WO2010088000A2

WO2010088000A2 - Antifibrotic compounds and uses thereof

Info

Publication number: WO2010088000A2
Application number: PCT/US2010/000287
Authority: WO
Inventors: Itzhak D. Goldberg
Original assignee: Angion Biomedica Corp.
Priority date: 2009-02-02
Filing date: 2010-02-02
Publication date: 2010-08-05
Also published as: WO2010088000A3

Abstract

The present invention provides compounds having formula (I), (II) and (III): F and pharmaceutically acceptable derivatives thereof, as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of any of a number of conditions or diseases involving fibrosis and where anti-fibrotic activity is beneficial.

Description

ANTIFIBROTIC COMPOUNDSAND USES THEREOF

BACKGROUND OF THE INVENTION

[0001] Numerous diseases and conditions responsible for significant morbidity as well as mortality have as an underlying disease mechanism the inappropriate or excessive production of fibrous connective tissue, a process generally known as fibrosis. Such diseases and conditions include fibrotic liver disease, cirrhosis, cardiac fibrosis and lung fibrosis including idiopathic pulmonary fibrosis. In addition to these, numerous other conditions and diseases exhibit a fibrotic component, including but not limited to hepatic ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, heart failure and renal disease including renal fibrosis. These conditions and diseases extract a major toll on the healths of afflicted individuals, and on the health care system. Means to affect the onset or progression of such conditions and diseases would be highly desirable.

SUMMARY OF THE INVENTION

[0002] In one embodiment, a method is provided for the prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutical composition thereof:

(I) or a pharmaceutically acceptable salt or N-oxide thereof, wherein Rl is

R3 is Co-₄ alkyl; and

R4 is hydrogen, one or more hydroxyl groups or optionally substituted alkoxy groups,

In another embodiment, R2 is

In yet another embodiment, R and R3 is hydrogen.

In a further embodiment, R2 is

and R3 is hydrogen and R4 is hydrogen.

[0003] In another embodiment, the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2

is

and the other substituents are as described above for

Formula (I).

[0004] In a further embodiment, the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2 is

; R3 is hydrogen; and the other substituents are as described above for Formula

(I). [0005] In another embodiment, the present invention is directed to a compound represented by

Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2 is

^H ;

R3 is Co^alkyl; and the other substituents are as described above for Formula (I).

[0006] In a further embodiment, the present invention is directed to a compound represented by

^H

R3 is hydrogen; and the other variables are as described above for Formula (I).

[0007] In another embodiment, the present invention is directed to a compound represented by

^{M N}

R3 is Co-.jalkyl; and the other variables are as described above for Formula (I).

[0008] In an embodiment, the present invention is directed to a compound represented by

Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2

is H ^{M N} ;

R3 is hydrogen; and the other variables are as described above for Formula (I).

[0009] In another embodiment, the present invention is also directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition thereof:

(H) or a pharmaceutically acceptable salt or N-oxide thereof, wherein

Rl 1 is aryl, C3_-6cycloalkyl or heterocyclyl, each of which optionally is substituted with 1-6 independent halogen; hydroxy; nitro; amino; acyl; substituted acyl; acylCi_-6 alkylsulfϊnyl; acylCi_-6alkylsulfonyl; acyloxy; Ci.6alkylaminoC]_-6alkyl carbamoyloxy; aryl; cyano; heterocyclyl; C_2-6alkenyl optionally substituted with acyl, substituted acyl, aryl or acyl- substituted aryl; C_2-6alkynyl optionally substituted with amino, acylamino or substituted acylamino; Ci-βalkyl optionally substituted with halogen, amino, Ci_-6alkylamino, acylamino, substituted acylamino, hydroxy, acyloxy, acylCi-_όalkanoyloxy, acyl, substituted acyl, acylC_1-6alkoxyimino, aryl or acyl substituted aryl; Ci-βalkylthio optionally substituted with acyl or substituted acyl; alkoxy optionally substituted with aryl, substituted aryl, hydroxy, acyloxy, amino, lower alkylamino, protected amino, heterocyclyl, acyl substituted pyridyl, substituted acyl substituted pyridyl, halogen, acyl Ci_-6alkylamino, N-protected acylCi-_δalkylamino, N- acylCi-6alkyl-N-lower alkylamino, acyl, substituted acyl, acylamino, substituted acylamino, Ci-oalkylhydrazinocarbonylamino, hydroxyimino, acylC_1-6alkoxyimino, substituted acylCi_-6alkoxyimino, acylCi_-6alkoxy, guanidino or N-protected guanidino; or C_2-6alkenyloxy optionally substituted with acyl or substituted acyl substituents;

R21 is hydrogen; lower alkyl optionally substituted with hydroxy, aryl or acyl; or cyclo(lower)alkyl;

R31 is hydrogen; halogen; hydroxy; acyloxy; substituted acyloxy; Ci-₆alkyl optionally substituted with hvdroxy or C_1-6alkoxy optionally substituted with aryl, amino, protected amino, acyl, hydroxy, cyano or Ci-βalkylthio; nitro; amino; acyl; substituted acyl; or C^cycloalkyloxy;

R41 is hydroxy; halogen; nitro; amino; protected amino; Ci_-6alkylamino; acyloxy; amino C_1-6alkylamino; N-protected aminoCi-όalkylamino; d^alkoxy optionally substituted with hydroxy, aryl, substituted aryl, acyl, substituted acyl, amino, Ci_-6alkylamino, acylamino, substituted acylamino, protected amino, heterocyclyl or guanidino; Ci-_όalkylthio optionally substituted with acyl, substituted acyl, amino, Ci_-6alkylamino, acylamino, substituted acylamino, protected amino, heterocyclyl, hydroxy, Ci_-6alkylsulfonyloxy, arylsulfonyloxy, arCi_-6alkoxy or substituted arCi^alkoxy; Ci.₆alkyl substituted with acyl, substituted acyl, amino, lower alkylamino, acylamino, substituted acylamino, protected amino, heterocyclyl, hydroxy, Ci-βalkylsulfonyloxy or arylsulfonyloxy; C_2-6alkenyl optionally substituted with acyl; C_2-6alkynyl optionally substituted with hydroxy, amino, protected aminoCi_-6alkylsulfonyloxy or arylsulfonyloxy; aminoCi-_όalkylsulfonyl; N-protected aminoC_t-βalkylsulfonyl; Ci-βalkylaminosulfonyl; heterocyclylsulfonyl; aminoCi_-6alkylsulfinyl; N-protected amino Ci-βalkylsulfinyl; piperidyloxy; or N-protected piperidyloxy;

R51 is hydrogen, Ci_-6alkyl, Ci_-6alkoxy or halogen; or together with R41 forms a fused aryl or heteroaryl ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O or S;

A is a single bond, O or NH;

O

Il

O — S—

Il

E is C Ci-βalkylene, C_2-6alkenylene, — U — , ° ; or E is a group of the formula -G-J- in which G is Ci-βalkylene and

R61 _ l _ J is O or ^N , wherein R61 is hydrogen or N-protective group;

X is -CH=CH-, -C=N- or S; and Y is CH or N.

[00010] In one aspect, the present invention is directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is S, and the other substituents are as described above for Formula II.

[00011] In an embodiment of this aspect, the present invention is directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is S; Rl 1 is optionally substituted aryl; and the other substituents are as described above for Formula II.

[00012] In another embodiment of this aspect, the present invention is directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is S; Rl 1 is optionally substituted heterocyclyl; and the other substituents are as described above for Formula II.

[00013] In still another embodiment of this aspect, the present invention is directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is S, Y is N, and the other substituents are as described above for Formula II.

[00014] The present invention is also directed to a method for the prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (III) or a pharmaceutical composition thereof:

(III)

or a pharmaceutically acceptable salt or N-oxide thereof, wherein

Rl 2 is aryl, C₃.₆cycloalkyl or heterocyclyl, each of which optionally is substituted with 1-6 independent halogen; hydroxy; nitro; protected amino, amino; acyl; substituted acyl; acylCi-_δalkylsulfinyl; acyl d-_όalkylsulfonyl; acyloxy; Ci.₆alkylaminoCi-₆alkyl carbamoyloxy; aryl; cyano; heterocyclyl; C₂.₆alkenyl optionally substituted with acyl, substituted acyl, aryl or acyl-substituted aryl; C_2-6alkynyl optionally substituted with amino, acylamino or substituted acylamino; Ci_-6alkyl optionally substituted with halogen, amino, Ci-₆alkylamino, acylamino, substituted acylamino, hydroxy, acyloxy, acyld-_όalkanoyloxy, acyl, substituted acyl, acyl Ci_-6alkoxyimino, aryl or acyl substituted aryl; Ci-₆alkylthio optionally substituted with acyl or substituted acyl; alkoxy optionally substituted with aryl, substituted aryl, hydroxy, acyloxy, amino, lower alkylamino, protected amino, heterocyclyl, acyl substituted pyridyl, substituted acyl substituted pyridyl, halogen, acylQ-ealkylamino, N-protected acylCi-βalkylamino, N- acylC_t-βalkyl-N-lower alkylamino, acyl, substituted acyl, acylamino, substituted acylamino, Ci-ealkylhydrazinocarbonylamino, hydroxyimino, acylCi.₆alkoxyimino, substituted acylCi-δalkoxyimino,

guanidino or N-protected guanidino; or C_2-6alkenyloxy optionally substituted with acyl or substituted acyl substituents;

R22 is hydrogen; Ci-βalkyl optionally substituted with hydroxy, aryl or acyl; or C₃-₆cycloalkyl;

R32 is hydrogen; halogen; hydroxy; acyloxy; substituted acyloxy; optionally substituted with hydroxy or Ci_-6alkoxy; Ci_-6alkoxy optionally substituted with aryl, amino, protected amino, acyl, hydroxy, cyano or Ci_-6alkylthio; nitro; amino; acyl; substituted acyl; or Cs-_όCycloalkyloxy;

Al is a single bond, O, or NH;

O Il <-> Il

El is Ci-₆alkylene, C_2-6alkenylene, — ^ — _} O . or El is a group of the formula -Gl-Jl- in which

O Gl is Ci-βalkylene or — ^ — and

R62 Jl is O or N , wherein R62 is hydrogen or N-protective group;

Xl is -CH=CH-, -C=N- or S; and

Yl is aryl optionally substituted with 1-6 independent acyl, protected aminoCi_-6alkanoyl, protected amino and nitro, amino and nitro or diamino substituents; or Yl is a heterocyclyl optionally substituted with 1-6 halogen, acyl, Ci-ήalkoxy, hydroxy, guanidino, mercapto, acylamino, amino, heterocyclyl, cyanoamino,

Ci-₆alkylamino, Ci.₆alkylamino(Ci.₆alkylamino), substituted heterocyclyl, Ci_-6alkylhydrazino, aryloxy, Q- _δalkylthio, aryl, protected amino, N-protected Ci.6alkylamino(Ci.₆alkyl)amino, N-protected aminoCi-6alkyl(N'- Ci-6alkyl)amino, aminoCi_-6alkyl(N- Ci_-6alkyl)amino, Ci_-6aUcylamino(Ci. ₆alkyl)(N- Ci.₆alkyl)amino, or Ci_-6alkoxy(Ci-₆alkyl)amino substituents, or a Ci_-6alkyl substituent further optionally substituted with aryl, arCi_-6alkoxy, cyano, hydroxyimino, mercapto, Ci- ₆alkylamino, acyloxy, halogen, Ci^alkoxy, protected hydroxy, hydroxy, Ci_-6alkoxyaryl, protected amino, amino, heterocyclyl, or substituted heterocyclyl sub-substituents; provided that when Yl is phenyl optionally substituted with C_halky, or acyl, then Al is a single bond, and O f ² El is -^N- .

[00015] In one aspect, the present invention is directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (III) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is S, and the other substituents are as described above for Formula (III).

[00016] The invention also encompasses a pharmaceutical composition that is comprised of a compound of Formula (I), (II), or (III) in combination with a pharmaceutically acceptable carrier.

[00017] Preferably the composition that is comprised of a pharmaceutically acceptable carrier and non-toxic therapeutically effective amount of a compound of Formula (I), (II) or (III) as described above (or a pharmaceutically acceptable salt or N-oxide thereof).

[00018] Non-limiting examples of compounds useful for the purposes herein include 3-

(((5,7-dimethoxyquinolin-4-yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2- carboxamide; 3-(((5-methoxyquinolin-4-yl)methyl)amino)-N-(4-

(trifluoromethoxy)phenyl)thiophene-2-carboxamide; 3-(((6-ethoxyquinolin-4-yl)methyl)amino)- N-(4-(trifluoromethoxy)phenyl)thiophene-2-carboxamide; 3-(((6-hydroxyquinolin-4- yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2-carboxamide; 3-(((6- isopropoxyquinolin-4-yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2- carboxamide; 3-(((6-methoxyquinolin-4-yl)methyl)amino)-N-(4-

(trifluoromethoxy)phenyl)thiophene-2-carboxamide; 3-(((7-(2-methoxyethoxy)quinolin-4- yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2-carboxamide; 3-(((7- ethoxyquinolin-4-yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2-carboxamide; 3-(((7-hydroxyquinolin-4-yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2- carboxamide; 3-(((7-isopropoxyquinolin-4-yl)methyl)amino)-N-(4- (trifluoromethoxy)phenyl)thiophene-2-carboxamide; 3-(((7-methoxyquinolin-4- yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2-carboxamide; 3-(((7- methoxyquinolin-4-yl)methyl)amino)-N-(4-(trifluoromethyl)pyridin-2-yl)thiophene-2- carboxamide; 3-(((7-methoxyquinolin-4-yl)methyl)amino)-N-(5-(trifluoromethyl)pyridin-3- yl)thiophene-2-carboxamide; N-(5-tert-butyl-lH-pyrazol-3-yl)-3-(((5,7-dimethoxyquinolin-4- yl)methyl)amino)thiophene-2-carboxamide; N-(5-tert-butyl- 1 H-pyrazol-3-yl)-3-(((5- methoxyquinolin-4-yl)methyl)amino)thiophene-2-carboxamide; N-(5-tert-butyl- 1 H-pyrazol-3- yl)-3-(((7-(2-methoxyethoxy)quinolin-4-yl)methyl)amino)thiophene-2-carboxamide; N-(5-tert- butyl-lH-pyrazol-3-yl)-3-(((7-methoxyquinolin-4-yl)methyl)amino)thiophene-2-carboxamide;N-

(6-hydroxypyridin-3-yl)-3-(((7-methoxyquinolin-4-yl)methyl)amino)thiophene-2-carboxamide and N-(isoquinolin-3-yl)-3-(((7-methoxyquinolin-4-yl)methyl)amino)thiophene-2-carboxamide.

[00019] In other non-limiting examples, compounds useful for the purposes herein include

N-(4-trifluoromethoxyphenyl) 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide; N-(4- bromo-3-methylphenyl) 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide; N-(2,2,3,3- tetrafluorobenzodioxan-6-yl) 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide; N-(4- chlorophenyl) 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide; 4- {[2-(4-bromo-3- methylphenylcarbamoyl)thiophen-3-ylamino]methyl}pyridine-2-carboxylic acid methylamide; N-methyl-4-(((2-((2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][l,4]dioxin-6-yl)carbamoyl)thiophen- 3-yl)amino)methyl)picolinamide; 4-{[2-(4-chlorophenylcarbamoyl)thiophen-3- ylamino]methyl}pyridine-2-carboxylic acid methylamide; N-(4-chlorophenyl) 3-[(1H- pyrrolo[2,3-b]pyridin-3-ylmethyl)amino]thiophene-2-carboxamide; 3-(((lH-pyrrolo[2,3- b]pyridin-3-yl)methyl)amino)-N-(4-bromo-3-methylphenyl)thiophene-2-carboxamide; 3-((( 1 H- pyrrolo[2,3-b]pyridin-3-yl)methyl)amino)-N-(2,2,3,3-tetrafluoro-2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)thiophene-2-carboxamide; N-methy l-4-(((2-((4- (trifluoromethoxy)phenyl)carbamoyl)thiophen-3-yl)amino)methyl)picolinamide; 3-(((1H- pyπOlo[2,3-b]pyridin-4-yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2- carboxamide; N-(4-chlorophenyl)-3-[(lH-pyrrolo[2,3-b]pyridin-4-ylmethyl)amino]thiophene-2- carboxamide; 3-(((lH-pyrrolo[2,3-b]pyridin-4-yl)methyl)amino)-N-(2,2,3,3-tetrafluoro-2,3- dihydrobenzo[b][ 1 ,4]dioxin-6-yl)thiophene-2-carboxamide; 4-methyl-N-(4- trifluoromethoxyphenyl)-3-[(quinolin-4- ylmethyl)amino]thiophene-2-carboxamide; N-(4- chlorophenyl)-4-methyl-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide; N-(4-bromo- 3-methylphenyl)-4-methyl-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide; 4-methyl- 3-[(quinolin-4-ylmethyl)amino]-N-(2,2,3,3-tetrafluoro-2,3-dihydro- 1 ,4- benzodioxin-6- yl)thiophene-2-carboxamide; 4-(((2-((4-(trifluoromethoxy)phenyl)carbamoyl)thiophen-3- yl)amino)methyl)quinoline 1 -oxide; 3-(((lH-pyrrolo[2,3-b]pyridin-3-yl)methyl)amino)-N-(4- (trifluoromethoxy)phenyl)thiophene-2-carboxamide; and 3-(pyridin-4-ylmethylamino)-N-(4- (trifluoromethoxy)phenyl)thiophene-2-carboxamide.

[00020] In another embodiment, the aforementioned Formulae and compounds have anti- fibrotic activities and thus are useful for the prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis.

