US20010027195A1

US20010027195A1 - Indeno [1,2-c]pyrazol-4-ones and their uses

Info

Publication number: US20010027195A1
Application number: US09/731,304
Authority: US
Inventors: David Nugiel; David Carini; Susan DiMeo; Eddy Yue
Original assignee: DuPont Merck Pharmaceutical Co
Current assignee: Bristol Myers Squibb Pharma Co
Priority date: 1998-04-21
Filing date: 2000-12-06
Publication date: 2001-10-04
Anticipated expiration: 2019-04-20
Also published as: US6407103B2

Abstract

The present invention relates to the synthesis of a new class of indeno[1,2-c]pyrazol-4-ones of formula (I):

that are potent inhibitors of the class of enzymes known as cyclin dependent kinases, which relate to the catalytic subunits cdk1-9 and their regulatory subunits know as cyclins A-H.

This invention also provides a novel method of treating cancer or other proliferative diseases by administering a therapeutically effective amount of one of these compounds or a pharmaceutically acceptable salt form thereof. Alternatively, one can treat cancer or other proliferative diseases by administering a therapeutically effective combination of one of the compounds of the present invention and one or more other known anti-cancer or anti-proliferative agents.

Description

FIELD OF THE INVENTION

This invention relates generally to novel 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

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).

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, nine kinase subunits (cdk 1-9) have been identified along with several regulatory subunits (cyclins A-H).(A. M. Senderowicz and E. A. Sausville Journal of the National Cancer Institute (2000), 92 (5), 376-387; and S. Mani; C. Wang; K. Wu; R. Francis; R. Pestell Exp. Opin. Invest. Drugs (2000) 9(8), 1849-1870).

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: G1l/S by cdk2/cyclin E, cdk4/cyclin D1 and cdk6/cyclinD2; S/G2 by cdk2/cyclin A and cdkl/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)

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 p ₁₆ ^INK4(an inhibitor of cdk4/D1), p₂₁ ^CIP1(a general cdk inhibitor), and p27^KIP1(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.

Protein kinases, in particular, CDK, play a role in the regulation of cellular proliferation. Therefore, CDK inhibitors could be useful in the treatment of cell proliferative disorders such as cancer, familial adenomatosis polyposis, neuro-fibromatosis, psoriasis, fungal infections, endotoxic shock, trasplantaion rejection, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis (U.S. Pat. No. 6,114,365). CDKs are also known to play a role in apoptosis.

Therefore CDK inhibitors, could be useful in the treatment of useful of cancer; viral infections, for example, herpevirus, poxyirus, Epstein-Barr virus, Sindbis virus and adenovirus; prevention of AIDS development in HIV-infected individuals; autoimmune diseases, for example, systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus; neurodegenerative disorders, for example, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases, for example, chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system, for example, osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain (U.S. Pat. No. 6,107,305).

It has also been discovered that some cyclin-dependent kinase inhibitors can be used in combination therapy with some other anticancer agents. For example, the cytotoxic activity of the cyclin-dependent kinase inhibitor, flavopiridol, has been used with other anticancer agents in cancer combination therapy. Cancer Research, 57, 3375 (1997).

Also, it has recenly been disclosed that CDK inhibitors may be useful in the chemoprevention of cancer. Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-malignant cells that have already suffered an insult or inhibiting tumor relapse (U.S. Pat. No. 6,107,305).

Furthermore, it has recently been discovered that cdk5 is involved in the phosphorylation of tau protein, and therefore CDK inhibitors may be useful in the treatment of Alzheimer's disease (J. Biochem., 117, 741-749, 1995).

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.

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

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.

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

The above compounds differ from the presently claimed invention in X _nis defined as halo, alkyl, haloalkyl, and haloalkoxy; n=0-2. In addition, R₁is defined as acyl and R₂is defined as alkyl or cycloalkyl.

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:

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

SUMMARY OF THE INVENTION

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 1-9 and their regulatory subunits know as cyclins A-H.

It is another object of this invention to provide a novel method of treating proliferative diseases associated with CDK activity by administering a therapeutically effective amount of one of the compounds of the invention or a pharmaceutically acceptable salt form thereof.

It is another object of this invention to provide a novel method of treating cancer associated with CDK activity by administering a therapeutically effective amount of one of the compounds of the invention or a pharmaceutically acceptable salt form thereof.

It is another object of this invention to provide a novel method of treating a proliferative disease, which comprises administering a therapeutically effective combination of one of the compounds of the present invention and one or more other known anti-cancer treatments such as radiation therapy, chemotoxic or chemostatic agents.

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

wherein R ₁, R₂and X are defined below or pharmaceutically acceptable salts thereof are cyclin dependent kinase inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

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).

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.

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

or stereoisomers, pharmaceutically acceptable salts, and prodrugs thereof, wherein:

X is selected from the groups: O, S, and NR;

R is selected from the groups: H, C _1-4alkyl, and NR⁵R^5a;

R ¹is selected from the groups: H, C_1-10alkyl substituted with 0-3 R^c, C_2-10alkenyl substituted with 0-3 R^c, C_2-10alkynyl substituted with 0-3 R^c, —NHR⁴, C_3-10membered carbocycle substituted with 0-5 R^a, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b;

R ^ais independently selected from the groups: R⁵

R ^5aN(CR⁶R^6a)_m, R⁵O(CR⁶R^6a)m, halo, —CN , N₃, NO₂, C_1-4alkyl, C_1-4haloalkyl, NR³R^3a, ═O, OR³, SR³, COR³, CO₂R³, CONR³R^3a, NHC(O)NR³R^3a, NHC(S)NR³R^3a, NR³C(O)OR³, NR³C(O)R³, SO₂NR³R^3a, SO₂R^3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;

alternatively, when two Ra's are present on adjacent carbon atoms they combine to form —OCH ₂O— or —OCH₂CH₂O—;

R ^bis independently selected from the groups: halo, —CN, NO₂, C_1-4alkyl, C_1-4haloalkyl, NR³R^3a, NR³C(O)OR³, NR³C(O)R³, OR³, COR³, CO₂R³, CONR³R^3a, CON(R⁶)((CH₂)_mR⁷), CO(CH₂)_mR⁷, NHC(O)NR³R^3a, NHC(S)NR³R^3a, SO₂NR³R^3a, and SO₂R^3b;

R ^cis independently selected from the groups: halo, —CN, NO₂, C_1-4alkyl, C_1-4haloalkyl, NR³R^3a, NR⁵NR⁵R^5a, NR³C(O)OR³, NR³C(O)R³, ═O, OR³, COR³, CO₂R³, CONR³R^3a, NHC(O)NR³R^3a, NHC(S)NR³R^3a, SO₂N³R^3a, SO₂R^3b, C_3-10membered carbocycle substituted with 0-5 R^a, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R³;

R ²is selected from the groups: H, C_1-10alkyl substituted with 0-3 R^c, C_2-10alkenyl substituted with 0-3 R^c, C_2-10alkynyl substituted with 0-3 R^c, —(CF₂)_mCF₃, C_3-10membered carbocycle substituted with 0-5 R^a, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b;

R ³is independently selected from the groups: H, halo, —CN, NO₂, C_1-4haloalkyl, R⁵R^5aN(CR⁶R^6a)m, NR⁵NR⁵R^5a, NR⁵C(O)OR⁵, NR⁵C(O)R⁵, ═O, R⁵O(CR⁶R^6a)m, COR⁵, CO₂R⁵, CONR⁵R^5a, NHC(O)NR⁵R^5a, NHC(S)NR⁵R^5a, SO₂NR⁵R^5a, SO₂R^5b, C_1-4alkyl, phenyl, and benzyl;

R ^3ais independently selected from the groups: H, C_1-4alkyl, phenyl, and benzyl;

alternatively, R ³and R^3a, together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom and substituted with 0-3 R^3c;

R ^3bis independently selected from the groups: H, C_1-4alkyl, phenyl, and benzyl;

R ^3cis independently selected from the groups: halo, —CN, N₃, NO₂, C_1-4alkyl, C_3-8cycloalkyl, C_4-10cycloalkylalkyl, C_1-4haloalkyl, NR³R^3b, R⁵R^5aN(CR⁶R^6a)m, ═O, OR³, R⁵O(CR⁶R^6a)m, COR³, CO₂R³, CONR³R³ ^b, NHC(O)NR³R³ ^b, NHC(S)NR³R³ ^b, NR³C(O)OR³, NR³C(O)R³, C(═NR⁵)R^5a, C(═NRS)NR^5aR^5b, SO₂NR³R³ ^b, SO₂R³ ^b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;

R ⁴is independently selected from the groups: H, —CN, C_1-4alkyl, C_1-4haloalkyl, NR³R^3a, NR³C(O)OR³, NR³C(O)R³, OR³, COR³, CO₂R³, CONR³R^3a, NHC(O)NR³R^3a, NHC(S)NR³R^3a, SO₂NR³R^3a, SO₂R^3b, C_3-10membered carbocycle substituted with 0-5 R^a, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R³;

R ⁵is independently selected from the groups: H, C_1-4alkyl, phenyl and benzyl;

R ⁵a is independently selected from the groups: H, C_1-4alkyl, phenyl and benzyl;

alternatively, R ⁵and R^5a, together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom;

R ^5bis independently selected from the groups: H, C_1-4alkyl, phenyl and benzyl;

R ⁶is idependently selected from the groups: H, C_1-4alkyl;

R ^6ais independently selected from the groups: H, C_1-4alkyl;

R ⁷is independently selected from the groups: NR³R^3a, membered carbocycle substituted with 0-3 R³, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R³; and

m is independently selected from 0, 1, 2, 3, and 4;

provided that: when R ²is a C_1-4unsubstituted, branched alkyl then R¹is not CH₃; or when R¹is NHR⁴and R⁴is NR³R^3athen R³and R^3acan not both be phenyl.

[2] In another embodiment, the invention describes novel compounds of formula (I):

X is selected from the groups: O, S, and NR;

R is selected from the groups: H, C _1-4alkyl, and NR⁵R^5a;

R ^ais independently selected from the groups: halo, —CN, N³, NO₂, C_1-4alkyl, C_1-4haloalkyl, NR³R^3a, ═O, OR³, COR³, CO₂R³, CONR³R^3a, NHC(O)NR³R^3a, NHC(S)NR³R^3a, NR³C(O)OR³, NR³C(O)R³, SO₂NR³R^3a, SO₂R^3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;

alternatively, when two R ^a's are present on adjacent carbon atoms they combine to form —OCH₂O— or —OCH₂CH₂O—;

R ³is independently selected from the groups: H, halo, —CN, NO₂, C_1-4haloalkyl, R⁵R^5aN(CR⁶R^6a)m, NR⁵NR⁵R^5a, NR⁵C(O)OR⁵, NR⁵C(O)R⁵, ═O, R⁵O(CR⁵R^6a)m, COR⁵, CO₂R⁵, CONR⁵R^5a, NHC(O)NR⁵R^5a, NHC (S)NR⁵R^5a, SO₂NR⁵R^5a, SO₂R^5b, C_1-4alkyl, phenyl, and benzyl;

alternatively, R ³and R_3a, together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom and substituted with 0-3 R^3c;

R ^3cis independently selected from the groups: halo, —CN, N₃, NO₂, C_1-4alkyl, C_3-8cycloalkyl, C_4-10cycloalkylalkyl, C_1-4haloalkyl, NR³R^3b, R⁵R^5aN(CR⁶R^6a)m, ═O, OR³, R⁵O(CR⁶R^6a)m, COR³, CO₂R³, CONR³R^3b, NHC(O)NR³R^3b, NHC(S)NR³R^3b, NR³C(O)OR³, NR³C(O)R³, C(═NR⁵)R^5a, C(═NR⁵)NR^5aR^5b, SO₂NR³R^3b, SO₂R^3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;

R ^5ais independently selected from the groups: H, C_1-4alkyl, phenyl and benzyl;

alternatively, R ⁵and R_5a, together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom;

R _5bis independently selected from the groups: H, C_1-4alkyl, phenyl and benzyl;

R ⁶is idependently selected from the groups: H, C_1-4alkyl;

R ^6ais independently selected from the groups: H, C_1-4alkyl;

R ⁷is independently selected from the groups: NR³R^3a, C_3-10membered carbocycle substituted with 0-3 R³, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R³; and

m is independently selected from 0, 1, 2, 3, and 4; provided that:

1) when R ²is a C_1-4unsubstituted, branched alkyl then R¹is not CH₃; or

2)when R ¹is NHR⁴and R⁴is NR³R^3athen R³and R^3acan not both be phenyl.

R ³and R^3acan not both be phenyl.

[3] In another embodiment, the invention describes novel compounds of embodiment [1], wherein X is O or S;

R ¹is H, C_1-10alkyl substituted with 0-3 R^c, —NHR⁴, C_3-10membered carbocycle substituted with 0-5 , or 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5;

R ^cis independently selected from the groups: halo, C_3-10membered carbocycle substituted with 0-5 R^a, 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R³, NR³R^3a;

R ³is H, C_1-4alkyl, phenyl, benzyl, or together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom and substituted with 0-3 R^3c;

R4 is H, C _1-4alkyl, NR³R^3a, C_3-10membered carbocycle substituted with 0-5 R^a, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R³;

R ²is selected from the groups: C_3-10membered carbocycle substituted with 0-5 R^a, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b, and C_1-10alkyl substituted with 0-3 R^c.

[4] In another embodiment, the invention describes novel compounds of embodiment [1], wherein X is O or S;

R ¹is C_1-4alkyl substituted with 0-3 R^c, wherein R^cis independently selected from the group consisting of: C_3-6membered carbocycle substituted with 0-5 R^a, 5-6 membered heterocycle substituted with 0-3 R³, NR³R^3a, and OR³; C_3-6membered carbocycle substituted with 0-5 R^a, wherein R^ais independently selected from the group consisting of:

R ⁵R^5aN(CR⁶R^6a)m—, R⁵O(CR⁶R^6a)m—, OR³, halo, C_1-4alkyl, —NR³O(O)R³, COR³, CO₂R³, N₃, NR³C(O)OR³, NR³R^3aCONR³R^3a, and 5-6 membered heterocycle; or when two R^a's are present on adjacent carbon atoms they combine to form —OCH₂O— or —OCH₂CH₂O—; or 5-6 membered heterocycle and substituted with 0-5 R^b, wherein R^bis independently selected from the group:

OR ³, halo, COR³, C_1-4alkyl, CO₂R³, NR³C(O)R³, NR³C(O)OR³, NR³R^3a, and CONR³R^3a;

R ²is C_3-6membered carbocycle substituted with 0-5 R^a, wherein R^ais independently selected from the groups:

R ⁵R^5aN(CR⁶R^6a)m, R⁵O(CR⁶R^6a)m, OR³, halo, C_1-4alkyl, NR³C(O)R³, COR³, CO₂R³, N³, NR³C(O)OR³, NR³R^3a, CONR³R^3a, and 5-6 membered heterocycle, or when two R^a's are present on adjacent carbon atoms they combine to form —OCH₂O— or —OCH₂CH₂O—; 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b, wherein R^bis independently selected from the group:

OR ³, halo, COR³, C_1-4alkyl, CO₂R³, NR³C(O)R³, NR³C(O)OR³, NR³R^3a, and CONR³R^3a; or C_1-10alkyl substituted with 0-3 R^c, wherein R^cis independently selected from the groups:

C _3-6membered carbocycle substituted with 0-5 R^a, 5-6 membered heterocycle substituted with 0-3 R³, NR³R^3a, and OR³.

[5] In another embodiment, the invention describes novel compounds of embodiment [1], wherein

X is O or S;

R ¹is selected from the groups: H, —NHR⁴, C_1-4alkyl substituted with 0-3 R^c, 3-6 membered carbocycle substituted with 0-5 R^a, and 5-6 membered heterocycle and substituted with 0-5 R^b;

R ²is selected from the group: C_3-6membered carbocycle substituted with 0-5 R^a, 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b, and C_1-10alkyl substituted with 0-3 R^c, C_2-10alkenyl substituted with 0-3 R^c;

R ⁴is independently selected from the groups: H, C_1-4alkyl, NR³R^3a, C_3-6membered carbocycle substituted with 0-5 R^a, and 5-6 membered heterocycle substituted with 0-3 R³;

R ³is independently selected from the group: H, halo, COR⁵, CO₂R⁵, R⁵R^5aN(CR⁶R^6a)m, R⁵O(CR⁶R^6a)m, CONR⁵R^5a, NR⁵C(O)OR⁵, NR⁵C(O)R⁵, C_1-4alkyl, phenyl, and benzyl;

R ^3ais independently selected from the group: H, C_1-4alkyl, phenyl, and benzyl; or

R ³and R^3a, together with the atoms to which they are attached, form a 5-6 membered heterocycle containing an additional 0-1 N, S, or O atom and substituted with 0-3 R^3c;

R ^cis independently selected from the groups: C_3-6membered carbocycle substituted with 0-5 R^a, 5-6 membered heterocycle substituted with 0-3 R³, NR³R^3a, and OR³;

R ^ais independently selected from the groups: R⁵R^5aN(CR⁶R⁶)m, R⁵O(CR⁶R^6a)m, OR³, halo, C_1-4alkyl, NR³C(O)R³, COR³, CO₂R³, N₃, NR³C(O)OR³, NR³R^3a, CONR³R^3a, 5-6 membered heterocycle; or when two R^a's are present on adjacent carbon atoms they combine to form —OCH₂O— or —OCH₂CH₂O—;

R ^bis independently selected from the group: OR³, halo, COR³, C_1-4alkyl, CO₂R³, NR³C(O)R³, NR³C(O)OR³, NR³R^3a, CONR³R^3a;

R ^3cis independently selected from the groups: OR³, halo, COR³, R⁵R^5aN(CR⁶R^6a)m−, R⁵O(CR⁶R^6a)m−, CO₂R³, N₃, NR³R^3a, C_1-4alkyl, NR³C(O)R³, NR³C(O)OR³, N³, NR³R^3b, CONR³R^3b, and 5-6 membered heterocycle; and

m is independently selected from the group consisting of 1 2, 3 and 4.

[6] In another embodiment, the invention describes novel compounds of embodiment [1], wherein

R ¹is selected from the group: —NHR⁴and C_1-2alkyl substituted with 1 R^c.

[7] In another embodiment, the invention describes novel compounds of embodiment [1], wherein X is O or S; and

R ¹is selected from the group: H, C_1-4alkyl substituted with 0-3 R^c, C_2-4alkenyl substituted with 0-3 R^c, C_2-4alkynyl substituted with 0-3 R^c, —NHR⁴, C_3-6carbocycle substituted with 0-5 R^a, and 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b.

[8] In another embodiment, the invention describes novel compounds of embodiment [1], wherein X is O or S; and

R ¹is selected from the group: H, C^1-4alkyl substituted with 0-3 R^c, C^2-4alkenyl substituted with 0-3 R^c, C_2-4alkynyl substituted with 0-3 R^c, —NHR⁴, C_3-6carbocycle substituted with 0-5 R^a, and 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b;

R ^ais independently at each occurrence selected from the group: —CH₂N(CH₃)₂, —CH₂NH₂, —SH, —SCH₃, —NR³C(O)R³, —N₃, halo, C_1-4alkyl, NR³R^3a, and OR³; alternatively, when two R^a's are present on adjacent carbon atoms they combine to form —OCH₂O— or —OCH₂CH₂O—;

R ^bis independently at each occurrence selected from the group: halo, C_1-4alkyl, NR³R^3a, OR³, COR³, and CO₂R³;

R ^cis independently at each occurrence selected from the group: halo, C_1-4alkyl, NR³R^3a, C_3-6carbocycle substituted with 0-5 R^a, and 5-7 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R³;

R ^3ais H or C_1-4alkyl; and

R ³is selected from the group: H, —CH₂CH₂OH, —C(O)CH₂NH₂, —C(O)CH₂N(CH3)2, —NR⁵R^5a, —C_1-4alkyl, phenyl, and benzyl.

[9] In another embodiment, the invention describes novel compounds of embodiment [1], wherein X is O or S;

R ¹is selected from the group: H, C_1-4alkyl substituted with 0-3 R^c, —NHR⁴, C_3-6carbocycle substituted with 0-5 R^a, and 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b;

R ^ais independently at each occurrence selected from the group: —CH₂N(CH₃)₂, —CH₂NH₂, —SH, —SCH₃, halo, C_1-4alkyl, NR³R^3a, and OR³; alternatively, when two R^a's are present on adjacent carbon atoms they combine to form —OCH₂O— or —OCH₂CH₂O—;

R ^cis independently at each occurrence selected from the group: —OH, chloro, C_1-4alkyl, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3,—NHCH2CH2OH, —N(CH3)2, phenyl substituted with 0-5 R^a, and 5-7 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R³.

[10] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R ¹is selected from the group: H, C_1-10alkyl substituted with 0-3 R^c, C_2-10alkenyl substituted with 0-3 R^c, C_2-10alkynyl substituted with 0-3 R^c;

R ²is selected from the group: H, —(CF₂)_mCF₃, C_3-10carbocycle substituted with 0-5 R^a, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b; and

R ^cis independently at each occurrence selected from the group: phenyl substituted with 0-5 R^a, and thiophenyl or pyridyl, which is substituted with 0-3 R³.

[11] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R ¹is selected from the group: H, C_1-10alkyl substituted with 0-3 R^c, C_2-10alkenyl substituted with 0-3 R^c, C_2-10alkynyl substituted with 0-3 R^c;

R ^cis independently at each occurrence selected from the group: thiophenyl, piperazinyl, piperidinyl, thiomorpholinyl, morpholinyl, pyrrolidinyl, and pyridyl, which is substituted with 0-3 substituents indepently selected from the group consiting of CH3, CH2CH2OH, CH2CH2NH2, —C(═O)NH2, —OCH3, CH2NH2, NHCH2CH3,OH, NH2, halo, —CH2N(CH3)2, —OCH2CH2O—, —OCH20—, —N(CH3)2, uridomethyl, and pyridyl.

[12] In another embodiment, the invention describes novel compounds of embodiment [1], wherein

R ¹is selected from the group: H, C_1-10alkyl substituted with 0-3 R^c, C_2-10alkenyl substituted with 0-3 R^c, C_2-10alkynyl substituted with 0-3 R^c;

R ²is selected from the group: H, —(CF₂)_mCF³, C_3-10carbocycle substituted with 0-5 R^a, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b; and

R ^cis phenyl substituted with 0-5 substituents indepently selected from the group consiting of CH3, CH2CH2OH, CH2CH2NH2, —C(═O)NH2, —OCH3, CH2NH2, NHCH2CH3,OH, NH2, halo, —CH2N(CH3)2, —OCH2CH2O—, —OCH2O—, —N(CH3)2, uridomethyl, and pyridyl.

[13] In another embodiment, the invention describes novel compounds of embodiment [1], wherein X is O or S;

R ¹is —NHR⁴or methylene substituted with 0-3 R^c;

R ^cis NR³R^3a;

R ⁴is selected from the group consisting of H, C1-4 alkyl, and NR³R^3a; and

R ³and R^3a, are independently hydrogen or C1-4alkyl, or R³and R^3a, together with the nitrogen atom to which they are attached, form a 4-8 membered heterocycle containing an additional 0-1 N, S, or O atom and substituted with 0-3 R^3c.

[14] In another embodiment, the invention describes novel compounds of embodiment [1], wherein X is O or S;

R ¹is —NHR⁴or methylene substituted with 0-3 R^c;

R ^cis NR³R^3a;

R ⁴is selected from the group consisting of H, C1-4 alkyl, and NR³R^3a; and

R ³and R^3a, are independently hydrogen or C1-4alkyl, or R³and R^3a, together with the nitrogen atom to which they are attached, form a 4-8 membered heterocycle containing an additional 0-1 N, S, or O atom and substituted with with 0-3 substituents independently selected from the group consisting of methyl, —CH2OCH3, —C(CH₃)₂OCH_3,—CH₂CH₂OH, —CH₂OH, —CH₂OCH₂Phenyl, —CH₂CH₂NH₂, —CH₂NH₂, —C(═NH)CH₃, and NH₂.

[15] In another embodiment, the invention describes novel compounds of embodiment [1], wherein X is O or S; and

R ¹is selected from the group: methylene substituted with a substituent selected from the group consisting of: halo, NR³R^3a, C_3-6carbocycle substituted with 0-5 R^a, and 5-7 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R³.

[16] In another embodiment, the invention describes novel compounds of embodiment [1], wherein X is O or S;

R ¹is selected from the group: methylene substituted with NR³R^3a; and

R ³and R^3a, together with the nitrogen atom to which they are attached, form pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thiomorpholinyl, pymorpholinyl, piperidinyl, piperazinyl, or piperadinyl, which is substituted with 0-3 R^3c.

[17] In another embodiment, the invention describes novel compounds of embodiment [1], wherein

R ¹is —NHR⁴;

R ⁴is NR3R3a; and

[18] In another embodiment, the invention describes novel compounds of embodiment [1], wherein

R ¹is —NHR⁴;

R ⁴is NR3R3a; and

R ³and R³a, together with the nitrogen atom to which they are attached, form pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thiomorpholinyl, pymorpholinyl, piperidinyl, piperazinyl, or piperadinyl, which is substituted with 0-3 substituents independently selected from the group consisting of methyl, —CH₂OCH₃, —C(CH₃)₂OCH₃, —CH₂CH₂OH, —CH₂OH, —CH₂OCH₂Phenyl, —CH₂CH₂NH₂, —CH₂NH₂, —C(═NH)CH₃, and NH2.

[19] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R ²is selected from the group: 5- to 7- membered monocyclic saturated, or partially saturated, heterocyclic ring substituted with 0-5 R^b.

[20] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R ²is selected from the group: 5- to 7- membered monocyclic aromatice heterocyclic ring substituted with 0-5 R^b.

[21] In another embodiment, the invention describes 6novel compounds of embodiment [1], wherein R ²is selected from the group: C_1-10alkyl substituted with 0-3 R^c, C_3-10carbocycle substituted with 0-5 R^a, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b.

[22] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R ²is selected from the group: C_1-6alkyl substituted with 0-3 R^c, C_3-6carbocycle substituted with 0-5 R^a, and 3-7 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b.

[23] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R ²is selected from the group: C_1-6alkyl substituted with C_3-10carbocycle substituted with 0-5 R^a, and C_1-6alkyl substituted with 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S.

[24] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R ²is selected from the group: phenyl substituted with 0-5 R^a, and cyclopropyl or cyclohexyl substituted with 0-2 R^a; and

R ^ais independently at each occurrence selected from the group: —CH₂N(CH₃)₂, —CH₂NH₂, —SR halo, —ON , N₃, NO₂, C_1-4alkyl, C_1-4haloalkyl, NR³R^3a, αO, OR³, COR³, CO₂R³, CONR³R^3a, NHC(O)NR³R^3a, NHC(S)NR³R^3a, NR³C(O)OR³, NR³C(O)R³, SO₂NR³R^3a, SO₂R^3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S.

[25] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R ²is selected from the group: phenyl substituted with 0-5 R^a, and cyclopropyl or cyclohexyl substituted with 0-2 R^a; and

R ^ais independently at each occurrence selected from the group: C_1-4alkyl, COR³, CO₂R³, and CONR³R^3a;

R ^3ais H or C_1-4alkyl.

[26] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R ²is selected from the group: phenyl substituted with 0-5 R^a, and cyclopropyl or cyclohexyl substituted with 0-2 R^a;

R ^3ais H or C_1-4alkyl;

R ³is C_1-4alkyl, C_1-4alkyl-NR5R5a; and

R ⁵and R^5a, together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom.

[27] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R ²is selected from the group: phenyl substituted with 0-5 R^a, and cyclopropyl or cyclohexyl substituted with 0-2 R^a;

R ^ais independently at each occurrence selected from the group: C_1-4alkyl, COR³, CO₂R³, and CONR³R^3a; and

R ^3ais H or C_1-4alkyl.

[28] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R ²is phenyl substituted with NR³R^3a, wherein R³and R^3atogether with the nitrogen atom to which they are attached, form a 4-8 membered heterocycle containing an additional 0-1 N, S, or O atom and substituted with 0-3 R^3c.

[29] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R ²is phenyl substituted with NR³R^3a; and

R ³and R^3a, together with the nitrogen atom to which they are attached, form a pyrrolinyl, pyrrolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, morpholinyl,thiomorpholinyl, homopiperazinyl or piperazinyl group, substituted with 0-3 R^3c.

[30] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R ²is phenyl substituted with NR³R^3a, wherein R³and R^3a, together with the nitrogen atom to which they are attached, form a piperidinyl, homopiperazinyl or piperazinyl group, substituted with 0-3 R^3c.

[31] In another embodiment, the invention describes novel compounds of embodiment [1], wherein R ²is phenyl substituted with NR³R^3a; and

R ³and R^3a, together with the nitrogen atom to which they are attached, form a piperidinyl, homopiperazinyl or piperazinyl group, substituted with 0-3 substituents independently selected from the group consisting of: —C(═NH)CH₃, pyrrolinyl, pyrrolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, morpholinyl,thiomorpholinyl, homopiperazinyl or piperazinyl group, pyridyl, C_1-4alkyl, —NR³R^3b.

[32] In another embodiment, the invention describes novel compounds of embodiment [1], which is selected from Table 1.

[33] In another embodiment, the invention describes novel compounds of embodiment [1], which is selected from Table 2.

[34] In another embodiment, the invention describes novel compounds of embodiment [1], which is selected from Table 3.

[35] In another embodiment, the invention describes novel compounds of embodiment [1], which is selected from Table 4.

