EP1786802A1 - Pyrimidinylimidazoles as tgf-beta inhibitors - Google Patents

Abstract

Compounds of formula (I) possess unexpectedly high affinity for Alk 5 and/or Alk 4, and can be useful as antagonists thereof for preventing and/or treating numerous diseases, including fibrotic disorders. The invention features a compound of the general formula (I) and uses thereof.

Description

PYRIMIDINYLIMIDAZOLES AS TGF-BETA INHIBITORS

[0001] This application claims priority to U.S. Serial No. 60/606,045, which was filed on August 31, 2004. The entire contents of the aforementioned application are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] TGF/3 (Transforming Growth Factor /3) is a member of a large family of dimeric polypeptide growth factors that includes, for example, activins, inhibins, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and mullerian inhibiting substance (MIS). TGF/3 exists in three isoforms (TGF/31, TGF/32, and TGF/33) and is present in most cells, along with its receptors. Each isoform is expressed in both a tissue-specific and developmentally regulated fashion. Each TGF/3 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 TGF/3. LAP is typically non-covalently associated with mature TGF/3 prior to secretion from the cell. The LAP-TGF/3 complex cannot bind to the TGF 'β receptors and is not biologically active. TGF β is generally released (and activated) from the complex by a variety of mechanisms including, for example, interaction with thrombospondin-1 or plasmin.

[0003] Following activation, TGF/3 binds at high affinity to the type II receptor (TGF/3RII), a constitutively active serine/threonine kinase. The ligand-bound type II receptor phosphorylates the TGF/3 type I receptor (AIk 5) 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 al., 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 TGF/3-responsive genes. See, e.g., Massague, J. Ann. Rev .Biochem. Med. 67: 773 (1998).

[0004] Activins are also members of the TGF/3 superfamily, which are distinct from TGF/3 in that they are homo- or heterodimers of activin /3a or /3b. Activins signal in a manner similar to TGF/3 , that is, by binding to a constitutive serine-threonine receptor kinase, activin type II receptor (ActRIIB), and activating a type I serine-threonine receptor, AIk 4, 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.

[0005] Indeed, TGF/3 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., Moses, H. L. Cancer Res. 55: 1452-1457 (1995). Hyperactivity of TGFjS 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 εΛ, 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); Sugiyama, M. et al., Gastroenterology 114: 550-558 (1998); Munz, B. et al., EMBOJ. 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 al, MoI. 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 TGFjS family to prevent and/or treat disorders involving this signaling pathway.

SUMMARY OF THE INVENTION

[0006] The invention is based on the discovery that compounds of formula (I) are unexpectedly potent antagonists of the TGF β family type I receptors, Alk5 and/or AIk 4. 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 TGFjS family signaling activity is desirable. [0007] In one aspect, a compound of the following formula: where R¹ can be heteroaryl.

[0008] Each R^a, independently, can be alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl. [0009] X can be cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or a bond. [0010] Y can be a bond, -C(O)-, -C(O)-O-, -O-C(O)-, -S(O)_P-O-, -O-S(O)_P-, -C(O)-N(R^b)-, -N(R^b)-C(O)-, -O-C(O)-N(R^b)-, -N(R^b)-C(O)-O-, -C(O)-N(R^b)-O-, -O-N(R^b)-C(O)-, -O-S(O)_p-N(R^b)-, -N(R^b)- S(O)_p-O-, -S(O)_p-N(R^b)-O-, -O-N(R^b)-S(O)_p-, -N(R^b)-C(O)-N(R^c)-, -N(R^b)-S(O)_p-N(R^c)-, -C(O)-N(R^b)-S(O)_p-, -S(O)_p-N(R^b)-C(O>, -C(O)-N(R^b)-S(O)_p-N(R^c)-, -C(O)-O-S(O)_p-N(R^b)-, -N(R^b)-S(O)_p-N(R^c)-C(O)-, -N(R^b)-S(O)_p-O-C(O)-, -S(O)_p-N(R^b)-, -N(R^b)-S(O)p-, -N(R^b)-, -S(O)p-, -O-, -S-, or -(C(R^b)(R^c))_q-. Each of R^b and R^c , independently, can be hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl. p can be 1 or 2, and q can be 1-4.

[0011] R² can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, aralkyl, arylalkenyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkenyl, (heterocycloalkenyl)alkyl, heteroaryl, heteroaralkyl, or (heteroaryl)alkenyl. [0012] Each of A¹ and A², independently, can be N or NR^b. It is to be understood that when A¹ is NR^b, A² is N, and vice versa. The variable, m, can be 0, 1, 2, or 3. In other words, the pyrimidinyl ring cari be unsubstituted or substituted with 1-3 R^a groups. Note that when m >2, two adjacent R^a groups can join together to form a 4- to 8-membered optionally substituted cyclic moiety. That is, the pyrimidinyl ring can fuse with a cyclic moiety to form a moiety, that can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl, aryloxy, heteroaryloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylthio, sulfoxy, sulfamoyl, oxo, or carbamoyl. [0013] Note also that if X is a bond, then Y is a bond; R² is hydrogen or alkyl; m is 1, 2, or 3; and at least one R^a is substituted at the 2-pyrimidinyl position (i.e., the position of the pyrimidinyl ring that is between the two nitrogen ring atoms).

[0014] In an embodiment, X can be aryl or heteroaryl. For example, X can be an optionally substituted phenyl (e.g., alkyl or cyano). Y can be a bond, -N(R^b)-C(O)-, -N(R^b)-S(O)₂-, -C(O)-, -C(O)-O-, -0-C(O)-, -C(O)-N(R^b)-, -S(OV, -O", -S(O)₂-N(R^b)-, - N(R^b)-, -N(R^b)-C(O)-O-, -N(R^b)-C(O)-N(R^c)-, -C(O)-N(R^b)-S(O)_p-N(R^c)-, or -C(O)-O-S(O)_p-N(R^b)-. R² can be hydrogen, Ci_-6 alkyl, aryl, heteroaryl, aryl-Ci^ alkyl, or heteroaryl-C^ alkyl. [0015] In an embodiment, X can be a 4- to 8-membered monocyclic cycloalkyl or heterocycloalkyl, or X can be a 4- to 8-membered bicyclic cycloalkyl or heterocycloalkyl. For example, X can be piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuran, cyclohexyl, cyclopentyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, 2-oxa-bicyclo[2.2.2]octane, 2-aza-bicyclo[2.2.2]octane, 3-aza-bicyclo[3.2.1]octane, or 1 -aza-bicyclo[2.2.2]octane.

[0016] In an embodiment, X can be piperidinyl, piperazinyl, or pyrrolidinyl. The piperdinyl, piperazinyl, or pyrrolidinyl can be bonded to Y via its nitrogen ring atom. Y can be a bond, -C(O)O-, -C(O)-N(R^b)-, -S(O)₂-, or -S(O)₂-N(R*³)-, wherein R^b is hydrogen or C_M alkyl. Alternatively, X can be cyclohexyl, cyclopentyl, or bicyclo[2.2.2]octane, and Y can be -N(R^b)-C(O)-, -N(R^b)-S(O)₂-, -C(O)-, -C(O)-O-, -0-C(O)-, -C(O)-N(R^b)-, -S(OV, -O-, -S(O)₂-N(R^b)-, - N(R^b)-, -N(R^b)-C(0)-0-, -C(O)-N(R^b)-O-, or -N(R^b)-C(O)-N(R^c)-. [0017] In an embodiment, Y can be -N(R^b)-C(0)-, -N(R^b)-S(O)₂-, -C(O)-, -C(O)-O-, -0-C(O)-, -C(O)-N(R^b)-, -S(OV, -O-, -S(O)₂-N(R^b)-, - N(R^b)-, -N(R^b)-C(O)-O-, -C(O)-N(R^b)-O-, -N(R^b)-C(0)-N(R^c)-, -C(O)-N(R^b)-S(O)_p-N(R^c)-, or -C(O)-O-S(O)_p-N(R^b)-. [0018] In an embodiment, X and Y are each a bond; R² can be hydrogen or C_1-6 alkyl (e.g., Ci_-4 alkyl such as methyl or t-butyl); m can be 1 or 2 (e.g., m can be 1); at least one R^a is substituted at the 2-pyrimidinyl position and this R^a can be Ci_-4 alkyl, C_3-6 cycloalkyl, or amino (e.g, -CH₃, - CF₃, cyclopropyl, -NH₂, -NH-C_1-4 alkyl, or -NH-cycloalkyl such as -NH-cyclopropyl). [0019] In an embodiment, R² can be hydrogen, C_1-6 alkyl, aryl, heteroaryl, aryl-Ci^ alkyl, or heteroaryl-Ci-₄ alkyl. In an embodiment, R² can be hydrogen, Ci_-4 alkyl, phenyl, pyridyl, imidazolyl, furanyl, thienyl, triazolyl, tetrazolyl, benzyl, phenylethyl, benzimidazolyl, benzothiazolyl, naphthylmethyl, naphthylethyl, or -Ci_-2 alkyl-pyridyl; each of which, independently, is optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, methyl, ethyl, aminocarbonyl, alkylcarbonylamino, sulfamoyl, alkoxycarbonyl, and alkylcarbonyloxy.

[0020] In another embodiment, R^" can be hydrogen, methyl, ethyl, n-butyl, t-butyl, benzyl or pyridylmethyl. For example, R² can be hydrogen, hydroxymethyl, or trifluoromethyl.

