RELATED APPLICATIONS

This application is a divisional application of U.S. patent application Ser. No. 11/234,564 filed Sep. 23, 2005, now allowed, which is a divisional of U.S. patent application Ser. No. 10/667,189 filed Sep. 17, 2003, now U.S. Pat. No. 6,958,354 issued Oct. 25, 2005, which claims the benefit of priority under 35 USC Â§119(e) to U.S. Provisional Application Nos. 60/412,146 filed Sep. 18, 2002, and 60/484,543 filed Jul. 2, 2003, each of which are herein incorporated in its entirety by reference.

BACKGROUND OF THE INVENTION

The present invention relates to novel pyrazole compounds, including derivatives thereof, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the present invention are potent inhibitors of the transforming growth factor (â€œTGFâ€ )-Î² signaling pathway. They are useful in the treatment of TGF-Î² related disease states including, for example, cancer and fibrotic diseases.

TGF-Î² activates both antiproliferative and tumor-promoting signaling cascades. Three mammalian TGF- isoforms have been identified (TGF-Î²I, -Î²II, and -Î²III). TGF-Î² production promotes tumor progression while its blockade enhances antitumor activity. Blockade of TGF-Î² enhances antitumor immune responses and inhibits metastasis. Thus there exists a need in the art for compounds that inhibit the TGF- signaling pathway. The present invention, as described below, answers such a need.

SUMMARY OF THE INVENTION

The present invention provides a novel compound containing a core pyrazole ring substituted with at least one substituted or unsubstituted 2-pyridyl moiety and at least one R¹moiety as set forth herein, and all pharmaceutically acceptable salts, prodrugs, tautomers, hydrates and solvates thereof. In a compound of the invention, the substituted or unsubstituted 2-pyridyl moiety and R¹moiety can be in an 1,2-, 1,3- or 1,4-relationship around the core pyrazole ring; preferably, in an 1,2- or ortho relationship.

The present invention provides a compound of formula (Ia):

and all pharmaceutically acceptable salts, prodrugs, tautomers, hydrates and solvates thereof, where R¹, R³, R⁴, R⁶and s are each as set forth herein, with the proviso that R¹contains at least one heteroatom.

In formula (Ia), as set forth above:

R¹is a saturated, unsaturated, or aromatic C₃-C₂₀mono-, bi- or polycyclic ring optionally containing at least one heteroatom selected from the group consisting of N, O and S, wherein R¹can optionally be further independently substituted with at least one moiety independently selected from the group consisting of: carbonyl, halo, halo(C₁-C₆)alkyl, perhalo(C₁-C₆)alkyl, perhalo(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy, oxo, mercapto, (C₁-C₆)alkylthio, (C₁-C₆)alkoxy, (C₅-C₁₀)aryl or (C₅-C₁₀)heteroaryl, (C₅-C₁₀)aryloxy or (C₅-C₁₀)heteroaryloxy, (C₅-C₁₀)ar(C₁-C₆)alkyl or (C₅-C₁₀)heteroar(C₁-C₆)alkyl, (C₅-C₁₀)ar(C₁-C₆)alkoxy or (C₅-C₁₀)heteroar(C₁-C₆)alkoxy, HOâ€”(Câ• O)â€”, ester, amido, ether, amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl, (C₅-C₁₀)heterocyclyl(C₁-C₆)alkyl, (C₁-C₆)alkyl- and di(C₁-C₆)alkylamino, cyano, nitro, carbamoyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl, (C₅-C₁₀)arylcarbonyl, (C₅-C₁₀)aryloxycarbonyl, (C₁-C₆)alkylsulfonyl, and (C₅-C₁₀)arylsulfonyl;

preferably, R¹can optionally be further independently substituted with zero to two moieties independently selected from the group consisting of, but not limited to, halo(C₁-C₆)alkyl, perhalo(C₁-C₆)alkyl, perhalo(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₅-C₁₀)ar(C₁-C₆)alkoxy or (C₅-C₃₀)heteroar(C₁-C₆)alkoxy, amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl, and (C₅-C₁₀)heterocyclyl(C₁-C₆)alkyl;