[00021] In certain embodiments, the diseases and conditions benefitted by treatment with an effective amount of a compound mentioned above or pharmaceutical composition thereof include but are not limited to fibrotic liver disease, hepatic ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, cardiac fibrosis, renal disease or lung (pulmonary) fibrosis. In other embodiments, the disease or condition is liver fibrosis associated with hepatitis C, hepatitis B, delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis, extrahepatic obstructions (stones in the bile duct), cholangiopathies (primary biliary cirrhosis and sclerosing cholangitis), autoimmune liver disease, and inherited metabolic disorders (Wilson's disease, hemochromatosis, and alpha- 1 antitrypsin deficiency); damaged and/or ischemic organs, transplants or grafts; ischemia/reperfusion injury; stroke; cerebrovascular disease; myocardial ischemia; atherosclerosis; renal failure; renal fibrosis; scleroderma; systemic sclerosis; dermal fibrosis and idiopathic pulmonary fibrosis. In still further embodiments, the treatment is for wounds for acceleration of healing; reducing post-surgical scarring; reducing adhesion formation; vascularization of a damaged and/or ischemic organ, transplant or graft; amelioration of ischemia/reperfusion injury in the brain, heart, liver, kidney, and other tissues and organs; normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction; development or augmentation of collateral vessel development after vascular occlusion or to ischemic tissues or organs; fibrotic diseases; hepatic disease including fibrosis and cirrhosis; lung fibrosis; radiocontrast nephropathy; fibrosis secondary to renal obstruction; renal trauma and transplantation; renal failure secondary to chronic diabetes and/or hypertension; muscular dystrophy, amyotrophic lateral sclerosis, and/or diabetes mellitus.

BRIEF DESCRIPTION OF THE FIGURES

[00022] The following figures are described in more detail in the examples section below:

Figure 1 A-B show the expression of PDGFRβ in epithelial cell lines, hepatic cells and fibroblasts;

Figure 2 shows that PDGF stimulates lung fibroblast proliferation but not lung epithelial cell proliferation;

Figure 3 shows in the bleomycin-induced lung fibrosis model that lung hydroxyproline content is significantly elevated; Figure 4 shows in the bleomycin-induced lung fibrosis model that phospho-PDGFRβ (Tyr751) , lung hydroxyproline content is elevated compared to sham treated animals;

Figure 5 shows in the bleomycin-induced lung fibrosis model that lung weight is significantly reduced by treatment of animals by a compound of the invention;

Figure 6 shows in the bleomycin-induced lung fibrosis model that interstitial collagen in lung tissue is significantly reduced by treatment with a compound of the invention;

Figure 7 shows in the bleomycin-induced lung fibrosis model that lung hydroxyproline content of lung tissue is significantly reduced by treatment with a compound of the invention;

Figure 8 shows in the bleomycin-induced lung fibrosis model that alpha SMA in lung tissue is significantly reduced by treatment with a compound of the invention;

Figure 9 shows in the bleomycin-induced lung fibrosis model that phospho-PDGFRβ in lung tissue is significantly reduced by treatment with a compound of the invention;

Figure 10 shows that a compound of the invention inhibits both KDR and PDGFR kinase activity;

Figures 11A-B show that a compound of the invention inhibits KDR signaling in endothelial cells (A) and PDGF signaling in hepatic stellate cells (B);

Figures 12A-B show that a compound of the invention significantly reduces liver weight (A) and hydroxyproline content of liver (B) in the TAA- induced liver fibrosis model.

Figures 13A-B show that a compound of the invention significantly reduces alpha SMA (A) and phospho-PDGFRβ expression in liver (B) in the TAA- induced liver fibrosis model.

Figure 14 shows that in the bleomycin-induced scleroderma model, a compound of the invention significantly reduces dermal hydroxyproline content to a level not different that normal;

Figure 15 shows that in the bleomycin-induced scleroderma model, a compound of the invention significantly reduces skin collagen content;

Figure 16 shows that in the bleomycin-induced scleroderma model, a compound of the invention significantly reduces dermal thickness;

Figure 17 A-B show that in the bleomycin-induced scleroderma model, a compound of the invention significantly reduces alphaSMA and phospho-PDGFR in skin.

DEFINITIONS [00023] As used herein, " Co-4alkyl" is used to mean an alkyl having 0-4 carbons - that is,

0. 1, 2, 3, or 4 carbons in a straight or branched configuration. An alkyl having no carbon is hydrogen when the alkyl is a terminal group. An alkyl having no carbon is a direct bond when the alkyl is a bridging (connecting) group.

[00024] As used herein unless otherwise specified, "alkyl", "alchemy", and "alkynyl" includes straight or branched configurations. Lower alkyls, alkenyls, and alkynyls have 1-6 carbons. Higher alkyls, alkenyls, and alkynyls have more than 6 carbons. As used herein unless otherwise specified, the terms "aryl" and "ar" are well known to chemists and include, for example, phenyl and naphthyl, as well as phenyl with one or more short alkyl groups (tolyl, xylyl, mesityl, cumenyl, di(t-butyl)phenyl). Phenyl, naphthyl, tolyl, and xylyl are preferred. "Substituted aryl" is an aryl substituted with suitable substituents such as, for example, acyl, substituted acyl, N-protected piperazinylsulfonyl, piperazinylsulfonyl, N-Ci- ₆alkylpiperazinylsulfonyl, hydroxy

heterocyclyl, halogen, nitro, amino, Q- ₆alkylamino, cyano, or Ci_-6alkoxy,

[00025] As used herein unless otherwise specified, "heterocyclyl" is well known to chemists and contains at least one N, S or O hetero-ring atom, and includes saturated, unsaturated, partially saturated, mono or polycyclic heterocyclic groups such as, for example, pyrrolyl, pyrrolinyl, imidazoylyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, imidazopyridyl, indazolyl, benzotriazolyl, tetrazolo-pyridazinyl, pyranyl, furyl, lH-tetrahydropyranyl, tetrahydrofuranyl, thienyl, oxazolyl, isoxazolyl, oxadiazoyl, oxazolinyl, moφholinyl, benzofuranyl, benzoxazolyl, benzoxadiazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, or benzodioxyl and the like. Such heterocyclyls are optionally substituted with lower alkyl or oxo substituents.

[00026] As used herein unless otherwise specified, "acyl" includes for example, carboxy, esterified carboxy, carbamoyl, lower alkylcarbamoyl, lower alkanoyl, aroyl, heterocyclylcarbonyl, and the like. Esterified carboxy includes substituted or unsubstituted lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t- butoxycarbonyl, hexyloxycarbonyl, 2-iodoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, dimethylaminopropoxycarbonyl, dimethylaminoethoxycarbonyl; substituted or unsubstituted aryloxycarbonyl such as phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl; substituted or unsubstituted ar(lower)alkoxycarbonyl such as benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, 3-methoxy-4- nitrobenzyloxycarbonyl; and N-containing heterocyclyloxycarbonyl such as N- methylpiperidyloxycarbonyl and the like.

[00027] As used herein unless otherwise specified, "halogen" is fluorine, chlorine, bromine or iodine.

[00028] As used herein unless otherwise specified, "Ci_-6alkylhydrazino" may be mono or

2,2-di(Ci-6alkyl)hydrazino such as 2-methylhydrazino, 2,2-dimethylhydrazino, 2-ethylhydrazino, 2,2-diethylhydrazino, or the like.

[00029] As used herein unless otherwise specified, " Ci-ealkylaminoCi-ealkyl" includes, for example, methylaminomethyl, dimethylaminomethyl, dimethylaminoethyl or the like.

[00030] " Ci_-6alkanoyl" includes substituted or unsubstituted alkanoyls such as formyl, acetyl, propionoyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl or the like.

[00031] "Aroyl" includes benzoyl, naphthoyl, toluoyl, di(t-butyl)benzoyl and the like.

[00032] As used herein unless otherwise specified, "N-protective group" in "protected amino", includes substituted or unsubstituted lower alkanyl (such as, for example, formyl, acetyl, propionyl, trifluoroacetyl), phthaloyl, lower alkoxycarbonyl (such as tbutoxycarbonyl, t- amyloxycarbonyl), substituted or unsubstituted aralkyloxycarbonyl (such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl), 9-fluorenylmethoxycarbonyl, substituted or unsubstituted arenesulfonyl(benzenesulfonyl, tosyl). Phthaloyl, t-butoxycarbonyl or 9fluorenylmethoxycarbonyl are preferred.

[00033] As used herein unless otherwise specified, "hydroxyl-protective group' includes substituted or unsubstituted arylmethyl (for example, benzyl, lower alkoxy benzyl), acyl, or substituted silyl (for example, t-butyldiphenylsilyl).

[00034] The above Formulas (I), (II), and (III) are shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formulas (I), (II), and (III) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be mixture of stereoisomers. [00035] The term "aliphatic", as used herein, includes both saturated and unsaturated, straight chain (i.e., unbranched) or branched aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, "aliphatic" is intended herein to include, but is not limited to, alkyl, alkenyl, or alkynyl moieties. Thus, as used herein, the term "alkyl" includes straight and branched alkyl groups. An analogous convention applies to other generic terms such as "alkenyl", "alkynyl" and the like. Furthermore, as used herein, the terms "alkyl", "alkenyl", "alkynyl" and the like encompass both substituted and unsubstiruted groups. In certain embodiments, as used herein, "lower alkyl" is used to indicate those alkyl groups (substituted, unsubstiruted, branched or unbranched) having 1-6 carbon atoms. "Lower alkenyl" and "lower alkynyl" respectively include corresponding 1-6 carbon moieties.

[00036] In certain embodiments, the alkyl, alkenyl and alkynyl groups employed in the invention contain 1-20; 2-20; 3-20; 4-20; 5-20; 6-20; 7-20 or 8-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-10; 2-10; 3-10; 4-10; 5-10; 6-10; 7-10 or 8-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8; 2-8; 3-8; 4-8; 5-8; 6-20 or 7-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-6; 2-6; 3-6; 4-6 or 5-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-4; 2-4 or 3-4 carbon atoms. Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, n-hexyl, sec-hexyl, moieties and the like, which again, may bear one or more substituents. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.

[00037] The term "alicyclic", as used herein, refers to compounds which combine the properties of aliphatic and cyclic compounds and include but are not limited to monocyclic, or polycyclic aliphatic hydrocarbons and bridged cycloalkyl compounds, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, "alicyclic" is intended herein to include, but is not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, which are optionally substituted with one or more functional groups. Illustrative alicyclic groups thus include, but are not limited to, for example, cyclopropyl, -CH₂- cyclopropyl, cyclobutyl, -CH₂-cyclobutyl, cyclopentyl, -CH₂-cyclopentyl, cyclohexyl, -CH₂- cyclohexyl, cyclohexenylethyl, cyclohexanylethyl, norborbyl moieties and the like, which again, may bear one or more substituents.

[00038] The term "alkoxy" or "alkyloxy", as used herein refers to a saturated (i.e., O- alkyl) or unsaturated (i.e., O-alkenyl and O-alkynyl) group attached to the parent molecular moiety through an oxygen atom. In certain embodiments, the alkyl group contains 1-20; 2-20; 3- 20; 4-20; 5-20; 6-20; 7-20 or 8-20 aliphatic carbon atoms. In certain other embodiments, the alkyl group contains 1-10; 2-10; 3-10; 4-10; 5-10; 6-10; 7-10 or 8-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8; 2-8; 3-8; 4-8; 5-8; 6-20 or 7-8 aliphatic carbon atoms. In still other embodiments, the alkyl group contains 1-6; 2-6; 3-6; 4-6 or 5-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains 1-4; 2-4 or 3-4 aliphatic carbon atoms. In a different embodiment the alkoxy group is optionally substituted with halogen, hydroxyl, O-alkyl, NO₂, NH₂, NH-alkyl, N- dialkyl, thioalkyl. Examples of alkoxy, include but are not limited to, methoxy, methoxyethanol, ethoxy, ethoxymethoxy, propoxy, isopropoxy, n-butoxy, /-butoxy, sec-butoxy, tert-butoxy, neopentoxy, n-hexoxy, and the like.

[00039] The term "thioalkyl" as used herein refers to a saturated (i.e., S-alkyl) or unsaturated (i.e., S-alkenyl and S-alkynyl) group attached to the parent molecular moiety through a sulfur atom. In certain embodiments, the alkyl group contains 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl group contains 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl group contains 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains 1-4 aliphatic carbon atoms. Examples of thioalkyl include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.

[00040] The term "alkylamino" refers to a group having the structure -NHR' wherein R' is aliphatic or alicyclic, as defined herein. The term "aminoalkyl" refers to a group having the structure NH₂R'-, wherein R' is aliphatic or alicyclic, as defined herein. In certain embodiments, the aliphatic or alicyclic group contains 1-20 aliphatic carbon atoms. In certain other embodiments, the aliphatic or alicyclic group contains 1-10 aliphatic carbon atoms. In still other embodiments, the aliphatic or alicyclic group contains 1-6 aliphatic carbon atoms. In yet other embodiments, the aliphatic or alicyclic group contains 1-4 aliphatic carbon atoms. In yet other embodiments, R' is an alkyl, alkenyl, or alkynyl group containing 1-8 aliphatic carbon atoms. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, iso- propylamino and the like.

[00041] Some examples of substituents of the above-described aliphatic (and other) moieties of compounds of the invention include, but are not limited to aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO₂; -CN; -CF₃; -CH₂CF₃; -CHCl₂; -CH₂OH; -CH₂CH₂OH; -CH₂NH₂; -CH₂SO₂CH₃; -C(O)R_x; -CO₂(R_x); -C(=0)N(Rχ)₂; -OC(=O)R_X; -OCO₂R_x; -0C(=0)N(R_x)₂; -N(R_x)₂; -OR_x; -SR_x; -S(O)R_x; -S(O)₂R_x; -NR_x(CO)R_x; -N(R_x)CO₂R_x; -N(R_x)S(O)₂R_x; -N(R_X)C(=O)N(R_X)₂; -S(O)₂N(R_X)₂; wherein each occurrence of R_x independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, saturated or unsaturated, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[00042] In general, the term "aromatic moiety", as used herein, refers to a stable mono- or polycyclic, unsaturated moiety having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted. In certain embodiments, the term "aromatic moiety" refers to a planar ring having p-orbitals perpendicular to the plane of the ring at each ring atom and satisfying the Huckel rule where the number of pi electrons in the ring is (4n+2) wherein n is an integer. A mono- or polycyclic, unsaturated moiety that does not satisfy one or all of these criteria for aromaticity is defined herein as "non-aromatic", and is encompassed by the term "alicyclic".

[00043] In general, the term "heteroaromatic moiety", as used herein, refers to a stable mono- or polycyclic, unsaturated moiety having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted; and comprising at least one heteroatom selected from O, S and N within the ring (i.e., in place of a ring carbon atom). In certain embodiments, the term "heteroaromatic moiety" refers to a planar ring comprising at least one heteroatom, having p- orbitals perpendicular to the plane of the ring at each ring atom, and satisfying the Huckel rule where the number of pi electrons in the ring is (4n+2) wherein n is an integer. [00044] It will also be appreciated that aromatic and heteroaromatic moieties, as defined herein may be attached via an alkyl or heteroalkyl moiety and thus also include -(alkyl)aromatic, -(heteroalkyl)aromatic, -(heteroalkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic moieties. Thus, as used herein, the phrases "aromatic or heteroaromatic moieties" and "aromatic, heteroaromatic, -(alkyl)aromatic, -(heteroalkyl)aromatic, -(heteroalkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic" are interchangeable. Substituents include, but are not limited to, any of the previously mentioned substituents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.

[00045] The term "aryl", as used herein, does not differ significantly from the common meaning of the term in the art, and refers to an unsaturated cyclic moiety comprising at least one aromatic ring. In certain embodiments, "aryl" refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Aryl rings of 6-10 members are embodied herein.

[00046] The term "heteroaryl", as used herein, does not differ significantly from the common meaning of the term in the art, and refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, and the like.