[0021] In an embodiment, R¹ can be benzo[l,3]dioxolyl, benzo[έ]thiophenyl, benzo-oxadiazolyl, benzothiadiazolyl, benzoimidazolyl, benzooxazolyl, benzothiazolyl,

2-oxo-benzooxazolyl, pyridyl, pyrimidinyl, 2,3-dihydro-benzo[l,4]dioxyl,

2,3-dihydro-benzofuryl, 2,3-dihydro-benzo[έ]thiophenyl, 3,4-dihydro-benzo[l ,4]oxazinyl,

3 -oxo-benzo[ 1 ,4] oxazinyl, 1 , 1 -dioxo-2,3 -dihydro- benzo [έ]thiophenyl,

[l,2,4]triazolo[l,5-a]pyridyl, [l,2,4]triazolo[4,3-a]pyridyl, quinolinyl, quinoxalinyl, quinazolinyl, isoquinolinyl, or cinnolinyl.

[0022] In an embodiment, m can be 0-2.

[0023] In an embodiment, R^a can be substituted at the 2-pyrimidinyl position.

[0024] In another embodiment, R^a can be C_1-4 alkyl, C_1-4 alkoxy, Ci_-4 alkylthio, halo, amino, aminocarbonyl, or alkoxycarbonyl.

[0025] In an embodiment, A¹ can be N and A² is NR^b, or A¹ is NR^b and A² is N; wherein R^b is hydrogen or Ci_-4 alkyl.

[0026] In an embodiment, m can be 0-2; R¹ can be heteroaryl; R² can be hydrogen, C₁^ alkyl, aryl, heteroaryl, -Ci_-4 alkyl-aryl, Or -Ci_-4 alkyl-heteroaryl; X can be a 4- to 8-membered monocyclic or bicyclic cycloalkyl or heterocycloalkyl; and Y can be -N(R^b)-C(O)-,

-N(R^b)-S(O)₂-, -C(O)-, -C(O)-O-, -0-C(O)-, -C(O)-N(R^b)-, -S(O)_P-, -O-, -S(O)₂-N(R^b)-,

-N(R^b)-, -N(R^b)-C(O)-O-, -N(R^b)-C(O)-N(R^c)-, -C(O)-N(R^b)-S(O)_p-N(R^c)-, or

-C(O)-O-S(O)_p-N(R^b)-.

[0027] In an embodiment, m can be 0-2; R¹ can be heteroaryl; R² can be hydrogen, Ci_-6 alkyl, aryl, heteroaryl, -Ci_-4 alkyl-aryl, or -Ci_-4 alkyl-heteroaryl; X can be piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuran, cyclohexyl, cyclopentyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, 2-oxa-bicyclo[2.2.2]octane,

2-aza-bicyclo[2.2.2]octane, 3-aza-bicyclo[3.2.1]octane, or l-aza-bicyclo[2.2.2]octane; and Y can be -N(R^b)-C(O)-, -N(R^b)-S(O)₂-, -C(O)-, -C(O)-O-, -0-C(O)-, -C(O)-N(R^b)-, -S(O)_P-, -O-,

-S(O)₂-N(R^b)-, - N(R^b)-, -N(R^b)-C(O)-O-, -N(R^b)-C(O)-N(R^c)-, -C(O)-N(R^b)-S(O)_p-N(R^c)-, or

-C(O)-O-S(O)_p-N(R^b)-.

[0028] In an embodiment, m can be 0-2; R¹ can be heteroaryl; R² can be hydrogen, Ci_-6 alkyl, aryl, heteroaryl, -Ci_-4 alkyl-aryl, Or -Ci_-4 alkyl-heteroaryl; and -X-Y- can be

[0029] In an embodiment, A¹ can be N and A² can be NH. Alternatively, A¹ can be NH and A² can be N. R² can be hydrogen, Ci_-4 alkyl, benzyl, or pyridylmethyl; m can be 1 and R^a can be substituted at the 2-pyrimidinyl position.

[0030] In an embodiment, m can be 0-2; R¹ can be heteroaryl; R² can be hydrogen, Ci_-6 alkyl, aryl, heteroaryl, aryl-Ci^ alkyl, or heteroaryl-C_M alkyl; X can be cyclohexyl, cyclopentyl, or bicyclo[2.2.2]octane; and Y can be -N(R^b)-C(0)-, -N(R^b)-S(O)₂-, -C(O)-, -C(O)-O-, -0-C(O)-,

-C(O)-N(R^b)-, -S(OV-, -O-, -S(O)₂-N(R^b)-, - N(R^b)-, -N(R^b)-C(O)-O-, -N(R^b)-C(0)-N(R^c)-,

-C(O)-N(R^b)-S(O)_p-N(R^c)-, or -C(O)-O-S(O)_p-N(R^b)-. Each of R^b and R^c, independently, can be hydrogen or Ci_-4 alkyl. A¹ can be N and A² can be NH, or alternatively, A¹ can be NH and A² can be N. R² can be hydrogen, Ci_-4 alkyl, benzyl, or pyridylmethyl; m can be 1 and R^a can be substituted at the 2-pyrimindyl position.

[0031] In an embodiment, X and Y can each be a bond; R² can be hydrogen or Ci_-4 alkyl; m can be 1; R^a can be -CH₃, -CF₃, cyclopropyl, -NH₂, -NH-Ci_-4 alkyl, or -NH-cycloalkyl; and R¹ can be benzo[l,3]dioxolyl, benzo[6]thiophenyl, benzooxadiazolyl, benzothiadiazolyl, benzoimidazolyl, benzooxazolyl, benzothiazolyl, 2-oxo-benzooxazolyl, pyridyl, pyrimidinyl,

2,3-dihydro-benzo[l ,4]dioxyl, 2,3-dihydro-benzofuryl, 2,3-dihydro-benzo[Z?]thiophenyl,

3,4-dihydro-benzo[l,4]oxazinyl, 3-oxo-benzo[l,4]oxazinyl, l,l-dioxo-2,3-dihydro- benzo[δ]thiophenyl, [l,2,4]triazolo[l,5-a]pyridyl, [l,2,4]triazolo[4,3-a]pyridyl, quinolinyl, quinoxalinyl, quinazolinyl, isoquinolinyl, or cinnolinyl.

[0032] The compound of formula (I) can be:

[0033] 4-[4-benzo[l,3]dioxol-5-yl-5-(2-methylsulfanyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- benzamide;

[0034] 4-[4-benzo[l,3]dioxol-5-yl-5-(2-methylsulfanyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- benzonitrile;

[0035] 4-[5-(2-methanesulfonyl-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;

[0036] 4-[5-(2-methoxy-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;

[0037] 4-[5-(2-hydroxy-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;

[0038] 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;

[0039] 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid;

[0040] 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;

[0041] 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;

[0042] 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methoxy-amide;

[0043] 4-[5-(2-amino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid;

[0044] {4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]oct-l-yl}-carbamic acid benzyl ester;

[0045] N- {4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)- 1 H-imidazol-

2-yl]-bicyclo[2.2.2]oct-l-yl}-acetamide;

[0046] N-{4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-

2-yl]-bicyclo[2.2.2]oct-l-yl}-methanesulfonamide;

[0047] N- {4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)- 1 H-imidazol-

2-yl]-bicyclo[2.2.2]oct-l-yl}-2,2,2-trifluoro-acetamide;

[0048] 4-[5-quinoxalin-6-yl-4-(2-trifluoromethyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol;

[0049] 4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol;

[0050] 6-[2-tert-butyl-5-(2-cyclopropyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;

(15686)

[0051] 6-[5-(2-byclopropyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;

[0052] {4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-methanol; [0053] 6-[5-(2-trifluoromethyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;

[0054] 6-[2-tert-butyl-5-(2-trifluoromethyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;

[0055] 4-[5-quinoxalin-6-yl-4-(2-trifluoromethyl-pyrimidin-4-yl)-lH-imidazol-2-yl]-piperidine-

1-carboxylic acid benzyl ester;

[0056] 4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;

[0057] 6-[5-(2-cyclopropyl-pyrimidin-4-yl)-2-(l-methanesulfonyl-piperidin-4-yl)-3H-imidazol-

4-yl] -quinoxaline;

[0058] 4-[5-(2-methyl-pyrimidin-4-yl)-4-[l,2,4]triazolo[4,3-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l -ol;

[0059] 4-[4-(2-methyl-pyrimidin-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;

[0060] 4-[4-(2-methyl-pyrimidin-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo [2.2.2] octane- 1 -carboxylic acid;

[0061] 4-[4-(2-methyl-pyrimidin-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;

[0062] 4-[4-(2-methyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-cyclohexanol; or

[0063]4-[4-(2-methyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-bicyclo[2.2.2]octan- l-ol.

[0064] In another aspect, a pharmaceutical composition includes a compound of formula (I) and a pharmaceutically acceptable carrier.

[0065] In another aspect, a method of inhibiting the TGF/3 signaling pathway in a subject includes administering to said subject an effective amount of a compound of formula (I).

[0066] In another aspect, a method of inhibiting the TGF/3 type I receptor in a cell, includes contacting said cell with an effective amount of a compound of formula (I).

[0067] In another aspect, a method of reducing the accumulation of excess extracellular matrix induced by TGF/3 in a subject includes administering to said subject an effective amount of a compound of formula (I).

