WO2007076127A2 - Condensed imidazoles or pyrazoles and their use as transforming growth factor modulators - Google Patents

Abstract

The invention relates to compounds of formula I that are modulators of Transforming Growth Factor β (TGF β) and are useful for treating TGF β related diseases. In Formula (I) one of Rl or R2 is heteroaryl and the other is aryl or heteroaryl, one of Xl or X2 is C and the other is N.

Description

TRANSFORMING GROWTH FACTOR MODULATORS

This application claims the benefit of the U.S. Provisional application No. 60/753,023, filed on December 22, 2005, which is incorporated herein by reference.

FIELD OF INVENTION

[001] The invention relates to modulators of Transforming Growth Factor β (TGF β), compositions thereof and methods of use. The invention also relates to the treatment of TGFβ-related diseases.

BACKGROUND OF INVENTION

[002] TGFβ (Transforming Growth Factor β) is a member of a large family of dim eric polypeptide growth factors that includes, for example, activins, inhibins, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and mullerian inhibiting substance (MIS). TGFβ exists in three isoforms (TGFβl, TGFβ2, and TGFβ3) and is present in most cells, along with its receptors. Each isoform is expressed in both a tissue-specific and developmentally regulated fashion. Each TGFβ isoform is synthesized as a precursor protein that is cleaved intracellularly into a C-terminal region (latency associated peptide (LAP)) and an N-terminal region known as mature or active TGFβ. LAP is typically non-covalently associated with mature TGFβ prior to secretion from the cell. The LAP-TGF β complex cannot bind to the TGFβ receptors and is not biologically active. TGFβ is generally released (and activated) from the complex by a variety of mechanisms including, for example- interaction with thrombospondin-1 or plasmin.

[003] Following activation, TGFβ binds at high affinity to the type II receptor (TGFβRII), a constitutively active serine/threonine kinase. The ligand-bound type II receptor phosphorylates the TGFβ type I receptor (Alk5) in a glycine/serine rich domain, which allows the type I receptor to recruit and phosphorylate downstream signaling molecules, Smad2 or Smad3. See, e.g., Huse, M. et ah, MoI. Cell, 8: 671-682 (2001). Phosphorylated Smad2 or Smad3 can then complex with Smad4, and the entire hetero-Smad complex translocates to the nucleus and regulates transcription of various TGFβ-responsive genes. See, e.g., Massague, J., Ann. Rev. Biochem. Med., 67: 773 (1998).

[004] Activins are also members of the TGFβ superfamily, which are distinct from TGFβ in that they are homo- or heterodimers of activin βa or βb. Activins signal in a manner similar to TGFβ, that is, by binding to a constitutive serine-threonine receptor kinase, activin type II receptor (ActRIIB), and activating a type I serine-threonine receptor, Alk4, to phosphorylate Smad2 or Smad3. The consequent formation of a hetero-Smad complex with Smad4 also results in the activin-induced regulation of gene transcription.

[005] Indeed, TGFβ and related factors such as activin regulate a large array of cellular processes, e.g., cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, inflammatory cell recruitment, immunosuppression, wound healing, and extracellular matrix production. See, e.g., Massague, J, Ann. Rev. Cell. Biol., 6: 594-641 (1990); Roberts, A.B. and Sporn M.B., Peptide Growth Factors and Their Receptors, 95: 419-472 Berlin: Springer- Verlag (1990); Roberts, A. B. and Sporn M. B., Growth Factors, 8: 1-9 (1993); and Alexandrow, M.G. and Moses, H.L., Cancer Res., 55: 1452-1457 (1995). Hyperactivity of TGFβ signaling pathway underlies many human disorders (e.g., excess deposition of extracellular matrix, an abnormally high level of inflammatory responses, fibrotic disorders, and progressive cancers). Similarly, activin signaling and overexpression of activin is linked to pathological disorders that involve extracellular matrix accumulation and fibrosis (see, e.g., Matsuse, T. et al., Am. J. Respir. Cell MoI. Biol, 13: 17-24 (1995); Inoue, S. et al., Biochem. Biophys. Res. Comm., 205: 441- 448 (1994); Matsuse, T. et al, Am. J. Pathol., 148: 707-713 (1996); De Bleser et al., Hepatology, 26: 905-912 (1997); Pawlowski, J.E., et al., J. CHn. Invest, 100: 639-648 (1997); Sugiyama, M. et al., Gastroenterology, 114: 550-558 (1998); Munz, B. et al., EMBO J., 18: 5205-5215 (1999)), inflammatory responses (see, e.g., Rosendahl, A. et al., Am. J. Repir. Cell MoI. Biol, 25: 60-68 (2001)), cachexia or wasting (see Matzuk, M.M. et al., Proc. Nat. Acad. ScL USA, 91 : 8817-8821 (1994); Coerver, K.A. et si., MoL Endocrinol., 10: 534- 543 (1996); Cipriano, S.C. et al., Endocrinology, 141 : 2319-27 (2000)), diseases of or pathological responses in the central nervous system (see Logan, A. et al., Eur. J. Neurosci., 11: 2367-2374 (1999); Logan, A. et al., Exp. Neurol, 159: 504-510 (1999); Masliah, E. et al., Neurochem. Int., 39: 393-400 (2001); De Groot, C.J.A. et al., J. Neuropathol. Exp. Neurol, 58: 174-187 (1999), John, G. R. et al., Nat. Med., 8: 1115-21 (2002)) and hypertension (see Dahly, A.J. et al., Am. J. Physiol. Regul Integr. Comp. Physiol, 283: R757-67 (2002)). Studies have shown that TGFβ and activin can act synergistically to induce extracellular matrix production (see, e.g., Sugiyama, M. et al., Gastroenterology, 114: 550-558, (1998)). It is therefore desirable to develop modulators (e.g., antagonists) to members of the TGFβ family to prevent and/or treat disorders involving this signaling pathway. SUMMARY OF THE INVENTION

[006] The invention is based on the discovery that compounds of formula (I) are potent antagonists of the TGFβ family type I receptors, Alk5 and/or Alk4. Thus, compounds of formula (I) can be employed in the prevention and/or treatment of diseases such as fibrosis (e.g., renal fibrosis, pulmonary fibrosis, and hepatic fibrosis), progressive cancers, or other diseases for which reduction of TGFβ family signaling activity is desirable. [007] In one aspect, the invention features compounds of formula (I) or a pharmaceutically acceptable salt or mixtures thereof,

I wherein the variables Ri, R₂, R3, R₄, Xi, X₂, i, and j are described herein. The invention also relates to compositions that comprise the above compounds and the use thereof.

[008] In another aspect, a pharmaceutical composition of this invention includes a compound of formula (I) and a pharmaceutically acceptable carrier.

[009] In another aspect, the invention also relates to a method of inhibiting the TGFβ signaling pathway in a subject, which includes administering to said subject in need thereof an effective amount of a compound of formula (I).

[0010] In another aspect, the invention relates to a method of inhibiting the TGFβ type I receptor in a cell, which includes contacting said cell with an effective amount of a compound of formula (I).

[0011] In another aspect, the invention relates to a method of reducing the accumulation of excess extracellular matrix induced by TGFβ in a subject in need thereof, which includes administering to said subject an effective amount of a compound of formula (I).

[0012] In another aspect, the invention relates to a method of treating or preventing flbrotic condition in a subject, which includes administering to said subject in need thereof an effective amount of a compound of formula (I). The fibrotic condition can be, e.g., mesothelioma, acute respiratory distress syndrome (ARDS), atherosclerosis, scleroderma, keloids, glomerulonephritis, diabetic nephropathy, lupus nephritis, hypertension-induced nephropathy, cholangitis, restenosis (e.g., coronary restenosis, peripheral restinosis, or carotid restenosis), ocular scarring, corneal scarring, hepatic fibrosis, biliary fibrosis, liver cirrhosis, cirrhosis due to fatty liver disease (alcoholic and nonalcoholic steatosis), primary sclerosing cholangitis, pulmonary fibrosis (such as idiopathic pulmonary fibrosis), renal fibrosis, sarcoidosis, acute lung injury, drug-induced lung injury, spinal cord injury, CNS scarring, systemic lupus erythematosus, Wegener's granulomatosis, cardiac fibrosis, post-infarction cardiac fibrosis, post-surgical fibrosis, connective tissue disease, radiation-induced fibrosis, chemotherapy-induced fibrosis, transplant arteriopathy, fibrosclerosis, fibrotic cancers, fibroids, fibroma, fibroadenomas, fibrosarcomas, wound healing, surgical scarring, chronic obstructive pulmonary disease, alimentary track or gastrointestinal fibrosis, or keloid. The fibrotic condition can be idiopathic in nature, genetically linked, or induced by radiation. [0013] In another aspect, the invention relates to a method of using the compounds of the invention for treating and preventing a vascular disease such as intimal thickening, vascular remodeling, or organ transplant-related vascular disease.

[0014] In another aspect, the invention relates to a method of inhibiting growth or metastasis of tumor cells and/or cancers in a subject, which includes administering to said subject in need thereof an effective amount of a compound of formula (I). [0015] In another aspect, the invention relates to a method of treating a disease or disorder mediated by an overexpression of TGFβ. The method includes administering to a subject in need of such treatment an effective amount of a compound of formula (I). The disease or disorder can be, for example, demyelination of neurons in multiple sclerosis, Alzheimer's disease, cerebral angiopathy, squamous cell carcinomas, multiple myeloma, melanoma, glioma, glioblastomas, leukemia, sarcomas, leiomyomas, mesothelioma, or carcinomas of the lung, breast, ovary, cervix, liver, biliary tract, gastrointestinal tract, pancreas, prostate, and head and neck.

[0016] Also within the scope of this invention are iV-oxide derivatives or pharmaceutically acceptable salts of each of the compounds of formula (I). For example, a nitrogen ring atom of the imidazole core ring or a nitrogen-containing heterocyclyl substituent can form an oxide in the presence of a suitable oxidizing agent such as w-chloroperbenzoic acid or H₂O₂. A compound of formula (I) that is acidic in nature (e.g., having a carboxyl or phenolic hydroxyl group) can form a pharmaceutically acceptable salt such as a sodium, potassium, calcium, or gold salt.

[0017] Also within the scope of the invention are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, and N- methylglycamine. A compound of formula (I) can be treated with an acid to form acid addition salts. Examples of such acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, /j-bromophenyl- sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, ascorbic acid, maleic acid, acetic acid, and other mineral and organic acids well known to those skilled in the art. The acid addition salts can be prepared by treating a compound of formula (I) in its free base form with a sufficient amount of an acid (e.g., hydrochloric acid) to produce an acid addition salt (e.g., a hydrochloride salt). The acid addition salt can be converted back to its free base form by treating the salt with a suitable dilute aqueous basic solution (e.g., sodium hydroxide, sodium bicarbonate, potassium carbonate, or ammonia).

[0018] Compounds of formula (I) can also be, e.g., in a form of achiral compounds, racemic mixtures, optically active compounds, pure diastereomers, or a mixture of diastereomers. [0019] Compounds of formula (I) exhibit high affinity to the TGFβ family type I receptors, Alk5 and/or Alk4, e.g., with IC5₀ and Ki values of less than 10 μM under conditions described below. Some compounds of formula (1) exhibit IC₅₀ and K; values of less than 1 μM (such as below 200 nM). Thus, compounds of formula (I) can be employed in the prevention and treatment of diseases mediated by TGFβ such as fibrosis (e.g., renal fibrosis, pulmonary fibrosis, or hepatic fibrosis), progressive cancers, or other diseases for which reduction of TGFβ family signaling activity is desirable.

[0020] Still within the scope of the invention are implantable devices each comprising a compound of formula (I) described above. Such implantable devices can be, e.g., a delivery pump or a stent, and can also be used for treating a disease or disorder mediated by an overexpression of TGFβ.

DETAILED DESCRIPTION OF THE INVENTION Definitions

[0021] As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito (1999), and "Advanced Organic Chemistry " 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York (2001), the entire contents of which are hereby incorporated by reference.

[0022] The term "modulating" as used herein means increasing or decreasing, e.g. activity, by a measurable amount. Compounds that modulate TGFβ activity by increasing the activity of the TGFβ receptors are called agonists. Compounds that modulate TGFβ activity by decreasing the activity of the TGFβ receptors are called antagonists. An agonist interacts with a TGFβ receptor to increase the ability of the receptor to transduce an intracellular signal in response to endogenous ligand binding. An antagonist interacts with a TGFβ receptor and competes with the endogenous ligand(s) or substrate(s) for binding site(s) on the receptor to decrease the ability of the receptor to transduce an intracellular signal in response to endogenous ligand binding.

[0023] As used herein, the term "aliphatic" encompasses the terms alkyl, alkenyl, and alkynyl, each of which is optionally substituted as set forth below.

[0024] As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1-8 (e.g., 1-6 or 1-4) carbon atoms. An alkyl group can be straight or branched. Examples of such alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, «-pentyl, n-heptyl, or 2-ethylhexyl. An alkyl group can be substituted (i.e., optionally substituted) with one or more substituents such as halo, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, cycloaliphaticcarbonyl, (heterocycloaliphatic)carbonyl, nitro, cyano, amino, amido, acyl, sulfonyl, sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, thioxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, or hydroxy. Without limitation, some examples of substituted alkyls include carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, hydroxyalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkylsulfonylamino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, cyanoalkyl, or haloalkyl. [0025] As used herein, an "alkenyl" group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl. An alkenyl group can be optionally substituted with one or more substituents such as halo, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, nitro, cyano, amino, amido, acyl (e.g., cycloaliphaticcarbonyl and (heterocycloaliphatic)carbonyl), sulfonyl, sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, thioxo, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, or hydroxy [0026] As used herein, an "alkynyl" group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and has at least one triple bond. An alkynyl group can be straight or branched. Examples of an alkynyl group include, but are not limited to, propargyl and butynyl. An alkynyl group can be optionally substituted with one or more substituents such as halo, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, (cycloaliphatic)carbonyl, (heterocycloaliphatic)carbonyl, nitro, cyano, amino, amido, acyl, sulfonyl, sulfϊnyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, thioxo, carboxy, carbamoyl, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, aralkyloxy, (heteroaryl)alkoxy, or hydroxyl.

[0001] As used herein, the term "amido" encompasses both "aminocarbonyl" and "carbonylamino." These terms, when used alone or in connection with another group, refers to an amido group such as N(R^X)₂-C(O)- or R^YC(O)-N(R^X)- when used terminally; and - C(O)-N(R^X)- or -N(R^X)-C(O)- when used internally, wherein R^x and R^γ are defined below. Examples of amido groups include alkylamido (such as alkylcarbonylamino and alkylcarbonylamino), (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, and cycloalkylamido

[0027] As used herein, an "amino" group refers to -NR^XR^Y wherein each of R^x and R^γ is independently hydrogen, alkyl, cycloaliphatic, aryl, heterocycloaliphatic, or heteroaryl, each of which being defined herein and being optionally substituted. Examples of amino groups include alkylamino, dialkylamino, and arylamino.

[0028] When the term "amino" is not the terminal group (e.g., alkylcarbonylamino), it is represented by -NR^X- in which R^x has the same meaning as defined above. [0029] As used herein, an "aryl" group used alone or as part of a larger moiety such as in "aralkyl," "aralkoxy," or "aryloxyalkyl" refers to monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, or tetrahydroindenyl); and tricyclic (e.g., fluorenyl tetrahydrofluorenyl, tetrahydroanthracenyl, or anthracenyl). The bicyclic and tricyclic groups include benzofused 2-3 membered carbocyclic rings. For example, a benzofused group includes phenyl fused with two or more C_4-8 carbocyclic moieties. An aryl is optionally substituted with one or more substituents including aliphatic (e.g., alkyl, alkenyl, or alkynyl), cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, oxo (on a non-aromatic carbocyclic ring of a benzofused bicyclic or tricyclic aryl), nitro, carboxy, amido, acyl (e.g., aliphaticcarbonyl, (cycloaliphatic)carbonyl,

((cycloaliphatic)aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloalϊphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl), sulfonyl (e.g., aliphaticsulfonyl and aminosulfonyl), sulfinyl (e.g., aliphaticsulfinyl), sulfanyl (e.g., aliphaticsulfanyl or mercapto), nitro, cyano, halo, hydroxyl, sulfoxy, urea, thiourea, sυlfamoyU sulfamide, and carbamoyl. Alternatively, an aryl can be unsubstituted. [0030] Non-limiting examples of substituted aryls include haloaryl (e.g., mono-, di- (such asp.m-dihaloaryl), or (trihalo)aryl); (carboxy)aryl (e.g., (alkoxycarbonyl)aryl, ((aryalkyl)carbonyloxy)aryl, or (alkoxycarbonyl)aryl), (amido)aryl (e.g., (aminocarbonyl)aryl, (((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl); aminoaryl (e.g., ((alkylsulfonyl)amino)aryl and ((dialkyl)amino)aryl); (cyanoalkyl)aryl; (alkoxy)aryl, (sulfamoyl)aryl (e.g., (aminosulfonyl)aryl); (alkylsulfonyl)aryl, (cyano)aryl; (hydroxyalkyl)aryl, ((alkoxy)alkyl)aryl, (hydroxyl)aryl, ((carboxy)alkyl)aryl, (((dialkyl)amino)alkyl)aryl, (nitroalkyl)aryl, (((alkylsulfonyl)amino)alkyl)aryl, ((heterocycloaliphatic)carbonyl)aryl, ((alkylsulfonyl)alkyl)aryl, (cyanoalkyl)aryl, (hydroxyalkyl)aryl, (alkylcarbonyl)aryl, alkylaryl, (trihaloalkyl)aryl, p-axnino-m- alkoxycarbonylaryl, j?-amino-w-cyanoaryl,/?-halo-m-aminoaryl, and (m- (heterocycloaliphatic)-o-(alkyl))aryl.