[00047] It will be appreciated that aryl and heteroaryl groups (including bicyclic aryl groups) can be unsubstituted or substituted, wherein substitution includes replacement of one or more of the hydrogen atoms thereon independently with any one or more of the following moieties including, but not limited to: aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO₂; -CN; -CF₃; -CH₂CF₃; -CHCl₂; CH₂OH; -CH₂CH₂OH; -CH₂NH₂; -CH₂SO₂CH₃; -C(=O)R_X; -CO₂(R_x); -C(=O)N(R_X)₂; -OC(=O)R_X; -OCO₂R_x; -OC(=O)N(R_X)₂; -N(R_X)₂; -OR_x; -SR_x; -S(O)R_x; -S(O)₂R_x; -NR_x(CO)R_x; -N(R_x)CO₂R_x; -N(R_x)S(O)₂R_x; -N(R_X)C(=O)N(R_X)₂; -S(O)₂N(R_X)₂; wherein each occurrence of R_x independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, saturated or unsaturated, and wherein any of the aromatic, heteroaromatic, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl substituents described above and herein may be substituted or unsubstituted. Additionally, it will be appreciated, that any two adjacent groups taken together may represent a 4, 5, 6, or 7-membered substituted or unsubstituted alicyclic or heterocyclic moiety. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[00048] The term "cycloalkyl", as used herein, refers specifically to groups having three to seven, preferably three to ten carbon atoms. Suitable cycloalkyls include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the case of aliphatic, alicyclic, heteroaliphatic or heterocyclic moieties, may optionally be substituted with substituents including, but not limited to aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO₂; -CN; -CF₃; -CH₂CF₃; -CHCl₂; -CH₂OH; -CH₂CH₂OH; -CH₂NH₂; -CH₂SO₂CH₃; -C(=O)R_X; -CO₂(R_x); -C(=O)N(R_X)₂; -OC(=O)R_X; -OCO₂R_x; -OC(=O)N(R_X)₂; -N(Rx)₂; -OR_x; -SR_x; -S(O)R_x; -S(O)₂R_x; -NR_x(CO)R_x; -N(R_x)CO₂R_x; -N(R_x)S(O)₂R_x; -N(R_X)C(=O)N(R_X)₂; -S(O)₂N(R_X)₂; wherein each occurrence of R_x independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, saturated or unsaturated, and wherein any of the aromatic, heteroaromatic, aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[00049] The term "heteroaliphatic", as used herein, refers to aliphatic moieties in which one or more carbon atoms in the main chain have been substituted with a heteroatom. Thus, a heteroaliphatic group refers to an aliphatic chain which contains one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms, e.g., in place of carbon atoms. Heteroaliphatic moieties may be linear or branched, and saturated or unsaturated. In certain embodiments, heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more moieties including, but not limited to aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO₂; -CN; -CF₃; -CH₂CF₃; -CHCl₂; -CH₂OH; -CH₂CH₂OH; -CH₂NH₂; -CH₂SO₂CH₃; -C(=O)R_X; -CO₂(R_x); -C(=O)N(R_X)₂; -OC(O)R_x; -OCO₂R_x; -0C(=0)N(R_x)₂; -N(R_X)₂; -OR_x; -SR_x; -S(O)R_x; -S(O)₂R_x; -NR_x(CO)R_x; -N(R_x)CO₂R_x; -N(R_x)S(O)₂R_x; -N(R_x)C(=0)N(R_x)₂; -S(O)₂N(R_X)₂; wherein each occurrence of R_x independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, saturated or unsaturated, and wherein any of the aromatic, heteroaromatic, aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[00050] The term "heterocycloalkyl", "heterocycle" or "heterocyclic", as used herein, refers to compounds which combine the properties of heteroaliphatic and cyclic compounds and include, but are not limited to, saturated and unsaturated mono- or polycyclic cyclic ring systems having 5-16 atoms wherein at least one ring atom is a heteroatom selected from O, S and N (wherein the nitrogen and sulfur heteroatoms may be optionally be oxidized), wherein the ring systems are optionally substituted with one or more functional groups, as defined herein. In certain embodiments, the term "heterocycloalkyl", "heterocycle" or "heterocyclic" refers to a non-aromatic 5, 6, 7, 8, 9 or 10-membered ring or a polycyclic group wherein at least one ring atom is a heteroatom selected from O, S and N (wherein the nitrogen and sulfur heteroatoms may be optionally be oxidized), including, but not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has O to 2 double bonds, each 6-membered ring has O to 2 double bonds and each 7-membered ring has O to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring. Representative heterocycles include, but are not limited to, heterocycles such as furanyl, thiofuranyl, pyranyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, dioxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, triazolyl, thiatriazolyl, oxatriazolyl, thiadiazolyl, oxadiazolyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, dithiazolyl, dithiazolidinyl, tetrahydrofuryl, and benzofused derivatives thereof. In certain embodiments, a "substituted heterocycle, or heterocycloalkyl or heterocyclic" group is utilized and as used herein, refers to a heterocycle, or heterocycloalkyl or heterocyclic group, as defined above, substituted by the independent replacement of one, two or three of the hydrogen atoms thereon with but are not limited to aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO₂; -CN; -CF₃; -CH₂CF₃; -CHCl₂; -CH₂OH; -CH₂CH₂OH; -CH₂NH₂; -CH₂SO₂CH₃; -C(=O)R_X; -CO₂(R_x); -C(=O)N(R_X)₂; -0C(=0)R_x; -OCO₂R_x; -0C(=0)N(R_x)₂; -N(Rx)₂; -OR_x; -SR_x; -S(O)R_x; -S(O)₂R_x; -NR_x(CO)R_x; -N(R_x)CO₂R_x; -N(R_x)S(O)₂R_x; -N(R_X)C(=O)N(R_X)₂; -S(O)₂N(R_X)₂; wherein each occurrence of R_x independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, saturated or unsaturated, and wherein any of the aromatic, heteroaromatic, aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted.

[00051] Additionally, it will be appreciated that any of the alicyclic or heterocyclic moieties described above and herein may comprise an aryl or heteroaryl moiety fused thereto. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[00052] The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.

[00053] The term "haloalkyl" denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.

[00054] The term "amino", as used herein, refers to a primary (-NH₂), secondary (-NHR_x), tertiary (-NR_xR_y) or quaternary (-N⁺R_xR_yR₂) amine, where R_x, R_y and R_z are independently an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, as defined herein. Examples of amino groups include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, iso-propylamino, piperidino, trimethylamino, and propylamino.

[00055] The term "acyl", as used herein, refers to a group having the general formula -

C(=O)R, where R is an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, as defined herein.

[00056] The term "C_2-6alkenylidene", as used herein, refers to a substituted or unsubstituted, linear or branched unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to six carbon atoms, having a free valence "-" at both ends of the radical, and wherein the unsaturation is present only as double bonds and wherein a double bond can exist between the first carbon of the chain and the rest of the molecule.

[00057] As used herein, the terms "aliphatic", "heteroaliphatic", "alkyl", "alkenyl",

"alkynyl", "heteroalkyl", "heteroalkenyl", "heteroalkynyl", and the like encompass substituted and unsubstituted, saturated and unsaturated, and linear and branched groups. Similarly, the terms "alicyclic", "heterocyclic", "heterocycloalkyl", "heterocycle" and the like encompass substituted and unsubstituted, and saturated and unsaturated groups. Additionally, the terms "cycloalkyl", "cycloalkenyl", "cycloalkynyl", "heterocycloalkyl", "heterocycloalkenyl", "heterocycloalkynyl", "aromatic", "heteroaromatic", "aryl", "heteroaryl" and the like encompass both substituted and unsubstituted groups.

[00058] The phrase, "pharmaceutically acceptable derivative", as used herein, denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof. Pharmaceutically acceptable derivatives thus include among others pro-drugs. A pro-drug is a derivative of a compound, usually with significantly reduced pharmacological activity, which contains an additional moiety, which is susceptible to removal in vivo yielding the parent molecule as the pharmacologically active species. An example of a pro-drug is an ester, which is cleaved in vivo to yield a compound of interest. Another example is an N-methyl derivative of a compound, which is susceptible to oxidative metabolism resulting in N-demethylation, particularly on the 1 position of the 3(5)-monosubstituted pyrazole derivatives of the invention. Pro-drugs of a variety of compounds, and materials and methods for derivatizing the parent compounds to create the pro-drugs, are known and may be adapted to the present invention. Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in more detail herein below. [00059] The term "tautomerization" refers to the phenomenon wherein a proton of one atom of a molecule shifts to another atom. See, Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pages 69-74 (1992). The term "tautomer" as used herein, refers to the compounds produced by the proton shift. Thus, the present invention encompasses the tautomeric moieties like parasols, pyridones and enols, etc.

[00060] The term "geometrical isomers" refers to cis-trans isomerism, syn-anti or E/Z isomerism based on the Cahn-Ingold-Prelog system. See March's Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Sixth Edition, Wiley-Interscience, pages 182-195 (2007). The term "geometrical isomers" as used herein, refers to compounds having double bond with an E or Z configuration or cis-trans isomers of monocyclic or fused ring systems.

[00061] By the term "protecting group", as used herein, it is meant that a particular functional moiety, e.g., O, S, or N, is temporarily blocked so that a reaction can be carried out selectively at another reactive site in a multifunctional compound. In preferred embodiments, a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; the protecting group must be selectively removed in good yield by readily available, preferably nontoxic reagents that do not attack the other functional groups; the protecting group forms an easily separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group has a minimum of additional functionality to avoid further sites of reaction. As detailed herein, oxygen, sulfur, nitrogen and carbon protecting groups may be utilized. For example, in certain embodiments, as detailed herein, certain exemplary oxygen protecting groups are utilized. These oxygen protecting groups include, but are not limited to methyl ethers, substituted methyl ethers (e.g., MOM (methoxymethyl ether), MTM (methylthiomethyl ether), BOM (benzyloxymethyl ether), PMBM or MPM (p- methoxybenzyloxymethyl ether), to name a few), substituted ethyl ethers, substituted benzyl ethers, silyl ethers (e.g., TMS (trimethylsilyl ether), TES (triethylsilylether), TIPS (triisopropylsilyl ether), TBDMS (t-butyldimethylsilyl ether), tribenzyl silyl ether, TBDPS (t- butyldiphenyl silyl ether), to name a few), esters (e.g., formate, acetate, benzoate (Bz), trifluoroacetate, dichloroacetate, to name a few), carbonates, cyclic acetals and ketals. In certain other exemplary embodiments, nitrogen protecting groups are utilized. These nitrogen protecting groups include, but are not limited to, carbamates (including methyl, ethyl and substituted ethyl carbamates (e.g., Troc), to name a few) amides, cyclic imide derivatives, N- Alkyl and N-Aryl amines, imine derivatives, and enamine derivatives, to name a few. Certain other exemplary protecting groups are detailed herein, however, it will be appreciated that the present invention is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can be readily identified using the above criteria and utilized in the present invention. Additionally, a variety of protecting groups are described in "Protective Groups in Organic Synthesis" Third Ed. Greene, T.W. and Wuts, P.G., Eds., John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.

[00062] As used herein, the term "isolated" when applied to the compounds of the present invention, refers to such compounds that are (i) separated from at least some components with which they are associated in nature or when they are made and/or (ii) produced, prepared or manufactured by the hand of man.

[00063] As used herein the term "biological sample" includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from an animal (e.g., mammal) or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof; or purified versions thereof. For example, the term "biological sample" refers to any solid or fluid sample obtained from, excreted by or secreted by any living organism, including single-celled micro-organisms (such as bacteria and yeasts) and multicellular organisms (such as plants and animals, for instance a vertebrate or a mammal, and in particular a healthy or apparently healthy human subject or a human patient affected by a condition or disease to be diagnosed or investigated). The biological sample can be in any form, including a solid material such as a tissue, cells, a cell pellet, a cell extract, cell homogenates, or cell fractions; or a biopsy, or a biological fluid. The biological fluid may be obtained from any site (e.g. blood, saliva (or a mouth wash containing buccal cells), tears, plasma, serum, urine, bile, seminal fluid, cerebrospinal fluid, amniotic fluid, peritoneal fluid, and pleural fluid, or cells therefrom, aqueous or vitreous humor, or any bodily secretion), a transudate, an exudate (e.g. fluid obtained from an abscess or any other site of infection or inflammation), or fluid obtained from a joint (e.g. a normal joint or a joint affected by disease such as rheumatoid arthritis, osteoarthritis, gout or septic arthritis). The biological sample can be obtained from any organ or tissue (including a biopsy or autopsy specimen) or may comprise cells (whether primary cells or cultured cells) or medium conditioned by any cell, tissue or organ. Biological samples may also include sections of tissues such as frozen sections taken for histological purposes. Biological samples also include mixtures of biological molecules including proteins, lipids, carbohydrates and nucleic acids generated by partial or complete fractionation of cell or tissue homogenates. Although the sample is preferably taken from a human subject, biological samples may be from any animal, plant, bacteria, virus, yeast, etc. The term animal, as used herein, refers to humans as well as non-human animals, at any stage of development, including, for example, mammals, birds, reptiles, amphibians, fish, worms and single cells. Cell cultures and live tissue samples are considered to be pluralities of animals. In certain exemplary embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig). An animal may be a transgenic animal or a human clone. If desired, the biological sample may be subjected to preliminary processing, including preliminary separation techniques.

DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS

OF THE INVENTION

[00064] Numerous diseases and conditions responsible for significant morbidity as well as mortality have as an underlying disease mechanism the inappropriate or excessive production of fibrous connective tissue, a process generally known as fibrosis. Such diseases and conditions include fibrotic liver disease, cirrhosis, cardiac fibrosis and lung fibrosis including idiopathic pulmonary fibrosis. In addition to these, numerous other conditions and diseases exhibit a fibrotic component, including but not limited to hepatic ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, heart failure and renal disease including renal fibrosis.

[00065] More specifically, hepatic diseases and conditions include liver fibrosis associated with hepatitis C, hepatitis B, delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis, extrahepatic obstructions (stones in the bile duct), cholangiopathies (primary biliary cirrhosis and sclerosing cholangitis), autoimmune liver disease, and inherited metabolic disorders (Wilson's disease, hemochromatosis, and alpha- 1 antitrypsin deficiency). Other conditions and diseases with a fibrotic component include damaged and/or ischemic organs, transplants or grafts; ischemia/reperfusion injury; stroke; cerebrovascular disease; myocardial ischemia; atherosclerosis; and renal failure.

[00066] Furthermore, anti-fibrotic compounds are useful for the treatment of wounds for acceleration of healing; reducing post-surgical scarring; reducing adhesion formation; vascularization of a damaged and/or ischemic organ, transplant or graft; amelioration of ischemia/reperfusion injury in the brain, heart, liver, kidney, and other tissues and organs; normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction; development or augmentation of collateral vessel development after vascular occlusion or to ischemic tissues or organs; fibrotic diseases; hepatic disease including fibrosis and cirrhosis; lung fibrosis; radiocontrast nephropathy; fibrosis secondary to renal obstruction; renal trauma and transplantation; renal failure secondary to chronic diabetes and/or hypertension; muscular dystrophy; amyotrophic lateral sclerosis; scleroderma, systemic sclerosis and dermal fibrosis; and/or diabetes mellitus.

[00067] Thus, in one embodiment, a method is provided for the prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutical composition thereof:

(I) or a pharmaceutically acceptable salt or N-oxide thereof, wherein Rl is

R2 is

R3 is Co-4 alkyl; and

In another embodiment, R2 is

In yet another embodiment, R2 and R3 is hydrogen.

In a further embodiment, R2 is

and R3 is hydrogen and R4 is hydrogen.

[00068] In another embodiment, the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2

is

and the other substituents are as described above for

Formula (I).

[00069] In a further embodiment, the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2

is

; R3 is hydrogen; and the other substituents are as described above for

Formula (I).

[00070] In another embodiment, the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2

is

and the other substituents are as described above for Formula (I).

[00071] In a further embodiment, the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2

is

; R3 is hydrogen; and the other variables are as described above for Formula (I). [00072] In another embodiment, the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2

is

and the other variables are as described above for Formula (I).

[00073] In an embodiment, the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R2

is

; R3 is hydrogen; and the other variables are as described above for Formula (I).

[00074] In another embodiment, the present invention is also directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition thereof:

(H)

or a pharmaceutically acceptable salt or N-oxide thereof, wherein

Rl 1 is aryl, C_3-6cycloalkyl or heterocyclyl, each of which optionally is substituted with 1-6 independent halogen; hydroxy; nitro; amino; acyl; substituted acyl; acylCi-₆ alkylsulfinyl; acylCi-₆alkylsulfonyl; acyloxy; Ci-βalkylaminoCi-ealkyl carbamoyloxy; aryl; cyano; heterocyclyl; C_2-6alkenyl optionally substituted with acyl, substituted acyl, aryl or acyl- substituted aryl; C_2-6alkynyl optionally substituted with amino, acylamino or substituted acylamino; Ci-₆alkyl optionally substituted with halogen, amino, Ci-βaUcylamino, acylamino, substituted acylamino, hydroxy, acyloxy,

acyl, substituted acyl, acylCi-_δalkoxyimino, aryl or acyl substituted aryl; Ci_-6alkylthio optionally substituted with acyl or substituted acyl; alkoxy optionally substituted with aryl, substituted aryl, hydroxy, acyloxy, amino, lower alkylamino, protected amino, heterocyclyl, acyl substituted pyridyl, substituted acyl substituted pyridyl, halogen, acyl Ci_-6alkylamino, N-protected acylCi._όalkylamino, N- acylCi-βalkyl-N-lower alkylamino, acyl, substituted acyl, acylamino, substituted acylamino, Ci-₆alkylhydrazinocarbonylamino, hydroxyimino, acylCi-βalkoxyimino, substituted acylCi-₆alkoxyimino, acylCi-βalkoxy, guanidino or N-protected guanidino; or C_2-6alkenyloxy optionally substituted with acyl or substituted acyl substituents;

R31 is hydrogen; halogen; hydroxy; acyloxy; substituted acyloxy; Ci_-6alkyl optionally substituted with hydroxy or Ci-βalkoxy optionally substituted with aryl, amino, protected amino, acyl, hydroxy, cyano or Ci_-6alkylthio; nitro; amino; acyl; substituted acyl; or C_3-6cycloalkyloxy;

R41 is hydroxy; halogen; nitro; amino; protected amino; Ci_-6alkylamino; acyloxy; amino Ci-₆alkylamino; N-protected aminoCi-_όalkylamino;

optionally substituted with hydroxy, aryl, substituted aryl, acyl, substituted acyl, amino, Ci_-6alkylamino, acylamino, substituted acylamino, protected amino, heterocyclyl or guanidino; d-_δalkylthio optionally substituted with acyl, substituted acyl, amino, Ci-βalkylamino, acylamino, substituted acylamino, protected amino, heterocyclyl, hydroxy, Ci.₆alkylsulfonyloxy, arylsulfonyloxy, arCi-βalkoxy or substituted arC_1-6alkoxy; Ci_-6alkyl substituted with acyl, substituted acyl, amino, lower alkylamino, acylamino, substituted acylamino, protected amino, heterocyclyl, hydroxy, Ci_-6alkylsulfonyloxy or arylsulfonyloxy; C_2-6alkenyl optionally substituted with acyl; C_2-6alkynyl optionally substituted with hydroxy, amino, protected aminoCi.₆alkylsulfonyloxy or arylsulfonyloxy; aminoCi_-6alkylsulfonyl; N-protected aminoCi_-6alkylsulfonyl; Ci-βalkylaminosulfonyl; heterocyclylsulfonyl; aminoCi.₆alkylsulfinyl; N-protected amino

piperidyloxy; or N-protected piperidyloxy;

A is a single bond, O or NH;

O Il o -s-

E is C Ci_-6alkylene, C_2-6alkenylene, — U — , ° ; or E is a group of the formula -G-J- in which G is C].6alkylene and R61

I J is O or ^N , wherein R61 is hydrogen or N-protective group;

X is -CH=CH-, -C=N- or S; and

Y is CH or N.

[00075] Compounds of Formula (II) are described in U.S. Patent No. 6,054,457.

[00076] In one aspect, the present invention is directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is S, and the other substituents are as described above for Formula II.

[00077] In an embodiment of this aspect, the present invention is directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is S; Rl 1 is optionally substituted aryl; and the other substituents are as described above for Formula II.

[00078] In another embodiment of this aspect, the present invention is directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is S; Rl 1 is optionally substituted heterocyclyl; and the other substituents are as described above for Formula II.