[0068] In another aspect, a method of treating or preventing fibrotic condition in a subject includes administering to said subject an effective amount of a compound of formula (I). The fibrotic condition can be, for example, scleroderma, lupus nephritis, connective tissue disease, wound healing, surgical scarring, spinal cord injury, CNS scarring, acute lung injury, pulmonary fibrosis (such as idiopathic pulmonary fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, drug-induced lung injury, glomerulonephritis, diabetic nephropathy, hypertension-induced nephropathy, alimentary track or gastrointestinal fibrosis, renal fibrosis, hepatic or biliary fibrosis (such as liver cirrhosis, primary biliary cirrhosis, fatty liver disease, primary sclerosing cholangitis), restenosis, cardiac fibrosis, opthalmic scarring, fibrosclerosis, fibrotic cancers, fibroids, fibroma, fibroadenomas, fibrosarcomas, transplant arteriopathy, or keloid. The fibrotic condition can be idiopathic in nature, genetically linked, or induced by radiation.

[0069] In another aspect, a method of inhibiting growth or metastasis of tumor cells and/or cancers in a subject includes administering to said subject an effective amount of a compound of formula (I).

[0070] In another aspect, a method of treating a disease or disorder mediated by an overexpression of TGF β 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.

[0071] An N-oxide derivative or a pharmaceutically acceptable salt of each of the compounds of formula (I) is also within the scope of this invention. 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 m-chloroperbenzoic acid or H₂O₂. [0072] 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. Also within the scope of the invention are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, and Ν-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,/>-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). Compounds of formula (1) can also be, e.g., in a form of achiral compounds, racemic mixtures, optically active compounds, pure diastereomers, or a mixture of diastereomers. [0073] Compounds of formula (I) exhibit surprisingly high affinity to the TGF/3 family type I receptors, AIk 5 and/or AIk 4, e.g., with ICs₀ and Kj values of less than 10 μM under conditions as described below in Examples 34 and 36, respectively. Some compounds of formula (I) exhibit IC5₀ and K; values of less than 1 μM (such as below 50 nM).

[0074] Compounds of formula (I) can also be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and/or alter rate of excretion. Examples of these modifications include, but are not limited to, esterifϊcation with polyethylene glycols, derivatization with pivolates or fatty acid substituents, conversion to carbamates, hydroxylation of aromatic rings, and heteroatom-substitution in aromatic rings. [0075] The present invention also features a pharmaceutical composition comprising a compound of formula (I) (or a combination of two or more compounds of formula (I)) and at least one pharmaceutically acceptable carrier. Also included in the present invention is a medicament composition including any of the compounds of formula (I), alone or in a combination, together with a suitable excipient.

[0076] The invention also features a method of inhibiting the TGF/3 family type I receptors, AIk 5 and/or AIk 4 (e.g., with an IC₅₀ value of less than 10 μM; such as, less than 1 μM; and for example, less than 5 nM) in a cell, including the step of contacting the cell with an effective amount of one or more compounds of formula (I). Also within the scope of the invention is a method of inihibiting the TGF/3 and/or activin signaling pathway in a cell or in a subject (e.g., a mammal such as a human), including the step of contacting the cell with or administering to the subject an effective amount of one or more of the compounds of formula (I). [0077] Also within the scope of the present invention is a method of treating a subject or preventing a subject from suffering a condition characterized by or resulted from an elevated level of TGF/3 and/or activin activity. The method includes the step of administering to the subject an effective amount of one or more of a compound of formula (I). The conditions include an accumulation of excess extracellular matrix; a fibrotic condition (which can be induced by drug or radiation), e.g., scleroderma, lupus nephritis, connective tissue disease, wound healing, surgical scarring, spinal cord injury, CNS scarring, acute lung injury, pulmonary fibrosis (such as idiopathic pulmonary fibrosis and radiation-induced pulmonary fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, diabetic nephropathy, hypertension-induced nephropathy, alimentary track or gastrointestinal fibrosis, renal fibrosis, hepatic or biliary fibrosis, liver cirrhosis, primary biliary cirrhosis, cirrhosis due to fatty liver disease (alcoholic and nonalcoholic steatosis), primary sclerosing cholangitis, restenosis, cardiac fibrosis, opthalmic scarring, fibrosclerosis, fibrotic cancers, fibroids, fibroma, fibroadenomas, fibrosarcomas, transplant arteriopathy, and keloid); TGF/3-induced growth or metastasis of tumor/cancer cells; and carcinomas (e.g, squamous cell carcinomas, multiple myeloma, melanoma, glioma, glioblastomas, leukemia, sarcomas, leiomyomas, mesothelioma, and carcinomas of the lung, breast, ovary, cervix, liver, biliary tract, gastrointestinal tract, pancreas, prostate, and head and neck); and other conditions such as cachexia, hypertension, ankylosing spondylitis, demyelination in multiple sclerosis, cerebral angiopathy and Alzheimer's disease. [0078] 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 an alkyl group include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, and 2-ethylhexyl. An alkyl group can be optionally substituted with one or more substituents such as alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl-carbonylamino, heterocycloalkyl- alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, or alkylcarbonyloxy.

[0079] 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 alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl-carbonylamino, heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, or alkylcarbonyloxy. [0080] 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 alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfmyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl- carbonylamino, heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, or alkylcarbonyloxy.

[0081] As used herein, an "amino" group refers to -NR^XR^Y wherein each of R^x and R^γ is independently hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, or heteroaralkyl. When the term "amino" is not the terminal group (e.g., alkylcarbonylamino), it is represented by -NR^X-. R^x has the same meaning as defined above.

[0082] As used herein, an "aryl" group refers to phenyl, naphthyl, or a benzofused group having 2 to 3 rings. For example, a benzofused group includes phenyl fused with one or two C_4-8 carbocyclic moieties, e.g., 1, 2, 3, 4-tetrahydronaphthyl, indanyl, or fluorenyl. An aryl 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, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0083] As used herein, an "aralkyl" group refers to an alkyl group (e.g., a C_1-4 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.

[0084] As used herein, a "cycloalkyl" group refers to an aliphatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, and bicyclo[3.2.3]nonyl. 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 bond. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, 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 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, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0085] As used herein, a "heterocycloalkyl" group refers to a 3- to 10-membered (e.g., 4- to 8- membered) saturated ring structure, in which one or more of the ring atoms is a heteroatom, e.g., N, O, or S. Examples of a heterocycloalkyl group include piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuryl, dioxolanyl, oxazolidinyl, isooxazolidinyl, morpholinyl, octahydro-benzofuryl, octahydro-chromenyl, octahydro-thiochromenyl, octahydro-indolyl, octahydro-pyrindinyl, decahydro-quinolinyl, octahydro-benzo[Z>]thiophenyl, 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 "heterocycloalkenyl" group, as used herein, refers to a 3- to 10- membered (e.g., 4- to 8-membered) 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. A heterocycloalkyl or heterocycloalkenyl group 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, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalky^alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalky^carbonylamino, (heterocycloalkytyalkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0086] A "heteroaryl" group, as used herein, refers to a monocyclic, bicyclic, or tricyclic ring structure having 5 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom, e.g.,

N, O, or S and wherein one ore more rings of the bicyclic or tricyclic ring structure is aromatic.

Some examples of heteroaryl are pyridyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, tetrazolyl, benzofuryl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, and benzo[l,3]dioxole. A heteroaryl is optionally substituted with one or more substiruents 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, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. A

"heteroaralkyl" group, as used herein, refers to an alkyl group (e.g., a C_M alkyl group) that is substituted with a heteroaryl group. Both "alkyl" and "heteroaryl" have been defined above.

[0087] As used herein, "cyclic moiety" includes cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, each of which has been defined previously.

[0088] As used herein, an "acyl" group refers to a formyl group or alkyl-C(=O)- where "alkyl" has been defined previously. Acetyl and pivaloyl are examples of acyl groups.

[0089] 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^y have been defined above and R^z can be alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl.

[0090] As used herein, a "carboxy" and a "sulfo" group refer to -COOH and -SO₃H, respectively.

[0091] As used herein, an "alkoxy" group refers to an alkyl-O- group where "alkyl" has been defined previously.

[0092] As used herein, a "sulfoxy" group refers to -O-SO-R^X or -SO-O-R^X, where R^x has been defined above.

[0093] As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine. [0094] As used herein, a "sulfamoyl" group refers to the structure -S(O)₂-NR^xR^y or -NR^X - S(O)₂-R² wherein R^x, R^y, and R^z have been defined above.

[0095] As used herein, a "sulfamide" group refers to the structure -NR^X -S(O)₂-NR^YR^Z wherein R^x, R^γ, and R^z have been defined above.

[0096] 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. R^x, R^γ, and R^z have been defined above. [0097] 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 area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "patient" refers to a mammal, including a human. [0098] An antagonist, as used herein, is a molecule that binds to the receptor without activating the receptor. It competes with the endogenous ligand(s) or substrate(s) for binding site(s) on the receptor and, thus inhibits the ability of the receptor to transduce an intracellular signal in response to endogenous ligand binding.

