WO2010144959A1

WO2010144959A1 - Analogues of anti-fibrotic agents

Info

Publication number: WO2010144959A1
Application number: PCT/AU2010/000745
Authority: WO
Inventors: Spencer John Williams; Steven Zammit; Darren James Kelly; Ian William James
Original assignee: Fibrotech Therapeutics Pty Ltd
Priority date: 2009-06-18
Filing date: 2010-06-16
Publication date: 2010-12-23

Abstract

The present invention relates to analogues of anti-fibrotic agents having the formula (I) with the substituents as described within the specification. The present invention also relates to methods for their preparation.

Description

ANALOGUES OF ANTI-FIBROTIC AGENTS Field of the invention The present invention relates to derivatives of the anti-fibrotic drug, Tranilast.

Background of the invention

Fibrosis is a common response to a range of tissue insults that may lead to organ dysfunction. Diseases that are characterised by such pathological fibrosis include hepatic cirrhosis, pulmonary interstitial fibrosis, glomerulonephritis, heart failure (ischaemic and non-ischaemic), diabetic nephropathy, scleroderma, excessive scar tissue post surgery or device insertion, progressive kidney disease, glomerulonephritis, hypertension, heart failure due to ischaemic heart disease, valvular heart disease or hypertensive heart disease and hypertrophic scars. In addition, the elaboration of pathological matrix also has a role in fibroproliferative tumor progression and metastasis. Studies conducted over more than a decade have consistently indicated a major role of TGF-β in organ fibrosis and dysfunction, such that blockade of its expression and action represent an important therapeutic target.

Existing agents for treating fibrosis may have any number of undesirable properties including toxicity, poor solubility or efficacy.

One anti-fibrotic agent is Tranilast (n-[3,4-dimethoxycinnamoyl] anthranilic acid) and is used in Japan for the treatment of fibrotic skin disorders such as keloids and scleroderma. Although the precise mechanisms and mode of action of Tranilast are not completely understood, its ability to inhibit ERK phosphorylation, a major intermediate in the TGF-β signalling pathway, may underlie its antifibrotic effects, with known actions of Tranilast including the inhibition of TGF-β-induced extracellular matrix production in a range of cell types. Tranilast has also been shown to attenuate TGF-β-induced collagen synthesis in cardiac fibroblasts using an experimental model of diabetic cardiac disease.

Tranilast has also been shown to reduce inflammation in allergic diseases, such as allergic rhinitis and bronchial asthma, and to have antiproliferative activity.

However, it has recently been shown that genetic factors in certain patients, specifically the presence of a Gilbert's syndrome UGT1A1 variant, confer susceptibility to Tranilast- induced hyperbilirubinemia. Such hyperbilirubinemia may be associated with inhibition of UGT1 A1 by Tranilast per se and/or the in vivo formation of a Tranilast derivative. Therefore, it would be desirable to provide further alternatives to existing agents with potential anti-fibrotic, anti-inflammatory and anti-proliferative or anti-neoplastic activity for the treatment or prevention of diseases associated with fibrosis.

Summary of the invention

The present invention provides a compound of Formula (I)

or a pharmaceutically acceptable drug or prodrug thereof, wherein;

X¹ (YZ) is C=O, C(F₂) Or SO₂;

X^ is NR¹⁰ or (CH₂)_P;

T is a double bond, a triple bond or when T is a single bond, one pair of R⁶ and R⁷ are

fused to form a cyclopropane ring of the formula

A is selected from the group consisting of C₃ to C₁₂ cycloalkyl, C₃ to C₁₂ cycloalkenyl, C₁ to C₁₂ heterocycloalkyl, C₁ to C₁₂ heterocycloalkenyl, C₆-C₁₈ aryl and C₆ to C₁₈ heteroaryl;

R¹, R⁴' and R⁵ are each independently selected from the group consisting of: H, OH, NO₂, CN, NH₂, optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionally substituted C₁-C₁₂ alkyloxy, optionally substituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂ alkynyloxy, optionally substituted C₁-C₁₀ heteroalkyloxy, optionally substituted C₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂ cycloalkenyloxy, optionally substituted C₁-C₁₂ heterocycloalkyloxy, optionally substituted C₁-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-C₁₈ aryloxy, optionally substituted C₁-C₁₆ heteroaryloxy, optionally substituted C₁-C₁₂ alkylamino, SR¹³, SO₃H, SO₂NR¹³R¹⁴, SO₂R¹³, SONR¹³R¹⁴, SOR¹³, COR¹³, COOH, COOR¹³, CONR¹³R¹⁴, NR¹³COR¹⁴, NR¹³COOR¹⁴, NR¹³SO₂R¹⁴, NR¹³CONR¹⁴R¹⁵, NR¹³R¹⁴, and acyl;

R² and R³, are each independently selected from the group consisting of: H, OH, NO₂, CN, NH₂, optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionally substituted C₁-C₁₂ alkyloxy, optionally substituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂ alkynyloxy, optionally substituted C₁-C₁₀ heteroalkyloxy, optionally substituted C₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂ cycloalkenyloxy, optionally substituted C₁-C₁₂ heterocycloalkyloxy, optionally substituted C₁-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-C₁₆ aryloxy, optionally substituted Ci-C₁₈ heteroaryloxy, optionally substituted C₁-C₁₂ alkylamino, SR¹³, SO₃H, SO₂NR¹³R¹⁴, SO₂R¹³, SONR¹³R¹⁴, SOR¹³, COR¹³, COOH, COOR¹³, CONR¹³R¹⁴, NR¹³COR¹⁴, NR¹³COOR¹⁴, NR¹³SO₂R¹⁴, NR¹³CONR¹⁴R¹⁵, NR¹³R¹⁴ and acyl; or R² and R³ may be fused to form a 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring each of which may be optionally substituted;

one pair of R⁶ and R⁷ are present when T is a double bond but R⁶ and R⁷ are not present when T is a triple bond, each R⁶ and R⁷ being independently selected from the group consisting of: H, NO₂, CN, optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂- C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionally substituted C₂-C₁₂ heterocycloalkyl, optionally substituted C₂-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈ aryl, optionally substituted C₁-C₁₈ heteroaryl, optionally substituted C₁-C₁₂ alkyloxy, optionally substituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂ alkynyloxy, optionally substituted C₁-C₁₀ heteroalkyloxy, optionally substituted C₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂ cycloalkenyloxy, optionally substituted C₁-C₁₂ heterocycloalkyloxy, optionally substituted C₁-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-C₁₈ aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy, optionally substituted C₁-C₁₂ alkylamino, SR¹³, SO₃H, SO₂NR¹³R¹⁴, SO₂R¹³, SONR¹³R¹⁴, SOR¹³, COR¹⁴, COOH, COOR¹³, CONR¹³R¹⁴, NR¹³COR¹⁴, NR¹³COOR¹⁴, NR¹³SO₂R¹⁴, NR¹³CONR¹⁴R¹⁵, NR¹³R¹⁴, and acyl;

R⁸ is selected from the group consisting of H, halogen, OH, NO₂, CN, NH₂, optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionally substituted C₂- C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionally substituted C₁-C₁₂ alkyloxy, optionally substituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂ alkynyloxy, optionally substituted C₁-C₁₀ heteroalkyloxy, optionally substituted C₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂ cycloalkenyloxy, optionally substituted C₁-C₁₂ heterocycloalkyloxy, optionally substituted C₁-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-C₁₈ aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy, optionally substituted C₁-C₁₂ alkylamino, SR¹³, SO₃H, SO₂NR¹³R¹⁴, SO₂R¹³, SONR¹³R¹⁴, SOR¹³, COR¹³, COOH, COOR¹³, CONR¹³R¹⁴, NR¹³COR¹⁴, NR¹³COOR¹⁴, NR¹³SO₂R¹⁴, NR¹³CONR¹⁴R¹⁵ and NR¹³R¹⁴ and acyl;

R⁹ is selected from the group consisting of OH, OR¹³, COOR¹³, CONR¹³R¹⁴, NR¹³R¹⁴, tetrazol-5-yl, SO₂R¹³, SO₂NR¹³R¹⁴ and CONHOR¹³;

R¹⁰ is selected from the group consisting of H, a N-protecting group, optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionally substituted C₂- C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃- C₁₂cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl, optionally substituted C₁-C₁₂ heterocycloalkenyl, optionally substituted C_β-C₁₈aryl, and optionally substituted CrC^heteroaryl;

R¹¹ and R¹² are independently selected from the group consisting of H, halogen, OH, NO₂, CN, NH₂, optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionally substituted C₂-C₁₂ heterocycloalkyl, optionally substituted C₂-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈ aryl, optionally substituted C₁-C₁₈ heteroaryl, optionally substituted C₁-C₁₂ alkyloxy, optionally substituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂ alkynyloxy, optionally substituted C₁-C₁₀ heteroalkyloxy, optionally substituted C₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂ cycloalkenyloxy, optionally substituted C₁-C₁₂ heterocycloalkyloxy, optionally substituted C₁-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-C₁₈ aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy, optionally substituted C₁-C₁₂ alkylamino, SR¹³, SO₃H, SO₂NR¹³R¹⁴, SO₂R¹³, SONR¹³R¹⁴, SOR¹³, COR¹³, COOH, COOR¹³, CONR¹³R¹⁴, NR¹³COR¹⁴, NR¹³COOR¹⁴, NR¹³SO₂R¹⁴, NR¹³CONR¹⁴R¹⁵, NR¹³R¹⁴, and acyl;

each R¹³, R¹⁴, R¹⁵ are each independently selected from the group consisting of H, -OH, optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl, optionally substituted C₁-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, and optionally substituted d-C^heteroaryl;

n is an integer selected from the group consisting of O, 1 , 2, 3, and 4;

m is an integer selected from the group consisting of 1 , 2, 3, and 4;

m + n is an integer selected from the group consisting of 1 , 2, 3, 4, and 5; and

p is an integer selected from the group consisting of O, 1 , 2, 3, 4, and 5;

and when X¹ (YZ) is C(F₂) or SO₂; or when T is a cyclopropane ring as defined above; or when R¹ and R⁵ are H and T is a double bond; or when X² is (CH₂)_P and p is O or 1 ; or when A is selected from the group consisting of C₃ to C₁₂ cycloalkyl, preferably C₄ to C₆ cycloalkyl, C₁ to C₁₂ heterocycloalkenyl, and C₆ to C₁₈ heteroaryl; then R² and R³ may also be independently selected from -X³-R¹⁶ or -X⁴-R¹⁷;

wherein X³ and X⁴ may be the same or different and are selected from the group consisting of a bond C, O, N and S; and

R¹⁶ and R¹⁷ may be the same or different and are selected from the group consisting of H, NHR¹³, NR¹³R¹⁴, OR¹³, halogen, C₁ to C₁₀ alkyl, C₃ to C₁₀ cyclokalkyl, C₃ to C₁₀ cycloalkylmethyl, C₃ to C₁₀alkene, C₃ to C₁₀ alkyne, aryl, C₅ to C₂₀ alkaryl, fused C₅ to C₂₀ aryl or alkaryl and a hydrocarbon chain containing a heterocyclic or fused ring, any of which may be optionally substituted;

providing that when X¹(YZ) is C=O, X² is NH and T is a double bond then A has the general formula:

wherein X⁵, X⁶, X⁷and X⁸ may be independently C, S, O or N; R¹⁸ is absent, H or COOR¹³ and R⁹ can be H when R¹⁸ is COOR¹³, more preferably COOH; but A cannot be phenyl and R¹ to R⁵ cannot be -CF₃;

and further providing that when X¹(YZ) is C=O, X² is NH and T is a cyclopropane ring as defined above then R⁹ cannot be tetrazol-5-yl; and

and even further providing that when X¹(YZ) is SO₂, then A has the general formula:

wherein X⁵, X⁶, X⁷ and X⁸ may be independently C, S, O or N and R⁹ can be H when R² and R³ are each independently a Ci-C₁₂ alkyloxy group containing at least one halogen atom, and more preferably when R² and R³ are each -OCHF₂.

