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): 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.

Description

FIELD OF THE INVENTION

This invention relates generally to novel 6-substituted pyrazolo[3,4-d]pyrimidin-4-ones which are useful as cyclin dependent kinase (cdk) inhibitors, pharmaceutical compositions comprising the same, methods for using the same for treating cancer and proliferative diseases, and intermediates and processes for making the same.

BACKGROUND OF THE INVENTION

One of the most important and fundamental processes in biology is the division of cells mediated by the cell cycle. This process ensures the controlled production of subsequent generations of cells with defined biological function. It is a highly regulated phenomenon and responds to a diverse set of cellular signals both within the cell and from external sources. A complex network of tumor promoting and suppressing gene products are key components of this cellular signaling process. Overexpression of the tumor promoting components or the subsequent loss of the tumor suppressing products will lead to unregulated cellular proliferation and the generation of tumors (Pardee, Science 246:603-608, 1989).

Cyclin dependent kinases play a key role in regulating the cell cycle machinery. These complexes consist of two components: a catalytic subunit (the kinase) and a regulatory subunit (the cyclin). To date, eight kinase subunits (cyclin dependent kinase 1-8) have been identified along with several regulatory subunits (cyclins A-H, K, N, and T). Each kinase associates with a specific regulatory partner and together make up the active catalytic moiety. Each transition of the cell cycle is regulated by a particular cyclin dependent kinase complex: G1/S by cyclin dependent kinase2/cyclin E, cyclin dependent kinase4/cyclin D1 and cyclin dependent kinase6/cyclinD2; S/G2 by cyclin dependent kinase2/cyclin A and cyclin dependent kinase1/cyclin A; G2/M by cyclin dependent kinase1/cyclinB. The coordinated activity of these kinases guides the individual cells through the replication process and ensures the vitality of each subsequent generation (Sherr, Cell 73:1059-1065, 1993; Draetta, Trends Biochem. Sci . 15:378-382, 1990).

An increasing body of evidence has shown a link between tumor development and cyclin dependent kinase related malfunctions. Overexpression of the cyclin regulatory proteins and subsequent kinase hyperactivity have been linked to several types of cancers (Jiang, Proc. Natl. Acad. Sci. USA 90:9026-9030, 1993; Wang, Nature 343:555-557, 1990). More recently, endogenous, highly specific protein inhibitors of cyclin dependent kinases were found to have a major affect on cellular proliferation (Kamb et al., Science 264:436-440, 1994; Beach, Nature 336:701-704, 1993). These inhibitors include p16 INK4 (an inhibitor of cyclin dependent kinase4/D1), p21 CIP1 (a general cyclin dependent kinase inhibitor), and p27 KIP1 (a specific cyclin dependent kinase2/E inhibitor). A recent crystal structure of p27 bound to cyclin dependent kinase2/A revealed how these proteins effectively inhibit the kinase activity through multiple interactions with the cyclin dependent kinase complex (Pavletich, Nature 382:325-331, 1996). These proteins help to regulate the cell cycle through specific interactions with their corresponding cyclin dependent kinase complexes. Cells deficient in these inhibitors are prone to unregulated growth and tumor formation.

Schmidt et al. describe in U.S. Pat. No. 3,211,731 (issued Oct. 12, 1965) pyrazolo[3,4-d]pyrimidines of the formula:

where:

R 1 represents hydrogen, alkyl, cycloalkyl, aralkyl, oxalkyl, hydroxyalkyl, halogenoalkyl, cycloalkylalkyl, heteroaralkyl, mono- or binuclear aryl or heteroaryl;

R 3 represents hydrogen or lower alkyl;

R 6 represents substituted or unsubstituted aralkyl or heteroaralkyl.

These compounds are claimed to have utility as coronary dilating agents.

SUMMARY OF THE INVENTION

The present invention describes a novel class of 6-substituted pyrazolo[3,4-d]pyrimidin-4-ones or pharmaceutically acceptable salt or prodrug forms thereof that are potent inhibitors of the class of enzymes known as cyclin dependent kinases.

It is another object of this invention to provide a novel method of treating cancer or other proliferative diseases by administering a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of this invention to provide a novel method of treating cancer or other proliferative diseases, which comprises administering a therapeutically effective combination of at least one of the compounds of the present invention and at least one other known anti-cancer or anti-proliferative agent.

These and other objectives, which will become apparant during the following detailed descriptions, have been achieved by the inventors, discovery that compounds of formula (I), alternatively represented by the tautomer (II):

wherein R 1 , R 2 , R 3 , R 4 , R 5 , Q, Y, and Z are defined below or pharmaceutically acceptable salts thereof, are cyclin dependent kinase inhibitors.

As described herein, the inhibitors of this invention are capable of inhibiting the cell-cycle machinery and consequently would be useful in modulating cell-cycle progression, which would ultimately control cell growth and differentiation. Such compounds would be useful for treating subjects having disorders associated with excessive cell proliferation, such as cancer, psoriasis, immunological disorders involving unwanted leukocyte proliferation, in the treatment of restenosis and other smooth muscle cell disorders, and the like.

DETAILED DESCRIPTION OF THE INVENTION

The present invention, in a first embodiment, describes a novel compound of the formula (I) or its tautomer, formula (II):

or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:

Q is selected from the group: H, OH, and CH 3 , and CH 2 CH 3 ;

Y is selected from the group: F, Cl, Br, and I;

Z is selected from the group: N and CR 6 ;

R 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 1 is substituted with 0-3 R 7 ;

R 2 is selected from the group: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, S—C 1-3 alkyl, O—C 1-3 alkyl, NH 2 , NH—C 1-3 alkyl, N(C 1-2 alkyl) 2 , OCF 3 , cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, 1-methylcyclopropyl, 1-methylcyclobutyl, CH 2 CN, CH 2 OH, CH 2 OCH 3 , CH 2 NH 2 , CH 2 NHC 1-3 alkyl, CH 2 NMe 2 , CF 3 , CHO, OCH 2 CH 2 OH, OCH(Me)CH 2 OH, OCH 2 CH(Me)OH, OCH 2 CH 2 NMe 2 , and CHF 2 ;

R 3 is selected from the group: H, F, Cl, Br, I, CF 3 , CHO, CHR g OH, COCF 3 , CH═NOH, CH═NOCH 3 , CH═NNH 2 , CH═NNHMe, CH═NNMe 2 , CH═CHR a , C 1-3 alkyl, C 1-3 alkoxy, CO 2 H, CONH 2 , CONH(C 1-3 alkyl), CON(C 1-3 alkyl) 2 , CO 2 C 1-3 alkyl, C(O)C 1-2 alkyl, NH 2 , NH(C 1-3 alkyl), and N(C 1-3 alkyl) 2 ;

R 4 is selected from the group: H, F, Cl, Br, I, CF 3 , C 1-3 alkyl, C 2-3 alkenyl, NH 2 , NH(C 1-3 alkyl), and N(C 1-3 alkyl) 2 ;

R 5 is selected from the group: H, C 1-3 alkyl, F, Cl, Br, I, CF 3 , and C 2-3 alkenyl;

R 6 is selected from the group: H, F, Cl, Br, I, CF 3 , —NO 2 , C 1-3 alkyl optionally substituted with 1-2 R, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, CO 2 H, CHO, CONR a R b , CO 2 C 1-3 alkyl, C(O)C 1-2 alkyl, CH 2 NHR a , CONR g NR a R b , NR a R b ; SO 2 NR a R b , CR═NNR a R b , CR═NOR f , and R h ;

R 7 is independently, at each occurrence, selected from the group: OH, C 1-6 alkoxy, OC 2-6 alkyl-CO 2 H, O—C 2-6 -alkyl-NR a R b , F, Cl, Br, I, CF 3 , OCF 3 , —CN, —NO 2 , CO 2 H, CO 2 (C 1-6 alkyl), CONR a R b , NR g CONHOR g , NR g CONHSO 2 R a , NHNR g C(O)OR a , NR g C(O)NR a R b , NH 2 , NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , —SO 2 NR a R b , NHSO 2 NHCO 2 C 1-4 alkyl, NR g SO 2 NR a R b , NR g SO 2 CHR e CH 2 NR a R b , NR g COCHR e NR a R b , NR g COCHR e NR b CH 2 R f R a , NR g COCH 2 CHR e NR a R b , NR g COCHR e CH 2 NR a R b , NR g CO(CH 2 ) m R a R b , NR g CONR e (CH 2 ) n NR a R b , NR g CO 2 (CHR e ) n NR a R b , CONR e NR a R b , NR g CONR e NR a R b , C 3-10 carbocycle, C 1-10 alkyl substituted with 0-3 R 8 , NHCONR h , NHCONHCH 2 R h , NHCOR h , NHCOCH 2 R h , C 2-10 alkenyl substituted with 0-3 R 8 , C 2-10 alkynyl substituted with 0-3 R 8 , and C 3-10 heterocycle containing 1-4 heteroatoms selected from O, N, and S;

R 3 is independently, at each occurrence, selected from the group: ═O, OH, C 3-6 cycloalkyl, C 1-6 alkoxy, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , F, Cl, Br, I, CO 2 H, COR a , CO 2 (benzyl), CO 2 (C 1-6 alkyl), and CONR a R b ;

R a is independently, at each occurrence, selected from the group: H, C 1-6 alkyl, C 3-7 cycloalkyl, and C 1-6 alkyl substituted with one R;

R is independently, at each occurrence, selected from the group: H, C 1-3 alkyl, C 3-6 cycloalkyl, CO 2 H, OH, and NR c R d ;

R b is independently, at each occurrence, selected from the group: H and C 1-6 alkyl;

alternatively, R a and R b or R a and R 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 a and R b and R 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 c is independently, at each occurrence selected from the group: H, R f , and CO 2 H;

R d is independently, at each occurrence, selected from the group: H and C 1-6 alkyl;

alternatively, R c and R 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 e is independently, at each occurrence, selected from the group: H and C 1-6 alkyl;

R f is C 1-4 alkyl substituted with 0-1 group selected from the group: NH 2 , NHMe, NMe 2 , OH, and OMe;

R g is independently, at each occurrence, selected from H and C 1-3 alkyl;

R h is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH 2 , NHMe, NMe 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.

In a preferred embodiment, the present invention provides a novel compound of the formula (I) or (II), wherein:

Q is selected from the group: H, OH, and CH 3 ;

Y is selected from the group: F, Cl, and Br;

Z is selected from the group: N and CR 6 ;

R 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 1 is substituted with 0-3 R 7 ;

R 2 is selected from the group: C 2-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, S—C 1-2 alkyl, O—C 1-2 alkyl, cyclopropyl, cyclobutyl, 1-methylcyclopropyl, CH 2 CN, CH 2 OH, CH 2 OCH 3 , CH 2 NH 2 , CH 2 NMe 2 , CF 3 , and CHO;

R 3 is independently selected from the group: H, F, Cl, CH 3 , CH 2 CH 3 , CHO, CHR g OH, COCF 3 , CH═NOH, CH═NOCH 3 , CH═NNH 2 , CH═NNHMe, CH═NNMe 2 , and CH═CHR a ;

R 4 is independently selected from the group: H, F, Cl, and CH 3 ;

R 5 is independently selected from the group: H, CH 3 , F, Cl, Br, and CF 3 ;

R 6 is independently selected from the group: H, F, Cl, Br, CF 3 , C 1-3 alkyl optionally substituted with R, CO 2 H, CONH 2 , CONHR a , CONHNR a R b , CHO, CH 3 , SO 2 NR a R b ; phenyl, and heteroaryl having 5-6 atoms in the ring and containing 1-2 N, O, or S atoms; and CH 2 NHR 8a ;

R 7 is independently, at each occurrence, selected from the group: OH, C 1-3 alkoxy, OC 2-6 alkyl-CO 2 H, O—C 2-6 -alkyl-NR a R b , F, Cl, Br, I, CF 3 , OCF 3 , —CN, CO 2 (C 1-6 alkyl), CONR a R b , NR g C(O)OR a , NR g C(O)NR a R b , NR g CONHOR g , NR g CONHSO 2 R a , NH 2 , NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , SO 2 NR a R b , NR g SO 2 NR a R b , NR g SO 2 NHCO 2 C 1-4 alkyl, NR g SO 2 CHR e CH 2 NR a R b , NR g COCHR e NR a R b , NR g COCHR e NR b CH 2 R f R a , NR g COCH 2 CHR e NR a R b , NR g COCHR e CH 2 NR a R b , NR g CO(CH 2 ) m NR a R b , NR g CONR e (CH 2 ) n NR a R b , NR g CO 2 (CHR e ) n NR a R b , CONR e NR a R b , NR g CONR e NR a R b , C 3-7 carbocycle, NHCONR h , NHCONHCH 2 R h , NHCOR h , NHCOCH 2 R h , C 1-0 alkyl substituted with 0-3 R 8 , C 2-6 alkenyl substituted with 0-3 R 8 , C 2-6 alkynyl substituted with 0-2 R 8 , and C 3-7 heterocycle containing 1-3 heteroatoms selected from O, N, and S;

R 8 is independently, at each occurrence, selected from the group: ═O, OH, C 1-6 alkoxy, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , COR a , and CONR a R b ;

R a is independently, at each occurrence, selected from the group: H, C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 alkyl substituted with one R;

R is independently, at each occurrence, selected from the group: H, C 1-3 alkyl, C 3-6 cycloalkyl, CO 2 H, and NR c R d ;

R b is independently, at each occurrence, selected from the group: H and C 1-6 alkyl;

alternatively, R a and R b or R a and R 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 a and R b and R 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 c is independently, at each occurence, selected from the group: H, R f , and CO 2 H;

R d is independently, at each occurrence, selected from the group: H and C 1-6 alkyl;

alternatively, R c and R 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 e is independently, at each occurrence, selected from the group: H and C 1-4 alkyl;

R f is C 1-4 alkyl substituted with 0-1 group selected from the group: NH 2 , NHMe, NMe 2 , OH, and OMe;

R g is independently, at each occurrence, selected from H and C 1-3 alkyl;

R h is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH 2 , NHMe, NMe 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.

In a more preferred embodiment, the present invention provides a novel compound of the formula (I) or (II), wherein:

Q is H;

Y is selected from the group: F, Cl, and Br;

Z is CR 6 ;

R 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 1 is substituted with 0-2 R 7 ;

R 2 is selected from the group: C 2-4 alkyl, cyclopropyl, cyclobutyl, 1-methylcyclopropyl, and CF 3 ;

R 3 is independently selected from the group: H, F, CH 3 , CHO, CHR g OH, COCF 3 , CH═NOH, CH═NOCH 3 , CH═NNH 2 , CH═NNHMe, CH═NNMe 2 , and CH═CHR a ;

R 4 is independently selected from the group: H and F;

R 5 is independently selected from the group: CH 3 , F, Cl, and Br;

R 6 is independently selected from the group: H, F, Cl, Br, CF 3 , CH 3 , CONH 2 , CONHR a , CONHNR a R b , SO 2 NR a R b ; CH 2 OH, CHO, phenyl, and heteroaryl having 5-6 atoms in the ring and containing 1-2 N, O, or S atoms; and CH 2 NHR a ;

R 7 is independently, at each occurrence, selected from the group: OH, O—C 2-6 -alkyl-NR a R b , F, Cl, Br, CF 3 , —CN, CONR a R b , NHC(O)OR a , NHC(O)NR a R b , NH 2 , NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , SO 2 NR a R b , NHSO 2 NR a R b , NHCONHOR e , NHCONHSO 2 R f , NHSO 2 NHCO 2 C 1-4 alkyl, NHSO 2 CHR e CH 2 NR a R b , NHCOCHR e NR a R b , NHCOCHR e NR b CH 2 R f R a , NHCOCH 2 CHR e NR a R b , NHCOCHR e CH 2 NR a R b , NHCO(CH 2 ) m NR a R b , NHCONR e (CH 2 ) n NR a R b , NHCO 2 (CHR e ) n NNR a R b , CONR e NR a R b , NHCONR e NR a R b , NHCONR h , NHCONHCH 2 R h , NHCOR h , NHCOCH 2 R h , C 3-7 carbocycle, C 1-6 alkyl substituted with 0-3 R 8 , C 2-6 alkenyl substituted with 0-3 R 8 , C 2-6 alkynyl substituted with 0-3 R 8 , and C 3-7 heterocycle containing 1-3 heteroatoms selected from O, N, and S;

R 8 is independently, at each occurrence, selected from the group: OH, C 1-3 alkoxy, NH 2 , NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , and CONR a R b ;

R a is independently, at each occurrence, selected from the group: H, C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 alkyl substituted with one R;

R is independently, at each occurrence, selected from the group: H, C 1-3 alkyl, and NR c R d ;

R b is independently, at each occurrence, selected from the group: H and C 1-6 alkyl;

alternatively, R a and R b or R a and R 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 a and R b and R 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 c is independently, at each occurrence, selected from the group: H and R f ;

R d is independently, at each occurrence, selected from the group: H and C 1-6 alkyl;

alternatively, R c and R 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 e is independently, at each occurrence, selected from the group: H and C 1-3 alkyl;

R f is C 1-4 alkyl substituted with 0-1 group selected from the group: NH 2 , NHMe, NMe 2 , OH, and OMe;

R h is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH 2 , NHMe, NMe 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.

In an even more preferred embodiment, the present invention provides a novel compound of formula (I) or (II), wherein:

Q is H;

Y is Cl;

Z is CR 6 ;

R 1 is selected from the group: phenyl, pyridyl, pyrrolyl, furyl, thienyl, indazolyl, benzoxazolyl, and benzothiazolyl, and R 1 is substituted with 0-2 R 7 ;

R 2 is selected from the group: CF 3 , C 2-3 alkyl and cyclopropyl;

R 3 is selected from the group: H, CH 3 , CH 2 OH, and CHO;

R 4 is H;

R 5 is independently selected from the group: CH 3 , F, Cl, and Br;

R 6 is independently selected from the group: H, F, Cl, Br, CH 3 , CONH 2 , CONHNR a R b , SO 2 NR a R b ; CH 2 OH, CHO, CH 2 NHR a , and CONHR a ;

R 7 is independently, at each occurrence, selected from the group: OH, O—C 2-6 -alkyl-NR a R b , F, Cl, Br, NHC(O)OR a , NHC(O)NR a R b , NH 2 , NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , CONR a R b , NHCONHOR e , NHCONHSO 2 R f , NHSO 2 NHCO 2 C 1-4 alkyl, NHSO 2 CHR e CH 2 NR a R b , NHCOCHR e NR a R b , NHCOCHR e NR b CH 2 R f R a , NHCOCH 2 CHR e NR a R b , NHCOCHR e CH 2 NR a R b , NHCO(CH 2 ) m NR a R b , NHCONR e (CH 2 ) n NR a R b , NHCO 2 (CHR e ) n NNR a R b , CONR e NR a R b , NHCONHNR a R b , C 1-4 alkyl substituted with 0-1 R 8 , and C 5-7 heterocycle containing 1-3 heteroatoms selected from O, N, and S;

R 8 is independently, at each occurrence, selected from the group: NH 2 , NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , and CONR a R b ;

R a is independently, at each occurrence, selected from the group: H, C 1-3 alkyl, C 3-6 cycloalkyl, and C 1-3 alkyl substituted with R;

R is independently, at each occurrence, selected from the group: H, C 1-3 alkyl, and NR c R d ;

R b is independently, at each occurrence, selected from the group: H and C 1-6 alkyl;

alternatively, R a and R b or R a and R 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 a and R b and R 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 c is independently, at each occurrence, selected from the group: H and R f ;

R d is independently, at each occurrence, selected from the group: H and C 1-3 alkyl;

alternatively, R c and R 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 e is independently, at each occurence, selected from the group: H and CH 3 ;

R f is C 1-4 alkyl substituted with 0-1 group selected from the group: NH 2 , NHMe, NMe 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.

In a further preferred embodiment, the compound of formula (I) or formula (II) is selected from:

a) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-hydroxy-3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

b) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

c) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-hydroxy-4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

d) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

e) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

f) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

g) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-acetamidobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

h) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(N-(t-butoxycarbonyl)glycinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

i) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(2-(N,N-dimethylamino)ethylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

j) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-amino-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

k) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(pyrid-2-ylmethylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

l) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-glycinamidobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

m) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(pyrid-4-ylmethylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

n) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(para-biphen-4-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

o) 1-(2,6-dichlorophenyl)-3-ethyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

p) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(4-methylpiperazin-1-ylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

q) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(dimethylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

r) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(2-(hydroxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

s) 1-(2,6-dichlorophenyl)-3-ethyl-6-(4-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

t) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(methoxyaminocarbonylmethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

u) 1-(2,6-dichlorophenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

v) 1-(2,6-dichlorophenyl)-3-ethyl-6-(4-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

w) 1-(2-chloro-6-methylphenyl)-3-ethyl-6-(4-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

x) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3,5-dihydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

y) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-hydroxy-3-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

z) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-amino-3-nitrobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

aa) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(methylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ab) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-(methanesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ac) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(methanesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ad) 1-(2,6-dichloro-4-(pyrid-3-ylaminocarbonyl)phenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]-pyrimidin-4-one;

ae) 1-(2,6-dichloro-4-(pyrid-4-ylaminocarbonyl)phenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]-pyrimidin-4-one;

af) 1-(2,6-dichloro-4-(cyclopropylaminocarbonyl)phenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ag) 1-(2,6-dichloro-4-(N-(pyrid-3-ylmethyl)aminocarbonyl)phenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ah) 1-(2,6-dichloro-4-(N-(pyrid-2-ylmethyl)aminocarbonyl)phenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ai) 1-(2,6-dichloro-4-(ethylaminocarbonyl)phenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

aj) 1-(2,6-dichloro-4-(benzylaminocarbonyl)phenyl)-3-ethyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ak) 1-(2,6-dichloro-4-(2-(dimethylamino)ethylaminocarbonyl)phenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

al) 1-(2,6-dichloro-4-(methylaminocarbonyl)phenyl)-3-ethyl-6-(4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

am) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-(N,N-dimethylglycinamido)-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

an) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(N,N-dimethylglycinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ao) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(N-methylglycinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ap) 1-(2,6-dichloro-4-bromophenyl)-3-ethyl-6-(4-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

aq) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(methoxycarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ar) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

as) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-hydroxy-4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

at) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

au) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(methanesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

av) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(difluoroacetamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

aw) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(acetamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ax) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(methylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ay) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

az) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(azetidin-3-ylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ba) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-aminoethylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bb) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(isopropylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bc) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-fluorobenzylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bd) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(pyrrolidin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

be) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(pyrid-2-ylmethylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bf) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-(t-butoxycarbonylamino)ethylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bg) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(pyrid-3-ylmethylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bh) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(pyrid-4-ylmethylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bi) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-(morpholin-4-yl)ethylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bj) 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(methylaminocarbonylmethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bk) 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(ethylaminocarbonylmethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bl) 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(piperazin-1-ylcarbonylmethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bm) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-methylpyrid-3-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

bn) 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(2-(dimethylamino)ethylaminocarbonylmethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bo) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2,2-dimethylhydrazin-1-ylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bp) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(1-hydroxybut-4-ylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bq) (+/−)1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-hydroxyprop-1-ylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

br) (+/−)1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(1-hydroxyprop-2-ylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bs) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(pyrid-3-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

bt) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bu) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(dimethylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bv) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(pyrid-4-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

bw) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N,N-dimethylglycinamido)-3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bx) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N,N-dimethylglycinamido)-3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

by) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(methylaminocarbonylamino)-3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bz) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-(3-(dimethylamino)propyl)aminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ca) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(benzoxazol-2-on-6-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

cb) 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(4-methylpiperazin-1-ylcarbonylmethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cc) 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(N-methyl,N-(2-(dimethylamino)ethyl)aminocarbonylmethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cd) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(methylaminocarbonylamino)-3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ce) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-methylpiperazin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cf) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(piperazin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cg) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(morpholin-4-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ch) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(imidazol-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ci) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-methyl-N-(1-methylpiperidin-4-yl)aminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cj) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(cyclopropylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ck) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N,N-dimethylglycinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cl) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(methylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cm) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-aminoindazol-5-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

cn) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-methyl,N-(2-(dimethylamino)ethyl)aminomethylcarbonylamino)benzyl)-pyrazolo[3,4-d]pyrimidin-4-one;

co) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-methylpiperazin-1-ylcarbonylmethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cp) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(azetidin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cq) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-hydroxy-4-(imidazol-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cr) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-methylpiperazin-1-ylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cs) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(3-(dimethylamino)prop-1-ylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ct) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-methylhomopiperazin-1-ylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cu) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-methylpiperazin-2-ylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cv) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(t-butoxycarbonylaminosulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cw) 1-(2-chloro-6-methylphenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cx) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-(morpholin-4-yl)ethylaminothiocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cy) 1-(2-chloro-6-methylphenyl)-3-isopropyl-6-(4-(N,N-dimethylglycinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cz) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-bromobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

da) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(piperazin-2-ylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

db) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(1,4-dimethylpiperazin-2-ylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dc) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-(dimethylamino)ethylsulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dd) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-amino-3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

de) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-hydantoin-3-ylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

df) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(2H-1,4-benzoxazin-3-on-7-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

dg) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-(2-(dimethylamino)ethyl)aminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dh) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-hydroxyethylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

di) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dj) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dk) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-glycinamidobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dl) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-methylglycinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dm) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-(dimethylamino)ethylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dn) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-(aminomethyl)piperidin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

do) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(homopiperazin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dp) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(ethylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dq) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(dimethylaminomethyl)-3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dr) (S)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-methylprolinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ds) (+/−)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-,N-dimethylalaninamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dt) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(1,4,7-triazacyclonon-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

du) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-amino-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dv) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-(morpholin-4-yl)ethylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dw) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(N-,N-dimethylglycinamido)-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dx) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-methylpiperazin-1-ylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dy) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(morpholin-4-ylaminocarbonylamino)benzyl)pyrazolo[3,4]pyrimidin-4-one;

dz) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(methoxyaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ea) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(methanesulfonamidocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

eb) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-methyl,N-(2-(dimethylamino)ethyl)aminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ec) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-methyl,N-(1-methylpiperidin-4-yl)aminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ed) (+/−)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(tetrahydrofur-2-ylmethylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ee) (+/−)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(1-hydroxypent-2-ylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ef) (+/−)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(1-hydroxyprop-2-ylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

eg) (+/−)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-hydroxyprop-1-ylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

eh) (+/−)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-(dimethylamino)prop-1-ylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ei) 1-(2,4,6-trichlorophenyl)-3-cyclopropyl-6-(3-hydroxy-4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ej) 1-(2,4,6-trichlorophenyl)-3-cyclopropyl-6-(indazol-6-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

ek) 1-(2,4,6-trichlorophenyl)-3-cyclopropyl-6-(indazol-5-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

el) 1-(2,4,6-trichlorophenyl)-3-cyclopropyl-6-(indazol-4-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

em) 1-(2,4,6-trichlorophenyl)-3-cyclopropyl-6-(benzoxazol-2-on-5-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

en) 1-(2,4,6-trichlorophenyl)-3-cyclopropyl-6-(3-hydroxy-4-nitrobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

eo) 1-(2,4,6-trichlorophenyl)-3-cyclopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ep) 1-(2,4,6-trichlorophenyl)-3-cyclopropyl-6-(4-(N,N-dimethylglycinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

eq) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(cis-3,4-dimethylpiperazin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

er) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(trans-2,5-dimethylpiperazin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

es) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(3-methylpiperazin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

et) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(5-(dimethylaminomethyl)-1-methylpyrrol-2-yl)pyrazolo[3,4-d]pyrimidin-4-one;

eu) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-methylpiperazin-1-ylaminocarbony)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ev) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(N-methyl, N-(2-(dimethylamino)ethyl)aminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ew) 1-(2-chloro-6-methylphenyl)-3-isopropyl-6-(4-(N-methyl,N-(1-methylpiperidin-4-yl)aminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ex) 1-(2-chloro-6-methylphenyl)-3-isopropyl-6-(4-(N-methyl-N-(1-methylpiperidin-4-yl)aminomethylcarboylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ey) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(N-methyl,N((3S,4S)-4-dimethylaminotetrahydrofur-3-yl)aminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ez) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(N-methyl, N-(2-(dimethylamino)ethyl)aminocarbonyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

fa) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-pyrrolidin-1-ylethylaminocarbonyamino)benzyl)pyrazolo[3,4-d] pyrimidin-4-one;

fb) 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(N-methyl, N-(2-(dimethylamino)ethyl)aminocarbonymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

fc) 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(N-(2-(dimethylamino)ethyl)aminocarbonymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

fd) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-(2-(dimethylamino)ethyl)aminocarbonyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

fe) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(methylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ff) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-methyl-N-(1-methylpiperidin-4-yl)aminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

fg) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-methyl, N-(2-(dimethylamino)ethyl)aminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

fh) 1-(2,6-dichloro-4-sulfonamidophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one; and

fi) 1-(4-aminomethyl-2, 6-dichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one.

