Title of Invention

"A PYRIDINYLPYRAZOLE COMPOUND"

Abstract

A pyridinylpyrazole compound of the following formula: wherein each of X1, X2, X3, and X4 is independently CRX or N; provided that only two of X1, X2, X3, and X4, can be N simultaneously; each of Y1 and Y2 is independently CRy or N; provided that at least one of Y1 and Y2 must be N; R1 and R2 are as herein described, m is 0, 1,2, 3, or 4; provided that when m > 2, two adjacent R1 groups can join together to form a 4- to 8-membered optionally substituted cyclic moiety; n is 0, 1, 2, or 3; provided that when n > 2, two adjacent R2 groups can join together to form a 4- to 8-membered optionally substituted cyclic moiety.

Full Text

The present invention relates to a pyridinylpyrazole compound. This non-provisional application claims benefit of priority of U.S. provisional application 60/408,811, filed September 6, 2002. BACKGROUND OF THE INVENTION TGFß (Transforming Growth Factor ß) is a member of a large family of dimeric polypeptide growth factors that includes activins, inhibins, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and mullerian inhibiting substance (MIS). TGFß exists in three isoforms (TGFßl, TGFß2, and TGFß3) and is present in most cells, along with its receptors. Each isoform is expressed in both a tissue-specific and developmentally regulated fashion. Each TGFß 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 TGFß. LAP is typically non-covalently associated with mature TGFß prior to secretion from the cell. The LAP- TGFß complex cannot bind to the TGFß receptors and is not biologically active. TGFß is generally released (and activated) from the complex by a variety of mechanisms including interaction with thrombospondin-1 or plasmin. Following activation, TGFß binds at high affinity to the type II receptor (TGFßRII), a. constitutively active serine/threonine kinase. The ligand-bound type II receptor phosphorylates the TGFß type I receptor (Alk 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., Mol. 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 TGFß-responsive genes. See, e.g., Massague, J. Arm. Rev .Biochem. Med. 67: 773 (1998). Activins are also members of the TGFß superfamily which are distinct from TGFß in that they are homo- or heterodimers of activin ßa or ßb. Activins signal in a similar manner to TGFfJ, that is, by binding to a constitutive serine-threonine receptor kinase, acttvin type II receptor (ActRIIB), and activating a type I serine=-threonine receptor, Allc 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. Indeed, TGFp 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 TGFp 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 librosis (see, e.g., Matsuse, T. et at., Am. J. Respir. C&llMol. Biol. 13: 17-24 (1995); Inoue, S. et al, Biochem. Biophys. Res. Comm. 205: 441-448 (1994); Matsuse, T. et al, Am../. Patliol. 148: 707-713 (1996); D.e Bleser et at., Hepatology 26: 905-912 (1997); Pawlowski, I.E., et al., J. dm. Invest. 100: 639-648 (1997), Sugiyama, M, et al., Gasfroenterology 114: 550-558 (1998); Munz, B. et al., EkfBOJ. 18: 5205-5215 (1999)) and inflammatory responses (see, e.g., Rosendahl, A. et al., Am. J. Repir. CellMol. Biol. 25: 60-68 (2001)). Studies have shown that TGFp and activin can act synergistically to induce extracellular matrix (see, e.g., Sugiyama, M. et al., Gastroenterology 114: 550-558, (1998)). It is therefore desirable to develop modulators (e.g., antagonists) to signaling pathway components of the TGF(3 family to prevent/treat disorders related to the malfunctioning of this signaling pathway. SUMMARY OF THE INVENTION Compounds of formula (I) are unexpectedly potent antagonists of the TGFp family type I receptors, Alk5 and/or Alk 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 TGFp family signaling activity is desirable. In one aspect, the invention features a compound of formula I: (I) Each of XL, X2, Xj, and X/i is independently CRX or N, provided that only two of Xj, Xj., X-j, and ^4 can beN simultaneously. Each of YI and YT is independently CRy or N, provided that at least one of YL and Yi must be N. In other words, the ring having YI and YI ring atoms can be a pyrimidinyl or pyridyl. Each R1 is independently aikyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulliinyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarboriyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl. Each R2 is independently alkyl, alkenyl, alkynyl, acyl, halo, hydroxy, -NH2; -NH(alkyl), -N(alkyl)2; -NH(cycloalkyl), -N(alkyl)(cycloalkyl), -NH(heterocycloalkyl), -NH(heteroaryl), -NH-alkyl-heterocycloalkyl, -NH-alkyl-heteroaryl, -NH(aralkyl), cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, aroyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, heteroaralkyl, heteroaroyl, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkoxy, cycloalkyloxy, cycloalkyl-alkoxy, aryloxy, arylalkoxy, heterocycloalkyloxy, (heterocycloalkyl)alkoxy, heteroaryloxy, heteroarylalkoxy, alkylsulfanyl, cycloalkylsulfanyl, (cycloalkyl)alkylsulfanyl, arylsulfanyl, aralkylsulfanyl, heterocycloalkylsulfanyl, (heterocycloalkyl)alkylsulfanyl, heteroarylsulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, alkylcarbonylamino, cycioalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkoxycarbonylaminoalkylamino, (heteroaryl)arylcarbonylaminoalkylamino, heteroaralkylcarbonyiaminoalkylamino, (heteroaryl)arylsulibnylamiaoalkylcarbonylaminoalkylamino, arylsulfonylaminoalkylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, or carbamoyl. m is 0, I, 2, 3, or 4; provided that when m > 2, two adjacent R1 groups can join together to form a 4- to 8-membered optionally substituted cyclic moiety, n is 0, 1, 2, or 3, provided that when n > 2, two adjacent R2 groups can join together to form a 4- Lo S-memberecLoptionally substituted cyclic moiety. See examples of the 4- to S-membered optionally substituted cyclic moiety below. Each of R* and Ry is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, cycloalkylcarbonyl, (cycloalkyl)alkylcarbonyl, aroyl, aralkylcarbonyl, heterocycloalkylcarbonyl, (heterocycloalkyl)acyl, heteroaroyl, (heteroaryl)acyl, aminocarbonyl, alkylcarbonylamino, (amino)aminocarbonyl, alkylsulfonylaminocarbonyl, alkylsulfonylamino, cycioalkylcarbonylamino, cycloalkylsulfonylamino, (cycloalkyl)alkylcarbonylamino, (cycloalkyl)alkylsulfonylamino, arj'lcarbonylamino, arylsulfonylamino, aralkylcarbonylamino., aralkylsulfonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)sulfonylamino, (heterocycloalkyl)alkylcarbonylamino, (heterocycloalkyl)alkylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfonylamino, heteroaralkylcarbonylamino, heteroaralkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfarnoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, (cycloalkyl)alkyl, (cycloalkyl)alkoxy., (cycloalkyl)alkylsulfanyl, hetero.cycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, (heterocycloalkyl)alkyl, (heterocycloalkyl)alkoxy, (heterocycloalkyl)alkylsulfanyl, aryl, aryloxy, arylsulfanyl, aralkyl, aralkyloxy, aralkylsulfanyl, arylalkenyl, arylalkynyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, heteroaralkyl, (heteroaryl)alkoxy, or (heteroaryl)alkylsulfanyl. As defined above, when ni > 2, two adjacent R1 groups can join together to form a 4- to 8-membered optionally substituted cyclic moiety. That is, the 2-pyridyl ring can 'fuse with a 4- to 8-membered cyclic moiety to form a moiety such as 7H-[IJpyrindinyl, 6)7-dihydro-5H-[l]pyrindinyl, 5,6,7,8-tetrahydro-quinolinyl, 5,7-dihydro-furo[3,4-blpyridinyl, or 3,4-dihydro-lH-thiopyrano[4,3-c]pyridinyl. The fused ring moiety can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl; see defmiton of "alkyl" below), alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, 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, sulfarnoyl, sulfamide, oxo, or carbamoyl. Similarly, when n > 2, two adjacent R" groups can join together to form a 4- to 8-membered optionally substituted cyclic moiety, thereby forming a ring fused with the pyridyl or pyrimidinyl group. Some examples of such a moiety are shown below: (Figure Removed) The 4- to 8-membered cyclic moiety formed by two adjacent R2 groups can be optionally substituted with substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl; see definiton of "alkyl" below), alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, allcylcarbonylamino, cycloalkylcarbonylamino, cycloalkyl-alkylcarbonylaminovarylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl-carbonylamino, heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. In one embodiment, each of Xi, X2, Xs, and X,i is independently CRX. In one embodiment, each of X2, X3j and X4 is independently -CH-, -C(CH3)-, -C(OH)-, -C(NH2)-, -C(CO-NH2)-, -C(CO-NHOH)-, -C(NH(unsubstituted alkyl))-, -C(MI(aryl))-, -C(NH(aralkyl))-, -C(NH(heteroaryl))-, -C(NH(heteroarylalkyl))-, -C(NH-CO-(unsubstituted alkyl))-, -C(NH-CO-(aryl))-, -C(NH-CO-(heteroaryl))-, -C(NH-CO-(aralkyl))-, -G(NH-CO-(heteroarylalkyl))-, -C(NH-SO2-(unsubstituted alkyl))-, -C(NH-SO2-(aryl))-1 -C(NH-S02-(heteroaryl))~, -C(NIi-SO2-(aralkyl))-, -CCNH-SO2-(heteroarylalkyl))-, -C(NH-S02-NH(unsubstituted alkyl))-, -C(NH-S02-NH(aryl))-, -C(NH-SO2-NH(heteroaryl))-, -C(NH-SO2-NH(aralkyl))-, -C(NH-S02-NH(heteroarylalkyl))-, -C(hydroxyalkyl)-, or -C(carboxy)-, and Xi is -CH- In one embodiment, both Y] are Y2 areN. In one embodiment, m is 0, 1, or 2 (e.g., m is 1). In one embodiment, R1 is substituted at the 5-position or the 6-position (i.e., R1 can be mono-substituted at either the 5-position or the 6-position or R1 can be di-substituted at both the 5- and the 6-positions). In one embodiment, R1 is CM alkyl, CM alkoxy, CM alkylthio, halo, amino, aminocarbonyl, or alkoxycarbonyl. In one embodiment, n is 1 or 2 (e.g., n is 1). In one embodiment, each R1 is independently unsubstituted allcyl (e.g., 6-inethyl, 6-ethyl, 6-n-propyl, or 6-isopropyl), hydroxyalkyl, haloalkyl (e,g., 6-trifluoromethyl)3 aminoalkyl, aryloxyalkyl, heteroaralkyloxyalkyl, unsubstituted alkenyl (e.g., 6-vinyl), alkoxy, acyi, halo, hydroxy., carboxy, cyano, guanadino, amidino, amino (e.g., -NH/j, monoalkylamino, dialkylamino, monoheterocycloalkylamino, monoheteroarylamino, mono(heterocyclylalkyl)amino, , mono(ara1kyl)amino, or mono(heteroaralkyl)amino), carboxy, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl (e.g., -COMJ.2, -CONH(alkyl), or--CO-N(alkyfb), alkylcarbonylamino (e.g., -NH-CO-alkyl or -N(alkyl)-CO-alkyl), alkoxycarbonyl, alkylcarbonyloxy, alkylsulfonyl, sulfamoyl (e.g., -SO2-NH2, -SO2-NH(alkyl), or -S02-N(alkyl)2), cycloalkyl (e.g., 6-cyclopropyl), heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, or heteroaralkyl. in one embodiment, each R2 is independently unsubstituted alkyl, hydroxyalkyl, haloalkyl, aminoalkyl (e.g., aminomethyl), aryloxyalkyl, heteroaralkyloxyalkyl, alkoxy, acyl, halo, hydroxy, carboxy, cyano, guanadino, amidino, -NH2, monoalkylamino, dialkylamino, monocycloalkylamino, monoheterocycloalkylamino (e.g., -Nli-piperidinyl Qr -NH-morpholino), monoheteroarylamino (e.g., -NH-tetrazolyl, -NH-pyrazolyl, or -NH-irnidazolyl), mono((heterocycloalkyl)alkyl)amino (e.g., -NH-(CH2)i-3-piperidinyl or -NH-(CH2)i-3-morpholino), mono(hetevoaralkyl)amino (e.g., -NH-(CH2)i-3-tetrazolyl, -NH-(CIl2)i-3-pyrazolyl, or ~NH-(CH2)]-3~imidazolyl), -N(alkyl)(cycloalkyl), mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -CONH2, -CONH(alkyl), -C0-N(alkyl)2> -NH-CO-alkyl, -N(alkyl)-CO-alkyl, -CO2-alkyl, -0-CO-alkyl, -S02-NH2, -SO2-NH(alkyl), -SO2-N(alkyl)2l -NH-S02-alkyl, -N(alkyl)-S02-alkyl, -NH-CO-NH(alkyl), -N(alkyl)-CO-NH(alkyl), -NH-SO2-NH(alkyl), -N(alkyl)-SO2-NH(alkyl), heterocycloalkyl, or heteroaryl (e.g., imidazolyl, pyrazolyl, tetrazolyl, or pyridyl). For example, R2 is substituted at the 3-position and is guanadino, amidino, -NH2, monoalkylamino, dialkylamino, monocycloalkylamino, monoheterocycloalkylamino, monoheteroarylamino, rnono((heterocycloalkyl)alkyl)amino, mono(heteroaralkyl)amino, -NH-CO-NH(alkyl), -N(alkyl)-CO-NH(alkyl), -NH-SO2-NH(alkyl)) -N(alkyl)-SO2-NH(alkyl), heterocycloalkyl, or heteroaryl. In one embodiment, each Rx is independently hydrogen, unsubstituted alkyl, hydroxyalkyl (e.g., hydroxy-CM alkyl such as hydroxyethyl),, haloalkyl (e.g., trifluoromethyl), aminoalkyl, aryloxyalkyl, heteroaralkyloxyalkyl, alkoxy (e.g., Ci.4 alkoxy such as methoxy or €.1.4 haloalkoxy such as -OCF3), halo (e.g., chloro or bromo), hydroxy, carboxy, cyano, guanadino, amidino, amino (e.g., -NH2, -Nll(alkyl), -N(alkyl)2, -NH(heterocycloalkyl), -NH(heteroaryl), -NH(heterocycloalkyl-alkyl), -NH(aralkyl), or -NH(heteroaralkyl)), carboxy, (heteroaryl)acyl, aminocarbonyl (e.g., -CO-NH2, -CO-NH-(CH2)0-3-COOH, -CO-NH-(CH2)0.3-OH, -CO-NtI-(CH2)o-3-heteroaryl (e.g., -CO-NH-(CH2y3-tetrazolyl, -CO-NH-(CH2)0.3-pyrazolyl, or -CO-NH-(CH2)0.3-imidazolyl), -CO-Nli-(CH2)o-3~heterocycloalkyl (e.g., -CO-NH-(CH2)0-3-piperidinyl or -CO-NH-(CH2)o-rmorpholino), or -CO-NH-(CH2)o-3-aryl (e.g., -CO-NH-(CH2)0-3-phenyl), heteroarylcarbonylamino, (heterocycloalkyl)alkoxy, (heteroaryl)alkoxy, (heteroaryl)alkylsulfanyl, heterocycloalkyl (e.g., morpholino, pyrazinyl, or piperidinyl), (heteroc}'cloalkyl)alkyl (e.g., morpholino-Ci-4 alkyl, pyrazinyl-Ci-4 alkyl, or piperidinyl-Ci-4 alkyl), heteroaryl (e.g., imidazolyl, pyrazolyl, tetrazolyl, or pyridyl), or heteroaralkyl (e.g., imidazolyl-Ci-4 alkyl, pyrazolyl-Ci.4 alkyl, tetrazolyl-Ci-4 alkyl, or pyridyI-Ci-4 alkyl). Some examples of -NH(alkyl) are -NH(haloalkyl) (e.g., -NHCF3), -NH(carboxyalkyl) (e.g., -NH(CH2),.3COOH), and -NH(hydroxyalkyl) (e.g., -NH(CH2)].3OH). Some examples of-NH(heteroaryl) are -NH(tetrazolyl), -NH(pyrazolyl), and -NH(imidazolyl). Some examples of -NH(heterocycloalkyl-alkyl) are -NH(piperazinylalkyl) (e.g., -NH(CH2)i.3-piperizine) and -NH(morpholino-alkyl) (e.g., -NlI(CH2)i-3-morpholine). Some examples of -NH(heteroaralkyl) are -iNH(tetrazolylalkyl) (e.g., -NH(CH2)i.3-tetrazole), -NH(pyrazolyl-alkyl) (e.g., -NH(CH2)o-3-pyi"azole), and -NH(imidazolyl-alkyl) (e.g., -NH(CH2)o-3-imidazole). In one embodiment, Ry is hydrogen, unsubstituted