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Generated: August 20, 2019

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Claims for Patent: 6,531,477

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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 Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Merck ELSPAR asparaginase VIAL 101063 001 1978-01-10 ➤ Sign Up DuPont Pharmaceuticals Company (Wilmington, DE) 2018-10-13 RX search
Sigma Tau ONCASPAR pegaspargase VIAL 103411 001 1994-02-01 ➤ Sign Up DuPont Pharmaceuticals Company (Wilmington, DE) 2018-10-13 RX search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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