In another embodiment, the present invention provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method of treating cancer or other proliferative diseases comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method of treating cancer or other proliferative diseases comprising administering to a host in need of such treatment a therapeutically effective amount of:

(a) a compound of formula (I) or (II), or a pharmaceutically acceptable salt form thereof; and,

(b) at least one compound selected from the group consisting of anti-cancer agents and anti-proliferative agents.

DEFINITIONS

As used herein, the following terms and expressions have the indicated meanings. The compounds of the present invention may contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.

The present invention is intended to include all isotopes of atoms occurring on the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include 13 C and 14 C.

The term “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. In addition, the term is intended to include both unsubstituted and substituted alkyl groups, the latter referring to alkyl moieties having one or more hydrogen substituents replaced by, but not limited to, halogen, hydroxyl, carbonyl, alkoxy, ester, ether, cyano, phosphoryl, amino, imino, amido, sulfhydryl, alkythio, thioester, sulfonyl, nitro, heterocyclo, aryl or heteroaryl. It will also be understood by those skilled in the art that the substituted moieties themselves can be substituted as well when appropriate.

The terms “halo” or “halogen” as used herein refer to fluoro, chloro, bromo and iodo. The term “aryl” is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as, but not limited to phenyl, indanyl or naphthyl. The terms “cycloalkyl” and “bicycloalkyl” are intended to mean any stable ring system, which may be saturated or partially unsaturated. Examples of such include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]nonane, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, “carbocycle” or “carbocyclic residue” is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic system” is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term “aromatic heterocyclic system” is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, EtOAc, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences , 18 th ed., Mack Publishing Company, Easton, Pa., 1990, p. 1445, the disclosure of which is hereby incorporated by reference.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

“Prodrugs”, as the term is used herein, are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (i.e., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same, and compositions containing the same. Prodrugs of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.

“Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O) group, then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties.

The term “therapeutically effective amount” of a compound of this invention means an amount effective to inhibit the class of enzymes known as cyclin dependent kinases or treat the symptoms of cancer or other proliferative diseases in a host.

As used herein, the term “anti cancer” or “anti-proliferative” agent includes, but is not limited to, 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, doxirubicin, idarubicin, mitoxantrone, losoxantrone, mitomycin-c, plicamycin, paclitaxel, docetaxel, topotecan, irinotecan, 9-amino camptothecan, 9-nitro camptothecan, GS-211, etoposide, teniposide, vinblastine, vincristine, vinorelbine, procarbazine, asparaginase, pegaspargase, octreotide, estramustine, and hydroxyurea.

DOSAGE AND FORMULATION

The cyclic dependent kinase inhibitor compounds of this invention can be administered as treatment for cancer or proliferative diseases by any means that produces contact of the active agent with the agent's site of action in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but preferably are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.001 to about 1000 milligrams per kilogram of body weight, with the preferred dose being about 0.1 to about 30 mg/kg.

Dosage forms of compositions suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts, and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences , 18 th ed., Mack Publishing Company, Easton, Pa., 1990, a standard reference text in this field, the disclosure of which is hereby incorporated by reference.

SYNTHESIS

The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those methods described below. Each of the references cited below are hereby incorporated herein by reference.

Key intermediates preparing the compounds of the present invention are pyrazole aminonitriles, aminocarboxamides, and aminoesters of the formulas II, III, and IV, respectively. The preparation of these intermediates is has precedence in the chemical literature, and several methods are summarized in Schemes A (A. O. Abdelhamid, A. S. Shawali, et al. J. Heterocycl. Chem ., 1984, 21, 1049.), B (C. C. Cheng and R. K. Robins, J. Org. Chem . 1956, 21, 1240.), C (P. Schmidt and J. Druey, Helv. Chem. Acta , 1956, 39, 986.), and D (Tominaga et al., J. Heterocycl. Chem ., 1990, 27, 775). A wide variety of starting hydrazines and aldehydes are commercially available or can be prepared by standard organic transformations. The substituents in the following schemes, which are designated R 1 , R 2 , and Q, have the same definition as that defined above in the Detailed Description.

Aminonitriles of the formula II can be converted to pyrazolo[3,4-d]pyrimidines of the present invention as shown in Scheme E. In summary, the aminocarboxamide is acylated, optionally in the presence of a suitable solvent such as dichloromethane by treatment with a suitable base such as triethylamine followed by an acid halide of the formula R 1 CHQCOX, preferably an acid chloride to give carboxamidonitriles of the formula V. Alternately carboxamidonitriles of the formula V can be prepared by coupling of aminonitriles II with carboxylic acids of the general formula R 1 CHQCO 2 H in the presence of a suitable base and coupling reagent in a suitable solvent. The coupling of amines and carboxylic acids has been reviewed (Klausnew and Bodansky Synthesis , 1972, 453-463), and the variety of reagents available for effecting it can be appreciated by those skilled in the art.

Transformation of carboxamidonitriles of the formula V to the compounds of the present invention can be accomplished by treatment with an excess of hydrogen peroxide in the presence of a suitable base, preferably a metal hydroxide or alkoxide base in a solvent, preferably water, an alcohol, or a water-alcohol mixture at a temperature in the range of about 0° C. up to 100° C.

Alternatively, carboxamidonitriles of the formula V can be transformed to the compounds of the present invention by heating, preferably for about an hour in concentrated, strong acid, preferably 85% H 3 PO 4 .

Scheme F shows an alternative means for preparing the compounds of the present invention. Amino carboximides of the formula III in a suitable solvent, preferably a lower alkanol, are treated with an excess of an ester of the formula R 1 CHQCO 2 R, where R is lower alkyl and an excess of a base, preferably a metal lower alkoxide, preferably at the boiling point of the solvent to give compounds of the present invention. Many arylacetic esters are commercialy available or can be prepared in one step from commercially available arylacetic acids by esterification with an excess of an alcohol, ROH, preferably at reflux with ethyl or methyl alcohol, used as solvent in the presence of an acid catalyst such as H 2 SO 4 or p-TsOH. Alternatively, a coupling reagent such as DCC can be used, preferably in a solvent such as CH 2 Cl 2 with a catalylst such as DMAP. Phenylacetic acids may be prepared by acid or base hydrolysis of arylacetonitriles which in turn may be prepared by treatment of aryl halides with CN − , preferably in solvents such as DMF, MeOH, EtOH, water, DMSO, or mixtures thereof. Further examples of arylacetic esters may be prepared from aryl carboxylic acids under Arndt-Eistert (Meier and Zeller Angew. Chem. Int. Ed. Engl . 1975, 14, 32-43.) or related homologation conditions.

Aminoesters of the formula IV can be converted to compounds of the present invention by reaction with an excess of a nitrile of the formula R 1 CHQCN and sodium. This reaction is preferably performed neat with heating.

Pyrazolo[3,4-d]pyrimidin-4-ones may be further elaborated as described below to give additional compounds of the present invention. Electrophilic aromatic substitution reactions can be performed on the R 1 aryl or heteroaryl group to introduce substituents. Such reactions include, but are not limited to nitration, acylation (Friedel-Crafts), halogenation, alkylation (Friedel-Crafts), chloromethylation, sulfonation, and aminomethylation (Mannich reaction). Conditions for performing these reactions are familiar to those skilled in the art of organic synthesis, generally involving reaction of the electrophile with the aryl or heteroaryl substrate in the presence of a catalyst. In the case of nitrations or Mannich reactions, the catalyst is preferably a protic acid which may serve as solvent, where the electrophile is generated in situ from saltpeter, or an amine and a carbonyl component, respectively. For other electrophilic aromatic substitution reactions, preferred catalysts are Lewis acids, including but not limited to FeX 3 , AlX 3 , and ZnX 2 , where X is halogen.

The compounds prepared above which have an amino group can be derivatized by reaction with electrophiles including, but not limited to acyl halides, anhydrides, isocyanates, chloroformates, sulfonyl halides, alkyl halides, lactones, or esters. Conditions for performing these addition reactions are familiar to those skilled in the art of organic synthesis, generally involving addition of the electrophile to the nucleophile, preferably in solution at a temperature between 0° C. and RT. Addition of a base may be necessary. It should be noted that the products of these reactions can react further with some electrophiles at the pyrimidinone nitrogen (N5). The resulting functional groups (amides, carbamates, etc.) are less stable to basic hydrolysis than the desired anilino- or aliphatic groups and can be cleaved back to the pyrimidinone having H on N5. Reaction of compounds bearing an amine group with agents such as haloacyl halides, α,β-unsaturated acid halides, or halosulfonyl halides gives intermediates which can react with nucleophiles such as primary or secondary amines, diamines, alkoxides, aminoalcohols or thiols.

The compounds prepared above, which have a carboxyl group, can be derivatized by activation and reaction with nucleophiles including, but not limited to amines and alcohols to give, respectively, amides and esters. The coupling of amines and carboxylic acids with carbodiimides has been reviewed (Klausnew and Bodansky Synthesis , 1972, 453-463), and the variety of additional reagents available for effecting it as well as the potential need for protecting groups (Green and Wuts “Protective Groups in Organic Synthesis” Second Edition, John Wiley & Sons, 1991) to mask reactive functionality can be appreciated by those skilled in the art. The preparation of esters from acids has been described above. Reduction of these amides and esters to amines and alcohols can be performed using a suitable hydride reducing agent.

The compounds prepared above which have an amino group can be derivatized by conversion to an electrophilic species by activation with phosgene or a phosgene equivalent ( Tetrahedron: Asymmetry 1995, 6, 745 ; J. Org. Chem . 1994, 59, 1937.), preferably in the presence of a base, and reaction with nucleophiles including, but not limited to amines, alcohols, and sulfonamides to give, respectively, ureas, carbamates, and sulfonylureas. Conditions for performing these reactions and the hazards associated with handling phosgene and phosgene equivalents are familiar to those skilled in the art of organic synthesis, and all appropriate precautions should be taken.

Further transformations which may be required to prepare compounds of the present invention include reductions of ketones, aldehydes, esters, acids, amides or reductive aminations by alumino- and borohydride reagents (J. Seyden-Penne “Reductions by the Alumino and Borohydrides in Organic Synthesis” VCH Publishers, Inc., 1991) and oxidations of groups including but not limited to alcohols, aldehydes, olefins, thioethers, sulfoxides, and heteroaryl groups (Milos Hudlicky “Oxidations in Organic Chemistry” American Chemical Society, 1990). Reduction of functional groups such as alkenes, alkynes, nitrogen, nitro- or cyano-groups could be accomplished by catalytic hydrogenation or by dissolving metal reduction. Further elaboration of intermediates containing electrophilic sites to compounds of the present invention could be accomplished by displacement with nucleophiles including, but not limited to, CN − , amines, alkoxides, mercaptans, or carbanions. Still other compounds of the present invention could be prepared by coupling of aryl halides, triflates, or stannames with the appropriate boronic acids (Stilk, J. K. Angew. Chem. Int. Ed. Engl . 1986, 25, 508; Suzuki, A. Pure Appl. Chem . 1985, 57, 1749.). The compounds prepared above, which have a carbonyl group, can be derivatized further by reaction with nucleophiles to give secondary alcohols. Such nucleophiles include, but are not limited to, Grignard reagents, alkyl-, alkenyl-, and alkynyl-lithium reagents, and allyl-stannanes, silanes, and the like. Compounds prepared as described above could be further elaborated by rearrangements such as the Beckmann (Gawley in Org. React . 1988, 35, 1-420.) or other rearrangements.

Further elaboration of the compounds prepared above can be accomplished by generation of an organomagnesium organolithium species by directed metallation (Beak and Meyers Acc. Chem. Res . 1986, 19, 356-363; Beak and Snieckus Acc. Chem. Res . 1982, 15, 306-312; Katritzky, Lam, and Sengupta Prog. Heterocycl. Chem . 1989, 1, 1-29) or from an aryl halide by lithium-halogen exchange (Parham and Bradsher, Acc. Chem. Res . 1982, 15, 300-305).

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

Abbreviations used in the Examples are defined as follows: “° C.” for degrees Celsius, “MS or mass spec.” for mass spectrum, “g” for gram or grams, “h” for hour or hours, “mg” for milligram or milligrams, “mL” for milliliter or milliliters, “mmol” for millimoles, “M” for molar, “min” for minute or minutes, “DMF” for dimethylformamide, “THF” for tetrahydrofuran, “Boc” for t-butoxycarbonyl, “Bop” for (benzotriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate, “EDC” for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, “BopCl” for bis(2-oxo-3-oxazolidinyl)phosphinic chloride, “ether” for diethyl ether, “aq” for aqueous, “RT” for ambient temperature, “HOAc” for acetic acid, “EtOAc” for ethyl acetate “p-TsOH” for para-toluenesulfonic acid, “DIEA” for N,N-diisopropylethylamine, “t-BuOH” for t-butanol, “EtOH” for ethanol, “MeOH” for methanol, “NBS” for N-bromosuccinimide, and “TFA” for trifluoroacetic acid. “Mass spec.” results refer to M/z for the product species composed entirely of the most prevalent isotopes of each of its constituent atoms, i.e. 12 for carbon, 1 for hydrogen, 35 for Cl, 14 for N, and 16 for O. Ionization techniques used give M + , (M+H ) + , or (M−H) − species. Proton ( 1 H) nuclear magnetic resonance (NMR) experiments were performed on dilute solutions in the solvent indicated at the frequency (generally 300 MHz) indicated. Chemical shifts are reported in ppm downfield from tetramethylsilane. The following abbreviations are used: “s” for singlet, “d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet, and “br.” for broad. Reported integrations are approximate. It is understood by those experienced in the interpretation of NMR spectra that some proton signals are absent, increased or diminished in measured intensity in a given spectrum due to factors such as poor instrument phase, rapid exchange with trace water or protons in the solvent, or because they resonate at a frequency outside that recorded (generally −0.2 to +15 ppm). It is also understood that chemical shifts for a given compound may vary due to factors such as concentation or pH of the sample. It is further understood that due to the precision in measurement of coupling constants, signals for coupled protons may have coupling constants that differ slightly.

Example 1

1-(2,4,6-Trichlorophenyl)-3-(methylthio)-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 176 mg (0.5 mmol) of 5-amino-3-(methylthio)-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 550 mg (3.0 mmol) of 3-methoxyphenylacetyl chloride followed by 2.3 mL (6.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 5 mL of 10% aq. HOAc, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:1 ether-hexanes. The off-white solid was briefly air-dried to give 220 mg (92%) of 1-(2,4,6-trichlorophenyl)-3-(methylthio)-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 245-248° C. Mass spec. Calc'd for C 20 H 16 N 4 O 2 SCl 3 : 481.0060. Found: 481.0076 (M+H) + .

Example 2

1-(2,4,6-Trichlorophenyl)-3-(methylthio)-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 55 mg (0.11 mmol) of 1-(2,4,6-trichlorophenyl)-3-(methylthio)-6-(3-methoxbenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 2 mL of CH 2 Cl 2 was added 1 mL (1 mmol) of 1 M boron tribromide in CH 2 Cl 2 . The solution was stirred 35 min. at ambient temperature, and it was then cooled to 0° C. The reaction was quenched with 4 mL of 1 M aq. HCl. The mixture was poured into water and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO 4 ), and concentrated under reduced pressure to afford 52 mg (98%) of 1-(2,4,6-trichlorophenyl)-3-(methylthio)-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid, m.p. 264-266° C. Mass spec. Calc'd for C 19 H 13 N 4 O 2 SCl 3 : 465.9825(M) + . Found: 465.9798.

Starting from 5-amino-3-(methylthio)-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide, the following compounds were prepared by methods similiar to those used to synthesize the compounds above:

TABLE I
Ex. #	R 1	m.p. (° C.)	MS
3	phenyl	234-238
4	imidazol-4-yl		441
5	4-pyridyl	283-287	452
6	3,4-dimethoxyphenyl	226-230	511
7	3-nitrophenyl	243-255	496
8	4-methoxyphenyl	263-267
9	4-hydroxyphenyl	294-296	467
10	2,5-dimethoxyphenyl	137-150	481
11	2,5-dihydroxyphenyl		483
12	4-aminophenyl		466
13	3,4-methylenedioxyphenyl	257-260
14	2-thienyl	218-222	457

Example 15

1-(2,4,6-Trichlorophenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

Part A: To a stirred solution of 320 mg (1.9 mmol) of 2-cyano-3-ethoxypentenamide in 7 mL of MeOH was added 465 mg (2.2 mmol) of 2,4,6-trichlorophenylhydrazine. The solution was stirred 3 h at reflux, treated with 2 mL of water, and allowed to stir an additional 1 h, cooling to RT. The white solid which precipitated was filtered, washed with 2:1 MeOH-water, and air-dried to afford 520 mg (82%) of 5-amino-3-ethyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide, mp 186-188° C., Mass Spec (CI+): 331.9989 (M) + .

Part B: To a stirred solution of 167 mg (0.5 mmol) of 5-amino-3-ethyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 550 mg (3.0 mmol) of 3-methoxyphenylacetyl chloride followed by 2.3 mL (6.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 5 mL of 10% aq. HOAc, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:1 ether-hexanes. The off-white solid was briefly air-dried to give 170 mg (76%) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 235-238° C. Mass Spec.: 463 (M+H) + .

Example 16

1-(2,4,6-Trichlorophenyl)-3-ethyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 80 mg (0.17 mmol) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 1 mL of CH 2 Cl 2 was added 1 mL (1 mmol) of 1 M boron tribromide in CH 2 Cl 2 . The solution was stirred 1 h at ambient temperature and then cooled to 0° C. The reaction was quenched with 4 mL of 1 M aq. HCl. The mixture was poured into water and extracted with 1:1 tetrahydrofuran-EtOAc. The organic extract was washed with brine, dried (MgSO 4 ), and concentrated under reduced pressure to afford 77 mg (100%) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid. Mass Spec.: 449 (M+H) + .

Example 17

1-(2,4,6-Trichlorophenyl)-3-ethyl-6-(4-(4-methoxyphenyl)benzyl))pyrazolo[3,4-d]pyrimidin-4-one

To a stirred mixture of 100 mg (0.2 mmol) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-bromobenzyl)pyrazolo[3,4-d]pyrimidin-4-one and 38 mg (0.25 mmol) of 4-methoxyphenylboronic acid in 10 mL of toluene, 0.5 mL of EtOH, and 2 mL of 2 M Na 2 CO 3 was added to 5 mg of Pd(Ph 3 P) 4 . The mixture was heated to reflux overnight, poured into water, and extracted with CHCl 3 . The organic extract was dried (MgSO 4 ), filtered through celite, chromatographed (elution with 5% MeOH/CH 2 Cl 2 ), and recrystallized to afford 64 mg (59%) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(4-methoxyphenyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a pale brown powder, mp 275-277° C., Mass spec.: 537 (M−H) − .

Starting from 5-amino-3-ethyl-1-(2,4,6 trichlorophenyl)pyrazole-4-carboxamide the following compounds were prepared by methods similiar to those used to synthesize the compounds above:

TABLE II
Ex. #	R 1	m.p. (° C.)	MS
18	3-indolyl	296-299	474
19	3-hydroxy-4-methylphenyl	amorphous
20	3-methoxy-4-methylphenyl	263-265
21	4-hydroxy-3-methylphenyl	260-263
22	4-methoxy-3-methylphenyl	245-247	479
23	phenyl	240-241	431
24	3,4,5-trimethoxyphenyl	224-226	523
25	4-bromophenyl	296-299	511
26	4-hydroxy-3-nitrophenyl	263-266
27	2-methoxyphenyl	188-191	463
28	4-pyridyl	277-280	432
29	3-amino-2-methylphenyl	242-243
30	3,4-dimethoxyphenyl	220-222	493
31	3,4-dihydroxyphenyl		465
32	2-pyridyl HOAc	164-169	433.0255
33	4-hydroxy-3-methoxyphenyl	260-280	479
34	4-methoxyphenyl	261-262	463
35	4-hydroxyphenyl	289-291	449
36	3-hydroxy-4-methoxyphenyl	237-240	479
37	3-aminophenyl	236-240	447.0418
38	4-aminophenyl	256-259	448
39	3-methylphenyl	238-240
40	5-methoxy-3-indolyl	295-298
41	3-amino-4-hydroxyphenyl	amorphous	464
42	3,4-dimethoxy-6-hydroxy-	203-205
	methylphenyl
43	3-(dimethylaminomethyl)phenyl	amorphous	492
	HCl salt
44	4-amino-3-nitrophenyl	amorphous	491
45	4-(dimethylamino)phenyl		476
46	3-(ethoxycarbonylmethyl)phenyl	168-169	517
47	3-(carboxymethyl)phenyl	192-194

Example 48

1-(2,4,6-Trichlorohenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

Part A: To a stirred solution of 106 g (500 mmol) of 2,4,6-trichlorophenyl hydrazine in 600 mL of absolute ethanol was added 48.1 mL (530 mmol) of isobutyraldehyde. The solution was stirred 2 h at RT and concentrated under reduced pressure to afford an oil. The crude oil was dissolved in 450 mL of dry DMF and cooled to 0° C. This solution was treated with 94.3 g (530 mmol) of NBS in four portions over 10 min. The solution was stirred 1 h at 0° C. and poured onto ice. The mixture was diluted with water and extracted with 800 mL of ether. The organic extract was washed twice with water and once with brine, dried (MgSO 4 ), and concentrated under reduced pressure to afford an oil. In a separate flask, 44.3 g (670 mmol) of malononitrile in 140 mL of EtOH was cooled to 0° C. and treated with 252 mL (670 mmol) of 2.66 M NaOEt in EtOH over 6 min. This solution was added in four portions over 5 min. to a rapidly stirred solution of the crude bromohydrazone in 350 mL of absolute EtOH. Using a heat pistol, this solution was maintained at reflux for 10 min. further. The reaction was cooled, quenched with 5% aq. HOAc, and extracted twice with ether. The combined organic extracts were washed (brine), dried (MgSO 4 ) and filtered over activated charcoal and celite, and concentrated under reduced pressure. The product was chromatographed on silica gel (gradient elution with 1:3 ether-hexanes and 2:1 ether-CH 2 Cl 2 ) to afford 93.5 g (57%) of 5-amino-4-cyano-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole as a white solid. 1 H NMR (CDCl 3 , 300 MHz) δ 7.51(s, 2H); 4.28(br. s, 2H); 3.05(septet, 1H, J=7.0 Hz); 1.36(d, 6H, J=7.0 Hz).

Part B: Thirty grams (91.0 mmol) of 5-amino-4-cyano-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole was dissolved in 80 mL of con. H 2 SO 4 and stirred 24 h at RT. The solution was added to cold aqueous NaOH, and the resulting precipitate was filtered, washed with water, and dried under vacuum to give 29.1 g (92%) of 5-amino-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide as a white solid. 1 H NMR (CDCl 3 , 300 MHz) δ 7.49(s, 2H); 5.06-5.63(m, 4 H); 3.06(septet, 1H, J=6.8 Hz); 1.39(d, 6H, J=6.9 Hz).

Part C: To a stirred solution of 167 mg (0.5 mmol) of 5-amino-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 550 mg (3.0 mmol) of 3-methoxyphenylacetyl chloride followed by 2.3 mL (6.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 5 mL of 10% aq. HOAc, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:1 ether-hexanes. The off-white solid was briefly air-dried to give 170 mg (76%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 204-205° C., Mass Spec: 477 (M+H) + .

Example 49

1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 65 mg (0.14 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 1 mL of CH 2 Cl 2 was added 1 mL (1 mmol) of 1 M boron tribromide in CH 2 Cl 2 . The solution was stirred 1 h at ambient temperature and then cooled to 0° C. The reaction was quenched with 4 mL of 1 M aq. HCl. The mixture was poured into water and extracted with 1:1 THF-EtOAc. The organic extract was washed with brine, dried (MgSO 4 ), and concentrated under reduced pressure to afford 63 mg (100%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous solid. 1 H NMR (300 MHz, DMSO) δ 12.46(br. s, 1H); 9.33(br. s, 1H); 7.96(s, 2H); 7.03(t, 1H, J=7.7 Hz); 6.55-7.08(m, 3H); 3.75(s, 2H); 3.19-3.36(m, 1H); 1.29(d, 6 H, J=7.0 Hz).

Starting from 5-amino-3-isopropyl-1-(2,4,6 trichlorophenyl)pyrazole-4-carboxamide the following compounds were prepared by methods similiar to those used to synthesize the examples above:

TABLE III
Ex. #	R 1	m.p. (° C.)	MS
50	3-hydroxy-4-methoxyphenyl		491
51	3-aminophenyl		462
52	4-aminophenyl	223-225	462
53	4-methoxyphenyl		475
54	4-amino-3-methoxyphenyl	238-240
55	4-amino-3-hydroxyphenyl	210-217 (dec.)	476
56	4-(dimethylaminomethyl)phenyl	278-281 (dec.)
	HCl salt
57	5-methoxy-2-methylindol-3-yl		528
58	5-hydroxy-2-methylindol-3-yl		514
59	4-bromophenyl	229-230
60	2-pyridyl	214-215	448.0506
61	4-pyridyl	273-275	448.0502
62	4-methylphenyl	205-206	461.0696
63	2-methylphenyl	194-195	461.0700
64	3-pyridyl	214-215	448.0506
65	4-methyl-3-pyridyl	225-227
66	3-amino-2-methylphenyl		474
67	4-(methylamino)phenyl	244-246	476
68	2H-1,4-benzoxazin-3-on-7-yl		516
69	4-chloro-3-pyridyl	245-248	480

Example 70

1-(2,4,6-Trichlorophenyl)-3-cyclopropyl-6-(3-hydroxy-4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 146 mg (0.42 mmol) of 5-amino-3-cyclopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 533 mg (2.53 mmol) of ethyl 3-hydroxy-4-methoxyphenylacetate followed by 1.91 mL (5.1 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 5 mL of 10% aq. HOAc, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:1 ether-hexanes. The off-white solid was briefly air-dried to give 46 mg (22%) of 1-(2,4,6-trichlorophenyl)-3-cyclopropyl-6-(3-hydroxy-4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one. Mass Spec.: 489 (M−H) − .