alkyl, hydroxyalkyl, haloalkyl (e.g., trifluoromethyl), aminoalkyl, aryloxyalkyl, heteroaralkyloxyalkyl, alkoxy, halo, hydroxy, carboxy, cyano, guanadino, amidino, amino (e.g., -NHi, -NH(alkyl), -N(alkyl)2, -NH(cycloalkyl), -NH(heterocycloalkyl), -NH(heteroaryl), -NH(heterocycloalkyl-alkyl), -NH(aralkyl), or -NH(heteroaralkyl)), carboxy, (heteroaryl)acyl, aminocarbonyl, heteroarylcarbonylamino, (heterocycloalkyl)alkoxy, (heteroaryl)alkoxy, (heteroaryl)alkylsulfanyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, or heteroaralkyl. In one embodiment, Xi isN. For example, Xi isN and each of Xa, X3, and X4 is independently CRX. In one embodiment, Xj is N, For example, Xo is N and each of Xi, Xa, and X4 is independently CRX. In one embodiment, XT, is N. For example, Xa is N and each of Xj, X2, and X^i is independently CRIn one embodiment, X4 is N. For example, X4 is N and each of Xi, Xi, and Xj is independently CRX. Some examples of a compound of formula (I) are 4-(2-pyridin-2-yl-pyrazolo[l,5-a]pyridm-3-yl)-pyrimidin-2-ylamine, 4-[2-(6-methyl-pyridin-2-yl)-pyra?.olo[l,5-a]pyridin-3-yl]-pyrimidin-2-ylamine, 2-(6-methyl-pyriclin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-pyrazolo[l,5-a]pyridine, 4-[2-(6-chloro-pyridin-2-yl)~ pyrazolo[l,5-c]pyrimidin-3-yl]-pyrimidin-2-ylamine, 2-(6-methyl-pyridin-2-yl)-3-(2-morpholin-4-yl-pyrimidin-4-yl)-pyrazolo[l)5-c]pyrimidine, 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyrazin-3-ylj-pynmidin-2-ylamme, 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyrimidin-3-yl]-pyrimidin-2-ylamine, and 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[L5-c]pyrimidin-3-yl]-pyrimidin-2-ylamine. An A^-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 HaOj. 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 N-methylglycamine. A compound of formula (I) can be treated with an acid to form acid addition salts. Examples of such an acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, p-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 a skilled person 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 (I) can also be, e.g., in a form of achiral compounds, racemic mixtures, optically active compounds, pure diastereomers, or a mixture of diastereomers. Compounds of formula (I) exhibit surprisingly high affinity to the TGF(3 family type I receptors, Alk 5 and/or Alk 4, e.g., with an ICso value of less than 10 |jM under conditions as described in Examples 2 and 3 below. Some compounds of formula (I) exhibit an ICso value of below 0.1 \iM. 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, esterification with polyethylene glycols, derivatization with pivolates or fatty acid substituents, conversion to carbamates, hydroxylation of aromatic rings, and heteroatom-substitution in aromatic rings. In another aspect, the present invention features a pharmaceutical composition comprising a compound of formula (I) (or a combination of two or more compounds of formula (I)) and a pharmaceutically acceptable carrier. AJso 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. In a further aspect, the invention features a method of inhibiting the TGFp family type I receptors, Alk 5 and/or AJk 4 (e.g., with an ICso value of less than 10 uM; preferably, less than 1 uM, more preferably, less than 0.1 uM) in a cell, including the step of contacting the cell with an effective amount of one or more compounds of formula (I). Also with the scope of the invention is a method of inhibiting the TGFp and/or activin signaling pathway in a cell or in a subject (e.g., a mammal such as human), including the step of contacting the cell with or administering to the subject an effective amount of one or more of a compound of formula (I). 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 TGFp and/or activin activity (e.g., from an overexpression of TGFP). 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 (e.g., scleroderma, lupus nephritis, connective tissue disease, wound healing, surgical scarring, spinal cord injury, CNS scarring, acute lung injury, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, diabetic nephropathy, hypertension-induced nephropathy, hepatic or biliary fibrosis, 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, and keloid), demyelination of neurons multiple sclerosis; Alzheimer's disease; cerebral angiopathy; and TGFP-induced metastasis of tumor cells and carcinomas (e.g, squamous cell carcinomas, multiple myeloma, melanoma, ghoma, glioblastomas, leukemia, and carcinomas of the lung, breast, ovary, cervix, liver, biliary tract, gastrointestinal tract,, pancreas, prostate, and head and neck). As used herein, an "alky!" 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-ethyIhexyl. An alkyl group can be optionally substituted with one or more substituents such as atkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfony], aminocarbonyl, alkylcarbonylamino. cycloalkylcarbonylamino, cycloalkyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarboriylamino, heterocycloalkyl-carbonylamino., heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, or alkylcarbonyloxy. 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, cyanb, halo, hydroxy, sulfo, mercapto, alkylsulfanyl, alkyl sulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, cycloalkyicarbonylamino, cycloalkyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl-carbonylamino, heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, or alkylcarbonyloxy. 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, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, cycloallcyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl-carbonylamino, heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, urea, thiourea, sulfarnoyl, sulfamide, alkoxycarbonyl, or alkylcarboriyloxy. As used herein, an "amino" group refers to -NR" R wherein each of Rx and K? is independently hydrogen, hydroxyl, alkyl, alkoxy, 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 -NRX-. Rx has the same meaning as defined above. 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^x carbocyclic moieties, e.g., 1, 2t 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. As used herein, an "aralkyl" group refers to an alkyl group (e.g., a d-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. 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 bicj'clo[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 trifluorornethyl), 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)carbonylamiiio, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbam,oyl. As used herein, a "heterocycloalkyl" group refers to a 3- to 10-membered (e.g., 4- to 8-membered) saturated ring staicture, 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-chrornenyl, octahydro-thiochromenyl, octahydro-indolyl, octahydro-pyrindinyl, decahydro-quinolinyl, octahydro-benzo[6]thiophenyl, 2-oxa-bicyclo[2.2.2]octyl, 1-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 S-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, 0, or S. A heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or.rnore 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. 