[36] In another embodiment, the invention describes novel compounds of embodiment [1], selected from:

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

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

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

3-(4-methanesulfonylphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-(N,N-dimethylamino)phenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;

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

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

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

3-(4-piperidinophenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-morpholinophenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;

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

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

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

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

3-(4-methoxyphenyl)-5-((4-aminophenyl)acetamido)indeno[1,2-ac]pyrazol-4-one;

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

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

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

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

3-(4-methoxyphenyl)-5-((4-(methoxycarbonylamino)phenyl) acetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-methoxyphenyl)-5-((4-(aminomethylcarbonylamino)phenyl) acetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-methoxyphenyl)-5-((4-((N,N-dimethylamino)methylcarbonyl amino)phenyl)acetamido)indeno[1,2-c]pyrazol-4-one;

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

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

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

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

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

3-(4-mnethoxyphenyl)-5-(piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-mnethoxyphenyl)-5-(4-(aminomethyl)piperidinoacetamnido) indeno[1,2-c]pyrazol-4-one;

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

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

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

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

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

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

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

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

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

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

3-(4-dimethoxyphenyl)-5-(3-thienylacetamido)indeno[1,2-c]pyrazol-4-one;

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

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

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

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

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

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

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

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

3-(4-methoxyphenyl)-5-((butylcarbamoyl)amino)indeno[1,2]pyrazol-4-one;

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

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

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

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

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

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

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

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

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

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

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

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

3-(4-(N,N-dimethylamino)phenyl)-5-(morpholinoacetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-(N,N-dimethylamino)phenyl)-5-(N,N-dimethylaminoacetamido)indeno[1,2-c]pyrazol-4-one;

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

3-(4-(N,N-dimethylamino)phenyl)-5-(4-methyl-piperazinoacetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-(N,N-dimethylamino)phenyl)-5-(4-(aminomethyl)-piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-(N,N-dimethylamino)phenyl)-5-(4-hydroxy-piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-morpholinophenyl)-5-(morpholinoacetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-morpholinophenyl)-5-(4-methylpiperazinoacetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-morpholinophenyl)-5-(4-hydroxy-piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-morpholinophenyl)-5-(4-(aminomethyl)-piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-(morpholinoacetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((N,N-dimethylamino)acetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-(4-methylpiperazinoacetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5(4-(aminomethyl)-piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-(aminocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-(morpholinocarbamoylamino)-indeno[1,2-c]pyrazol-4-one;

3-(4-(4-methylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(4-ethylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(4-isopropylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(4-t-butoxycarbonylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(N,N-dimethylamino)phenyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;

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

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

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

3-(ethyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(n-propyl)-5-(carbamoylamino)aminoindeno[1,2-c]pyrazol-4-one;

3-(i-propyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(c-propyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(c-hexyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(2-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(3-methyl-2-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-methyl-2-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-carboethoxy-2-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(3-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-methyl-3-pyrrolyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(2,5-dimethyl-3-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(2-furanyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(i-propyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;

3-(c-propyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;

3-(c-hexyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;

3-(2-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;

3-(5-methoxy-2-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;

3-(5-methyl-2-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;

3-(5-carboethoxy-2-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;

3-(3-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;

3-(5-chloro-3-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;

3-(2,5-dimethyl-3-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;

3-(2-furanyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;

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

3-(c-hexyl)-5-((4-carbamoylpiperidino)acetamido)indeno[1,2-c]pyrazol-4-one;

3-(ethyl)-5-(4-(aminomethyl)piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;

3-(i-propyl)-5-(4-(aminomethyl)piperidinoacetamido) indeno[1,2-c]pyrazol-4-one;

3-(c-propyl)-5-(4-(aminomethyl)piperidinoacetamido) indeno[1,2-c]pyrazol-4-one;

3-(c-hexyl)-5-(4-(aminomethyl)piperidinoacetamido) indeno[1,2-c]pyrazol-4-one;

3-(i-propyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-carboethoxy-2-thienyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-carboxyl-2-thienyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(2,5-dimethyl-3-thienyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(i-propyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-methoxycarbonyl-4-piperidinyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-methyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-chloro-3-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(2,5-dimethyl-3-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-carboethoxy-2-thienyl)-5-(morpholinylcarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-carboxyl-2-thienyl)-5-(morpholinylcarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(benzylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-((4-methylpiperazino)carbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-((2-(1-methyl-2-pyrrolidinyl)ethyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-((N,N-dimethylamino)aminocarbonyl)-2-thienyl-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-((2-(N,N-dimethylamino)ethyl)aminocarbonyl)-2-thienyl-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(2-pyrrolidinoethyl)aminocarbonyl)-2-thienyl-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(2-morpholinoethyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(morpholinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-((3-(2-pyrrolidon-1-yl)propyl)aminocarbonyl)-2-thienyl-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-((2-(3-pyridyl)ethyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-((3-(1-imidazolyl)propyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-((2-(2-pyridyl)ethyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-((2-pyridyl)methyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-((2-piperidinoethyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((N,N-dimethylamino)carbamoylamino)-indeno[1,2-c]pyrazol-4-one;

3-(4-(4-methylpiperazino)phenyl)-5-((N,N-dimethylamino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((4-methylpiperazino)carbamoylamino)-indeno[1,2-c]pyrazol-4-one;

3-(4-(4-methylpiperazino)phenyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(4-ethylpiperazino)phenyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(4-isopropylpiperazino)phenyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((2,6-dimethylpiperidino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((4-(2-hydroxyethyl)piperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((2(R)-(methoxymethyl)pyrrolidino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((2(S)-(methoxymethyl)pyrrolidino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((2(R)-(1-methoxy-1-methylethyl)-pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((2(S)-(1-methoxy-1-methylethyl)-pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((2(R)-(hydroxymethyl)-pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((2(S)-(hydroxymethyl)-pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((2(R)-(benzyloxymethyl)-pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((2(S)-(benzyloxymethyl)-pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(3-methylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(cis-3,5-dimethylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(cis-3,4,5-trimethylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(4-isopropylpiperazino)-2-methylphenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-homopiperazinophenyl)-5-(morpholinocarbamoylamino)-indeno[1,2-c]pyrazol-4-one;

3-(4-(4-methylhomopiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(4-ethylhomopiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(4-isopropylhomopiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-homopiperazino-2-methylphenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(4-ethylhomopiperazino)-2-methylphenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(4-isopropylhomopiperazino)-2-methylphenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(4-(N,N-dimethylamino)piperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(4-(N,N-diethylamino)piperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(4-piperidinopiperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(4-pyrrolidinopiperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

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

3-(1-methyl-3-pyrrolyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-pyrrolidinoaminocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-piperidinoaminocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-piperidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-piperazinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-methylpiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-ethylpiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-(2-hydroxyethyl)piperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-(cyclopropylmethyl)piperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-(t-butoxycarbonyl)piperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-(2-pyridyl)piperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(((1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptyl)carbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(((1S,4S)-(+)-2-methyl-2,5-diazabicyclo[2.2.1]heptyl)carbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-(N,N-dimethylamino)piperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-pyrrolidinopiperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-piperidinopiperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-cyclohexylaminocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-piperidylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-((1-(t-butoxycarboxyl)piperidin-4-yl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-(1-methylpiperidin-4-yl)methylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(3-(N,N-dimethylamino)piperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(3-p-toluenesulfonylamino)piperidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(3-hydroxypiperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-((3-piperidyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-((3-quinuclidyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-((3-aminocyclohexyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-((3-(t-butoxycarbonylamino)cyclohexyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(2-(N,N-dimethylaminomethyl)piperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(2-(N,N-diethylaminomethyl)piperidinocarbonyl)-2--thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-pyrrolidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(3-aminopyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(3(S)-N-methylamino)pyrrolidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(3(S)-acetamidopyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(3(S)-(N-methylacetamido)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(3(S)-(N-methyl-t-butoxycarbonylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(3-(N,N-dimethylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(3(R)-(N,N-dimethylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(3(S)-(N,N-dimethylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-((1-methylpyrrolidin-3-yl)methylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(2(R)-(pyrrolidinomethyl)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(2(S)-(hydroxymethyl)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(2(R)-(methoxymethyl)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(2(S)-(phenylaminomethyl)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(2(R)-(methoxymethyl)pyrrolidinoaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-homopiperidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-homopiperazinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-methylhomopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-ethylhomopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-(cyclopropylmethyl)homopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-(t-butoxycarbonyl)homopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-acetylhomopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-((4-methylaminophenyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-((4-acetamidophenyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-(diethylamino)phenylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-((1-methyl-3-cyclopropylpyrazo-5-yl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-methyl-3-pyrrolyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-carboethoxy-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-carboxyl-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-methylpiperazinocarbonyl)-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-piperazinocarbonyl-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-(t-butoxycarbonyl)piperazinocarbonyl)-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-methylhomopiperazinocarbonyl)-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-homopiperazinocarbonyl-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(4-(t-butoxycarbonyl)homopiperazinocarbonyl)-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(c-propyl)-5-(4-carbamoylpiperidinoacetamido)indeno[1,2-c]pyrazol-4-one;

3-ethyl-5-(4-methylpiperazinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(c-propyl)-5-(4-methylpiperazinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(c-hexyl)-5-(4-methylpiperazinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-ethyl-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(c-propyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(c-hexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-ethoxycarbonylpiperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-phenoxycarbonylpiperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(imidazol-1-ylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(2-thienylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-carbamoylpiperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(ethylcarbamoyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(2-(1-methylpyrrolidin-2-yl)ethylaminocarbamoyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(4-(dimethylamino)piperidinocarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(piperazinocarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(4-(t-butoxycarbonyl)piperazinocarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(((lS,4S)-(+)-2,5-diazabicyclo[2.2.1]hept-2-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(((IS,4S)-(+)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(3-aminopropylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(3-(dimethylamino)propylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(3-(t-butoxycarbonylamino)propylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(4-aminobutylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(4-(dimethylamino)butylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(4-(t-butoxycarbonylamino)butylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-((1-methylpiperidin-4-yl)carbonyl)piperidin- ⁴-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-((1-(t-butoxycarbonyl)piperidin- ⁴-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(cis-4-aminocyclohexylcarbonyl)piperidin- ⁴-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(4-aminocyclohexylcarbonyl)piperidin- ⁴-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(cis-4-(dimethylamino)cyclohexylcarbonyl)piperidin- ⁴-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(4-(t-butoxycarbonylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(trans-4-(t-butoxycarbonylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(piperidin-3-ylcarbonyl)piperidin- ⁴-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(1-methylpiperidin-3-ylcarbonyl)piperidin- ⁴-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(1-(t-butoxycarbonyl)piperidin-3-ylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(3-aminocyclohexylcarbonyl)piperidin- ⁴-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(3-(dimethylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(trans-4-methoxycyclohexylcarbonyl)piperidin- ⁴-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(cis-4-methoxycyclohexylcarbonyl)piperidin- ⁴-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(4-aminobenzylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(4-(dimethylamino)benzylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(4-(t-butoxycarbonylamino)benzylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(4-aminophenylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(4-(dimethylamino)phenylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(4-(t-butoxycarbonylamino)phenylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(trans-4-carboxylcyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(trans-4-(methoxycarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(trans-4-(3-(dimethylamino)pyrrolidinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(trans-4-(piperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(trans-4-(4-methylpiperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(trans-4-(homopiperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(trans-4-(4-methylhomopiperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one; or pharmaceutically acceptable salt form thereof.

[37] In another embodiment, the invention describes novel compounds of embodiment [1], selected from:

3-(4-piperazinophenyl)-5-(morpholinocarbamoylamino)-indeno[1,2-c]pyrazol-4-one;

3-(4-homopiperazinophenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(2,4-dimethylthiazol-5-yl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(2,4-dimethylthiazol-5-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(2,4-dimethylthiazol-5-yl)-5-((1-methyl-1-phenylamino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(2,4-dimethylthiazol-5-yl)-5-((2,6-dimethylpiperidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one; and

3-(2,4-dimethylthiazol-5-yl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one; or pharmaceutically acceptable salt form thereof.

[38] In another embodiment, the invention describes a pharmaceutical composition, comprising a pharmaceutically acceptable carrier, a compound according to embodiment [1] or a pharmaceutically acceptable salt or prodrug form thereof, and a cytostatic or cytotoxic agent.

[39] In another embodiment, the invention describes a method of treating a cell proliferative disease associated with CDK activity in a patient in need thereof,comprising administrering to said patient a pharmaceutically effective amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof, wherein the proliferative diseases is selected from the group consisting of: Alzheimer's disease, viral infections, auto-immune diseases, fungal disease, cancer, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis, neurodegenerative disorders and post-surgical stenosis and restenosis.

[40] In another embodiment, the invention describes a method of treating cancer associated with CDK activity in a patient in need thereof,comprising administrering to said patient a pharmaceutically effective amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof, wherein the cancer is selected from the group consisting of: carcinoma such as bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.

[41] In another embodiment, the invention describes a method of treating a disease associated with apoptosis in a patient in need thereof, comprising administrering to said patient a pharmaceutically effective amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof, wherein the disease associated with apoptosis is selected from the group consisting of: cancer, viral infections, autoimmune diseases and neurodegenerative disorder.

[42] In another embodiment, the invention describes a method of inhibiting tumor angiogenesis and metastasis in a patient in need thereof, comprising administrering to said patient a pharmaceutically effective amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.

[43] In another embodiment, the invention describes a method of modulating the level of cellular RNA and DNA synthesis in a patient in need thereof, comprising administering to said patient a CDK inhibitory effective amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.

[44] In another embodiment, the invention describes a method of treating viral infections in a patient in need thereof, comprising administering to said patient a CDK inhibitory effective amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof, wherein the viral infections is selected from the group consiting of HIV, human papilloma virus, herpesvirus, poxyirus, Epstein-Barr virus, Sindbis virus and adenovirus.

[45] In another embodiment, the invention describes a method of chemopreventing cancer in a patient, comprising administering to said patient in need thereof, a CDK inhibitory effective amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.

[46] In another embodiment, the invention describes a method of inhibiting CDK activity comprising combining an effective amount of a compound according to embodiment [1], with a composition containing CDK.

[47] In another embodiment, the invention describes a method of treating cancer associated with CDK activity in a patient in need thereof,comprising administrering to said patient a pharmaceutically effective amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof, in combination (administered together or sequentially) with known anti-cancer treatments such as radiation therapy or with cytostatic or cytotoxic agents, wherein such agents are selected from the group consisting of: DNA interactive agents, such as cisplatin or doxorubicin; topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents, such as paclitaxel, docetaxel or the epothilones; hormonal agents, such as tamoxifen; thymidilate synthase inhibitors, such as 5-fluorouracil; and anti-metabolites, such as methoxtrexate.

[48] In another embodiment, the invention describes a method treating cell proliferative diseases associated with CDK activity in a patient in need thereof, comprising administrering to said patient a pharmaceutically effective amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof, in combination (administered together or sequentially) with known anti-proliferating agents selected from the group consisting of:, altretamine, busulfan, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, thiotepa, cladribine, fluorouracil, floxuridine, gemcitabine, thioguanine, pentostatin, methotrexate, 6-mercaptopurine, cytarabine, carmustine, lomustine, streptozotocin, carboplatin, cisplatin, oxaliplatin, iproplatin, tetraplatin, lobaplatin, JM216, JM335, fludarabine, aminoglutethimide, flutamide, goserelin, leuprolide, megestrol acetate, cyproterone acetate, tamoxifen, anastrozole, bicalutamide, dexamethasone, diethylstilbestrol, prednisone, bleomycin, dactinomycin, daunorubicin, doxirubicin, idarubicin, mitoxantrone, losoxantrone, mitomycin-c, plicamycin, paclitaxel, docetaxel, CPT-11, epothilones , topotecan, irinotecan, 9-amino camptothecan, 9-nitro camptothecan, GS-211, etoposide, teniposide, vinblastine, vincristine, vinorelbine, procarbazine, asparaginase, pegaspargase, methoxtrexate, octreotide, estramustine, and hydroxyurea.

[49] In another embodiment, the invention describes a method of inhibiting CDK1 activity, comprising adminsitering to a patient in need thereof an efective CDKl inhibitory amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.

[50] In another embodiment, the invention describes a method of inhibiting CDK2 activity, comprising adminsitering to a patient in need thereof an efective CDK2 inhibitory amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.

[51] In another embodiment, the invention describes a method of inhibiting CDK3 activity, comprising adminsitering to a patient in need thereof an efective CDK3 inhibitory amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.

[52] In another embodiment, the invention describes a method of inhibiting CDK4 activity, comprising adminsitering to a patient in need thereof an efective CDK4 inhibitory amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.

[53] In another embodiment, the invention describes a method of inhibiting CDK5 activity, comprising adminsitering to a patient in need thereof an efective CDK5 inhibitory amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.

[54] In another embodiment, the invention describes a method of inhibiting CDK6 activity, comprising adminsitering to a patient in need thereof an efective CDK6 inhibitory amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.

[55] In another embodiment, the invention describes a method of inhibiting CDK7 activity, comprising adminsitering to a patient in need thereof an efective CDK7 inhibitory amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.

[56] In another embodiment, the invention describes a method of inhibiting CDK8 activity, comprising adminsitering to a patient in need thereof, an efective CDK8 inhibitory amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.

[57] In another embodiment, the invention describes a method of inhibiting CDK9 activity, comprising adminsitering to a patient in need thereof an efective CDK9 inhibitory amount of a compound according to embodiment [1], or a pharmaceutically acceptable salt or prodrug form thereof.

[58] In another embodiment, the invention describes a pharmaceutical kit for treating a cell proliferative disease associated with CDK activity, said kit comprising a plurality of separate containers, wherein at least one of said containers contains a compound accordig to embodiment [1],, or a pharmaceutically acceptable salt or prodrug form thereof, and at least another of said containers contains one or more compounds selected from the group consisting of cytostatic or cytotoxic agents, such as for example, but not limited to, DNA interactive agents, such as carboplatin, cisplatin or doxorubicin; topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents, such as paclitaxel, taxane, docetaxel or the epothilones; hormonal agents, such as tamoxifen; thymidilate synthase inhibitors, such as 5-fluorouracil; and anti-metabolites, such as methoxtrexate, and said containers optionally contain a pharmaceutical carrier, which kit may be effectively utilized for carrying out combination therapies according to the invention.

It is a further object of the invention to provide a method of treating a patient having a disorder associated with excessive cell proliferation, comprising administering to the patient a therapeutically effective amount of a compound of embodiment [1], such that the excessive cell proliferation in the patient is reduced.

It is appreciated that certain feactures of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. For example, R ¹of embodiment [6] may be combined with R2 of embodiment [19] to form a single embodiment. Conversely, various feactures of the invention which are, for brevity, described in the context of a single embodiment, may also be provided seperately or in any suitable subcombination.

DETAILED DESCRIPTION OF THE INVENTION

As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

Definitions

As used herein, the following terms and expressions have the indicated meanings.

The term “compounds of the invention”, and equivalent expressions, are meant to embrace compounds of the invention as herein before described i.e. compounds of formula (I), which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.

The term “derivative” means a chemically modified compound wherein the modification is considered routine by the ordinary skilled chemist, such as an ester or an amide of an acid, protecting groups, such as a benzyl group for an alcohol or thiol, and tert-butoxycarbonyl group for an amine.

The term “effective amount” means an amount of a compound/composition according to the present invention effective in producing the desired therapeutic effect.

The term “amine protecting group” means an easily removable group which is known in the art to protect an amino group against undesirable reaction during synthetic procedures and to be selectively removable. The use of amine protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991), incorporated herein by reference. Preferred amine protecting groups are acyl, including formyl, acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl, acylisothiocyanate, aminocaproyl, benzoyl and the like, and acyloxy including methoxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilylethxoycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl (BOC), 1,1-dimethylpropynyloxycarbonyl, benzyloxycarbonyl (CBZ), p-nitrobenzyloxycarbony, 2,4-dichlorobenzyloxycarbonyl, and the like.

The term “acid labile amine protecting group” means an amine protecting group as defined above which is readily removed by treatment with acid while remaining relatively stable to other reagents. A preferred acid labile amine protecting group is tert-butoxycarbonyl (BOC).

The term “hydrogenation labile amine protecting group” means an amine protecting group as defined above which is readily removed by hydrogenation while remaining relatively stable to other reagents. A preferred hydrogenation labile amine protecting group is benzyloxycarbonyl (CBZ).

The term “hydrogenation labile acid protecting group” means an acid protecting group as defined above which is readily removed by hydrogenation while remaining relatively stable to other reagents. A preferred hydrogenation labile acid protecting group is benzyl.

The term “analogue” means a compound which comprises a chemically modified form of a specific compound or class thereof, and which maintains the pharmaceutical and/or pharmacological activities characteristic of said compound or class.

The term “patient” includes both human and other mammals.

The term “pharmaceutical composition” means a composition comprising a compound of formula (I) and at least one component selected from the group comprising pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. Examples of suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monosterate and gelatin. Examples of suitable carriers, diluents, solvents or vehicles include water, ethanol, polyols, suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Examples of excipients include lactose, milk sugar, sodium citrate, calcium carbonate, dicalcium phosphate phosphate. Examples of disintegrating agents include starch, alginic acids and certain complex silicates. Examples of lubricants include magnesium stearate, sodium lauryl sulphate, talc, as well as high molecular weight polyethylene glycols.

The term “solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, and the like.

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

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

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

As used herein, the term “heterocycle” or “heterocyclic system” is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom 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.

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.

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

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, 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.

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.

The term “Pharmaceutically acceptable prodrugs” as used herein means those prodrugs of the compounds useful according to the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.

The term “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. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality. 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. Functional groups which may be rapidly transformed, by metabolic cleavage, in vivo form a class of groups reactive with the carboxyl group of the compounds of this invention. They include, but are not limited to such groups as alkanoyl (such as acetyl, propionyl, butyryl, and the like), unsubstituted and substituted aroyl (such as benzoyl and substituted benzoyl), alkoxycarbonyl (such as ethoxycarbonyl), trialkylsilyl (such as trimethyl- and triethysilyl), monoesters formed with dicarboxylic acids (such as succinyl), and the like. Because of the ease with which the metabolically cleavable groups of the compounds useful according to this invention are cleaved in vivo, the compounds bearing such groups act as pro-drugs. The compounds bearing the metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group. A thorough discussion of prodrugs is provided in the following: Design of Prodrugs, H. Bundgaard, ed., Elsevier, 1985; Methods in Enzymology, K. Widder et al, Ed., Academic Press, 42, p.309-396, 1985; A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; “Design and Applications of Prodrugs” p.113-191, 1991; Advanced Drug Delivery Reviews, H. Bundgard, 8, p.1-38, 1992; Journal of Pharmaceutical Sciences, 77, p. 285, 1988; Chem. Pharm. Bull., N. Nakeya et al, 32, p. 692, 1984; Pro-drugs as Novel Delivery Systems, T. Higuchi and V. Stella, Vol. 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference.

“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.

The term “Treating” refers to:

(i) preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it;

(ii) inhibiting the disease, disorder or condition, i.e., arresting its development; and

(iii) relieving the disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.

Preparation of Comounds of the Invention

It will be apparent to those skilled in the art that certain compounds of formula (I) can exhibit isomerism, for example geometrical isomerism, e.g., E or Z isomerism, and optical isomerism, e.g., R or S configurations. Geometrical isomers include the cis and trans forms of compounds of the invention having alkenyl moieties. 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.

Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallization techniques, or they are separately prepared from the appropriate isomers of their intermediates, for example by the application or adaptation of methods described herein.

The compounds of the present invention are useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof. All forms are within the scope of the invention.

Where the compound of the present invention is substituted with a basic moiety, acid addition salts are formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on CDK inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures.

According to a further feature of the invention, acid addition salts of the compounds of this invention are prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.

The acid addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.

Where the compound of the invention is substituted with an acidic moiety, base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on CDK inherent in the free acid are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including for example alkali and alkaline earth-metal salts, within the scope of the invention are those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.

Metal salts of compounds of the present invention may be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the chosen metal in an aqueous or organic solvent with the free acid form of the compound. The aqueous solvent employed may be water or it may be a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as ethyl acetate. Such reactions are normally conducted at ambient temperature but they may, if desired, be conducted with heating.

Amine salts of compounds of the present invention may be obtained by contacting an amine in an aqueous or organic solvent with the free acid form of the compound. Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitrites such as acetonitrile, or ketones such as acetone. Amino acid salts may be similarly prepared.

The base addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.

Pharmaceutically acceptable salts also include quaternary lower alkyl ammonium salts. The quaternary salts are prepared by the exhaustive alkylation of basic nitrogen atoms in compounds, including nonaromatic and aromatic basic nitrogen atoms, according to the invention, i.e., alkylating the non-bonded pair of electrons of the nitrogen moieties with an alkylating agent such as methylhalide, particularly methyl iodide, or dimethyl sulfate. Quaternarization results in the nitrogen moiety becoming positively charged and having a negative counter ion associated therewith.

As will be self-evident to those skilled in the art, some of the compounds of this invention do not form stable salts. However, acid addition salts are more likely to be formed by compounds of this invention having a nitrogen-containing heteroaryl group and/or wherein the compounds contain an amino group as a substituent. Preferable acid addition salts of the compounds of the invention are those wherein there is not an acid labile group.

As well as being useful in themselves as active compounds, salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.

Compounds according to the invention, for example, starting materials, intermediates or products, are prepared as described herein or by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature.

Compounds useful according to the invention may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, for example those described by R. C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.

In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T. W. Green and P. G. M. Wuts in “Protective Groups in Organic Chemistry” John Wiley and Sons, 1991; J. F. W. McOmie in “Protective Groups in Organic Chemistry” Plenum Press, 1973.

Preferred methods of synthesizing the compounds of the invention include, but are not limited to, those methods described below. Each of the references cited below are hereby incorporated herein by reference.

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 deacetylated 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.

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

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 Qshkaya, 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, R ¹COCH₃. 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.

Another method for making the indeno[1,2-c]pyrazol-4-one ring system is exemplified 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.

The ureas and semicarbazides (R ¹═NHR⁴, X═O) of this invention can be prepared by treating the aniline intermediates in Schemes 1-4, for example 4 or 6c, with an isocyanate (RNCO) or an aminoisocyanate (RR′NNCO). These reagents are readily prepared in advance by one skilled in the art, or they can be generated in situ employing a precursor, such as an O-phenylcarbamate (RNHCO₂Ph or RR′NNHCO₂Ph), in the presense of base. Alternatively, the ureas and semicarbazides can be prepared by treatment of the anilines intermediates above with phenyl chloroformate in the presense of base to give an intermediate phenyl carbamate, followed by exposure of the phenyl carbamate to an amine or a hydrazine at elevated temperatures in an appropriate solvent.

The thioureas and thiosemicarbazides (X═S) of this invention can be prepared as described above by treating the aniline intermediates with phenyl thionochloroformate, followed by exposure of the resulting phenyl thiocarbamate to the appropriate amine or hydrazine derivative. The thioamides, thioureas, and thiosemicarbazides can also be prepared from the corresponding amides, ureas, and semicarbazides by treatment with a reagent such as phosphorous pentasulfide or Lawesson's reagent.

The amidines and guanidines (X═NR) of this invention can be prepared as described in Schemes 1-4 by treatment of the intermediate anilines with a wide variety of reagents known to one skilled in the art. These reagents include, but are not limited to, imidates and iminoyl chlorides for the production of amidines and isothioures and carbodiimides for the production of guanidines. Alternatively, the amidines and guanidines of this invention can be prepared from the corresponding thioamides, thioureas, and thiosemicarbazides. For example, a thiourea can be S-alkylated by treatment with an akylating agent such as methyl iodide or methyl triflate to provide the corresponding isothiourea. Treatment of this intermediate with the requisite amine or hydrazine at elevated temperatures in an appropriate solvent then provides the desired quanidine derivative.

Many of the compounds of this invention are synthesized from the indeno[1,2-c]pyrazol-4-ones prepared in Schemes 1-4 by the further synthetic elaboration of the R ¹and R²groups. As required the pyrazole ring can be protected by a wide range of protecting groups known to one skilled in the art with the selection of a protecting depending on the chemistry to be employed.

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

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. [0577]

Example I

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

[0578]
Step 1. Synthesis of 2 from Dimethyl 3-nitrophthalate. [0579]
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 C[0580] ₁₂H₁₄NO₅: 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.
Step 2. Synthesis of Triketone 11 from 2. [0581]
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 C[0582] ₁₉H₁₆NO₅: 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.
Step 3. Synthesis of 12 from 11. [0583]
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 C[0584] ₁₉H₁₆N₃O₃: 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

[0585]
Step 1. Synthesis of 13 from 12. [0586]
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 C[0587] ₁₇H₁₄N₃O₂: 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.
Step 2. Synthesis of 14 from 13. [0588]
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 (MgSO[0589] ₄) 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-(cyclopropanecarboxamido)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example II using cyclopropanecarboxoyl chloride as the starting material. mp 289° C.; CIMS m/e calc'd for C[0590] ₂₁H₁₈N₃O₃: 360.1348, found: 360.1330.

Example IV

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

Prepared in a similar fashion as described for example II using 2-methylpropanoyl chloride as the starting material. mp 288° C.; CIMS m/e calc'd for C[0591] ₂₁H₂₀N₃O₃: 362.1505, found: 362.1535.

Example V

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

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 C[0592] ₂₀H₁₈N₃O₃: 348.1348, found: 348.1313.

Example VI

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

Prepared in a similar fashion as described for example II using cyclopentanecarboxoyl chloride as the starting material. mp 267° C.; CIMS m/e calc'd for C[0593] ₂₃H₂₂N₃O₃: 388.1661, found: 388.1626.

Example VII

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

Prepared in a similar fashion as described for example II using cyclobutanecarboxoyl chloride as the starting material. mp 297° C.; CIMS m/e calc'd for C[0594] ₂₂H₂₀N₃O₃: 374.1505, found: 374.1530.

Example VIII

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

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 C[0595] ₂₅H₂₀N₃O₃: 410.1505, found: 410.1533.

Example IX

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

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 C[0596] ₂₁H₂₀N₃O₃: 362.1505, found: 362.1500.

Example X

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

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 C[0597] ₂₅H₁₉N₃O₃Cl: 444.1115, found: 444.1110.

Example XI

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

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 C[0598] ₂₆H₂₂N₃O₄: 440.1610, found: 440.1620.

Example XII

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

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 C[0599] ₂₆H₂₂N₃O₄: 440.1610, found: 440.1630.

Example XIII

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

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 C[0600] ₂₇H₂₄N₃O₅: 470.1716, found: 470.1731.

Example XIV

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

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 C[0601] ₂₇H₂₄N₃O₅: 470.1716, found: 470.1739.

Example XV

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

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 C[0602] ₁₉H₁₆N₃O₃: 334.1192, found: 334.1169.

Example XVI

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

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 C[0603] ₂₀H₁₈N₃O₄: 364.1297, found: 364.1288.

Example XVII

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

[0604]
Step 1. Synthesis of 15 from 11. [0605]
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 C[0606] ₁₇H₁₄NO₄: 296.0923, Found: 296.0901.
Step 2. Synthesis of 16 from 15. [0607]
A suspension of 15 (20 mg, 0.07 mmol) in acetone (2 mL) was treated with NaHCO[0608] ₃(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-thienylacetamido)indeno[1,2-c]pyrazol-4-one

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 C[0609] ₂₃H₁₈N₃O₃S: 416.1069, found: 416.1088.

Example XIX

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

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 C[0610] ₂₆H₂₂N₃O₄: 440.1610, found: 440.1622.

Example XX

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

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 C[0611] ₂₅H₁₈N₃O₃Cl₂: 478.0725, found: 478.0744.

Example XXI

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

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 C[0612] ₂₅H₁₈N₃O₃Cl₂: 478.0725, found: 478.0734.

Example XXII

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

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 C[0613] ₂₅H₁₉N₃O₃Cl: 444.1115, found: 444.1111.

Example XXIII

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

[0614]
A suspension of 14 (15 mg, 0.04 mol) in EtOH (1 mL) was treated with conc. NH[0615] ₄OH (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

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 C[0616] ₂₁H₂₁N₄O₄: 393.1563, found: 393.1539.

Example XXV

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

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 C[0617] ₂₁H₂₁N₄O₃: 377.1614, found: 377.1640.

Example XXVI

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

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 C[0618] ₂₃H₂₄N₅O₃: 418.1879, found: 418.1899.

Example XXVII

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

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 C[0619] ₂₄H₂₆N₅O₃: 432.2036, found: 432.2030.

