Claims for Patent: 6,531,477

Summary for Patent: 6,531,477

Title:	6-substituted pyrazolo [3,4-d] pyrimidin-4-ones useful as cyclin dependent kinase inhibitors
Abstract:	The present invention relates to the synthesis of a novel class of pyrazolo[3,4-d]pyrimidin-4-ones of formula (I), alternatively represented by the tautomer (II): ##STR1## that are potent inhibitors of the class of enzymes known as cyclin dependent kinases, which relate to the catalytic subunits cyclin dependent kinase 1-8 and their regulatory subunits know as cyclins A-H, K, N, and T. This invention also provides a novel method of treating cancer or other proliferative diseases by administering a therapeutically effective amount of one of these compounds or a pharmaceutically acceptable salt form thereof. Alternatively, one can treat cancer or other proliferative diseases by administering a therapeutically effective combination of one of the compounds of the present invention and one or more other known anti-cancer or anti-proliferative agents.
Inventor(s):	Markwalder; Jay A. (London University, PA), Seitz; Steven P. (Swarthmore, PA), Sherk; Susan R. (Wilmington, DE)
Assignee:	DuPont Pharmaceuticals Company (Wilmington, DE)
Application Number:	09/416,584
Patent Claims:	1. A compound of formula (I) or its ##STR56## tautomer, formula (II): or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein: Q is selected from the group: H, OH, and CH.sub.3, and CH.sub.2 CH.sub.3 ; Y is selected from the group: F, Cl, Br, and I; Z is selected from the group: N and CR.sup.6 ; R.sup.1 is selected from the group: phenyl, tropone, naphthyl, and a 5-10 membered aromatic heterocycle containing from 1-4 heteroatoms selected from O, N, and S, and R.sup.1 is substituted with 0-3 R.sup.7 ; R.sup.2 is selected from the group: C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, S--C.sub.1-3 alkyl, O--C.sub.1-3 alkyl, NH.sub.2, NH--C.sub.1-3 alkyl, N(C.sub.1-2 alkyl).sub.2, OCF.sub.3, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, 1-methylcyclopropyl, 1-methylcyclobutyl, CH.sub.2 CN, CH.sub.2 OH, CH.sub.2 OCH.sub.3, CH.sub.2 NH.sub.2, CH.sub.2 NHC.sub.1-3 alkyl, CH.sub.2 NMe.sub.2, CF.sub.3, CHO, OCH.sub.2 CH.sub.2 OH, OCH(Me)CH.sub.2 OH, OCH.sub.2 CH(Me)OH, OCH.sub.2 CH.sub.2 NMe.sub.2, and CHF.sub.2 ; R.sup.3 is selected from the group: H, F, Cl, Br, I, CF.sub.3, CHO, CHR.sup.g OH, COCF.sub.3, CH.dbd.NOH, CH.dbd.NOCH.sub.3, CH.dbd.NNH.sub.2, CH.dbd.NNHMe, CH.dbd.NNMe.sub.2, CH.dbd.CHR.sup.a, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, CO.sub.2 H, CONH.sub.2. CONH(C.sub.1-3 alkyl), CON(C.sub.1-3 alkyl).sub.2, CO.sub.2 C.sub.1-3 alkyl, C(O)C.sub.1-2 alkyl, NH.sub.2, NH(C.sub.1-3 alkyl), and N(C.sub.1-3 alkyl).sub.2 ; R.sup.4 is selected from the group: H, F, Cl, Br, I, CF.sub.3, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, NH.sub.2, NH(C.sub.1-3 alkyl), and N(C.sub.1-3 alkyl).sub.2 ; R.sup.5 is selected from the group: H, C.sub.1-3 alkyl, F, Cl, Br, I, CF.sub.3, and C.sub.2-3 alkenyl; wherein when Z is C, Q is H, R.sup.1 is phenyl substituted with C.sub.1-4 alkyl, hydroxy, alkoxy, amino, substituted amino, mercapto, halogen, trifluoromethyl or nitro, then either R.sup.2 is selected from the group: C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, S--C.sub.1-3 alkyl, O--C.sub.1-3 alkyl, NH.sub.2, NH--C.sub.1-3 alkyl, N(C.sub.1-2 alkyl).sub.2, OCF.sub.3, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, 1-methylcyclopropyl, 1-methylcyclobutyl, CH.sub.2 CN, CH.sub.2 OH, CH.sub.2 OCH.sub.3, CH.sub.2 NH.sub.2, CH.sub.2 NHC.sub.1-3 alkyl, CH.sub.2 NMe.sub.2, CF.sub.3, CHO, OCH.sub.2 CH.sub.2 OH, OCH(Me)CH.sub.2 OH, OCH.sub.2 CH(Me)OH, OCH.sub.2 CH.sub.2 NMe.sub.2, and CHF.sub.2 ; or, R.sup.3 is selected from the group consisting of: CHO, CHR.sup.g OH, COCF.sub.3, CH.dbd.NOH, CH.dbd.NOCH.sub.3, CH.dbd.NNH.sub.2, CH.dbd.NNHMe, CH.dbd.NNMe.sub.2, CH.dbd.CHR.sup.a, CO.sub.2 H, CONH.sub.2, CONH(C.sub.1-3 alkyl), CON(C.sub.1-3 alkyl).sub.2, CO.sub.2 C.sub.1-3 alkyl, C(O)C.sub.1-2 alkyl, NH(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl).sub.2 and alkenyl; or, R.sup.4 is