[0099] As compounds of formula (I) are antagonists of TGF/3 receptor type I (Alk5) and/or activin receptor type I (Alk4), these compounds are useful in inhibiting the consequences of TGF/3 and/or activin signal transduction such as the production of extracellular matrix (e.g., collagen and fibronectin), the differentiation of stromal cells to myofibroblasts, and the stimulation of and migration of inflammatory cells. Thus, compounds of formula (I) inhibit pathological inflammatory and fibrotic responses and possess the therapeutic utility of treating and/or preventing disorders or diseases for which reduction of TGF/3 and/or activin activity is desirable (e.g., various types of fibrosis or progressive cancers). In addition, the compounds of formula (I) are useful for studying and researching the role of TGFjS receptor type I (Alk5) and/or activin receptor type I (Alk4), such as their role in cellular processes, for example, signal transduction, production of extracellular matrix, the differentiation of stromal cells to myofibroblasts, and the stimulation of and migration of inflammatory cells. [0100] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. [0101] Other features and advantages ot the invention will be apparent from the following detailed description, and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

[0102] In general, the invention features compounds of formula (I), which exhibit surprisingly high affinitiy for the TGF β family type I receptors, AIk 5 and/or AIk 4. Synthesis of the Compounds of formula (I)

[0103] Compounds of formula (I) may be prepared by a number of known methods from commercially available or known starting materials. In one method, compounds of formula (I) are prepared according to Schemes Ia, Ib, or Ic below. Specifically, in Scheme Ia, optionally substituted 2-methylpyrimidine (II) is deprotonated by LDA before reacting with R¹ -substituted carboxylic acid methoxy-methyl-amide (V) to form an R¹-(6-methylpyrimidinyl)-ketone (III). R¹ has been defined above. The methoxy-methyl-amide can be prepared by reacting a corresponding acid chloride (i.e., R'-CO-CI) with N, 0-dimethylhydroxylamine hydrochloride. The R¹-(6-methylpyrimidinyl)-ketone (III) can then be treated with sodium nitrite in acetic acid to afford an α-keto-oxime (IV), which can undergo further reaction with an appropriate substituted (and optionally protected) aldehyde (VI) in the presence of ammonium acetate to yield a compound of formula (I).

Scheme Ia

1. NH₄OAc

(IV)

(I)

[0104] In another method, the above-described compounds of formula (I) can be prepared according to Scheme Ib below. Specifically, l,l-dimethoxy-propan-2-one can first react with dimethoxymethyl-dimethyl-amine at an elevated temperature to produce the intermediate 4- dimethylamino-l,l-dimethoxy-but-3-en-2-one, which can then react with an R^a-substituted amidine to form an R^a-substituted pyrimidine-2-carbaldehyde (Ila). This carbaldehyde (Ha) can then reacted with aniline and diphenyl phosphite to form a resulting N.P-acetal, which can further couple with an R¹ -substituted aldehyde to produced an (R'-methyty-pyrirnidinyl-ketone (πia). See, e.g., Journet et al., Tetrahedron Lett 39: 1717-1720 (1998). Treatment of the (R¹- methyl)-pyrimidinyl-ketone (Ilia) with sodium nitrite in acetic acid produces an ce-keto-oxime (IVa), which can undergo reaction with an appropriate substituted (and optionally protected) aldehyde (VI) to yield a compound of formula (I) as described in Scheme Ia above.

Scheme Ib

(Ilia)

(Ila)

1. NH₄OAc

[0105] In another methodj the above-described compounds of formula (I) can be prepared according to Scheme Ic below. Specifically, an (R'-methyty-pyrimidinyl-ketone (Ilia) (described above) can be oxidized to form a pyrimidinyl-diketone (IVb), which can undergo reaction with an appropriate substituted (and optionally protected) aldehyde (VI) to yield a compound of formula (I) as described above.

Scheme Ic

1. NH₄OAc

(I)

[0106] If compound (VI) is in its protected form, appropriate deprotecting agents can be applied to the resulting compound after the coupling reaction of compound (IV) or (IVa) and compound (VI) to yield a compound of formula (I). See, e.g., T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York (1981), for suitable protecting groups. [0107] Alternatively, a compound of formula (I) can be prepared by reacting intermediate (IV) or (FVa) with an aldehyde (VII) to yield a further intermediate (VIII), which can then react with compound (IX) to yield a compound of formula (I). Note that moieties Y' and Y" are precursors of moiety Y. See Scheme 2 below. In addition, desired substitutions at R^a can be obtained by selecting, for example, the appropriate compound (Ha) intermediate.

Scheme 2

(I)

[0108] In some embodiments, moiety X in compound (VTI) is a nitrogen-containing heterocycloalkyl (e.g., piperidine). The nitrogen ring atom can be protected by a nitrogen protecting group (e.g., Cbz, Boc, or FMOC) before coupling to compound (IV) or (IVa) and deprotected afterwards (see first step of Scheme 3) to yield compound (Villa). This compound can further react with various compounds (IX) to produce a compound of formula (I). See second steps of Scheme 3 below. It should be noted that compound (VIII) or compound (Villa) can be a compound of formula (I) as well.

Scheme 3

(using Pd/C

(D

[0109] Similarly, when moiety X in compound (VII) is a cycloalkyl (e.g., cyclopentyl, cyclohexyl, or bicyclo[2.2.2]octane), it can be further functionalized to form a compound of formula (I) as depicted in Schemes 4, 5a, 5b, and 5c below. Scheme 4

Pd/C

Scheme 5a

(I)

(D

Scheme 5b

(I) (I)

(I) (I)

(I) (I)

(I)

(can be further modified according to Scheme 5c below)

(I)

(can be further modified according to Scheme 5c below)

(6) D ^RlE²A^S,^O T*H^CF^I

(I) (I)

(I)

Trifluoroactic ^anhy^dridΘ

(7) Pyridine, THF

(I) (I)

(I)

(I)

Scheme 5c

(D

[0110] As is well known to a skilled person in chemistry, desired substitutions can be placed on the pyrimidinyl ring in the last steps of the synthesis. See Scheme 6 below, for example.

Scheme 6

R²

[0111] Compounds of formula (I) wherein R^b is not hydrogen can be prepared by known methods. For example, compounds of formula (I) wherein A¹ is N and A² is NH (or vice versa) can be treated with R.1 (e.g., alkyl locude) and CSCO₃ to produce a compound of formula (I) wherein R^b is alkyl. See, e.g., Liverton, et al., J. Med. Chem., 42: 2180-2190 (1999). [0112] As will be obvious to a skilled person in the art, some starting materials and intermediates may need to be protected before undergoing synthetic steps as described above. For suitable protecting groups, see, e.g., T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York (1981). Uses of Compounds of formula (D

[0113] As discussed above, hyperactivity of the TGF]S 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. and Ruoslahti E. J. CHn. Invest. 90: 1-7 (1992) and Border, W.A. and Noble, N.A. N Engl. J. Med. 331 : 1286-1292 (1994). Studies have been shown that the expression of TGFjS and/or activin mRΝA and the level of TGFjS and/or activin are increased in patients suffering from various fibrotic disorders, e.g., fibrotic kidney diseases, alcohol- induced and autoimmune hepatic fibrosis, myelofibrosis, bleomycin-induced pulmonary fibrosis, and idiopathic pulmonary fibrosis. Elevated TGFβ and/or activin is has also been demonstrated in cachexia, demyelination of neurons in multiple sclerosis, Alzheimer's disease, cerebral angiopathy and hypertension.

[0114] Compounds of formula (I), which are antagonists of the TGFjS family type I receptors AIk 5 and/or AIk 4, and inhibit TGFjS and/or activin signaling pathway, are therefore useful for treating and/or preventing fibrotic disorders or diseases mediated by an increased level of TGFjS and/or activin activity. As used herein, a compound inhibits the TGFjS family signaling pathway when it binds (e.g., with an IC₅₀ value of less than 10 μM; such as, less than 1 /xM; and for example, less than 5 nM) to a receptor of the pathway (e.g., AIk 5 and/or AIk 4), 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 TGFjS 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 scleroderma, glomerulonephritis, diabetic nephropathy, lupus nephritis, hypertension-induced nephropathy, ocular or corneal scarring, alimentary track or gastrointestinal fibrosis, renal fibrosis, hepatic or biliary fibrosis, acute lung injury, pulmonary fibrosis (such as idiopathic pulmonary fibrosis and radiation-induced pulmonary fibrosis), post- infarction cardiac fibrosis, 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-induced fibrosis, chemotherapy- induced fibrosis, and surgically-induced scarring including surgical adhesions, laminectomy, and coronary restenosis.

[0115] Increased TGF/3 activity is also found to manifest in patients with progressive cancers. Studies have shown that in many cancers, the tumor cells, stromal cells, and/or other cells within a tumor generally overexpress TGF /3. This leads to stimulation of angiogenesis and cell motility, suppression of the immune system, and/or increased interaction of tumor cells with the extracellular matrix. See, e.g., Hojo, M. et al., Nature 397: 530-534 (1999) and Lammerts E. et al., Int. J. Cancer 102: 453-462 (2002). As a result, the tumors grow more readily, become more invasive and metastasize to distant organs. See, e.g., Maehara, Y. et al., J. CHn. 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 TGF/3 type I receptor and inhibit TGF/5 signaling pathways, are also useful for treating and/or preventing various cancers which overexpress TGF/3 or benefit from TGF/3's above-mentioned pro-tumor activities. Such 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. [0116] 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 TGF/3 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.

[0117] Not only are compounds of formula (I) useful in treating disorders or diseases mediated by high levels of TGF/3 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 TGF/3 and/or activin production have been associated with fibrosis and hypertension. Indeed, high serum TGF/3 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 TGF/3 and/or activin in serum and of TGF/3 and/or activin mRNA in tissue can be measured and used as diagnostic or prognostic markers for disorders or diseases mediated by overexpression of TGF/3 and/or activin, and polymorphisms in the gene for TGF/3 that determine the production of TGF/3 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).

ADMINISTRATION OF COMPOUNDS OF FORMULA (T)

[0118] 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. [0119] Compounds of formula (I) 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. Solubilizing 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).