Starting from 5-amino-3-cyclopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide the following compounds were prepared by methods similiar to those used to synthesize the examples above:

TABLE IV
Ex. #	R 1	m.p. (° C.)	MS
71	Indazol-4-yl		483
72	Indazol-5-yl	274-283	483
73	Indazol-6-yl		483
74	4-Aminophenyl		460
75	Benzoxazol-2-on-5-yl		500
76	3-Hydroxy-4-nitrophenyl	259-260	506
77	4-(N,N-dimethylglycinamido)phenyl	250-253

Example 78

1-(2,4,6-Trichlorophenyl)-3-trifluoromethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 186 mg (0.50 mmol) of 5-amino-3-trifluoromethyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 555 mg (3.0 mmol) of 3-methoxyphenylacetyl chloride followed by 2.26 mL (6.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 23 h at reflux, and the heating mantle was then removed. The reaction was treated with 10 mL of 10% aq. HOAc, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:3 ether-hexanes. The off-white solid was briefly air-dried to give 230 mg (91%) of 1-(2,4,6-trichlorophenyl)-3-trifluoromethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one. Mass spec.: 503 (M+H) + .

Example 79

1-(2,4,6-Trichlorophenyl)-3-trifluoromethyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 60 mg (0.12 mmol) of 1-(2,4,6-trichlorophenyl)-3-trifluoromethyl-6-(3-methoxy-4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 2 mL of CH 2 Cl 2 was added 2 mL of a 1M solution of BBr 3 in CH 2 Cl 2 . The solution was stirred 2.5 h at RT and quenched with 1 N aq. HCl. The mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO 4 ), and concentrated under reduced pressure. The crude product was chromatographed on silica gel (elution with 1:1 hexanes-THF, then THF) to afford 1-(2,4,6-trichlorophenyl)-3-trifluoromethyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, as an off-white solid. Mass spec.: 487 (M−H) − .

Starting from 5-amino-3-(trifluoromethyl)-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide the following compounds were prepared by methods similiar to those used to synthesize the compounds above:

TABLE V
Ex. #	R 1	m.p. (° C.)	MS
80	3-aminophenyl		488
81	4-aminophenyl		488
82	4-methoxyphenyl	263-265	501
83	4-hydroxyphenyl		487
84	4-pyridyl		474
85	3-hydroxy-4-methoxyphenyl		517
86	4-hydroxy-3-methoxyphenyl		517

Example 87

1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(3-(N,N-dimethylglycinamido)-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one

Part A: To a stirred, cooled (0° C.) solution of 110 mg (0.23 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-amino-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 4 mL of THF was added 0.084 mL (0.6 mmol) of triethylamine followed by 0.024 mL (0.3 mmol) of chloroacetyl chloride. The solution was stirred 2 h, warming to ambient temperature. The reaction was quenched by dropwise addition of 5 mL of 0.5 N aq. HCl, and the resulting solid was collected by filtration. The product was washed with water then 1:1 ether-hexanes and air-dried to afford 96 mg (76%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(chloroacetamido)-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 237-238° C. 1 H NMR (300 MHz, DMSO) δ 12.42(s, 1H); 9.69(s, 1H); 7.93(s, 2H); 7.15(d, 1H, J=7.3 Hz); 7.07(t, 1H, J=7.7 Hz); 6.95(d, 1H, J=8.7 Hz); 4.25(s, 2H); 3.90(s, 2H); 3.20-3.33(m, 1H); 2.07(s, 3H); 1.30(d, 6H, J=6.9 Hz).

Part B: To a stirred solution of of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(chloroacetamido)-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 2 mL of THF was added 1 mL of 40% aq. dimethylamine. The solution was stirred overnight at ambient temperature and treated with water until a precipitate formed. The precipitate was filtered, washed with water and 1:1 ether-hexanes, and air-dried to afford 46 mg (75%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(N,N-dimethylglycinamido)-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid, mp 219-222° C. Mass spec. (ESI−): 561((M−H) − ).

By allowing m-substituted anilines to react with suitable acylating agents and performing further synthetic manipulations as necessary, the following compounds wherein R 1 =phenyl were prepared by methods similiar to those used to synthesize the compounds above:

TABLE VI
Ex.	R 2	R 7 (meta)	R 7 (ortho)	mp (° C.)	MS
88	Et	CH 3 SO 2 NH	H		524
89	i-Pr	CH 3 SO 2 NH	H		538
90	i-Pr	CF 2 HCONH	H		538
91	i-Pr	CH 3 CONH	H		502
92	i-Pr	CH 3 NHCONH	H		517
93	i-Pr	HOCH 2 CH 2 NHCONH	H		547
94	i-Pr	HO(CH 2 ) 4 NHCONH	H		577
95	i-Pr	(Fluorophen-4-yl)CH 2 NHCONH	H		613
96	i-Pr	(Fluorophen-3-yl)CH 2 NHCONH	H		613
97	i-Pr	Morpholin-4-ylCONH	H		575
98	i-Pr	PhCH 2 N(CH 3 )CONH	H		609
99	i-Pr	Tetrahydrofur-2-ylCH 2 NHCONH	H		585
100	i-Pr	4-hydroxypiperid-1-ylCONH	H		589
101	i-Pr	Pyrid-2-ylCH 2 NHCONH	H		596
102	i-Pr	Pyrid-3-ylCH 2 NHCONH	H		596
103	i-Pr	4-Methylpiperazin-1-ylNHCONH	H		603
104	i-Pr	Pyrid-3-ylNHCONH	H		582
105	i-Pr	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )CONH	H		590
106	Et	(CH 3 ) 2 NCH 2 CONH	Me	218-221	547
107	i-Pr	(Methoxyphen-2-yl)CH 2 NHCONH	H		625
108	i-Pr	(Methoxyphen-4-yl)CH 2 NHCONH	H		625
109	i-Pr	2-hydroxypiperid-1-ylCONH	H		589
110	Et	CH 3 CONH	H		488

Example 111

1-(2,4,6-Trichlorophenyl)-3-ethyl-6-(4-methanesulfonylaminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 45 mg (0.1 mmol) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 2 mL of ether-CH 2 Cl 2 was added 0.5 mL of pyridine followed by 0.020 mL (0.26 mmol) of methanesulfonyl chloride. The solution was stirred 39 h at ambient temperature and poured into 1 N aq. HCl. The mixture was extracted with EtOAc, then hexanes. The combined organic extracts were washed with water then brine, dried (MgSO 4 ), and concentrated under reduced pressure to afford 52 mg of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-methanesulfonylaminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous solid. Mass spec. (ESI+): 526 (M+H) + .

Example 112

1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(piperazin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

Part A: To a stirred, cooled (0° C.) solution of 9.26 g (20 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 45 mL of THF and 10 mL of DMF was added 3.90 mL (28 mmol) of triethylamine followed by 1.99 mL (25 mmol) of chloroacetyl chloride over 5 min. The solution was stirred 30 min. at 0° C. and quenched by addition of 150 mL of 0.1 N aq. HCl. The resulting solid was collected by filtration, washed with water then 1:1 ether-hexanes, and air-dried to afford 10.2 g (95%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(chloroacetamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a white solid. 1 H NMR (300 MHz, DMSO) δ 12.49(s, 1H); 9.74(s, 1H); 7.97(s, 2H); 7.46(d, 2H, J=8.0 Hz); 7.20(d, 2H, J=8.8 Hz); 4.19(s, 2H); 3.80(s, 2H); 3.20-3.33(m, 1H); 1.28(d, 6H, J=6.9 Hz).

Part B: To a stirred solution of 300 mg (0.55 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(chloroacetamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one in 6 mL of 1:1 DMF-THF was added 1 g of piperazine. The solution was stirred overnight at ambient temperature and poured into water. The mixture was extracted twice with EtOAc, and the combined organic extracts were washed (brine), dried (MgSO 4 ), and concentrated under reduced pressure to afford 230 mg (71%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(piperazin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid. Mass spec. (ESI+): 588 ((M+H) + ).

Example 113

(S)-1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(N-t-butoxycarbonylprolinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 105 mg (0.22 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one and 235 mg (1.09 mmol) of Boc-L-proline in 2 mL of DMF was added 0.35 mL (2.5 mmol) of triethylamine followed by 490 mg (1.11 mmol) of Bop. The solution was stirred overnight at ambient temperature then poured into EtOAc. This solution was washed sequentally with 0.5 M HCl then dilute aq. Na 2 CO 3 then brine, dried (MgSO 4 ), and concentrated under reduced pressure. The crude product was recrystallized from EtOAc-hexanes to afford 116 mg (80%) of (S)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-t-butoxycarbonylprolinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a white solid, mp 225-226° C., Mass spec.: 657 M−H − ).

Example 114

(S)-1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(prolinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

Fifty mg (0.076 mmol) of (S)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-t-butoxycarbonylprolinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one was dissolved in 2 mL of 4 M HCl, and the solution was stirred 1 h at RT. The solution was concentrated under reduced pressure to afford 45 mg (100%) of (S)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(prolinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a white, amorphous solid. 1 H NMR (300 MHz, DMSO) δ 12.42(s, 1H); 10.67(s, 1H); 7.97(s, 2H); 7.49(d, 2H, J=8.5 Hz); 7.23(d, 2H, J=8.4 Hz); 4.27-4.31(m, 1H); 3.82(s, 2H); 3.18-3.34(m, 5H); 2.28-2.40(m, 1H); 1.84-1.95(m, 3H); 1.28(d, 6H, J=6.9 Hz).

Example 115

1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(dimethylaminomethyl)-3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 464 mg (1.0 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 10 mL of glacial HOAc was added 0.4 mL of 37% aq. formaldehyde followed by 0.5 mL of 40% aq. dimethylamine. The solution was stirred overnight at RT, and it was then heated to just below reflux for 20 min. The solution was poured into water and extracted with EtOAc. The organic extract was washed (brine), dried (MgSO 4 ), and chromatographed on silica gel (elution with EtOAc) to afford, after removal of solvent, 135 mg (26%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(dimethylaminomethyl)-3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white, amorphous solid. Mass spec. (ESI+): 520 (M+H) − .

Example 116

1-(2,4,6-Trichlorophenyl)-3-ethyl-6-(3-pyridylmethyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 167 mg (0.5 mmol) of 1-(2,4,6-trichlorophenyl)-3-ethyl-4-carboxamido-5-aminopyrazolo in 5 mL of ethanol was added 480 mg (3.0 mmol) of ethyl 3-pyridyl acetate followed by 1.13 mL (3.0 mmol) of 2.66 M NaOEt in ethanol. The solution was stirred overnight at reflux, and the product was precipitated by treatment with 10 mL of 10% aq. HOAc. The mixture was filtered, and the product was washed with 1:1 MeOH-water then 1:1 ether-hexanes and air dried to afford 210 mg (97%) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-pyridylmethyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid, mp 257-260° C. 1 H NMR (300 MHz, DMSO) δ 12.56(s, <1H (exchanges with solvent)); 8.46(d, 1H, J=1.5); 8.40(dd, 1H, J=4.8, 1.5 Hz); 7.96(s, 2H); 7.60-7.64(m, 1H); 7.25-7.30(m, 1H); 3.90(s, 2H); 2.83(q, 2H, J=7.3 Hz); 1.23(t, 3H, J=7.5 Hz).

Example 117

(+/−)-1-(2,4,6-Trichlorophenyl)-3-ethyl-6-(α-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 167 mg (0.50 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-4-carboxamido-5-aminopyrazole in 6 mL of ethanol was added 544 mg (3.0 mmol) of (+/−) ethyl mandelate followed by 1.13 mL (3.0 mmol) of 2.66 M NaOEt in ethanol. The solution was stirred overnight at reflux, and the product was precipitated by treatment with 10 mL of 10% aq. HOAc. The mixture was filtered, and the product was washed with 1:1 MeOH-water then 1:1 ether-hexanes and air dried to afford 210 mg (94%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(α-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid, mp 246-248° C. Mass spec. (ESI−): 449 (M−H) − .

Example 118

1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(ethenesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred, cooled (0° C.) solution of 231 mg (0.5 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one and 0.14 mL (1.0 mmol) of Et 3 N in 4 mL of THF was added 0.063 mL (0.6 mmol) of 2-chloroethanesulfonyl chloride. The solution was stirred 1 h, warming to ambient temperature. The solution was poured into 10% aq. citric acid and extracted with EtOAc. The organic extract was washed (brine), dried (MgSO 4 ), and concentrated under reduced pressure. The crude product was chromatographed (elution with 1:1 EtOAc-hexanes) to afford 221 mg (80%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(ethenesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid. 1 H NMR (300 MHz, DMSO) δ 12.47(br. s, 1H); 9.92(br. s, 1H); 7.97(s, 2H); 7.17(d, 2H, J=8.4 Hz); 7.02(d, 2H, J=8.4 Hz); 6.69(dd, 1H, J=16.5, 9.9 Hz); 6.04(d, 1H, J=16.5 Hz); 5.96(d, 1H, J=9.9 Hz); 3.78(s, 2H); 3.18-3.32(m, 1H); 1.28(d, 6H, J=7.0 Hz).

Example 119

1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(2-(dimethylamino)ethanesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred, solution of 23 mg (0.042 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(ethenesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one in 1 mL of THF was added 1 mL of 2M diethylamine in THF. The solution was stirred 3 h and concentrated under reduced pressure. The product was dissolved in 1 mL of benzene and 0.05 mL of MeOH, frozen, and lyophilized to afford 25 mg (100%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-(dimethylamino)ethenesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous white solid. 1 H NMR (300 MHz, DMSO) δ 7.96(s, 2H); 7.19(d, 2H, J=8.5 Hz); 7.08(d, 2H, J=8.8 Hz); 3.79(s, 2H); 3.18-3.32(m, 1H); 3.13(t, 2H, J=7.5 Hz); 2.53(t, 2H, J=7.5 Hz); 1.99(s, 6H); 1.28(d, 6H, J=7.0 Hz).

Example 120

1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(hydroxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 347 mg (1.0 mmol) of 5-amino-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 777 mg (4.0 mmol) of ethyl 4-(hydroxymethyl)phenylacetate followed by 2.0 mL (5.33 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 25 mL of 5% aq. HOAc, cooled to ambient temperature, and extracted with EtOAc. The organic extract was washed twice with water and once with brine, dried (MgSO 4 ), and chromatographed on silica gel (elution with 1:1 EtOAc-hexanes) to give, after removal of solvent, 320 mg (67%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(hydroxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a white, amorphous solid. 1 H NMR (300 MHz, CDCl 3 ) d 11.46(br. s, 1H); 7.54(s, 2H); 7.42(d, 2H, J=8.1 Hz); 7.31(d, 2H, J=8.5 Hz); 4.66(s, 2H); 4.00(s, 2H); 3.47(septet, 1H, J=7.0 Hz); 1.48(d, 6H, J=7.0 Hz).

Example 121

(+/−)-1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(1,4-dimethyliperazine-2-ylcarboxamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

Part A: To a stirred, cooled (0° C.) solution of 463 mg (1.0 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one and 0.28 mL (2.0 mmol) of Et 3 N in 8 mL of THF was added 0.131 mL (1.2 mmol) of 2,3-dichloropropanoyl chloride. The solution was stirred 0.5 h, warming to ambient temperature. The solution was quenched with water and filtered. The solid was washed with 0.1 N aq. HCl, then water, then 1:1 hexanes-ether. The product was air-dried briefly to afford 390 mg (71%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-chloroacrylamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous solid. 1 H NMR (300 MHz, DMSO) δ 12.49(br. s, 1H); 10.14(br. s, 1H); 7.97(s, 2H); 7.53(d, 2H, J=8.4 Hz); 7.22(d, 2H, J=8.4 Hz); 6.36(d, 1H, J=2.6 Hz); 6.03(d, 1H, J=2.5 Hz); 3.82(s, 2H); 3.18-3.32(m, 1H); 1.28(d, 6H, J=7.0 Hz).

Part B: To a stirred, solution of 112 mg (0.2 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-cloroacrylamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one in 2 mL of THF was added 0.5 mL of N,N′-dimethylethylene diamine. The solution was stirred overnight, poured into water, and extracted with EtOAc. The organic extract was washed (brine), dried (MgSO 4 ), and concentrated under reduced pressure to afford 102 mg (84%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(1,4-dimethylpiperazine-2-ylcarboxamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous white solid. Mass spec. (ESI+): 602.1608 (M+H) + .

Example 122

1-(2,6-Dichlorophenyl)-3-isopropyl-6-(4-(carbethoxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

The amino carboxamide, 5-amino-3-isopropyl-1-(2,6-dichlorophenyl)pyrazole-4-carboxamide (0.30 g, 0.96 mmol), p-diethyl phenylenediacetate (8 eq, 1.92 g, 7.66 mmol) and sodium ethoxide (21% in ethanol, 8 eq, 2.90 mL, 7.66 mmol) were refluxed overnight in ethanol (20 mL). The reaction was cooled and 10% aq HOAc was added. The mixture was extracted with EtOAc, washed with water and brine, dried over MgSO 4 and evaporated to dryness. The oily solid was purified by silica gel column chromatography with 1:1 hexane/ether as the eluent. The product, 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(carbethoxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one (0.44 g, 93% yield), was recovered as a white solid, mp 168-169° C. Mass Spec.: 499 (M+H) + .

Example 123

1-(2,6-Dichlorophenyl)-3-isopropyl-6-(4-(carboxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

The ester, 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(carbethoxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one (1.20 g, 2.4 mmol) was stirred at RT overnight with THF (50 mL), water (15 mL) and 1 N lithium hydroxide (7.20 mL). The solution was evaporated to near dryness, diluted with 1 N hydrochloric acid, vigorously stirred and the solid was collected by filtration and dried under high vacuum to give 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-carboxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one (1.01 g, 89% yield) as a white solid, mp 212-214° C. Mass Spec.: 471 (M+H) + .

Example 124

1-(2,6-Dichlorophenyl)-3-isopropyl-6-(4-(2-(N,N-dimethylamino)ethylaminocarbonylmethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

The acid, 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-carboxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one (0.100 g, 0.21 mmol) and N,N-dimethyethylenediamine (5 eq, 0.12 mL, 1.06 mmol) were suspended in DMF (3 mL). DIEA (5 eq, 0.18 mL, 1.06 mmol) was added and the suspension was stirred at RT for ten minutes. BOP (1.5 eq, 0.141 g, 0.32 mmol) was added and the reaction was stirred at RT overnight. The suspension was diluted with water, extracted with EtOAc, washed with water and brine, dried over MgSO 4 and evaporated to dryness. The oily residue was crystallized from a mixture of EtOAc, hexane and ether to give 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(2-(N,N-dimethylamino)ethylaminocarbonylmethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one (0.039 g, 34% yield) as a white solid, mp 170-172° C. Mass Spec.: 541 (M+H) + .

Example 125

1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(2-(morpholine-4-yl)ethylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

A flask equipped with a reflux condensor was flame-dried in vacuo and a nitrogen atmosphere was introduced. The flask was charged with triphosgene (1.37 g, 4.62 mmol). The reagent was dissolved in dry 1,2-dichloroethane (25 mL), and triethylamine (0.64 mL, 4.62 mmol) was added. The reaction was cooled to −30° C., and 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one (1.1 g, 2.38 mmol) was added. Stirring was continued for 10 minutes and the reaction was the warmed to reflux. After heating for one hour, the reaction was cooled, diluted with methylene chloride, and washed sequentially with water and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated to give the isocyanate (1.2 g). This material was of sufficient quality for the subsequent transformations.

The isocyanate (75.5 mg, 0.155 mmol) was dissolved in dry methylene chloride (2.0 mL) under a nitrogen atmosphere. 4-(2-aminoethyl)morpholine (30 μΛ, 0.232 mmol) was added, and stirring was continued for 1 hour. The precipitate was filtered and rinsed with three portions of methylene chloride and dried in vacuo to give 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-(morphline-4-yl)ethylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one (68 mg, 0.110 mmol, 71%). Mass spec. (ESI+) 618 (M+H) + .

Example 126

1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(2-hydroxyethylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

Alternatively, the ureas may be prepared by the following procedure, which is suitable for parallel synthesis. The isocyanate (74 mg, 0.152 mmol) was dissolved in dry methylene chloride (3.0 mL) under a nitrogen atmosphere. Ethanolamine (14 μΛ, 0.227 mmol) was added and stirring continued for 15 minutes. Methanol (1.0 mL) was added to generate a homogeneous solution. The acidic ion exchange resin AG 50W-X8 (158 mg) was added. The reaction was then filtered and the solvents removed by evaporation. The product 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-hydroxyethylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one was obtained in excellent yield (78 mg, 93%). Mass spec. (ESI−) 547 (M−H) − .

Example 127

1-(2-Chloro-6-methylphenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one

Part A: To a stirred suspension of 14.2 g (100 mmol) of 2-chloro-6-methylaniline in 40 mL conc. HCl at 0° C. was added a solution of 6.9 g (100 mmol) of sodium nitrite in 40 mL water dropwise via addition funnel. After stirring one hour at 0° C. a solution of 67.6 g (300 mmol) tin(II) chloride dihydrate in 70 mL conc. HCl was added dropwise via addition funnel. The reaction was sealed and placed in the refrigerator for 24 h. The mixture was filtered and the solid was washed with brine and then petroleum ether. The solid was taken up in 250 mL of 2 N NaOH, stirred 10 min. and filtered. This solid was dissolved in 100 mL diethyl ether and acidified with 4 N HCl in dioxane. The solid was collected by suction filtration, washed with diethyl ether and dried to afford 10.25 g (53%) of 2-chloro-6-methylhydrazine hydrochloride, mp 220-222 (dec)° C. Mass Spec (CI+): 157 (M+H) + .

Part B: To a stirred suspension of 3.0 g (15.5 mmol) of 2-chloro-6-methylhydrazine hydrochloride in 20 mL ethanol was added 2.2 mL (15.5 mmol) of triethylamine followed after 10 min by 1.5 mL (16.5 mmol) of isobutyraldehyde. The solution was stirred at room temperature for 2 h, poured into water and extracted with diethyl ether. The organic extract was washed with brine, dried (MgSO 4 ), and concentrated under reduced pressure to give 2.95 g (90%) of the imine intermediate as a liquid. The imine was taken up in 15 mL dimethylformamide, cooled to 0° C., and 2.99 g (16.8 mmol) of N-bromosuccinimide was added in small portions. After stirring at 0° C. for 30 min the reaction was diluted with diethyl ether and water. The layers were separated and the aqueous phase with extracted with diethyl ether. The organic extracts were combined, washed with water and brine, dried (MgSO 4 ) and concentrated under reduced pressure to give the bromohydrazone intermediate.

To a stirred solution of the bromohydrazone in 25 mL ethanol was added an ice cold solution of the anion of malononitrile prepared by adding 10.4 mL (28 mmol) of sodium ethoxide to 1.82 g (28 mmol) of malononitrile in 25 mL ethanol at 0° C. The mixture was heated to reflux for 30 min and then concentrated to one third the volume under reduced pressure. This solution was treated with 10% glacial acetic acid, diluted with water, and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO 4 ), and concentrated under reduced pressure. Purification by column chromatography on silica gel using 2:1 hexanes-EtOAc as eluant afforded 1.82 g (47%) of 5-amino-4-cyano-3-isopropyl-1-(2-chloro-6-methylphenyl)pyrazole, mp 116-118° C. Mass Spec. (CI+): 275 (M+H) + .

Part C: A mixture of 1.5 g (5.5 mmol) of 5-amino-4-cyano-3-isopropyl-1-(2-chloro-6-methylphenyl)pyrazole in 5 mL conc. H 2 SO 4 was stirred at room temperature for 24 hours. The reaction was slowly quenched with ice and then diluted with water. The solution was made basic with saturated Na 2 CO 3 , stirred 2 h and filtered. The solid was recrystallized from hexanes/EtOAc to afford 847 mg (53%) of 5-amino-3-isopropyl-1-(2-chloro-6-methylphenyl)pyrazole-4-carboxamide, mp 72-74° C. Mass Spec. (ES−): 291 (M−H) − .

Part D: To a stirred solution of 1.4 g (4.8 mmol) 5-amino-3-isopropyl-1-(2-chloro-6-methyl-phenyl)pyrazole-4-carboxamide in 100 mL absolute ethanol was added 5.14 g (28.8 mmol) of 4-amino-phenylacetate followed by 10.7 mL (28.8 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux and the heating mantle was then removed. The reaction was treated with water and 10% aq. HOAc, cooled to ambient temperature, and filtered. The solid purified by column chromatography on silica gel using 1:1 hexanes-EtOAc as eluant to afford 743 mg (38%) of 1-(2-chloro-6-methylphenyl)-3-isopropyl-6-(4-aminobenzyl)-pyrazolo[3,4-d]pyrimidin-4-one, mp 206-207° C. Mass Spec. (CI+): 408 (M+H) + .

Example 128

1-(2-Chloro-6-methylphenyl)-3-isopropyl-6-(4-(N,N-dimethylglycinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one Hydrochloride Salt

To a stirred solution of 500 mg (1.22 mmol) of 1-(2-chloro-6-methylphenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 10 mL dry CH 2 Cl 2 was added 0.85 mL (6.1 mmol) triethylamine followed by 632 mg (6.1 mmol) N,N-dimethylglycine and then 1.17 g (6.1 mmol) of 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). The reaction was stirred for 18 h at ambient temperature and then transferred directly to a flash column of silica gel and eluted with 5% MeOH in CH 2 Cl 2 . The isolated solid was dissolved in 20 mL dioxane and 1.1 mL of 4 N HCl in dioxane was added. The solid was collected by suction filtration and dried to give 490 mg (76%) of 1-(2-chloro-6-methylphenyl)-3-isopropyl-6-(4-(N,N-dimethylglycinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one hydrochloride salt, mp 297-299° C.

Example 129

1-(2,6-Dichloro-4-methylcarboxamidophenyl)-3-ethyl-6-(4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

Part A: To a stirred suspension of 4.33 g (18.5 mmol) of ethyl 4-amino-3,5-dichlorobenzoate in 8 mL conc. HCl at 0° C. was added a solution of 1.28 g (18.5 mmol) of sodium nitrite in 8 mL water dropwise. After stirring at 0° C. for 45 min, a solution of 12.52 g (55.5 mmol) tin(II) chloride in 14 mL conc. HCl was added dropwise. The reaction was sealed and placed in the refrigerator for 18 h. The solid was collected by suction filtration, washed with brine and then 2:1 petroleum ether-diethyl ether, treated with 1 N NaOH, and filtered. This solid was dissolved in diethyl ether, acidified with 4 N HCl in dioxane, filtered and washed with diethyl ether to give 2.85 g (54%) of ethyl 3,5-dichloro-4-hydrazinobenzoate hydrochloride, mp 225-227 (dec)° C. Mass Spec.: (CI+) 249 (M+).

Part B: A mixture of 2.5 g (8.75 mmol) ethyl 3,5-dichloro-4-hydrazinobenzoate hydrochloride, 1.1 g (7.3 mmol) 1-(ethoxypropylidine)malononitrile and 1.22 mL (8.75 mmol) triethylamine in 100 mL of ethanol was stirred at reflux for 66 h. The reaction was taken to one-third the volume via rotary evaportation under reduced pressure and the remaining solution was treated with water, stirred 30 min and filtered. Recrystallization from hexanes/EtOAc gave 1.16 g (45%) of 5-amino-4-cyano-3-ethyl-1-(2,6-dichloro-4-carboethoxyphenyl)pyrazole, mp 173-175° C. Mass Spec.: (CI+) 353 (M+).