selected from the group consisting of C.sub.2-3 alkenyl; or, R.sup.5 is selected from the group consisting of C.sub.2-3 alkenyl; R.sup.6 is selected from the group: H, F, Cl, Br, I, CF.sub.3, --NO.sub.2, C.sub.1-3 alkyl optionally substituted with 1-2 R, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 alkoxy, CO.sub.2 H, CHO, CONR.sup.a R.sup.b, CO.sub.2 C.sub.1-3 alkyl, C(O)C.sub.1-2 alkyl, CH.sub.2 NHR.sup.a, CONR.sup.g NR.sup.a R.sup.b, NR.sup.a R.sup.b ; SO.sub.2 NR.sup.a R.sup.b, CR.dbd.NNR.sup.a R.sup.b, CR.dbd.NOR.sup.f, and R.sup.h ; R.sup.7 is independently, at each occurrence, selected from the group: OH, C.sub.1-6 alkoxy, OC.sub.2-6 alkyl-CO.sub.2 H, O--C.sub.2-6 -alkyl-NR.sup.a R.sup.b, F, Cl, Br, I, CF.sub.3, OCF.sub.3, --CN, --NO.sub.2, CO.sub.2 H, CO.sub.2 (C.sub.1-6 alkyl), CONR.sup.a R.sup.b, NR.sup.g CONHOR.sup.g, NR.sup.g CONHSO.sub.2 R.sup.a, NHNR.sup.g C(O)OR.sup.a, NR.sup.g C(O)NR.sup.a R.sup.b, NH.sub.2, NH(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl).sub.2, --SO.sub.2 NR.sup.a R.sup.b, NHSO.sub.2 NHCO.sub.2 C.sub.1-4 alkyl, NR.sup.g SO.sub.2 NR.sup.a R.sup.b, NR.sup.g SO.sub.2 CHR.sup.e CH.sub.2 NR.sup.a R.sup.b, NR.sup.g COCHR.sup.e NR.sup.a R.sup.b, NR.sup.g COCHR.sup.e NR.sup.b CH.sub.2 R.sup.f R.sup.a, NR.sup.g COCH.sub.2 CHR.sup.e NR.sup.a R.sup.b, NR.sup.g COCHR.sup.e CH.sub.2 NR.sup.a R.sup.b, NR.sup.g CO(CH.sub.2).sub.m NR.sup.a R.sup.b, NR.sup.g CONR.sup.e (CH.sub.2).sub.n NR.sup.a R.sup.b, NR.sup.g CO.sub.2 (CHR.sup.e)NR.sup.a R.sup.b, CONR.sup.e NR.sup.a R.sup.b, NR.sup.g CONR.sup.e NR.sup.a R.sup.b, C.sub.3-10 carbocycle, C.sub.1-10 alkyl substituted with 0-3 R.sup.8, NHCONR.sup.h, NHCONHCH.sub.2 R.sup.h, NHCOR.sup.h, NHCOCH.sub.2 R.sup.h, C.sub.2-10 alkenyl substituted with 0-3 R.sup.8, C.sub.2-10 alkynyl substituted with 0-3 R.sup.8, and C.sub.3-10 heterocycle containing 1-4 heteroatoms selected from O, N, and S; R.sup.8 is independently, at each occurrence, selected from the group: .dbd.O, OH, C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy, NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, F, Cl, Br, I, CO.sub.2 H, COR.sup.a, CO.sub.2 (benzyl), CO.sub.2 (C.sub.1-6 alkyl), and CONR.sup.a R.sup.b ; R.sup.a is independently, at each occurrence, selected from the group: H, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, and C.sub.1-6 alkyl substituted with one R; R is independently, at each occurrence, selected from the group: H, C.sub.1-3 alkyl, C.sub.3-6 cycloalkyl, CO.sub.2 H, OH, and NR.sup.c R.sup.d ; R.sup.b is independently, at each occurrence, selected from the group: H and C.sub.1-6 alkyl; alternatively, R.sup.a and R.sup.b or R.sup.a and R.sup.e, together with the atoms to which they are attached, form a heterocycle having 5-7 atoms in the ring and containing 0-1 additional N, O, or S atom; alternatively, R.sup.a and R.sup.b and R.sup.e, together with the atoms to which they are attached, form a bicyclic heterocycle having 9-11 atoms in the ring and containing one additional N, S, or O atom; R.sup.c is independently, at each occurrence selected from the group: H, R.sup.f, and CO.sub.2 H; R.sup.d is independently, at each occurrence, selected from the group: H and C.sub.1-6 alkyl; alternatively, R.sup.c and R.sup.d, together with the atoms to which they are attached, form a 5-7 membered ring and containing 0-3 additional N, S, or O atoms; R.sup.e is independently, at each occurrence, selected from the group: H and C.sub.1-6 alkyl; R.sup.f is C.sub.1-4 alkyl substituted with 0-1 group selected from the group: NH.sub.2, NHMe, NMe.sub.2, OH, and OMe; R.sup.g is independently, at each occurrence, selected from H and C.sub.1-3 alkyl; R.sup.h is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH.sub.2, NHMe, NMe.sub.2, OH, and OMe; n at each occurrence is independently selected from 2, 3, 4, 5, and 6; and m at each occurrence is independently selected from 3, 4, 5, and 6. 