[0120] Optionally, compounds of formula (I) can be administered in conjunction with one or more other agents that inhibit the TGF/3 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, immunotherapeutics, chemotherapeutics, as well as agents that antagonize ligand binding or activation of the TGF/3 receptors, e.g., anti-TGF/3, anti-TGF/3 receptor antibodies, or antagonists of the TGF/3 type II receptors. Compounds of formula (I) can also be administered in conjunction with other treatments, e.g., radiation. The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims. Example 1

4-[l-Hydroxy-4-(2-methyl-pyrimidin-4-yl)-5-[l,2,4]triazoIo[l,5-a]pyridin-6-yl-lH- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester

Synthesis of the title compound is described in parts (a)-(b) below.

(a) l-(2-Methyl-pyrimidin-4-yl)-2-[l,2,4]triazolo[l,5-a]pyridin-6-yl-ethane-l,2-dione 2- oxime (IVa)

[0121] Sodium nitrite (1.03 g, 15 mmol) was added to a solution of l-(2-methyl-pyrimidin-4- yl)-2-[l,2,4]triazolo[l,5-a]pyridin-6-yl-ethanone (prepared according to Scheme Ib above) (2.5 g, 10 mmol) in a mixture of HOAc/THF/H₂O (6:4:1, 55 mL). The mixture was stirred at 0 ⁰C for 1 hour and then room temperature for 1 hour. Solvent was removed under reduced pressure. Residue was dissolved in water and NaOH (3N) was added until the pH was greater than 8. The aqueous solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give 1.8 g (64%) of the title compound as a yellow foam.

(b) 4-[l-Hydroxy-4-(2-methyl-pyrimidin-4-yI)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yI-lH- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxyIic acid methyl ester

[0122] 4-Formyl-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester (0.170 g, 1.0 mmol) was added to a solution of l-(2-methyl-pyrimidin-4-yl)-2-[l,2,4]triazolo[l,5-a]pyridin-6-yl-ethane- 1,2-dione 2-oxime (0.282 g, 1 mmol) and ammonium acetate (1.54 g, 20 mmol) in acetic acid (5 mL). The mixture was refluxed for 3 hours. Solvent was removed under reduced pressure. The reaction mixture was then quenched with an ammonia/ice mixture. The aqueous solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give 0.40Og (87%) of the title compound as a yellow solid.

Example 2

4-[4-(2-Methyl-pyrimidin-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo [2.2.2] octane-1-carboxylic acid methyl ester

[0123] Triethylphosphite (0.343 uL, 2.0 mmol) was added to a solution of 4-[l-hydroxy-4-(2- methyl-pyrimidin-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester (0.40 g, 0.87 mmol; see Example 1 above) in DMF (10 mL). The mixture was heated at 110 ⁰C for 18 hours. The solvent was removed. The residue was portioned between ethyl acetate and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to give a yellow oil. HPLC purification gave 0.30 g (77%) of the title compound as a yellow oil. ¹H NMR (300 MHz, Methanol-d₄) δ 9.32 (s, IH), 8.69 (d, IH, J = 5.7 Hz), 8.58 (s, IH), 7.93 (m, 2H), 7.74 (d, IH, J = 5.7 Hz), 3.68 (s, 3H), 2.65 (s, 3H), 2.15 (m, 6H), 1.99 (m, 6H). MS (ES+) m/z (M+l) 444.24. Example 3

4- [4-(2-Methyl-pyrimidin-4-yl)-5- [1 ,2,4] triazolo [1 ,5-a] pyridin-6-yl-lH-imidazoI-2-yl] - bicyclo [2.2.2] octane-1-carboxylic acid

[0124] Lithium hydroxide monohydrate (0.046 g, 1.12 mmol) was added to a solution of 4-[4- (2-methyl-pyrimidin-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester (0.25 g, 0.56 mmol) in a mixture of THF/MeOH/H₂O (2/1/1, 4 mL). The mixture was stirred for 3 hours, and the solvent was removed. The residue was diluted with water (30 mL). Citric acid was added to the solution to make the pH lower than 7. The aqueous solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give 0.180 g (75%) of the title compound as a yellow solid. ¹H NMR (300 MHz, Methanol-d₄) δ 9.29 (s, IH), 8.65 (d, IH, J = 5.4 Hz), 8.54 (s, IH), 7.91 (m, 2H), 7.67 (d, IH, J = 5.7 Hz), 2.64 (s, 3H), 2.14 (m, 6H), 2.00 (m, 6H). MS (ES+) m/z (M+l) 430.28. Example 4

4-[4-(2-Methyl-pyrimidin-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yI-lH-imidazol-2-yI]- bicyclo [2.2.2] octane-1-carboxylic acid amide

[0125] HATU (0.265 g, 0.70 mmol) was added to a solution of 4-[4-(2-methyl-pyrimidin-4-yl)- 5-[l ,2,4]triazolo[l ,5-a]pyridin-6-yl-lH-imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid (0.150 g, 0.35 mmol) and potassium carbonate (0.1242 g, 1.75 mmol) in DMF (5 mL). The mixture was stirred for 10 minutes. NH₃ was bubbled into the reaction mixture for 10 minutes. The mixture was stirre for an additional 2 hours. The mixture was filtered, and DMF was removed under reduced pressure. The residue was dissolved in DMSO and the DMSO solution was filtered. HPLC purification of the DMSO solution gave 0.040 g (27%) of the title compound as a yellow solid. ¹H NMR (300 MHz, Methanol-d₄) δ 9.30 (s, IH), 8.67 (d, IH, J = 6.0 Hz), 8.56 (s, IH), 7.92 (m, 2H), 7.69 (d, IH, J = 6.0 Hz), 2.65 (s, 3H), 2.15 (m, 6H), 1.99 (m, 6H). MS (ES+) m/z (M+l) 429.25.

Example 5

4-[4-(2-Methyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-bicyclo[2.2.2]octan-l- ol Synthesis of the title compound is described in parts (a)-(b) below.

(a) l-(2-Methyl-pyrimidin-4-yl)-2-quinoxalin-6-yl-ethane-l,2-dione (IVb)

[0126] To a solution of 2-(2-methyl-pyrimidin-4-yl)-l-quinoxalin-6-yl-ethanone (0.500 g, 1.9 mmol; prepared according to Scheme Ib above)) in DMSO (5 mL) was added NBS (0.337 g, 1.9 mmol) and then stirred at room temperature for 3 days. The mixture was partitioned between ether and water. Ether was washed with brine, dried over sodium sulfate, filtered and concentrated to give 0.200 g (38%) of l-(2-methyl-pyrimidin-4-yl)-2-quinoxalin-6-yl-ethane- 1 ,2-dione as a yellow solid.

(b) 4-[4-(2-MethyI-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-bicyclo[2.2.2]octan- l-ol

[0127] 4-Hydroxy-bicyclo[2.2.2]octane-l-carbaldehyde (0.130 g, 0.86 mmol) was added to a solution of l-(2-methyl-pyrimidin-4-yl)-2-quinoxalin-6-yl-ethane-l,2-dione (0.200 g, 0.72 mmol) and ammonium acetate (0.554 g, 7.2 mmol) in acetic acid (10 mL). The mixture was reflux for 3 hours. Solvent was removed under reduced pressure. Reaction mixture was then quenched with ammonia/ice mixture. The aqueous solution was extracted with ethyl acetate. Ethyl acetate was washed with brine, dried over sodium sulfate, filtered, and concentrated. HPLC purification eluting with acetonitrile:water gave 0.06 g (20%) of the title compound as a yellow solid. ¹H NMR (300 MHz, Methanol^) δ 8.99 (m, 2H), 8.63 (d, IH, J = 5.8 Hz), 8.43 (d, IH, J = 1.8 Hz), 8.25 (d, IH, J = 8.7 Hz), 8.03 (m, IH), 7.47 (d, IH, J = 5.7 Hz), 2.30 (m, 6H), 1.87 (m, 6H). MS (ES⁺) m/z (M+l) 413.28.

Example 6

4-[l-Hydroxy-4-(6-methyl-pyridin-2-yl)-5-(2-methylsulfanyI-pyrimidin-4-yl)-lH-imidazol- 2-yl]-bicyclo [2.2.2] octane-l-carboxylic acid methyl ester

Synthesis of the title compound is described in parts (a)-(b) below. (a) l-(6-Methyl-pyridin-2-yl)-2-(4-methyIsulfanyl-pyrimidin-2-yl)-ethane-l,2-dione 2- oxime (IV)

[0128] Sodium nitrite (0.479 g, 6.9 mmol) was added to a solution of l-(6-methyl-pyridin-2-yl)- 2-(4-methylsulfanyl-pyrimidin-2-yl)-ethanone (1.2 g, 4.6 mmol; prepared according to Scheme 1 above) in a mixture of HOAc/THF/H₂O (6:4:1, 35 mL). The mixture was stirred at 0⁰C for 1 hour and then at room temperature for another hour. Solvent was removed under reduced pressure. Residue was dissolved in water, to which NaOH (3N) was added until pH was larger than 8. The aqueous solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give 1.3 g (98%) of the title oxime as a yellow foam.

(b) 4-[l-Hydroxy-4-(6-methyl-pyridin-2-yl)-5-(2-methyIsulfanyl-pyrimidin-4-yl)-lH- imidazol-2-yl]-bicyclo [2.2.2] octane-1-carboxylic acid methyl ester

[0129] 4-Formyl-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester (0.72 g, 2.5 mmol) was added to a solution of l-(6-methyl-pyridin-2-yl)-2-(4-methylsulfanyl-pyrimidin-2-yl)-ethane-

1,2-dione 2-oxime (0.6 g, 2.1 mmol) and ammonium acetate (3.1 g, 40 mmol) in acetic acid (30 mL). The mixture was reflux for 2 hours. Solvent was removed under reduced pressure.

