HK1233266B - Anti-fibrotic pyridinones - Google Patents

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of priority to U.S. Appl. No. 61/974,334, filed April 2, 2014

BACKGROUND Field

Pyridinone compounds, method of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent or diagnose diseases, disorders, or conditions associated with fibrosis are provided.

Y. M. Yutilov, et al. (Chemistry of Heterocyclic Compounds, 1994, 30(8), pp.928-933) discloses some imidazol[4,5-c]pyridine-4-ones and imidazol[4,5-c]pyridine-2-ones and halogenated compounds thereof.

A Chinese patetent application CN 1386 737 A discloses N-aryl substutitued pyridone derivatives and the synthetic methof thereof.

Essa Hu, et al. (Journal of Medicinal Chemistry, 2008, 51, pp.3065-3068) discloses aryl aminoquinazoline pyridones as potent inhibitors of receptor tyrosine kinase c-Kit.

An international patetent application WO 2008/011109 A2 discloses bicyclic heteroaryl aminoquinazoline pyridones as potent inhibitors of receptor tyrosine kinase c-Kit and the medical use thereof in treatment of c-Kit mediated diseases, including various inflammatory, fibrotic and/or mast cell mediated disease such as mastocytosis.

An international patetent application WO 2009/149188 A1 discloses N-aryl substutitued pyridone derivatives and the medical use thereof in treatment of various inflammatory condition such as inflammatory pulmonary fibrosis.

Description

Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. Examples of fibrosis include, but are not limited to pulmonary fibrosis, liver fibrosis, dermal fibrosis, and renal fibrosis. Pulmonary fibrosis, also called idiopathic pulmonary fibrosis (IPF), interstitial diffuse pulmonary fibrosis, inflammatory pulmonary fibrosis, or fibrosing alveolitis, is a lung disorder and a heterogeneous group of conditions characterized by abnormal formation of fibrous tissue between alveoli caused by alveolitis comprising cellular infiltration into the alveolar septae with resulting fibrosis. The effects of IPF are chronic, progressive, and often fatal.

There continues to be a need for safe and effective drugs to treat fibrotic conditions such as idiopathic pulmonary fibrosis.

SUMMARY

The invention relates to a compound selected from compounds 717 to 722, 724 to 726, 729 to 732, 735 and 736 or a pharmaceutically acceptable salt thereof The compounds are useful in methods of treating a fibrotic condition, comprising administering a therapeutically effective amount of a compound selected from compounds 717 to 722, 724 to 726, 729 to 732, 735 and 736, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a subject in need thereof. The method may comprise identifying the subject as having or at risk of having said fibrotic condition. The compound, the pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof may be administered by inhalation. In some such embodiments, the fibrotic condition is selected from the group consisting of pulmonary fibrosis, dermal fibrosis, pancreatic fibrosis, liver fibrosis, and renal fibrosis. In some embodiment, the fibrotic condition is idiopathic pulmonary fibrosis. The subject receiving such method of treatment may be a human.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed. The use of "or" or "and" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting. As used in this specification, whether in a transitional phrase or in the body of the claim, the terms "comprise(s)" and "comprising" are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases "having at least" or "including at least." When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

As used herein, common organic abbreviations are defined as follows:

Ac

Acetyl

AC2O

Acetic anhydride

aq.

Aqueous

Bn

Benzyl

Bz

Benzoyl

BOC or Boc

tert-Butoxycarbonyl

Bu

n-Butyl

cat.

Catalytic

Cbz

Carbobenzyloxy

CDI

1,1'-carbonyldiimidazole

°C

Temperature in degrees Centigrade

DBU

1,8-Diazabicyclo[5.4.0]undec-7-ene

DCE

1,2-Dichloroethane

DCM

Methylene chloride

DIEA

Diisopropylethylamine

DMA

Dimethylacetamide

DME

Dimethoxyethane

DMF

N,N'-Dimethylformamide

DMSO

Dimethylsulfoxide

DPPA

Diphenylphosphoryl azide

ee%

Enantiomeric excess

Et

Ethyl

EtOAc or EA

Ethyl acetate

g

Gram(s)

h or hr

Hour(s)

HATU

2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate

HOBT

N-Hydroxybenzotriazole

iPr

Isopropyl

LCMS

Liquid chromatography-mass spectrometry

LDA

Lithium diisopropylamide

LiHMDS

Lithium bis(trimethylsilyl)amide

m or min

Minute(s)

mCPBA

meta-Chloroperoxybenzoic Acid

MeOH

Methanol

MeCN

Acetonitrile

mL

Milliliter(s)

MTBE

Methyl tertiary-butyl ether

NH4OAc

Ammonium acetate

PE

Petroleum ether

PG

Protecting group

Pd/C

Palladium on activated carbon

Pd(dppf)Cl2

1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride

Ph

Phenyl

ppt

Precipitate

PMBC

4-Methoxybenzyl chloride

RCM

Ring closing metathesis

rt

Room temperature

sBuLi

sec-Butylithium

SFC

Supercritical fluid chromatography

TBAF

Tetrabutylammonium fluoride

TEA

Triethylamine

TCDI

1,1'-Thiocarbonyl diimidazole

Tert, t

tertiary

TFA

Trifluoroacetic acid

TFAA

Trifluoroacetic acid anhydride

THF

Tetrahydrofuran

TLC

Thin-layer chromatography

TMEDA

Tetramethylethylenediamine

TMSNCO

trimethylsilyl isocyanate

µL

Microliter(s)

"Solvate" refers to the compound formed by the interaction of a solvent and a compound described herein or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.

The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of a compound and, which are not biologically or otherwise undesirable for use in a pharmaceutical. In many cases, the compounds disclosed herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297, Johnston et al., published September 11, 1987 .

As used herein, "C_a to C_b" or "C_a-b" in which "a" and "b" are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from "a" to "b", inclusive, carbon atoms. Thus, for example, a "C₁ to C₄ alkyl" or "C_1-4 alkyl" group refers to all alkyl groups having from 1 to 4 carbons, that is, CH₃-, CH₃CH₂-, CH₃CH₂CH₂-, (CH₃)₂CH-, CH₃CH₂CH₂CH₂-, CH₃CH₂CH(CH₃)- and (CH₃)₃C-.

The term "halogen" or "halo," as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; e.g., "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 9 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be designated as "C_1-4 alkyl" or similar designations. By way of example only, "C_1-4 alkyl" indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

As used herein, "alkoxy" refers to the formula -OR wherein R is an alkyl as is defined above, such as "C_1-9 alkoxy", including but not limited to methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, and the like.

As used herein, "alkylthio" refers to the formula -SR wherein R is an alkyl as is defined above, such as "C_1-9 alkylthio" and the like, including but not limited to methylmercapto, ethylmercapto, n-propylmercapto, 1-methylethylmercapto (isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec-butylmercapto, tert-butylmercapto, and the like.

As used herein, "alkenyl" refers to a straight or branched hydrocarbon chain containing one or more double bonds. The alkenyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl" where no numerical range is designated. The alkenyl group may also be a medium size alkenyl having 2 to 9 carbon atoms. The alkenyl group could also be a lower alkenyl having 2 to 4 carbon atoms. The alkenyl group may be designated as "C_2-4 alkenyl" or similar designations. By way of example only, "C_2-4 alkenyl" indicates that there are two to four carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl, 1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl, buta-1,2,-dienyl, and buta-1,2-dien-4-yl. Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl, and the like.

As used herein, "alkynyl" refers to a straight or branched hydrocarbon chain containing one or more triple bonds. The alkynyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl" where no numerical range is designated. The alkynyl group may also be a medium size alkynyl having 2 to 9 carbon atoms. The alkynyl group could also be a lower alkynyl having 2 to 4 carbon atoms. The alkynyl group may be designated as "C_2-4 alkynyl" or similar designations. By way of example only, "C_2-4 alkynyl" indicates that there are two to four carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl. Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.

As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the chain backbone. The heteroalkyl group may have 1 to 20 carbon atom, although the present definition also covers the occurrence of the term "heteroalkyl" where no numerical range is designated. The heteroalkyl group may also be a medium size heteroalkyl having 1 to 9 carbon atoms. The heteroalkyl group could also be a lower heteroalkyl having 1 to 4 carbon atoms. The heteroalkyl group may be designated as "C_1-4 heteroalkyl" or similar designations. The heteroalkyl group may contain one or more heteroatoms. By way of example only, "C_1-4 heteroalkyl" indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.

As used herein, "alkylene" means a branched, or straight chain fully saturated di-radical chemical group containing only carbon and hydrogen that is attached to the rest of the molecule via two points of attachment (i.e., an alkanediyl). The alkylene group may have 1 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkylene where no numerical range is designated. The alkylene group may also be a medium size alkylene having 1 to 9 carbon atoms. The alkylene group could also be a lower alkylene having 1 to 4 carbon atoms. The alkylene group may be designated as "C_1-4 alkylene" or similar designations. By way of example only, "C_1-4 alkylene" indicates that there are one to four carbon atoms in the alkylene chain, i.e., the alkylene chain is selected from the group consisting of methylene, ethylene, ethan-1,1-diyl, propylene, propan-1,1-diyl, propan-2,2-diyl, 1-methyl-ethylene, butylene, butan-1,1-diyl, butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 1-methyl-propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, and 1-ethyl-ethylene.