In some embodiments at least one of R¹, R², R³, R⁴, and R⁵ is selected from the group consisting of C₁-C₁₂ alkyloxy containing at least one halogen atom, C₁-C₁₂ alkenyloxy containing at least one halogen atom, and C₁-C₁₂ alkynyloxy containing at least one halogen atom. In another embodiment at least one of R² and R³ is selected from the group consisting of a C₁-C₁₂ alkyloxy group containing at least one halogen atom, a C₂-C₁₂ alkenyloxy containing at least one halogen atom, a C₂-C₁₂ alkynyloxy containing at least one halogen atom and a C₃-C₁₂ cycloalkyloxy containing at least one halogen atom and the other R² or R³ is selected from the group consisting of an optionally substituted C₁-C₁₂ alkyloxy group, an optionally substituted C₂-C₁₂ alkenyloxy, an optionally substituted C₂- C₁₂ alkynyloxy and an optionally substituted C₃-C₁₂ cycloalkyloxy.

In some embodiments, the C₁-C₁₂ alkyloxy group is of Formula (A):

Formula (A)

- wherein: R²⁴, R²⁵, and R²⁶ are each independently selected from the group consisting of: H, halogen, OH, NO₂, CN, NH₂, optionally substituted C₁-C₁₂ alkyl, and optionally substituted C₂-C₁₂ alkenyl;

- R²⁷, R²⁸, R²⁹, and R³⁰ are each independently selected from the group consisting of: H, halogen, OH, NO₂, CN₁ and NH₂; - at least one of R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, and R³⁰ is or contains a halogen atom;

- q is an integer selected from the group consisting of: O, 1 , 2, 3, 4, 5, 6, 7, 8, 9, and 10; and

- r is an integer selected from the group consisting of: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

In some embodiments q and r are 0, and at least two of R²⁴, R²⁵, and R²⁶ are a halogen.

The halogen may be selected from the group consisting of: fluorine, chlorine, bromine, and iodine. Preferably, the halogen is fluorine. In some embodiments at least one of R¹, R², R³, R⁴, and R⁵ is selected from the group consisting Of-O-CHF_2, -OCF_3, -OCF₂CHF₂. In some embodiments R³ is the group -O-CHF₂. In some embodiments R² and R³ are the group -Q-CHF₂. In some aspects, R¹ and R⁵ are H and R² and R³ are O- R¹⁶ and O-R¹⁷, wherein R¹⁶ and R¹⁷ are independently and preferably selected from the group consisting of unsubstituted C₁-C₆ alkyl, preferably methyl or ethyl; C₁-C₆ fluoro substituted alkyl, preferably, F₃CO, F₂HCO, F₂HCF₂CO; or are fused to form a 5 or 6 membered ring, preferably R² and R³ form a bridging difluoromethylenedioxy group or a bridging tetrafluoroethylenedioxy group.

In some embodiments T is a double bond while in other embodiments T is a triple bond.

In some embodiments R⁹ is selected from the group consisting of: COOR¹¹ and CONR¹¹R¹². In some embodiments R⁹ is selected from the group consisting of: COOH, CONH₂, and CONHCH₃.

In some embodiments R⁹ is NR¹¹R¹² while in some embodiments R⁹ is NH₂.

In some embodiments n is 1.

In some embodiments R⁸ is halogen.

In one form of the invention, T is a single bond and one pair of R⁶ and R⁷ are fused to

form a cyclopropane ring of the formula

In some embodiments R² and R³ form a bridging difluoromethylenedioxy group or a bridging tetrafluoroethylenedioxy group.

In some embodiments R⁶ is CH₃. In some embodiments R⁷ is CH₃ or CN. In some embodiments R⁸ is H or Me.

In preferred embodiments m is 1 and R⁹ is selected from COR¹³ and CONR¹³R¹⁴.

In other preferred embodiments R⁹ is selected from the group consisting of COOH,

CONH₂, CONHOH and CONHCH₃.

In certain embodiments R⁹ is the group tetrazol-5-yl. In some embodiments R⁹ is selected from the group consisting of SO₂R , SO₂NR¹ R .

In some more particular embodiments R⁹ is selected from the group consisting of SO₂Me, SO₂NH₂, SO₂NHMe, SO₂NMe₂.

In some embodiments R⁹ is NR¹³R¹⁴ and in more particular embodiments R⁹ is NH₂. In some embodiments R⁸ is a halogen. In some embodiments X² is NH.

According to a further form of the invention, there is provided a compound of the formula (II)

(H)

Preferred compounds of the invention have the formula (Ma)

(Ha) or a pharmaceutically acceptable salt or prodrug thereof, wherein; A, R¹, R², R³, R⁴, R⁵, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined above in relation to compounds of formula (I).

A further aspect of the present invention is represented by a compound of the Formula (III)

(III) or a pharmaceutically acceptable salt or prodrug thereof, wherein;

A, T, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and X² are as defined above in relation to compounds of formula (I).

Yet another aspect of the present invention is represented by a compound of the Formula (IV)

(IV)

or a pharmaceutically acceptable salt or prodrug thereof, wherein;

A further aspect of the present invention may be represented by a compound of Formula (V)

(V) or a pharmaceutically acceptable salt or prodrug thereof, wherein;

Het represents a heterocyclic ring and T, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, X¹ (YZ) and X² are as defined above in relation to compounds of formula (I).

According to a further aspect of the present invention, there is provided a compound of formula (Vl)

(Vl) or a pharmaceutically acceptable salt or prodrug thereof, wherein; T, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and p are as defined above in relation to compounds of formula (I).

In preferred embodiments, R⁶ and R⁷ are H in the compounds of formulas (III), (IV), (V) and (Vl).

In some embodiments T is preferably a double bond in the compounds of formulas (III), (IV), (V) and (Vl).

In the compounds of formula (V), certain preferred embodiments have X¹(YZ) as being C=O. In other embodiments X² is NH or NR¹³ wherein R¹³ is preferably C₁ to C₆ alkyl, most preferably a methyl group. In preferred embodiments of formula (V), X¹(YZ) is C=O and X² is NH.

In preferred embodiments of the compounds of formulae (II) and (Ha), R¹¹ and R¹² are selected from the group consisting of H, CN or halogen. Preferably, R¹¹ and R¹² are H. When R¹¹ and/or R¹² are halogen, the halogen is preferably fluorine.

When R⁹ is present in the compounds of formulae (II), (Ma), (III), (IV), (V) and (Vl), R⁹ is preferably selected from the group consisting of CO₂H, CO₂R¹³, SO₂R¹³, SO₂NH₂,

SONHR¹³, SONR¹³ ₂, CONH₂, CONHR¹³, CONHOR¹³ and 5-tetrazolyl, wherein R¹³ is preferably C₁ to C₆ alkyl, most preferably a methyl group. Alternatively, R⁹ is selected from the group consisting Of CO₂H, CO₂R¹³, SO₂R¹³, SO₂NH₂, SONHR¹³, SONR¹³ ₂ and 5- tetrazolyl.

In preferred embodiments of the formulae (II), (Ha), (III), (IV), (V) and (Vl), R¹ and R⁵ are H and R² and R³ are 0-R¹⁶ and O-R¹⁷, wherein R¹⁶ and R¹⁷ are independently and preferably selected from the group consisting of unsubstituted C₁-C₆ alkyl, preferably methyl or ethyl; C₁-C₆ fluoro substituted alkyl, preferably, F₃CO, F₂HCO, F₂HCF₂CO; or are fused to form a 5 or 6 membered ring, preferably a fluoro substituted 1 ,4 dioxane or a fluoro substituted 1 ,3-dioxolane; or a C₁ to C₆ alkenyl, preferably -CH₂CCH.

In preferred embodiments of the formulae (II), (Ha), (III), (IV), (V) and (Vl), R¹⁰ is H or a C₁ to C₆ alkyl, preferably, methyl.

In preferred embodiments of the formulae (II), (Ha), (III) and (IV), A has the general formula selected from the group consisting of

wherein X⁵, X⁶, X⁷ and X⁸ may be independently C, S, O or N.

In a particularly preferred embodiments, A has the general formula

wherein X⁴, X⁵, X⁶ and X⁷ may be C or N. More preferably, not more than two of X⁴, X⁵, X⁶ and X⁷ may be N. Non-limiting examples of suitable compounds of formula (Ha) include

Particular examples of compounds of formula (III) are as follows

R⁹ = SO₂Me, SO₂NH₂, 5-tetrazolyl R⁹ = NH₂, CONH₂, CONHMe, CONHOH

Particular examples of compounds of formula (IV) are as follows

R⁹ = SO₂Me, SO₂NH₂, 5-tetrazolyl R⁹ = NH₂, CONH₂, CONHMe, CONHOH

R⁹ = SO₂Me, SO₂NH₂, 5-tetrazolyl R⁹ = NH₂, CONH₂, CONHMe, CONHOH

Specific compounds of formula (V) include

R⁹ = NH₂, CONH₂, CONHMe, CONHOH

R⁹ = SO₂Me₁ SO₂NH₂, SONHMe, SONMe₂

Some specific examples of compounds of formula Vl are as follows:

R⁹ = SO₂Me, SO₂NH₂, 5-tetrazolyl R⁹ = NH₂, CONH₂, CONHMe, CONHOH

wherein p is O or 1.

Further derivatives include

In addition to compounds of formulae (I), (II), (Ma)₁ (III), (IV), (V) and (Vl), the embodiments disclosed are also directed to pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites.

The compounds of the present invention may have anti-fibrotic, anti-inflammatory, anti- proliferative or anti-neoplastic activity and may, therefore, find use as an alternative and/or adjunct to Tranilast.

Detailed Description

In this specification a number of terms are used which are well known to a skilled addressee. Nevertheless for the purposes of clarity a number of terms will be defined.

As used herein, the term unsubstituted means that there is no substituent or that the only substituents are hydrogen.

The term "optionally substituted" as used throughout the specification denotes that the group may or may not be further substituted or fused (so as to form a polycyclic system), with one or more non-hydrogen substituent groups. In certain embodiments the substituent groups are one or more groups independently selected from the group consisting of halogen, =O, =S, -CN, -NO₂, -CF₃, -OCF₃, -OCHF₂, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycycloalkyl, alkoxyheterocycloalkyl, alkoxyaryl, alkoxyheteroaryl, alkoxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -COOH, - COR¹¹, -C(O)OR¹¹, CONHR¹¹, NHCOR¹¹, NHCOOR¹¹, NHCONHR¹¹, C(=N0H)R¹¹, -SH, -SR¹¹, -OR¹¹, and acyl, wherein R¹¹ is H, optionally substituted d-C₁₂alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-Ci₂ alkynyl, optionally substituted C₁- C₁₀ heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl, optionally substituted C₁-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈ aryl, optionally substituted C₁-C₁₈ heteroaryl, and acyl.

"Alkyl" as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, such as a C₁-C₁₄ alkyl, a C₁-C₁₀ alkyl or a C₁-C₆ unless otherwise noted. Examples of suitable straight and branched C₁-C₆ alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like. The group may be a terminal group or a bridging group.

"Alkylamino" includes both mono-alkylamino and dialkylamino, unless specified. "Mono- alkylamino" means a -NH-Alkyl group, in which alkyl is as defined above. "Dialkylamino" means a -N(alkyl)₂ group, in which each alkyl may be the same or different and are each as defined herein for alkyl. The alkyl group may be a C₁-C₆ alkyl group. The group may be a terminal group or a bridging group.

"Arylamino" includes both mono-arylamino and di-arylamino unless specified.

Mono-arylamino means a group of formula arylNH-, in which aryl is as defined herein. Di-arylamino means a group of formula (aryl)₂N- where each aryl may be the same or different and are each as defined herein for aryl. The group may be a terminal group or a bridging group.

"Acyl" means an alkyl-CO- group in which the alkyl group is as described herein. Examples of acyl include acetyl and benzoyl. The alkyl group may be a C₁-C₆ alkyl group. The group may be a terminal group or a bridging group.

"Alkenyl" as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched such as a group having 2-14 carbon atoms, 2-12 carbon atoms, or 2-6 carbon atoms, in the normal chain. The group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z. Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl. The group may be a terminal group or a bridging group.

"Alkoxy" refers to an -O-alkyl group in which alkyl is defined herein. The alkoxy may be a C₁-C₆ alkoxy. Examples include, but are not limited to, methoxy and ethoxy. The group may be a terminal group or a bridging group.

"Alkenyloxy" refers to an -O- alkenyl group in which alkenyl is as defined herein. Preferred alkenyloxy groups are C₂-C₆ alkenyloxy groups. The group may be a terminal group or a bridging group.

"Alkynyloxy" refers to an -O-alkynyl group in which alkynyl is as defined herein. Preferred alkynyloxy groups are C₂-C₆ alkynyloxy groups. The group may be a terminal group or a bridging group.