Reaction mixture was then quenched with ammonia/ice mixture. The aqueous solution was extracted with ethyl acetate. Ethyl acetate was washed with brine, dried over sodium sulfate, filtered, and concentrated to 0.9 g (92%) of the title methyl ester as a yellow solid.

Example 7

4-[4-(6-MethyI-pyridin-2-yl)-5-(2-methylsulfanyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2] octane-1-carboxylic acid methyl ester

[0130] Trimethylphosphite (1.0 mL, 9.7 mmol) was added to a solution of 4-[l-hydroxy-4-(6- methyl-pyridin-2-yl)-5-(2-methylsulfanyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester (0.9 g, 1.93 mmol; see Example 6 above) in

DMF (10 mL). The mixture was stirred at 110⁰C for 18 hours. Solvent was removed to give a yellow oil. Column chromatography eluting with ethyl acetate:hexanes (50:50) gave 0.8 g

(97%) of the title compound as a yellow solid. ¹H NMR (300 MHz, DMSOd₆) δ 12.25 (s, IH),

8.51 (m, IH), 7.71 (m, 2H), 7.59 (d, IH, J = 6.0 Hz), 7.22 (t, IH, J = 3.0 Hz), 3.61 (s, 3H), 3.29

(s, 3H), 2.11 (s, 3H), 1.98 (m, 6H), 1.83 (m, 6H). MS (ES+) m/z (M+l) 450.15.

Example 8

4- [5-(2-Methanesulfonyl-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-l H-imidazol-2-yl] - bicyclo [2.2.2] octane-1-carboxylic acid methyl ester

[0131] Hydrogen peroxide (0.19 mL,6.68 mmol), 4N H₂SO₄ (0.06 mL), and NaWO₄H₂O (10 mg) were added to a solution of 4-[4-(6-methyl-pyridin-2-yl)-5-(2-methylsulfanyl-pyrimidin-4- yl)-lH-imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester (0.60 g, 1.34 mmol; see Example 7 above) in methonal (20 mL). The mixture was stirred at 50⁰C for 10 hours. The mixture was then quenched with water and stirred for 30 minutes. Saturated Na₂S₂O₃ aqueous solution was added to neutralize the excess hydrogen peroxide. The aqueous solution was extracted with ethyl acetate. Ethyl acetate was washed with brine, dried over sodium sulfate, filtered, and concentrated. Column chromatography eluting with ethyl acetate gave 0.5 g (91%) of the title compound as a yellow solid. ¹H NMR (300 MHz, Methanol-d₄) δ 8.98 (m, IH), 8.43

(m, IH), 8.22 (m, IH), 8.09 (m, IH), 7.84 (m, IH), 3.68 (s, 3H), 3.26 (s, 3H), 2.86 (s, 3H), 2.11 (m, 6h), 1.99 (m, 6H). MS (ES+) m/z (M+l) 482.02. Example 9

4-[5-(2-Methanesulfonyl-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yI]- bicyclo [2.2.2] octane-1-carboxylic acid methyl ester

[0132] 4-[5-(2-Methanesulfonyl-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-iniidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester (0.30 g, 0.62 mmol; see Example 8 above) was dissolved in cyclopropylamine (10 mL) and the mixture was placed in a sealed tube. The mixture was heated at 80⁰C for 18 hours. Solvent was removed to give 0.285 g (99%) of the title compound as a yellow solid. ¹H NMR (300 MHz, Acetone-de) δ 8.56 (m, IH), 8.49 (m, IH), 8.24 (m, IH), 7.65 (m, 2H), 3.63 (s, 3H), 2.87 (m, IH), 2.61 (s, 3H), 2.05 (m, 6H), 1.91 (m, 6H), 0.75 (m, 2H), 0.64 (m, 2H). MS (ES+) m/z (M+l) 459.17. Example 10

4-[5-(2-Cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridm-2-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2] octane-1-carboxylic acid

[0133] Lithium hydroxide monohydrate (0.10 g, 2.44 mmol) was added to 4-[5-(2- Cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester (0.28 g, 0.61 mmol) in a mixture of THFMeOHTH₂O (2/1/1, 5 mL). The mixture was stirred for 3 h. Solvent was removed. Residue was diluted with water (30 mL). Citric acid was added to the solution to make the pH lower than 7. The aqueous solution was extracted with ethyl acetate. Ethyl acetate was washed with brine, dried over sodium sulfate, filtered and concentrated to give 0.27 g (99%) of the title compound as a yellow solid. ¹H NMR (300 MHz, Methanol-d*) δ 8.50 (m, IH), 8.29 (m, 2H), 7.66 (m, IH), 7.30 (m, IH), 2.75 (m, IH), 2.65 (s, 3H), 2.07 (m, 6H), 1.97 (m, 6H), 0.86 (m, 2H), 0.62 (m, 2H). MS (ES+) m/z (M+l) 445.10. Example 11

4-[5-(2-Cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2] octane-1-carboxylic acid amide

[0134] HATU (0.17 g, 0.45 mmol) was added to a solution of 4-[5-(2-Cyclopropylamino- pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid (0.10 g, 0.225 mmol; see Example 10 above) and potassium carbonate (0.155 g, 1.13 mmol) in anhydrous DMF (5 mL). The mixture was stirred for 30 minutes. Ammonia was bubbled through the mixture for 10 minutes. The mixture was continued to stir for 2 hours. The mixture was then filtered and concentrated. HPLC purification eluting with acetonitrile: water gave 0.070 g (70%) of the title compound as a yellow solid. ¹H NMR (300 MHz, Methanol-d₄) δ 8.50 (d, IH, J = 5.7 Hz), 8.30 (m, 2H), 7.67 (m, IH), 7.32 (d, IH, J = 5.7 Hz), 2.75 (m, IH), 2.65 (s, 3H), 2.08 (m, 6H), 1.95 (m, 6H), 0.84 (m, 2H), 0.61 (m, 2H). MS (ES+) m/z (M+l) 444.21. [0135] The compounds listed in the following Table were prepared in an analogous manner to those described in the methods and examples above.

[0136] The TGF/3 inhibitory activity of compounds of formula (I) can be assessed by methods described in the following examples.

Example 34

Cell-Free Assay for Evaluating Inhibition of Autophosphorylation of TGFjS Type I

Receptor

[0137] The serine-threonine kinase activity of TGFjS 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-TGF/3RI. The His-tagged receptor cytoplasmic kinase domains were purified from infected insect cell cultures using the Gibco-BRL FastBac

HTb baculovirus expression system.

[0138] 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 μL 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 non-specific binding was defined as counts measured in the presence of EDTA or no-kinase control.

[0139] 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).

[0140] 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 50 nM.

Example 35

Cell-Free Assay for Evaluating Inhibition of Activin Type I Receptor Kinase Activity

[0141] Inhibition of the Activin type I receptor (AIk 4) kinase autophosphorylation activity by test compounds of formula (I) can be determined in a similar manner to that described above in Example 34 except that a similarly His-tagged form of AIk 4 (His-Alk 4) is used in place of the

Example 36

TGFjS Type I Receptor Ligand Displacement FIashPlate Assay

[0142] 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 MgCl₂, 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-TGFjS Type I receptor in the same assay buffer (Hepes, NaCl₂, MgCl₂, MnCl₂, DTT, and 30% Brij^® added fresh) was added to a nickel coated FIashPlate (PE, NEN catalog number: SMP107), while the control wells contained only buffer (i.e., no His-TGF/3 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 K; values of less than 10 μM; some exhibited K; values of less than 1 μM; and some even exhibited Kj values of less than 50 nM. Example 37

Assay for Evaluating Cellular Inhibition of TGF/S Signaling and Cytotoxicity [0143] Biological activity of the compounds of formula (I) was determined by measuring their ability to inhibit TGF/3-induced PAI-Luciferase reporter activity in HepG2 cells. [0144] 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 (Ix). 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 TGF/3 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 TGF/3-induced

PAI-Luciferase reporter activity in HepG2 cells. Compounds of formula (I) typically exhibited

IC₅₀ values of less 10 μM.

[0145] 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 (I) typically exhibited LD₂₅ values greater than 10 μM.

Example 38

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

[0146] 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 37 except that 100 ng/mL of activin is added to serum starved cells in place of the 2.5 ng/mL TGF/3.

