Acylsemicarbazides as cyclin dependent kinase inhibitors useful as anti-cancer and anti-proliferative agents

FIELD OF THE INVENTION

[0001] This invention relates generally to novel 5-substituted-indeno[1,2-c]pyrazol-4-ones which are useful as cyclin dependent kinase (cdk) inhibitors, pharmaceutical compositions comprising the same, methods for using the same for treating proliferative diseases, and intermediates and processes for making the same.

BACKGROUND OF THE INVENTION

[0002] 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. Over expression 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).

[0003] Cyclin dependent kinases (cdks) 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, six kinase subunits (cdk 1-7) have been identified along with several regulatory subunits (cyclins A-H). 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 cdk complex: G1/S by cdk2/cyclin E, cdk4/cyclin D1 and cdk6/cyclinD2; S/G2 by cdk2/cyclin A and cdk1/cyclin A; G2/M by cdk1/B. 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)

[0004] An increasing body of evidence has shown a link between tumor development and cdk related malfunctions. Over expression 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 cdks 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 p16INK4 (an inhibitor of cdk4/D1), p21CIP1 (a general cdk inhibitor), and p27KIP1 (a specific cdk2/E inhibitor). A recent crystal structure of p27 bound to cdk2/A revealed how these proteins effectively inhibit the kinase activity through multiple interactions with the cdk complex (Pavletich, Nature 382:325-331, 1996). These proteins help to regulate the cell cycle through specific interactions with their corresponding cdk complexes. Cells deficient in these inhibitors are prone to unregulated growth and tumor formation.

[0005] This body of evidence has led to an intense search for small molecule inhibitors of the cdk family as an approach to cancer chemotherapy. There are no known examples of molecules related to the current invention which describe 5-substituted-indeno[1,2-c]pyrazoles as cdk inhibitors. There is one case describing indeno[1,2-c]pyrazoles having anticancer activity. There are two other examples which describe indeno[1,2-c]pyrazoles having unrelated utilities and structures.

[0006] A series of indeno[1,2-c]pyrazoles having anticancer activity are described in JP 60130521 and JP 62099361 with the following generic structure:

[0007] No substitution is claimed on the indenophenyl portion of the molecule and the molecules are not indicated to be cdk inhibitors. In addition, we discovered that substitution at the 5-position was critical for cdk inhibitory activity.

[0008] A series of indeno[1,2-c]pyrazoles having herbicidal activity are described in GB 2223946 with the following generic structure:

[0009] The above compounds differ from the presently claimed invention in Xn is defined as halo, alkyl, haloalkyl, and haloalkoxy; n=0-2. In addition, R1 is defined as acyl and R2 is defined as alkyl or cycloalkyl.

[0010] A series of 1-(6′-substituted-4′-methylquinol-2′-yl)-3-methylindeno[1,2-c]pyrazoles having CNS activity are described by Quraishi, Farmaco 44:753-8, 1989 with the following generic structure:

[0011] Compounds of this series are not considered to be part of the presently claimed invention.

SUMMARY OF THE INVENTION

[0012] The present invention describes a novel class of indeno[1,2-c]pyrazol-4-ones or pharmaceutically acceptable salt forms thereof that are potent inhibitors of the class of enzymes known as cyclin dependent kinases, which relate to the catalytic subunits cdk 1-7 and their regulatory subunits know as cyclins A-H.

[0013] 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 one of these compounds or a pharmaceutically acceptable salt form thereof.

[0014] 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 one of the compounds of the present invention and one or more other known anti-cancer or anti-proliferative agents.

[0015] These and other objectives have been achieved by the inventors' discovery that compounds of formula (I):

[0016] wherein R1, R2 and X are defined below or pharmaceutically acceptable salts thereof are cyclin dependent kinase inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0017] The invention pertains to novel cyclin dependent kinase inhibitors (cdks) and specifically, but not exclusively, as inhibitors of cdk/cyclin complexes. The inhibitors of this invention are indeno[1,2-c]pyrazol-4-one analogs. Certain analogs were selective for their activity against cdks 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.

[0018] 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 the treatment of cancer, psoriasis, immunological disorders involving unwanted leukocyte proliferation, in the treatment of restinosis and other smooth muscle cell disorders, and the like.

[0019] The present invention, in a first embodiment, describes a novel compound of formula (I):

[0020] or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:

[0021] X is selected from the group: O, S, and NR;

[0022] R is selected from the group: H, C1-4 alkyl, and NR5R5a;

[0023] R1 is selected from the group: H, C1-10 alkyl substituted with 0-3 Rc, C2-10 alkenyl substituted with 0-3 Rc, C2-10 alkynyl substituted with 0-3 Rc, —NHR4, C3-10 carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;

[0024] R2 is selected from the group: H, C1-10 alkyl substituted with 0-3 Rc, C2-10 alkenyl substituted with 0-3 Rc, C2-10 alkynyl substituted with 0-3 Rc, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;

[0025] R is selected from the group: H, halo, —CN, NO2, C1-4 haloalkyl, NR5R5a, NR5NR5R5a, NR5C(O)OR5 NR5C(O)R5═O, OR5, COR5, CO2R5, CONR5R5a, NHC(O)NR5R5a, NHC(S)NR5R5a, SO2NR5R5a, SO2R5b, C1-4 alkyl, phenyl, benzyl, C1-4 alkyl substituted with 1-3 Rc, C5-10 alkyl substituted with C2-10 alkenyl optionally substituted with 0-3 R6, C2-10 alkynyl substituted with 0-3 R6, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 R6, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R6; and

[0026] provided that if R3 is phenyl, it is substituted with 1-5 Ra;

[0027] R4 is independently at each occurrence selected from the group: H, —CN, C1-4 alkyl, C1-4 haloalkyl, NR3R3a NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, SO2R3b, C3-10 carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;

[0028] provided that at least one R3 is present and that this R3 is selected from the group: C1-4 alkyl substituted with 1-3 R6, C5-10 alkyl substituted with C2-10 alkenyl optionally substituted with 0-3 R6, C2-10 alkynyl substituted with 0-3 R6, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 R6, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R6;

[0029] Ra is independently at each occurrence selected from the group: halo, —CN, N3, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3, R3a, ═O, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, NR3C(O)OR3, NR3C(O)R3, SO2NR3R3a, SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;

[0030] alternatively, when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—;

[0031] Rb is independently at each occurrence selected from the group: halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, and SO2R3b;

[0032] Rc is independently at each occurrence selected from the group: halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R NR5NR5R5a, NR3C(O)OR3, NR3C(O)R3, ═O, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, SO2R3b, C3-10 carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;

[0033] R3a is selected from the group: H, C1-4 alkyl, phenyl, and benzyl;

[0034] alternatively, R3 and R3a, together with the nitrogen atom to which they are attached, form a heterocycle having 4-8 atoms in the ring containing an additional 0-1 N, S, or O atom and substituted with 0-3 R3c;

[0035] R3b is selected from the group: H, C1-4 alkyl, phenyl, and benzyl;

[0036] R3c is independently at each occurrence selected from the group: halo, —CN, N3, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3b, ═O, OR3, COR3, CO2R3, CONR3R3b, NHC(O)NR3R3b, NHC(S)NR3R3b, NR3C(O)OR3, NR3C(O)R3, SO2NR3R3b, SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;

[0037] R5 is independently selected from the group: H, C1-4 alkyl, phenyl and benzyl;

[0038] R5a is independently selected from the group: H, C1-4 alkyl, phenyl and benzyl;

[0039] R5b is independently selected from the group: H, C1-4 alkyl, phenyl and benzyl;

[0040] R6 is independently at each occurrence selected from the group: halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR5R5, NR5NR5R5a, NR5C(O)OR5, NR5C(O)R5, ═O, OR5, COR5, CO2R5, CONR5R5a, NHC(O)NR5R5a, NHC(S)NR5R5a, SO2NR5R5a, SO2R5b, C3-10 carbocycle substituted with 0-5 R5, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R5; and

[0041] m is selected from 0, 1, 2, and 3.

[0042] In a preferred embodiment, the present invention provides a novel compound of formula (I), wherein:

[0043] X is selected from the group: O, S, and NR;

[0044] R is selected from the group: H, C1-4 alkyl, and NR5R5a;

[0045] R1 is selected from the group: H, C1-5 alkyl substituted with 0-3 Rc, C2-5 alkenyl substituted with 0-3 Rc, C2-5 alkynyl substituted with 0-3 Rc, —NHR4, C3-6 carbocycle substituted with 0-5 Ra, and 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;

[0046] R2 is selected from the group: H, C1-5 alkyl substituted with 0-3 Rc, C2-5 alkenyl substituted with 0-3 R3, C2-5 alkynyl substituted with 0-3 Rc, —(CF2)mCF3, C3-6 carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;

[0047] R3 is selected from the group: H, halo, —CN, NO2, C1-4 haloalkyl, NR5R5a, NR5NR5R5a, NR5C(O)OR5, NR5C(O)R5, ═O, OR5, COR5, CO2R5, CONR5R5a, NHC(O)NR5R5a, NHC(S)NR5R5a, SO2NR5R5a, SO2R5b, C1-4 alkyl, phenyl, benzyl, C1-4 alkyl substituted with 1-3 Rc, C5-10 alkyl substituted with C2-10 alkenyl optionally substituted with 0-3 R6, C2-10 alkynyl substituted with 0-3 R6, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 R6, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R6; and

[0048] provided that if R3 is phenyl, it is substituted with 1-5 Ra;

[0049] R4 is independently at each occurrence selected from the group: H, —CN, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, SO2R3b, C3-10 carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;

[0050] provided that at least one R3 is present and that this R3 is selected from the group: C1-4 alkyl substituted with 1-3 R6, C5-10 alkyl substituted with C2-10 alkenyl optionally substituted with 0-3 R6, C2-10 alkynyl substituted with 0-3 R6, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 R6, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R6;

[0051] Ra is independently at each occurrence selected from the group: halo, —CN, N3, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, ═O, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;

[0052] alternatively, when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—;

[0053] Rb is independently at each occurrence selected from the group: halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, and SO2R3b;

[0054] Rc is independently at each occurrence selected from the group: halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, NR5NR5R5a, ═O, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, SO2R3b, C3-10 carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;

[0055] R3a is selected from the group: H, C1-4 alkyl, phenyl, and benzyl;

[0056] alternatively, R3 and R3a, together with the nitrogen atom to which they are attached, form a heterocycle having 4-8 atoms in the ring containing an additional 0-1 N, S, or O atom and substituted with 0-3 R3c;

[0057] R3b is selected from the group: H, C1-4 alkyl, phenyl, and benzyl;

[0058] R3c is independently at each occurrence selected from the group: halo, —CN, N3, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3b, ═O, OR3, COR3, CO2R3, CONR3R3b, NHC(O)NR3R3b, NHC(S)NR3R3b, NR3C(O)OR3, NR3C(O)R3, SO2NR3R3, SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;

[0059] R5 is independently selected from the group: H, C1-4 alkyl, phenyl, and benzyl;

[0060] R5a is independently selected from the group: H, C1-4 alkyl, phenyl and benzyl;

[0061] R5b is independently selected from the group: H, C1-4 alkyl, phenyl, and benzyl;

[0062] R6 is independently at each occurrence selected from the group: halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR5R5, NR5NR5R5a, NR5C(O)OR5, NR5C(O)R5, ═O, OR5, COR5, CO2R5, CONR5R5a, NHC(O)NR5R5a, NHC(S)NR5R5a, SO2NR5R5a, SO2R5b, C3-10 carbocycle substituted with 0-5 R5, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R5; and

[0063] m is selected from 0, 1, 2, and 3.

[0064] In a more preferred embodiment, the present invention provides a novel compound of formula (I), wherein:

[0065] X is selected from the group: O and S;

[0066] R1 is selected from the group: H, C1-5 alkyl substituted with 0-3 Rc, C2-5 alkenyl substituted with 0-3 Rc, —NHR4, C3-6 carbocycle substituted with 0-5 Ra, and 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;

[0067] R2 is selected from the group: H, C1-5 alkyl substituted with 0-3 Rc, C2-s alkenyl substituted with 0-3 Rc, —(CF2)mCF3, C3-6 carbocycle substituted with 0-5 Ra, and 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;

[0068] R3 is selected from the group: H, halo, —CN, NO2, C1-4 haloalkyl, NR5R5a, NR5NR5R5a, NR5C(O)OR5, NR5C(O)R5, ═O, OR5, COR5, CO2R5, CONR5R5a, NHC(O)NR5R5a, NHC(S)NR5R5a, SO2NR5R5a, SO2R5b, C1-4 alkyl, phenyl, benzyl, C1-4 alkyl substituted with 1-3 Rc, C5-10 alkyl substituted with C2-10 alkenyl optionally substituted with 0-3 R6, C2-10 alkynyl substituted with 0-3 R6, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 R6, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R6; and

[0069] provided that if R3 is phenyl, it is substituted with 1-5 Ra;

[0070] R4 is independently at each occurrence selected from the group: H, —CN, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, SO2R3b, C3-10 carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;

[0071] provided that at least one R3 is present and that this R3 is selected from the group: C1-4 alkyl substituted with 1-3 R6, C5-10 alkyl substituted with C2-10 alkenyl optionally substituted with 0-3 R6, C2-10 alkynyl substituted with 0-3 R6, (CF2)mCF3, C3-10 carbocycle substituted with 0-5 R6, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R6;

[0072] Ra is independently at each occurrence selected from the group: halo, —CN, N3, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)R3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, SO2NR3R3a, SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;

[0073] alternatively, when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—;

[0074] Rb is independently at each occurrence selected from the group: halo, —CN, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, SO2NR3R3a, and SO2R3b;

[0075] Rc is independently at each occurrence selected from the group: halo, —CN, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR5NR5R5a, NR3C(O)OR3, NR3C(O)R3, ═O, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, SO2NR3R3a, SO2R3b, C3-10 carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;

[0076] R3a is selected from the group: H, C1-4 alkyl, phenyl, and benzyl;

[0077] alternatively, R3 and R3a, together with the nitrogen atom to which they are attached, form a heterocycle having 5-6 atoms in the ring containing an additional 0-1 N, S, or O atom and substituted with 0-3 R3c;

[0078] R3b is selected from the group: H, C1-4 alkyl, phenyl, and benzyl;

[0079] R3c is independently at each occurrence selected from the group: halo, —CN, N3, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3b, ═O, OR3, COR3, CO2R3, CONR3R3b, NHC(O)NR3R3b, NHC(S)NR3R3b, NR3C(O)OR3, NR3C(O)R3, SO2NR3R3b, SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;

[0080] R5 is independently selected from the group: H, C1-4 alkyl, phenyl, and benzyl;

[0081] R5a is independently selected from the group: H, C1-4 alkyl, phenyl and benzyl;

[0082] R5b is independently selected from the group: H, C1-4 alkyl, phenyl, and benzyl;

[0083] R6 is independently at each occurrence selected from the group: halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR5R5, NR5NR5R5a, NR5C(O)OR5, NR5C(O)R5, ═O, OR5, COR5, CO2R5, CONR5R5a, NHC(O)NR5R5a, NHC(S)NR5R5a, SO2NR5R5a, SO2R5b, C3-10 carbocycle substituted with 0-5 R5, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R5; and

[0084] m is selected from 0, 1, 2, and 3.

[0085] In a even more preferred embodiment, the present invention provides a novel compound of formula (I), wherein:

[0086] X is selected from the group: O and S;

[0087] R1 is selected from the group: H, C1-5 alkyl substituted with 0-2 Rc, —NHR4, C3-6 carbocycle substituted with 0-5 Ra, and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;

[0088] R2 is selected from the group: H, C1-5 alkyl substituted with 0-3 Rc, —(CF2)mCF3, C3-6 carbocycle substituted with 0-5 Ra, and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-3 Rb;

[0089] R3 is selected from the group: H, halo, —CN, NO2, C1-4 haloalkyl, NR5R5a, NR5NR5R5a, NR5C(O)OR5, NR5C(O)R5, ═O, OR5, COR5, CO2R5, CONR5R5a, NHC(O)NR5R5a, NHC(S)NR5R5a, SO2NR5R5a, SO2R5b, C1-4 alkyl, phenyl, benzyl, C1-4 alkyl substituted with 1-3 Rc, C5-10 alkyl substituted with C2-10 alkenyl optionally substituted with 0-3 R6, C2-10 alkynyl substituted with 0-3 R6, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 R6, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R6; and

[0090] provided that if R3 is phenyl, it is substituted with 1-5 Ra;

[0091] R4 is independently at each occurrence selected from the group: H, —CN, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, SO2R3b, C3-10 carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;

[0092] provided that at least one R3 is present and that this R3 is selected from the group: C1-4 alkyl substituted with 1-3 R6, C5-10 alkyl substituted with C2-10 alkenyl optionally substituted with 0-3 R6, C2-10 alkynyl substituted with 0-3 R6, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 R6, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R6;

[0093] Ra is independently at each occurrence selected from the group: halo, —CN, N3, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, SO2NR3R3a, SO2R3b, and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;

[0094] alternatively, when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—;

[0095] Rb is independently at each occurrence selected from the group: halo, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, SO2NR3R3a, and SO2R3b;

[0096] Rc is independently at each occurrence selected from the group: halo, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR5NR5R5a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, SO2NR3R3a, SO2R3b, C3-10 carbocycle substituted with 0-5 Ra, and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;

[0097] R3a is selected from the group: H, C1-4 alkyl, phenyl, and benzyl;

[0098] alternatively, R3 and R3a, together with the nitrogen atom to which they are attached, form a heterocycle having 5-6 atoms in the ring containing an additional 0-1 N, S, or O atom and substituted with 0-3 R3c;

[0099] R3b is selected from the group: H, C1-4 alkyl, phenyl, and benzyl;

[0100] R3c is independently at each occurrence selected from the group: halo, —CN, N3, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3b, ═O, OR3, COR3, CO2R3, CONR3R3b, NHC(O)NR3R3b, NHC(S)NR3R3b, NR3C(O)OR3, NR3C(O)R3, SO2NR3R3b, SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;

[0101] R5 is independently selected from the group: H and C1-4 alkyl;

[0102] R5a is independently selected from the group: H, C1-4 alkyl, phenyl and benzyl;

[0103] R5b is independently selected from the group: H and C1-4 alkyl;

[0104] R6 is independently at each occurrence selected from the group: halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR5R5, NR5NR5R5a, NR5C(O)OR5, NR5C(O)R5, ═O, OR5, COR5, CO2R5, CONR5R5a, NHC(O)NR5R5a, NHC(S)NR5R5a, SO2NR5R5a, SO2R5b, C3-10 carbocycle substituted with 0-5 R5, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R5; and

[0105] m is selected from 0, 1, 2, and 3.

[0106] In a most preferred embodiment, the compounds of formula (I) are selected from:

[0107] 3-(4-methoxyphenyl)-5-(2-benzoylhydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one;

[0108] 3-(4-methoxyphenyl)-5-(2-isonicotinoylhydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one;

[0109] 3-(4-methoxyphenyl)-5-(2-nictinoylhydrazinecarbox amido)indeno[1,2-c]pyrazol-4-one;

[0110] 3-(4-methoxyphenyl)-5-(2-(3,4-dihydroxybenzoyl)hydrazine carboxamido)indeno[1,2-c]pyrazol-4-one;

[0111] 3-(4-methoxyphenyl)-5-(2-(4-hydroxybenzoyl)hydrazine carboxamido)indeno[1,2-c]pyrazol-4-one;

[0112] 3-(4-methoxyphenyl)-5-(2-(3-aminobenzoyl)hydrazine carboxamido)indeno[1,2-c]pyrazol-4-one;

[0113] 3-(4-methoxyphenyl)-5-(2-(4-aminobenzoyl)hydrazine carboxamido)indeno[1,2-c]pyrazol-4-one;

[0114] 3-(4-methoxyphenyl)-5-(2-(2-aminobenzoyl)hydrazine carboxamido)indeno[1,2-c]pyrazol-4-one;

[0115] 3-(4-methoxyphenyl)-5-(2-(4-N,N-dimethylaminobenzoyl) hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one;

[0116] 3-(4-methoxyphenyl)-5-(2-phenethylacetylhydrazine carboxamido)indeno[1,2-c]pyrazol-4-one;

[0117] 3-(4-methoxyphenyl)-5-(2-(2-hydroxybenzoyl)hydrazine carboxamido)indeno[1,2-c]pyrazol-4-one; and

[0118] 3-(4-methoxyphenyl)-5-(2-methoxycarbonyl hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one;

[0119] or pharmaceutically acceptable salt form thereof.

[0120] Another embodiment of the present invention is a pharmaceutical composition comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I).

[0121] Another embodiment of the present invention is a method of treating cancer and proliferative diseases comprising: administering to a host in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically effective salt form thereof.

DEFINITIONS

[0122] 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.

[0123] 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.

[0124] 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, adamantly, or tetrahydronaphthyl (tetralin).

[0125] 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).

[0126] 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 which 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.

[0127] 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, b-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.

[0128] 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.

[0129] 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, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990, p. 1445, the disclosure of which is hereby incorporated by reference.

[0130] 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.

[0131] “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.

[0132] “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.

[0133] 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, hydroxyurea.

SYNTHESIS

[0134] 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.

[0135] An approach to preparing indeno[1,2-c]pyrazol-4-ones is presented in Scheme 1 and can be used to prepare compounds of the present invention. The nitro group of dimethyl 3-nitrophthalate was reduced to the amine using catalytic hydrogenation. The aniline was acylated using acetic anhydride and pyridine as a base. A mixture of the resulting acetamide 2 and an acetophenone were treated with a strong base in an appropriate solvent at elevated temperature to give the desired triketone 3. Additional means of preparing triketones are known to one skilled in the art as described in Kilgore et al, Industrial and Engineering Chemistry 34:494-497, 1946, the contents of which are hereby incorporated herein by reference. The triketone was treated with hydrazine at elevated temperature in an appropriate solvent to give the indeno[1,2-c]pyrazol-4-one ring system. Additional means of preparing indeno[1,2-c]pyrazol-4-ones are known to one skilled in the art as described in Lemke et al., J. Heterocyclic Chem. 19:1335-1340, 1982; Mosher and Soeder, J. Heterocyclic Chem. 8:855-59, 1971; Hrnciar and Svanygova Collect. Czech. Chem. Commun. 59:2734-40, 1994 the contents of which are hereby incorporated herein by reference. The amide was deacylated by heating with a strong acid in an appropriate solvent to give aniline 4. This aniline was acylated under standard conditions using an acid chloride in an appropriate solvent to give the desired product 5.

[0136] An alternative method for making compounds of the present invention is shown in Scheme 2. The intermediate triketone 3 can be deacylated with strong acid and reacylated with an appropriate acid chloride using methods known to those skilled in the art. Subsequently, triketone 6 can the be converted to the indeno[1,2-c]pyrazol-4-one ring system using the same conditions described previously in Scheme 1.

[0137] Another method for preparing the triketones 6 of Scheme 2 employs the condensation of a 1,3-diketone 6a with 3-nitrophthalic anhydride as described in Rotberg and Oshkaya, Zh. Organ. Khim. 8:84-87, 1972; Zh. Organ. Khim. 9:2548-2550, 1973, the contents of which are hereby incorporated herein by reference. The 1,3-diketones, when not commercially available can be readily prepared by one skilled in the art by the acetylation or trifluoroacetylation of the requisite methyl ketone, R1COCH3. Reduction of the nitro derivative 6b to the aniline 6c can be accomplished in a variety of ways including catalyic hydrogenation, treatment with zinc or iron under acidic conditions, or treatment with other reducing agents such as sodium dithionite or stannous chloride. Subsequently the aniline 6c can be converted to the indeno[1,2-c]pyrazol-4-ones of this invention by acylation followed by treatment with hydrazine as described previously in Scheme 2.

[0138] Another method for making the indeno[1,2-c]pyrazol-4-one ring system is shown in Scheme 4. Dimethyl hydrazine was reacted with 3-acetylpyridine with no solvent to give the hydrazone 7. This was treated in a similar fashion as described in Scheme 1 to give the desired intermediate 8. Additional means of preparing similar intermediates are known to one skilled in the art as described in Rappoport, J. Org. Chem. 49:2948-2953, 1984, the contents of which are hereby incorporated herein by reference. This intermediate was carried through the sequence in a similar fashion as described in Scheme 1.

[0139] Another approach to preparing indeno[1,2-c]pyrazol-4-ones is presented in Scheme 5 and can be used to prepare compounds of the present invention. Treating the intermediate 5-aminoindeno[1,2-c]pyrazol-4-one with 2-(trimethylsilyl) ethoxymethylmethyl chloride (SEMCL) and a suitable base in an inert solvent under reflux gives the SEM protected intermediate. The aniline is converted to the carbamate with phenylchloroformate using methods known to those skilled in the art. This intermediate is reacted with carbaztes in DMSO at elevated temperatures and then the SEM group is removed by treating with acid in a polar protic solvent to give the desired acylsemicarbazide-containing indenopyrazole analogs.

[0140] Other features of the invention will become apparent during the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

[0141] Abbreviations used in the Examples are defined as follows: “° C.” for degrees Celsius, “CIMS” for chemical ionization mass spectroscopy, “eq” for equivalent or equivalents, “g” for gram or grams, “h” for hour or hours, “mg” for milligram or milligrams, “mL” for milliliter or milliliters, “mmol” for millimolar, “M” for molar, “min” for minute or minutes, “p-TsOH” for para-toluenesulphonic acid, “DMF” for dimethylformamide, and “TFA” for trifluoroacetic acid.

Example I

Preparation of 3-(4-methoxyphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one

[0142]

[0143] Step 1. Synthesis of 2 from dimethyl 3-nitrophthalate.

[0144] A solution of dimethyl 3-nitrophthalate (25 g, 105 mmol) in methanol (100 mL) was treated with 5% Pd/C (2.5 g) and hydrogenated on a Parr Shaker at 50 psi for 2 h. The solution was filtered (Celite), the filtrate collected and the solvent removed at reduced pressure. The residue was dissolved in acetic anhydride (20 mL) treated with pyridine (0.05 mL) and heated to 80° C. for 1 min. The reaction was cooled and stirred at 25° C. for 2 h. The solvent was removed at reduced pressure and the residue recrystallized from ethanol to give the product as a white solid (21 g, 79%). mp 104-105° C.; CIMS m/e calc'd for C12H14NO5: 252.0872, found 252.0888; Analysis calc'd for C12H13NO5: C, 57.37; H, 5.22; N, 5.58; found: C, 57.67; H, 5.29; N, 5.77.

[0145] Step 2. Synthesis of Triketone 11 from 2.