Example XXVIII

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

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 C[0620] ₂₅H₂₈N₅O₄: 462.2141, found: 462.2128.

Example XXIX

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

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 C[0621] ₂₄H₂₅N₄O₃: 417.1927, found: 417.1955.

Example XXX

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

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 C[0622] ₂₅H₂₈N₅O₃: 446.2192, found: 446.2166.

Example XXXI

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

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 C[0623] ₂₁H₂₁N₄O₃: 377.1614, found: 377.1644.

Example XXXII

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

Prepared in a similar fashion as described for example XXIII using thiomorpholine as the starting material. mp 298 IC; CIMS m/e calc'd for C[0624] ₂₃H₂₃N₄O₃S: 435.1491, found: 435.1477.

Example XXXIII

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

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 C[0625] ₂₃H₂₃N₄O₄: 419.1719, found: 419.1744.

Example XXXIV

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

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 C[0626] ₂₃H₂₃N₄O₃: 403.1770, found: 403.1761.

Example XXXV

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

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 C[0627] ₂₅H₂₂N₅O₃: 440.1723, found: 440.1762.

Example XXXVI

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

[0628]
A suspension of 18 (10 mg, 0.02 mmol) in dioxane (1 mL) was treated with aqueous sat. NaHCO[0629] ₃(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-(methoxycarbonylamino)phenyl)acetamido) indeno[1,2-c]pyrazol-4-one

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 C[0630] ₂₇H₂₃N₄O₅: 483.1668, found: 483.1633.

Example XXXVIII

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

Prepared in a similar fashion as described for example XXIII and XXXII using chloroacetyl chloride and conc. NH[0631] ₄OH 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-dimethylamino)methylcarbonylamino)phenyl)acetamido) indeno[1,2-c]pyrazol-4-one

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 C[0632] ₂₉H₂₈N₅O₄: 510.2141, found: 510.2121.

Example XL

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

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 C[0633] ₂₅H₁₉N₆O₃: 451.1519, found: 451.1544.

Example XLI

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

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 C[0634] ₂₅H₂₁N₄O₃: 425.1614, found: 425.1643.

Example XLII

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

[0635]
Step 1. Synthesis of 20 from 15. [0636]
A suspension of 15 (0.5 g, 1.7 mmol) in acetone (10 mL) was treated with NaHCO[0637] ₃(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.
Step 2. Synthesis of 21 from 20. [0638]
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 (MgSO[0639] ₄) 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)amino)indeno[1,2-c]pyrazol-4-one

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 C[0640] ₂₁H₂₁N₄O₃: 377.1614, found: 377.1633.

Example XLIV

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

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 C[0641] ₂₅H₂₂N₅O₃: 440.1723, found: 440.1700.

Example XLV

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

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 C[0642] ₂₄H₂₀N₅O₃: 426.1566, found: 426.1533.

Example XLVI

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

[0643]
A suspension of 12 (20 mg, 0.07 mmol) in CH[0644] ₂Cl₂(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

[0645]
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 C[0646] ₁₈H₁₄N₃O₃: 320.1035, Found: 320.1040.

Example XLVIII

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

[0647]
Step 1. Synthesis of 24 from 3-acetylpyridine. [0648]
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/CH[0649] ₂Cl₂) 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.
Step 2. Synthesis of 25 from 24. [0650]
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 C[0651] ₁₇H₁₃N₄O₂: 305.1039, Found: 305.1048.

Example XLIX

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

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 C[0652] ₁₇H₁₃N₄O₂: 305.1039, found: 305.1046.

Example L

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

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 C[0653] ₁₆H₁₁N₄O₂: 291.0882, found: 291.0882.

Example LI

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

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 C[0654] ₁₈H₁₃N₃O₂: 304.1065, found: 304.1086.

Example LII

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

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 C[0655] ₁₉H₁₅N₃O₂S: 350.0956, found: 350.0963.

Example LIII

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

Prepared by oxidation of the product of example LII. mp >300° C.; CIMS m/e calc'd for C[0656] ₁₉H₁₅N₃O₄S: 382.0860, found: 382.0862.

Example LIV

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

Prepared in a similar fashion as described for example I using 4′-(N,N-dimethylamino)acetophenone as the starting material. mp >300° C.; CIMS m/e calc'd for C[0657] ₂₀H₁₈N₄O₂: 347.1496, found: 347.1508.

Example LV

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

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 C[0658] ₂₄H₂₆N₅O₃: 432.2036, found: 432.2020.

Example LVI

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

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 C[0659] ₂₂H₂₄N₅O₂: 390.1930, found: 390.1948.

Example LVII

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

Prepared in a similar fashion as described for example I using 41-(1-piperidinyl)acetophenone as the starting material. mp 291° C.; CIMS m/e calc'd for C[0660] ₂₃H₂₂N₄O₂: 387.1801, found: 387.1821.

Example LVIII

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

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 C[0661] ₂₂H₂₀N₄O₃: 388.1528, found: 388.1535.

Example LIX

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

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 C[0662] ₂₀H₁₇N₃O₃: 348.1325, found: 348.1348.

Example LX

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

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 C[0663] ₂₂H₂₁N₃O₂: 360.1701, found: 360.1712.

Example LXI

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

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 C[0664] ₂₀H₁₇N₃O₂: 331.1310, found: 331.1321.

Example LXII

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

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 C[0665] ₂₁H₁₉N₃O₂: 346.1555, found: 346.1554.

Example LXIII

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

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 C[0666] ₁₈H₁₅N₄O₃: 335.1144, found: 335.1113.

Example LXIV

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

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 C[0667] ₂₀H₂₀N₅O₃: 378.1566, found: 378.1555.

Example LXV

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

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 C[0668] ₁₉H₁₇N₄O₃: 349.1300, found: 349.1311.

Example LXVI

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

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 C[0669] ₂₂H₂₂N₅O₄: 420.1671, found: 420.1655.

Example LXVII

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

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 C[0670] ₂₄H₂₆N₅O₃: 432.2035, found: 432.2020.

Example LXVIII

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

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 C[0671] ₂₃H₂₅N₆O₃: 433.1987, found: 433.1999.

Example LXIX

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

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 C[0672] ₂₆H₂₉N₆O₄: 489.2250, found: 489.2209.

Example LXX

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

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 catc'd for C[0673] ₂₈H₂₇N₆O₃: 495.2144, found: 495.2111.

Example LXXI

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

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 C[0674] ₂₅H₂₉N₆O₃: 461.2300, found: 461.2333.

Example LXXII

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

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 C[0675] ₂₅H₂₆N₅O₄: 460.1984, found: 460.1998.

Example LXXIII

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

Prepared in a similar fashion as described for example XXIII using 4-hydroxypiperidine as the starting material. mp >300° C.; CIMS m/e calc'd for C[0676] ₂₄H₂₅N₄O₄: 433.1875, found: 433.1844.

Example LXXIV

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

Prepared in a similar fashion as described for example XXIII using 4-(hydroxmethyl)piperidine as the starting material. mp >300° C.; CIMS m/e calc'd for C[0677] ₂₅H₂₇N₄O₄: 447.2032, found: 447.2002.

Example LXXV

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

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 C[0678] ₂₄H₂₅N₆O₆: 493.1835, found: 493.1802.

Example LXXVI

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

Prepared in a similar fashion as described for example XXIII using 4-dimethylaminopiperidine as the starting material. mp >300° C.; CIMS m/e calc'd for C[0679] ₂₆H₃₀N₅O₅: 492.2246, found: 492.2220.

Example LXXVII

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

Prepared in a similar fashion as described for example XXIII using 4-aminopiperidine as the starting material. mp >300° C.; CIMS m/e calc'd for C[0680] ₂₄H₂₆N₅O₅: 464.1933, found: 464.1975.

Example LXXVIII

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

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 C[0681] ₂₅H₂₉N₆O₂: 445.2352, found: 445.2359.

Example LXXIX

Preparation of 3-(4-(N,N-dimethylamino)phenyl)-5-(4-(aminomethyl)piperidinoacetamido)indeno[1,2-c]pyrazol-4-one

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 C[0682] ₂₆H₃₁N₆O₂: 459.2508, found: 459.2508.

Example LXXX

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

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 C[0683] ₂₅H₂₈N₅O₃: 446.2192, found: 446.2206.

Example LXXXI

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

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 C[0684] ₂₆H₂₈N₅O₄: 474.2141, found: 474.2151.

Example LXXXII

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

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 C[0685] ₂₇H₃₁N₆O₃: 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

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 C[0686] ₂₇H₃₀N₅O₄: 488.2298, found: 488.2290.

Example LXXXIV

Preparation of 3-(4-morpholinophenyl)-5-(4-(aminomethyl)piperidinoacetamido)indeno[1,2-c]pyrazol-4-one

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 C[0687] ₂₈H₃₃N₆O₃: 501.2614, found: 501.2619.

Example LXXXV

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

Prepared in a similar fashion as described for examples I, XXVII, and XLII employing the 4-(dimethylamino) acetophenone and 1-amino-4-methylpiperazine as the starting materials. mp >300° C.; ESI-MS m/e calc'd for C[0688] ₂₄H₂₈N₇O₂: 446.2304, found: 446.2310.

Example LXXXVI

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

Prepared in a similar fashion as described for example XLII using phenylthionochloroformate and 1-amino-4-methylpiperazine as the starting materials. mp >300° C.; CIMS m/e calc'd for C[0689] ₂₃H₂₅N₆O₂S: 449.1760, found: 449.1777.

Example LXXXVII

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

[0690]
Step 1. Synthesis of 26 from 3-nitrophthalic Anhydride. [0691]
A solution of 3-nitrophthalic anhydride (2.5 g, 13 mmol) and 2-thenoyltrifluoroacetone (2.87 g, 13 mmol) in acetic anhydride (7.3 mL, 78 mmol) was treated with triethylamine (3.6 mL, 26 mmol) and stirred at 25° C. for 12 h. The solution was diluted with 1 N HCl (25 mL) and the precipate collected and washed with 0.1 M HCl (2×25 mL) and hexane (3×25 mL) to give the product as a yellow solid (1.5 g, 38%). mp 140-141° C.; APIMS (M+H) calc'd for C[0692] ₁₄H₈NO₅S: 302.29, found: 302.20.
Step 2. Synthesis of Triketone 27 from 26. [0693]
A solution of 26 (1 g, 3.3 mmol) in EtOH (12 mL) and water (12 mL) was treated with zinc (7.1 g, 110 mmol) and calcium chloride (240 mg, 2.2 mmol) and heated to reflux for 1.5 h. The reaction was filtered (Celite) and washed with EtOH/H20 (1:1, 3×200 mL), EtOAc (3×100 mL), MeOH (2×100 mL), and i-PrOH (2×100 mL). The filtrate was concentrated at reduced pressure to give an aqueous residue which was extracted with EtOAc (4×200 mL). The combined organic extracts were separated, dried (Na[0694] ₂SO₄), filtered, and concentrated at reduced pressure to give a reddish foam (˜0.9 g, 100%). mp >300° C.; ESIMS (M−H) calc'd for C₁₄H₈NO₃S: 270.29, found: 270.20.
Step 3. Synthesis of 28 from 27. [0695]
A solution of 27 (900 mg, 3.3 mmol) in acetic anhydride (20 mL) was refluxed for 1.5 h. The reaction mixture was treated heptane and the solvents were concentrated at reduced pressure to give a dark residue which was diluted with EtOAc (100 mL) and washed with H[0696] ₂O (3×75 mL) and brine (2×50 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated at reduced pressure to give a reddish-brown foam. Purification (SiO₂, 1:1 EtOAc/hexane) gave the product as a red oil (600 mg, 58%). mp >300° C.; ESIMS (M−H) calc'd for C₁₆H₁₀NO₄S: 313.33, found: 313.10.
Step 4. Synthesis of LXXXVII from 28. [0697]
A solution of 28 (200 mg, 0.64 mmol) in EtOH (2 mL) was treated with hydrazine hydrate (0.04 mL, 1.3 mmol) and p-TsOH (6 mg, 0.032 mmol). The reaction was heated to reflux and stirred for 12 h. The reaction was cooled to 25° C. and the solid filtered. Purification by reverse phase HPLC (CH[0698] ₃CN/H₂O) gave the product (16 mg, 9%). mp 269° C.; CIMS (M+H) calc'd for C₁₆H₁₂N₃O₂S: 310.0650, found: 310.0635.

Example LXXXVIII

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

Prepared in a similar fashion as described for example LXXXVII using 1-cyclopropyl-4,4,4-trifluoro-1,3-butanedione as the starting material. mp 220-221° C.; CIMS (M+H) calc'd for C[0699] ₁₅H₁₄N₃O₂: 268.1086, found: 268.1078.

Example LXXXVIX

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

Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 1-methyl-3-pyrrolyl analog of 15 as the starting materials. mp >300° C.; ESIMS (M+H) calc'd for C[0700] ₁₆H₁₄N₅O₂: 308.1148, found: 308.1166.

Example XC

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

Prepared in a similar fashion as described for example LXXXVII and XLII using the 3-methyl-2-thienyl analog of 26 as the starting material. mp 275° C.; ESIMS (M+H) calc'd for C[0701] ₁₇H₁₄N₃O₂S: 324.0811, found: 324.0807.

Example XCI

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

Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the ethyl analog of 15 as the starting materials. mp >250° C.; CIMS (M+H) calc'd for C[0702] ₁₃H₁₃N₄O₂: 257.1039, found: 257.1033.

Example XCII

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

Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the n-propyl analog of 15 as the starting materials. mp 187-189° C.; CIMS (M+H) calc'd for C[0703] ₁₄H₁₅N₄O₂: 271.1195, found: 271.1187.

Example XCIII

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

Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 1-propyl analog of 15 as the starting materials. mp >250° C.; CIMS (M+H) calc'd for C[0704] ₁₄H₁₅N₄O₂: 271.1195, found: 271.1196.

Example XCIV

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

Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the c-propyl analog of 15 as the starting materials. mp 252-253° C.; ESIMS (M−H) calc'd for C[0705] ₁₄H₁₁N₄O₂: 267.0881, found: 267.0884.

Example XCV

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

Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the c-hexyl analog of 15 as the starting materials. mp 178-179° C.; ESIMS (M+H) calc'd for C[0706] ₁₇H₁₉N₄O₂: 311.1507, found: 311.1500.

Example XCVI

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

Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 2-thienyl analog of 15 as the starting materials. mp 214° C.; CIMS m+ calc'd for C[0707] ₁₅H₁₀N₄O₂S: 310.0517, found: 310.0524.

Example XCVII

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

Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 3-methyl-2-thienyl analog of 15 as the starting materials. mp 270° C.; ESIMS (M+H) calc'd for C[0708] ₁₆H₁₃N₄O₂S: 325.0759, found: 325.0744.

Example XCVIII

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

Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 5-methyl-2-thienyl analog of 15 as the starting materials. mp >280° C.; ESIMS (M+H) calc'd for C[0709] ₁₆H₁₃N₄O₂S: 325.0759, found: 325.0761.

Example XCIX

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

Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 5-ethylcarboxyl-2-thienyl analog of 15 as the starting materials. mp >280° C.; ESIMS (M+H) calc'd for C[0710] ₁₈H₁₅N₄O₄S: 383.0813, found: 383.0788.

Example C

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

Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 3-thienyl analog of 15 as the starting materials. mp >280° C.; ESIMS (M+H) calc'd for C[0711] ₁₅H₁₁N₄O₂S: 311.0603, found: 311.0594.

Example CI

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

Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 5-chloro-3-thienyl analog of 15 as the starting materials. mp >300° C.; ESIMS (M+H) calc'd for C[0712] ₁₅H₁₀N₄O₂SCl: 345.0209, found: 345.0213.

Example CII

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

Prepared in a similar fashion as described for example LXXXVII and XLII 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 C[0713] ₁₇H₁₅N₄O₂S: 339.0916, found: 339.0905.

Example CIII

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

Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 2-furanyl analog of 15 as the starting materials. mp 278° C.; ESIMS (M+H) calc'd for C[0714] ₁₅H₁₁N₄O₃: 295.0831, found: 295.0838.

Example CIV

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

Prepared in a similar fashion as described for example LXXXVII and XLII 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 C[0715] ₁₆H₂₀N₅O₂: 314.1616, found: 314.1599.

Example CV

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

Prepared in a similar fashion as described for example LXXXVII and XLII using 1,1-dimethylhydrazine and the c-propyl analog of 15 as the starting materials. mp XXX° C.; ESIMS (M+H) calc'd for C[0716] ₁₆H₁₈N₅O₂: 312.1460, found: 312.1487.

Example CVI

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

Prepared in a similar fashion as described for example LXXXVII and XLII 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 C[0717] ₁₉H₂₄N₅O₂: 354.1929, found: 354.1932.

Example CVII

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

Prepared in a similar fashion as described for example LXXXVII and XLII using 1,1-dimethylhydrazine and the 2-thienyl analog of 15 as the starting materials. mp 279° C.; ESIMS (M+H) calc'd for C[0718] ₁₇H₁₆N₅O₂S: 354.1024, found: 354.1025.

Example CVIII

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

Prepared in a similar fashion as described for example LXXXVII and XLII 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 C[0719] ₁₈H₁₈N₅O₃S: 384.1130, found: 384.1119.

Example CIX

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

Prepared in a similar fashion as described for example LXXXVII and XLII 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 C[0720] ₁₈H₁₈N₅O₂S: 368.1181, found: 368.1171.

Example CX

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

Prepared in a similar fashion as described for example LXXXVII and XLII 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 C[0721] ₂₀H₂₀N₅O₄S: 426.1236, found: 426.1251.

Example CXI

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

Prepared in a similar fashion as described for example LXXXVII and XLII using 1,1-dimethylhydrazine and the 3-thienyl analog of 15 as the starting materials. mp 202° C.; ESIMS (M+H) calc'd for C[0722] ₁₇H₁₆N₅O₂S: 354.1025, found: 354.1031.

Example CXII

Prepared in a similar fashion as described for example LXXXVII and XLII using ammonia and the 1-methyl-3-pyrrolyl analog of 15 as the starting materials. mp >300° C.; ESIMS (M+H) calc'd for C[0723] ₁₆H₁₄N₅O₂: 308.1147, found: 308.1166.

Example CXIII

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

Prepared in a similar fashion as described for example LXXXVII and XLII 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 C[0724] ₁₉H₂₀N₅O₂S: 382.1338, found: 382.1357.

Example CXIV

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

Prepared in a similar fashion as described for example LXXXVII and XLII using 1,1-dimethylhydrazine and the 2-furanyl analog of 15 as the starting materials. mp 202° C.; ESIMS (M+H) calc'd for C[0725] ₁₇H₁₆N₅O₃: 338.1253, found: 338.1248.

Example CXV

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

Prepared in a similar fashion as described for example XXIII using isonipecotamide and the 1-propyl analog of 14 as the starting materials. mp 224-225° C.; ESIMS (M+H) calc'd for C[0726] ₂₁H₂₆N₅O₃: 396.2035, found: 396.2036.

Example CXVI

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

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 C[0727] ₂₄H₃₀N₅O₃: 436.2348, found: 436.2345.

Example CXVII

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

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 C[0728] ₂₀H₂₆N₅O₂: 368.2086, found: 368.2078.

Example CXVIII

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

Prepared in a similar fashion as described for example XXIII using 4-(aminomethyl)piperidine and the 1-propyl analog of 14 as the starting materials. mp 218-220° C.; ESIMS (M+H) calc'd for C[0729] ₂₁H₂₈N₅O₂: 382.2242, found: 382.2227.

Example CXIX

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

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 C[0730] ₂₁H₂₆N₅O₂: 380.2086, found: 380.2079.

Example CXX

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

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 C[0731] ₂₄H₃₂N₅O₂: 422.2555, found: 422.2540.

Example CXXI

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

Prepared in a similar fashion as described for example LXXXVII and XLII 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 C[0732] ₁₉H₂₅N₆O₂: 369.2038, found: 369.2039.

Example CXXII

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

Prepared in a similar fashion as described for example LXXXVII and XLII 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 C[0733] ₂₃H₂₅N₆O₄S: 481.1657, found: 481.1642.

Example CXXIII

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

[0734]
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 (Na[0735] ₂SO₄), 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-methylpiperazino)carbamoylamino)indeno [1,2-c]pyrazol-4-one

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 C[0736] ₂₂H₂₅N₆O₂S: 437.1760, found: 437.1771.

Example CXXV

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

Prepared in a similar fashion as described for example LXXXVI using 4-aminomorpholine and the 1-propyl analog of 15 as the starting materials. mp 256-258° C.; ESIMS (M−H) calc'd for C[0737] ₁₈H₂₀N₅O₃: 354.1566, found: 354.1543.

Example CXXVI

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

[0738]
Step 1. Synthesis of 29A from 4-acetylpiperidine hydrochloride. [0739]
A solution of 4-acetylpiperidine hydrochloride (8.18 g, 0.05 mol) in THF (100 mL) at 0° C. was treated with triethylamine (13.93 mL, 0.1 mol) and stirred for 15 min. The reaction mixture was treated with a solution of di-t-butyldicarbonate (10.91 g, 0.05 mol) in THF (50 mL) and stirred at 25° C. for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried (MgSO[0740] ₄), filtered, and concentrated at reduced pressure to give a pale yellow oil (10.7 g, 94%). The 4-acetyl-N-BOC-piperidine in EtOH (20 mL) was added dropwise to a solution of ethyl trifluoroacetate (6.25 g, 0.044 mol) and sodium ethoxide [freshly prepared from sodium (1.Olg, 0.044 mol) and EtOH (100 mL)] and stirred at 25° C. for 16 h. The solution was quenched with aqueous H₂SO₄(50 mls, 0.044 mol) and extracted with EtOAc (200 mL). The organic layer was separated, dried (MgSO₄), filtered, and concentrated at reduced pressure to give a pale yellow liquid (14.8 g, 92%). CI-MS (M+H) calc'd for C₁₄H₂₀F₃NO₄: 323.1344, found: 323.1337.
Step 2. Synthesis of 29B from 29A. [0741]
Prepared in a similar fashion as described for example LXXXVII, Step 1, using 3-nitrophthalic anhydride and 29A as the starting materials. mp 132-134° C.; ESI-MS (M+H) calc'd for C[0742] ₂₀H₂₃N₂O₇: 403.1505, found: 403.1521.
Step 3. Synthesis of 29C from 29B. [0743]
Prepared in a similar fashion as described for example LXXXVII, Step 2, using 29B as the starting material. mp 187-189° C.; ESI-MS (M+H) calc'd for C[0744] ₂₀H₂₅N₂O₅: 373.1763, found: 373.1777.
Step 4. Synthesis of 29D from 29C. [0745]
A suspension of C (8.0 g, 21.5 mmol) in acetone (200 mL) was treated with NaHCO[0746] ₃(16.0 g) and phenyl chloroformate (4.04 g, 25.8 mol) and heated to 50° C. for 16 h. The reaction mixture was cooled, poured into water (200 mL), and extracted with EtOAc (400 mL). The organic layer was separated, dried (MgSO₄), filtered, and concentrated at areduced pressure to give a crude residue. Trituration with hexane gave the product as a pale yellow solid (1.1 g, 79%). mp 121-123° C.; ESI-MS (M+H) calc'd for C₂₇H₂₉N₂O₇: 493.1975, found: 493.1982.
Step 5. Synthesis of 29E from 29D. [0747]
A solution of 29D (4.93 g, 0.01 mol) in dimethylsulfoxide (30 mL) was treated with 4-aminomorpholine (2.04 g, 0.02 mol) and heated to 90° C. in a sealed tube for 6 hours. The solvent was removed at reduced pressure and the residue was taken up in water (30 mL). The solid was filtered to give the product as a yellow solid (5.0 g, 99%). mp 164-166° C.; ESI-MS (M+H) calc'd for C[0748] ₂₅H₃₃N₄O₇: 501.2349, found: 501.2357.
Step 6. Synthesis of 29F from 29E. [0749]
Prepared in a similar fashion as described for example LXXXVII, Step 4, using 29E (5.0 g, 0.01 mol) as the starting material to give the product as a yellow solid (3.8 g, 77%). mp 201-203° C.; ESI-MS (M−H) calc'd for C[0750] ₂₅H₃₁N₆O₅: 495.2356, found: 495.2383.
Step 7. Synthesis of 29G from 29F. [0751]
A solution of 29F (1.8 g, 3.6 mmol) in methylene chloride (25 mL) was treated with trifluoroacetic acid (2.8 mL, 36 mmol) and stirred at 25° C. for 3 h. The organic solvent was removed at reduced pressure and rediluted with methylene chloride (25 mL). Removal of the organic solvent again at reduced pressure gave a solid which was treated with ether (25 mL) and stirred at 25° C. for 16 h. The solid was filtered to give the product as a yellow solid (1.8 g, 98%). mp 282-284° C.; ESI-MS (M+H) calc'd for C[0752] ₂₀H₂₅N₆O₃: 397.1988, found: 397.1993.
Step 8. Synthesis of CXXVI from 29G. [0753]
A suspension of 29G (0.03 g, 0.059 mmol) in acetone (1 mL) was treated with NaHCO[0754] ₃(0.06 g) and methyl chloroformate (6.69 mg, 0.071 mmol) and heated to 50° C. for 2 h. The reaction was cooled, poured into water (20 mL), and extracted with EtOAc (40 mL). The organic layer was separated, dried (MgSO₄), filtered, and the concentrated at reduced pressure to give a yellow solid. Purification using reverse phase HPLC (CH₃CN/water) gave the product as an off-white solid (7.7 mg, 23%). mp 216-218° C.; ESI-MS (M+H) calc'd for C₂₂H₂₇N₆O₅: 455.2043, found: 455.2036.

Example CXXVII

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

Prepared in a similar fashion as described for example LXXXVII and XLII 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 C[0755] ₂₀H₂₀N₅O₃S: 410.1287, found: 410.1308.

Example CXXVIII

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

Prepared in a similar fashion as described for example LXXXVII and XLII 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 C[0756] ₁₉H₁₇N₅O₃SCl: 430.0741, found: 430.0757.

Example CXXIX

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

Prepared in a similar fashion as described for example LXXXVII and XLII 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 C[0757] ₂₁H₂₂N₅O₃S: 424.1443, found: 424.1431.

Example CXXX

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

Prepared in a similar fashion as described for example LXXXVII and XLII 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 C[0758] ₂₂H₂₂N₅O₅S: 468.1341, found: 468.1331.

Example CXXXI

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

Prepared in a similar fashion as described for example CXXIII using CXXX as starting material. mp 273° C.; ESIMS (M+H) calc'd for C[0759] ₂₀H₁₈N₅O₅S: 440.1028, found: 440.1026.

Example CXXXII

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

[0760]
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 C[0761] ₂₇H₂₅N₅O₄S: 529.1659, found: 529.1682.

Example CXXXIII

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-amino-4-methylpiperazine as the starting materials. mp 190° C. (TFA salt); ESIMS (M+H) calc'd for C[0762] ₂₅H₂₉N₈O₄S: 537.2032, found: 537.2055.

Example CXXXIV

Preparation of 3-(5-((2-(1-methyl-2-pyrrolidinyl)ethyl) aminocarbonyl)-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and 2-(2-aminoethyl)-1-methylpyrrolidine as the starting materials. mp 235° C. (TFA salt); ESIMS (M+H) calc'd for C[0763] ₂₇H₃₂N₇O₄S: 550.2236, found: 550.2229.

Example CXXXV

Preparation of 3-(5-((N,N-dimethylamino) aminocarbonyl)-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and l,l-dimethylhydrazine as the starting materials. mp 201° C. (TFA salt); ESIMS (M+H) calc'd for C[0764] ₂₂H₂₄N₇O₄S: 482.1610, found: 482.1588.

Example CXXXVI

Preparation of 3-(5-(2-((N,N-dimethylamino)ethyl) aminocarbonyl)-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and N,N-dimethylethylenediamine as the starting materials. mp 190° C. (TFA salt); ESIMS (M+H) calc'd for C[0765] ₂₄H₂₈N₇O₄S: 510.1923, found: 510.1922.

Example CXXXVII

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-(2-aminoethyl)pyrrolidine as the starting materials. mp 224° C. (TFA salt); ESIMS (M+H) calc'd for C[0766] ₂₆H₃₀N₇O₄S: 536.2080, found: 536.2091.

Example CXXXVIII

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-(2-aminoethyl)morpholine as the starting materials. mp 241° C. (TFA salt); ESIMS (M+H) calc'd for C[0767] ₂₆H₃₀N₇O₅S: 552.2029, found: 552.2043.

Example CXXXIX

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-aminomorpholine as the starting materials. mp 271° C. (TFA salt); ESIMS (M+H) calc'd for C[0768] ₂₄H₂₆N₇O₅S: 524.1716, found: 524.1719.

Example CXL

Preparation of 3-(5-((3-(2-pyrrolidon-1-yl)propyl) aminocarbonyl)-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-(3-aminopropyl)-2-pyrrolidinone as the starting materials. mp 260° C. (TFA salt); ESIMS (M+H) calc'd for C[0769] ₂₇H₃₀N₇O₅S: 564.2029, found: 564.2031.

Example CXLI

Preparation of 3-(5-((2-(3-pyridyl)ethyl) aminocarbonyl)-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and 3-(2-aminoethyl)pyridine as the starting materials. mp 203° C. (TFA salt); ESIMS (M+H) calc'd for C[0770] ₂₇H₂₆N₇O₄S: 544.1766, found: 544.1760.

Example CXLII

Preparation of 3-(5-((3-(1-imidazolyl)propyl) aminocarbonyl)-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-(3-aminopropyl)imidazole as the starting materials. mp 263° C. (TFA salt); ESIMS (M+H) calc'd for C[0771] ₂₆H₂₇N₈O₄S: 547.1875, found: 547.1872.

Example CXLIII

Preparation of 3-(5-((2-(2-pyridyl)ethyl) aminocarbonyl)-2-thienyl)-5-(morpholinylcarbamoylamino)indeno [1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and 2-(2-aminoethyl)pyridine as the starting materials. mp >280° C. (TFA salt); ESIMS (M+H) calc'd for C[0772] ₂₇H₂₆N₇O₄S: 544.1767, found: 544.1778.

Example CXLIV

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 2-(aminomethyl)pyridine as the starting materials. mp 239° C. (TFA salt); ESIMS (M+H) calc'd for C[0773] ₂₆H₂₄N₇O₄S: 530.1610, found: 530.1603.

Example CXLV

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-(2-aminoethyl)piperidine as the starting materials. mp 228° C. (TFA salt); ESIMS (M+H) calc'd for C[0774] ₂₇H₃₂N₇O₄S: 550.2236, found: 550.2236.

Example CXLVI

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-aminopyrrolidine as the starting materials. mp 213-215° C. (TFA salt); ESI-MS (M+H) calc'd for C[0775] ₂₄H₂₆N₇O₄S: 508.1764, found: 508.1774.

Example CXLVII

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-aminopiperidine as the starting materials. mp 189-191° C. (TFA salt); ESI-MS (M+H) calc'd for C[0776] ₂₅H₂₈N₇O₄S: 522.1923, found: 522.1920.

