Preparation of pyrazoline derivatives with Raf kinase inhibitory activity.

Abstract

The present invention provides certain pyrazoline compds. (shown as I; variables defined below; e.g. 2-[3-(pyridin-3-yl)-1-[[5-(pyridin-2-yl)-2-thienyl]carbonyl]-4,5-dihydro-1H-pyrazol-5-yl]phenol) useful as inhibitors of Raf kinases. The invention also provides pharmaceutical compns. and methods of using the compns. in the treatment of cancer. Semiquant. IC50 values for B-Raf kinase are reported for many examples of I. For I: R1 is a (un)substituted 5- or 6-membered N-contg. heteroaryl ring, which ring optionally is fused to an aryl, heteroaryl, heterocyclyl, or cycloaliph. ring, each of which is (un)substituted. R2 is a (un)substituted 5- or 6-membered aryl or heteroaryl ring, which ring optionally is fused to an aryl, heteroaryl, heterocyclyl, or cycloaliph. ring, each of which is (un)substituted. R3 = H, fluoro, C1-4 aliph., and C1-4 fluoroaliph.; R4 is H, fluoro, or a C1-4 aliph. or C1-4 fluoroaliph. (un)substituted, or R3 and R4, taken together with the C to which they are bound, form an (un)substituted 3- to 6-membered cycloaliph. or 4- to 7-membered heterocyclic ring. L1 = -C(O)NRa(CRbRc)m-, -C(O)C(Rb):C(Rb)(CRbRc)m-, -C(O)(CRbRc)m-, and -SO2(CRbRc)m-, wherein the C(O) or SO2 functionality, resp., is bound to the N of the pyrazoline ring; Cy1 is a bivalent radical derived from a ring system = (un)substituted 5- or 6-membered arom. rings having 0-4 ring N atoms and optionally 1-2 addnl. ring heteroatoms = O and S, which 5- or 6-membered arom. ring optionally is fused to an aryl, heteroaryl, heterocyclyl, or cycloaliph. ring, each of which is (un)substituted; et al. L2 is -(CRbRc)- or -(CRbRc)nX(CRbRc)n-; X = -O-, -C(O)-, -S-, -SO-, -SO2-, -NRa-, -C(Rf):C(Rf)-, -C≡C-, -NRaC(O)-, - C(O)NRa-, -SO2NRa, -NRaSO2-, and -NRaC(O)NRa-; Cy2 is a radical derived from a ring system = (un)substituted 5- or 6-membered arom. rings having 0-4 ring N atoms and optionally 1-2 addnl. ring heteroatoms = O and S, which 5- or 6-membered arom. ring optionally is fused to an aryl, heteroaryl, heterocyclyl, or cycloaliph. ring, each of which is (un)substituted; et al; provided that R1 is not 6-bromo-1,2-dihydro-2-oxo-4-phenyl-3-quinolinyl; addnl. details are given in the claims. Although the methods of prepn. are not claimed, prepns. and/or characterization data for >400 examples of I are included. For example, 2-[3-(pyridin-3-yl)-1-[[5-(pyridin-2-yl)-2-thienyl]carbonyl]-4,5-dihydro-1H-pyrazol-5-yl]phenol was prepd. in 3 steps (73, 94, and 72 % yields, resp.) starting from salicylaldehyde and 1-(pyridin-3-yl)ethanone and involving the following intermediates: (2E)-3-(2-hydroxyphenyl)-1-(pyridin-3-yl)prop-2-en-1-one and 2-[5-(pyridin-3-yl)-4,5-dihydro-1H-pyrazol-3-yl]phenol. [on SciFinder(R)]