[0146] A solution of 2 (1 g, 4.0 mmol) in dry DMF (2 mL) was treated with sodium hydride (0.15 g, 60% suspension in oil, 0.4 mmol) in one portion. After 1 h, 4-methoxyacetophenone (0.6 g, 4.0 mmol) was added in one portion and the reaction heated to 90° C. A second portion of sodium hydride (0.15 g, 60% suspension in oil, 0.4 mmol) was added and the exothermic reaction turns deep red. After 20 min, the reaction was cooled to 25° C., diluted with water (20 mL), extracted with EtOAc (10 mL) and the aqueous phase separated. The aqueous phase was acidified with 2 N HCl to pH 2 and the crude product collected. Recrystalization with ethanol gave the desired product as a yellow solid (0.4 g, 30%). mp 174-175° C.; CIMS m/e calc'd for C19H16NO5: 338.1028, found 338.1022; Analysis calc'd for C19H15NO5: C, 67.65; H, 4.48; N, 4.15; found: C, 67.87; H, 4.29; N, 3.99.

[0147] Step 3. Synthesis of 12 from 11.

[0148] A solution of 11 (0.2 g, 0.6 mmol) in EtOH (5 mL) was treated with hydrazine hydrate (0.1 mL, 1.8 mmol) and p-TsOH (3 mg). The reaction was heated to reflux and stirred for 2 h. The reaction was cooled to 25° C. and the product collected as a yellow solid (0.1 g, 50%). mp 268° C.; CIMS m/e calc'd for C19H16N3O3: 334.1192, found: 334.1168; Analysis calc'd for C19H15N3O3: C, 68.46; H, 4.54; N, 12.61; found: C, 68.81; H, 4.39; N, 12.45.

Example II

Preparation of 3-(4-methoxyphenyl)-5-(chloroacetamido)indeno[1,2-c]pyrazol-4-one

[0149]

[0150] Step 1. Synthesis of 13 from 12.

[0151] A suspension of 12 (1.0 g, 3.0 mmol) in MeOH (10 mL) was treated with conc. HCl (1 mL) and heated to reflux. After 2 h, the reaction was cooled and the product was collected as a greenish solid (0.7 g, 81%). mp 273° C.; CIMS m/e calc'd for C17H14N3O2: 292.1086, found: 292.1080; Analysis calc'd for C17H13N3O2: C, 69.85; H, 4.83; N, 14.37; found: C, 69.99; H, 4.59; N, 14.44.

[0152] Step 2. Synthesis of 14 from 13.

[0153] A suspension of 13 (20 mg, 0.07 mmol) in dioxane (2 mL) was treated with aqueous sat. NaHCO3 (1 mL) and chloroacetyl chloride (30 mL, 0.21 mmol). The reaction was heated to 50° C. and stirred for 2 h. The reaction was cooled, poured into water (2 mL), extracted with EtOAc (10 mL), the organic layer separated, dried (MgSO4) and the solvent removed at reduced pressure. The solid residue was recrystallized from EtOH to give the product as a yellow solid (9 mg, 35%). mp 274° C.; CIMS m/e calc'd for C19H15N3O3Cl: 368.0802, found: 368.0818.

Example III

Preparation of 3-(4-methoxyphenyl)-5-(cyclopropylamido)indeno[1,2-c]pyrazol-4-one

[0154] Prepared in a similar fashion as described for example II using cyclopropylacetyl chloride as the starting material. mp 289° C.; CIMS m/e calc'd for C21H18N3O3: 360.1348, found: 360.1330.

Example IV

Preparation of 3-(4-methoxyphenyl)-5-(isopropylamido)indeno[1,2-c]pyrazol-4-one

[0155] Prepared in a similar fashion as described for example II using isopropylacetyl chloride as the starting material. mp 288° C.; CIMS m/e calc'd for C21H20N3O3: 362.1505, found: 362.1535.

Example V

Preparation of 3-(4-methoxyphenyl)-5-(ethylamido)indeno[1,2-c]pyrazol-4-one

[0156] Prepared in a similar fashion as described for example II using propionyl chloride as the starting material. mp 287° C.; CIMS m/e calc'd for C20H18N3O3: 348.1348, found: 348.1313.

Example VI

Preparation of 3-(4-methoxyphenyl)-5-(cyclopentylamido)indeno[1,2-c]pyrazol-4-one

[0157] Prepared in a similar fashion as described for example II using cyclopentylacetyl chloride as the starting material. mp 267° C.; CIMS m/e calc'd for C23H22N3O3: 388.1661, found: 388.1626.

Example VII

Preparation of 3-(4-methoxyphenyl)-5-(cyclobutylamido)indeno[1,2-c]pyrazol-4-one

[0158] Prepared in a similar fashion as described for example II using cyclobutylacetyl chloride as the starting material. mp 297° C.; CIMS m/e calc'd for C22H20N3O3: 374.1505, found: 374.1530.

Example VIII

Preparation of 3-(4-methoxyphenyl)-5-(phenylacetamido)indeno[1,2-c]pyrazol-4-one

[0159] Prepared in a similar fashion as described for example II using phenylacetyl chloride as the starting material. mp 280° C.; CIMS m/e calc'd for C25H20N3O3: 410.1505, found: 410.1533.

Example IX

Preparation of 3-(4-methoxyphenyl)-5-(butylamido)indeno[1,2-c]pyrazol-4-one

[0160] Prepared in a similar fashion as described for example II using butyryl chloride as the starting material. mp 282° C.; CIMS m/e calc'd for C21H20N3O3: 362.1505, found: 362.1500.

Example X

Preparation of 3-(4-methoxyphenyl)-5-((4-chlorophenyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0161] Prepared in a similar fashion as described for example II using 4-chlorophenylacetyl chloride as the starting material. mp 238° C.; CIMS m/e calc'd for C25H19N3O3Cl: 444.1115, found: 444.1110.

Example XI

Preparation of 3-(4-methoxyphenyl)-5-((3-methoxyphenyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0162] Prepared in a similar fashion as described for example II using 3-methoxyphenylacetyl chloride as the starting material. mp>300° C.; CIMS m/e calc'd for C26H22N3O4: 440.1610, found: 440.1620.

Example XII

Preparation of 3-(4-methoxyphenyl)-5-((4-methoxyphenyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0163] Prepared in a similar fashion as described for example II using 4-methoxyphenylacetyl chloride as the starting material. mp 280° C.; CIMS m/e calc'd for C26H22N3O4: 440.1610, found: 440.1630.

Example XIII

Preparation of 3-(4-methoxyphenyl)-5-((3,4-dimethoxyphenyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0164] Prepared in a similar fashion as described for example II using 3,4-dimethoxyphenylacetyl chloride as the starting material. mp>300° C.; CIMS m/e calc'd for C27H24N3O5: 470.1716, found: 470.1731.

Example XIV

Preparation of 3-(4-methoxyphenyl)-5-((2,5-dimethoxyphenyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0165] Prepared in a similar fashion as described for example II using 2,5-dimethoxyphenylacetyl chloride as the starting material. mp 226° C.; CIMS m/e calc'd for C27H24N3O5: 470.1716, found: 470.1739.

Example XV

Preparation of 3-(2-methoxyphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one

[0166] Prepared in a similar fashion as described for example I using 2-methoxyacetophenone as the starting material. mp 276° C.; CIMS m/e calc'd for C19H16N3O3: 334.1192, found: 334.1169.

Example XVI

Preparation of 3-(3,4-dimethoxyphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one

[0167] Prepared in a similar fashion as described for example I using 3,4-dimethoxyacetophenone as the starting material. mp>300° C.; CIMS m/e calc'd for C20H18N3O4: 364.1297, found: 364.1288.

Example XVII

Preparation of 3-(4-methoxyphenyl)-5-((3,4-ethylenedioxyphenyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0168]

[0169] Step 1. Synthesis of 15 from 11.

[0170] A suspension of 11 (5 g, 14.8 mmol) in MeOH (50 mL) was treated with conc. HCl (3 mL) and heated to reflux. After stirring for 2 h, the reaction was cooled to 0° C. and the product collected as a yellow solid (4.2 g, 96%). mp 173° C.; CIMS m/e calc'd for C17H14NO4: 296.0923, Found: 296.0901.

[0171] Step 2. Synthesis of 16 from 15.

[0172] A suspension of 15 (20 mg, 0.07 mmol) in acetone (2 mL) was treated with NaHCO3 (10 mg) and the acid chloride of (3,4-methylenedioxyphenyl)acetic acid (prepared by heating the acid in a benzene:thionyl chloride 4:1 mixture at 50° C. for 2 h, removing the volatile components at reduced pressure, and using the crude acid chloride without further purification). The reaction was heated to 50° C. and stirred for 2 h. The reaction was cooled, poured into water (4 mL), extracted with EtOAc (10 mL), dried (MgSO4), filtered and concentrated. The crude triketone was suspended in EtOH (2 mL), treated with hydrazine hydrate (0.05 mL) and p-TsOH (1 mg) and heated to reflux for 2 h. The reaction was cooled to 0° C. and the product filtered to give a yellow solid (6.5 mg, 20%). mp 297° C.; CIMS m/e calc'd for C26H20N3O5: 454.1403, Found: 454.1398.

Example XVIII

Preparation of 3-(4-dimethoxyphenyl)-5-((3-thiophene)acetamido)indeno[1,2-c]pyrazol-4-one

[0173] Prepared in a similar fashion as described for example XVII using the acid chloride of 3-thiopheneacetic acid as the starting material. mp 293° C.; CIMS m/e calc'd for C23H18N3O3S: 416.1069, found: 416.1088.

Example XIX

Preparation of 3-(4-methoxyphenyl)-5-((2-methoxyphenyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0174] Prepared in a similar fashion as described for example XVII using the acid chloride of 2-methoxyphenylacetic acid as the starting material. mp 255° C.; CIMS m/e calc'd for C26H22N3O4: 440.1610, found: 440.1622.

Example XX

Preparation of 3-(4-methoxyphenyl)-5-((3,4-dichlorophenyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0175] Prepared in a similar fashion as described for example XVII using the acid chloride of 3,4-dichlorophenylacetic acid as the starting material. mp 299° C.; CIMS m/e calc'd for C25H18N3O3Cl2: 478.0725, found: 478.0744.

Example XXI

Preparation of 3-(4-methoxyphenyl)-5-((2,4-dichlorophenyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0176] Prepared in a similar fashion as described for example XVII using the acid chloride of 2,4-dichlorophenylacetic acid as the starting material. mp 286° C.; CIMS m/e calc'd for C25H18N3O3Cl2: 478.0725, found: 478.0734.

Example XXII

Preparation of 3-(4-methoxyphenyl)-5-((2-chlorophenyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0177] Prepared in a similar fashion as described for example XVII using the acid chloride of 2-chlorophenylacetic acid as the starting material. mp 300° C.; CIMS m/e calc'd for C25H19N3O3Cl: 444.1115, found: 444.1111.

Example XXIII

Preparation of 3-(4-methoxyphenyl)-5-(aminoacetamido)indeno[1,2-c]pyrazol-4-one

[0178]

[0179] A suspension of 14 (15 mg, 0.04 mmol) in EtOH (1 mL) was treated with conc. NH4OH (1 mL), placed in a sealed tube and heated to 80° C. for 3 h. The reaction was cooled and the solvent removed at reduced pressure. The residue was recrystallized from EtOH to give the product as a yellow solid (9 mg, 62%). mp>300° C.; CIMS m/e calc'd for C20H19N4O3: 363.1457, Found: 363.1431.

Example XXIV

Preparation of 3-(4-methoxyphenyl)-5-((2-hydroxyethyl)aminoacetamido)indeno[1,2-c]pyrazol-4-one

[0180] Prepared in a similar fashion as described for example XXIII using hydroxylamine as the starting material. mp 243° C.; CIMS m/e calc'd for C21H21N4O4: 393.1563, found: 393.1539.

Example XXV

Preparation of 3-(4-methoxyphenyl)-5-(N,N-dimethylaminoacetamido)indeno[1,2-c]pyrazol-4-one

[0181] Prepared in a similar fashion as described for example XXIII using dimethylamine as the starting material. mp 279° C.; CIMS m/e calc'd for C21H21N4O3: 377.1614, found: 377.1640.

Example XXVI

Preparation of 3-(4-methoxyphenyl)-5-(piperazinylacetamido)indeno[1,2-c]pyrazol-4-one

[0182] Prepared in a similar fashion as described for example XXIII using piperazine as the starting material. mp 277° C.; CIMS m/e calc'd for C23H24N5O3: 418.1879, found: 418.1899.

Example XXVII

Preparation of 3-(4-methoxyphenyl)-5-(4-methylpiperazinylacetamido)indeno[1,2-c]pyrazol-4-one

[0183] Prepared in a similar fashion as described for example XXIII using 4-methylpiperizine as the starting material. mp>300° C.; CIMS m/e calc'd for C24H26N5O3: 432.2036, found: 432.2030.

Example XXVIII

Preparation of 3-(4-methoxyphenyl)-5-(4-(2-hydroxyethyl)piperazinylacetamido)indeno[1,2-c]pyrazol-4-one

[0184] Prepared in a similar fashion as described for example XXIII using 4-hydroxyethylpiperizine as the starting material. mp>300° C.; CIMS m/e calc'd for C25H28N5O4: 462.2141, found: 462.2128.

Example XXIX

Preparation of 3-(4-methoxyphenyl)-5-(piperidinylacetamido)indeno[1,2-c]pyrazol-4-one

[0185] Prepared in a similar fashion as described for example XXIII using piperidine as the starting material. mp 291° C.; CIMS m/e calc'd for C24H25N4O3: 417.1927, found: 417.1955.

Example XXX

Preparation of 3-(4-methoxyphenyl)-5-(4-aminomethylpiperidinylacetamido)indeno[1,2-c]pyrazol-4-one

[0186] Prepared in a similar fashion as described for example XXIII using 4-aminomethylpiperidine as the starting material. mp>300° C.; CIMS m/e calc'd for C25H28N5O3: 446.2192, found: 446.2166.

Example XXXI

Preparation of 3-(4-methoxyphenyl)-5-(ethylaminoacetamido)indeno[1,2-c]pyrazol-4-one

[0187] Prepared in a similar fashion as described for example XXIII using ethylamine as the starting material. mp 250° C.; CIMS m/e calc'd for C21H21N4O3: 377.1614, found: 377.1644.

Example XXXII

Preparation of 3-(4-methoxyphenyl)-5-(thiomorpholinylacetamido)indeno[1,2-c]pyrazol-4-one

[0188] Prepared in a similar fashion as described for example XXIII using thiomorpholine as the starting material. mp 298° C.; CIMS m/e calc'd for C23H23N4O3S: 435.1491, found: 435.1477.

Example XXXIII

Preparation of 3-(4-methoxyphenyl)-5-(morpholinylacetamido)indeno[1,2-c]pyrazol-4-one

[0189] Prepared in a similar fashion as described for example XXIII using morpholine as the starting material. mp 295° C.; CIMS m/e calc'd for C23H23N4O4: 419.1719, found: 419.1744.

Example XXXIV

Preparation of 3-(4-methoxyphenyl)-5-(pyrrolidinylacetamido)indeno[1,2-c]pyrazol-4-one

[0190] Prepared in a similar fashion as described for example XXIII using pyyrolidine as the starting material. mp 279° C.; CIMS m/e calc'd for C23H23N4O3: 403.1770, found: 403.1761.

Example XXXV

Preparation of 3-(4-methoxyphenyl)-5-(4-pyridinylaminomethylacetamido)indeno[1,2-c]pyrazol-4-one

[0191] Prepared in a similar fashion as described for example XXIII using 4-aminomethylpyridine as the starting material. mp>300° C.; CIMS m/e calc'd for C25H22N5O3: 440.1723, found: 440.1762.

Example XXXVI

Preparation of 3-(4-methoxyphenyl)-5-((4-acetamidophenyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0192]

[0193] A suspension of 18 (10 mg, 0.02 mmol) in dioxane (1 mL) was treated with aqueous sat. NaHCO3 (0.5 mL) and acetyl chloride (0.01 mL) and heated at 50° C. for 1 h. The reaction was cooled, poured into water (5 mL), extracted with EtOAc (10 mL), the organic layer separated, dried (MgSO4) and the solvent removed at reduced pressure. The residue was recrystallized from EtOH to give the product as a yellow solid (5.6 mg, 61%). mp 268° C.; CIMS m/e calc'd for C27H23N4O4: 467.1719, Found: 467.1730.

Example XXXVII

Preparation of 3-(4-methoxyphenyl)-5-((4-methoxycarbonylaminophenyl)acetamido) indeno[1,2-c]pyrazol-4-one

[0194] Prepared in a similar fashion as described for example XXXII using methylchloroformate as the starting material. mp 257° C.; CIMS m/e calc'd for C27H23N4O5: 483.1668, found: 483.1633.

Example XXXVIII

Preparation of 3-(4-methoxyphenyl)-5-((4-aminomethylcarbonylaminophenyl)acetamido) indeno[1,2-c]pyrazol-4-one

[0195] Prepared in a similar fashion as described for example XXIII and XXXII using chloroacetyl chloride and conc. NH4OH as the starting materias. mp 228° C.; CIMS m/e calc'd for C27H24N5O4: 482.1828, found: 482.1844.

Example XXXIX

Preparation of 3-(4-methoxyphenyl)-5-((4-N,N-dimethylaminomethylcarbonylaminophenyl)acetamido) indeno[1,2-c]pyrazol-4-one

[0196] Prepared in a similar fashion as described for example XXIII and XXXII using chloroacetyl chloride and dimethyl amine as the starting materias. mp>300° C.; CIMS m/e calc'd for C29H28N5O4: 510.2141, found: 510.2121.

Example XL

Preparation of 3-(4-methoxyphenyl)-5-((4-azidophenyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0197] A solution of example XXXVI (20 mg, 0.04 mmol) in DMF (2 mL) was treated with 5% palladium on carbon (5 mg) and hydrogentaed at atmospheric pressure using a hydrogen baloon. After 2 h, the solution was filtered (Celite), and the solvent removed at reduced pressure. The residue was recrystallized from EtOH to give the product as a yellow solid (15 mg, 78%). mp>300° C.; CIMS m/e calc'd for C25H19N6O3: 451.1519, found: 451.1544.

Example XLI

Preparation of 3-(4-methoxyphenyl)-5-((4-aminophenyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0198] Prepared in a similar fashion as described for example XXVII using the acid chloride of 4-azidophenylacetic acid as the starting material. mp 283° C.; CIMS m/e calc'd for C25H21N4O3: 425.1614, found: 425.1643.

Example XLII

Preparation of 3-(4-methoxyphenyl)-5-(phenylcarbamoyl)aminoindeno [1,2-c]pyrazol-4-one

[0199]

[0200] Step 1. Synthesis of 20 from 15.

[0201] A suspension of 15 (0.5 g, 1.7 mmol) in acetone (10 mL) was treated with NaHCO3 (0.5 g) and phenyl chloroformate. The mixture was heated to 50° C. for 2 h. The reaction was cooled, poured into water (20 mL), extracted with EtOAc (40 mL), the organic layer separated, dried (MgSO4) and the solvent removed at reduced pressure. The residue was suspended in EtOH (10 mL) and treated with hydrazine hydrate (0.16 mL, 5.1 mmol) and p-TsOH (10 mg). The mixture was heated to reflux and stirred for 3 h. The reaction was cooled to 0° C. and the product collected as a yellow solid (0.25 g, 36%). mp 195° C.; CIMS m/e calc'd for C24H18N3O4: 412.1297, Found: 412.1308.

[0202] Step 2. Synthesis of 21 from 20.

[0203] A solution of 20 (20 mg, 0.05 mmol) in DMSO (2 mL) was treated with aniline (20 mL, mmol) and dimethylaminopyridine (1 mg). The mixture was heated to 80° C. for 2 h. The reaction was cooled, poured into water (4 mL), extracted with EtOAc (15 mL), the organic layer separated, dried (MgSO4) and the solvent removed at reduced pressure. The residue was recrystallized from EtOH to give the product as a yellow solid (9 mg, 44%). mp>300° C.; CIMS m/e calc'd for C24H19N4O3: 411.1457, Found: 411.1432.

Example XLIII

Preparation of 3-(4-methoxyphenyl)-5-(butylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0204] Prepared in a similar fashion as described for example XLII using butyl amine as the starting material. mp 252° C.; CIMS m/e calc'd for C21H21N4O3: 377.1614, found: 377.1633.

Example XLIV

Preparation of 3-(4-methoxyphenyl)-5-(4-aminobenzylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0205] Prepared in a similar fashion as described for example XLII using 4-aminobenzyl amine as the starting material. mp>300° C.; CIMS m/e calc'd for C25H22N5O3: 440.1723, found: 440.1700.

Example XLV

Preparation of 3-(4-methoxyphenyl)-5-(4-pyridylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0206] Prepared in a similar fashion as described for example XLII using 4-aminomethylpyridine as the starting material. mp>300° C.; CIMS m/e calc'd for C24H20N5O3: 426.1566, found: 426.1533.

Example XLVI

Preparation of 3-(4-hydroxyphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one

[0207]

[0208] A suspension of 12 (20 mg, 0.07 mmol) in CH2Cl2 (2 mL) was treated with excess BBr3 (1.0 mL, 1.0 M in CH2Cl2) and stirred for 20 h. The reaction was slowly poured into aqueous sat. NaHCO3 (5 mL), extracted with EtOAc (10 mL), dried (MgSO4) and concentrated. The residue was recrystallized from EtOH to give the desired product as a yellow solid (7.5 mg, 33%). mp>300° C.; CIMS m/e calc'd for C18H14N3O3: 320.1035, Found: 320.1050.

Example XLVII

Preparation of 3-(4-methoxyphenyl)-5-(formamido)indeno[1,2-c]pyrazol-4-one

[0209]

[0210] A suspension of 13 (20 mg, 0.06 mmol) in formic acid (2 mL) was heated to 100° C. for 2 h. The reaction mixture was cooled and the solvent removed at reduced pressure. The residue was recrystallized from EtOH to give the desired product as a yellow solid (12 mg, 63%). mp 280° C.; CIMS m/e calc'd for C18H14N3O3: 320.1035, Found: 320.1040.

Example XLVIII

Preparation of 3-(3-pyridyl)-5-(acetamido)indeno [1,2-c]pyrazol-4-one

[0211]

[0212] Step 1. Synthesis of 24 from 3-acetylpyridine.

[0213] A solution of 3-acetylpyridine (1.0 g, 8.3 mmol) in benzene (3 mL) was treated with 1,1-dimethylhydrazine (0.62 mL, 8.3 mmol) and p-TsOH (5 mg). The mixture was heated to 85° C. and stirred for 3 h. The reaction was cooled and the solvent removed at reduced pressure. This crude hydrazone was treated with 1.0 M NaN(TMS)2 in THF (16.6 mL, 16.6 mmol) at 25° C. over 5 min. After 30 min dimethyl 3-acetamidophthalate (2.1 g, 8.3 mmol) was added in one portion and the reaction heated to reflux. Stirring was continued for 6 h. The reaction was cooled and quenched by the slow addition of TFA. The solvent was removed at reduced pressure and the residue chromatographed (silica, 2.5-5% MeOH/CH2Cl2) to give the product as a yellow solid (0.35 g, 14%). mp 265° C.; CIMS m/e calc'd for C17H13N2O4: 309.0875, Found: 309.0888.

[0214] Step 2. Synthesis of 25 from 24.

[0215] A suspension of 24 (30 mg, 0.09 mmol) in EtOH (2 mL) was treated with hydrazine hydrate (0.05 mL) and p-TsOH (1 mg) and heated to reflux. After stirring for 2 h. the reaction was cooled and the product filtered to give a yellow solid (12 mg, 44%). mp>300° C.; CIMS m/e calc'd for C17H13N4O2: 305.1039, Found: 305.1048.

Example XLIX

Preparation of 3-(4-pyridyl)-5-(acetamido)indeno [1,2-c]pyrazol-4-one

[0216] Prepared in a similar fashion as described for example XLVIII using 4-acetylpyridine as the starting material. mp>300° C.; CIMS m/e calc'd for C17H13N4O2: 305.1039, found: 305.1046.

Example L

Preparation of 3-(4-pyridyl)-5-(formamido)indeno [1,2-c]pyrazol-4-one

[0217] Prepared in a similar fashion as described for example XLVII using 4-acetylpyridine as the starting material. mp>300° C.; CIMS m/e calc'd for C16H11N4O2: 291.0882, found: 291.0882.

Example LI

Preparation of 3-phenyl-5-(acetamido)indeno [1,2-c]pyrazol-4-one

[0218] Prepared in a similar fashion as described for example I using acetophenone as the starting material. mp>300° C.; CIMS m/e calc'd for C18H13N3O2: 304.1065, found: 304.1086.

Example LII

Preparation of 3-(4-methylthiophenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one

[0219] Prepared in a similar fashion as described for example I using 4′-methylthioacetophenone as the starting material. mp 283° C.; CIMS m/e calc'd for C19H15N3O2S: 350.0956, found: 350.0963.

Example LIII

Preparation of 3-(4-methylsulphonylphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one

[0220] Prepared by oxidation of the product of example LII. mp>300° C.; CIMS m/e calc'd for C19H15N3O4S: 382.0860, found: 382.0862.

Example LIV

Preparation of 3-(4-N,N-dimethylaminophenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one

[0221] Prepared in a similar fashion as described for example I using 4′-N,N,-dimethylaminoacetophenone as the starting material. mp>300° C.; CIMS m/e calc'd for C20H18N4O2: 347.1496, found: 347.1508.

Example LV

Preparation of 3-(4-N,N-dimethylaminophenyl)-5-(morpholinylacetamido)indeno[1,2-c]pyrazol-4-one

[0222] Prepared in a similar fashion as described for examples II and XXIII employing the product of example LIV and morpholine as the starting materials. mp>300° C.; CIMS m/e calc'd for C24H26N5O3: 432.2036, found: 432.2020.

Example LVI

Preparation of 3-(4-N,N-dimethylaminophenyl)-5-(dimethylaminoacetamido)indeno[1,2-c]pyrazol-4-one

[0223] Prepared in a similar fashion as described for examples II and XXIII employing the product of example LIV and dimethylamine as the starting materials. mp>300° C.; CIMS m/e calc'd for C22H24N5O2: 390.1930, found: 390.1948.

Example LVII

Preparation of 3-(4-(1-piperidinyl)phenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one

[0224] Prepared in a similar fashion as described for example I using 4′-(1-piperidinyl)acetophenone as the starting material. mp 291° C.; CIMS m/e calc'd for C23H22N4O2: 387.1801, found: 387.1821.

Example LVIII

Preparation of 3-(4-morpholinyl)phenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one

[0225] Prepared in a similar fashion as described for example I using 4′-morpholinylacetophenone as the starting material. mp>300° C.; CIMS m/e calc'd for C22H20N4O3: 388.1528, found: 388.1535.

Example LIX

Preparation of 3-(4-ethoxyphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one

[0226] Prepared in a similar fashion as described for example I using 4′-ethoxyacetophenone as the starting material. mp 288° C.; CIMS m/e calc'd for C20H17N3O3: 348.1325, found: 348.1348.

Example LX

Preparation of 3-(4-butylphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one

[0227] Prepared in a similar fashion as described for example I using 4′-butylacetophenone as the starting material. mp 259° C.; CIMS m/e calc'd for C22H21N3O2: 360.1701, found: 360.1712.