2. A compound according to claim 1, wherein: Q is selected from the group: H, OH, and CH.sub.3 ; Y is selected from the group: F, Cl, and Br; Z is selected from the group: N and CR.sup.6 ; R.sup.1 is selected from the group: phenyl and a 5-10 membered aromatic heterocycle containing from 1-4 heteroatoms selected from O, N, and S, and R.sup.1 is substituted with 0-3 R.sup.7 ; R.sup.2 is selected from the group: C.sub.2-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, S--C.sub.1-2 alkyl, O--C.sub.1-2 alkyl, cyclopropyl, cyclobutyl, 1-methylcyclopropyl, CH.sub.2 CN, CH.sub.2 OH, CH.sub.2 OCH.sub.3, CH.sub.2 NH.sub.2, CH.sub.2 NMe.sub.2, CF.sub.3, and CHO; R.sup.3 is independently selected from the group: H, F, Cl, CH.sub.3, CH.sub.2 CH.sub.3, CHO, CHR.sup.g OH, COCF.sub.3, CH.dbd.NOH, CH.dbd.NOCH.sub.3, CH.dbd.NNH.sub.2, CH.dbd.NNHMe, CH.dbd.NNMe.sub.2, and CH.dbd.CHR.sup.a, R.sup.4 is independently selected from the group: H, F, Cl, and CH.sub.3 ; R.sup.5 is independently selected from the group: H, CH.sub.3, F, Cl, Br, and CF.sub.3 ; R.sup.6 is independently selected from the group: H, F, Cl, Br, CF.sub.3, C.sub.1-3 alkyl optionally substituted with R, CO.sub.2 H, CONH.sub.2, CONHR.sup.a, CONHNR.sup.a R.sup.b, CHO, CH.sub.3, SO.sub.2 NR.sup.a R.sup.b ; phenyl, and heteroaryl having 5-6 atoms in the ring and containing 1-2 N, O, or S atoms; and CH.sub.2 NHR.sup.a ; R.sup.7 is independently, at each occurrence, selected from the group: OH, C.sub.1-3 alkoxy, OC.sub.2-6 alkyl-CO.sub.2 H, O--C.sub.2-6 -alkyl-NR.sup.a R.sup.b, F, Cl, Br, I, CF.sub.3, OCF.sub.3, --CN, CO.sub.2 (C.sub.1-6 alkyl), CONR.sup.a R.sup.b, NR.sup.g C(O)OR.sup.a, NR.sup.g C(O)NR.sup.a R.sup.b, NR.sup.g CONHOR.sup.g, NR.sup.g CONHSO.sub.2 R.sup.a, NH.sub.2, NH(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl).sub.2, SO.sub.2 NR.sup.a R.sup.b, NR.sup.g SO.sub.2 NR.sup.a R.sup.b, NR.sup.g SO.sub.2 NHCO.sub.2 C.sub.1-4 alkyl, NR.sup.g SO.sub.2 CHR.sup.e CH.sub.2 NR.sup.a R.sup.b, NR.sup.g COCHR.sup.e NR.sup.a R.sup.b, NR.sup.g COCHR.sup.e NR.sup.b CH.sub.2 R.sup.f R.sup.a, NR.sup.g COCH.sub.2 CHR.sup.e NR.sup.a R.sup.b, NR.sup.g COCHR.sup.e CH.sub.2 NR.sup.a R.sup.b, NR.sup.g CO(CH.sub.2).sub.m NR.sup.a R.sup.b, NR.sup.g CONR.sup.e (CH.sub.2).sub.n NR.sup.a R.sup.b, NR.sup.g CO.sub.2 (CHR.sup.e).sub.n NR.sup.a R.sup.b, CONR.sup.e NR.sup.a R.sup.b, NR.sup.g CONR.sup.e NR.sup.a R.sup.b, C.sub.3-7 carbocycle, NHCONR.sup.h, NHCONHCH.sub.2 R.sup.h, NHCOR.sup.h, NHCOCH.sub.2 R.sup.h, C.sub.1-10 alkyl substituted with 0-3 R.sup.8, C.sub.2-6 alkenyl substituted with 0-3 R.sup.8, C.sub.2-6 alkynyl substituted with 0-2 R.sup.8, and C.sub.3-7 heterocycle containing 1-3 heteroatoms selected from O, N, and S; R.sup.8 is independently, at each occurrence, selected from the group: .dbd.O, OH, C.sub.1-6 alkoxy, NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, COR.sup.a, and CONR.sup.a R.sup.b ; R.sup.a is independently, at each occurrence, selected from the group: H, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, and C.sub.1-6 alkyl substituted with one R; R is independently, at each occurrence, selected from the group: H, C.sub.1-3 alkyl, C.sub.3-6 cycloalkyl, CO.sub.2 H, and NR.sup.c R.sup.d ; R.sup.b is independently, at each occurrence, selected from the group: H and C.sub.1-6 alkyl; alternatively, R.sup.a and R.sup.b or R.sup.a and R.sup.e, together with the atoms to which they are attached, form a heterocycle having 5-7 atoms in the ring and containing an additional 0-1 N, O, or S atom; alternatively, R.sup.a and R.sup.b and R.sup.e, together with the atoms to which they are attached, form a bicyclic heterocycle having 9-11 atoms in the ring and containing one additional N, S, or O atom; R.sup.c is independently, at each occurence, selected from the group: H, R.sup.f, and CO.sub.2 H; R.sup.d is independently, at each occurrence, selected from the group: H and C.sub.1-6 alkyl; alternatively, R.sup.c and R.sup.d, together with the atoms to which they are attached, form a 5-7 membered ring and containing 0-3 additional N, S, or O atoms; R.sup.e is independently, at each occurrence, selected from the group: H and C.sub.1-4 alkyl; R.sup.f is C.sub.1-4 alkyl substituted with 0-1 group selected from the group: NH.sub.2, NHMe, NMe.sub.2, OH, and OMe; R.sup.g is independently, at each occurrence, selected from H and C.sub.1-3 alkyl; R.sup.h is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH.sub.2, NHMe, NMe.sub.2, OH, and OMe; n at each occurrence is independently selected from 2, 3, 4, 5, and 6; and m at each occurrence is independently selected from 3, 4, 5, and 6. 