[0031] As used herein, an "araliphatic" such as an "aralkyl" group refers to an aliphatic group (e.g., a Ci₄ alkyl group) that is substituted with an aryl group. "Aliphatic," "alkyl," and "aryl" are defined herein. An example of an araliphatic such as an aralkyl group is benzyl.

[0032] As used herein, an "aralkyl" group refers to an alkyl group (e.g., a C₁.₄ alkyl group) that is substituted with an aryl group. Both "alkyl" and "aryl" have been defined above. An example of an aralkyl group is benzyl. An aralkyl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonyl amino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, sulfanyl (e.g., mercapto and alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. [0033] As used herein, a "bicyclic ring system" includes 8-12 (e.g., 9, 10, or 11) membered structures that form two rings, wherein the two rings have at least one atom in common (e.g., 2 atoms in common). Bicyclic ring systems include bicycloaliphatics (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclic heteroaryls. [0034] As used herein, a "cycloaliphatic" group encompasses a "cycloalkyl" group and a "cycloalkenyl" group, each of which being optionally substituted as set forth below. [0035] As used herein, a "cycloalkyl" group refers to a saturated carbocyclic mono- or bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbomyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, adamantyl, azacycloalkyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl. A "cycloalkenyl" group, as used herein, refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4- cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo[2.2.2]octenyl, and bicyclo[3.3.1]nonenyl. A cycloalkyl or cycloalkenyl group can be optionally substituted with one or more substituents such as aliphatic (e.g., alkyl, alkenyl, and alkynyl), cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido (e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonyl amino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, and (heteroaraliphatic)carbonyiamino), nitro, carboxy (e.g., HOOC-, alkoxycarbonyl, and alkylcarbonyloxy), acyl (e.g., (cycloaliphaticjcarbonyl, ((cycloaliphatic) aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,

((heterocycloaliphatic)aliphatic)carbonyl, and (heteroaraliphatic)carbonyl), nitro, cyano, halo, hydroxy, sulfonyl (e.g., alkylsulfonyl and arylsulfonyl), sulfinyl (e.g., alkylsulfinyl), sulfanyl (e.g., mercapto and alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. [0036] As used herein, a "cyclic moiety" includes cycloaliphatic, heterocyclo aliphatic, aryl, or heteroaryl, each of which has been defined previously.

[0037] As used herein, the term "heterocycloaliphatic" encompasses a heterocycloalkyl group and a heterocycloalkenyl group, each of which being optionally substituted as set forth below.

[0038] As used herein, a "heterocycloalkyl" group refers to a 3-10 membered mono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- or bi cyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examples of a heterocycloalkyl group include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octahydrobenzo[£]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza- bicyclo[3.2.1]octyl, anad 2,6-dioxa-tricyclo[3.3.1.0³'⁷]nonyl. A monocyclic heterocycloalkyl group can be fused with a phenyl moiety such as tetrahydroisoquinoline. A "heterocycloalkenyl" group, as used herein, refers to a mono- or bicylic (e.g., 5- to 10- membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, O, or S). Monocyclic and bicycloheteroaliphatics are numbered according to standard chemical nomenclature. [0039] A heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or more substituents such as aliphatic (e.g., alkyl, alkenyl, or alkynyl), cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido (e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic) aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic) aliphatic)carbonylamino, (heteroaryl)carbonylamino, and (heteroaraliphatic)carbonylamino), nitro, carboxy (e.g., HOOC-, alkoxycarbonyl, and alkylcarbonyloxy), acyl (e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, and (heteroaraliphatic)carbonyl), nitro, cyano, halo, hydroxy, sulfonyl (e.g., alkylsulfonyl and arylsulfonyl), sulfinyl (e.g., alkylsulfinyl), sulfanyl (e.g., mercapto and alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. [0040] A "heteroaryl" group, as used herein, refers to a monocyclic, bicyclic, or tricyclic ring structure having 4 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof) and wherein one or more rings of the bicyclic or tricyclic ring structure is aromatic. A heteroaryl group includes a benzofused ring system having 2. to 3 rings. For example, a benzofused group includes benzo fused with one or two 4 to 8 membered heterocycloaliphatic moieties (e.g., indolizyl, indolyl, isoindolyl, 3H- indolyl, indolinyl, benzo[6]furyl, benzo[έ]thiophenyl, quinolinyl, or isoquinolinyl). Some examples of heteroaryl are azetidinyl, pyridyl, 1 H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[l,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyljCinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyI, benzo- 1,2,5-thiadiazolyl, or 1,8-naphthyridyl.

[0041] Without limitation, monocyclic heteroaryls include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-ρyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature. [0042] Without limitation, bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H- indolyl, indolinyl, benzo[&]furyl, benzo[6] thiophenyl, quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl, benzo[ό]furyl, bexo[&]thiophenyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature.

[0043] A heteroaryl is optionally substituted with one or more substituents such as aliphatic (e.g., alkyl, alkenyl, or alkynyl), cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliρhatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl), nitro, carboxy, amido, acyl (e.g., aliphaticcarbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic) aliphatic)carbonyl, and (heteroaraliphatic)carbonyl), sulfonyl (e.g., aliphaticsulfonyl and aminosulfonyl), sulfϊnyl (e.g., aliphaticsulfinyl), sulfanyl (e.g., mercapto and aliphaticsulfanyl), nitro, cyano, halo, hydroxyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, or carbamoyl. Alternatively, a heteroaryl can be unsubstituted.

[0044] Non-limiting examples of substituted heteroaryls include (halo)heteroaryl (e.g., mono- and di-(halo)heteroaryl), (carboxy)heteroaryl (e.g., (alkoxycarbonyl)heteroaryl), cyanoheteroaryl, aminoheteroaryl (e.g., ((alkylsulfonyl)amino)heteroaryl and((dialkyl)amino)heteroaryl), (amido)heteroaryl (e.g., aminocarbonylheteroaryl, ((alkylcarbonyl)amino)heteroaryl, ((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl, (((heteroaryl)amino)carbonyl)heteroaryl, ((heterocycloaliphatic)carbonyl)heteroaryl, and ((alkylcarbonyl)amino)heteroaryl), (cyanoalkyl)heteroaryl, (alkoxy)heteroaryl, (sulfamoyl)heteroaryl (e.g., (aminosulfonyl)heteroaryl), (sulfonyl)heteroaryl (e.g., (alkylsulfonyl)heteroaryl), (hydroxyalkyl)heteroaryl, (alkoxyalkyl)heteroaryl, (hydroxyl)heteroaryl, ((carboxy)alkyl)heteroaryl, (((dialkyl)amino)alkyl)heteroaryl, (heterocycloaliphatic)heteroaryl, (eycloaliphatic)heteroaryl, (nitroalkyl)heteroaryl, (((alkylsulfonyl)amino)alkyl)heteroaryl, ((alkylsulfonyl)alkyl)heteroaryl, (cyanoalkyl)heteroaryl, (acyl)heteroaryl (e.g., (alkylcarbonyl)heteroaryl), (alkyl)heteroaryl, and (haloalkyl)heteroaryl (e.g., trihaloalkylheteroaryl).

[0045] A "heteroaraliphatic (such as a heteroaralkyl group) as used herein, refers to an aliphatic group (e.g., a Cμ alkyl group) that is substituted with a heteroaryl group. "Aliphatic," "alkyl," and "heteroaryl" have been defined above.

[0046] A "heteroaralkyl" group, as used herein, refers to an alkyl group (e.g., a Q_-4 alkyl group) that is substituted with a heteroaryl group. Both "alkyl" and "heteroaryl" have been defined above. A heteroaralkyl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifiuoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, sulfanyl (e.g., mercapto and alkyl sulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. [0047] As used herein, a "cyclic moiety" includes cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, each of which has been defined previously.

[0048] As used herein, an "acyl" group refers to a formyl group or R^W-C(O)- (such as alkyl-

C(O)-, also referred to as "alkylcarbonyl") where alkyl has been defined previously and R^w is aliphatic, cylcoaliphatic, heterocycloaliphatic, each of which can be optionally substituted with aliphatic (e.g., alkyl, alkenyl, or alkynyl), cycloaliphatic, (cycloaliphatic)aliphatic,; heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy,

(cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy,

(heteroaraliphatic)oxy, aroyl, heteroaroyl, cyano, halo, hydroxyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, and carbamoyl. Acetyl and pivaloyl are examples of acyl groups.

[0049] As used herein, an "alkoxy" group refers to an alkyl-O- group where "alkyl" has been defined previously.

[0050] As used herein, an "aroyl" (or "arylcarbonyl") group referes to an Ar-CO- group, wherein Ar is an aryl group as previously defined.

[0051] As used herein, a "heteroaroyl" (or "heteroarylcarbonyl") group refers to a HetAr-

CO- group wherein HetAr is a heteroaryl group as defined above.

[0052] As used herein, a "carbamoyl" group refers to a group having the structure -O-CO-

NR^XR^Y or -NR^X-CO-O-R^Z wherein R^x and R^γ have been defined above and R^z can be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.

[0053] As used herein, a "carboxy" group refers to -COOH, -COOR^X, -OC(O)H, -0C(O)R^x when used as a terminal group; or -OC(O)- or -C(O)O- when used as an internal group.

[0054] As used herein, a "haloaliphatic" group refers to an aliphatic group substituted with

1-3 halogen. For instance, the term haloalkyl includes the group -CF₃.

[0055] As used herein, a "mercapto" group refers to -SH.

[0056] As used herein, a "sulfo" group refers to -SO₃H or -Sθ₃R^x when used terminally, or

-S(O)3- when used internally.

[0057] As used herein, a "sulfamide" group refers to the structure -NR^X-S(O)₂-NR^YR^Z when used terminally and -NR^X- S(O)₂-NR ^γ- when used internally, wherein R^x, R^γ, and R^z have been defined above.

[0058] As used herein, a "sulfamoyl" group refers to the structure -S(O)₂-NR^XR^Y or -NR^X-

S(O)₂-R² when used terminally; or -S(O)₂-NR^X- or -NR^X -S(O)₂- when used internally, wherein R^x, R^γ, and R^z are defined above. [0059] As used herein, a "sulfanyl" group refers to -S-R^x and encompasses mercapto (-SH) when used terminally, and -SR^X- when used internally, wherein R^x has been defined above.

Examples of sulfanyls include alkylsulfanyl.

[0060] As used herein a "sulfinyl" group refers to -S(O)-R^X when used terminally and -

S(O)- when used internally, wherein R^x has been defined above.

[0061] As used herein, a "sulfonyl" group refers to-S(0)2-R^x when used terminally and -

S(O)₂- when used internally, wherein R^x has been defined above.

[0062] As used herein, a "sulfoxy" group refers to -O-SO-R^X or -SO-O-R^X, when used terminally and -O-S(O)- or -S(O)-O- when used internally, where R^x has been defined above.

[0063] As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine.

[0064] As used herein, an "alkoxycarbonyl," which is encompassed by the term carboxy, used alone or in connection with another group refers to a group such as alkyl-O-C(O)-.

[0065] As used herein, an "alkoxyalkyl" refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl has been defined above.

[0066] As used herein, a "carbonyl" refer to -C(O)-.

[0067] As used herein, an "oxo" refers to =O.

[0068] As used herein, a "thioxo" refers to =S.

[0069] As used herein, an "aminoalkyl" refers to the structure (R^x)₂N-alkyl-.

[0070] As used herein, a "cyanoalkyl" refers to the structure (NC)-alkyl-

[0071] As used herein, a "urea" group refers to the structure -NR^X-CO-NR^YR^Z and a

"thiourea" group refers to the structure -NR^X-CS-NR^YR^Z when used terminally and -NR^X-

CO-NR^Y- or

-NR^X-CS-NR^Y- when used internally, wherein R^x, R^γ, and R^z have been defined above.

[0072] As used herein, a "guanidine" group refers to the structure -N=C(N (R^x

R^Y))N(R^XR^Y) wherein R^x and R^γ have been defined above.

[0073] As used herein, the term "amidino" group refers to the structure -C=(NR^X)N(R^XR^Y) wherein R^x and R^γ have been defined above.

[0074] As used herein, a "bridged bicyclic ring system" refers to a bicyclic heterocyclicalipahtic ring system or bicyclic cycloaliphatic ring system in which the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza- bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. A bridged bicyclic ring system can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalky^carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyOcarbonylamino, (heterocycloalkylalky^carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, sulfanyl (e.g., mercapto and alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0075] The terms "terminally" and "internally" refer to the location of a group within a substiruent. A group is terminal when the group is present at the end of the substituent not further bonded to the rest of the chemical structure. Carboxyalkyl, i.e., R^xO(O)C-alkyK is an example of a carboxy group used terminally. A group is internal when the group is present in the middle of a substituent to at the end of the substituent bound to the rest of the chemical structure. Alkylcarboxy (e.g., alkyl-C(O)O- or alkyl-OC(O)-) and alkylcarboxyaryl (e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally.

[0076] The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." As described herein, compounds of the invention can optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. As described herein, the variables Ri, R₂, R₃, and R₄, and other variables contained therein formula (I) encompass specific groups, such as alkyl and aryl. Unless otherwise noted, each of the specific groups for the variables Ri, R₂, R₃, and R₄, and other variables contained therein can be optionally substituted with one or more substituents described herein. Each substituent of a specific group is further optionally substituted with one to three of halo, cyano, oxoalkoxy, hydroxyl, amino, nitro, aryl, haloalkyl, and alkyl. For instance, an alkyl group can be substituted with alkylsulfanyl and the alkylsulfanyl can be optionally substituted with one to three of halo, cyano, oxoalkoxy, hydroxyl, amino, nitro, aryl, haloalkyl, and alkyl. As an additional example, the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, alkoxy, hydroxyl, nitro, haloalkyl, and alkyl. When two alkoxy groups are bound to the same atom or adjacent atoms, the two alkxoy groups can form a ring together with the atom(s) to which they are bound. [0077] In general, the term "substituted," whether preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. A ring substituent, such as a heterocycloalkyl, can be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.

[0078] The phrase "stable or chemically feasible," as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.

[0079] As used herein, an effective amount is defined as the amount required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surface areacan be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970).

[0080] As used herein, a "patient" or "subject" refers to a mammal, including a human. [0081] As used herein the term "electron withdrawing group" refers to a substituent that draws electrons to itself more than a hydrogen atom would if it occupied the same position in a molecule. See, e.g., March, J., "Advanced Organic Chemistry," 4^th Ed., pp. 18-19 and 36, Wiley-Interscience, New York (1992). Examples of electron withdrawing groups include but are not limited to -C(O)-, -S(O)-, or -S(O)₂-.