[00079] In still another embodiment of this aspect, the present invention is directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is S, Y is N, and the other substituents are as described above for Formula II. [00080] The present invention is also directed to a method for the prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (III) or a pharmaceutical composition thereof:

(III)

or a pharmaceutically acceptable salt or N-oxide thereof, wherein

Rl 2 is aryl, C_3-6cycloalkyl or heterocyclyl, each of which optionally is substituted with 1-6 independent halogen; hydroxy; nitro; protected amino, amino; acyl; substituted acyl; acylCi.6alkylsulfinyl; acyl Ci.6alkylsulfonyl; acyloxy; Ci-ealkylaminoCi-βalkyl carbamoyloxy; aryl; cyano; heterocyclyl; C_2-6alkenyl optionally substituted with acyl, substituted acyl, aryl or acyl-substituted aryl; C_2-6alkynyl optionally substituted with amino, acylamino or substituted acylamino; Ci_-6alkyl optionally substituted with halogen, amino, Ci_-6alkylamino, acylamino, substituted acylamino, hydroxy, acyloxy, acylCi_₆alkanoyloxy, acyl, substituted acyl, acyl Ci_-6alkoxyimino, aryl or acyl substituted aryl; Ci.₆alkylthio optionally substituted with acyl or substituted acyl; alkoxy optionally substituted with aryl, substituted aryl, hydroxy, acyloxy, amino, lower alkylamino, protected amino, heterocyclyl, acyl substituted pyridyl, substituted acyl substituted pyridyl, halogen, acylCi-βalkylamino, N-protected acylCi-βalkylamino, N- acylCi_-6alkyl-N-lower alkylamino, acyl, substituted acyl, acylamino, substituted acylamino, Ci.₆alkylhydrazinocarbonylamino, hydroxyimino, acylCi-βalkoxyimino, substituted acylCi_-6alkoxyimino, acylC_1-6alkoxy, guanidino or N-protected guanidino; or C_2-6alkenyloxy optionally substituted with acyl or substituted acyl substituents;

R22 is hydrogen; Q^alkyl optionally substituted with hydroxy, aryl or acyl; or C_3-6Cycloalkyl;

R32 is hydrogen; halogen; hydroxy; acyloxy; substituted acyloxy;

optionally substituted with hydroxy or

Ci_-6alkoxy optionally substituted with aryl, amino, protected amino, acyl, hydroxy, cyano or Ci.₆alkylthio; nitro; amino; acyl; substituted acyl; or Cs^cycloalkyloxy; Al is a single bond, O, or NH;

O Il o -s-

El is Ci-6alkylene, C_2-6alkenylene, — " — , ° ; or El is a group of the formula -Gl-Jl- in which

O Gl is C_1-6alkylene or — " — and

R62 Jl is O or N , wherein R62 is hydrogen or N-protective group;

Xl is -CH=CH-, -C=N- or S; and

Yl is aryl optionally substituted with 1-6 independent acyl, protected aminoCi_-6alkanoyl, protected amino and nitro, amino and nitro or diamino substituents; or Yl is a heterocyclyl optionally substituted with 1-6 halogen, acyl, Ci^alkoxy, hydroxy, guanidino, mercapto, acylamino, amino, heterocyclyl, cyanoamino,

Ci-βalkylamino, Ci-βalkylaminoCCi-ealkylamino), substituted heterocyclyl, Ci_-6alkylhydrazino, aryloxy, C_1- βalkylthio, aryl, protected amino, N-protected Ci.₆alkylamino(Ci_-6alkyl)amino, N-protected aminoCi_-6alkyl(N'- Ci_-6alkyl)amino, aminoCi_-6alkyl(N- Ci-₆alkyl)amino, Ci_-6alkylamino(Ci- 6alkyl)(N- C_1-6alkyl)amino, or Ci_-6alkoxy(Ci_-6alkyl)amino substituents, or a Ci_-6alkyl substituent further optionally substituted with aryl, arCi_-6alkoxy, cyano, hydroxyimino, mercapto, Ci- _δalkylamino, acyloxy, halogen, Ci^alkoxy, protected hydroxy, hydroxy, Ci_₆alkoxyaryl, protected amino, amino, heterocyclyl, or substituted heterocyclyl sub-substituents; provided that when Yl is phenyl optionally substituted with C_halky! or acyl, then Al is a single bond, and

[00081] Compounds of Formula (III) are described in U.S. Patent No. 6,316,482.

[00082] In one aspect, the present invention is directed to a method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (III) or a pharmaceutical composition, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is S, and the other substituents are as described above for Formula (III). [00083] As used herein, " Co-4alkyl" is used to mean an alkyl having 0-4 carbons - that is,

[00084] As used herein unless otherwise specified, "alkyl", "alkenyl", and "alkynyl" includes straight or branched configurations. Lower alkyls, alkenyls, and alkynyls have 1-6 carbons. Higher alkyls, alkenyls, and alkynyls have more than 6 carbons. As used herein unless otherwise specified, the terms "aryl" and "ar" are well known to chemists and include, for example, phenyl and naphthyl, as well as phenyl with one or more short alkyl groups (tolyl, xylyl, mesityl, cumenyl, di(t-butyl)phenyl). Phenyl, naphthyl, tolyl, and xylyl are preferred. "Substituted aryl" is an aryl substituted with suitable substituents such as, for example, acyl, substituted acyl, N-protected piperazinylsulfonyl, piperazinylsulfonyl, N-Ci- ₆alkylpiperazinylsulfonyl, hydroxy

heterocyclyl, halogen, nitro, amino, Ci- _όalkylamino, cyano, or Ci-βalkoxy,

[00085] As used herein unless otherwise specified, "heterocyclyl" is well known to chemists and contains at least one N, S or O hetero-ring atom, and includes saturated, unsaturated, partially saturated, mono or polycyclic heterocyclic groups such as, for example, pyrrolyl, pyrrolinyl, imidazoylyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, imidazopyridyl, indazolyl, benzotriazolyl, tetrazolo-pyridazinyl, pyranyl, furyl, lH-tetrahydropyranyl, tetrahydrofuranyl, thienyl, oxazolyl, isoxazolyl, oxadiazoyl, oxazolinyl, moφholinyl, benzofuranyl, benzoxazolyl, benzoxadiazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, or benzodioxyl and the like. Such heterocyclyls are optionally substituted with lower alkyl or oxo substituents.

[00086] As used herein unless otherwise specified, "acyl" includes for example, carboxy, esterified carboxy, carbamoyl, lower alkylcarbamoyl, lower alkanoyl, aroyl, heterocyclylcarbonyl, and the like. Esterified carboxy includes substituted or unsubstituted lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t- butoxycarbonyl, hexyloxycarbonyl, 2iodoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, dimethylaminopropoxycarbonyl, dimethylaminoethoxycarbonyl; substituted or unsubstituted aryloxycarbonyl such as phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl; substituted or unsubstituted ar(lower)alkoxycarbonyl such as benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, 3methoxy-4- nitrobenzyloxycarbonyl; and N-containing heterocyclyloxycarbonyl such as N- methylpiperidyloxycarbonyl and the like.

[00087] As used herein unless otherwise specified, "halogen" is fluorine, chlorine, bromine or iodine.

[00088] As used herein unless otherwise specified, "Ci_-6alkylhydrazino" may be mono or

2,2-di(Ci_-6alkyl)hydrazino such as 2-methylhydrazino, 2,2-dimethylhydrazino, 2-ethylhydrazino, 2,2-diethylhydrazino, or the like.

[00089] As used herein unless otherwise specified, " Ci-oalkylaminoCi-oalkyl" includes, for example, methylaminomethyl, dimethylaminomethyl, dimethylaminoethyl or the like.

[00090] " C_1-6alkanoyl" includes substituted or unsubstituted alkanoyls such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl or the like.

[00091] "Aroyl" includes benzoyl, naphthoyl, toluoyl, di(t-butyl)benzoyl and the like.

[00092] As used herein unless otherwise specified, "N-protective group" in "protected amino", includes substituted or unsubstituted lower alkanyl (such as, for example, formyl, acetyl, propionyl, trifluoroacetyl), phthaloyl, lower alkoxycarbonyl (such as tbutoxycarbonyl, t- amyloxycarbonyl), substituted or unsubstituted aralkyloxycarbonyl (such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl), 9fluorenylmethoxycarbonyl, substituted or unsubstituted arenesulfonyl(benzenesulfonyl, tosyl). Phthaloyl, t-butoxycarbonyl or 9fluorenylmethoxycarbonyl are preferred.

[00093] As used herein unless otherwise specified, "hydroxy 1-protective group' includes substituted or unsubstituted arylmethyl (for example, benzyl, lower alkoxy benzyl), acyl, or substituted silyl (for example, t-butyldiphenylsilyl).

[00094] The above Formulas (I), (II), and (III) are shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formulas (I), (II), and (III) and pharmaceutically acceptable salts three of. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be mixture of stereoisomers. [00095] The invention also encompasses a pharmaceutical composition that is comprised of a compound of Formula (I), (II), or (III) in combination with a pharmaceutically acceptable carrier.

[00096] Preferably the composition that is comprised of a pharmaceutically acceptable carrier and non-toxic therapeutically effective amount of a compound of Formula (I), (II) or (III) as described above (or a pharmaceutically acceptable salt or N-oxide thereof).

[00097] Non-limiting examples of compounds useful for the purposes herein include 3-

(trifluoromethoxy)phenyl)thiophene-2-carboxarnide; 3-(((7-(2-methoxyethoxy)quinolin-4- yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2-carboxamide; 3-(((7- ethoxyquinolin-4-yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2-carboxamide; 3-(((7-hydroxyquinolin-4-yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2- carboxamide; 3-(((7-isopropoxyquinolin-4-yl)methyl)amino)-N-(4- (trifluoromethoxy)phenyl)thiophene-2-carboxamide; 3-(((7-methoxyquinolin-4- yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2-carboxamide; 3-(((7- methoxyquinolin-4-yl)methyl)amino)-N-(4-(trifluoromethyl)pyridin-2-yl)thiophene-2- carboxamide; 3-(((7-methoxyquinolin-4-yl)methyl)amino)-N-(5-(trifluoromethyl)pyridin-3- yl)thiophene-2-carboxamide; N-(5-tert-butyl-lH-pyrazol-3-yl)-3-(((5,7-dimethoxyquinolin-4- yl)methyl)amino)thiophene-2-carboxamide; N-(5-tert-butyl-lH-pyrazol-3-yl)-3-(((5- methoxyquinolin-4-yl)methyl)amino)thiophene-2-carboxamide; N-(5-tert-butyl- 1 H-pyrazol-3- yl)-3-(((7-(2-methoxyethoxy)quinolin-4-yl)methyl)amino)thiophene-2-carboxamide; N-(5-tert- butyl- 1 H-pyrazol-3 -yl)-3 -(((7-methoxyquinolin-4-yl)methyl)amino)thiophene-2-carboxamide;N- (6-hydroxypyridin-3-yl)-3-(((7-methoxyquinolin-4-yl)methyl)amino)thiophene-2-carboxamide and N-(isoquinolin-3-yl)-3-(((7-methoxyquinolin-4-yl)methyl)amino)thiophene-2-carboxamide.

[00098] In other non-limiting examples, compounds useful for the purposes herein include

N-(4-trifluoromethoxyphenyl) 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide; N-(4- bromo-3-methylphenyl) 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide; N-(2,2,3,3- tetrafluorobenzodioxan-6-yl) 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide; N-(4- chlorophenyl) 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide; 4-{[2-(4-bromo-3- methylphenylcarbamoyl)thiophen-3-ylamino]methyl}pyridine-2-carboxylic acid methylamide; N-methyl-4-(((2-((2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][l,4]dioxin-6-yl)carbamoyl)thiophen- 3-yl)amino)methyl)picolinamide; 4- { [2-(4-chlorophenylcarbamoyl)thiophen-3- ylamino]methyl}pyridine-2-carboxylic acid methylamide; N-(4-chlorophenyl) 3-[(1H- pyrrolo[2,3-b]pyridin-3-ylmethyl)amino]thiophene-2-carboxamide; 3-(((lH-pyrrolo[2,3- b]pyridin-3-yl)methyl)amino)-N-(4-bromo-3-methylphenyl)thiophene-2-carboxamide; 3-(((1H- pyrrolo[2,3-b]pyridin-3-yl)methyl)amino)-N-(2,2,3,3-tetrafluoro-2,3- dihydrobenzofb] [ 1 ,4]dioxin-6-yl)thiophene-2-carboxamide; N-methyl-4-(((2-((4- (trifluoromethoxy)phenyl)carbamoyl)thiophen-3-yl)amino)methyl)picolinamide; 3-(((1H- pyrrolo[2,3-b]pyridin-4-yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2- carboxamide; N-(4-chlorophenyl)-3-[(lH-pyrrolo[2,3-b]pyridin-4-ylmethyl)amino]thiophene-2- carboxamide; 3-(((lH-pyrrolo[2,3-b]pyridin-4-yl)methyl)amino)-N-(2,2,3,3-tetrafluoro-2,3- dihydrobenzo[b][ 1 ,4]dioxin-6-yl)thiophene-2-carboxamide; 4-methyl-N-(4- trifluoromethoxyphenyl)-3-[(quinolin-4- ylmethyl)amino]thiophene-2-carboxamide; N-(4- chlorophenyl)-4-methyl-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide; N-(4-bromo- 3-methylphenyl)-4-methyl-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide; 4-methyl- 3-[(quinolin-4-ylmethyl)amino]-N-(2,2,3,3-tetrafluoro-2,3-dihydro-l,4- benzodioxin-6- yl)thiophene-2-carboxamide; 4-(((2-((4-(trifluoromethoxy)phenyl)carbamoyl)thiophen-3- yl)amino)methyl)quinoline 1-oxide; 3-(((lH-pyrrolo[2,3-b]pyridin-3-yl)methyl)amino)-N-(4- (trifluoromethoxy)phenyl)thiophene-2-carboxamide; and 3 -(pyridin-4-ylmethylamino)-N-(4- (trifluoromethoxy)phenyl)thiophene-2-carboxamide.

[00099] In another embodiment, the aforementioned Formulae and compounds have anti- fibrotic activities and thus are useful for the prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis.

[000100] In certain embodiments, the diseases and conditions benefitted by treatment with an effective amount of a compound mentioned above or pharmaceutical composition thereof include but are not limited to fibrotic liver disease, hepatic ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, cardiac fibrosis, renal disease or lung (pulmonary) fibrosis. In other embodiments, the disease or condition is liver fibrosis associated with hepatitis C, hepatitis B, delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis, extrahepatic obstructions (stones in the bile duct), cholangiopathies (primary biliary cirrhosis and sclerosing cholangitis), autoimmune liver disease, and inherited metabolic disorders (Wilson's disease, hemochromatosis, and alpha- 1 antitrypsin deficiency); damaged and/or ischemic organs, transplants or grafts; ischemia/reperfusion injury; stroke; cerebrovascular disease; myocardial ischemia; atherosclerosis; renal failure; renal fibrosis and idiopathic pulmonary fibrosis. In still further embodiments, the treatment is for wounds for acceleration of healing; reducing postsurgical scarring; reducing adhesion formation; vascularization of a damaged and/or ischemic organ, transplant or graft; amelioration of ischemia/reperfusion injury in the brain, heart, liver, kidney, and other tissues and organs; normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction; development or augmentation of collateral vessel development after vascular occlusion or to ischemic tissues or organs; fibrotic diseases; hepatic disease including fibrosis and cirrhosis; lung fibrosis; radiocontrast nephropathy; fibrosis secondary to renal obstruction; renal trauma and transplantation; renal failure secondary to chronic diabetes and/or hypertension; muscular dystrophy, amyotrophic lateral sclerosis, scleroderma, systemic sclerosis and dermal fibrosis and/or diabetes mellitus.

[000101] It will be appreciated that for each of the classes and subclasses described above and herein, any one or more occurrences of aliphatic and/or heteroaliphatic may independently be substituted or unsubstituted, linear or branched, saturated or unsaturated; any one or more occurrences of alicyclic and/or heteroalicyclic may independently be substituted or unsubstituted, saturated or unsaturated; and any one or more occurrences of aryl and/or heteroaryl may independently be substituted or unsubstituted.

[000102] Some of the foregoing compounds can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., stereoisomers and/or diastereomers. Thus, inventive compounds and pharmaceutical compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers. In certain embodiments, the compounds of the invention are enantiopure compounds. In certain other embodiments, mixtures of stereoisomers or diastereomers are provided.

[000103] Furthermore, certain compounds, as described herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated. The invention additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of stereoisomers. In addition to the above-mentioned compounds per se, this invention also encompasses pharmaceutically acceptable derivatives of these compounds and compositions comprising one or more compounds of the invention and one or more pharmaceutically acceptable excipients or additives.

[000104] Compounds of the invention may be prepared by crystallization of compound of Formula (I), (II) and (III) under different conditions and may exist as one or a combination of polymorphs of compound of general formulas (I), (II) and (III) forming part of this invention. For example, different polymorphs may be identified and/or prepared using different solvents, or different mixtures of solvents for recrystallization; by performing crystallizations at different temperatures; or by using various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffractogram and/or other techniques. Thus, the present invention encompasses inventive compounds, their derivatives, their tautomeric and geometrical isomeric forms, their stereoisomers, their positional isomer, their polymorphs, their pharmaceutically acceptable salts their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. Tautomeric forms of compounds of the present invention include, pyrazoles, pyridones and enols, etc., and geometrical isomers include E/Z isomers of compounds having double bonds and cis-trans isomers of monocyclic or fused ring systems, etc.

2) Pharmaceutical Compositions

[000105] As discussed above this invention provides novel compounds that have biological properties useful for the treatment of any of a number of conditions or diseases in which an anti- fϊbrotic agent has a therapeutically useful role.

[000106] Accordingly, in another aspect of the present invention, pharmaceutical compositions are provided, which comprise any one or more of the compounds described herein (or a prodrug, pharmaceutically acceptable salt or other pharmaceutically acceptable derivative thereof), and optionally comprise a pharmaceutically acceptable carrier. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. Alternatively, a compound of this invention may be administered to a patient in need thereof in combination with the administration of one or more other therapeutic agents. For example, additional therapeutic agents for conjoint administration or inclusion in a pharmaceutical composition with a compound of this invention may be an approved agent to treat the same or related indication, or it may be any one of a number of agents undergoing approval in the Food and Drug Administration that ultimately obtain approval for the treatment of any disorder related to fibrosis. It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or a pro-drug or other adduct or derivative of a compound of this invention which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

[000107] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art. For example, S.M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting a free base or free acid function with a suitable reagent, as described generally below. For example, a free base function can be reacted with a suitable acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[000108] Additionally, as used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

[000109] Furthermore, the term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the issues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood, or N-demethylation of a compound of the invention where R¹ is methyl. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. By way of example, N-methylated pro-drugs of the 3(5)-monosubstituted pyrazoles of the invention are embraced herein.