3. A compound according to claim 2, wherein: Q is H; Y is selected from the group: F, Cl, and Br; Z is CR.sup.6 ; R.sup.1 is selected from the group: phenyl, pyridyl, pyrazyl pyrimidyl, pyridazyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, and a 5 membered aromatic heterocycle containing 1-2 heteroatoms selected from O, N, and S, and R.sup.1 is substituted with 0-2 R.sup.7 ; R.sup.2 is selected from the group: C.sub.2-4 alkyl, cyclopropyl, cyclobutyl, 1-methylcyclopropyl, and CF.sub.3 ; R.sup.3 is independently selected from the group: H, F, CH.sub.3, CHO, CHR.sup.g OH, COCF.sub.3, CH.dbd.NOH, CH.dbd.NOCH.sub.3, CH.dbd.NNH.sub.2, CH.dbd.NNHMe, CH.dbd.NNMe.sub.2, and CH.dbd.CHR.sup.a ; R.sup.4 is independently selected from the group: H and F; R.sup.5 is independently selected from the group: CH.sub.3, F, Cl, and Br; R.sup.6 is independently selected from the group: H, F, Cl, Br, CF.sub.3, CH.sub.3, CONH.sub.2, CONHR.sup.a, CONHNR.sup.a R.sup.b, SO.sub.2 NR.sup.a R.sup.b ; CH.sub.2 OH, CHO, phenyl, and heteroaryl having 5-6 atoms in the ring and containing 1-2 N, O, or S atoms; and CH.sub.2 NHR.sup.a ; R.sup.7 is independently, at each occurrence, selected from the group: OH, O--C.sub.2-6 -alkyl-NR.sup.a R.sup.b, F, Cl, Br, CF.sub.3, --CN, CONR.sup.a R.sup.b, NHC(O)OR.sup.a, NHC(O)NR.sup.a R.sup.b, NH.sub.2, NH(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl).sub.2, SO.sub.2 NR.sup.a R.sup.b, NHSO.sub.2 NR.sup.a R.sup.b, NHCONHOR.sup.e, NHCONHSO.sub.2 R.sup.f, NHSO.sub.2 NHCO.sub.2 C.sub.1-4 alkyl, NHSO.sub.2 CHR.sup.e CH.sub.2 NR.sup.a R.sup.b, NHCOCHR.sup.e NR.sup.a R.sup.b, NHCOCHR.sup.e NR.sup.b CH.sub.2 R.sup.f R.sup.a, NHCOCH.sub.2 CHR.sup.e NR.sup.a R.sup.b, NHCOCHR.sup.e CH.sub.2 NR.sup.a R.sup.b, NHCO(CH.sub.2).sub.m NR.sup.a R.sup.b, NHCONR.sup.e (CH.sub.2).sub.n NR.sup.a R.sup.b, NHCO.sub.2 (CHR.sup.e).sub.n NNR.sup.a R.sup.b, CONR.sup.e NR.sup.a R.sup.b, NHCONR.sup.e NR.sup.a R.sup.b, NHCONR.sup.h, NHCONHCH.sub.2 R.sup.h, NHCOR.sup.h, NHCOCH.sub.2 R.sup.h, C.sub.3-7 carbocycle, C.sub.1-6 alkyl substituted with 0-3 R.sup.8, C.sub.2-6 alkenyl substituted with 0-3 R.sup.8, C.sub.2-6 alkynyl substituted with 0-3 R.sup.8, and C.sub.3-7 heterocycle containing 1-3 heteroatoms selected from O, N, and S; R.sup.8 is independently, at each occurrence, selected from the group: OH, C.sub.1-3 alkoxy, NH.sub.2, NH(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl).sub.2, and CONR.sup.a R.sup.b ; R.sup.a is independently, at each occurrence, selected from the group: H, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, and C.sub.1-6 alkyl substituted with one R; R is independently, at each occurrence, selected from the group: H, C.sub.1-3 alkyl, and NR.sup.c R.sup.d ; R.sup.b is independently, at each occurrence, selected from the group: H and C.sub.1-6 alkyl; alternatively, R.sup.a and R.sup.b or R.sup.a and R.sup.e, together with the atoms to which they are attached, form a heterocycle having 5-7 atoms in the ring and containing 0-1 additional N, O, or S atom; alternatively, R.sup.a and R.sup.b and R.sup.e, together with the atoms to which they are attached, form a bicyclic heterocycle having 9-11 atoms in the ring and containing one additional N, S, or O atom; R.sup.c is independently, at each occurrence, selected from the group: H and R.sup.f ; R.sup.d is independently, at each occurrence, selected from the group: H and C.sub.1-6 alkyl; alternatively, R.sup.c and R.sup.d, together with the atoms to which they are attached, form a 5-7 membered ring and containing 0-2 additional N, S, or O atoms; R.sup.e is independently, at each occurrence, selected from the group: H and C.sub.1-3 alkyl; R.sup.f is C.sub.1-4 alkyl substituted with 0-1 group selected from the group: NH.sub.2, NHMe, NMe.sub.2, OH, and OMe; R.sup.h is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH.sub.2, NHMe, NMe.sub.2, OH, and OMe; n at each occurrence is independently selected from 2, 3, 4, 5, and 6; and m at each occurrence is independently selected from 3, 4, 5, and 6. 