Part C: A solution of 1.64 g (4.64 mmol) of 5-amino-4-cyano-3-ethyl-1-(2,6-dichloro-4-carboethoxyphenyl)-pyrazole in 8 mL conc. H 2 SO 4 was stirred at room temperature for 4 hours. The reaction was quenched carefully with ice and diluted with water. The solid was collected by suction filtration, washed with water and dried to give 1.26 g (73%) of 5-amino-3-ethyl-1-(2,6-dichloro-4-carboethoxyphenyl)pyrazole-4-carboxamide, mp 194-196° C. Mass Spec.: (CI+) 371 (M+).

Part D: To a stirred solution of 500 mg (1.35 mmol) of 5-amino-3-ethyl-1-(2,6-dichloro-4-carboethoxyphenyl)pyrazole-4-carboxamide in 10 mL ethanol was added 1.45 g (8.1 mmol) of methyl 4-methoxyphenylacetate followed by 2.6 mL (8.1 mmol) of 2.66 M sodium ethoxide in ethanol. The reaction was heated at relux for 18 h and then 10% aq. HOAc was added. After stirring an additional hour at relux, the heat was removed and the reaction solution was poured into ice water, stirred 10 min. and filtered. The solid was washed with water and diethyl ether and dried to give 480 mg (75%) of 1-(2,6-dichloro-4-carboxyphenyl)-3-ethyl-6-(4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 277° C. Mass Spec.: (ES−) 471 (M−H) − .

Part E: To a stirred solution of 100 mg (0.21 mmol) of 1-(2,6-dichloro-4-carboxyphenyl)-3-ethyl-6-(4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one was added 0.3 mL (2.1 mmol) of triethylamine followed by 71 mg (1.05 mmol) of methylamine hydrochloride and then 202 mg (1.05 mmol) of EDC. The reaction was stirred at ambient temperature for 18 h, transferred directly to a flash column of silica gel and eluted with 5% MeOH in CH 2 Cl 2 to give 14 mg (14%) of 1-(2,6-dichloro-4-(methylcarboxamido)phenyl)-3-ethyl-6-(4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 280-282° C. Mass Spec.: (CI+) 486 (M+).

Example 130

1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(t-butoxycarbonylaminosulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred, cooled solution of 0.11 mL (1.26 mmol) of chlorosulfonyl isocyanate in 5 mL of CH 2 Cl 2 was added 0.13 mL of t-BuOH. The solution was stirred 10 min. and added to a stirred, cooled (0° C.) solution of 231 mg (0.5 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one and 0.2 mL (1.4 mmol) of Et 3 N in 5 mL of CH 2 Cl 2 . The solution was stirred 1 h warming to ambient temperature, and it was then poured into 1 N aq. HCl. The mixture was extracted with EtOAc, and the organic extract was washed (brine), dried (MgSO 4 ), concentrated under reduced pressure, and chromatographed on silica gel (elution with 1:1 EtOAc-hexanes, then EtOAc) to afford 250 mg (78%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(t-butoxycarbonylaminosulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a white solid. 1 H NMR (300 MHz, DMSO) δ 12.44(s, 1H); 11.12(br. s, 1H); 9.70(br. s, 1H); 7.97(s, 2H); 7.21(d, 2H, J=8.4 Hz); 7.02(d, 2H, J=8.4 Hz); 3.78(s, 2H); 3.19-3.30(m, 1H); 1.27(d, 6H, J=6.9 Hz); 1.21(s, 9H).

Example 131

1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(3-aminoindazol-5-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 139 mg (0.40 mmol) of 5-amino-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 3 mL of absolute ethanol was added 329 mg (1.50 mmol) of ethyl 3-aminoindazol-5-ylacetate followed by 1.13 mL (3.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 16 h at reflux, and the heating mantle was then removed. The reaction was treated with 8 mL of 10% aq. HOAc, poured into water, and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO 4 ), concentrated under reduced pressure, and chromatographed on silica gel (gradient elution with 5% to 10% MeOH—CH 2 Cl 2 ) to give, after removal of solvent, 123 mg (61%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-aminoindazol-5-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one as a white, amorphous solid. Mass spec.: 502.0712 (M+H) + .

Example 132

1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(benzoxazol-2-on-6-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred, cooled (0° C.) solution of 309 mg (0.063 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-amino-3-hydroxybenz)pyrazolo[3,4-d]pyrimidin-4-one in 1 mL of THF was added 0.13 mL (1.0 mmol) of triethylamine followed by 0.05 mL (0.095 mmol) of 1.93 M phosgene in toluene. The solution was stirred 15 min., treated with 4 mL of 0.1 N aq. NaOH, and stirred 64 h at RT. The reaction was poured into 1 N aq. HCl and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO 4 plus activated charcoal and celite), and concentrated under reduced pressure to afford 26 mg (81%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(benzoxazol-2-on-6-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous solid. 1 H NMR (300 MHz, DMSO) δ 12.48(s, 1H); 11.57(br. s, 1H); 7.98(s, 2H); 7.03(dd, 1H, J=8.1, 1.4 Hz); 6.97(d, 1H, J=8.1 Hz); 3.84(s, 2H); 3.19-3.30(m, 1H); 1.28(d, 6H, J=7.0 Hz).

Example 133

1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(2-(dimethylamino)ethoxycarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred, cooled (−78° C.) solution of 0.10 mL (1.0 mmol) of N,N-dimethylethanolamine in 1 mL of THF was added 0.56 mL (0.90 mmol) of 1.6 M n-BuLi in hexanes over 2 min. The solution was stirred 5 min. at −78° C. and treated with 49 mg (0.10 mmol) of the isocyanate prepared in Example 107 above. The mixture was stirred 10 min., becoming homogeneous as it warmed to 0° C. The reaction was diluted with 5% aq. HOAc, then made slightly basic with saturated aq. NaHCO 3 . The mixture was extracted with EtOAc, and the organic extract was washed (brine), dried (MgSO 4 ), and concentrated under reduced pressure to afford 43 mg(74%) of 1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(2-(dimethylamino)ethoxycarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a white solid, mp. 218-220° C. Mass spec: 577 (M+H) + .

Example 134

1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(1-methylpyrroy-2-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 1.74 g (5.0 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-4-carboxamido-5-aminopyrazole in 30 mL of ethanol was added 2.9 mL (20 mmol) of methyl 1-methyl-2-pyrroleacetate followed by 7.50 mL (20 mmol) of 2.66 M NaOEt in ethanol. The solution was stirred overnight at reflux, and the product was precipitated by treatment with 40 mL of 10% aq. HOAc. The mixture was filtered, and the product was washed with 1:1 MeOH-water then 1:1 ether-hexanes and air dried to afford 2.07 g (92%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(1-methylpyrroy-2-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid, mp 219-221° C. Mass spec. (ESI+): 450 (M+H) + .

Example 135

1-(3-Formyl-2,4,6-trichlorophenyl)-3-isoproyl-6-(1-methylpyrroy-2-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred, cooled (−60° C.) solution of 902 mg (2.0 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(1-methylpyrroy-2-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one in 10 mL of THF was added 2.56 mL (4.1 mmol) of 1.6 M n-BuLi in hexanes over 2 min. The solution was stirred 10 min. at −60° C. and treated with 1 mL DMF. The reaction solidified and was broken up by stirring, shaking, and warming to ambient temperature. The reaction was quenched with deuteromethanol then aq. HOAc. The mixture was extracted with EtOAc, and the organic extraxt was washed (brine), dried (MgSO 4 ), and concentrated under reduced pressure. The crude product was re-crystallized from EtOAc-hexanes to afford 560 mg (60%) of 1-(3-formyl-2,4,6-trichlorophenyl)-3-isopropyl-6-(1-methylpyrroy-2-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one as an orange solid. Mass spec. (ESI−): 450 (M−H) − .

Example 136

1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(4-methylpiperazin-1-ylaminocarbonyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

Part A: To a stirred solution of 7.5 g(153 mmol) sodium cyanide in 75 mL of THF was added 40 mL of DMF followed by 11.5 g (50.2 mmol) of of methyl 4-(bromomethyl)benzoate in 30 mL of DMF over 10 min. The solution was stirred 18 and treated with 100 mL water. The mixture was filtered, rinsed with water, and air-dried briefly to give 6.7 g (76%) of 4-(carbomethoxy)phenylacetonitrile as a white solid. 1 H NMR (300 MHz, DMSO) δ 7.95(d, 2H, J=8.4 Hz); 7.47(d, 2H, J=8.5 Hz); 4.14(s, 2H); 3.82(s, 3H).

Part B: The above nitrile ester was stirred with 120 mL of 6 N aq. HCl for 18 h at reflux and then cooled. The mixture was diluted with 160 mL water and then filtered. The white solid was rinsed with water, air-dried briefly, and placed in a vacuum oven at 75° C. for 1 h. This affords 6.89 g (100%) of 4-(carboxy)phenylacetic acid. 1 H NMR (300 MHz, DMSO) δ 7.92(d, 2H, J=8.5 Hz); 7.49(d, 2H, J=8.4 Hz); 3.63 (s, 2H).

Part C: To a stirred solution of 2.0 g (11.1 mmol) of 4-(carboxy)phenylacetic acid in 28 mL of absolute ethanol was added 0.5 mL of conc. Sulfuric acid. The solution was stirred 2 h at reflux and then cooled. The reaction was made basic with sodium carbonate and extracted with ether. The organic extract was washed (brine), dried (MgSO 4 ), and concentrated under reduced pressure to afford 2.3 g (88%) of ethyl 4-(carbethoxy)phenylacetate as an oil. 1 H NMR (300 MHz, CDCl 3 ) δ 8.01(d, 2H, J=8.4 Hz); 7.36(d, 2H, J=8.1 Hz); 4.37(q, 2H, J=7.1 Hz); 4.16(q, 2H, J=7.2 Hz); 1.39(t, 3H, J=7.2 Hz); 1.25(t, 3H, J=7.2 Hz).

Part D: To a stirred solution of 174 mg (0.50 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-4-carboxamido-5-aminopyrazole in 6 mL of ethanol was added 473 mg (2.0 mmol) of ethyl 4-(carbethoxy)phenylacetate followed by 0.94 mL (2.5 mmol) of 2.66 M NaOEt in ethanol. The solution was stirred overnight at reflux, and the product was precipitated by treatment with 8 mL of 10% aq. HOAc then 2 mL of saturated aq. NaHCO 3 . The mixture was filtered, and the product was washed with 1:1 MeOH-water then 1:1 ether-hexanes and air dried to afford 232 mg (89%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(carbethoxy)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid, mp 233-235° C. Mass spec. (ESI+): 519.0754 (M+H) + .

Part E: To a stirred solution of 130 mg (0.250 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(carbethoxy)benzyl)pyrazolo[3,4-d]pyrimidin-4-one in 2 mL of THF was added 42 mg (1.0 mmol) of lithium hydroxide hydrate in 2 mL of water followed by 0.25 mL of methanol. The solution was stirred 3.5 h at RT and 10 min. at reflux. The reaction was diluted with ether, and washed twice with 0.1 N aq. NaOH. The combined aq. washings were acidified, and the resulting mixture was extracted with chloroform, then EtOAc. The combined organic extracts were dried (MgSO 4 ) and concentrated under reduced pressure to afford 123 mg (100%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(carboxy)benzyl)pyrazolo[3,4-d]pyrimidin-4-on as a white solid, mp. 294-295° C.

Part F: To a stirred solution of 49 mg (0.10 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(carboxy)benzyl)pyrazolo[3,4-d]pyrimidin-4-one and 0.06 mL (0.5 mmol) of 1-amino-4-methylpiperazine in 1 mL of DMF was added 0.052 mL of DIEA followed by 48 mg (0.15 mmol) of TBTU. The solution was stirred 16 h at 45° C., cooled to RT, and poured into water. The mixture was extracted with EtOAc, and the organic extract was concentrated under reduced pressure. Chromatography with 4:1 chloroform-MeOH afforded 34 mg (58%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-methylpiperazin-1-ylaminocarbonyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-on as a white solid. Mass spec: (ESI+) 588 (M +H) + .

Example 137

1-(4-(Acetamidophenyl-3-yl)-2,6-dichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

A solution of 1-(4-bromo-2,6-dichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one (200 mg, 0.383 mmol) and 3-acetamidobenzeneboronic acid (82 mg, 0.458 mmol) in a 25% solution of ethanol in toluene was stirred at RT under nitrogen for 30 min. Sodium carbonate solution (0.38 mL of a 2N solution, 0.766 mmol) was added followed by tetrabutylammonium bromide (6.1 mg, 0.019 mmol) and tetrakis(triphenylphosphine)palladium(0) (2 mg, catalytic). The reaction was stirred at reflux overnight, cooled to RT, filtered through Celite, washed with EtOAc, and concentrated. Purification by column chromatography using 1:1 hexanes-EtOAc as eluent afforded 114 mg (52%) of the title as a white solid, mp 224-225° C. Mass Spec: 576 (M+H) + .

Example 138

1-(2,6-Dichloro-4-formylphenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

A two-neck flask was flame-dried, charged with 1-(4-bromo-2,6-dichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one (250 mg, 0.48 mmol) and 4 mL of THF, and placed under an argon atmosphere. The solution was cooled to 0° C. and isopropylmagnesium chloride (0.26 mL, 0.523 mmol) was added dropwise via syringe. The reaction was stirred at −78° C. for 2 min and DMF (0.08 mL, 1.06 mmol) was added via syringe. The reaction was stirred at −78° C. for 15 min and at RT for 30 min. The reaction was quenched with 10% aq. citric acid and extracted with EtOAc. The organic extract was washed with water then brine, dried (MgSO 4 ), and evaporated. Purification by column chromatography on silica gel using 2:1 hexanes-EtOAc as eluent afforded 68 mg (30%) of the title as a white solid, mp 212-214° C. Mass Spec: 469 (M−H) − .

Starting from the appropriate 3-substituted 5-amino-1-arylpyrazole-4-carboxamides the following compounds were prepared by methods similiar to those used to synthesize compounds in the examples and tables above:

TABLE VII
Ex#	Y	R 2	R 1	mp. (° C.)	MS
139	Cl	Et	4-Methoxyphenyl	amorphous	393
140	Cl	Et	4-Hydroxyphenyl	amorphous	379
141	Cl	Et	3-Methoxyphenyl	amorphous	393
142	Cl	Et	3-Hydroxyphenyl	amorphous	379
143	Cl	i-Pr	3-Hydroxyphenyl	227-228	395
144	Cl	i-Pr	4-Aminophenyl	amorphous	394
145	Cl	i-Pr	3-Methoxyphenyl		407
146	Cl	i-Pr	4-Methoxyphenyl	amorphous	407
147	Cl	i-Pr	4-Hydroxyphenyl	amorphous	395
148	Cl	Et	4-(N,N-dimethyl-		479
			glycinamido)phenylHCl
149	Cl	SCH 3	4-Hydroxyphenyl	243-244	397
150	Cl	SCH 3	4-Methoxyphenyl	227-228	413
151	Br	Et	3-Methoxyphenyl	178-180	439
152	Br	Et	4-Aminophenyl	246-249	424
153	Br	Et	3-Hydroxyphenyl	199-201	425
154	F	Et	3-Methoxyphenyl	193-194	379
155	F	Et	3-Hydroxyphenyl	235-237	365
156	Br	Et	4-(N,N-dimethyl-	156-158	509
			glycinamido)phenyl
157	F	Et	4-Aminophenyl	231-233	364

TABLE VIII
Ex	R 6	R 7	mp. (° C.)	MS
158	H	CH 3 NHCH 2 CH 2 N(CH 3 )COCH 2	154-155	541
159	H	H 2 NCH 2 CH 2 NHCOCH 2	140-142	513
160	H	Piperazin-1-ylCOCH 2	181-183	539
161	H	CH 3 CH 2 NHCOCH 2	242-244	496
162	H	CH 3 NHCOCH 2	249-250	482
163	H	1-CH 3 -piperazin-4-ylCOCH 2	236-237	553
164	H	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )COCH 2	134-136	555
165	Cl	4-CH 3 -piperazin-1-ylCOCH 2	205-207	587

TABLE IX
Ex#	R 5	R 6	R 2	R 1	mp. (° C.)	MS
166	Cl	CF 3	Et	3-Methoxyphenyl	192-193	497
167	Cl	CF 3	Et	4-Aminophenyl	235-236	495
168	Cl	CF 3	Et	4-Methoxyphenyl	240-241	497
169	Cl	Br	Et	4-Hydroxyphenyl	284-286	493
170	Cl	Br	Et	3-Hydroxyphenyl	242-244	495
171	Cl	H	Et	4-Hydroxyphenyl	262-263	413
172	Cl	H	Et	4-Aminoxyphenyl	159-161	414
173	Cl	H	Et	3-Hydroxyphenyl	242-244	413
174	Cl	Br	Et	3-Methoxyphenyl	232-233	507
175	Cl	Br	Et	4-Methoxyphenyl	252-253	507
176	Cl	H	Et	4-Methoxyphenyl	220-222	427
177	Cl	H	Et	3-Methoxyphenyl	186-187	427
178	F	H	SCH 3	4-Hydroxyphenyl	267-268	415
179	F	H	SCH 3	3-Hydroxyphenyl	252-253	415
180	Cl	Br	SCH 3	4-Hydroxyphenyl	255-256	511
181	F	H	SCH 3	4-Methoxyphenyl	193-194	429
182	F	H	SCH 3	3-Methoxyphenyl	244-245	431
183	Cl	Br	SCH 3	4-Methoxyphenyl	267-268	524
184	Me	H	Et	4-Hydroxyphenyl	255-256	395
185	Me	Cl	SCH 3	4-Methoxyphenyl	252-255	459
186	Me	H	SCH 3	4-Methoxyphenyl	233-235	425
187	Me	Cl	Et	4-Methoxyphenyl	245-246	441
188	Me	Cl	SCH 3	4-Hydroxyphenyl	277-279	445
189	Me	Cl	Et	4-Hydroxyphenyl	amorphous	429
190	Me	H	SCH 3	4-Hydroxyphenyl	264-266	413
191	Me	H	Et	4-Methoxyphenyl	220-221	409
192	Me	H	Et	4-Hydroxyphenyl	257-259	395
193	Me	H	Et	3-Methoxyphenyl	188-190	409
194	Me	H	Et	4-Hydroxyphenyl	255-256	395
195	Cl	CO 2 H	Et	4-Methoxyphenyl	292-294
196	Cl	CO 2 H	Et	4-Hydroxyphenyl	308-310	457
197	Cl	CO 2 H	Et	3-Methoxyphenyl	amorphous	471
198	Cl	CO 2 H	Et	3-Hydroxyphenyl	280-282
199	Me	H	i-Pr	4-Aminophenyl	205-206	408
200	Me	H	i-Pr	4-(N,N-Dimethylglycin	277-279	491
				amido)phenyl
201	Cl	CONHMe	Et	4-Methoxyphenyl	278-280	486
202	Me	H	Et	4-Methoxyphenyl	220-221	409
203	Me	H	Et	4-Hydroxyphenyl	257-259	395
204	Me	H	Et	3-Methoxyphenyl	188-190	409
205	Cl	CO 2 H	Et	4-Aminophenyl	226-228	458
206	Cl	Cl	t-Bu	3-Hydroxy-4-methoxy		505
				phenyl
207	Cl	Cl	CHF 2	3-Hydroxy-4-methoxy		499
				phenyl
208	Cl	Cl	CH 2 OH	3-Methoxyphenyl	227-229
209	Cl	Cl	i-Pr	3-(Ethoxycarbonyl-	174-175
				methyl)phenyl
210	Cl	Cl	i-Pr	3-(carboxymethyl)	210-211
				phenyl
211	Cl	Cl	i-Pr	3-(2-hydroxyethyl)		489
				phenyl
212	Cl	Cl	n-Bu	3-Hydroxy-4-methoxy		505
				phenyl
213	Me	H	i-Pr	4-(1-CH 3 -piperidin-4-		576
				ylN(CH 3 )CH 2 CONH)phenyl
214	Me	H	i-Pr	4-(1-CH 3 -piperidin-4-		562
				ylN(CH 3 )CONH)phenyl
215	Me	Cl	i-Pr	4-(1-CH 3 -piperidin-4-		596
				ylN(CH 3 )CONH)phenyl
216	Me	Cl	i-Pr	4-(1-CH 3 -piperidin-4-	108-110	610
				ylN(CH 3 )CH 2 CONH)phenyl
217	Me	Cl	i-Pr	4-aminophenyl	212-213	442
218	Me	Cl	i-Pr	4-(morpholin-4-	256-258	555
				ylCONH)phenyl
219	Me	Cl	i-Pr	4-(4-CH 3 -piperazin-1-	154-156	568
				ylCONH)phenyl
220	Me	Cl	i-Pr	4-(4-CH 3 -piperazin-1-	199-210	582
				ylCH 2 CONH)phenyl
221	Me	Cl	i-Pr	4-(Me 2 NCH 2 CONH)phenyl	>300	561
				HCl
222	Me	Cl	i-Pr	4-(morpholin-4-yl	246-249	569
				CH 2 CONH)phenyl
223	Cl	Cl	i-Pr	5-(Me 2 NCH 2 )-1-methyl	182-184	507
				pyrrol-2-yl
224	Cl	CH 2 NH 2	i-Pr	3-Methoxyphenyl		472
225	Cl	SO 2 NH 2	i-Pr	3-Methoxyphenyl	244-245	520

TABLE X
Ex#	R 1	mp. (° C.)	MS
226	4-(N,N-Dimethyl glycinamido)phenyl	235-237	533
227	3-Hydroxyphenyl	227-229	449

TABLE XI
	Ex.	R 6	mp (° C.)	MS
	228	CONHCH 2 CH 2 N(CH 3 ) 2	203-205	543
	229	CONHCH 2 CH 2 CH 3	229-231	512
	230	CCNHCH(CH 3 ) 2	233-235	512
	231	CONHCH 2 Ph	239-240	560
	232	CO-(4-CH 3 -piperazin)-1-yl	128-130	555
	233	CONHCH 2 pyridin-3-yl	amorphous	563
	234	CONHCH 2 pyridin-2-yl	188-190	563
	235	CONHCH 2 pyridin-4-yl	238-239	563
	236	CONHCH 2 CH 3	226-228	498
	237	CONHPh	amorphous	546
	238	CONHC(CH 3 ) 3	222-224	528
	239	CO-piperazin-1-yl	amorphous	541
	240	CONHcyclo-C 3 H 5	236-239	510
	241	CONHpyridin-3-yl	256-258	549
	242	CONHpyridin-4-yl	amorphous	549
	243	CONH(4-CH 3 -piperazin)-1-yl	amorphous	570
	244	CONHpyridin-2-yl	237-239	549
	245	CONHOCH 3	204-206	502

TABLE XII
	Ex.#	R 5	mp (° C.)	MS
	246	CONHCH 2 CH 2 N(CH 3 ) 2	263-265	529
	247	CONHCH 2 Ph	247-249	546

By reacting a p-substituted aniline with suitable acylating agents and performing further synthetic manipulations as necessary, the following compounds were prepared:

