was treated with KOH (179 mg, 3.2 mmol), and the ensuing mixture was heated at reflux for 16 h. The cooled reaction mixture was concentrated under reduced pressure, and the residue was acidified, using HCl (2 M aqueous solution), to pH 1. The suspension thus fonned was diluted with brine (50 mL) and the extracted with ethyl acetate (3x50 mL). The combined organic phases were dried (Na₂S0₄), filtered, and the concentrated under reduced pressure. The residue was subjected to flash chromatography (silica, 100: 1 v/v DCM/MeOH elution). Concentration of the appropriate fractions {Rj = 0.5 in 10: 1 v/v DCM/MeOH) gave a colourless oil that upon recrystallization (hexane/DCM) afforded compound 35 (91 mg, 97%) as a white, crystalline solid.

1H NMR (400 MHz, CDCI₃) δ 8.12 (dd, J = 7.8 and 1.5 Hz, 1 H), 7.71 (td, J = 7.7 and 1.6 Hz, l H), 7.57 (m, 2H), 7.34 (dd, J = 7.8 and 0.9 Hz, l H), 7.1 1-7.00 (complex m, 2H), 6.80 (d, J= 8.0 Hz, 1H), 6.40 (s, IH), 2.42 (dd, J= 15.2 and 7.2 Hz, 1H), 2.28 (dd, J =

15.2 and 7.2 Hz, 1H), 1.78 (m, 1H), 0.85 (d,J = 8.4 Hz, 3H), 0.83 (d,J= 8.4 Hz, 3H).

¹ C NMR (100 MHz, CDC1₃) δ 169.8, 141.4, 138.7, 138.4, 133.9, 132.4, 131.3, 128.6,

128.5, 121.1, 120.0, 119.7, 119.7, 109.5, 101.4,36.4, 27.8,22.7, 22.6.

IR (KBr) v_max2952, 2863, 1697, 1683, 1494, 1460, 1298, 1271, 1088, 923, 743, 732, 708 cm^"1.

MS (ESI, +ve): m/z 316 ([M+Naf , 100%), 294 (|\MI| .5).

HRMS Found: (M il) , 294.1496. Ci₉Hi₉N0₂ requires

294.1494.

m.p. = 163- 164 °C.

Example 23 - Compound 36

36

[0106] A magnetically stirred solution of compound 35 (90 mg, 0.31 mmol) in MeOH/DCM (8 mL of a 1 : 1 v/v mixture) under a nitrogen atmosphere was treated with MoOPH (296 mg, 0.68 mmol), and the ensuing yellow mixture was stirred in dark for 16 h before being passed through a pad of Celite*. The filtrate was washed with H₂0 (2x50 mL), brine (100 mL) before being dried (Na₂S0₄), filtered, and then concentrated under reduced pressure. The residue was subjected to flash chromatography (silica, 10:1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (R/ = 0.6 in 2:1 v/v hexane/ethyl acetate), compound 36 (64 mg, 68%) as a yellow oil.

1H NMR (400 MHz, CD₃OD) δ 8.13 (dd, J= 7.8 and 1.6 Hz, IH), 7.79-7.72 (complex m, 2H), 7.59 (m, IH), 7.54 (d, J= 8.1 Hz, IH), 7.39-7.29 (complex m, 2H), 7.07 (m, IH), 2.29 (dd,J= 14.3 and 6.2 Hz, IH), 1.99 (dd,J= 14.3 and 6.8 Hz, IH), 1.55 (m, IH), 0.77 (d,J= 6.6 Hz, 3H), 0.74 (d,J= 6.7 Hz, 3H).

¹ C NMR (100 MHz, CDC1₃) δ 193.3, 161.5, 156.2, 139.6, 138.4, 135.8, 131.4, 126.2, 125.1, 122.5, 121.9, 120.7, 118.1, 110.0, 93.0,41.0, 24.1,23.8,23.1.

IR (KBr) v_max 2959, 2872, 1725, 1616, 1597, 1488, 1467, 1369, 1314, 1234, 1072, 1019, 932, 764, 748, 713 cm^"1. MS (ESI, +ve): m/z 330 (| M · \^'a | . 100%), 308 (| M I I | . 85).

HRMS Found: (M i l ) , 308.1285. C 19H 17 O3 requires (M+H)⁺, 308.1287.

Example 24 - Compound 38

[0107] A magnetically stirred and degassed mixture of compound 5 (1.39 g, 20.8 mmol), compound 37 (6.45 g, 18.9 mmol), Cul (359 mg, 1.9 mmol), 1 , 10-phenanthroline (680 mg, 3.8 mmol) and Cs₂C0₃ (9.30 g, 28.4 mmol) in anhydrous toluene (40 mL) was heated at 100 °C under a nitrogen atmosphere for 48 h. The cooled reaction mixture was then passed through a pad of TLC-grade silica and the filtrate concentrated under reduced pressure. The residue so formed was subjected to flash chromatography (silica, 30: 1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (Rf = 0.5 in 8: 1 v/v hexane/ethyl acetate), compound 38 (5.21 g, 99%) as a clear, colorless syrup.

1H NMR (400 MHz, CDCI₃) £ 7.85 (d, J = 2.4 Hz, l H), 7.59 (dd, J = 8.5 and 2.4 Hz, 2H), 7.18 (m, 1H), 6.71 (m, 2H), 6.25 (m, 2H), 3.65 (s, 3H).

¹³C NMR (100 MHz, CDC1₃) δ 166.1 , 139.4, 135.3, 133.5, 129.4, 128.3, 122.0, 120.5, 1 10.2, 52.8.

IR v_max 2950, 1729, 1594, 1563, 1498, 1435, 1400, 1329, 1288, 1267, 1238, 1 123, 1094, 1015, 966, 922, 826, 727 cm ¹.

MS (ESI, +ve): m/z 282 and 280 [(M+H) , both 50%], 250 and 248 (96 and 100).