Example LXI

Preparation of 3-(4-ethylphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one

[0228] Prepared in a similar fashion as described for example I using 4′-ethylacetophenone as the starting material. mp 294° C.; CIMS m/e calc'd for C21H17N3O2: 331.1310, found: 331.1321.

Example LXII

Preparation of 3-(4-n-propylphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one

[0229] Prepared in a similar fashion as described for example I using 4′-n-propylacetophenone as the starting material. mp 269° C.; CIMS m/e calc'd for C21H19N3O2: 346.1555, found: 346.1554.

Example LXIII

Preparation of 3-(4-methoxyphenyl)-5-carbamoylaminoindeno[1,2-c]pyrazol-4-one

[0230] Prepared in a similar fashion as described for example XLII using concentrated ammonium hydroxide as the starting material. mp>300° C.; CIMS m/e calc'd for C18H15N4O3: 335.1144, found: 335.1113.

Example LXIV

Preparation of 3-(4-methoxyphenyl)-5-(dimethylaminocarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0231] Prepared in a similar fashion as described for example XLII using dimethylamino hydrazine as the starting material. mp>300° C.; CIMS m/e calc'd for C20H20N5O3: 378.1566, found: 378.1555.

Example LXV

Preparation of 3-(4-methoxyphenyl)-5-(methylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0232] Prepared in a similar fashion as described for example XLII using methylamine as the starting material. mp>300° C.; CIMS m/e calc'd for C19H17N4O3: 349.1300, found: 349.1311.

Example LXVI

Preparation of 3-(4-methoxyphenyl)-5-(morpholinocarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0233] Prepared in a similar fashion as described for example XLII using N-aminomorpholine as the starting material. mp>300° C.; CIMS m/e calc'd for C22H22N5O4: 420.1671, found: 420.1655.

Example LXVII

Preparation of 3-(4-methoxyphenyl)-5-(cis-2-aminocyclohexanylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0234] Prepared in a similar fashion as described for example XLII using cis-1,2-diaminocyclohexane as the starting material. mp>300° C.; CIMS m/e calc'd for C24H26N5O3: 432.2035, found: 432.2020.

Example LXVIII

Preparation of 3-(4-methoxyphenyl)-5-(4-methylpiperazinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0235] Prepared in a similar fashion as described for example XLII using (4-amino)methylpiperazine as the starting material. mp>300° C.; CIMS m/e calc'd for C23H25N6O3: 433.1987, found: 433.1999.

Example LXIX

Preparation of 3-(4-methoxyphenyl)-5-(4-uridomethylpiperadinylacetamido)indeno[1,2-c]pyrazol-4-one

[0236] Prepared in a similar fashion as described for example XXIII using example XXX as the starting material. mp>300° C.; CIMS m/e calc'd for C26H29N6O4: 489.2250, found: 489.2209.

Example LXX

Preparation of 3-(4-methoxyphenyl)-5-(4-(2-pyridyl)piperazinylacetamido)indeno[1,2-c]pyrazol-4-one

[0237] Prepared in a similar fashion as described for example XXIII using 4-(2-pyridyl)piperazine as the starting material. mp>300° C.; CIMS m/e calc'd for C28H27N6O3: 495.2144, found: 495.2111.

Example LXXI

Preparation of 3-(4-methoxyphenyl)-5-(4-(aminoethyl)piperazinylacetamido)indeno[1,2-c]pyrazol-4-one

[0238] Prepared in a similar fashion as described for example XXIII using 4-(aminoethyl)piperazine as the starting material. mp>300° C.; CIMS m/e calc'd for C25H29N6O3: 461.2300, found: 461.2333.

Example LXXII

Preparation of 3-(4-methoxyphenyl)-5-(4-amidopiperadinylacetamido)indeno[1,2-c]pyrazol-4-one

[0239] Prepared in a similar fashion as described for example XXIII using isonipecotamide as the starting material. mp>300° C.; CIMS m/e calc'd for C25H26N5O4: 460.1984, found: 460.1998.

Example LXXIII

Preparation of 3-(4-methoxyphenyl)-5-(4-hydroxypiperadinylacetamido)indeno[1,2-c]pyrazol-4-one

[0240] Prepared in a similar fashion as described for example XXIII using 4-hydroxypiperadine as the starting material. mp>300° C.; CIMS m/e calc'd for C24H25N4O4: 433.1875, found: 433.1844.

Example LXXIV

Preparation of 3-(4-methoxyphenyl)-5-(4-hydroxmethylypiperadinylacetamido)indeno[1,2-c]pyrazol-4-one

[0241] Prepared in a similar fashion as described for example XXIII using 4-hydroxmethylypiperadine as the starting material. mp>300° C.; CIMS m/e calc'd for C25H27N4O4: 447.2032, found: 447.2002.

Example LXXV

Preparation of 3-(4-methoxyphenyl)-5-(4-amidopiperazinylacetamido)indeno[1,2-c]pyrazol-4-one

[0242] Prepared in a similar fashion as described for example XXIII using 4-amidopiperazine as the starting material. mp>300° C.; CIMS m/e calc'd for C24H25N6O6: 493.1835, found: 493.1802.

Example LXXVI

Preparation of 3-(4-methoxyphenyl)-5-(4-dimethylaminopiperadinylacetamido)indeno[1,2-c]pyrazol-4-one

[0243] Prepared in a similar fashion as described for example XXIII using 4-dimethylaminopiperadine as the starting material. mp>300° C.; CIMS m/e calc'd for C26H30N5O5: 492.2246, found: 492.2220.

Example LXXVII

Preparation of 3-(4-methoxyphenyl)-5-(4-aminopiperadinylacetamido)indeno[1,2-c]pyrazol-4-one

[0244] Prepared in a similar fashion as described for example XXIII using 4-aminopiperadine as the starting material. mp>300° C.; CIMS m/e calc'd for C24H26N5O5: 464.1933, found: 464.1975.

Example LXXVIII

Preparation of 3-(4-(dimethylamino)phenyl)-5-((4-methyl-1-piperazinyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0245] Prepared in a similar fashion as described for examples II and XXIII employing the product of example LIV and 1-methylpiperazine as the starting materials. mp>300° C.; ESI-MS m/e calc'd for C25H29N6O2: 445.2352, found: 445.2359.

Example LXXIX

Preparation of 3-(4-(dimethylamino)phenyl)-5-((4-amino methyl-1-piperidinyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0246] Prepared in a similar fashion as described for examples II and XXIII employing the product of example LIV and 4-(aminomethyl)piperidine as the starting materials. ESI-MS m/e calc'd for C26H31N6O2: 459.2508, found: 459.2508.

Example LXXX

Preparation of 3-(4-(dimethylamino)phenyl)-5-((4-hydroxy-1-piperidinyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0247] Prepared in a similar fashion as described for examples II and XXIII employing the product of example LIV and 4-hydroxypiperidine as the starting materials. mp 267° C.; ESI-MS m/e calc'd for C25H28N5O3: 446.2192, found: 446.2206.

Example LXXXI

Preparation of 3-(4-(4-morpholinyl)phenyl)-5-(4-morpholinyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0248] Prepared in a similar fashion as described for examples II and XXIII employing the product of example LVIII and morpholine as the starting materials. mp 258° C.; ESI-MS m/e calc'd for C26H28N5O4: 474.2141, found: 474.2151.

Example LXXXII

Preparation of 3-(4-(4-morpholinyl)phenyl)-5-((4-methyl-1-piperazinyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0249] Prepared in a similar fashion as described for examples II and XXIII employing the product of example LVIII and 1-methylpiperazine as the starting materials. mp 258° C.; ESI-MS m/e calc'd for C27H31N6O3: 487.2457, found: 487.2447.

Example LXXXIII

Preparation of 3-(4-(4-morpholinyl)phenyl)-5-((4-hydroxy-1-piperidinyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0250] Prepared in a similar fashion as described for examples II and XXIII employing the product of example LVIII and 4-hydroxypiperidine as the starting materials. mp 245° C.; ESI-MS m/e calc'd for C27H30NSO4: 488.2298, found: 488.2290.

Example LXXXIV

Preparation of 3-(4-(4-morpholinyl)phenyl)-5-((4-amino methyl-1-piperidinyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0251] Prepared in a similar fashion as described for examples II and XXIII employing the product of example LVIII and 4-(aminomethyl)piperidine as the starting materials. mp 240° C.; ESI-MS m/e calc'd for C28H33N6O3: 501.2614, found: 501.2619.

Example LXXXV

Preparation of 3-(4-(dimethylamino)phenyl)-5-((((4-methyl-1-piperazinyl)amino)carbonyl)amino)indeno[1,2-c]pyrazol-4-one

[0252] Prepared in a similar fashion as described for examples I, XXVII, and XLII employing the 4-(dimethylamino) acetophenone and l-amino-4-methylpiperazine as the starting materials. mp>300° C.; ESI-MS m/e calc'd for C24H28N7O2: 446.2304, found: 446.2310.

Example LXXXVI

Preparation of 3-(i-propyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one

[0253]

[0254] Step 1. Synthesis of 26 from 3-nitrophthalic Anhydride.

[0255] A solution of 3-nitrophthalic anhydride (9.7 g, 50 mmol) and 1,1,1-trifluoro-5-methyl-2,4-hexanedione (9.1 g, 50 mmol) in acetic anhydride (28.3 mL, 300 mmol) was treated with triethylamine (13.95 mL, 100 mmol) and stirred at 25° C. for 4 h. The solution was diluted with 1 N HCl (200 mL) and the precipate collected and washed with water (200 mL) and hexane (400 mL) to give the product as a yellow solid (11.1 g, 85%). mp 127-129° C.; CIMS (M+H) calc'd for C13H12NO5: 262.0715, found: 262.0694.

[0256] Step 2. Synthesis of Triketone 27 from 26.

[0257] A solution of 26 (11 g, 42 mmol) in EtOH (224 mL) and water (56 mL) was treated with zinc (90 g, 1.4 mol) and calcium chloride (3 g, 27 mmol) and heated to reflux for 16 h. The reaction was filtered (Celite) and the filtrate was concentrated at reduced pressure to give an aqueous residue which was extracted with EtOAc (100 mL). The organic layer was separated and washed with sat. EDTA (100 ml) and brine (100 mL), dried (MgSO4), filtered, and concentrated at reduced pressure to give a yellow solid. Trituration with hexane gave the product as a yellow solid (7.1 g, 73%). mp 241-243° C.; CIMS (M+H) calc'd for C13H14NO3: 232.0974, found: 232.0962.

[0258] Step 3. Synthesis of 28 from 27.

[0259] A solution of 27 (500 mg, 2.16 mmol) in CH2Cl2 (5 mL) was treated with Et3N (0.36 mL, 2.59 mmol) and stirred at 25° C. for 15 min. The reaction mixture was treated with acetyl chloride (0.18 mL, 2.38 mmol) and stirred at 25° C. for 1 h. The reaction mixture was quenched with 1 N HCl (20 mL) and extracted with EtOAc (20 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated at reduced pressure to give a brown residue. Trituration with hexane gave the product as a tan solid (484 mg, 82%). mp 241-243° C.; CIMS (M+H) calc'd for C15H16NO4: 274.1079, found: 274.1093.

[0260] Step 4. Synthesis of 29 from 28.

[0261] A solution of 28 (240 mg, 0.88 mmol) in BuOH (5 mL) was treated with hydrazine hydrate (0.055 mL, 1.76 mmol) and p-TsOH (8.4 mg, 0.044 mmol). The reaction was heated to reflux and stirred for 4 h. The reaction was cooled to 25° C. and the solvent removed at reduced pressure. Recrystalization with i-propyl alcohol gave the product collected as an off-white solid (173 mg, 73%). mp>250° C.; ESIMS (M+H) calc'd for C15H16N3O2: 270.1242, found: 270.1258.

Example LXXXVII

Preparation of 3-(c-propyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one

[0262] Prepared in a similar fashion as described for example LXXXVI using the c-propyl analog of 26 as the starting material. mp 220-221° C.; CIMS (M+H) calc'd for C15H14N3O2: 268.1086, found: 268.1078.

Example LXXXVIII

Preparation of 3-(t-butyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one

[0263] Prepared in a similar fashion as described for example LXXXVI using the t-butyl analog of 26 as the starting material. mp>250° C.; CIMS (M+H) calc'd for C16H18N3O2: 284.1399, found: 284.1395.

Example LXXXIX

Preparation of 3-(2-thienyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one

[0264] Prepared in a similar fashion as described for example LXXXVI using the 2-thienyl analog of 26 as the starting material. mp 269° C.; CIMS (M+H) calc'd for C16H12N3O2S: 310.0650, found: 310.0635.

Example XC

Preparation of 3-(3-methyl-2-thienyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one

[0265] Prepared in a similar fashion as described for example LXXXVI using the 3-methyl-2-thienyl analog of 26 as the starting material. mp 275° C.; ESIMS (M+H) calc'd for C17H14N3O2S: 324.0811, found: 324.0807.

Example XCI

Preparation of 3-(ethyl)-5-(carbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0266] Prepared in a similar fashion as described for example LXXXVI using ammonia and the ethyl analog of 15 as the starting materials. mp>250° C.; CIMS (M+H) calc'd for C13H13N4O2: 257.1039, found: 257.1033.

Example XCII

Preparation of 3-(n-propyl)-5-(carbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0267] Prepared in a similar fashion as described for example LXXXVI using ammonia and the n-propyl analog of 15 as the starting materials. mp 187-189° C.; CIMS (M+H) calc'd for C14H15N4O2: 271.1195, found: 271.1187.

Example XCIII

Preparation of 3-(i-propyl)-5-(carbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0268] Prepared in a similar fashion as described for example LXXXVI using ammonia and the i-propyl analog of 15 as the starting materials. mp>250° C.; CIMS (M+H) calc'd for C14H15N4O2: 271.1195, found: 271.1196.

Example XCIV

Preparation of 3-(c-propyl)-5-(carbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0269] Prepared in a similar fashion as described for example LXXXVI using ammonia and the c-propyl analog of 15 as the starting materials. mp 252-253° C.; ESIMS (M−H) calc'd for C14H11N4O2: 267.0881, found: 267.0884.

Example XCV

Preparation of 3-(c-hexyl)-5-(carbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0270] Prepared in a similar fashion as described for example LXXXVI using ammonia and the c-hexyl analog of 15 as the starting materials. mp 178-179° C.; ESIMS (M+H) calc'd for C17H19N4O2: 311.1507, found: 311.1500.

Example XCVI

Preparation of 3-(2-thienyl)-5-(carbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0271] Prepared in a similar fashion as described for example LXXXVI using ammonia and the 2-thienyl analog of 15 as the starting materials. mp 214° C.; CIMS m+calc'd for C15H10N4O2S: 310.0517, found: 310.0524.

Example XCVII

Preparation of 3-(3-methyl-2-thienyl)-5-(carbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0272] Prepared in a similar fashion as described for example LXXXVI using ammonia and the 3-methyl-2-thienyl analog of 15 as the starting materials. mp 270° C.; ESIMS (M+H) calc'd for C16H13N4O2S: 325.0759, found: 325.0744.

Example XCVIII

Preparation of 3-(5-methyl-2-thienyl)-5-(carbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0273] Prepared in a similar fashion as described for example LXXXVI using ammonia and the 5-methyl-2-thienyl analog of 15 as the starting materials. mp>280° C.; ESIMS (M+H) calc'd for C16H13N4O2S: 325.0759, found: 325.0761.

Example XCIX

Preparation of 3-(5-ethylcarboxyl-2-thienyl)-5-(carbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0274] Prepared in a similar fashion as described for example LXXXVI using ammonia and the 5-ethylcarboxyl-2-thienyl analog of 15 as the starting materials. mp>280° C.; ESIMS (M+H) calc'd for C18H15N4O4S: 383.0813, found: 383.0788.

Example C

Preparation of 3-(3-thienyl)-5-(carbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0275] Prepared in a similar fashion as described for example LXXXVI using ammonia and the 3-thienyl analog of 15 as the starting materials. mp>280° C.; ESIMS (M+H) calc'd for C15H11N4O2S: 311.0603, found: 311.0594.

Example CI

Preparation of 3-(5-chloro-3-thienyl)-5-(carbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0276] Prepared in a similar fashion as described for example LXXXVI using ammonia and the 5-chloro-3-thienyl analog of 15 as the starting materials. mp>300° C.; ESIMS (M+H) calc'd for C15H10N4O2SCl: 345.0209, found: 345.0213.

Example CII

Preparation of 3-(2,5-dimethyl-3-thienyl)-5-(carbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0277] Prepared in a similar fashion as described for example LXXXVI using ammonia and the 2,5-dimethyl-3-thienyl analog of 15 as the starting materials. mp>280° C.; ESIMS (M+H) calc'd for C17H15N4O2S: 339.0916, found: 339.0905.

Example CIII

Preparation of 3-(2-furanyl)-5-(carbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0278] Prepared in a similar fashion as described for example LXXXVI using ammonia and the 2-furanyl analog of 15 as the starting materials. mp 278° C.; ESIMS (M+H) calc'd for C15H11N4O3: 295.0831, found: 295.0838.

Example CIV

Preparation of 3-(i-propyl)-5-(N,N-dimethylaminocarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0279] Prepared in a similar fashion as described for example LXXXVI using 1,1-dimethylhydrazine and the i-propyl analog of 15 as the starting materials. mp 231-233° C.; ESIMS (M+H) calc'd for C16H20N5O2: 314.1616, found: 314.1599.

Example CV

Preparation of 3-(c-propyl)-5-(N,N-dimethylaminocarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0280] Prepared in a similar fashion as described for example LXXXVI using 1,1-dimethylhydrazine and the c-propyl analog of 15 as the starting materials. mp XXX ° C.; ESIMS (M+H) calc'd for C16H18N5O2: 312.1460, found: 312.1487.

Example CVI

Preparation of 3-(c-hexyl)-5-(N,N-dimethylaminocarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0281] Prepared in a similar fashion as described for example LXXXVI using 1,1-dimethylhydrazine and the c-hexyl analog of 15 as the starting materials. mp 229-231° C.; ESIMS (M+H) calc'd for C19H24N5O2: 354.1929, found: 354.1932.

Example CVII

Preparation of 3-(2-thienyl)-5-(N,N-dimethylaminocarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0282] Prepared in a similar fashion as described for example LXXXVI using 1,1-dimethylhydrazine and the 2-thienyl analog of 15 as the starting materials. mp 279° C.; ESIMS (M+H) calc'd for C17H16N5O2S: 354.1024, found: 354.1025.

Example CVIII

Preparation of 3-(5-methoxy-2-thienyl)-5-(N,N-dimethylaminocarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0283] Prepared in a similar fashion as described for example LXXXVI using 1,1-dimethylhydrazine and the 5-methoxy-2-thienyl analog of 15 as the starting materials. mp 280° C.; ESIMS (M+H) calc'd for C18H18N5O3S: 384.1130, found: 384.1119.

Example CIX

Preparation of 3-(5-methyl-2-thienyl)-5-(N,N-dimethylaminocarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0284] Prepared in a similar fashion as described for example LXXXVI using 1,1-dimethylhydrazine and the 5-methyl-2-thienyl analog of 15 as the starting materials. mp>280° C.; ESIMS (M+H) calc'd for C18H18N5O2S: 368.1181, found: 368.1171.

Example CX

Preparation of 3-(5-ethylcarboxyl-2-thienyl)-5-(N,N-dimethylaminocarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0285] Prepared in a similar fashion as described for example LXXXVI using 1,1-dimethylhydrazine and the 5-ethylcarboxyl-2-thienyl analog of 15 as the starting materials. mp 252° C.; ESIMS (M+H) calc'd for C20H20N5O4S: 426.1236, found: 426.1251.

Example CXI

Preparation of 3-(3-thienyl)-5-(N,N-dimethylaminocarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0286] Prepared in a similar fashion as described for example LXXXVI using 1,1-dimethylhydrazine and the 3-thienyl analog of 15 as the starting materials. mp 202° C.; ESIMS (M+H) calc'd for C17H16N5O2S: 354.1025, found: 354.1031.

Example CXII

Preparation of 3-(1-methyl-3-pyrrolyl)-5-(carbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0287] Prepared in a similar fashion as described for example LXXXVI using ammonia and the 1-methyl-3-pyrrolyl analog of 15 as the starting materials. mp>300° C.; ESIMS (M+H) calc'd for C16H14N5O2: 308.1147, found: 308.1166.

Example CXIII

Preparation of 3-(2,5-dimethyl-3-thienyl)-5-(N,N-dimethylaminocarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0288] Prepared in a similar fashion as described for example LXXXVI using 1,1-dimethylhydrazine and the 2,5-dimethyl-3-thienyl analog of 15 as the starting materials. mp 252° C.; ESIMS (M+H) calc'd for C19H20NSO2S: 382.1338, found: 382.1357.

Example CXIV

Preparation of 3-(2-furanyl)-5-(N,N-dimethylaminocarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0289] Prepared in a similar fashion as described for example LXXXVI using 1,1-dimethylhydrazine and the 2-furanyl analog of 15 as the starting materials. mp 202° C.; ESIMS (M+H) calc'd for C17H16N5O3: 338.1253, found: 338.1248.

Example CXV

Preparation of 3-(i-propyl)-5-(4-carbamoylpiperidinylacetamido)indeno[1,2-c]pyrazol-4-one

[0290] Prepared in a similar fashion as described for example XXIII using isonipecotamide and the i-propyl analog of 14 as the starting materials. mp 224-225° C.; ESIMS (M+H) calc'd for C21H26N5O3: 396.2035, found: 396.2036.

Example CXVI

Preparation of 3-(c-hexyl)-5-(4-carbamoylpiperidinylacetamido)indeno[1,2-c]pyrazol-4-one

[0291] Prepared in a similar fashion as described for example XXIII using isonipecotamide and the c-hexyl analog of 14 as the starting materials. mp 228-229° C.; ESIMS (M+H) calc'd for C24H30N5O3: 436.2348, found: 436.2345.

Example CXVII

Preparation of 3-(ethyl)-5-(4-aminomethylpiperidinylacetamido)indeno[1,2-c]pyrazol-4-one

[0292] Prepared in a similar fashion as described for example XXIII using 4-(aminomethyl)piperidine and the ethyl analog of 14 as the starting materials. mp 174-176° C.; ESIMS (M+H) calc'd for C20H26N5O2: 368.2086, found: 368.2078.

Example CXVIII

Preparation of 3-(i-propyl)-5-(4-aminomethylpiperidinylacetamido)indeno[1,2-c]pyrazol-4-one

[0293] Prepared in a similar fashion as described for example XXIII using 4-(aminomethyl)piperidine and the i-propyl analog of 14 as the starting materials. mp 218-220° C.; ESIMS (M+H) calc'd for C21H28N5O2: 382.2242, found: 382.2227.

Example CXIX

Preparation of 3-(c-propyl)-5-(4-aminomethylpiperidinylacetamido)indeno[1,2-c]pyrazol-4-one

[0294] Prepared in a similar fashion as described for example XXIII using 4-(aminomethyl)piperidine and the c-propyl analog of 14 as the starting materials. mp 138-140° C.; ESIMS (M+H) calc'd for C21H26N5O2: 380.2086, found: 380.2079.

Example CXX

Preparation of 3-(c-hexyl)-5-(4-aminomethylpiperidinylacetamido)indeno[1,2-c]pyrazol-4-one

[0295] Prepared in a similar fashion as described for example XXIII using 4-(aminomethyl)piperidine and the c-hexyl analog of 14 as the starting materials. mp 196-198° C.; ESIMS (M+H) calc'd for C24H32N5O2: 422.2555, found: 422.2540.

Example CXXI

Preparation of 3-(i-propyl)-5-(4-methylpiperazinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0296] Prepared in a similar fashion as described for example LXXXVI using 1-amino-4-methylpiperazine and the i-propyl analog of 15 as the starting materials. mp 231-233° C.; ESIMS (M+H) calc'd for C19H25N6O2: 369.2038, found: 369.2039.

Example CXXII

Preparation of 3-(5-ethylcarboxyl-2-thienyl)-5-(4-methylpiperazinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0297] Prepared in a similar fashion as described for example LXXXVI using 1-amino-4-methylpiperazine and the 5-ethylcarboxyl-2-thienyl analog of 15 as the starting materials. mp 249° C.; ESIMS (M+H) calc'd for C23H25N6O4S: 481.1657, found: 481.1642.

Example CXXIII

Preparation of 3-(5-carboxyl-2-thienyl)-5-(4-methylpiperazinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0298] A solution of CXXII (30 mg, 0.05 mmol) in 3:1 THF/water (2 mL) was treated with LiOH (23 mg, 0.5 mmol) and the reaction was stirred at 25° C. for 12 h and then heated to reflux for 1 h. The organic solvent was removed at reduced pressure and the residue was partioned between EtOAc (5 mL) and water (5 mL). The organic layer was separated and the aqueous phase was adjusted to pH=2 with 1 M HCl and re-extracted with EtOAc (5 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated at reduced pressure to give a crude residue. Purification by reverse phase HPLC gave the product as a yellow solid (10.4 mg, 46%). mp 270° C.; ESIMS (M+H) calc'd for C21H21N6O4S: 453.1344, found: 453.1353.

Example CXXIV

Preparation of 3-(2,5-dimethyl-3-thienyl)-5-(4-methylpiperazinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0299] Prepared in a similar fashion as described for example LXXXVI using 1-amino-4-methylpiperazine and the 2,5-dimethyl-3-thienyl analog of 15 as the starting materials. mp 250° C.; ESIMS (M+H) calc'd for C22H25N6O2S: 437.1760, found: 437.1771.

Example CXXV

Preparation of 3-(i-propyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0300] Prepared in a similar fashion as described for example LXXXVI using 4-aminomorpholine and the i-propyl analog of 15 as the starting materials. mp 256-258° C.; ESIMS (M−H) calc'd for C18H20N5O3: 354.1566, found: 354.1543.

Example CXXVI

Preparation of 3-(N-methylcarbamoyl-4-piperidinyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0301] Prepared in a similar fashion as described for example LXXXVI using 4-aminomorpholine and the N-methylcarbamoyl-4-piperidinyl analog of 15 as the starting materials. mp 216-218° C.; ESIMS (M+H) calc'd for C22H27N6O5: 455.2042, found: 455.2036.

Example CXXVII

Preparation of 3-(5-methyl-2-thienyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0302] Prepared in a similar fashion as described for example LXXXVI using 4-aminomorpholine and the 5-methyl-2-thienyl analog of 15 as the starting materials. mp 261° C.; ESIMS (M+H) calc'd for C20H20N5O3S: 410.1287, found: 410.1308.

Example CXXVIII

Preparation of 3-(5-chloro-3-thienyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0303] Prepared in a similar fashion as described for example LXXXVI using 4-aminomorpholine and the 5-chloro-3-thienyl analog of 15 as the starting materials. mp 259° C.; ESIMS (M+H) calc'd for C19H17N5O3SCl: 430.0741, found: 430.0757.