4. A compound according to claim 3 wherein: Q is H; Y is Cl; Z is CR.sup.6 ; R.sup.1 is selected from the group: phenyl, pyridyl, pyrrolyl, furyl, thienyl, indazolyl, benzoxazolyl, and benzothiazolyl, and R.sup.1 is substituted with 0-2 R.sup.7 ; R.sup.2 is selected from the group: CF.sub.3, C.sub.2-3 alkyl and cyclopropyl; R.sup.3 is selected from the group: H, CH.sub.3, CH.sub.2 OH, and CHO; R.sup.4 is H; R.sup.5 is independently selected from the group: CH.sub.3, F, Cl, and Br; R.sup.6 is independently selected from the group: H, F, Cl, Br, CH.sub.3, CONH.sub.2, CONHNR.sup.a R.sup.b, SO.sub.2 NR.sup.a R.sup.b ; CH.sub.2 OH, CHO, CH.sub.2 NHR.sup.a, and CONHR.sup.a ; R.sup.7 is independently, at each occurrence, selected from the group: OH, O--C.sub.2-6 -alkyl-NR.sup.a R.sup.b, F, Cl, Br, NHC(O)OR.sup.a, NHC(O)NR.sup.a R.sup.b, NH.sub.2, NH(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl).sub.2, CONR.sup.a R.sup.b, NHCONHOR.sup.e, NHCONHSO.sub.2 R.sup.f, NHSO.sub.2 NHCO.sub.2 C.sub.1-4 alkyl, NHSO.sub.2 CHR.sup.e CH.sub.2 NR.sup.a R.sup.b, NHCOCHR.sup.e NR.sup.a R.sup.b, NHCOCHR.sup.e NR.sup.b CH.sub.2 R.sup.f R.sup.a, NHCOCH.sub.2 CHR.sup.e NR.sup.a R.sup.b, NHCOCHR.sup.e CH.sub.2 NR.sup.a R.sup.b, NHCO(CH.sub.2).sub.m NR.sup.a R.sup.b, NHCONR.sup.e (CH.sub.2).sub.n NR.sup.a R.sup.b, NHCO.sub.2 (CHR.sup.e).sub.n NNR.sup.a R.sup.b, CONR.sup.e NR.sup.a R.sup.b, NHCONHNR.sup.a R.sup.b, C.sub.1-4 alkyl substituted with 0-1 R.sup.8, and C.sub.5-7 heterocycle containing 1-3 heteroatoms selected from O, N, and S; R.sup.8 is independently, at each occurrence, selected from the group: NH.sub.2, NH(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl).sub.2, and CONR.sup.a R.sup.b ; R.sup.a is independently, at each occurrence, selected from the group: H, C.sub.1-3 alkyl, C.sub.3-6 cycloalkyl, and C.sub.1-3 alkyl substituted with R; R is independently, at each occurrence, selected from the group: H, C.sub.1-3 alkyl, and NR.sup.c R.sup.d ; R.sup.b is independently, at each occurrence, selected from the group: H and C.sub.1-6 alkyl; alternatively, R.sup.a and R.sup.b or R.sup.a and R.sup.e, together with the atoms to which they are attached, form a heterocycle having 5-7 atoms in the ring and containing 0-1 additional N, O, or S atom; alternatively, R.sup.a and R.sup.b and R.sup.e, together with the atoms to which they are attached, form a bicyclic heterocycle having 9-11 atoms in the ring and containing one additional N, S, or O atom; R.sup.c is independently, at each occurrence, selected from the group: H and R.sup.f ; R.sup.d is independently, at each occurrence, selected from the group: H and C.sub.1-3 alkyl; alternatively, R.sup.c and R.sup.d, together with the atoms to which they are attached, form a 5-6 membered ring and containing 0-2 additional N, S, or O atoms; R.sup.e is independently, at each occurence, selected from the group: H and CH.sub.3 ; R.sup.f is C.sub.1-4 alkyl substituted with 0-1 group selected from the group: NH.sub.2, NHMe, NMe.sub.2, OH, and OMe; n at each occurrence is independently selected from 2, 3, 4, 5, and 6; and m at each occurrence is independently selected from 3, 4, 5, and 6. 5. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of claims 1-4. 6. A method of inhibiting cyclin dependent kinase comprising: administering to a host in need of such treatment a therapeutically effective amount of a first compound of formula (I) or its tautomer, formula (II): ##STR57## or a steroisomer or pharmaceutically acceptable salt form thereof, wherein: Q is selected from the group: H, OH, and CH.sub.3, and CH.sub.2 CH.sub.3 ; Y is selected from the group: F, Cl, Br, and I; Z is selected from the group: N and CR.sup.6 ; R.sup.1 is selected from the group: phenyl, tropone, naphthyl, and a 5-10 membered aromatic heterocycle containing from 1-4 heteroatoms selected from O, N, and S, and R.sup.1 is substituted with 0-3 