As used herein, "alkenylene" means a straight or branched chain di-radical chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond that is attached to the rest of the molecule via two points of attachment. The alkenylene group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkenylene where no numerical range is designated. The alkenylene group may also be a medium size alkenylene having 2 to 9 carbon atoms. The alkenylene group could also be a lower alkenylene having 2 to 4 carbon atoms. The alkenylene group may be designated as "C_2-4 alkenylene" or similar designations. By way of example only, "C_2-4 alkenylene" indicates that there are two to four carbon atoms in the alkenylene chain, i.e., the alkenylene chain is selected from the group consisting of ethenylene, ethen-1,1-diyl, propenylene, propen-1,1-diyl, prop-2-en-1,1-diyl, 1-methyl-ethenylene, but-1-enylene, but-2-enylene, but-1,3-dienylene, buten-1,1-diyl, but-1,3-dien-1,1-diyl, but-2-en-1,1-diyl, but-3-en-1,1-diyl, 1-methyl-prop-2-en-1,1-diyl, 2-methyl-prop-2-en-1,1-diyl, 1-ethyl-ethenylene, 1,2-dimethyl-ethenylene, 1-methyl-propenylene, 2-methyl-propenylene, 3-methyl-propenylene, 2-methyl-propen-1,1-diyl, and 2,2-dimethyl-ethen-1,1-diyl.

The term "aromatic" refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups provided that the entire ring system is aromatic.

As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) containing only carbon in the ring backbone. When the aryl is a ring system, every ring in the system is aromatic. The aryl group may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the term "aryl" where no numerical range is designated. In some embodiments, the aryl group has 6 to 10 carbon atoms. The aryl group may be designated as "C_6-10 aryl," "C₆ or C₁₀ aryl," or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

As used herein, "aryloxy" and "arylthio" refers to RO- and RS-, in which R is an aryl as is defined above, such as "C_6-10 aryloxy" or "C_6-10 arylthio" and the like, including but not limited to phenyloxy.

An "aralkyl" or "arylalkyl" is an aryl group connected, as a substituent, via an alkylene group, such as "C_7-4 aralkyl" and the like, including but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C_1-4 alkylene group).

As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the ring backbone. When the heteroaryl is a ring system, every ring in the system is aromatic. The heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heteroaryl" where no numerical range is designated. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group may be designated as "5-7 membered heteroaryl," "5-10 membered heteroaryl," or similar designations. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

A "heteroaralkyl" or "heteroarylalkyl" is heteroaryl group connected, as a substituent, via an alkylene group. Examples include but are not limited to 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C_1-4 alkylene group).

As used herein, "carbocyclyl" means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When the carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion. Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic. Thus, carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls. The carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term "carbocyclyl" where no numerical range is designated. The carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms. The carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms. The carbocyclyl group may be designated as "C_3-6 carbocyclyl" or similar designations. Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.

A "(carbocyclyl)alkyl" is a carbocyclyl group connected, as a substituent, via an alkylene group, such as "C_4-10 (carbocyclyl)alkyl" and the like, including but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. In some cases, the alkylene group is a lower alkylene group.

As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, "cycloalkenyl" means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic. An example is cyclohexenyl.

As used herein, "heterocyclyl" means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system. The heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heterocyclyl" where no numerical range is designated. The heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members. The heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members. The heterocyclyl group may be designated as "3-6 membered heterocyclyl" or similar designations. In preferred six membered monocyclic heterocyclyls, the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

A "(heterocyclyl)alkyl" is a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

As used herein, "acyl" refers to -C(=O)R, wherein R is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.

An "O-carboxy" group refers to a "-OC(=O)R" group in which R is selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

A "C-carboxy" group refers to a "-C(=O)OR" group in which R is selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. A non-limiting example includes carboxyl (i.e., -C(=O)OH).

A "cyano" group refers to a "-CN" group.

A "cyanato" group refers to an "-OCN" group.

An "isocyanato" group refers to a "-NCO" group.

A "thiocyanato" group refers to a "-SCN" group.

An "isothiocyanato" group refers to an " -NCS" group.

A "sulfinyl" group refers to an "-S(=O)R" group in which R is selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

A "sulfonyl" group refers to an "-SO₂R" group in which R is selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An "S-sulfonamido" group refers to a "-SO₂NR_AR_B" group in which R_A and R_B are each independently selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An "N-sulfonamido" group refers to a "-N(R_A)SO₂R_B" group in which R_A and R_b are each independently selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An "O-carbamyl" group refers to a "-OC(=O)NR_AR_B" group in which R_A and R_B are each independently selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An "N-carbamyl" group refers to an "-N(R_A)OC(=O)R_B" group in which R_A and R_B are each independently selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An "O-thiocarbamyl" group refers to a "-OC(=S)NR_AR_B" group in which R_A and R_B are each independently selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An "N-thiocarbamyl" group refers to an "-N(R_A)OC(=S)R_B" group in which R_A and R_B are each independently selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

A "C-amido" group refers to a "-C(=O)NR_AR_B" group in which R_A and R_B are each independently selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An "N-amido" group refers to a "-N(R_A)C(=O)R_B" group in which R_A and R_B are each independently selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An "amino" group refers to a "-NR_AR_B" group in which R_A and R_B are each independently selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. A non-limiting example includes free amino (i.e., -NH₂).

An "aminoalkyl" group refers to an amino group connected via an alkylene group.

An "alkoxyalkyl" group refers to an alkoxy group connected via an alkylene group, such as a "C_2-8 alkoxyalkyl" and the like.

As used herein, a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group. Unless otherwise indicated, when a group is deemed to be "substituted," it is meant that the group is substituted with one or more substituents independently selected from C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ heteroalkyl, C₃-C₇ carbocyclyl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), C₃-C₇-carbocyclyl-C₁-C₆-alkyl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10 membered heterocyclyl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10 membered heterocyclyl-C₁-C₆-alkyl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), aryl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), aryl(C₁-C₆)alkyl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10 membered heteroaryl(C₁-C₆)alkyl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), halo, cyano, hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C₁-C₆)alkyl (e.g., -CF₃), halo(C₁-C₆)alkoxy (e.g., -OCF₃), C₁-C₆ alkylthio, arylthio, amino, amino(C₁-C₆)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). Wherever a group is described as "optionally substituted" that group can be substituted with the above substituents.

It is to be understood that certain radical naming conventions can include either a mono-radical or a di-radical, depending on the context. For example, where a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical. For example, a substituent identified as alkyl that requires two points of attachment includes di-radicals such as -CH₂-, -CH₂CH₂-, -CH₂CH(CH₃)CH₂-, and the like. Other radical naming conventions clearly indicate that the radical is a di-radical such as "alkylene" or "alkenylene."

When two R groups are said to form a ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring) "together with the atom to which they are attached," it is meant that the collective unit of the atom and the two R groups are the recited ring. The ring is not otherwise limited by the definition of each R group when taken individually. For example, when the following substructure is present: and R¹ and R² are defined as selected from the group consisting of hydrogen and alkyl, or R¹ and R² together with the nitrogen to which they are attached form a heterocyclyl, it is meant that R¹ and R² can be selected from hydrogen or alkyl, or alternatively, the substructure has structure: where ring A is a heteroaryl ring containing the depicted nitrogen.

Similarly, when two "adjacent" R groups are said to form a ring "together with the atom to which they are attached," it is meant that the collective unit of the atoms, intervening bonds, and the two R groups are the recited ring. For example, when the following substructure is present: and R¹ and R² are defined as selected from the group consisting of hydrogen and alkyl, or R¹ and R² together with the atoms to which they are attached form an aryl or carbocylyl, it is meant that R¹ and R² can be selected from hydrogen or alkyl, or alternatively, the substructure has structure: where A is an aryl ring or a carbocylyl containing the depicted double bond.

Wherever a substituent is depicted as a di-radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated. Thus, for example, a substituent depicted as -AE- or includes the substituent being oriented such that the A is attached at the leftmost attachment point of the molecule as well as the case in which A is attached at the rightmost attachment point of the molecule.

As used herein, "isosteres" of a chemical group are other chemical groups that exhibit the same or similar properties. For example, tetrazole is an isostere of carboxylic acid because it mimics the properties of carboxylic acid even though they both have very different molecular formulae. Tetrazole is one of many possible isosteric replacements for carboxylic acid. Other carboxylic acid isosteres contemplated include -SO₃H, -SO₂HNR, -PO₂(R)₂, -PO₃(R)₂,-CONHNHSO₂R, -COHNSO₂R, and -CONRCN, where R is selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. In addition, carboxylic acid isosteres can include 5-7 membered carbocycles or heterocycles containing any combination of CH₂, O, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions. The following structures are non-limiting examples of carbocyclic and heterocyclic isosteres contemplated. The atoms of said ring structure may be optionally substituted at one or more positions with R as defined above.