[0082] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

Description of the Compounds

[0083] The invention pertains to compounds of formula I

I wherein:

Ri is aryl or heteroaryl each optionally substituted with 1 to 3 R_a;

R₂ is aryl or heteroaryl, each optionally substituted with 1 to 3 R_b, provided that at least one of Ri and R2 is heteroaryl optionally substituted with 1 to 3 Rb_;

Ring A is a saturated or partially unsaturated 5 to 8 membered cycloaliphatic, a 5 to 8 membered heterocycloaliphatic containing 1 to 3 heteroatoms, phenyl, or a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms;

Ring B is a partially unsaturated non-aromatic 5 to S membered heterocycloaliphatic containing one to three heteroatoms; each of Ra and R_b is independently aliphatic, alkoxy, acyl, halo, hydroxy, amino, amido (e.g., aminocarbonyl or alkylcarbonylamino), nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy (e.g., alkoxycarbonyl, or alkylcarbonyloxy), sulfo, sulfanyl (e.g., mercaptoalkylsulfanyl, cycloalkylsulfanyl, heterocycloalkylsulfanyl, arylsulfanyl, or heteroarylsulfanyl), sulfϊnyl, sulfonyl, urea, thiourea, sulfamoyl (e.g., alkylsulfonylamino), sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, aryl, aryloxy, aroyl, heteroaryl, heteroaryloxy, or heteroaroyl; any two of R_a or any two of Rb on adjacent atoms, together with the atoms to which they are attached, may form a 5 to 8 membered cycloaliphatic or a 5 to 8 membered heterocycloaliphatic; each OfR₃ and R₄ is independently aliphatic, acyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy (e.g., alkoxycarbonyl or alkylcarbonyloxy), cyano, halo, hydroxy, sulfanyl (e.g., mercapto or alkylsulfanyl), sulfinyl, sulfonyl, amido (e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl-carbonylamino, heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylamino, or heteroaralkylcarbonylamino), carbamoyl, urea, thiourea, sulfamoyl, sulfamide, oxo, thioxo, - N₃, =N-OR_f, or =N-N(Rf)₂, or two of R₃ or two OfR₄ on the same atom , together with the atom to which they are attached, may form a 3 to 8 membered cycloaliphatic or heterocycloaliphatic ring, or two of R3 or two OfR₄ on adjacent atoms, together with the atoms to which they are attached, may form a 3 to 8 membered cycloaliphatic or a 3 to 8 membered heterocycloaliphatic ring; each of the optional heteroatoms of Rings A and B are O, S, or N, and the S and N atoms in Rings A and B may form part of the groups -S(O)_m- and -N(R_f)-; each R_f is independently H, alkyl, aryl, heteroaryl, acyl (e.g., alkylcarbonyl), aroyl, heteroaroyl, amino (e.g., aminocarbonyl, alkylaminocarbonyl, or arylaminocarbonyl), sulfamoyl, sulfamide, or carboxy (e.g., alkoxycarbonyl or alkylcarbonyloxy);

Xi is C and X₂ is N or Xi is N and X₂ is C; i is 0 to 4; j is 0 to 4; and each m is independently 0 to 2.

[0084] In some embodiments, the ring juncture between rings A and B is in the trans configuration.

[00851 In some embodiments, Xi is C and X₂ is N to provide imidazole compounds of the invention.

[0086] In some embodiments, Xi is N and X₂ is C to provide pyrazole compounds of the invention. [0087] In some embodiments, Ri is an optionally substituted aryl, such as a mono- or bi- carbocyclic aromatic group. Ri can be an optionally substituted mono-carbocyclic aromatic ("monocyclic aryl") group, e.g., an optionally substituted phenyl. Rj can be an optionally substituted bi-carbocyclic aromatic ("bicyclic aryl") group, e.g., naphthyl, indenyl, or azulenyl. Ri can be an optionally substituted benzofused bicyclic aryl moiety, e.g., tetrahydronaphthalyl.

[0088] In some embodiments, Ri is an optionally substituted heteroaryl, such as a mono- or bi-heterocyclic aromatic group. Ri can be an optionally substituted mono-heterocyclic aromatic ("monocyclic heteroaryl") group, e.g., furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazaloyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, each of which are optionally substituted. Rj can be an optionally substituted 5-membered mono-heterocyclic aromatic group, e.g., furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazaloyl, isoxazolyl, isothiazolyl, and triazolyl, each of which is optionally substituted. Ri can be an optionally substituted 6-membered mono-heterocyclic aromatic group, e.g., pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, each of which is optionally substituted.

[0089] In some embodiments, Ri is an optionally substituted bicyclic heteroaryl, e.g., indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothiopenyl, lH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and pteridinyl, each of which is optionally substituted. Ri can be an optionally substituted 9-membered bi-heterocyclic aromatic group, e.g., indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothiopenyl, lH-indazolyl, benzimidazolyl, benzthiazolyl, and purinyl, each of which is optionally substituted. Ri can be an optionally substituted 10-membered bi-heterocyclic aromatic group, e.g., 4H- quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and pteridinyl, each of which are optionally substituted. Ri can be an optionally substituted benzofused bicyclic heteroaryl moiety covered under the term heteroaryl, e.g., indolinyl and tetrahydoquinolinyl.

[0090] In some embodiments, Ri is an optionally substituted pyridinyl or pyrimidinyl. For example, Ri is an optionally substituted pyridin-2-yl (e.g., 6-aliphatic pyridin-2-yl). [0091] In some embodiments, R₂ is an optionally substituted aryl, such as a mono- or bi- carbocyclic aromatic group. R₂ can be an optionally substituted mono-carbocyclic aromatic ("monocyclic aryl") group, e.g., an optionally substituted phenyl. R₂ can be an optionally substituted bi-carbocyclic aromatic ("bicyclic aryl") group, e.g., naphthyl, indenyl, or azulenyl. R₂ can be an optionally substituted benzofused bicyclic aryl moiety, e.g., tetrahydronaphthalyl.

[0092] In some embodiments, R₂ is an optionally substituted heteroaryl, such as a mono- or bi-heterocyclic aromatic group. R₂ can be an optionally substituted mono-heterocyclic aromatic ("monocyclic heteroaryl") group, e.g., furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazaloyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, each of which are optionally substituted. R₂ can be an optionally substituted 5-membered mono-heterocyclic aromatic group, e.g., furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazaloyl, isoxazolyl, isothiazolyl, and triazolyl, each of which is optionally substituted. R₂ can be an optionally substituted 6-membered mono-heterocyclic aromatic group, e.g., pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, each of which is optionally substituted.

[0093] In some embodiments, R₂ is an optionally substituted bicyclic heteroaryl, e.g., indolizinyl, indolyl. isoindolyl, benzofaranyl, benzothiopenyl, lH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and pteridinyl, each of which is optionally substituted. R₂ can be an optionally substituted 9-membered bi-heterocyclic aromatic group, e.g., indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothiopenyl, lH-indazolyl, benzimidazolyl, benzthiazolyl, and purinyl, each of which is optionally substituted. R₂ can be an optionally substituted 10-membered bi-heterocyclic aromatic group, e.g., 4H- quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and pteridinyl, each of which are optionally substituted. R₂ can be an optionally substituted benzofused bicyclic herteroaryl moiety covered under the term heteroaryl, e.g., indolinyl and tetrahydoquinolinyl.

[0094] In some embodiments, R₂ is an optionally substituted pyridinyl or pyrimidinyl. For example, R₂ is an optionally substituted pyridin-2-yl (e.g., 6-aliphatic pyridin-2-yl). [0095] Examples of bicyclic heteroaryl Ri or R₂ substituents include, but are not limited to

[0096] In some embodiments, Ring A is a 5- or 6-membered saturated, or partially unsaturated cycloaliphatic or heterocycloaliphatic ring wherein Ring B, Ri, R₂, R3 and R4 are as previously described.

[0097] In some embodiments, Ring A is a 6-membered aryl or heteroaryl ring wherein

Ring B, Ri, R₂, R₃ and R₄ are as previously described.

[0098] In some embodiments, Ring A contains one degree of unsaturation. [0099] In some embodiments, Ring A contains two degrees of unsaturation.

[00100] In some embodiments, Ring A is a 5-membered cycloaliphatic or heterocycloaliphatic ring.

[00101] In some embodiments, Ring A is a 6-membered cycloaliphatic or heterocycloaliphatic ring.

[00102] In some embodiments, Ring A is a 7-membered cycloaliphatic or heterocycloaliphatic ring.

[00103] In some embodiments, Ring B is a 5-, 6- or 7-membered partially unsaturated cycloaliphatic or heterocycloaliphatic ring wherein ring A, Ri, R₂, R₃ and R₄ are as previously described.

[00104] In some embodiments, Ring B contains one degree of unsaturation.

[00105] In some embodiments, Ring B contains two degrees of unsaturation provided that

Ring B is non-aromatic.

[00106] In some embodiments, Ring B is a 5-membered cycloaliphatic or heterocycloaliphatic ring.

[00107] In some embodiments, Ring B is a 6-membered cycloaliphatic or heterocycloaliphatic ring.

[00108] In certain embodiments, Ring B is a 7-membered cycloaliphatic or heterocycloaliphatic ring.

[00109] All combinations and permutaions of the above embodiments are within the scope of the invention. Thus, for example, in a specific compound Ri and R₂ can both be heteroaryl, Ring A can be a 6-membered cycloaliphatic and Ring B can be a 6-membered partially unsaturated heterocycloaliphatic.

[00110] Non-limiting examples of compounds of formula (I) are shown in Table 1.

TABLE 1

SYNTHESIS OF THE COMPOUNDS OF FORMULA I

[00111] Compounds of formula (I) may be prepared by a number of known methods from commercially available or known starting materials and as illustrated below. In the following synthetic schemes substituents on Ring A are described, where appropriate, as cis- or trans- which refers to the stereochemical relationship of the substituent relative to the bond between Xi and the A ring and as illustrated in Figure 1. In general, the ring juncture between the A and B rings is trans- unless otherwise noted. In the schemes, some compounds are shown with a specific stereochemistry and regiochemisty. The invention, however, encompasses all isomeric forms.

CIS- TRANS-

Figure 1

[00112] In general, compounds wherein Xi is C and X₂ is N may be prepared according to Scheme I. Scheme I:

[00113] Referring to Scheme I, the intermediate imidazole 1-3 is prepared by reaction of a diketone 1-1 with a cyclic aldehyde 1-2 (step I-A), wherein Q represents a radical which can be directly cyclizied (step I-B) or first derivatized (not shown) and subsequently cyclizied (step I-B) to the tricyclic compound 1-4. The radicals R₃ and R₄ can be modified by known methods (step I-C) to give compounds 1-5 wherein R'₃ and R'₄ represents modifications to R₃ and R4. Examples of Q radicals include, but are not limited to, olefins, protected hydroxyalkyl, alkylsulfonate esters and alkylhalides.

[00114] In one method, compounds of formula I, wherein Xi is C and X₂ is N and ring B is a 5- or 6-membered carbocyclic ring, may be prepared according to Scheme II. Scheme II:

[00115] In Step A, a diketone 1 is reacted with an allyl-aldehyde 2 in the presence of an ammonium salt and an organic acid in a suitable solvent to provide the imidazole 3. The diketones 1 are commercially available or may be prepared according to known procedures. See, e.g., U.S. Pat. No. 6,465,493; U.S. Publication 2004/0110797. Suitable ammonium salts include, but are not limited to, ammonium acetate and ammonium chloride. Examples of suitable solvents include, but are not limited to, dimethoxyethane, methyl-f-butyl ether, dioxane, dimethylformamide, methanol, ethanol, and acetic acid.

[00116] To produce compounds in which Ring B is a 6-membered cycloaliphatic, the allyl compound 3 is reacted with a borane hydride followed by oxidation with an oxidizing agent under known reaction conditions (see, e.g., H.C. Brown, Hydroboration, W.A.Benjamin, New York (1962)) to provide the alcohol 4. Subsequent cyclization of the alcohol 4 to the 6- membered Ring B compound 7 (step E) may be achieved by contacting an alcohol 4 with iodine in the presence of a tertiary phosphine such as triphenylphosphine and an organic base. Alternatively, cyclization can be achieved by contacting an alcohol 4 with a azodicarboxylate such as diethylazodicarboxylate and diisopropylazodicarboylate, in the presence of a tertiary phosphine such as triphenylphosphine. Suitable borane hydrides include, but are not limited to, diborane and 9-borobicyclo[3.3.1]nonane (9-BBN). Suitable oxidizing agents include, but are not limited to, hydrogen peroxide and m-chloroperbenzoic acid. Examples of suitable phosphines include, but are not limited to, tri-aryl phosphines, e.g., triphenylphosphine. Organic bases include, but are not limited to, imidazole, triethylamine, di-isopropylethyl amine and diazabicycloundecane.

[00117] To produce compounds in which Ring B is a 5-membered cycloaliphatic, the olefin 3 can be converted to the alcohol 5 (step C) by known oxidation-reduction methods. For example, olefin 3 can be converted to the alcohol 5 via ozonolysis followed by reduction of the resultant aldehyde. Alternatively, olefin 3 can be converted to the alcohol 5 by contacting olefin 3 with osmium tetroxide-periodate followed by a reduction. Cyclization of alcohol 5 to the 5-membered ring compound 6 is achieved under conditions as described above for step E.

[00118] In another method, scheme III illustrates preparation of compounds of the invention wherein X₁ is C and X₂ is N and Ring B is a 7-membered cycloaliphatic. Scheme III

[00119] Reaction of the diketone 1 with the aldehyde 2 in the presence of an ammonium salt and allylamine under conditions as described above for step A provides a di-olefm compound 8.

[00120] The di-allylimidazole of formula 8 is subjected to a metathesis reaction using a ruthenium catalyst (Grubb's reaction, see, e.g., Grubbs, et al., J. Org. Chern., 62: 7310 (1997); Grubbs et al., J. Amer. Chem Soc, 125, 11360 (2003); Martin et al., Chem. Rev., 104: 2199 (2004); McReynolds et al., Chem. Rev., 2004, 104, 2239; McDonald et al., J. Am. Chem. Soc, 126, 2495 (2004); J. Am. Chem. Soc, 122. 8168 (2000); Georg et al., Tetrahedron Lett., 45: 5309 (2004); and U.S. Pat. Nos. 5,831,108 and 6,111,121) to give an imidazole of formula 9. Examples of suitable ruthenium catalysts include, but are not limited to, benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (Grubbs 1^st catalyst), 1,3-bis- (2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene) (tricyclohexylphosphine)ruthenium and 1 ,3-(bis(mesityl)-2-imidazolidinylidene)dichloro-(o- isopropoxyphenylmethylene)ruthenium. Suitable solvents for this reaction include, e.g., methylenechloride, ethylenedichloride and tetrahydrofuran. In certain methods, compounds of structure 9 may be reduced under known olefin hydrogenation conditions to produce saturated analogs of compound 9.

[00121] In a further method, compounds of the invention wherein X₁ is C and X₂ is N and Ring A is a 6-membered aromatic ring may be prepared according to Scheme IV.

Scheme IV

11

[00122] Referring to scheme IV, reaction of the diketone 1 with the cyclicimino compound of formula 10 wherein n is 1 to 3 in the presence of an ammonium salt under conditions similar to step A provides compounds in which ring A is aromatic. The imine compounds of formula 10 are commercially available or may be prepared by known methods (see, e.g., Nicolaou, K.C. et al., Angewandt Chemie, International Edition, 42 (34): 4077 (2003); and Larsen, R.D., et al., J. Org. Chem., 56: 6034-6038 (1991).

[00123] In other methods, compounds of formula (I) are produced by modifying the substituents on rings A and/or B. For example, when R₃ is a protected hydroxyl (-OPg), compound analogs are generated by removing the hydroxyl protecting group, Pg, to provide the corresponding alcohol. The alcohol can be converted by known methods to alcohol derivatives such esters, thioesters, carbamates, halides, nitriles, alkylethers, arylethers, and the like. The alcohol may also be converted to the corresponding amine, ketone or olefin. In some examples, R₃ is a ketone. Reduction of the ketone with, for example, sodium borohydride leads to the corresponding alcohol. The stereochemistry of the derived alcohol may be inverted by known methods, e.g., the Mitsunobu Reaction (O. Mitsunobu, Synthesis, 1981, pp. 1-28). The amines and ketones maybe further derivatized to provide substituted amines or homologated lactams.

[00124J In another method, R₃ may be -CHiOPg. Removal of the protecting group provides the alcohol which can be converted to alcohol derivatives described above. Additionally, the alcohol can be oxidized to provide compounds containing an aldehyde or a carboxylic acid functionality. The aldehyde and carboxylic acid functionality can be further modified by known methods.

[00125] The cyclic aldehydes 2 of scheme II may be produced by known methods. In one example, a cyclohexane carboxaldehyde of formula 2 wherein two of R₃ together form a cyclic ketal can be prepared as outlined in scheme V and as further illustrated, e.g., in Preparation 1.

Scheme V

[00126] In another example, a cyclopentane carboxaldehyde of formula 2 can be prepared as outlined in scheme VI and as further illustrated in the Examples. Scheme VI

[00127] Embodiments wherein Ring A is a heterocyclic ring can be prepared, for example, as shown in Scheme VII. Scheme VII

[00128] Reaction of the diketo compound 1 with the piperidine aldehyde 12 in the presence of an ammonium salt as previously described provides the compound of the invention 14.

Piperidine aldehyde 12 can be made by oxidation of aldehyde 13, which in turn, is formed by reaction of the hydroxymethyl piperidine 13a with chloroacetyl chloride. See, e.g., Example

16.