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, fur'yl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, iudolyl, tetrazolyl, benzofuryl, berizthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, and benzo[l,3]dioxole. A heteroaiyl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyi), 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 CM alkyl group) that is substiLuted with a heteroaryl group. Both "alkyl" and "heteroaryl" have been defined above, As used herein, "cyclic moiety" includes cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl., each of which has been defined previously. As used herein, an "acyl" group refers to a formyl group or alkyl-C(=O)-vvhere "alkyl" has been defined previously. Acetyl and pivaloyl are examples of acyl groups. As used herein, a. "carbamoyl" group refers to a group having the structure -O-CO-NRXRY or -NRX-CO-O-RZ wherein Rx and RY have been defined above and Rz is alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, or heteroaralkyl. As used herein, a "carboxy" and a "sulfo" group refer to -COOH and -SOs'H, respectively. As used herein, an "alkoxy" group refers to an alkyl-0- group where "alkyl" has been defined previously. As used herein, a "sulfoxy" group refers to^O-SO-Rx or ~SO-O-RX, where Rx has been defined above. As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine. As used herein, a "sulfamoyl" group refers to the structure -SC>2-NRXRY or -NRX -SO2-RZ wherein Rx, RY, and Rz have been defined above. As used herein, a "sulfamide" group refers to the staicture -NRX -8(0)2-NRYRZ wherein Rx, RY, and Rz have been defined above. As used herein, a "urea" group refers to the structure -NRX-CO-NRYRZ and a "thiourea" group refers to the structure -NRX-CS-NRYRZ. Rx, RY, and Rz have been defined above. As used herein, an effective amount is defined as the amount which is 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 Cheinother. Rep., 50: 219 (1966). Body surface area may be approximately determined from height and. weight of the i patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsiey, New York, 537 (1970). As used herein, "patient" refers to a mammal, including a human. An antagonist 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. As compounds of formula (1) are antagonists of TGFp receptor type I (AIk5) and/or activin receptor type I (Alk4), these compounds are useful in inhibiting the consequences of TGFp1 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 (1) inhibit pathological inflammatory and fibrotic responses and possess the therapuetica! utility of treating and/or preventing disorders or diseases for which reduction of TGFp and/or activin activity is desirable (e.g., various types of fibrosis or progressive cancers). 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. Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. DETAILED DESCRIPTION OF THE INVENTION In general, the invention features compounds of formula (I), which exhibit surprisingly high affinity for the TGFp family type I receptors, AJk 5 and/or AJk 4. Synthesis of Compounds of formulalll 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 Scheme 1 below. Specifically, a compound of formula (II) (where Xi, Xj, Xa, and X^ have each been defined before) can undergo dipolar cycloadditiorrwith an acetylene of formula (III) in an inert solvent (e.g., CHiClj) with an appropriate base (e.g., KOH) to form an intermediate, a compound of formula (IV) as shown below. This intermediate can then react with an amine of formula (V) where RA is a lower alkyl (e.g., d-4 alkyl such as methyl) and RB is an appropriate leaving group (e.g., Ci-4 alkoxy such as ethoxy) to form a further intermediate, a compound of formula (VI). Further reaction of this intermediate with reagents such as an optionally substituted guanidine (wherein R shown below in Scheme 1 can be hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl., or heteroaryl) or thiourea leads to compounds of formula (I). Alternatively, the intermediate compound of formula (IV) can be alkylated by reacting with diethoxy ketone in a polar solvent (e.g., dioxane) at an elevated temperature (e.g., 90°C) to result in a further intermediate, a compound of formula (VII). This intermediate can then react with a reagent such as guanidine carbonate at an elevated temperature (e.g., IOO°C) to form a compound of formula (I) with an aminopyrimidinone substituent. This compound of formula (I) can be further derivatized to other compounds of formula (I) (e.g., by converting the aminopyrimidinone substituent to a diaminopyrimidine substituent as shown in Scheme 1). Scheme 1 o, Jl H2N NHR (Figure Removed)Some other methods for derivatizing compounds of formula (I) are shown in Scheme 2 below. (Figure Removed)Scheme 3 shows a yet another method for preparing compounds of formula (I). Specifically, a compound of formula (II) can cyclize with an acetylene of formula (YRI) to form an intermediate compound of formula (IX). Reaction of this intermediate with NaOH, followed by a brominating agent (N-bromosuccinimide) yields a compound of formula (X). Further reaction of a compound of formula (X) with either reagent of formula (XI) or formula (XII) produces compounds of formula (I). For references, see Stille, Ahgew. Chem. In. Ed. Engl. 25, 508 (1996) and Suzuki et al., Synth. Comrmm. 11, 513 (1981). Scheme 3 (Figure Removed)cetylenes of formula (111) and formula (VTl'I), starting compound of the synthetic procedures illustrated in Schemes 1 and 3, respectively, can be prepared according to Scheme 4 below. Specifically, 2-halopyridine (XIII) can first react with trimethylsilylacetylene to form a trimethylsilanylethynyl substituted pyridine (XIV), which is then deprotected with a base (e.g., NaOH, K^COs, or tetrabutylammonium fluoride.) to yield 2-ethynylpyridine of formula (XV). Further reaction of this compound with acetic anhydride and methyl chloroformate produces a compound of formula (111) and formula (VIII), respectively. Still further, compounds of formula (I) can be prepared according to Scheme 5 below. Specifically, a diary 1 acetylene of formula (5CVI) or a ketone of formula (XVII) can cyclize with an aminating agent (e.g., O-(mesitylsulfonyl)-hydroxylamine) to yield a compound of formula (XVIII), which can be brominated (e.g., by using N-bromosuccmimide) to form a compound of formula (X). Further reaction of a compound of formula (X) with either reagent of formula (XI) or formula (XII) produces compounds of formula (I). Starting compounds of formula (XVI1) can be prepared according to methods analogous to that illustrated in Scheme 4 above, e.g., by coupling an appropriate pyridyl acetylene with 2-halopyridine. For reference, see Yamanake et al., Chem. Pharm. Bull. 1890 (1988), Compounds of formula (XVII) can also be prepared according to known methods, e.g., see Cassity et al., J. Org. Chem. 2286 (1978). In addition to Scheme 2, a compound of formula (I) can be modified to other compounds of formula (I) according to Schemes 6 and 7 below. Note that R° represents alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, or heteroaralkyl. eme 6 (Figure Removed)(I) As will be obvious to a skilled person in the art, some 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 (I) As discussed above, hyperactivity of the TGFp 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, VV.A. and Ruoslahti E../ Clin. 