"Alkoxycarbonyl" refers to an -C(O)-O-alkyl group in which alkyl is as defined herein. The alkyl group may be a C₁-C₆ alkyl group. Examples include, but not limited to, methoxycarbonyl and ethoxycarbonyl. The group may be a terminal group or a bridging group.

"Alkylsulfinyl" means a -S(O)-alkyl group in which alkyl is as defined above. The alkyl group is preferably a C₁-C₆ alkyl group. Exemplary alkylsulfinyl groups include, but not limited to, methylsulfinyl and ethylsulfinyl. The group may be a terminal group or a bridging group. "Alkylsulfonyl" refers to a -S(O)₂-alkyl group in which alkyl is as defined above. The alkyl group may be a Ci-C₆ alkyl group. Examples include, but not limited to methylsulfonyl and ethylsulfonyl. The group may be a terminal group or a bridging group.

"Alkynyl" as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched and may have from 2-14 carbon atoms, 2-12 carbon atoms, or 2-6 carbon atoms in the normal chain. Exemplary structures include, but are not limited to, ethynyl and propynyl. The group may be a terminal group or a bridging group.

"Alkylaminocarbonyl" refers to an alkylamino-carbonyl group in which alkylamino is as defined above. The group may be a terminal group or a bridging group.

"Cycloaikyl" refers to a saturated or partially saturated, monocyclic or fused or spiro polycyclic, carbocycle that may contain from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. The group may be a terminal group or a bridging group.

"Cycloalkenyl" means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and may have from 5-10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. The cycloalkenyl group may be substituted by one or more substituent groups. The group may be a terminal group or a bridging group.

The above discussion of alkyl and cycloaikyl substituents also applies to the alkyl portions of other substituents, such as without limitation, alkoxy, alkyl amines, alkyl ketones, arylalkyl, heteroarylalkyl, alkylsulfonyl and alkyl ester substituents and the like.

"Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which the cycloaikyl and alkyl moieties are as previously described. Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. The group may be a terminal group or a bridging group. "Halogen" represents fluorine, chlorine, bromine or iodine.

"Heterocycloalkyl" refers to a saturated or partially saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen. The heterocycloalkyl group may have from 1 to 3 heteroatoms in at least one ring. Each ring may be from 3 to 10 membered, such as 4 to 7 membered. Examples of suitable heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1 ,3-diazapane, 1 ,4-diazapane, 1 ,4- oxazepane, and 1 ,4-oxathiapane. The group may be a terminal group or a bridging group.

"Heterocycloalkenyl" refers to a heterocycloalkyl as described above but containing at least one double bond. The group may be a terminal group or a bridging group.

"Heterocycloalkylalkyl" refers to a heterocycloalkyl-alkyl group in which the heterocycloalkyl and alkyl moieties are as previously described. Exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl) methyl. The group may be a terminal group or a bridging group.

"Heteroalkyl" refers to a straight- or branched-chain alkyl group that may have from 2 to 14 carbons, such as 2 to 10 carbons in the chain, one or more of which has been replaced by a heteroatom selected from S, O, P and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like. The group may be a terminal group or a bridging group. As used herein reference to the normal chain when used in the context of a bridging group refers to the direct chain of atoms linking the two terminal positions of the bridging group.

"Aryl" as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) that may have from 5 to 12 atoms per ring. Examples of aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C_5-7 cycloalkyl or C_5-7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. The group may be a terminal group or a bridging group. "Arylalkenyl" means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Exemplary arylalkenyl groups include phenylallyl. The group may be a terminal group or a bridging group.

"Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C_1-5 alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl and naphthelenemethyl. The group may be a terminal group or a bridging group.

"Heteroaryl" either alone or as part of a group refers to groups containing an aromatic ring (such as a 5 or 6 membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur. Examples of heteroaryl include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1 H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, phenoxazine, 2-, 3- or 4- pyridyl, 2-, 3-, 4-, 5-, or 8- quinolyl, 1-, 3-, 4-, or 5- isoquinolinyl 1-, 2-, or 3- indolyl, and 2-, or 3-thienyl. The group may be a terminal group or a bridging group.

"Heteroarylalkyl" means a heteroaryl-alkyl group in which the heteroaryl and alkyl moieties are as previously described. The heteroarylalkyl groups may contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. The group may be a terminal group or a bridging group.

"Lower alkyl" as a group means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 6 carbon atoms in the chain, for example 1 to 4 carbons such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl). The group may be a terminal group or a bridging group.

As would be understood by the skilled person, throughout the synthesis of the compounds of Formula (I) it may be necessary to employ a protecting group on the amino group and/or on the carboxyl group in order to reversibly preserve a reactive amino or carboxyl functionality while reacting other functional groups on the compound. In such a case, the free amino group and/or the free carboxyl groups of the compounds of Formula (I) can be liberated either by deprotection of the amino group followed by deprotection of the acid moieties or vice versa.

Examples of suitable amino protecting groups that may be used include formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, and urethane-type blocking groups such as benzyloxycarbonyl (¹CBz¹), 4-phenylbenzyloxycarbonyl, 2- methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4- chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4- dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4- nitrobenzyloxycarbonyl, 4cyanobenzyloxycarbonyl, t-butoxycarbonyl ('tBoc'), 2-(4-xenyl)- isopropoxycarbonyl, 1 ,1-diphenyleth-i-yloxycarbonyl, 1 ,1-diphenylprop-i-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)-prop-2-yloxycarbonyl, cyclopentanyloxy- carbonyl, i-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1- methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfono)- ethoxycarbonyl, 2-(methylsulfono)ethoxycarbonyl, 2-(triphenylphosphino)- ethoxycarbonyl, fluorenylmethoxycarbonyl ("FMOC"), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5- benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2- trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4- (decycloxy)benzyloxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonlyl and the like; benzoylmethylsulfono group, 2-nitrophenylsulfenyl, diphenylphosphine oxide, and the like. The actual amino protecting group employed is not critical so long as the dehvatised amino group is stable to the condition of subsequent reaction(s) and can be selectively removed as required without substantially disrupting the remainder of the molecule including any other amino protecting group(s). Preferred amino-protecting groups are t-butoxycarbonyl (Boc), and benzyloxycarbonyl (Cbz). Further examples of these groups are found in: Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, Second edition; Wiley-lnterscience: 1991; Chapter 7; McOmie, J. F. W. (ed.), Protective Groups in Organic Chemistry, Plenum Press, 1973; and Kocienski, P. J., Protecting Groups, Second Edition, Theime Medical Pub., 2000.

Examples of carboxyl protecting groups that may be used include methyl, ethyl, n-propyl, i-propyl, p-nitrobenzyl, p-methylbenzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4- dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4- methylenedioxybenzyl, benzhydryl, 4,4'-dinnethoxybenzhyclryl, 2,2'4,4'- tetramethoxybenzhydryl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4_I4'-dimethoxytrityl, 4,4,'4"- trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2- trichloroethyl, β-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonoethyl, A- nitrobenzylsulfonoethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl, and the like. Preferred carboxyl protecting groups are methyl and t-butyl. Further examples of these groups are found in: Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, Second edition; Wiley-lnterscience: 1991 ; McOmie, J. F. W. (ed.), Protective Groups in Organic Chemistry, Plenum Press, 1973; and Kocienski, P. J., Protecting Groups, Second Edition, Theime Medical Pub., 2000.

It is understood that included in the family of compounds of Formula (I) are isomeric forms including diastereoisomers, enantiomers, tautomers, and geometrical isomers in "E" or "Z" configurational isomer or a mixture of E and Z isomers. It is also understood that some isomeric forms such as diastereomers, enantiomers, and geometrical isomers can be separated by physical and/or chemical methods and by those skilled in the art.

Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof, are intended to be within the scope of the subject matter described and claimed.

In the cyclopropane derivatives of the present invention, it is understood that the general formula and representative compounds refer to both cis and trans isomers as either single isomers or any mixture thereof and all isomers and mixtures thereof are intended to fall within the scope of the subject matter described and claimed. Where R⁶ and R⁷ are different, it will be understood that either the R or S configurations or any mixture thereof is included within the scope of the subject matter described and claimed.

Additionally, formulae (I), (II), (Ma), (III), (IV), (V) and (Vl) are intended to cover, where applicable, solvated as well as unsolvated forms of the compounds. Thus, each formula includes compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.

In addition to compounds of the formulae (I), (II), (Ma), (III), (IV), (V) and (Vl), the compounds of the various embodiments include pharmaceutically acceptable salts, prodrugs, N-oxides and active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites.

The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the above-identified compounds, and include pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of compounds of Formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. Suitable pharmaceutically acceptable base addition salts of compounds of Formula (I) include metallic salts made from lithium, sodium, potassium, magnesium, calcium, aluminium, and zinc, and organic salts made from organic bases such as choline, diethanolamine, morpholine. Other examples of organic salts are: ammonium salts, quaternary salts such as tetramethylammonium salt; amino acid addition salts such as salts with glycine and arginine. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.

"Prodrug" means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of formula (I). For example an ester prodrug of a compound of formula (I) containing a hydroxyl group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of formula (I) containing a hydroxyl group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-β-hydroxynaphthoates, gestisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates. As another example an ester prodrug of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. (Examples of ester prodrugs are those described by F.J. Leinweber, Drug Metab. Res., 18:379, 1987). The term "pharmaceutically acceptable" refers generally to a substance or composition that is compatible chemically and/or toxicologically with the other ingredients including a formulation, and/or the subject being treated.

The term "compounds of the present invention" (unless specifically identified otherwise) refers generally to compounds, prodrugs thereof, pharmaceutically acceptable salts of the compounds and/or prodrugs, and hydrates or solvates of the compounds, salts, and/or prodrugs, as well as all stereoisomers (including diastereoisomers and enantiomers), tautomers and isotopically labelled compounds. The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.

The term "derivative thereof when used in reference to compounds of the present invention refers generally to prodrugs, pharmaceutically acceptable salts of the compounds and/or prodrugs, and hydrates or solvates of the compounds, salts, and/or prodrugs.

The compounds of the present invention may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are commercially available or can be synthesised using known procedures or adaptations thereof. Whilst the preparation of particular compounds is outlined below, the skilled person will also recognize that the chemical reactions described may be readily adapted to prepare a number of other agents of the various embodiments. For example, the synthesis of non-exemplified compounds may be successfully performed by modifications apparent to those skilled in the art, e.g. by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. A list of suitable protecting groups in organic synthesis can be found in T. W. Greene's Protective Groups in Organic Synthesis, 3^rd Edition, John Wiley & Sons, 1991. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the various embodiments.

Reagents useful for synthesizing compounds may be obtained or prepared according to techniques known in the art. To produce compounds of the present invention in which T is a single bond the cinnamoyl benzamide (1) can be reduced by hydrogenation with a suitable catalyst, such as palladium on carbon, RhCI(PPh₃)₃, or by any other methods known in the art (see J. March, Advanced Organic Chemistry, John Wiley & Sons, New York 1985, pp. 694).

The compounds of the invention and intermediates in their synthesis can be isolated from a reaction mixture using standard work-up and purification procedures. Suitable procedures include solvent extraction, chromatography (thin or thick layer chromatography, HPLC, flash chromatography, MPLC₁ etc.), recrystallisation etc.

The present invention includes salts of the compounds of Formula (I). The salts may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically acceptable, acid addition salts, or they may be useful for identification, characterisation or purification. The salts can exist in conjunction with the acidic or basic portion of the molecule and can exist as acid addition, primary, secondary, tertiary, or quaternary ammonium, alkali metal, or alkaline earth metal salts. Generally, acid addition salts are prepared by the reaction of an acid with a compound of Formula (I). The alkali metal and alkaline earth metal salts are generally prepared by the reaction of the hydroxide form of the desired metal salt with a compound of Formula (I).

Acid addition salts are preferably the pharmaceutically acceptable, non-toxic addition salts with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric, salicyclic, o-acetoxybenzoic, or organic sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic, or naphthalene-2-sulphonic acid.