[00129] Embodiments wherein Xj is N, X₂ is C, Ring B contains two heteroatoms and Ring

A is aromatic can, in general, be prepared as illustrated in Scheme VIII. Scheme VIII

X=CH₂, O, N R_f

17 18

[00130] Refering to Scheme VIII, wherein X is CH₂, O, S or NR_x, the acid 15 is converted to the corresponding acid chloride using known conditions and reagents such as oxalyl choride or thionyl chloride. Reaction of the acid chloride with N-aminophthalimide in the presence of a tertiary organic base such as pyridine or triethylamine gives the hydrazide 16. Ring closure of 16 with phenyliodine (III) bistrifluroacetate (Y. Kikugawa, J. Org. Chem., 68, 6739-6744 (2003)) gives the N-amϊnoqxiinolone 17. Reaction of 17 with the ketone 18 in the presence of toluene sulfonic acid yields an intermediate hydrazone (not shown) which is cyclized with a strong base such as sodium hexamethyldisilazide to provide compounds of the invention wherein Ring A is aromatic, Ring B is partially unsaturated heterocycloaliphatic, Xi is N and X₂ is C.

[00131] Embodiments wherein Xi is N and X₂ is C, Ring B is heterocycloaliphatic and Ring A is cycloaliphatic can, in general, be prepared as described above but substituting a cycloaliphatic hydrazide which may be obtained as shown in Scheme IX.

Scheme IX

20

21

[00132] In Scheme IX, the lactone 18 is converted to the chloroacid chloride 19 which reacts with hydrazine to give the corresponding hydrazide (not shown). Cyclization of the hydrazide is performed by treatment with a strong base such as sodium hydride or lithium di- isopropylamide to give the N-aminolactam 20, which is used in the preparation of compounds 21 wherein Xi is N and X₂ is C, Ring B is heterocycloaliphatic and Ring A is cycloaliphatic by reacting compound 20 with a ketone followed by dehydration.

METHODS OF USE AND COMPOSITIONS Uses of Compounds of Formula (I)

[00133] As discussed above, hyperactivity of the TGFβ family signaling pathways can result in excess deposition of extracellular matrix and increased inflammatory responses, which can then lead to fibrosis in tissues and organs (e.g., lung, kidney, and liver) and ultimately result in organ failure. See, e.g., Border, W.A. et al., J. CHn. Invest, 90: 1-7 (1992), and Border, W.A. et al., N. Engl. J. Med., 331 : 1286-1292 (1994). Studies have been shown that the expression of TGFβ and/or activin mRNA and the level of TGFβ and/or activin are increased in patients suffering from various fibrotic disorders, e.g., fibxotic kidney diseases, alcohol- induced and autoimmune hepatic fibrosis, myelofibrosis, and bleomycin-induced pulmonary fibrosis.

[00134] Compounds of formula (I), which are antagonists of the TGFβ family type I receptors Alk5 and/or Alk4, and inhibit TGFβ and/or activin signaling pathway, are therefore useful for treating and/or preventing fibrotic disorders or diseases mediated by an increased level of TGFβ and/or activin activity. As used herein, a compound inhibits the TGFβ family signaling pathway when it binds (e.g., with an IC₅₀ value of less than 10 μM; such as, less than 1 μM; and for example, less than 5 nM) to a receptor of the pathway (e.g., Alk5 and/or Alk4), thereby competing with the endogenous ligand(s) or substrate(s) for binding site(s) on the receptor and reducing the ability of the receptor to transduce an intracellular signal in response to the endogenous ligand or substrate binding. The aforementioned disorders or diseases include any condition (a) marked by the presence of an abnormally high level of TGFβ and/or activin; and/or (b) an excess accumulation of extracellular matrix; and/or (c) an increased number and synthetic activity of myofibroblasts. These disorders or diseases include, but are not limited to, fibrotic conditions such as mesothelioma, acute respiratory distress syndrome (ARDS), atherosclerosis, scleroderma, keloids, glomerulonephritis, diabetic nephropathy, lupus nephritis, hypertension-induced nephropathy, cholangitis, restinosis, ocular or corneal scarring, hepatic or biliary fibrosis, liver cirrhosis, cirrhosis due to fatty liver disease (alcoholic and nonalcoholic steatosis), renal fibrosis, sarcoidosis, acute lung injury, drug-induced lung injury, spinal cord injury, CNS scarring, systemic lupus erythematosus, Wegener's granulomatosis, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis), cardiac fibrosis, post-infarction cardiac fibrosis, post-surgical fibrosis, connective tissue disease, fibrosclerosis, fibrotic cancers, fibroids, fibroma, fibroadenomas, and fibrosarcomas. Other fibrotic conditions for which preventive treatment with compounds of formula (I) can have therapeutic utility include radiation therapy-induced fibrosis, chemotherapy-induced fibrosis, and surgically induced scarring including surgical adhesions, transplant arteriopathy, laminectomy, and coronary restenosis.

[00135] Increased TGFβ activity is also found to manifest in patients with progressive cancers. Studies have shown that in late stages of various cancers, both the tumor cells and the stromal cells within the tumors generally overexpress TGFβ. This leads to stimulation of angiogenesis and cell motility, suppression of the immune system, and increased interaction of tumor cells with the extracellular matrix. See, e.g., Hojo, M. et al., Nature 397: 530-534 (1999). As a result, the tumor cells become more invasive and metastasize to distant organs. See, e.g., Maehara, Y. et al., J. Clin. Oncol, 17: 607-614 (1999) and Picon, A. et al., Cancer Epidemiol. Biomarkers Prev., 7: 497-504 (1998). Thus, compounds of formula (I), which are antagonists of the TGFβ type I receptor and inhibit TGFβ signaling pathways, are also useful for treating and/or preventing various late stage cancers (including carcinomas) which overexpress TGFβ. Such late stage cancers include carcinomas of the lung, breast, liver, biliary tract, gastrointestinal tract, head and neck, pancreas, prostate, cervix, as well as multiple myeloma, melanoma, glioma, and glioblastomas.

[00136] Importantly, it should be pointed out that because of the chronic, and in some cases localized, nature of disorders or diseases mediated by overexpression of TGFβ and/or activin (e.g., fibrosis or cancers), small molecule treatments (such as treatment disclosed in the present invention) are favored for long-term treatment. [00137] Not only are compounds of formula (I) useful in treating disorders or diseases mediated by high levels of TGFβ and/or activin activity, these compounds can also be used to prevent the same disorders or diseases. It is known that polymorphisms leading to increased TGFβ and/or activin production have been associated with fibrosis and hypertension. Indeed, high serum TGFβ levels are correlated with the development of fibrosis in patients with breast cancer who have received radiation therapy, chronic graft- versus-host-disease, idiopathic interstitial pneumonitis, veno-occlusive disease in transplant recipients, and peritoneal fibrosis in patients undergoing continuous ambulatory peritoneal dialysis. Thus, the levels of TGFβ and/or activin in serum and of TGFβ and/or activin mRNA in tissue can be measured and used as diagnostic or prognostic markers for disorders or diseases mediated by overexpression of TGFβ and/or activin, and polymorphisms in the gene for TGFβ that determine the production of TGFβ and/or activin can also be used in predicting susceptibility to disorders or diseases. See, e.g., Blobe, G.C. et al., N. Engl. J. Med, 342(18): 1350-1358 (2000); Matsuse, T. et al., Am. J. Respir. Cell MoI. Biol, 13: 17-24 (1995); Inoue, S. et al., Biochem. Biophys. Res. Comm., 205: 441-448 (1994); Matsuse, T. et al, Am. J. Pathol, 148: 707-713 (1996); De Bleser et al., Hepatology, 26: 905-912 (1997); Pawlowski, J.E., et al., J. Clin. Invest., 100: 639-648 (1997); and Sugiyama, M. et al., Gastroenterology, 114: 550-558 (1998).

[00138] In some embodiments, the inhibitors described herein are effective at treating, preventing, or reducing intimal thickening, vascular remodeling, restenosis (e.g., coronary, peripheral, or carotid restenosis), vascular diseases (e.g., intimal thickening, vascular remodeling, organ transplant-related, cardiac, and renal), and hypertension (e.g., primary and secondary, systolic, pulmonary, and hypertension-induced vascular remodeling resulting in target organ damage).

[00139] Without wishing to be bound by any particular theory, one possible explanation for the efficacy of the compounds described herein may be their inhibitory effect on the TGFβ and activin pathways.

[00140] The pathological activation of the TGFβ and activin pathway plays a critical role in the progression of fibrotic diseases. The critical serine-threonine kinase in the TGFβ type I receptor (TGFβRI) and the activin type I receptor (Alk4) are attractive targets for blockade of the TGFβ pathway for several important reasons. TGFβRI kinase activity is required for TGFβ signaling as is Alk4 for activin signaling. Kinases have proven to be useful targets for development of small molecule drugs. There is a good structural understanding of the TGFβRI kinase domain allowing the use of structure-based drug discovery and design to aid in the development of inhibitors.

[00141] TGFβ or activin-mediated pathological changes in vascular flow and tone are often the cause of morbidity and mortality in a number of diseases (Gibbons G.H. and Dzau VJ. N Eng. J. Med 330:1431-1438 (1994)). Typically, the initial response of the vasculature to injury is an infiltration of adventitial inflammatory cells and induction of activated myofibroblasts or smooth muscle cells (referred to as myofibroblasts from hereon). TGFβ is initially produced by infiltrating inflammatory cells and activates myofibroblasts or smooth muscle cells. These activated myofibroblasts can also secrete TGFβ as well as respond to it. Within the first few days following injury, myofibroblasts secreting TGFβ migrate from the various layers of the vascular wall towards the lumen where they undergo proliferation and extracellular matrix secretion resulting in intimal thickening. Additionally, TGFβ induces activated myofibroblasts to contract which results in lumenal narrowing. These vascular remodeling processes, intimal thickening and vascular contraction, restrict blood flow to the tissues supported by the effected vasculature and result in tissue damage. Activin is also produced in response to injury and shows very similar actions in inducing activated myofibroblasts or activated smooth muscle cells intimal thickening and vascular remodeling. See, for example, scientific articles by Pawlowski et al. J. Clin. Invest. 100:639-648 (1997); Woodruff TK. Biochem Pharmacol. 55:953-963 (1998); Molloy et al. J Endocrinol. 161(2):179-85 (1999); and Harada K et al. J Clin Endocrinol Metab. 81(6):2125-30 (1996). [00142] In coronary, peripheral or carotid artery disease, balloon angioplasty or stent placement is used to increase lumen size and blood flow. However, the physical damage created by stretching the vessel wall causes injury to the vessel wall tissue. TGFβ elevation following injury induces myofibroblasts in 2-5 days and frequently results in restenosis within 6 months of balloon angioplasty or within a few years of stent placement in human patients. Following balloon angioplasty, both intimal thickening as well vascular remodeling due to myofibroblast contraction, causes narrowing of the lumen and decreased blood flow. Stent placement physically prevents remodeling, but hyperplasia and extracellular matrix deposition by activated myofibroblasts proliferating at the luminal side of the stent results in intimal thickening within the stented vessel resulting in the eventual impairment of blood flow.

[00143] The treatment of arterial stenotic disease by surgical grafts, e.g. coronary bypass or other bypass surgery, also can elicit restenosis in the grafted vessel. In particular, vein grafts undergo intimal thickening and vascular remodeling through a similar mechanism involving TGFβ-induced intimal thickening and vascular remodeling. In this case, the injury is either due to the overdistention of the thin-walled vein graft placed into an arterial vascular context or due to anastamotic or ischemic injury during the transplantation of the graft. [00144] The loss of patency in arteriovenous or synthetic bridge graft fistulas is another vascular remodeling response involving increased TGFβ production. See, e.g., Ikegaya, N. et al., J. Am. Soc. Nephrol, 11:928-35 (2000); Heine G.H. et al., Kidney Int., 64:1101-7 (2003). Loss of fistula patency causes complications for renal dialysis or other treatments requiring chronic access to the circulatory system (Ascher E., Ann Vase Surg., 15:89-97 (2001)). Blockade of TGFβ by TGFβRI inhibitors will beneficial for preventing restenosis and extending arteriovenous fistula patency.

[00145] Elevated TGFβ is implicated in chronic allograft vasculopathy both in animals and humans. Vascular injury, intimal thickening and vascular remodeling is a characteristic pathology in chronic allograft failure. The fibrotic response in chronic allograft failure initiates in the vasculature of the donor organ. Chronic allograft vasculopathy in allografted hearts often manifests within 5 years of transplantation and is the main cause of death in long term survivors of cardiac transplant. Both early detection of cardiac allograft vasculopathy measured as intimal thickening by intravascular ultrasound as well as the elevation of plasma TGFβ has been suggested as a prognostic marker for late cardiac allograft failure (Mehra, M.R. et al., Am. J. Transplant., 4: 1 184 (2004)). Cardiac biopsies of grafted hearts also suggest that graft tissue expression of TGFβ correlates significantly to vasculopathy and the number of rejection episodes (Aziz, T. et al., J. Thorac. Cardiovasc. Surg., 119: 700 (2000)). Finally, patients with high-producing TGFβ genotypes are more susceptible to earlier onset cardiac-transplant coronary vasculopathy (Densem, CG. et al., J. Heart Lung Transplant., 19: 551 (2000); Aziz, T. et al., J. Thorac. Cardiovasc. Surg., 119: 700 (2000); Holweg, C.T., Transplantation, 71:1463 (2001)).

[00146] Elevation of TGFβ can be induced by ischemic, immune and inflammatory responses to the allograft organ. Animal models of acute and chronic renal allograft rejection identify the elevation of TGFβ as a significant contributor to graft failure and rejection (Nagano, H. et al., Transplantation, 63: 1101 (1997); Paul, L.C. et al, Am. J. Kidney Dis., 28: 441 (1996); Shihab, F.S. et al., Kidney Int., 50: 1904 (1996)). Rodent models of chronic allograft nephropathy (CAN) show elevation of TGFβ mRNA and immunostaining. In renal allografts TGFβ immunostaining is strongly positive in interstitial inflammatory andfibrotic cells, but also in blood vessels and glomeruli. In humans, the loss of renal function 1 year post renal allograft correlates with TGFβ staining in the grafted kidney (Cuhaci, B. et al., Transplantation, 68: 785 (1999)). Graft biopsies show also that renal dysfunction correlates with chronic vascular remodeling, i.e., vasculopathy, and the degree of TGFβ expression correlates significantly with chronic vasculopathy (Viklicky, O. et al., Physiol Res,, 52: 353 (2003)).

[00147] The use of immunosuppressive agents such as cyclosporine A in organ transplantation has not prevented vasculopathy and chronic allograft nephropathy suggesting non-immune mechanisms are involved in allograft failure. In fact, cyclosporinA and other immunosuppressants have been shown to induce TGFβ expression and may contribute to vasculopathy (Moien-Afshari, F. et al., Pharmacol Ther., 100: 141 (2003); Jain, S. et al., Transplantation, 69: 1759 (2000)).

[00148] TGFβ is implicated in chronic allograft rejection in both renal and lung transplants due to the clear TGFβ-related fibrotic pathology of this condition as well as the ability of immune suppressants, especially cyclosporin A, to induce TGFβ (Jain, S. et al., supra). TGFβ blockade improved renal function while decreasing collagen deposition, renal TGFβ expression as well as vascular afferent arteriole remodeling in a cyclosporine A-induced renal failure model using an anti-TGFβ monoclonal antibody (Islam, M. et al., Kidney Int. , 59: 498 (2001); Khanna, A.K. et al., Transplantation, 67: 882 (1997)). These data are strongly indicative of a causal role for TGFβ in the development and progression of chonic allograft vasculopathy and chronic allograft failure.

[00149] Hypertension is a major cause of morbidity and mortality in the U.S. population affecting approximately 1 in 3 individuals. The effect of hypertension on target organs include increased incidence of cardiac failure, myocardial infarction, stroke, renal failure, aneurysm and microvascular hemorrhage. Hypertension-induced damage to the vasculature results in vascular remodeling and intimal thickening which are a major causative factor in many of these morbidities (Weber, W.T., Curr. Opin. Cardiol, 15: 264-72 (2000)). Animal experiments suggest that TGFβ is elevated upon induction of hypertension and anti-TGFβ monoclonal antibody blockade of this pathway decreases blood pressure and renal pathology in hypertensive rats (Xu, C. et al., J. Vase. Surg., 33: 570 (2001); Dahly, AJ. et al., Am. J. Physiol. Regul. Integr. Comp. Physiol, 283: R757 (2002)). In humans, plasma TGFβ is elevated in hypertensive individuals compared to normotensive controls and plasma TGFβ is also higher in hypertensive individuals with manifest target organ disease compared to hypertensive individuals without apparent target organ damage (Derhaschnig, U. et al., Am. J. Hypertens., 15: 207 (2002); Suthanthiran, M., Proc. Natl. Acad. ScL USA, 97: 3479 (2000)).