Example CXLVIII

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and piperidine as the starting materials. ESI-MS (M+H) calc'd for C[0777] ₂₅H₂₇N₆O₄S: 507.1815, found: 507.1833.

Example CXLIX

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and piperazine as the starting materials. mp 241-242° C. (TFA salt); ESI-MS (M+H) calc'd for C[0778] ₂₄H₂₆N₇O₄S: 508.5732, found: 508.1758.

Example CL

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-methylpiperazine as the starting materials. mp 186-187° C. (TFA salt); ESI-MS (M+H) calc'd for C[0779] ₂₅H₂₈N₇O₄S: 522.1923, found: 522.1928.

Example CLI

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-ethylpiperazine as the starting materials. mp 186-188° C. (TFA salt); ESI-MS (M+H) calc'd for C[0780] ₂₆H₃₀N₇O₄S: 536.2080, found: 536.2081.

Example CLII

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-(2-hydroxyethyl)piperazine as the starting materials. mp 186-187° C. (TFA salt); ESI-MS (M+H) calc'd for C[0781] ₂₆H₃₀N₇O₅S: 552.2029, found: 552.2032.

Example CLIII

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-(cyclopropylmethyl)piperazine as the starting materials. mp 211-212° C. (TFA salt); ESI-MS (M+H) calc'd for C[0782] ₂₈H₃₂N₇O₄S: 562.2236, found: 562.2249.

Example CLIV

Preparation of 3-(5-(4-(t-butoxycarbonyl)piperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-t-butoxycarbonylpiperazine as the starting materials. mp 225-226° C. (TFA salt); ESI-MS (M+H) calc'd for C[0783] ₂₉H₃₄N₇O₆S: 608.2290, found: 608.2320.

Example CLV

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-(2-pyridyl)piperazine as the starting materials. mp 201-202° C. (TFA salt); ESI-MS (M+H) calc'd for C[0784] ₂₉H₂₉N₈O₄S: 585.2032, found: 585.2002.

Example CLVI

Preparation of 3-(5-(((1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptyl)carbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno [1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and (1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C[0785] ₂₅H₂₆N₇o₄S: 520.1767, found: 520.1765.

Example CLVII

Preparation of 3-(5-(((1S,4S)-(+)-2-methyl-2,5-diazabicyclo[2.2.l]heptyl)carbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and (lS,4S)-(+)-2-methyl-2,5-diazabicyclo[2.2.1]heptane as the starting materials. mp 224-225° C. (TFA salt); ESI-MS (M+H) calc'd for C[0786] ₂₆H₂₈N₇O₄S: 534.1923, found: 534.1934.

Example CLVIII

Preparation of 3-(5-(4-(N,N-dimethylamino)piperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-(N,N-dimethylamino)piperidine as the starting materials. mp 185-186° C. (TFA salt); ESI-MS (M+H) calc'd for C[0787] ₂₇H₃₂N₇O₄S: 550.2240, found: 550.2250.

Example CLIX

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-pyrrolidinopiperidine as the starting materials. mp 228° C. (TFA salt); ESI-MS (M+H) calc'd for C[0788] ₂₉H₃₄N₇O₄S: 576.2393, found: 576.2410.

Example CLX

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-piperidinopiperidine as the starting materials. ESI-MS (M+H) calc'd for C[0789] ₃₀H₃₆N₇O₄S: 590.2549, found: 590.2536.

Example CLXI

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and cyclohexylamine as the starting materials. mp 264-267° C. (TFA salt); ESI-MS (M+H) calc'd for C[0790] ₂₆H₂₉N₆O₄S: 521.1971, found: 521.1971.

Example CLXII

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-aminopiperidine as the starting materials. mp 224-226° C. (TFA salt); ESI-MS (M+H) calc'd for C[0791] ₂₅H₂₈N₇O₄S: 522.1923, found: 522.1933.

Example CLXIII

Preparation of 3-(5-((1-(t-butoxycarboxyl)piperidin-4-yl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-amino-1-(t-butoxycarbonyl)piperidine as the starting materials. mp 229-230° C. (TFA salt); ESI-MS (M+H) calc'd for C[0792] ₃₀H₃₄N₇O₄S: 620.2291, found: 620.2304.

Example CLXIV

Preparation of 3-(5-(4-(1-methylpiperidin-4-yl)methylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-methyl-4-(methylamino)piperidine as the starting materials. mp 230° C. (TFA salt); ESI-MS (M+H) calc'd for C[0793] ₂₇H₃₂N₇O₄S: 550.2236, found: 550.2241.

Example CLXV

Preparation of 3-(5-(3-(N,N-dimethylamino)piperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and 3-(N,N-dimethylamino)piperidine as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C[0794] ₂₇H₃₂N₇O₄S: 550.2236, found: 550.2232.

Example CLXVI

Preparation of 3-(5-(3-p-toluenesulfonylamino)piperidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno [1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and 3-(p-toluenesulfonylamino)piperidine as the starting materials. mp 193-194° C. (TFA salt); ESI-MS (M+H) calc'd for C[0795] ₃₂H₃₄N₇O₆S: 676.2018, found: 676.2025.

Example CLXVII

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 3-hydroxypiperidine as the starting materials. ESI-MS (M+H) calc'd for C[0796] ₂₅H₂₇N₆O₅S: 523.1764, found: 523.1765.

Example CLXVIII

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 3-aminopiperidine as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C[0797] ₂₅H₂₈N₇O₄S: 522.1923, found: 522.1934.

Example CLXIX

Preparation of 3-(5-((3-quinuclidyl)aminocarbonyl)-2-thienyl)-S-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and (S)-(−)-3-aminoquinuclidine as the starting materials. mp 245-246° C. (TFA salt); ESI-MS (M+H) calc'd for C[0798] ₂₇H₃₀N₇O₄S: 548.2080, found: 548.2084.

Example CLXX

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 1,3-diaminocyclohexane as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C[0799] ₂₆H₃₀N₇O₄S: 536.2080, found: 536.2078.

Example CLXXI

Preparation of 3-(5-((3-(t-butoxycarbonylamino)cyclohexyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-amino-3-(t-butoxycarbonylamino)cyclohexane as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C31H38N706S: 636.2604, found: 636.2625. [0800]

Example CLXXII

Preparation of 3-(5-(2-(N,N-dimethylaminomethyl)piperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and 2-(dimethylaminomethyl)piperidine as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C[0801] ₂₈H₃₄N₇O₄S: 564.2393, found: 564.2388.

Example CLXXIII

Preparation of 3-(5-(2-(N,N-diethylaminomethyl)piperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and 2-(diethylaminomethyl)piperidine as the starting materials. mp 210-212° C. (TFA salt); ESI-MS (M+H) calc'd for C[0802] ₃₀H₃₈N₇O₄S: 592.2706, found: 592.2706.

Example CLXXIV

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and pyrrolidine as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C[0803] ₂₄H₂₅N₆O₄S: 493.1658, found: 493.1679.

Example CLXXV

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 3-aminopyrrolidine as the starting materials. mp 201-202° C. (TFA salt); ESI-MS (M+H) calc'd for C[0804] ₂₄H₂₆N₇O₄S: 508.5793, found: 508.1775.

Example CLXXVI

Preparation of 3-(5-(3(S)-N-methylamino)pyrrolidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno [1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and (S)-3-N-methylaminopyrrolidine as the starting materials. ESI-MS (M+H) calc'd for C[0805] ₂₅H₂₈N₇O₄S: 522.1920, found: 522.1920.

Example CLXXVII

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and (S)-3-N-acetamidopiperidine as the starting materials. mp 264-265° C. (TFA salt); ESI-MS (M+H) calc'd for C[0806] ₂₆H₂₈N₇O₅S: 550.1873, found: 550.1896.

Example CLXXVIII

Preparation of 3-(5-(3(S)-(N-methylacetamido)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and (S)-3-(N-acetyl-N-methylamino)piperidine as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C[0807] ₂₇H₃₀N₇O₅S: 564.2029, found: 564.2054.

Example CLXXIX

Preparation of 3-(5-(3(S)-(N-methyl-t-butoxycarbonylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and (S)-3-(N-t-butoxycarbonyl-N-methylamino)piperidine as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C[0808] ₃₀H₃₆N₇O₆S: 622.2448, found: 622.2472.

Example CLXXX

Preparation of 3-(5-(3-(N,N-dimethylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and 3-(N,N-dimethylamino)pyrrolidine as the starting materials. mp 216-217° C. (TFA salt); ESI-MS (M+H) calc'd for C[0809] ₂₆H₃₀N₇O₄S: 536.2079, found: 536.2070.

Example CLXXXI

Preparation of 3-(5-(3(R)-(N,N-dimethylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and (R)-3-(N,N-dimethylamino)pyrrolidine as the starting materials. mp 265° C. (TFA salt); ESI-MS (M+H) calc'd for C[0810] ₂₆H₃₀N₇O₄S: 536.298, found: 536.2105.

Example CLXXXII

Preparation of 3-(5-(3(S)-(N,N-dimethylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and (S)-3-(N,N-dimethylamino)pyrrolidine as the starting materials. mp 264-265° C. (TFA salt); ESI-MS (M+H) calc'd for C[0811] ₂₆H₃₀N₇O₄S: 536.2980, found: 536.2096.

Example CLXXXIII

Preparation of 3-(5-((1-methylpyrrolidin-3-yl)methylaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-methyl-3-(methylamino)pyrrolidine as the starting materials. mp 151-153° C. (TFA salt); ESI-MS (M+H) calc'd for C[0812] ₂₆H₃₀N₇O₄S: 536.2080, found: 536.2088.

Example CLXXXIV

Preparation of 3-(5-(2(R)-(pyrrolidinomethyl)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and (R)-2-(pyrrolidinomethyl)pyrrolidine as the starting materials. mp 166-167° C. (TFA salt); ESI-MS (M+H) calc'd for C[0813] ₂₉H₃₄N₇O₄S: 536.2393, found: 576.2416.

Example CLXXXV

Preparation of 3-(5-(2(S)-(hydroxymethyl)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and (S)-2-(hydroxymethyl)pyrrolidine as the starting materials. mp 267-268° C. (TFA salt); ESI-MS (M+H) calc'd for C[0814] ₂₅H₂₇N₆O₅S: 523.1764, found: 523.1754.

Example CLXXXVI

Preparation of 3-(5-(2(R)-(methoxymethyl)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and (R)-2-(methoxymethyl)pyrrolidine as the starting materials. mp 262° C. (TFA salt); ESI-MS (M+H) calc'd for C[0815] ₂₆H₂₉N₆O₄S: 537.1920, found: 537.1936.

Example CLXXXVII

Preparation of 3-(5-(2(S)-(phenylaminomethyl)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and (S)-2-(phenylaminomethyl)pyrrolidine as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C[0816] ₃₁H₃₂N₇O₄S: 598.2236, found: 598.2225.

Example CLXXXVIII

Preparation of 3-(5-(2(R)-(methoxymethyl)pyrrolidinoaminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and (R)-1-amino-2-(methoxymethyl)pyrrolidine as the starting materials. mp 266-267° C. (TFA salt); ESI-MS (M+H) calc'd for C[0817] ₂₆H₃₀N₇O₅S: 552.2029, found: 552.2036.

Example CLXXXIX

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and homopiperidine as the starting materials. ESI-MS (M+H) calc'd for C[0818] ₂₆H₂₉N₆O₄S: 521.1971, found: 521.1943.

Example CXC

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and homopiperazine as the starting materials. mp 209° C. (TFA salt); ESI-MS (M+H) calc'd for C[0819] ₂₅H₂₈N₇O₄S: 522.1923, found: 522.1901.

Example CXCI

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-methylhomopiperazine as the starting materials. mp 207-208° C. (TFA salt); ESI-MS (M+H) calc'd for C[0820] ₂₆H₃₀N₇O₄S: 536.2080, found: 536.2086.

Example CXCII

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-ethylhomopiperazine as the starting materials. mp 192-193° C. (TFA salt); ESI-MS (M+H) calc'd for C[0821] ₂₇H₃₂N₇O₄S: 550.2237, found: 550.2241.

Example CXCIII

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-(cyclopropylmethyl)homopiperazine as the starting materials. mp 194-196° C. (TFA salt); ESI-MS (M+H) calc'd for C[0822] ₂₉H₃₄N₇O₄S: 576.2393, found: 576.2410.

Example CXCIV

Preparation of 3-(5-(4-(t-butoxycarbonyl)homopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-t-butoxycarbonylhomopiperazine as the starting materials. mp 210-211° C. (TFA salt); ESI-MS (M+H) calc'd for C[0823] ₃₀H₃₆N₇O₆S: 622.2488, found: 622.2450.

Example CXCV

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 1-acetylhomopiperazine as the starting materials. mp 274-275° C. (TFA salt); ESI-MS (M+H) calc'd for C[0824] ₂₇H₃₀N₇O₅S: 564.2029, found: 564.2056.

Example CXCVI

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-(methylamino)aniline as the starting materials. mp 230° C. (TFA salt); ESI-MS (M+H) calc'd for C[0825] ₂₇H₂₆N₇O₄S: 544.1767, found: 544.1772.

Example CXCVII

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-(acetamido)aniline as the starting materials. mp 253-254° C. (TFA salt); ESI-MS (M+H) calc'd for C[0826] ₃₀H₂₈N₄O₆S: 572.1730, found: 572.1723.

Example CXCVIII

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

Prepared in a similar fashion as described for example CXXXII using CXXXI and 4-(diethylamino)aniline as the starting materials. mp 198-199° C. (TFA salt); ESI-MS (M+H) calc'd for C[0827] ₃₀H₃₂N₇O₄S: 586.2236, found: 586.2224.

Example CXCIX

Preparation of 3-(5-((1-methyl-3-cyclopropylpyrazo-5-yl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using CXXXI and 5-amino-3-cyclopropyl-1-methylpyrazole as the starting materials. mp 290° C. (TFA salt); ESI-MS (M+H) calc'd for C[0828] ₂₇H₂₇N₈O₄S: 559.1876, found: 559.1849.

Example CC

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

Prepared in a similar fashion as described for example LXXXVII and XLII using 4-aminomorpholine and the 1-methyl-3-pyrrolyl analog of 15 as the starting materials. mp 301° C.; ESI-MS (M+H) calc'd for C[0829] ₂₀H₂₁N₆O₃: 393.1675, found: 393.1669.

Example CCI

Preparation of 3-(5-carboethoxy-2-thienyl)-5-(2 (R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example LXXXVII and XLII using 1-amino-2(R)-(methoxymethyl)pyrrolidine and the 5-carboethoxy-2-thienyl analog of 15 as the starting materials. mp 221-222° C.; ESI-MS (M+H) calc'd for C[0830] ₂₄H₂₆N₅O₅S: 496.1655, found: 496.1658.

Example CCII

Preparation of 3-(5-carboxyl-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXIII using CCI as the starting material. mp 258-259° C. (TFA salt); ESI-MS (M+H) calc'd for C[0831] ₂₂H₂₂N₅O₅S: 468.1342, found: 468.1346.

Example CCIII

Preparation of 3-(5-(4-methylpiperazinocarbonyl)-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 1-methylpiperazine and CCII as the starting materials. mp 181-183° C. (TFA salt); ESI-MS (M+H) calc'd for C[0832] ₂₇H₃₂N₇O₄S: 550.2236, found: 550.2251.

Example CCIV

Preparation of 3-(5-piperazinocarbonyl-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using piperazine and CCII as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C[0833] ₂₆H₃₁N₇O₄S: 536.2080, found: 536.2091.

Example CCV

Preparation of 3-(5-(4-(t-butoxycarbonyl)piperazinocarbonyl)-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 1-t-butoxycarbonylpiperazine and CCII as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C[0834] ₃₁H₃₈N₇O₆S: 636.2604, found: 636.2633.

Example CCVI

Preparation of 3-(5-(4-methylhomopiperazinocarbonyl)-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 1-methylhomopiperazine and CCII as the starting materials. mp 176-177° C. (TFA salt); ESI-MS (M+H) calc'd for C[0835] ₂₈H₃₄N₇O₄S: 564.2393, found: 564.2388.

Example CCVII

Preparation of 3-(5-homopiperazinocarbonyl-2-thienyl)-5-(2(R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one [0836]
Prepared in a similar fashion as described for example CXXXII using homopiperazine and CCII as the starting materials. mp 185-186° C. (TFA salt); ESI-MS (M+H) calc'd for C[0837] ₂₇H₃₂N₇O₄S: 550.2236, found: 550.2231.

Example CCVIII

Preparation of 3-(5-(4-(t-butoxycarbonyl)homopiperazinocarbonyl)-2-thienyl)-5-(2 (R)-(methoxymethyl)pyrrolidinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 1-t-butoxycarbonylhomopiperazine and CCII as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C[0838] ₃₂H₄₀N₇O₆S: 650.2761, found: 650.2753.

Example CCIX

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

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 C[0839] ₁₉H₁₁N₃O₂: 370.0804, found: 370.0809.

Example CCX

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

[0840]
Step 1. Synthesis of 30 [0841]
To a suspension of 139 g (680 mmol) of 4-piperazinoacetophenone in 700 mL of tetrahydrofuran at 25° C. was added slowly over 20 min. a solution of 157 g (720 mmol) of di-tert-butyl dicarbonate in 300 mL of tetrahydrofuran. The resulting mixture was refluxed for 15 h. After cooling the mixture was filtered, and the filtrate was concentrated under vacuum to provide an off-white solid. This crude product was recrystallized from diethyl ether/hexane to afford 192 g of the 30 as a white solid. NMR (CDCl[0842] ₃) 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).
Step 2. Synthesis of 31 from 30 [0843]
To a solution of 192 g (630 mmol) of 30 and 90 mL (750 mmol) of ethyl trifluoroacetate in 1000 mL of tetrahydrofuran at 25° C. was added slowly over 15 min. 280 mL (750 mmol) of 21% sodium ethoxide in ethanol, and the resulting solution then was stirred at 25° C. for 16 h. The reaction mixture was diluted with 500 mL of water, and to this mixture was added 45 mL of acetic acid. The resulting precipitate was recovered by filtration. The solids were washed with diethyl ether/hexane and dried to furnish 236 g of 31 as an orange solid. NMR (CDCl[0844] ₃) 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).
Step 3. Synthesis of 32 from 31 [0845]
A suspension of 117 g (610 mmol) of 3-nitrophthalic anhydride in 560 mL of acetic anhydride was heated until the mixture became homogeneous, and the solution then was allowed to cool to room temperature. To this solution was added 236 g (590 mmol) of 31. The resulting mixture was cooled to 0° C., and 165 mL (1200 mmol) of triethylamine was added slowly over 10 min. The mixture was allowed to warm to 25° C., was stirred at 25° C. for 1 h, and then was heated to 65° C. for 0.5 h. After cooling to room temperature, the reaction mixture was poured into a well-stirred solution of 1200 mL of 1.0 N hydrochloric acid and 2000 mL of ethanol. The resulting precipitate was recovered by filtration, washed with ethanol, and dried to provide 140 g of 32 as an orange solid. NMR (acetone-d[0846] ₆) δ 8.34 (d, 2H, J=9 Hz), 8.05 (m, 3H), 7.07 (d, 2H, J=9 Hz), 3.59 (br s, 8H), 1.48 (s, 9H).
Step 4. Synthesis of 33 from 32 [0847]
To a solution of 12.00 g (25 mmol) of 32 in 500 mL of ethanol and 50 mL of conc. ammonium hydroxide at 25° C. was added 500 mL of water, followed by 15.3 g (88 mmol) of sodium dithionite. The resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was filtered, and the filtrate was reduced to ˜½ the original volume under vacuum. This solution was adjusted to pH 3 employing hydrochloric acid and then extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over anhyd. sodium sulfate, filtered, and concentrated. The resulting solids were recrystallized from ethanol/water to provide 8.40 g of 33 as a green solid. NMR (DMSO-d[0848] ₆) δ 8.20 (d, 2H, J=9 Hz), 7.44 (t, 1H, J=8 Hz), 7.02 (d, 2H, J=9 Hz), 6.96 (d, 1H, J=8 Hz), 6.91 (d, 1H, J=8 Hz), 6.70 (br s, 2H), 3.46 (br s, 8H), 1.43 (s, 9H).
Step 5. Synthesis of 35 from 33 and 34. [0849]
A solution of 4.50 g (10 mmol) of 33, 4.45 g (20 mmol) of 34, 3.68 g (30 mmol) of 4-dimethylaminopyridine, and 80 mL of DMSO was stirred at 90° C. for 2.5 h. After cooling to room temperature the reaction mixture was poured into a well-stirred solution of 80 mL of ethanol and 30 mL of 1N hydrochloric acid. The resulting solution was diluted further by the slow addition of 120 mL of water. A precipitate formed. It was recovered by filtration, washed with 50% aqueous ethanol, and dried to provide 3.83 g of 35 as an orange solid. NMR (DMSO-d[0850] ₆) δ 10.95 (br s, 1H), 8.60 (d, 1H, J=8.5 Hz), 8.38 (br s, 1H), 8.24 (d, 2H, J=9 Hz), 7.69 (t, 1H, J=8.5 Hz), 7.32 (d, 1H, J=8.5 Hz), 7.04 (d, 2H, J=9 Hz), 3.86 (m, 4H), 3.74 (m, 4H), 2.91 (m, 4H), 2.73 (m, 4H), 1.44 (s, 9H).
Step 6. Synthesis of CCX from 35. [0851]
A mixture of 3.82 g (6.6 mmol) of 35, 0.64 mL (13.2 mmol) of hydrazine monohydrate, 0.090 g (1.32 mmol) of hydrazine hydrochloride, and 130 mL of ethanol was refluxed for 18 h. While still at reflux the solution was diluted by the dropwise addition of 30 mL of water. The mixture then was allowed to cool to room temperature. The resulting precipitate was recovered by filtration, washed with 80% aqueous ethanol, and dried to afford 1.80 g of CCX as a yellow solid. mp 242° C.; ESI-MS m/e calc'd for C[0852] ₃₀H₃₆N₇O₅: 574.2778, found: 574.2762.

Example CCXI

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

A solution of CCX (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 of the yellow product as its TFA-salt. mp 263° C.; ESI-MS m/e calc'd for C[0853] ₂₅H₂₈N₇O₃: 474.2254, found: 474.2280.

Example CCXII

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

Prepared in a similar fashion as described for examples CCX and CCXI employing 2-(4-(4-t-butoxycarbonyl-1-piperazinyl)benzoyl)-4-amino-1,3-indanedione obtained in example CCX and ammonia as the starting materials. mp 257° C. (TFA salt); ESI-MS m/e calc'd for C[0854] ₂₁H₂₁N₆O₂: 389.1726, found: 389.1724.

Example CCXIII

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

Prepared in a similar fashion as described for examples CCX and CCXI employing 2-(4-(4-t-butoxycarbonylpiperazino)benzoyl)-4-amino-1,3-indanedione obtained in example CCX and hydrazine as the starting materials. mp 257° C. (TFA salt); ESI-MS m/e calc'd for C[0855] ₂₁H₂₂N₇O₂: 404.1835, found: 404.1834.

Example CCXIV

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

Prepared employing 2-(4-(4-t-butoxycarbonylpiperazino)benzoyl)-4-amino-1,3-indanedione obtained in example CCX 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 CCXI, afforded the example compound. mp 243° C. (TFA salt); ESI-MS m/e calc'd for C[0856] ₂₄H₂₇N₆O₂: 431.2196, found: 431.2198.

Example CCXV

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

Prepared employing 2-(4-(4-t-butoxycarbonylpiperazino)benzoyl)-4-amino-1,3-indanedione obtained in example CCX 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 CCXI, afforded the example compound. mp 259° C. (TFA salt); ESI-MS m/e calc'd for C[0857] ₂₆H₂₉N₆O₃: 473.2301, found: 473.2302.

Example CCXVI

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

Prepared employing 2-(4-(4-t-butoxycarbonylpiperazino)benzoyl)-4-amino-1,3-indanedione obtained in example CCX 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 CCXI, afforded the example compound. ESI-MS m/e calc'd for C[0858] ₂₇H₃₂N₇O₂: 486.2618, found: 486.2608.

Example CCXVII

Preparation of 3-(4-piperazinophenyl)-5-(4-(aminomethyl)piperidinoacetamido)indeno[1,2-c]pyrazol-4-one

Prepared employing 2-(4-(4-t-butoxycarbonylpiperazino)benzoyl)-4-amino-1,3-indanedione obtained in example CCX 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 CCXI, afforded the example compound. mp 239° C. (TFA salt); ESI-MS m/e calc'd for C[0859] ₂₈H₃₄N₇O₂: 500.2774, found: 500.2772.

Example CCXVIII

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

[0860]
To a solution of CCXI (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 C[0861] ₂₆H₃₀N₇O₃: 488.2410, found: 488.2420.

Example CCXIX

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

Prepared in a similar fashion as described for example CCXVIII employing CCXI and acetaldehyde as the starting materials. mp 245° C. (TFA salt); ESI-MS m/e calc'd for C[0862] ₂₇H₃₂N₇O₃: 502.2567, found: 502.2555.

Example CCXX

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

Prepared in a similar fashion as described for example CCXVIII employing CCXI and acetone as the starting materials. mp 253° C. (TFA salt); ESI-MS m/e calc'd for C[0863] ₂₈H₃₄N₇O₃: 516.2723, found: 516.2726.

Example CCXXI

Preparation of 3-(4-piperazinophenyl)-5-((N,N-dimethylamino)carbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1,1-dimethylhydrazine as the starting materials. mp 238° C. (TFA salt); ESI-MS m/e calc'd for C[0864] ₂₃H₂₆N₇O₂: 432.2148, found: 432.2150.

Example CCXXII

Preparation of 3-(4-(4-methylpiperazino)phenyl)-5-((N,N-dimethylamino)carbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CCXVIII employing CCXI as the starting material. mp 192° C. (TFA salt); ESI-MS m/e calc'd for C[0865] ₂₄H₂₈N₇O₂: 446.2305, found: 446.2313.

Example CCXXIII

Preparation of 3-(4-piperazinophenyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1-amino-4-methylpiperazine as the starting materials. mp 254° C. (TFA salt); ESI-MS m/e calc'd for C[0866] ₂₆H₃₁N₈O₂: 487.2570, found: 487.2574.

Example CCXXIV

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

Prepared in a similar fashion as described for example CCXVIII employing CCXXIII as the starting material. mp 293° C. (TFA salt); ESI-MS m/e calc'd for C[0867] ²⁷H³³N⁸ _O ₂: 501.2727, found: 501.2731.

Example CCXXV

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

Prepared in a similar fashion as described for example CCXVIII employing CCXXIII and acetaldehyde as the starting materials. ESI-MS m/e calc'd for C[0868] ₂₈H₃₅N₈O₂: 515.2883, found: 515.2894.

Example CCXXVI

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

Prepared in a similar fashion as described for example CCXVIII employing CCXXIII and acetone as the starting materials. mp 272° C. (TFA salt); ESI-MS m/e calc'd for C[0869] ₂₇H₃₃N₈O₂: 529.3039, found: 529.3053.

Example CCXXVII

Preparation of 3-(4-piperazinophenyl)-5-((2,6-dimethylpiperidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1-amino-2,6- dimethylpiperidine as the starting materials. mp 270° C. (TFA salt); ESI-MS m/e calc'd for C[0870] ₂₈H₃₄N₇O₂: 500.2774, found: 500.2786.

Example CCXXVIII

Preparation of 3-(4-piperazinophenyl)-5-((4-(2-hydroxyethyl)piperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1-amino-4-(2-hydroxyethyl)piperazine as the starting materials. mp 279° C. (TFA salt); ESI-MS m/e calc'd for C[0871] ₂₇H₃₃N₈O₃: 517.2676, found: 517.2865.

Example CCXXIX

Preparation of 3-(4-piperazinophenyl)-5-((2(R)-(methoxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c] pyrazol-4-one

Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1-amino-2(R)-(methoxymethyl)pyrrolidine as the starting materials. ESI-MS m/e calc'd for C[0872] ₂₇H₃₂N₇₀₃: 502.2567, found: 502.2574.

Example CCXXX

Preparation of 3-(4-piperazinophenyl)-5-((2(S)-(methoxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1-amino-2(S)-(methoxymethyl)pyrrolidine as the starting materials. ESI-MS m/e calc'd for C[0873] ₂₇H₃₂N₇O₃: 502.2566, found: 502.2570.

Example CCXXXI

Preparation of 3-(4-piperazinophenyl)-5-((2(R)-(1-methoxy-1-methylethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1-amino-2(R)-(1-methoxy-1-methylethyl)pyrrolidine as the starting materials. mp 221° C. (TFA salt); ESI-MS m/e calc'd for C[0874] ₂₉H₃₆N₇O₃: 530.2879, found: 530.2878.

Example CCXXXII

Preparation of 3-(4-piperazinophenyl)-5-((2(S)-(1-methoxy-1methylethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1-amino-2(S)-(1-methoxy-1-methylethyl)pyrrolidine as the starting materials. mp 218° C. (TFA salt); ESI-MS m/e calc'd for C[0875] ₂₉H₃₆N₇O₃: 530.2880, found: 530.2895.

Example CCXXXIII

Preparation of 3-(4-piperazinophenyl)-5-((2(R)-(hydroxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1-amino-2(R)-(hydroxymethyl)pyrrolidine as the starting materials. mp 193° C. (TFA salt); ESI-MS m/e calc'd for C[0876] ₂₆H₃₀N₇O₃: 488.2411, found: 488.2380.

Example CCXXXIV

Preparation of 3-(4-piperazinophenyl)-5-((2(S)-(hydroxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c] pyrazol-4-one

Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and I-amino-2(S)-(hydroxymethyl)pyrrolidine as the starting materials. mp 190 ° C. (TFA salt); ESI-MS m/e calc'd for C[0877] ₂₆H₃₀N₇O₃: 488.2410, found: 488.2401.

Example CCXXXV

Preparation of 3-(4-piperazinophenyl)-5-((2(R)-(benzyloxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-a] pyrazol-4-one

Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1-amino-2(R)-(benzyloxymethyl)pyrrolidine as the starting materials. mp 207° C. (TFA salt); ESI-MS m/e calc'd for C[0878] ₃₃H₃₆N₇O₃: 578.2880, found: 578.2889.

Example CCXXXVI

Preparation of 3-(4-piperazinophenyl)-5-((2(S)-(benzyloxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c] pyrazol-4-one

Prepared in a similar fashion as described for example CCXI employing 33 from example CCX and 1-amino-2(S)-(benzyloxymethyl)pyrrolidine as the starting materials. ESI-MS m/e calc'd for C[0879] ₃₃H₃₆N₇O₃: 578.2879, found: 578.2897.

Example CCXXXVII

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

Prepared in a similar fashion as described for example CCXI and CCX employing 4-(4-tert-butoxycarbonyl-3-methylpiperazino)acetophenone as the starting materials. mp 230° C. (TFA salt); ESI-MS m/e calc'd for C[0880] ₂₆H₃₀N₇O₃: 488.2410, found: 488.2416.