R.sup.7 ; R.sup.2 is selected from the group: C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, S--C.sub.1-3 alkyl, O--C.sub.1-3 alkyl, NH.sub.2, NH--C.sub.1-3 alkyl, N(C.sub.1-2 alkyl).sub.2, OCF.sub.3, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, 1-methylcyclopropyl, 1-methylcyclobutyl, CH.sub.2 CN, CH.sub.2 OH, CH.sub.2 OCH.sub.3, CH.sub.2 NH.sub.2, CH.sub.2 NHC.sub.1-3 alkyl, CH.sub.2 NMe.sub.2, CF.sub.3, CHO, OCH.sub.2 CH.sub.2 OH, OCH(Me)CH.sub.2 OH, OCH.sub.2 CH(Me)OH, OCH.sub.2 CH.sub.2 NMe.sub.2, and CHF.sub.2 ; R.sup.3 is selected from the group: H, F, Cl, Br, I, CF.sub.3, CHO, CHR.sup.g OH, COCF.sub.3, CH.dbd.NOH, CH.dbd.NOCH.sub.3, CH.dbd.NNH.sub.2, CH.dbd.NNHMe, CH.dbd.NNMe.sub.2, CH.dbd.CHR.sup.a, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, CO.sub.2 H, CONH.sub.2, CONH(C.sub.1-3 alkyl), CON(C.sub.1-3 alkyl).sub.2, CO.sub.2 C.sub.1-3 alkyl, C(O)C.sub.1-2 akyl, NH.sub.2, NH(C.sub.1-3 alkyl), and N(C.sub.1-3 alkyl).sub.2 ; R.sup.4 is selected from the group: H, F, Cl, Br, I, CF.sub.3, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, NH.sub.2, NH(C.sub.1-3 alkyl), and N(C.sub.1-3 alkyl).sub.2 ; R.sup.5 is selected from the group: H, C.sub.1-3 alkyl, F, Cl, Br, I, CF.sub.3, and C.sub.2-3 alkenyl; R.sup.6 is selected from the group: H, F, Cl, Br, I, CF.sub.3, --NO.sub.2, C.sub.1-3 alkyl optionally substituted with 1-2 R, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 alkoxy, CO.sub.2 H, CHO, CONR.sup.a R.sup.b, CO.sub.2 C.sub.1-3 alkyl, C(O)C.sub.1-2 alkyl, CH.sub.2 NHR.sup.a, CONR.sup.g NR.sup.a R.sup.b, NR.sup.a R.sup.b ; SO.sub.2 NR.sup.a R.sup.b, CR.dbd.NNR.sup.a R.sup.b, CR.dbd.NOR.sup.f, and R.sup.h ; R.sup.7 is independently, at each occurrence, selected from the group: OH, C.sub.1-6 alkoxy, OC.sub.2-6 alkyl-CO.sub.2 H, O--C.sub.2-6 -alkyl-NR.sup.a R.sup.b, F, Cl, Br, I, CF.sub.3, OCF.sub.3, --CN, --NO.sub.2, CO.sub.2 H, CO.sub.2 (C.sub.1-6 alkyl), CONR.sup.a R.sup.b, NR.sup.g CONHOR.sup.g, NR.sup.g CONHSO.sub.2 R.sup.a, NHNR.sup.g C(O)OR.sup.a, NR.sup.g C(O)NR.sup.a R.sup.b, NH.sub.2, NH(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl).sub.2, --SO.sub.2 NR.sup.a R.sup.b, NHSO.sub.2 NHCO.sub.2 C.sub.1-4 alkyl, NR.sup.g SO.sub.2 NR.sup.a R.sup.b, NR.sup.g SO.sub.2 CHR.sup.e CH.sub.2 NR.sup.a R.sup.b, NR.sup.g COCHR.sup.e NR.sup.a R.sup.b, NR.sup.g COCHR.sup.e NR.sup.b CH.sub.2 R.sup.f R.sup.a, NRgCOCH2CHReNRaRb, NR.sup.g COCHR.sup.e CH.sub.2 NR.sup.a R.sup.b, NR.sup.g CO(CH.sub.2).sub.m NR.sup.a R.sup.b, NR.sup.g CONR.sup.e (CH.sub.2).sub.n NR.sup.a R.sup.b, NR.sup.g CO.sub.2 (CHR.sup.e).sub.n NR.sup.a R.sup.b, CONR.sup.e NR.sup.a R.sup.b, NR.sup.g CONR.sup.e NR.sup.a R.sup.b, C.sub.3-10 carbocycle, C.sub.1-10 alkyl substituted with 0-3 R.sup.8, NCONR.sup.h, NHCONHCH.sub.2 R.sup.h, NHCOR.sup.h, NHCOCH.sub.2 R.sup.h, C.sub.2-10 alkenyl substituted with 0-3 R.sup.8, C.sub.2-10 alkynyl substituted with 0-3 R.sup.8, and C.sub.3-10 heterocycle containing 1-4 heteroatoms selected from O, N, and S; R.sup.8 is independently, at each occurrence, selected from the group: .dbd.O, OH, C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy, NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, F, Cl, Br, I, CO.sub.2 H, COR.sup.a, CO.sub.2 (benzyl), CO.sub.2 (C.sub.1-6 alkyl), and CONR.sup.a R.sup.b ; R.sup.a is independently, at each occurrence, selected from the group: H, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, and C.sub.1-6 alkyl substituted with one R; R is independently, at each occurrence, selected from the group: H, C.sub.1-3 alkyl, C.sub.3-6 cycloalkyl, CO.sub.2 H, OH, and NR.sup.c R.sup.d ; R.sup.b is independently, at each occurrence, selected from the group: H and C.sub.1-6 alkyl; alternatively, R.sup.a and R.sup.b or R.sup.a and R.sup.e, together with the atoms to which they are attached, form a heterocycle having 5-7 atoms in the ring and containing 0-1 additional N, O, or S atom; alternatively, R.sup.a and R.sup.b and R.sup.e, together with the atoms to which they are attached, form a bicycle heterocycle having 9-11 atoms in the ring and containing one additional N, S, or O