There is also evidence suggesting that high TGFy-producing genotypes of TGFβ are a risk factor for development of hypertension (Lijnen, P.J., Am. J. Hypertens., 16: 604 (2003); Suthanthiran, M., supra). Thus the inhibition of the TGFβ pathway may provide an effective therapeutic approach for hypertension or hypertension-induced organ damage. [00150] The vascular injury response in the pulmonary vasculature results in pulmonary hypertension which can lead to overload of the right heart and cardiac failure (Runo, J.R. et al., Lancet, 361(9368): 1533-44 (2003); Sitbon, O. et al., Prog Cardiovasc Dis., 45: 115-28 (2002); Jeffery, T.K. et al., Cardiovasc Dis., 45:173-202 (2002)). Prevention of pulmonary vascular remodeling by TGFβRI inhibitors can be of practical utility in diseases such as primary or secondary pulmonary hypertension (Sitbon O et al 2002 Prog Cardiovasc Dis. 45: 115-28; Humbert M et al. J Am Coll Cardiol. 200443:13S-24S). Inhibition of the progression of vascular remodeling over time will prevent the progression of pulmonary pathology in these life threatening diseases. Secondary pulmonary hypertension occurs often as a manifestation of scleroderma and is one of the primary causes of morbidity and mortality in scleroderma patients (Denton, CP. et al., Rheum Dis Clin North Am., 29:335-49 (2003)). Pulmonary hypertension is also a sequalae of mixed connective tissue disease, chronic obstructive pulmonary disease (COPD) and lupus erythematosis (Fagan, K.A. et al., Prog. Cardiovasc. Dis., 45: 225-34 (2002); Presberg, K.W. et al., Curr. Opin. PuIm. Med., 9:131-8 (2003)).

[00151] Many of the diseases described above involving vascular remodeling are particularly severe in diabetic patients (Reginelli, J.P. et al., J. Invasive Cardiol., 14 Suppl E:2E-10E (2002)). Elevated glucose in diabetes can itself induce TGFβ which leads to the increased vascular remodeling and intimal thickening response to vascular injury (Ziyadeh, F., J. Am. Soc Nephrol., .15 (Suppl 1): S55-7 (2004)). In particular, diabetic patients have significantly higher rates of restenosis, vein graft stenosis, peripheral artery disease, chronic allograft nephropathy and chronic allograft vasculopathy (Reginelli, J.P. et al., J. Invasive Cardiol., 14 Suppl E-.2E-10E (2002); Eisen, H. et al., J. Heart Lung Transplant, 23: S207-13 (2004); Valentine, H., J. Heart Lung Transplant, 23:S187-93 (2004)). Thus, blockade of TGFβ is of particular utility in diabetic patients at risk for hypertension-related organ failure, diabetic nephropathy, restenosis or vein graft stenosis in coronary or peripheral arteries, and chronic failure of allograft organ transplants (Endemann, D.H. et al., Hypertension, 43 (2): 399-404 (2004); Ziyadeh, F., J. Am. Soc. Nephrol, 15 (Suppl. 1): S55-7 (2004); Jerums, G. et al., Arch. Biochem. Biophys., 419:55-62 (2003)).

[00152] TGFβRI and Alk4 antagonists are effective at treating, preventing, or reducing intimal thickening, vascular remodeling, restenosis (e.g., coronary, peripheral, or carotid restenosis), vascular diseases (e.g., organ transplant-related, cardiac, and renal), and hypertension (e.g., systolic, pulmonary, and hypertension-induced vascular remodeling resulting in target organ damage). Changes in vascular remodeling and intimal thickening may be qualified by measuring the intimal versus medial vascular thickness. Administration of Compounds of Formula (I)

[00153] As defined above, an effective amount is the amount required to confer a therapeutic effect on the treated patient. For a compound of formula (I), an effective amount can range, for example, from about 1 mg/kg to about 150 mg/kg (e.g., from about 1 mg/kg to about 100 mg/kg). Effective doses will also vary, as recognized by those skilled in the art, dependant on route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments including use of other therapeutic agents and/or radiation therapy. [00154] Compounds of formula (1) can be administered in any manner suitable for the administration of pharmaceutical compounds, including, but not limited to, pills, tablets, capsules, aerosols, suppositories, liquid formulations for ingestion or injection or for use as eye or ear drops, dietary supplements, and topical preparations. The pharmaceutically acceptable compositions include aqueous solutions of the active agent, in an isotonic saline, 5% glucose or other well-known pharmaceutically acceptable excipient. Solubiliziπg agents such as cyclodextrins, or other solubilizing agents well-known to those familiar with the art, can be utilized as pharmaceutical excipients for delivery of the therapeutic compounds. As to route of administration, the compositions can be administered orally, intranasally, transdermally, intradermally, vaginally, intraaurally, intraocularly, buccally, rectally, transmucosally, or via inhalation, implantation (e.g., surgically), or intravenous administration. The compositions can be administered to an animal (e.g., a mammal such as a human, non-human primate, horse, dog, cow, pig, sheep, goat, cat, mouse, rat, guinea pig, rabbit, hamster, gerbil, or ferret, or a bird, or a reptile, such as a lizard). [00155] In certain embodiments, the compounds of formula (I) can be administered by any method that permits the delivery of the compound to combat vascular injuries. For instance, the compounds of formula (I) can be delivered by any method described above. Additionally, the compounds of formula (I) can be administered by implantation (e.g., surgically) via an implantable device. Examples of implantable devices include, but are not limited to, stents, delivery pumps, vascular filters, and implantable control release compositions. Any implantable device can be used to deliver the compound provided that: (1) the device, compound and any pharmaceutical composition including the compound are biocompatible, and (2) that the device can deliver or release an effective amount of the compound to confer a therapeutic effect on the treated patient.

[00156] Delivery of therapeutic agents via stents, delivery pumps (e.g., mini-osmotic pumps), and other implantable devices is known in the art. See, e.g., Hofma et al., Current Interventional Cardiology Reports, 3: 28-36 (2001), the entire contents of which, including references cited therein, are incorporated herein. Other descriptions of implantable devices, such as stents, can be found in U.S. Pat. Nos. 6,569,195 and 6,322,847; and PCT International Publication Numbers WO04/0044405; WO04/0018228; WO03/0229390; WO03/0228346; WO03/0225450; WO03/0216699; and WO03/0204168, each of which is incorporated herein by reference in its entirety.

[00157] A delivery device, such as stent, includes a compound of formula (I). The compound may be incorporated into or onto the stent using methodologies known in the art. In some embodiments, a stent can include interlocked meshed cables. Each cable can include metal wires for structural support and polyermic wires for delivering the therapeutic agent. The polymeric wire can be dosed by immersing the polymer in a solution of the therapeutic agent. Alternatively, the therapeutic agent can be embedded in the polymeric wire during the formation of the wire from polymeric precursor solutions. In other embodiments, stents or implatable devices can be coated with polymeric coatings that include the therapeutic agent. The polymeric coating can be designed to control the release rate of the therapeutic agent. [00158] Controlled release of therapeutic agents can utilize various technologies. Devices are known having a monolithic layer or coating incorporating a heterogeneous solution and/or dispersion of an active agent in a polymeric substance, where the diffusion of the agent is rate limiting, as the agent diffuses through the polymer to the polymer-fluid interface and is released into the surrounding fluid. In some devices, a soluble substance is also dissolved or dispersed in the polymeric material, such that additional pores or channels are left after the material dissolves. A matrix device is generally diffusion limited as well, but with the channels or other internal geometry of the device also playing a role in releasing the agent to the fluid. The channels can be pre-existing channels or channels left behind by released agent or other soluble substances.

[00159] Erodible or degradable devices typically have the active agent physically immobilized in the polymer. The active agent can be dissolved and/or dispersed throughout the polymeric material. The polymeric material is often hydrolytically degraded over time through hydrolysis of labile bonds, allowing the polymer to erode into the fluid, releasing the active agent into the fluid. Hydrophilic polymers have a generally faster rate of erosion relative to hydrophobic polymers. Hydrophobic polymers are believed to have almost purely surface diffusion of active agent, having erosion from the surface inwards. Hydrophilic polymers are believed to allow water to penetrate the surface of the polymer, allowing hydrolysis of labile bonds beneath the surface, which can lead to homogeneous or bulk erosion of polymer.

[00160] The implantable device coating can include a blend of polymers each having a different release rate of the therapeutic agent. For instance, the coating can include a polylactic acid/polyethylene oxide (PLA-PEO) copolymer and a polylactic acid/polycaprolactone (PLA-PCL) copolymer. The polylactic acid/polyethylene oxide (PLA- PEO) copolymer can exhibit a higher release rate of therapeutic agent relative to the polylactic acid/polycaprolactone (PLA-PCL) copolymer. The relative amounts and dosage rates of therapeutic agent delivered over time can be controlled by controlling the relative amounts of the faster releasing polymers relative to the slower releasing polymers. For higher initial release rates the proportion of faster releasing polymer can be increased relative to the slower releasing polymer. If most of the dosage is desired to be released over a long time period, most of the polymer can be the slower releasing polymer. The stent can be coated by spraying the stent with a solution or dispersion of polymer, active agent, and solvent. The solvent can be evaporated, leaving a coating of polymer and active agent. The active agent can be dissolved and/or dispersed in the polymer. In some embodiments, the copolymers can be extruded over the stent body.

[00161] In still other embodiments, compounds of formula (I) can be administered in conjunction with one or more other agents that inhibit the TGFβ signaling pathway or treat the corresponding pathological disorders (e.g., fibrosis or progressive cancers) by way of a different mechanism of action. Examples of these agents include angiotensin converting enzyme inhibitors, nonsteroid, steroid anti-inflammatory agents, and chemotherapeutics or ■ radiation, as well as agents that antagonize lϊgand binding or activation of the TGFβ receptors, e.g., anti-TGFβ, anti-TGFβ receptor antibodies, or antagonists of the TGFβ type II receptors.

[00162] The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.

[00163] Optionally, compounds of formula (I) can be administered in conjunction with one or more other agents that inhibit the TGFβ signaling pathway or treat the corresponding pathological disorders (e.g., fibrosis or progressive cancers) by way of a different mechanism of action. Examples of these agents include angiotensin converting enzyme inhibitors, nonsteroid and steroid anti-inflammatory agents, as well as agents that antagonize ligand binding or activation of the TGFβ receptors, e.g., antϊ-TGFβ, anti-TGFβ receptor antibodies, or antagonists of the TGFβ type II receptors.

[00164] The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.

EXAMPLES

Preparation 1: 7-Vinyl-l,4-dioxa-spiro[4.5] decane-8-carbaldehyde

Step a: [3-(tert-Butyl-dimethyI-siIanyIoxy)-buta-l,3-dienyll-dimethyI-amine: [00165J To a 200 mL flask was added 4-dimethylaminobut-3,4-en-2-one (Aldrich Chemical Co., Milwaukee, WI; 3.0 g; 20.5 mmol) and THF (100 mL). The flask was cooled to -78 ⁰C and a 0.5 M solution of KHMDS (56 mL; 28.0 mmol) in toluene was added dropwise via addition funnel. The reaction was stirred while warming to 0⁰C over 1 hour. The reaction mixture was cooled to -78 ⁰C and a solution of TBSCl (4.39 g; 29.2 mmol) in THF (25 mL) was added via addition funnel. The reaction was allowed to stir while warming to 20⁰C. The reaction was diluted with ether (500 mL) and then filtered through celite and concentrated in vacuo. The resulting oil (5.92 g; 98% yield) was pure and needed no further purification.

¹H-NMR (400 MHz, CDCl₃) (J = Hz) δ 6.6.60 (d; IH; J = 13.3), 4.80 (d; IH; J = 13.3), 3.95 (s; IH), 3.86 (s; IH), 2.73 (si 6H), 1.00 (s; 9H), 0.22 (s; 6H). ¹³C-NMR (400 MHz, CDCl₃) δ 156.5, 140.9, 95.9, 85.9, 40.6, 25.9, 18.3, -4.6.

Step b: 4-(tert-Butyl-dimethyl-sUanyloxy)-2-dimethylamino-cyclohex-3- enecarboxylic acid methyl ester.

[00166] A 1.0 L round-bottom flask was charged with the diene of step Ia (56.6 g; 249 mmol) toluene (500 mL) and methyl acrylate (29.3 mL; 323 mmol). The reaction was heated to 50 ⁰C and stirred overnight. The mixture was concentrated in vacuo to yield product (68.2 g; 87% yield) as a mixture of stereoisomer.

¹H-NMR (400 MHz, CDCl₃) (J = Hz) δ 4.95 (m; IH), 3.71 (m; 4H), 2.60 (m; IH), 2.24 (m; 6H), 2.08 (m; 2H), 1.93 (m; 2H), 0.93 (s; 9H), 0.18 (s; 6H).

Step c: [4-(tert-Butyl-dimethyl-silanyloxy)-2-dimethylamino-cyclohex-3-eiiyl]- methanol.

[00167] To a 1-L round-bottom flask was added the ester of step Ib (68.2 g; 217 mmol) and THF (250 mL). The solution was cooled to -78 ⁰C and a 1.0 M solution of LAH in THF (435 mL; 435 mmol) was added via addition funnel. The reaction was stirred for 4h at -78 ⁰C to room temperature. The reaction was cooled to -78 ⁰C and quenched with EtOAc (150 mL). The reaction was warmed to 0⁰C and poured into a flask containing EtOAc (1.0 L). The mixture was stirred vigorously and solid sodium sulfate (5 g) was added followed by water (50 mL). The resulting suspension was filtered through silica gel and concentrated in vacuo to give crude product (35.13 g; 56% yield) as a mixture of diastereomers. The crude material was used without further purification.

Step d: 4-Hydroxymethyl-cyclohex-2-enone.

[00168] To a 1-L round-bottom flask was added the alcohol of step Ic (22.6 g; 79.0 mmol), THF (300 mL) and a 35% solution of HF in water (8.08 mL; 182 mmol). The reaction was allowed to stir at 20 ⁰C for 12 hours and then concentrated in vacuo. The residue was diluted with EtOAc (250 mL), washed with 10% HCl (250 mL ) and brine (250 mL). The organic layer was then treated with solid NaHCO₃ for 1 hour, dried (MgSO₄), filtered and concentrated in vacuo. The crude oil (5.3 g; 53% yield) was used without further purification.

¹H-NMR (400 MHz, CDCl₃) (J = Hz) δ 6.82 (d; IH), 6.03 (d; IH), 4.04 (m; 2H), 2.79 (m IH), 2.54 (m; IH), 2.39 (m; IH)₅ 2.11 (m; IH), 1.80 9m; IH).

Step e: 4-(tert-Butyl-dimethyl-s£Ianyloxymethyl)-cyclohex-2-enone. [00169] A 200 mL round-bottom flask was charged with the alcohol of step Id (3.80 g; 30.1 mmol), DMF (100 mL), imidazole (2.46 g; 36.1 mmol) and TBSCl (5.0 g; 33.1 mmol). The reaction was allowed to stir for 72 hours and then diluted with ether (200 mL). The mixture was washed with 5% HCl (200 mL), saturated NaCl (200 mL), dried (MgSO₄), filtered and concentrated in vacuo. The crude oil was purified by flash chromatography (silica gel, hexanes/EtOAc 1 :0 to 5:1) to give pure product (5.0 g; 69% yield) as a colorless oil. ¹H-NMR (400 MHz, CDCl₃) (J = Hz) δ 6.90 (m; IH), 5.97 (m; IH), 3.54 (m; 2H), 2.50 (m; 3H), 2.02 (m; IH), 1.61 (m; IH), 0.84 (s; 9H), 0.02 (s; 6H). ¹³C-NMR (400 MHz, CDCl₃) δ 199.6, 151.8, 129.9, 65.4, 39.2, 36.6, 25.8, 18.2, -3.6, -5.5. MS (ES+) m/z 241.08 [MH+].

Step f: 4-(tert-Butyl-dimethyl-siIanyIoxymethyl)-3-vinyl-cyclohexanone. [00170] To a flame dried 200 mL round-bottom flask was added copper(I) bromide- dimethylsulfide complex (1.80 g; 8.74 mmol), THF (30 mL), and TMEDA (2.50 mL; 16.6 mmol). The mixture was stirred until all the CuBr had dissolved and then cooled to -78 ⁰C. To the mixture was added a 1.0 M solution of vinylmagnessium bromide in THF (16.6 mL; 16.6 mmol). The reaction was stirred for 20 minutes and then trimethylsilyl chloride (3.16 mL: 25.0 mmol) was added followed immediately by a solution of the enone of step Ie (2.0 g; 8.32 mmol) in THF (10 mL). The reaction was allowed to stir while warming to 20⁰C over 3 hours. The reaction was quenched with saturated NH₄CI (30 mL) and stirred for 30 minutes. The mixture was extracted with ether (100 mL), and the organic layer was washed with 10% HCl (100 mL), brine (100 mL), dried (MgSO₄), filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, hexanes/EtOAc 1 :0 to 10:1) to give pure product (1.73 g; 76% yield) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) (J = Hz) δ 5.65 (m; IH), 5.01 (m; 2H), 3.66 (dd; IH; J = 9.8, 2.5), 3.48 (dd; IH; 9.8, 5.7), 2.38 (m; 5H), 2.16 (m; IH), 1.82 (m; 2H), 0.88 (s; 9H), 0.01 (s; 6H). ¹³C-NMR (400 MHz, CDCl₃) δ 210.7, 140.1, 115.4, 64.5, 46.6, 44.2, 42.6, 40.5, 28.5, 25.8, 18.2, -5.5.