each R³is independently selected from the group consisting of: hydrogen, halo, halo(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, phenyl, (C₅-C₁₀)heteroaryl, (C₅-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, phenoxy, (C₅-C₁₀)heteroaryl-Oâ€”, (C₅-C₁₀)heterocyclic-Oâ€”, (C₃-C₁₀)cycloalkyl-Oâ€”, (C₁-C₆)alkyl-Sâ€”, (C₁-C₆)alkyl-SO₂â€”, (C₁-C₆)alkyl-NHâ€”SO₂â€”, O₂Nâ€”, NCâ€”, amino, Ph(CH₂)_1-6HNâ€”, (C₁-C₆)alkyl HNâ€”, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂â€”NHâ€”, amino(Câ• O)â€”, aminoO₂Sâ€”, (C₁-C₆)alkyl-(Câ• O)â€”NHâ€”, (C₁-C₆)alkyl-(Câ• O)â€”[(((C₁-C₆)alkyl)-N]â€”, phenyl-(Câ• O)â€”NHâ€”, phenyl-(Câ• O)â€”[(C₁-C₆)alkyl)-N]â€”, (C₁-C₆)alkyl-(Câ• O)â€”, phenyl-(Câ• O)â€”, (C₅-C₁₀)heteroaryl-(Câ• O)â€”, (C₅-C₁₀)heterocyclic-(Câ• O)â€”, (C₃-C₁₀)cycloalkyl-(Câ• O)â€”, HOâ€”(Câ• O)â€”, (C₁-C₆)alkyl-Oâ€”(Câ• O)â€”, H₂N(Câ• O)â€”, (C₁-C₆)alkyl-NHâ€”(Câ• O)â€”, [(C₁-C₆)alkyl]₂-Nâ€”(Câ• O)â€”, phenyl-[((C₁-C₆)alkyl)-N]-(Câ• O)â€”, (C₅-C₁₀)heteroaryl-NHâ€”(Câ• O)â€”, (C₅-C₁₀)heterocyclic-NHâ€”(Câ• O)â€”, (C₃-C₁₀)cycloalkyl-NHâ€”(Câ• O)â€” and (C₁-C₆)alkyl-(Câ• O)â€”Oâ€”; preferably, R³is hydrogen or (C₁-C₆)alkyl; more preferably, R³is hydrogen or methyl;

where alkyl, alkenyl, alkynyl, phenyl, heteroaryl, heterocyclic, cycloalkyl, alkoxy, phenoxy, amino of R³is optionally substituted by at least one substituent independently selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, halo, H₂Nâ€”, Ph(CH₂)_1-6HNâ€”, and (C₁-C₆)alkylHNâ€”;

s is an integer from one to five; preferably, one to two; more preferably, one;