Example CCXXXVIII

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

Prepared in a similar fashion as described for example CCXI and CCX employing 4-(cis-4-tert-butoxycarbonyl-3,5-dimethylpiperazino)acetophenone as the starting materials. mp 237° C. (TFA salt); ESI-MS m/e calc'd for C[0881] ₂₇H₃₂N₇O₃: 502.2567, found: 502.2571.

Example CCXXXIX

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

Prepared in a similar fashion as described for example CCXVIII employing CCXXXVIII as the starting material. mp 240° C. (TFA salt); ESI-MS m/e calc'd for C[0882] ₂₈H₃₄N₇O₃: 516.2723, found: 516.2734.

Example CCXL

Preparation of 3-(4-(4-isopropylpiperazino)-2-methylphenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CCXVIII, CCXI, and CCX employing 4-(4-tert-butoxycarbonylpiperazino)-2-methylacetophenone as the starting materials. ESI-MS m/e calc'd for C[0883] ₂₉H₃₆N₇O₃: 530.2879, found: 530.2893.

Example CCXLI

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

Prepared in a similar fashion as described for example CCXI and CCX employing 4-(4-tert-butoxycarbonylhomopiperazino)acetophenone as the starting materials. mp 253° C. (TFA salt); ESI-MS m/e calc'd for C[0884] ₂₆H₃₀N₇O₃: 488.2410, found: 488.2406.

Example CCXLII

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

Prepared in a similar fashion as described for example CCXVIII employing CCXLI as the starting material. ESI-MS m/e calc'd for C[0885] ₂₇H₃₂N₇O₃: 502.2567, found: 502.2581.

Example CCXLIII

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

Prepared in a similar fashion as described for example CCXVIII employing CCXLI and acetaldehyde as the starting materials. mp 240° C. (TFA salt); ESI-MS m/e calc'd for C[0886] ₂₈H₃₄N₇O₃: 516.2723, found: 516.2732.

Example CCXLIV

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

Prepared in a similar fashion as described for example CCXVIII employing CCXLI and acetone as the starting materials. mp 245° C. (TEA salt); ESI-MS mie calc'd for C[0887] ₂₉H₃₆N₇O₃: 530.2880, found: 530.2876.

Example CCXLV

Preparation of 3-(4-homopiperazino-2-methylphenyl)-5-(morpholinocarbamoylamino) indeno[1,2-c] pyrazol-4-one

Prepared in a similar fashion as described for example CCXI and CCX employing 4-(4-tert-butoxycarbonylhomopiperazino)-2-methylacetophenone as the starting materials. mp 209° C. (TFA salt); ESI-MS m/e calc'd for C[0888] ₂₇H₃₂N₇O₃: 502.2566, found: 502.2580.

Example CCXLVI

Preparation of 3-(4-(4-ethylhomopiperazino)-2-methylphenyl)-5-(morpholinocarbamoylamino)indeno [1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CCXVIII employing CCXLV and acetaldehyde as the starting materials. mp 217° C. (TFA salt); ESI-MS m/e calc'd for C[0889] ₂₉H₃₆N₇O₃:530.2880, found: 530.2891.

Example CCXLVII

Preparation of 3-(4-(4-isopropylhomopiperazino)-2-methylphenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CCXVIII employing CCXLV and acetone as the starting materials. mp 197° C. (TFA salt); ESI-MS m/e calc'd for C[0890] ₃₀H₃₈N₇O₃: 544.3036, found: 544.3059.

Example CCXLVIII

Preparation of 3-(4-(4-(N,N-dimethylamino)piperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

[0891]
Step 1. Synthesis of 36. [0892]
Prepared in a similar fashion as described for example CCX employing 4-(4,4-ethylenedioxypiperidino)acetophenone as starting material. [0893]
Step 2. Synthesis of 37 from 36. [0894]
A mixture of 12.40 g (23.4 mmol) of 36, 500 mL of acetone, 125 mL of water, and 25 mL of trifluoroacetic acid was refluxed for 24 h. After cooling to room temperature the mixture was concentrated under vacuum. The residue was slurried in 95% aqueous ethanol, and the mixture was adjusted to pH 7 employing aqueous sodium hydroxide solution. The resulting mixture was filtered. The recovered solids were washed with 95% aqueous ethanol and dried to afford 10.68 g of 37 as a yellow solid. NMR (DMSO-d[0895] ₆) δ 13.46 (br s, 1H), 10.96 (br s, 1H), 8.30 (d, 1H, J=9 Hz), 8.27 (s, 1H), 8.14 (d, 2H, J=9 Hz), 7.43 (t, 1H, J=9 Hz), 7.18 (d, 2H, J=9 Hz), 7.10 (d, 1H, J=9 Hz), 3.90-3.75 (m, 8H), 3.34 (s, 8H), 2.92 (m, 2H), 2.72 (m, 2H), 2.45 (t, 4H, J=6 Hz).
Step 3. Synthesis of CCXLVIII from 37. [0896]
To a mixture of 1.00 g (2 mmol) of 37, 200 mL of 2M dimethylamine in methanol, 200 mL of acetonitrile, and 1 mL of acetic acid at 25° C. was added 2.60 g (40 mmol) of sodium cyanoborohydride, and the reaction mixture was stirred at 25° C. for 20 h. The mixture was diluted with 200 mL of water and then acidified (pH<2) employing conc. hydrochloric acid. After 30 min. gas evolution had ceased, and the solution was made strongly basic (pH>12) employing conc. aqueous sodium hydroxide solution. The solution was stirred for 20 min. and then was adjusted to pH 10 by the addition of 1N hydrochloric acid. The resulting precipitate was recovered by filtration, washed with water, and dried. These solids were dissolved in 10 mL of trifluoroacetic acid, and the solution was diluted with 50 mL of anhydrous ethanol. A yellow precipitate formed, was recovered by filtration, and was dried under vacuum to provide 0.41 g of the product as its TFA-salt. mp 258° C.; ESI-MS m/e calc'd for C[0897] ₂₈H₃₄N₇O₃: 516.2723, found: 516.2737.

Example CCXLIX

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

Prepared in a similar fashion as described for example CCXLVIII employing 37, morpholine, and methanesulfonic acid as the starting materials. mp 249° C. (MSOH salt); ESI-MS m/e calc'd for C[0898] ₃₀H₃₆N₇O₄: 558.2828, found: 558.2817.

Example CCL

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

Prepared in a similar fashion as described for example CCXLVIII employing 37 and piperidine as the starting materials. mp 233° C. (TFA salt); ESI-MS m/e calc'd for C[0899] ₃₁H₃₈N₇O₃: 556.3036, found: 556.3039.

Example CCLI

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

Prepared in a similar fashion as described for example CCXLVIII employing 37 and pyrrolidine as the starting materials. mp 247° C. (TFA salt); ESI-MS m/e calc'd for C[0900] ₃₀H₃₆N₇O₃: 542.2879, found: 542.2860.

Example CCLII

Preparation of 3-(4-(4-(N,N-diethylamino)piperidino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CCXLVIII employing 37 and diethylamine as the starting materials. mp 251° C. (TFA salt); ESI-MS m/e calc'd for C[0901] ₃₀H₃₈N₇O₃: 544.3036, found: 544.3035.

Example CCLIII

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

[0902]
Step 1. Synthesis of 38 from 35. [0903]
A mixture of 4.43 g (7.7 mmol) of 35 (example CCX), 3.15 g (20.7 mnmol) of 4-methoxybenzylhydrazine, 0.29 g (1.50 mmol) of 4-methoxybenzylhydrazine hydrochloride, and 150 mL of ethanol was refluxed for 22 h. While the reaction mixture was maintained at reflux 30 mL of water was added dropwise, and the mixture then was allowed to cool to room temperature. The resulting precipitate was recovered by filtration, washed with 95% aqueous ethanol, and dried to furnish 1.40 g of 38. NMR (CDCl[0904] ₃) δ 11.04 (s, 1H), 8.32 (d, 1H, J=9 Hz), 8.19 (d, 2H, J=9 Hz), 7.28 (d, 2H, J=9 Hz), 7.24 (t, 1H, J=9 Hz), 7.02 (d, 2H, J=9 Hz), 6.88 (d, 2H, J=9 Hz), 6.68 (d, 1H, J=9 Hz), 5.52 (s, 1H), 5.38 (s, 2H), 4.00 (m, 4H), 3.78 (s, 3H), 3.62 (m, 4H), 3.27 (m, 4H), 3.08 (m, 2H), 2.72 (m, 2H), 1.49 (s, 9H).
Step 2. Synthesis of 39 from 38. [0905]
A solution of 1.38 g of 38 in 20 mL of trifluoroacetic acid was stirred at 25° C. for 0.5 h. The excess trifluoroacetic acid was removed under vacuum, and the residue was recyrstallized from ethanol to afford 1.25 g of 39 as its TFA-salt. ESI-MS m/e=594 (M+H)[0906] ⁺.
Step 3. Synthesis of 40 from 39. [0907]
A solution of 0.18 g (0.25 mmol) of 39, 0.27 g (2.5 mmol) of methyl acetimidate hydrochloride, 0.31 g (2.5 mmol) of 4-dimethylaminopyridine, and 10 mL of methanol was refluxed for 48 h. To the hot solution was added 2 mL of water, and the miture was allowed to cool to room temperature. The resulting precipitate was washed with 95% aqueous ethanol and dried to provide 0.125 g of 40 as an orange solid. [0908]
Step 4. Synthesis of CCLIII from 40. [0909]
A solution of 0.122 g of 40 in 10 mL of trifluoroacetic acid was stirred at 25° C. for 120 h and then concentrated under vacuum. The residue was purified by reverse-phase preparative HPLC to afford 0.045 g of CCLIII as its TFA-salt. mp 240° C.; ESI-MS m/e calc'd for C[0910] ₂₇H₃₁N₈O₃: 515.2519, found: 515.2529.

Example CCLIV

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

Prepared in a similar fashion as described for example CCLIII employing 39 and 2-bromopyridine as the starting materials. ESI-MS m/e calc'd for C[0911] ₃₀H₃₁N₈O₃: 551.2519, found: 551.2514.

Example CCLV

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

Prepared in a similar fashion as described for example XXIII using isonipecotamide and the c-propyl analog of 14 as the starting materials. mp 178-180° C. (TFA salt); ESI-MS (M+H) calc'd for C[0912] ₂₁H₂₄N₅O₃: 394.1879, found: 394.1876.

Example CCLVI

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

Prepared in a similar fashion as described for example XLII using 1-amino-4-methylpiperazine and the ethyl analog of 15 as the starting materials. mp 244-246° C. (TFA salt); ESI-MS (M+H) calc'd for C[0913] ₁₈H₂₃N₆O₂: 355.1882, found: 355.1858.

Example CCLVII

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

Prepared in a similar fashion as described for example XLII using 1-amino-4-methylpiperazine and the c-propyl analog of 15 as the starting materials. mp 215-217° C. (TFA salt); ESI-MS (M+H) calc'd for C[0914] ₁₉H₂₃N₆O₂: 367.1882, found: 367.1862.

Example CCLVIII

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

Prepared in a similar fashion as described for example XLII using 1-amino-4-methylpiperazine and the c-hexyl analog of 15 as the starting materials. mp 241-242° C. (TFA salt); ESI-MS (M+H) calc'd for C[0915] ₂₂H₂₉N₆O₂: 409.2352, found: 409.2371.

Example CCLIX

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

Prepared in a similar fashion as described for example XLII using 4-aminomorpholine and the ethyl analog of 15 as the starting materials. mp 253-254° C. (TFA salt); ESI-MS (M+H) calc'd for C[0916] ₁₇H₂₀N₅O₃: 342.1566, found: 342.1555.

Example CCLX

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

Prepared in a similar fashion as described for example XLII using 4-aminomorpholine and the c-propyl analog of 15 as the starting materials. ESI-MS (M+H) calc'd for C[0917] ₁₈H₂₀N₅O₃: 354.1566, found: 354.1548.

Example CCLXI

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

Prepared in a similar fashion as described for example XLII using 4-aminomorpholine and the c-hexyl analog of 15 as the starting materials. mp >260° C. (TFA salt); ESI-MS (M+H) calc'd for C[0918] ₂₁H₂₆N₅O₃: 396.2036, found: 396.2021.

Example CCLXII

Preparation of 3-(1-ethoxycarbonylpiperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXVI using ethylchloroformate and 29G as the starting materials. mp 206-207° C. (TFA salt); ESI-MS (M+H) calc'd for C[0919] ₂₃H₂₉N₆O₅: 469.2199, found: 469.2170.

Example CCLXIII

Preparation of 3-(1-phenoxycarbonylpiperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXVI using phenylchloroformate and 29G as the starting materials. mp 250-252° C. (TFA salt); ESI-MS (M+H) calc'd for C[0920] ₂₇H₂₉N₆O₅: 517.2199, found: 517.2182.

Example CCLXIV

Preparation of 3-(1-(imidazol-1-ylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

[0921]
A solution of 29G (0.255 g, 0.5 mmol) in dimethylformamide (10 mL) was treated with carbonyldiimidazole (0.16 g, 1 mmol) and stirred at 50° C. for 2 h. The reaction mixture was cooled, poured into water (20 mL), and extracted with EtOAc (40 mL). The organic layer was separated, dried (MgSO[0922] ₄), filtered, and concentrated at reduced pressure to give a yellow oil. Purification using reverse phase HPLC (CH₃CN/water) gave the product as a yellow solid (18.5 mg, 6%). mp 202-204° C. (TFA salt); ESI-MS (M+H) calc'd for C₂₄H₂₇N₈O₄: 491.2155, found: 491.2138.

Example CCLXV

Preparation of 3-(1-(2-thienylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 29G and 2-thiophenecarboxylic acid as the starting materials. mp 218-220° C. (TFA salt); ESI-MS (M+H) calc'd for C[0923] ₂₅H₂₇N₆O₄S: 507.1815, found: 507.1822.

Example CCLXVI

Preparation of 3-(1-carbamoylpiperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

[0924]
Step 1. Synthesis of 29H from 29G [0925]
Prepared in a similar fashion as described for example CXXVI using 29G and 4-nitrophenylchloroformate as the starting materials to give the product as a tan solid (1.22 g, 72%). mp 255-257° C.; ESI-MS (M+H) calc'd for C[0926] ₂₇H₂₈N₇O₇: 562.2050, found: 562.2032.
Step 2. Synthesis of CCLXVI from 29H. [0927]
A suspension of 29H (0.20 g, 0.36 mmol) in dimethylsulfoxide (1 mL) was treated with conc. NH[0928] ₄OH (0.048 mL, 0.72 mmol) and heated to 90° C. for 6 h. The reaction mixture was cooled and the solvent removed at reduced pressure to give an yellow oil. Purification using reverse phase HPLC (CH₃CN/water) gave the product as a pale yellow solid (11.3 mg, 57%). mp 258-259° C. (TFA salt); ESI-MS (M+H) calc'd for C₂₁H₂₆N₇O₄: 440.2046, found: 440.2068.

Example CCLXVII

Preparation of 3-(1-(ethylcarbamoyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CCLXVI using 29H and ethylamine as the starting materials. mp 215-216° C. (TFA salt); ESI-MS (M−H) calc'd for C[0929] ₂₃H₂₈N₇O₄: 466.2203, found: 466.2208.

Example CCLXVIII

Preparation of 3-(1-(2-(1-methylpyrrolidin-2-yl)ethylaminocarbamoyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CCLXVI using 29H and 2-(2-aminoethyl)-1-methylpyrrolidine as the starting materials. mp 91-93° C. (TFA salt); ESI-MS (M+H) calc'd for C[0930] ₂₈H₃₉N₈O₄: 551.3094, found: 551.3095.

Example CCLXIX

Preparation of 3-(1-(4-(dimethylamino)piperidinocarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CCLXVI using 29H and 4-(dimethylamino)piperidine as the starting materials. mp 172-174° C. (TFA salt); ESI-MS (M+H) calc'd for C[0931] ₂₈H₃₉N₈O₄: 551.3109, found: 551.3109.

Example CCLXX

Preparation of 3-(1-(piperazinocarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXVI, step 7, using CCLXXI as the starting material. mp 195-197° C. (TFA salt); ESI-MS (M+H) calc'd for C[0932] ₂₅H₃₃N₈O₄: 509.2625, found: 509.2635.

Example CCLXXI

Preparation of 3-(1-(4-(t-butoxycarbonyl)piperazinocarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CCLXVI using 29H and 1-(t-butoxycarbonyl)piperazine as the starting materials. mp 231-232° C. (TFA salt); ESI-MS (M+H) calc'd for C[0933] ₃₀H₄₁N₈O₆: 609.3149, found: 609.3123.

Example CCLXXII

Preparation of 3-(1-(((1S,4S)-(+)-2,5-diazabicyclo[2.2.1]hept-2-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXVI, step 7, using the 3-(1-((5-t-butoxycarbonyl-(1S,4S)-(+)-2,5-diazabicyclo[2.2.1]hept-2-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one as the starting material. mp 196-198° C. (TFA salt); ESI-MS (M+H) calc'd for C[0934] ₂₆H₃₃N₈O₄: 521.2613, found: 521.2613.

Example CCLXXIII

Preparation of 3-(1-(((1S,4S)-(+)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CCLXVI using 29H and (1S,4S)-(+)-2-methyl-2,5-diazabicyclo[2.2.1]heptane as the starting materials. mp 224-225° C. (TFA salt); ESI-MS (M+H) calc'd for C[0935] ₂₇H₅N₈O₄: 535.2781, found: 535.2783.

Example CCLXXIV

Preparation of 3-(1-(3-aminopropylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXVI, step 7, using CCLXXVI as the starting material. mp 172-174° C. (TFA salt); ESI-MS (M+H) calc'd for C[0936] ₂₄H₃₂N₇O₄: 482.2516, found: 482.2497.

Example CCLXXV

Preparation of 3-(1-(3-(dimethylamino)propylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 29G and 4-(dimethylamino)butyric acid as the starting materials. mp 145-147° C. (TFA salt); ESI-MS (M+H) calc'd for C[0937] ₂₆H₃₅N₇O₄: 510.2829, found: 510.2830.

Example CCLXXVI

Preparation of 3-(1-(3-(t-butoxycarbonylamino)propylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 29G and 5-(t-butoxycarbonylamino)butyric acid as the starting materials. mp 73-75° C.; ESI-MS (M+H) calc'd for C[0938] ₂₉H₄₀N₇O₆: 582.3040, found: 582.3050.

Example CCLXXVII

Preparation of 3-(1-(4-aminobutylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXVI, step 7, using CCLXXIX as the starting material. mp 103-105° C. (TFA salt); ESI-MS (M+H) calc'd for C[0939] ₂₅H₃₄N₇O₄: 496.2672, found: 496.2648.

Example CCLXXVIII

Preparation of 3-(1-(4-(dimethylamino)butylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 29G and 5-(dimethylamino)valeric acid as the starting materials. mp 68-70° C. (TFA salt); ESI-MS (M+H) calc'd for C[0940] ₂₇H₃₈N₇O₄: 524.2985, found: 524.2978.

Example CCLXXIX

Preparation of 3-(1-(4-(t-butoxycarbonylamino)butylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 29G and 5-(t-butoxycarbonylamino)valeric acid as the starting material. mp 98-99° C. (TFA salt); ESI-MS (M+H) calc'd for C[0941] ₃₀H₄₂N₇O₆: 596.3197, found: 596.3182.

Example CCLXXX

Preparation of 3-(1-((1-methylpiperidin-4-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 29G and 1-methylpiperidine-4-carboxylic acid as the starting materials. mp 148-150° C. (TFA salt); ESI-MS (M+H) calc'd for C[0942] ₂₇H₃₆N₇O₄: 522.2829, found: 522.2840.

Example CCLXXXI

Preparation of 3-(1-((1-(t-butoxycarbonyl)piperidin-4-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 29G and 1-(t-butoxycarbonyl)piperidine-4-carboxylic acid as the starting materials. mp 220-222° C.; ESI-MS (M+H) calc'd for C[0943] ₃₁H₄₂N₇O₆: 608.3197, found: 608.3174.

Example CCLXXXII

Preparation of 3-(1-(cis-4-aminocyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXVI, step 7, using CCLXXXV as the starting material. mp 212-214° C. (TFA salt); ESI-MS (M+H) calc'd for C[0944] ₂₇H₃₆N₇O₄: 522.2829, found: 522.2818.

Example CCLXXXIII

Preparation of 3-(1-(4-aminocyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXVI, step 7, using CCLXXXVI as the starting material. mp 202-204° C. (TFA salt); ESI-MS (M+H) calc'd for C[0945] ₂₇H₃₆N₇O₄: 522.2829, found: 522.2857.

Example CCLXXXIV

Preparation of 3-(1-(cis-4-(dimethylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 29G and 4-(dimethylamino)cyclohexane carboxylic acid as the starting materials. mp 123-125° C. (TFA salt); ESI-MS (M+H) calc'd for C[0946] ₂₉H₃₉N₇O₄: 550.3142, found: 550.3148.

Example CCLXXXV

Preparation of 3-(1-(4-(t-butoxycarbonylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 29G and 4-(t-butoxycarbonylamino)cyclohexane carboxylic acid as the starting materials. mp 210-212° C. (TFA salt); ESI-MS (M+H) calc'd for C[0947] ₃₂H₄₄N₇O₆: 622.3353, found: 622.3340.

Example CCLXXXVI

Preparation of 3-(1-(trans-4-(t-butoxycarbonylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 29G and 4-(t-butoxycarbonylamino)cyclohexane carboxylic acid as the starting materials. mp 178-180° C.; ESI-MS (M+H) calc'd for C[0948] ₃₂H₄₄N₇O₆: 622.3353, found: 622.3349.

Example CCLXXXVII

Preparation of 3-(1-(piperidin-3-ylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXVI, step 7, using CCLXXXIX as the starting material. mp 169-170° C. (TFA salt); ESI-MS (M+H) calc'd for C[0949] ₂₆H₃₄N₇O₄: 508.2672, found: 508.2669.

Example CCLXXXVIII

Preparation of 3-(1-(1-methylpiperidin-3-ylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 29G and 1-methylpiperidine-3-carboxylic acid as the starting materials. mp 158-160° C. (TFA salt); ESI-MS (M+H) calc'd for C[0950] ₂₇H₃₆N₇O₄: 522.2829, found: 522.2842.

Example CCLXXXIX

Preparation of 3-(1(1-(t-butoxycarbonyl)piperidin-3-ylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 29G and 1-t-butoxycarbonylpiperidine-3-carboxylic acid as the starting materials. mp 196-198° C.; ESI-MS (M+H) calc'd for C[0951] ₃₁H₄₁N₇O₆: 608.3197, found: 608.3198.

Example CCXC

Preparation of 3-(1-(3-aminocyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXVI, step 7, using 3-(1-(3-t-butoxycarbonylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one as the starting material. mp 201-203° C. (TFA salt); ESI-MS (M+H) calc'd for C[0952] ₂₇H₃₆N₇O₄: 522.2829, found: 522.2815.

Example CCXCI

Preparation of 3-(1-(3-(dimethylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 29G and 1-(dimethylamino)cyclohexane-3-carboxylic acid as the starting materials. mp 153-155° C. (TFA salt); ESI-MS (M+H) calc'd for C[0953] ₂₉H₄₀N₇O₄: 550.3142, found: 550.3131.

Example CCXCII

Preparation of 3-(1-(trans-4-methoxycyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 29G and 4-trans-methoxycyclohexane carboxylic acid as the starting materials. mp 246-248° C. (TFA salt); ESI-MS (M+H) calc'd for C[0954] ₂₈H₃₇N₆O₅: 537.2825, found: 537.2841.

Example CCXCIII

Preparation of 3-(1-(cis-4-methoxycyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 29G and 4-cis-methoxycyclohexane carboxylic acid as the starting materials. mp 178-180° C. (TFA salt); ESI-MS (M+H) calc'd for C[0955] ₂₈H₃₇N₆O₅: 537.2825, found: 537.2828.

Example CCXCIV

Preparation of 3-(1-(4-aminobenzylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXVI, step 7, using CCXCVI as the starting material. mp 177-179° C. (TFA salt); ESI-MS (M+H) calc'd for C[0956] ₂₈H₃₂N₇O₄: 530.2516, found: 530.2519.

Example CCXCV

Preparation of 3-(1-(4-(dimethylamino)benzylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 29G and 4-(dimethylamino)phenyl acetic acid as the starting materials. mp 107-109° C. (TFA salt); ESI-MS (M+H) calc'd for C[0957] ₃₀H₃₆N₇O₄: 558.2829, found: 558.2834.

Example CCXCVI

Preparation of 3-(1-(4-(t-butoxycarbonylamino)benzylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 29G and 4-(t-butoxycarbonylamino)phenyl acetic acid as the starting materials. mp 177-178° C.; ESI-MS (M+H) calc'd for C[0958] ₃₃H₄₀N₇O₆: 630.3040, found: 630.3040.

Example CCXCVII

Preparation of 3-(1-(4-aminophenylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXVI, step 7, using CCXCIX as the starting material. mp 198-200° C. (TFA salt); ESI-MS (M+H) calc'd for C[0959] ₂₇H₃₀N₇O₄: 516.2359, found: 516.2376.

Example CCXCVIII

Preparation of 3-(1-(4-(dimethylamino)phenylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXIII using 29G and 4-(dimethylamino)benzoic acid as the starting materials. mp 189-191° C. (TFA salt); ESI-MS (M+H) calc'd for C[0960] ₂₉H₃₄N₇O₄: 544.2672, found: 544.2647.

Example CCXCIX

Preparation of 3-(1-(4-(t-butoxycarbonylamino)phenylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXIII using 29G and 4-(t-butoxycarbonylamino)benzoic acid as the starting materials. mp 212-214° C.; ESI-MS (M+H) calc'd for C[0961] ₃₂H₃₈N₇O₆: 616.2884, found: 616.2884.

Example CCC

Preparation of 3-(trans-4-carboxylcyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXIII using CCCI as the starting material. mp 264-266° C. (TFA salt); ESI-MS (M+H) calc'd for C[0962] ₂₂H₂₆N₅O₅: 440.1934, found: 440.1905.

Example CCCI

Preparation of 3-(trans-4-(methoxycarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example XLII using 4-aminomorpholine and the trans-4-(methoxycarbonyl)cyclohexyl analog of 15 as the starting materials. mp 259-261° C. (TFA salt); ESI-MS (M+H) calc'd for C[0963] ₂₃H₂₈N₅O₅: 454.2090, found: 454.2100.

Example CCCII

Preparation of 3-(trans-4-(3-(dimethylamino)pyrrolidinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 3-(dimethylamino)pyrrolidine and acid CCC as the starting materials. mp 191-193° C. (TFA salt); ESI-MS (M+H) calc'd for C[0964] ₂₈H₃₈N₇O₄: 536.2985, found: 536.2970.

Example CCCIII

Preparation of 3-(trans-4-(piperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for exampleCXXVI, step 7, using 3-(trans-4-(4-(t-butoxycarbonyl)piperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one as the starting material. mp 247-248° C. (TFA salt); ESI-MS (M+H) calc'd for C[0965] ₂₆H₃₄N₇O₄: 508.2672, found: 508.2670.

Example CCCIV

Preparation of 3-(trans-4-(4-methylpiperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXII using 1-methylpiperazine and CCC as the starting materials. mp 228-230° C. (TFA salt); ESI-MS (M+H) calc'd for C[0966] ₂₇H₃₆N₇O₄: 522.2829, found: 522.2844.

Example CCCV

Preparation of 3-(trans-4-(homopiperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXVI, step 7, using 3-(trans-4-(4-(t-butoxycarbonyl)homopiperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one as the starting material. mp >265° C. (TFA salt); ESI-MS (M+H) calc'd for C[0967] ₂₇H₃₆N₇O₄: 522.2829, found: 522.2833.

Example CCCVI

Preparation of 3-(trans-4-(4-methylhomopiperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

Prepared in a similar fashion as described for example CXXXIII using 1-methylhomopiperazine and CCC as the starting materials. mp 218-220° C. (TFA salt); ESI-MS (M+H) calc'd for C[0968] ₂₈H₃₈N₇O₄: 536.2985, found: 536.2988.

Example CCCVII

Preparation of 3-(2,4-dimethylthiazol-5-yl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one

[0969]
Step 1. Synthesis of Nitrotriketone 4a from 1a. [0970]
Ethyl trifluoroacetate (22.9 g, 161 mmol) and 2,4-dimethyl-5-acetylthiazole (25.0 g, 161 mmol) were added to a solution sodium ethoxide, freshly prepared from sodium (3.71 g, 161 mmol) and ethanol (500 mL), and stirred at 23° C. for 12 h. Half of the volume of organic solvent was concentrated in vacuo and the reaction mixture was diluted with 6 M HCl (400 mL) and extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with brine (2×300 mL), dried (MgSO[0971] ₄), filtered, and concentrated in vacuo to give 1,3-diketone 2a as an orange oil which was used without purification.
3-Nitrophthalic anhydride (31.1 g, 161 mmol) was added to a solution of diketone 2a in acetic anhydride (91.2 mL, 968 mmol). The reaction mixture was cooled to 0° C. and triethylamine (67.3 mL, 484 mmol) was added dropwise over 1 h. The reaction mixture was warmed to 23° C. and stirred for 12 h, heated to 50° C. for 30 min, and then cooled to 23° C. The reaction mixture was slowly poured into 1 M HCl (484 mL, diluted with 1 L of water). The solid which precipitated was filtered and washed repeatedly with water (3×150 mL) to give a brown solid (24.4 g, 46%, 2 steps). ESI-MS (M−H) found for C[0972] ₁₅H₉N₂O₅S: 329.
Step 2. Synthesis of Aniline 5a from 4a. [0973]
A solution of nitrotriketone 4a (24.4 g, 73.9 mmol), zinc powder (160 g, 2.4 mol), and calcium chloride (5.3 g, 48 mmol) in 4:1 ethanol/water (370 mL) was heated to reflux for 1 h. The reaction mixture was filtered over celite and washed with methanol (3×150 mL) and ethyl acetate (3×150 mL). The filtrate was concentrated in vacuo to give a crude brown solid. Purification by flash column chromatography (silica, chloroform→2% methanol/chloroform→5% methanol/chloroform→7% methanol/chloroform) gave aniline 5a (13.0 g, 59%) as a brown solid. ESI-MS (M−H) found for C[0974] ₁₅H₁₁N₂O₃S: 299.
Step 3. Synthesis of Carbamate 6a from 5a. [0975]
A solution of aniline 5a (840 mg, 2.8 mmol), phenyl chloroformate (0.42 mL, 3.4 mmol), and sodium carbonate (1.6 g) in acetone (14 mL) was heated to 50° C. for 4 h. The reaction mixture was cooled to 23° C. and diluted with water (20 mL) and ethyl acetate (20 mL). The organic layer was separated and washed with brine (20 mL), dried (MgSO[0976] ₄), filtered, and concentrated in vacuo to give a crude brown solid. Trituration with ether gave carbamate 6a (1.18 g, 99%) as a brown solid. ESI-MS (M−H) found for C₂₂H₁₅N₂O₅S: 419.
Step 4. Synthesis of Urea 15a from 6a. [0977]
A solution of carbamate 6a (1.18 g, 2.8 mmol) and ammonium hydroxide (0.47 mL, 3.4 mmol) in N,N-dimethylformamide (5 mL) was heated to 90° C. for 1 h. The solvent was concentrated in vacuo to give a crude residue. Purification using reverse phase HPLC (acetonitrile/water/trifluoroacetic acid) gave the product as a yellow solid (117 mg, 12%). ESI-MS (M−H) found for C[0978] ₁₆H₁₂N₃O₄S: 342.
Step 5. Synthesis of Pyrazole 16a from 15a. [0979]
A solution of urea 15a (117 mg, 0.34 mmol), hydrazine (21 μL, 0.68 mmol), and p-toluenesulfonic acid (3.2 mg, 17 μmol) in ethanol (1.7 mL) was refluxed for 4 h. The reaction mixture was cooled to 23° C. and concentrated in vacuo to give a crude residue. Purification using reverse phase HPLC (acetonitrile/water/trifluoroacetic acid) gave the product as its TFA-salt (10 mg, 9%). ESI-MS (M+H) calc'd for C[0980] ₁₆H₁₄N₅O₂S: 340.0868, found: 340.0895.