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 TGFp and/or activin niRNA. and the level of TGFp 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. Compounds of formula (I), which are antagonists of the TGFP family type I receptors, Alk 5 and/or Alk 4, and inhibit TGFP and/or activin signaling pathway, are therefore useful for treating and/or preventing fibrotic disorders or diseases mediated by an increased level of TGFJ3 and/or activin activity. As used herein, a compound inhibits the TGFp family signaling pathway when it binds (e.g., with an ICjo value of less than 10 uM; preferably, less than 1 uM; more preferably, less than 0.1 u.M) to a receptor of the pathway (e.g., Alk 5 and/or Alk 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 conditions (a) marked by the presence of an abnormally high level of TGFp 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, idiopathic pulmonary fibrosis, glomerulonephritis, diabetic nephropathy, lupus nephritis, hypertension-induced nephropathy, ocular or corneal scarring, hepatic or biliary fibrosis, acute lung injury, 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 therapy- induced fibrosis, chemotherapy-induced fibrosis, surgically induced scarring including surgical adhesions, laminectoray, and coronary restenosis. increased TGFp activity is also found to manifest in patients with progressive cancers. Studies have shown that in late stages of various cancers, both the tumor cells and the stromal cells within the tumors generally overexpress TGF(3. This leads to stimulation of angiogenesis and cell motility, suppression of the immune system, , and increased interaction of tumor cells with the extracellular matrix. See, e.g., Hojo, M. et al,, Nature 397: 530-534 (1999). As a result, the tumors cells become more invasive and metastasize to distant organs. See, e.g., Maehara, Y. et al.; J. Clin. Oncol. 17: 607-614 (1999) and Picon., A. et al., Cancer Epidemiol. Biomarkers Prev. 7: 497-504 (1998), Thus, compounds of formula (I), which are antagonists of the TGFji type I receptor and inhibit TGFJ3 signaling pathway, are also useful for treating and/or preventing various late stage cancers which overexpress TGF(3. Such late stage cancers include carcinomas of the lung, breast, liver; biliary tract, gastrointestinal tract, head and neck, pancreas, prostate, cervix as well as multiple myeloma, melanoma, gliorna, and glioblastomas. 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 TGFp 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. Not only are compounds of formula (I) useful in treating disorders or diseases mediated by high levels of TGFJ3 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 TGFfi 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 TGFJ3 and/or activin in serum and of TGFjJ and/or activin mRNA in tissue can be measured and used as diagnostic or prognostic markers for disorders or diseases mediated by rexpression of TGFP and/or activin, and polymorphisms in the gene for TGF|3 that determine the production of TGFP 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. CellMol. Biol. 13: 17-24 (1995), Inoue, S. et al., Biochem. Biophys. Res. Comm. 205: 441-448 (1994); Matsuse, T. et al, Am. J. Palhol. 148: 707-713 (1996); De Bleser et al., Hepatology • 26: 905-912 (1997); Pawlowski, I.E., et al., J. Cliri. Invest. 100: 639-648 (1997); and Sugiyama, M. etal., Gastroenterology 114: 550-558 (1998). Administration of Compounds of formula (I) As defined above, an effective amount is the amount which is required to confer a therapeutic effect on the treated patient. For a compound of formula (I), an effective amount can range 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. 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 a 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, ferret, lizard, reptile, or bird). Optionally, compounds of formula (I) can be administered in conjunction with one or more other agents that inhibit the TGFp signaling pathway or treat the coiTesponding pathological disorders (e.g., fibrosis or progressive cancers) by way of a different mechanism of action. Examples of these agents include arigiotensin converting enzyme inhibitors, nonsteroid, steroid anti-inflammatory agents, and chemotherapeutics or radiation, as well as agents that antagonize ligand binding or activation of the TGFJ3 receptors, e.g., anti-TGFp, anti-TGFp receptor antibodies, or antagonists of the TGFp type II receptors. The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims. Synthetic procedures illustrated in Schemes 1 and'2 above were employed in the preparation of the title compound below. Example 1 4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyridin-3-yI]-pyriraidin-2-yla3nine Synthesis of the title compound is described in parts (a)-(f) below. (a) 2-methyl-6-trimethylsilanylethynyI-pyridiue Anhydrous triemylamine (45 mL), PdCl2(PPh3)2 (0.48 mmol), and copper(I) iodide (1.45 mmol) were added to a solution of 6-bromo-2-methylpyridine (48.2 mmol) in anhydrous DMF (110 mL). (Trimethylsilyl)acetylene (62.6 mmol) was added dropwise to the resulting orange solution. After stirring overnight at room temperature, the reaction was concentrated in vacua and diluted with ether (100 mL), hexanes (100 mL) and water (100 mL). This emulsion was filtered through a celite plug, rinsing with ether. The separated organic phase was washed with water (Ix), dried (MgSO4) and concentrated in vacua to give 8.86 g of a dark brown oil identified as 2-methyl-6-trimethylsilanylethynyl-pyridine. THNMR (CDC13, 400 MHz) : 0.24 (s, 9H), 2.53 (s, 3H), 7.06 (d, J = 7.78 Hz, 1H), 7.26 (d, J 7.64 Hz, 1H), 7.50 (dd, J = 7.75, 7.74 Hz, 1H); MS (ESP+) 190.09 (M+l).. (b) 2-ethynyl-6-rnethyl-pyridine A solution of 2-methyl-6-trimethylsilanylethynyl-pyridine (46,8 mmol) in saturated potassium carbonate/methanol (115 mL) was stirred at RT for 1 h, concentrated in vacua, dissolved in ether (200 mL), washed with water (2 x 100 mL), dried (MgSO^) and concentrated in vacua to give 4.8 g of a dark brown oil identified as 2-ethynyl-6-methyl-pyridine. 