R⁴is selected from the group consisting of: hydrogen, halo, halo(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, phenyl, (C₅-C₁₀)heteroaryl, (C₅-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, phenoxy, (C₅-C₁₀)heteroaryl-Oâ€”, (C₅-C₁₀)heterocyclic-Oâ€”, (C₃-C₁₀)cycloalkyl-Oâ€”, (C₁-C₆)alkyl-Sâ€”, (C₁-C₆)alkyl-SO₂â€”, (C₁-C₆)alkyl-NHâ€”SO₂â€”, O₂Nâ€”, NCâ€”, amino, Ph(CH₂)_1-6NHâ€”, alkylNHâ€”, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂â€”NHâ€”, amino(Câ• O)â€”, aminoSO₂â€”, (C₁-C₆)alkyl-(Câ• O)â€”NHâ€”, (C₁-C₆)alkyl-(Câ• O)â€”((C₁-C₆)alkyl)-N]â€”, phenyl-(Câ• O)â€”NHâ€”, phenyl-(Câ• O)â€”((C₁-C₆)alkyl)-N]â€”, (C₁-C₆)alkyl-(Câ• O)â€”, phenyl-(Câ• O)â€”, (C₅-C₁₀)heteroaryl-(Câ• O)â€”, (C₅-C₁₀)heterocyclic-(Câ• O)â€”, (C₃-C₁₀)cycloalkyl-(Câ• O)â€”, HOâ€”(Câ• O)â€”, (C₁-C₆)alkyl-Oâ€”(Câ• O)â€”, H₂N(Câ• O)â€”, (C₁-C₆)alkyl-NHâ€”(Câ• O)â€”, ((C₁-C₆)alkyl)₂-Nâ€”(Câ• O)â€”, phenyl-NHâ€”(Câ• O)â€”, phenyl-((C₁-C₆)alkyl)-N]â€”(Câ• O)â€”, (C₅-C₁₀)heteroaryl-NHâ€”(Câ• O)â€”, (C₅-C₁₀)heterocyclic-NHâ€”(Câ• O)â€”, (C₃-C₁₀)cycloalkyl-NHâ€”(Câ• O)â€” and (C₁-C₆)alkyl-(Câ• O)â€”Oâ€”; preferably, R⁴is hydrogen, (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, amino, (C₁-C₆)alkylamino, (C₁-C₆)alkyl-(Câ• O)â€”, or (C₃-C₁₀)cycloalkyl-(Câ• O)â€”;

where alkyl, alkenyl, alkynyl, phenyl, heteroaryl, heterocyclic, cycloalkyl, alkoxy, phenoxy, and amino of R⁴is optionally substituted by at least one substituent independently selected from the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, halo, H₂Nâ€”, Ph(CH₂)_1-6â€”NHâ€”, and (C₁-C₆)alkylNHâ€”; and

R⁶is selected from the group consisting of hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, (C₅-C₁₀)heteroaryl, (C₅-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl-(SO₂)â€”, phenyl-(SO₂)â€”, H₂Nâ€”(SO₂)â€”, (C₁-C₆)alkyl-NHâ€”(SO₂)â€”, ((C₁-C₆)alkyl)₂Nâ€”(SO₂)â€”, phenyl-NHâ€”(SO₂)â€”, (phenyl)₂Nâ€”(SO₂)â€”, (C₁-C₆)alkyl-(Câ• O)â€”, phenyl-(Câ• O)â€”, (C₅-C₁₀)heteroaryl-(Câ• O)â€”, (C₅-C₁₀)heterocyclic-(Câ• O)â€”, (C₃-C₁₀)cycloalkyl-(Câ• O)â€”, (C₁-C₆)alkyl-Oâ€”(Câ• O)â€”, (C₅-C₁₀)heterocyclic-Oâ€”(Câ• O)â€”, (C₃-C₁₀)cycloalkyl-Oâ€”(Câ• O)â€”, H₂Nâ€”(Câ• O)â€”, (C₁-C₆)alkyl-NHâ€”(Câ• O)â€”, phenyl-NHâ€”(Câ• O)â€”, (C₅-C₁₀)heteroaryl-NHâ€”(Câ• O)â€”, (C₅-C₁₀)heterocyclic-NHâ€”(Câ• O)â€”, (C₃-C₁₀)cycloalkyl-NHâ€”(Câ• O)â€”, ((C₁-C₆)alkyl)₂Nâ€”(Câ• O)â€”, (phenyl)₂Nâ€”(Câ• O)â€”, phenyl-[((C₁-C₆)alkyl)-N]-(Câ• O)â€”, (C₅-C₁₀)heteroaryl-[((C₁-C₆)alkyl)-N]â€”(Câ• O)â€”, (C₃-C₁₀)heterocyclic-[((C₁-C₆)alkyl)-N]-(Câ• O)â€”, and (C₃-C₁₀)cycloalkyl-[((C₁-C₆)alkyl)-N](Câ• O)â€”; preferably, R⁶is hydrogen or (C₁-C₆)alkyl; more preferably, hydrogen or methyl;