atom; R.sup.c is independently, at each occurrence, selected from the group: H, R.sup.f, and CO.sub.2 H; R.sup.d is independently, at each occurrence, selected from the group: H and C.sub.1-6 alkyl; alternatively, R.sup.c and R.sup.d, together with the atoms to which they are attached, form a 5-7 membered ring and containing 0-3 additional N, S, or O atoms; R.sup.e is independently, at each occurrence, selected from the group: H and C.sub.1-6 alkyl; R.sup.f is C.sub.1-4 alkyl substituted with 0-1 group selected from the group: NH.sub.2, NHMe, NMe.sub.2, OH and OMe; R.sup.g is independently, at each occurrence, selected from H and C.sub.1-3 alkyl; R.sup.h is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH.sub.2, NHMe, NMe.sub.2, OH and OMe; n at each occurrence is independently selected from 2, 3, 4, 5, and 6; and m at each occurrence is independently selected from 3, 4, 5, and 6; or a pharmaceutically acceptable salt thereof. 7. A method of inhibiting cyclin dependent kinase according to claim 6 further comprising the administration of a therapeutically effective amount of one or more additional compounds selected from the group of consisting of anti-cancer agents and anti-proliferative agents. 8. A method of inhibiting cyclin dependent kinase according to claim 7 wherein the anti cancer or anti proliferative agent is selected from the group consisting of: altretamine, busulfan, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, thiotepa, cladribine, fluorouracil, floxuridine, gemcitabine, thioguanine, pentostatin, methotrexate, 6-mercaptopurine, cytarabine, carmustine, lomustine, streptozotocin, carboplatin, cisplatin, oxaliplatin, iproplatin, tetraplatin, lobaplatin, JM216, JM335, fludarabine, aminoglutethimide, flutamide, goserelin, leuprolide, megestrol acetate, cyproterone acetate, tamoxifen, anastrozole, bicalutamide, dexamethasone, diethylstilbestrol, prednisone, bleomycin, dactinomycin, daunorubicin, doxorubicin, idarubicin, mitoxantrone, losoxantrone, mitomycin-c, plicamycin, paclitaxel, docetaxel, topotecan, irinotecan, 9-amino camptothecan, 9-nitro camptothecan, GS-211, etoposide, teniposide, vinblastine, vinblastine, vincristine, vinorelbine, procarbazine, asparaginase, pegaspargase, octreotide, estramustine, and hydroxyurea. 9. A method of treating cyclin dependent kinase-associated disorders comprising: administering to a host in need of such treatment a therapeutically effective amount of a first compound of formula (I) or its tautomer, formula (II): ##STR58## or a steroisomer or pharmaceutically acceptable salt form thereof, wherein: Q is selected from the group: H, OH, and CH.sub.3, and CH.sub.2 CH.sub.3 ; Y is selected from the group: F, Cl, Br, and I; Z is selected from the group: N and CR.sup.6 ; R.sup.1 is selected from the group: phenyl, tropone, naphthyl, and a 5-10 membered aromatic heterocycle containing from 1-4 heteroatoms selected from O, N, and S, and R.sup.1 is substituted with 0-3 R.sup.7 ; R.sup.2 is selected from the group: C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, S--C.sub.1-3 alkyl, O--C.sub.1-3 alkyl, NH.sub.2, NH--C.sub.1-3 alkyl, N(C.sub.1-2 alkyl).sub.2, OCF.sub.3, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, 1-methylcyclopropyl, 1-methylcyclobutyl, CH.sub.2 CN, CH.sub.2 OH, CH.sub.2 OCH.sub.3, CH.sub.2 NH.sub.2, CH.sub.2 NHC.sub.1-3 alkyl, CH.sub.2 NMe.sub.2, CF.sub.3, CHO, OCH.sub.2 CH.sub.2 OH, OCH(Me)CH.sub.2 OH, OCH.sub.2 CH(Me)OH, OCH.sub.2 CH.sub.2 NMe.sub.2, and CHF.sub.2 ; R.sup.3 is selected from the group: H, F, Cl, Br, I, CF.sub.3, CHO, CHR.sup.g OH, COCF.sub.3, CH.dbd.NOH, CH.dbd.NOCH.sub.3, CH.dbd.NNH.sub.2, CH.dbd.NNHMe, CH.dbd.NNMe.sub.2, CH.dbd.CHR.sup.a, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, CO.sub.2 H, CONH.sub.2, CONH(C.sub.1-3 alkyl), CON(C.sub.1-3 alkyl).sub.2, CO.sub.2 C.sub.1-3 alkyl, C(O)C.sub.1-2 akyl, NH.sub.2, NH(C.sub.1-3 alkyl), and N(C.sub.1-3 alkyl).sub.2 ; R.sup.4 is selected from the group: H, F, Cl, Br, I, CF.sub.3, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, NH.sub.2, NH(C.sub.1-3 alkyl), and N(C.sub.1-3 alkyl).sub.2 ; R.sup.5 