[000110] As described above, the pharmaceutical compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogenfree water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[000111] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut (peanut), corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[000112] In one embodiment, liquid compositions or liquid formulations comprising compounds of the invention are provided that have increased solubility as compared to compounds of the invention dissolved in aqueous buffer such as phosphate-buffered saline. In one embodiment, such liquid compositions with increased solubility are provided by a composition comprising polyethylene glycol, polysorbate or a combination thereof. In one embodiment, the polyethylene glycol is polyethylene glycol 300. In another embodiment the polysorbate is polysorbate 80. In another embodiment the polyethylene glycol is present at about 40% to about 60% (v/v). In another embodiment the polysorbate is present at about 5% to about 15% (v/v). In another embodiment the polyethylene glycol is present at about 50% (v/v). In another embodiment the polysorbate is present at about 10% (v/v). In one formulation, the polyethylene glycol is present at 50% (v/v) together with polysorbate 80 at 10% (v/v). The balance of the solution can be a saline solution, a buffer or a buffered saline solution, such as phosphate-buffered saline. The pH of the solution can be from about pH 5 to about pH 9, and in other embodiments, about from pH 6 to about pH 8. In one embodiment the pH of the buffer is 7.4. In the foregoing embodiments, the compound of the invention is soluble at a concentration higher than in buffer alone, and can be present at about 0.8 to about 10 milligrams per milliliter of solution, or even higher. These formulations offer the preparation of convenient dosing solutions of practical volumes for single dose administration, by any route, in particular a parenteral route. In one embodiment, the route is intravenous, subcutaneous or intraperitoneal. Such compositions with a higher solubility permit achievement of more elevated blood concentrations that provide efficacy when the threshold Cmax (maximal blood concentration after administration) should be achieved for optimal efficacy.

[000113] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[000114] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[000115] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension or crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include (poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

[000116] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[000117] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[000118] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. [000119] In other embodiments, solid dosage forms of compounds embodied herein are provided. In some embodiment, such solid dosage forms have improved oral bioavailability. In one embodiment, a formulation is prepared in a solid formulation comprising about 20% (w/w) compound of the invention, about 10-20% (w/w) GLUCIRE® 44/14, about 10-20% (w/w) vitamin E succinate (TPS), 0 to about 60% polyethylene glycol 400, 0 to about 40% Lubrizol, 0 to about 15% Cremophor RH 40 (w/w), and about 1% (w/w) BHT. Formulations containing Cremophor RH 20 are liquid at room temperature but waxy solids at 4 C. The foregoing examples of one or more agents to aid in preparing formulations of inventive compound are merely illustrative and non-limiting.

[000120] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose and starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[000121] In other embodiments solid dosage forms are provided. In certain embodiments, such solid dosage forms provide a higher than about a 20% oral bioavailability. As will be shown in the examples below, compounds of the invention can be co-precipitated with one or more agents such as mannitol, a combination of mannitol and lactobionic acid, a combination of mannitol and gluconic acid, a combination of mannitol and methanesulfonic acid, a combination of microcrystalline cellulose and oleic acid or a combination of pregelatinized starch and oleic acid. The foregoing examples of one or more agents to aid in preparing formulations of inventive compound are merely illustrative and non-limiting. Non-limiting examples of inventive compounds in such solid dosage forms include

[000122] The present invention encompasses pharmaceutically acceptable topical formulations of inventive compounds. The term "pharmaceutically acceptable topical formulation", as used herein, means any formulation which is pharmaceutically acceptable for intradermal administration of a compound of the invention by application of the formulation to the epidermis. In certain embodiments of the invention, the topical formulation comprises a carrier system. Pharmaceutically effective carriers include, but are not limited to, solvents (e.g., alcohols, poly alcohols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffered solutions (e.g., hypotonic or buffered saline) or any other carrier known in the art for topically administering pharmaceuticals. A more complete listing of art-known carriers is provided by reference texts that are standard in the art, for example, Remington's Pharmaceutical Sciences, 16th Edition, 1980 and 17th Edition, 1985, both published by Mack Publishing Company, Easton, Pa., the disclosures of which are incorporated herein by reference in their entireties. In certain other embodiments, the topical formulations of the invention may comprise excipients. Any pharmaceutically acceptable excipient known in the art may be used to prepare the inventive pharmaceutically acceptable topical formulations. Examples of excipients that can be included in the topical formulations of the invention include, but are not limited to, preservatives, antioxidants, moisturizers, emollients, buffering agents, solubilizing agents, other penetration agents, skin protectants, surfactants, and propellants, and/or additional therapeutic agents used in combination to the inventive compound. Suitable preservatives include, but are not limited to, alcohols, quaternary amines, organic acids, parabens, and phenols. Suitable antioxidants include, but are not limited to, ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents like EDTA and citric acid. Suitable moisturizers include, but are not limited to, glycerine, sorbitol, polyethylene glycols, urea, and propylene glycol. Suitable buffering agents for use with the invention include, but are not limited to, citric, hydrochloric, and lactic acid buffers. Suitable solubilizing agents include, but are not limited to, quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates. Suitable skin protectants that can be used in the topical formulations of the invention include, but are not limited to, vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.

[000123] In certain embodiments, the pharmaceutically acceptable topical formulations of the invention comprise at least a compound of the invention and a penetration enhancing agent. The choice of topical formulation will depend or several factors, including the condition to be treated, the physicochemical characteristics of the inventive compound and other excipients present, their stability in the formulation, available manufacturing equipment, and costs constraints. As used herein the term " penetration enhancing agent " means an agent capable of transporting a pharmacologically active compound through the stratum corneum and into the epidermis or dermis, preferably, with little or no systemic absorption. A wide variety of compounds have been evaluated as to their effectiveness in enhancing the rate of penetration of drugs through the skin. See, for example, Percutaneous Penetration Enhancers, Maibach H. I. and Smith H. E. (eds.), CRC Press, Inc., Boca Raton, FIa. (1995), which surveys the use and testing of various skin penetration enhancers, and Buyuktimkin et al, Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh T. K., Pfister W. R., Yum S. I. (Eds.), Interpharm Press Inc., Buffalo Grove, 111. (1997). In certain exemplary embodiments, penetration agents for use with the invention include, but are not limited to, triglycerides (e.g., soybean oil), aloe compositions (e.g., aloe- vera gel), ethyl alcohol, isopropyl alcohol, octolyphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethylsulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate) and N-methyl pyrrolidone.

[000124] In certain embodiments, the compositions may be in the form of ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. In certain exemplary embodiments, formulations of the compositions according to the invention are creams, which may further contain saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmito-oleic acid, cetyl or oleyl alcohols, stearic acid being particularly preferred. Creams of the invention may also contain a non-ionic surfactant, for example, polyoxy-40-stearate. In certain embodiments, the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Formulations for intraocular administration are also included. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are made by dissolving or dispensing the compound in the proper medium. As discussed above, penetration enhancing agents can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[000125] It will also be appreciated that the compounds and pharmaceutical compositions of the present invention can be formulated and employed in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated with or administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another anti-inflammatory agent), or they may achieve different effects (e.g., control of any adverse effects). In non-limiting examples, one or more compounds of the invention may be formulated with at least one cytokine, growth factor or other biological, such as an interferon, e.g., alpha interferon, or with at least another small molecule compound. Non-limiting examples of pharmaceutical agents that may be combined therapeutically with compounds of the invention include: antivirals and antifibrotics such as interferon alpha, combination of interferon alpha and ribavirin, Lamivudine, Adefovir dipivoxil and interferon gamma; anticoagulants such as heparin and warfarin; antiplatelets e.g., aspirin, ticlopidine and clopidogrel; other growth factors involved in regeneration, e.g., VEGF and FGF and mimetics of these growth factors ; antiapoptotic agents; and motility and morphogenic agents.

[000126] In certain embodiments, the pharmaceutical compositions of the present invention further comprise one or more additional therapeutically active ingredients (e.g., antiinflammatory and/or palliative). For purposes of the invention, the term "Palliative" refers to treatment that is focused on the relief of symptoms of a disease and/or side effects of a therapeutic regimen, but is not curative. For example, palliative treatment encompasses painkillers, antinausea medications and anti-sickness drugs.

[000127] 3) Research Uses, Clinical Uses, Pharmaceutical Uses and Methods of Treatment

[000128] Research Uses

Clinical uses of compounds with antifibrotic activity

[000129] 1. Fibrotic Liver Disease: Liver fibrosis is the scarring response of the liver to chronic liver injury; when fibrosis progresses to cirrhosis, morbid complications can develop. In fact, end-stage liver fibrosis or cirrhosis is the seventh leading cause of death in the United States, and afflicts hundreds of millions of people worldwide; deaths from end-stage liver disease in the United States are expected to triple over the next 10-15 years, mainly due to the hepatitis C epidemic. In addition to the hepatitis C virus, many other forms of chronic liver injury also lead to end-stage liver disease and cirrhosis, including other viruses such as hepatitis B and delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis, extrahepatic obstructions (stones in the bile duct), cholangiopathies (primary biliary cirrhosis and sclerosing cholangitis), autoimmune liver disease, and inherited metabolic disorders (Wilson's disease, hemochromatosis, and alpha- 1 antitrypsin deficiency).

[000130] Treatment of liver fibrosis has focused to date on eliminating the primary injury. For extrahepatic obstructions, biliary decompression is the recommended mode of treatment whereas patients with Wilson's disease are treated with zinc acetate. In chronic hepatitis C infection, interferon has been used as antiviral therapies with limited response: -20% when used alone or ~ 50% response when used in combination with ribavirin. In addition to the low-level of response, treatment with interferon with or without ribavirin is associated with numerous severe side effects including neutropenia, thrombocytopenia, anemia, depression, generalized fatigue and flu-like symptoms, which are sufficiently significant to necessitate cessation of therapy. Treatments for other chronic liver diseases such as hepatitis B, autoimmune hepatitis and Wilson's disease are also associated with many side effects, while primary biliary cirrhosis, primary sclerosing cholangitis and non-alcoholic fatty liver disease have no effective treatment other than liver transplantation.

[000131] The advantage of treating fibrosis rather than only the underlying etiology, is that antifibrotic therapies should be broadly applicable across the full spectrum of chronic liver diseases. While transplantation is currently the most effective cure for liver fibrosis, mounting evidence indicates that not only fibrosis, but even cirrhosis is reversible. Unfortunately patients often present with advanced stages of fibrosis and cirrhosis, when many therapies such as antivirals can no longer be safely used due to their side effect profile. Such patients would benefit enormously from effective antifibrotic therapy, because attenuating or reversing fibrosis may prevent many late stage complications such as infection, ascites, and loss of liver function and preclude the need for liver transplantation. The compounds of the invention are beneficial for the treatment of the foregoing conditions, and generally are antifibrotic agents for this and other organ or tissues.

[000132] 2. Hepatic Ischemia-Reperfusion Injury: Currently, transplantation is the most effective therapeutic strategy for liver fibrosis. However, in spite of the significant improvement in clinical outcome during the last decade, liver dysfunction or failure is still a significant clinical problem after transplantation surgery. Ischemia-reperfusion (IR) injury to the liver is a major alloantigen-independent component affecting transplantation outcome, causing up to 10% of early organ failure, and leading to the higher incidence of both acute and chronic rejection. Furthermore, given the dramatic organ shortage for transplantation, surgeons are forced to consider cadaveric or steatotic grafts or other marginal livers, which have a higher susceptibility to reperfusion injury. In addition to transplantation surgery, liver IR injury is manifested in clinical situations such as tissue resections (Pringle maneuver), and hemorrhagic shock.

[000133] The damage to the postischemic liver represents a continuum of processes that culminate in hepatocellular injury. Ischemia activates Kupffer cells, which are the main sources of vascular reactive oxygen species (ROS) formation during the initial reperfiision period. In addition to Kupffer cell-induced oxidant stress, with increasing length of the ischemic episode, intracellular generation of ROS by xanthine oxidase and in particular mitochondria may also contribute to liver dysfunction and cell injury during reperfiision. Endogenous antioxidant compounds, such as superoxide dismutase, catalase, glutathione, alphatocopherol, and beta- carotene, may all limit the effects of oxidant injury but these systems can quickly become overwhelmed by large quantities of ROS. Work by Lemasters and colleagues, has indicated that in addition to formation of ROS, intracellular calcium dyshomeostasis is a key constributor to liver IR injury. Cell death of hepatocytes and endothelial cells in this setting is characterized by swelling of cells and their organelles, release of cell contents, eosinophilia, karyolysis, and induction of inflammation, characteristic of oncotic necrosis. More recent reports indicate that liver cells also die by apoptosis, which is morphologically characterized by cell shrinkage, formation of apoptotic bodies with intact cell organelles and absence of an inflammatory response.

[000134] Indeed, minimizing the adverse effects of IR injury could significantly increase the number of patients that may successfully undergo liver transplantation. Pharmacologic interventions that reduce cell death and/or enhance organ regeneration represent a therapeutic approach to improve clinical outcome in liver transplantation, liver surgery with vascular exclusion and trauma and can therefore reduce recipient/patient morbidity and mortality. The compounds of the invention are beneficial for the treatment of the foregoing conditions.

[000135] 3. Cerebral Infarction. Stroke and cerebrovascular disease are a leading cause of morbidity and mortality in the US: at least 600,000 Americans develop strokes each year, and about 160,000 of these are fatal. Research on the pathophysiological basis of stroke has produced new paradigms for prevention and treatment, but translation of these approaches into improved clinical outcomes has proved to be painfully slow. Preventive strategies focus primarily on reducing or controlling risk factors such as diabetes, hypertension, cardiovascular disease, and lifestyle; in patients with severe stenosis, carotid endarterectomy may be indicated. Cerebral angioplasty is used investigationally, but the high restenosis rates observed following coronary angioplasty suggest this approach may pose unacceptable risk for many patients. Therapeutic strategies focus primarily on acute treatment to reduce injury in the ischemic penumbra, the region of reversibly damaged tissue surrounding an infarct. Thrombolytic therapy has been shown to improve perfusion to the ischemic penumbra, but it must be administered within three hours of the onset of infarction. Several neuroprotective agents that block specific tissue responses to ischemia are promising, but none have yet been approved for clinical use. While these therapeutic approaches limit damage in the ischemic penumbra, they do not address the underlying problem of inadequate blood supply due to occluded arteries. An alternative strategy is to induce formation of collateral blood vessels in the ischemic region; this occurs naturally in chronic ischemic conditions, but stimulation of vascularization via therapeutic angiogenesis has potential therapeutic benefit.

[000136] Recent advances in imaging have confirmed the pathophysiological basis of the clinical observations of evolving stroke. Analysis of impaired cerebral blood flow (CBF) in the region of an arterial occlusion supports the hypothesis that a central region of very low CBF, the ischemic core, is irreversibly damaged, but damage in surrounding or intermixed zones where CBF is of less severely reduced, the ischemic penumbra, can be limited by timely reperfusion. The compounds of the invention are beneficial for the treatment of the foregoing conditions.

[000137] 4. Ischemic heart disease is a leading cause of morbidity and mortality in the US, afflicting millions of Americans each year at a cost expected to exceed $300 billion/year. Numerous pharmacological and interventional approaches are being developed to improve treatment of ischemic heart disease including reduction of modifiable risk factors, improved revascularization procedures, and therapies to halt progression and/or induce regression of atherosclerosis. Atherosclerosis comprises a fibrotic component, and compounds described herein are useful for prevention and treatment as well as intervention in the development of heart failure.

[000138] 5. Renal Disease. Chronic renal dysfunction is a progressive, degenerative disorder that ultimately results in acute renal failure and requires dialysis as an intervention, and renal transplantation as the only potential cure. Initiating conditions of renal dysfunction include ischemia, diabetes, underlying cardiovascular disease, or renal toxicity associated with certain chemotherapeutics, antibiotics, and radiocontrast agents. Most end-stage pathological changes include extensive fibrinogenesis, epithelial atrophy, and inflammatory cell infiltration into the kidneys.

[000139] Acute renal failure is often a complication of diseases including diabetes or renal ischemia, procedures such as heminephrectomy, or as a side effect of therapeutics administered to treat disease. The widely prescribed anti-tumor drug c/s-diamminedichloroplatinum (cisplatin), for example, has side effects that include a high incidence of nephrotoxicity and renal dysfunction, mainly in the form of renal tubular damage that leads to impaired glomerular filtration. Administration of gentamicin, an aminoglycoside antibiotic, or cyclosporin A, a potent immunosuppressive compound, causes similar nephrotoxicity. The serious side effects of these effective drugs restrict their use. The development of agents that protect renal function and enhance renal regeneration after administration of nephrotoxic drugs will be of substantial benefit to numerous patients, especially those with malignant tumors, and may allow the maximal therapeutic potentials of these drugs to be realized. The compounds of the invention are beneficial for the treatment of the renal diseases mentioned above.