Example CXXIX

Preparation of 3-(2,5-dimethyl-3-thienyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0304] Prepared in a similar fashion as described for example LXXXVI using 4-aminomorpholine and the 2,5-dimethyl-3-thienyl analog of 15 as the starting materials. mp>280° C.; ESIMS (M+H) calc'd for C21H22N5O3S: 424.1443, found: 424.1431.

Example CXXX

Preparation of 3-(5-ethylcarboxyl-2-thienyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0305] Prepared in a similar fashion as described for example LXXXVI using 4-aminomorpholine and the 5-ethylcarboxyl-2-thienyl analog of 15 as the starting materials. mp 258° C.; ESIMS (M+H) calc'd for C22H22N5O5S: 468.1341, found: 468.1331.

Example CXXXI

Preparation of 3-(5-carboxyl-2-thienyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0306] Prepared in a similar fashion as described for example LXXXVI (HYDROLYSIS OF PREVIOUS ESTER). mp 273° C.; ESIMS (M+H) calc'd for C20H18N5O5S: 440.1028, found: 440.1026.

Example CXXXII

Preparation of 3-(5-benzylcarboxamido-2-thienyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0307] A solution of benzylamine (0.01 mL, 0.09 mmol) in DMF (1 mL) was treated with acid CXXXI (40 mg, 0.09 mmol) and stirred at 25° C. The reaction was treated with TBTU (29 mg, 0.09 mmol) and stirred at 25° C. for 30 min. Triethylamine (0.01 mL, 0.09 mmol) was added and the reaction stirred at 25° C. for 12 h. After adding more TBTU (15 mg, 0.045 mmol) and triethylamine (0.01 mL, 0.09 mmol) the reaction was stirred at 25° C. for an additional 4 h. The reaction was diluted with EtOAc (10 mL) and water (10 mL) and the aqueous layer was extracted with EtOAc (5×10 mL). The combined organic layers were dried (Na2SO4), filtered, and the solvent removed at reduced pressure. Purification of the residue using reverse phase HPLC gave the product as a yellow solid (21 mg, 42%). mp 275° C.; ESIMS (M+H) calc'd for C27H25N5O4S: 529.1659, found: 529.1682.

Example CXXXIII

Preparation of 3-(5-(4-methylpiperazinyl)carboxamido-2-thienyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0308] Prepared in a similar fashion as described for example CXXXII using 1-amino-4-methylpiperazine as the starting material. mp 190° C.; ESIMS (M+H) calc'd for C25H29N8O4S: 537.2032, found: 537.2055.

Example CXXXIV

Preparation of 3-(5-(2-(1-methylpyrrolidinyl)ethyl)carboxamido-2-thienyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0309] Prepared in a similar fashion as described for example CXXXII using 2-(2-aminoethyl)-1-methylpyrrolidine as the starting material. mp 235° C.; ESIMS (M+H) calc'd for C27H32N7O4S: 550.2236, found: 550.2229.

Example CXXXV

Preparation of 3-(5-(N,N-dimethylamino)carboxamido-2-thienyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0310] Prepared in a similar fashion as described for example CXXXII using 1,1-dimethylhydrazine as the starting material. mp 201° C.; ESIMS (M+H) calc'd for C22H24N7O4S: 482.1610, found: 482.1588.

Example CXXXVI

Preparation of 3-(5-(2-(N,N-dimethylamino)ethyl)carboxamido-2-thienyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0311] Prepared in a similar fashion as described for example CXXXII using N,N-dimethylethylenediamine as the starting material. mp 190° C.; ESIMS (M+H) calc'd for C24H28N7O4S: 510.1923, found: 510.1922.

Example CXXXVII

Preparation of 3-(5-(2-(pyrrolidinyl)ethyl)carboxamido-2-thienyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0312] Prepared in a similar fashion as described for example CXXXII using 1-(2-aminoethyl)pyrrolidine as the starting material. mp 224° C.; ESIMS (M+H) calc'd for C26H30N7O4S: 536.2080, found: 536.2091.

Example CXXXVIII

Preparation of 3-(5-(2-(morpholinyl)ethyl)carboxamido-2-thienyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0313] Prepared in a similar fashion as described for example CXXXII using 4-(2-aminoethyl)morpholine as the starting material. mp 241° C.; ESIMS (M+H) calc'd for C26H30N7O5S: 552.2029, found: 552.2043.

Example CXXXIX

Preparation of 3-(5-morpholinylcarboxamido-2-thienyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0314] Prepared in a similar fashion as described for example CXXXII using 4-aminomorpholine as the starting material. mp 271° C.; ESIMS (M+H) calc'd for C24H26N7O5S: 524.1716, found: 524.1719.

Example CXL

Preparation of 3-(5-(3-(pyrrolidonyl)propyl)carboxamido-2-thienyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0315] Prepared in a similar fashion as described for example CXXXII using 1-(3-aminopropyl)-2-pyrrolidinone as the starting material. mp 260° C.; ESIMS (M+H) calc'd for C27H30N7O5S: 564.2029, found: 564.2031.

Example CXLI

Preparation of 3-(5-(2-(3-pyridyl)ethyl)carboxamido-2-thienyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0316] Prepared in a similar fashion as described for example CXXXII using 3-(2-aminoethyl)pyridine as the starting material. mp 203° C.; ESIMS (M+H) calc'd for C27H26N7O4S: 544.1766, found: 544.1760.

Example CXLII

Preparation of 3-(5-(3-(imidazolyl)propyl)carboxamido-2-thienyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0317] Prepared in a similar fashion as described for example CXXXII using 1-(3-aminopropyl)imidazole as the starting material. mp 263° C.; ESIMS (M+H) calc'd for C26H27N8O4S: 547.1875, found: 547.1872.

Example CXLIII

Preparation of 3-(5-(2-(2-pyridyl)ethyl)carboxamido-2-thienyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0318] Prepared in a similar fashion as described for example CXXXII using 2-(2-aminoethyl)pyridine as the starting material. mp>280° C.; ESIMS (M+H) calc'd for C27H26N7O4S: 544.1767, found: 544.1778.

Example CXLIV

Preparation of 3-(5-((2-pyridyl)methyl)carboxamido-2-thienyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0319] Prepared in a similar fashion as described for example CXXXII using 2-(aminomethyl)pyridine as the starting material. mp 239° C.; ESIMS (M+H) calc'd for C26H24N7O4S: 530.1610, found: 530.1603.

Example CXLV

Preparation of 3-(5-(2-(piperidinyl)ethyl)carboxamido-2-thienyl)-5-(morpholinylcarbamoyl)aminoindeno[1,2-c]pyrazol-4-one

[0320] Prepared in a similar fashion as described for example CXXXII using 1-(2-aminoethyl)piperidine as the starting material. mp 228° C.; ESIMS (M+H) calc'd for C27H32N7O4S: 550.2236, found: 550.2236.

Example CXLVI

Preparation of 3-(4-(trifluoromethyl)phenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one

[0321] Prepared in a similar fashion as described for example LXXXVI employing 1-(4-(trifluoromethyl)phenyl)-4,4,4-trifluoro-1,3-butanedione as the starting material. mp>300° C.; ESI−-MS m/e calc'd for C19H11N3O2: 370.0804, found: 370.0809.

Example CXLVII

Preparation of 3-(4-(4-t-butoxycarbonyl-1-piperazinyl)phenyl)-5-(((4-morpholinylamino)carbonyl)amino)indeno[1,2-c]pyrazol-4-one

[0322]

[0323] Step 1. Synthesis of 30.

[0324] A solution of 4-piperazinoacetophenone (24.8 g, 121 mmol) and di-tert-butyl dicarbonate (27.8 g, 128 mmol) in 480 mL of tetrahydrofuran was refluxed for 16 h. After cooling to room temperature the solution was concentrated under vacuum. The resulting solids were washed with hexane and dried under vacuum to afford 29.4 g (80%) of the product as an off-white solid. NMR (CDCl3) δ 7.89 (d, 2H, J=9 Hz), 6.87 (d, 2H, J=9 Hz), 3.59 (m, 4H), 3.33 (m, 4H), 2.53 (s, 3H), 1.49 (s, 9H)

[0325] Step 2. Synthesis of 31 from 30.

[0326] To a solution of 30 (11.35 g, 37 mmol) and ethyl trifluoroacetate (5.40 mL, 45 mmol) in 50 mL of tetrahydrofuran at 25° C. was added dropwise over 15 min. 21% sodium ethoxide in ethanol (16.8 mL, 45 mmol), and the resulting solution then was stirred at 25° C. for 14 h. The reaction mixyure was diluted with water, adjusted to pH 5 with conc. hydrochloric acid, and extracted with ethyl acetate. The combined extracts was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting solid was washed with diethyl ether and dried to furnish 12.1 g (81%) of the product as an orange solid. NMR (CDCl3) δ 7.87 (d, 2H, J=9 Hz), 6.87 (d, 2H, J=9 Hz), 6.45 (s, 1H), 3.60 (m, 4H), 3.41 (m, 4H), 1.48 (s, 9H).

[0327] Step 3. Synthesis of CXLVII from 31.

[0328] Prepared in a similar fashion as described for examples LXXVI and XLII employing 31 and 4-aminomorpholine as starting materials. mp 242° C.; ESI-MS m/e calc'd for C30H36N7O5574.2778, found: 574.2762.

Example CXLVIII

Preparation of 3-(4-(1-piperazinyl)phenyl)-5-(((4-morpholinylamino)carbonyl)amino)indeno[1,2-c]pyrazol-4-one

[0329] A solution of CXLVII (0.58 g, 1.0 mmol) in 20 mL of trifluoroacetic acid was stirred at 25° C. for 2 h. The reaction mixture was concentrated under vacuum, and the residue was recrystallized from ethanol to provide 0.53 g (89%) of the yellow product as its TFA-salt. mp 263° C.; ESI-MS m/e calc'd for C25H28N7O3: 474.2254, found: 474.2280.

Example CXLIX

Preparation of 3-(4-(1-piperazinyl)phenyl)-5-((aminocarbonyl)amino)indeno[1,2-c]pyrazol-4-one

[0330] Prepared in a similar fashion as described for examples XLII and CXLVIII employing 2-(4-(4-t-butoxycarbonyl-1-piperazinyl)benzoyl)-4-amino-1,3-indanedione obtained in example CXLVII and ammonia as the starting materials. mp 257° C.; ESI-MS m/e calc'd for C21H21N6O2: 389.1726, found: 389.1724.

Example CL

Preparation of 3-(4-(1-piperazinyl)phenyl)-5-((hydrazinocarbonyl)amino)indeno[1,2-c]pyrazol-4-one

[0331] Prepared in a similar fashion as described for examples XLII and CXLVIII employing 2-(4-(4-t-butoxycarbonyl-1-piperazinyl)benzoyl)-4-amino-1,3-indanedione obtained in example CXLVII and hydrazine as the starting materials. mp 257° C.; ESI-MS m/e calc'd for C21H22N7O2: 404.1835, found: 404.1834.

Example CLI

Preparation of 3-(4-(1-piperazinyl)phenyl)-5-((dimethylamino)acetamido)indeno[1,2-c]pyrazol-4-one

[0332] Prepared employing 2-(4-(4-t-butoxycarbonyl-1-piperazinyl)benzoyl)-4-amino-1,3-indanedione obtained in example CXLVII as the starting material. Chloroacetylation and treatment with dimethylamine in a similar fashion as described for examples II and XXIII, followed by treatment with hydrazine and removal of the t-butoxycarbonyl group in a similar fashion as described for examples I and CXLVIII, afforded the example compound. mp 243° C.; ESI-MS m/e calc'd for C24H27N6O2: 431.2196, found: 431.2198.

Example CLII

Preparation of 3-(4-(1-piperazinyl)phenyl)-5-((4-morpholinyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0333] Prepared employing 2-(4-(4-t-butoxycarbonyl-1-piperazinyl)benzoyl)-4-amino-1,3-indanedione obtained in example CXLVII as the starting material. Chloroacetylation and treatment with morpholine in a similar fashion as described for examples II and XXIII, followed by treatment with hydrazine and removal of the t-butoxycarbonyl group in a similar fashion as described for examples I and CXLVIII, afforded the example compound. mp 259° C.; ESI-MS m/e calc'd for C26H29N6O3: 473.2301, found: 473.2302.

Example CLIII

Preparation of 3-(4-(1-piperazinyl)phenyl)-5-((4-methyl-1-piperazinyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0334] Prepared employing 2-(4-(4-t-butoxycarbonyl-1-piperazinyl)benzoyl)-4-amino-1,3-indanedione obtained in example CXLVII as the starting material. Chloroacetylation and treatment with 1-methylpiperazine in a similar fashion as described for examples II and XXIII, followed by treatment with hydrazine and removal of the t-butoxycarbonyl group in a similar fashion as described for examples I and CXLVIII, afforded the example compound. ESI-MS m/e calc'd for C27H32N7O2: 486.2618, found: 486.2608.

Example CLIV

Preparation of 3-(4-(1-piperazinyl)phenyl)-5-((4-amino methyl-1-piperidinyl)acetamido)indeno[1,2-c]pyrazol-4-one

[0335] Prepared employing 2-(4-(4-t-butoxycarbonyl-1-piperazinyl)benzoyl)-4-amino-1,3-indanedione obtained in example CXLVII as the starting material. Chloroacetylation and treatment with 4-(aminomethyl)piperidine in a similar fashion as described for examples II and XXIII, followed by treatment with hydrazine and removal of the t-butoxycarbonyl group in a similar fashion as described for examples I and CXLVIII, afforded the example compound. mp 239° C.; ESI-MS m/e calc'd for C28H34N7O2: 500.2774, found: 500.2772.

Example CLV

Preparation of 3-(4-(4-methyl-1-piperazinyl)phenyl)-5-(((4-morpholinylamino)carbonyl)amino)indeno[1,2-c]pyrazol-4-one

[0336]

[0337] To a solution of CXLVITI (0.17 g, 0.29 mmol) in 10 mL of methanol and 2 mL of water at 25° C. was added sequentially 37% aqueous formaldehyde (0.45 g, 5.8 mmol), sodium cyanoborohydride (0.18 g, 2.9 mmol), and 4 drops of acetic acid. The resulting solution was stirred at 25° C. for 16 h. The mixture was diluted with water. It then was made acidic (˜pH 1) with conc. hydrochloric acid and stirred for 10 min. The solution next was made basic (˜pH 13) with 50% aqueous sodium hydroxide and finally adjusted to pH 10 with 1 N hydrochloric acid. The mixture was extracted with 4:1 chloroform/isopropanol. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and filtered. To the filtrate was added excess trifluoroacetic acid, and the solution was concentrated under vacuum. The residue was recrystallized from isopropanol to furnish 0.16 g (92%) of the yellow product as its TFA-salt. mp 245° C.; ESI-MS m/e calc'd for C26H30N7O3: 488.2410, found: 488.2420.

Example CLVI

Preparation of 3-(4-(4-ethyl-1-piperazinyl)phenyl)-5-(((4-morpholinylamino)carbonyl)amino)indeno[1,2-c]pyrazol-4-one

[0338] Prepared in a similar fashion as described for example CLV employing CXLVIII and acetaldehyde as the starting materials. mp 245° C.; ESI-MS m/e calc'd for C27H32N7O3: 502.2567, found: 502.2555.

Example CLVII

Preparation of 3-(4-(4-isopropyl-1-piperazinyl)phenyl)-5-(((4-morpholinylamino)carbonyl)amino)indeno[1,2-c]pyrazol-4-one

[0339] Prepared in a similar fashion as described for example CLV employing CXLVIII and acetone as the starting materials. mp 253° C.; ESI-MS m/e calc'd for C28H34N7O3: 516.2723, found: 516.2726.

Example CLVIII

Preparation of 3-(4-methoxyphenyl)-5-(2-benzoylhydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one

[0340] Step 1. Synthesis of 31 from 13.

[0341] A suspension of aniline 31 (0.5 g, 1.7 mmol) in dioxane (10 mL) was treated with triethylamine (0.48 mL, 3.4 mmol) in one portion at room temperature. Then 2-(trimethylsilyl) ethyloxy chloride (SEMCl) (0.48 mL, 2.6 mmol) was added in one portion and the mixture heated to reflux for 2 h. The reaction was cooled, diluted with EtOAc (20 mL) washed with water (10 mL), dried (MgSO4) and the solvent removed at reduced pressure. The residue was taken up in benzene (3 mL), applied to a plug of silica gel (10 g) and eluted with EtOAc/Hexane (1:3) until all the yellow color was washed from the silica gel plug. The solvent was evaporated and the residue taken on to the next step. This material was dissolved in dioxane (10 mL) and treated with K2CO3 (0.36 g, 2.6 mmol) in one portion. Then phenylchloroformate (0.27 mL, 2.23 mmol) was added in one portion and the reaction heated to 50 C for 2 h. The reaction was cooled and the solvent removed at reduced pressure. The residue was recrystalized from EtOH to give a yellow solid (0.4 g, 43%). mp OC; CIMS m/e calculated for C30H32N3O5Si: 542.2111, found: 542.2101;

[0342] Step 2. Synthesis of Ex. CLVIII from 31.

[0343] Compound 31 (0.015 g, 0.03 mmol) in DMSO (0.2 mL) was treated with phenylcarbazte (0.008 g, 0.06 mmol) in one portion and heated to 80 C for 30 minutes. The solvent was removed at reduced pressure heating to 65 C. The residue was disolved in EtOH (0.5 mL) and treated with 4N HCl/dioxane (0.4 mL). The mixture was heated to 80 C for 20 minutes and then cooled. The desired product was filtered and air dried (0.008 g, 62%). mp>300° C.; CIMS m/e calculated for C26H27N4O4: 459.2032, found: 459.1999;

Example CLIX

Preparation of 3-(4-methoxyphenyl)-5-(2-isonicotinoylhydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one

[0344] Prepared in a similar fashion as described for example CLVIII using 4-pyridylcarbazate as the starting material. mp 248° C.; CIMS m/e calculated for C24H19N6O4: 455.1468, found: 455.1400;

Example CLX

Preparation of 3-(4-methoxyphenyl)-5-(2-nictinoylhydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one

[0345] Prepared in a similar fashion as described for example CLVIII using 3-pyridylcarbazate as the starting material. mp 227° C.; CIMS m/e calc'd for C24H19N6O4: 455.1468, found: 455.1487;

Example CLXI

Preparation of 3-(4-methoxyphenyl)-5-(2-(3,4-dihydroxy benzoyl)hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one

[0346] Prepared in a similar fashion as described for example CLVIII using 3,4-dihydroxyphenyl carbazate as the starting material. mp>300° C.; CIMS m/e calc'd for C25H20N5O6: 486.1414, found: 486.1497;

Example CLXII

Preparation of 3-(4-methoxyphenyl)-5-(2-(4-hydroxy benzoyl)hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one

[0347] Prepared in a similar fashion as described for example CLVIII using 4-hydroxyphenyl carbazate as the starting material. mp 283° C.; CIMS m/e calc'd for C25H20N5O5: 470.1464, found: 470.1544;

Example CLXIII

Preparation of 3-(4-methoxyphenyl)-5-(2-(3-aminobenzoyl)hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one

[0348] Prepared in a similar fashion as described for example CLVIII using 3-aminophenyl carbazate as the starting material. mp 250° C.; CIMS m/e calc'd for C25H21N6O4: 469.1624, found: 469.1513;

Example CLXIV

Preparation of 3-(4-methoxyphenyl)-5-(2-(4-aminobenzoyl)hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one

[0349] Prepared in a similar fashion as described for example CLVIII using 4-aminophenyl carbazate as the starting material. mp 247° C.; CIMS m/e calc'd for C25H21N6O4: 469.1624, found: 469.1528;

Example CLXV

Preparation of 3-(4-methoxyphenyl)-5-(2-(2-aminobenzoyl)hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one

[0350] Prepared in a similar fashion as described for example CLVIII using 2-aminophenyl carbazate as the starting material. mp 257° C.; CIMS m/e calc'd for C25H21N6O4: 469.1624, found: 469.1548;

Example CLXVI

Preparation of 3-(4-methoxyphenyl)-5-(2-(4-N,N-dimethylamino benzoyl)hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one

[0351] Prepared in a similar fashion as described for example CLVIII using 4-N,N-dimethylaminophenyl carbazate as the starting material. mp 259° C.; CIMS m/e calc'd for C27H25N6O4: 497.1937, found: 497.1876;

Example CLXVII

Preparation of 3-(4-methoxyphenyl)-5-(2-phenethylacetyl hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one

[0352] Prepared in a similar fashion as described for example CLVIII using benzyl carbazate as the starting material. mp 269° C.; CIMS m/e calc'd for C26H22N5O4: 468.1672, found: 468.1313;

Example CLXVIII

Preparation of 3-(4-methoxyphenyl)-5-(2-(2-hydroxy benzoyl)hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one

[0353] Prepared in a similar fashion as described for example CLVIII using 2-hydroxyphenyl carbazate as the starting material. mp 280° C.; CIMS m/e calc'd for C25H20N5O5: 470.1464, found: 470.1419;

Example CLXIX

Preparation of 3-(4-methoxyphenyl)-5-(2-methoxycarbonyl hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one

[0354] Prepared in a similar fashion as described for example CLVIII using carbazic acid methyl ester as the starting material. mp>300° C.; CIMS m/e calc'd for C20H28N5O5: 408.1308, found: 408.1397;

Utility

Inhibition of Kinase/Cyclin Complex Enzymatic Activity

[0355] Several of the compounds disclosed in this invention were assayed for their inhibitory activity against cdk4/D1 and cdk2/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 cdk2/cyclinE is purified from insect cells expressing His-tagged cdk2 and cyclin E. The cdk/cyclin lysate is combined in a microtitre-type plate along with a kinase compatible buffer, 32P-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 32P 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 IC50 was found to be less than 1 μM.

Inhibition of HCT116 Cancer Cell Proliferation

[0356] 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 IC50 was found to be less than 10 μM.