It is also contemplated that when chemical substituents are added to a carboxylic isostere, the compound retains the properties of a carboxylic isostere. It is contemplated that when a carboxylic isostere is optionally substituted with one or more moieties selected from R as defined above, then the substitution and substitution position is selected such that it does not eliminate the carboxylic acid isosteric properties of the compound. Similarly, it is also contemplated that the placement of one or more R substituents upon a carbocyclic or heterocyclic carboxylic acid isostere is not a substitution at one or more atom(s) that maintain(s) or is/are integral to the carboxylic acid isosteric properties of the compound, if such substituent(s) would destroy the carboxylic acid isosteric properties of the compound.

"Subject" as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.

The term "mammal" is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats, mice guinea pigs, or the like.

The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press.

A therapeutic effect relieves, to some extent, one or more of the symptoms of a disease or condition, and includes curing a disease or condition. "Curing" means that the symptoms of a disease or condition are eliminated; however, certain long-term or permanent effects may exist even after a cure is obtained (such as extensive tissue damage).

"Treat," "treatment," or "treating," as used herein refers to administering a compound or pharmaceutical composition to a subject for prophylactic and/or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to administering treatment to a subject already suffering from a disease or condition.

Where the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers or as mixtures of such isomers, including racemates. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. Furthermore, compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included in the scope of the compounds disclosed herein including any polymorphic forms. In addition, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included in the scope of the compounds disclosed herein.

The skilled artisan will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be fairly represented by other chemical structures, even when kinetically; the artisan recognizes that such structures may only represent a very small portion of a sample of such compound(s). Such compounds are considered within the scope of the structures depicted, though such resonance forms or tautomers are not represented herein.

Isotopes may be present in the compounds described. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

Compounds

In some examples, the compound of formula (III) is selected from the group consisting of Compounds 717 to 722, 724 to 726, 729 to 732, 735 and 736 or a pharmaceutically acceptable salt thereof of Table 1.

Some embodiments described herein relate to a compound selected from the group consisting of Compounds 717 to 722. 724 to 726, 729 to 732, 735 and 736 of Table 1, or pharmaceutically acceptable salts thereof.

Administration and Pharmaceutical Compositions

Some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of a compound selected from compounds 717 to 722, 724 to 726, 729 to 732, 735 and 736 , or pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

The compounds are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease states previously described. While human dosage levels have yet to be optimized for the compounds of the preferred examples, generally, a daily dose for most of the compounds described herein is from about 0.25 mg/kg to about 120 mg/kg or more of body weight, from about 0.5 mg/kg or less to about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of body weight, or from about 1.5 mg/kg to about 10 mg/kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be from about 17 mg per day to about 8000 mg per day, from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200 mg to about 3000 mg per day. The amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.

Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred examples.

The compounds useful as described above can be formulated into pharmaceutical compositions for use in treatment of these conditions. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005).

In addition to the selected compound useful as described above, come examples include compositions containing a pharmaceutically-acceptable carrier. The term "pharmaceutically-acceptable carrier", as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances, which are suitable for administration to a mammal. The term "compatible", as used herein, means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction, which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations. Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration preferably to an animal, preferably mammal being treated.

Some examples of substances, which can serve as pharmaceutically-acceptable carriers or components thereof, are 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 methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.

The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice. The preparation of a single or unit dosage form however, does not imply that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, though a single administration is not specifically excluded. The skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.

The compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration. The skilled artisan will appreciate that oral and nasal compositions include compositions that are administered by inhalation, and made using available methodologies. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. Pharmaceutically-acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references,: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).

Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.

The pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for peroral administration is well-known in the art. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.

Peroral compositions also include liquid solutions, emulsions, suspensions, and the like. The pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.

Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.

Compositions described herein may optionally include other drug actives.

Inhalable Formulations

In some embodiments, a compound described herein can be prepared in inhalable formulations for administration via an atomizer. An atomizer allows a stream of air to move at a high velocity over the tip of a tube dipped in a solution. The pressure at the tip of the tube is lowered and the solution is drawn into the air flow. The solution disperses into a fine spray or droplets that are carried into the inhaled stream of air.

In some embodiments the inhalable solution formulations described herein are administered with a nebulizer that is placed in the mouth. The spray, mist or fine droplets produced by atomizers or nebulizers allow the compound described herein to reach the bronchioles in the lungs. Various nebulizers suitable for this use include jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. A jet nebulizer utilizes air pressure breakage of an aqueous solution into aerosol droplets. An ultrasonic nebulizer utilizes shearing of the aqueous solution by a piezoelectric crystal. Vibrating mesh nebulizers rely upon either piezoelectric or mechanical pulses to generate respirable liquid droplets. A vibrating mesh nebulizer consists of a liquid storage container in fluid contact with a diaphragm and inhalation and exhalation valves. Commercial examples of nebulizers that can be used include Respirgard II^®, Aeroneb^®, Aeroneb^® Pro, and Aeroneb^® Go produced by Aerogen; AERx^® and AERx Essence^™ produced by Aradigm; Porta-Neb^®, Freeway Freedom^™, Sidestream,, Ventstream and I-neb produced by Respironics, Inc.; and PARI LC-Plus^®, PARI LC-Star^®, and e-Flow^7m produced by PARI, GmbH.

By non-limiting example, a compound disclosed herein is placed in a liquid nebulization inhaler and prepared in dosages to deliver from about 7 to about 700 mg from a dosing solution of about 1 to about 5 ml, preferably from about 14 to about 350 mg in about 1 to about 5 ml, and most preferably from about 28 to about 280 mg in about 1 to about 5 ml with mass median aerodynamic diameter (MMAD) particles sizes between about 2 to about 5 um being produced.

By non-limiting example, a nebulized compound disclosed herein may be administered in the prescribed respirable delivered dose in less than about 20 min, preferably less than about 10 min, more preferably less than about 7 min, more preferably less than about 5 min, more preferably less than about 3 min, and in some cases most preferable if less than about 2 min.

In some embodiments, the inhalable formulations described herein comprise a propellant and are pressure packaged for administration of a compound described herein using pressurized aerosols. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount.

In some embodiments, the inhalable formulations described herein are administered with a metered dose spray bottle that delivers a specific volume of a solution, suspension, emulsion or colloidal dispersion for inhalation.

In some examples, dry powder inhalable formulations are administered with an insufflator. An insufflator consists of a rubber bulb connected to a container and a delivery pipe. As the bulb is squeezed, air is blown into the container and causes the powder to move. The particles are carried out via the delivery tube and are inhaled.

In some examples, dry powder inhalable formulations are administered with a puffer. The dry powder is placed in the puffer and the puffer is squeezed. A portion of the powder is ejected from the spout into the air and is inhaled. Capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator may be formulated containing a dry powder formulation.

In some examples, a propellant driven inhaler (pMDI) releases a metered dose of a compound described herein upon each actuation. In such applications, the compound can be formulated as a suspension or solution of a drug substance in a suitable propellant such as a halogenated hydrocarbon. The propellants for use with the MDIs may be any propellants known in the art. Examples of propellants include chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluorometbane, and dichlorotetrafluoroethane; hydrofluoroalkanes (HFAs); and carbon dioxide.

Excipients

In some embodiments, the compounds described herein are administered via an inhalable formulation comprising one or more excipients. Alternatively, the compounds may be administered without excipients.

The excipients described herein include, but not limited to, pharmaceutical grades of carbohydrates (monosaccharides, disaccharides, polysaccharides such as hyaluronic acid, heparin/heparan sulfate, dermatan sulfate, chondroitin sulfate, keratin sulfate, alginic acid and salts thereof, and cellulose; oligosaccharides, polyols, and combinations and derivatives thereof), organic and inorganic salts, polymers including natural biodegradable protein polymers, natural biodegradable polysaccharide polymers, synthetic polymers and synthetic biodegradable polymers, amino acids, phospholipids, wetting agents, emulsifiers, surfactants, poloxamers, pluronics, and ion exchange resins, and combinations thereof.

In some embodiments, the compound described herein is in an inhalable formulation for delivery to the lungs that comprises one or more pH adjusting agents. Examples of pH adjusting agents or buffering agents, include, but are not limited to acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

In some embodiments, the compound described herein is in an inhalable formulation for delivery to the lungs of a mammal that comprises one or more tonicity agents. Tonicity agents are used to adjust the composition of the formulation to the desired isotonic range. Tonicity agents include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Non-limiting examples of these salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate. Other exemplary tonicity agents include mannitol, dextrose,

In some embodiments, the compound described herein is in an inhalable formulation for delivery to the lungs of a mammal that comprises one or more preservatives to inhibit microbial activity. Non-limiting examples of suitable preservatives include benzoic acid, boric acid, p-hydroxybenzoates, alcohols, mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

In certain embodiments, the formulations described herein optionally include one or more stabilizers (e.g., antioxidants) to enhance chemical stability where required. Non-limiting examples of suitable antioxidants include, ascorbic acid, methionine, sodium thiosulfate and sodium metabisulfite. In some embodiments, antioxidants are selected from metal chelating agents, thiol containing compounds and other general stabilizing agents.