'H NMR (CDCI3, 400 MHz) : 2.53 (s, 3H), 3.10 (s,. IH), 7.10 (d, J = 7.81 Hz, IH), 7.27 (d, J = 7.67 Hz, IH), 7.52 (dd, J = 7.75, 7.74 Hz, 1H);MS (+/-) no mol. lou. (c) 4-(6-methyI-pyridin-2-yl)-but-3-yu-2-one A solution of 2-ethynyl-6-methyl-pyridine (41.00 mmol) in anhydrous THF (30 mL) was added dropwise to a solution of 1.0 M ethyl magnesium bromide/THF (61.5 mmol) in anhydrous THF (30 mL) at 0°C under a nitrogen atmosphere with gas evolution. After stirring for 30 min, the solution was cannulated into a solution of acetic anhydride (82.0 mmol) in anhydrous THF (30 mL)'at 0°C under a nitrogen atmosphere. After a further 45 min. the reaction was quenched with saturated ammonium chloride. After warming to RT, the reaction was diluted with water. The aqueous phase was extracted with ether (2 x 100 mL). The combined organic phases were washed with saturated ammonium chloride (2x), dried/decolorized (MgSCVcharcoal) and concentrated in vacua to give 6.54 g of a brown oil identified as 4-(6-metiiyl-pyndin-2-yl)-but-3-yn-2-one. *H NMR (CDCb, 400 MHz) : 2.45 (s, 3H), 2.56 (s, 3H), 7.19 (d, J = 7.83 Hz, IH), 7.38 (d, J = 7.58 Hz, IH), 7.59 (dd, J = 7.76, 7.76 Hz, IH); MS(+/-) no mol. ion. (d) l-[2-(6-methyl-pyridin-2-yl)-pyrazoIo[i,5-a]pyridin-3-yl]-ethanone 1-Aminopyridinium iodide (82.0 mmol) was added to a solution of 4-(6-methyl-pyridin-2~yl)-but-3-yn-2-one (41.0 mmol) in methylene chloride (60 mL) at RT. After cooling to 0 °C, a solution of potassium hydroxide (106.6 mmol) in water (60 mL) was added and the biphasic mixture stirred briskly. After 5 minutes, the reaction was allowed to warm to RT. After 3.5 h, the reaction was diluted with 1:1 methylene chloride/water (120 mL) and the pH was adjusted to 7 with cone, hydrochloric acid. The aqueous phase was extensively extracted with methylene chloride. The combined organic phases were washed with water, dried (MgSO^) and concentrated in vacua to give a dark brown solid. The solid was dissolved in ethyl acetate (200 mL) and extracted with diluted 1 N hydrochloric acid. The combined aqueous phases were washed with ethyl acetate (Ix), adjusted to pH 8 with solid bicarbonate and extracted with ethyl acetate (3 x). The combined organic phases were washed with water (Ix), brine (Ix), dried/decolorized (MgSCVcharcoal) and concentrated in vacua to give 5.24 g of a tan solid identified as l-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyridin-3-yl]-ethanone. *H NMR (CDC13, 300 MHz) : 2.26 (s, 3H), 2.64 (s, 3H), 7.01 (dd, J = 6.90, 6.90 Hz, Hi), 7.29 (d, J = 7.80 Hz, 1H), 7.47 (dd, J = 7.20, 8.70 Hz, 1H), 7.56 ( d, J - 7.50 Hz, 1H), 7.77 (dd, J = 6.60, 7.80 Hz, 1H), 8.40 (d, J = 9.00 Hz, 1H), 8.51 (d, J = 6.60 Hz, 1H); MS (+/-) no mol. ion. (e) 3-dimethyIamino-l-[2-(6-methyI-pyridin-2-yI)-pyrazolo[l,5-a]pyridin-3-yl]-propenone A solution of l-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-a.]pyridin-3-yl]-ethanone (20.85 mrnol) in N, N-dimethylformamide diethylacetal (80 mL) was warmed to 135 °C under a nitrogen atmosphere. After 3 days, the reaction was concentrated /// racuo to a constant mass and identified as 3-dimethylamino-l-[2-(6- methyl-pyridin-2-yi)-pyrazolo[l,5-a]pyridin-3-yl]-propenone. HNIvIR (DMSO-d6, 300 MHz: 2.47 (s, 9H), 4.96 (d, J = 12.6 Hz, 1H), 7.07 (ddd, J = 1.50, 6.90, 6.90 Hz, 1H), 7.30 (d, J = 7 78 Hz, 1H), 7.38-7.41 (m, 1H), 7.40 (d, J = 12.3 Hz, 1H), 7.44 (d, J - 7.50 Hz, 1H), 7 76 (dd, J = 7.50, 7.80 Hz, 1H), 8.19 (dd, J = 0.903 8.25 Hz, 1H), 8,71 (dd, 0.90, 6.45 Hz, 1H); MS (ESP+) 307.12 (M+l). (f) 4-[2-(6-methyl-pyridin-2-yl)-pyrazoIo[l,5-a]pyridin-3-yI]-pyrimidin-2- ylamine 21 wt % Sodium ethoxide/ethanol (48.99 mmol) was added to a slurry of guanidine HC1 (48.99 mmol) in anhydrous isopropyl alcohol (50 mL). Sodium chloride precipitated immediately. To this suspension was added a solution of 3-dimethylamino-l-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyridin-3-yl]-propenone (20.85 mmol) in anhydrous isopropyl alcohol (50 mL). The dark suspension was then warmed to reflux overnight. The warm reaction was poured onto ice (130 g), the flask rinsed with water and the rinse added to the ice slurry. The suspension was allowed to stir for 1.5 h, filtered, washed with cold water and air dried to give 2.63 g of a tan solid identified as 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyridin-3-yl]-pyrimidin-2-ylamine. The aqueous mother liquor was concentrated in vacua, slurried with isopropyl alcohol, filtered, washed with isopropyl alcohol, water and methylene chloride and air dried to give 1.25 g of a tan powder identified as 4-[2-(6-methyl-pyndin-2-yl)-pyrazolo[l,5-a]pyridin-3-yl]-pyrimidin-2-ylamine. The crops were combined for a final reslurry in methylene chloride, solids filtered and air dried to , give 3.62 g of tan solid. 'HNMR (DMSO-d6, 300 MHz) : 2.44 (s, 3H), 6.24 (d, J = 5.40 Hz, 1H), 6.50 (br s, 2H), 7.06 (ddd, J = 1.40, 6.75, 6.90 Hz, 1H), 7.31 (d, J = 7.80 Hz, 1H), 7.41 (ddd, J= 1.05, 6.75, 7.80 Hz, 1H), 7.51 (d, J= 7.50Hz, 1H), 7.79 (d, J = 7.50, 7.80 Hz, 1H), 7.94 (d, J = 5.40 Hz, 1H), 8.55 (dd, J= 1.05, 9.15 Hz, 1H), 8.75 (dd, J = 0.90, 6.45 Hz, 1H); MS (ESP+) 303.12 (M+l). The TGFp or activin inhibitory activity of compounds of formula (I) can be assessed by methods described in the following examples'. Example 2 Cell-Free Assay for Evaluating Inhibition of Autophosphorylation of TGFp Type 1 Receptor The serine-threonine kinase activity of TGFp type I receptor was measured as the aulophovsphorylation activity of the cytoplasmic domain of the receptor containing an N-termina! poly histidine, TEV cleavage site-tag, e.g., His-TGFpRI. The His-tagged receptor cytoplasmic kinase domains were purified from infected insect cell cultures using the Gibco-BRL FastBac HTb baculoviais expression system. To a 96-well Nickel FlashPlate (NEN Life Science, Perkin Elmer) was added 20 ul of 1.25 u€i 33P-ATP/25 joM 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 ul of test compounds of formula (I) prepared in 5% DMSO solution were added to the FlashPlate. The assay was then initated with the addition of 20 ul of assay buffer containing 12.5 pmol of His-TGFpRI 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 with no test compound and non-specific binding was defined as counts measured in the presence of EDTA or no-kinase control. 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-tGFpRI SDS-PAGE band was quantitated on a Storm Phosphoimager (Molecular Dynamics). Compounds of formula (I) typically exhibited ICso values of less than 10 uM; some exhibited ICso values of less than 0.1 uJVI. Example 3 Cell-Free Assay for Evaluating Inhibition of Activin Type I Receptor Kinase Activity Inhibition of the Activin type I receptor (Alk 4) kinase autophosphorylation activity by test compounds of formula (I) can be determined in a similar manner as described above in Example 2 except that a similarly His-tagged form of Alk 4 (His-Alk 4) was used in place of the His-TGFpRI. Example 4 Assay for Evaluating Cellular Inhibition of TGFp Signaling and Cytotoxkity Biological activity of compounds of formula (I) were determined by measuring their ability to inhibit TGF{3-induced PAI-Luciferase reporter activity in HepG2 cells. HepG2 cells were stably transfected with thePAI-luciferase reporter grown in DMEM medium containing 10% FBS, penicillin (100 U/ml), streptomycin (100 ug/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/welt in 96 well plates and starved for 3-6 hours in media with 0.5% FBS at 37°C in a 5% CC>2 incubator. The cells were then stimulated with ligand either 2.5 ng/ml TGFJ3 in the starvation media containing 1% DMSO and the presence or