- RHO KINASE INHIBITORS
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The present invention relates to compounds of formula (I): and pharmaceutically acceptable salts thereof, wherein R1 and X are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of Rho Kinase-mediated disorders selected from hypertension, atherosclerosis, restenosis, stroke, myocardial infarction, heart failure, coronary artery disease, peripheral artery disease, coronary vasospasm, cerebral vasospasm, ischemia/reperfusion injury, pulmonary hypertension, angina, erectile dysfunction, renal disease, organ failure, asthma, glaucoma, cancer, Alzheimer's disease, multiple sclerosis, spinal cord injury, neuropathic pain, rheumatoid arthritis, psoriasis inflammatory bowel disease, and combinations of such disorders.
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- PHARMACEUTICAL COMPOUNDS
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The invention provides compounds which are pyrimidines of formula (I): wherein R2 is bonded at ring position 2 and -YR1 is bonded at ring position 5 or 6, or YR1 is bonded at ring position 2 and R2 is bonded at ring position 6; R is an indol-4-yl group which is substituted at the 5- or 6-position; either: (a) Y is selected from -O-(CH2)n-, -NH-(CH2)n-,. -NHC(O)-(CH2)n and -C(O)NH-(CH2)n- wherein n is 0 or an integer of 1 to 3, and R1 is selected from an unsaturated 5- to 12-membered carbocyclic or heterocyclic group which is unsubstituted or substituted and a group -NR3R4 wherein R3 and R4, which are the same or different, are each independently selected from H, C1-C6 alkyl which is unsubstituted or substituted, C3 - C10 cycloalkyl which is unsubstituted or substituted, -C(O)R, -C(O)N(R)2 and -S(O)mR, or R3 and R4 together form, with the nitrogen atom to which they are attached, a saturated 5-, 6- or 7- membered N-containing heterocyclic group which is unsubstituted or substituted; (b) Y is a direct bond and R1 is selected from an unsaturated 5- to 12-membered carbocyclic or heterocyclic group which is unsubstituted or substituted, and a group -NR3R4 wherein R3 and R4, which are the same or different, are each independently selected from H, C1-C6 alkyl which is unsubstituted or substituted, C3-C10 cycloalkyl which is unsubstituted or substituted, -C(O)R, -C(O)N(R)2 and -S(O)mR; R is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl and a 5- to 12-membered aryl or heteroaryl group, which group is unsubstituted or substituted; and m is 1 or 2; or a pharmaceutically acceptable salt thereof. These compounds are inhibitors of PO K and may thus be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour associated with PB kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.
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- Heterocyclic cyclopentyl tetrahydroisoquinoline and tetrahydropyridopyridine modulators of chemokine receptor activity
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The present invention is directed to compounds of the formula I: Wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, X, n and the broken lines are as defined herein which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptor CCR-2.
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Page/Page column 71
(2008/06/13)
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- Optimization of a pyrazoloquinolinone class of Chk1 kinase inhibitors
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The development of 2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-ones as inhibitors of Chk1 kinase is described. Introduction of a fused ring at the C7/C8 positions of the pyrazoloquinolinone provided an increase in potency while guidance from overlapping inhibitor bound Chk1 X-ray crystal structures contributed to the discovery of a potent and solubilizing propyl amine moiety in compound 52 (Chk1 IC50 = 3.1 nM).
- Brnardic, Edward J.,Garbaccio, Robert M.,Fraley, Mark E.,Tasber, Edward S.,Steen, Justin T.,Arrington, Kenneth L.,Dudkin, Vadim Y.,Hartman, George D.,Stirdivant, Steven M.,Drakas, Bob A.,Rickert, Keith,Walsh, Eileen S.,Hamilton, Kelly,Buser, Carolyn A.,Hardwick, James,Tao, Weikang,Beck, Stephen C.,Mao, Xianzhi,Lobell, Robert B.,Sepp-Lorenzino, Laura,Yan, Youwei,Ikuta, Mari,Munshi, Sanjeev K.,Kuo, Lawrence C.,Kreatsoulas, Constantine
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p. 5989 - 5994
(2008/03/14)
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- HETEROCYCLIC CYCLOPENTYL TETRAHYDROISOQUINOLINE AND TETRAHYDROPYRIDOPYRIDINE MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
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The present invention is directed to compounds of formula (I), wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, X, n and the broken lines are as defined herein which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptor CCR-2.
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