HRMS (ESI, +ve) Found: (M i l ) . 279.9972. C₁₂Hi₁ ⁷⁹BrN0₂ requires (M i l ) . 279.9973. Example 25 - Compo

[0108] Anhydrous D F/THF (90 mL of a 4:5 v/v mixture) maintained with magnetic stirring at 0 °C under a nitrogen atmosphere was treated with POCl₃ (5.50 mL, 59.5 mmol) and the resulting orange reaction mixture was stirred at 0 °C for 0.75 h before being treated, dropwise, with a solution of compound 38 (6.47 g, 23.2 mmol) in anhydrous THF (40 mL). The mixture so-formed was warmed to 20 °C then stirred at this temperature for 3 h before being quenched with ice (100 g). The ensuing mixture was neutralized using NaHC0₃ (saturated aqueous solution) then extracted with diethyl ether (3 x 150 mL). The combined organic phases were washed with brine (1 x 300 mL) before being dried (NaiSC^), filtered and then concentrated under reduced pressure. The residue thus obtained was subjected to flash chromatography (silica, 12: 1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (R/ = 0.3 in 4: 1 v/v hexane/ethyl acetate), compound 39 (5.89 g, 83%) as a clear, colorless syrup.

1H NMR (400 MHz, CDCI₃) 9.48 (s, 1H), 8.16 (d, J = 2.4 Hz, lH), 7.71 (dd, J = 8.3 and 2.4 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 7.09 (dd, J = 4.0 and 1.7 Hz, lH), 6.94 (m, lH), 6.43 (broadened s, 1H), 3.68 (s, 3H).

¹³C NMR (100 MHz, CDCI₃) £ 178.7, 164.1, 138.5, 135.6, 134.0, 133.2, 131.6, 130.4, 129.9, 123.8, 122.5, 1 10.9, 52.6.

IR v_max 3100, 2843, 1727, 1646, 1489, 1415, 1361, 1284, 1246, 1088, 1075, 1039, 836, 761 , 745 cm

MS (ESI, +ve): m/z 332 and 330 | ( M · a) . 95 and 100%], 310 and 308 (both 6).

HRMS (ESI, +ve) Found: (M i l ) . 307.9927. C_]3Hn⁷⁹BrN0₃ requires ( M i l ) , 307.9922. Example 26 - Compo

[0109] A magnetically stirred mixture of compound 39 (5.89 g, 19.2 mmol) and CF₃COOAg in dry THF (80 mL) maintained at 0 °C under a nitrogen atmosphere was treated with I₂ (9.99 g, 39.3 mmol) and the resulting deep-red reaction mixture was slowly warmed to 20 °C over 16 h while being protected from light. After this time the recation mixture was filtered through a pad of TLC-grade silica and the filtrate concentrated under reduced pressure. The residue thus obtained was subjected to flash chromatography (silica, 9: 1 v/v hexane/THF elution) to afford, after concentration of the appropriate fractions {Rj = 0.5 in 4: 1 v/v hexane/ethyl acetate), compound 40 (8.21 g, 77%) as a white, crystalline solid.

1H NMR (400 MHz, CDC1 ) £ 9.13 (s, 1H), 8.27 (d, J = 2.3 Hz, ΓΗ), 7.79 (dd, J = 8.4 and 2.3 Hz, IH), 7.21 (s, IH), 7.09 (d, J = 8.4 Hz, 1H), 3.70 (s, 3H).

1³C NMR (100 MHz, CDC1₃) £ 176.5, 163.2, 139.4, 138.5, 136.3, 134.7, 131.8, 130.0, 129.7, 124.0, 100.2, 78.1, 52.9.

IR Vmax 3446, 31 10, 2950, 1730, 1670, 1488, 1435, 1380, 1351 , 1287, 1254, 1096, 835 cm ¹.

MS (ESI, +ve): m/z 584 and 582 [(M+Naf, 100 and 97%], 562 and 560 [(M+H)\ both 33].

HRMS (ESI, +ve) Found: (M+H) , 559.7855. Ci₃H_y ⁷⁹Br¹²⁷I₂N0₃ requires (M+H) , 559.7855.

Example 27 - Compound 42

42 [0110] A magnetically stirred and degassed mixture of compound 40 (4.84 g, 8.66 mmol), compound 41 (2.51 g, 18.2 mmol), Pd(PPh₃)₂Cl₂ (610 mg, 0.87 mmol) and Na₂C0₃ (3.70 g, 34.6 mmol) in MeCN/H₂0 (75 mL of a 3:2 v/v mixture) was heated at 60 °C for 48 h while being maintained under a nitrogen atmosphere throughout this period. The cooled reaction mixture was passed through a pad of TLC-grade silica and the filtrate concentrated under reduced pressure. The residue thus obtained was subject to flash chromatography (silica, 2: 1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (Rf = 0.3 in 1 : 1 v/v hexane/ethyl acetate), compound 42 (3.02 g, 71 %) as a pale-yellow foam.

lH NMR (400 MHz, CD₃OD) £ 9.38 (s, 1 H), 8.00 (d, J = 2.3 Hz, 1 H), 7.69 (dd, J = 8.3 and 2.3 Hz, l H), 7.36 (s, lH), 7.21 (d, J = 8.3 Hz, 1 H), 7.07 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.67 (d, J = 8.6 Hz, 2H), 6.61 (d, J = 8.6 Hz, 2H), 3.69 (s, 3H) (signals due to protons of phenolic hydroxyl groups not observed).

¹³C NMR (100 MHz, CD₃OD) £ 180.1 , 165.6, 159.0, 157.2, 142.0, 138.7, 136.3, 134.3, 133.9, 133.6, 133.3, 132.5, 130.2, 127.1 , 127.0, 124.5, 123.0, 122.3, 1 16.2, 1 16.1 , 53.0. IR v_raax 3315, 2954, 2873, 1732, 1712, 1636, 1612, 1457, 1434, 1419, 1258, 1230, 1 159, 1 100, 830, 736 cm ¹.

MS (ESI, +ve): m/z 516 and 514 [(M+Na) , 93 and 100%], 494 and 492 | (M I I ) . 20 and 19].

HRMS (ESI, +ve) Found: (M+Naf, 514.0265. C25H₁₈ ⁷⁹BrN a0₅ requires (M a ) . 514.0266.