Example 39

Assay for TGF/3-Induced Collagen Expression

Preparation of Immortalized Collagen Promotor-Green Fluorescent Protein Cells

[0147] 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 ofTGFβ-induced Collagen-GFP Expression

[0148] 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 (I) are then added to wells with no TGF/3 (in triplicates), as well as wells with 1 ng/mL TGF/3 (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 TGF/3-induced to non-induced for each test sample. OTHER EMBODIMENTS

[0149] 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 the following formula:

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

R¹ is heteroaryl; each R^a, independently, is alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl;

X is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or a bond;

Y is a bond, -C(O)-, -C(O)-O-, -O-C(O)-, -S(O)_P-O-, -O-S(O)_P-, -C(O)-N(R^b)-, -N(R^b)-C(O)-, -O-C(O)-N(R^b)-, -N(R^b)-C(O)-O-, -C(O)-N(R^b)-O-, -O-N(R^b)-C(O)-, -O-S(O)_p-N(R^b)-, -N(R^b)- S(O)_p-O-, -S(O)_p-N(R^b)-O-, -O-N(R^b)-S(O)_p-, -N(R^b)-C(O)-N(R^c)-, -N(R^b)-S(O)_p-N(R^c)-, -C(O)-N(R^b)-S(O)_p-, -S(O)_p-N(R^b)-C(O)-, -C(O)-N(R^b)-S(O)_p-N(R^c)-, -C(O)-O-S(O)_p-N(R^b)-, -N(R^b)-S(O)_p-N(R^c)-C(O)-, -N(R^b)-S(O)_p-O-C(O)-, -S(O)_p-N(R^b)-, -N(R^b)-S(O)_p-, -N(R^b)-, -S(0)_p-, -0-, -S-, or -(C(R^b)(R^c))_q-, wherein each of R^b and R^c, independently, is hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl; p is 1 or 2; and q is 1-4; R² is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,

(cycloalkenyl)alkyl, aryl, aralkyl, arylalkenyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkenyl, (heterocycloalkenyl)alkyl, heteroaryl, heteroaralkyl, or

(heteroaryl)alkenyl; each of A and A , independently, is N or NR ; and m is 0, 1, 2, or 3; provided that when m ≥2, two adjacent R^a groups can join together to form a 4- to 8-membered optionally substituted cyclic moiety, and further provided that if

X is a bond, then Y is a bond; R² is hydrogen or alkyl; m is 1, 2, or 3; and at least one R^a is substituted at the 2-pyrimidinyl position.

2. The compound of claim 1, wherein X is aryl or heteroaryl.

3. The compound of claim 2, wherein X is an optionally substituted phenyl.

4. The compound of claim 2, wherein Y is a bond, -N(R^b)-C(O)-, -N(R^b)-S(O)₂-, -C(O)-, -C(O)-O-, -0-C(O)-, -C(0)-N(R^b)-, -S(OV, -O-, -S(0)₂-N(R^b)-, - N(R^b)-, -N(R^b)-C(0)-0-, -N(R^b)-C(0)-N(R^c)-, -C(O)-N(R^b)-S(O)_p-N(R^c)-, or -C(0)-0-S(0)_p-N(R^b)-.

5. The compound of claim 2, wherein R² is hydrogen, C_1-6 alkyl, aryl, heteroaryl, aryl-C_1-4 alkyl, or heteroaryl-C_1-4 alkyl.

6. The compound of claim 1, wherein X is a 4- to 8-membered monocyclic or bicyclic cycloalkyl or heterocycloalkyl.

7. The compound of claim 1, wherein X is piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuran, cyclohexyl, cyclopentyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, 2-oxa-bicyclo[2.2.2]octane, 2-aza-bicyclo[2.2.2]octane, 3-aza-bicyclo[3.2.1]octane, or l-aza-bicyclo[2.2.2]octane.

8. The compound of claim 1, wherein X is piperidinyl, piperazinyl, or pyrrolidinyl.

9. The compound of claim 8, wherein the piperdinyl, piperazinyl, or pyrrolidinyl is bonded to Y via its nitrogen ring atom.

10. The compound of claim 9, wherein Y is a bond, -C(O)O-, -C(O)-N(R^b)-, -S(O)₂-, or -S(O)₂-N(R^b)-, wherein R^b is hydrogen or C_1-4 alkyl.

11. The compound of claim 1, wherein X is cyclohexyl, cyclopentyl, or bicyclo[2.2.2]octane.

12. The compound of claim 11, wherein Y is -N(R^b)-C(O)-, -N(R^b)-S(O)₂-, -C(O)-, -C(O)-O-, -O-C(O)-, -C(O)-N(R^b)-, -S(O)p-, -O-, -S(0)₂-N(R^b)-, - N(R^b)-, -N(R^b)-C(O)-O-, -C(0)-N(R^b)-0-, or -N(R^b)-C(O)-N(R^c)-.

13. The compound of claim 1, wherein Y is -N(R^b)-C(0)-, -N(R^b)-S(O)₂-, -C(O)-, -C(O)-O-, -O-C(O)-, -C(0)-N(R^b)-, -S(O)p-, -0-, -S(O)₂-N(R^b)-, - N(R^b)-, -N(R^b)-C(0)-0-, -C(O)- N(R^b)-0-, -N(R^b)-C(0)-N(R^c)-, -C(0)-N(R^b)-S(0)_p-N(R°)-, or -C(O)-O-S(O)_p-N(R^b)-.

14. The compound of claim 1, wherein X and Y are each a bond; R² is hydrogen or C_1-6 alkyl; m is 1 or 2; and the R^a that is substituted at the 2-pyrimidinyl position is C_1-4 alkyl, C_3-6 cycloalkyl, or amino.

15. The compound of claim 14, wherein R² is H or C_1-4 alkyl; m is 1; and R^a is -CH₃, -CF₃, cyclopropyl, -NH₂, -NH-C_1-4 alkyl, or -NH-cycloalkyl.

16. The compound of claim 1, wherein R² is hydrogen, C_1-6 alkyl, aryl, heteroaryl, aryl-C_1-4 alkyl, or heteroaryl-C_1-4 alkyl.

17. The compound of claim 1, wherein R² is hydrogen, C_1-4 alkyl, phenyl, pyridyl, imidazolyl, furanyl, thienyl, triazolyl, tetrazolyl, benzyl, phenylethyl, benzimidazolyl, benzothiazolyl, naphthylmethyl, naphthylethyl, or -C_1-2 alkyl-pyridyl; each of which, independently, is optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, methyl, ethyl, aminocarbonyl, alkylcarbonylamino, sulfamoyl, alkoxycarbonyl, and alkylcarbonyloxy.

18. The compound of claim 1, wherein R² is hydrogen, methyl, ethyl, n-butyl, t-butyl, benzyl or pyridylmethyl.

19. The compound of claim 1, wherein R¹ is benzo[l,3]dioxolyl, benzo[£]thiophenyl, benzo-oxadiazolyl, benzothiadiazolyl, benzoimidazolyl, benzooxazolyl, benzothiazolyl, 2-oxo-benzooxazolyl, pyridyl, pyrimidinyl, 2,3-dihydro-benzo[l,4]dioxyl, 2,3-dihydro-benzofuryl, 2,3-dihydro-benzo[έ]thiophenyl, 3,4-dihydro-benzo[l,4]oxazinyl, 3-oxo-benzo[l,4]oxazinyl, l,l-dioxo-2,3-dihydro- benzo[ό]thiophenyl, [l,2,4]triazolo[l,5-a]pyridyl, [l,2,4]triazolo[4,3-a]pyridyl, quinolinyl, quinoxalinyl, quinazolinyl, isoquinolinyl, or cinnolinyl.

20. The compound of claim 1, wherein m is 0-2.

21. The compound of claim 1, wherein R^a is substituted at the 2-pyrimidinyl position.

22. The compound of claim 1, wherein R^a is C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, halo, amino, aminocarbonyl, or alkoxycarbonyl.

23. The compound of claim 1, wherein R^b is hydrogen or C_1-4 alkyl.

24. The compound of claim 1, wherein m is 0-2; R¹ is heteroaryl; R² is hydrogen, C_1-6 alkyl, aryl, heteroaryl, -C_1-4 alkyl-aryl, or -C_1-4 alkyl-heteroaryl; X is a 4- to 8-membered monocyclic or bicyclic cycloalkyl or heterocycloalkyl; and Y is -N(R^b)-C(O)-, -N(R^b)-S(O)₂-, -C(O)-, -C(O)-O-, -O-C(O)-, -C(O)-N(R^b)-, -S(O)_P-, -O-, -S(O)₂-N(R^b)-, -N(R^b)-, -N(R^b)-C(O)-O-, -N(R^b)-C(O)-N(R^c)-, -C(O)-N(R^b)-S(O)_p-N(R^c)-, or -C(O)-O-S(O)_p-N(R^b)-.

1 0

25. The compound of claim 1, wherein m is 0-2; R is heteroaryl; R is hydrogen, C_1-6 alkyl, aryl, heteroaryl, -C_1-4 alkyl-aryl, or -C_1-4 alkyl-heteroaryl; X is piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuran, cyclohexyl, cyclopentyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, 2-oxa-bicyclo[2.2.2]octane, 2-aza-bicyclo[2.2.2]octane, 3-aza-bicyclo[3.2.1]octane, or l-aza-bicyclo[2.2.2]octane; and Y is -N(R^b)-C(O)-, -N(R^b)-S(O)₂-, -C(O)-, -C(O)-O-, -0-C(O)-, -C(0)-N(R^b)-, -S(O)_P-, -O-, -S(O)₂-N(R^b)-, - N(R^b)-, -N(R^b)-C(0)-0-, -N(R^b)-C(O)-N(R^c)-, -C(O)-N(R^b)-S(O)_p-N(R^c)-, or -C(O)-O-S(O)_p-N(R^b)-.