The present invention also includes esters of the compounds of Formula (I), such esters being for example aliphatic esters such as alkyl esters. The esters of the compounds of Formula (I) may be pharmaceutically acceptable metabolically labile esters. These are ester derivatives of compounds of Formula (I) that are hydrolysed in vivo to afford the compound of Formula (I) and a pharmaceutically acceptable alcohol. Examples of metabolically labile esters include esters formed with alkanols in which the alkanol moiety may be optionally substituted by an alkoxy group, for example methanol, ethanol, propanol and methoxyethanol. The compounds of the various embodiments may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available. The person skilled in the art will recognise that the chemical reactions described may be readily adapted to prepare a number of other compounds. For example, the synthesis of non-exemplified compounds may be successfully performed by modifications apparent to those skilled in the art, e.g. by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. A list of suitable protecting groups in organic synthesis can be found in T. W. Greene's Protective Groups in Organic Synthesis, 3^rd Edition, John Wiley & Sons, 1991. Reagents useful for synthesizing compounds may be obtained or prepared according to techniques known in the art.

The utility of compounds of Formula (I) can be tested using any of the following methods: (i) In a renal cell line by measuring proline incorporation after transforming growth factor-β stimulation;

(ii) Matrix synthesis may be stimulated by platelet derived growth factor (PDGF). Accordingly, mesangial cells incubated with PDGF can be used to demonstrate proline incorporation, which is an indicator of matrix synthesis and thereby a model for fibrosis; or

(iii) Matrix synthesis may be stimulated by both angiotensin Il or transforming growth factor beta (TGF-β). Accordingly, neonatal cardiac fibroblasts incubated with angiotensin Il or TGF-β can be used to demonstrate proline incorporation, which is an indicator of matrix synthesis and thereby a model for fibrosis.

Compounds of formula (II) may suitably be prepared according to scheme I;

Scheme 1

In a preferred form of the preparation according to Scheme 1 , the cyclopropanation step is performed with with excess CH₂N₂ and a catalytic quantity of Pd(OAc)₂ in a 1 :1 mixture of CH₂CI₂ and diethyl ether. It is also preferred that an esterification step in which the cinnamic acid derivative is reacted with sulphuric acid in methanol to provide the corresponding methyl ester precedes the cyclopropanation step. Preferably, a hydrolysis step in which the cyclopropanated derivative is hydroiysed with aqueous NaOH/MeOH to provide the cyclopropanated carboxylic acid derivative follows the cyclopropanation step.

Thus according to one form of the invention, there is provided a method of preparing a compound of formula II, the method including;

(a) cyclopropanation of a compound of the formula

to obtain a compound of the formula

and

(b) condensing the compound obtained in step (a) with a compound of formula

An exemplary preparation is shown below:

An alternative method for preparing a compound of formula Ma is shown below in Scheme 2.

Scheme 2

According to a further aspect of the invention, there is provided a method of preparing a compound of Formula Ma including the steps of: (a) reacting a compound of the formula

to obtain an acid chloride of the formula

and (b) condensing the acid chloride prepared in step (a) with a compound of the formula

H₅N

An example of preparing a suitable compound of formula Ma is shown below:

A further method of preparing a compound of formula Ma is shown in scheme 3 below:

Scheme 3

Compounds of formula III may be prepared according to scheme 4 below;

Scheme 4

Thus, according to a further aspect of the invention, there is provided a method for preparing a compound of formula III including the steps of; (a) reacting a terminal alkene of the formula

to provide a sulfonyl chloride compound of the formula

and

(b) condensing the sulfonyl chloride prepared in step (a) with a compound of formula

An example of preparing a compound of formula III is as follows:

An alternative method for preparing a compound of formula III is shown below in Scheme 5.

Scheme 5

Thus, according to a further aspect of the invention, there is provided a method of preparing a compound of Formula III including the steps of: (a) reacting a sulfonate compound of the formula

to provide a sulfonyl chloride compound of the formula

(b) condensing the sulfonyl chloride compound prepared in step (a) with a compound of the formula

If desired, the method of preparing the compound of Formula III as described immediately above may also include an initial step of reacting an aldehyde compound of the formula ό

to provide the sulfonate compound of the formula

Compounds of Formula IV in which X² is NH may be prepared according to scheme 6 below.

Scheme 6

Thus according to a further aspect of the invention, there is provided a method for preparing a compound of formula IV in which X² is NH that includes the steps of; (a) reacting a terminal alkene of the formula

to provide a compound of formula

and (b) condensing the compound prepared in step (a) with a compound of the formula

A specific example for the preparation of a compound of formula IV is as follows:

Compounds of formula IV in which X² is CH₂ may be prepared by forming the °c,β- unsaturated ketone and then converting the ketone to the difluorovinyl species using morpholino-SF3 (See Tetrahedron Letters (2004), 45(7), 1527; Synthesis (1963), 787) according to scheme 7 below:

Scheme 7

Thus, according to a further aspect of the invention, there is provided a method for the preparation of compounds of formula IV in which X² is CH₂ that includes the steps of; (a) reacting a compound of the formula

to provide a ketone of the formula

(b) converting the ketone prepared in step (a) to a compound of the formula

A specific example of such a method is shown below:

Compounds of formula V in which X² is NH may be made by reaction with Meldrum's acid followed by condensation of the malonic-type acid with a suitable aldehyde as shown in the following Scheme 8:

Meldrum's acid toluene

Scheme 8

A specific example of such a preparation is shown below:

piperidine toluene

Compounds of formula V may also be prepared by Knoevenagel condensation of a suitable aldehyde with malonic acid then coupling of the cinnamic acid with an aryl amine according to scheme 9 below.

malonic acid piperidine

Scheme 9

A specific example of such a synthesis is shown below: malonic acid piperidine

Another specific example of such a synthesis in which the 3,4-dimethoxycinnamic acid is converted to the corresponding acid chloride prior to reaction with a heterocyclic amine is shown below:

malonic acid piperidine

oxalyl chloride CH₂CI₂

Compounds of the formula Vl may be prepared by a method as shown in Schemes and 10 and 11 below:

Scheme 10

Scheme 11

Thus according to a further broad form of the invention there is provide a method of preparing a compound of formula (Vl) including the step of: reacting a compound of the formula

with a compound of the formula

to obtain a compound of the formula

A further form of the invention provides a method of preparing a compound of formula

(Vl) including the step of reacting a compound of formula

with I a compound of formula

to provide a compound of formula

Specific examples of such a synthesis are shown below:

Examples of materials and methods for use with the compounds of the present invention will now be provided. In providing these examples, it is to be understood that the specific nature of the following description is not to limit the generality of the above description. Examples

Experimental

Electrospray ionization (ESI) high resolution mass spectra (HRMS) were obtained on a Finnigan hybrid LTQ-FT mass spectrometer (Thermo Electron Corp.). Proton nuclear magnetic resonance (¹H NMR) and proton decoupled carbon nuclear magnetic resonance (¹³C NMR) spectra were obtained on Unity 400, Innova 400 or Innova 500 instruments (Melbourne, Australia) operating at 400 or 500 MHz for ¹H and at 100 or 125 MHz for ¹³C. All signals were referenced to solvent peaks (CDCI₃: 7.26 ppm for ¹H and 77.0 ppm for ¹³C; DMSO-cfe: 2.49 ppm for ¹H and 39.5 ppm for ¹³C). Infrared (IR) spectra were obtained using a PerkinElmer Spectrum One FT-IR spectrometer with zinc selenide/diamond Universal ATR Sampling Accessory. Melting points were obtained using a Reichert-Jung hot stage apparatus and are corrected. Analytical thin layer chromatography (TLC) was conducted on 2 mm thick silica gel GF₂₅₄. Compounds were visualised with solutions of 20% w/w phosphomolybdic acid in ethanol, 20% w/w potassium permanganate in water or under UV (365 nm). Flash chromatography was performed with Merck Silica Gel 60. Petrol refers to the fraction boiling at 40-60 ⁰C. All other reagents were used as received.

Example 1 - Synthesis of compounds of Formula (I)

(E)-1-[[3-(3, 4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]cyclohexanecarboxylic acid (FT101)

A suspension of (E)-3-(3,4-dimethoxyphenyl)-2-propenoic acid (0.25 g, 1.2 mmol) in CH₂CI₂ (5 mL) was treated with oxalyl chloride (0.41 mL, 4.8 mmol). The solution was stirred at rt for 1 h and the solvent was removed under reduced pressure to give the acid chloride as a yellow solid. 1-Aminocyclohexanecarboxylix acid (0.21 g, 1.4 mmol) was added to a solution of the acid chloride (1.2 mmol) in pyridine (2.0 mL) and the suspension was stirred at rt for 16 h. The solution was diluted with water and the precipitate was collected by filtration. The crude product was recrystallised from EtOAc providing (£)-1-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]cyclohexanecarboxylic acid (40 mg, 10%) as a colourless crystalline solid; mp 171-173 ⁰C; δ_H (500 MHz, DMSO-cfe) 1.23 (m, 2H, CH₂), 1.45-1.53 (m, 4H, CH₂), 1.67 (m, 2H, CH₂), 2.00 (m, 2H, CH₂), 3.77 (S, 3H₁ OCH₃), 3.79 (s, 3H, OCH₃), 6.67 (d, J = 15.5 Hz, 1 H, CH=CHCO), 6.98 (d, J₅,₆ = 8.0 Hz, 1 H, H5), 7.09 (d, J₅,₆ = 8.0 Hz, 1H, H6), 7.13 (s, 1H, H2), 7.28 (d, J = 15.5 Hz, 1 H₁ CH=CHCO), 7.92 (s, 1 H, NH), 12.05 (s, 1 H, CO₂H); δ_c (125 MHz, DMSO- d₆) 21.0, 25.0, 31.8, 55.3, 55.5, 57.8, 109.7, 111.7, 120.0, 121.4, 127.7, 138.6, 148.9, 150.1 , 164.8, 175.5; HRMS (ESI) calculated for C₁₈H₂₃NO₅ [M+Na]⁺ 351.1468, found 351.1467; v_max 1137, 1239, 1260, 1516, 1599, 1653, 1731, 2932, 3236, 3334 cm^"1.

(E)-[6-[[3-(3,4-Dimethoxyphenyl)-1-oxo-2-propenyl]amino]]-2-pyhdinecarboxylic acid (FT103)

A suspension of (E)-3-(3,4-dimethoxyphenyl)-2-propenoic acid (0.25 g, 1.2 mmol) in CH₂CI₂ (5 mL) was treated with oxalyl chloride (0.41 ml_, 4.8 mmol). The solution was stirred at rt for 1 h and the solvent was removed under reduced pressure to give the acid chloride as a yellow solid. 3-Aminopicolinic acid (0.25 g, 1.4 mmol) was added to a solution of the acid chloride (1.2 mmol) in pyridine (2.0 mL) and the suspension was stirred at rt for 4 d. The solution was diluted with water and the precipitate was collected by filtration providing (£)-2-(3,4-dimethoxystyryl)-4H-pyrido[2,3-d][1 ,3]oxazin-4-one (80 mg, 20%) as a brown solid; mp 206-207 ⁰C; δ_H (500 MHz, DMSO-Cl₆) 3.80 (s, 3H, OCH₃), 3.83 (S, 3H, OCH₃), 6.84 (d, J = 15.5 Hz, 1 H, CH=CHCO), 6.99 (d, J_s-_tV = 8.0 Hz, 1H, H5¹), 7.25 (d, J₅₇,. = 8.0 Hz, 1H, H6¹), 7.38 (s, 1H, H2"), 7.58 (d, J = 15.5 Hz, 1 H, CH=CHCO), 7.71 (dd, J₃,₄ = 8.0, J_4,5 = 5.0 Hz, 1H, H4), 7.87 (d, J₄,₅ = 5.0 Hz, 1 H, H5), 8.47 (d, J₃,₄ = 8.0 Hz, 1H, H3), 11.49 (s, 1H, NH); δ_c (125 MHz, DMSO-(Z₆) 55.5, 55.6, 110.4, 111.6, 119.2, 122.8, 127.1 , 127.9, 129.8, 134.0, 137.9, 141.5, 142.3, 149.0, 150.8, 164.8, 166.9; HRMS (ESI) calculated for C₁₇H₁₆N₂O₅ [M+H]⁺ 329.1132, found 329.1131 ; v_max 808, 1141 , 1259, 1508, 1667, 2938 cm^"1.