absence of test compounds of of formula (I) and incubated as described above for 24 hours. The media was washed out in the following day and the luciferase reporter activity was detected using the LucLite Luciferase Reporter Gene Assay kit (Packard, cat. no. 601691 1) as recommended. The plates were read on a Wallac Microbeta plate reader, the reading of which was used to determine the ICjo values of compounds of formula (I) for inhibiting TGFp-induced PAI-Luciferase reporter activity in HepG2 cells. Compounds of formula (I) typically exhibited ICso values of less 10 uM. Cytotoxicity was determined using the same cell culture conditions as described above. Specifically, cell viability was determined after overnight incubation with the CytoLite cell viability kit (Packard, cat. no. 6016901). Compounds of formula (1) typically exhibited LD25 values greater than 10 Example 5 Assay for Evaluating Cellular Inhibition of TGFp Signaling The cellular inhibition of activin signaling activity by test compounds of formula (I) were determined in a similar manner as described above in Example 4 except that lOOng/ml of activin is added to serum starved cells in place of the 2.5ng/mlTGFp. Example 6 Assay for TGFp-induced Collagen Expression Preparation of Immortalized Collagen Promolor-Green Fluorescent Protein Cells Fibroblasts were derived from the skin of adult transgenic mice expressing Green Fluorescent Protein (GFP) under the control of the collagen 1 Al promoter (see Krempen, K. et al., Gene Exp. 8: 151-163 (1999)). Cells were immortalised with a temperature sensitive large T antigen that is active at 33°C. Cells are expanded at 33°C then transferred to 37°C so that the large T 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 ofTGFfi-indi/ced Collageu-GFP Expression Cells are thawed, plated in complete DMEM (contains nonessential amino acids, ImM sodium pyruvate and 2mM L-glutamine) with 10 % fetal calf serum and incubated overnight at 37°C, 5% COx The following day, the cells are trypsinized and transferred into 96 well format with 30,000 cells per well in 50 u.1 complete DMEM containing 2 % fetal calf serum, but without phenol red. The cells are incubated at 37°C for 3 to 4 hours to allow them to adhere to the plate, solutions containing test compounds of formula (I) are then added to triplicate wells with no TGF|3, as well as triplicate wells with 1 ng/ml TGFp. DMSO was also added to all of the wells at a final concentration of 0.1%. GFP fluorescence emission at 530 nm following excitation at 485 nm was measured at 48 hours after the addition of solution containing test compounds on a CytoFluor microplate reader (PerSeptive Biosystems). The data are then expressed as the ratio of TGFp-induced to non-induced for each test sample. Other Embodiments 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. We Claim: 1. A pyridinylpyrazole compound of the following formula: (Formula Removed) wherein each of X1, X2, X3, and X4 is independently CRX or N; provided that only two of X1, X2, X3, and X4, can be N simultaneously; each of Y1 and Y2 is independently CRy or N; provided that at least one of Y1 and Y2 must be N; each R1 is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; each R2 is independently alkyl, alkenyl, alkynyl, acyl, halo, hydroxy, -NH2, -NH(alkyl), -N(alkyl)2, -NH(cycloalkyl), -N(alkyl)(cycloalkyl), - NH(heterocycloalkyl), -NH(heteroaryl), -NH-alkyl-heterocycloalkyl, - NH-alkyl-heteroaryl, -NH(aralkyl), cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, aroyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, heteroaralkyl, heteroaroyl, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkoxy, cycloalkyloxy, cycloalkyl-alkoxy, aryloxy, arylalkoxy, heterocycloalkyloxy, (heterocycloalkyl)alkoxy, heteroaryloxy, heteroarylalkoxy, alkylsulfanyl, cycloalkylsulfanyl, (cycloalkyl)alkylsulfanyl, arylsulfanyl, aralkylsulfanyl, heterocycloalkylsulfanyl, (heterocycloalkyl)alkylsulfanyl, heteroarylsulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkyl) alkylcarbonylamino, heteroarylcarbonylamino, hetcroaralkylcarbonylamino, alkoxycarbonylaminoalkylamino, (heteroaryl)arylcarbonylaminoalkylamino, heteroaralkylcarbonylaminoalkylamino, (heteroaryl)arylsulfonylaminoalkylcarbonylaminoalkylamino, arylsulfonylaminoalkylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, or carbamoyl; m is 0, 1, 2, 3, or 4; provided that when m > 2, two adjacent R1 groups can join together to form a 4- to 8-membered optionally substituted cyclic moiety; n is 0, 1,2, or 3; provided that when n > 2, two adjacent R2 groups can join together to form a 4- to 8-menlbered optionally substituted cyclic moiety; and each of Rx and Ry is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, cycloalkylcarbonyl, (cycloalkyl)alkylcarbonyl, aroyl, aralkylcarbonyl, heterocycloalkylcarbonyl, (heterocycloalkyl)acyl, heteroaroyl, (heteroaryl)acyl, aminocarbonyl, alkylcarbonylamino, (amino)aminocarbonyl, alkylsulfonylaminocarbonyl, alkylsulfonylamino, cycloalkylcarbonylamino, cycloalkylsulfonylamino, (cycloalkyl)alkylcarbonylamino, (cycloalkyl) alkylsulfonylamino, arylcarbonylamino, arylsulfonylamino, aralkylcarbonylamino, aralkylsulfonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)sulfonylamino, (heterocycloalkyl)alkylcarbonylamino, (heterocycloalkyl)alkylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfonylamino, heteroaralkylcarbonylamino, heteroaralkylsulfonylami.no, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, (cycloalkyl)alkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, (heterocycloalkyl)alkyl, (heterocycloalkyl)alkoxy, (heterocycloalkyl)alkylsulfanyl, aryl, aryloxy, arylsulfanyl, aralkyl, aralkyloxy, aralkylsulfanyl, arylalkenyl, arylalkynyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, heteroaralkyl, (heteroaryl)alkoxy, or (heteroaryl)alkylsulfanyl; or a pharmaceutically acceptable salt or N-oxide thereof. 2. The compound as claimed in claim 1, wherein each of X1, X2, X3, and X4 is independently CRX. 3. The compound as claimed in claim 1, wherein each Rx is independently hydrogen, unsubstituted alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, aryloxyalkyl, heteroaralkyloxyalkyl, alkoxy, halo, hydroxy, carboxy, cyano, guanadino, amidino, amino, carboxy, (heteroaryl)acyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, heteroarylcarbonylamino, (heterocycloalkyl)alkoxy, (heteroaryl)alkoxy, (heteroaryl)alkylsulfanyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, or heteroaralkyl. 4. The compound as claimed in claim 1, wherein each Rx is independently hydrogen, unsubstituted alkyl, hydroxyalkyl, trifluoromethyl, alkoxy, halo, hydroxy, cyano, guanadino, amidino, -NH2, -NT-(unsubstituted alkyl), -NH(hydroxyalkyl), -NH(alkoxyalkyl), -NH(carboxyalkyl), -N(unsubstituted alkyl)2, - NH(heterocycloalkyl), -NH(heteroaryl), -NH(heterocycloalkyl)alkyl), -NH(aralkyl), NH(heteroaralkyl), -NH-CO-alkyl, -NH-CO-heteroaryl, heterocycloalkyl, or heteroaryl. 5. The compound as claimed in claim 1, wherein each Rx is independently hydrogen. 