Example 28 - Compound 43

43

[0111 ] A magnetically stirred solution of compound 42 (1.26 g, 2.57 mmol) and N,N-di- iso -propyl ethyl amine (3.32 g, 25.7 mmol) in dry dichloromethane (25 mL) maintained at 0 °C under a nitrogen atmosphere was treated with freshly prepared MOMCl ( 12 mL of an 2.14 M solution in dry dichloromethane, 25.7 mmol). The resulting light-yellow reaction mixture was warmed to 20 °C over 16 h then treated, successively, with NH₄CI (50 mL of a saturated aqueous solution) and H₂0 (100 raL) before being extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine (1 x 150 mL) then dried (Na₂S0₄), filtered and concentrated under reduced pressure. The residue thus obtained was subjected to flash chromatography (silica, 4: 1 v/v hexane/ethyl acetate elution) and concentration of the appropriate fractions (R/ = 0.6 in 1 : 1 v/v hexane/ethyl acetate) gave compound 43 (1.51 g, 99%) as a pale-yellow foam.

1H MR (400 MHz, CDC1₃) 9.47 (_s, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.56 (dd, J = 8.4 and 2.3 Hz, 1H), 7.24 (s, 1 H), 7.13 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.4 Hz, 1H), 6.95-6.89 (complex m, 4H), 6.81 (d, J = 8.8 Hz, 2H), 5.14 (s, 2H), 5.1 1 (s, 2H), 3.70 (s, 3H), 3.47 (s, 3H), 3.45 (s, 3H).

¹ C NMR (100 MHz, CDC1₃) £ 178.5, 164.0, 157.4, 156.0, 139.5, 137.2, 135.3, 133.8, 132.5, 132.2, 132.0, 130.9, 129.2, 128.2, 125.2, 123.4, 123.0, 122.4, 1 16.2, 1 16.0, 94.5, 94.4, 56.3, 56.1, 52.6.

IR v_max 2953, 2902, 2827, 1732, 1662, 1461 , 1286, 1235, 1 151 , 1077, 994, 836 cm ¹. MS (ESI, +ve): m/z 604 and 602 [(M+Na)⁺, 100 and 97%], 582 and 580 | ( M 11 ) , 33 and 28].

HRMS (ESI, +ve) Found: (M+Naf , 602.0794. C₂9H₂₆ ⁷⁹BrNNa0₇ requires (M a) . 602.0790.

Example 29 - Compound 44

44

[0112] A magnetically stirred suspension of -PrPPh₃I (1.44 g, 3.16 mmol) in dry THF (20 mL) maintained at -78 °C under a nitrogen atmosphere was treated with /?-BuLi (1.82 mL of a 1.6 M solution in hexane, 2.91 mmol), and the ensuing red suspension stirred at -78 °C for 0.5 h before being added, over 0.17 h, to a magnetically solution of compound 43 (1.41 g, 2.43 mmol) in dry THF (40 mL) maintained at -78 °C. The reaction mixture thus formed was transferred to an ice-water bath and maintained at ca. 0 °C for 1 h then treated, successively, with NH₄C1 (10 mL of a saturated aqueous solution) and water (40 mL) before being extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine (1 x 100 mL) then dried (Na₂S0₄), filtered and concentrated under reduced pressure. The residue thus obtained was subjected to flash chromatography (silica, 15: 1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (Rf = 0.6 in 4: 1 v/v hexane/ethyl acetate), compound 44 (1.16 g, 79%) as a pale-yellow foam.

1H NMR (400 MHz, CDC1₃) S I.93 (d, J = 2.4 Hz, l H), 7.55 (dd, J = 8.4 and 2.4 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.4 Hz, 1H), 6.90 (m, 4H), 6.78 (d, J = 8.8 Hz, 2H), 6.45 (s, lH), 5.49 (s, l H), 5.14 (s, 2H), 5.1 1 (s, 2H), 3.64 (s, 3H), 3.48 (s, 3H), 3.46 (s, 3H), 1.97 (s, 3H), 1.77 (s, 3H).

¹³C NMR (100 MHz, CDCI₃) δ 164.9, 156.4, 155.3, 137.6, 135.3, 135.0, 133.6, 132.8,

132.3, 132.2(4), 132.2(0), 130.4, 129.5, 129.1, 126.0, 122.8, 121.4, 116.1, 1 15.9, 1 14.5,

109.4, 94.7, 94.6, 56.2, 56.0, 52.6, 27.0, 20.3.

I R Vmax 2951, 2900, 1733, 1515, 1486, 1284, 1232, 1 151, 1077, 999, 834, 731 cm ¹.

MS (ESI, +ve): m/z 630 and 628 | (M · a) . 100 and 90%], 608 and 606 | ( M I I ) . 38 and

40].

HRMS (ESI, +ve) Found: (M i l ) . 606.1494. C₃₂H₃₃ ⁷⁹BrN0₆ requires (M i l ) . 606.1491.

Example 30 - Compo

45

[0113] A magnetically stirred mixture of compound 44 (2.76 g, 4.57 mmol) and Ph₂S (44 mg, 0.23 mmol) in dry THF (80 mL) was treated with palladium on carbon (1.05 g of 10% w/w material), and the ensuing black suspension stirred at 20 °C under a balloon of hydrogen for 48 h then filtered through a pad of TLC-grade silica. The filtrate was concentrated under reduced pressure and the residue subjected to flash chromatography (silica, 9: 1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (R/ = 0.6 in 4: 1 v/v hexane/ethyl acetate), compound 45 (2.62 g, 94%) as a pale-yellow foam.

1H NMR (400 MHz, CDC1₃) 7.92 (d, J = 2.4 Hz, 1H), 7.60 (dd, J = 8.4 and 2.4 Hz, IH), 7.18-7.1 1 (complex m, 3H), 6.91-6.85 (complex m, 4H), 6.76 (d, J = 8.7 Hz, 2H), 6.24 (s, IH), 5.13 (s, 2H), 5.10 (s, 2H), 3.64 (s, 3H), 3.47 (s, 3H), 3.46 (s, 3H), 2.25 (dd, J = 15.2 and 7.0 Hz, IH), 2.16 (dd, J = 15.2 and 7.2 Hz, IH), 1.70 (m, IH), 0.88 (m, 6H). ¹³C NMR (100 MHz, CDC1₃) £ 164.8, 156.3, 155.1, 138.0, 135.2, 133.9, 133.8, 132.8, 132.3, 132.2, 130.7, 129.6, 128.9, 126.4, 122.0, 121.6, 116.1 , 115.8, 107.8, 94.7, 94.6, 56.3, 56.1 , 52.6, 36.3, 27.8, 22.7(8), 22.7(5).