Example CCCVIII

Preparation of 3-(2,4-dimethylthiazol-5-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one

[0981]
Prepared in a similar fashion as described for example CCCVII using 6a and morpholine as the starting materials. mp >300° C. (TFA salt); ESI-MS (M+H) calc'd for C[0982] ₂₀H₂₁N₆O₃S: 425.1396, found: 425.1424.

Example CCCIX

Preparation of 3-(2,4-dimethylthiazol-5-yl)-5-((1-methyl-1-phenylamino)carbamoylamino)indeno[1,2-c]pyrazol-4-one

[0983]
Step 1. Synthesis of Acetamide 8a from 5a. [0984]
A solution of aniline 5a (3.3 g, 10.8 mmol) in N,N-dimethylformamide (54 mL) was treated with acetyl chloride (0.81 mL, 11.4 mmol) and triethylamine (1.7 mL, 11.9 mmol) and refluxed for 4 h. The reaction mixture was cooled to 23° C. and diluted with ethyl acetate (100 mL) and water (100 mL). The aqueous layer was separated and washed with ethyl acetate (100 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO[0985] ₄), filtered, and concentrated in vacuo to give a crude brown solid. The solid was dissolved in a small amount of methylene chloride (˜10 mL) and treated with ether. The solid which precipatated was filtered and washed with ether (3×100 mL) to give a brown solid (1.6 g, 43%). ESI-MS (M—H) found for C₁₇H₁₃N₂O₄S: 341.
Step 2. Synthesis of pyrazole 9a from 8a. [0986]
A solution of triketone 8a (1.6 g, 4.7 mmol), hydrazine (0.71 mL, 9.4 mmol), and p-toluenesulfonic acid (44 mg, 0.23 mmol) in ethanol (23 mL) was refluxed for 4 h. The reaction mixture was cooled to 23° C. and the solid was filtered and washed with ethanol (20 mL) and ether (20 mL). Recrystalization of the precipatate from ethanol gave the product as a brown solid (400 mg, 25%). ESI-MS (M—H) found for C[0987] ₁₇H₁₃N₄O₂S: 337.
Step 3. Synthesis of aniline 10a from 9a. [0988]
A solution of pyrazole 9a (400 mg, 1.2 mmol) and concentrated hydrochloric acid (2 mL) in methanol was refluxed for 3 h. The reaction mixture was cooled to 23° C. and concentrated in vacuo to give the product as a yellow solid (350 mg, 99%). ESI-MS (M−H) found for C[0989] ₁₅H₁₁N₄OS: 295.
Step 4. Synthesis of aniline 11a from 10a. [0990]
A solution of aniline 10a (350 mg, 1.2 mmol) in dioxane (6 mL) was treated with triethylamine (0.69 mL, 5 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.52 mL, 3 mmol) and heated to reflux for 3 h. The reaction mixture was cooled to 23° C. and diluted with EtOAc (20 mL) and water (20 mL). The aqueous layer was separated and extracted with ethyl acetate (20 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO[0991] ₄), filtered, and concentrated in vacuo to give a yellow solid. The yellow solid was treated with methylene chloride (50 mL) and methanol (50 mL) and filtered. The filtrate was concentrated in vacuo to give a crude brown residue. Purification by flash column chromatography (silica, 10% ethyl acetate/hexane→20% ethyl acetate/hexane≦40% ethyl acetate/hexane→80% ethyl acetate/hexane) gave aniline 11a (235 mg, 47%) as a brown solid. ESI-MS (M+H) found for C₂₁H₂₇N₄O₂SSi: 427.
Step 5. Synthesis of carbamate 12a from 11a. [0992]
Prepared in a similar fashion as described for example 1, step 3, using aniline 11a as the starting material. ESI-MS (M+H) found for C[0993] ₂₈H₃₁N₄₀ ₄SSi: 547.
Step 6. Synthesis of pyrazole 17a from 12a. [0994]
A solution of carbamate 12a (167 mg, 0.3 mmol) and 1-methyl-1-phenylhydrazine (72 μL, 0.6 mmol) in dimethyl sulfoxide (2 mL) was heated to 90° C. for 1 h. The solvent was concentrated in vacuo to give a crude residue which was diluted with 1:1 acetonitrile/water (3 mL). The solid which precipitated was filtered to give the product as a yellow solid (110 mg, 63%). ESI-MS (M+H) found for C[0995] ₂₉H₃₅N₆O₃SSi: 574.
Step 7. Synthesis of pyrazole 18a from 17a. [0996]
A solution of 17a (110 mg, 0.2 mmol) in ethanol (10 mL) was treated with 4M hydrochloric acid in dioxane (10 mL) and heated to 70° C. for 1 h. The reaction mixture was cooled to 23° C. and the solid which precipitated was filtered to give the product as its HCl-salt (50 mg, 59%). mp=250° C.; ESI-MS (M+H) calc'd for C[0997] ₂₃H₂₁N₆O₂S: 445.1447, found: 445.1432.

Example CCCX

Preparation of 3-(2,4-dimethylthiazol-5-yl)-5-((2,6-dimethylpiperidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one

[0998]
Prepared in a similar fashion as described for example 3 using 12a and 1-amino-2,6-dimethylpiperidine as the starting materials. ESI-MS (M+H) found for C[0999] ₂₃H₃₇N₆O₂S: 451.

Example CCCXI

Preparation of 3-(2,4-dimethylthiazol-5-yl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one

[1000]
Step 1. Synthesis of semicarbazide 19a from aniline 5a. [1001]
A solution of aniline 5a (13.0 g, 43.3 mmol), N-(4-methylpiperazinyl)-O-(phenyl)carbamate (20.4 g, 86.7 mmol), and triethylamine (18.1 mL, 130 mmol) in dimethylsulfoxide (217 mL) was heated to 90° C. for 1 h. The reaction mixture was cooled to 23° C. and diluted with water (500 mL). The solid which precipitated was collected and washed with water (300 mL), ethanol (300 mL), and ether (300 mL) and dried to give a brown solid (15.6 g, 82%). ESI-MS (M+H) calc'd for C[1002] ₂₁H₂₄N₅O₄S: 442.1549, found: 442.1531.
Step 2. Synthesis of pyrazole 20a from semicarbazide 19a. [1003]
A solution of semicarbazide 19a (15.6 g, 35.3 mmol), hydrazine (6.7 mL, 212 mmol), and acetic acid (4.0 mL, 71 mmol) was refluxed in ethanol (354 mL) for 84 h. The reaction mixture was cooled to 23° C., filtered, washed with ethanol (300 mL) and ether (300 mL), and dried to give a yellow solid which was dissolved in 10% acetic acid in water (20 mL). The solution was adjusted to pH=7 with 10% sodium hydroxide. The solid which precipitated was filtered and dried to give the free base (6.8 g, 29%) as a yellow solid. The free base was dissolved in 1M hydrochloric acid (31 mL) and the water was removed with a lyophilizer to give the product as a light brown powder (7.9 g, 99% from the free base). mp=278° C.; ESI-MS (M+H) calc'd for C[1004] ₂₁H₂₄N₇O₂S: 438.1712, found: 438.1714.

The compounds in the following tables are produced by suitabl methods from among the methods of the above examples.

TABLE 1

Example			mass	mp
#	R¹	R²	(M + H)⁺	(° C.)

I	Methyl	4-MeOC₆H₄	334	268
II	ClCH₂	4-MeOC₆H₄	382	274
III	cyclopropyl	4-MeOC₆H₄	360	289
IV	isopropyl	4-MeOC₆H₄	362	288
V	ethyl	4-MeOC₆H₄	348	287
VI	cyclopentyl	4-MeOC₆H₄	388	267
VII	cyclobutyl	4-MeOC₆H₄	374	297
VIII	benzyl	4-MeOC₆H₄	410	280
IX	n-propyl	4-MeOC₆H₄	362	282
X	4-ClC₆H₄CH₂	4-MeOC₆H₄	444	238
XI	3-MeOC₆H₄CH₂	4-MeOC₆H₄	440	>300
XII	4-MeOC₆H₄CH₂	4-MeOC₆H₄	440	280
XIII	3,4-diMeOC₆H₄CH₂	4-MeOC₆H₄	470	>300
XIV	2,5-diMeOC₆H₄CH₂	4-MeOC₆H₄	470	226
XV	Methyl	2-MeOC₆H₄	334	276
XVI	Methyl	3,4-diMeOC₆H₄	364	>300
XVII	3,4-(OCH₂O)C₆H₄CH₂	4-MeOC₆H₄	454	297
XVIII	3-thiophenylCH₂	4-MeOC₆H₄	416	293
XIX	2-MeOC₆H₄CH₂	4-MeOC₆H₄	440	255
XX	3,4-diClOC₆H₄CH₂	4-MeOC₆H₄	479	299
XXI	2,4-diClOC₆H₄CH₂	4-MeOC₆H₄	479	286
XXII	2-ClC₆H₄CH₂	4-MeOC₆H₄	444	300
XXIII	H₂NCH₂	4-MeOC₆H₄	349	>300
XXIV	HOCH₂CH₂NHCH₂	4-MeOC₆H₄	393	243
XXV	Me₂NCH₂	4-MeOC₆H₄	377	279
XXVI	PiperazinoCH₂	4-MeOC₆H₄	418	277
XXVII	4-Me-piperazinoCH₂	4-MeOC₆H₄	432	>300
XXVIII	4-HOCH₂CH₂-pipierazino-CH₂	4-MeOC₆H₄	462	>300
XXIX	piperisinoCH₂	4-MeOC₆H₄	417	291
XXX	4-NH₂CH₂-piperidinoCH₂	4-MeOC₆H₄	446	>300
XXXI	CH₃CH₂NHCH₂	4-MeOC₆H₄	377	250
XXXII	thiomorpholinoCH₂	4-MeOC₆H₄	435	298
XXXIII	morpholinoCH₂	4-MeOC₆H₄	419	295
XXXIV	pyrrolidinoCH₂	4-MeOC₆H₄	403	279
XXXV	4-pyridylCH₂NHCH₂	4-MeOC₆H₄	440	>300
XXXVI	4-CH₃CONHC₆H₄CH₂	4-MeOC₆H₄	467	268
XXXVII	4-CH₃OCONHC₆H₄CH₂	4-MeOC₆H₄	483	257
XXXVIII	4-NH₂CH₂CONHC₆H₄CH₂	4-MeOC₆H₄	482	228
XXXIX	4-Me₂NCH₂CONHC₆H₄CH₂	4-MeOC₆H₄	510	>300
XL	4-N₃C₆H₄CH₂	4-MeOC₆H₄	451	>300
XLI	4-NH₂C₆H₄CH₂	4-MeOC₆H₄	425	283
XLII	C₆H₅NH	4-MeOC₆H₄	411	>300
XLIII	CH₃CH₂CH₂NH	4-MeOC₆H₄	377	252
XLIV	4-NH₂C₆H₄CH₂NH	4-MeOC₆H₄	440	>300
XLV	4-pyridylCH₂NH	4-MeOC₆H₄	426	>300
XLVI	Methyl	4-HOC₆H₄	320	>300
XLVII	H	4-MeOC₆H₄	320	280
XLVII	Methyl	3-pyridyl	305	>300
XLIX	Methyl	4-pyridyl	305	>300
L	H	4-pyridyl	291	>300
LI	Methyl	C₆H₅	305	>300
LII	Methyl	4-MeSC₆H₄	351	283
LIII	Methyl	4-MeSO₂C₆H₄	383	>300
LVI	Methyl	4-Me₂NC₆H₄	348	>300
LV	morpholinoCH₂	4-Me₂NC₆H₄	432	>300
LVI	Me₂NCH₂	4-Me₂NC₆H₄	390	>300
LVII	Methyl	4-(piperidino)C₆H₄	388	291
LVIII	Methyl 4-(morpholino)C₆H₄	389	>300
LIX	Methyl	4-CH₃CH₂OC₆H₄	349	288
LX	Methyl	4-CH₃CH₂CH₂CH₂C₆H₄	361	259
LXI	Methyl	4-CH₃CH₂C₆H₄	332	294
LXII	Methyl	4-CH₃CH₂CH₂C₆H₄	347	269
LXIII	NH₂	4-MeOC₆H₄	335	>300
LXIV	Me₂NNH	4-MeOC₆H₄	378	>300
LXV	MeNH	4-MeOC₆H₄	349	>300
LXVI	morpholinoNH	4-MeOC₆H₄	420	>300
LXVII	cis-1,2-	4-MeOC₆H₄	432	>300
	diaminocyclohexanyl
LXVIII	4-methylpiperazinoNH	4-MeOC₆H₄	433	>300
LXVIX	4-uridomethylpiperidino-	4-MeOC₆H₄	489	>300
	CH₂
LXX	4-(2-pyridyl)piperazinol-	4-MeOC₆H₄	495	>300
	CH₂
LXXI	4-	4-MeOC₆H₄	461	>300
	(aminoethyl)piperazinoCH₂
LXXII	4-carbamoylpiperidinoCH₂	4-MeOC₆H₄	460	>300
LXXIII	4-hydroxypiperidinoCH₂	4-MeOC₆H₄	433	>300
LXXIV	4-	4-MeOC₆H₄	447	>300
	hydroxymethylpiperidino-
	CH₂
LXXV	4-amidopiperazinoCH₂	4-MeOC₆H₄	493	>300
LXXVI	4-	4-MeOC₆H₄	492	>300
	dimethylaminopiperidino-
	CH₂
LXXVII	4-aminopiperidinoCH₂	4-MeOC₆H₄	464	>300
LXXVIII	4-Me-piperazinoCH₂	4-Me₂NC₆H₄	445	>300
LXXIX	4-NH₂CH₂-piperidinoCH₂	4-Me₂NC₆H₄	459	NA
LXXX	4-OH-piperidinoCH₂	4-Me₂NC₆H₄	446	267
LXXXI	morpholinoCH₂	4-(morpholino)C₆H₄	474	258
LXXXII	4-Me-piperazinoCH₂	4-(morpholino)C₆H₄	487	258
LXXXIII	4-OH-pipieridinoCH₂	4-(morpholino)C₆H₄	488	245
LXXXIV	4-NH₂CH₂-piperidinoCH₂	4-(morpholino)C₆H₄	501	240
LXXXV	4-Me-piperazinoNH	4-Me₂NC₆H₄	446	>300
LXXXVI	4-Me-piperazinoNH(X = S)	4-MeOC₆H₄	449	>300
LXXXVII	Methyl	c-propyl	268	220
LXXXVIII	NH₂	1-Me-3-pyridyl	308	>300
LXXXIX	Methyl	2-thienyl	310	269
XC	Methyl	3-Me-2-thienyl	324	275
XCI	NH₂	Ethyl	257	>250
XCII	NH₂	n-propyl	271	187
XCIII	NH₂	i-propyl	271	>250
XCIV	NH₂	c-propyl	267	252
			(M − H)⁻
XCV	NH₂	c-hexyl	311	178
XCVI	NH₂	2-thienyl	310	214
			(M⁺)
XCVII	NH₂	3-Me-2-thienyl	325	270
XCVIII	NH₂	5-Me-2-thienyl	325	>280
XCIX	NH₂	5-CO₂Et-2-thienyl	383	>280
C	NH₂	3-thienyl	311	>280
CI	NH₂	5-Cl-3-thienyl	345	>300
CII	NH₂	2,5-diMe-3-thienyl	339	>280
CIII	NH₂	2-furanyl	295	278
CIV	Me₂NNH	i-propyl	314	231
CV	Me₂NNH	c-propyl	312	NA
CVI	Me₂NNH	c-hexyl	354	229
CVII	Me₂NNH	2-thienyl	354	279
CVIII	Me₂NNH	5-MeO-2-thienyl	384	280
CIX	Me₂NNH	5-Me-2-thienyl	368	>280
CX	Me₂NNH	5-CO₂Et-2-thienyl	426	252
CXI	Me₂NNH	3-thienyl	354	202
CXII	NH₂	1-methyl-3-pyrrolyl	308	>300
CXIII	Me₂NNH	2,5-diMe-3-thienyl	382	252
CXIV	Me₂NNH	2-furanyl	338	202
CXV	4-NH₂CO-piperidinylCH₂	i-propyl	396	224
CXVI	4-NH₂CO-piperidinylCH₂	c-hexyl	436	228
CXVII	4-NH₂CH₂-piperidinolCH₂	ethyl	368	174
CXVIII	4-NH₂CH₂-piperidinoCH₂	i-propyl	382	218
CXVIX	4-NH₂CH₂-piperidinoCH₂	c-propyl	380	138
CXX	4-NH₂CH₂-piperidinoCH₂	c-hexyl	422	196
CXXI	4-CH₃-piperazinoNH	i-propyl	369	231
CXXII	4-CH₃-piperazinoNH	5-CO₂Et-2-thienyl	481	249
CXXIII	4-CH₃-piperazinoNH	5-CO₂H-2-thienyl	453	270
CXXIV	4-CH₃-piperazinoNH	2,5-diMe-3-thienyl	437	250
CXXV	morpholinoNH	i-propyl	354	256
			(M − H)⁻
CXXVI	morpholinoNH	1-CO₂Me-4-piperidinyl	455	216
CXXVII	morpholinoNH	5-Me-2-thienyl	410	261
CXXVIII	morpholinoNH	5-Cl-3-thienyl	430	259
CXXIX	morpholinoNH	2,5-diMe-3-thienyl	424	>280
CXXX	morpholinoNH	5-CO₂Et-2-thienyl	468	258
CXXXI	morpholinoNH	5-CO₂H-2-thienyl	440	273
CXXXII	morpholinoNH	5-CONHBn-2-thienyl	529	275
CXXXIII	morpholinoNH	5-CO(4-Me-piperazino)-	537	190
		2-thienyl
CXXXIV	morpholinoNH	5-CONHCH₂CH₂(1-Me-2-	550	235
		pyrrolidinyl)-2-thienyl
CXXXV	morpholinoNH	5-CONHNMe₂-2-thienyl	482	201
CXXXVI	morpholinoNH	5-CONHCH₂CH₂NMe₂-2-	510	190
		thienyl
CXXXVII	morpholinoNH	5-	536	224
		CONHCH₂CH₂(pyrrolidino)-
		2-thienyl
CXXXVIII	morpholinoNH	5-	552	241
		CONHCH₂CH₂(morpholino)-
		2-thienyl
CXXXIX	morpholinoNH	5-CONH(morpholino)-2-	524	271
		thienyl
CXL	morpholinoNH	5-CONHCH₂CH₂CH₂(1-	564	260
		pyrrolidonyl)-2-thienyl
CXLI	morpholinoNH	5-CONHCH₂CH₂(3-	544	203
		pyridyl)-2-thienyl
CXLII	morpholinoNH	5-CONHCH₂CH₂CH₂(1-	547	263
		imidazolyl)-2-thienyl
CXLIII	morpholinoNH	5-CONHCH₂CH₂(2-	544	>280
		pyridyl)-2-thienyl
CXLIV	morpholinoNH	5-CONHCH₂(2-pyridyl)-2-	530	239
		thienyl
CXLV	morpholinoNH	5-CONHCH₂CH₂(piper-	550	228
		idino)-2-thienyl
CXLVI	morpholinoNH	5-pyrrolidino-	508	213*
		aminocarbonyl-2-thienyl
CXLVII	morpholinoNH	5-piperidino-	522	189*
		aminocarbonyl-2-thienyl
CXLVIII	morpholinoNH	5-piperidino-carbonyl-	507	N/A
		2-thienyl
CXLIX	morpholinoNH	5-piperazino-carbonyl-	508	241*
		2-thienyl
CL	morpholinoNH	5-(4-Me-	522	186*
		piperazino)carbonyl-2-
		thienyl
CLI	morpholinoNH	5-(4-Et-	536	186*
		piperazino)carbonyl-2-
		thienyl
CLII	morpholinoNH	5-((4-CH₂CH₂OH)-	552	186*
		piperazino)carbonyl-2-
		thienyl
CLIII	morpholinoNH	5-(4-cyclopropylmethyl-	562	211*
		piperazino)carbonyl-2-
		thienyl
CLIV	morpholinoNH	5-(4-t-CO₂t-Bu-	608	225*
		piperazino)carbonyl-2-
		thienyl
CLV	morpholinoNH	5-(4-(2-pyridyl)-	585	202*
		piperazino)carbonyl-2-
		thienyl
CLVI	morpholinoNH	5-(1S,4S)-2,5-	520	>300*
		diazobicyclo[2.2.1]hept-
		yl)carbonyl-2-thienyl
CLVII	morpholinoNH	5-((1S,4S)-2-Me-2,5-	534	244*
		dizaobicyclo[2.2.1]hept-
		yl)carbonyl-2-thienyl
CLVIII	morpholinoNH	5-(4-NMe₂-	550	185*
		piperidino)carbonyl-2-
		thienyl
CLIX	morpholinoNH	5-(4-pyrrolidino-	576	228*
		piperidino)carbonyl-2-
		thienyl
CLX	morpholinoNH	5-(4-piperidino-	590	N/A
		piperidino)carbonyl-2-
		thienyl
CLXI	morpholinoNH	5-(cyclohexyl-	521	264*
		aminocarbonyl)-2-thienyl
CLXII	morpholinoNH	5-(4-piperidyl-	522	224*
		aminocarbonyl)-2-thienyl
CLXIII	morpholinoNH	5-((1-CO₂t-Bu-4-	620	229*
		piperidyl)amino-
		carbonyl)-2-thienyl
CLXIV	morpholinoNH	5-(N-(1-Me-4-	550	230*
		piperidyl)-N-methyl-
		aminocarbonyl)-2-
		thienyl
CLXV	morpholinoNH	5-(3-NMe₂-	550	>300*
		piperidinocarbonyl)-2-
		thienyl
CLXVI	morpholinoNH	5-(3-(p-	676	193*
		toluenesulfonyl-
		amino)piperidino-
		carbonyl)-2-thienyl
CLXVII	morpholinoNH	5-(3-OH-piperidino-	523	N/A
		carbonyl)-2-thienyl
CLXVIII	morpholinoNH	5-((3-piperidyl)-	522	>300*
		aminocarbonyl)-2-
		thienyl
CLXIX	morpholinoNH	5-((3-quinuclidyl)-	548	245*
		aminocarbonyl)-2-
		thienyl
CLXX	morpholinoNH	5-(3-(aminocyclohexyl)-	536	>300*
		aminocarbonyl)-2-
		thienyl
CLXXI	morpholinoNH	5-(3-(t-butoxy-	636	>300*
		carbonylaminocyclo-
		hexyl)aminocarbonyl)-2-
		thienyl
CLXXII	morpholinoNH	5-(2-(Me₂NCH₂)-	564	>300*
		piperidinocarbonyl)-2-
		thienyl
CLXXIII	morpholinoNH	5-(2-Et₂NCH₂)-	592	210*
		piperidinocarbonyl)-2-
		thienyl
CLXXIV	morpholinoNH	5-pyrrolidino-	493	>300*
		carbonyl)-2-thienyl
CLXXV	morpholinoNH	5-(3-NH₂-	508	201*
		pyrrolidinocarbonyl)-2-
		thienyl
CLXXVI	morpholinoNH	5-(3(S)-	522	N/A
		(NHMe)pyrrolidino-
		carbonyl)-2-thienyl
CLXXVII	morpholinoNH	5-(3(S)-(NHCOCH₃)-	550	264*
		pyrrolidinocarbonyl)-2-
		thienyl
CLXXVIII	morpholinoNH	5-(3(S)-(N(Me)COCH₃)-	564	>300*
		pyrrolidinocarbonyl)-2-
		thienyl
CLXXIX	morpholinoNH	5-(3(S)-(N(Me)CO₂t-	622	>300*
		Bu)pyrrolidino-
		carbonyl)-2-thienyl
CLXXX	morpholinoNH	5-(3-NMe₂-	536	216*
	pyrrolidinocarbonyl)-2-
		thienyl
CLXXXI	morpholinoNH	5-(3(R)-(NMe₂)-	536	265*
		pyrrolidinocarbonyl)-2-
		thienyl
CLXXXII	morpholinoNH	5-(3(S)-(NMe₂)-	536	264*
		pyrrolidinocarbonyl)-2-
		thienyl
CLXXXIII	morpholinoNH	5-((1-Me-3-	536	151*
		pyrrolidinyl)methylamino-
		carbonyl)-2-thienyl
CLXXXIV	morpholinoNH	5-(2(R)-	576	166*
		(pyrrolidinomethyl)pyrro-
		lidino-carbonyl)-2-
		thienyl
CLXXXV	morpholinoNH	5-(2(S)-	523	267*
		(CH₂OH)pyrrolidino-
		carbonyl)-2-thienyl
CLXXXVI	morpholinoNH	5-(2(R)-(CH₃OCH₂)-	537	262*
		pyrrolidinocarbonyl)-2-
		thienyl
CLXXXVII	morpholinoNH	5-(2(S)-	598	>300*
		(phenylaminomethyl)-
		pyrrolidinocarbonyl)-2-
		thienyl
CLXXXVIII	morpholinoNH	5-(2(R)-(CH₃OCH₂)-	552	266*
		pyrrolidinoamino-
		carbonyl)-2-thienyl
CLXXXIX	morpholinoNH	5-homopiperidino-	521	N/A
		carbonyl-2-thienyl
CXC	morpholinoNH	5-homopiperazino-	522	209*
		carbonyl-2-thienyl
CXCI	morpholinoNH	5-(4-Me-homopiperazino-	536	207*
		carbonyl)-2-thienyl
CXCII	morpholinoNH	5-(4-Et-homopiperazino-	550	192*
		carbonyl)-2-thienyl
CXCIII	morpholinoNH	5-((4-	576	194*
		(cyclohexylmethyl)-
		homopiperazino)-
		carbonyl)-2-thienyl
CXCIV	morpholinoNH	5-(4-(CO₂t-Bu)-	622	210*
		homopiperazino-
		carbonyl)-2-thienyl
CXCV	morpholinoNH	5-(4-(COCH₃)-	564	274*
		homopiperazino-
		carbonyl)-2-thienyl
CXCVI	morpholinoNH	5-((4-methylamino-	544	230*
		phenyl)aminocarbonyl)-
		2-thienyl
CXCVII	morpholinoNH	5-((4-acetamidophenyl)-	572	253*
		aminocarbonyl)-2-
		thienyl
CXCVIII	morpholinoNH	5-(4-(NEt₂)-	586	198*
		phenylaminocarbonyl)-2-
		thienyl
CXCIX	morpholinoNH	5-(1-Me-3-cyclopropyl-	559	290*
		5-pyrazolyl)amino-
		carbonyl-1-thienyl
CC	morpholinoNH	1-Me-3-pyrrolyl	393	301
CCI	2(R)-(CH₃OCH₂)-	5-CO₂Et-2-thienyl	496 221
	pyrrolidinoNH
CCII	2(R)-(CH₃OCH₂)-	5-CO₂H-2-thienyl	468	258*
	pyrrolidinoNH
CCIII	2(R)-(CH₃OCH₂)-	5-(4-Me-piperazino-	550	181*
	pyrrolidinoNH	carbonyl)-2-thienyl
CCIV	2(R)-(CH₃OCH₂)-	5-piperazino-carbonyl-	536	>300*
	pyrroldinoNH	2-thienyl
CCV	2(R)-(CH₃OCH₂)-	5-(4-(CO₂t-Bu)-	636	>300*
	pyrrolidinoNH	piperazinocarbonyl)-2-
		thienyl
CCVI	2(R)-(CH₃OCH₂)-	5-(4-Me-homopiperazino-	564	176*
	pyrrolidinoNH	carbonyl)-2-thienyl
CCVII	2(R)-(CH₃OCH₂)-	5-homopiperazino-	550	185*
	pyrrolidinoNH	carbonyl-2-thienyl
CCVIII	2(R)-(CH₃OCH₂)-	5-(4-(CO₂t-Bu)-	650	>300*
	pyrrolidinoNH	homopiperazino-
		carbonyl)-2-thienyl
CCIX	Methyl	4-CF₃C₆H₄	370	>300
			(M − H)⁻
CCX	morpholinoNH	4-(4-Boc-	574	242
		piperazino)C₆H₄
CCXI	morpholinoNH	4-(piperazino)C₆H₄	474	263*
CCXII	NH₂	4-(piperazino)C₆H₄	389	257*
CCXIII	NH₂NH	4-(piperazino)C₆H₄	404	257*
CCXIV	Me₂NCH₂	4-(piperazino)C₆H₄	431	243*
CCXV	morpholinylCH₂	4-(piperazino)C₆H₄	473	259*
CCXVI	4-Me-piperazinoCH₂	4-(piperazino)C₆H₄	486	NA
CCXVII	4-NH₂CH₂-piperidinoCH₂	4-(piperazino)C₆H₄	500	239*
CCXVIII	morpholinoNH	4-(4-Me-piperazino)C₆H₄	488	245*
CCXIX	morpholinoNH	4-(4-Et-piperazino)C₆H₄	502	245*
CCXX	morpholinoNH	4-(4-i-Pr-	516	253*
		piperazino)C₆H₄
CCXXI	Me₂NNH	4-(piperazino)C₆H₄	432	238*
CCXXII	Me₂NNH	4-(4-Me-piperazino)C₆H₄	446	192*
CCXXIII	4-CH₃-piperazinoNH	4-(piperazino)C₆H₄	487	254*
CCXXIV	4-CH₃-piperazinoNH	4-(4-Me-piperazino)C₆H₄	501	293*
CCXXV	4-CH₃-piperazinoNH	4-(4-Et-piperazino)C₆H₄	515	NA
CCXXVI	4-CH₃-piperazinoNH	4-(4-i-Pr-	529	272*
		piperazino)C₆H₄
CCXXVII	2,6-diCH₃-piperidinoNH	4-(piperazino)C₆H₄	500	270*
CCXXVIII	4-HOCH₂CH₂-piperazino-NH	4-(piperazino)C₆H₄	517	279*
CCXXIX	2(R)-CH₃OCH₂-	4-(piperazino)C₆H₄	502	NA
	pyrrolidinoNH
CCXXX	2(S)-CH₃OCH₂-	4-(piperazino)C₆H₄	502	NA
	pyrrolidinoNH
CCXXXI	2(R)-CH₃OC(CH₃)₂-	4-(piperazino)C₆H₄	530	221*
	pyrrolidinoNH
CCXXXII	2(S)-CH₃OC(CH₃)₂-	4-(piperazino)C₆H₄	530	218*
	pyrrolidinoNH
CCXXXIII	2(R)-HOCH₂-pyrrolidinoNH	4-(piperazino)C₆H₄	488	193*
CCXXXIV	2(S)-HOCH₂-pyrrolidinoNH	4-(piperazino)C₆H₄	488	190*
CCXXXV	2(R)-PhOCH₂-	4-(piperazino)C₆H₄	578	207*
	pyrrolidinoNH
CCXXXVI	2(S)-PhOCH₂-	4-(piperazino)C₆H₄	578	NA
	pyrrolidinoNH
CCXXXVII	morpholinoNH	4-(3-Me-piperazino)C₆H₄	488	230*
CCXXXVIII	morpholinoNH	4-(cis-3,5-diMe-	502	237*
		piperazino)C₆H₄
CCXXX	morpholinoNH	4-(cis-3,4,5-triMe-	516	240*
		piperazino)C₆H₄
CCXXXI	morpholinoNH	4-(4-i-Pr-piperazino)-	530	NA
		2-Me—C₆H₄
CCXLI	morpholinoNH	4-(homopiperazino)-C₆H₄	488	253*
CCXLII	morpholinoNH	4-(4-Me-	502	NA
		homopiperazino)-C₆H₄
CCXLIII	morpholinoNH	4-(4-Et-	516	240*
		homopiperazino)-C₆H₄
CCXLIV	morpholinoNH	4-(4-i-Pr-	530	245*
		homopiperazino)-C₆H₄
CCXLV	morpholinoNH	4-(homopiperazino)-2-	502	209*
		Me—C₆H₄
CCXLVI	morpholinoNH	4-(4-Et-	530	217*
		homopiperazino)-2-Me-
		C₆H₄
CCXLVII	morpholinoNH	4-(4-i-Pr-	544	197*
		homopiperazino)-2-
		Me—C₆H₄
CCXLVIII	morpholinoNH	4-(4-Me₂N-	516	258*
		piperidino)C₆H₄
CCXLIX	morpholinoNH	4-(4-morpholino-	558	249#
		piperidino)C₆H₄
CCL	morpholinoNH	4-(4-piperidino-	556	233*
		piperidino)C₆H₄
CCLI	morpholinoNH	4-(4-pyrrolidino-	542	247*
		piperidino)C₆H₄
CCLII	morpholinoNH	4-(4-Et₂N-	544	251*
		piperidino)C₆H₄
CCLIII	morpholinoNH	4-(4-C(═NH)CH₃-	515	240*
		piperazino)C₆H₄
CCLIV	morpholinoNH	4-(4-(2-pyridinyl)-	551	NA
		piperazino)C₆H₄
CCLV	4-NH₂CO-piperidinoCH₂	c-propyl	394	178*
CCLVI	4-CH₃-piperazinoNH	ethyl	355	244*
CCVLVII	4-CH₃-piperazinoNH	c-propyl	367	215*
CCLVIII	4-CH₃-piperazinoNH	c-hexyl	409	241*
CCLIX	morpholinoNH	ethyl	342	253*
CCLX	morpholinoNH	c-propyl	354	N/A
CCLXI	morpholinoNH	c-hexyl	396	>260*
CCLXII	morpholinoNH	1-CO₂Et-piperidin-4-yl	469	206*
CCLXIII	morpholinoNH	1-CO₂Ph-piperidin-4-yl	517	250*
CCLXIV	morpholinoNH	1-Coimidazolyl-	491	202*
		piperidin-4-yl
CCLXV	morpholinoNH	1-(2-	507	218*
		thienylcarbonyl)piperidin-
		4-yl
CCLXVI	morpholinoNH	1-CONH₂-piperidin-4-yl	440	258*
CCLXVII	morpholinoNH	1-CONHEt-piperidin-4-yl	466	215*
CCLXVIII	morpholinoNH	1-(2-(1-Me-pyrrolidin-	551	91*
		2-
		yl)ethylaminocarbamoyl)-
		piperidin-4-yl
CCLXIX	morpholinoNH	1-(4-Nme₂-	551	172*
		piperidinocarbonyl)-
		piperidin-4-yl
CCLXX	morpholinoNH	1-(piperazinocarbonyl)-	509	195*
		piperidin-4-yl
CCLXXI	morpholinoNH	1-(4-(CO₂t-Bu)-	609	231
		piperiazinocarbonyl)-
		piperidin-4-yl
CCLXXII	morpholinoNH	1-((1S,4S)-(+)-2,5-	521	196*
		diazabicyclo[2.2.1]hept-
		yl)carbonyl)-piperidin-
		4-yl
CCLXXIII	morpholinoNH	1-((1S,4S)-(+)-2-	535	225*
		methyl-2,5-
		diazabicyclo[2.2.1]hept-
		yl)carbonyl)-pipieridin-
		4-yl
CCLXXIV	morpholinoNH	1-(CO(CH₂)₃NH₂)-	483	172*
		piperidin-4-yl
CCLXXV	morpholinoNH	1-(CO(CH₂)₃Nme₂)-	482	172*
		piperidin-4-yl
CCLXXVI	morpholinoNH	1-(CO(CH₂)₃NHCO₂t-Bu)-	582	73
		piperidin-4-yl
CCLXXVII	morpholinoNH	1-(CO(CH₂)₄NH₂)-	496	103*
		piperidin-4-yl
CCLXXVIII	morpholinoNH	1-(CO(CH₂)₄Nme₂)-	524	68*
		piperidin-4-yl
CCLXXIX	morpholinoNH	1-(CO(CH₂)₄NHCO₂t-Bu)-	596	98*
		piperidin-4-yl
CCLXXX	morpholinoNH	1-(1-e-piperidin-4-	522	148*
		ylcarbonyl)piperidin-4-
		yl
CCLXXXI	morpholinoNH	1-(1-CO₂t-Bu-piperidin-	608	220
		4-yl-
		carbonyl)piperidin-4-yl
CCLXXXII	morpholinoNH	1-(cis-4-NH₂-	522	212*
		cyclohexylcarbonyl)piper-
		idin-4-yl
CCLXXXIII	morpholinoNH	1-(4-NH₂-	522	202*
		cyclohexylcarbonyl)piper-
		idin-4-yl
CCLXXXIV	morpholinoNH	1-(cis-4-Nme₂-	522	202*
		cyclohexylcarbonyl)piper-
		idin-4-yl
CCLXXXV	morpholinoNH	1-(4-NHCO₂t-Bu)-	622	210*
		cyclohexylcarbonyl)piper-
		idin-4-yl
CCLXXXVI	morpholinoNH	1-(trans-4-(NHCO₂t-	622	178
		Bu)cyclohexylcar-
		bonyl)piperidin-4-yl
CCLXXXVII	morpholinoNH	1-(piperidin-3-	508	169*
		ylcarbonyl)piperidin-4-
		yl
CCLXXXVIII	morpholinoNH	1-(1-Me-piperidin-3-	522	158*
		ylcarbonyl)piperidin-4-
		yl
CCLXXXIX	morpholinoNH	1-(1-CO₂t-Bu-piperidin-	608	196
		3-ylcarbonyl)piperidin-
		4-yl
CCXC	morpholinoNH	1-(3-NH₂-	522	201*
		cyclohexylcarbonyl)piper-
		idin-4-yl
CCXCI	morpholinoNH	1-(3-Nme₂-	550	153*
		cyclohexylcarbonyl)piper-
		idin-4-yl
CCXCII	morpholinoNH	1-(trans-4-Ome-	537	246*
		cyclohexylcarbonyl)piper-
		idin-4-yl
CCXCIII	morpholinoNH	1-(cis-4-Ome-	537	178*
		cyclohexylcarbonyl)pipre-
		idin-4-yl
CCXCIV	morpholinoNH	1-(4-NH₂-	530	177*
		benzylcarbonyl)piper-
		idin-4-yl
CCXCV	morpholinoNH	1-(4-Nme₂-	558	107*
		benzylcarbonyl)piper-
		idin-4-yl
CCXCVI	morpholinoNH	1-(4-NHCO₂C(CH₃)₃-	630	177
		benzylcarbonyl)piper-
		idin-4-yl
CCXCVII	morpholinoNH	1-(4-NH₂-	516	198*
		phenylcarbonyl)piper-
		idin-4-yl
CCXCVIII	morpholinoNH	1-(4-Nme₂-	544	189*
		phenylcarbonyl)piper-
		idin-4-yl
CCXCIX	morpholinoNH	1-(4-(NHCO₂t-Bu)-	616	212
		phenylcarbonyl)piper-
		idin-4-yl
CCC	morpholinoNH	trans-4-CO₂H-cyclohexyl	440	264*
CCCI	morpholinoNH	trans-4-CO₂Me-	454	259*
		cyclohexyl
CCCII	morpholinoNH	trans-4-(3-Nme₂-	536	191*
		pyrrolidinocarbonyl)-
		cyclohexyl
CCCIII	morpholinoNH	trans-4-	508	248*
		(piperazinocarbonyl)-
		cyclohexyl
CCCIV	morpholinoNH	trans-4-(4-Me-	522	228*
	piperazinocarbonyl)-
		cyclohexyl
CCCV	morpholinoNH	trans-4-	522	>265*
		(homopiperazinocar-
		bonyl)cyclohexyl
CCCVI	morpholinoNH	trans-4-(4-	536	220*
		methylhomopiperazinocar-
		bonyl)cyclohexyl