[000140] 6. Lung (Pulmonary) Fibrosis. Idiopathic pulmonary fibrosis (IPF) accounts for a majority of chronic interstitial lung diseases, and has an estimated incidence rate of 10.7 cases for 100,000 per year, with an estimated mortality of 50-70%. IPF is characterized by an abnormal deposition of collagen in the lung with an unknown etiology. Although the precise sequence of the pathogenic sequelae is unknown, disease progression involves epithelial injury and activation, formation of distinctive subepithelial fibroblast/myofibroblast foci, and excessive extracellular matrix accumulation. The development of this pathological process is preceded by an inflammatory response, often dominated by macrophages and lymphocytes, which is mediated by the local release of chemoattractant factors and upregulation of cell-surface adhesion molecules. Lung injury leads to vasodilatation and leakage of plasma proteins into interstitial and alveolar spaces, as well as activation of the coagulation cascade and deposition of fibrin. Fibroblasts migrate into this provisional fibrin matrix where they synthesize extracellular matrix molecules. In non-pathogenic conditions, excess fibrin is usually degraded by plasmin, a proteinase that also has a role in the activation of matrix metalloproteinases (MMPs). Activated MMPs degrade extracellular matrix and participate in fibrin removal, resulting in the clearance of the alveolar spaces and the ultimate restoration of injured tissues. In pathological conditions, however, these processes can lead to progressive and irreversible changes in lung architecture, resulting in progressive respiratory insufficiency and an almost universally terminal outcome in a relatively short period of time. Fibrosis is the final common pathway of a variety of lung disorders, and in this context, the diagnosis of pulmonary fibrosis implies the recognition of an advanced stage in the evolution of a complex process of abnormal repair. While many studies have focused on inflammatory mechanisms for initiating the fibrotic response, the synthesis and degradation the extracellular matrix represent the central event of the disease. It is this process that presents a very attractive site of therapeutic intervention. [000141] The course of IPF is characterized by progressive respiratory insufficiency, leading to death within 3 to 8 years from the onset of symptoms. Management of interstitial lung disease in general, and in particular idiopathic pulmonary fibrosis, is difficult, unpredictable and unsatisfactory. Attempts have been made to use antiinflammatory therapy to reverse inflammation, relief, stop disease progression and prolong survival. Corticosteroids are the most frequently used antiinflammatory agents and have been the mainstay of therapy for IPF for more than four decades, but the efficacy of this approach is unproven, and toxicities are substantial. No studies have compared differing dosages or duration of corticosteroid treatment in matched patients. Interpretation of therapy efficacy is obscured by several factors including heterogeneous patient populations, inclusion of patients with histologic entities other than usual interstitial pneumonia, lack of objective, validated endpoints, and different criteria for "response." Cytotoxic drugs such as Azathioprine and cyclophosohamide have also being used in combination with low dose oral corticosteroids. The results of such treatments vary from no improvement to significant prolongation of survival. Overall, currently available treatments for lung fibrosis are sub-optimal. Potential new therapies have emerged from the use of animal models of pulmonary fibrosis and recent advances in the cellular and molecular biology of inflammatory reactions. Such therapies involve the use of cytokines, oxidants and growth factors that are elaborated during the fibrotic reaction. Despite the use of newer strategies for treatment, the overall prognosis for patients with interstitial lung disease has had little quantifiable change, and the population survival remains unchanged for the last 30 years. Interferon gamma (IFN) may be effective in the treatment of IPF in some patients but its role is controversial. Literature indicated that IFN-gamma may be involved in small airway disease in silicotic lung. Others showed that IFN gamma mediates, bleomycin-induced pulmonary inflammation and fibrosis. The compounds of the invention are beneficial for the treatment of the foregoing condition, among other fibrotic diseases.

[000142] 7. Fibrosis of the skin. Scleroderma, also known as systemic sclerosis (SSc), is a connective tissue disorder characterized by abnormal thickening and formation of scar tissue in the skin (cutaneous fibrosis), lung and other organs. Scleroderma/SSc affects many body systems, but is primarily characterized by thickening and tightening of the skin. Excessive extracellular matrix (ECM) protein (principally collagen) deposition in the skin, lung and other organs is a hallmark of systemic sclerosis (SSc). Many patients who suffer from SSc also have a loss of pulmonary function. Scleroderma/SSc affects approximately 400,000 to 900,000 people in the United States every year. Mortality and morbidity in SSc are very high and are directly related to the extent of fibrosis in the involved organs. According to one study, the total cost attributed to scleroderma/SSc in the United States reached $1.5 billion annually. In this study, morbidity represented the major cost burden, associated with $820 million (55%) of the total costs. There is no known cure for scleroderma/SSc and the underlying cause remains unknown, though it is attributed to having an autoimmune component.

Exemplary assays

[000143] Efficacy of the compounds of the invention on the aforementioned disorders and diseases or the potential to be of benefit for the prophylaxis or treatment thereof may be demonstrated in various studies, ranging from biochemical effects evaluated in vitro and effects on cells in culture, to in-vivo models of disease, wherein direct clinical manifestations of the disease can be observed and measured, or wherein early structural and/or functional events occur that are established to be involved in the initiation or progression of the disease. The positive effects of the compounds of the invention have been demonstrated in a variety of such assays and models, for a number of diseases and disorders. One skilled in the art can readily determine following the guidance described herein whether a compound of the invention has antifibrotic activity.

[000144] Hepatic Disease. Antifibrotic Activity in Hepatic Stellate Cells. Serum starved (activated) LX2 cells (an immortalized human hepatic stellate cell line) that are treated with a compound of the invention show a decrease in collagen I mRNA expression, as well as expression of other fibrotic marker genes, related to significant antifibrotic activity. Liver Disease endpoints. The rat model of thioacetamide (TAA)-induced liver fibrosis and the rat bile duct ligation model of fibrosis shows improvements by the compounds of the invention, in a panel of functional and histological tests: gross morphology, mass, portal pressure, presence of ascites, enzymes (AST, ALT), collagen content, interstitial fibrosis and alpha-smooth muscle actin and MMP-2.

[000145] Protection Against Renal Dysfunction. Clinical model: arterial occlusion. In a mouse model of transient unilateral renal artery occlusion, male ICR mice are anesthetized and the left renal artery occluded with a microvascular clamp. After 30 minutes, the clamp is removed and the kidney allowed to reperfuse. Ten minutes into reperfusion the nonischemic contralateral kidney is excised. Animals are treated daily with vehicle or compound of the invention (lmg/kg, i.p.) until the day of sacrifice. Serum creatinine, BUN and urine protein levels, measured at 1, 4 and 7 days postischemia are used to determine the ability of compounds of the invention to restore function to injured kidneys. In order to create a more severe renal injury, animals are subjected to 45 minutes of ischemia. Protection against Hgcb-induced renal injury. In a study mice are injected with a high dose of HgCl₂ (7 mg/kg, s.c.) and divided into treatment groups. Animals in the first group receive vehicle or a compound of the invention (1 mg/kg, i.p.) on the day of toxin injection and daily thereafter for 3 days, and are euthanized on day 4. Blood samples that are collected prior to HgCl₂ injection, on day 2 and on day 4 are analyzed for serum creatinine. In the second group, treatment with vehicle or compound begins on the day following toxin injection (i.e., 24h delayed treatment) and daily thereafter until day 6. Mice are euthanized on day 7. Blood samples collected prior to HgCl₂ injection, on day 4 and day 7 are analyzed for serum creatinine and BUN. Serum creatinine, BUN, and development of tubular necrosis are measured to indicate positive clinical activity. Protection against urethral obstruction. The effects of the compounds of invention on renal injury secondary to ureteral obstruction are examined in a mouse model of transient unilateral renal artery occlusion. Kidneys from mice subject to unilateral ureteral obstruction for 2 weeks are examined for histological evidence of injury and protection by compound treatment. Immunohistochemical staining is performed for fibronectin, proliferating cell nuclear antigen, and TUNEL (for an assessment of apoptosis). Tri chrome staining is also performed to assess the extent of collagen formation as an indication of interstitial fibrosis.

[000146] Cerebral infarction / stroke. Neuroprotective Effects in Brain Tissue. Cerebral infarction is induced in rats by middle cerebral artery occlusion (MCAO) for 24 hr. Test compound or vehicle is administered by i.p. at 2 mg/kg at -24, 0, and 8 hr. Sections of the brain are then examined for cell death by staining with a tetrazolium compound (2,3,5- Triphenyl-2H-tetrazolium chloride, or TTC). Normal rat brains exhibit a red staining due to TTC reduction whereas areas containing dead cells are white.

[000147] Lung fibrosis. In order to assess the effects of inventive compounds on pulmonary fibrosis a well-established mouse model of bleomycin-induced lung injury is used. Male C57BL/6 mice (20-3Og, n=10/group) are treated with bleomycin (0.06U/20 gram body weight) or saline via intratracheal administration. Bleomycin-treated mice are divided into 2 groups. Compounds of the invention or vehicle is administered daily until sacrifice on day 12 or day 20. Lung samples from the mice are then harvested for analysis. Tissues are sectioned and stained with modified Masson's Trichrome and are analyzed for interstitial fibrosis. The Ashcroft scale is used to obtain a numerical fibrotic score with each specimen being scored independently by two histopathologists, and the mean of their individual scores considered as the fibrotic score. Lung weight and hydroxyproline content are also measured as a means to assess the extent of fibrosis. [000148] Scleroderma. A model is used in which bleomycin is subcutaneously injected into the skin is conducted in mice. Dermal hydroxyproline, dermal collagen, and dermal thickness are measures of the extent of pathology.

Pharmaceutical Uses and Methods of Treatment

[000149] As discussed above, certain of the compounds as described herein exhibit activity generally as anti-fibrotic agents. More specifically, compounds of the invention demonstrate the ability to inhibit fibrosis. Thus, in certain embodiments, compounds of the invention are useful for the treatment of any of a number of conditions or diseases in which inhibitors of fibrosis have a therapeutically useful role, in particular antifibrotic activities.

[000150] In certain embodiments, the method involves the administration of a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to a human or animal) in need of it. Subjects for which the benefits of the compounds of the invention are intended for administration include, in addition to humans, livestock, domesticated, zoo and companion animals.

[000151] As discussed above this invention provides method for use of compounds that have biological properties useful for modulating the fibrotic process. In certain embodiments, the inventive compounds are useful for the treatment of wounds for acceleration of healing (wound healing may be accelerated by promoting cellular proliferation, particularly of vascular cells), reducing post-surgical scarring, reducing adhesion formation such as from the consequences of surgery or infection, normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction, development or augmentation of collateral vessel development after vascular occlusion or to ischemic tissues or organs, fibrotic diseases, hepatic disease including fibrosis and cirrhosis, lung fibrosis, renal failure, renal fibrosis, cerebral infarction (stroke), diabetes mellitus, and vascularization of grafted or transplanted tissues or organs. Renal conditions for which compounds of the invention may prove useful include: radiocontrast nephropathy; fibrosis secondary to renal obstruction; indication for renal trauma and transplantation; renal failure secondary to chronic diabetes and/or hypertension. Benefit in treatment of amyotrophic lateral sclerosis, diabetes mellitus and muscular dystrophy are also embodied herein.

[000152] Thus, as described above, in another aspect of the invention, a method for the treatment of disorders related to anti-fibrotic activity is provided comprising administering a therapeutically effective amount of a compound of Formula (I), (II) or (III) as described herein, to a subject in need thereof. In certain embodiments of special interest the inventive method is used for the treatment of hepatic disease, stroke, myocardial infarction and other ischemic or fϊbrotic diseases. Other diseases of interest include scleroderma, systemic sclerosis and dermal fibrosis. In another aspect, agonists may be used to preserve organs and tissues identified for transplantation, and may be infused into the donor, perfused into the harvested organs and tissues or provided as a bath, and administered to the recipient. It will be appreciated that the compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for the treatment of conditions or diseases in which anti-fibrotics have a therapeutically useful role. Thus, the expression "effective amount" as used herein, refers to a sufficient amount of agent to modulate fibrosis and to exhibit a therapeutic effect. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular therapeutic agent, its mode and/or route of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of therapeutic agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.

[000153] Furthermore, after formulation with an appropriate pharmaceutically acceptable carrier in a desired dosage, the pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, subcutaneously, intradermally, intra-ocularly, topically (as by powders, ointments, or drops), buccally, as an oral or nasal spray, or the like, depending on the severity of the disease or disorder being treated. In certain embodiments, the compounds of the invention may be administered at dosage levels of about 0.001 mg/kg to about 50 mg/kg, preferably from about 0. 1 mg/kg to about 10 mg/kg for parenteral administration, or preferably from about 1 mg/kg to about 50 mg/kg, more preferably from about 10 mg/kg to about 50 mg/kg for oral administration, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. It will also be appreciated that dosages smaller than 0.001 mg/kg or greater than 50 mg/kg (for example 50-100 mg/kg) can be administered to a subject. In certain embodiments, compounds are administered orally or parenterally.

[000154] Moreover, pharmaceutical compositions comprising one or more compounds of the invention may also contain other compounds or agents for which co-administration with the compound(s) of the invention is therapeutically advantageous. As many pharmaceutical agents are used in the treatment of the diseases and disorders for which the compounds of the invention are also beneficial, any may be formulated together for administration. Synergistic formulations are also embraced herein, where the combination of at least one compound of the invention and at least one other compounds act more beneficially than when each is given alone. Non-limiting examples of pharmaceutical agents that may be combined therapeutically with compounds of the invention include (non-limiting examples of diseases or conditions treated with such combination are indicated in parentheses): antivirals and antifibrotics, such as interferon alpha (hepatitis B, and hepatitis C), combination of interferon alpha and ribavirin (hepatitis C), Lamivudine (hepatitis B), Adefovir dipivoxil (hepatitis B), interferon gamma (idiopathic pulmonary fibrosis, liver fibrosis, and fibrosis in other organs); anticoagulants, e.g.,heparin and warfarin (ischemic stroke); antiplatelets e.g., aspirin, ticlopidine and clopidogrel (ischemic stroke); other growth factors involved in regeneration, e.g., VEGF and FGF and mimetics of these growth factors; antiapoptotic agents; and motility and morphogenic agents.

TREATMENT KIT

[000155] In other embodiments, the present invention relates to a kit for conveniently and effectively carrying out the methods in accordance with the present invention. In general, the pharmaceutical pack or kit comprises one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Such kits are especially suited for the delivery of solid oral forms such as tablets or capsules. Such a kit preferably includes a number of unit dosages, and may also include a card having the dosages oriented in the order of their intended use. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered. Alternatively, placebo dosages, or calcium dietary supplements, either in a form similar to or distinct from the dosages of the pharmaceutical compositions, can be included to provide a kit in which a dosage is taken every day. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

EQUIVALENTS

[000156] The representative examples that follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. It should further be appreciated that the contents of those cited references are incorporated herein by reference to help illustrate the state of the art.

[000157] The following examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and the equivalents thereof.

EXEMPLIFICATION

[000158] The compounds of this invention and their preparation can be understood further by the examples that illustrate some of the processes by which these compounds are prepared or used. It will be appreciated, however, that these examples do not limit the invention. Variations of the invention, now known or further developed, are considered to fall within the scope of the present invention as described herein and as hereinafter claimed.

1) General Description of Synthetic Methods:

[000159] The practitioner has a well-established literature of small molecule chemistry to draw upon, in combination with the information contained herein, for guidance on synthetic strategies, protecting groups, and other materials and methods useful for the synthesis of the compounds of this invention.

[000160] The various references cited herein provide helpful background information on preparing compounds similar to the inventive compounds described herein or relevant intermediates, as well as information on formulation, uses, and administration of such compounds which may be of interest.

[000161] Moreover, the practitioner is directed to the specific guidance and examples provided in this document relating to various exemplary compounds and intermediates thereof. [000162] The compounds of this invention and their preparation can be understood further by the examples that illustrate some of the processes by which these compounds are prepared or used. It will be appreciated, however, that these examples do not limit the invention. Variations of the invention, now known or further developed, are considered to fall within the scope of the present invention as described herein and as hereinafter claimed.

[000163] According to the present invention, any available techniques can be used to make or prepare the inventive compounds or compositions including them. For example, a variety of solution phase synthetic methods such as those discussed in detail below may be used. Alternatively or additionally, the inventive compounds may be prepared using any of a variety combinatorial techniques, parallel synthesis and/or solid phase synthetic methods known in the art.

[000164] It will be appreciated as described below, that a variety of inventive compounds can be synthesized according to the methods described herein. The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Company (Milwaukee, WI), Bachem (Torrance, CA), Sigma (St. Louis, MO), or are prepared by methods well known to a person of ordinary skill in the art following procedures described in such references as Fieser and Fieser 1991, "Reagents for Organic Synthesis", vols 1-17, John Wiley and Sons, New York, NY, 1991; Rodd 1989 "Chemistry of Carbon Compounds", vols. 1-5 and supps, Elsevier Science Publishers, 1989; "Organic Reactions", vols 1-40, John Wiley and Sons, New York, NY, 1991; March 2001, "Advanced Organic Chemistry", 5th ed. John Wiley and Sons, New York, NY; and Larock 1990, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 2^nd ed. VCH Publishers. These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to a person of ordinary skill in the art having regard to this disclosure.

[000165] The starting materials, intermediates, and compounds of this invention may be isolated and purified using conventional techniques, including filtration, distillation, crystallization, chromatography, and the like. They may be characterized using conventional methods, including physical constants and spectral data.

General Reaction Procedures:

[000166] Unless mentioned specifically, reaction mixtures are stirred using a magnetically driven stirrer bar. An inert atmosphere refers to either dry argon or dry nitrogen. Reactions are monitored either by thin layer chromatography, by proton nuclear magnetic resonance (NMR) or by high-pressure liquid chromatography (HPLC), of a suitably worked up sample of the reaction mixture.

General Work Up Procedures;

[000167] Unless mentioned specifically, reaction mixtures are cooled to room temperature or below then quenched, when necessary, with either water or a saturated aqueous solution of ammonium chloride. Desired products are extracted by partitioning between water and a suitable water-immiscible solvent (e.g. ethyl acetate, dichloromethane, diethyl ether). The desired product containing extracts are washed appropriately with water followed by a saturated solution of brine. On occasions where the product containing extract is deemed to contain residual oxidants, the extract is washed with a 10% solution of sodium sulphite in saturated aqueous sodium bicarbonate solution, prior to the aforementioned washing procedure. On occasions where the product containing extract is deemed to contain residual acids, the extract is washed with saturated aqueous sodium bicarbonate solution, prior to the aforementioned washing procedure (except in those cases where the desired product itself had acidic character). On occasions where the product containing extract is deemed to contain residual bases, the extract is washed with 10% aqueous citric acid solution, prior to the aforementioned washing procedure (except in those cases where the desired product itself had basic character). Post washing, the desired product containing extracts are dried over anhydrous magnesium sulphate, and then filtered. The crude products are then isolated by removal of solvent(s) by rotary evaporation under reduced pressure, at an appropriate temperature (generally less than 45°C).