1TABLE 1

ExampleR1R2massmp#R1R2(M + H)(° C.)IMethyl4-MeOC6H4334268IIClCH24-MeOC6H4382274IIIcyclopropyl4-MeOC6H4360289IVisopropyl4-MeOC6H4352288Vethyl4-MeOC6H4348287VIcyclopentyl4-MeOC6H4388267VIIcyclobutyl4-MeOC6H4374297VIIIbenzyl4-MeOC6H4410280IXn-propyl4-MeOC6H4362282X4-ClC6H4CH24-MeOC6H4444238XI3-MeOC6H4CH24-MeOC6H4440>300XII4-MeOC6H4CH24-MeOC6H4440280XIII3,4-diMeOC6H4CH24-MeOC6H4470>300XIV2,5-diMeOC6H4CH24-MeOC6H4470226XVMethyl2-MeOC6H4334276XVIMethyl3,4-diMeOC6H4364>300XVII3,4-(OCH2O)C6H4CH24-MeOC6H4454297XVIII3-thiophenylCH24-MeOC6H4416293XIX2-MeOC6H4CH24-MeOC6H4440255XX3,4-diClOC6H4CH24-MeOC6H4479299XXI2,4-diClOC6H4CH24-MeOC6H4479286XXII2-ClC6H4CH24-MeOC6H4444300XXIIIH2NCH24-MeOC6H4349>300XXIVHOCH2CH2NHCH24-MeOC6H4393243XXVMe2NCH24-MeOC6H4377279XXVIpiperaziflylCH24-MeOC6H4418277XXVII4-Me-piperaziflylCH24-MeOC6H4432>300XXVIII4-HOCH2CH2-4-MeOC6H4462>300piperazinylCH2XXIXpiperidinylCH24-MeOC6H4417291XXX4-NH2CH2-4-MeOC6H4446>300piperidinylCH2XXXICH3CH2NHCH24-MeOC6H4377250XXXIIthiornorpholiraylCH24-MeOC6H4435298XXXIIImorpholinylCH24-MeOC6H4419295XXXIVpyrrolidinylCH24-MeOC6H4403279XXXV4-pyridylCH2NHCH24-MeOC6H4440>300XXXVI4-CH3CONHC6H4CH24-MeOC6H4467268XXXVII4-CH3OCONHC6H4CH24-MeOC6H4483257XXXVIII4-NH2CH2CONHC6H4CH24-MeOC6H4482228XXXIX4-Me2NCH2CONHC6H4CH24-MeOC6H4510>300XL4-N3C6H4CH24-MeOC6H4451>300XLI4-NH2C6H4CH24-MeOC6H4425283XLIIC6C6H5NH4-MeOC6H4411>300XLIIICH3CH2CH2NH4-MeOC6H4377252XLIV4-NH2C6H4CH2NH4-MeOC6H4440>300XLV4-pyridylCH2NH4-MeOC6H4426>300XLVIMethyl4-HOC6H4320>300XLVIIH4-MeOC6H4320280XLVIIIMethyl3-pyridyl305>300XLIXMethyl4-pyridyl305>300LH4-pyridyl291>300LIMethylC6C6H5305>300LIIMethyl4-MeSC6H4351283LIIIMethyl4-MeSO2C6H4383>300LVIMethyl4-Me2NC6H4348>300LVmorpholinylCH24-Me2NC6H4432>300LVIMe2NCH24-Me2NC6H4390>300LVIIMethyl4-(piperdinyl)C6H4388291LVIIIMethyl4-389>300(morpholinyl) C6H4LIXMethyl4-CH3CH2OC6H4349288LXMethyl4-CH3CH2CH2CH2C6H4361259LXIMethyl4-CH3CH2C6H4332294LXIIMethyl4-CH3CH2CH2C6H4347269LXIIINH24-MeOC6H4335>300LXIVMe2NNH4-MeOC6H4378>300LXVMeNH4-MeOC6H4349>300LXVImorpholiriylNH4-MeOC6H4420>300LXVIIcis-1,2-4-MeOC6H4432>300diaminocyclohexanylLXVIII4-4-MeOC6H4433>300methylpiperazinylNHLXVIX4-4-MeOC6H4489>300uridomethylpiperadinylCH2LXX4-(2-4-MeOC6H4495>300pyridyl)piperazinylCH2LXXI4-4-MeOC6H4461>300(aminoethyl)piperazliylCH2LXXII4-amidopiperidinylCH24-MeOC6H4460>300LXXIII4-4-MeOC6H4433>300hydroxypiperidiflYl CH2LXXIV4-4-MeOC6H4447>300hydroxymethylpiperidinylCH2LXXV4-amidopiperaziflylCH24-MeOC6H4493>300LXXVI4-4-MeOC6H4492>300dimethylamiflOpiperadinylCH2LXXVII4-aminopiperadinylCH24-MeOC6H4464>300LXXVIII4-Me-piperazinylCH24-Me2NC6H4445>300LXXIX4-NH2CH2-4-Me2NC6H4459NApiperidinylCH2LXXX4-OH-piperidiflYlCH24-Me2NC6H4446267LXXXImorpholinylCH24-474258(morpholinyl) C6H4LXXXII4-Me-piperazinylCH24-258(morpholinyl) C6H4LXXXIII4-OH-piperidinylCH24-488245(morpholinyl) C6H4LXXXIV4NH2CH24-501240(morpholinyl) C6H4piperidinyl CH2LXXXV4-Me-piperazinylNH4-Me2NC6H4446>300LXXXVIMethyli-propyl270>250LXXXVIIMethylc-propyl268220LXXXVIIIMethylt-butyl284>250LXXXIXMethyl2-thienyl310269XCMethyl3-Me-2-thienyl324275XCINH2Ethyl257>250XCIINH2n-propyl271187XCIIINH2i-propyl271>250XCIVNH2c-propyl267252(M-H)XCVNH2c-hexyl311178XCVINH22-thienyl310214(M+)XCVIINH23-Me-2-thienyl325270XCVIIINH25-Me-2-thienyl325>280XCIXNH25-CO2Et-2-thienyl383>280CNH23-thienyl311>280CINH25-Cl-3-thienyl345>300CIINH22,5-diMe-3-thienyl339>280CIIINH22-furanyl295278CIVMe2NNHi-propyl314231CVMe2NNHc-propyl312CVIMe2NNHc-hexyl354229CVIIMe2NNH2-thienyl354279CVIIIMe2NNH5-MeO-2-thienyl384280CIXMe2NNH5-Me-2-thienyl368>280CXMe2NNH5-CO2Et-2-thienyl426252CXIMe2NNH3-thienyl354202CXIINH2i-methyl-3-308>300pyrrolylCXIIIMe2NNH2,5-diMe-3-thienyl382252CXIVMe2NNH2-furanyl338202CXV4-NH2CO-1-propyl396224piperidinylCH2CXVI4-NH2CO-c-hexyl436228piperidinylCH2CXVII4-NH2CH2-ethyl368174piperidinylCH2CXVIII4-NH2CH2-i-propyl382218piperidinylCH2CXVIX4-NH2CH2-c-propyl380138piperidinylCH2CXX4-NH2CH2-c-hexyl422196piperidinylCH2CXXI4-CH3-piperazinylNH1-propyl369231CXXII4-CH3-piperazinylNH5-CO2Et-2-thienyl481249CXXIII4-CH3-piperazinylNH5-CO2H-2-thienyl453270CXXIV4-CH3-piperazinylNH2,5-diMe-3-thienyl437250CXXVmorpholinylNH1-propyl354256(M-H)CXXVImorpholinylNH4-CO2Me-455216piperidinylCXXVIImorpholinylNH5-Me-2-thienyl410261CXXVIIImorpholinylNH5-Cl-3-thienyl430259CXXIXmorpholinylNH2,5-diMe-3-thienyl424>280CXXXmorpholinylNH5-CO2Et-2-thienyl468258CXXXImorpholinylNH5-CO2H-2-thienyl440273CXXXIImorpholinylNH5-CONHBn-2-thienyl529275CXXXIIImorpholinylNH5-CONH(4-Me-537190piperazinyl) -2-thienylCXXXIVmorpholinylNH5-CONHCH2CH2(1-Me-5502352-pyrrolidinyl) -2-thienylCXXXVmorpholinylNH5-CONHNMe2-2-482201thienylCXXXVImorpholinylNH5-CONHCH2CH2NMe2-5101902-thienylCXXXVIImorpholinylNH5-CONHCH2CH2(1-536224pyrrolidinyl) -2-thienylCXXXVIIImorpholinylNH5-CONHCH2CH2(1-552241morpholinyl) -2-thienylCXXXIXmorpholinylNH5-CONHmorpholinyl-5242712 -thienylCXLmorpholinylNH5-CONHCH2CH2CH2(1-564260pyrrolidonyl) -2-thienylCXLImorpholinylNH5-CONHCH2CH2(3-544203pyridyl) -2-thienylCXLIImorpholinylNH5-CONHCH2CH2CH2(1-547263imidazolyl) -2-thienylCXLIIImorpholLinylNH5-CONHCH2CH2(2-544>280pyridyl) -2-thienylCXLIVmorpholinylNH5-CONHCH2(3-530239pyridyl) -2-thienylCXLVmorpholinylNH5-CONHCH2CH2(1-550228piperidinyl) -2-thienylCXLVIMethyl4-CF3C6H4370>300(M-H)CXLVIImorpholinylNH4-(4-BoC-574242piperazinyl) C6H4CXLVIIImorpholinylNH4-474263(piperazinyl) C6H4CXLIXNH24-389257(piperazinyl) C6H4CLNHhd 2NH4-404257(piperazinyl) C6H4CLIMe2NCH24-431243(piperazinyl) C6H4CLIImorpholiny-CH24-473259(piperazinyl) C6H4CLIII4-Me-piperazinylCH24-486NA(piperazinyl) C6H4CLIV4NH2CH24-500239(piperazinyl) C6H4piperidinylCH2CLVmorpholinylNH4-(4-Me-488245piperazinyl) C6H4CLVImorpholinylNH4-(4-Et-502245piperazinyl) C6H4CLVIImorpholinylNH4-(4-i-Pr-516253piperazinyl) C6H4CLVIIIC6H5C(O)NHNH4-MeOC6H4459>300CLIX4-pyridylC(O)NHNH4-MeOC6H4455248CLX3-pyridylC(O)NHNH4-MeOC6H4455227CLXI3,4-dihydroxy-4-MeOC6H4486>300C6H3C(0) NHNHCLXII4-hydroxy-4-MeOC6H4470283C6H4C(0)NHNHCLXIII3-amino-C6H4C(0)NHNH4-MeOC6H4469250CLXIV4-amino-C6H4C(O)NHNH4-MeCC6H4469247CLXV2-amino-C6H4C(O)NHNH4-MeOC6H4469257CLXVI4-N,N-dimethylamino-4-MCOC6H4497259C6H4C (0) NHNHCLXVIIC6HSCH2C(0)NHNH4-Me0C6H4468269CLXVIII2-hydroxy-4-MeOC6H4470280C6H4C(0)NHNHCLXIXMeOC(0)NHNH4-MeOC6H4408>300

[0357]