26. The compound of claim 1, wherein m is 0-2; R¹ is heteroaryl; R² is hydrogen, C_1-6 alkyl, aryl, heteroaryl, -C_1-4 alkyl-aryl, or -C_1-4 alkyl-heteroaryl; and -X-Y- is

27. The compound of claim 26, wherein A¹ is N and A² is NH, or A¹ is NH and A² is N.

28. The compound of claim 27, wherein R² is hydrogen, C_1-4 alkyl, benzyl, or pyridylmethyl.

29. The compound of claim 28, wherein m is 1 and R^a is substituted at the 2-pyrimidinyl position.

30. The compound of claim 1, wherein m is 0-2; R¹ is heteroaryl; R² is hydrogen, C_1-6 alkyl, aryl, heteroaryl, aryl-C_1-4 alkyl, or heteroaryl-C_1-4 alkyl; X is cyclohexyl, cyclopentyl, or bicyclo[2.2.2]octane; and Y is -N(R^b)-C(0)-, -N(R^b)-S(O)₂-, -C(O)-, -C(O)-O-, -O-C(O)-, -C(0)-N(R^b)-, -S(OV, -O-, -S(O)₂-N(R^b)-, - N(R^b)-, -N(R^b)-C(0)-0-, -N(R^b)-C(O)-N(R^c)-, -C(O)-N(R^b)-S(O)p-N(R^c)-, or -C(O)-O-S(O)_p-N(R^b)-, wherein each of R^b and R^c, independently, is hydrogen or C_1-4 alkyl.

31. The compound of claim 30, wherein A¹ is N and A² is NH, or A¹ is NH and A² is N.

32. The compound of claim 31, wherein R² is hydrogen, C_1-4 alkyl, benzyl, or pyridylmethyl.

33. The compound of claim 32, wherein m is 1 and R^a is substituted at the 2-pyrimidinyl position.

34. The compound of claim 1, wherein X and Y are each a bond; R² is hydrogen or C_1-4 alkyl; m is 1; R^a is -CH₃, -CF₃, cyclopropyl, -NH₂, -NH-C_1-4 alkyl, or -NH-cycloalkyl; and R¹ is benzo[l,3]dioxolyl, benzo[ό]thiophenyl, benzo-oxadiazolyl, benzothiadiazolyl, benzoimidazolyl, benzooxazolyl, benzothiazolyl, 2-oxo-benzooxazolyl, pyridyl, pyrimidinyl, 2,3-dihydro-benzo[l,4]dioxyl, 2,3-dihydro-benzofuryl, 2,3-dihydro-benzo[έ]thiophenyl,

3 ,4-dihydro-benzo [ 1 ,4] oxazinyl, 3-oxo-benzo[ 1 ,4]oxazinyl, 1 , 1 -dioxo-2,3 -dihydro- benzo[δ]thiophenyl, [l,2,4]triazolo[l,5-a]pyridyl, [l,2,4]triazolo[4,3-a]pyridyl, quinolinyl, quinoxalinyl, quinazolinyl, isoquinolinyl, or cinnolinyl.

35. The compound of claim 1, wherein the compound is selected from the group consisting of:

4- [4-benzo [ 1 ,3] dioxol-5-yl-5-(2-methylsulfanyl-pyrimidin-4-yl)- 1 H-imidazol-2-yl] - benzamide;

4-[4-benzo[l,3]dioxol-5-yl-5-(2-methylsulfanyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- benzonitrile;

4-[5-(2-methanesulfonyl-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;

4-[5-(2-methoxy-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;

4-[5-(2-hydroxy-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;

4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;

4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2] octane- 1 -carboxylic acid;

4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide; 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;

4-[5-(2-cyclopropylammo-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methoxy-amide;

4- [5 -(2-amino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)- 1 H-imidazol-2-yl] - bicyclo [2.2.2] octane- 1 -carboxylic acid;

{4-[5-(2-cyclopropylaniino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]oct-l-yl}-carbamic acid benzyl ester;

N-{4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]oct-l-yl}-acetamide;

N-{4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridm-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]oct-l-yl}-methanesulfonamide;

N-{4-[5-(2-cyclopropylammo-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-iniidazol-2- yl]-bicyclo[2.2.2]oct-l-yl}-2,2,2-trifluoro-acetamide;

4-[5-quinoxalm-6-yl-4-(2-trifluoromethyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol;

4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-qumoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol;

6-[2-tert-butyl-5-(2-cyclopropyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;

6-[5-(2-byclopropyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;

{4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]oct- 1 -yl} -methanol;

6-[5-(2-trifluoromethyl-pyriniidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;

6-[2-tert-butyl-5-(2-trifluoromethyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;

4-[5-quinoxalin-6-yl-4-(2-trifluoromethyl-pyrimidin-4-yl)-lH-imidazol-2-yl]-piperidine-

1 -carboxylic acid benzyl ester;

4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;

6-[5-(2-cyclopropyl-pyrimidin-4-yl)-2-(l-metrianesulfonyl-piperidin-4-yl)-3H-imidazol-

4-yl] -quinoxaline;

4-[5-(2-methyl-pyrimidin-4-yl)-4-[l,2,4]triazolo[4,3-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol; 4-[4-(2-methyl-pyrimidm-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;

4-[4-(2-methyl-pyrimidin-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo [2.2.2] octane- 1 -carboxylic acid;

4- [4-(2-methyl-pyrimidin-4-yl)-5 - [ 1 ,2,4] triazolo [ 1 ,5 -a]pyridin-6-yl- 1 H-imidazol-2-yl] - bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;

4-[4-(2-methyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-cyclohexanol; and

4-[4-(2-methyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-bicyclo[2.2.2]octan- l-ol.

36. The compound of claim 1, wherein the compound is selected from the group consisting of:

4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;

4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2] octane- 1 -carboxylic acid;

4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;

4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;

4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridm-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methoxy-amide;

4-[5-(2-amino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid;

N-{4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]oct-l-yl}-acetamide;

N-{4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl] -bicyclo [2.2.2] oct- 1 -yl } -methanesulfonamide ;

N-{4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]oct-l-yl}-2,2,2-trifluoro-acetamide;

6-[2-tert-butyl-5-(2-trifluoromethyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;

6-[5-(2-byclopropyl-pyrimidm-4-yl)-3H-imidazol-4-yl]-quinoxaline; 6-[2-tert-butyl-5-(2-cyclopropyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;

6-[5-(2-cyclopropyl-pyrimidin-4-yl)-2-(l-methanesulfonyl-piperidin-4-yl)-3H-imidazol-

4-yl] -quinoxaline;

6-[5-(2-trifluoromethyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;

{4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-methanol;

4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol;

4-[4-(2-methyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-bicyclo[2.2.2]octan- l-ol;

4-[4-(2-methyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-cycloliexanol;

4-[4-(2-metb.yl-pyrimidin-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;

4-[4-(2-meth.yl-pyrimidin-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid;

4-[4-(2-methyl-pyrimidin-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester; and

4-[5-(2-methyl-pyrimidin-4-yl)-4-[l,2,4]triazolo[4,3-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol.

37. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

38. A pharmaceutical composition comprising a compound of claim 35 and a pharmaceutically acceptable carrier.

39. A method of inhibiting the TGF/3 signaling pathway in a subject, comprising administering to the subject an effective amount of a compound of claim 1.

40. A method of inhibiting the TGF/3 signaling pathway in a subject, comprising administering to the subject an effective amount of a compound of claim 35.

41. A method of inhibiting the TGF/3 type I receptor in a cell, comprising contacting the cell with an effective amount of a compound of claim 1.

42. A method of inhibiting the TGF/3 type I receptor in a cell, comprising contacting the cell with an effective amount of a compound of claim 35.

43. A method of reducing the accumulation of excess extracellular matrix induced by TGF/3 in a subject, comprising administering to the subject an effective amount of a compound of claim 1.

44. A method of reducing the accumulation of excess extracellular matrix induced by TGF/3 in a subject, comprising administering to the subject an effective amount of a compound of claim 35.

45. A method of treating or preventing fibrotic condition in a subject, comprising administering to the subject an effective amount of a compound of claim 1.

46. A method of treating or preventing fibrotic condition in a subject, comprising administering to the subject an effective amount of a compound of claim 35.

47. The method of claim 45 or 46, wherein the fibrotic condition is induced by radiation.

48. The method of claim 45 or 46, wherein the fibrotic condition is selected from the group consisting of scleroderma, lupus nephritis, connective tissue disease, wound healing, surgical scarring, spinal cord injury, CNS scarring, acute lung injury, idiopathic pulmonary fibrosis, radiation-induced pulmonary fibrosis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, diabetic nephropathy, hypertension-induced nephropathy, alimentary track or gastrointestinal fibrosis, renal fibrosis, hepatic or biliary fibrosis, liver cirrhosis, primary biliary cirrhosis, fatty liver disease, primary sclerosing cholangitis, restenosis, cardiac fibrosis, opthalmic scarring, fibrosclerosis, a fibrotic cancer, a fibroid, fibroma, a fibroadenoma, a fibrosarcoma, transplant arteriopathy, and keloid.

49. A method of inhibiting growth or metastasis of tumor cells or cancer in a subject, comprising administering to the subject an effective amount of a compound of claim 1.

50. A method of inhibiting growth or metastasis of tumor cells or cancer in a subject, comprising administering to the subject an effective amount of a compound of claim 35.

51. A method of treating a disease or disorder mediated by an overexpression of TGFjS, comprising administering to a subject in need of such treatment an effective amount of a compound of claim 1.

52. A method of treating a disease or disorder mediated by an overexpression of TGFjS, comprising administering to a subject in need of such treatment an effective amount of a compound of claim 35.

53. The method of claim 51 or 52, wherein the disease or disorder is selected from the group consisting of demyelination of neurons in multiple sclerosis, Alzheimer's disease, cerebral angiopathy, squamous cell carcinomas, multiple myeloma, melanoma, glioma, glioblastomas, leukemia, sarcomas, leiomyomas, mesothelioma, and carcinomas of the lung, breast, ovary, cervix, liver, biliary tract, gastrointestinal tract, pancreas, prostate, and head and neck.