IR v_max 2952, 2899, 1737, 1515, 1486, 1283, 1233, 1151, 1078, 999, 836 cm^"1.

MS (ESI, +ve): m/z 610 and 608 | (\M I ) . 100 and 92%], 632 and 630 | (M \a) . 90 and

88].

HRMS (ESI, +ve) Found: (M+H)\ 608.1647. C₃₂H₃₅ ⁷⁹BrN0₆ requires (M+H) , 608.1648.

Example 31 - Compound 46

46

[0114] A magnetically stirred mixture of compound 45 (647 mg, 1.06 mmol), acrolein diethyl acetal (1.38 g, 10.6 mmol), tetra-«-butyl ammonium acetate (640 mg, 2.12 mmol), K₂C0₃ (220 mg, 1.59 mmol), KC1 (80 mg, 1.06 mmol) and Pd(OAc)₂ (120 mg, 0.53 mmol) in anhydrous DMF (10 raL) was heated at 100 °C in a sealed tube for 48 h. The cooled reaction mixture was filtered through a pad of TLC-grade silica and the filtrate concentrated under reduced pressure. The residue thus obtained was subjected to flash chromatography (silica, 9: 1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (R/ = 0.5 in 4: 1 v/v hexane/ethyl acetate), compound 46 (453 mg, 65%) as a clear, yellow oil. 1H NMR [400 MHz, (CD₃)₂CO] 7.86 (s, 1H), 7.73 (d, J= 8.1 Hz, 1H), 7.37 (d, J= 8.1 Hz, 1H), 7.18 (d,J= 8.6 Hz, 2H), 7.00 (d,J= 8.5 Hz, 2H), 6.88 (d,J= 8.6 Hz, 2H), 6.80 (m, 3H), 6.36 (dd, J= 16.2 and 4.9 Hz, lH), 6.27 (s, 1H), 5.15 (s, 2H), 5.10 (m, 3H), 3.73-3.64 (complex m, 5H), 3.55 (m, 2H), 3.43 (s, 3H), 3.39 (s, 3H), 2.33 (dd, J= 15.0 and 7.1 Hz, 1H), 2.23 (dd, J= 15.0 and 7.2 Hz, 1H), 1.70 (m, IH), 1.20 (m, 6H), 0.89 (m, 6H).

¹ C NMR [100 MHz, (CD )₂CO] δ 166.5, 157.4, 156.2, 138.9, 137.4, 134.5, 133.3, 132.8, 132.2, 131.9, 131.4, 130.7, 129.7, 129.5, 127.7, 122.6, 116.9, 116.5, 108.5, 101.9, 95.4, 95.3, 61.7, 56.3, 56.1, 52.7, 37.2, 28.6, 23.1, 15.9, 15.8.

IR Vmax 2853, 2898, 1719, 1515,1302, 1232, 1198, 1150, 1077, 997, 921,837, 788 cm^"1. MS (ESI, +ve): m/z 680 |(M \^'a)\ 15%], 658 | ( M II) .100].

HRMS (ESI, +ve) Found: (M il) .658.3389. C^s Os requires (M il) .658.3380. Example 32 - Compound 47

47

[0115] A magnetically stirred solution of compound 46 (453 mg, 0.69 mmol) in THF/water/ethanol (20 mL of a 1:1:2 v/v/v mixture) was treated with KOH (386 mg, 6.9 mmol) and the ensuing mixture stirred at 20 °C for 24 h then acidified, using HC1 (2 M aqueous solution), to pH 2. The mixture thus obtained was diluted with brine (50 mL) and then extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine (3 x 100 mL) before being dried (Na₂S0₄), filtered, and then concentrated under reduced pressure. The residue thus obtained was subjected to flash chromatography (silica, 3:1 v/v hexane/acetone elution) to afford, after concentration of the appropriate fractions (R = 0.6 in 1:1 v/v hexane/acetone), compound 47 (353 mg, 90%) as a light- yellow oil. 1H NMR (400 MHz, CDC1₃) 9.71 (d, J = 7.5 Hz, lH), 8.06 (d, J= 1.6 Hz, IH), 7.71 (dd,J= 8.3 and 2.1 Hz, 1H), 7.45 (d,J= 16.0 Hz, 1H), 7.31 (d,J= 8.2 Hz, IH), 7.12 (d, J= 8.6 Hz, 2H), 6.91-6.84 (complex m, 4H), 6.75 (dd, J= 16.0 and 7.6 Hz, 1H), 6.69 (d, J= 8.4 Hz, 2H), 6.24 (s, 1H), 5.12 (s, 2H), 5.04 (s, 2H), 3.46 (s, 3H), 3.41 (s, 3H), 2.29 (dd, J= 15.2 and 7.0 Hz, IH), 2.19 (dd, J= 15.2 and 7.2 Hz, lH), 1.66 (m, 1H), 0.85 (m, 6H) (signal due to carboxylic acid group proton not observed).

¹ C NMR (100 MHz, CDCI₃) δ 193.4, 169.1, 156.3, 155.1, 150.1, 141.7, 133.6(3), 133.5(9), 132.5, 131.9, 131.8, 130.5, 130.2, 129.6, 129.0, 126.3, 122.3, 116.1, 115.9, 108.4, 94.7, 94.6, 56.2, 56.1, 36.4, 27.9, 22.7(2), 22.6(8).

IRv_max2954, 1680, 1515, 1232, 1198, 1150, 1121, 1078, 999, 920, 837, 731 cm^"1.

MS (ESI, +ve): m/z 570 |(M II) .100%].

HRMS (ESI, +ve) Found: (M il) .570.2496. C,.,H, ,,ΝΟτ requires (M il) .570.2492.