6. The compound as claimed in claim 1, wherein each of X2, X3, and X4 is independently -CH-, -C(CH3)-, -C(OH)-, -C(NH2)-, -C(CO-NH2)-, -C(CO-NHOH)-, -C(NH(unsubstituted alkyl))-, -C(NH(aryl))-, -£(NH(aralkyl))-, -C(NH(heteroaryl))-, -C(NH(heteroarylalkyl))-, C(NH-CO-(unsubstituted alkyl))-, -C(NH-CO-(aryl))-, -C(NH-CO-(heteroaryl))-, -C(NH-CO-(aralkyl))-, -C(NH-CO-(heteroarylalkyl))-, -C(NH-S02-(unsubstituted alkyl))-, -C(NH-S02-(aryl))-, -C(NH-S02-(heteroaryl))-, -C(NH-S02-(aralkyl))-, -C(NH-S02-NH(heteroaryl))-, -C(NH-S02-NH(aralkyl))-, -C(NH-S02-NH(heteroarylalkyl))-, -C(hydroxyalkyl)-, or -C(carboxy)-, and Xi is -CH. 7. The compound as claimed in claim 1, wherein m is 0, 1, or 2. 8. The compound as claimed in claim 7, wherein each R1 is independently unsubstituted alkyl, hydroxyalkyl, haloalkyl aminoalkyl, aryloxyalkyl, heteroaralkyloxyalkyl, unsubstituted alkenyl, alkoxy, acyl, halo, hydroxy, carboxy, cyano, guanadino, amidino, amino, carboxy, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkoxycarbonyl, alkylcarbonyloxy, alkylsulfonyl, sulfamoyl, cycloalkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, or heteroaralkyl. 9. The compound as claimed in claim 7, wherein m is 1 and R1 is 6-alkyl, 6-alkenyl, or 6-cycloalkyl. 10. The compound as claimed in claim 7, wherein both Y1and Y2 are N. 11. The compound as claimed in claim 10, wherein n is 1 or 2 and each R2 is independently unsubstituted alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, aryloxyalkyl, heteroaralkyloxyalkyl, alkoxy, acyl, halo, hydroxy, carboxy, cyano, guanadino, amidino, -NH2, monoalkylamino, dialkylamino, monocycloalkylamino, monoheterocycloalkyl-amino, monoheteroaryl-amino, mono(heterocycloalkyl)alkyl)amino, mono(heteroaralkyl)amino, N (alkyl) (cycloalkyl), mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, CONH2, -CONH(alkyl), -CO-N(alkyl)2, -NH-CO-alkyl, -N(alkyl)-CO-alkyl, C02-alkyl, -O-CO-alkyl, -SO2-NH2, -S02-NH(alkyl), -S02-N(alkyl)2, -NH- S02-alkyl, -N(alkyl)-S02-alkyl, -NH-CO-NH (alkyl), -N(alkyl)-CO- NH(alkyl), -NH-S02-NH(alkyl), -N(alkyl)-S02-NH(alkyl), heterocycloalkyl, or heteroaryl. 12. The compound as claimed in claim 11, wherein R2 is substituted at the 3-position and is guanadino, amidino, -NH2, monoalkylamino, dialkylamino, monocycloalkylamino, monoheterocycloalkylamino, monoheteroarylamino, mono((heterocycloalkyl)alkyl)amino, mono(heteroaralkyl)amino, -NH-CO-NH(alkyl), -N(alkyl)-CO-NH(alkyl), -NH-S02-NH(alkyl), -N(alkyl)-S02-NH(alkyl), heterocycloalkyl, or heteroaryl. 13. The compound as claimed in claim 12, wherein m is 1 and R1 is 6-methyl, 6-ethyl, 6-propyl, 6-trifTuoromethyl, 6-vinyl, or 6-cyclopropyl. 14. The compound as claimed in claim 1, wherein m is 0, 1, or 2. 15. The compound as claimed in claim 14, wherein R1 is substituted at the 5-position or the 6-position. 16. The compound as claimed in claim 15, wherein R1 is C1-4alkyl, C1-4alkoxy, C1-4alkylthio, halo, amino, aminocarbonyl, or alkoxycarbonyl. 17. The compound as claimed in claim 14, wherein each R1 is independently unsubstituted alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, aryloxyalkyl, heteroaralkyloxyalkyl, unsubstituted alkenyl, alkoxy, acyl, halo, hydroxy, carboxy, cyano, guanadino, amidino, -NH2, monoalkylamino, dialkylamino, monocycloalkylamino, monoheterocycloalkylamino, monoheteroarylamino, mono(heterocyclylalkyl)amino, mono(aralkyl)amino, mono(heteroaralkyl)amino, N(alkyl)(cycloalkyl), mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -CONH2, -CONH(alkyl), -CO-N(alkyl)2, -NH-CO-alkyl, -N(alkyl)-CO-alkyl, -C02-alkyl, -O-CO-alkyl, -S02-NH2, -S02-NH(alkyl), -S02-N(alkyl)2, cycloalkyl, heterocycloalkyl, or heteroaryl. 18. The compound as claimed in claim 17, wherein m is 1 and R1 is 6-methyl, 6-ethyl, 6-propyl, 6-trifluoromethyl, 6-ethyl, 6-vinyl, or 6-cyclopropyl. 19. The compound as claimed in claim 1, wherein both Y1 and Y2 are N. 20. The compound as claimed in claim 19, wherein n is 1 or 2 and each R2 is independently unsubstituted alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, aryloxyalkyl, heteroaralkyloxyalkyl, alkoxy, acyl, halo, hydroxy, carboxy, cyano, guanadino, amidino, -NH2, monoalkylamino, dialkylamino, monoycloalkylamino, monoheterocycloalkylamino, monoheteroaryl-amino, mono((heterocycloalkyl)alkyl)amino, mono(heteroaralkyl)amino, N(alkyl)(cycloalkyl), mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, CONH2, -CONH(alkyl), -CO-N(alkyl)2, -NH-CO-alkyl, -N(alkyl)-CO-alkyl, - COs-alkyl, -O-CO-alkyl, -S02-NH2, -S02-NH(alkyl), -S02-N(alkyl)2, - NH-S02-alkyl, -N(alkyl)-S02-alkyl, -NH-CO-NH(alkyl), -N(alkyl)-CO- NH(alkyl), -NH-S02-NH(alkyl), -N(alkyl)-S02-NH(alkyl), heterocycloalkyl, or heteroaryl. 21. The compound as claimed in claim 20, wherein n is 1 and each R2 is independently guanadino, amidino, -NH2, monoalkylamino, dialkylamino, monocycloalkylamino, monoheterocycloalkylamino, monoheteroarylamino, mono((heterocycloalkyl)alkyl)amino, mono(heteroaralkyl)amino, -NH-CO-NH(alkyl), -N(alkyl)-CO-NH(alkyl), -NH-S02-NH(alkyl), -N(alkyl)-S02-NH(alkyl), heterocycloalkyl, or heteroaryl. 22. The compound as claimed in claim 21, wherein R2 is substituted at the 3-position. 23. The compound as claimed in claim 1, wherein each of X2, X3, and X4 is independently -CH-, -C(OH)-, -C(NH2)-, -C(NH(unsubstituted alkyl))-, -C(NH(aryl))-, -C(NH(aralkyl))-, -C(NH(heteroaryl))-, C(NH(heteroarylalkyl))-, -C(NH-CO-(unsubstitdted alkyl))-, -C(NH-CO-(aryl))-, -C(NH-CO-(heteroaryl))-, -C(NH-CO-(aralky)-, -C(NH-CO-(heteroarylalkyl))-, -C(NH-S02-(unsubstituted alkyl))-, -C(NH-S02-(aryl))-, -C(NH-S02-(heteroary))-, -C(NH-S02-(aralkyl)-, -C(NH-S02-(heteroarylalkyl))-, -C(NH-S02-NH(unsubstituted alkyl))-, -C(NH-S02-NH(aryl)-, -C(NH-S02-NH(heteroaryl))-, -C(NH-S02-NH(aralkyl))-, -C(NH-S02-NH(heteroarylalkyl))-, -C(hydroxyalkyl)-, or -C(carboxy)-. 24. The compound as claimed in claim 1, wherein Xi is -CH-. 25. The compound as claimed in claim 1, wherein Xi is N. 26. The compound as claimed in claim 1, wherein X2 is N. 27. The compound as claimed in claim 1, wherein X3 is N. 28. The compound as claimed in claim 1, wherein X4 is N. 29. The compound as claimed in claim 1, said compound being 4-(2-pyridin-2-yl-pyrazolo[ 1,5-a]pyridin-3-yl)-pyrimidin-2-ylamine, 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[ 1,5-a]pyridin-3-yl]-pyrimidin-2-ylamine, 2-(6-methyl-pyridin-2-yl)3-(2-methylsulfanyl-pyrimidin-4-yl)-pyrazolo[l,5-a]pyridine, 4-[2-(6-chloro-pyridin-2-yl)-pyrazolo[l,5-c]pyrimidin-3-yl]-pyrimidin-2-ylamine, 2-(6-methyl-pyridin-2-yl)-3-(2-morpholin-4-yl-pyrimidin-4-yl)-pyrazolo[ 1,5-c]pyrimidine, 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyrazin-3-yl]-pyrimidin-2-ylamine, 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyrimidin-3-yl]-pyrimidin-2-ylamine, 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-c]pyrimidin-3-yl]-pyrimidin-2-ylamine, or a pharmaceutically acceptable salt or N-oxide thereof. 30. The compound as claimed in claim 1 as and when used for the preparation of a pharmaceutical composition.

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