In some embodiments, the compound described herein is in an inhalable formulation for delivery to the lungs that comprises one or more propellants. Non-limiting exemplary propellants include one or mixture of chlorofluorocarbons, such as dichlorodifiuoromethane, trichlorofiuoromethane, dichlorotetrafluoroethane or the like, as well as hydrofluorocarbons, such as 1,1,1,2-tetrafluoroethane (HFC-134a) and 1,1,1,2,3,3,3 - heptafluoropropane (HFC-227) or the like, carbon dioxide or other suitable gas. In certain examples, the propellants are used with a co-solvent. Non-limiting exemplary co-solvents include alcohols such as ethyl alcohol, isopropyl alcohol, propylene glycol, hydrocarbons such as propane, butane, isobutane, pentane, isopentane, neopentane, and other propellants such as those commonly referred to as Propellants 11, 12, 114, 113, 142b, 152a 124, and dimethyl ether.

In some embodiments, the compound described herein is in an inhalable formulation for delivery to the lungs that comprises one or more surfactants. Non-limiting examples of surfactants for inhalable formulations include and are not limited to oils derived from natural sources, such as, corn oil, olive oil, cotton seed oil and sunflower seed oil; sorbitan esters, such as Sorbitan trioleate available under the trade name Span 85, Sorbitan mono-oleate available under the trade name Span 80, Sorbitan monolaurate available under the trade name Span 20, Polyoxyethylene (20) sorbitan monolaurate available under the trade name Tween 20, Polyoxyethylene (20) sorbitan mono-oleate available under the trade name Tween 80; lecithins derived from natural sources such as those available under the trade name Epikuron particularly Epikuron 200. Oleyl polyoxyethylene (2) ether available under the trade name Brij 92, Stearyl polyoxyethylene (2) available under the trade name Brij 72, Lauryl polyoxyethylene (4) ether available under the trade name Brij 30, Oleyl polyoxyethylene (2) ether available under the trade name Genapol 0-020, Block copolymers of oxyethylene and oxypropylene available under the trade name Synperonic, Oleic acid, Synthetic lecithin, Diethylene glycol dioleate, Tetrahydrofurfuryl oleate, Ethyl oleate, Isopropyl myristate, Glyceryl trioleate, Glyceryl monolaurate, Glyceryl mono- oleate, Glyceryl monostearate, Glyceryl monoricinoleate, Cetyl alcohol, Stearyl alcohol, Polyethylene glycol 400, and Cetyl pyridinium chloride.

In some examples, the solution, emulsion, suspension and/or colloidal dispersion formulations also include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and/or emulsifiers. Non-limiting exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, sodium lauryl sulfate, sodium doccusate, cholesterol, cholesterol esters, taurocholic acid, phosphotidylcholine, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.

In some examples, the inhalable formulations described herein are stable (e.g., with respect to pH, active ingredient) over a period of any of at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 4 months, at least about 5 months, at least about 6 months, or greater than 6 months.

In certain examples, the inhalable formulations described herein are designed for minimal pulmonary toxicity, irritation and/or allergic challenge to pulmonary tissues and include, for example, low amounts of excipients such as surfactants, preservatives and/or co-solvents.

Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.

A liquid composition, which is formulated for topical ophthalmic use, is formulated such that it can be administered topically to the eye. The comfort should be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort. In the case that comfort cannot be maximized, the liquid should be formulated such that the liquid is tolerable to the patient for topical ophthalmic use. Additionally, an ophthalmically acceptable liquid should either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often prepared using a physiological saline solution as a major vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH with an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.

Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate and phenylmercuric nitrate. A useful surfactant is, for example, Tween 80. Likewise, various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.

Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. For many compositions, the pH will be between 4 and 9. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

Other excipient components, which may be included in the ophthalmic preparations, are chelating agents. A useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.

For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound disclosed herein are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.

For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various examples, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7. Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332. Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

The compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration. In other examples, the compositions are provided in solution ready to administer parenterally. In still other examples, the compositions are provided in a solution that is further diluted prior to administration. In examples that include administering a combination of a compound described herein and another agent, the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.

The actual dose of the active compounds described herein depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.

Method of Treatment

The compounds of the invention are for use in a method of treating a fibrotic condition, which can include administering a therapeutically effective amount of a compound selected from compounds 717 to 722, 724 to 726, 729 to 732, 735 and 736, or a pharmaceutically acceptable salt thereof, to a subject. The methods include identifying a subject at risk for or having a fibrotic condition and administering a compound to the subject in an effective amount for therapeutic treatment or prophylactic treatment of the fibrotic condition. The compound selected from compounds 717 to 722, 724 to 726, 729 to 732, 735 and 736, the pharmaceutical acceptable salt thereof, or the pharmaceutical composition thereof may be administered by inhalation.

A "fibrotic condition," "fibroproliferative condition," "fibrotic disease," "fibroproliferative disease," "fibrotic disorder," and "fibroproliferative disorder" are used interchangeably to refer to a condition, disease or disorder that is characterized by dysregulated proliferation or activity of fibroblasts and/or abnormal accumulation of fibronectin and/or pathologic or excessive accumulation of collagenous tissue. Typically, any such disease, disorder or condition is amenable to treatment by administration of a compound having anti-fibrotic activity. Fibrotic disorders include, but are not limited to, pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis from a known etiology, dermal fibrosis, pancreatic fibrosis, liver fibrosis (e.g., hepatic fibrosis associated with chronic active hepatitis), and renal fibrosis.

In some embodiments, the subject is a human.

The terms "therapeutically effective amount," as used herein, refer to an amount of a compound sufficient to cure, ameliorate, slow progression of, prevent, or reduce the likelihood of onset of the identified disease or condition, or to exhibit a detectable therapeutic, prophylactic, or inhibitory effect. The effect can be detected by, for example, the assays disclosed in the following examples. The precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically and prophylactically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

For any compound, the therapeutically or prophylactically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.

Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED₅₀(the dose therapeutically effective in 50% of the population) and LD₅₀(the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, ED₅₀/LD₅₀. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. However, pharmaceutical compositions that exhibit narrow therapeutic indices are also within the scope of the invention. The data obtained from cell culture assays and animal studies may be used in formulating a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that include an ED₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

The exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

In one aspect, treating a condition described herein results in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects. Preferably, the average survival time is increased by more than about 30 days; more preferably, by more than about 60 days; more preferably, by more than about 90 days; and even more preferably by more than about 120 days. An increase in survival time of a population may be measured by any reproducible means. In a preferred aspect, an increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound. In an another preferred aspect, an increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.

In another aspect, treating a condition described herein results in a decrease in the mortality rate of a population of treated subjects in comparison to a population of subjects receiving carrier alone. In another aspect, treating a condition described herein results in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. In a further aspect, treating a condition described herein results a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the examples, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof. Preferably, the mortality rate is decreased by more than about 2%; more preferably, by more than about 5%; more preferably, by more than about 10%; and most preferably, by more than about 25%. In a preferred aspect, a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means. In another preferred aspect, a decrease in the mortality rate of a population may be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound. In another preferred aspect, a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease related deaths per unit time following completion of a first round of treatment with an active compound.

In another aspect, treating a condition described herein results in a reduction in the rate of cellular proliferation. Preferably, after treatment, the rate of cellular proliferation is reduced by at least about 5%; more preferably, by at least about 10%; more preferably, by at least about 20%; more preferably, by at least about 30%; more preferably, by at least about 40%; more preferably, by at least about 50%; even more preferably, by at least about 60%; and most preferably, by at least about 75%. The rate of cellular proliferation may be measured by any reproducible means of measurement. In a preferred aspect, the rate of cellular proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.

In another aspect, treating a condition described herein results in a reduction in the proportion of proliferating cells. Preferably, after treatment, the proportion of proliferating cells is reduced by at least about 5%; more preferably, by at least about 10%; more preferably, by at least about 20%; more preferably, by at least about 30%; more preferably, by at least about 40%; more preferably, by at least about 50%; even more preferably, by at least about 60%; and most preferably, by at least about 75%. The proportion of proliferating cells may be measured by any reproducible means of measurement. In a preferred aspect, the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of nondividing cells in a tissue sample. In another preferred aspect, the proportion of proliferating cells is equivalent to the mitotic index.

In another aspect, treating a condition described herein results in a decrease in size of an area or zone of cellular proliferation. Preferably, after treatment, size of an area or zone of cellular proliferation is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least about 10%; more preferably, reduced by at least about 20%; more preferably, reduced by at least about 30%; more preferably, reduced by at least about 40%; more preferably, reduced by at least about 50%; even more preferably, reduced by at least about 60%; and most preferably, reduced by at least about 75%. Size of an area or zone of cellular proliferation may be measured by any reproducible means of measurement. In a preferred aspect, size of an area or zone of cellular proliferation may be measured as a diameter or width of an area or zone of cellular proliferation.