Example 33 - Compound 48

48

[0116] A magnetically stirred solution of compound 47 (540 mg, 0.95 mmol) in dry methanol (25 mL) maintained under a nitrogen atmosphere at 20 °C was treated with MoOPH (825 mg, 1.9 mmol). The ensuing yellow-colored reaction mixture was stirred, while being protected from light, at 20 °C for 16 h then filtered through a pad of TLC- grade silica. The filtrate was concentrated under reduced pressure and the residue thus obtained subjected to flash chromatography (silica, 2:1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (R_j = 0.3 in 2:1 v/v hexane/ethyl acetate), compound 48 (277 mg, 50%) as a light-yellow oil.

1H NMR (400 MHz, CDCI₃) 39.69 (d, J= 7.5 Hz, 1H), 8.24 (d, J= 2.1 Hz, IH), 7.50 (dd, J= 8.8 and 2.2 Hz, IH), 7.40 (d, J= 16.0 Hz, IH), 7.19-7.06 (complex m, 6H), 6.88 (d, J = 8.8 Hz, 2H), 6.66 (dd, J = 16.0 and 7.5 Hz, IH), 6.34 (d, J = 8.6 Hz, IH), 5.26-5.21 (complex m, 2H), 5.14-5.09 (complex m, 2H), 3.53 (s, 3H), 3.44 (s, 3H), 2.35 (dd,J= 14.1 and5.7Hz, 1H), 1.97(dd,J = 14.1 and 7.0 Hz, lH), 1.83-1.71 (complex m, 1H), 0.94 (d, J= 6.7 Hz, 3H), 0.83 (d, J= 6.7 Hz, 3H).

¹ C NMR (100 MHz, CDC1₃) δ 193.8, 193.2, 167.4, 161.3, 159.4, 156.5, 149.8, 139.1, 133.4, 131.7, 130.4, 130.2(9), 130.2(7), 129.3, 122.3, 122.1, 122.0, 118.4, 117.0, 116.4, 116.1, 94.6, 94.4, 91.2, 56.6, 56.2, 42.4, 24.1, 23.1.

IR v_max2959, 1740, 1702, 1679, 1607, 1498, 1389, 1237, 1152, 1121, 1079, 989 cm ¹. MS (ESI, +ve): m/z 606 [(M+Na , 90%], 584 |(M H) .100].

HRMS (ESI, +ve) Found: (M+Na)^', 606.2107. Ca-^NNaOs requires (M a) . 606.2104.

Example 34 - Compound 49

49

[0117] A magnetically stirred mixture of compound 48 (62 mg, 0.11 mmol), (7ί)-3,3'- (C₇F₇)₂-BINOL (38 mg, 0.05 mmol), potassium l-(/-butyloxycarbonyl)-3- indoletrifluoroborate (137 mg, 0.43 mmol) and molecular sieves (300 mg of 4 A powdered material) in dry toluene (3 mL) was heated at 80 °C in a sealed tube for 48 h. The cooled reaction mixture was filtered through a pad of TLC-grade silica and the filtrate concentrated under reduced pressure. The residue thus obtained was subjected to flash chromatography (silica, 2:1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (R/ = 0.2 in 2:1 v/v hexane/ethyl acetate), compound 49 (59 mg, 65%) as a mixture of diastereoisomers and as a clear, light-yellow oil.

1H NMR (400 MHz, CDCI₃) 9.81 (s, lH), 8.19-8.03 (m, 2H), 7.49 (s, lH), 7.34-6.99 (complex m, lOH), 6.88 (m, 2H), 6.28 (m, 1H), 5.27-5.17 (complex m, 2H), 5.11 (m, 2H), 4.80 (m, 1H), 3.57-3.49 (complex m, 3H), 3.46 (m, 3H), 3.42-3.07 (complex m, 2H), 2.32 (m, lH), 2.00-1.87 (complex m, lH), 1.77-1.66 (complex m, lOH), 0.96-0.90 (complex 3H), 0.84-0.77 (complex m, 3H).

¹ C MR (100 MHz, CDC1₃) δ 199.9, 199.8, 194.1(0), 194.0(7), 168.5(3), 168.5(1), 161.9, 161.8, 159.1, 156.2, 149.7, 139.4(2), 139.3(6), 136.2, 136.1, 135.9, 134.7, 134.5, 130.6, 130.3, 130.2, 130.1, 129.7(1), 129.6(5), 129.2(0), 129.1(5), 124.9, 122.9, 122.8(4), 122.7(8), 122.6(2), 122.6(0), 122.4, 122.3, 122.2, 122.0, 121.7, 121.6, 119.3(3), 119.2(7), 118.2, 118.1, 116.8, 116.7, 116.0, 115.6(0), 115.5(7), 115.2(8), 115.2(7), 94.5(4), 94.5(2), 94.4, 91.3, 91.2, 84.2, 56.5, 56.1, 49.0, 48.9, 42.1, 42.0, 35.9, 35.8, 29.8, 28.3, 24.0, 23.9, 23.1.

MS (ESI, +ve): m/z 801 [(M+H) , 100%].

HRMS (ESI, +ve) Found: (M il) .801.3381. C47H49N2O10 requires (M il) .801.3387. Crystallographic Study Crystallographic Data for Compound 14

[0118] CsoHsiNOs, M = 485.58, T = 150 K, triclinic, space group PI, Z = 2, a = 8.4206(3) A, h = 13.0965(9) A, c = 13.5607(7) A; a = 62.238(6)°, β = 82.896(4)°, γ = 77.063(4)°; V - 1289.42(14) A³, D_x = 1.251 g cm ³, 5075 unique data (26 = 144.8°), R = 0.038 [for 4676 reflections with / > 2.0σ(/)]; Rw = 0.099 (all data), S = 1.00.

Crystallographic Data for Compound 2

[0119] C₂₇H₂₃NO₄, M= 425.48, T = 150 K, monoclinic, space group 2,/a, Z = 4, a = 10.16164(12) A, b = 18.7826(3) A, c = 11.49157(17) A; β = 97.3768(13)°; V = 2175.15(5) A³, D_x = 1.299 g cm ³, 8421 unique data (26»_max = 144.6°), R = 0.048 [for 7160 reflections with / > 2.0σ(/)]; Rw = 0.096 (all data), S = 1.00.