Step g: (7-Vinyl-l,4-dioxa-spiro[4.5]dec-8-yl)-methanol.

[00171] To a 50 mL round-bottom flask was added the ketone of step Ih (2.8 g; 10.4 mmol), ethylene glycol (4.07 mL; 73.0 mmol), triethyl ortho formate (5.20 mL; 31.2 mmol), and/>- toluenesulfonic acid monohydrate (100 mg; 0.52 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with ether (125 mL), washed with water (125 mL), dried (MgSO₄), filtered and concentrated in vacuo. The crude oil was purified by flash chromatography silica gel, hexanes/EtOAc 1 :0 to 0: 1) to give pure product (1.24 g; 69% yield) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) (J = Hz) δ 5.31 (m; IH), 5.02 (d; IH; J = 17.2), 4.94 (d; IH, J = 10.2), 3.90 (s; 4HO, 3.62 (m; IH), 3.38 (m; IH), 2.11 (m; 2H), 1.83 (m; IH), 1.75 (m; IH), 1.63 (m; IH), 1.40 (m; 4H). ¹³C-NMR (400 MHz, CDCl₃) δ 141.8, 114.9, 108.5, 65.8, 64.3, 43.1, 41.1, 34.2, 26.4.

Step h: 7-Vinyl-l,4-dioxa-spiro[4.5]decane-8-carbaldehyde.

[00172] To a 100 mL round-bottom flask was added alcohol (1.87 g; 9.5 mmol), DCM (30 mL) and Dess-Martin periodinane (4.21 g; 9.9 mmol). The reaction was allowed to stir for 1 hour at 20 ⁰C and then diluted with ether (100 mL), filtered through celite and concentrated in vacuo. The crude oil was purified by flash chromatography silica gel, hexanes/EtOAc 1 :0 to 0:1) to give pure product (1.80 g; 97% yield) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) (J = Hz) δ 9.51 (s; IH), 5.65 (m; IH), 5.02 (m; 2H), 3.92 (s; 4H), 2.55 (m; IH), 2.08 (2 3H), 1.80 (m; 3H), 1.67 (m; IH) 1.48 (m; 2H). ¹³C-NMR (400 MHz, CDCI₃) δ 204.4, 139.6, 115.7, 107.8, 64.3, 53.1, 40.2, 40.0, 33.1, 23.3. Example 1:

Step Ia:

[00173] A 10 mL round-bottom flask was charged with l-benzo[l,3]dioxol-5yl-2-(6-methyl- pyridin-2yl)-ethane-l,2-dione (1.23 g: 4.6 minol), 7-vinyl-l,4-dioxa-spiro[4.5]decane-S- carbaldehyde (0.9 g; 4.6 ramol), MTBE (32 mL), AcOH (8 mL) and ammonium acetate (3.54 g; 46 mmol). The reaction was heated to 80⁰C for 12 hours and then cooled to room temperature. The reaction mixture was extracted with EtOAc (100 mL) and the organic was washed with water (100 mL), saturated NaCl (100 mL), dried (MgSO₄), filtered and concentrated in vacuo. The crude oil was purified by flash chromatography silica gel, hexanes/EtOAc 1 :0 to 0:1) to give pure product Ia (1.20 g; 59% yield) as a colorless oil. ¹H-NMR (400 MHz, CDCl₃) (J = Hz) δ 7.44 (t; IH; J = 7.7), 7.35 (d; IH; J = 7.8), 7.19 (m; 2H), 6.93 (d; IH: J = 7.5), 6.84 (d; IH; J = 8.4), 5.99 (s; 2H), 5.62 (m; IH), 4.88 (m; 2H), 3.96 (m; 2H), 3.82 (m; 2H), 2.61 (m; 2H), 2.41 (s; 3H), 1.90 (m; 4H), 1.52 (m; 2H). ¹³C- NMR (400 MHz, CDCl₃) B 157.7, 150.8, 149.1, 147.5, 147.0, 140.4, 136.7, 122.6, 120.7, 117.9, 114.8, 109.5, 108.4, 108.1, 101.0, 64.4, 43.4, 42.6, 40.6, 34.4, 29.5, 23.9, 14.2. MS (ES+) m/∑ 446.35 [MH+].

Step Ib:

[00174] A 250 mL round-bottom flask was charged with product Ia (3.69 mg; 8.28 mmol), THF (10 mL) and a solution of 1.0 M borane-THF complex in THF (83 mL, 83 mmol). The reaction was stirred at 20 ⁰C and stirred until starting material was consumed in about an hour. To the reaction mixture was then slowly added 6.0 N NaOH (50 mL) and hydrogen peroxide (50 mL). The mixture was heated to 60⁰C for Ih and then cooled to room temperature. The reaction mixture was extracted with EtOAc (50 mL) and the organic was washed with sat. NaCl (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude oil was purified by flash chromatography silica gel, DCM/MeOH 20:1 w/ 0.5% 2.0M NH3 in EtOH) to give pure product Ib (1.74 g; 45% yield) as a white solid. ¹H-NMR (400 MHz, CDCl₃) (J = Hz) δ 7.75 (m; IH), 7.46 (m; IH), 7.31 (m; IH), 7.15 (m; 2H), 6.98 (m; IH), 6.82 (m; IH), 5.98 (s, 2H), 3.95 (m; 4H), 3.51 (m; 2H), 2.61 (m; 2H),, 2.38 (s; 3H), 2.00 to 1.70 (m; 5H), 1.65 to 1.30 (m; 3H). MS (ES+) m/z 464.47 [MH+]. Step Ic:

[00175] A 250 mL round-bottom flask was charged with triphenylphosphine (1.0 g, 3.8 mmol.), product Ib (0.40 g, 5.9 mmol.) and iodine (1.0 g, 3.9 mmol.) and DCM (50 mL). The mixture was stirred at room temperature for 10 minutes. Then product Ib (0.40g; 0.86 mmol) in DCM (10 mL) was introduced to the mixture. The reaction mixture was stirred for additional 10 minutes before the mixture was washed with Na₂S₂O₃ (25 mL) and brine (50 mL). The crude product was purified by flash chromatography silica gel (MeOH/DCM from 0 to 8%) to give pure product (0.32 g; 84%) as a white solid, the title compound. MS (ES+) m/z 446.51 [MH+]. Example 2;

[00176J To a 100 mL round-bottom flask was added the ketal of Example 1 (270 mg; 0.59 mmol), MeCN (5 mL), and 1.0 M HCl (4 mL). The reaction mixture was heated to 60 ⁰C for 3 hours. The reaction mixture was diluted with EtOAc (25 mL) and the organic was washed with saturated sodium bicarbonate, saturated NaCl (50 mL), dried (MgSO₄), filtered and concentrated in vacuo. The crude oil was purified by flash chromatography silica gel, DCM/MeOH 20: 1 w/ 0.5% 2.0M NH₃ in EtOH to give pure product (210 mg; 90% yield) as a white solid, the title compound.

¹H-NMR (400 MHz, CDCl₃) (J = Hz) δ 7.24 (t; IH; J = 7.7), 6.98 (d; IH; J = 7.8), 6.79 (d; IH; J = 7.6), 6.73 (m; 3H), 5.90 (s; 2H), 3.73 (dd; IH; J = 12.9 & 5.0), 3.65 (m; IH), 3.04 (m; IH), 2.80 (m; IH), 2.48 (m; 2H), 2.40 (s; 3H), 2.22 (t; IH; J = 12.6), 1.89 (m; 2H), 1.74 (m; 2H). ¹³C-NMR (400 MHz, CDCl₃) δ 209.0, 157.9, 152.7, 147.6, 146.0, 137.4, 135.9, 129.6,124.4, 123.9, 120.5, 118.8, 110.9, 108.4, 101.2, 47.1, 43.5, 40.9, 40.3, 38.6, 29.8, 28.8, 24.8. MS (ES+) m/z 402.40 [MH+]. Example 3:

[00177] A 250 mL round-bottom flask was charged with the ketone of Example 2 (0.22 g, 0.55 mmol.), methanol (15 mL) and sodium borohydride (0.10 g, 2.6 mmol.) The mixture was stirred at room temperature for 5 minutes. The reaction was quenched by hydrochloric acid (1.0 N, 2 mL). The mixture was diluted with ethyl acetate (35 mL) and washed with brine (50 mL). The crude product was purified by flash chromatography silica gel (MeOH/DCM from 0 to 10%) to give pure product (0.16 g; 73%) as a white solid, the title compound.

¹H-NMR (400 MHz, DMSO-dό), (J = Hz), δ 7.67 (t, IH, J = 7.6), 7.29 (d, IH, J = 7.2), 7.07 (s, IH), 7.04 (t, IH, J = 7.2), 6.96 (d, IH, J = 7.6), 6.92 (t, IH, J = 7.2), 6.12 (s, 2H)₃ 3.81 (m, 2H), 3.75 (m. IH), 2.72 (m, IH), 2.63 (s, 3H), 2.11 (m, 2H), 1.92 (m, IH), 1.76 (m, 2H), 1.56 (m, 2H), 1.27 (m, 2H). MS (ES+) m/z 404.47 [MH+]. Example 4:

[00178] The title compound was obtained following the procedures described for compound of example 3 making variations. MS (ES+) m/z 412.50 [MH+]. Example 5:

Step 5a:

[00179] A 250 mL round-bottom flask was charged with l-benzo[l,3]dioxol-5yl-2-(6- methyl-pyridin-2yl)-ethane-l,2-dione (1.0 g, 4.0 mmol), 7-vinyl-l,4-dioxa-spiro[4,5]decane- 8-carbaldehyde ( 0.80 g, 4.0 mmol), allylamine (0.27 g, 4.8 mmol), MTBE (55 mL), AcOH (4 mL) and ammonium acetate (0.34 g, 4.4 mmol). The reaction was heated to 65 ⁰C for 12h and then cooled to room temperature. The reaction mixture was diluteded with EtOAc (150 mL) and the organic was washed with brine (100 mL), sat. NaCI (100 mL), dried (MgSO₄), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, hexanes/EtOAc 1:0 to 0:1) to give 1.53 g (85%) of product 5a. MS (ES+) m/z 486.57 [MH+].

Step 5b:

[00180] A 100 mL round-bottom flask was charged with product 5a (0.50 g, 0.5 mmol), Grubb's 1^st catalyst (0.3 g), and DCM (20 mL). The reaction mixture was stirred at room temperature for 48h. The mixture was filtered through silica gel pad and eluted with EtOAc (50 mL). The crude product was purified by flash chromatography silica gel, hexanes/EtOAc 1 :0 to 0:1) to give 0.38 g (81%) of pure product, the title compound.

¹H-NMR (400 MHz, DMSO-d6), (J = Hz), δ 7.55 (t, IH, J = 7.4), 7.45 (d, IH, J = 8.4), 6.92 (m, 3H), 6.78 (d, IH₅ J = 8.4), 6.08 (s, 2H), 5.72 (t, IH, J = 9.2), 5.50 (d, IH, J = 12.0), 4.64 (d, IH, J = 8.4), 4.11 (m, IH), 3.92 (s, 4H), 3.15 (m, IH), 2.51 (s, 3H), 2.16 (m, IH), 1.85 (d, 2H, J = 11.2), 1.62 (m, 2H), 1.59 (m, 2H). MS (ES+) m/z 458.20 [MH+]. Example 6:

[00181] The title compound was obtained from the compound of step 5b following the deprotection procedure described in example 2.

¹H-NMR (400 MHz, DMSO-d6), (J = Hz), δ 8.01 (t, IH, J = 7.6), 7.49 (d, IH, J = 7.6), 7.14 (t, IH, J = 8.0), 7.12 (d, IH, J = 7.2), 7.04 (s, IH), 6.90 (d, IH, J = 7.6), 6.17 (s, 2H), 5.82 (t, IH, J = 8.8), 5.56 (d, IH, J = 13.6), 4.82 (d, IH, J = 17.2), 4.29 (d, IH, J = 8.0), 4.25 (d, IH, J = 7.6), 3.87 (t, IH, J = 11.6), 2.69 (s, 3H), 2.63 (d, 2H, J = 8.4), 2.51 (m, 2H), 2.41 (m, 2H). MS (ES+) m/z 414.17 [MH+]. Example 7:

[00182] The title compound was obtained following the procedures described for compound of example 6 making substitutions.

¹H-NMR (400 MHz, DMSO-d6), (J = Hz), δ 9.07(d, 2H, J = 6.0), 8.26 (d, IH, J = 8.4), 8.22 (s, IH), 7.89 (t, IH, J = 8.0), 7.86 (d, IH, J = 7.6), 7.41 (d, IH, J = 7.6), 7.26 (d, IH, J = 7.6), 5.82 (m, IH), 5.58 (d, IH, J = 7.6), 4.93 (m, IH), 4.35 (m, IH), 3.89 (t, IH, J = 7.6), 2.65 (m, 2H), 2.55 (s, 3H), 2.52 (m, IH), 2.49 (m, 3H), 2.42 (m, 2H). MS (ES+) m/z 422.19 [MH+]. Example 8:

[00183} A 100-mL flask was charged with 3-Benzo[l,3]dioxol-5-yl-2-(6-methyl-pyridin-2- yl)-6a,9,10,10a-tetrahydro-4H, 7/f-l,3a-diaza-benzo[e]azulen-8-one (54 mg, 0.13 mmol) in methanol (5 mL). Sodium borohydride (50 mg, 1.3 mmol) was introduced. The mixture was allowed to stir at room temperature for 5 minutes. The reaction was quenched with diluted HCl. The crude product was extracted with ethyl acetate. The cis and trans products were separated with preparative HPLC to yield 21 mg of trans and 11 mg of cis isomer (57%). Trans isomer ¹H-NMR (400 MHz, DMSO-d6), (J = Hz), δ 7.92 (d, IH, J = 8.0), 7.43 (d, IH, J - 8.8), 7.11 (d, IH, J = 8.0), 7.09 (s, IH), 7.03 (d, IH, J = 8.8), 6.89 (t, IH, J = 8.0), 6.16 (s, 2H), 5.75 (t, IH, J = 10.6), 5.59 (d, IH, J = 8.8), 4.80 (d, IH, J = 16.4), 4.23 (d, IH, J = 8.4), 4.19 (d, IH, J = 8.0), 3.54 (m, IH), 3.30 (t, IH, J = 11.6), 2.65 (s, 3H), 2.27 (m, 2H), 2.04 (m, 2H), 1.92 (m, 2H). MS (ES+) m/z 416.19 [MH+]. Cis isomer:

¹H-NMR (400 MHz, DMSO-d6), (J = Hz), δ 7.86 (d, IH, J = 8.0), 7.37 (d, IH, J = 8.8), 7.17 (d, IH, J = 8.0), 7.04 (s, IH), 7.03 (d, IH, J = 8.8), 6.88 (t, IH, J = 8.0), 6.15 (s, 2H), 5.74 (t, IH, J = 10.6), 5.55 (d, IH, J = 8.8), 4.79 (d, IH, J = 16.4), 4.23 (d, IH, J = 8.4), 4.05 (m, 2H), 3.35 (m, IH), 2.62 (s, 3H), 2.32 (m, 2H), 1.91 (m, 2H), 1.55 (t, 2H, J - 8.8). MS (ES+) Wz 416.19 [MH+]. Example 9:

[00184] Into a 1 -neck round-bottom flask were added l-([l,2,4]triazolo[l,5-a]pyridin-6-yl)- 2-(6-methylpyridin-2-yl)ethane-l,2-dione (0.49 g, 0.0018 mol), 6,7-dimethoxy-3,4-dihydro- isoquinoline (0.42 g, 0.0022 mol), ammonium acetate (0.6 g, 0.007 mol) and 2-methoxy-2- methylpropane (9 mL, 0.07 mol). To the resulting suspension was added acetic acid (1.5 mL, 0.026 mol). The resulting mixture was refluxed overnight. LCMS showed product and no diketone peak. The solvent was rotovaped and 50 mL CH₂Cl₂ and 50 mL saturated Na₂CO₃ aqueous solution and 20 mL water were added. After extracted with CH₂Cl₂, the organic layer was combined and dried over Na₂SO₄. The organic solution was then filtered and rotovaped to driness. The residue was chromatographed (30-60% Acetone/Hexane) to give the title compound (0.3 g, 37%).