The methods described herein may include identifying a subject in need of treatment. In a preferred embodiment, the methods include identifying a mammal in need of treatment. In a highly preferred embodiment, the methods include identifying a human in need of treatment. Identifying a subject in need of treatment may be accomplished by any means that indicates a subject who may benefit from treatment. For example, identifying a subject in need of treatment may occur by clinical diagnosis, laboratory testing, or any other means known to one of skill in the art, including any combination of means for identification.

As described elsewhere herein, the compounds described herein may be formulated in pharmaceutical compositions, if desired, and can be administered by any route that permits treatment of the disease or condition. A preferred route of administration is oral administration. Administration may take the form of single dose administration, or the compound of the examples can be administered over a period of time, either in divided doses or in a continuous-release formulation or administration method (e.g., a pump). However the compounds of the examples are administered to the subject, the amounts of compound administered and the route of administration chosen should be selected to permit efficacious treatment of the disease condition.

Further examples include administering a combination of compounds to a subject in need thereof. A combination can include a compound, composition, pharmaceutical composition described herein with an additional medicament.

Some examples include co-administering a compound, composition, and/or pharmaceutical composition described herein, with an additional medicament. By "coadministration," it is meant that the two or more agents may be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered. In some examples, the agents are administered simultaneously. In some such such examples, administration in combination is accomplished by combining the agents in a single dosage form. In some examples, the agents are administered sequentially. In some examples the agents are administered through the same route, such as orally. In some other examples, the agents are administered through different routes, such as one being administered orally and another being administered i.v. Thus, for example, the combination of active ingredients may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art. When delivered in alternation therapy, the methods described herein may comprise administering or delivering the active ingredients sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in simultaneous therapy, effective dosages of two or more active ingredients are administered together. Various sequences of intermittent combination therapy may also be used.

Pulmonary Fibrosis

Pulmonary fibrosis also called idiopathic pulmonary fibrosis (IPF), interstitial diffuse pulmonary fibrosis, inflammatory pulmonary fibrosis, or fibrosing alveolitis, is a lung disorder and a heterogeneous group of conditions characterized by abnormal formation of fibrous tissue between alveoli caused by alveolitis comprising cellular infiltration into the alveolar septae with resulting fibrosis. The effects of IPF are chronic, progressive, and often fatal. The compounds and methods described herein are useful in the treatment of pulmonary fibrosis, such as IPF.

Renal Fibrosis

Irrespective of the nature of the initial insult, renal fibrosis is considered to be the common final pathway by which kidney disease progresses to end-stage renal failure. The compounds and methods described herein are useful in the treatment of renal fibrosis.

Synthesis

The compounds disclosed herein may be synthesized by methods described below, or by modification of these methods. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc., known to those skilled in the art. In general, during any of the processes for preparation of the compounds disclosed herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973); and P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999). The protecting groups may be removed at a convenient subsequent stage using methods known from the art. Synthetic chemistry transformations useful in synthesizing applicable compounds are known in the art and include e.g. those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989 , or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995.

EXAMPLES

Additional examples are disclosed in further detail in the following examples.

Example 5-E Synthesis of Compound 46 (Scheme XII)

To the mixture of XII-1 (10.0 g, 10 mmol) dissolved in HBr 48% (200 mL), Br₂ (12.5 mL, 13.4 mmol) was added dropwise under ice-water cooling bath, maintaining the temperature below 40°C. After that, the mixture was heated at 110°C for 5 hrs. The reaction mixture was cooled to rt, filtered and washed with little water. The filter cake is basified to pH 7~8 with saturated aq. NaHCO₃ and extracted with EtOAc (200 mL×3). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated to yield XII-2 (17.2 g, 71% yield). ¹H NMR (DMSO-d₆ , 400 MHz) δ 7.95 (s, 1H), 5.20 (brs, 4H).

XII-2 (5.0 g, 18.9 mmol) and aqueous glyoxal (40%, 5 mL) was dissolved in n-BuOH (15 mL), the mixture was stirred at 80°C for 2 hrs. The reaction mixture was cooled to rt, a solid was precipitated out, filtered, washed with PE and dried in vacuum to afford XII-3 (5.0 g, 92% yield) as a yellow solid, which was used in next step without further purification. ¹H NMR (CDCl₃, 400 MHz) δ 9.18 (d, J = 2.0 Hz, 1H), 9.11 (d, J = 2.0 Hz, 1H), 8.84 (s, 1H).

XII-3 (5.0 g, 17.3 mmol) and NaOMe (1.4 g, 26 mmol) were dissolved in MeOH (60 mL), and then the mixture was stirred at 60°C for 0.5 h. Removed the solvent, diluted with EtOAc (100 mL), washed with brine, dried over Na₂SO₄ and concentrated to give XII-4 (3.7 g, 89% yield) as a light yellow solid, which was used in next step without further purification. ¹H NMR (CDCl₃, 300 MHz) δ 9.05 (d, J = 1.8 Hz, 1H), 8.88 (d, J = 1.8 Hz, 1H), 8.46 (s, 1H), 4.17 (s, 3H).

XII-4 (2.0 g, 8.4 mmol) and NaSEt (3.2 g, 38 mmol) was dissolved in DMF (30 mL), the mixture was stirred at 60°C for 1.5 hrs. The reaction mixture was cooled to rt, diluted with water (30 mL) and acidified to pH=6~7 with conc. HCl. The precipitate was collected by filtration, washed with water and dried in vacuum to afford XII-5 (1.9 g, 100% yield) as a brown solid. ¹H NMR (DMSO-d₆ , 400 MHz) δ 8.84 (d, J= 2.0 Hz, 1H), 8.57 (d, J = 1.6 Hz, 1H), 7.95 (s, 1H).

To a solution of XII-5 (2.0 g, 10 mmol) in DCM (100 mL), copper (II) acetate (3.6 g, 20 mmol), XII-6 (2.0 g, 12 mmol), pyridine (3 mL), pyridine-N-oxide (1.9 g, 20 mmol) and finely ground, activated 4Å molecular sieves (3.0 g) were added. The mixture was stirred at rt. for 18 hrs under O₂ atmosphere. The solvent was evaporated and the residue was diluted with AcOEt (150 mL) and filtered. The filtrate was washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by flash chromatography on silica gel with petroleum ether/EtOAc (1:1~1:2) to yield XII-7 (400 mg, 12 % yield) as a yellow solid. MS (ESI) m/z (M+H)⁺ 386.

Compound 46 was prepared following the similar procedure for obtaining Compound 42 (75 mg, 72 % yield). ¹H NMR (CD₃OD, 400 MHz) δ 9.01 (d, J = 2.0 Hz, 1H), 8.89 (d, J = 2.0 Hz, 1H), 7.83 ( s, 1H), 7.73-7.70 (m, 2H), 7.68-7.65 (m, 2H), 7.51 (d, J = 8.0 Hz, 2H),7.21-7.16 (m, 2H). MS (ESI) m/z (M+H)⁺ 401.9.

Compound 717 was prepared from XII-4 in three steps according to the scheme above following the similar procedure as described in Example 5-E. ¹H NMR (400MHz, CDCl₃) δ 8.96 (d, J=2.0 Hz, 1H), 8.90 (d, J=2.0 Hz, 1H), 8.12 (s, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.55 - 7.54 (m, 2H), 7.50 - 7.47 (m, 3H), 3.98 (s, 1H). MS (ESI) m/z (M+H)⁺ 304.0. The corresponding HCl salts were also prepared following the similar procedure described herein. ¹H NMR (400MHz, MeOH-d⁴) δ 9.11 (d, J=2.0 Hz, 1H), 8.93 (s, 1H), 8.81 (s, 1H), 8.73 (s, 1H), 8.21 (s, 1H), 7.59-7.53 (m, 5H), 4.17 (s, 3H). MS (ESI) m/z (M+H)⁺ 304.1.

Compound 721 was prepared in two steps from 8-bromopyrido[3,4-b]pyrazin-5-ol by first undergoing copper acetate catalyzed coupling with (4-(trifluoromethoxy)phenyl)boronic acid to form 8-bromo-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-b]pyrazin-5(6H)-one, followed by Pd(dppf)Cl₂ catalyzed coupling with pyridin-4-ylboronic acid to afford the final product. LCMS [ESI] m/z [M+1]⁺ 385.1. ¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (d, J=2.0 Hz, 1H), 9.02 (d, J=2.0 Hz, 1H), 8.93 (d, J=5.2 Hz, 2H), 8.54 (s, 1H), 8.46 (d, J=4.4 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H).