where alkyl, alkenyl, alkynyl, phenyl, benzyl, heteroaryl, heterocyclic, cycloalkyl, alkoxy, phenoxy, amino of R⁶is optionally substituted with at least one moiety independently selected from the group consisting of halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, phenyl, benzyl, (C₅-C₁₀)heterocyclic, (C₅-C₁₀)heteroaryl, (C₁-C₆)alkyl-SO₂â€”, formyl, NCâ€”, (C₁-C₆)alkyl-(Câ• O)â€”, (C₃-C₁₀)cycloalkyl-(Câ• O)â€”, phenyl-(Câ• O)â€”, (C₅-C₁₀)heterocyclic-(Câ• O)â€”, (C₅-C₁₀)heteroaryl-(Câ• O)â€”, HOâ€”(Câ• O)â€”, (C₁-C₆)alkyl-Oâ€”(Câ• O)â€”, (C₃-C₁₀)cycloalkyl-Oâ€”(Câ• O)â€”, (C₅-C₁₀)heterocyclic-Oâ€”(Câ• O)â€”, (C₁-C₆)alkyl-NHâ€”(Câ• O)â€”, (C₃-C₁₀)cycloalkyl-NHâ€”(Câ• O)â€”, phenyl-NHâ€”(Câ• O)â€”, (C₅-C₁₀)heterocyclic-NHâ€”(Câ• O)â€”, (C₅-C₁₀)heteroaryl-NHâ€”(Câ• O)â€”, ((C₁-C₆)alkyl)₂-Nâ€”(Câ• O)â€”, phenyl-[((C₁-C₆)alkyl)-N](Câ• O)â€”, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-Oâ€”, phenoxy, (C₅-C₁₀)heterocyclic-Oâ€”, (C₅-C₁₀)heteroaryl-Oâ€”, (C₁-C₆)alkyl-(Câ• O)â€”Oâ€”, (C₃-C₁₀)cycloalkyl-(Câ• O)â€”Oâ€”, phenyl-(Câ• O)â€”Oâ€”, (C₅-C₁₀)heterocyclic-(Câ• O)â€”Oâ€”, (C₅-C₁₀)heteroaryl-(Câ• O)â€”Oâ€”, O₂Nâ€”, amino, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂-amino, formamidyl, (C₁-C₆)alkyl-(Câ• O)â€”NHâ€”, (C₃-C₁₀)cycloalkyl-(Câ• O)â€”NHâ€”, phenyl-(Câ• O)â€”NHâ€”, (C₅-C₁₀)heterocyclic-(Câ• O)â€”NHâ€”, (C₅-C₁₀)heteroaryl-(Câ• O)â€”NHâ€”, (C₁-C₆)alkyl-(Câ• O)-[((C₁-C₆)alkyl)-N]â€”, phenyl-(Câ• O)-[(C₁-C₆)alkyl-N]â€”, (C₁-C₆)alkyl-SO₂NHâ€”, (C₃-C₁₀)cycloalkyl-SO₂NHâ€”, phenyl-SO₂NHâ€”, (C₅-C₁₀)heterocyclic-SO₂NHâ€” and (C₅-C₁₀)heteroaryl-SO₂NHâ€”; preferably, R⁶is substituted with zero to two groups independently selected from the group consisting of (C₁-C₆)alkyl and (C₃-C₁₀)cycloalkyl;

wherein the phenyl or heteroaryl moiety of a R⁶substituent is optionally further substituted with at least one radical independently selected from the group consisting of halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, perfluoro(C₁-C₆)alkyl and perfluoro(C₁-C₆)alkoxy; with the proviso that R¹contains at least one heteroatom.