General Purification Procedures:

[000168] Unless mentioned specifically, chromatographic purification refers to flash column chromatography on silica, using a single solvent or mixed solvent as eluent. Suitably purified desired product containing elutes are combined and concentrated under reduced pressure at an appropriate temperature (generally less than 45°C) to constant mass.

1) Synthesis of Exemplary Compounds:

[000169] Compounds of Formula I described herein can be prepared following the guidance found in US Patent Nos. 6,949,563 and 7,101,893; Published U.S. Patent Application Nos. 2005/0154014, 2006/0247275 and 20070293426, and Garton et el., Cancer Res 2006 Jan 15 66(2): 1015-24, the entire contents of which are hereby incorporated by reference. Compounds of Formula II can be prepared by following the guidance in 6,054,457, incorporated herein by reference in its entirety. Compounds of Formula III can be prepared following the guidance of 6,316,482, incorporated herein by reference in its entirety.

[000170] The foregoing are merely exemplary of synthetic routes to the compound of the invention. The foregoing compounds, compositions and methods of the invention are illustrated by the following examples, which are merely exemplary of aspects of the invention and are not limiting.

2) Biological Activity:

[000171] Antifibrotic Activity of compounds of the invention in vitro and in vivo. The antifibrotic effects of compounds of the invention in the immortalized human hepatic stellate cell line LX2 are determined. Serum starved LX2 cells are treated for 24 hours with compounds of the invention at doses ranging from 12 to 24 ug/ml. RNA is then isolated and real time PCR is performed to evaluate changes in collagen I mRNA. Results typically indicate a 70% to 90% decrease in collagen I mRNA expression in cells treated with instant compounds.

[000172] Evaluation of the antifibrotic effects of compounds of Formula (I) in two distinct rat models of liver fibrosis. A rat model of thioacetamide (TAA)-induced liver fibrosis and the rat bile duct ligation model of fibrosis shows improvements by the compounds of the invention. In the TAA model, rats are treated with TAA (200 mg/kg) three times a week for 6 weeks, at which point they are sacrificed. In the bile duct ligation model, rats are subjected to bile duct ligation for 4 weeks and are sacrificed. In both models, test compound is injected, i.p. daily, for the entire duration of fibrosis induction. A panel of functional and histological tests are conducted: gross morphology, mass, portal pressure, presence of ascites, enzymes (AST, ALT), collagen content, interstitial fibrosis and alpha-smooth muscle actin and MMP-2.

[000173] Effect of compounds of the invention on bleomycin-induced apoptosis of bronchial epithelial cells. Compounds of the invention are shown to inhibit bleomycin-induced apoptosis of bronchial epithelial cells, a well-established mouse model of lung injury and pulmonary fibrosis. Male C57BL/6 mice (20-3Og, n=10/group) are treated with bleomycin (0.06U/20 gram body weight) or saline via intratracheal administration. Bleomycin-treated mice are divided into 2 groups. Compounds of the invention or vehicle is administered daily until sacrifice on day 12 or day 20. Right lung samples from the mice are then harvested for histochemical analysis. Tissues are sectioned and are stained with modified Masson's Trichrome and are analyzed for interstitial fibrosis. The Ashcroft scale is used to obtain a numerical fibrotic score with each specimen being scored independently by two histopathologists, and the mean of their individual scores are considered as the fibrotic score. The other lung is analyzed for hydroxyproline content. Further experiments are described in the examples below.

[000174] Oral administration in chronic kidney disease (CKD). The effects of delayed, orally administered compound are examined in a standard and well-characterized mammalian model of CKD. Adult male Sprague-Dawley rats are subjected to 5/6 nephrectomy via ligation of 2 of the 3 branches of the left renal artery and excision of the right kidney. Three days after ablation, blood samples are obtained and serum creatinine (SCr) is determined. Rats with SCr values between 0.8 and 1.2 mg/dL (baseline SCr for rats is 0.2 mg/dL), indicating adequate and sustained renal ablation, are entered into the study. One week following surgery, animals are randomized to vehicle (n=15) or compound. Six weeks following surgery (i.e. 5 weeks into treatment) animals are sacrificed. Urine and kidney samples are obtained for evaluation of proteinuria, histopathology and pharmacodynamic markers of compound action. Oral administration of compound is found to be therapeutic in CKD, attenuating mortality, reducing proteinuria and kidney collagen content (hydroxyproline and Sirius red staining). In another study, daily oral treatment is started 2 weeks after surgery and continued for 10 weeks. At 10 weeks, evaluation shows similar survival in both treatment groups vs. untreated animals, and a dose-responsive reduction in kidney collagen content.

[000175] Delayed treatment in liver fibrosis. Adult male SD rats are administered thioacetamide (TAA, 200 mg/kg, ip), thrice/week for 4-8 weeks until the appearance of hepatic fibrosis. Treatment with inventive compound (ip, PO) concomitant with or subsequent to TAA administration attenuates progression of hepatic fibrosis - reducing liver profibrotic genes and liver collagen content. The following protocols are studied all of which are found to be benefitted from treatment: 1) liver fibrosis induced with TAA during weeks 1-8, IV compound treatment during weeks 9-12, 2) liver fibrosis induced with TAA during weeks 1-6, IV compound treatment weeks 4-8, 3) liver fibrosis induced with TAA during weeks 1-8, oral compound treatment weeks 9-12, and 4) liver fibrosis induced with TAA during weeks 1-4, oral compound treatment weeks 5-9.

Example 1 PDGFR as a target for anti-fibrotic therapeutics

[000176] A series of experiments was conducted to explore the biology of PDGFR as a potential molecular target of anti-fibrotic agents. PDGFRβ was found to be predominantly expressed in mesenchymal lung and liver cell lines that the receptor is activated in the fibrotic lungs of mice treated with bleomycin. The expression of PDGFRβ in a number of human lung cell lines with epithelial (BEAS-2B, HBEPC, NL20) or mesenchymal (HPF, IMR90) characteristics was determined using Western blot analysis (Cell Signaling antibody # 3169) (Figure IA). High expression levels were found in the fibroblast cell lines HPF and IMR90, while epithelial cell lines showed much lower expression of PDGFRβ.

[000177] In cell lines derived from the liver, much higher expression of PDGFRβ was seen in the fibroblast cell line FL62891 and Hepatic Stellate Cells (Sciencell, Catalog # 5300) than in the epithelial cell lines THLE2 and THLE3 (Figure IB). These data therefore indicate high expression of the receptor in cell types that are critically involved in the development of lung or liver fibrosis and confirm PDGFR as a potential target for anti-fibrotic agents using cell lines commonly employed in our laboratory.

Example 2 PDGF stimulates lung fibroblast proliferation but not lung epithelial cell proliferation.

[000178] The functional consequences of PDGFRβ activation were determined in the epithelial human lung cell lines BEAS-2B and the fibroblast cells line HPF. Cells were plated at 200-400 cells per well in a 96-well plate, starved the next day in media devoid of serum and allowed to grow for another three days in the presence of serum (5%) or of PDGF-BB (50 n/mL). After three days, the number of viable cells was determined using the luminescent cell titer glo reagent (Promega), which measures the cellular ATP content. PDGF-BB was found to stimulate the growth of the pulmonary fibroblast cell line HPF to a similar extent as serum (FCS) did, whereas proliferation of the epithelial cell line BEAS-2B was not stimulated by PDGF-BB (Figure 2). This is consistent with the observation that BEAS-2B cells do not express the PDGFRβ, while the HPF cells have significant expression of the receptor. PDGF may therefore act primarily as a growth factor for mesenchymal fibroblast cells.

Example 3 PDGFR is activated in bleomycin-induced lung fibrosis.

[000179] The expression and activation state of PDGFRβ was determined in lung tissue isolated from mice with bleomycin-induced pulmonary fibrosis. Four mice received intratracheal instillation of bleomycin and four mice received a sham operation. Animals were sacrificed and lungs were isolated four weeks later. Lung weight and the hydroxyproline content in the left lungs were determined and protein lysates were prepared from the right lungs for Western analysis. As expected, the lung hydroxyproline content was significantly elevated in the lungs isolated from bleomycin exposed animals compared to sham operated controls (Figure 3), indicating that the bleomycin-exposed animals had developed robust fibrosis. A subtle increase was found in total PDGFRβ expression and a marked elevation of Tyrosine 751 phosphorylation of the PDGFRβ receptor in the fibrotic lungs (Figure 4). Since phosphorylation of tyrosine 751 in PDGFRβ is indicative of receptor activation, this indicates that the receptor is activated in fibrotic tissue in the experimental model system. The activation state was determined of PDGFR in fibrotic lungs by immuno-histochemistry and found similar results. Overall these data indicate that PDGFR is an attractive target for anti-fibrotic agents for pulmonary fibrosis.

Example 4 Compound of the invention prevents bleomycin-induced lung fibrosis in mice

[000180] Lung weight. The normal lung weight of a -23 g C57BL/6 mice is 57 mg (n=8). A single intra-tracheal instillation of bleomycin resulted after three weeks in a marked increase in lung weight in the vehicle-treated animals to 132.9 mg (n=14). In comparison, bleomycin exposed animals that received daily doses inventive compound (200 mg/kg QD) starting the day after bleomycin instillation, had significantly lesser increase in lung weight (67.6 mg; n=15; p<0.001) (Figure 5).

[000181] Interstitial collagen - picosirius red staining and hydroxyproline content. Interstitial deposition of collagen is a hallmark indicator of fibrosis. We routinely quantify interstitial collagen using two different methodologies: (1) a hydroxyproline content on the right lungs and (2) picosirius red staining on histological sections from the left lungs. In the bleomycin-instilled animals, the collagen level was determined by picosirius red stain followed by Bioquant quantitative analysis of histochemical lung sections. As shown in Figure 6, the picosirius red staining was markedly elevated in lungs from animals treated with bleomycin compared to non-treated controls. On the other hand, picosirius red staining was markedly less in bleomycin exposed compound-treated animals compared to vehicle controls (p<0.003). Similar results were obtained by determining the total hydroxyproline content of the right lungs from animals in the various treatment groups (Figure 7). A highly significant correlation was found between the picosirius red signal and the hydroxyproline concentrations from the same animals (pO.OOOl; data not shown). These data indicate that the compound has strong therapeutic activity in preventing bleomycin-induced pulmonary fibrosis in mice.

[000182] αSMA expression. αSMA is an important fibrotic marker protein expressed in response to various cytokines and fibrosis-inducing challenges. To determine the effect of ANG-3154 treatment on αSMA expression in vivo, we performed quantitative immunohistochemistry on section from normal, bleomycin-exposed animals and bleomycin exposed, compound treated animals. We used a mouse monoclonal antibody (Sigma 5691) for the immuno histochemical detection of αSMA. As expected (Figure 8), bleomycin resulted in a marked elevation in αSMA expression. Bleomycin-exposed animals that were treated with compound; on the other hand, had significantly reduced αSMA expression compared to bleomycin treated animals. These data further support the conclusion that compound of the invention has strong therapeutic effect in preventing bleomycin-induced pulmonary fibrosis in mice.

[000183] Phospho-PDGFRβ. To determine whether a compound inhibits one of its molecular targets in vivo in the lung, we developed methods to quantify phosphorylated PDGFRβ in the lung by immuno-histochemistry. Slides were stained using a 1/50 dilution of a rabbit polyclonal antibody (Abeam ab51046) which recognizes the activated receptor phosphorylated on tyrosine residue Y751. As shown in Figure 9, there was a marked elevation in the phospho-PDGFRβ signal in the lungs from animals treated with bleomycin (p=0.004). This is consistent with the earlier observed increase in phospho-PDGFRβ signal detected by Western analysis (see above). Bleomycin-treated animals that received compound, however, had significantly lower phospho-PDGFR signal compared to vehicle control. These results therefore indicate that the PDGFR target is inhibited in the lung at the doses used in this study.

Example 5 Compounds of the invention are inhibitors of PDGFR and KDR

[000184] Inhibiting PDGFR and KDR is potentially the most critical biochemical pathway for receptor-tyrosine kinase inhibitors as potential anti-fϊbrotic agents. Inventive compounds inhibit KDR and PDGF kinase activity. To test the potency of compounds in inhibiting the activity of the VEGF receptor KDR and of the PDGF receptor PDGFRβ in a biochemical assay, compounds were tested at various concentrations for ability to inhibit the kinase activity of recombinant enzymes. The cytoplasmic kinase domains of KDR (residues 790-1356) and PDGFRβ (residues 557-1106) expressed as GST fusion proteins in a baculovirus expression system were used. One inventive compound completely inhibited the enzymatic activity of KDR with an IC50 of 74 nM and of PDGFRβ with an IC50 of 340 nM (Figure 10). We conclude that ANG-3154 is a potent inhibitor of KDR and PDGFR enzymatic activity. Example 6

Inventive compound inhibits KDR signaling in endothelial cells and PDGF signaling in hepatic stellate Cells

[000185] To test the potency of a compound in inhibiting the activity of the VEGF receptor KDR and of the PDGF receptor PDGFRβ in cells, a series of concentrations of compound were used to inhibit VEGF-induced KDR phosphorylation in human umbilical vein endothelial cells (HUVEC) and PDGF-BB-induced PDGFRβ phosphorylation in hepatic stellate cells (HSC). 100,000 HUVEC cells were plated in 6 well tissue culture-treated microwell plates, allowed to adhere, and starved overnight in medium lacking serum. Compound or vehicle controls were added at the desired concentrations for 2 hours, before treatment for 15 minutes with VEGF and preparation of cell lysates for Western analysis. Compound inhibited the phosphorylation of the KDR in response to VEGF with an estimated IC50 of -100 nM (Figure HA). Similarly, the potency of compound to inhibit PDGF-BB-induced PDGFRβ phosphorylation in HSC was determined by plating 100,000 cells in 6 well plates, starving cells overnight, treating with compound or vehicle for 2 hours, before treatment for 15 minutes with PDGF-BB and preparation of cell lysates for Western analysis. The compound inhibited the phosphorylation of the PDGFRβ with an estimated IC50 of -10 nM (Figure HB). Overall, these observations indicate that the compound can potently inhibit the cellular activity of KDR or PDGFRβ.

Example 7 Inventive compound prevents TAA-induced liver Ωbrosis in mice

[000186] The thioacetamde (TAA)-induced liver fibrosis model was set up the evaluate compounds of the invention.

[000187] Liver weight and hydroxyproline. In a preliminary study to develop a TAA- induced liver fibrosis in mice, mice were treated with TAA at 200 mg/kg, IP, 3 times a week (Mon, Wed, and Fri) for 5 weeks. These mice were treated with compound orally, 5 times a week (Mon-Fri) for 4 weeks starting a week after TAA treatment. Compound treatment resulted in a significant reduction in liver weight (Figure 12A) and hydroxyproline content (Figure 12B) per liver compared to vehicle treated TAA-exposed animals (p=0.0001 in liver weight and p = 0.04 for hydroxyproline).

[000188] αSMA and phospho PDGFRβ expression. The effect of compound treatment on αSMA expression and phospho-PDGFRβ in vivo by quantitative immuno-histochemistry on liver sections from normal, TAA-exposed animals and TAA-exposed compound treated mice, as done previously for lung samples from bleomycin-exposed animals. As expected, TAA resulted in a marked elevation in αSMA expression and phospho-PDGFRβ signal. TAA-exposed animals that were treated with compound, on the other hand, had significantly reduced αSMA expression (Figure 13A) and phospho-PDGFβ (Figure 13B) signals, compared to vehicle TAA-treated animals. These data further support the conclusion that the compound has strong activity to prevent TAA-induced liver fibrosis in mice.

Example 8 Inventive compound decreases dermal Ωbrosis

[000189] In a study of bleomycin induced scleroderma, C57BL/6 mice (Jackson Labs) were given 500 ug/ml of bleomycin (Sigma) in 100 ul and injected subcutaneously into the shaved backs of mice with a 27 gauge needle daily for three weeks. Vehicle (n=12) or compound of the invention (n=12) (200mg/kg, oral) was administered daily concomitantly with bleomycin for 3 weeks. Saline was given instead of bleomycin in a sham operated group (n=4). All sham groups are labeled as normal in all the figures. At the end of treatment period, mice were euthanized by CO2 inhalation on the day following final treatment. The treated sites of truncal skin tissue ~ lcm area were harvested for histological analysis and 6mm diameter skin punch biopsies were taken for hydroxyproline content. Dermal hydroxyproline content: Hydroxyproline analyses was performed on skin punch biopsies (6mm) from each mouse according to the method as described by Woessner et al. Results were expressed as micrograms of hydroxyproline per 6mm diameter skin tissue. The efficiency of the hydrolysis was verified with rat tail collagen by comparison to standard hydroxyproline (Sigma).

[000190] Hydroxyproline was markedly elevated in bleomycin treated vehicle group compared to sham operated mice. Compound treatment decreased hydroxyproline content significantly (p<0.001) to the bleomycin treated animals (Figure 14).

[000191] Histological evaluation of dermal collagen by trichrome staining. The dorsal skin tissue of mice was removed on the day following the final compound or vehicle injection. Skin samples (4 cm²) were removed from the dorsal side immediately below the neck in a manner that minimized stress. Dorsal tissue was separated into several portions/sections. Samples were fixed for 16 h in buffered saline containing formalin, cut into 2-3-mm-wide longitudinal strips, dehydrated, embedded in paraffin and were stained with Masson's Trichrome staining according to routine histological methods for collagen estimation. Photographs were taken from a microscope that is connected to a computerized digital camera. Bioquant image analysis computer program was used to quantify the degree of fibrosis configured to quantitate stained vs non stained regions within each field. The mean of each mice in two sections for each mice and each group was compared and analyzed statistically.

[000192] Trichrome staining was markedly elevated in bleomycin treated sites when compared to sham operated controls. On the other hand, trichrome staining was markedly less in bleomycin exposed compound-treated animals compared to vehicle controls (p<0.005) (Figure 15).