(E)-[6-[[3-(3,4-Dimethoxyphenyl)-1-oxo-2-propenyl]amino]]-3-pyhdinecarboxylic acid (FT104)

A suspension of (£)-3-(3,4-dimethoxyphenyl)-2-propenoic acid (1.0 g, 4.8 mmol) in CH₂CI₂ (10 mL) was treated with oxalyl chloride (1.6 ml_, 19 mmol). The solution was stirred at rt for 1 h and the solvent was removed under reduced pressure to give the acid chloride as a yellow solid. 4-Aminonicotinic acid (0.73 g, 5.3 mmol) was added to a solution of the acid chloride (4.8 mmol) in pyridine (5.0 mL) and the suspension was heated to reflux and stirred for 5 d. The solution was diluted with water and the precipitate was collected by filtration providing (£)-[6-[[3-(3,4-Dimethoxyphenyl)-1-oxo-2- propenyl]amino]]-3-pyridinecarboxylic acid (0.25 g, 16%) as a colourless solid; mp 258- 260 ⁰C; δ_H (500 MHz, DMSO-d₆) 3.80 (s, 3H, OCH₃), 3.83 (s, 3H, OCH₃), 6.82 (d, J = 15.5 Hz, 1H₁ CH=CHCO), 7.00 (d, J₅._iβ. = 8.0 Hz, 1 H, H5'), 7.23 (dd, J₆._>β. = 8.0, J₂,₆. = 2.0 Hz, 1 H₁ H6'), 7.33 (s, J₂, ₆. = 2.0 Hz, 1H, H2'), 7.62 (d, J = 15.5 Hz, 1H, CH=CHCO), 8.60 (d, J_5,6 = 8.0 Hz, 1 H, H5), 8.63 (d, J_5j6 = 8.0 Hz, 1H, H6), 9.03 (s, 1H, H2); HRMS (ESI) calculated for C₁₇H₁₄N₂O₄ [M+H]⁺ 329.1132, found 329.1129; v_max 1140, 1262, 1488, 1623, 2938, 3543 cm^"1.

2-(3, 4-dimethoxyphenyl)cyclopropanecarboxylic acid

Concentrated sulfuric acid (1.0 mL) was added to a solution of (£)-3,4- dimethoxycinnamic acid (2.0 g, 9.6 mmol) in MeOH (50 mL). The solution was heated to reflux for 4 h, cooled to rt and then quenched with saturated aqueous NaHCO₃. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with water, brine, dried and concentrated providing methyl ester (2.2 g, 95%). A cooled solution of the methyl ester (0.11 g, 0.49 mmol) and Pd(OAc)₂ (6 mg, 0.027 mmol) in CH₂CI₂ (3 mL) and ether (3 mL) was treated with excess CH₂N₂ at 0 ⁰C The suspension was filtered and the filtrate was concentrated. The crude residue was dissolved in MeOH (5 mL) and treated with 1 M NaOH (5 mL). The mixture was stirred at rt for 16 h and then concentrated under reduced pressure to remove the MeOH. The aqueous phase was washed with 50% EtOAc/petrol, acidified with 1 M HCI and then extracted with EtOAc. The combined organic fractions were washed with water, brine, dried and concentrated providing 2-(3,4-dimethoxyphenyl)cyclopropanecarboxylic acid (96 mg, 87%) as a colourless crystalline solid; δ_H (500 MHz, DMSO-cfe) 1.36 (ddd, J = 5.0, J = 4.0, J = 2.0 Hz, 1H, CH), 1.62 (ddd, J = 2.0, J = 4.0, J = 2.0 Hz, 1H, CH)₁ 1.84 (ddd, J = 2.0, J = 4.0, J = 2.0 Hz, 1 H, CH), 2.57 (ddd, J = 2.0, J = 4.0, J = 3.0 Hz, 1 H, CH), 3.85 (s, 3H, OCH₃), 3.87 (s, 3H, OCH₃), 6.65 (d, J_5β = 8.0, 1H, H6), 6.66 (s, 1 H, H2), 6.78 (d, J_5i6 = 8.0 Hz, 1H, H5); δ_c (125 MHz, DMSO-Cf₆) 7.1 , 23.6, 26.9, 55.8, 55.9, 110.1 , 111.3, 118.2, 131.9, 147.9, 148.9, 179.8.

2-(2-(3, 4-dimethoxyphenyl)cyclopropanecarboxamido)benzoic acid (FT111)

A suspension of 2-(3,4-dimethoxyphenyl)cyclopropanecarboxylic acid (96 mg, 0.41 mmol) in CH₂CI₂ (1 mL) was treated with oxalyl chloride (0.14 ml_, 1.6 mmol). The solution was stirred at rt for 1 h and the solvent was removed under reduced pressure to give the acid chloride. Anthranilic acid (0.11 g, 0.82 mmol) was added to a solution of the acid chloride (0.41 mmol) in pyridine (2.0 mL) and the suspension was stirred at rt for 16 h. The solution was acidified with 1 M HCI and the solvent was decanted and discarded. The crude residue was dissolved in EtOAc and the organic phase was extracted into 1 M NaHCO₃ and discarded. The aqueous phase was then acidified with 1 M HCI and extracted with EtOAc. The combined organic fractions were washed with water, brine, dried and concentrated providing 2-(2-(3,4- dimethoxyphenyl)cyclopropanecarboxamido)benzoic acid (65 mg, 46%) as a pale brown solid; mp 159-163 ⁰C; δ_H (500 MHz, DMSO-cfe) 1.39 (m, 1H, CH), 1.48 (m, 1 H, CH), 1.94 (m, 1H, CH), 2.40 (m, 1 H, CH), 3.72 (s, 3H, OCH₃), 3.76 (s, 3H, OCH₃), 6.72 (d, J₅₆ = 8.0, 1H, H6¹), 6.81 (s, 1H, H2"), 6.87 (d, J₅,₆ = 8.0 Hz, 1H, H5¹), 7.13 (t, J₃,₄ = J_4|5 = 7.9 Hz, 1 H, H4), 7.56 (t, J_4,5 = J_5,6 = 7.9 Hz, 1H, H5), 7.97 (d, J₃₄ = 7.9 Hz, 1H, H3), 8.46 (d, J_SA = 7.9 Hz, 1H, H6), 11.58 (s, 1H, NH); δ_c (125 MHz, DMSO-Cf₆) 15.9, 25.2, 27.5, 55.5, 55.6, 110.0, 110.3, 112.0, 117.8, 120.0, 122.5, 131.0, 132.8, 133.6, 140.6, 147.4, 148.8, 169.4, 170.1 ; HRMS (ESI) calculated for C₁₉H₁₉NO₅ [M-H]^" 340.1191 , found 340.1186; v_max 1023, 1140, 1255, 1516, 1671, 2836, 2921, 3326 cm^"1.

2-(3, 4-bis(difluoromethoxy)phenyl)cyclopropanecarboxylic acid

Concentrated sulfuric acid (0.25 mL) was added to a solution of (£)-3,4- dimethoxycinnamic acid (0.50 g, 1.8 mmol) in MeOH (15 mL). The solution was heated to reflux for 16 h, cooled to rt and then quenched with saturated aqueous NaHCO₃. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with water, brine, dried and concentrated providing methyl ester (0.51 g, 97%). A solution of the methyl ester (0.13 g, 0.44 mmol) and Pd(OAc)₂ (5 mg, 0.022 mmol) in CH₂CI₂ (3 ml.) and ether (3 mL) was treated with excess CH₂N₂. The suspension was filtered and the filtrate was concentrated. The crude residue was dissolved in MeOH (5 mL) and treated with 1 M NaOH (5 mL). The mixture was stirred at rt for 16 h and then concentrated under reduced pressure to remove the MeOH. The aqueous phase was washed with 50% EtOAc/petrol, acidified with 1 M HCI and then extracted with EtOAc. The combined organic fractions were washed with water, brine, dried and concentrated providing 2-(3,4-bis(difluoromethoxy)phenyl)cyclopropanecarboxylic acid (0.12 g, 92%) as a colourless oil; δ_H (500 MHz, DMSO-d₆) 1.38 (ddd, J = 5.0, J = 4.0, J = 2.0 Hz, 1 H, CH), 1.69 (ddd, J = 2.0, J = 4.0, J = 2.0 Hz, 1 H, CH), 1.89 (ddd, J = 2.0, J = 4.0, J = 2.0 Hz, 1H, CH), 2.59 (ddd, J = 2.0, J = 4.0, J = 3.0 Hz, 1H, CH), 6.49 (t, J = 73 Hz, 1H, OCHF₂), 6.51 (t, J = 73 Hz, 1 H, OCHF₂), 6.97 (d, J_5β = 8.0, 1 H, H6), 7.01 (s, 1 H, H2), 7.18 (d, J_5β = 8.0 Hz, 1 H, H5); δ_c (125 MHz, DMSO-d₆) 17.4, 24.0, 26.1 , 115.7 (t, J = 261 Hz), 115.7 (t, J = 261 Hz), 120.6, 122.6, 124.4, 138.7, 140.9, 142.4, 179.1.

2-(2-(3, 4-bis(difluoromethoxy)phenyl)cyclopropanecarboxamido)benzoic acid (FT112)

A suspension of 2-(3,4-dimethoxyphenyl)cyclopropanecarboxylic acid (0.12 g, 0.41 mmol) in CH₂CI₂ (5 mL) was treated with oxalyl chloride (0.14 mL, 1.6 mmol). The solution was stirred at rt for 2 h and the solvent was removed under reduced pressure to give the acid chloride. Anthranilic acid (0.11 g, 82 mmol) was added to a solution of the acid chloride (0.41 mmol) in pyridine (2.0 mL) and the suspension was stirred at rt for 16 h. The solution was acidified with 1 M HCI and the resulting precipitate was collected by filtrated. The crude solid was triturated with 75% CH₂CI₂/petrol providing 2-(2-(3,4- bis(difluoromethoxy)phenyl)cyclopropanecarboxamido)benzoic acid (90 mg, 53%) as a colourless solid; mp 177-178 ⁰C; δ_H (500 MHz, DMSO-Cf₆) 1.43 (m, 1H, CH), 1.53 (m, 1 H, CH), 2.09 (m, 1 H, CH), 2.49 (m, 1H, CH), 6.98-7.35 (m, 6H₁ H4, HZ, H5', H6', OCHF₂), 7.57 (t, J₄,5 = J₅,6 = 7.9 Hz, 1 H, H5), 7.96 (d, J₃,₄ = 7.9 Hz, 1 H, H3), 8.42 (d, J₅,₆ = 7.9 Hz, 1 H, H6), 11.31 (s, 1H, NH); δ_c (125 MHz, DMSO-d₆) 16.4, 24.5, 27.7, 116.4 (t, J = 258 Hz), 116.5 (t, J = 258 Hz), 116.9, 118.6, 120.3, 121.3, 122.8, 123.9, 131.0, 133.9, 139.5, 139.9, 140.5, 142.0, 169.4, 169.7; HRMS (ESI) calculated for C₁₉H₁₅F₄NO₅ [M-H]- 412.0814, found 412.0808; v_max 1053, 1143, 1378, 1511 , 1537, 1661 , 3010 cm^"1. (E)-2-[3-(3, 4-Dimethoxyphenyl)-1-oxo-2-propenyl]benzoic acid (FT114)

A solution of 3,4-dimethoxybenzldehyde (0.37 g, 2.2 mmol) and 2-acetylbenzoic acid (0.33 g, 2.0 mmol) was dissolved in MeOH (10 mL) and treated with 50% aqueous KOH (1 mL). The mixture was heated to reflux for 16 h and then concentrated under reduced pressure to remove the MeOH. Water was added and the aqueous phase was acidified with 1 M HCI. The crude product was collected by filtration and recrystallised from EtOH providing (E)-2-[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]benzoic acid (0.45 g, 72%) as a yellow crystalline solid; mp 221-223 ⁰C; δ_H (500 MHz, DMSO-d₆) 3.79 (s, 3H, OCH₃), 3.82 (s, 3H, OCH₃), 6.96 (d, J₅,₆. = 8.0 Hz, 1 H, H5¹), 7.09 (d, J = 17.0 Hz, 1H, CH=CHCO), 7.13 (d, J = 17.0 Hz, 1 H, CH=CHCO), 7.20 (d,

= 8.0 Hz, 1H, H6¹), 7.32 (s, 1 H, H2¹), 7.45 (d, J_3,4 = 8.0 Hz, 1H, H3), 7.60 (t, J₄₅ = J_5β = 8.0 Hz, 1H, H5), 7.67 (t, •AM = As = 8.0 Hz, 1 H, H4), 7.90 (d, J_5β = 8.0 Hz, 1H, H6), 13.10 (br s, 1H, CO₂H); δ_c (125 MHz₁ DMSO-cfc) 55.5, 55.6, 110.5, 111.5, 123.2, 125.1 , 127.0, 127.4, 129.6, 130.3, 131.8, 141.8, 144.6, 149.0, 151.1, 167.5, 195.5; HRMS (ESI) calculated for C₁₈H₁₆O₅ [M+H]⁺ 313.1071, found 313.1071 ; v_max 1138, 1251 , 1584, 1707, 2844, 2913 cm^"1.