2

TABLE 2

Example

Number
R1
R2

100
2-pyridylmethyl
4-MeOC6H4

101
2-pyridylmethyl
3-MeOC6H4

102
2-pyridylmethyl
4-NH2C6H4

103
2-pyridylmethyl
3-NH2C6H4

104
2-pyridylmethyl
2 -NH2C6H4

105
2-pyridylmethyl
4-Me2NC6H4

106
2-pyridylmethyl
3-Me2NC6H4

107
2-pyridylmethyl
2-Me2NC6H4

108
2-pyridylmethyl
4-pyridyl

109
2-pyridylmethyl
3-pyridyl

110
2-pyridylmethyl
2-pyridyl

111
2-pyridylmethyl
2-thiazolyl

112
2-pyridylmethyl
2-pyrazolyl

113
2-pyridylmethyl
5-isoquinolyl

114
2-pyridylmethyl
3,4-

methylenedioxyC6H3

115
2-pyridylmethyl
3,4-

ethylenedioxyC6H3

116
2-pyridylmethyl
2-imidazolyl

117
2-pyridylmethyl
2-oxazolyl

118
2-pyridylmethyl
4-isoxazolyl

119
2-pyridylmethyl
4-HOC6H4

120
2-pyridylmethyl
3-HOC6H4

121
2-pyridylmethyl
3,4-diHOC6H4

122
2-pyridylmethyl
4-NH2CH2C6H4

123
2-pyridylmethyl
3-NH2CH2C6H4

124
3-pyridylmethyl
4-MeOC6H4

125
3-pyridylmethyl
3 -MeOC6H4

126
3-pyridylmethyl
4-NH2C6H4

127
3-pyridylmethyl
3-NH2C6H4

128
3-pyridylmethyl
2-NH2C6H4

129
3-pyridylmethyl
4-Me2NC6H4

130
3-pyridylmethyl
3-Me2NC6H4

131
3-pyridylmethyl
2-Me2NC6H4

132
3-pyridylmethyl
4-pyridyl

133
3-pyridylmethyl
3-pyridyl

134
3-pyridylmethyl
2-pyridyl

135
3-pyridylmethyl
2-thiazolyl

136
3-pyridylmethyl
2-pyrazolyl

137
3-pyridylmethyl
5-isoqunolyl

138
3-pyridylmethyl
3,4-

methylenedioxyC6H3

139
3-pyridylmethyl
3,4-

methylenedioxyC6H3

140
3-pyridylmethyl
2-imidazolyl

141
3-pyridylmethyl
2-oxazolyl

142
3-pyridylmethyl
4-isoxazolyl

143
3-pyridylmethyl
4-HOC6H4

144
3-pyridylmethyl
3-HOC6H4

145
3-pyridylmethyl
3,4-diHOC6H4

146
3-pyridylmethyl
4-NH2CH2C6H4

147
3-pyridylmethyl
3-NH2CH2C6H4

148
4-pyridylmethyl
4-MeOC6H4

149
4-pyridylmethyl
3-MeOC6H4

150
4-pyridylmethyl
4-NH2C6H4

151
4-pyridylmethyl
3-NH2C6H4

152
4-pyridylmethyl
2-NH2C6H4

153
4-pyridylmethyl
4-Me2NC6H4

154
4-pyridylmethyl
3-Me2NC6H4

155
4-pyridylmethyl
2-Me2NC6H4

156
4-pyridylmethyl
4-pyridyl

157
4-pyridylmethyl
3-pyridyl

158
4-pyridylmethyl
2-pyridyl

159
4-pyridylmethyl
2-thiazolyl

160
4-pyridylmethyl
2-pyrazolyl

161
4-pyridylmethyl
5-isoquinolyl

162
4-pyridylmethyl
3,4-

methylenedioxyC6H3

163
4-pyridylmethyl
3,4-

ethylenedioxyC6H3

164
4-pyridylmethyl
2-imidazolyl

165
4-pyridylmethyl
2 -oxazolyl

166
4-pyridylmethyl
4-isoxazolyl

167
4-pyridylmethyl
4-HOC6H4

168
4-pyridylmethyl
3-HOC6H4

169
4-pyridylmethyl
3, 4-diHOC6H4

170
4-pyridylmethyl
4-NH2CH2C6H4

171
4-pyridylmethyl
3-NH2CH2C6H4

172
2-NH2C6H4CH2
4-MeOC6H4

173
2 -NH2C6H4CH2
3 -MeOC~H4

174
2-NH2C6H4CH2
4-NH2C6H4

175
2-NH2C6H4CH2
3-NH2C6H4

176
2-NH2C6H4CH2
2-NH2C6H4

177
2-NH2C6H4CH2
4-Me2NC6H4

178
2-NH2CSH4CH2
3-Me2NC6H4

179
2-NH2C6H4CH2
2-Me2NC6H4

180
2-NH2C6H4CH2
4-pyridyl

181
2-NH2C6H4CH2
3-pyridyl

182
2-NH2C6H4CH2
2-pyridyl

183
2-NH2C6H4CH2
2-thiazolyl

184
2-NH2C6H4CH2
2-pyrazolyl

185
2-NH2C6H4CH2
5- isoquinolyl

186
2-NH2C6H4CH2
3,4-

methylenedioxyC6H3

187
2-NH2C6H4CH2
3,4-

ethylenedioxyC6H3

188
2-NH2C6H4CH2
2-imidazolyl

189
2-NH2C6H4CH2
2-oxazolyl

190
2-NH2C6H4CH2
4-isoxazolyl

191
2-NH2C6H4CH2
4-HOC6H4

192
2-NH2C6H4CH2
3-HOC6H4

193
2-NH2C6H4CH2
3,4-diHOC6H4

194
2-NH2C6H4CH2
4-NH2CH2C6H4

195
2-NH2C6H4CH2
3-NH2CH2C6H4

196
3-NH2C6H4CH2
3-MeOC6H4

197
3-NH2C6H4CH2
4-NH2C6H4

198
3-NH2C6H4CH2
3-NH2C6H4

199
3-NH2C6H4CH2
2-NH2C6H4

200
3-NH2C6H4CH2
4-Me2NC6H4

201
3-NH2C6H4CH2
3-Me2NC6H4

202
3-NH2C6H4CH2
2-Me2NC6H4

203
3-NH2C6H4CH2
4-pyridyl

204
3-NH2C6H4CH2
3-pyridyl

205
3-NH2C6H4CH2
2-pyridyl

206
3-NH2C6H4CH2
2-thiazolyl

207
3-NH2C6H4CH2
2-pyrazolyl

208
3-NH2C6H4CH2
5-isoquinolyl

209
3-NH2C6H4CH2
3,4-

methylenedioxyC6H3

210
3-NH2C6H4CH2
3,4-

ethylenedioxyC5H3

211
3-NH2C6H4CH2
2-imidazolyl

212
3-NH2C6H4CH2
2-oxazolyl

213
3-NH2C6H4CH2
4-isoxazolyl

214
3-NH2C6H4CH2
4-HOC6H4

215
3-NH2C6H4CH2
3-HOC6H4

216
3-NH2C6H4CH2
3,4-diHOC6H4

217
3-NH2C6H4CH2
4-NH2CH2C6H4

218
3-NH2C6H4CH2
3-NH2CH2C6H4

219
4-NH2C6H4CH2
3-MeOC6H4

220
4-NH2C6H4CH2
4-NH2C6H4

221
4-NH2C6H4CH2
3-NH2C6H4

222
4-NH2C6H4CH2
2-NH2C6H4

223
4-NH2C6H4CH2
4-Me2NC6H4

224
4-NH2C6H4CH2
3-Me2NC6H4

225
4-NH2C6H4CH2
2-Me2NC6H4

226
4-Nh2C6H4Ch2
4-pyridyl

227
4-NH2C6H4CH2
3-pyridyl

228
4-NH2C6H4CH2
2-pyridyl

229
4-NH2C6H4CH2
2-thiazolyl

230
4-NH2C6H4CH2
2-pyrazolyl

231
4-NH2C6H4CH2
5-isoquinolyl

232
4-NH2C6H4CH2
3,4-

methylenedioxyC6H3

233
4-NH2C6H4CH2
3,4-

ethylenedioxyC6H3

234
4-NH2C6H4CH2
2-imidazolyl

235
4-NH2C6H4CH2
2-oxazolyl

236
4-NH2C6H4CH2
4-isoxazolyl

237
4-NH2C6H4CH2
4-HOC6H4

238
4-NH2C6H4CH2
3-HOC6H4

239
4-NH2C6H4CH2
3,4-diHOC6H4

240
4-NH2C6H4CH2
4-NH2CH2C6H4

241
4-NH2C6H4CH2
3-NH2CH2C6H4

242
2-MeOC6H4CH2
3-MeOC6H4

243
2-MeOC6H4CH2
4-NH2C6H4

244
2-MeOC6H4CH2
3-NH2C6H4

245
2-MeOC6H4CH2
2-NH2C6H4

246
2-MeOC6H4CH2
4-Me2NC6H4

247
2-MeOC6H4CH2
3-Me2NC6H4

248
2-MeOC6H4CH2
2-Me2NC6H4

249
2-MeOC6H4CH2
4-pyridyl

250
2-MeOC6H4CH2
3-pyridyl

251
2-MeOC6H4CH2
2-pyridyl

252
2-MeOC6H4CH2
2-thiazolyl

253
2-MeOC6H4CH2
2-pyrazolyl

254
2-MeOC6H4CH2
5-isoquinolyl

255
2-MeOC6H4CH2
3,4-

methylenediOXyC6H3

256
2-MeOC6H4CH2
3,4-

ethylenediOXyC6H3

257
2-MeOC6H4CH2
2-imidazolyl

258
2-MeOC6H4CH2
2-oxazolyl

259
2-MeOC6H4CH2
4-isoxazolyl

260
2-MeOC6H4CH2
4-HOC6H4

261
2-MeOC6H4CH2
3-HOC6H4

262
2-MeOC6H4CH2
3,4-diHOC6H4

263
2-MeOC6H4CH2
4-NH2CH2C6H4

264
2-MeOC6H4CH2
3-NH2CH2C6H4

265
3-MeOC6H4CH2
3-MeOC6H4

266
3-MeQC6H4CH2
4-NH2C6H4

267
3-MeOC6H4CH2
3-NH2C6H4

268
3-MeOC6H4CH2
2-NH2C6H4

269
3-MeOC6H4CH2
4-Me2NC6H4

270
3-MeOC6H4CH2
3-Me2NC6H4

271
3-MeOC6H4CH2
2-Me2NC6H4

272
3-MeOC6H4CH2
4-pyridyl

273
3-MeOC6H4CH2
3-pyridyl

274
3-MeOC6H4CH2
2-pyridyl

275
3-MeOC6H4CH2
2-thiazolyl

276
3-MeOC6H4CH2
2-pyrazolyl

277
3-MeOC6H4CH2
5-isoquinolyl

278
3-MeOC6H4CH2
3,4-

methylenedioxyC6H3

279
3-MeOC6H4CH2
3,4-

ethylenedioxyC6H3

280
3-MeQC6H4CH2
2-imidazolyl

281
3-MeOCEH4CH2
2-oxazolyl

282
3-MeOC6H4CH2
4-isoxazolyl

283
3-MeOC6H4CH2
4-HOC6H4

284
3-MeOC6H4CH2
3-HOC6H4

285
3-MeOC6H4CH2
3,4-diHOC6H4

286
3-MeOC6H4CH2
4-NH2CH2C6H4

287
3-MeOC6H4CH2
3-NH2CH2C6H4

288
4-MeOC6H4CH2
3-MeOC6H4

289
4-MeOC6H4CH2
4-NH2C6H4

290
4-MeOC6H4CH2
3-NH2C6H4

291
4-MeOC6H4CH2
2-NH2C6H4

292
4-MCOC6H4CH2
4-Me2NC6H4

293
4-MeOC6H4CH2
3-Me2NC6H4

294
4-MeOC6H4CH2
2-Me2NC6H4

295
4-MeOC6H4CH2
4-pyridyl

296
4-MeOC6H4CH2
3-pyridyl

297
4-MeQC6H4CH2
2-pyridyl

298
4-MeOC6H4CH2
2-thiazolyl

299
4-MeOC6H4CH2
2-pyrazolyl-

300
4-MeOC6H4CH2
5-isoquinolyl

301
4-MeOC6H4CH2
3,4-

methylenedioxyC6H3

302
4-MeOC6H4CH2
3,4-

ethylenedioxyC6H3

303
4-MeOC6H4CH2
2-imidazolyl

304
4-MeQC6H4CH2
2-oxazolyl

305
4-MeOC6H4CH2
4-isoxazolyl

306
4-MeOC6H4CH2
4-HOC6H4

307
4-MeOC6H4CH2
3-HOC6H4

308
4-MeOC6H4CH2
3,4-diHOC6H4

309
4-MeOC6H4CH2
4-NH2CH2C6H4

310
4-MeOC6H4CH2
3-NH2CH2C6H4

311
2-HOC6H4CH2
4-MeOC6H4

312
2-HOC6H4CH2
3-MeOC6H4

313
2-HOC6H4CH2
4-NH2C6H4

314
2-HOC6H4CH2
3-NH2C6H4

315
2-HOC6H4CH2
2-NH2C6H4

316
2-HOC6H4CH2
4-Me2NC6H4

317
2-HOC6H4CH2
3-Me2NC6H4

313
2-HOC6H4CH2
2-Me2NC6H4

319
2-HOC6H4CH2
4-pyridyl

320
2-HOC6H4CH2
3-pyridyl

321
2-HOC6H4CH2
2-pyridyl

322
2-HOC6H4CH2
2-thiazolyl

323
2-HOC6H4CH2
2-pyrazolyl

324
2-HOC6H4CH2
5-isoquinolyl

325
2-HOC6H4CH2
3,4-

methylenedioxyC6H3

326
2-HOC6H4CH2
3,4-

ethylenedioxyC6H3

327
2-HOC6H4CH2
2-imidazolyl

328
2-HOC6H4CH2
2-oxazolyl

329
2-HOC6H4CH2
4-isoxazolyl

330
2-HOC6H4CH2
4-HOC6H4

331
2-HOC6H4CH2
3-HOC6H4

332
2-HOC6H4CH2
3,4-diHOC6H4

333
2-HOC6H4CH2
4-NH2CH2C6H4

334
2-HOC6H4CH2
3-NH2CH2C6H4

335
3-HOC6H4CH2
4-MeOC6H4

336
3-HOC6H4CH2
3-MeOC6H4

337
3-HOC6H4CH2
4-NH2C6H4

338
3-HOC6H4CH2
3-NH2C6H4

339
3-HOC6H4CH2
2-NH2C6H4

340
3-HOC6H4CH2
4-Me2NC6H4

341
3-HOC6H4CH2
3-Me2NC6H4

342
3-HOC6H4CH2
2-Me2NC6H4

343
3-HOC6H4CH2
4-pyridyl

344
3-HOC6H4CH2
3-pyridyl

345
3-HOC6H4CH2
2-pyridyl

346
3-HOC6H4CH2
2-thiazolyl

347
3-HOC6H4CH2
2-pyrazolyl

348
3-HOC6H4CH2
5-isoquinolyl

349
3-HOC6H4CH2
3,4-

methylenedioxyC6H3

350
3-HOC6H4CH2
3,4-

ethylenedioxyC6H3

351
3-HOC6H4CH2
2-imidazolyl

352
3-HOC6H4CH2
2-oxazolyl

353
3-HOC6H4CH2
4-isoxazolyl

354
3-HOC6H4CH2
4-HOC6H4

355
3-HOC6H4CH2
3-HOC6H4

356
3-HOC6H4CH2
3,4-diHOC6H4

357
3-HOC6H4CH2
4-NH2CH2C6H4

358
3-HOC6H4CH2
3-NH2CH2C6H4

359
4-HOC6H4CH2
4-MeOC6H4

360
4-HOC6H4CH2
3-MeOC6H4

361
4-HOC6H4CH2
4-NH2C6H4

362
4-HOC6H4CH2
3-NH2C6H4

363
4-HOC6H4CH2
2-NH2C6H4

364
4-HOC6H4CH2
4-Me2NC6H4

365
4-HOC6H4CH2
3-Me2NC6H4

366
4-HOC6H4CH2
2-Me2NC6H4

367
4-HOC6H4CH2
4-pyridyl

368
4-HOC6H4CH2
3-pyridyl

369
4-HOC6H4CH2
2-pyridyl

370
4-HOC6H4CH2
2-thiazolyl

371
4-HOC6H4CH2
2-pyrazolyl

372
4-HOC6H4CH2
5-isoquinolyl

373
4-HOC6H4CH2
3,4-

methylenedioxyC6H3

374
4-HOC6H4CH2
3,4-

ethylenedioxyC6H3

375
4-HOC6H4CH2
2-imidazolyl

376
4-HOC6H4CH2
2-oxazolyl

377
4-HOC6H4CH2
4-isoxazolyl

378
4-HOC6H4CH2
4-HOC6H4

379
4-HOC6H4CH2
3-HOC6H4

380
4-HOC6H4CH2
314-diHOC6H4

381
4-HOC6H4CH2
4-NH2CH2C6H4

382
4-HOC6H4CH2
3-NH2CH2C6H4

383
4-ClC6H4CH2
3-MeOC6H4

384
4-ClC6H4CH2
4-NH2C6H4

385
4-ClC6H4CH2
3-NH2C6H4

386
4-ClC6H4CH2
2-NH2C6H4

387
4-ClC6H4CH2
4-Me2NC6H4

388
4-ClC6H4CH2
3-Me2NC6H4

389
4-ClC6H4CH2
2-Me2NC6H4

390
4-ClC6H4CH2
4-pyridyl

391
4-ClC6H4CH2
3-pyridyl

392
4-ClC6H4CH2
2-pyridyl

393
4-ClC6H4CH2
2-thiazolyl

394
4-ClC6H4CH2
2-pyrazolyl

395
4-ClC6H4CH2
5-isoquinolyl

396
4-ClC6H4CH2
3,4-

methylenedioxyC6H3

397
4-ClC6H4CH2
3,4-

ethylenedioxyC6H3

398
4-ClC6H4CH2
2-imidazolyl

399
4-ClC6H4CH2
2-oxazolyl

400
4-ClC6H4CH2
4-isoxazolyl

401
4-ClC6H4CH2
4-HOC6H4

402
4-ClC6H4CH2
3-HOC6H4

403
4-ClC6H4CH2
3,4-diHOC6H4

404
4-ClC6H4CH2
4-NH2CH2C6H4

405
4-ClC6H4CH2
3-NH2CH2C6H4

406
2-NH2CH2C6H4CH2
4-MeOC6H4

407
2-NH2CH2C6H4CH2
3-MeOC6H4

408
2-NH2CH2C6H4CH2
4-NHC6H4

409
2-NH2CH2C6H4CH2
3-NH2C6H4

410
2-NH2CH2C6H4CH2
2-NH2C6H4

411
2-NH2CH2C6H4CH2
4-Me2NC6H4

412
2-NH2CH2C6H4CH2
3-Me2NC6H4

413
2-NH2CH2C6H4CH2
2-Me2NC6H4

414
2-NH2CH2C6H4CH2
4-pyridyl

415
2-NH2CH2C6H4CH2
3-pyridyl

416
2-NH2CH2C6H4CH2
2-pyridyl

417
2-NH2CH2C6H4CH2
2-thiazolyl

418
2-NH2CH2C6H4CH2
2-pyrazolyl

419
2-NH2CH2C6H4CH2
5-isoquinolyl

420
2-NH2CH2C6H4CH2
3,4-

methylenedioxyC6H3

421
2-NH2CH2C6H4CH2
3,4-

ethylenedioxyC6H3

422
2-NH2CH2C6H4CH2
2-imidazolyl

423
2-NH2CH2C6H4CH2
2-oxazolyl

424
2-NH2CH2C6H4CH2
4-isoxazolyl

425
2-NH2CH2C6H4CH2
4-HOC6H4

426
2-NH2CH2C6H4CH2
3-HOC6H4

427
2-NH2CH2C6H4CH2
3,4-diHOC6H4

428
2-NH2CH2C6H4CH2
4-NH2CH2C6H4

429
2-NH2CH2C6H4CH2
3-NH2CH2C6H4

430
3-NH2CH2C6H4CH2
4-MOOC6H4

431
3-NH2CH2C6H4CH2
3-MeOC6H4

432
3-NH2CH2C6H4CH2
4-NH2C6H4

433
3-NH2CH2C6H4CH2
3-NH2C6H4

434
3-NH2CH2C6H4CH2
2-NH2C6H4

435
3-NH2CH2C6H4CH2
4-Me2NC6H4

436
3-NH2CH2C6H4CH2
3-Me2NC6H4

437
3-NH2CH2C6H4CH2
2-Me2NC6H4

438
3-NH2CH2C6H4CH2
4-pyriclyl

439
3-NH2CH2C6H4CH2
3-pyridyl

440
3-NH2CH2C6H4CH2
2-pyridyl

441
3-NH2CH2C6H4CH2
2-thiazolyl

442
3-NH2CH2C6H4CH2
2-pyrazolyl

443
3-NH2CH2C6H4CH2
5-isoquinolyl

444
3-NH2CH2C6H4CH2
3,4-

methylenedioxyC6H3

445
3-NH2CH2C6H4CH2
3,4-

ethylenediOxyC6H3

446
3-NH2CH2C6H4CH2
2-imidazolyl

447
3-NH2CH2C6H4CH2
2-oxazolyl

448
3-NH2CH2C6H4CH2
4-isoxazolyl

449
3-NH2CH2C6H4CH2
4-HOC6H4

450
3-NH2CH2C6H4CH2
3-HOC6H4

451
3-NH2CH2C6H4CH2
3,4-diHOC6H4

452
3-NH2CH2C6H4CH2
4-NH2CH2C6H4

453
3-NH2CH2C6H4CH2
3-NH2CH2C6H4

454
4-NH2CH2C6H4CH2
4-MeOC6H4

455
4-NH2CH2C6H4CH2
3-MeOC6H4

456
4-NH2CH2C6H4CH2
4-NH2C6H4

457
4-NH2CH2C6H4CH2
3-NH2C6H4

458
4-NH2CH2C6H4CH2
2-NH2C6H4

459
4-NH2CH2C6H4CH2
4-Me2NC6H4

460
4-NH2CH2C6H4CH2
3-Me2NC6H4

461
4-NH2CH2C6H4CH2
2-Me2NC6H4

462
4-NH2CH2C6H4CH2
4-pyridyl

463
4-NH2CH2C6H4CH2
3-pyridyl

464
4-NH2CH2C6H4CH2
2-pyridyl

465
4-NH2CH2C6H4CH2
2-thiazolyl

466
4-NH2CH2C6H4CH2
2-pyrazolyl

467
4-NH2CH2C6H4CH2
5-isoquinolyl

468
4-NH2CH2C6H4CH2
3,4-

methylenedioxyC6H3

469
4-NH2CH2C6H4CH2
3,4-

ethylenedioxyC6H3

470
4-NH2CH2C6H4CH2
2-imidazolyl

471
4-NH2CH2C6H4CH2
2-oxazolyl

472
4-NH2CH2C6H4CH2
4-isoxazolyl

473
4-NH2CH2C6H4CH2
4-HOC6H4

474
4-NH2CH2C6H4CH2
3-HOC6H4

475
4-NH2CH2C6H4CH2
3,4-diHOC6H4

476
4-NH2CH2C6H4CH2
4-NH2CH2C6H4

477
4-NH2CH2C6H4CH2
3-NH2CH2C6H4

478
2-Me2NCH2C6H4CH2
4-MeOC6H4

479
2-Me2NCH2C6H4CH2
3-MCOC6H4

480
2-Me2NCH2C6H4CH2
4-NH2C6H4

481
2-Me2NCH2C6H4CH2
3-NH2C6H4

482
2-Me2NCH2C6H4CH2
2-NH2C6H4

483
2-Me2NCH2C6H4CH2
4-Me2NC6H4

484
2-Me2NCH2C6H4CH2
3-Me2NC6H4

485
2-Me2NCH2C6H4CH2
2-Me2NC6H4

486
2-Me2NCH2C6H4CH2
4-pyridyl

487
2-Me2NCH2C6H4CH2
3-pyridyl

488
2-Me2NCH2C6H4CH2
2-pyridyl

489
2-Me2NCH2C6H4CH2
2-thiazolyl

490
2-Me2NCH2C6H4CH2
2-pyrazolyl

491
2-Me2NCH2C6H4CH2
5-isoquinolyl

492
2-Me2NCH2C6H4CH2
3,4-

methylenedioxyC6H3

493
2-Me2NCH2C6H4CH2
3,4-

ethylenedioxyC6H3

494
2-Me2NCH2C6H4CH2
2-imidazolyl

495
2-Me2NCH2C6H4CH2
2-oxazolyl

496
2-Me2NCH2C6H4CH2
4-isoxazolyl

497
2-Me2NCH2C6H4CH2
4-HOC6H4

498
2-Me2NCH2C6H4CH2
3-HOC6H4

499
2-Me2NCH2C6H4CH2
3,4-diHOC6H4

500
2-Me2NCH2C6H4CH2
4-NH2CH2C6H4

501
2-Me2NCH2C6H4CH2
3-NH2CH2C6H4

502
3-Me2NCH2C6H4CH2
4-MeOC6H4

503
3-Me2NCH2C6H4CH2
3-MeOC6H4

504
3-Me2NCH2C6H4CH2
4-NH2C6H4

505
3-Me2NCH2C6H4CH2
3-NH2C6H4

506
3-Me2NCH2C6H4CH2
2-NH2C6H4

507
3-Me2NCH2C6H4CH2
4-Me2NC6H4

508
3-Me2NCH2C6H4CH2
3-Me2NC6H4

509
3-Me2NCH2C6H4CH2
2-Me2NC6H4

510
3-Me2NCH2C6H4CH2
4-pyridyl

511
3-Me2NCH2C6H4CH2
3-pyridyl

512
3-Me2NCH2C6H4CH2
2-pyridyl

513
3-Me2NCH2C6H4CH2
2-thiazolyl

514
3-Me2NCH2C6H4CH2
2-pyrazolyl

515
3-Me2NCH2C6H4CH2
5-isoquinolyl

516
3-Me2NCH2C6H4CH2
3,4-

methylenedioxyC6H3

517
3-Me2NCH2C6H4CH2
3,4-

ethylenedioxyC6H3

518
3-Me2NCH2C6H4CH2
2-imidazolyl

519
3-Me2NCH2C6H4CH2
2-oxazolyl

520
3-Me2NCH2C6H4CH2
4-isoxazolyl

521
3-Me2NCH2C6H4CH2
4-HOC6H4

522
3-Me2NCH2C6H4CH2
3-HOC6H4

523
3-Me2NCH2C6H4CH2
3,4-diHOC6H4

524
3-Me2NCH2C6H4CH2
4-NH2CH2C6H4

525
3-Me2NCH2C6H4CH2
3-NH2CH2C6H4

526
4-Me2NCH2C6H4CH2
4-MeOC6H4

527
4-Me2NCH2C6H4CH2
3-MeOC6H4

528
4-Me2NCH2C6H4CH2
4-NH2C6H4

529
4-Me2NCH2C6H4CH2
3-NH2C6H4

530
4-Me2NCH2C6H4CH2
2-NH2C6H4

531
4-Me2NCH2C6H4CH2
4-Me2NC6H4

532
4-Me2NCH2C6H4CH2
3-Me2NC6H4

533
4-Me2NCH2C6H4CH2
2-Me2NC6H4

534
4-Me2NCH2C6H4CH2
4-pyridyl

535
4-Me2NCH2C6H4CH2
3-pyridyl

536
4-Me2NCH2C6H4CH2
2-pyridyl

537
4-Me2NCH2C6H4CH2
2-thiazolyl

538
4-Me2NCH2C6H4CH2
2-pyrazolyl

539
4-Me2NCH2C6H4CH2
5-isoquinolyl

540
4-Me2NCH2C6H4CH2
3,4-

methylenedioxyC6H3

541
4-Me2NCH2C6H4CH2
3,4-

ethylenedioxyC6H3

542
4-Me2NCH2C6H4CH2
2-imdazolyl

543
4-Me2NCH2C6H4CH2
2-oxazolyl

545
4-Me2NCH2C6H4CH2
4-isoxazolyl

546
4-Me2NCH2C6H4CH2
4-HOC6H4

547
4-Me2NCH2C6H4CH2
3-HOC6H4

548
4-Me2NCH2C6H4CH2
3,4-diHOC6H4

549
4-Me2NCH2C6H4CH2
4-NH2CH2C6H4

550
4-Me2NCH2C6H4CH2
3-NH2CH2C6H4

551
H
3-MeOC6H4

552
H
4-NH-C6H4

553
H
3-NH2C6H4

554
H
2-NH2C6H4

555
H
4-Me2NC6H4

556
H
3-Me2NC6H4

557
H
2-Me2NC6H4

558
H
3-pyridyl

559
H
2-pyridyl

560
H
2-thiazolyl

561
H
2-pyrazolyl

562
H
5-isoquinolyl

563
H
3,4-

methylenedioxyC6H3

564
H
3,4-

ethylenedioxyC6H3

565
H
2-imidazolyl

566
H
2-oxazolyl

567
H
4-isoxazolyl

568
H
4-HOC6H4

569
H
3-HOC6H4

570
H
3,4-diHOC6H4

571
H
4-NH2CH2C6H4

572
H
3-NH2CH2C6H4

573
Me
3-MeOC6H4

574
Me
4-NH2C6H4

575
Me
3-NH2C6H4

576
Me
2-NH2C6H4

577
Me
4-Me-NC6H4

578
Me
3-Me2NC6H4

579
Me
2-Me2NC6H4

580
Me
3-pyridyl

581
Me
2-pyridyl

582
Me
2-thiazolyl

583
Me
2-pyrazolyl

584
Me
5-isoquinolyl

585
Me
3,4-

ethylenedioxyC6H3

586
Me
2-imidazolyl

587
Me
2-oxazolyl

588
Me
4-isoxazolyl

589
Me
3-HOC6H4

590
Me
3,4-diHOC-H-

591
Me
4-NH2CH2C6H4

592
Me
3-NH2CH2C6H4

593
Et
3-MeOC6H4

594
Et
4-NH2C6H4

595
Et
3-NH2C6H4

596
Et
2-NH2C6H4

597
Et
4-Me2NC6H4

598
Et
3-Me2NC6H4

599
Et
2-Me2NC6H4

600
Et
4-pyridyl

601
Et
3-pyridyl

601
Et
2-pyridyl

603
Et
2-thiazolyl

604
Et
2-pyrazolyl

605
Et
5-isoquinolyl

606
Et
3,4-

methylenedioxyC6H3

607
Et
3,4-

ethylenedioxyC6H3

608
Et
2-imidazolyl

609
Et
2-oxazolyl

610
Et
4-isoxazolyl

611
Et
4-HOC6H4

612
Et
3-HOC-H-

613
Et
3,4-diHOC6H4

614
Et
4-NH2CH2C6H4

615
Et
3-NH2CH2C6H4

616
Me2NCH2
3-MeOC6H4

617
Me2NCH2
4-NH2C6H4

618
Me2NCH2
3-NH2C6H4

619
Me2NCH2
2-NH2C6H4

620
Me2NCH2
4-Me2NC6H4

621
Me2NCH2
3-Me2NC6H4

622
Me2NCH2
2-Me2NC6H4

623
Me2NCH2
4-pyridyl

624
Me2NCH2
3-pyridyl

625
Me2NCH2
2-pyridyl

626
Me2NCH2
2-thiazolyl

627
Me2NCH2
2-pyrazolyl

628
Me2NCH2
5-isoquinolyl

629
Me2NCH2
3,4-

methylenedioxyC6H3

630
Me2NCH2
3,4-

ethylenedioxyC6H3

631
Me2NCH2
2-imidazolyl

632
Me2NCH2
2-oxazolyl

633
Me2NCH2
4-isoxazolyl

634
Me2NCH2
4-HOC6H4

635
Me2NCH2
3-HOC6H4

636
Me2NCH2
3,4-diHOC6H4

637
Me2NCH2
4-NH2CH2C6H4

638
Me2NCH2
3-NH2CH2C6H4

639
ELNHCH2
3-MeOC6H4

640
EtNHCH2
4-NH2C6H4

641
EtNHCH2
3-NH2C6H4

642
EtNHCH2
2-NH2C6H4

643
EtNHCH2
4-Me2NC6H4

644
EtNHCH2
3-Me2NC6H4

645
EtNHCH2
2-Me2NC6H4

646
EtNHCH2
4-pyridyl

647
EtNHCH2
3-pyridyl

648
EtNHCH2
2-pyridyl

649
EtNHCH2
2-thiazolyl

650
EtNHCH2
2-pyrazolyl

651
EtNHCH2
5-isoquinolyl

652
EtNHCH2
3,4-

methylenedioxyC6H3

653
EtNHCH2
3,4-

ethylenedioxyC6H3

654
EtNHCH2
2-imidazolyl

655
EtNHCH2
2-oxazolyl

656
EtNHCH2
4-isoxazolyl

657
EtNHCH2
4-HOC6H4

658
EtNHCH2
3-HOC6H4

659
EtNHCH2
3,4-diHOC6H4

660
EtNHCH2
4-NH2CH2C6H4

661
EtNHCH2
3-NH2CH2C6H4

662
HOCH2CH2NHCH2
3-Me2C-H-

663
HOCH2CH2NHCH2
4-NH2C6H4

664
HOCH2CH2NHCH2
3-NH2C6H4

665
HOCH2CH2NHCH2
2-NH2C6H4

666
HOCH2CH2NHCH2
4-Me2NC6H4

667
HOCH2CH2NHCH2
3-Me2NC6H4

668
HOCH2CH2NI-ICH2
2-Me2NC6H4

669
HOCH2CH2NHCH2
4-pyridyl

670
HOCH2CH2NHCH2
3-pyridyl

671
HOCH2CH2NHCH2
2-pyridyl

672
HOCH2CH2NHCH2
2-thiazolyl

673
HOCH2CR2NHCH2
2-pyrazolyl

674
HOCH2CH2NHCH2
5-isoquinolyl

675
HOCH2CH2NHCH2
3,4-

methylenedioxyC6H3

676
HOCH2CH2NHCH2
3,4-

ethylenedioxyC6H3

677
HOCH2CH2NHCH2
2-imidazolyl

678
HOCH2CH2NHCH2
2-oxazolyl

679
HOCH2CH2NHCH2
4-isoxazolyl

680
HOCH2CH2NHCH2
4-HOC6H4

681
HOCH2CH2NHCH2
3-HOC6H4

682
HOCH2CH2NHCH2
3,4-diHOC6H4

683
HOCH2CH2NHCH2
4-NH2CH2C6H4

684
HOCH2CH2NHCH2
3-NH2CH2C6H4

685
H2NCH2CH2NHCH2
4-Me2C6H4

686
H2NCH2CH2NHCH2
3-MeOC6H4

687
H2NCH2CH2NHCH2
4-NH2C6H4

688
H2NCH2CH2NHCH2
3-NH2C6H4

689
H2NCH2CH2NHCH2
2-NH2C6H4

690
H2NCH2CH2NHCH2
4-Me2NC6H4

691
H2NCH2CH2NIICH2
3-Me2NC6H4

692
H2NCH2CH2NHCH2
2-Me2NC6H4

693
H2NCH2CH2NHCH2
4-pyridyl

694
H2NCH2CH2NHCH2
3-pyridyl

695
H2NCH2CH2NHCH2
2-pyridyl

696
H2NCH2CH2NHCH2
2-thiazolyl

697
H2NCH2CH2NHCH2
2-pyrazolyl

698
H2NCH2CH2NHCH2
5-isoquinolyl

699
H2NCH2CH2NHCH2
3,4-

methylenedioxyC6H3

700
H2NCH2CH2NHCH2
3,4-

ethylenedioxyC6H3

701
H2NCH2CH2NHCH2
2-imidazolyl

702
H2NCH2CH2NHCH2
2-oxazolyl

703
H2NCH2CH2NHCH2
4-isoxazolyl

704
H2NCH2CH2NHCH2
4-HOC6H4

705
H2NCH2CH2NHCH2
3-HOC6H4

706
H2NCH2CH2NHCH2
3,4-diHOC6H4

707
H2NCH2CH2NHCH2
4-N112CH2C6H4

708
H2NCH2CH2NHCH2
3-NH2CH2C6H4

709
Me2NCH2CH2NHCH2
4-MeOC6H4

710
Me2NCH2CH2NHCH2
3-MeOC6H4

111
Me2NCH2CH2NHCH2
4-NH2C6H4

712
Me2NCH2CH2NHCH2
3-NH2C6H4

713
Me2NCH2CH2NHCH2
2-NH2C6H4

714
Me2NCH2CH2NHCH2
4-Me2NC6H4

715
Me2NCH2CH2NHCH2
3-Me2NC6H4

716
Me2NCH2CH2NHCH2
2-Me2NC6H4

717
Me2NCH2CH2NHCH2
4-pyridyl

718
Me2NCH2CH2NHCH2
3-pyridyl

719
Me2NCH2CH2NHCH2
2-pyridyl

720
Me2NCH2CH2NHCH2
2-thiazolyl

721
Me2NCH2CH2NHCH2
2-pyrazolyl

722
Me2NCH2CH2NHCH2
5-isoquinolyl

723
Me2NCH2CH2NHCH2
BA-

methylenedioxyC6H3

724
Me2NCH2CH2NHCH2
3,4-

ethylenedioxyC6H3

725
Me2NCH2CH2NHCH2
2-imidazolyl

726
Me2NCH2CH2NHCH2
2-oxazolyl

727
Me2NCH2CH2NHCH2
4-isoxazolyl

728
Me2NCH2CH2NHCH2
4-H0C6H4

729
Me2NCH2CH2NHCH2
3-HOC6H4

730
Me2NCH2CH2NHCH2
3 ,4-diHOC6H4

731
Me2NCH2CH2NHCH2
4-NH2CH2C6H4

732
Me2NCH2CH2NHCH2
3-NH2CH2C6H4

733
1-morpholinylmethyl
3-MeOC6H4

734
1-morpholinylmethyl
4-NH-C6H4

735
1-morphoinlylmethyl
3-NH2C6H4

736
1-morpholinylmethyl
2-NH2C6H4

737
1-morpholinylmethyl
4-Me2NC6H4

738
1-morpholinylmethyl
3-Me2NC6H4

739
1-morpholinylmethyl
2-Me2NC6H4

740
1-morpholinylmethyl
4-pyridyl

741
1-morpholinylmethyl
3-pyridyl

742
1-morpholinylmethyl
2-pyridyl

743
1-morpholinylmethyl
2-thiazolyl

744
1-morpholinylmethyl
2-pyrazolyl

745
1-morpholinylmethyl
5-isoquinolyl

746
1-morpholinylmethyl
3,4-

methylenedioxyC6H3

747
1-morpholinylmethyl
3,4-

ethylenedioxyC6H3

748
1-morpholinylmethyl
2-imidazolyl

749
1-morpholinylmethyl
2-oxazolyl

750
1-morpholinylmethyl
4-isoxazolyl

751
1-morpholinylmethyl
4-HOC6H4

752
1-morpholinylmethyl
3-HOC6H4

753
1-morpholinylmethyl
3,4-diHOC6H4

754
1-morpholinylmethyl
4-NH2CH2C6H4

755
1-morpholinylmethyl
3-NH2CH2C6H4

756
1-thiomorpholinylmethyl
3-MeOC6H4

757
1-thiomorpholinylmethyl
4-NH2C6H4

758
1-thiomorpholinylmethyl
3-NH2C6H4

759
1-thiomorpholinylmethyl
2-NH2C6H4

760
1-thiomorpholinylmethyl
4-Me-NC6H4

761
1-thiomorpholinylmethyl
3-Me2NC6H4

762
1-thiomorpholinylmethyl
2-Me2NC6H4

763
1-thiomorpholinylmethyl
4-pyridyl

764
1-thiomorpholinylmethyl
3-pyridyl

765
1-thiomorpholinylmethyl
2-pyridyl

766
1-thiomorpho1inylmethyl
2-thiazolyl

767
1-thiomorpholinylmethyl
2-pyrazolyl

768
1-thiomorpholinylmethyl
5-isoquinolyl

769
1-thiomorpholinylmethyl
3,4-

methylenedioxyC6H3

770
1-thiomorpholinylmethyl
3,4-

ethylenedioxyC6H3

771
l-thiomorpholinylmethyl
2-imidazolyl

772
1-thiomorpholinylmethyl
2-oxazolyl

773
1-thiomorpholinylmethyl
4-isoxazolyl

774
1-thiomorpholinylmethyl
4-HOC6H4

775
1-thiomorpholinylmethyl
3-HOC6H-

776
1-thiomorpholinylmethyl
3,4-diHOC6H4

777
1-thiomorpholinylmethyl
4-Me2CH2C6H4

778
1-thiomorpholinylmethyl
3-NH2CH2C6H4

779
1-piperazinylmethyl
3-Me2C6H4

780
1-piperazinylmethyl
4-NH2C6H4

781
1-piperazinylmethyl
3-NH2C6H4

782
1-piperazinylmethyl
2-NH2C6H4

783
1-piperazinylmethyl
4-Me-NC-H-

784
1-piperazinylmethyl
3-Me2NC6H4

785
1-piperazinylmethyl
2-Me2NC6H4

786
1-piperazinylmethyl
4-pyridyl

787
1-piperazinylmethyl
3-pyridyl

788
1-piperazinylmethyl
2-pyridyl

789
1-piperazinylmethyl
2-thiazolyl

790
1-piperazinylmethyl
2-pyrazolyl

791
1-piperazinylmethyl
5-isoquinolyl

792
1-piperazinylmethyl
3,4-

methylenedioxyC6H3

793
1-piperazinylmethyl
3,4-

ethylenedioxyC6H3

794
1-piperazinylmethyl
2-imidazolyl

795
1-piperazinylmethyl
2-oxazolyl

796
1-piperazinylmethyl
4-isoxazolyl

797
1-piperazinylmethyl
4-HOC6H4

798
1-piperazinylmethyl
3-HOC6H4

799
1-piperazinylmethyl
3,4-diHOC6H4

800
1-piperazinylmethyl
4-NH2CH2C6H4

801
1-piperazinylmethyl
3-NH2CH2C6H4

[0358]