[000193] Dermal Thickness Measurements. Skin was removed from the interscapular region of the back, was fixed and embedded in paraffin, sectioned (4-μm thick), and stained with hematoxylin/eosin (H&E). The H&E stained cross-sections of skin was viewed under the microscope and photographed under (40 X). Photographs were taken using a microscope equipped with a computerized digital camera. Microscope was calibrated with markings on a Haemacytometer. The dermal thickness was determined by measuring the maximal distance between the epidermal-dermal junction with homogeneous collagen bundles with cellular infiltrates and the dermal subcutaneous fat junction at two different skin sections and 6 different fields for each mouse H&E stained sections. Dermal thickness was calculated from the haemacytometer calibration. The mean of each mice and each group was compared.

[000194] The mean dermal thickness increased significantly compared to sham operated mice and decreased significantly with compound-treated group (p<0.006) compared to vehicle group in bleomycin treated dermal sites (Figure 16). These data indicate that the compound of the invention has strong anti-fibrotic activity to prevent bleomycin-induced scleroderma/SSc in mice.

[000195] Immuno-histochemistry for alpha-SMA and phospho-PDGFRbeta. Cryostat sections (4 um) prepared from vehicle and compound-treated rat skin tissues were air-dried, fixed in 10% buffered formalin for 5 minutes, and washed in PBS for 10 minutes. Endogenous peroxidase was blocked with 3% hydrogen peroxide in PBS and then sections were incubated with alphaSMA (Sigma) and phospho PDGFRbeta (Abeam) antibodies at a dilution of 1 :500 in PBS containing 1% bovine serum albumin for one hour and washed in PBS for 10 minutes. Sections were incubated with immunoglobulin G-peroxidase-conjugated secondary antibodies (Sigma) at a dilution of 1 :150, washed in PBS for 10 minutes, incubated with 0.5 mg/mL diaminobenzidine tetrahydrochloride 2-hydrate plus 0.05% H₂O₂ for 10 minutes, and again washed in PBS. Immuno-histochemical staining for alphaSMA and phospho-PDGFRβ beta were quantitated (n=12 per group) using Bioquant computerized image analysis software. More than 5 fields from each section and each group were averaged. alphaSMA staining and phospho- PDGFRβ staining elevated in bleomycin treated groups compared to sham operated controls and decreased significantly with bleomycin treated ANG3154 treatment compared to vehicle group (p<0.05).

Claims

WHAT IS CLAIMED IS:

1. A method for the prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutical composition thereof:

(I) or a pharmaceutically acceptable salt or N-oxide thereof, wherein Rl is

R2 is

R3 is Co-4 alkyl; and

2. The method of claim 1 wherein R2 is

3. The method of claim 1 wherein R2 is and R3 is hydrogen.

4. The method of claim 1 wherein R2 is

and R3 is hydrogen and R4 is hydrogen.

5. The method of claim 1 wherein R2 is

; and R3 is C_0-4alkyl.

6. The method of claim 1 wherein thereof, wherein R2 is

and R3 is hydrogen.

7. The method of cjaim 1 wherein R2 is

8. The method of claim 1 wherein R2 is

; and R3 is hydrogen.

9. The method of claim 1 wherein R2 is ; and R3 is Co-4alkyl.

10. The method of claim 1 wherein R2 is

; and R3 is hydrogen.

11. A method for the prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II) or a pharmaceutical composition thereof:

(H)

or a pharmaceutically acceptable salt or N-oxide thereof, wherein

Rl 1 is aryl, C₃.₆cycloalkyl or heterocyclyl, each of which optionally is substituted with 1-6 independent halogen; hydroxy; nitro; amino; acyl; substituted acyl; acy ICi_-6 alky lsulfinyl; acylCu_όalkylsulfonyl; acyloxy; Ci_-6alkylaminoCi_-6alkyl carbamoyloxy; aryl; cyano; heterocyclyl; C_2-6alkenyl optionally substituted with acyl, substituted acyl, aryl or acyl- substituted aryl; C_2-6alkynyl optionally substituted with amino, acylamino or substituted acylamino; Ci_-6alkyl optionally substituted with halogen, amino, Ci_-6alkylamino, acylamino, substituted acylamino, hydroxy, acyloxy, acylCi_-6alkanoyloxy, acyl, substituted acyl, acylCi.₆alkoxyimino, aryl or acyl substituted aryl; Ci_-6alkylthio optionally substituted with acyl or substituted acyl; alkoxy optionally substituted with aryl, substituted aryl, hydroxy, acyloxy, amino, lower alkylamino, protected amino, heterocyclyl, acyl substituted pyridyl, substituted acyl substituted pyridyl, halogen, acyl Ci_-6alkylamino, N-protected

N- acylCi.₆alkyl-N-lower alkylamino, acyl, substituted acyl, acylamino, substituted acylamino, Ci_-6alkylhydrazinocarbonylamino, hydroxyimino, acylCi_-6alkoxyimino, substituted acylCi.βalkoxyimino,

R31 is hydrogen; halogen; hydroxy; acyloxy; substituted acyloxy; Ci_-6alkyl optionally substituted with hvdroxv or Ci_-6alkoxy optionally substituted with aryl, amino, protected amino, acyl, hydroxy, cyano or Ci_-6alkylthio; nitro; amino; acyl; substituted acyl; or C₃_6cycloalkyloxy;

R41 is hydroxy; halogen; nitro; amino; protected amino; d-_όalkylamino; acyloxy; amino Ci-₆alkylamino; N-protected aminoCi.₆alkylamino; Ci_-6alkoxy optionally substituted with hydroxy, aryl, substituted aryl, acyl, substituted acyl, amino, Ct-βalkylamino, acylamino, substituted acylamino, protected amino, heterocyclyl or guanidino; Ci-₆alkylthio optionally substituted with acyl, substituted acyl, amino, Ci.₆alkylamino, acylamino, substituted acylamino, protected amino, heterocyclyl, hydroxy, Ci_-6alkylsulfonyloxy, arylsulfonyloxy,

or substituted arCi_-6alkoxy; Ci.6alkyl substituted with acyl, substituted acyl, amino, lower alkylamino, acylamino, substituted acylamino, protected amino, heterocyclyl, hydroxy, Ci_-6alkylsulfonyloxy or arylsulfonyloxy; C_2-6alkenyl optionally substituted with acyl; C_2-6alkynyl optionally substituted with hydroxy, amino, protected aminoCi_-6alkylsulfonyloxy or arylsulfonyloxy; aminoCi-_δalkylsulfonyl; N-protected aminoCi-_δalkylsulfonyl; Ci_-6alkylaminosulfonyl; heterocyclylsulfonyl; aminoCi_-6alkylsulfinyl; N-protected amino Ci-_όalkylsulfmyl; piperidyloxy; or N-protected piperidyloxy;

R51 is hydrogen,

or halogen; or together with R41 forms a fused aryl or heteroaryl ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O or S;

A is a single bond, O or NH;

O

Il o -s-

E is C Ci-₆alkylene, C_2-6alkenylene, — U — , ° ; or E is a group of the formula -G-J- in which G is Ci_-6alkylene and

R61 J is O or N ₅ wherein R61 is hydrogen or N-protective group;

X is -CH=CH-, -C=N- or S; and Y is CH or N.

12. The method of claim 11 wherein X is S.

13. The method of claim 11 wherein X is S; and Rl 1.

14. The method of claim 11 wherein X is S; and Rl 1 is optionally substituted heterocyclyl.

15. The method of claim 11 wherein X is S; and Y is N.

16. A method for the prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (III) or a pharmaceutical composition thereof:

(III)

or a pharmaceutically acceptable salt or N-oxide thereof, wherein

Rl 2 is aryl, C_3-6cycloalkyl or heterocyclyl, each of which optionally is substituted with 1-6 independent halogen; hydroxy; nitro; protected amino, amino; acyl; substituted acyl; acylC_1-6alkylsulfinyl; acyl d-όalkylsulfonyl; acyloxy; Cu_όalkylaminoCi-ealkyl carbamoyloxy; aryl; cyano; heterocyclyl; C_2-6alkenyl optionally substituted with acyl, substituted acyl, aryl or acyl-substituted aryl; C_2-6alkynyl optionally substituted with amino, acylamino or substituted acylamino; C_1-6alkyl optionally substituted with halogen, amino, Ci-βalkylamino, acylamino, substituted acylamino, hydroxy, acyloxy, acylCi-βalkanoyloxy, acyl, substituted acyl, acyl Ci-βalkoxyimino, aryl or acyl substituted aryl; Ci_-6alkylthio optionally substituted with acyl or substituted acyl; alkoxy optionally substituted with aryl, substituted aryl, hydroxy, acyloxy, amino, lower alkylamino, protected amino, heterocyclyl, acyl substituted pyridyl, substituted acyl substituted pyridyl, halogen, acylCi_-6alkylamino, N-protected acylCi_-6alkylamino, N- acylCi_-6alkyl-N-lower alkylamino, acyl, substituted acyl, acylamino, substituted acylamino, Ci-ealkylhydrazinocarbonylamino, hydroxyimino, acylCi-βalkoxyimino, substituted acylCi-6alkoxyimino, acylCi_6alkoxy, guanidino or N-protected guanidino; or C_2-6alkenyloxy optionally substituted with acyl or substituted acyl substituents;

R22 is hydrogen;

optionally substituted with hydroxy, aryl or acyl; or C_3-6cycloalkyl;

R32 is hydrogen; halogen; hydroxy; acyloxy; substituted acyloxy; Ci_₆alkyl optionally substituted with hydroxy or Ci_-6alkoxy; Ci_-6alkoxy optionally substituted with aryl, amino, protected amino, acyl, hydroxy, cyano or Ci-₆alkylthio; nitro; amino; acyl; substituted acyl; or C_3-6cycloalkyloxy;

Al is a single bond, O, or NH;

O

Il o -s-

El is Ci_-6alkylene, C_2-6alkenylene, — U — , ° ; or El is a group of the formula -Gl-Jl- in which O

Gl is Ci-βalkylene or — U — and

R62 Jl is O or ^N , wherein R62 is hydrogen or N-protective group;

Xl is -CH=CH-, -C=N- or S; and

Yl is aryl optionally substituted with 1-6 independent acyl, protected aminoCi_-6alkanoyl, protected amino and nitro, amino and nitro or diamino substituents; or Yl is a heterocyclyl optionally substituted with 1-6 halogen, acyl, Ci-βalkoxy, hydroxy, guanidino, mercapto, acylamino, amino, heterocyclyl, cyanoamino, aminoCi.₆alkyl(Ci-₆alkyl)amino, Ci-₆alkylamino, Ci-δalkylaminoCCi-ealkylamino), substituted heterocyclyl,

aryloxy, Ci- ₆alkylthio, aryl, protected amino, N-protected Ci_-6alkylamino(Ci_-6alkyl)amino, N-protected aminoCi_-6alkyl(N'- Ci_-6alkyl)amino, aminoCi_-6alkyl(N- Ci_-6alkyl)amino, Ci_-6alkylamino(Ci. ₆alkyl)(N- Ci_6alkyl)amino, or

substituents, or a Ci_-6alkyl substituent further optionally substituted with aryl, arCi.₆alkoxy, cyano, hydroxyimino, mercapto, Ci- ₆alkylamino, acyloxy, halogen, Cuβalkoxy, protected hydroxy, hydroxy, Ci_-6alkoxyaryl, protected amino, amino, heterocyclyl, or substituted heterocyclyl sub-substituents; provided that when Yl is phenyl optionally substituted with Ci^alkyl or acyl, then Al is a single bond, and

O f ²

El is -^N- .

17. The method of claim 16 wherein X is S.

18. The method of any one of claims 1, 11 and 16 wherein the compound is

3-(((5,7-dimethoxyquinolin-4-yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2- carboxamide;

3-(((5-methoxyquinolin-4-yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2- carboxamide;

3-(((6-ethoxyquinolin-4-yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2- carboxamide;

3-(((6-hydroxyquinolin-4-yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2- carboxamide; 3-(((6-isopropoxyquinolin-4-yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2- carboxamide;

3-(((6-methoxyquinolin-4-yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2- carboxamide;

3-(((7-(2-methoxyethoxy)quinolin-4-yl)methyl)amino)-N-(4- (trifluoromethoxy)phenyl)thiophene-2-carboxamide;

3-(((7-ethoxyquinolin-4-yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2- carboxamide;

3-(((7-hydroxyquinolin-4-yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2- carboxamide;

3-(((7-isopropoxyquinolin-4-yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2- carboxamide;

3-(((7-methoxyquinolin-4-yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2- carboxamide;

3-(((7-methoxyquinolin-4-yl)methyl)amino)-N-(4-(trifluoromethyl)pyridin-2-yl)thiophene-2- carboxamide;

3-(((7-methoxyquinolin-4-yl)methyl)amino)-N-(5-(trifluoromethyl)pyridin-3-yl)thiophene-2- carboxamide;

N-(5-tert-buty 1- 1 H-pyrazol-3 -yl)-3 -(((5 ,7-dimethoxyquinolin-4-yl)methyl)amino)thiophene-2- carboxamide;

N-(5-tert-butyl-lH-pyrazol-3-yl)-3-(((5-methoxyquinolin-4-yl)methyl)amino)thiophene-2- carboxamide;

N-(5-tert-butyl-lH-pyrazol-3-yl)-3-(((7-(2-methoxyethoxy)quinolin-4- yl)methyl)amino)thiophene-2-carboxamide;

N-(5-tert-butyl-lH-pyrazol-3-yl)-3-(((7-methoxyquinolin-4-yl)methyl)amino)thiophene-2- carboxamide;

N-(6-hydroxypyridin-3-yl)-3-(((7-methoxyquinolin-4-yl)methyl)amino)thiophene-2- carboxamide; or

N-(isoquinolin-3-yl)-3-(((7-methoxyquinolin-4-yl)methyl)amino)thiophene-2-carboxamide.

19. The method of any one of claims 1, 11 and 16 wherein the compound is N-(4-trifluoromethoxyphenyl) 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide; N-(4-bromo-3-methylphenyl) 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide;

N-(2,2,3,3-tetrafluorobenzodioxan-6-yl) 3-[(quinolin-4-ylmethyl)amino]thiophene-2- carboxamide;

N-(4-chlorophenyl) 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide;

4-{[2-(4-bromo-3-methylphenylcarbamoyl)thiophen-3-ylamino]methyl}pyridine-2-carboxylic acid methylamide;

N-methyl-4-(((2-((2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][l,4]dioxin-6-yl)carbamoyl)thiophen- 3-yl)amino)methyl)picolinamide;

4-{[2-(4-chlorophenylcarbamoyl)thiophen-3-ylamino]methyl}pyridine-2-carboxylic acid methylamide;

N-(4-chlorophenyl) 3-[(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)amino]thiophene-2-carboxamide;

3-(((lH-pyrrolo[2,3-b]pyridin-3-yl)methyl)amino)-N-(4-bromo-3-methylphenyl)thiophene-2- carboxamide;

3-(((lH-pyrrolo[2,3-b]pyridin-3-yl)methyl)amino)-N-(2,2,3,3-tetrafluoro-2,3- dihydrobenzo[b][l,4]dioxin-6-yl)thiophene-2-carboxamide;

N-methyl-4-(((2-((4-(trifluoromethoxy)phenyl)carbamoyl)thiophen-3- yl)amino)methyl)picolinamide;

3-(((lH-pyrrolo[2,3-b]pyridin-4-yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2- carboxamide;

N-(4-chlorophenyl)-3-[(lH-pyrrolo[2,3-b]pyridin-4-ylmethyl)amino]thiophene-2-carboxamide;

3-(((lH-pyrrolo[2,3-b]pyridin-4-yl)methyl)amino)-N-(2,2,3,3-tetrafluoro-2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)thiophene-2-carboxamide;

4-methyl-N-(4-trifluoromethoxyphenyl)-3-[(quinolin-4- ylmethyl)amino]thiophene-2- carboxamide;

N-(4-chlorophenyl)-4-methyl-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide;

N-(4-bromo-3-methylphenyl)-4-methyl-3-[(quinolin-4-ylmethyl)amino]thiophene-2- carboxamide; 4-methyl-3 - [(quinolin-4-y lmethy l)amino] -N-(2 ,2 ,3 ,3 -tetrafluoro-2 , 3 -dihydro- 1 ,4- benzodioxin- 6-yl)thiophene-2-carboxamide;

4-(((2-((4-(trifluoromethoxy)phenyl)carbamoyl)thiophen-3-yl)amino)methyl)quinoline 1 -oxide;

3-(((lH-pyrrolo[2,3-b]pyridin-3-yl)methyl)amino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2- carboxamide;

3-(pyridin-4-ylmethylamino)-N-(4-(trifluoromethoxy)phenyl)thiophene-2-carboxamide.

20. The method of any one of claims 1-19 wherein the disease or condition is fibrotic liver disease, hepatic ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, renal disease or lung (pulmonary) fibrosis.

21. The method of any one of claims 1-19 wherein the disease or condition is liver fibrosis associated with hepatitis C, hepatitis B, delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis, extrahepatic obstructions (stones in the bile duct), cholangiopathies (primary biliary cirrhosis and sclerosing cholangitis), autoimmune liver disease, and inherited metabolic disorders (Wilson's disease, hemochromatosis, and alpha- 1 antitrypsin deficiency); damaged and/or ischemic organs, transplants or grafts; ischemia/reperfusion injury; stroke; cerebrovascular disease; myocardial ischemia; cardiac fibrosis, atherosclerosis; renal failure; renal fibrosis; dermal fibrosis; scleroderma; systemic sclerosis; and idiopathic pulmonary fibrosis.

22. The method of any one of claims 1-19 wherein the treatment is for wounds for acceleration of healing; reducing post-surgical scarring; reducing adhesion formation; visualization of a damaged and/or ischemic organ, transplant or graft; amelioration of ischemia/reperfusion injury in the brain, heart, liver, kidney, and other tissues and organs; normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction; development or augmentation of collateral vessel development after vascular occlusion or to ischemic tissues or organs; fibrotic diseases; hepatic disease including fibrosis and cirrhosis; lung fibrosis; radiocontrast nephropathy; fibrosis secondary to renal obstruction; renal trauma and transplantation; renal failure secondary to chronic diabetes and/or hypertension; muscular dystrophy, amyotrophic lateral sclerosis, and/or diabetes mellitus.