(E)-2-[3-Methoxy-4-(difluoromethoxy)phenyl)-1-oxo-2-propenyl]benzoic acid (FT115)

A solution of 3,4-bis(difluoromethoxy)benzaldehyde (0.26 g, 1.1 mmol) and 2- acetylbenzoic acid (0.16 g, 1.0 mmol) was dissolved in MeOH (10 mL) and treated with 50% aqueous KOH (1 mL). The mixture was heated to reflux for 16 h and then concentrated under reduced pressure to remove the MeOH. Water was added and the aqueous phase was acidified with 1 M HCI. The crude product was collected by filtration and recrystallised from CH₂CI₂/petrol providing (£)-2-[3-methoxy-4- (difluoromethoxy)phenyl)-1-oxo-2-propenyl]benzoic acid (40 mg, 11%) as a colourless solid; mp 161-168 .⁰C; δ_H (500 MHz, DMSO-Cf₆) 3.90 (s, 3H, OCH₃), 7.09-7.18 (m, 4H, OCHF₂, CH=CHCO, CH=CHCO, H5¹), 7.46 (d, J₃₄ = 8.0 Hz, 1 H, H3), 7.56-7.62 (m, 3H, H5, H2\ H6'), 7.68 (t, J_3,4 = J_4,5 = 8.0 Hz, 1H, H4), 7.89 (d, J_5,6 = 8.0 Hz, 1H, H6), 13.10 (br s, 1H, CO₂H); δ_c (125 MHz, DMSO-d₆) 56.1 , 113.3, 116.6 (t, J = 256 Hz), 120.1 , 126.1 , 127.2, 127.5, 127.8, 129.6, 129.8, 130.3, 130.7, 131.9, 141.6, 143.0, 152.4, 167.5, 195.3; HRMS (ESI) calculated for C₁₈H₁₄F₂O₅ [M+H]⁺ 349.0882, found 349.0882; v_max 1048, 1114, 1250, 1270, 1590, 1711, 2619, 2942 cm^'1.

(E)-2-[3,4-Bis(difluoromethoxy)phenyl)-1-oxo-2-propenyl]benzoic acid (FT116)

A solution of 3,4-bis(difluoromethoxy)benzaldehyde (0.52 g, 2.2 mmol) and 2- acetylbenzoic acid (0.33 g, 2.0 mmol) was dissolved in MeOH (10 ml_) and treated with 50% aqueous KOH (1 ml_). The mixture was stirred at rt for 16 h and then concentrated under reduced pressure to remove the MeOH. Water was added and the aqueous phase was acidified with 25% AcOH. The crude product was collected by filtration and recrystallised from toluene/petrol providing (£)-2-[3,4-bis(difluoromethoxy)phenyl)-1-oxo- 2-propenyl]benzoic acid (0.31 g, 40%) as a colourless crystalline solid; mp 118-119 ⁰C; 7.18 (d, J = 15.6 Hz, 1H, CH=CHCO), 7.23 (d, J = 15.6 Hz, 1H, CH=CHCO), 7.24 (t, J = 73 Hz, 1H, OCHF₂), 7.26 (t, J = 73 Hz, 1 H, OCHF₂), 7.35 (d, J₅',* = 8.0 Hz, 1H, H5'), 7.45 (d, J_3,4 = 8.0 Hz, 1 H, H3), 7.61-7.71 (m, 3H, H4, H5, H6¹), 7.75 (s, 1H, H2"), 7.91 (d, J_5|6 = 8.0 Hz, 1H, H6), 13.10 (br s, 1 H, CO₂H); δ_c (125 MHz, DMSO-d₆) 55.5, 55.6, 116.2 (t, J = 268 Hz), 116.4 (t, J = 268 Hz)₁ 120.2, 120.6, 126.8, 127.5, 128.4, 129.7, 129.9, 130.2, 132.0, 132.6, 141.4, 141.6, 141.8, 143.0, 167.4, 195.5; HRMS (ESI) calculated for C₁₈H₁₂F₄O₅ [M+H]⁺ 385.0694, found 385.0694; v_max 1072, 1035, 1277, 1667, 1688, 2833, 3011 cm^"1.

(E)-2-[3-Methoxy-4-(propargyloxy)phenyl)-1-oxo-2-propenyl]benzoic acid (FT117)

A solution of 3-methoxy-4-propargyloxybenzaldehyde (0.21 g, 1.1 mmol) and 2- acetylbenzoic acid (0.16 g, 1.0 mmol) was dissolved in MeOH (10 ml.) and treated with 50% aqueous KOH (1 mL). The mixture was stirred at rt for 16 h and then concentrated under reduced pressure to remove the MeOH. Water was added and the aqueous phase was acidified with 25% AcOH. The crude product was collected by filtration and recrystallised from toluene providing (E)-2-[3-Methoxy-4-(propargyloxy)phenyl)-1-oxo-2- propenyl]benzoic acid (0.17 g, 52%) as a colourless crystalline solid; mp 146-147 ⁰C; δ_H (500 MHz, DMSO-Cf₆) 3.67 (t, J = 2.4 Hz, 1 H, C≡CH), 3.90 (s, 3H, OCH₃), 4.93 (d, J = 2.4 Hz, 2H, OCH₂), 7.12 (d, J_{5 ,6}. = 8.0 Hz, 1 H, H5'),7.23 (s, 2H, CH=CHCO, CH=CHCO), 7.31 (dd, J_{5 , 6}. = 8.0 Hz, J_{2 , 6}. = 2.0 Hz), 7.45 (d, J₂₆. = 2.0 Hz, 1H, H2¹), 7.56 (d, J₃,₄ = 8.0 Hz, 1H, H3), 7.70 (t, J₄,₅ = J₅,₆ = 8.0 Hz, 1H, H5), 7.78 (t, J₃,₄ = J₄,₅ = 8.0 Hz, 1 H, H4), 8.00 (d, J₅₆ = 8.0 Hz₁ 1H, H6), 13.12 (br s, 1 H, CO₂H); δ_c (125 MHz, DMSO-cfe) 55.7, 55.9, 78.5, 78.9, 111.0, 113.5, 122.6, 125.6, 127.4, 128.0, 129.6, 129.7, 130.3, 131.9, 141.7, 144.3, 148.7, 149.3, 167.5, 195.5; HRMS (ESI) calculated for C₂₀H₁₆O₅ [M+H]⁺ 337.1070, found 337.1070; v_max 1141, 1253, 1507, 1585, 1701, 2960, 3290 cm^"1.

(E)-2-[4-(3, 4-Dimethoxyphenyl)-2-oxobut-3-enyl]benzoic acid (FT118)

A solution of 3,4-dimethoxybenzldehyde (0.18 g, 1.1 mmol) and 2-(2-oxopropyl)benzoic acid (0.18 g, 2.0 mmol) was dissolved in MeOH (10 mL) and treated with 50% aqueous KOH (1 mL). The mixture was stirred at rt for 16 h and then concentrated under reduced, diluted with water and the solution was was acidified with 25% AcOH. The crude product was collected by filtration and recrystallised from toluene providing (E)-2-[4-(3,4- dimethoxyphenyl)-2-oxobut-3-enyl]benzoic (54 mg, 17%) as a yellow crystalline solid; mp 152-154 ⁰C; δ_H (500 MHz, DMSO-cfe) 3.80 (s, 3H, OCH₃), 3.81 (s, 3H, OCH₃), 4.41 (s, 2H, CH₂), 6.88 (d, J = 16.0 Hz, 1H, CH=CHCO), 7.00 (d, J₅,₆. = 8.0 Hz, 1 H, H5¹), 7.25- 7.30 (m, 2H, H3, H6¹), 7.35 (s, 1 H₁ H2'), 7.37 (t, J₄,₅ = J₅,₆ = 8.0 Hz, 1 H₁ H5), 7.51 (t, J₃,₄ = J₄₅ = 8.0 Hz₁ 1 H₁ H4), 7.51 (d, J = 16.0 Hz, 1H₁ CH=CHCO), 7.90 (d, J_5|6 = 8.0 Hz, 1 H, H6), 12.78 (br s, 1 H, CO₂H); δ_c (125 MHz, DMSO-Cf₆) 46.1, 55.5, 55.6, 110.4, 111.6, 123.0, 124.4, 126.7, 127.2, 130.3, 130.7, 131.7, 132.5, 137.0, 142.0, 149.0, 150.9, 168.2, 196.5; HRMS (ESI) calculated for C₁₉H₁₈O₅ [M+H]⁺ 327.1227, found 327.1227; v_max 1140, 1260, 1510, 1687, 2835, 2933 cm^"1.

(E)-Ethyl 2-(3, 4-bis(difluoromethoxy)phenyl)ethenesulfonate

A solution of 1.6 M nBuLi in hexane (1.6 mL, 2.5 mmol) was added to a cooled solution of ethyl diethylphosphorylmethanesulfonate (0.68 g, 2.6 mmol) in THF (25 mL) at -78 ⁰C.

The solution was stirred at -78 ⁰C for 10 mins, warmed to at 0 ⁰C₁ stirred for 10 mins and then cooled back to -78 ⁰C. A solution of 3,4-bis(difluoromethoxy)benzaldehyde (0.50 g, 2.1 mmol) in THF (5.0 mL) was added to the cooled mixture. The reaction was stirred at - 78 ⁰C for 1 h, warmed to 0 ⁰C and stirred for 16 h. The reaction was quenched with water and the aqueous phase was extracted with EtOAc. The combined organic fractions were washed with water, brine, dried and concentrated. The crude residue was purified by column chromatography, eluting with 20% EtOAc/petrol, to afford (E)-ethyl 2-(3,4- bis(difluoromethoxy)phenyl)ethenesulfonate (0.69 g, 94%) as a colourless oil; δ_H (500 MHz, CDCI₃) 1.41 (t, J = 7.0 Hz, 3H, CH₃), 4.41 (q, J = 7.0 Hz, 2H, CH₂), 6.56 (t, J = 73 Hz, 1H, OCHF₂), 6.58 (t, J = 73 Hz, 1 H, OCHF₂), 6.73 (d, J = 16.0 Hz, 1H, CH=CHCO), 7.32 (d, J_{5 , 6}. = 8.0 Hz, 1H, H5'), 7.39 (d, J₅;_& = 8.0 Hz, 1H, H6¹), 7.42 (s, 1H, H2'), 7.54 (d, J = 16.0 Hz, 1H, CH=CHCO); δ_c (125 MHz, CDCI₃) 14.9, 67.1 , 115.4 (t, J = 255 Hz), 115.5 (t, J = 255 Hz), 122.2, 122.4, 123.1 , 126.9, 130.6, 142.0, 142.4, 144.5.

(E)-2-[3, 4-Bis(difluoromethoxy)phenyl]-N-phenylethenesulfonamide (FT119)

A solution of (E)-ethyl 2-(3,4-bis(difluoromethoxy)phenyl)ethenesulfonate (100 mg, 0.29 mmol) and tetrabutylammonium iodide (160 mg, 0.44 mmol) in acetone (5.0 mL) was heated to reflux for 16 h. The solution was concentrated under reduced pressure and dissolved in CH₂CI₂ (5.0 mL) and triphenylphosphine (300 mg, 1.2 mmol) was added. The solution was cooled to 0 ⁰C and sulfuryl chloride (47 μL, 0.58 mmol) was added to the reaction mixture. The solution was allowed to warm to rt and stirred for 16 h. The solvent was removed under reduced pressure and the crude chloride was purified by column chromatography, eluting with 5-20% EtOAc/petrol, providing the sulfonyl chloride (90 mg, 90%) as a colourless oil. A solution of the sulfonyl chloride (90 mg, 0.26 mmol) in CH₂CI₂ (3.0 mL) was added to a cooled solution of aniline (52 μL, 0.58 mmol) in pyridine (2.0 mL) at 0 ⁰C. The reaction mixture was warmed to rt, stirred for 4 h and acidified with 1 M HCI. The aqueous phase was extracted with CH₂CI₂ and the combined organic fractions were washed with water, brine, dried and concentrated to provide (£)-2-[3,4- bis(difluoromethoxy)phenyl]-N-phenylethenesulfonamide (55 mg, 54%) as a dark purple coloured oil; (δ_H (500 MHz, CDCI₃) 6.55 (t, J = 73 Hz, 1 H, OCHF₂), 6.57 (t, J = 73 Hz, 1 H, OCHF₂), 6.82 (d, J = 16.0 Hz, 1 H, CH=CHCO), 6.93 (s, 1H, NH), 7.20 (t, J_3|4 = J_A,S = 8.0 Hz, 1H, H4), 7.28-7.36(m, 7H, H2, H3, H5, H6, H2'H5\ H6'), 7.43 (d, J = 16.0 Hz, 1 H, CH=CHCO); δ_c (125 MHz, CDCI₃) 115.4 (t, J = 255 Hz), 115.5 (t, J = 255 Hz), 121.1 , 122.0, 122.3, 125.5, 126.0, 126.7, 129.5, 130.9, 136.1 , 140.5, 142.3, 144.1 ; HRMS (ESI) calculated for C₁₆H₁₃F₄NO₄S [M+H]⁺ 392.0574 found 392.0575; v_max 1043, 1136, 1274, 1497, 1599, 3057, 3261 crrT¹.