TABLE XIII
Ex.#	R 2	R 7 (para)	R 7 (meta)	mp (° C.)	MS
248	c-Pr	(CH 3 ) 2 NCH 2 CONH	H		545
249	Et	CH 3 CONH	H		488
250	Et	CH 3 OCONH	H		504
251	Et	CH 3 NHCONH	H		503
252	i-Pr	CH 3 OCONH	H		518
253	i-Pr	CH 3 OCON(Me)	H		532
254	Et	(CH 3 ) 2 NCH 2 CONH	H		531
255	i-Pr	CH 3 NHCONH	HO		535
256	i-Pr	CH 3 NHCON(Me)	H	235-237	531
257	i-Pr	4-CH 3 -piperazin-1-ylN(Me)	H		616
258	i-Pr	(CH 3 ) 2 NCH 2 CON(Me)	H	235-237	561
259	i-Pr	CH 3 NHCON(Me)	H	235-237	531
260	i-Pr	(CH 3 ) 2 NCH 2 CONH	HO	255-258	563
261	i-Pr	(+/−)-(CH 3 ) 2 NCH(CH 3 )CONH	H		561
262	i-Pr	(CH 3 ) 2 NCH 2 CONH	MeO	amorphous	577
263	i-Pr	CH 3 NHCONH	MeO	258-261
264	i-Pr	imidazol-1-ylCH 2 CONH	HO		586
265	i-Pr	(CH 3 ) 2 NCH 2 CONH	H	255-257	547
266	i-Pr	4-CH 3 -piperazin-1-yl	H		602
		CH 2 CONH
267	i-Pr	CH 3 NHCONH	H	268-274	519
268	i-Pr	morpholin-4-ylCH 2 CONH	H	252-255	589
269	i-Pr	azetidin-1-ylCH 2 CONH	H		559
270	i-Pr	(CH 3 ) 2 NCH 2 CH 2 SO 2 NH	H		597.1011
271	i-Pr	EtO 2 CCH 2 NHCONH	H	229-230	589
272	i-Pr	hydantoin-1-yl	H	>300	543
273	i-Pr	HOCH 2 CH 2 NHCONH	H	160-162	547.0799
274	i-Pr	HO 2 C(CH 2 ) 2 CONH	H	256-258	560
275	i-Pr	imidazol-1-ylCH 2 CONH	H	276-278	570
276	i-Pr	Morpholin-4-ylCH 2 CH 2	H		634
		NHCSNH
277	i-Pr	HO 2 CCH 2 NHCONH	H		561
278	i-Pr	HO 2 C(CH 2 ) 3 CONH	H		574
279	i-Pr	H 2 NCH 2 CONH	H	>300	519
280	i-Pr	CH 3 NHCH 2 CONH	H	amorphous	533.1029
281	i-Pr	4-F-phenyl CH 2 NHCH 2 CONH	H	217-223	627
282	i-Pr	pyrrolidin-1-ylCH 2 CONH	H	235-240	573
283	i-Pr	pyrid-2-ylCH 2 NHCH 2 CONH	H		610
284	i-Pr	pyrid-3-ylCH 2 NHCH 2 CONH	H	145-150	610
285	i-Pr	pyrid-4-ylCH 2 NHCH 2 CONH	H	180-185	610
286	i-Pr	BocNHCH 2 CH 2 NHCH 2 CONH	H		662.1829
287	i-Pr	HOCH 2 CH(CH 3 )NHCH 2 CONH	H	190-192	577
288	i-Pr	CH 3 CH(OH)CH 2 NHCH 2 CONH		152-160	577
289	i-Pr	H 2 NCH 2 CH 2 NHCH 2 CONH	H		562
290	i-Pr	morpholin-4-ylCH 2 CH 2	H		632
		NHCH 2 CONH
291	i-Pr	1-CH 3 -piperidin-4-yl	H		630
		N(CH 3 ) CH 2 CONH
292	i-Pr	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )CH 2 CONH	H	188-190	604
293	i-Pr	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )CONH	H		590
294	i-Pr	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )CH 2 CONH	OH		606
295	i-Pr	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )CH 2 CONH	OMe		620
296	i-Pr	(CH 3 ) 2 NCH(CH 3 )CONH	H		561
297	i-Pr	1-CH 3 -L-prolylNH	H
298	i-Pr	Homopiperazin-1-yl	H		602.1610
		CH 2 CONH
299	i-Pr	CH 3 CH 2 NHCH 2 CONH	H		547
300	i-Pr	4-(H 2 NCH 2 )piperidin-1-yl	H	amorphous	616
		CH 2 CONH
301	i-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCH 2 CONH	H	133-135	590.1610
302	i-Pr	cyclo-C 3 H 5 NHCH 2 CONH	H	213-216	559
303	i-Pr	Piperidin-4-ylCH 2 NH	H		616
		CH 2 CONH
304	i-Pr	HO(CH 2 ) 3 NHCH 2 CONH	H	200-205	575
305	i-Pr	1-Bocpiperidin-4-ylCH 2 NH	H		716
		CH 2 CONH
306	i-Pr	HOCH 2 CH 2 NHCH 2 CONH	H	210-212	563
307	i-Pr	cyclo-C 4 H 7 NHCH 2 CONH	H	225-228	573
308	i-Pr	azetidin-3-ylCONH	H		545
309	i-Pr	D-prolylNH.HCl	H	225-226	559
310	i-Pr	Boc-D-prolylNH	H		559.1185
311	i-Pr	L-prolylNH.HCl	H	225-226	659.1707
312	i-Pr	Boc-L-prolylNH	H		657
313	i-Pr	piperidin-1-ylCH 2 CH 2 —	H	213-215	630
		NHCH 2 CONH
314	i-Pr	(CH 3 ) 2 CHNHCH 2 CONH	H	130-135	559
315	i-Pr	BocNHCH 2 CH 2 CONH	H		631
316	i-Pr	piperazin-2-yl-CONH	H	amorphous	547.1286
317	i-Pr	4-Me-piperazin-2-yl-CONH	H	amorphous	588.1448
318	i-Pr	piperidin-1-ylNHCONH	H	264-266	588
319	i-Pr	H 2 NCH 2 CH 2 NHCONH.F 3 CCO 2 H	H		548
320	i-Pr	pyrid-2-ylNHCONH	H	277-281
321	i-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCONH	H	220-222	576
322	i-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCONH	OMe	244-248	606
323	i-Pr	BocNHCH 2 CH 2 NHCONH	H	208-210	646
324	i-Pr	HO(CH 2 ) 4 NHCONH	H	208-210	577
325	i-Pr	(CH 3 ) 2 NNHCONH	H	240-242	546
326	i-Pr	(CH 3 ) 2 N(CH 2 ) 3 NHCONH	H		590
327	i-Pr	(CH 3 ) 2 N(CH 2 ) 3 NHCONH	OMe	226-228	620
328	i-Pr	4-CH 3 -homo-piperazin-1-	H		602
		yl-CONH
329	i-Pr	CH 3 SO 2 NHCONH	H		581
330	i-Pr	CH 3 ONHCONH	H		534
331	i-Pr	1-CH 3 -piperidin-4-yl	H		616
		N(CH 3 )CONH
332	i-Pr	1-CH 3 -piperidin-4-yl	OH		632
		N(CH 3 )CONH
333	i-Pr	1-CH 3 -piperidin-4-yl	OMe	243-245	646
		N(CH 3 )CONH
334	i-Pr	tetrahydrofur-2-yl	H		587
		CH 2 NHCONH
335	i-Pr	CH 3 (CH 2 ) 2 CH(OH)CH 2 NHCONH	H		589
336	i-Pr	HOCH 2 CH(CH 3 )NHCONH	H	156-158	561
337	i-Pr	CH 3 CH(OH)CH 2 NHCONH	H		561
338	i-Pr	HOCH 2 CH 2 NHCONH	H	222-225	547
339	i-Pr	morpholin-4-ylNHCONH	H	272-274	588
340	i-Pr	(CH 3 ) 2 NCH(CH 3 )CH 2 NHCONH	H		590
341	i-Pr	4-CH 3 -piperazin-1-yl	H		603
		NHCONH
342	i-Pr	4-CH 3 -piperazin-1-yl	OH		619
		NHCONH
343	i-Pr	4-CH 3 -piperazin-1-yl	OMe	245-246	633
		NHCONH
344	i-Pr	morpholin-4-yl	H		618
		CH 2 CH 2 NHCONH
345	i-Pr	4-CH 3 -piperazin-1-ylCONH	H		588
346	i-Pr	piperazin-1-ylCONH.HCl	H		574
347	Et	4-CH 3 -piperazin-1-ylCONH	H		574
348	Et	(CH 3 ) 2 NCH 2 CH 2 NHCONH	H		563
349	Et	pyrid-2-ylNHCONH	H	amorphous	582
350	Et	pyrid-4-ylNHCONH	H	amorphous	582
351	i-Pr	H	MeN		533
			HCO
			NHC
			H 2
352	i-Pr	(+/−)-2-(Me 2 NCH 2 )piperid-	H		630
		1-ylCONH
353	i-Pr	(+/−)-2-(Me 2 NCH 2 )piperid-	OH		646
		1-ylCONH.CF 3 CO 2 H
354	i-Pr	(+/−)-2-(Me 2 NCH 2 )piperid-	OMe	131-135	660
		1-ylCONH
355	i-Pr	CH 3 NCH 2 CH 2 N(CH 3 )CONH	OMe	146-148	606
356	i-Pr	(CH 3 ) 2 NCH 2 CH 2 NCO	H	278-280	561
357	i-Pr	(CH 3 )NCH 2 CH 2 N(CH 3 )CO	H		561
358	i-Pr	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )CO	H		575

Following procedures similar to those used to synthesize the examples above, the following compounds were prepared or could be prepared:

TABLE XIV
Ex. #	R 2	R 7 (para)	R 7 (meta)	MS
1	i-Pr	pyrrolidin-1-ylCH 2 CH 2 NHCH 2 CONH	H	616
2	i-Pr	pyrrolidin-1-ylCH 2 CH 2 NHCONH	OMe	632
3	i-Pr	pyrrolidin-1-ylCH 2 CH 2 NHCONH	OH	618
4	i-Pr	pyrrolidin-1-ylCH 2 CH 2 NHCONH	H	602
5	i-Pr	2-CH 3 -piperazin-1-ylCONH	H
6	i-Pr	3-CH 3 -piperazin-1-ylCH 2 CONH	H	602
7	i-Pr	trans-2,5-di-CH 3 -piperazin-1-	H	616
		ylCH 2 CONH
8	i-Pr	cis-2,6-di-CH 3 -piperazin-1-	H
		ylCH 2 CONH
9	i-Pr	cis-3,4-di-CH 3 -piperazin-1-	H	616
		ylCH 2 CONH
10	i-Pr	cis-3,5-di-CH 3 -piperazin-1-	H
		ylCH 2 CONH
11	i-Pr	trans-2,6-di-CH 3 -piperazin-1-	H
		ylCH 2 CONH
12	i-Pr	trans-3,5-di-CH 3 -piperazin-1-	H
		ylCH 2 CONH
13	i-Pr	(R)-1-Ethylpyrrolidin-2-	H
		ylCH 2 NHCONH
14	i-Pr	(S)-1-Ethylpyrrolidin-2-	H
		ylCH 2 NHCONH
15	i-Pr	5-CH 3 -pyrazin-2-	H
		ylCH 2 NHCH 2 CONH
16	i-Pr	(CH 3 ) 2 NCH 2 CH 2 CH 2 OCONH	H	591
17	i-Pr	(+/−)—N—(CH 3 )piperidin-3-	H	617
		ylCH 2 OCONH
18	i-Pr	(+/−)—N—(CH 3 )piperidin-3-ylOCONH	H	603
19	i-Pr	(+/−)—N—(CH 3 )piperidin-2-	H	617
		ylCH 2 OCONH
20	i-Pr	(+/−)—N—(CH 3 )pyrrolidin-3-	H	589
		ylOCONH
21	i-Pr	2-CH 3 -piperazin-1-ylCH 2 CONH	H
22	i-Pr	pyrrolidin-1-ylCH 2 CH 2 NHCH 2 CONH	H
23	i-Pr	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )CONH	H	590
24	i-Pr	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )CO	H	575
25	i-Pr	2-CH 3 -piperazin-1-ylCONH	H
26	i-Pr	3-CH 3 -piperazin-1-ylCH 2 CONH	H
27	i-Pr	trans-2,5-di-CH 3 -piperazin-1-	H
		ylCH 2 CONH
28	i-Pr	cis-2,6-di-CH 3 -piperazin-1-	H
		ylCH 2 CONH
29	i-Pr	cis-3,5-di-CH 3 -piperazin-1-	H
		ylCH 2 CONH
30	i-Pr	trans-2,6-di-CH 3 -piperazin-1-	H
		ylCH 2 CONH

TABLE XV
(a)
(b)
Ex. #	R 2	R 7
1	i-Pr	1-CH 3 -piperazin-4-ylCH 2 CONH
2	i-Pr	BocNHSO 2 NH
3	i-Pr	morpholin-4-ylCH 2 CONH
4	i-Pr	azetidin-1-ylCH 2 CONH
5	i-Pr	(CH 3 ) 2 NCH 2 CH 2 SO 2 NH
6	i-Pr	EtO 2 CCH 2 NHCONH
7	i-Pr	HOCH 2 CH 2 NHCONH
8	i-Pr	Hydantoin-1-yl
9	i-Pr	HOCH 2 CH 2 NHCONH
10	i-Pr	HO 2 C(CH 2 ) 2 CONH
11	i-Pr	imidazol-1-ylCH 2 CONH
12	i-Pr	Morpholin-4-ylCH 2 CH 2 NHCSNH
13	i-Pr	HO 2 CCH 2 NHCONH
14	i-Pr	HO 2 C(CH 2 ) 3 CONH
15	i-Pr	(CH 3 ) 2 NCH 2 CONH
16	i-Pr	H 2 NCH 2 CONH
17	i-Pr	CH 3 NHCH 2 CONH
18	i-Pr	4-F-phenylCH 2 NHCH 2 CONH
19	i-Pr	pyrrolidin-1-ylCH 2 CONH
20	i-Pr	pyrid-2-ylCH 2 NHCH 2 CONH
21	i-Pr	pyrid-3-ylCH 2 NHCH 2 CONH
22	i-Pr	pyrid-4-ylCH 2 NHCH 2 CONH
23	i-Pr	BocNHCH 2 CH 2 NHCH 2 CONH
24	i-Pr	HOCH 2 CH(CH 3 )NHCH 2 CONH
25	i-Pr	CH 3 CH(OH)CH 2 NHCH 2 CONH
26	i-Pr	H 2 NCH 2 CH 2 NHCH 2 CONH
27	i-Pr	morpholin-4-ylCH 2 CH 2 NHCH 2 CONH
28	i-Pr	1-CH 3 -piperidin-4-ylN(CH 3 )CH 2 CONH
29	i-Pr	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )CH 2 CONH
30	i-Pr	piperazin-1-ylCH 2 CONH
31	i-Pr	(CH 3 ) 2 NCH(CH 3 )CONH
32	i-Pr	1-CH 3 -L-prolylNH
33	i-Pr	homopiperazin-1-ylCH 2 CONH
34	i-Pr	CH 3 CH 2 NHCH 2 CONH
35	i-Pr	4-(CH 2 NH 2 )piperidin-1-ylCH 2 CONH
36	i-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCH 2 CONH
37	i-Pr	H 2 NCH 2 CONH
38	i-Pr	cyclo-C 3 H 5 NHCH 2 CONH
39	i-Pr	piperidin-4-ylCH 2 NHCH 2 CONH
40	i-Pr	HO(CH 2 ) 3 NHCH 2 CONH
41	i-Pr	1-Bocpiperidin-4-ylCH 2 NHCH 2 CONH
42	i-Pr	HOCH 2 CH 2 NHCH 2 CONH
43	i-Pr	cyclo-C 4 H 7 NHCH 2 CONH
44	i-Pr	azetidin-3-ylCONH
45	i-Pr	D-prolylNH.HCl
46	i-Pr	Boc-D-prolylNH
47	i-Pr	L-prolylNH.HCl
48	i-Pr	Boc-L-prolylNH
49	i-Pr	piperidin-1-ylCH 2 CH 2 NHCH 2 CONH
50	i-Pr	(CH 3 ) 2 CHNHCH 2 CONH
51	i-Pr	BocNHCH 2 CH 2 CONH
52	i-Pr	pyrrolidin-1-ylCH 2 CH 2 NHCH 2 CONH
53	i-Pr	2-CH 3 -piperazin-1-ylCONH
54	i-Pr	3-CH 3 -piperazin-1-ylCH 2 CONH
55	i-Pr	trans-2,5-di-CH 3 -piperazin-1-ylCH 2 CONH
56	i-Pr	cis-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH
57	i-Pr	cis-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH
58	i-Pr	trans-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH
59	i-Pr	trans-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH
60	i-Pr	(R)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH
61	i-Pr	(S)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH
62	i-Pr	5-CH 3 -pyrazin-2-ylCH 2 NHCH 2 CONH
63	i-Pr	piperazin-2-yl-CONH
64	i-Pr	4-Me-piperazin-2-ylCONH

TABLE XVI
(a)
(b)
(c)
Ex. #	R 2	R 7
1	cyc-Bu	(CH 3 ) 2 NCH 2 CONH
2	cyc-Bu	1-CH 3 -piperazin-4-ylCH 2 CONH
3	cyc-Bu	CH 3 NHCONH
4	cyc-Bu	morpholin-4-ylCH 2 CONH
5	cyc-Bu	azetidin-1-ylCH 2 CONH
6	cyc-Bu	(CH 3 ) 2 NCH 2 CH 2 SO 2 NH
7	cyc-Bu	EtO 2 CCH 2 NHCONH
8	cyc-Bu	Hydantoin-1-yl
9	cyc-Bu	HOCH 2 CH 2 NHCONH
10	cyc-Bu	HO 2 C(CH 2 ) 2 CONH
11	cyc-Bu	imidazol-1-ylCH 2 CONH
12	cyc-Bu	Morpholin-4-ylCH 2 CH 2 NHCSNH
13	cyc-Bu	HO 2 CCH 2 NHCONH
14	cyc-Bu	HO 2 C(CH 2 ) 3 CONH
15	cyc-Bu	H 2 NCH 2 CONH
16	cyc-Bu	CH 3 NHCH 2 CONH
17	cyc-Bu	4-F-phenylCH 2 NHCH 2 CONH
18	cyc-Bu	pyrrolidin-1-ylCH 2 CONH
19	cyc-Bu	pyrid-2-ylCH 2 NHCH 2 CONH
20	cyc-Bu	pyrid-3-ylCH 2 NHCH 2 CONH
21	cyc-Bu	pyrid-4-ylCH 2 NHCH 2 CONH
22	cyc-Bu	BocNHCH 2 CH 2 NHCH 2 CONH
23	cyc-Bu	HOCH 2 CH(CH 3 )NHCH 2 CONH
24	cyc-Bu	CH 3 CH(OH)CH 2 NHCH 2 CONH
25	cyc-Bu	H 2 NCH 2 CH 2 NHCH 2 CONH
26	cyc-Bu	morpholin-4-ylCH 2 CH 2 NHCH 2 CONH
27	cyc-Bu	1-CH 3 -piperidin-4-ylN(CH 3 )CH 2 CONH
28	cyc-Bu	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )CH 2 CONH
29	cyc-Bu	(CH 3 ) 2 NCH(CH 3 )CONH
30	cyc-Bu	1-CH 3 -L-prolylNH
31	cyc-Bu	Homopiperazin-1-ylCH 2 CONH
32	cyc-Bu	CH 3 CH 2 NHCH 2 CONH
33	cyc-Bu	4-(CH 2 NH 2 )piperidin-1-ylCH 2 CONH
34	cyc-Bu	(CH 3 ) 2 NCH 2 CH 2 NHCH 2 CONH
35	cyc-Bu	cyclo-C 3 H 5 NHCH 2 CONH
36	cyc-Bu	Piperidin-4-ylCH 2 NHCH 2 CONH
37	cyc-Bu	HO(CH 2 ) 3 NHCH 2 CONH
38	cyc-Bu	1-Bocpiperidin-4-ylCH 2 NHCH 2 CONH
39	cyc-Bu	HOCH 2 CH 2 NHCH 2 CONH
40	cyc-Bu	cyclo-C 4 H 7 NHCH 2 CONH
41	cyc-Bu	azetidin-3-ylCONH
42	cyc-Bu	D-prolylNH.HCl
43	cyc-Bu	Boc-D-prolylNH
44	cyc-Bu	L-prolylNH.HCl
45	cyc-Bu	Boc-L-prolylNH
46	cyc-Bu	piperidin-1-ylCH 2 CH 2 NHCH 2 CONH
47	cyc-Bu	(CH 3 ) 2 CHNHCH 2 CONH
48	cyc-Bu	BocNHCH 2 CH 2 CONH
49	cyc-Bu	piperazin-2-yl-CONH
50	cyc-Bu	4-Me-piperazin-2-yl-CONH
51	cyc-Bu	piperidin-1-ylNHCONH
52	cyc-Bu	H 2 NCH 2 CH 2 NHCONH.F 3 CCO 2 H
53	cyc-Bu	pyrid-2-ylNHCONH
54	cyc-Bu	(CH 3 ) 2 NCH 2 CH 2 NHCONH
55	cyc-Bu	BocNHCH 2 CH 2 NHCONH
56	cyc-Bu	HO(CH 2 ) 4 NHCONH
57	cyc-Bu	(CH 3 ) 2 NNHCONH
58	cyc-Bu	(CH 3 ) 2 N(CH 2 ) 3 NHCONH
59	cyc-Bu	1-CH 3 -homopiperazin-4-yl-CONH
60	cyc-Bu	CH 3 SO 2 NHCONH
61	cyc-Bu	CH 3 ONHCONH
62	cyc-Bu	(CH 3 ) 2 NCH 2 CH 2 NHCONH
63	cyc-Bu	1-CH 3 -piperidin-4-ylN(CH 3 )CONH
64	cyc-Bu	tetrahydrofur-2-ylCH 2 NHCONH
65	cyc-Bu	CH 3 (CH 2 ) 2 CH(OH)CH 2 NHCONH
66	cyc-Bu	HOCH 2 CH(CH 3 )NHCONH
67	cyc-Bu	CH 3 CH(OH)CH 2 NHCONH
68	cyc-Bu	HOCH 2 CH 2 NHCONH
69	cyc-Bu	morpholin-4-ylNHCONH
70	cyc-Bu	(CH 3 ) 2 NCH(CH 3 )CH 2 NHCONH
71	cyc-Bu	1-CH 3 -piperazin-4-ylNHCONH
72	cyc-Bu	morpholin-4-ylCH 2 CH 2 NHCONH
73	cyc-Bu	1-CH 3 -piperazin-4-ylCONH
74	cyc-Bu	pyrid-2-ylNHCONH
75	cyc-Bu	pyrid-4-ylNHCONH
76	cyc-Bu	pyrrolidin-1-ylCH 2 CH 2 NHCH 2 CONH
77	cyc-Bu	2-CH 3 -piperazin-1-ylCONH
78	cyc-Bu	3-CH 3 -piperazin-1-ylCH 2 CONH
79	cyc-Bu	trans-2,5-di-CH 3 -piperazin-1-ylCH 2 CONH
80	cyc-Bu	cis-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH
81	cyc-Bu	cis-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH
82	cyc-Bu	trans-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH
83	cyc-Bu	trans-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH
84	cyc-Bu	(R)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH
85	cyc-Bu	(S)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH
86	cyc-Bu	5-CH 3 -pyrazin-2-ylCH 2 NHCH 2 CONH

TABLE XVII
Ex.#	R 2	R 7 (para)	R 7 (meta)
1	i-Pr	(CH 3 ) 2 NCH 2 CONH	Me
2	i-Pr	1-CH 3 -piperazin-4-ylCH 2 CONH	Me
3	i-Pr	CH 3 NHCONH	Me
4	i-Pr	morpholin-4-ylCH 2 CONH	Me
5	i-Pr	azetidin-1-ylCH 2 CONH	Me
6	i-Pr	(CH 3 ) 2 NCH 2 CH 2 SO 2 NH	Me
7	i-Pr	EtO 2 CCH 2 NHCONH	Me
8	i-Pr	Hydantoin-1-yl	Me
9	i-Pr	HOCH 2 CH 2 NHCONH	Me
10	i-Pr	HO 2 C(CH 2 ) 2 CONH	Me
11	i-Pr	imidazol-1-ylCH 2 CONH	Me
12	i-Pr	Morpholin-4-ylCH 2 CH 2 NHCSNH	Me
13	i-Pr	HO 2 CCH 2 NHCONH	Me
14	i-Pr	HO 2 C(CH 2 ) 3 CONH	Me
15	i-Pr	H 2 NCH 2 CONH	Me
16	i-Pr	CH 3 NHCH 2 CONH	Me
17	i-Pr	4-F-phenylCH 2 NHCH 2 CONH	Me
18	i-Pr	pyrrolidin-1-ylCH 2 CONH	Me
19	i-Pr	pyrid-2-ylCH 2 NHCH 2 CONH	Me
20	i-Pr	pyrid-3-ylCH 2 NHCH 2 CONH	Me
21	i-Pr	pyrid-4-ylCH 2 NHCH 2 CONH	Me
22	i-Pr	BocNHCH 2 CH 2 NHCH 2 CONH	Me
23	i-Pr	HOCH 2 CH(CH 3 )NHCH 2 CONH	Me
24	i-Pr	CH 3 CH(OH)CH 2 NHCH 2 CONH	Me
25	i-Pr	H 2 NCH 2 CH 2 NHCH 2 CONH	Me
26	i-Pr	morpholin-4-ylCH 2 CH 2 NHCH 2 CONH	Me
27	i-Pr	1-CH 3 -piperidin-4-ylN(CH 3 )CH 2 CONH	Me
28	i-Pr	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )CH 2 CONH	Me
29	i-Pr	(CH 3 ) 2 NCH(CH 3 )CONH	Me
30	i-Pr	1-CH 3 -L-prolylNH	Me
31	i-Pr	Homopiperazin-1-ylCH 2 CONH	Me
32	i-Pr	CH 3 CH 2 NHCH 2 CONH	Me
33	i-Pr	4-(CH 2 NH 2 )piperidin-1-ylCH 2 CONH	Me
34	i-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCH 2 CONH	Me
35	i-Pr	cyclo-C 3 H 5 NHCH 2 CONH	Me
36	i-Pr	Piperidin-4-ylCH 2 NHCH 2 CONH	Me
37	i-Pr	HO(CH 2 ) 3 NHCH 2 CONH	Me
38	i-Pr	1-Bocpiperidin-4-ylCH 2 NHCH 2 CONH	Me
39	i-Pr	HOCH 2 CH 2 NHCH 2 CONH	Me
40	i-Pr	cyclo-C 4 H 7 NHCH 2 CONH	Me
41	i-Pr	azetidin-3-ylCONH	Me
42	i-Pr	D-prolylNH.HCl	Me
43	i-Pr	Boc-D-prolylNH	Me
44	i-Pr	L-prolylNH.HCl	Me
45	i-Pr	Boc-L-prolylNH	Me
46	i-Pr	piperidin-1-ylCH 2 CH 2 NHCH 2 CONH	Me
47	i-Pr	(CH 3 ) 2 CHNHCH 2 CONH	Me
48	i-Pr	BocNHCH 2 CH 2 CONH	Me
49	i-Pr	piperazin-2-yl-CONH	Me
50	i-Pr	4-Me-piperazin-2-yl-CONH	Me
51	i-Pr	piperidin-1-ylNHCONH	Me
52	i-Pr	H 2 NCH 2 CH 2 NHCONH.F 3 CCO 2 H	Me
53	i-Pr	pyrid-2-ylNHCONH	Me
54	i-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCONH	Me
55	i-Pr	BocNHCH 2 CH 2 NHCONH	Me
56	i-Pr	HO(CH 2 ) 4 NHCONH	Me
57	i-Pr	(CH 3 ) 2 NNHCONH	Me
58	i-Pr	(CH 3 ) 2 N(CH 2 ) 3 NHCONH	Me
59	i-Pr	1-CH 3 -homopiperazin-4-yl-CONH	Me
60	i-Pr	CH 3 SO 2 NHCONH	Me
61	i-Pr	CH 3 ONHCONH	Me
62	i-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCONH	Me
63	i-Pr	1-CH 3 -piperidin-4-ylN(CH 3 )CONH	Me
64	i-Pr	tetrahydrofur-2-ylCH 2 NHCONH	Me
65	i-Pr	CH 3 (CH 2 ) 2 CH(OH)CH 2 NHCONH	Me
66	i-Pr	HOCH 2 CH(CH 3 )NHCONH	Me
67	i-Pr	CH 3 CH(OH)CH 2 NHCONH	Me
68	i-Pr	HOCH 2 CH 2 NHCONH	Me
69	i-Pr	morpholin-4-ylNHCONH	Me
70	i-Pr	(CH 3 ) 2 NCH(CH 3 )CH 2 NHCONH	Me
71	i-Pr	1-CH 3 -piperazin-4-ylNHCONH	Me
72	i-Pr	morpholin-4-ylCH 2 CH 2 NHCONH	Me
73	i-Pr	1-CH 3 -piperazin-4-ylCONH	Me
74	i-Pr	pyrid-2-ylNHCONH	Me
75	i-Pr	pyrid-4-ylNHCONH	Me
76	i-Pr	pyrrolidin-1-ylCH 2 CH 2 NHCH 2 CONH	Me
77	i-Pr	2-CH 3 -piperazin-1-ylCONH	Me
78	i-Pr	3-CH 3 -piperazin-1-ylCH 2 CONH	Me
79	i-Pr	trans-2,5-di-CH 3 -piperazin-1-ylCH 2 CONH	Me
80	i-Pr	cis-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH	Me
81	i-Pr	cis-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH	Me
82	i-Pr	trans-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH	Me
83	i-Pr	trans-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH	Me
84	i-Pr	(R)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH	Me
85	i-Pr	(S)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH	Me
86	i-Pr	5-CH 3 -pyrazin-2-ylCH 2 NHCH 2 CONH	Me