3

TABLE 3

Example

Number
R1
R2

802
2-pyridylmethyl
4-MeOC6H4

803
2-pyridylmethyl
3-MeOC6H4

804
2-pyridylmethyl
4-NH2C6H4

805
2-pyridylmethyl
3-NH2C6H4

806
2-pyridylmethyl
2-NH2C6H4

807
2-pyridylmethyl
4-Me2NC6H4

808
2-pyridylmethyl
3-Me2NC6H4

809
2-pyridylmethyl
2-Me2NC6H4

810
2-pyridylmethyl
4-pyridyl

811
2-pyridylmethyl
3-pyridyl

812
2-pyridylmethyl
2-pyridyl

813
2-pyridylmethyl
2-thiazolyl

814
2-pyridylmethyl
2-pyrazolyl

815
2-pyridylmethyl
5-isoquinolyl

816
2-pyridylmethyl
3,4-

methylenedioxyC6H3

817
2-pyridylmethyl
3,4-

ethylenedioxyC6H3

818
2-pyridylmethyl
2-imidazolyl

819
2-pyridylmethyl
2-oxazolyl

820
2-pyridylmethyl
4-isoxazolyl

821
2-pyridylmethyl
4-HOC6H4

822
2-pyridylmethyl
3-HOC6H4

823
2-pyridylmethyl
3,4-diHOC6H4

824
2-pyriclymethyl
4-NH2CH2C6H4

825
2-pyridyirmthyl
3-NH2CH2C6H4

826
3-pyridyirmthyl
4-MeOC6H4

827
3-pyridylmethyl
3-MeOC6H4

828
3-pyridylmethyl
4-NH2C6H4

829
3-pyridylmethyl
3-NH2C6H4

830
3-pyridylmethyl
2-NH2C6H4

831
3-pyridylmethyl
4-Me2NC6H4

832
3-pyridylmethyl
3-Me2NC6H4

833
3-pyridylmethyl
2-Me2NC6H4

834
3-pyridylmethyl
4-pyridyl

835
3-pyridyilmethyl
3-pyridyl

836
3-pyridylmethyl
2-pyridyl

837
3-pyridylmethyl
2-thiazolyl

838
3-pyridylmethyl
2-pyrazolyl

839
3-pyridylmethyl
5-isoquinolyl

840
3-pyridylmethyl
3,4-

methylenedioxyC6H3

841
3-pyridylmethyl
3,4-

ethylenedioxyC6H3

842
3-pyridylmethyl
2-imidazolyl

843
3-pyridylmethyl
2-oxazolyl

844
3-pyridylmethyl
4-isoxazolyl

845
3-pyridylmethyl
4-HOC6H4

846
3-pyridylmethyl
3-HOC6H4

847
3-pyridylmethyl
3,4-diHOC6H4

848
3-pyridylmethyl
4-NH2CH2C6H4

849
3-pyridylmethyl
3-NH2CH2C6H4

850
4-pyridylmethyl
4-MeOC6H4

851
4-pyridylmethyl
3-MeOC6H4

852
4-pyridylmethyl
4-NH2C6H4

853
4-pyridylmethyl
3-NH2C6H4

854
4-pyridylmethyl
2-NH2C6H4

855
4-pyridylmethyl
4-Me2NC6H4

856
4-pyridylmethyl
3-Me2NC6H4

857
4-pyridylmethyl
2-Me2NC6H4

858
4-pyridylmethyl
4-pyridyl

859
4-pyridylmethyl
3-pyridyl

860
4-pyridylmethyl
2-pyridyl

861
4-pyridylmethyl
2-thiazolyl

862
4-pyridylmethyl
2-pyrazolyl

863
4-pyridylmethyl
5-isoquinolyl

864
4-pyridylmethyl
3,4-

methylenedioxyC6H3

865
4-pyridylmethyl
3,4-

ethyl enedioxyC6H3

866
4-pyridylmethyl
2-imidazolyl

867
4-pyridylmethyl
2-oxazolyl

868
4-pyridylmethyl
4-isoxazolyl

869
4-pyridylmethyl
4-HOC6H4

870
4-pyridylmethyl
3-HOC6H4

871
4-pyridylmethyl
3,4-diHOC6H4

872
4-pyridylmethyl
4-NH2CH2C6H4

873
4-pyridylmethyl
3-NH2CH2C6H4

874
2-NH2C6H4
4-MeOC6H4

875
2-NH2C6H4
3-MeOC6H4

876
2-NH2C6H4
4-NH2C6H4

877
2-NH2C6H4
3-NH2C6H4

878
2-NH2C6H4
2-NH2C6H4

879
2-NH2C6H4
4-Me2NC6H4

880
2-NH2C6H4
3-Me2NC6H4

881
2-NH2C6H4
2-Me2NC6H4

882
2-NH2C6H4
4-pyridyl

883
2-NH2C6H4
3-pyridyl

884
2-NH2C6H4
2-pyridyl

885
2-NH2C6H4
2-thiazolyl

886
2-NH2C6H4
2-pyrazolyl

887
2-NH2C6H4
5-isoquinolyl

888
2-NH2C6H4
3,4-

methylenedioxyC6H3

889
2-NH2C6H4
3,4-

ethylenedioxyC6H3

890
2-NH2C6H4
2-imidazolyl

891
2-NH2C6H4
2-oxazolyl

892
2-NH2C6H4
4-isoxazolyl

893
2-NH2C6H4
4-HOC6H4

894
2-NH2C6H4
3-HOC6H4

895
2-NH2C6H4
3,4-diHOC6H4

896
2-NH2C6H4
4-NH2CH2C6H4

897
2-NH2C6H4
3-NH2CH2C6H4

898
3-NH2C6H4
4-MeOC6H4

899
3-NH2C6H4
3-MeOC6H4

900
3-NH2C6H4
4-NH2C6H4

901
3-NH2C6H4
3-NH2C6H4

902
3-NH2C6H4
2-NH2C6H4

903
3-NH2C6H4
4-Me2NC6H4

904
3-NH2C6H4
3-Me2NC6H4

905
3-NH2C6H4
2-Me2NC6H4

906
3-NH2C6H4
4-pyridyl

907
3-NH2C6H4
3-pyridyl

908
3-NH2C6H4
2-pyridyl

909
3-NH2C6H4
2-thiazolyl

910
3-NH2C6H4
2-pyrazolyl

911
3-NH2C6H4
5-isoquinolyl

912
3-NH2C6H4
3,4-

methylenedioxyC6H3

913
3-NH2C6H4
3,4-

ethylenedioxyC6H3

914
3-NH2C6H4
2-imidazolyl

915
3-NH2C6H4
2-oxazolyl

916
3-NH2C6H4
4-isoxazolyl

917
3-NH2C6H4
4-HOC6H4

918
3-NH2C6H4
3-HOC6H4

919
3-NH2C6H4
3,4-diHOC6H4

920
3-NH2C6H4
4-NH2CH2C6H4

921
3-NH2C6H4
3-NH2CH2C6H4

922
4-NH2C6H4
4-NH2CH2C6H4

923
4-NH2C6H4
3-MeOC6H4

924
4-NH2C6H4
4-NH2C6H4

925
4-NH2C6H4
3-NH2C6H4

926
4-NH2C6H4
2-NH2C6H4

927
4-NH2C6H4
4-Me2NC6H4

928
4-NH2C6H4
3-Me2NC6H4

930
4-NH2C6H4
2-Me2NC6H4

931
4-NH2C6H4
4-pyridyl

932
4-NH2C6H4
3-pyridyl

933
4-NH2C6H4
2-pyridyl

934
4-NH2C6H4
2-thiazolyl

935
4-NH2C6H4
2-pyrazolyl

936
4-NH2C6H4
5-isoquinolyl

937
4-NH2C6H4
3,4-

methylenedioxyC6H3

938
4-NH2C6H4
3,4-

ethylenedioxyC6H3

939
4-NH2C6H4
3,4-

ethylenedioxyC6H3

940
4-NH2C6H4
2-oxazolyl

941
4-NH2C6H4
4-isoxazolyl

942
4-NH2C6H4
4-HOC6H4

943
4-NH2C6H4
3-HOC6H4

944
4-NH2C6H4
3,4-diHOC6H4

945
4-NH2C6H4
4-NH2CH2C6H4

946
4-NH2C6H4
3-NH2CH2C6H4

947
2-MeOC6H4
4-MeOC6H4

948
2-MeOC6H4
3-MeOC6H4

949
2-MeOC6H4
4-NH2C6H4

950
2-MeOC6H4
3-NH2C6H4

951
2-MeOC6H4
2-NH2C6H4

952
2-MeOC6H4
4-Me2NC6H4

953
2-MeOC6H4
3-Me2NC6H4

954
2-MeOC6H4
2-Me2NC6H4

955
2-MeOC6H4
4-pyridyl

956
2-MeOC6H4
3-pyridyl

957
2-MeOC6H4
2-pyridyl

958
2-MeOC6H4
2-thiazolyl

959
2-MeOC6H4
2-pyrazolyl

960
2-MeOC6H4
5-isoquinolyl

961
2-MeOC6H4
3,4-

methylenedioxy6H3

962
2-MeOC6H4
3,4-

ethylenedioxy6H3

963
2-MeOC6H4
2-imidazolyl

964
2-MeOC6H4
2-oxazolyl

965
2-MeOC6H4
4-isoxazolyl

966
2-MeOC6H4
4-HOC6H4

967
2-MeOC6H4
3-HOC6H4

968
2-MeOC6H4
3,4-diHOC6H4

969
2-MeOC6H4
4-NH2CH2C6H4

970
2-MeOC6H4
3-NH2CH2C6H4

971
3-MeOC6H4
4-MeOC6H4

972
3-MeOC6H4
3-MeOC6H4

973
3-MeOC6H4
4-NH2C6H4

974
3-MeOC6H4
3-NH2C6H4

975
3-MeOC6H4
2-NH2C6H4

976
3-MeOC6H4
4-Me2NC6H4

977
3-MeOC6H4
3-Me2NC6H4

978
3-MeOC6H4
2-Me2NC6H4

979
3-MeOC6H4
4-pyridyl

980
3-MeOC6H4
3-pyridyl

981
3-MeOC6H4
2-pyridyl

982
3-MeOC6H4
2-thiazolyl

983
3-MeOC6H4
2-pyrazolyl

984
3-MeOC6H4
5-isoquinolyl

985
3-MeOC6H4
3,4-

methylenedioxyC6H3

986
3-MeOC6H4
3,4-

ethylenedioxyC6H3

987
3-MeOC6H4
2-imidazolyl

988
3-MeOC6H4
2-oxazolyl

989
3-MeOC6H4
4-isoxazolyl

990
3-MeOC6H4
4-HOC6H4

991
3-MeOC6H4
3-HOC6H4

992
3-MeOC6H4
3,4-diHOC6H4

993
3-MeOC6H4
4-NH2CH2C6H4

994
3-MeOC6H4
3-NH2CH2C6H4

995
4-MeOC6H4
4-MeOC6H4

996
4-MeOC6H4
3-MeOC6H4

997
4-MeOC6H4
4-NH2C6H4

998
4-MeOC6H4
3-NH2C6H4

999
4-MeOC6H4
2-NH2C6H4

1000
4-MeOC6H4
4-Me2NC6H4

1001
4-MeOC6H4
3-Me2NC6H4

1002
4-MeOC6H4
2-Me2NC6H4

1003
4-MeOC6H4
4-pyridyl

1004
4-MeOC6H4
3-pyridyl

1005
4-MeOC6H4
2-pyridyl

1006
4-MeOC6H4
2-thiazolyl

1007
4-MeOC6H4
2-pyrazolyl

1008
4-MeOC6H4
5-isoquinolyl

1009
4-MeOC6H4
3,4-

methylenedioxy6H3

1010
4-MeOC6H4
3,4-

ethylenedioxyC6H3

1011
4-MeOC6H4
2-imidazolyl

1012
4-MeOC6H4
2-oxazolyl

1013
4-MeOC6H4
4-isoxazolyl

1014
4-MeOC6H4
4-HOC6H4

1015
4-MeOC6H4
3-HOC6H4

1016
4-MeOC6H4
3,4-diHOC6H4

1017
4-MeOC6H4
4-NH2CH2C6H4

1018
4-MeOC6H4
3-NH2CH2C6H4

1019
2-HOC6H4
4-MeOC6H4

1020
2-HOC6H4
3-MeOC6H4

1021
2-HOC6H4
4-NH2C6H4

1022
2-HOC6H4
3-NH2C6H4

1023
2-HOC6H4
2-NH2C6H4

1024
2-HOC6H4
4-Me2NC6H4

1025
2-HOC6H4
3-Me2NC6H4

1026
2-HOC6H4
2-Me2NC6H4

1027
2-HOC6H4
4-pyridyl

1028
2-HOC6H4
3-pyridyl

1029
2-HOC6H4
2-pyridyl

1030
2-HOC6H4
2-thiazolyl

1031
2-HOC6H4
2-pyrazolyl

1032
2-HOC6H4
5-isoquinolyl

1033
2-HOC6H4
3,4-

methylenedioXyC6H3

1034
2-HOC6H4
3,4-

ethylenedioxyC6H3

1035
2-HOC6H4
2-imidazolyl

1036
2-HOC6H4
2-oxazolyl

1037
2-HOC6H4
4-isoxazolyl

1038
2-HOC6H4
4-HOC6H4

1039
2-HOC6H4
3-HOC6H4

1040
2-HOC6H4
3,4-diHOC6H4

1041
2-HOC6H4
4-NH2CH2C6H4

1042
2-HOC6H4
3-NH2CH2C6H4

1043
3-HOC6H4
4-MeOC6H4

1044
3-HOC6H4
3-MeOC6H4

1045
3-HOC6H4
4-NH2C6H4

1046
3-HOC6H4
3-NH2C6H4

1047
3-HOC6H4
2-NH2C6H4

1048
3-HOC6H4
4-Me2NC6H4

1049
3-HOC6H4
3-Me2NC6H4

1050
3-HOC6H4
2-Me2NC6H4

1051
3-HOC6H4
4-pyridyl

1052
3-HOC6H4
3-pyridyl

1053
3-HOC6H4
2-pyridyl

1054
3-HOC6H4
2-thiazolyl

1055
3-HOC6H4
2-pyrazolyl

1056
3-HOC6H4
5-isoquinolyl

1057
3-HOC6H4
3,4-

methylenedioxyC6H3

1058
3-HOC6H4
3,4-

ethylenedioxyC6H3

1059
3-HOC6H4
2-imidazolyl

1060
3-HOC6H4
2-oxazolyl

1061
3-HOC6H4
4-isoxazolyl

1062
3-HOC6H4
4-HOC6H4

1063
3-HOC6H4
3-HOC6H4

1064
3-HOC6H4
3,4-diHOC6H4

1065
3-HOC6H4
4-NH2CH2C6H4

1066
3-HOC6H4
3-NH2CH2C6H4

1067
4-HOC6H4
4-MeOC6H4

1068
4-HOC6H4
3-MeOC6H4

1069
4-HOC6H4
4-NH2C6H4

1070
4-HOC6H4
3-NH2C6H4

1071
4-HOC6H4
2-NH2C6H4

1072
4-HOC6H4
4-Me2NC6H4

1073
4-HOC6H4
3-Me2NC6H4

1074
4-HOC6H4
2-Me2NC6H4

1075
4-HOC6H4
4-pyridyl

1076
4-HOC6H4
3-pyridyl

1077
4-HOC6H4
2-pyridyl

1078
4-HOC6H4
2-thiazolyl

1079
4-HOC6H4
2-pyrazolyl

1080
4-HOC6H4
5-isoquinolyl

1081
4-HOC6H4
3,4-

methylenedioxyC6H3

1082
4-HOC6H4
3,4-

ethylenedioxyC6H3

1083
4-HOC6H4
2-imidazolyl

1084
4-HOC6H4
2-oxazolyl

1085
4-HOC6H4
4-isoxazolyl

1086
4-HOC6H4
4-HOC6H4

1087
4-HOC6H4
3-HOC6H4

1088
4-HOC6H4
3,4-diHOC6H4

1089
4-HOC6H4
4-NH2CH2C6H4

1090
4-HOC6H4
3-NH2CH2C6H4

1091
4-C1C6H4
4-MeOC6H4

1092
4-ClC6H4
3-MeOC6H4

1093
4-ClC6H4
4-NH2C6H4

1094
4-ClC6H4
3-NH2C6H4

1095
4-ClC6H4
2-NH2C6H4

1096
4-ClC6H4
4-Me2NC6H4

1097
4-ClC6H4
3-Me2NC6H4

1098
4-ClC6H4
2-Me2NC6H4

1099
4-ClC6H4
4-pyridyl

1100
4-ClC6H4
3-pyridyl

1101
4-ClC6H4
2-pyridyl

1102
4-ClC6H4
2-thiazolyl

1103
4-ClC6H4
2-pyrazolyl

1104
4-ClC6H4
5-isoquinolyl

1105
4-ClC6H4
3,4-

methylenedioxyC6H3

1106
4-ClC6H4
3,4-

ethylenedioxyC6H3

1107
4-ClC6H4
2-imidazolyl

1108
4-ClC6H4
2-oxazolyl

1109
4-ClC6H4
4-isoxazolyl

1110
4-ClC6H4
4-HOC6H4

1111
4-ClC6H4
3-HOC6H4

1112
4-ClC6H4
3,4-diHOC6H4

1113
4-ClC6H4
4-NH2CH2C6H4

1114
4-ClC6H4
3-NH2CH2C6H4

1115
2-NH2CH2C6H4
4-MeOC6H4

1116
2-NH2CH2C6H4
3-MeOC6H4

1117
2-NH2CH2C6H4
4-NH2C6H4

1118
2-NH2CH2C6H4
3-NH2C6H4

1119
2-NH2CH2C6H4
2-NH2C6H4

1120
2-NH2CH2C6H4
4-Me2NC6H4

1121
2-NH2CH2C6H4
3-Me2NC6H4

1122
2-NH2CH2C6H4
2-Me2NC6H4

1123
2-NH2CH2C6H4
4-pyridyl

1124
2-NH2CH2C6H4
3-pyridyl

1125
2-NH2CH2C6H4
2-pyridyl

1126
2-NH2CH2C6H4
2-thiazolyl

1127
2-NH2CH2C6H4
2-pyrazolyl

1128
2-NH2CH2C6H4
5-isoquinolyl

1129
2-NH2CH2C6H4
3,4-

methylenedioxyC6H3

1130
2-NH2CH2C6H4
3,4-

ethylenedioxyC6H3

1131
2-NH2CH2C6H4
2-imidazolyl

1132
2-NH2CH2C6H4
2-oxazolyl

1133
2-NH2CH2C6H4
4-isoxazolyl

1134
2-NH2CH2C6H4
4-HOC6H4

1135
2-NH2CH2C6H4
3-HOC6H4

1136
2-NH2CH2C6H4
3,4-diHOC6H4

1137
2-NH2CH2C6H4
4-NH2CH2C6H4

1138
2-NH2CH2C6H4
3-NH2CH2C6H4

1139
3-NH2CH2C6H4
4-MeOC6H4

1140
3-NH2CH2C6H4
3-MCOC6H4

1141
3-NH2CH2C6H4
4-NH2C6H4

1142
3-NH2CH2C6H4
3-NH2C6H4

1143
3-NH2CH2C6H4
2-NH2C6H4

1144
3-NH2CH2C6H4
4-Me2NC6H4

1145
3-NH2CH2C6H4
3-Me2NC6H4

1146
3-NH2CH2C6H4
2-Me2NC6H4

1147
3-NH2CH2C6H4
4-pyridyl

1148
3-NH2CH2C6H4
3-pyridyl

1149
3-NH2CH2C6H4
2-pyridyl

1150
3-NH2CH2C6H4
2-thiazolyl

1151
3-NH2CH2C6H4
2-pyrazolyl

1152
3-NH2CH2C6H4
5-isoquinolyl

1153
3-NH2CH2C6H4
3,4-

methylenedioxyC6H3

1154
3-NH2CH2C6H4
3,4-

ethylenedioxyC6H3

1155
3-NH2CH2C6H4
2-imidazolyl

1156
3-NH2CH2C6H4
2-oxazolyl

1157
3-NH2CH2C6H4
4-isoxazolyl

1158
3-NH2CH2C6H4
4-HOC6H4

1159
3-NH2CH2C6H4
3-HOC6H4

1160
3-NH2CH2C6H4
3,4-diHOC6H4

1161
3-NH2CH2C6H4
4-NH2CH2C6H4

1162
3-NH2CH2C6H4
3-NH2CH2C6H4

1163
4-NH2CH2C6H4
4-MeOC6H4

1164
4-NH2CH2C6H4
3-MeOC6H4

1165
4-NH2CH2C6H4
4-NH2C6H4

1166
4-NH2CH2C6H4
3-NH2C6H4

1167
4-NH2CH2C6H4
2-NH2C6H4

1168
4-NH2CH2C6H4
4-Me2NC6H4

1169
4-NH2CH2C6H4
3-Me2NC6H4

1170
4-NH2CH2C6H4
2-Me2NC6H4

1171
4-NH2CH2C6H4
4-pyridyl

1172
4-NH2CH2C6H4
3-pyridyl

1173
4-NH2CH2C6H4
2-pyridyl

1174
4-NH2CH2C6H4
2-thiazolyl

1175
4-NH2CH2C6H4
2-pyrazolyl

1176
4-NH2CH2C6H4
5-isoquinolyl

1177
4-NH2CH2C6H4
3,4-

methylenedioxy6H3

1178
4-NH2CH2C6H4
3,4-

ethylenedioxy6H3

1179
4-NH2CH2C6H4
2-imidazolyl

1180
4-NH2CH2C6H4
2-oxazolyl

1181
4-NH2CH2C6H4
4-isoxazolyl

1182
4-NH2CH2C6H4
4-HOC6H4

1183
4-NH2CH2C6H4
3-HOC6H4

1184
4-NH2CH2C6H4
3,4-diHOC6H4

1185
4-NH2CH2C6H4
4-NH2CH2C6H4

1186
4-NH2CH2C6H4
3-NH2CH2C6H4

1187
2-Me2NCH2C6H4
4-MeOC6H4

1188
2-Me2NCH2C6H4
3-MeOC6H4

1189
2-Me2NCH2C6H4
4-NH2C6H4

1190
2-Me2NCH2C6H4
3-NH2C6H4

1191
2-Me2NCH2C6H4
2-NH2C6H4

1192
2-Me2NCH2C6H4
4-Me2NC6H4

1193
2-Me2NCH2C6H4
3-Me2NC6H4

1194
2-Me2NCH2C6H4
2-Me2NC6H4

1195
2-Me2NCH2C6H4
4-pyridyl

1196
2-Me2NCH2C6H4
3-pyridyl

1197
2-Me2NCH2C6H4
2-pyridyl

1198
2-Me2NCH2C6H4
2-thiazolyl

1199
2-Me2NCH2C6H4
2-pyrazolyl

1200
2-Me2NCH2C6H4
5-isoquinolyl

1201
2-Me2NCH2C6H4
3,4-

methylenedioxyC6H3

1202
2-Me2NCH2C6H4
3,4-

ethylenedioxyC6H3

1203
2-Me2NCH2C6H4
2-imidazolyl

1204
2-Me2NCH2C6H4
2-oxazolyl

1205
2-Me2NCH2C6H4
4-isoxazolyl

1206
2-Me2NCH2C6H4
4-HOC6H4

1207
2-Me2NCH2C6H4
3-HOC6H4

1208
2-Me2NCH2C6H4
3,4-diHOC6H4

1209
2-Me2NCH2C6H4
4-NH2CH2C6H4

1210
2-Me2NCH2C6H4
3-NH2CH2C6H4

1211
3-Me2NCH2C6H4
4-MeOC6H4

1212
3-Me2NCH2C6H4
3-MeOC6H4

1213
3-Me2NCH2C6H4
4-NH2C6H4

1214
3-Me2NCH2C6H4
3-NH2C6H4

1215
3-Me2NCH2C6H4
2-NH2C6H4

1216
3-Me2NCH2C6H4
4-Me2NC6H4

1217
3-Me2NCH2C6H4
3-Me2NC6H4

1218
3-Me2NCH2C6H4
2-Me2NC6H4

1219
3-Me2NCH2C6H4
4-pyridyl

1220
3-Me2NCH2C6H4
3-pyridyl

1221
3-Me2NCH2C6H4
2-pyridyl

1222
3-Me2NCH2C6H4
2-thiazolyl

1223
3-Me2NCH2C6H4
2-pyrazolyl

1224
3-Me2NCH2C6H4
5-isoquinolyl

1225
3-Me2NCH2C6H4
3,4-

methylenedioxyC6H3

1226
3-Me2NCH2C6H4
3,4-

ethylenedioxyC6H3

1227
3-Me2NCH2C6H4
2-imidazolyl

1228
3-Me2NCH2C6H4
2-oxazolyl

1229
3-Me2NCH2C6H4
4-isoxazolyl

1230
3-Me2NCH2C6H4
4-HOC6H4

1231
3-Me2NCH2C6H4
3-HOC6H4

1232
3-Me2NCH2C6H4
3,4-diHOC6H4

1233
3-Me2NCH2C6H4
4-NH2CH2C6H4

1234
3-Me2NCH2C6H4
3-NH2CH2C6H4

1235
4-Me2NCH2C6H4
4-MeOC6H4

1236
4-Me2NCH2C6H4
3-MeOC6H4

1237
4-Me2NCH2C6H4
4-NH2C6H4

1238
4-Me2NCH2C6H4
3-NH2C6H4

1239
4-Me2NCH2C6H4
2-NH2C6H4

1240
4-Me2NCH2C6H4
4-Me2NC6H4

1241
4-Me2NCH2C6H4
3-Me2NC6H4

1242
4-Me2NCH2C6H4
2-Me2NC6H4

1243
4-Me2NCH2C6H4
4-pyridyl

1244
4-Me2NCH2C6H4
3-pyridyl

1245
4-Me2NCH2C6H4
2-pyridyl

1246
4-Me2NCH2C6H4
2-thiazolyl

1247
4-Me2NCH2C6H4
2-pyrazolyl

1248
4-Me2NCH2C6H4
5-isoquinolyl

1249
4-Me2NCH2C6H4
3,4-

methylenedioxyC6H3

1250
4-Me2NCH2C6H4
3,4-

ethylenedioxyC6H3

1251
4-Me2NCH2C6H4
2-imidazolyl

1252
4-Me2NCH2C6H4
2-oxazolyl

1253
4-Me2NCH2C6H4
4-isoxazolyl

1254
4-Me2NCH2C6H4
4-HOC6H4

1255
4-Me2NCH2C6H4
3-HOC6H4

1256
4-Me2NCH2C6H4
3,4-diHOC6H4

1257
4-Me2NCH2C6H4
4-NH2CH2C6H4

1258
4-Me2NCH2C6H4
3-NH2CH2C6H4

1259
H
4-MeOC6H4

1260
H
3-MeOC6H4

1261
H
4-NH2C6H4

1262
H
3-NH2C6H4

1263
H
2-NH2C6H4

1264
H
4-Me2NC6H4

1265
H
3-Me2NC6H4

1266
H
2-Me2NC6H4

1267
H
4-pyridyl

1268
H
3-pyridyl

1269
H
2-pyridyl

1270
H
2-thiazolyl

1271
H
2-pyrazolyl

1272
H
5-isoquinolyl

1273
H
3,4-

methylenedioxyC6H3

1274
H
3,4-

methylenedioxyC6H3

1275
H
2-imidazolyl

1276
H
2-oxazolyl

1277
H
4-isoxazolyl

1278
H
4-HOC6H4

1279
H
3-HOC6H4

1280
H
3,4-diHOC6H4

1281
H
4-NH2CH2C6H4

1282
H
3-NH2CH2C6H4

1283
Me
4-MeOC6H4

1284
Me
3-MeOC6H4

1285
Me
4-NH-hd 2C6H4

1286
Me
3-NH2C6H4

1287
Me
2-NH2C6H4

1288
Me
4-Me2NC6H4

1289
Me
3-Me2NC6H4

1290
Me
2-Me2NC6H4

1291
Me
4-pyridyl

1292
Me
3-pyridyl

1293
Me
2-pyridyl

1294
Me
2-thiazolyl

1295
Me
2-pyrazolyl

1296
Me
5-isoquinolyl

1297
Me
3,4-

methylenedioxyC6H3

1298
Me
3,4-

ethylenedioxy6H3

1299
Me
2-imidazolyl

1300
Me
2-oxazolyl

1301
Me
4-isoxazolyl

1302
Me
4-HOC6H4

1303
Me
3-HOC6H4

1304
Me
3,4-diHOC6H4

1305
Me
4-NH2CH2C6H4

1306
Me
3-NH2CH2C6H4

1307
Et
4-MeOC6H4

1308
Et
3-MeOC6H4

1309
Et
4-NH2C6H4

1310
Et
3-NH2C6H4

1311
Et
2-NH2C6H4

1312
Et
4-Me2NC6H4

1313
Et
3-Me2NC6H4

1314
Et
2-Me2NC6H4

1315
Et
4-pyridyl

1316
Et
3-pyridyl

1317
Et
2-pyridyl

1318
Et
2-thiazolyl

1319
Et
2-pyrazolyl

1320
Et
5-isoquinolyl

1321
Et
3,4-

methylenedioxyC6H3

1322