is selected from the group: H, C.sub.1-3 alkyl, F, Cl, Br, I, CF.sub.3, and C.sub.2-3 alkenyl; R.sup.6 is selected from the group: H, F, Cl, Br, I, CF.sub.3, --NO.sub.2, C.sub.1-3 alkyl optionally substituted with 1-2 R, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 alkoxy, CO.sub.2 H, CHO, CONR.sup.a R.sup.b, CO.sub.2 C.sub.1-3 alkyl, C(O)C.sub.1-2 alkyl, CH.sub.2 NHR.sup.a, CONR.sup.g NR.sup.a R.sup.b, NR.sup.a R.sup.b ; SO.sub.2 NNR.sup.a R.sup.b, CR.dbd.NNR.sup.a R.sup.b, CR.dbd.NOR.sup.f, and R.sup.h ; R.sup.7 is independently, at each occurrence, selected from the group: OH, C.sub.1-6 alkoxy, OC.sub.2-6 alkyl-CO.sub.2 H, O--C.sub.2-6 -alkyl-NR.sup.a R.sup.b, F, Cl, Br, I, CF.sub.3, OCF.sub.3, --CN, --NO.sub.2, CO.sub.2 H, CO.sub.2 (C.sub.1-6 alkyl), CONR.sup.a R.sup.b, NR.sup.g CONHOR.sup.g, NR.sup.g CONHSO.sub.2 R.sup.a, NHNR.sup.g C(O)OR.sup.a, NR.sup.g C(O)NR.sup.a R.sup.b, NH.sub.2, NH(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl).sub.2, --SO.sub.2 NR.sup.a R.sup.b, NHSO.sub.2 NHCO.sub.2 C.sub.1-4 alkyl, NR.sup.g SO.sub.2 NR.sup.a R.sup.b, NR.sup.g SO.sub.2 CHR.sup.e CH.sub.2 NNR.sup.a R.sup.b, NR.sup.g COCHR.sup.e NNR.sup.a R.sup.b, NR.sup.g COCHR.sup.e NR.sup.b CH.sub.2 R.sup.f R.sup.a, NR.sup.g COCH.sub.2 CHR.sup.e NR.sup.a R.sup.b, NR.sup.g COCHR.sup.e CH.sub.2 NR.sup.a R.sup.b, NR.sup.g CO(CH.sub.2).sub.m NR.sup.a R.sup.b, NR.sup.g CONR.sup.e (CH.sub.2).sub.n NR.sup.a R.sup.b, NR.sup.g CO.sub.2 (CHR.sup.e).sub.n NR.sup.a R.sup.b, CONR.sup.e NR.sup.a R.sup.b, NR.sup.g CONR.sup.e NR.sup.a R.sup.b, C.sub.3-10 carbocycle, C.sub.1-10 alkyl substituted with 0-3 R.sup.8, NCONR.sup.h, NHCONHCH.sub.2 R.sup.h, NHCOR.sup.h, NHCOCH.sub.2 R.sup.h, C.sub.2-10 alkenyl substituted with 0-3 R.sup.8, C.sub.2-10 alkynyl substituted with 0-3 R.sup.8, and C.sub.3-10 heterocycle containing 1-4 heteroatoms selected from O, N, and S; R.sup.8 is independently, at each occurrence, selected from the group: .dbd.O, OH, C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy, NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, F, Cl, Br, I, CO.sub.2 H, COR.sup.a, CO.sub.2 (benzyl), CO.sub.2 (C.sub.1-6 alkyl), and CONR.sup.a R.sup.b ; R.sup.a is independently, at each occurrence, selected from the group: H, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, and C.sub.1-6 alkyl substituted with one R; R is independently, at each occurrence, selected from the group: H, C.sub.1-3 alkyl, C.sub.3-6 cycloalkyl, CO.sub.2 H, OH, and NR.sup.c R.sup.d ; R.sup.b is independently, at each occurrence, selected from the group: H and C.sub.1-6 alkyl; alternatively, R.sup.a and R.sup.b or R.sup.a and R.sup.e, together with the atoms to which they are attached, form a heterocycle having 5-7 atoms in the ring and containing 0-1 additional N, O, or S atom; alternatively, R.sup.a and R.sup.b and R.sup.e, together with the atoms to which they are attached, form a bicycle heterocycle having 9-11 atoms in the ring and containing one additional N, S, or O atom; R.sup.c is independently, at each occurrence, selected from the group: H, R.sup.f, and CO.sub.2 H; R.sup.d is independently, at each occurrence, selected from the group: H and C.sub.1-6 alkyl; alternatively, R.sup.c and R.sup.d, together with the atoms to which they are attached, form a 5-7 membered ring and containing 0-3 additional N, S, or O atoms; R.sup.e is independently, at each occurrence, selected from the group: H and C.sub.1-6 alkyl; R.sup.f is C.sub.1-4 alkyl substituted with 0-1 group selected from the group: NH.sub.2, NHMe, NMe.sub.2, OH and OMe; R.sup.g is independently, at each occurrence, selected from H and C.sub.1-3 alkyl; R.sup.h is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH.sub.2, NHMe, NMe.sub.2, OH and OMe; n at each occurrence is independently selected from 2, 3, 4, 5, and 6; and m at each occurrence is independently selected from 3, 4, 5, and 6; or a pharmaceutically acceptable salt thereof.

Details for Patent 6,531,477

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2018-10-13
Servier Pharmaceuticals Llc	ONCASPAR	pegaspargase	Injection	103411	02/01/1994		2018-10-13