TABLE XVIII
Ex.#	R 2	R 7 (meta)	R 7 (ortho)
1	i-Pr	1-CH 3 -piperazin-4-ylCH 2 CONH	Me
2	i-Pr	CH 3 NHCONH	Me
3	i-Pr	morpholin-4-ylCH 2 CONH	Me
4	i-Pr	azetidin-1-ylCH 2 CONH	Me
5	i-Pr	(CH 3 ) 2 NCH 2 CH 2 SO 2 NH	Me
6	i-Pr	EtO 2 CCH 2 NHCONH	Me
7	i-Pr	Hydantoin-1-yl	Me
8	i-Pr	HOCH 2 CH 2 NHCONH	Me
9	i-Pr	HO 2 C(CH 2 ) 2 CONH	Me
10	i-Pr	imidazol-1-ylCH 2 CONH	Me
11	i-Pr	Morpholin-4-ylCH 2 CH 2 NHCSNH	Me
12	i-Pr	HO 2 CCH 2 NHCONH	Me
13	i-Pr	HO 2 C(CH 2 ) 3 CONH	Me
14	i-Pr	H 2 NCH 2 CONH	Me
15	i-Pr	CH 3 NHCH 2 CONH	Me
16	i-Pr	4-F-phenylCH 2 NHCH 2 CONH	Me
17	i-Pr	pyrrolidin-1-ylCH 2 CONH	Me
18	i-Pr	pyrid-2-ylCH 2 NHCH 2 CONH	Me
19	i-Pr	pyrid-3-ylCH 2 NHCH 2 CONH	Me
20	i-Pr	pyrid-4-ylCH 2 NHCH 2 CONH	Me
21	i-Pr	BocNHCH 2 CH 2 NHCH 2 CONH	Me
22	i-Pr	HOCH 2 CH(CH 3 )NHCH 2 CONH	Me
23	i-Pr	CH 3 CH(OH)CH 2 NHCH 2 CONH	Me
24	i-Pr	H 2 NCH 2 CH 2 NHCH 2 CONH	Me
25	i-Pr	morpholin-4-ylCH 2 CH 2 NHCH 2 CONH	Me
26	i-Pr	1-CH 3 -piperidin-4-ylN(CH 3 )CH 2 CONH	Me
27	i-Pr	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )CH 2 CONH	Me
28	i-Pr	(CH 3 ) 2 NCH(CH 3 )CONH	Me
29	i-Pr	1-CH 3 -L-prolylNH	Me
30	i-Pr	Homopiperazin-1-ylCH 2 CONH	Me
31	i-Pr	CH 3 CH 2 NHCH 2 CONH	Me
32	i-Pr	4-(CH 2 NH 2 )piperidin-1-ylCH 2 CONH	Me
33	i-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCH 2 CONH	Me
34	i-Pr	cyclo-C 3 H 5 NHCH 2 CONH	Me
35	i-Pr	Piperidin-4-ylCH 2 NHCH 2 CONH	Me
36	i-Pr	HO(CH 2 ) 3 NHCH 2 CONH	Me
37	i-Pr	1-Bocpiperidin-4-ylCH 2 NHCH 2 CONH	Me
38	i-Pr	HOCH 2 CH 2 NHCH 2 CONH	Me
39	i-Pr	cyclo-C 4 H 7 NHCH 2 CONH	Me
40	i-Pr	azetidin-3-ylCONH	Me
41	i-Pr	D-prolylNH.HCl	Me
42	i-Pr	Boc-D-prolylNH	Me
43	i-Pr	L-prolylNH.HCl	Me
44	i-Pr	Boc-L-prolylNH	Me
45	i-Pr	piperidin-1-ylCH 2 CH 2 NHCH 2 CONH	Me
46	i-Pr	(CH 3 ) 2 CHNHCH 2 CONH	Me
47	i-Pr	BocNHCH 2 CH 2 CONH	Me
48	i-Pr	piperazin-2-yl-CONH	Me
49	i-Pr	4-Me-piperazin-2-yl-CONH	Me
50	i-Pr	piperidin-1-ylNHCONH	Me
51	i-Pr	H 2 NCH 2 CH 2 NHCONH.F 3 CCO 2 H	Me
52	i-Pr	pyrid-2-ylNHCONH	Me
53	i-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCONH	Me
54	i-Pr	BocNHCH 2 CH 2 NHCONH	Me
55	i-Pr	HO(CH 2 ) 4 NHCONH	Me
56	i-Pr	(CH 3 ) 2 NNHCONH	Me
57	i-Pr	(CH 3 ) 2 N(CH 2 ) 3 NHCONH	Me
58	i-Pr	1-CH 3 -homopiperazin-4-yl-CONH	Me
59	i-Pr	CH 3 SO 2 NHCONH	Me
60	i-Pr	CH 3 ONHCONH	Me
61	i-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCONH	Me
62	i-Pr	1-CH 3 -piperidin-4-ylN(CH 3 )CONH	Me
63	i-Pr	tetrahydrofur-2-ylCH 2 NHCONH	Me
64	i-Pr	CH 3 (CH 2 ) 2 CH(OH)CH 2 NHCONH	Me
65	i-Pr	HOCH 2 CH(CH 3 )NHCONH	Me
66	i-Pr	CH 3 CH(OH)CH 2 NHCONH	Me
67	i-Pr	HOCH 2 CH 2 NHCONH	Me
68	i-Pr	morpholin-4-ylNHCONH	Me
69	i-Pr	(CH 3 ) 2 NCH(CH 3 )CH 2 NHCONH	Me
70	i-Pr	1-CH 3 -piperazin-4-ylNHCONH	Me
71	i-Pr	morpholin-4-ylCH 2 CH 2 NHCONH	Me
72	i-Pr	1-CH 3 -piperazin-4-ylCONH	Me
73	i-Pr	pyrid-2-ylNHCONH	Me
74	i-Pr	pyrid-4-ylNHCONH	Me
75	i-Pr	pyrrolidin-1-ylCH 2 CH 2 NHCH 2 CONH	Me
76	i-Pr	2-CH 3 -piperazin-1-ylCONH	Me
77	i-Pr	3-CH 3 -piperazin-1-ylCH 2 CONH	Me
78	i-Pr	trans-2,5-di-CH 3 -piperazin-1-ylCH 2 CONH	Me
79	i-Pr	cis-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH	Me
80	i-Pr	cis-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH	Me
81	i-Pr	trans-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH	Me
82	i-Pr	trans-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH	Me
83	i-Pr	(R)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH	Me
84	i-Pr	(S)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH	Me
85	i-Pr	5-CH 3 -pyrazin-2-ylCH 2 NHCH 2 CONH	Me

TABLE XIX
Ex.#	R 2	R 7 (para)	R 7 (ortho)
1	i-Pr	(CH 3 ) 2 NCH 2 CONH	Me
2	i-Pr	1-CH 3 -piperazin-4-ylCH 2 CONH	Me
3	i-Pr	CH 3 NHCONH	Me
4	i-Pr	morpholin-4-ylCH 2 CONH	Me
5	i-Pr	azetidin-1-ylCH 2 CONH	Me
6	i-Pr	(CH 3 ) 2 NCH 2 CH 2 SO 2 NH	Me
7	i-Pr	EtO 2 CCH 2 NHCONH	Me
8	i-Pr	Hydantoin-1-yl	Me
9	i-Pr	HOCH 2 CH 2 NHCONH	Me
10	i-Pr	HO 2 C(CH 2 ) 2 CONH	Me
11	i-Pr	imidazol-1-ylCH 2 CONH	Me
12	i-Pr	Morpholin-4-ylCH 2 CH 2 NHCSNH	Me
13	i-Pr	HO 2 CCH 2 NHCONH	Me
14	i-Pr	HO 2 C(CH 2 ) 3 CONH	Me
15	i-Pr	H 2 NCH 2 CONH	Me
16	i-Pr	CH 3 NHCH 2 CONH	Me
17	i-Pr	4-F-phenylCH 2 NHCH 2 CONH	Me
18	i-Pr	pyrrolidin-1-ylCH 2 CONH	Me
19	i-Pr	pyrid-2-ylCH 2 NHCH 2 CONH	Me
20	i-Pr	pyrid-3-ylCH 2 NHCH 2 CONH	Me
21	i-Pr	pyrid-4-ylCH 2 NHCH 2 CONH	Me
22	i-Pr	BocNHCH 2 CH 2 NHCH 2 CONH	Me
23	i-Pr	HOCH 2 CH(CH 3 )NHCH 2 CONH	Me
24	i-Pr	CH 3 CH(OH)CH 2 NHCH 2 CONH	Me
25	i-Pr	H 2 NCH 2 CH 2 NHCH 2 CONH	Me
26	i-Pr	morpholin-4-ylCH 2 CH 2 NHCH 2 CONH	Me
27	i-Pr	1-CH 3 -piperidin-4-ylN(CH 3 )CH 2 CONH	Me
28	i-Pr	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )CH 2 CONH	Me
29	i-Pr	(CH 3 ) 2 NCH(CH 3 )CONH	Me
30	i-Pr	1-CH 3 -L-prolylNH	Me
31	i-Pr	Homopiperazin-1-ylCH 2 CONH	Me
32	i-Pr	CH 3 CH 2 NHCH 2 CONH	Me
33	i-Pr	4-(CH 2 NH 2 )piperidin-1-ylCH 2 CONH	Me
34	i-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCH 2 CONH	Me
35	i-Pr	cyclo-C 3 H 5 NHCH 2 CONH	Me
36	i-Pr	Piperidin-4-ylCH 2 NHCH 2 CONH	Me
37	i-Pr	HO(CH 2 ) 3 NHCH 2 CONH	Me
38	i-Pr	1-Bocpiperidin-4-ylCH 2 NHCH 2 CONH	Me
39	i-Pr	HOCH 2 CH 2 NHCH 2 CONH	Me
40	i-Pr	cyclo-C 4 H 7 NHCH 2 CONH	Me
41	i-Pr	azetidin-3-ylCONH	Me
42	i-Pr	D-prolylNH.HCl	Me
43	i-Pr	Boc-D-prolylNH	Me
44	i-Pr	L-prolylNH.HCl	Me
45	i-Pr	Boc-L-prolylNH	Me
46	i-Pr	piperidin-1-ylCH 2 CH 2 NHCH 2 CONH	Me
47	i-Pr	(CH 3 ) 2 CHNHCH 2 CONH	Me
48	i-Pr	BocNHCH 2 CH 2 CONH	Me
49	i-Pr	piperazin-2-yl-CONH	Me
50	i-Pr	4-Me-piperazin-2-yl-CONH	Me
51	i-Pr	piperidin-1-ylNHCONH	Me
52	i-Pr	H 2 NCH 2 CH 2 NHCONH.F 3 CCO 2 H	Me
53	i-Pr	pyrid-2-ylNHCONH	Me
54	i-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCONH	Me
55	i-Pr	BocNHCH 2 CH 2 NHCONH	Me
56	i-Pr	HO(CH 2 ) 4 NHCONH	Me
57	i-Pr	(CH 3 ) 2 NNHCONH	Me
58	i-Pr	(CH 3 ) 2 N(CH 2 ) 3 NHCONH	Me
59	i-Pr	1-CH 3 -homopiperazin-4-yl-CONH	Me
60	i-Pr	CH 3 SO 2 NHCONH	Me
61	i-Pr	CH 3 ONHCONH	Me
62	i-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCONH	Me
63	i-Pr	1-CH 3 -piperidin-4-ylN(CH 3 )CONH	Me
64	i-Pr	tetrahydrofur-2-ylCH 2 NHCONH	Me
65	i-Pr	CH 3 (CH 2 ) 2 CH(OH)CH 2 NHCONH	Me
66	i-Pr	HOCH 2 CH(CH 3 )NHCONH	Me
67	i-Pr	CH 3 CH(OH)CH 2 NHCONH	Me
68	i-Pr	HOCH 2 CH 2 NHCONH	Me
69	i-Pr	morpholin-4-ylNHCONH	Me
70	i-Pr	(CH 3 ) 2 NCH(CH 3 )CH 2 NHCONH	Me
71	i-Pr	1-CH 3 -piperazin-4-ylNHCONH	Me
72	i-Pr	morpholin-4-ylCH 2 CH 2 NHCONH	Me
73	i-Pr	1-CH 3 -piperazin-4-ylCONH	Me
74	i-Pr	pyrid-2-ylNHCONH	Me
75	i-Pr	pyrid-4-ylNHCONH	Me
76	i-Pr	pyrrolidin-1-ylCH 2 CH 2 NHCH 2 CONH	Me
77	i-Pr	2-CH 3 -piperazin-1-ylCONH	Me
78	i-Pr	3-CH 3 -piperazin-1-ylCH 2 CONH	Me
79	i-Pr	trans-2,5-di-CH 3 -piperazin-1-ylCH 2 CONH	Me
80	i-Pr	cis-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH	Me
81	i-Pr	cis-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH	Me
82	i-Pr	trans-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH	Me
83	i-Pr	trans-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH	Me
84	i-Pr	(R)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH	Me
85	i-Pr	(S)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH	Me
86	i-Pr	5-CH 3 -pyrazin-2-ylCH 2 NHCH 2 CONH	Me

TABLE XX
	(a)
	(b)
	(c)
	Ex. #	R 2	R 7
	1	Et	1-CH 3 -piperazin-4-ylCH 2 CONH
	2	Et	CH 3 NHCONH
	3	Et	morpholin-4-ylCH 2 CONH
	4	Et	azetidin-1-ylCH 2 CONH
	5	Et	(CH 3 ) 2 NCH 2 CH 2 SO 2 NH
	6	Et	EtO 2 CCH 2 NHCONH
	7	Et	Hydantoin-1-yl
	8	Et	HOCH 2 CH 2 NHCONH
	9	Et	HO 2 C(CH 2 ) 2 CONH
	10	Et	imidazol-1-ylCH 2 CONH
	11	Et	Morpholin-4-ylCH 2 CH 2 NHCSNH
	12	Et	HO 2 CCH 2 NHCONH
	13	Et	HO 2 C(CH 2 ) 3 CONH
	14	Et	H 2 NCH 2 CONH
	15	Et	CH 3 NHCH 2 CONH
	16	Et	4-F-phenylCH 2 NHCH 2 CONH
	17	Et	pyrrolidin-1-ylCH 2 CONH
	18	Et	pyrid-2-ylCH 2 NHCH 2 CONH
	19	Et	pyrid-3-ylCH 2 NHCH 2 CONH
	20	Et	pyrid-4-ylCH 2 NHCH 2 CONH
	21	Et	BocNHCH 2 CH 2 NHCH 2 CONH
	22	Et	HOCH 2 CH(CH 3 )NHCH 2 CONH
	23	Et	CH 3 CH(OH)CH 2 NHCH 2 CONH
	24	Et	H 2 NCH 2 CH 2 NHCH 2 CONH
	25	Et	morpholin-4-ylCH 2 CH 2 NHCH 2 CONH
	26	Et	1-CH 3 -piperidin-4-ylN(CH 3 )CH 2 CONH
	27	Et	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )CH 2 CONH
	28	Et	(CH 3 ) 2 NCH(CH 3 )CONH
	29	Et	1-CH 3 -L-prolylNH
	30	Et	Homopiperazin-1-ylCH 2 CONH
	31	Et	CH 3 CH 2 NHCH 2 CONH
	32	Et	4-(CH 2 NH 2 )piperidin-1-ylCH 2 CONH
	33	Et	(CH 3 ) 2 NCH 2 CH 2 NHCH 2 CONH
	34	Et	cyclo-C 3 H 5 NHCH 2 CONH
	35	Et	Piperidin-4-ylCH 2 NHCH 2 CONH
	36	Et	HO(CH 2 ) 3 NHCH 2 CONH
	37	Et	1-Bocpiperidin-4-ylCH 2 NHCH 2 CONH
	38	Et	HOCH 2 CH 2 NHCH 2 CONH
	39	Et	cyclo-C 4 H 7 NHCH 2 CONH
	40	Et	azetidin-3-ylCONH
	41	Et	D-prolylNH.HCl
	42	Et	Boc-D-prolylNH
	43	Et	L-prolylNH.HCl
	44	Et	Boc-L-prolylNH
	45	Et	piperidin-1-ylCH 2 CH 2 NHCH 2 CONH
	46	Et	(CH 3 ) 2 CHNHCH 2 CONH
	47	Et	BocNHCH 2 CH 2 CONH
	48	Et	piperazin-2-yl-CONH
	49	Et	4-Me-piperazin-2-yl-CONH
	50	Et	piperidin-1-ylNHCONH
	51	Et	H 2 NCH 2 CH 2 NHCONH.F 3 CCO 2 H
	52	Et	pyrid-2-ylNHCONH
	53	Et	(CH 3 ) 2 NCH 2 CH 2 NHCONH
	54	Et	BocNHCH 2 CH 2 NHCONH
	55	Et	HO(CH 2 ) 4 NHCONH
	56	Et	(CH 3 ) 2 NNHCONH
	57	Et	(CH 3 ) 2 N(CH 2 ) 3 NHCONH
	58	Et	1-CH 3 -homopiperazin-4-yl-CONH
	59	Et	CH 3 SO 2 NHCONH
	60	Et	CH 3 ONHCONH
	61	Et	(CH 3 ) 2 NCH 2 CH 2 NHCONH
	62	Et	1-CH 3 -piperidin-4-ylN(CH 3 )CONH
	63	Et	tetrahydrofur-2-ylCH 2 NHCONH
	64	Et	CH 3 (CH 2 ) 2 CH(OH)CH 2 NHCONH
	65	Et	HOCH 2 CH(CH 3 )NHCONH
	66	Et	CH 3 CH(OH)CH 2 NHCONH
	67	Et	HOCH 2 CH 2 NHCONH
	68	Et	morpholin-4-ylNHCONH
	69	Et	(CH 3 ) 2 NCH(CH 3 )CH 2 NHCONH
	70	Et	1-CH 3 -piperazin-4-ylNHCONH
	71	Et	morpholin-4-ylCH 2 CH 2 NHCONH
	72	Et	1-CH 3 -piperazin-4-ylCONH
	73	Et	pyrid-2-ylNHCONH
	74	Et	pyrid-4-ylNHCONH
	75	Et	pyrrolidin-1-ylCH 2 CH 2 NHCH 2 CONH
	76	Et	2-CH 3 -piperazin-1-ylCONH
	77	Et	3-CH 3 -piperazin-1-ylCH 2 CONH
	78	Et	trans-2,5-di-CH 3 -piperazin-1-ylCH 2 CONH
	79	Et	cis-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH
	80	Et	cis-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH
	81	Et	trans-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH
	82	Et	trans-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH
	83	Et	(R)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH
	84	Et	(S)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH
	85	Et	5-CH 3 -pyrazin-2-ylCH 2 NHCH 2 CONH

TABLE XXI
	(a)
	(b)
	(c)
	Ex. #	R 2	R 7
	1	cyc-Pr	1-CH 3 -piperazin-4-ylCH 2 CONH
	2	cyc-Pr	CH 3 NHCONH
	3	cyc-Pr	morpholin-4-ylCH 2 CONH
	4	cyc-Pr	azetidin-1-ylCH 2 CONH
	5	cyc-Pr	(CH 3 ) 2 NCH 2 CH 2 SO 2 NH
	6	cyc-Pr	EtO 2 CCH 2 NHCONH
	7	cyc-Pr	Hydantoin-1-yl
	8	cyc-Pr	HOCH 2 CH 2 NHCONH
	9	cyc-Pr	HO 2 C(CH 2 ) 2 CONH
	10	cyc-Pr	imidazol-1-ylCH 2 CONH
	11	cyc-Pr	Morpholin-4-ylCH 2 CH 2 NHCSNH
	12	cyc-Pr	HO 2 CCH 2 NHCONH
	13	cyc-Pr	HO 2 C(CH 2 ) 3 CONH
	14	cyc-Pr	H 2 NCH 2 CONH
	15	cyc-Pr	CH 3 NHCH 2 CONH
	16	cyc-Pr	4-F-phenylCH 2 NHCH 2 CONH
	17	cyc-Pr	pyrrolidin-1-ylCH 2 CONH
	18	cyc-Pr	pyrid-2-ylCH 2 NHCH 2 CONH
	19	cyc-Pr	pyrid-3-ylCH 2 NHCH 2 CONH
	20	cyc-Pr	pyrid-4-ylCH 2 NHCH 2 CONH
	21	cyc-Pr	BocNHCH 2 CH 2 NHCH 2 CONH
	22	cyc-Pr	HOCH 2 CH(CH 3 )NHCH 2 CONH
	23	cyc-Pr	CH 3 CH(OH)CH 2 NHCH 2 CONH
	24	cyc-Pr	H 2 NCH 2 CH 2 NHCH 2 CONH
	25	cyc-Pr	morpholin-4-ylCH 2 CH 2 NHCH 2 CONH
	26	cyc-Pr	1-CH 3 -piperidin-4-ylN(CH 3 )CH 2 CONH
	27	cyc-Pr	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )CH 2 CONH
	28	cyc-Pr	(CH 3 ) 2 NCH(CH 3 )CONH
	29	cyc-Pr	1-CH 3 -L-prolylNH
	30	cyc-Pr	Homopiperazin-1-ylCH 2 CONH
	31	cyc-Pr	CH 3 CH 2 NHCH 2 CONH
	32	cyc-Pr	4-(CH 2 NH 2 )piperidin-1-ylCH 2 CONH
	33	cyc-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCH 2 CONH
	34	cyc-Pr	cyclo-C 3 H 5 NHCH 2 CONH
	35	cyc-Pr	Piperidin-4-ylCH 2 NHCH 2 CONH
	36	cyc-Pr	HO(CH 2 ) 3 NHCH 2 CONH
	37	cyc-Pr	1-Bocpiperidin-4-ylCH 2 NHCH 2 CONH
	38	cyc-Pr	HOCH 2 CH 2 NHCH 2 CONH
	39	cyc-Pr	cyclo-C 4 H 7 NHCH 2 CONH
	40	cyc-Pr	azetidin-3-ylCONH
	41	cyc-Pr	D-prolylNH.HCl
	42	cyc-Pr	Boc-D-prolylNH
	43	cyc-Pr	L-prolylNH.HCl
	44	cyc-Pr	Boc-L-prolylNH
	45	cyc-Pr	piperidin-1-ylCH 2 CH 2 NHCH 2 CONH
	46	cyc-Pr	(CH 3 ) 2 CHNHCH 2 CONH
	47	cyc-Pr	BocNHCH 2 CH 2 CONH
	48	cyc-Pr	piperazin-2-yl-CONH
	49	cyc-Pr	4-Me-piperazin-2-yl-CONH
	50	cyc-Pr	piperidin-1-ylNHCONH
	51	cyc-Pr	H 2 NCH 2 CH 2 NHCONH.F 3 CCO 2 H
	52	cyc-Pr	pyrid-2-ylNHCONH
	53	cyc-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCONH
	54	cyc-Pr	BocNHCH 2 CH 2 NHCONH
	55	cyc-Pr	HO(CH 2 ) 4 NHCONH
	56	cyc-Pr	(CH 3 ) 2 NNHCONH
	57	cyc-Pr	(CH 3 ) 2 N(CH 2 ) 3 NHCONH
	58	cyc-Pr	1-CH 3 -homopiperazin-4-yl-CONH
	59	cyc-Pr	CH 3 SO 2 NHCONH
	60	cyc-Pr	CH 3 ONHCONH
	61	cyc-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCONH
	62	cyc-Pr	1-CH 3 -piperidin-4-ylN(CH 3 )CONH
	63	cyc-Pr	tetrahydrofur-2-ylCH 2 NHCONH
	64	cyc-Pr	CH 3 (CH 2 ) 2 CH(OH)CH 2 NHCONH
	65	cyc-Pr	HOCH 2 CH(CH 3 )NHCONH
	66	cyc-Pr	CH 3 CH(OH)CH 2 NHCONH
	67	cyc-Pr	HOCH 2 CH 2 NHCONH
	68	cyc-Pr	morpholin-4-ylNHCONH
	69	cyc-Pr	(CH 3 ) 2 NCH(CH 3 )CH 2 NHCONH
	70	cyc-Pr	1-CH 3 -piperazin-4-ylNHCONH
	71	cyc-Pr	morpholin-4-ylCH 2 CH 2 NHCONH
	72	cyc-Pr	1-CH 3 -piperazin-4-ylCONH
	73	cyc-Pr	pyrid-2-ylNHCONH
	74	cyc-Pr	pyrid-4-ylNHCONH
	75	cyc-Pr	pyrrolidin-1-ylCH 2 CH 2 NHCH 2 CONH
	76	cyc-Pr	2-CH 3 -piperazin-1-ylCONH
	77	cyc-Pr	3-CH 3 -piperazin-1-ylCH 2 CONH
	78	cyc-Pr	trans-2,5-di-CH 3 -piperazin-1-ylCH 2 CONH
	79	cyc-Pr	cis-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH
	80	cyc-Pr	cis-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH
	81	cyc-Pr	trans-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH
	82	cyc-Pr	trans-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH
	83	cyc-Pr	(R)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH
	84	cyc-Pr	(S)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH
	85	cyc-Pr	5-CH 3 -pyrazin-2-ylCH 2 NHCH 2 CONH

TABLE XXII
	(a)
	(b)
	(c)
Ex. #	R 2	R 7
1	1-Methylcyc-Pr	1-CH 3 -piperazin-4-ylCH 2 CONH
2	1-Methylcyc-Pr	CH 3 NHCONH
3	1-Methylcyc-Pr	morpholin-4-ylCH 2 CONH
4	1-Methylcyc-Pr	azetidin-1-ylCH 2 CONH
5	1-Methylcyc-Pr	(CH 3 ) 2 NCH 2 CH 2 SO 2 NH
6	1-Methylcyc-Pr	EtO 2 CCH 2 NHCONH
7	1-Methylcyc-Pr	Hydantoin-1-yl
8	1-Methylcyc-Pr	HOCH 2 CH 2 NHCONH
9	1-Methylcyc-Pr	HO 2 C(CH 2 ) 2 CONH
10	1-Methylcyc-Pr	imidazol-1-ylCH 2 CONH
11	1-Methylcyc-Pr	Morpholin-4-ylCH 2 CH 2 NHCSNH
12	1-Methylcyc-Pr	HO 2 CCH 2 NHCONH
13	1-Methylcyc-Pr	HO 2 C(CH 2 ) 3 CONH
14	1-Methylcyc-Pr	H 2 NCH 2 CONH
15	1-Methylcyc-Pr	CH 3 NHCH 2 CONH
16	1-Methylcyc-Pr	4-F-phenylCH 2 NHCH 2 CONH
17	1-Methylcyc-Pr	pyrrolidin-1-ylCH 2 CONH
18	1-Methylcyc-Pr	pyrid-2-ylCH 2 NHCH 2 CONH
19	1-Methylcyc-Pr	pyrid-3-ylCH 2 NHCH 2 CONH
20	1-Methylcyc-Pr	pyrid-4-ylCH 2 NHCH 2 CONH
21	1-Methylcyc-Pr	BocNHCH 2 CH 2 NHCH 2 CONH
22	1-Methylcyc-Pr	HOCH 2 CH(CH 3 )NHCH 2 CONH
23	1-Methylcyc-Pr	CH 3 CH(OH)CH 2 NHCH 2 CONH
24	1-Methylcyc-Pr	H 2 NCH 2 CH 2 NHCH 2 CONH
25	1-Methylcyc-Pr	morpholin-4-ylCH 2 CH 2 NHCH 2 CONH
26	1-Methylcyc-Pr	1-CH 3 -piperidin-4-ylN(CH 3 )CH 2 CONH
27	1-Methylcyc-Pr	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )CH 2 CONH
28	1-Methylcyc-Pr	(CH 3 ) 2 NCH(CH 3 )CONH
29	1-Methylcyc-Pr	1-CH 3 -L-prolylNH
30	1-Methylcyc-Pr	Homopiperazin-1-ylCH 2 CONH
31	1-Methylcyc-Pr	CH 3 CH 2 NHCH 2 CONH
32	1-Methylcyc-Pr	4-(CH 2 NH 2 )piperidin-1-ylCH 2 CONH
33	1-Methylcyc-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCH 2 CONH
34	1-Methylcyc-Pr	cyclo-C 3 H 5 NHCH 2 CONH
35	1-Methylcyc-Pr	Piperidin-4-ylCH 2 NHCH 2 CONH
36	1-Methylcyc-Pr	HO(CH 2 ) 3 NHCH 2 CONH
37	1-Methylcyc-Pr	1-Bocpiperidin-4-ylCH 2 NHCH 2 CONH
38	1-Methylcyc-Pr	HOCH 2 CH 2 NHCH 2 CONH
39	1-Methylcyc-Pr	cyclo-C 4 H 7 NHCH 2 CONH
40	1-Methylcyc-Pr	azetidin-3-ylCONH
41	1-Methylcyc-Pr	D-prolylNH.HCl
42	1-Methylcyc-Pr	Boc-D-prolylNH
43	1-Methylcyc-Pr	L-prolylNH.HCl
44	1-Methylcyc-Pr	Boc-L-prolylNH
45	1-Methylcyc-Pr	piperidin-1-ylCH 2 CH 2 NHCH 2 CONH
46	1-Methylcyc-Pr	(CH 3 ) 2 CHNHCH 2 CONH
47	1-Methylcyc-Pr	BocNHCH 2 CH 2 CONH
48	1-Methylcyc-Pr	piperazin-2-yl-CONH
49	1-Methylcyc-Pr	4-Me-piperazin-2-yl-CONH
50	1-Methylcyc-Pr	piperidin-1-ylNHCONH
51	1-Methylcyc-Pr	H 2 NCH 2 CH 2 NHCONH.F 3 CCO 2 H
52	1-Methylcyc-Pr	pyrid-2-ylNHCONH
53	1-Methylcyc-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCONH
54	1-Methylcyc-Pr	BocNHCH 2 CH 2 NHCONH
55	1-Methylcyc-Pr	HO(CH 2 ) 4 NHCONH
56	1-Methylcyc-Pr	(CH 3 ) 2 NNHCONH
57	1-Methylcyc-Pr	(CH 3 ) 2 N(CH 2 ) 3 NHCONH
58	1-Methylcyc-Pr	1-CH 3 -homopiperazin-4-yl-CONH
59	1-Methylcyc-Pr	CH 3 SO 2 NHCONH
60	1-Methylcyc-Pr	CH 3 ONHCONH
61	1-Methylcyc-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCONH
62	1-Methylcyc-Pr	1-CH 3 -piperidin-4-ylN(CH 3 )CONH
63	1-Methylcyc-Pr	tetrahydrofur-2-ylCH 2 NHCONH
64	1-Methylcyc-Pr	CH 3 (CH 2 ) 2 CH(OH)CH 2 NHCONH
65	1-Methylcyc-Pr	HOCH 2 CH(CH 3 )NHCONH
66	1-Methylcyc-Pr	CH 3 CH(CH)CH 2 NHCONH
67	1-Methylcyc-Pr	HOCH 2 CH 2 NHCONH
68	1-Methylcyc-Pr	morpholin-4-ylNHCONH
69	1-Methylcyc-Pr	(CH 3 ) 2 NCH(CH 3 )CH 2 NHCONH
70	1-Methylcyc-Pr	1-CH 3 -piperazin-4-ylNHCONH
71	1-Methylcyc-Pr	morpholin-4-ylCH 2 CH 2 NHCONH
72	1-Methylcyc-Pr	1-CH 3 -piperazin-4-ylCONH
73	1-Methylcyc-Pr	pyrid-2-ylNHCONH
74	1-Methylcyc-Pr	pyrid-4-ylNHCONH
75	1-Methylcyc-Pr	pyrrolidin-1-ylCH 2 CH 2 NHCH 2 CONH
76	1-Methylcyc-Pr	2-CH 3 -piperazin-1-ylCONH
77	1-Methylcyc-Pr	3-CH 3 -piperazin-1-ylCH 2 CONH
78	1-Methylcyc-Pr	trans-2,5-di-CH 3 -piperazin-1-ylCH 2 CONH
79	1-Methylcyc-Pr	cis-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH
80	1-Methylcyc-Pr	cis-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH
81	1-Methylcyc-Pr	trans-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH
82	1-Methylcyc-Pr	trans-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH
83	1-Methylcyc-Pr	(R)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH
84	1-Methylcyc-Pr	(S)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH
85	1-Methylcyc-Pr	5-CH 3 -pyrazin-2-ylCH 2 NHCH 2 CONH