[0120] Crystallographic Data for Compound 22

[0121] 2(C₂₈H₂₇ 0₃).CH₂Cl₂, M= 468.01, T= 150 K, monoclinic, space group Pl_xln, Z = 8, a = 10.5581(1) A, b = 24.5948(3) A, c = 19.2677(2) A; β = 93.3707(10)°; V = 4994.67(9) A³, D_x = 1.245 g cm ³, 9706 unique data (26 x = 144.2°), R = 0.051 [for 8763 reflections with / > 2.0σ(7)]; Rw = 0.126 (all data), S = 1.00. Structure Determination

[0122] Images were measured on a Nonius Kappa CCD diffractometer (MoKa, graphite monochromator, λ = 0.71073 A) and data extracted using the DENZO package (DENZO-SMN. Z. Otwinowski and W. Minor, W. Processing of X-ray diffraction data collected in oscillation mode. In Methods in Enzymology, Volume 276: Macromolecular Crystallography, Part A; C. W. Carter Jr. and R. M. Sweet, Eds.; Academic Press: New York, 1997; pp. 307-326). Structure solution was by direct methods (SIR92) (A. Altomare, et al, J. Appl. Crystallogr., 1994, 27, 435). The structure of compounds 2, 14 and 22 were refined using the CRYSTALS program package (P. W. Betteridge, et al, J. Appl. Crystallogr., 2003, 36, 1487).

Cytotoxicty Assay

[0123] Cell lines were cultivated in 10 cm dishes (Corning, Inc.) in nonsmall cell lung cancer (NSCLC) cell-culture medium: RPMI/L-glutamine medium (Invitrogen, Inc.), 1000 U/mL penicillin (Invitrogen, Inc.), 1 mg/mL streptomycin (Invitrogen, Inc.), and 5% fetal bovine serum (Atlanta Biologicals, Inc.). Cell lines were grown in a humidified environment in the presence of 5% C0₂ at 37 °C. For cell viability assays, HCC366, A549, and H2286 cells (60 μΥ) were plated individually at a density of 1200, 100 and 500 cells/well, respectively, in 384-well microtiter assay plates (Bio-one; Greiner, Inc.). After incubating the assay plates overnight under the growth conditions described above, purified compounds were dissolved and diluted in DM SO and subsequently added to each plate with final compound concentrations ranging from 50 μΜ to 1 nM and a final DMSO concentration of 0.5%. After an incubation of 96 h under growth conditions, Cell Titer Glo reagent (Promega, Inc.) was added to each well (10 mL of a 1 :2 dilution in NSCLC culture medium) and mixed. Plates were incubated for 10 min at room temperature, and luminescence was determined for each well using an Envision multimodal plate reader (Perkin-Elmer, Inc.). Relative luminescence units were normalized to the untreated control wells (cells plus DMSO only). Data were analyzed using the Assay Analyzer and Condoseo modules of the Screener Software Suite (GeneData, Inc.). [0124] As shown in Table 3, the compounds of the present invention are active against the nonsmall cell lung cancer cell lines HCC366 and A549. The AC₅₀ is the concentration at which activity reaches 50% of maximum level.

Table 3

Brefeldin A -6.80 -6.98

+ve control

Claims

Claims:

1. A process for the preparation of a compound of Formula (I)

comprising the step of oxidative cyclization of a compound of Formula (II)

(Π) wherein m is 0 or 1 ; n is 0 or 1 ;

W is O, S, NH or CH₂; Z is O, S or NH;

R¹ is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted amino, optionally substituted alkylthio, optionally substituted C_{1 -6}alkoxy, optionally substituted C_3-7cycloalkyl, optionally substituted C_3-7heterocycloalkyl, and C_1-6haloalkyl;

R' ^" are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted Ci_-6alkyl, C_1-6haloalkyl, C_\. ₆alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, - C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶; or when m is 1 ,

(i) R^A4 and R^A5 may optionally together fonn a bond and R^A3 and R^A6 are as defined above or together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R²; or

(ii) R^A4 and R^A5 together with the carbon atoms to which they are attached form a saturated or unsaturated carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R ; or (iii) R^A3R^A4C-CR^A5R^A6 forms an aryl or heteroaryl group, wherein the aryl or heteroaryl groups are optionally substituted by one or more R~; each R² is independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci-ealkyl, Ci-6haloalkyl, Ci^alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

R³ is hydrogen or C_1-6alkyl;

4 5

when two R or R substituents are attached to adjacent carbon atoms on the respective aryl or heteroaryl groups, they are joined to form a methylenedioxy, -CH₂-0-CH₂-, group; R⁶ is selected from the group consisting of hydrogen, optionally substituted Ci_-6alkyl, optionally substituted C3.₇cycloalkyl and optionally substituted Ci-ehaloalkyl;

7 8

2. The process according to claim 1 for the preparation of a compound of Formula

comprising the step of oxidative cyclization of a compound of Formula (Ila)

(Ila) wherein p is 0, 1, 2, 3 or 4;

W is O, S, NH or CH₂; Z is O, S or NH;

R¹ is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted amino, optionally substituted Ci_ 6alkyloxy, optionally substituted alkylthio, optionally substituted C_3-7cycloalkyl, optionally substituted C_3-7heterocycloalkyl, and C_1-6haloalkyl; each R" is independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, C_1-6haloalkyl, Ci_-6alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alky lhetero aryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

Y is selected from the group consisting of hydrogen, Ci_-6alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, cycloalkyl,

X and Y, together with the carbon atoms to which they are attached, form an optionally substituted aryl or heteroaryl group; wherein each aryl or heteroaryl group is optionally substituted by one or more R⁴;

R is hydrogen or C_1-6alkyl;

R" and R^J are each independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, Ci-ealkyloxy, optionally substituted C_3-7cycloalkyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and - NR⁷C(0)R⁶; or 4 5

7 8

3. The process according to claim 1 or 2 for the preparation of a compound of Formula (lb)

comprising the step of oxidative cyclization of a compound of Formula (lib)

wherein p is 0, 1, 2, 3 or 4; q is O, 1, 2, 3 or 4; r is 0, 1 , 2, 3 or 4;

R¹ is selected from the group consisting of hydrogen, optionally substituted Ci_-6alkyl, optionally substituted amino, optionally substituted Cj. ealkyloxy, optionally substituted alkylthio, optionally substituted C3.₇cycloalkyl, optionally substituted C ^heterocycloalkyl, and C_1-6haloalkyl; each R² is independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, C_1-6haloalkyl, C_1-6alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