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	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	2-Me₂NC₆H₄
132	3-pyridylmethyl	4-pyridyl
133	3-pyridylmethyl	2-pyridyl
135	3-pyridylmethyl	2-thiazolyl
136	3-pyridylmethyl	2-pyrazolyl
137	3-pyridylmethyl	5-isoquinolyl
138	3-pyridylmethyl	3,4-methylenedioxyC₆H₃
139	3-pyridylmethyl	3,4-ethylenedioxyC₆H₃
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-MeOC₆H₄
174	2-NH₂C₆H₄CH₂	4-NH₂C₆H₄
175	2-NH₂C₆H₄CH₂	3-NH₂C₆H₄
176	2-NH₂C₆H₄CH₂	2-NH₂C₆H₄
177	2-NH₂C₆H₄CH₂	4-Me₂NC₆H₄
178	2-NH₂C₆H₄CH₂	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-ethylenedioxyC₆H₃
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	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-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-MeOC₆H₄CH₂	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-MeOC₆H₄CH₂	2-imidazolyl
281	3-MeOC₆H₄CH₂	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-MeOC₆H₄CH₂	4-Me₂NC₆H₄
293	4-MeOC₆H₄CH₂	3-Me₂NC₆H₄
294	4-MeOC₆H₄CH₂	2-Me₂NC₆H₄
295	4-MeOC₆H₄CH₂	4-pyridyl
296	4-MeOC₆H₄CH₂	3-pyridyl
297	4-MeOC₆H₄CH₂	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-MeOC₆H₄CH₂	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
318	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	3,4-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-NH₂C₆H₄
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-MeOC₆H₄
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-pyridyl
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-MeOC₆H₄
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-Me₂OC₆H₄
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-imidazolyl
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-NH₂C₆H₄
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	4-isoquinolyl
563	H	3,4-methylenedioxyC₆H₃
564	H	3,4-ethylenedioxyC₆H₃
565	H	2-imidazolyl
566	H	2-oxazolyl
567	H	4-isoxazolyl
568	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-Me₂NC₆H₄
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-diHOC₆H₄
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-HOC₆H₄
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	EtNHCH₂	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-MeOC₆H₄
663	HOCH₂CH₂NHCH₂	4-NH₂C₆H₄
664	HOCH₂CH₂NHCH₂	3-NH₂C₆H₄
665	HOCH₂CH₂NHCH₂	2-NH₂C₆H₄
666	HOCH₂CH₂NHCH₂	4-Me₂NC₆H₄
667	HOCH₂CH₂NHCH₂	3-Me₂NC₆H₄
668	HOCH₂CH₂NHCH₂	2-Me₂NC₆H₄
669	HOCH₂CH₂NHCH₂	4-pyridyl
670	HOCH₂CH₂NHCH₂	3-pyridyl
671	HOCH₂CH₂NHCH₂	2-pyridyl
672	HOCH₂CH₂NHCH₂	2-thiazolyl
673	HOCH₂CH₂NHCH₂	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-MeOC₆H₄
686	H₂NCH₂CH₂NHCH₂	3-MeOC₆H₄
687	H₂NCH₂CH₂NHCH₂	4-NH₂C₆H₄
688	H₂NCH₂CH₂NHCH₂	3-NH₂C₆H₄
689	H₂NCH₂CH₂NHCH₂	2-NH₂C₆H₄
690	H₂NCH₂CH₂NHCH₂	4-Me₂NC₆H₄
691	H₂NCH₂CH₂NHCH₂	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-NH₂CH₂C₆H₄
708	H₂NCH₂CH₂NHCH₂	3-NH₂CH₂C₆H₄
709	Me₂NCH₂CH₂NHCH₂	4-MeOC₆H₄
710	Me₂NCH₂CH₂NHCH₂	3-MeOC₆H₄
711	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	3,4-methylenedioxyC₆H₃
724	Me₂NCH₂CH₂NHCH₂	3,4-ethylenedioxyC₆H₃
725	Me₂NCH₂CH₂NHCH₂	2-imidazolyl
726	Me₂NCH₂CH₂NHCH₂	2-oxazolyl
727	Me₂NCH₂CH₂NHCH₂	4-isoxazolyl
728	Me₂NCH₂CH₂NHCH₂	4-HOC₆H₄
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-NH₂C₆H₄
735	1-morpholinylmethyl	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-Me₂NC₆H₄
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-thiomorpholinylmethyl	2-thiazolyl
767	1-thiomorpholinylmethyl	2-pyrazolyl
768	1-thiomorpholinylmethyl	5-isoquinolyl
769	1-thiomorpholinylmethyl	3,4-methylenedioxyC₆H₃
771	1-thiomorpholinylmethyl	2-imidazolyl
772	1-thiomorpholinylmethyl	2-oxazolyl
773	1-thiomorpholinylmethyl	4-isoxazolyl
774	1-thiomorpholinylmethyl	4-HOC₆H₄
775	1-thiomorpholinylmethyl	3-HOC₆H₄
776	1-thiomorpholinylmethyl	3,4-diHOC₆H₄
777	1-thiomorpholinylmethyl	4-NH₂CH₂C₆H₄
778	1-thiomorpholinylmethyl	3-NH₂CH₂C₆H₄
779	1-piperazinylmethyl	3-MeOC₆H₄
780	1-piperazinylmethyl	4-NH₂C₆H₄
781	1-piperazinylmethyl	3-NH₂C₆H₄
782	1-piperazinylmethyl	2-NH₂C₆H₄
783	1-piperazinylmethyl	4-Me₂NC₆H₄
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

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-pyridylmethyl	4-NH₂CH₂C₆H₄
825	2-pyridylmethyl	3-NH₂CH₂C₆H₄
826	3-pyridylmethyl	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-pyridylmethyl	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-ethylenedioxyC₆H₃
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-MeOC₆H₄
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	2-imidazolyl
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-methylenedioxyC₆H₃
962	2-MeOC₆H₄	3,4-ethylenedioxyC₆H₃
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-methylenedioxyC₆H₃
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-ClC₆H₄	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-MeOC₆H₄
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	4-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-methylenedioxyC₆H₃
1178	4-NH₂CH₂C₆H₄	3,4-ethylenedioxyC₆H₃
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-oyrazolyl
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	3-0NH₂C₆H₄
1239	4-Me₂NCH₂C₆H₄	2-NH₂C₆H₄
1240	4-Me₂NCH₂C₆H₄	4-Me₂C₆H₄
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-ethylenedioxyC₆H₃
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-NH₂C₆H₄
1286	Me	3-NH₂C₆H₄
1287	Me	2-NH₂C₆H₄
1288	Me	4-Me₂C₆H₄
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-ethylenedioxyC₆H₃
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	3-MeOC₆H₄
1309	Et	4-NH₂C₆H₄
1310	Et	2-NH₂C₆H₄
1311	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-methylenedioxC₆H₃
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-methylenedioxyC₆H₃
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-MNe₂NC₆H₄
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	3-MeOC₆H₄
1405	2-MeOC₆H₄CH₂	4-NH₂C₆H₄
1406	2-MeOC₆H₄CH₂	3-NH₂C₆H₄
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-methylenedioxyC₆H₃
1490	2-HOC₆H₄CH₂	3,4-ethylenedioxyC₆H₃
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
1515	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	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-NH₂CH₂C₆H₄
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-Me₂NC₆H₄
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

TABLE 4

Example
Number	R¹	R²

1714	4-Me₂NCH₂C₆H₄CH₂	3-NH₂CH₂C₆H₄
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	piperazinoCH₂	4-MeOC₆H₄
1741	4-Me-piperazinoCH₂	4-MeOC₆H₄
1742	4-HOCH₂CH₂—	4-MeOC₆H₄
	piperazinoCH₂
1743	piperidinoCH₂	4-MeOC₆H₄
1744	4-NH₂CH₂—	4-MeOC₆H₄
	piperidinoCH₂
1745	CH₃CH₂NHCH₂	4-MeOC₆H₄
1746	thiomorpholinoCH₂	4-MeOC₆H₄
1747	morpholinoCH₂	4-MeOC₆H₄
1748	pyyrolidinoCH₂	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	morpholinoCH₂	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

The compounds useful according to the invention optionally are supplied as salts. Those salts which are pharmaceutically acceptable are of particular interest since they are useful in administering the foregoing compounds for medical purposes. Salts which are not pharmaceutically acceptable are useful in manufacturing processes, for isolation and purification purposes, and in some instances, for use in separating stereoisomeric forms of the compounds of this invention. The latter is particularly true of amine salts prepared from optically active amines. [1009]
Where the compound useful according to the invention contains a carboxy group, or a sufficiently acidic bioisostere, base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form. [1010]
Also, where the compound useful according to the invention contains a basic group, or a sufficiently basic bioisostere, acid addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. [1011]
The foregoing compounds useful according to the invention may also be mixed another therapeutic compound to form pharmaceutical compositions (with or without diluent or carrier) which, when administered, provide simultaneous administration of a combination of active ingredients resulting in the combination therapy of the invention. [1012]
While it is possible for the compounds useful according to the invention to be administered alone it is preferably to present them as pharmaceutical compositions. The pharmaceutical compositions, both for veterinary and for human use, useful according to the present invention comprise at lease one compound of the invention, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients. [1013]
In certain preferred embodiments, active ingredients necessary in combination therapy may be combined in a single pharmaceutical composition for simultaneous administration. [1014]
The choice of vehicle and the content of active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the active compound, the particular mode of administration and the provisions to be observed in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used for preparing tablets. To prepare a capsule, it is advantageous to use lactose and high molecular weight polyethylene glycols. When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used. [1015]
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the oily phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the emulsifying wax, and the way together with the oil and fat make up the emulsifying ointment base which forms the oily dispersed phase of a cream formulation. Emulgents and emulsion stabilizers suitable for use in the formulation of the present invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate. [1016]
If desired, the aqueous phase of the cream base may include, for example, a least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogue. [1017]
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used. Solid compositions of may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols, and the like. [1018]
The pharmaceutical compositions can be administered in a suitable formulation to humans and animals by topical or systemic administration, including oral, inhalational, rectal, nasal, buccal, sublingual, vaginal, parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), intracisternal and intraperitoneal. It will be appreciated that the preferred route may vary with for example the condition of the recipient. [1019]
The formulations can be prepared in unit dosage form by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. [1020]
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tables may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compounds moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. [1021]
Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of the invention. [1022]
If desired, and for more effective distribution, the compounds can be microencapsulated in, or attached to, a slow release or targeted delivery systems such as a biocompatible, biodegradable polymer matrices (e.g. poly(d,l-lactide co-glycolide)), liposomes, and microspheres and subcutaneously or intramuscularly injected by a technique called subcutaneous or intramuscular depot to provide continuous slow release of the compoundis) for a period of 2 weeks or longer. The compounds may be sterilized, for example, by filtration through a bacteria retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. [1023]
Actual dosage levels of active ingredient in the compositions of the invention may be varied so as to obtain an amount of active ingredient that is effective to obtain a desired therapeutic response for a particular composition and method of administration. The selected dosage level therefore depends upon the desired therapeutic effect, on the route of administration, on the desired duration of treatment and other factors. [1024]
Total daily dose of the compounds useful according to this invention administered to a host in single or divided doses may be in amounts, for example, of from about 0.001 to about 100 mg/kg body weight daily and preferably 0.01 to 10 mg/kg/day. Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the body weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination with other drugs and the severity of the particular disease being treated. [1025]
The amount of each component administered is determined by the attending clinicians taking into consideration the etiology and severity of the disease, the patient's condition and age, the potency of each component and other factors. [1026]
The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials with elastomeric stoppers, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. [1027]
Administration of a compound of the present invention in combination with additional therapeutic agents, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety. The combination of a compound of the present invention with such additional therapeutic agents is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the therapeutic effect of the compound and agent when administered in combination is greater than the additive effect of the either the compound or agent when administered alone. In general, a synergistic effect is most clearly demonstrated at levels that are (therapeutically) sub-optimal for either the compound of the present invention or a known anti-proliferative agent alone, but which are highly efficacious in combination. Synergy can be in terms of improved inhibitory response without substantial increases in toxicity over individual treatments alone, or some other beneficial effect of the combination compared with the individual components. [1028]
The compounds of the invention, their methods or preparation and their biological activity will appear more clearly from the examination of the following examples which are presented as an illustration only and are not to be considered as limiting the invention in its scope. [1029]
Procedures for evaluating the biological activity of compounds or compositions according to the invention are carried out as described herein or by the application or adaptation of known procedures, by which is meant procedures used heretofore or as described in the literature. [1030]

Utility

Inhibition of Kinase/Cyclin Complex Enzymatic Activity

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, [1031] 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 IC₅₀was found to be less than 1 μM.

Inhibition of HCT 116 Cancer Cell Proliferation

To test the cellular activity of several compounds disclosed in this invention, we examined the effect of these compounds on cultured HCT116 cells and determined their effect on cell-cycle progression by the calorimetric cytotoxcity test using sulforhodamine B (Skehan et al. J. Natl. Cancer Inst. 82:1107-12, 1990). Briefly, HCT116 cells are cultured in the presence of test compounds at increasing concentrations. At selected time points, groups of cells are fixed with trichloroacetic acid and stained with sulforhodamine B (SRB). Unbound dye was removed by washing and protein-bound dye was extracted for determination of optical density. A compound was considered active if its IC[1032] ₅₀was found to be less than 10 μM.

Claims

What is claimed is:

1. A compound according to formula (I):

X is selected from the groups: O, S, and NR;

R is selected from the groups: H, C_1-4alkyl, and NR⁵R^5a;

R¹is selected from the groups: H, C_1-10alkyl substituted with 0-3 R^c, C_2-10alkenyl substituted with 0-3 R^c, C_2-10alkynyl substituted with 0-3 R^c, —NHR⁴, C_3-10membered carbocycle substituted with 0-5 R^a, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b;

Ra is independently selected from the groups: R⁵R^5aN(CR⁶R^6a)m, R⁵O(CR⁶R^6a)m, halo, —CN, N₃, NO₂, C_1-4alkyl, C_1-4haloalkyl, NR³R^3a, ═O, OR³, SR³, COR³, CO₂R³, CONR³R^3a, NHC(O)NR³R^3a, NHC(S)NR³R^3a, NR³C(O)OR³, NR³C(O)R³, SO₂NR³R^3a, SO₂R^3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;

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

R^bis independently selected from the groups: halo, —CN, NO₂, C_1-4alkyl, C_1-4haloalkyl, NR³R^3a, NR³C(O)OR³, NR³C(O)R³, OR³, COR³, CONR³R^3a, CON(R⁶)((CH₂)_mR⁷), CO(CH₂)_mR⁷, NHC(O)NR³R^3a, NHC(S)NR³R^3a, SO₂NR³R^3a, and SO₂R^3b;

R^cis independently selected from the groups: halo, —CN, NO₂, C_1-4alkyl, C_1-4haloalkyl, NR³R^3a, NR⁵NR⁵R^5a, NR³C(O)OR³, NR³C(O)R³, ═O, OR³, COR³, CO₂R³, CONR³R^3a, NHC(O)NR³R^3a, NHC(S)NR³R^3a, SO₂N³R^3a, SO₂R^3b, C_3-10membered carbocycle substituted with 0-5 R^a, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R³;

R²is selected from the groups: H, C^1-10alkyl substituted with 0-3 R^c, C_2-10alkenyl substituted with 0-3 R^c, C_2-10alkynyl substituted with 0-3 R^c, —(CF₂)_mCF³, C_3-10membered carbocycle substituted with 0-5 R^a, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b;

R³is independently selected from the groups: H, halo, —CN, NO₂, C_1-4haloalkyl, R⁵R^5aN(CR⁶R^6a)m, NR⁵NR⁵R^5a, NR⁵C(O)OR⁵, NR⁵C(O)R⁵, ═O, R⁵O(CR⁶R^6a)m, COR⁵, CO₂R⁵, CONR⁵R^5a, NHC(O)NR⁵R^5a, NHC(S)NR⁵R^5a, SO₂NR⁵R^5a, SO₂R^5b, C_1-4alkyl, phenyl, and benzyl;

R^3ais independently selected from the groups: H, C_1-4alkyl, phenyl, and benzyl;

alternatively, R³and R^3a, together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom and substituted with 0-3 R^3c;

R^3bis independently selected from the groups: H, C_1-4alkyl, phenyl, and benzyl;

R^3cis independently selected from the groups: halo, —CN N₃, NO₂, C_1-4alkyl, C_3-8cycloalkyl, C_4-10cycloalkylalkyl, C_1-4haloalkyl, NR³R^3b, R⁵R^5aN(CR⁶R^6a)m, ═O, OR³, R⁵O(CR⁶R^6a)m, COR³, CO₂R³, CONR³R³ ^b, NHC(O)NR³R³ ^b, NHC(S)NR³R³ ^b, NR³C(O)OR³, NR³C(O)R³, C(═NR⁵)R^5a, C(═NR⁵)NR^5aR^5b, SO₂NR³R³ ^b, SO₂R^3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;

R⁴is independently selected from the groups: H, —CN, C_1-4alkyl, C_1-4haloalkyl, NR³R^3a, NR³C(O)OR³, NR³C(O)R³, OR³, COR³, CO₂R³, CONR³R^3a, NHC(O)NR³R^3a, NHC(S)NR³R^3a, SO₂NR³R^3a, SO₂R^3b, C_3-10membered carbocycle substituted with 0-5 R^a, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R³;

R⁵is independently selected from the groups: H, C_1-4alkyl, phenyl and benzyl;

R^5ais independently selected from the groups: H, C_1-4alkyl, phenyl and benzyl;

alternatively, R⁵and R^5a, together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom;

R_5bis independently selected from the groups: H, C_1-4alkyl, phenyl and benzyl;

R⁶is idependently selected from the groups: H, C_1-4alkyl;

R^6ais independently selected from the groups: H, C_1-4alkyl;

R⁷is independently selected from the groups: NR³R^3a, C_3-10membered carbocycle substituted with 0-3 R³, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R³; and

m is independently selected from 0, 1, 2, 3, and 4;

provided that: when R²is a C_1-4unsubstituted, branched alkyl then R¹is not CH₃; or when R¹is NHR⁴and R⁴is NR³R^3athen R³and R^3acan not both be phenyl.

2. A compound according to

claim 1

, wherein

X is O or S;

R¹is H, C_1-10alkyl substituted with 0-3 R^c, —NHR⁴, C_3-10membered carbocycle substituted with 0-5 R^a, or 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5;

R^cis independently selected from the groups: halo, C_3-10membered carbocycle substituted with 0-5 R^a, 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R³, NR³R^3a;

R³is H, C_1-4alkyl, phenyl, benzyl, or together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom and substituted with 0-3 R^3c;

R4 is H, C_1-4alkyl, NR³R^3a, C_3-10membered carbocycle substituted with 0-5 R^a, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R³;

R²is selected from the groups: C_3-10membered carbocycle substituted with 0-5 R^a, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b, and C_1-10alkyl substituted with 0-3 R^c.

3. A compound according to

claim 1

, wherein

X is O or S;

R¹is C_1-4alkyl substituted with 0-3 R^c, wherein R^cis independently selected from the group consisting of: C_3-6membered carbocycle substituted with 0-5 R^a, 5-6 membered heterocycle substituted with 0-3 R³, NR³R^3a, and OR³; C_3-6membered carbocycle substituted with 0-5 R^a, wherein R^ais independently selected from the group consisting of: R⁵R^5aN(CR⁶R^6a)m—, R⁵O(CR⁶R^6a)m—, OR³, halo, C_1-4alkyl, —NR³C(O)R³, COR³, CO₂R³, N³, NR³C(O)OR³, NR³R^3a, CONR³R^3a, and 5-6 membered heterocycle; or when two R^a's are present on adjacent carbon atoms they combine to form —OCH₂O— or —OCH₂CH₂O—; or 5-6 membered heterocycle and substituted with 0-5 R^b, wherein R^bis independently selected from the group: OR³, halo, COR , C_1-4alkyl, CO₂R³, NR³C(O)R³, NR³C(O)OR³, NR³R^3a, and CONR³R^3a;

R²is C_3-6membered carbocycle substituted with 0-5 R^a, wherein R^ais independently selected from the groups: R⁵R^5aN(CR⁶R^6a)m, R⁵O(CR⁶R^6a)m, OR³, halo, C_1-4alkyl, NR³C(O)R³, COR³, CO₂R³, N³, NR³C(O)OR³, NR³R^3a, CONR³R^3a, and 5-6 membered heterocycle, or when two R^a's are present on adjacent carbon atoms they combine to form —OCH₂O— or —OCH₂CH₂O—; 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b, wherein R^bis independently selected from the group: OR³ ₁halo, COR³, C_1-4alkyl, CO₂R³, NR³C(O)R³, NR³C(O)OR³, NR³R^3a, and CONR³R^3a; or C_1-10alkyl substituted with 0-3 R^c, wherein R^cis independently selected from the groups: C_3-6membered carbocycle substituted with 0-5 R^a, 5-6 membered heterocycle substituted with 0-3 R³, NR³R^3a, and OR³.