TABLE XXIII
	(a)
	(b)
	(c)
	Ex. #	R 2	R 7
	1	i-Bu	1-CH 3 -piperazin-4-ylCH 2 CONH
	2	i-Bu	CH 3 NHCONH
	3	i-Bu	morpholin-4-ylCH 2 CONH
	4	i-Bu	azetidin-1-ylCH 2 CONH
	5	i-Bu	(CH 3 ) 2 NCH 2 CH 2 SO 2 NH
	6	i-Bu	EtO 2 CCH 2 NHCONH
	7	i-Bu	Hydantoin-1-yl
	8	i-Bu	HOCH 2 CH 2 NHCONH
	9	i-Bu	HO 2 C(CH 2 ) 2 CONH
	10	i-Bu	imidazol-1-ylCH 2 CONH
	11	i-Bu	Morpholin-4-ylCH 2 CH 2 NHCSNH
	12	i-Bu	HO 2 CCH 2 NHCONH
	13	i-Bu	HO 2 C(CH 2 ) 3 CONH
	14	i-Bu	H 2 NCH 2 CONH
	15	i-Bu	CH 3 NHCH 2 CONH
	16	i-Bu	4-F-phenylCH 2 NHCH 2 CONH
	17	i-Bu	pyrrolidin-1-ylCH 2 CONH
	18	i-Bu	pyrid-2-ylCH 2 NHCH 2 CONH
	19	i-Bu	pyrid-3-ylCH 2 NHCH 2 CONH
	20	i-Bu	pyrid-4-ylCH 2 NHCH 2 CONH
	21	i-Bu	BocNHCH 2 CH 2 NHCH 2 CONH
	22	i-Bu	HOCH 2 CH(CH 3 )NHCH 2 CONH
	23	i-Bu	CH 3 CH(OH)CH 2 NHCH 2 CONH
	24	i-Bu	H 2 NCH 2 CH 2 NHCH 2 CONH
	25	i-Bu	morpholin-4-ylCH 2 CH 2 NHCH 2 CONH
	26	i-Bu	1-CH 3 -piperidin-4-ylN(CH 3 )CH 2 CONH
	27	i-Bu	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )CH 2 CONH
	28	i-Bu	(CH 3 ) 2 NCH(CH 3 )CONH
	29	i-Bu	1-CH 3 -L-prolylNH
	30	i-Bu	Homopiperazin-1-ylCH 2 CONH
	31	i-Bu	CH 3 CH 2 NHCH 2 CONH
	32	i-Bu	4-(CH 2 NH 2 )piperidin-1-ylCH 2 CONH
	33	i-Bu	(CH 3 ) 2 NCH 2 CH 2 NHCH 2 CONH
	34	i-Bu	cyclo-C 3 H 5 NHCH 2 CONH
	35	i-Bu	Piperidin-4-ylCH 2 NHCH 2 CONH
	36	i-Bu	HO(CH 2 ) 3 NHCH 2 CONH
	37	i-Bu	1-Bocpiperidin-4-ylCH 2 NHCH 2 CONH
	38	i-Bu	HOCH 2 CH 2 NHCH 2 CONH
	39	i-Bu	cyclo-C 4 H 7 NHCH 2 CONH
	40	i-Bu	azetidin-3-ylCONH
	41	i-Bu	D-prolylNH.HCl
	42	i-Bu	Boc-D-prolylNH
	43	i-Bu	L-prolylNH.HCl
	44	i-Bu	Boc-L-prolylNH
	45	i-Bu	piperidin-1-ylCH 2 CH 2 NHCH 2 CONH
	46	i-Bu	(CH 3 ) 2 CHNHCH 2 CONH
	47	i-Bu	BocNHCH 2 CH 2 CONH
	48	i-Bu	piperazin-2-yl-CONH
	49	i-Bu	4-Me-piperazin-2-yl-CONH
	50	i-Bu	piperidin-1-ylNHCONH
	51	i-Bu	H 2 NCH 2 CH 2 NHCONH.F 3 CCO 2 H
	52	i-Bu	pyrid-2-ylNHCONH
	53	i-Bu	(CH 3 ) 2 NCH 2 CH 2 NHCONH
	54	i-Bu	BocNHCH 2 CH 2 NHCONH
	55	i-Bu	HO(CH 2 ) 4 NHCONH
	56	i-Bu	(CH 3 ) 2 NNHCONH
	57	i-Bu	(CH 3 ) 2 N(CH 2 ) 3 NHCONH
	58	i-Bu	1-CH 3 -homopiperazin-4-yl-CONH
	59	i-Bu	CH 3 SO 2 NHCONH
	60	i-Bu	CH 3 ONHCONH
	61	i-Bu	(CH 3 ) 2 NCH 2 CH 2 NHCONH
	62	i-Bu	1-CH 3 -piperidin-4-ylN(CH 3 )CONH
	63	i-Bu	tetrahydrofur-2-ylCH 2 NHCONH
	64	i-Bu	CH 3 (CH 2 ) 2 CH(OH)CH 2 NHCONH
	65	i-Bu	HOCH 2 CH(CH 3 )NHCONH
	66	i-Bu	CH 3 CH(OH)CH 2 NHCONH
	67	i-Bu	HOCH 2 CH 2 NHCONH
	68	i-Bu	morpholin-4-ylNHCONH
	69	i-Bu	(CH 3 ) 2 NCH(CH 3 )CH 2 NHCONH
	70	i-Bu	1-CH 3 -piperazin-4-ylNHCONH
	71	i-Bu	morpholin-4-ylCH 2 CH 2 NHCONH
	72	i-Bu	1-CH 3 -piperazin-4-ylCONH
	73	i-Bu	pyrid-2-ylNHCONH
	74	i-Bu	pyrid-4-ylNHCONH
	75	i-Bu	pyrrolidin-1-ylCH 2 CH 2 NHCH 2 CONH
	76	i-Bu	2-CH 3 -piperazin-1-ylCONH
	77	i-Bu	3-CH 3 -piperazin-1-ylCH 2 CONH
	78	i-Bu	trans-2,5-di-CH 3 -piperazin-1-ylCH 2 CONH
	79	i-Bu	cis-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH
	80	i-Bu	cis-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH
	81	i-Bu	trans-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH
	82	i-Bu	trans-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH
	83	i-Bu	(R)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH
	84	i-Bu	(S)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH
	85	i-Bu	5-CH 3 -pyrazin-2-ylCH 2 NHCH 2 CONH

TABLE XXIV
	(a)
	(b)
	(c)
	Ex. #	R 5	R 2	R 7
	1	Me	Et	1-CH 3 -piperazin-4-ylCH 2 CONH
	2	Me	Et	CH 3 NHCONH
	3	Me	Et	morpholin-4-ylCH 2 CONH
	4	Me	Et	azetidin-1-ylCH 2 CONH
	5	Me	Et	(CH 3 ) 2 NCH 2 CH 2 SO 2 NH
	6	Me	Et	EtO 2 CCH 2 NHCONH
	7	Me	Et	Hydantoin-1-yl
	8	Me	Et	HOCH 2 CH 2 NHCONH
	9	Me	Et	HO 2 C(CH 2 ) 2 CONH
	10	Me	Et	imidazol-1-ylCH 2 CONH
	11	Me	Et	Morpholin-4-ylCH 2 CH 2 NHCSNH
	12	Me	Et	HO 2 CCH 2 NHCONH
	13	Me	Et	HO 2 C(CH 2 ) 3 CONH
	14	Me	Et	H 2 NCH 2 CONH
	15	Me	Et	CH 3 NHCH 2 CONH
	16	Me	Et	4-F-phenylCH 2 NHCH 2 CONH
	17	Me	Et	pyrrolidin-1-ylCH 2 CONH
	18	Me	Et	pyrid-2-ylCH 2 NHCH 2 CONH
	19	Me	Et	pyrid-3-ylCH 2 NHCH 2 CONH
	20	Me	Et	pyrid-4-ylCH 2 NHCH 2 CONH
	21	Me	Et	BocNHCH 2 CH 2 NHCH 2 CONH
	22	Me	Et	HOCH 2 CH(CH 3 )NHCH 2 CONH
	23	Me	Et	CH 3 CH(OH)CH 2 NHCH 2 CONH
	24	Me	Et	H 2 NCH 2 CH 2 NHCH 2 CONH
	25	Me	Et	morpholin-4-ylCH 2 CH 2 NHCH 2 CONH
	26	Me	Et	1-CH 3 -piperidin-4-ylN(CH 3 )CH 2 CONH
	27	Me	Et	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )CH 2 CONH
	28	Me	Et	(CH 3 ) 2 NCH(CH 3 )CONH
	29	Me	Et	1-CH 3 -L-prolylNH
	30	Me	Et	Homopiperazin-1-ylCH 2 CONH
	31	Me	Et	CH 3 CH 2 NHCH 2 CONH
	32	Me	Et	4-(CH 2 NH 2 )piperidin-1-ylCH 2 CONH
	33	Me	Et	(CH 3 ) 2 NCH 2 CH 2 NHCH 2 CONH
	34	Me	Et	cyclo-C 3 H 5 NHCH 2 CONH
	35	Me	Et	Piperidin-4-ylCH 2 NHCH 2 CONH
	36	Me	ET	HO(CH 2 ) 3 NHCH 2 CONH
	37	Me	Et	1-Bocpiperidin-4-ylCH 2 NHCH 2 CONH
	38	Me	ET	HOCH 2 CH 2 NHCH 2 CONH
	39	Me	Et	cyclo-C 4 H 7 NHCH 2 CONH
	40	Me	Et	azetidin-3-ylCONH
	41	Me	Et	D-prolylNH.HCl
	42	Me	Et	Boc-D-prolylNH
	43	Me	Et	L-prolylNH.HCl
	44	Me	Et	Boc-L-prolylNH
	45	Me	Et	piperidin-1-ylCH 2 CH 2 NHCH 2 CONH
	46	Me	Et	(CH 3 ) 2 CHNHCH 2 CONH
	47	Me	Et	BocNHCH 2 CH 2 CONH
	48	Me	Et	piperazin-2-yl-CONH
	49	Me	Et	4-Me-piperazin-2-yl-CONH
	50	Me	Et	piperidin-1-ylNHCONH
	51	Me	Et	H 2 NCH 2 CH 2 NHCONH.F 3 CCO 2 H
	52	Me	Et	pyrid-2-ylNHCONH
	53	Me	Et	(CH 3 ) 2 NCH 2 CH 2 NHCONH
	54	Me	Et	BocNHCH 2 CH 2 NHCONH
	55	Me	Et	HO(CH 2 ) 4 NHCONH
	56	Me	Et	(CH 3 ) 2 NNHCONH
	57	Me	Et	(CH 3 ) 2 N(CH 2 ) 3 NHCONH
	58	Me	Et	1-CH 3 -homopiperazin-4-yl-CONH
	59	Me	Et	CH 3 SO 2 NHCONH
	60	Me	Et	CH 3 ONHCONH
	61	Me	Et	(CH 3 ) 2 NCH 2 CH 2 NHCONH
	62	Me	Et	1-CH 3 -piperidin-4-ylN(CH 3 )CONH
	63	Me	Et	tetrahydrofur-2-ylCH 2 NHCONH
	64	Me	Et	CH 3 (CH 2 ) 2 CH(OH)CH 2 NHCONH
	65	Me	Et	HOCH 2 CH(CH 3 )NHCONH
	66	Me	Et	CH 3 CH(OH)CH 2 NHCONH
	67	Me	Et	HOCH 2 CH 2 NHCONH
	68	Me	Et	morpholin-4-ylNHCONH
	69	Me	Et	(CH 3 ) 2 NCH(CH 3 )CH 2 NHCONH
	70	Me	Et	1-CH 3 -piperazin-4-ylNHCONH
	71	Me	Et	morpholin-4-ylCH 2 CH 2 NHCONH
	72	Me	Et	1-CH 3 -piperazin-4-ylCONH
	73	Me	Et	pyrid-2-ylNHCONH
	74	Me	Et	pyrid-4-ylNHCONH
	75	Me	Et	pyrrolidin-1-ylCH 2 CH 2 NHCH 2 CONH
	76	Me	Et	2-CH 3 -piperazin-1-ylCONH
	77	Me	Et	3-CH 3 -piperazin-1-ylCH 2 CONH
	78	Me	Et	trans-2,5-di-CH 3 -piperazin-1-ylCH 2 CONH
	79	Me	Et	cis-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH
	80	Me	Et	cis-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH
	81	Me	Et	trans-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH
	82	Me	Et	trans-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH
	83	Me	Et	(R)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH
	84	Me	Et	(S)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH
	85	Me	Et	5-CH 3 -pyrazin-2-ylCH 2 NHCH 2 CONH

TABLE XXV
	(a)
	(b)
	(c)
Ex. #	R 5	R 2	R 7
1	Me	cyc-Pr	1-CH 3 -piperazin-4-ylCH 2 CONH
2	Me	cyc-Pr	CH 3 NHCONH
3	Me	cyc-Pr	morpholin-4-ylCH 2 CONH
4	Me	cyc-Pr	azetidin-1-ylCH 2 CONH
5	Me	cyc-Pr	(CH 3 ) 2 NCH 2 CH 2 SO 2 NH
6	Me	cyc-Pr	EtO 2 CCH 2 NHCONH
7	Me	cyc-Pr	Hydantoin-1-yl
8	Me	cyc-Pr	HOCH 2 CH 2 NHCONH
9	Me	cyc-Pr	HO 2 C(CH 2 ) 2 CONH
10	Me	cyc-Pr	imidazol-1-ylCH 2 CONH
11	Me	cyc-Pr	Morpholin-4-ylCH 2 CH 2 NHCSNH
12	Me	cyc-Pr	HO 2 CCH 2 NHCONH
13	Me	cyc-Pr	HO 2 C(CH 2 ) 3 CONH
14	Me	cyc-Pr	H 2 NCH 2 CONH
15	Me	cyc-Pr	CH 3 NHCH 2 CONH
16	Me	cyc-Pr	4-F-phenylCH 2 NHCH 2 CONH
17	Me	cyc-Pr	pyrrolidin-1-ylCH 2 CONH
18	Me	cyc-Pr	pyrid-2-ylCH 2 NHCH 2 CONH
19	Me	cyc-Pr	pyrid-3-ylCH 2 NHCH 2 CONH
20	Me	cyc-Pr	pyrid-4-ylCH 2 NHCH 2 CONH
21	Me	cyc-Pr	BocNHCH 2 CH 2 NHCH 2 CONH
22	Me	cyc-Pr	HOCH 2 CH(CH 3 )NHCH 2 CONH
23	Me	cyc-Pr	CH 3 CH(OH)CH 2 NHCH 2 CONH
24	Me	cyc-Pr	H 2 NCH 2 CH 2 NHCH 2 CONH
25	Me	cyc-Pr	morpholin-4-ylCH 2 CH 2 NHCH 2 CONH
26	Me	cyc-Pr	1-CH 3 -piperidin-4-ylN(CH 3 )CH 2 CONH
27	Me	cyc-Pr	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )CH 2 CONH
28	Me	cyc-Pr	(CH 3 ) 2 NCH(CH 3 )CONH
29	Me	cyc-Pr	1-CH 3 -L-prolylNH
30	Me	cyc-Pr	Homopiperazin-1-ylCH 2 CONH
31	Me	cyc-Pr	CH 3 CH 2 NHCH 2 CONH
32	Me	cyc-Pr	4-(CH 2 NH 2 )piperidin-1-ylCH 2 CONH
33	Me	cyc-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCH 2 CONH
34	Me	cyc-Pr	cyclo-C 3 H 5 NHCH 2 CONH
35	Me	cyc-Pr	Piperidin-4-ylCH 2 NHCH 2 CONH
36	Me	cyc-Pr	HO(CH 2 ) 3 NHCH 2 CONH
37	Me	cyc-Pr	1-Bocpiperidin-4-ylCH 2 NHCH 2 CONH
38	Me	cyc-Pr	HOCH 2 CH 2 NHCH 2 CONH
39	Me	cyc-Pr	cyclo-C 4 H 7 NHCH 2 CONH
40	Me	cyc-Pr	azetidin-3-ylCONH
41	Me	cyc-Pr	D-prolylNH.HCl
42	Me	cyc-Pr	Boc-D-prolylNH
43	Me	cyc-Pr	L-prolylNH.HCl
44	Me	cyc-Pr	Boc-L-prolylNH
45	Me	cyc-Pr	piperidin-1-ylCH 2 CH 2 NHCH 2 CONH
46	Me	cyc-Pr	(CH 3 ) 2 CHNHCH 2 CONH
47	Me	cyc-Pr	BocNHCH 2 CH 2 CONH
48	Me	cyc-Pr	piperazin-2-yl-CONH
49	Me	cyc-Pr	4-Me-piperazin-2-yl-CONH
50	Me	cyc-Pr	piperidin-1-ylNHCONH
51	Me	cyc-Pr	H 2 NCH 2 CH 2 NHCONH.F 3 CCO 2 H
52	Me	cyc-Pr	pyrid-2-ylNHCONH
53	Me	cyc-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCONH
54	Me	cyc-Pr	BocNHCH 2 CH 2 NHCONH
55	Me	cyc-Pr	HO(CH 2 ) 4 NHCONH
56	Me	cyc-Pr	(CH 3 ) 2 NNHCONH
57	Me	cyc-Pr	(CH 3 ) 2 N(CH 2 ) 3 NHCONH
58	Me	cyc-Pr	1-CH 3 -homopiperazin-4-yl-CONH
59	Me	cyc-Pr	CH 3 SO 2 NHCONH
60	Me	cyc-Pr	CH 3 ONHCONH
61	Me	cyc-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCONH
62	Me	cyc-Pr	1-CH 3 -piperidin-4-ylN(CH 3 )CONH
63	Me	cyc-Pr	tetrahydrofur-2-ylCH 2 NHCONH
64	Me	cyc-Pr	CH 3 (CH 2 ) 2 CH(OH)CH 2 NHCONH
65	Me	cyc-Pr	HOCH 2 CH(CH 3 )NHCONH
66	Me	cyc-Pr	CH 3 CH(OH)CH 2 NHCONH
67	Me	cyc-Pr	HOCH 2 CH 2 NHCONH
68	Me	cyc-Pr	morpholin-4-ylNHCONH
69	Me	cyc-Pr	(CH 3 ) 2 NCH(CH 3 )CH 2 NHCONH
70	Me	cyc-Pr	1-CH 3 -piperazin-4-ylNHCONH
71	Me	cyc-Pr	morpholin-4-ylCH 2 CH 2 NHCONH
72	Me	cyc-Pr	1-CH 3 -piperazin-4-ylCONH
73	Me	cyc-Pr	pyrid-2-ylNHCONH
74	Me	cyc-Pr	pyrid-4-ylNHCONH
75	Me	cyc-Pr	pyrrolidin-1-ylCH 2 CH 2 NHCH 2 CONH
76	Me	cyc-Pr	2-CH 3 -piperazin-1-ylCONH
77	Me	cyc-Pr	3-CH 3 -piperazin-1-ylCH 2 CONH
78	Me	cyc-Pr	trans-2,5-di-CH 3 -piperazin-1-ylCH 2 CONH
79	Me	cyc-Pr	cis-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH
80	Me	cyc-Pr	cis-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH
81	Me	cyc-Pr	trans-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH
82	Me	cyc-Pr	trans-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH
83	Me	cyc-Pr	(R)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH
84	Me	cyc-Pr	(S)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH
85	Me	cyc-Pr	5-CH 3 -pyrazin-2-ylCH 2 NHCH 2 CONH

TABLE XXVI
	(a)
	(b)
	(c)
Ex. #	R 5	R 2	R 7
1	Me	i-Pr	1-CH 3 -piperazin-4-ylCH 2 CONH
2	Me	i-Pr	CH 3 NHCONH
3	Me	i-Pr	morpholin-4-ylCH 2 CONH
4	Me	i-Pr	azetidin-1-ylCH 2 CONH
5	Me	i-Pr	(CH 3 ) 2 NCH 2 CH 2 SO 2 NH
6	Me	i-Pr	EtO 2 CCH 2 NHCONH
7	Me	i-Pr	Hydantoin-1-yl
8	Me	i-Pr	HOCH 2 CH 2 NHCONH
9	Me	i-Pr	HO 2 C(CH 2 ) 2 CONH
10	Me	i-Pr	imidazol-1-ylCH 2 CONH
11	Me	i-Pr	Morpholin-4-ylCH 2 CH 2 NHCSNH
12	Me	i-Pr	HO 2 CCH 2 NHCONH
13	Me	i-Pr	HO 2 C(CH 2 ) 3 CONH
14	Me	i-Pr	H 2 NCH 2 CONH
15	Me	i-Pr	CH 3 NHCH 2 CONH
16	Me	i-Pr	4-F-phenylCH 2 NHCH 2 CONH
17	Me	i-Pr	pyrrolidin-1-ylCH 2 CONH
18	Me	i-Pr	pyrid-2-ylCH 2 NHCH 2 CONH
19	Me	i-Pr	pyrid-3-ylCH 2 NHCH 2 CONH
20	Me	i-Pr	pyrid-4-ylCH 2 NHCH 2 CONH
21	Me	i-Pr	BocNHCH 2 CH 2 NHCH 2 CONH
22	Me	i-Pr	HOCH 2 CH(CH 3 )NHCH 2 CONH
23	Me	i-Pr	CH 3 CH(OH)CH 2 NHCH 2 CONH
24	Me	i-Pr	H 2 NCH 2 CH 2 NHCH 2 CONH
25	Me	i-Pr	morpholin-4-ylCH 2 CH 2 NHCH 2 CONH
26	Me	i-Pr	1-CH 3 -piperidin-4-ylN(CH 3 )CH 2 CONH
27	Me	i-Pr	(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )CH 2 CONH
28	Me	i-Pr	(CH 3 ) 2 NCH(CH 3 )CONH
29	Me	i-Pr	1-CH 3 -L-prolylNH
30	Me	i-Pr	Homopiperazin-1-ylCH 2 CONH
31	Me	i-Pr	CH 3 CH 2 NHCH 2 CONH
32	Me	i-Pr	4-(CH 2 NH 2 )piperidin-1-ylCH 2 CONH
33	Me	i-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCH 2 CONH
34	Me	i-Pr	cyclo-C 3 H 5 NHCH 2 CONH
35	Me	i-Pr	Piperidin-4-ylCH 2 NHCH 2 CONH
36	Me	i-Pr	HO(CH 2 ) 3 NHCH 2 CONH
37	Me	i-Pr	1-Bocpiperidin-4-ylCH 2 NHCH 2 CONH
38	Me	i-Pr	HOCH 2 CH 2 NHCH 2 CONH
39	Me	i-Pr	cyclo-C 4 H 7 NHCH 2 CONH
40	Me	i-Pr	azetidin-3-ylCONH
41	Me	i-Pr	D-prolylNH.HCl
42	Me	i-Pr	Boc-D-prolylNH
43	Me	i-Pr	L-prolylNH.HCl
44	Me	i-Pr	Boc-L-prolylNH
45	Me	i-Pr	piperidin-1-ylCH 2 CH 2 NHCH 2 CONH
46	Me	i-Pr	(CH 3 ) 2 CHNHCH 2 CONH
47	Me	i-Pr	BocNHCH 2 CH 2 CONH
48	Me	i-Pr	piperazin-2-yl-CONH
49	Me	i-Pr	4-Me-piperazin-2-yl-CONH
50	Me	i-Pr	piperidin-1-ylNHCONH
51	Me	i-Pr	H 2 NCH 2 CH 2 NHCONH.F 3 CCO 2 H
52	Me	i-Pr	pyrid-2-ylNHCONH
53	Me	i-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCONH
54	Me	i-Pr	BocNHCH 2 CH 2 NHCONH
55	Me	i-Pr	HO(CH 2 ) 4 NHCONH
56	Me	i-Pr	(CH 3 ) 2 NNHCONH
57	Me	i-Pr	(CH 3 ) 2 N(CH 2 ) 3 NHCONH
58	Me	i-Pr	1-CH 3 -homopiperazin-4-yl-CONH
59	Me	i-Pr	CH 3 SO 2 NHCONH
60	Me	i-Pr	CH 3 ONHCONH
61	Me	i-Pr	(CH 3 ) 2 NCH 2 CH 2 NHCONH
62	Me	i-Pr	1-CH 3 -piperidin-4-ylN(CH 3 )CONH
63	Me	i-Pr	tetrahydrofur-2-ylCH 2 NHCONH
64	Me	i-Pr	CH 3 (CH 2 ) 2 CH(OH)CH 2 NHCONH
65	Me	i-Pr	HOCH 2 CH(CH 3 )NHCONH
66	Me	i-Pr	CH 3 CH(OH)CH 2 NHCONH
67	Me	i-Pr	HOCH 2 CH 2 NHCONH
68	Me	i-Pr	morpholin-4-ylNHCONH
69	Me	i-Pr	(CH 3 ) 2 NCH(CH 3 )CH 2 NHCONH
70	Me	i-Pr	1-CH 3 -piperazin-4-ylNHCONH
71	Me	i-Pr	morpholin-4-ylCH 2 CH 2 NHCONH
72	Me	i-Pr	1-CH 3 -piperazin-4-ylCONH
73	Me	i-Pr	pyrid-2-ylNHCONH
74	Me	i-Pr	pyrid-4-ylNHCONH
75	Me	i-Pr	pyrrolidin-1-ylCH 2 CH 2 NHCH 2 CONH
76	Me	i-Pr	2-CH 3 -piperazin-1-ylCONH
77	Me	i-Pr	3-CH 3 -piperazin-1-ylCH 2 CONH
78	Me	i-Pr	trans-2,5-di-CH 3 -piperazin-1-ylCH 2 CONH
79	Me	i-Pr	cis-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH
80	Me	i-Pr	cis-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH
81	Me	i-Pr	trans-2,6-di-CH 3 -piperazin-1-ylCH 2 CONH
82	Me	i-Pr	trans-3,5-di-CH 3 -piperazin-1-ylCH 2 CONH
83	Me	i-Pr	(R)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH
84	Me	i-Pr	(S)-1-Ethylpyrrolidin-2-ylCH 2 NHCONH
85	Me	i-Pr	5-CH 3 -pyrazin-2-ylCH 2 NHCH 2 CONH

UTILITY

Certain analogs were selective for their activity against cyclin dependent kinases and their cyclin bound complexes and were less active against other known serine/threonine kinases such as Protein Kinase A (PKA) and Protein Kinase C (PKC). In addition, these inhibitors were less active against tyrosine kinases such as c-Abl.