R³ is hydrogen or C_1-6alkyl;

R⁴ and R⁵ are each independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, C_1-6alkyloxy, optionally substituted C₃.₇cycloalkyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and - NR⁷C(0)R⁶; or when two R or two R^" substituents are attached to adjacent carbon atoms on the respective phenyl rings, they are joined to form a methylenedioxy, -CH₂- O-CH2-, group;

7 8

4. The process according to claim 1 , for the preparation of a compound of Formula

comprising the step of oxidative cyclisation of a compound of Formula (lie)

wherein p is 0, 1 , 2, 3 or 4; s is 0, 1 , 2, 3 or 4; W is O, S, NH or CH₂; Z is O, S or NH;

R¹ is selected from the group consisting of hydrogen, optionally substituted Ci_-6alkyl, optionally substituted amino, optionally substituted C_\. ₆alkyloxy, optionally substituted alkylthio, optionally substituted C_3-7cycloalkyl, optionally substituted C _-7heterocycloalkyl, and C_{1 -6}haloalkyl; each R² is independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, C_{1 -6}haloalkyl, C_1-6alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

R³ is hydrogen or C_1-6alkyl; each R⁴ is independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, C_1-6alkyloxy, optionally substituted C_3- vcycloalkyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

R⁶ is selected from the group consisting of hydrogen, optionally substituted Ci_-6alkyl, optionally substituted C _-7c-ycloalkyl and optionally substituted C_1-6haloalkyl;

7 8

R' and R° are independently selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl and optionally substituted C_3- ₇cycloalkyl; or 7 8

5. The process according to claim 3, wherein the compound of Formula (lib) is prepared by coupling of a compound of Formula (Illb)

(nib) wherein

U' and IT are independently selected from Br, I, CF^SO_.r and CF3CF2CF2CF2SO3-;

V is -CHO or -C(0)R⁹;

R⁹ is selected from the group consisting of optionally substituted Ci_-6alkyl, optionally substituted C₃.₇cycloalkyl and optionally substituted C_1-6haloalkyl;

R², R³ and p are as defined in claim 3: with a compound of Formula (IVb)

(IVb) wherein are each independently H or C_1-6alkyl; or

R¹⁰ and R^{1 1}, together with the oxygen atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by one or more C_1-3alkyl;

4

R' and q are as defined in claim 3: to form a compound of Formula (Vb)

(Vb) followed by coupling of a compound of Formula (VIb)

wherein

R⁵ and r are as defined in claim 3: with the compound of Fonnula (Vb) to fonn a compound of Fonnula (Vllb) C0₂R³

6. A compound of Fonnula (I), as defined in claim 1 , prepared according to the process of claim 1.

7. A compound of Formula (I)

wherein m is 0 or 1 ; n is 0 or 1 ;

W is O, S, NH or CH₂;

Z is O, S or NH;

R is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted amino, optionally substituted Ci. ₆alkyloxy, optionally substituted alkylthio, optionally substituted C_3-7cycloalkyl, optionally substituted C3.₇heterocycloalkyl, and C_{1 -6}haloalkyl;

R^A1"A6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted Ci-ealkyl, Ci-ehaloalkyl, Ci_ ₆alkyloxy, optionally substituted C3_-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, - C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶; or when m is 1 ,

(i) R^A2 and R ³ may optionally together form a bond and R^A1 and R^A4 are as defined above or together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R²; or

(i) R^A4 and R^A5 may optionally together form a bond and R^A3 and

_RA6

are as defined above or together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R²; or (ii) R^M and R^A5 together with the carbon atoms to which they are attached form a saturated or unsaturated carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic groups are optionally substituted by one or more R²; or

R" and R^J are each independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, C_1-6alkyloxy, optionally substituted C3.₇cycloa.kyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and - NR⁷C(0)R⁶; or when two R or two R^" substituents are attached to adjacent carbon atoms on the respective phenyl rings, they are joined to form a methylenedioxy, -CH₂- O-CH2-, group;

7 8

8. The compound according to claim 7 of Formula (la)

(la) wherein p is 0, 1, 2, 3 or 4; W is O, S, NH or CH₂; Z is O, S or NH; R¹ is selected from the group consisting of hydrogen, optionally substituted Ci_-6alkyl, optionally substituted amino, optionally substituted Q. ₆alkyloxy, optionally substituted alkylthio, optionally substituted C_3-7cycloalkyl, optionally substituted C_3-7heterocycloalkyl, and C_1-6haloalkyl; each R is independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci-ealkyl, C_1-6haloalkyl, Ci_-6alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

Y is selected from the group consisting of hydrogen, Ci- alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, cycloalkyl,

R" and R^J are each independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, C_1-6alkyloxy, optionally substituted C3-₇cyc.oa.kyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and - NR⁷C(0)R⁶; or

4 5

when two R or R substituents are attached to adjacent carbon atoms on the respective aryl or heteroaryl groups, they are joined to form a methyl enedioxy, -CH₂-0-CH₂-, group; R⁶ is selected from the group consisting of hydrogen, optionally substituted Ci_-6alkyl, optionally substituted C3.₇cycloalkyl and optionally substituted Ci-ehaloalkyl;

7 8

9. The compound according to claim 7 or 8 of Formula (lb)

(lb)

wherein p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; r is 0, 1 , 2, 3 or 4;

R is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted amino, optionally substituted C i_ ₆alkyloxy, optionally substituted alkylthio, optionally substituted C_3-7cycloalkyl, optionally substituted C _-7heterocycloalkyl, and C_1-6haloalkyl; each R² is independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci_-6alkyl, C_1-6haloalkyl, C_1-6alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

4 5

7 8

The compound according to claim 7 of Formula (Ic)

R¹ is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted amino, optionally substituted Ci_ 6alkyloxy, optionally substituted alkylthio, optionally substituted C_3-7c-ycloalkyl, optionally substituted C_3-7heterocycloalkyl, and C_1-6haloalkyl; each R^" is independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, C_1-6haloalkyl, C_1-6alkyloxy, optionally substituted C_3-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶; each R⁴ is independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci- alkyl, C_1-6alkyloxy, optionally substituted C_3- vcycloalkyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶; R⁶ is selected from the group consisting of hydrogen, optionally substituted Ci_-6alkyl, optionally substituted C3.₇cycloalkyl and optionally substituted Ci-ehaloalkyl;