Compound 722 was prepared by reacting XII-7 with 3-(tributylstannyl)pyridazine following the similar procedure described in the synthesis of Compound 719 as a yellow solid. ¹H NMR (400 MHz, DMSO-d ₆) δ ppm 7.61 (d, J=8Hz, 2H) 7.78-7.82 (m, 3H) 8.30- 8.32 (m, 1H) 8.39 (s, 1H) 9.00 (d, J=2 Hz, 1H) 9.07 (d, J=2Hz, 1H) 9.23 - 9.24 (m, 1H). HCl salt Compound 722a: ¹H NMR (400 MHz, DMSO-d6) ppm 7.61 (d, J=8.4Hz, 2H) 7.79 (d, J=8.8 Hz, 2H) 7.82 - 7.86 (m, 1H) 8.33 - 8.36 (m, 1H) 8.40 (s, 1 H) 9.00 (d, J=2.4Hz, 1H) 9.07 (d, J=2 Hz, 1H) 9.25-9.26 (m, 1H).

Compound 726 was prepared following the similar procedure described in the preparation of Compound 722, using 4-(tributylstannyl)pyridazine instead to afford a white solid. ¹H NMR (400 MHz, DMSO-d6) ppm 7.59 (d, J=8.4Hz, 2H) 7.76 (d, J=8.8Hz, 2H) 8.01-8.03 (dd, J₁ =2.4Hz, J₂ =5.6 Hz, 1H) 8.37 (s, 1H) 8.98 (d, J=2Hz, 1H) 9.06 (d, J=2Hz, 1H) 9.26 (d, J=4.4Hz, 1H) 9.57 (s, 1H). HCl salt Compound 726a: ¹H NMR (400 MHz, DMSO-d6) ppm 7.63 (d, J=8.4Hz, 2H) 7.80 (d, J=8.8Hz, 2H) 8.39 - 8.41 (dd, J ₁ =2.0Hz, J₂ =5.2Hz, 1H) 8.54 (s, 1H) 9.03 (d, J=2Hz, 1H) 9.11 (d, J=2Hz, 1H) 9.44 (d, J=5.2Hz, 1H) 9.76 (d, J=1.2Hz, 1H).

Compound 730 was prepared by copper acetate catalyzed coupling of XII-5c with (4-chloro-2-methylphenyl)boronic acid following the similar condition described in the synthesis of Compound 717 as a yellow solid. ¹H NMR (CDCl₃, 400 MHz ): δ8.98 (d, J=2.0Hz, 1H), 8.91 (d, J=1.6Hz, 1H), 8.13 (s, 1H), 7.77 (s, 1H), 7.49 (s, 1H), 7.39 (s, 1H), 7.35-7.33 (m, 1H), 7.25-7.23 (m, 1H), 3.98 (s, 3H), 2.21 (s, 3H). MS (ESI) m/z (M+H) ⁺ 351.9. HCl salt Compound 730a: ¹H NMR (DMSO-d₆ , 400MHz): δ9.10 (d, J=2.0 Hz, 1H), 8.92 (s, 1H), 8.35 (s, 1H), 7.98 (d, J=1.6Hz, 2H), 7.55 (s, 1H), 7.44 (s, 2H), 3.85 (s, 3H), 2.09 (s, 3H). MS (ESI) m/z (M+H) ⁺ 351.9.

Compound 735 was prepared following the similar procedure described in the synthesis of Compound 397 using (4-chloro-2-methylphenyl)boronic acid in place of XII-6a and XII-8b in place of XII-8a. MS (ESI) m/z (M+H)⁺ 338.2.

Compound 736 was prepared following the similar procedure described in the synthesis of Compound 397 using phenyl boronic acid in place of XII-6a and XII-8b in place of XII-8a. MS (ESI) m/z (M+H)⁺ 290.

Example 5-H Synthesis of Compounds 54-59 (Scheme XV)

To a solution of XV-1 (15 g, 96.2 mmol) in AcOH (120 mL) were added Br₂ (16.7 g, 105.8 mmol). After addition, the reaction mixture was stirred at 70°C for 30min. Then the reaction mixture was poured into ice-water, the resulting precipitate was collected by filtration, washed with water and dried in reduced pressure to afford XV-2 as a yellow solid (14 g, 60% yield). ¹H NMR (DMSO-d₆ , 400MHz) δ 7.85 (s, 1H).

XV-2 (2 g, 8.5 mmol) was added into POCl₂OPh (10 mL), and then the reaction mixture was heated at refluxed for 2hrs. The mixture was cooled to rt and neutralize with saturated aq. Na₂CO₃, the mixture was extracted with EtOAc. The combined organic phase was dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=10:1) to afford XV-3 as a pale yellow solid. (1.5 g, 65% yield). ¹HNMR (CDCl₃, 300MHz) δ 8.71 (s, 1 H).

To a solution of XV-3 (544 mg, 2 mmol) in 10 mL of DMF was added BnNH₂ (268 mg, 2 mmol) at 0°C. The mixture was stirred for 18h at rt. TLC (PE: EA=5:1) analysis showed the reaction completed. The mixture was diluted with water, extracted with EtOAc (30 mL×3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered, concentrated to give yellow oil. Purification by column chromatography gave XV-4 as a white solid (400 mg, 58% yield). MS (ESI) m/z [M+H]⁺ 342.2.

To a solution of XV-4 (200 mg, 0.58 mmol, 1 eq.) in 6 mL of AcOH was added Fe powder (131 mg, 2.34 mmol, 4 eq.). The mixture was heated at 70-80°C and stirred for 3hrs. TLC (PE: EA=5:1) analysis showed the reaction completed. The mixture was cooled down to rt, neutralized with saturated aq. K₃PO₄, extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered, concentrated to give yellow oil. Purification by prep-TLC gave crude XV-5 (182 mg, 100% crude yield). MS (ESI) m/z (M+H)⁺ 313.9.

The mixture of XV-5 (1.5 g, 4.8 mmol, 1 eq) and 20 mL of formic acid was heated at 100°C for 18hrs. The reaction mixture was cooled down to rt, neutralized with saturated aq. K₃PO₄, extracted with EtOAc (100 mL×3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered, concentrated to give XV-6 (1.2 g, 82% yield). MS (ESI) m/z (M+H)⁺ 304.0.

The preparation of XV-8 followed the similar procedure for obtaining X-6 (1.1 g, 61% yield). MS (ESI) m/z (M+H)⁺ 465.9.

XV-12: To a solution of XV-11 (1 eq.) in DMF was added NaH (1.5 eq.) at 0°C. The mixture was stirred at 0°C for 30 min. After that, MeI (1.5 eq.) was added. The resulting mixture was stirred for 16hrs at rt. TLC (PE: EA=1:1) analysis showed the reaction completed. The mixture was diluted with water, extracted with EtOAc. The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by prep-HPLC to yield XV-12.

Alternative synthesis of Compound 59

The alternative synthesis of Compound 59 was performed according to the standard procedure as described herein. XV-8c: ¹H NMR (CDCl₃, 400 MHz ) δ 7.70 (s, 1H), 7.46 (d, J=8.8Hz, 2H), 7.34-7.31 (m, 3H), 4.07 (s, 3H). HCl salt compound 59a: ¹H NMR (DMSO-d₆ , 400MHz) δ 8.43 (s, 1H), 7.97 (s, 1H), 7.67 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.38 (s, 1H), 3.89 (s, 3H), 3.61 (s, 3H). MS (ESI) m/z (M+H)⁺ 390.1.

Alternative synthesis of XV-6c

To a solution of compound 1 (200 g, 1.26 mol) in DCM (300 mL) was CH₃NH₂ (260 g, 2.5 mol) at -5°C to 30°C. After addition, the mixture was stirred for 30 mins at rt. TLC showed the reaction was completed. The appeared solid was collected by filtration, the solid was washed with DCM to give one of the part crude compound 2 (178.3 g, 91.9 %) as a yellow solid. The filtrate was concentrated and the residue was washed with DCM (50 mL) to give another part of the crude compound 2 (14.7 g, 8.1 %) as a yellow solid.

A mixture of compound 2 (50.0 g, 0.33 mol) in conc. HCl (200 mL) was heated to 90°C. To this hot solution was added SnCl₂ • 2H₂O (147.0 g, 0.65 mol) in ten portions over a 60s period. This formed emulsion was stirred at 90°C for 1h. After cooling to 0°C, aq. NaOH (about 500 mL, 20%) was added dropwise to the mixture and adjusted to pH (5-6), in this process more precipitate formed. The solution was adjusted to pH=9 with 2M ammonia, and the resulting emulsion was diluted with water, extracted with DCM. The combined organic layers were dried over Na₂SO₄, and concentrated to give compound 3(43 g, yield 83%) as yellow solid.

A mixture of compound 3 (43.0 g, 0.27 mol) and HCOOH (125.0 g, 0.55 mol) in 12M HCl (250 mL) was stirred at reflux for 18hs. After evaporation to dryness, the resulting solid was suspended in EA and stirred at rt for 30 mins, filtered. The filter cake was dissolved in MeOH and adjusted pH to 8 with ion exchange resin, filtered, the filtrate was concentrated to afford the Compound 715 (37 g, yield 92 %) as yellow solid. MS (ESI) m/z (M+H)⁺ 150.1. ¹H NMR (Methanol-d₄ , 400 MHz): δ 9.26 (s, 1H), 7.48 (d, J=7.2Hz, 1H), 6.83 (d, J=7.2Hz, 1H), 3.98 (s, 2H).