(E)-Ethyl 2-(3, 4-dimethoxyphenyl)ethenesulfonate

A solution of 1.6 M nBuLi in hexane (1.4 ml_, 2.2 mmol) was added to a cooled solution of ethyl diethylphosphorylmethanesulfonate (0.58 g, 2.2 mmol) in THF (25 mL) at -78 ⁰C. The solution was stirred at -78 ⁰C for 10 mins, warmed to at 0 ⁰C, stirred for 10 mins and then cooled back to -78 ⁰C. A solution of 3,4-dimethoxybenzaldehyde (0.30 g, 1.8 mmol) in THF (5.0 mL) was added to the cooled mixture. The reaction was stirred at -78 ⁰C for 1 h, warmed to 0 ⁰C and stirred for 16 h. The reaction was quenched with water and the aqueous phase was extracted with EtOAc. The combined organic fractions were washed with water, brine, dried and concentrated. The crude residue was purified by column chromatography, eluting with 20% EtOAc/petrol, to afford (£)-ethyl 2-(3,4- dimethoxyphenyl)ethenesulfonate (0.47 g, 96%) as a colourless crystalline solid; δ_H (500 MHz, CDCI₃) 1.40 (t, J = 7.0 Hz, 3H, CH₃), 3.92 (s, 3H, OCH₃), 3.93 (a, 3H, OCH₃), 4.22 (q, J = 7.0 Hz, 2H, CH₂), 6.59 (d, J = 16.0 Hz, 1 H, CH=CHCO), 6.90 (d, J₅-_? = 8.0 Hz, 1H, H5'), 7.00 (s, 1H, H2'), 7.11 (d, J₅- _β- = 8.0 Hz, 1 H, H6'), 7.53 (d, J = 16.0 Hz, 1 H, CH=CHCO); δ_c (125 MHz, CDCI₃) 14.9, 55.9, 56.0, 66.6, 109.9, 111.1, 118.5, 123.3, 124.8, 144.6, 149.4, 152.0.

(E)-2-(2-(3, 4-Dimethoxyphenyl)vinylsulfonamido)benzoic acid (FT120)

A solution of (£)-ethyl 2-(3,4-dimethoxyphenyl)ethenesulfonate (200 mg, 0.73 mmol) and tetrabutylammonium iodide (320 mg, 1.1 mmol) in acetone (10 mL) was heated to reflux for 16 h. The solution was concentrated under reduced pressure and the sodium salt was dissolved in CH₂CI₂ (5.0 mL) and added to a cooled solution of sulfuryl chloride (210 μL, 2.6 mmol) and triphenylphosphine (710 mg, 3.1 mmol) in CH₂CI₂ (5.0 mL) at 0 ⁰C. The solution was allowed to warm to rt and stirred for 16 h. The solvent was removed under reduced pressure and the crude chloride was purified by column chromatography, eluting with 20% EtOAc/petrol, providing the sulfonyl chloride (150 mg, 78%) as a yellow oil. A solution of the sulfonyl chloride (150 mg, 0.57 mmol) in CH₂CI₂ (2.0 mL) was added to a cooled solution of anthranilic acid (160 mg, 1.14 mmol) in pyridine (2.0 mL) at 0 ⁰C. The reaction mixture was warmed to rt, stirred for 16 h and diluted with water. The aqueous phase was ashed with 50% EtOAc/petrol and the organic phase was discarded. The aqueous phase was acidified with 1 M HCI and extracted with CH₂CI₂. The combined organic fractions were washed with water, brine, dried and concentrated. The crude product was recrystallised from CH₂CI₂ to provide (£)-2-(2-(3,4- dimethoxyphenyl)vinylsulfonamido)benzoic acid (30 mg, 14%) as a colourless crystalline solid; mp 194-196 ⁰C; δ_H (400 MHz, CDCI₃) 3.88 (s, 3H, OCH₃), 3.90 (s, 3H, OCH₃), 6.70 (d, J = 16.0 Hz, 1 H, CH=CHCO), 6.84 (d, J₅^ = 8.0 Hz, 1 H, H5'), 6.94 (s, 1H, H2'), 7.05 (d, J₅-V = 8.0 Hz, 1 H, H6¹), 7.11 (t, J₃,₄ = J₄,₅ = 8.0 Hz, 1 H, H4), 7.57 (t, J₄,s = J_Sfi = 8.0 Hz, 1H, H5), 7.58 (d, J = 16.0 Hz, 1H, CH=CHCO), 7.72 (d, J₃₄ = 8.0 Hz, 1 H, H3), 8.10 (d, J_5,6 = 8.0 Hz, 1H, H6), 10.36 (s, 1H, NH); δ_c (100 MHz, CDCI₃) 55.9, 56.0, 109.9, 111.1, 114.0, 117.9, 121.9, 122.6, 123.3, 124.9, 132.3, 135.7, 141.2, 143.5, 149.3, 151.9, 171.5; HRMS (ESI) calculated for C₁₇H₁₇NO₆S [M-H]^" 362.0704, found 362.0699; v_max 1136, 1267, 1513, 1682, 2975, 3277 cm^"1.

Proline Incorporation

A well-characterized cloned rat mesangial cell line [30] (gift of D Nikolic-Patterson) is cultured in DMEM with FBS, 100U/ml_ penicillin, and 100ug/mL streptomycin in a humidified 5% CO₂ atmosphere at 37°C. Cells are plated into 24-well culture dishes in DMEM/10%FBS at low density and allowed to adhere overnight. Cells are used between passages 20 and 40. The subconfluent cells are starved overnight in DMEM/0.1%FBS containing 15OuM L-ascorbic acid, prior to 4 hours of pre-treatment with or without tranilast or the FT compounds, followed by the addition of 5ng/mL ThTGF-P₁I (R&D Systems) and 1uCi/mL of L-(2,3,4,5-³H)-proline. Control wells have the compounds but no TGF-P₁ added. Cells are incubated for a further 44 hours during which time their appearance is visually monitored. The cells are then washed three times in ice-cold PBS, twice in ice cold 10% TCA and solubilized in 75OuL 1M NaOH for 45 minutes at 37⁰C or overnight at 4⁰C. A 50OuL aliquot is neutralized with 50OuL 1M HCI and 1OmL scintillation fluid (Instagel Plus - Perkin-Elmer) added. Counts are performed on a beta counter.

To normalize the praline incorporation counts to take into account the proliferative effects of TGF-βi, a BioRad protein assay is performed on a 100-15OuL aliquot of the remaining solubilized cells. The sample is neutralized with an equal amount of 1 M HCI prior to the assay. The BSA standards used to construct the standard curve have the same amount of 1 M NaOH and 1 M HCI added as is present in the samples for assay.

Proline incorporation is expressed as cpm/ug protein. In order to compare inter-assay results, the incorporation is expressed as percentage reduction of TGF stimulated proline incorporation, where TGF alone gives 0% reduction and the zero control gives 100% reduction.

Mesangial cells

Compounds in bold have minimal effect on cell appearance and viability N. B suppressed MTT result indicates reduced cell viability

Ppt - compound precipitated during the assay.

The details of specific embodiments described in this invention are not to be construed as limitations. Various equivalents and modifications may be made without departing from the essence and scope of this invention, and it is understood that such equivalent embodiments are part of this invention.

Claims

1. A compound of Formula (I)

or a pharmaceutically acceptable drug or prodrug thereof, wherein;

X¹ (YZ) is C=O, C(F₂) Or SO₂;

X^z is NR¹⁰ or (CH₂)_P;

fused to form a cyclopropane ring of the formula

R¹, R⁴' and R⁵ are each independently selected from the group consisting of: H, OH, NO₂, CN, NH₂, optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionally substituted C₁-C₁₂ alkyloxy, optionally substituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂ alkynyloxy, optionally substituted C₁-C₁₀ heteroalkyloxy, optionally substituted C₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂ cycloalkenyloxy, optionally substituted C₁-C₁₂ heterocycloalkyloxy, optionally substituted C₁-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-C₁₈ aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy, optionally substituted C₁-C₁₂ alkylamino, SR¹³, SO₃H₁ SO₂NR¹³R¹⁴, SO₂R¹³, SONR¹³R¹⁴, SOR¹³, COR¹³, COOH, COOR¹³, CONR¹³R¹⁴, NR¹³COR¹⁴, NR¹³COOR¹⁴, NR¹³SO₂R¹⁴, NR¹³CONR¹⁴R¹⁵, NR¹³R¹⁴, and acyl;

R² and R³, are each independently selected from the group consisting of: H, OH, NO₂, CN, NH₂, optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionally substituted C₁-C₁₂ alkyloxy, optionally substituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂ alkynyloxy, optionally substituted C₁-C₁₀ heteroalkyloxy, optionally substituted C₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂ cycloalkenyloxy, optionally substituted C₁-C₁₂ heterocycloalkyloxy, optionally substituted C₁-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-C₁₈ aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy, optionally substituted C₁-C₁₂ alkylamino, SR¹³, SO₃H₁ SO₂NR¹³R¹⁴, SO₂R¹³, SONR¹³R¹⁴, SOR¹³, COR¹³, COOH, COOR¹³, CONR¹³R¹⁴, NR¹³COR¹⁴, NR¹³COOR¹⁴, NR¹³SO₂R¹⁴, NR¹³CONR¹⁴R¹⁵, NR¹³R¹⁴ and acyl; or R² and R³ may be fused to form a 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring each of which may be optionally substituted;

one pair of R⁶ and R⁷ are present when T is a double bond but R⁶ and R⁷ are not present when T is a triple bond, each R⁶ and R⁷ being independently selected from the group consisting of: H, NO₂, CN, optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂- C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionally substituted C₂-C₁₂ heterocycloalkyl, optionally substituted C₂-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈ aryl, optionally substituted C₁-C₁₈ heteroaryl, optionally substituted C₁-C₁₂ alkyloxy, optionally substituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂ alkynyloxy, optionally substituted C₁-C₁₀ heteroalkyloxy, optionally substituted C₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂ cycloalkenyloxy, optionally substituted C₁-C₁₂ heterocycloalkyloxy, optionally substituted C₁-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-C₁₈ aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy, optionally substituted C₁-C₁₂ alkylamino, SR¹³, SO₃H, SO₂NR¹³R¹⁴, SO₂R¹³, SONR¹³R¹⁴, SOR¹³, COR¹⁴, COOH, COOR¹³, CONR¹³R¹⁴, NR¹³COR¹⁴, NR¹³COOR¹⁴, NR¹³SO₂R¹⁴, NR¹³CONR¹⁴R¹⁵, NR¹³R¹⁴, and acyl; R⁸ is selected from the group consisting of H, halogen, OH, NO₂, CN, NH₂, optionally substituted Ci-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionally substituted C₂- C₁₂ alkynyl, optionally substituted C₁-Ci₀ heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionally substituted C₁-C₁₂ alkyloxy, optionally substituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂ alkynyloxy, optionally substituted C₁-C₁₀ heteroalkyloxy, optionally substituted C₃-C₁₂ cycloalkyloxy, optionally substituted C₃-Ci₂ cycloalkenyloxy, optionally substituted Ci-C₁₂ heterocycloalkyloxy, optionally substituted C₁-Ci₂ heterocycloalkenyloxy, optionally substituted C₆-Ci₈ aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy, optionally substituted C₁-C₁₂ alkylamino, SR¹³, SO₃H, SO₂NR¹³R¹⁴, SO₂R¹³, SONR¹³R¹⁴, SOR¹³, COR¹³, COOH, COOR¹³, CONR¹³R¹⁴, NR¹³COR¹⁴, NR¹³COOR¹⁴, NR¹³SO₂R¹⁴, NR¹³CONR¹⁴R¹⁵ and NR¹³R¹⁴ and acyl;