4. A compound according to

claim 1

, wherein

X is O or S;

R¹is selected from the groups: H, —NHR⁴, C_1-4alkyl substituted with 0-3 R^c, C_3-6membered carbocycle substituted with 0-5 R^a, and 5-6 membered heterocycle and substituted with 0-5 R^b;

R²is selected from the group: C_3-6membered carbocycle substituted with 0-5 R^a, 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b, and C_1-10alkyl substituted with 0-3 R^c, C_2-10alkenyl substituted with 0-3 R^c;

R⁴is independently selected from the groups: H, C_1-4alkyl, NR³R^3a, 3-6 membered carbocycle substituted with 0-5 R^a, and 5-6 membered heterocycle substituted with 0-3 R³;

R³is independently selected from the group: H, halo, COR⁵, CO₂R⁵, R⁵R^5aN(CR⁶R^6a)m, R⁵O(CR⁶R^6a)m, CONR⁵R^5a, NR⁵C(O)OR⁵, NR⁵C(O)R⁵, C_1-4alkyl, phenyl, and benzyl;

R^3ais independently selected from the group: H, C_1-4alkyl, phenyl, and benzyl; or R³and R^3a, together with the atoms to which they are attached, form a 5-6 membered heterocycle containing an additional 0-1 N, S, or O atom and substituted with 0-3 R^3c;

R^cis independently selected from the groups: C_3-6membered carbocycle substituted with 0-5 R^a, 5-6 membered heterocycle substituted with 0-3 R³, NR³R^3a, and OR³;

R^ais independently selected from the groups: R⁵R^5aN(CR⁶R^6a)m, R⁵O(CR⁶R^6a)m, OR³, halo, C_1-4alkyl,

NR³C(O)R³, COR³, CO₂R³, N₃, NR³C(O)OR³, NR³R^3a, CONR³R^3a, 5-6 membered heterocycle; or when two R^a's are present on adjacent carbon atoms they combine to form —OCH₂O— or —OCH₂CH₂O—;

R^bis independently selected from the group: OR³, halo, COR³, C_1-4alkyl, CO₂R³, NR³C(O)R³, NR³C(O)OR³, NR³R^3a, CONR³R^3a;

R^3cis independently selected from the groups: OR³, halo, COR³, R⁵R^5aN(CR⁶R^6a)m—, R⁵O)(CR⁶R⁶)m—, CO₂R³, N₃, NR³R^3b, C_1-4alkyl, NR³C(O)R³, NR³C(O)OR³, N₃, NR³R^3b, CONR³R^3b, and 5-6 membered heterocycle; and

m is independently selected from the group consisting of 1 2, 3 and 4.

5. A compound according to

claim 1

, wherein

R¹is selected from the group: —NHR⁴and C_1-2alkyl substituted with 1 R^c.

6. A compound according to

claim 1

wherein

X is O or S; and

R¹is selected from the group: H, C_1-4alkyl substituted with 0-3 R^c, C_2-4alkenyl substituted with 0-3 R^c, C_2-4alkynyl substituted with 0-3 R^C, —NHR⁴, C_3-6carbocycle substituted with 0-5 R^a, and 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b.

7. A compound according to

claim 1

wherein

X is O or S; and

R¹is selected from the group: H, C_1-4alkyl substituted with 0-3 R^c, C_2-4alkenyl substituted with 0-3 R^c, C_2-4alkynyl substituted with 0-3 R^c, —NHR⁴, C_3-6carbocycle substituted with 0-5 R^a, and 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b;

R^ais independently at each occurrence selected from the group: —CH₂N(CH₃)₂, —CH₂NH₂, —SH, —SCH₃, —NR₃C(O)R₃, —N₃, halo, C_1-4alkyl, NR³R^3a, and OR³; alternatively, when two R^a's are present on adjacent carbon atoms they combine to form —OCH₂O— or —OCH₂CH₂O—;

R^bis independently at each occurrence selected from the group: halo, C_1-4alkyl, NR³R^3a, OR³, COR³, and CO₂R³;

R^cis independently at each occurrence selected from the group: halo, C_1-4alkyl, NR³R^3a, C_3-6carbocycle substituted with 0-5 R^a, and 5-7 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R³;

R^3ais H or C_1-4alkyl; and

R³is selected from the group: H, —CH₂CH₂OH, —C(O)CH₂NH₂, —C(O)CH₂N(CH3)2, —NR⁵R^5a, —C_1-4alkyl-NR⁵R^5a, C_1-4alkyl, phenyl, and benzyl.

8. A compound according to

claim 1

wherein

X is O or S;

R¹is selected from the group: H, C_1-4alkyl substituted with 0-3 R^c, —NHR⁴, C_3-6carbocycle substituted with 0-5 R^a, and 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b;

R^ais independently at each occurrence selected from the group: —CH₂N(CH₃)₂, —CH₂NH₂, —SH, —SCH₃, halo, C_1-4alkyl, NR³R^3a, and OR³; alternatively, when two R^a's are present on adjacent carbon atoms they combine to form —OCH₂O— or —OCH₂CH₂O —;

R^cis independently at each occurrence selected from the group: —OH, chloro, C_1-4alkyl, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3, —NHCH2CH2OH, —N(CH3)2, phenyl substituted with 0-5 R^a, and 5-7 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R ³.

9. A compound according to

claim 1

wherein

R¹is selected from the group: H, C_1-10alkyl substituted with 0-3 R^c, C_2-10alkenyl substituted with 0-3 R^c, C_2-10alkynyl substituted with 0-3 R^c;

R²is selected from the group: H, —(CF₂)_mCF₃, C_3-10carbocycle substituted with 0-5 R^a, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b; and

R^cis independently at each occurrence selected from the group: phenyl substituted with 0-5 R^a, and thiophenyl or pyridyl, which is substituted with 0-3 R³.

10. A compound according to

claim 1

wherein

R^cis independently at each occurrence selected from the group: thiophenyl, piperazinyl, piperidinyl, thiomorpholinyl, morpholinyl, pyrrolidinyl, and pyridyl, which is substituted with 0-3 substituents indepently selected from the group consiting of CH3, CH2CH2OH, CH2CH2NH2, —C(═O)NH2, —OCH3, CH2NH2, NHCH2CH3,OH, NH2, halo, —CH2N(CH3)2, —OCH2CH2O—,—OCH2O—, —N(CH3)2, uridomethyl, and pyridyl.

11. A compound according to

claim 1

wherein

R^cis phenyl substituted with 0-5 substituents indepently selected from the group consiting of CH3, CH2CH2OH, CH2CH2NH2, —C(═O)NH2, —OCH3, CH2NH2, NHCH2CH3, OH, NH2, halo, —CH2N(CH3)2, —OCH2CH2O—, —OCH2O—, —N(CH3)2, uridomethyl, and pyridyl.

12. A compound according to

claim 1

wherein

X is O or S;

R¹is —NHR⁴or methylene substituted with 0-3 R^c;

R^cis NR³R^3a;

R⁴is selected from the group consisting of H, C1-4 alkyl, and NR³R^3a; and

R³and R^3a, are independently hydrogen or C1-4alkyl, or R³and R^3a, together with the nitrogen atom to which they are attached, form a 4-8 membered heterocycle containing an additional 0-1 N, S, or O atom and substituted with 0-3 R^3c.

13. A compound according to

claim 1

wherein

X is O or S;

R¹is —NHR⁴or methylene substituted with 0-3 R^c;

R^cis NR³R^3a;

R⁴is selected from the group consisting of H, C1-4 alkyl, and NR³R^3a; and

R³and R^3a, are independently hydrogen or C1-4alkyl, or R³and R^3a, together with the nitrogen atom to which they are attached, form a 4-8 membered heterocycle containing an additional 0-1 N, S, or O atom and substituted with with 0-3 substituents independently selected from the group consisting of methyl, —CH₂OCH₃, —C(CH₃)₂OCH₃, —CH₂CH₂OH, —CH₂OH, —CH₂OCH₂Phenyl, —CH₂CH₂NH₂, —CH₂NH₂, —C(═NH)CH₃, and NH2.

14. A compound according to

claim 1

wherein

X is O or S; and

R¹is selected from the group: methylene substituted with a substituent selected from the group consisting of: halo, NR³R_3a, C_3-6carbocycle substituted with 0-5 R^a, and 5-7 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R³.

15. A compound according to

claim 1

wherein

X is O or S;

R¹is selected from the group: methylene substituted with NR³R^3a; and

R³and R^3a, together with the nitrogen atom to which they are attached, form pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thiomorpholinyl, pymorpholinyl, piperidinyl, piperazinyl, or piperadinyl, which is substituted with 0-3 R^3c.

16. A compound according to

claim 1

wherein

R¹is —NHR⁴;

R⁴is NR3R3a; and

17. A compound according to

claim 1

wherein

R¹is —NHR⁴;

R⁴is NR3R3a; and

R³and R³a, together with the nitrogen atom to which they are attached, form pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thiomorpholinyl, pymorpholinyl, piperidinyl, piperazinyl, or piperadinyl, which is substituted with 0-3 substituents independently selected from the group consisting of methyl, —CH₂OCH₃, —C(CH₃)₂OCH₃, —CH₂CH₂OH, —CH₂OH, —CH₂OCH₂Phenyl, —CH₂CH₂NH₂, —CH₂NH₂, —C(═NH)CH₃, and NH2.

18. A compound according to

claim 1

, wherein

R²is selected from the group: 5- to 7- membered monocyclic saturated, or partially saturated, heterocyclic ring substituted with 0-5 R^b.

19. A compound according to

claim 1

, wherein

R²is selected from the group: 5- to 7- membered monocyclic aromatice heterocyclic ring substituted with 0-5 R^b.

20. A compound according to

claim 1

, wherein

R²is selected from the group: C_1-10alkyl substituted with 0-3 R^c, C_3-10carbocycle substituted with 0-5 R^a, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b.

21. A compound according to

claim 1

, wherein

R²is selected from the group: C_1-6alkyl substituted with 0-3 R^c, C_3-6carbocycle substituted with 0-5 R^a, and 3-7 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b.

22. A compound according to

claim 1

, wherein

R²is selected from the group: C_1-6alkyl substituted with C_3-10carbocycle substituted with 0-5 R^a, and C_1-6alkyl substituted with 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S.

23. A compound according to

claim 1

, wherein

R²is selected from the group: phenyl substituted with 0-5 R^a, and cyclopropyl or cyclohexyl substituted with 0-2 R^a; and

R^ais independently at each occurrence selected from the group: —CH₂N(CH₃)₂, —CH₂NH₂, —SR³halo, —CN , N₃, NO₂, C_1-4alkyl, C_1-4haloalkyl, NR³R^3a, ═O, OR³, COR³, CO₂R³, CONR³R^3a, NHC(O)NR³R^3a, NHC(S)NR³R^3a, NR³C(O)OR³, NR³C(O)R³, SO₂NR³R^3a, SO₂R^3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S.

24. A compound according to

claim 1

, wherein

R^ais independently at each occurrence selected from the group: C_1-4alkyl, COR³, CO₂R³, and CONR³R^3a;

R^3ais H or C_1-4alkyl.

25. A compound according to

claim 1

, wherein

R²is selected from the group: phenyl substituted with 0-5 R^a, and cyclopropyl or cyclohexyl substituted with 0-2 R^a;

Ra is independently at each occurrence selected from the group: C_1-4alkyl, COR³, CO₂R³, and CONR³R^3a;

R^3ais H or C_1-4alkyl;

R³is C_1-4alkyl, C_1-4alkyl-NR5R5a; and

R⁵and R^5a, together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom.

26. A compound according to

claim 1

, wherein

R^ais independently at each occurrence selected from the group: C_1-4alkyl, COR³, CO₂R³, and CONR³R^3a; and

R^3ais H or C_1-4alkyl.

27. A compound according to

claim 1

, wherein

R²is phenyl substituted with NR³R^3a, wherein R³and R^3a, together with the nitrogen atom to which they are attached, form a 4-8 membered heterocycle containing an additional 0-1 N, S, or O atom and substituted with 0-3 R^3c.

28. A compound according to

claim 25

, wherein

R²is phenyl substituted with NR³R^3a; and

R³and R^3a, together with the nitrogen atom to which they are attached, form a pyrrolinyl, pyrrolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, morpholinyl,thiomorpholinyl, homopiperazinyl or piperazinyl group, substituted with 0-3 R^3c.

29. A compound according to

claim 25

, wherein

R²is phenyl substituted with NR³R^3awherein R³and R^3a, together with the nitrogen atom to which they are attached, form a piperidinyl, homopiperazinyl or piperazinyl group, substituted with 0-3 R^3c.

30. A compound according to

claim 25

, wherein

R²is phenyl substituted with NR³R^3aand

R³and R^3a, together with the nitrogen atom to which they are attached, form a piperidinyl, homopiperazinyl or piperazinyl group, substituted with 0-3 substituents independently selected from the group consisting of: —C(═NH)CH₃, pyrrolinyl, pyrrolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, morpholinyl,thiomorpholinyl, homopiperazinyl or piperazinyl group, pyridyl, C_1-4alkyl, —NR³R^3b.

31. A compound according to

claim 1

which is selected from Table 1.

32. A compound according to

claim 1

which is selected from Table 2.

33. A compound according to

claim 1

which is selected from Table 3.

34. A compound according to

claim 1

which is selected from Table 4.

35. A compound according to

claim 1

, wherein the compound is selected from:

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

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

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

3-(4-methanesulfonylphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-(N,N-dimethylamino)phenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;

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

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

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

3-(4-piperidinophenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-morpholinophenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

3-(4-dimethoxyphenyl)-5-(3-thienylacetamido)indeno[1,2-c]pyrazol-4-one;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

3-(4-morpholinophenyl)-5-(morpholinoacetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-(morpholinoacetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-(4-(aminomethyl)-piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-(aminocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-(morpholinocarbamoylamino)-indeno[1,2-c]pyrazol-4-one;

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

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

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

3-(ethyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(n-propyl)-5-(carbamoylamino)aminoindeno[1,2-c]pyrazol-4-one;

3-(i-propyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(c-propyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(c-hexyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(2-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(3-methyl-2-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-methyl-2-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-carboethoxy-2-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(3-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-methyl-3-pyrrolyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(2,5-dimethyl-3-thienyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(2-furanyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(i-propyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;

3-(c-propyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;

3-(c-hexyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;

3-(2-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;

3-(3-thienyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;

3-(2-furanyl)-5-((N,N-dimethylaminocarbamoyl)amino)indeno[1,2-c]pyrazol-4-one;

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

3-(c-hexyl)-5-((4-carbamoylpiperidino)acetamido)indeno[1,2-c]pyrazol-4-one;

3-(ethyl)-5-(4-(aminomethyl)piperidinoacetamido)indeno[1,2-c]pyrazol-4-one;

3-(i-propyl)-5-(4-(aminomethyl)piperidinoacetamido) indeno[1,2-c]pyrazol-4-one;

3-(c-propyl)-5-(4-(aminomethyl)piperidinoacetamido) indeno[1,2-c]pyrazol-4-one;

3-(c-hexyl)-5-(4-(aminomethyl)piperidinoacetamido) indeno[1,2-c]pyrazol-4-one;

3-(i-propyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-carboethoxy-2-thienyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-carboxyl-2-thienyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(2,5-dimethyl-3-thienyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(i-propyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-methyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-chloro-3-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(2-pyrrolidinoethyl)aminocarbonyl)-2-thienyl-5-(morpholinocarbamoylamino)indeno [1,2-c]pyrazol-4-one;

3-(5-((3-(2-pyrrolidon-1-yl)propyl)aminocarbonyl)-2-thienyl-5-(morpholinocarbamoylamino) indeno[1,2-c]pyrazol-4-one;

3-(5-((2-(3-pyridyl)ethyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino) indeno [17 2-c]pyrazo-1-4-one;

3-(5-((3-(1-imidazolyl)propyl)aminocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino) indeno [1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((4-methylpiperazino)carbamoylamino)-indeno[1,2-c]pyrazol-4-one; 3-(4-(4-methylpiperazino)phenyl)-5-((4-methylpiperazino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(4-ethylpiperazino)phenyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(4-isopropylpiperazino)phenyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinopheny)5((2,6-dimethylpiperidino)-carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((4-(2-hydroxyethyl)piperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((2(R)-(methoxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((2(S)-(methoxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((2(R)-(1-methoxy-1-methylethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((2(S)-(1-methoxy-1-methylethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((2(R)-(hydroxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((2(S)-(hydroxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((2(R)-(benzyloxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((2(S)-(benzyloxymethyl)pyrrolidino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(cis-3,5-dimethylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one; 3-(4-(cis-3,4,5-trimethylpiperazino)phenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-methyl-3-pyrrolyl)-5-(carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(2-(N,N-diethylaminomethyl)piperidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-pyrrolidinocarbonyl-2-thienyl)-5-(morpholinocarbamnoylamino) indeno[1,2-c]pyrazol-4-one;

3-(5-(3-aininopyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamnoylamino) indeno [1,2-c]pyrazol-4-one;

3-(5(3(S)-N-methylamino)pyrrolidinocarbonyl-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5(3(S)-(N-methyl-t-butoxycarbonylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(5-(3(S)-(N,N-dimethylamino)pyrrolidinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno[1,2-clpyrazol-4-one;

3-(5-(4-ethylhomopiperazinocarbonyl)-2-thienyl)-5-(morpholinocarbamoylamino)indeno(1,2-c]pyrazol-4-one;

3-(1-methyl-3-pyrrolyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(c-propyl)-5-(4-carbamoylpiperidinoacetamido)indeno[1,2-c]pyrazol-4-one;

3-ethyl-5-(4-methylpiperazinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(c-propyl)-5-(4-methylpiperazinocarbamoylamino) indeno [1,2-c]pyrazol-4-one;

3-(c-hexyl)-5-(4-methylpiperazinocarbamoylamino) indeno [1,2-c]pyrazol-4-one;

3-ethyl-5-(morpholinocarbamoylamino) indeno [1,2-c]pyrazol-4-one;

3-(c-propyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one; 3-(c-hexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-ethoxycarbonylpiperidin-4-yl)-5-(morpholinocarbamoylamino) indeno[1,2-c]pyrazol-4-one;

3-(1-(2-(1-methylpyrrolidin-2-yl) ethylaminocarbamoyl)piperidin-4-yl)-5-(morpholinocarbamoylamino) indeno [1,2-c]pyrazol-4-one;

3-(1-(piperazinocarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino) indeno[1,2-c]pyrazol-4-one;

3-(1-(4-(-butoxycarbonyl)piperazinoarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino) indeno [1,2-c]pyrazol-4-one;

3-(1-(((1S,4S)-(+)-2,5-diazabicyclo[2.2.1]hept-2-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(((1S,4S)-(+)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamnino) indeno [1,2-c]pyrazol-4-one;

3-(1-(3-aminopropylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno [1,2-c]pyrazol-4-one;

3-(1-(3-(t-butoxycarbonylamino)propylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylainino)indeno[1,2-c]pyrazol-4-one;

3-(1-(4-(dimethylamino)butylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamnino)indeno[1,2-c]pyrazol-4-one;

3-(1-(4-(t-butoxycarbonylamino)butylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamnoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-((1-methylpiperidin-4-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamroylamino) indeno [1,2-c]pyrazol-4-one;

3-(1-((1-(t-butoxycarbonyl)piperidin-4-yl) carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino) indeno [1,2-c]pyrazol-4-one;

3-(1-(cis-4-aminocyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino) indeno [1,2-c]pyrazol-4-one;

3-(1-(4-aminocyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3(1-(cis-4-(dimethylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(trans-4-(t-butoxycarbonylamino)cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino) indeno [1,2-c]pyrazol-4-one;

3-(1-(piperidin-3-ylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(1-methylpiperidin-3-ylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(3-aminocyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(3-(dimethylamino) cyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino) indeno [1,2-c]pyrazol-4-one;

3-(1-(trans-4-methoxycyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(1-(cis-4-methoxycyclohexylcarbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(trans-4-(homopiperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one; 3-(trans-4-(4-methylhomopiperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

or pharmaceutically acceptable salt form thereof.

36. A compound according to

claim 1

, wherein the compound is selected from:

3-(4-piperazinophenyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-piperazinophenyl)-5-((N,N-dimethylamino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

3-(4-(4-methylpiperazino)phenyl)-5-((4-methylpiperazino)carbamoylamino)indeno[1,2-c]pyrazol-4-one;

or pharmaceutically acceptable salt form thereof.

37. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier, a compound according to

claim 1

or a pharmaceutically acceptable salt or prodrug form thereof, and a cytostatic or cytotoxic agent.

38. A method of treating a cell proliferative disease associated with CDK activity in a patient in need thereof,comprising administrering to said patient a pharmaceutically effective amount of a compound according to

claim 1

, or a pharmaceutically acceptable salt or prodrug form thereof, wherein the proliferative diseases is selected from the group consisting of: Alzheimer's disease, viral infections, auto-immune diseases, fungal disease, cancer, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis, neurodegenerative disorders and post-surgical stenosis and restenosis.

39. A method of treating cancer associated with CDK activity in a patient in need thereof, comprising administrering to said patient a pharmaceutically effective amount of a compound according to

claim 1

, or a pharmaceutically acceptable salt or prodrug form thereof, wherein the cancer is selected from the group consisting of: carcinoma such as bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.

40. A method of treating a disease associated with apoptosis in a patient in need thereof, comprising administrering to said patient a pharmaceutically effective amount of a compound according to

claim 1

, or a pharmaceutically acceptable salt or prodrug form thereof, wherein the disease associated with apoptosis is selected from the group consisting of: cancer, viral infections, autoimmune diseases and neurodegenerative disorder.

41. A method of inhibiting tumor angiogenesis and metastasis in a patient in need thereof, comprising administrering to said patient a pharmaceutically effective amount of a compound according to

claim 1

, or a pharmaceutically acceptable salt or prodrug form thereof.

42. A method of modulating the level of cellular RNA and DNA synthesis in a patient in need thereof, comprising administering to said patient a CDK inhibitory effective amount of a compound according to

claim 1

, or a pharmaceutically acceptable salt or prodrug form thereof.

43. A method of treating viral infections in a patient in need thereof, comprising administering to said patient a CDK inhibitory effective amount of a compound according to

claim 1

, or a pharmaceutically acceptable salt or prodrug form thereof, wherein the viral infections is selected from the group consiting of HIV, human papilloma virus, herpesvirus, poxyirus, Epstein-Barr virus, Sindbis virus and adenovirus.

44. A method of chemopreventing cancer in a patient, comprising administering to said patient in need thereof, a CDK inhibitory effective amount of a compound according to

claim 1

, or a pharmaceutically acceptable salt or prodrug form thereof.

45. A method of inhibiting CDK activity comprising combining an effective amount of a compound according to

claim 1

, with a composition containing CDK.

46. A method of treating cancer associated with CDK activity in a patient in need thereof, comprising administrering to said patient a pharmaceutically effective amount of a compound according to

claim 1

, or a pharmaceutically acceptable salt or prodrug form thereof, in combination (administered together or sequentially) with known anti-cancer treatments such as radiation therapy or with cytostatic or cytotoxic agents, wherein such agents are selected from the group consisting of: DNA interactive agents, such as cisplatin or doxorubicin; topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents, such as paclitaxel, docetaxel or the epothilones; hormonal agents, such as tamoxifen; thymidilate synthase inhibitors, such as 5-fluorouracil; and anti-metabolites, such as methoxtrexate.

47. A method treating cell proliferative diseases associated with CDK activity in a patient in need thereof, comprising administrering to said patient a pharmaceutically effective amount of a compound according to

claim 1

, or a pharmaceutically acceptable salt or prodrug form thereof, in combination (administered together or sequentially) with known anti-proliferating agents selected from the group consisting of:, altretamine, busulfan, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, thiotepa, cladribine, fluorouracil, floxuridine, gemcitabine, thioguanine, pentostatin, methotrexate, 6-mercaptopurine, cytarabine, carmustine, lomustine, streptozotocin, carboplatin, cisplatin, oxaliplatin, iproplatin, tetraplatin, lobaplatin, JM216, JM335, fludarabine, aminoglutethimide, flutamide, goserelin, leuprolide, megestrol acetate, cyproterone acetate, tamoxifen, anastrozole, bicalutamide, dexamethasone, diethylstilbestrol, prednisone, bleomycin, dactinomycin, daunorubicin, doxirubicin, idarubicin, mitoxantrone, losoxantrone, mitomycin-c, plicamycin, paclitaxel, docetaxel, CPT-11, epothilones , topotecan, irinotecan, 9-amino camptothecan, 9-nitro camptothecan, GS-211, etoposide, teniposide, vinblastine, vincristine, vinorelbine, procarbazine, asparaginase, pegaspargase, methoxtrexate, octreotide, estramustine, and hydroxyurea.

48. A method of inhibiting CDKl activity, comprising adminsitering to a patient in need thereof an efective CDKl inhibitory amount of a compound according to

claim 1

, or a pharmaceutically acceptable salt or prodrug form thereof.

49. A method of inhibiting CDK2 activity, comprising adminsitering to a patient in need thereof an efective CDK2 inhibitory amount of a compound according to

claim 1

, or a pharmaceutically acceptable salt or prodrug form thereof.

50. A method of inhibiting CDK3 activity, comprising adminsitering to a patient in need thereof an efective CDK3 inhibitory amount of a compound according to

claim 1

, or a pharmaceutically acceptable salt or prodrug form thereof.

51. A method of inhibiting CDK4 activity, comprising adminsitering to a patient in need thereof an efective CDK4 inhibitory amount of a compound according to

claim 1

, or a pharmaceutically acceptable salt or prodrug form thereof.

52. A method of inhibiting CDK5 activity, comprising adminsitering to a patient in need thereof an efective CDK5 inhibitory amount of a compound according to

claim 1

, or a pharmaceutically acceptable salt or prodrug form thereof.

53. A method of inhibiting CDK6 activity, comprising adminsitering to a patient in need thereof an efective CDK6 inhibitory amount of a compound according to

claim 1

, or a pharmaceutically acceptable salt or prodrug form thereof.

54. A method of inhibiting CDK7 activity, comprising adminsitering to a patient in need thereof an efective CDK7 inhibitory amount of a compound according to

claim 1

, or a pharmaceutically acceptable salt or prodrug form thereof.

55. A method of inhibiting CDK8 activity, comprising adminsitering to a patient in need thereof, an efective CDK8 inhibitory amount of a compound according to

claim 1

, or a pharmaceutically acceptable salt or prodrug form thereof.

56. A method of inhibiting CDK9 activity, comprising adminsitering to a patient in need thereof an efective CDK9 inhibitory amount of a compound according to

claim 1

, or a pharmaceutically acceptable salt or prodrug form thereof.

57. A pharmaceutical kit for treating a cell proliferative disease associated with CDK activity, said kit comprising a plurality of separate containers, wherein at least one of said containers contains a compound accordig to

claim 1

, or a pharmaceutically acceptable salt or prodrug form thereof, and at least another of said containers contains one or more compounds selected from the group consisting of cytostatic or cytotoxic agents, such as for example, but not limited to, DNA interactive agents, such as carboplatin, cisplatin or doxorubicin; topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents, such as paclitaxel, taxane, docetaxel or the epothilones; hormonal agents, such as tamoxifen; thymidilate synthase inhibitors, such as 5-fluorouracil; and anti-metabolites, such as methoxtrexate, and said containers optionally contain a pharmaceutical carrier, which kit may be effectively utilized for carrying out combination therapies according to the invention.

58. A method of inhibiting the division of a cell which comprises contacting the cell with a composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of the formula (I):

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

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

R is selected from the group: H, C_1-4alkyl, and NR⁵R^5a;

R¹is selected from the group: H, C_1-10alkyl substituted with 0-3 R^c, C_2-10alkenyl substituted with 0-3 R^c, C_2-10alkynyl substituted with 0-3 R^c, —NHR⁴, C_3-10carbocycle substituted with 0-5 R^a, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b;

R^ais independently at each occurrence selected from the group: halo, —CN , N₃, NO₂, C_1-4alkyl, C_1-4haloalkyl, NR³R^3a, ═O, OR³, COR³, CO₂R³, CONR³R^3a, NHC(O)NR³R^3a, NHC(S)NR³R^3a, NR³C(O)OR³, NR³C(O)R³, SO₂NR³R^3a, SO₂R^3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;

alternatively, when two R^a's are present on adjacent carbon atoms they combine to form —OCH₂O— or —OCH₂CH₂O—;

R^bis independently at each occurrence selected from the group: halo, —CN, NO₂, C_1-4alkyl, C_1-4haloalkyl, NR³R^3a, NR³C(O)OR³, NR³C(O)R³, OR³, COR³, CO₂R³, CONR³R^3a, NHC(O)NR³R^3a, NHC(S)NR³R^3a, SO₂NR³R^3a, and SO₂R^3b;

R^cis independently at each occurrence selected from the group: halo, —CN, NO₂, C_1-4alkyl, C_1-4haloalkyl, NR³R^3a, NR⁵NR⁵R^5a, NR³C(O)OR³, NR³C(O)R³, ═O, OR³, COR³, CO₂R³, CONR R^3a, NHC(O)NR³R^3a, NHC(S)NR R^3a, SO₂N R^3a, SO₂R^3b, C_3-10carbocycle substituted with 0-5 R^a, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R³;

R²is selected from the group: H, C_1-10alkyl substituted with 0-3 R^c, C_2-10alkenyl substituted with 0-3 R^c, C_2-10alkynyl substituted with 0-3 R^c, —(CF₂)_mCF₃, C_3-10carbocycle substituted with 0-5 R^a, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R^b;

R³is selected from the group: H, halo, —CN, NO₂, C_1-4haloalkyl, NR⁵R^5a, NR⁵NR⁵R^5a, NR⁵C(O)OR⁵, NR⁵C(O)R⁵, ═O, OR⁵, COR⁵, CO₂R⁵, CONR⁵R^5a, NH(O)NR⁵R^5a, NHC(S)NR⁵R^5a, SO₂NR⁵R^5a, SO₂R^5b, C_1-4alkyl, phenyl, and benzyl;

R^3ais selected from the group: H, C_1-4alkyl, phenyl, and benzyl;

alternatively, R³and R^3a, together with the nitrogen atom to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or O atom;

R^3bis selected from the group: H, C_1-4alkyl, phenyl, and benzyl;

R⁴is independently at each occurrence selected from the group:

H, —CN, C_1-4alkyl, C_1-4haloalkyl, NR³R^3a, NR³C(O)OR³, NR³C(O)R³, OR³, COR³, CO₂R³, CONR³R^3a, NHC(O)NR³R^3a, NHC(S)NR³R^3a, SO₂NR³R^3a, SO₂R^3b, C_3-10carbocycle substituted with 0-5 R^a, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R³;

R⁵is independently selected from the group: H, C_1-4alkyl, phenyl and benzyl;

R^5ais independently selected from the group: H, C_1-4alkyl, phenyl and benzyl;

R^5bis independently selected from the group: H, C_1-4alkyl, phenyl and benzyl; and

m is selected from 0, 1, 2, and 3.,

provided that R²my not be an unsubstituted branched alkyl group when R¹is CH₃.