7 8

R and R when attached to the same nitrogen atom are combined to fonn a 3- to-membered ring having from 0 to 2 additional heteroatoms as ring members. 1. A compound of Formula (II)

wherein m is 0 or 1 ; n is 0 or 1 ;

W is O, S, NH or CH₂;

Z is O, S or H;

R is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted amino, optionally substituted alkylthio, optionally substituted C_1-6alkoxy, optionally substituted C_3-7cycloalkyl, optionally substituted C _-7heterocycloalkyl, and C_1-6haloalkyl; R^A1"A6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted Ci_-6alkyl,

(i) R^A4 and R^A5 may optionally together form a bond and R^A3 and

_RA6

R³ is hydrogen or C_1-6alkyl;

R" and R^J are each independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci-ealkyl, Ci^alkyloxy, optionally substituted C_3-7cycloalkyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and - NR⁷C(0)R⁶; or 4 5

7 8

R and R when attached to the same nitrogen atom are combined to form a 3- to -membered ring having from 0 to 2 additional heteroatoms as ring members.

12. The compound according to claim 1 1 of Formula (Ila)

wherein p is 0, 1 , 2, 3 or 4;

W is O, S, NH or CH₂;

Z is O, S or NH;

R is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted amino, optionally substituted Ci. 6alkyloxy, optionally substituted alkylthio, optionally substituted C_3-7c-ycloalkyl, optionally substituted C_3-7heterocycloalkyl, and C_1-6haloalkyl; each R² is independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_1-6alkyl, C_{1 -6}haloalkyl, Ci_-6alkyloxy, optionally substituted C3-₇cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

R³ is hydrogen or C_1-6alkyl;

R⁴ and R⁵ are each independently selected from the group consisting of halogen, hydroxyl, optionally substituted C_{1 -6}alkyl, Ci^alkyloxy, optionally substituted C₃-₇cycloalkyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and - NR⁷C(0)R⁶; or

4 5

R⁶ is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted C_3-7cycloalkyl and optionally substituted Ci-ehaloalkyl; 7 8

7 8

R and R when attached to the same nitrogen atom are combined to form a 3- to-membered ring having from 0 to 2 additional heteroatoms as ring members.

The compound according to claim 1 1 or 12 of Formula (lib)

wherein p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; r is 0, 1 , 2, 3 or 4;

R¹ is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted amino, optionally substituted C i_ 6alkyloxy, optionally substituted alkylthio, optionally substituted C_3-7cycloalkyl, optionally substituted Qwheterocycloalkyl, and C_1-6haloalkyl; each R^" is independently selected from the group consisting of halogen, hydroxyl, optionally substituted Ci_-6alkyl, C_1-6haloalkyl, C_1-6alkyloxy, optionally substituted C _-7cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, -CN, -C(0)OR⁶, -C(0)NR⁷R⁸, and -NR⁷C(0)R⁶;

R³ is hydrogen or C_1-6alkyl;

R⁴ and R⁵ are each independently selected from the group consisting of halogen, hydroxyl, optionally substituted Cj_₆alkyl, C]_₆alkyloxy, optionally substituted C_3-7cycloalkyl, -CN, -NR⁷R⁸, -C(0)OR⁶, -C(0)NR⁷R⁸, and - NR⁷C(0)R⁶; or

4 5

when two R or two R substituents are attached to adjacent carbon atoms on the respective phenyl rings, they are joined to form a methyl enedioxy, -CH₂- 0-CH₂-, group;

R⁶ is selected from the group consisting of hydrogen, optionally substituted C_1-6alkyl, optionally substituted C _-7cycloalkyl and optionally substituted C^haloalkyl;

7 8

R' and R° are independently selected from the group consisting of hydrogen, optionally substituted Ci-ealkyl and optionally substituted C - ₇cycloalkyl; or

7 8

14. The compound according to claim 1 1 of Formula (lie)

7 8

15. A compound selected from the group consisting of: a compound of Formula (Illb):

(nib) wherein

U¹ and IT are independently selected from Br, I, CF₃SO₃- and CF3CF2CF2CF2SO3-;

V is -CHO or -C(0)R⁹;

R⁹ is selected from the group consisting of optionally substituted C_1-6alkyl, optionally substituted C_3-7cycloalkyl and optionally substituted C_1-6haloalkyl;

R", R' and p are as defined in claim 3; a compound of Formula (IVb):

(IVb) wherein are each independently H or C_1-6alkyl; or

R¹⁰ and R^{1 1}, together with the oxygen atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by one or more C_1-3alkyl; and q are as defined in claim 3; a compound of Formula (Vb):

(Vb) a compound of Formula (VIb):

wherein

R and r are as defined in claim 3: and a compound of Formula (Vllb): C0₂R^J

(Vllb)

16. A compound selected from the group consisting of:

150

17. A pharmaceutical composition comprising a compound prepared by the process of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a compound of any one of claims 6 to 16, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, carrier or diluent.

18. A method for the treatment of a disease state or condition mediated by the discoidin domain receptor 2 (DDR2), comprising administering to a subject in need thereof a therapeutically effective amount of a compound prepared by the process of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a compound of any one of claims 6 to 16, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17.

19. The method according to claim 18, wherein the disease state or condition is selected from the group consisting of cancer, osteoarthritis, fibrosis, rheumatoid arthritis, osteoporosis, cartilage injury, choroidal neovascularization and liver cirrhosis.

20. The method according to claim 19, wherein the cancer is a lymphoma, sarcoma or carcinoma.

21. The method according to claim 19 or claim 20, wherein the cancer is of the lung, breast or ovary.

22. The method according to claim 19, wherein the cancer is non-small-cell lung cancer or squamous cell carcinoma of the lung.

23. The method according to claim 19, wherein the fibrosis is of the lung, liver or kidney.

24. Use of a compound prepared by the process of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a compound of any one of claims 6 to 16, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease state or condition mediated by the discoidin domain receptor 2 (DDR2).