¹H-NMR (400 MHz, CDCl₃), (J = Hz), δ 8.89 (s, IH), 8.41 (s, IH), 7.79 (d, IH, J = 8.8), 7.73 (s, IH), 7.71(d, IH, J = 8.0), 7.64 (dd, IH, J = 9.2, 4.0), 7.55 (t, IH, J = 7.6), 6.96 (d, IH, J = 7.6), 6.77 (s, IH), 4.07(t, 2H, J=8.0), 4.02 (s, 3H), 3.94 (s, 3H), 3.11 (t, 2H, J=8.0), 2.32 (s, 3H).

MS (ES+) m/z 438.72 [MH+]. Example 10:

[00185] The compound of Example 9 (0.18 g, 0.00041 mol) was dissoved in CH₂Cl₂ at RT and 1.0 M of boron tribromide in hexane (1.0 mL) was added to the solution. The mixture was stirred for 2 hours. The reaction was quenched with NaHCO₃ aq. and was extracted with CH₂CI₂. The organic layers were combined, dried over Na₂SO₄, filtered and rotovaped to give the title compound (0.14g, 83%).

¹H-NMR (300 MHz, MeOD), (J = Hz), δ 9.13 (s, IH), 8.47 (s, IH), 7.90 (d, IH, J = 9.3), 7.71 (m, 2H), 7.55 (s, IH), 7.29 (d, IH, J = 7.8), 7.23 (d, IH, J = 7.8), 6.76 (s, IH), 4.06 (t, 2H, J=6.9), 3.04 (t, 2H, J=6.9), 2.55 (s, 3H). MS (ES+) m/z 410.72 [MH+]. Example 11:

[001861 A mixture of l-(5-fluoro-6-methyl-pyridm-2-yl)-2-[l,2,4]triazolo[l,5-a]pyridin-6- yl-ethane-l,2-dione (0.552 g, 0.00194 mol), 3,4-dihydro-isoquinoline (0.3 g, 0.002 mol) , ammonium acetate (0.627 g, 0.008 mol) and acetic acid (1.57 mL, 0.0276 mol) in 7 mL of 2- methoxy-2-methylpropane was refhαxed for 15 hours. Additional (0.3 g, 0.001 mol) diketone was added and the reaction mixture refluxed for 2 hours. After cooling to room temperature, the mixture was partitioned between CH₂Cl₂ and a saturated aqueous solution OfNa₂CO₃. The organic phases were dried over MgSO₄, filtered and concentrated under vacuum. The resulting crude material that was purified by reverse phase preparative HPLC. Fractions containing the product by LC-MS were combined, concentrated and partitioned between CH2CI₂ and a saturated aqueous solution OfNa₂CO₃. The organic phase was dried over MgSO₄, filtered and concentrated under vacuum and triturated with Et₂O to afford the title compound as a white solid (0.130 g, 17%).

¹H-NMR (300 MHz, CDCl₃): 8.91 (s, IH), 8.44 (m, IH), 8.25 (m, broad, IH), 7.92 (m, broad, IH), 7.83 (dd, IH, J = 9 Hz, 2.8 Hz), 7.67-7.64 (m, IH), 7.44-7.27 (m, 4H), 4.12 (t, 2H, J = 6.5 Hz), 3.2 (t, 2H, J= 6.5Hz), 2.27 (d, 3H, J= 2.5 Hz). MS (ES+) m/z 396 [M+]. Example 12:

isomer 1 isomer 2

[00187] A mixture of l-(5-fluoro-6-methyl-pyridin-2-yl)-2-[l,2,4]triazolo[l,5-a]pyridin-6- yl-ethane-l,2-dione (0.552 g, 0.00194 mol), 7-methyl-3,4-dihydro-isoquinoline (0.29 g, 0.002 mol), ammonium acetate (0.627 g, 0.008 mol) and acetic acid (1.57 mL, 0.0276 mol) in 7 mL of 2-methoxy-2-methylpropane was reflux ed for about 15 hours. Additional (0.3 g, 0.001 mol) dione was added and the reaction mixture refluxed for 2 hours. After cooling to room temperature, the mixture was partitioned between CH₂Cl₂ and a saturated aqueous solution of Na₂CCb. The organics were dried over MgSQ₄, filtered and concentrated under vacuum. The resulting crude material was purified by reverse phase preparative HPLC to afford the 2 regioisomers. The fractions corresponding to isomer 1 were concentrated, partitioned between CH2CI2 and a saturated aqueous solution of Na2CC»₃. The organic phase was dried over MgSO-_t, filtered and concentrated under vacuum and the resulting material triturated with hot MeOH to afford the title compound, isomer I₃ as a white solid (0.150g, 19%). Isomer 2 was crystallized from the HPLC fractions upon standing at room temperature. The crystals of 3-(5-fluoro-6-methyl-pyridin-2-yl)-8-methyl-2-[l ,2,4]triazolo[ 1 ,5-a]pyridin-6-yl- 5,6-dihydro-imidazo[2,l-a]isoquinoline were collected as a white solid (60 mg, 7%). Isomer 1: ¹H-NMR (300 MHz, CDCl₃): 8.91 (s, IH), 8.43 (s, IH), 8.12 (s, broad. IH), 7.90 (s, broad, IH), 7.84-7.81 (m, IH), 7.65 (dd, IH, J = 9.2 Hz, 1.8 Hz), 7.27 (t, IH, J= 8.8 Hz), 7.19 (s, broad, 2H), 4.09 (t, 2H, 7= 6.7 Hz), 3.16 (t, 2H, J= 6.7 Hz), 2.45 (s, 3H), 2.27 (d, 3H, J= 2.5 Hz); MS (ES+) m/z 410 [M+].

Isomer 2: ¹H-NMR (300 MHz, CDCl₃): 8.92 (s, IH), 8.33 (s, IH), 8.09 (s, broad, IH), 7.77 (dd, IH, J= 9.5 Hz, 1.5 Hz), 7.69 (dd, IH, J= 9 Hz, 1 Hz), 7.34 (t, IH, J= 8.4 Hz), 7.21- 7.17 (m, 3H), 4.31 (t, 2H, J= 7 Hz)₅ 3.17 (t, 2H, J= 7 Hz), 2.65 (d, 3H, J= 2.5 Hz), 2.43 (s, 3H). MS (ES+) m/z 410 [M+]. Example 13:

isomer 1

[00188] By a procedure similar to Example 12 with little variations, the title compounds were obtained. isomer 1: ¹H-NMR (300 MHz, CDCl₃): 8.91 (s, IH)₅ 8.43, (s, IH), 7.86 (s, broad, IH), 7.82

(d, IH, J= 9.9Hz), 7.66 (dd, IH, J= 9 Hz, 1.6 Hz), 7.60 (t, IH, J- 8.3 Hz), 7.2 (d, IH, J=

7.5 Hz)₅ 6.99 (d, IH, J= 7.5 Hz), 6.93 (dd, IH, J= 8.3 Hz, 2.4 Hz), 4.10 (t, 2H, J= 6.9 Hz),

3.95 (s, 3H), 3.14 (t, 2H, J= 6.9 Hz), 2.32 (s, 3H); MS (ES+) m/z 409 [MH+]. isomer 2: ¹H-NMR (300 MHz, CDCl₃): 8.95 (s, IH), 8.33 (s, IH), 7.79 (dd, IH, J= 9.3 Hz,

1.7 Hz)₅ 7.75 (s, broad, IH), 7.68 (dd, IH, J= 9.3 Hz, 0.7 Hz), 7.60 (t, IH, J= 7.7 Hz), 7.20

(d, IH, J= 7.8 Hz), 7.16 (d, IH, J= 7.8 Hz), 6.92 (dd, IH, J = 8.3Hz, 2.8 Hz), 4.33 (t, 2H, J

= 6.8 Hz), 3.93 (s, 3H), 3.15 (t, 2H, J= 6.8 Hz), 2.69 (s, 3H); MS (ES+) m/z 410 [M+].

Example 14:

[00189] Boron tribromide (0.061g, 0.00024 mol) was added to a solution of isomer 1 of Example 13 (0.09g, 0.0002 mol) in 2 mL CH₂Cl₂ cooled with an iPrOH-dry ice bath. The bath was removed and the mixture stirred 30 min to give a yellow suspension that was partitioned between CH2CI₂ and H₂O. The aqueous layer was evaporated to dryness, the resulting solid was crystallized from hot CHCI₃ containing a minimal amount of MeOH to afford the title compound hydrobromide salt as a yellow solid.

¹H-NMR (300 MHz, dmso-d₆): 9.41 (s, IH), 8.67 (s, IH), 8.03 (m, 2H), 7.8 (dd, IH, J= 8.8 Hz, 2.3 Hz), 7.60 (d, IH, J= 2.2 Hz), 7.58 (d, IH, J= 8 Hz), 7.44 (d, IH, J= 8 Hz), 7.27 (d, IH, J= 8.5 Hz), 6.92 (dd, IH, J= 8 Hz, 2.2 Hz), 4.17 (t, 2H, J= 6.7 Hz), 3.08 (t, 2H, J= 6.7 Hz), 2.71 (s, 3H); MS (ES+) m/z 394 [M+]. Example 15:

Example 15a Example 15b

[00190] Pyrrazole compounds of the invention 15a and 15b are prepared according to the general procedure and known methods as shown in Scheme VIII.

Example 15a: ¹H-NMR (300 MHz, DMSO-d6), (J = Hz), δ 9.08 (s, IH), 8.51 (s, IH)₅ 7.95 (dd, IH, J=1.5, 9.5), 7.84-7.73 (m, 3H), 7.66 (dd, IH, J=I.5, 9.5), 7.48-7.39 (m, 2H), 7.31- 7.18 (m, 2H), 3.10 (td, 2H, J=2.0, 8.0), 3.02 (td, 2H, J=2.0, 8.0), 2.26 (s, 3H). MS (ES+) m/z 379.1 [MH+].

Example 15b: ¹H-NMR (300 MHz, DMSO-d6), (J = Hz), δ 9.06 (s, IH), 8.52 (d, J=I .0, IH), 7.93 (d, IH, J=8.0), 7.80 (m, 3H), 7.64 (d, IH, J=9.0), 7.21 (m, 4H), 5.53 (s, 2H), 2.26 (s, 3H). MS (ES+) m/z 381.1 [MH+]. Example 16:

isomer 1 isomer 2

Step 16a

[00191} 2-Piperidinemethanol (1.0 g, 0.0087 mol) was dissolved in methylene chloride (30 mL, 0.4 mol) with triethylamine (1.4 mL, 0.010 mol). The reaction mixture was cooled down to 0 ⁰C. Chloroacetyl chloride (0.83 mL, 0.010 mol) was added to the solution and the reaction was warmed up to RT for 10 hours. The reaction was then quenched with 30 ml IN HCl aq. The organic layer was separated and washed with 30 ml saturated Na₂CO₃ aqoues solution. The organic layers were combined and dried over Na₂SO₄, filtered, concentrated to give 1.4 g crude light brown oil, product 16a. LC-MS: (1.58 min, m/z 191.4). Step 16b:

[00192] Product 16a (0.60 g, 0.0031 mol) was dissolved in Methylene chloride (30 mL, 0.4 mol) and cooled to 0 ⁰C. Dess-Martin periodinane (1.5 g, 0.0035 mol) was added to the solution in one portion. The reaction mixture was stirred at room temperature for 2 hours. LC-MS showed completion of reaction. The majority of the solvent was removed and 50 ml OfEt₂O was added to extract the product. The ether solution was concentrated and the residue was purified by silica gel column (CH₂CI₂ to 2%MeOH/CH₂Cl₂) to give 0.5 g of the product 16b. MS (ES+) m/z 189.7/191.1 [MH+].

Step 16c:

[00193] Into a 1-neck round-bottom flask was added l-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2- (6-methylρyridin-2-yl)ethane-l,2-dione (1.2 g, 0.0044 mol), Product 16b (0.60 g, 0.0032 mol) , ammonium acetate (2.0 g, 0.025 mol) and ethanol (20 mL, 0.3 mol). The resulting mixture was heated at 70 ⁰C for 10 hours. The majority of the solvent was removed and 50 ml Na₂CO₃ aqeous solution and 50 ml CH₂CI2 were added to the residue. The aqueous layer was extracted 3 times with CH₂Cl₂. The organic layers were combined and dried over Na2SU4, filtered, concentrated to give crude brown oil. The residue was chromatographed (3% MeOH in CH₂Cl₂) to give 0.75 g of the title compound (51%). MS (ES+) m/z 459.9 [MH+].

Step 16d:

[00194] Into a 1-Neck round-bottom flask was added the compound from step 14c (700 mg, 0.002 mol), LiOH-H₂O (0.14 g), and methanol (3.0 mL, 0.074 mol), tetrahydrofuran (3.0 mL, 0.037 mol), water (4.0 mL). The resulting mixture was stirred at room temperature for 3 hours. LC-MS showed the completion of the hydrolysis. MS (ES+) m/z 417.9 [MH+].

[00195] Ethyl acetate (50 mL) was added to the solution and the organic phase washed with aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude yellow solid obtained was dissolved in tetrahydrofuran (5.0 mL). Methanesulphonic anhydride (52 mg, 0.00030 mol) was added at RT and followed by triethylamine (0.083 mL, 0.00060 mol). The reaction was stirred for 1 hour at room temperature, then heated to 80 ⁰C for 3 days. The mixture ws cooled to room temperature again, ethyl acetate (50 ml) was added to the solution and the organic phase washed with aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The residue was purified by HPLC (5-50% ACN/H2O) to give two regio-isomers: isomer 1: (8.0 mg):1H-NMR (300 MHz₅ MeOD), (J = Hz), δ 9.07 (s, IH)₅ 8.47 (s, IH)₅ 7.99 (t, IH₅ J=7.95), 7.91 (d, IH, J=9.0), 7.67 (d, IH, J=9.0), 7.52 (d, IH₅ J=7.5), 7.35 (d, IH, J=8.10), 4.50-4.70 (m, 2H), 3.60 (in, IH), 2.70 (m, 2H), 2.55 (s, 3H), 2.50 (m, IH), 1.2-2.0 (m, 5H). MS (ES+) m/z 399.8 [MH+]. isomer 2: (10 mg ):1H-NMR (300 MHz₅ MeOD)₅ (J = Hz), δ 8.86 (s, IH), 8.39 (s, IH), 7.65 (m, 3H)₅ 7.34 (d, IH₅ J=7.8), 7.26 (d, IH, J=7.8), 7.52 (d, IH, J=7.5), 7.35 (d, IH, J=8.10), 4.60-4.70 (m, 2H), 3.20 (m, IH), 2.70 (m, 2H), 2.56 (s, 3H), 2.41 (m, IH), 1.2-2.0 (m, 5H). MS (ES+) m/z 399.8 [MH+].

[00196] The TGFβ inhibitory activity of compounds of formula (I) can be assessed by methods described in the following examples.

Example 17 Cell-Free Assay for Evaluating Inhibition of TGFp Autophosphorylation of TGFβ Type I Receptor

[00197] The serine-threonine kinase activity of TGFβ type I receptor was measured as the autophosphorylation activity of the cytoplasmic domain of the receptor containing an N- terminal poly histidine, TEV cleavage site-tag, e.g., His-TGFβRI. The His-tagged receptor cytoplasmic kinase domains were purified from infected insect cell cultures using the Gibco- BRL FastBac HTb baculovirus expression system.

[00198] To a 96- well Nickel FlashPlate (NEN Life Science, Perkin Elmer) was added 20 μL of 1.25 μCi 33P-ATP/25 μM ATP in assay buffer (50 mM Hepes, 60 mM NaCl, 1 mM MgCl₂, 2 mM DTT, 5 mM MnCl₂, 2% glycerol, and 0.015% Brij^® 35). 10 μL of each test compound of formula (I) prepared in 5% DMSO solution were added to the FlashPlate. The assay was then initiated with the addition of 20 uL of assay buffer containing 12.5 pmol of His-TGFβRI to each well. Plates were incubated for 30 minutes at room temperature and the reactions were then terminated by a single rinse with TBS. Radiation from each well of the plates was read on a TopCount (Packard). Total binding (no inhibition) was defined as counts measured in the presence of DMSO solution containing no test compound and nonspecific binding was defined as counts measured in the presence of EDTA or no-kinase control.

[00199] Alternatively, the reaction performed using the above reagents and incubation conditions but in a microcentrifuge tube was analyzed by separation on a 4-20% SDS-PAGE gel and the incorporation of radiolabel into the 40 kDa His-TGFβRI SDS-PAGE band was quantitated on a Storm Phosphoimager (Molecular Dynamics). [00200] Compounds of formula (I) typically exhibited IC50 values of less than 10 μM; some exhibited IC₅₀ values of less than 1 μM; and some even exhibited IC₅₀ values of less than 200 nM.