Preparation of Compound 718: To a mixture of XV-8c (2 g, 5.15 mmol) in DMF (20 mL) was added pyridin-4-ylboronic acid (950 mg, 7.73 mmol), K₃PO₄ (2.19 g, 10.31 mmol), Pd(PPh₃)₄ (297.7 mg, 0.257 mmol). The reaction mixture was stirred at 110°C for 12hrs under N₂ atmosphere. The solid was filtered; the filtrate was mixed with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was washed with DCM/MeOH (10:1). The filter cake was recrystallized from methanol to give Compound 718 (810 mg, yield 51 %) as white solid. ¹H NMR (CDCl₃, 400MHz): δ 8.74-8.72 (m, 2H), 7.74 (s, 1H), 7.52-7.49 (m, 2H), 7.39-7.37 (m, 2H), 7.34 (d, J=8.0Hz, 2H), 7.12 (s, 1H), 3.47 (s, 3H). MS (ESI) m/z (M+H)⁺ 387.0. The corresponding HCl salt Compound 718a was prepared by mixing Compound 718 in HCl/MeOH (4M) and stred at rt for 16hr as a light gree solid. ¹H NMR (DMSO-d₆ , 400MHz): δ 8.92 (d, J=6.4 Hz, 2H), 8.26 (s, 1H), 8.19 (d, J=6.4 Hz, 2H), 7.81 (s, 1H), 7.66-7.64 (m, 2H), 7.54 (d, J=8.8 Hz, 2H), 3.54 (s, 3H). MS (ESI) m/z (M+H)⁺ 387.0.

Preparation of Compound 719: To a mixture of XV-8c (1 g, 2.58 mmol) in dioxane (100 mL) was added 4-(tributylstannyl)pyridazine (2.24 g, 5.15 mmol), Pd(PPh₃)₂Cl₂ (181 mg, 0.257 mmol). The reaction mixture was stirred at 120°C for 16hrs under N₂ protection. The solid was filtered; the filtrate was mixed with water and extracted with DCM. The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was washed with DCM/MeOH (10:1). The filter cake was purified by prep-HPLC (neutral system) to give Compound 719 (258.5 mg, yield 25.9 %) as a white solid. ¹H NMR (CDCl₃, 400 MHz ): δ9.34 (s, 1H), 9.32 (d, J=5.2Hz, 1H), 7.76 (s, 1H), 7.57 (m, 1H), 7.50 (d, J=8.8Hz, 2H), 7.35 (d, J=8.8 Hz, 2H), 7.17 (s, 1H), 3.50 (s, 3H). MS (ESI) m/z (M+H)⁺ 388.0. HCl salt Compound 719a was prepapred following the similar procedure as described herein as a yellow solid.

Compound 720 was prepared in two steps following the similar procedure described in the alternative synthesis of Compound 59 by first reacting XV-6c with phenyl boronic acid, followed by Pd(PPh₃)₄/K₃PO₄ catalyzed Suzuki coupling with XV-9c as a white solid. ¹H NMR (CDCl₃, 400 MHz ): δ 7.66 (s, 1H), 7.56 (s, 1H), 7.49 (s, 1H), 7.43 (m, 5H), 7.08 (s, 1H), 3.97 (s, 3H), 3.54 (s, 3H). MS (ESI) m/z (M+H)⁺ 306.0. HCl salt Compound 720a was also prepared. ¹H NMR (400MHz, CDOD₃-d⁴) δ 9.43 (s, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.68 (s, 1H), 7.59 - 7.52 (m, 5H), 4.06 (s, 3H), 3.84 (s, 3H). MS (ESI) m/z (M+H)⁺306.1.

Compound 725 was prepared following the similar procedure for the preparation of Compound 720 using (4-chlorophenyl)boronic acid in place of phenyl boronic acid as a white solid. ¹H NMR (CDCl₃, 400 MHz ): δ 7.66 (s, 1H), 7.56 (s, 1H), 7.50 (s, 1H), 7.44-7.42 (m, 2H), 7.38 - 7.36 (m, 2H), 7.02 (s, 1H), 3.97 (s, 3H), 3.53 (s, 3H). MS (ESI) m/z (M+H)⁺ 340.1. HCl salt Compound 725a: ¹H NMR (400MHz,CDCD₃-d₄) δ 9.45 (s, 1H), 8.22 (s, 1H), 8.09 (s, 1H), 7.72 (s, 1H), 7.62-7.54 (m, 4H), 4.11 (s, 3H), 3.85 (s, 3H). MS (ESI) m/z (M+H)⁺ 340.0.

Compound 729 was prepared in two steps from 7-bromo-1-methyl-1H-imidazo[4,5-c]pyridin-4-ol by first undergoing copper acetate catalyzed coupling with (4-chloro-2-methylphenyl)boronic acid, followed by Pd(PPh₃)₄/K₃PO₄ catalyzed coupling with XV-9c to afford the final product as a white solid. ¹H NMR (DMSO-d, 400MHz) δ 8.03 (s, 1H), 7.92 (s, 1H), 7.62 (s, 1H), 7.48 (s, 1H), 7.39-7.36 (m, 1H), 7.28 (d, J=8.8Hz, 1H), 7.07 (s, 1H), 3.85 (s, 3H), 3.54 (s, 3H), 2.03 (s, 3H). MS (ESI) m/z (M+H)⁺ 354.1. HCl salt Compound 729a: ¹H NMR (DMSO-d, 400MHz) δ 8.88 (br. s., 1H), 7.96 (s, 1H), 7.64 (s, 1H), 7.51 (d, J=2.0 Hz, 1H), 7.40-7.38 (m, 1H), 7.32-7.30 (m, 2H), 3.85 (s, 3H), 3.62 (s, 3H), 2.04 (s, 3H). MS (ESI) m/z (M+H)⁺ 354.0.

Compound 731 was prepared in two steps from XV-6c following the similar procedure described in the alternative synthesis of Compound 59 using (4-ethoxy-2-methylphenyl)boronic acid in place of XV-7 and using Pd(PPh₃)₄/K₃PO₄ in place of Pd(dppf)Cl₂/K₂CO₃ to afford an off white solid. ¹H NMR (CDCl₃, 400 MHz ): δ 7.65 (s, 1H), 7.55 (s, 1H), 7.46 (s, 1H), 7.11 (d, J=8.8Hz, 1H), 6.91 (s, 1H), 6.82 (d, J=2.4Hz, 1H), 6.77 (dd, J=2.4, 8.8Hz, 1H), 4.03 (q, J=6.8Hz, 2H), 3.96 (s,3H), 3.54 (s, 3H), 2.12 (s, 3H), 1.39 (t, J=6.8Hz, 3H). MS (ESI) m/z (M+H)⁺ 364.1. HCl salt Compound 731a: ¹H NMR (400MHz, DMSO-d⁶) δ 9.06 (s, 1H), 7.97 (s, 1H), 7.65 (s, 1H), 7.31 (s, 1H), 7.18 (d, J=8.8 Hz, 1H), 6.94 (d, J=2.4 Hz, 1H), 6.84 (dd, J=2.7, 8.8 Hz, 1H), 4.06 (q, J=6.8 Hz, 2H),3.87 (s, 3H), 3.66 (s, 3H), 2.02 (s, 3H), 1.33 (t, J=7.2 Hz, 3H). MS (ESI) m/z (M+H)⁺364.1.

Compound 732 was prepared by Pd118/K₃PO₄ catalyzed coupling between XV-8c and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine to afford a white solid. ¹H NMR (CDCl₃, 400 MHz ): δ 8.27 (s, 1H), 7.72 (d, J=6.4Hz, 3H), 7.64 (s, 1H), 7.50 (d, J=8.8Hz, 2H), 7.33 (d, J=8.4Hz, 2H), 7.23-7.21 (m, 1H), 7.15 (s, 1H), 3.50 (s, 3H). MS (ESI) m/z (M+H)⁺ 426.1. HCl salt Compound 732a: ¹H NMR (DMSO-d₆ , 400MHz): δ 9.11 (s, 1H), 8.39 (d, J=6.8 Hz, 2H), 8.25 (s, 1H), 8.17 (d, J=1.2 Hz, 1H), 8.05 (d, J=9.2 Hz, 1H), 7.66 - 7.63 (m, 3H), 7.54 (d, J=8.4 Hz, 2H), 3.52 (s, 3H). MS (ESI) m/z (M+H)⁺ 426.1.

Example 29 Synthesis of Compound 724 (Scheme L)

A solution of L-1 (20.00 g, 103.64 mmol, 1.00 eq) in ethanolic NH₃ (600 ml of absolute ethanol saturated at 5°C with dry NH₃) was stirred at rt for 7h. Then, the reaction solution was concentrated in vacuum to get a residue. The residue was triturated with boiling chloroform (120 ml). The resulting insoluble solid was filtered and dried in vacuum. Crystallization of this material from EA (200 ml) gave L-2 (7.20 g, 41.62 mmol, 40% yield) as a brown solid.