Inhibition of Kinase/Cyclin Complex Enzymatic Activity

Several of the compounds disclosed in this invention were assayed for their inhibitory activity against cyclin dependent kinase4/D1, cyclin dependent kinase1/B kinase, cyclin dependent kinase2/A kinase, and cyclin dependent kinase2/E kinase complexes. Briefly, the in vitro assays employ cell lysates from insect cells expressing either of the kinases and subsequently their corresponding regulatory units. The cyclin dependent kinase2/cyclinE is purified from insect cells expressing His-tagged cyclin dependent kinase 2 and cyclin E. The cyclin dependent kinase/cyclin lysate is combined in a microtitre-type plate along with a kinase compatible buffer, 32 P-labeled ATP at a concentration of 50 mM, a GST-Rb fusion protein and the test compound at varying concentrations. The kinase reaction is allowed to proceeded with the radiolabled ATP, then effectively stopped by the addition of a large excess of EDTA and unlabeled ATP. The GST-Rb labeled protein is sequestered on a GSH-Sepharose bead suspension, washed, resuspended in scintillant, and the 32 P activity detected in a scintillation counter. The compound concentration which inhibits 50% of the kinase activity was calculated for each compound. A compound was considered active if its IC 50 was found to be less than 1 μM.

Inhibition of HCT 116 Cancer Cell Proliferation

To test the cellular activity of several compounds disclosed in this invention, we examined the effect of these compounds on cultured HCT116 cells and determined their effect on cell-cycle progression by the calorimetric cytotoxcity test using sulforhodamine B (Skehan et al. J. Natl. Cancer Inst . 82:1107-12, 1990). Briefly, HCT116 cells are cultured in the presence of test compounds at increasing concentrations. At selected time points, groups of cells are fixed with trichloroacetic acid and stained with sulforhodamine B (SRB). Unbound dye was removed by washing and protein-bound dye was extracted for determination of optical density. A compound was considered active if its IC 50 was found to be less than 10 μM.

Claims

1. A compound of formula (I) or its tautomer, formula (II):or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:Q is selected from the group: H, OH, and CH3, and CH2CH3; Y is selected from the group: F, Cl, Br, and I; Z is selected from the group: N and CR6; R1 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 R1 is substituted with 0-3 R7; R2 is selected from the group: C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, S—C1-3 alkyl, O—C1-3 alkyl, NH2, NH—C1-3 alkyl, N(C1-2 alkyl)2, OCF3, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, 1-methylcyclopropyl, 1-methylcyclobutyl, CH2CN, CH2OH, CH2OCH3, CH2NH2, CH2NHC1-3 alkyl, CH2NMe2, CF3, CHO, OCH2CH2OH, OCH(Me)CH2OH, OCH2CH(Me)OH, OCH2CH2NMe2, and CHF2; R3 is selected from the group: H, F, Cl, Br, I, CF3, CHO, CHRgOH, COCF3, CH═NOH, CH═NOCH3, CH═NNH2, CH═NNHMe, CH═NNMe2, CH═CHRa, C1-3 alkyl, C1-3 alkoxy, CO2H, CONH2. CONH(C1-3 alkyl), CON(C1-3 alkyl)2, CO2C1-3 alkyl, C(O)C1-2 alkyl, NH2, NH(C1-3 alkyl), and N(C1-3 alkyl)2; R4 is selected from the group: H, F, Cl, Br, I, CF3, C1-3 alkyl, C2-3 alkenyl, NH2, NH(C1-3 alkyl), and N(C1-3 alkyl)2; R5 is selected from the group: H, C1-3 alkyl, F, Cl, Br, I, CF3, and C2-3 alkenyl; wherein when Z is C, Q is H, R1 is phenyl substituted with C1-4 alkyl, hydroxy, alkoxy, amino, substituted amino, mercapto, halogen, trifluoromethyl or nitro, then either R2 is selected from the group: C2-4 alkenyl, C2-4 alkynyl, S—C1-3 alkyl, O—C1-3 alkyl, NH2, NH—C1-3 alkyl, N(C1-2 alkyl)2, OCF3, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, 1-methylcyclopropyl, 1-methylcyclobutyl, CH2CN, CH2OH, CH2OCH3, CH2NH2, CH2NHC1-3 alkyl, CH2NMe2, CF3, CHO, OCH2CH2OH, OCH(Me)CH2OH, OCH2CH(Me)OH, OCH2CH2NMe2, and CHF2; or, R3 is selected from the group consisting of: CHO, CHRgOH, COCF3, CH═NOH, CH═NOCH3, CH═NNH2, CH═NNHMe, CH═NNMe2, CH═CHRa, CO2H, CONH2, CONH(C1-3 alkyl), CON(C1-3 alkyl)2, CO2C1-3 alkyl, C(O)C1-2 alkyl, NH(C1-3 alkyl), N(C1-3 alkyl)2 and alkenyl; or, R4 is selected from the group consisting of C2-3 alkenyl; or, R5 is selected from the group consisting of C2-3 alkenyl; R6 is selected from the group: H, F, Cl, Br, I, CF3, —NO2, C1-3 alkyl optionally substituted with 1-2 R, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, CO2H, CHO, CONRaRb, CO2C1-3 alkyl, C(O)C1-2 alkyl, CH2NHRa, CONRgNRaRb, NRaRb; SO2NRaRb, CR═NNRaRb, CR═NORf, and Rh; R7 is independently, at each occurrence, selected from the group: OH, C1-6 alkoxy, OC2-6 alkyl-CO2H, O—C2-6-alkyl-NRaRb, F, Cl, Br, I, CF3, OCF3, —CN, —NO2, CO2H, CO2(C1-6 alkyl), CONRaRb, NRgCONHORg, NRgCONHSO2Ra, NHNRgC(O)ORa, NRgC(O)NRaRb, NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, —SO2NRaRb, NHSO2NHCO2C1-4 alkyl, NRgSO2NRaRb, NRgSO2CHReCH2NRaRb, NRgCOCHReNRaRb, NRgCOCHReNRbCH2RfRa, NRgCOCH2CHReNRaRb, NRgCOCHReCH2NRaRb, NRgCO(CH2)mNRaRb, NRgCONRe(CH2)nNRaRb, NRgCO2(CHRe)NRaRb, CONReNRaRb, NRgCONReNRaRb, C3-10 carbocycle, C1-10 alkyl substituted with 0-3 R8, NHCONRh, NHCONHCH2Rh, NHCORh, NHCOCH2Rh, C2-10 alkenyl substituted with 0-3 R8, C2-10 alkynyl substituted with 0-3 R8, and C3-10 heterocycle containing 1-4 heteroatoms selected from O, N, and S; R8 is independently, at each occurrence, selected from the group: ═O, OH, C3-6 cycloalkyl, C1-6 alkoxy, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, F, Cl, Br, I, CO2H, CORa, CO2(benzyl), CO2(C1-6 alkyl), and CONRaRb; Ra is independently, at each occurrence, selected from the group: H, C1-6 alkyl, C3-7 cycloalkyl, and C1-6 alkyl substituted with one R; R is independently, at each occurrence, selected from the group: H, C1-3 alkyl, C3-6 cycloalkyl, CO2H, OH, and NRcRd; Rb is independently, at each occurrence, selected from the group: H and C1-6 alkyl; alternatively, Ra and Rb or Ra and Re, 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, Ra and Rb and Re, 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; Rc is independently, at each occurrence selected from the group: H, Rf, and CO2H; Rd is independently, at each occurrence, selected from the group: H and C1-6 alkyl; alternatively, Rc and Rd, 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; Re is independently, at each occurrence, selected from the group: H and C1-6 alkyl; Rf is C1-4 alkyl substituted with 0-1 group selected from the group: NH2, NHMe, NMe2, OH, and OMe; Rg is independently, at each occurrence, selected from H and C1-3 alkyl; Rh is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH2, NHMe, NMe2, 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 CH3; Y is selected from the group: F, Cl, and Br; Z is selected from the group: N and CR6; R1 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 R1 is substituted with 0-3 R7; R2 is selected from the group: C2-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, S—C1-2 alkyl, O—C1-2 alkyl, cyclopropyl, cyclobutyl, 1-methylcyclopropyl, CH2CN, CH2OH, CH2OCH3, CH2NH2, CH2NMe2, CF3, and CHO; R3 is independently selected from the group: H, F, Cl, CH3, CH2CH3, CHO, CHRgOH, COCF3, CH═NOH, CH═NOCH3, CH═NNH2, CH═NNHMe, CH═NNMe2, and CH═CHRa, R4 is independently selected from the group: H, F, Cl, and CH3; R5 is independently selected from the group: H, CH3, F, Cl, Br, and CF3; R6 is independently selected from the group: H, F, Cl, Br, CF3, C1-3 alkyl optionally substituted with R, CO2H, CONH2, CONHRa, CONHNRaRb, CHO, CH3, SO2NRaRb; phenyl, and heteroaryl having 5-6 atoms in the ring and containing 1-2 N, O, or S atoms; and CH2NHRa; R7 is independently, at each occurrence, selected from the group: OH, C1-3 alkoxy, OC2-6alkyl-CO2H, O—C2-6-alkyl-NRaRb, F, Cl, Br, I, CF3, OCF3, —CN, CO2(C1-6 alkyl), CONRaRb, NRgC(O)ORa, NRgC(O)NRaRb, NRgCONHORg, NRgCONHSO2Ra, NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, SO2NRaRb, NRgSO2NRaRb, NRgSO2NHCO2C1-4 alkyl, NRgSO2CHReCH2NRaRb, NRgCOCHReNRaRb, NRgCOCHReNRbCH2RfRa, NRgCOCH2CHReNRaRb, NRgCOCHReCH2NRaRb, NRgCO(CH2)mNRaRb, NRgCONRe(CH2)nNRaRb, NRgCO2(CHRe)nNRaRb, CONReNRaRb, NRgCONReNRaRb, C3-7 carbocycle, NHCONRh, NHCONHCH2Rh, NHCORh, NHCOCH2Rh, C1-10 alkyl substituted with 0-3 R8, C2-6 alkenyl substituted with 0-3 R8, C2-6 alkynyl substituted with 0-2 R8, and C3-7 heterocycle containing 1-3 heteroatoms selected from O, N, and S; R8 is independently, at each occurrence, selected from the group: ═O, OH, C1-6 alkoxy, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, CORa, and CONRaRb; Ra is independently, at each occurrence, selected from the group: H, C1-6 alkyl, C3-6 cycloalkyl, and C1-6 alkyl substituted with one R; R is independently, at each occurrence, selected from the group: H, C1-3 alkyl, C3-6 cycloalkyl, CO2H, and NRcRd; Rb is independently, at each occurrence, selected from the group: H and C1-6 alkyl; alternatively, Ra and Rb or Ra and Re, 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, Ra and Rb and Re, 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; Rc is independently, at each occurence, selected from the group: H, Rf, and CO2H; Rd is independently, at each occurrence, selected from the group: H and C1-6 alkyl; alternatively, Rc and Rd, 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; Re is independently, at each occurrence, selected from the group: H and C1-4 alkyl; Rf is C1-4 alkyl substituted with 0-1 group selected from the group: NH2, NHMe, NMe2, OH, and OMe; Rg is independently, at each occurrence, selected from H and C1-3 alkyl; Rh is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH2, NHMe, NMe2, 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 CR6; R1 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 R1 is substituted with 0-2 R7; R2 is selected from the group: C2-4 alkyl, cyclopropyl, cyclobutyl, 1-methylcyclopropyl, and CF3; R3 is independently selected from the group: H, F, CH3, CHO, CHRgOH, COCF3, CH═NOH, CH═NOCH3, CH═NNH2, CH═NNHMe, CH═NNMe2, and CH═CHRa; R4 is independently selected from the group: H and F; R5 is independently selected from the group: CH3, F, Cl, and Br; R6 is independently selected from the group: H, F, Cl, Br, CF3, CH3, CONH2, CONHRa, CONHNRaRb, SO2NRaRb; CH2OH, CHO, phenyl, and heteroaryl having 5-6 atoms in the ring and containing 1-2 N, O, or S atoms; and CH2NHRa; R7 is independently, at each occurrence, selected from the group: OH, O—C2-6-alkyl-NRaRb, F, Cl, Br, CF3, —CN, CONRaRb, NHC(O)ORa, NHC(O)NRaRb, NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, SO2NRaRb, NHSO2NRaRb, NHCONHORe, NHCONHSO2Rf, NHSO2NHCO2C1-4 alkyl, NHSO2CHReCH2NRaRb, NHCOCHReNRaRb, NHCOCHReNRbCH2RfRa, NHCOCH2CHReNRaRb, NHCOCHReCH2NRaRb, NHCO(CH2)mNRaRb, NHCONRe(CH2)nNRaRb, NHCO2(CHRe)nNNRaRb, CONReNRaRb, NHCONReNRaRb, NHCONRh, NHCONHCH2Rh, NHCORh, NHCOCH2Rh, C3-7 carbocycle, C1-6 alkyl substituted with 0-3 R8, C2-6 alkenyl substituted with 0-3 R8, C2-6 alkynyl substituted with 0-3 R8, and C3-7 heterocycle containing 1-3 heteroatoms selected from O, N, and S; R8 is independently, at each occurrence, selected from the group: OH, C1-3 alkoxy, NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, and CONRaRb; Ra is independently, at each occurrence, selected from the group: H, C1-6 alkyl, C3-6 cycloalkyl, and C1-6 alkyl substituted with one R; R is independently, at each occurrence, selected from the group: H, C1-3 alkyl, and NRcRd; Rb is independently, at each occurrence, selected from the group: H and C1-6 alkyl; alternatively, Ra and Rb or Ra and Re, 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, Ra and Rb and Re, 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; Rc is independently, at each occurrence, selected from the group: H and Rf; Rd is independently, at each occurrence, selected from the group: H and C1-6 alkyl; alternatively, Rc and Rd, 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; Re is independently, at each occurrence, selected from the group: H and C1-3alkyl; Rf is C1-4 alkyl substituted with 0-1 group selected from the group: NH2, NHMe, NMe2, OH, and OMe; Rh is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH2, NHMe, NMe2, 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 CR6; R1 is selected from the group: phenyl, pyridyl, pyrrolyl, furyl, thienyl, indazolyl, benzoxazolyl, and benzothiazolyl, and R1 is substituted with 0-2 R7; R2 is selected from the group: CF3, C2-3 alkyl and cyclopropyl; R3 is selected from the group: H, CH3, CH2OH, and CHO; R4 is H; R5 is independently selected from the group: CH3, F, Cl, and Br; R6 is independently selected from the group: H, F, Cl, Br, CH3, CONH2, CONHNRaRb, SO2NRaRb; CH2OH, CHO, CH2NHRa, and CONHRa; R7 is independently, at each occurrence, selected from the group: OH, O—C2-6-alkyl-NRaRb, F, Cl, Br, NHC(O)ORa, NHC(O)NRaRb, NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, CONRaRb, NHCONHORe, NHCONHSO2Rf, NHSO2NHCO2C1-4 alkyl, NHSO2CHReCH2NRaRb, NHCOCHReNRaRb, NHCOCHReNRbCH2RfRa, NHCOCH2CHReNRaRb, NHCOCHReCH2NRaRb, NHCO(CH2)mNRaRb, NHCONRe(CH2)nNRaRb, NHCO2(CHRe)nNNRaRb, CONReNRaRb, NHCONHNRaRb, C1-4 alkyl substituted with 0-1 R8, and C5-7 heterocycle containing 1-3 heteroatoms selected from O, N, and S; R8 is independently, at each occurrence, selected from the group: NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, and CONRaRb; Ra is independently, at each occurrence, selected from the group: H, C1-3 alkyl, C3-6 cycloalkyl, and C1-3 alkyl substituted with R; R is independently, at each occurrence, selected from the group: H, C1-3 alkyl, and NRcRd; Rb is independently, at each occurrence, selected from the group: H and C1-6 alkyl; alternatively, Ra and Rb or Ra and Re, 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, Ra and Rb and Re, 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; Rc is independently, at each occurrence, selected from the group: H and Rf; Rd is independently, at each occurrence, selected from the group: H and C1-3 alkyl; alternatively, Rc and Rd, 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; Re is independently, at each occurence, selected from the group: H and CH3; Rf is C1-4 alkyl substituted with 0-1 group selected from the group: NH2, NHMe, NMe2, 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): or a steroisomer or pharmaceutically acceptable salt form thereof, wherein:Q is selected from the group: H, OH, and CH3, and CH2CH3; Y is selected from the group: F, Cl, Br, and I; Z is selected from the group: N and CR6; R1 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 R1 is substituted with 0-3 R7; R2 is selected from the group: C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, S—C1-3 alkyl, O—C1-3 alkyl, NH2, NH—C1-3 alkyl, N(C1-2 alkyl)2, OCF3, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, 1-methylcyclopropyl, 1-methylcyclobutyl, CH2CN, CH2OH, CH2OCH3, CH2NH2, CH2NHC1-3 alkyl, CH2NMe2, CF3, CHO, OCH2CH2OH, OCH(Me)CH2OH, OCH2CH(Me)OH, OCH2CH2NMe2, and CHF2; R3 is selected from the group: H, F, Cl, Br, I, CF3, CHO, CHRgOH, COCF3, CH═NOH, CH═NOCH3, CH═NNH2, CH═NNHMe, CH═NNMe2, CH═CHRa, C1-3 alkyl, C1-3alkoxy, CO2H, CONH2, CONH(C1-3 alkyl), CON(C1-3 alkyl)2, CO2C1-3 alkyl, C(O)C1-2 akyl, NH2, NH(C1-3 alkyl), and N(C1-3 alkyl)2; R4 is selected from the group: H, F, Cl, Br, I, CF3, C1-3 alkyl, C2-3 alkenyl, NH2, NH(C1-3 alkyl), and N(C1-3 alkyl)2; R5 is selected from the group: H, C1-3 alkyl, F, Cl, Br, I, CF3, and C2-3 alkenyl; R6 is selected from the group: H, F, Cl, Br, I, CF3, —NO2, C1-3 alkyl optionally substituted with 1-2 R, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, CO2H, CHO, CONRaRb, CO2C1-3 alkyl, C(O)C1-2 alkyl, CH2NHRa, CONRgNRaRb, NRaRb; SO2NRaRb, CR═NNRaRb, CR═NORf, and Rh; R7 is independently, at each occurrence, selected from the group: OH, C1-6 alkoxy, OC2-6 alkyl-CO2H, O—C2-6-alkyl-NRaRb, F, Cl, Br, I, CF3, OCF3, —CN, —NO2, CO2H, CO2(C1-6 alkyl), CONRaRb, NRgCONHORg, NRgCONHSO2Ra, NHNRgC(O)ORa, NRgC(O)NRaRb, NH2, NH(C1-3 alkyl), N(C1-3 alkyl), N(C1-3 alkyl)2, —SO2NRaRb, NHSO2NHCO2C1-4 alkyl, NRgSO2NRaRb, NRgSO2CHReCH2NRaRb, NRgCOCHReNRaRb, NRgCOCHReNRbCH2RfRa, NRgCOCH2CHReNRaRb, NRgCOCHReCH2NRaRb, NRgCO(CH2)mNRaRb, NRgCONRe(CH2)nNRaRb, NRgCO2(CHRe)nNRaRb, CONReNRaRb, NRgCONReNRaRb, C3-10 carbocycle, C1-10 alkyl substituted with 0-3 R8, NCONRh, NHCONHCH2Rh, NHCORh, NHCOCH2Rh, C2-10 alkenyl substituted with 0-3 R8, C2-10 alkynyl substituted with 0-3 R8, and C3-10 heterocycle containing 1-4 heteroatoms selected from O, N, and S; R8 is independently, at each occurrence, selected from the group: ═O, OH, C3-6 cycloalkyl, C1-6 alkoxy, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, F, Cl, Br, I, CO2H, CORa, CO2(benzyl), CO2(C1-6 alkyl), and CONRaRb; Ra is independently, at each occurrence, selected from the group: H, C1-6 alkyl, C3-7 cycloalkyl, and C1-6 alkyl substituted with one R; R is independently, at each occurrence, selected from the group: H, C1-3 alkyl, C3-6 cycloalkyl, CO2H, OH, and NRcRd; Rb is independently, at each occurrence, selected from the group: H and C1-6 alkyl; alternatively, Ra and Rb or Raand Re, 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, Ra and Rb and Re, 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; Rc is independently, at each occurrence, selected from the group: H, Rf, and CO2H; Rd is independently, at each occurrence, selected from the group: H and C1-6 alkyl; alternatively, Rc and Rd, 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; Re is independently, at each occurrence, selected from the group: H and C1-6 alkyl; Rf is C1-4 alkyl substituted with 0-1 group selected from the group: NH2, NHMe, NMe2, OH and OMe; Rg is independently, at each occurrence, selected from H and C1-3 alkyl; Rh is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH2, NHMe, NMe2, 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): or a steroisomer or pharmaceutically acceptable salt form thereof, wherein:Q is selected from the group: H, OH, and CH3, and CH2CH3; Y is selected from the group: F, Cl, Br, and I; Z is selected from the group: N and CR6; R1 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 R1 is substituted with 0-3 R7; R2 is selected from the group: C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, S—C1-3 alkyl, O—C1-3 alkyl, NH2, NH—C1-3 alkyl, N(C1-2 alkyl)2, OCF3, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, 1-methylcyclopropyl, 1-methylcyclobutyl, CH2CN, CH2OH, CH2OCH3, CH2NH2, CH2NHC1-3 alkyl, CH2NMe2, CF3, CHO, OCH2CH2OH, OCH(Me)CH2OH, OCH2CH(Me)OH, OCH2CH2NMe2, and CHF2; R3 is selected from the group: H, F, Cl, Br, I, CF3, CHO, CHRgOH, COCF3, CH═NOH, CH═NOCH3, CH═NNH2, CH═NNHMe, CH═NNMe2, CH═CHRa, C1-3 alkyl, C1-3 alkoxy, CO2H, CONH2, CONH(C1-3 alkyl), CON(C1-3 alkyl)2, CO2C1-3 alkyl, C(O)C1-2 akyl, NH2, NH(C1-3 alkyl), and N(C1-3 alkyl)2; R4 is selected from the group: H, F, Cl, Br, I, CF3, C1-3 alkyl, C2-3 alkenyl, NH2, NH(C1-3 alkyl), and N(C1-3 alkyl)2; R5 is selected from the group: H, C1-3 alkyl, F, Cl, Br, I, CF3, and C2-3 alkenyl; R6 is selected from the group: H, F, Cl, Br, I, CF3, —NO2, C1-3 alkyl optionally substituted with 1-2 R, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, CO2H, CHO, CONRaRb, CO2C1-3 alkyl, C(O)C1-2 alkyl, CH2NHRa, CONRgNRaRb, NRaRb; SO2NNRaRb, CR═NNRaRb, CR═NORf, and Rh; R7 is independently, at each occurrence, selected from the group: OH, C1-6 alkoxy, OC2-6 alkyl-CO2H, O—C2-6-alkyl-NRaRb, F, Cl, Br, I, CF3, OCF3, —CN, —NO2, CO2H, CO2(C1-6 alkyl), CONRaRb, NRgCONHORg, NRgCONHSO2Ra, NHNRgC(O)ORa, NRgC(O)NRaRb, NH2, NH(C1-3 alkyl), N(C1-3 alkyl), N(C1-3 alkyl)2, —SO2NRaRb, NHSO2NHCO2C1-4 alkyl, NRgSO2NRaRb, NRgSO2CHReCH2NNRaRb, NRgCOCHReNNRaRb, NRgCOCHReNRbCH2RfRa, NRgCOCH2CHReNRaRb, NRgCOCHReCH2NRaRb, NRgCO(CH2)mNRaRb, NRgCONRe(CH2)nNRaRb, NRgCO2(CHRe)nNRaRb, CONReNRaRb, NRgCONReNRaRb, C3-10 carbocycle, C1-10 alkyl substituted with 0-3 R8, NCONRh, NHCONHCH2Rh, NHCORh, NHCOCH2Rh, C2-10 alkenyl substituted with 0-3 R8, C2-10 alkynyl substituted with 0-3 R8, and C3-10 heterocycle containing 1-4 heteroatoms selected from O, N, and S; R8 is independently, at each occurrence, selected from the group: ═O, OH, C3-6 cycloalkyl, C1-6 alkoxy, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, F, Cl, Br, I, CO2H, CORa, CO2(benzyl), CO2(C1-6 alkyl), and CONRaRb; Ra is independently, at each occurrence, selected from the group: H, C1-6 alkyl, C3-7 cycloalkyl, and C1-6 alkyl substituted with one R; R is independently, at each occurrence, selected from the group: H, C1-3 alkyl, C3-6 cycloalkyl, CO2H, OH, and NRcRd; Rb is independently, at each occurrence, selected from the group: H and C1-6 alkyl; alternatively, Ra and Rb or Ra and Re, 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, Ra and Rb and Re, 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; Rc is independently, at each occurrence, selected from the group: H, Rf, and CO2H; Rd is independently, at each occurrence, selected from the group: H and C1-6 alkyl; alternatively, Rc and Rd, 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; Re is independently, at each occurrence, selected from the group: H and C1-6 alkyl; Rf is C1-4 alkyl substituted with 0-1 group selected from the group: NH2, NHMe, NMe2, OH and OMe; Rg is independently, at each occurrence, selected from H and C1-3 alkyl; Rh is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH2, NHMe, NMe2, 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.