Example 18: Cell-Free Assay for Evaluating Inhibition of Activin Type I Receptor

Kinase Activity

[00201] Inhibition of the Activin type I receptor (AIk 4) kinase autophosphorylation activity by test compounds of formula (I) are determined in a similar manner to that described above in Example 17 except that a similarly His-tagged form of AIk 4 (His- AIk 4) is used in place ofthe His-TGFβRI.

Example 19: TGFβ Type I Receptor Ligand Displacement FlashPlate Assay

[00202] 50 nM of tritiated 4-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinoline (custom-ordered from PerkinElmer Life Science, Inc., Boston, MA) in assay buffer (50 mM Hepes, 60 mM

NaCl₂, 1 mM MgCI₂, 5 mM MnCl₂, 2 mM 1,4-dithiothreitol (DTT), 2% Brij^® 35; pH 7.5) was premixed with a test compound of formula (I) in 1% DMSO solution in a v-bottom plate.

Control wells containing either DMSO without any test compound or control compound in

DMSO were used. To initiate the assay, His-TGFβ Type I receptor in the same assay buffer

(Hepes, NaCl₂, MgCl₂, MnCl₂, DTT, and 30% Brij^® added fresh) was added to a nickel coated FlashPlate (PE, NEN catalog number: SMP 107), while the control wells contained only buffer (i.e., no His-TGFβ Type I receptor). The premixed solution of tritiated 4-(3- pyridin-2-yl-lH-pyrazol-4-yl)-quinoline and test compound of formula (I) was then added to the wells. The wells were aspirated after an hour at room temperature and radioactivity in wells (emitted from the tritiated compound) was measured using TopCount (PerkinElmer

Lifesciences, Inc., Boston MA).

Compounds of formula (I) typically exhibited Ki values of less than 10 μM; some exhibited

Ki values of less than 1 μM; and some even exhibited Ki values of less than 5Θ nM.

Example 20: Assay for Evaluating Cellular Inhibition of TGFβ Signaling and

Cytotoxicity

[00203] Biological activity of the compounds of formula (I) was determined by measuring their ability to inhibit TGFβ-induced PAI-Luciferase reporter activity in HepG2 cells.

[00204] HepG2 cells were stably transfected with the PAI-luciferase reporter grown in

DMEM medium containing 10% FBS, penicillin (100 U/mL), streptomycin (100 μg/mL), L- glutamine (2 mM), sodium pyruvate (1 mM), and non-essential amino acids (once). The transfected cells were then plated at a concentration of 2.5 x 104 cells/well in 96- well plates and starved for 3-6 hours in media with 0.5% FBS at 37 ⁰C in a 5% CO₂ incubator. The cells were then stimulated with 2.5 ng/mL TGFβ ligand in the starvation media containing 1% DMSO either in the presence or absence of a test compound of formula (I) and incubated as described above for 24 hours. The media was washed out the following day and the luciferase reporter activity was detected using the LucLite Luciferase Reporter Gene Assay kit (Packard, Cat. No. 6016911) as recommended. The plates were read on a Wallac Microbeta plate reader, the reading of which was used to determine the IC50 values of compounds of formula (I) for inhibiting TGFβ-induced PAI-Luciferase reporter activity in HepG2 cells. Compounds of formula (I) typically exhibited ICJ_O values of less 10 uM. [00205] Cytotoxicity was determined using the same cell culture conditions as described above. Specifically, cell viability was determined after overnight incubation with the CytoLite cell viability kit (Packard, Cat. No. 6016901). Compounds of formula (1) typically exhibited LD₂s values greater than 10 μM.

Example 21: Assay for Evaluating Inhibition of TGFβ Type I Receptor Kinase Activity in Cells

[00206] The cellular inhibition of activin signaling activity by the test compounds of formula (I) is determined in a similar manner as described above in Example 20 except that 100 ng/mL of activin is added to serum starved cells in place of the 2.5 ng/mL TGFβ. Example 22: Assay for TGFβ-induced Collagen Expression

Preparation of Immortalized Collagen Promotor-Green Fluorescent Protein CeUs

[00207] Fibroblasts are derived from the skin of adult transgenic mice expressing Green Fluorescent Protein (GFP) under the control of the collagen IAl promoter (see Krempen, K. et al., Gene Exp., 8: 151-163 (1999)). Cells are immortalized with a temperature sensitive large T antigen that is in an active stage at 33 ⁰C. Cells are expanded at 33 ⁰C and then transferred to 37 ⁰C at which temperature the large T antigen becomes inactive (see Xu, S. et al., Exp. Cell Res., 220: 407-414 (1995)). Over the course of about 4 days and one split, the cells cease proliferating. Cells are then frozen in aliquots sufficient for a single 96-well plate.

Assay of TGFβ-induced Collagen-GFP Expression

[00208] Cells are thawed, plated in complete DMEM (contains non-essential amino acids, ImM sodium pyruvate and 2mM L-glutamine) with 10% fetal calf serum, and then incubated for overnight at 37 ⁰C, 5% CO₂. The cells are trypsinized in the following day and transferred into 96-well format with 30,000 cells per well in 50 μL complete DMEM containing 2% fetal calf serum, but without phenol red. The cells are incubated at 37 ⁰C for 3 to 4 hours to allow them to adhere to the plate. Solutions containing a test compound of formula (T) are then added to wells with no TGFβ (in triplicates), as well as wells with 1 ng/mL TGFβ (in triplicates). DMSO is also added to all of the wells at a final concentration of 0.1%. GFP fluorescence emission at 530 nm following excitation at 485 ran is measured at 48 hours after the addition of solutions containing a test compound on a CytoFluor microplate reader (PerSeptive Biosystems). The data are then expressed as the ratio of TGFβ-induced to non-induced for each test sample. Example 23: Assay for Evaluating Inhibition and/or Prevention of Restenosis:

Stenotic fibrotic response: Balloon Catheter Injury of the Rat Carotid Artery [00209] The ability of compounds of formula (I) to prevent the stenotic fibrotic response is tested by administration of the test compounds to rats that have undergone balloon catheter injury of the carotid artery. The test compounds are administerd intervenously, subcutaneously, p.o., orally, or parentally.

[00210] Sprague Dawley rats (400 g, 3 to 4 months old) are anesthetized by inter paratenal i.p. injection with 2.2 mg/kg xylazine (AnaSed, Lloyd laboratories) and 50 mg/kg ketamine (Ketalar, Parke-Davis). The left carotid artery and the aorta are denuded with a 2F balloon catheter according to the procedure described in Clowes et al., Lab Invest., 49: 327-333 (1983). Test compounds of formula (I) are each administered to the treatment group (n=5-10 rats) (intervenously, p.o., or subcutaneously; qod, once per day, bid, tid or by continuous subcutaneous infusion via an Alzet minipump) starting the day of surgery and subsequently for 14 more days. The control group (n=5 rats) received the same volume of vehicle administered using the same regimen as the test compound-treated rats. The animals were sacrificed under anesthesia 14 days post-balloon injury. Perfusion fixation was carried out under physiological pressure with phosphate buffered (0.1 mol/L, pH 7.4) 4% paraformadehyde. The injured carotid artery was excised, post-fixed and embedded for histological and morphometic analysis. Sections (5 μm) were cut from the proximal, middle and distal segments of the denuded vessel and analyzed using image analysis software. The circumference of the lumen and the lengths of the internal elastic lamina (IEL) and the external elastic lamina (EEL) were determined by tracing along the luminal surface the perimeter of the neointima (IEL) and the perimeter of the tunica media (EEL) respectively. The lumen (area within the lumen), medial (area between the IEL and EEL) and intimal (area between the lumen and the IEL) areas were also determined using morphometric analysis. Statistical analysis used ANOVA to determine statistically significant differences between the means of treatment groups (p < 0.05). Multiple comparisons between groups were then performed using the Scheffe test. The Student t test was used to compare the means between 2 groups, and differences were considered significant if P < 0.05. All data are shown as mean + SEM.

[00211] Statistically significant decreases were seen in intimal area, intimal/medial ratio in injured arteries of test compound-treated rats compared to those of the vehicle-treated rats. Conversely, the lumen area, IEL and EEL lengths showed a statistically significant increase in injured arteries of test compound-treated rats compared to those of the vehicle-treated rats. These results show that inhibition of the TGFβRI kinase prevents the stenotic response to balloon-catheter arterial injury by inhibiting the fibrotic expansion of the neointima and vessel remodeling.

OTHER EMBODIMENTS

[00212] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula I

wherein:

Ri is aryl or heteroaryl each optionally substituted with 1 to 3 R₃;

R2 is aryl or heteroaryl each optionally substituted with I to 3 R_b, provided that at least one of Ri and R₂ is heteroaryl optionally substituted with 1 to 3 R_b;

Ring A is a saturated or partially unsaturated 5- to 8-membered cycloaliphatic, a 5- to 8-membered heterocycloaliphatic containing 1 to 3 heteroatoms, phenyl, or a 5- to 6- membered heteroaryl containing 1 to 3 heteroatoms;

Ring B is a partially unsaturated non-aromatic 5- to 8-membered heterocycloaliphatic containing 1 to 3 heteroatoms; each of R_a and Rb is independently an aliphatic, alkoxy, acyl, halo, hydroxy, amino, amido, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, sulfanyl, sulfinyl, sulfonyl, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, aryl, aryloxy, aroyl, heteroaryl, heteroaryloxy, or heteroaroyl; or any two of R_a or any two of R_b on adjacent atoms, together with the atoms to which they are attached, may form a 5- to 8-membered cycloaliphatic or a 5- to 8-membered heterocycloaliphatic; each of R3 and R₄ is independently aliphatic, acyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy, cyano, halo, hydroxy, sulfanyl, sulfinyl, sulfonyl, amido, carbamoyl, urea, thiourea, sulfamoyl, sulfamide, oxo, thioxo, -N₃, =N-OR_f, or =N-N(Rf)₂; or any two of R3 or any two OfR₄ on the same atom, together with the atom to which they are attached, may form a 3- to 8-membered cycloaliphatic or heterocycloaliphatic ring; or any two of R₃ or any two OfR₄ on adjacent atoms, together with the atoms to which they are attached, may form a 3- to 8-membered cycloaliphatic or a 3- to 8-membered heterocycloaliphatic ring; each of the optional heteroatoms of Rings A and B is O, S, or N, and the S and N atoms in Rings A and B may be part of the groups -S(O)_m- and -N(R_f)-; each R_f is independently H, alkyl, aryl, heteroaryl, acyl, aroyl, heteroaroyl, amino, sulfamoyl, sulfamide, or carboxy;

Xi is C and X₂ is N or Xi is N and X₂ is C; i is an integer from 0 to 4; j is an integer from 0 to 4; and each m is independently an integer from 0 to 2.

2. The compound of claim 1, wherein Ri is an optionally substituted aryl and R₂ is an optionally substituted heteroaryl.

3. The compound of claim 1, wherein Ri and R₂ are both an optionally substituted heteroaryl.

4. The compound of claim 1, wherein Ri is an optionally substituted heteroaryl and R₂ is an optionally substituted aryl.

5. The compound of claim 3 or 4, wherein Rj is pyridinyl or pyrimidinyl, and is optionally substituted with 1 to 3 R_a.

6. The compound of claim 5, wherein Ri is pyridinyl optionally substituted with 1 to 3 R_a.

7. The compound of claim 6, wherein Ri is pyridin-2-yl substituted with at least one R_a.

8. The compound of claim 7, wherein Rj is 6-methyl-pyridin-2-yl.

9. The compound of claim 1 , wherein R₂ is a bicyclic heteroaryl optionally substituted with 1 to 3 Rb.

10. The compound of claim 1, wherein Ri is a bicyclic heteroaryl optionally substituted with 1 to 3 R_b.

11. The compound of claim 9 or 10, wherein the bicyclic heteroaryl is

12. The compound of claim 9, wherein Ra is benzodioxolyl, quinazolinyl or imidazopyridinyl, each optionally substituted with 1 to 3 R_b.

13. The compound of claim 12, wherein Ri is pyridinyl or pyrimidinyl each optionally substituted with 1 to 3 R_a.

14. The compound of claim 10, wherein Rj is benzodioxolyl, quinazolinyl or imidazopyridinyl, each optionally substituted with 1 to 3 R_a.

15. The compound of claim 14, wherein R₂ is pyridinyl or pyrimidinyl each optionally substituted with 1 to 3 R_b-

16. The compound of any of claims 2 to 15, wherein Ring A is a 5- to 8-membered cycloaliphatic, or a 5- to 8-membered heterocycloaliphatic containing 1 to 3 heteroatoms; and Ring B is a partially unsaturated non-aromatic heterocycloaliphatic.

17. The compound of any of claims 2 to 15, wherein Ring A is an optionally sustituted phenyl or an optionally substituted 5 to 8 membered heteroaryl and Ring B is a partially unsaturated non-aromatic heterocycloaliphatic.

18. The compound of any of claims 1 to 17, wherein Ring B contains one degree of unsaturation.

19. The compound of any of claims 1 to IS, where in Xi is C and X₂ is N.

20. The compound of any of claims 1 to 18, wherein Xi is N and X₂ is C.

.

21. The compound of claim 19 or 20, wherein Ri is an optionally substituted aryl and R₂ is an optionally substituted heteroaryl.

22. The compound of claim 19 or 20, wherein each of Ri and R₂ is an optionally substituted heteroaryl.

23. A compound which is

24. A compound which is

25. A compound which is

26. A compound which is

27. A compound which is

28. A pharmaceutical composition comprising a compound of any of claims 1 to 27, and a pharmaceutically acceptable carrier.

29. A method of inhibiting the TGFβ signaling pathway in a subject, comprising administering to said subject in need thereof an effective amount of a compound of any of claims 1 to 27.

30. A method of inhibiting the TGFβ type I receptor in a cell, comprising contacting said cell with an effective amount of a compound of any of claims 1 to 27.

31. A method of reducing the accumulation of excess extracellular matrix induced by TGFβ in a subject, comprising administering to said subject in need thereof an effective amount of a compound of any of claims 1 to 27.

32. A method of treating or preventing a fibrotic condition in a subject, comprising administering to said subject in need thereof an effective amount of a compound of any of claims 1 to 27.

33. The method of claim 32, wherein the fibrotic condition is selected from the group consisting of mesothelioma, acute respiratory distress syndrome (ARDS), atherosclerosis, scleroderma, keloids, glomerulonephritis, diabetic nephropathy, lupus nephritis, hypertension-induced nephropathy, cholangitis, restenosis, ocular scarring, corneal scarring, hepatic fibrosis, biliary fibrosis, liver cirrhosis, cirrhosis due to fatty liver disease (alcoholic and nonalcoholic steatosis), pulmonary fibrosis, renal fibrosis, sarcoidosis, acute lung injury, drug-induced lung injury, spinal cord injury, CNS scarring, systemic lupus erythematosus, Wegener's granulomatosis, cardiac fibrosis, post-infarction cardiac fibrosis, post-surgical fibrosis, connective tissue disease, radiation-induced fibrosis, chemotherapy-induced fibrosis, transplant arteriopathy, fibrosclerosis, fibrotic cancers, fibroids, fibroma, fibroadenomas, and fibrosarcomas.

34. A method of inhibiting metastasis of tumor cells in a subject, comprising administering to said subject in need thereof an effective amount of a compound of any of claims 1 to 27.

35. A method of treating a carcinoma mediated by an overexpression of TGFβ in a subject, comprising administering to said subject in need thereof an effective amount of a compound of any of claims 1 to 27.

36. The method of claim 35, wherein said carcinoma is selected from the group consisting of carcinomas of the lung, breast, liver, biliary tract, gastrointestinal tract, head, neck, pancreas, prostate, cervix, multiple myeloma, melanoma, glioma, and glioblastomas.

37. A method of treating or preventing restinosis, vascular disease, or hypertension in a subject, comprising administering to the subject in need thereof a compound of any of claims 1 to 27.

38. The method of claim 37, wherein the restinosis is coronary restenosis, peripheral restenosis, or carotid restenosis.

39. The method of claim 37, wherein the vascular disease is intimal thickening, vascular remodeling, or organ transplant-related vascular disease.

40. The method of claim 39, wherein the vascular disease is intirnal thickening or vascular remodeling.

41. The method of claim 37, wherein the hypertension is primary hypertension, secondary hypertension, systolic hypertension, pulmonary hypertension, or hypertension-induced vascular remodeling.

42. The method of claim 37, wherein the compound is administered locally.

43. The method of claim 37, wherein the compound is administered via an implantable device.

44. The method of claim 43, wherein the device is a delivery pump.

45. The method of claim 43, wherein the device is a stent.

46. An implantable device, comprising a compound of any of claims 1 to 27.

47. A method of treating a disease or disorder mediated by overexpression of TGFβ, comprising using the implantable device of claim 46.