To a solution of L-2 (7.20 g, 41.62 mmol, 1.00 eq) in MeCN (140 mL) was added K₂CO₃ (11.49 g, 83.24 mmol, 2.00 eq) and CD₃I (15.09 g, 104.05 mmol, 2.50 eq) at rt. The resulting mixture was stirred at 80°C for 3 h. Additional CD₃I (15.09 g, 104.05 mmol, 2.50 eq) was added, and the solution was stirred at 80 C for additional 2h. Then, the reaction mixture was poured into water (100 mL) and extracted with EA. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified to afford L-3 (8.5 g, crude) as yellow solid

To a solution of L-3 (8.50 g, 44.74 mmol, 1.00 eq) in MeCN (250 mL) was added NBS (7.96 g, 44.74 mmol, 1.00eq) at 20°C. The reaction mixture was stirred at 80°C for 12 h. Then, the solution was concentrated under vacuum to afford residue which was diluted with EA. The mixture was filtered and the filtrate was washed by 5% sodium hydroxide (aq.) and brine. The organic phase was concentrated under vacuum to give L-4 (6.5 g, 24.25 mmol, 58% yield/2 steps) as a brown solid.

To a solution of L-4 (6.50 g, 24.25 mmol, 1.00 eq) in EtOH (40 mL) and H₂O (10 mL) was added NH₄Cl (12.85 g, 242.50 mmol, 10.00 eq) at 5°C. After addition, the mixture was warmed to 90°C and Fe (6.79 g, 121.3 mmol, 5.00 eq) was added. The mixture was stirred at 90°C for 2h. The mixture solution was filtered and the filtrated was concentrated to remove ethanol and diluted with EA, then washed with water and brine, dry over Na₂SO₄, filtered and concentrated in vacuum. The residue was purified to afford L-5 (5.10 g, 21.43 mmol, 88% yield) as a brown solid.

A mixture of L-5 (5.10 g, 21.43 mmol, 1.00 eq) in HCOOH (50 mL) was heated to reflux at 110°C overnight. Then, the mixture was concentrated in vacuum. The resulting solid was triturated with methanol to give L-6 (5.50 g, 90%) as a brown solid.

To a solution of L-6 (2.75 g, 11.96 mmol, 1.00 eq) in DMF (100 mL) was Cu(OAc)₂ (4.33 g, 23.92 mmol, 2.00 eq), PyO (3.41 g, 35.87 mmol, 3.00 eq), Py (9.45 g, 119.6 mmol, 10.00 eq), 4A MS (3g) and L-7 (4.93 g, 23.92 mmol, 2.00 eq). The mixture was stirred at 40°C under oxygen atmosphere overnight. Then, the solid was filtered off and the filter cake was washed with DCM. The filtrate was concentrated. The residue was diluted with water and extracted with DCM. The combined organic layer was washed with ammonium hydroxide and brine, dried over sodium sulfate, filtered and concentrated. The residue was triturated with PE/EtOAc (2:1) to give L-8 (2.35g, 6.03 mmol, 50% yield) as a blue solid.

Synthesis of Compound 9:

To a solution of L-10 (5.00 g, 34.02 mmol, 1.00 eq) in THF (113 mL) was added NaH (1.63 g, 40.82 mmol, 1.20 eq) at 0 °C. The mixture was stirred at rt. for 30 min. Then CD₃I (6.41 g, 44.23 mmol, 1.30 eq) was added at 0°C. The resulting mixture was stirred at rt overnight. The reaction mixture was poured into water and extracted with EA. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuum to afford the desired L-11 (4.40 g, crude) as a light oil.

To a solution of L-11 (3.90 g, 23.93 mmol, 1.00 eq) in dioxane (80 mL) was added BDP (6.08 g, 23.93 mmol, 1.00 eq), DPPF (782.39 mg, 1.2 mmol, 0.05 eq), AcOK (5.78 g, 83.74 mmol, 3.50 eq) and Pd(dppf)Cl₂ (887.67 mg, 1.2 mmol, 0.05 eq). The mixture was stirred at 110°C under N₂ for 2h. The solid was filtered off and the filter cake was washed with EA. The filtrate was concentrated in vacuum to give the crude product. The residue was purified by flash column chromatography on silica gel (PE/EA=10/1 to 5/1) to afford L-9 (2 g, 9.48 mmol, 40% yield) as a light oil.

To a solution of L-8 (2.35 g, 6.03 mmol, 1.00 eq) and L-9 (1.91 g, 9.04 mmol, 1.50 eq) in DMF (50 mL) was added K₃PO₄ (2.55 g, 12.05 mmol, 2.00 eq) and Pd(PPh₃)₄ (0.35 g, 0.3 mmol, 0.05 eq). The reacting equipment was flushed with nitrogen gas for 5 times. The mixture was stirred at 110°C for 12h. After cooling, the residue was poured into crushed ice water. The product precipitated and was collected by filtration. The resulting solid was slurry with EA/MeOH (10/1) five times to give Compound 724 (0.5 g, 1.27 mmol, 20% yield) as a grey white solid. ¹H NMR (DMSO-d₆ , 400MHz) 8.05 (s, 1H), 7.94 (s, 1H), 7.65 (s, 1H), 7.60 (d, J=8.8Hz, 2H), 7.51 (d, J=8.8Hz, 2H). H RMS (TOF): >99% deuterium content. LCMS: t = 2.320 min, [M+1]⁺ = 396.1.

Example 30 ET-1 Assay Assay of Inhibitory Effect on TGF-b induced Endothelin-1 Production

Fibroblasts (primary human lung and dermal, HFL-1, 3T3 etc) are seeded in 96-well plates at ~15000 cells/well and serum starved for 0-48 hours. After media exchange, compounds serially diluted in DMSO are added to the cells. After a brief incubation of -30 min, stimulants (TGFb, serum, LPA etc) are added followed by further incubation for 16-48 hours. Media is then harvested and stored frozen in plate format for later endothelin-1 (ET-1) determination by ELISA. Toxicity measurements are made using the ATPlite kit (Perkin-Elmer). ET-1 is quantified using an ELISA kit (R&D Systems). The amount of ET-1 produced in the assay wells are back-calculated using the ELISA standard. The ability of a compound to inhibit ET-1 production is typically analyzed by fitting dose-response curves to a 4-parameter logistic function to obtain an EC50 value. A measure of cytotoxicity (CC50) is likewise reported from the same experiment using the ATPlite data.

Example 31 Cell Proliferation Assay Assay of Inhibitory Effect on Cell Proliferation (BrdU Incorporation)

Fibroblasts (primary human lung and dermal, HFL-1, 3T3 etc) were plated on a 96-well plate and serum starved for 24-48 hours. The media were then exchanged for media containing stimulants (LPA, TGFb, serum etc) and cultured further for 16-24 hours before BrdU addition. After culturing for another 8 hours, cells were washed with PBS and the amount of BrdU incorporated into the cells was assayed by absorbance at 450 nm using the Cell proliferation ELISA system (RPN250, Amersham LIFE SCIENCE). The difference between the amount of BrdU incorporated in the stimulant-added well and the amount of BrdU incorporated in the well containing no stimulant represented the amount of BrdU incorporation accelerated by stimulant. The increase of BrdU incorporation without the addition of test compounds was set as 100% and the concentration of compound with 50% inhibition in the increase of BrdU incorporation (IC₅₀ value) was determined. The test compounds were added 0-30 min before stimulant addition.

Claims (14)

1. A compound selected from the group consisting of Compounds 717 to 722, 724 to 726, 729 to 732, 735 and 736: 717 718 719 720 721 722 724 725 726 729 730 731 732 735 736 or a pharmaceutically acceptable salt thereof.
2. The compound of Claim 1, wherein the compound is Compound 732.
3. The compound of Claim 1, wherein the compound is Compound 724.
4. The compound of Claim 1, wherein the compound is selected from the group consisting of Compounds 717 - 722, 725, 726, 729-731, 735 and 736.
5. A compound of Claim 1 for use as a medicament.
6. A compound of Claim 1 for use in the treatment of a fibrotic condition in a subject in need thereof.
7. The compound for use of Claim 6, wherein the fibrotic condition is selected from pulmonary fibrosis, dermal fibrosis, pancreatic fibrosis, liver fibrosis, and renal fibrosis.
8. The compound for use of Claim 7, wherein the fibrotic condition is idiopathic pulmonary fibrosis.
9. The compound for use of any one of Claims 6 to 8, wherein the compound is for administration by inhalation.
10. The compound for use of any one of Claims 6 to 9, wherein the subject is a human.
11. A pharmaceutical composition comprising an effective amount of a compound of Claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
12. A pharmaceutical composition of Claim 11 for use in the treatment of a fibrotic condition in a subject in need thereof.
13. The pharmaceutical composition for use of Claim 12, wherein the fibrotic condition is idiopathic pulmonary fibrosis.
14. The pharmaceutical composition for use of any one of Claims 12 to 13, wherein the pharmaceutical composition is for administration by inhalation.