Et
3,4-

ethylenedioxyC6H3

1323
Et
2-imidazolyl

1324
Et
2-oxazolyl

1325
Et
4-isoxazolyl

1326
Et
4-HOC6H4

1327
Et
3-HOC6H4

1328
Et
3,4-diHOC6H4

1329
Et
4-NH2CH2C6H4

1330
Et
3-NH2CH2C6H4

1331
2-NH2C6H4CH2
4-MeOC6H4

1332
2-NH2C6H4CH2
3-MeOC6H4

1333
2-NH2C6H4CH2
4-NH2C6H4

1334
2-NH2C6H4CH2
3-NH2C6H4

1335
2-NH2C6H4CH2
2-NH2C6H4

1336
2-NH2C6H4CH2
4-Me2NC6H4

1337
2-NH2C6H4CH2
3-Me2NC6H4

1338
2-NH2C6H4CH2
2-Me2NC6H4

1339
2-NH2C6H4CH2
4-pyridyl

1340
2-NH2C6H4CH2
3-pyridyl

1341
2-NH2C6H4CH2
2-pyridyl

1342
2-NH2C6H4CH2
2-thiazolyl

1343
2-NH2C6H4CH2
2-pyrazolyl

1344
2-NH2C6H4CH2
5-isoquinolyl

1345
2-NH2C6H4CH2
3,4-

methylenedioxy6H3

1346
2-NH2C6H4CH2
3,4-

ethylenedioxyC6H3

1347
2-NH2C6H4CH2
2-imidazolyl

1348
2-NH2C6H4CH2
2-oxazolyl

1349
2-NH2C6H4CH2
4-isoxazolyl

1350
2-NH2C6H4CH2
4-HOC6H4

1351
2-NH2C6H4CH2
3-HOC6H4

1352
2-NH2C6H4CH2
3,4-diHOC6H4

1353
2-NH2C6H4CH2
4-NH2CH2C6H4

1354
2-NH2C6H4CH2
3-NH2CH2C6H4

1355
3-NH2C6H4CH2
4-MeOC6H4

1356
3-NH2C6H4CH2
3-MeOC6H4

1357
3-NH2C6H4CH2
4-NH2C6H4

1358
3-NH2C6H4CH2
3-NH2C6H4

1359
3-NH2C6H4CH2
2-NH2C6H4

1360
3-NH2C6H4CH2
4-Me2NC6H4

1361
3-NH2C6H4CH2
3-Me2NC6H4

1362
3-NH2C6H4CH2
2-Me2NC6H4

1363
3-NH2C6H4CH2
4-pyridyl

1364
3-NH2C6H4CH2
3-pyridyl

1365
3-NH2C6H4CH2
2-pyridyl

1366
3-NH2C6H4CH2
2-thiazolyl

1367
3-NH2C6H4CH2
2-pyrazolyl

1367
3-NH2C6H4CH2
5-isoquinolyl

1369
3-NH2C6H4CH2
3,4

methylenedioxyC6H3

1370
3-NH2C6H4CH2
3,4-

ethylenedioxyC6H3

1371
3-NH2C6H4CH2
2-imidazolyl

1372
3-NH2C6H4CH2
2-oxazolyl

1373
3-NH2C6H4CH2
4-isoxazolyl

1374
3-NH2C6H4CH2
4-HOC6H4

1375
3-NH2C6H4CH2
3-HOC6H4

1376
3-NH2C6H4CH2
3,4-diHOC6H4

1377
3-NH2C6H4CH2
4-NH2CH2C6H4

1378
3-NH2C6H4CH2
3-NH2CH2C6H4

1379
4-NH2C6H4CH2
4-MeOC6H4

1380
4-NH2C6H4CH2
3-MeOC6H4

1381
4-NH2C6H4CH2
4-NH2C6H4

1382
4-NH2C6H4CH2
3-NH2C6H4

1383
4-NH2C6H4CH2
2-NH2C6H4

1384
4-NH2C6H4CH2
4-Me2NC6H4

1385
4-NH2C6H4CH2
3-Me2NC6H4

1386
4-NH2C6H4CH2
2-Me2NC6H4

1387
4-NH2C6H4CH2
4-pyridyl

1388
4-NH2C6H4CH2
3-pyridyl

1389
4-NH2C6H4CH2
2-pyridyl

1390
4-NH2C6H4CH2
2-thiazolyl

1391
4-NH2C6H4CH2
2-pyrazolyl

1392
4-NH2C6H4CH2
5-isoquinolyl

1393
4-NH2C6H4CH2
3,4

methylenedioxyC6H3

1394
4-NH2C6H4CH2
3,4

ethylenedioxyC6H3

1395
4-NH2C6H4CH2
2-imidazolyl

1396
4-NH2C6H4CH2
2-oxazolyl

1397
4-NH2C6H4CH2
4-isoxazolyl

1398
4-NH2C6H4CH2
4-HOC6H4

1399
4-NH2C6H4CH2
3-HOC6H4

1400
4-NH2C6H4CH2
3,4-diHOC6H4

1401
4-NH2C6H4CH2
4-NH2CH2C6H4

1402
4-NH2C6H4CH2
3-NH2CH2C6H4

1403
2-MeOC6H4CH2
4-MeOC6H4

1404
2-MeOC6H4CH2
3-MeOC6H4

1405
2-MeOC6H4CH2
4-NH2C6H4

1406
2-MeOC6H4CH2
3-NH2CH4

1407
2-MeOC6H4CH2
2-NH2C6H4

1408
2-MeOC6H4CH2
4-Me2NC6H4

1409
2-MeOC6H4CH2
3-Me2NC6H4

1410
2-MeOC6H4CH2
2-Me2NC6H4

1411
2-MeOC6H4CH2
4-pyridyl

1412
2-MeOC6H4CH2
3-pyridyl

1413
2-MeOC6H4CH2
2-pyridyl

1414
2-MeOC6H4CH2
2-thiazolyl

1415
2-MeOC6H4CH2
2-pyrazolyl

1416
2-MeOC6H4CH2
5-isoquinolyl

1417
2-MeOC6H4CH2
3,4-

methylenedioxyC6H3

1418
2-MeOC6H4CH2
3,4-

ethylenedioxyC6H3

1419
2-MeOC6H4CH2
2-imidazolyl

1420
2-MeOC6H4CH2
2-oxazolyl

1421
2-MeOC6H4CH2
4-isoxazolyl

1422
2-MeOC6H4CH2
4-HOC6H4

1423
2-MeOC6H4CH2
3-HOC6H4

1424
2-MeOC6H4CH2
3,4-diHOC6H4

1425
2-MeOC6H4CH2
4-NH2CH2C6H4

1426
2-MeOC6H4CH2
3-NH2CH2C6H4

1427
3-MeOC6H4CH2
4-MeOC6H4

1428
3-MeOC6H4CH2
3-MeOC6H4

1429
3-MeOC6H4CH2
4-NH2C6H4

1430
3-MeOC6H4CH2
3-NH2C6H4

1431
3-MeOC6H4CH2
2-NH2C6H4

1432
3-MeOC6H4CH2
4-Me2NC6H4

1433
3-MeOC6H4CH2
3-Me2NC6H4

1434
3-MeOC6H4CH2
2-Me2NC6H4

1435
3-MeOC6H4CH2
4-pyridyl

1436
3-MeOC6H4CH2
3-pyridyl

1437
3-MeOC6H4CH2
2-pyridyl

1438
3-MeOC6H4CH2
2-thiazolyl

1439
3-MeOC6H4CH2
2-pyrazolyl

1440
3-MeOC6H4CH2
5-isoquinolyl

1441
3-MeOC6H4CH2
3,4

methylenedioxyC6H3

1442
3-MeOC6H4CH2
3,4-

ethylenedioxyC6H3

1443
3-MeOC6H4CH2
2-imidazolyl

1444
3-MeOC6H4CH2
2-oxazolyl

1445
3-MeOC6H4CH2
4-isoxazolyl

1446
3-MeOC6H4CH2
4-HOC6H4

1447
3-MeOC6H4CH2
3-HOC6H4

1448
3-MeOC6H4CH2
3,4-diHOC6H4

1449
3-MeOC6H4CH2
4-NH2CH2C6H4

1450
3-MeOC6H4CH2
3-NH2CH2C6H4

1451
4-MeOC6H4CH2
4-MeOC6H4

1452
4-MeOC6H4CH2
3-MeOC6H4

1453
4-MeOC6H4CH2
4-NH2C6H4

1454
4-MeOC6H4CH2
3-NH2C6H4

1455
4-MeOC6H4CH2
2-NH2C6H4

1456
4-MeOC6H4CH2
4-Me2NC6H4

1457
4-MeOC6H4CH2
3-Me2NC6H4

1458
4-MeOC6H4CH2
2-Me2NC6H4

1459
4-MeOC6H4CH2
4-pyridyl

1460
4-MeOC6H4CH2
3-pyridyl

1461
4-MeOC6H4CH2
2-pyridyl

1462
4-MeOC6H4CH2
2-thiazolyl

1463
4-MeOC6H4CH2
2-pyrazolyl

1464
4-MeOC6H4CH2
5-isoquinolyl

1465
4-MeOC6H4CH2
3,4-

methylenedioxyC6H3

1466
4-MeOC6H4CH2
3,4-

ethylenedioxyC6H3

1467
4-MeOC6H4CH2
2-imidazolyl

1468
4-MeOC6H4CH2
2-oxazolyl

1469
4-MeOC6H4CH2
4-isoxazolyl

1470
4-MeOC6H4CH2
4-HOC6H4

1471
4-MeOC6H4CH2
3-HOC6H4

1472
4-MeOC6H4CH2
3,4-diHOC6H4

1473
4-MeOC6H4CH2
4-NH2CH2C6H4

1474
4-MeOC6H4CH2
3-NH2CH2C6H4

1475
2-HOC6H4CH2
4-MeOC6H4

1476
2-HOC6H4CH2
3-MeOC6H4

1477
2-HOC6H4CH2
4-NH2C6H4

1478
2-HOC6H4CH2
3-NH2C6H4

1479
2-HOC6H4CH2
2-NH2C6H4

1480
2-HOC6H4CH2
4-Me2NC6H4

1481
2-HOC6H4CH2
3-Me2NC6H4

1482
2-HOC6H4CH2
2-Me2NC6H4

1483
2-HOC6H4CH2
4-pyridyl

1484
2-HOC6H4CH2
3-pyridyl

1485
2-HOC6H4CH2
2-pyridyl

1486
2-HOC6H4CH2
2-thiazolyl

1487
2-HOC6H4CH2
2-pyrazolyl

1488
2-HOC6H4CH2
5-isoquinolyl

1489
2-HOC6H4CH2
3,4-

methylenedioxy6H3

1490
2-HOC6H4CH2
3,4-

ethylenedioxy6H3

1491
2-HOC6H4CH2
2-imidazolyl

1492
2-HOC6H4CH2
2-oxazolyl

1493
2-HOC6H4CH2
4-isoxazolyl

1494
2-HOC6H4CH2
4-HOC6H4

1495
2-HOC6H4CH2
3-HOC6H4

1496
2-HOC6H4CH2
3,4-diHOC6H4

1497
2-HOC6H4CH2
4-NH2CH2C6H4

1498
2-HOC6H4CH2
3-NH2CH2C6H4

1499
3-HOC6H4CH2
4-MeOC6H4

1500
3-HOC6H4CH2
3-MeOC6H4

1501
3-HOC6H4CH2
4-NH2C6H4

1502
3-HOC6H4CH2
3-NH2C6H4

1503
3-HOC6H4CH2
2-NH2C6H4

1504
3-HOC6H4CH2
4-Me2NC6H4

1505
3-HOC6H4CH2
3-Me2NC6H4

1506
3-HOC6H4CH2
2-Me2NC6H4

1507
3-HOC6H4CH2
4-pyridyl

1508
3-HOC6H4CH2
3-pyridyl

1509
3-HOC6H4CH2
2-pyridyl

1510
3-HOC6H4CH2
2-thiazolyl

1511
3-HOC6H4CH2
2-pyrazolyl

1512
3-HOC6H4CH2
5-isoquinolyl

1513
3-HOC6H4CH2
3,4-

methylenedioxyC6H3

1514
3-HOC6H4CH2
3,4-

ethylenedioxyC6H3

1514
3-HOC6H4CH2
2-imidazolyl

1516
3-HOC6H4CH2
2-oxazolyl

1517
3-HOC6H4CH2
4-isoxazolyl

1518
3-HOC6H4CH2
4-HOC6H4

1519
3-HOC6H4CH2
3-HOC6H4

1520
3-HOC6H4CH2
3,4-diHOC6H4

1521
3-HOC6H4CH2
4-NH2CH2C6H4

1522
3-HOC6H4CH2
3-NH2CH2C6H4

1523
4-HOC6H4CH2
4-MeOC6H4

1524
4-HOC6H4CH2
3-MeOC6H4

1525
4-HOC6H4CH2
4-NH2C6H4

1526
4-HOC6H4CH2
3-NH2C6H4

1527
4-HOC6H4CH2
2-NH2C6H4

1528
4-HOC6H4CH2
4-Me2NC6H4

1529
4-HOC6H4CH2
3-Me2NC6H4

1530
4-HOC6H4CH2
2-Me2NC6H4

1531
4-HOC6H4CH2
4-pyridyl

1532
4-HOC6H4CH2
3-pyridyl

1533
4-HOC6H4CH2
2-pyridyl

1534
4-HOC6H4CH2
2-thiazolyl

1535
4-HOC6H4CH2
2-pyrazolyl

1536
4-HOC6H4CH2
5-isoquinolyl

1537
4-HOC6H4CH2
3,4-

methylenedioxyC6H3

1538
4-HOC6H4CH2
3,4

ethylenedioxyC6H3

1539
4-HOC6H4CH2
2-imidazolyl

1540
4-HOC6H4CH2
2-oxazolyl

1541
4-HOC6H4CH2
4-isoxazolyl

1542
4-HOC6H4CH2
4-HOC6H4

1543
4-HOC6H4CH2
3-HOC6H4

1544
4-HOC6H4CH2
3,4-diHOC6H4

1545
4-HOC6H4CH2
4-NH2CH2C6H4

1546
4-HOC6H4CH2
3-NH2CH2C6H4

1547
4-ClC6H4CH2
4-MeOC6H4

1548
4-ClC6H4CH2
3-MeOC6H4

1549
4-ClC6H4CH2
4-NH2C6H4

1550
4-ClC6H4CH2
3-NH2C6H4

1551
4-ClC6H4CH2
2-NH2C6H4

1552
4-ClC6H4CH2
4-Me2NC6H4

1553
4-ClC6H4CH2
3-Me2NC6H4

1554
4-ClC6H4CH2
2-Me2NC6H4

1555
4-ClC6H4CH2
4-pyridyl

1556
4-ClC6H4CH2
3-pyridyl

1557
4-ClC6H4CH2
2-pyridyl

1558
4-ClC6H4CH2
2-thiazolyl

1559
4-ClC6H4CH2
2-pyrazolyl

1560
4-ClC6H4CH2
5-isoquinolyl

1561
4-ClC6H4CH2
3,4

methylenedioxyC6H3

1562
4-ClC6H4CH2
3,4

ethylenedioxyC6H3

1563
4-ClC6H4CH2
2-imidazolyl

1564
4-ClC6H4CH2
2-oxazolyl

1565
4-ClC6H4CH2
4-isoxazolyl

1566
4-ClC6H4CH2
4-HOC6H4

1567
4-ClC6H4CH2
3-HOC6H4

1568
4-ClC6H4CH2
3,4-diHOC6H4

1569
4-ClC6H4CH2
4-NH2CH2C6H4

1570
4-ClC6H4CH2
3-NH2CH2C6H4

1571
2-NH2CH2C6H4CH2
4-MeOC6H4

1572
2-NH2CH2C6H4CH2
3-MeOC6H4

1573
2-NH2CH2C6H4CH2
4-NH2C6H4

1574
2-NH2CH2C6H4CH2
3-NH2C6H4

1575
2-NH2CH2C6H4CH2
2-NH2C6H4

1576
2-NH2CH2C6H4CH2
4-Me2NC6H4

1577
2-NH2CH2C6H4CH2
3-Me2NC6H4

1578
2-NH2CH2C6H4CH2
2-Me2NC6H4

1579
2-NH2CH2C6H4CH2
4-pyridyl

1580
2-NH2CH2C6H4CH2
3-pyridyl

1581
2-NH2CH2C6H4CH2
2-pyridyl

1582
2-NH2CH2C6H4CH2
2-thiazolyl

1583
2-NH2CH2C6H4CH2
2-pyrazolyl

1584
2-NH2CH2C6H4CH2
5-isoquinolyl

1585
2-NH2CH2C6H4CH2
3,4-

methylenedioxyC6H3

1586
2-NH2CH2C6H4CH2
3,4-

ethylenedioxyC6H3

1587
2-NH2CH2C6H4CH2
2-imidazolyl

1588
2-NH2CH2C6H4CH2
2-oxazolyl

1589
2-NH2CH2C6H4CH2
4-isoxazolyl

1590
2-NH2CH2C6H4CH2
4-HOC6H4

1591
2-NH2CH2C6H4CH2
3-HOC6H4

1592
2-NH2CH2C6H4CH2
3,4-diHOC6H4

1593
2-NH2CH2C6H4CH2
4-NH-I2CH2C6H4

1594
2-NH2CH2C6H4CH2
3-NH2CH2C6H4

1595
3-NH2CH2C6H4CH2
4-MeOC6H4

1596
3-NH2CH2C6H4CH2
3-MeOC6H4

1597
3-NH2CH2C6H4CH2
4-NH2C6H4

1598
3-NH2CH2C6H4CH2
3-NH2C6H4

1599
3-NH2CH2C6H4CH2
2-NH2C6H4

1600
3-NH2CH2C6H4CH2
4-Me2NC6H4

1601
3-NH2CH2C6H4CH2
3-Me2NC6H4

1602
3-NH2CH2C6H4CH2
2-Me2NC6H4

1603
3-NH2CH2C6H4CH2
4-pyridyl

1604
3-NH2CH2C6H4CH2
3-pyridyl

1605
3-NH2CH2C6H4CH2
2-pyridyl

1606
3-NH2CH2C6H4CH2
2-thiazolyl

1607
3-NH2CH2C6H4CH2
2-pyrazolyl

1608
3-NH2CH2C6H4CH2
5-isoquinolyl

1609
3-NH2CH2C6H4CH2
3,4-

methylenedioxyC6H3

1610
3-NH2CH2C6H4CH2
3,4-

ethylenedioxyC6H3

1611
3-NH2CH2C6H4CH2
2-imidazolyl

1612
3-NH2CH2C6H4CH2
2-oxazolyl

1613
3-NH2CH2C6H4CH2
4-isoxazolyl

1614
3-NH2CH2C6H4CH2
4-HOC6H4

1615
3-NH2CH2C6H4CH2
3-HOC6H4

1616
3-NH2CH2C6H4CH2
3,4-diHOC6H4

1617
3-NH2CH2C6H4CH2
4-NH2CH2C6H4

1618
3-NH2CH2C6H4CH2
3-NH2CH2C6H4

1619
4-NH2CH2C6H4CH2
4-MeOC6H4

1620
4-NH2CH2C6H4CH2
3-MeOC6H4

1621
4-NH2CH2C6H4CH2
4-NH2C6H4

1622
4-NH2CH2C6H4CH2
3-NH2C6H4

1623
4-NH2CH2C6H4CH2
2-NH2C6H4

1624
4-NH2CH2C6H4CH2
4-Me2NC6H4

1625
4-NH2CH2C6H4CH2
3-Me2NC6H4

1626
4-NH2CH2C6H4CH2
2-Me2NC6H4

1627
4-NH2CH2C6H4CH2
4-pyridyl

1628
4-NH2CH2C6H4CH2
3-pyridyl

1629
4-NH2CH2C6H4CH2
2-pyridyl

1630
4-NH2CH2C6H4CH2
2-thiazolyl

1631
4-NH2CH2C6H4CH2
2-pyrazolyl

1632
4-NH2CH2C6H4CH2
5-isoquinolyl

1633
4-NH2CH2C6H4CH2
3,4

methylenedioxyC6H3

1634
4-NH2CH2C6H4CH2
3,4

ethylenedioxyC6H3

1635
4-NH2CH2C6H4CH2
2-imidazolyl

1636
4-NH2CH2C6H4CH2
2-oxazolyl

1637
4-NH2CH2C6H4CH2
4-isoxazolyl

1638
4-NH2CH2C6H4CH2
4-HOC6H4

1639
4-NH2CH2C6H4CH2
3-HOC6H4

1640
4-NH2CH2C6H4CH2
3,4-diHOC6H4

1641
4-NH2CH2C6H4CH2
4-NH2CH2C6H4

1642
4-NH2CH2C6H4CH2
3-NH2CH2C6H4

1643
2-Me2NCH2C6H4CH2
4-MeOC6H4

1644
2-Me2NCH2C6H4CH2
3-MeOC6H4

1645
2-Me2NCH2C6H4CH2
4-NH2C6H4

1646
2-Me2NCH2C6H4CH2
3-NH2C6H4

1647
2-Me2NCH2C6H4CH2
2-NH2C6H4

1648
2-Me2NCH2C6H4CH2
4-Me2NC6H4

1649
2-Me2NCH2C6H4CH2
3-Me2NC6H4

1650
2-Me2NCH2C6H4CH2
2-Me2NC6H4

1651
2-Me2NCH2C6H4CH2
4-pyridyl

1652
2-Me2NCH2C6H4CH2
3-pyridyl

1653
2-Me2NCH2C6H4CH2
2-pyridyl

1654
2-Me2NCH2C6H4CH2
2-thiazolyl

1655
2-Me2NCH2C6H4CH2
2-pyrazolyl

1656
2-Me2NCH2C6H4CH2
5-isoquinolyl

1657
2-Me2NCH2C6H4CH2
3,4

methylenedioxyC6H3

1658
2-Me2NCH2C6H4CH2
3,4

ethylenedioxyC6H3

1659
2-Me2NCH2C6H4CH2
2-imidazolyl

1660
2-Me2NCH2C6H4CH2
2-oxazolyl

1661
2-Me2NCH2C6H4CH2
4-isoxazolyl

1662
2-Me2NCH2C6H4CH2
4-HOC6H4

1663
2-Me2NCH2C6H4CH2
3-HOC6H4

1664
2-Me2NCH2C6H4CH2
3,4-diHOC6H4

1665
2-Me2NCH2C6H4CH2
4-NH2CH2C6H4

1666
2-Me2NCH2C6H4CH2
3-NH2CH2C6H4

1667
3-Me2NCH2C6H4CH2
4-MeOC6H4

1668
3-Me2NCH2C6H4CH2
3-MeOC6H4

1669
3-Me2NCH2C6H4CH2
4-NH2C6H4

1670
3-Me2NCH2C6H4CH2
3-NH2C6H4

1671
3-Me2NCH2C6H4CH2
2-NH2C6H4

1672
3-Me2NCH2C6H4CH2
4-Me2HC6H4

1673
3-Me2NCH2C6H4CH2
3-Me2NC6H4

1674
3-Me2NCH2C6H4CH2
2-Me2NC6H4

1675
3-Me2NCH2C6H4CH2
4-pyridyl

1676
3-Me2NCH2C6H4CH2
3-pyridyl

1677
3-Me2NCH2C6H4CH2
2-pyridyl

1678
3-Me2NCH2C6H4CH2
2-thiazolyl

1679
3-Me2NCH2C6H4CH2
2-pyrazolyl

1680
3-Me2NCH2C6H4CH2
5-isoquinolyl

1681
3-Me2NCH2C6H4CH2
3,4-

methylenedioxyC6H3

1682
3-Me2NCH2C6H4CH2
3,4

ethylenedioxyC6H3

1683
3-Me2NCH2C6H4CH2
2-imidazolyl

1684
3-Me2NCH2C6H4CH2
2-oxazolyl

1685
3-Me2NCH2C6H4CH2
4-isoxazolyl

1686
3-Me2NCH2C6H4CH2
4-HOC6H4

1687
3-Me2NCH2C6H4CH2
3-HOC6H4

1688
3-Me2NCH2C6H4CH2
3,4-diHOC6H4

1689
3-Me2NCH2C6H4CH2
4-NH2CH2C6H4

1690
3-Me2NCH2C6H4CH2
3-NH2CH2C6H4

1691
4-Me2NCH2C6H4CH2
4-MeOC6H4

1692
4-Me2NCH2C6H4CH2
3-MeOC6H4

1693
4-Me2NCH2C6H4CH2
4-NH2C6H4

1694
4-Me2NCH2C6H4CH2
3-NH2C6H4

1695
4-Me2NCH2C6H4CH2
2-NH2C6H4

1696
4-Me2NCH2C6H4CH2
4-Me2NC6H4

1697
4-Me2NCH2C6H4CH2
3-Me2NC6H4

1698
4-Me2NCH2C6H4CH2
2-Me2NC6H4

1699
4-Me2NCH2C6H4CH2
4-pyridyl

1700
4-Me2NCH2C6H4CH2
3-pyridyl

1701
4-Me2NCH2C6H4CH2
2-pyridyl

1702
4-Me2NCH2C6H4CH2
2-thiazolyl

1703
4-Me2NCH2C6H4CH2
2-pyrazolyl

1704
4-Me2NCH2C6H4CH2
5-isoquinolyl

1705
4-Me2NCH2C6H4CH2
3,4-

methylenedioxyC6H3

1706
4-Me2NCH2C6H4CH2
3,4-

ethylenedioxyC6H3

1707
4-Me2NCH2C6H4CH2
2-imidazolyl

1708
4-Me2NCH2C6H4CH2
2-oxazolyl

1709
4-Me2NCH2C6H4CH2
4-isoxazolyl

1710
4-Me2NCH2C6H4CH2
4-HOC6H4

1711
4-Me2NCH2C6H4CH2
3-HOC6H4

1712
4-Me2NCH2C6H4CH2
3,4-diHOC6H4

1713
4-Me2NCH2C6H4CH2
4-NH2CH2C6H4

1714
4-Me2NCH2C6H4CH2
3-NH2CH2C6H4

[0359]

4

TABLE 4

Example

Number
R1
R2

1715
Methyl
4-MeOC6H4

1716
ClCH2
4-MeOC6H4

1717
cyclopropyl
4-MeOC6H4

1718
isopropyl
4-MeOC6H4

1719
ethyl
4-MeOC6H4

1720
cyclopentyl
4-MeOC6H4

1721
cyclobutyl
4-MeOC6H4

1722
benzyl
4-MeOC6H4

1723
n-propyl
4-MeOC6H4

1724
4-ClC6H4CH2
4-MeOC6H4

1725
3-MeOC6H4CH2
4-MeOC6H4

1726
4-MeOC6H4CH2
4-MeOC6H4

1727
3,4-diMeOC6H4CH2
4-MeOC6H4

1728
2,5-diMeOC6H4CH2
4-MeOC6H4

1729
Methyl
2-MeOC6H4

1730
Methyl
3,4-diMeOC6H4

1731
3,4-(OCH2O)C6H4CH2
4-MeOC6H4

1732
3-thiophenylCH2
4-MeOC6H4

1733
2-MeOC6H4CH2
4-MeOC6H4

1734
3,4-diClOC6H4CH2
4-MeOC6H4

1735
2,4-diClOC6H4CH2
4-MeOC6H4

1736
2-ClC6H4CH2
4-MeOC6H4

1737
H2NCH2
4-MeOC6H4

1738
HOCH2NHCH2CH2
4-MeOC6H4

1739
Me2NCH2
4-MeOC6H4

1740
piperazinylCH2
4-MeOC6H4

1741
4-Me-piperazinylCH2
4-MeOC6H4

1742
4-HOCH2CH2—
4-MeOC6H4

piperazinylCH2

1743
piperidinylCH2
4-MeOC6H4

1744
4-NH2CH2—
4-MeOC6H4

piperidinylCH2

1745
CH3CH2NHCH2
4-MeOC6H4

1746
thiomorpholinylCH2
4-MeOC6H4

1747
morpholinylCH2
4-MeOC6H4

1748
pyyrolidinylCH2
4-MeOC6H4

1749
4-pyridylCH2NHCH2
4-MeOC6H4

1750
4-CH3CONHC6H4CH2
4-MeOC6H4

1751
4-CH3OCONHC6H4CH2
4-MeOC6H4

1752
4-NH2CH2CONHC6H4CH2
4-MeOC6H4

1753
4-Me2NCH2CONHC6H4CH2
4-MeOC6H4

1754
4-N3C6H4CH2
4-MeOC6H4

1755
4-NH2C6H4CH2
4-MeOC6H4

1756
C6H5NH
4-MeOC6H4

1757
CH3CH2CH2NH
4-MeOC6H4

1758
4-NH2C6H4CH2NH
4-MeOC6H4

1759
4-pyridyCH2NH
4-MeOC6H4

1760
Methyl
4-HOC6H4

1761
H
4-MeOC6H4

1762
Methyl
3-pyridyl

1763
Methyl
4-pyridyl

1764
H
4 -pyridyl

1765
Methyl
C6H5

1766
Methyl
4-MeSC6H4

1767
Methyl
4-MeSO2C6H4

1768
Methyl
4-Me2NC6H4

1769
MorpholinylCH2
4-Me2NC6H4

1770
Me2NCH2
4-Me2NC6H4

1771
Me2NCH2
4-(piperdinyl)C6H4

1772
Me2NCH2
4-(morpholinyl)-

C6H4

1773
Me2NCH2
4-CH3CH2OC6H4

1774
Me2NCH2
4-CH3CH2CH2CH2C6H4

1775
Me2NCH2
4-CH3CH2C6H4

1776
Me2NCH2
4-CH3CH2CH2C6H4

	Number	Date	Country
Parent	09906963	Jul 2001	US
Child	10427540	May 2003	US
Parent	09692023	Oct 2000	US
Child	09906963	Jul 2001	US

Acylsemicarbazides as cyclin dependent kinase inhibitors useful as anti-cancer and anti-proliferative agents

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CPC

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Abstract

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Provisional Applications (1)

Continuation in Parts (2)