R¹⁰ is selected from the group consisting of H, a N-protecting group, optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionally substituted C₂- C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃- C₁₂cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl, optionally substituted C₁-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, and optionally substituted C_TC^heteroaryl;

R¹¹ and R¹² are independently selected from the group consisting of H, halogen, OH, NO₂, CN, NH₂, optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionally substituted C₂-C₁₂ heterocycloalkyl, optionally substituted C₂-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈ aryl, optionally substituted C₁-C₁₈ heteroaryl, optionally substituted C₁-C₁₂ alkyloxy, optionally substituted C₂-C₁₂ alkenyloxy, optionally substituted C₂-C₁₂ alkynyloxy, optionally substituted Ci-C₁₀ heteroalkyloxy, optionally substituted C₃-C₁₂ cycloalkyloxy, optionally substituted C₃-C₁₂ cycloalkenyloxy, optionally substituted Ci-C₁₂ heterocycloalkyloxy, optionally substituted C₁-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-Ci₈ aryloxy, optionally substituted C₁-C₁₈ heteroaryloxy, optionally substituted C₁-Ci₂ alkylamino, SR¹³, SO₃H, SO₂NR¹³R¹⁴, SO₂R¹³, SONR¹³R¹⁴, SOR¹³, COR¹³, COOH₁ COOR¹³, CONR¹³R¹⁴, NR¹³COR¹⁴, NR¹³COOR¹⁴, NR¹³SO₂R¹⁴, NR¹³CONR¹⁴R¹⁵, NR¹³R¹⁴, and acyl;

each R¹³, R¹⁴, R¹⁵ are each independently selected from the group consisting of H, -OH, optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₁-C₁₀ heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl, optionally substituted C₃-C₁₂ cycloalkenyl, optionally substituted C₁-C₁₂ heterocycloalkyl, optionally substituted C₁-C₁₂ heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, and optionally substituted C^C^heteroaryl;

n is an integer selected from the group consisting of O, 1 , 2, 3, and 4;

m is an integer selected from the group consisting of 1 , 2, 3, and 4;

p is an integer selected from the group consisting of O, 1 , 2, 3, 4, and 5;

R¹⁶ and R¹⁷ may be the same or different and are selected from the group consisting of H, NHR¹³, NR¹³R¹⁴, OR¹³, halogen, C₁ to C₁₀ alkyl, C₃ to C₁₀ cyclokalkyl, C₃ to C₁₀ cycloalkylmethyl, C₃ to C₁₀alkene, C₃ to C₁₀ alkyne, aryl, C₅ to C₂₀ alkaryl, fused C₅ to C₂₀ aryl or alkaryl and a hydrocarbon chain containing a heterocyclic or fused ring, any of which may be optionally substituted; providing that when X¹ (YZ) is C=O, X² is NH and T is a double bond then A has the general formula:

wherein X⁵, X⁶, X⁷ and X⁸ may be independently C₁ S, O or N;

R¹⁸ is absent, H or COOR¹³ and R⁹ can be H when R¹⁸ is COOR¹³, more preferably

COOH; but A cannot be phenyl and R¹ to R⁵ cannot be -CF₃;

and even further providing that when X¹ (YZ) is SO₂, then A has the general formula:

wherein X⁵, X⁶, X⁷and X⁸ may be independently C, S, O or N and R⁹ can be H when R² and R³ are each independently a C₁-C₁₂ alkyloxy group containing at least one halogen atom, and more preferably when R² and R³ are each -OCHF₂.

2. A compound according to claim 1, wherein at least one of R¹, R², R³, R⁴, and R⁵ is selected from the group consisting of a C₁-C₁₂ alkyloxy containing at least one halogen atom, a C₁-C₁₂ alkenyloxy containing at least one halogen atom, and a C₁-C₁₂ alkynyloxy containing at least one halogen atom.

3. A compound according to claim 2, wherein the C₁-C₁₂ alkyloxy group is of Formula (A):

Formula (A)

- wherein: R²⁴, R²⁵, and R²⁶ are each independently selected from the group consisting of: H, halogen, OH, NO₂, CN, NH₂, optionally substituted C₁-C₁₂ alkyl, and optionally substituted C₂-C₁₂ alkenyl; R²⁷, R²⁸, R²⁹, and R³⁰ are each independently selected from the group consisting of: H, halogen, OH, NO₂, CN, and NH₂; - at least one of R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, and R³⁰ is or contains a halogen atom; q is an integer selected from the group consisting of: O, 1 , 2, 3, 4, 5, 6, 7, 8, 9, and 10; and r is an integer selected from the group consisting of: O, 1 , 2, 3, 4, 5, 6, 7, 8, 9, and 10.

4. A compound according to claim 3, wherein q and r are 0, and at least two of R²⁴, R²⁵, and R²⁶ are a halogen.

5. A compound according to any one of claims 1 to 4, wherein the halogen is fluorine.

6. A compound according to claim 1 , wherein at least one of R¹, R², R³, R⁴, and R⁵ is selected from the group consisting Of-O-CHF₂, -0-CF₃ -OCF₂CHF₂.

7. A compound according to any one of claims 1 to 6, wherein T is a double bond.

8. A compound according to any one of claims 1 to 6, wherein T is a triple bond.

9. A compound according to any one of claims 1 to 6, wherein T is a single bond and one pair of R⁶ and R⁷ are fused to form a cyclopropane ring of the formula

10. A compound according to any one of claims 1 to 9, wherein R² and R³ form a bridging difluoromethylenedioxy group or a bridging tetrafluoroethylenedioxy group.

11. A compound according to any one of claims 1 to 10 wherein R⁶ is CH₃.

12. A compound according to any one of claims 1 to 11 wherein R⁷ is CH₃ or CN.

13. A compound according to any one of claims 1 to 12, wherein R⁸ is either H or Me.

14. A compound according to any one of claims 1 to 13 wherein m is 1 and R⁹ is selected from COR¹³ and CONR¹³R¹⁴.

15. A compound according to claim 14 wherein R⁹ is selected from the group consisting of COOH₁ CONH₂, CONHOH and CONHCH₃.

16. A compound according to any one of claims 1 to 13 wherein R⁹ is the group tetrazol-5-yl.

17. A compound according to any one of claims 1 to 13 wherein R⁹ is selected from the group consisting of SO₂R¹³, SO₂NR¹³R¹⁴.

18. A compound according to claim 17 wherein R⁹ is selected from the group consisting of SO₂Me, SO₂NH₂, SO₂NHMe, SO₂NMe₂.

19. A compound according to any one of claims 1 to 13, wherein R⁹ is NR¹³R¹⁴.

20. A compound according to claim 19, wherein R⁹ is NH₂.

21. A compound according to any one of claims 1 to 20, wherein R⁸ is a halogen.

22. A compound according to any one of claims 1 to 21 , wherein X² is NH.

23. A compound having the formula (Ha)

(Ha) or a pharmaceutically acceptable salt or prodrug thereof, wherein; A, R¹, R², R³, R⁴, R⁵, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined in claim 1.

24. A compound having the formula (III)

(III) or a pharmaceutically acceptable salt or prodrug thereof, wherein; A, T, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and X² are as defined in claim 1.

25. A compound of the formula Formula (IV)

(IV) or a pharmaceutically acceptable salt or prodrug thereof, wherein; A, T, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and X² are as defined in claim 1.

26. A compound having the Formula (V)

or a pharmaceutically acceptable salt or prodrug thereof, wherein;

T, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, X¹ (YZ) and X² are as defined in claim 1 and Het represents a heterocyclic ring.

27. A compound of formula (Vl)

(Vl)

or a pharmaceutically acceptable salt or prodrug thereof, wherein; T, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and p are as defined in claim 1.

28. The compound of any one of claims 23 to 27 wherein R⁶ and R⁷ are H.

29. The compound of any one of claims 23 to 28, wherein R¹¹ and R¹² are selected from H, halogen, or CN.

30. The compound of any one of claims 23 to 29 wherein R⁹ is selected from CO₂H, CO₂R¹³, SO₂R¹³, SO₂NH₂, SONHR¹³, SONR¹³ ₂and 5-tetrazolyl.

31. The compound of any one of claims 23 to 30, wherein, R¹ and R⁵ are H and R² and R³ are O-R¹⁶ and O-R¹⁷, wherein R¹⁶ and R¹⁷ are independently and preferably selected form the group consisting of unsubstituted C₁-C₆ alkyl, preferably methyl or ethyl; C₁-C₆ fluoro substituted alkyl, preferably, F₃CO, F₂HCO, F₂HCF₂CO; or are fused to form a 5 or 6 membered ring, preferably a fluoro substituted 1 ,4-dioxane or a fluoro substituted 1 ,3-dioxolane; or a C₁ to C₆ alkenyl, preferably -CH₂CCH.

32. The compound of any one of claims 23 to 31 , wherein A has the general formula selected from the group consisting of

wherein X⁵, X⁶, X⁷and X^B may be independently C, S, O or N.

33. The compound of claim 32, wherein A has the general formula

wherein X⁴, X⁵, X⁶ and X⁷ may be C or N.

34. A compound selected from the group consisting of

R⁹ = NH₂, CONH₂, CONHMe₁ CONHOH

R⁸ = Hydrogen, Halogen

35. A compound selected from the group consisting of

R⁹ = SO₂Me, SO₂NH₂, 5-tetrazolyl R⁹ = NH₂, CONH₂, CONHMe, CONHOH

wherein p is O or 1.

36. A compound selected from the group consisting of

R⁹ = SO₂Me₁ SO₂NH₂, 5-tetrazolyl R⁹ = NH₂, CONH₂, CONHMe, CONHOH

37. A com ound selected from the group consisting of

R⁹ = SO₂Me, SO₂NH₂, 5-tetrazolyl R⁹ = NH₂, CONH₂, CONHMe, CONHOH

R⁹ = SO₂Me, SO₂NH₂, 5-tetrazolyl R⁹ = NH₂, CONH₂, CONHMe, CONHOH

38. A compound selected from the group consisting of

R⁹ = NH₂, CONH₂, CONHMe, CONHOH

R⁹ = SO₂Me, SO₂NH₂, SONHMe, SONMe₂

39. A method for the preparation of a compound of formula (Ma) according to claim 23, the method including

(a) cyclopropanation of a compound of the formula

to obtain a compound of the formula

and

(b) condensing the compound obtained in step (a) with a compound of formula

40. A method for preparing a compound of formula (Na) according to claim 23 including cyclopropanation of a compound of the formula

to obtain a compound of formula

41. A method of preparing a compound of Formula (Ma) according to claim 23 including the steps of (a) reacting a compound of the formula

to obtain an acid chloride of the formula

and

(b) condensing the acid chloride prepared in step (a) with a compound of the formula

42. A method for the preparation of a compound of formula (III) according to claim 24 including the steps of (a) reacting a terminal alkene of the formula

to provide a sulfonyl chloride compound of the formula

and

43. A method for the preparation of a compound of formula (IV) according to claim 25 in which X² is NH that includes the steps of; (a) reacting a terminal alkene of the formula

to provide a compound of formula

and

(b) condensing the compound prepared in step (a) with a compound of the formula

44. A method for the preparation of compounds of formula (IV) according to claim 25 in which X² is CH₂ that includes the steps of

(a) reacting a compound of the formula

to provide a ketone of the formula

and

(b) converting the ketone prepared in step (a) to a compound of the formula

45. A method of preparing a compound of formula (Vl) according to claim 27 where p is 0, including the step of reacting a compound of the formula

with a compound of the formula

to obtain a compound of the formula

46. A method of preparing a compound of formula (Vl) according to claim 27 where p is 1 , including the step of reacting a compound of formula

with a compound of formula

to provide a compound of formula

47. Use of a compound according to any one of claims 1 to 38 for the treatment or prevention of diseases associated with fibrosis.

48. Use of a compound according to any one of claims 1 to 38 in the preparation of a medicament for the treatment or prevention of diseases associated with fibrosis.

49. A compound according to any one of claims 1 to 38 substantially as hereinbefore described with reference to the examples.