ES2349142T3 - USEFUL DITIOLOPIRROLONE DERIVATIVES IN THE TREATMENT OF PROLIFERATIVE DISEASES. - Google Patents

Abstract

A compound of the formula shown below: Code XYZ BLI-066 2,4-dimethoxy-phenyl H N-methyl-3-pyridinium chloride BLI-081 2,4-dimethoxy-phenyl H 2-furyl BLI-090 2, 4-dimethoxy-phenyl H 2,4-dimethoxy-phenyl BLI-093 2,4-dimethoxy-phenyl H 4-trifluoromethylphenyl WBL-007 2,4-dimethoxy-phenyl H 2-thiophenyl R3 2,4-dimethoxy-phenyl H 3,5-Difluorophenyl R4 2,4-dimethoxy-phenyl H 2,3,4-trifluorophenyl WBL-018 2,4-dimethoxy-phenyl H 4-fluoro-phenyl 0037 2,4-dimethoxy-phenyl H Thiophene-2- methyl 0038 2,4-dimethoxy-phenyl H 4-nitrophenyl 0040 2,4-dimethoxy-phenyl H 4-N, N-dimethylamino-phenyl 0041 2,4-dimethoxy-phenyl H 4-aminophenyl 0042 2,4-dimethoxy- phenyl H 0043 2,4-dimethoxy-phenyl H 0044 2,4-dimethoxy-phenyl H 0047 2,4-dimethoxy-phenyl H 3-trifluoromethylphenyl 0052 2,4-dimethoxy-phenyl H 0054 4-iso-butylphenyl H 4- trifluoromethylphenyl 0055 4-iso-butylphenyl H 2-furyl 0056 4-iso-butylphenyl H 2-thiophenyl 0057 4-iso-butylphenyl H 3-trifluoromethylphenyl 0058 2,4-dimethoxy-phenyl H 3,5-di-trifluoromet ilphenyl 0059 4-iso-butylphenyl H 3,5-di-trifluoromethylphenyl 0062 2,4-dimethoxy-phenyl H 0066 2,4-dimethoxy-phenyl H 0068 2,4-dimethoxy-phenyl H 0069 2,4-dimethoxy-phenyl H WBI-4 4-isopropylphenyl H WBI-5 4-isobutylphenyl H WBI-6 methyl H 0096 4-isopropanyl-phenyl H 3,5-dihydroxy-4-isopropanyl-phenyl 0102 2,4-dimethoxy-phenyl H 3,5 -dihydroxy-4-isopropanyl-phenyl 0107 Benzyl H 3,5-dihydroxy-4-isopropanyl-phenyl 0110 methyl H 3,5-dihydroxy-4-isopropanyl-phenyl 0113 Benzyl H 2-thiophenyl 0116 Benzyl H 0122 2,4- dimethoxy-phenyl Methyl 0125 4-isopropanyl-phenyl 0126 2,4-dimethoxy-phenyl H 0128 4-isopropanyl-phenyl HH Pyridin-3-yl 0135 Benzyl H Pyridin-3-yl 0136 Benzyl H 0137 Benzyl H 2,4-dimethoxy -phenyl H 2- (2-thiophenyl) -vinyl 2,4-dimethoxy-phenyl H 1-methylimidazol-5-yl 4-methyl-phenyl H 2-thiophenyl 2,4-dimethoxy-phenyl Methyl 2-thiophenyl 2,4 -dimethoxy-phenyl benzyl 2-furyl 2,4-dimethoxy-phenyl H 1-methyl-pyrrolyl 2,4-dimethoxy-phenyl H 2-thiazolyl 2,4-dimethoxy-phenyl H N-methyl-2-indolyl or

Description

The present invention provides novel dithiolopyrrolone compounds and their salts, which are useful in the treatment of cancer and other proliferative diseases. The present invention also provides therapeutic compositions comprising particularly useful types of dithiolopyrrolones, the salts of the

5 themselves, and the uses of compounds of these types, particularly in the treatment of proliferative diseases such as cancer. The present invention also provides a process for the manufacture of dithiolopyrrolones.

Cancer is one of the leading causes of death in humans and animals. Millions of people in the world are diagnosed every year of having

10 cancer and a large proportion of them die of cancer. Despite extensive worldwide efforts over many years, cancer remains a difficult disease to treat, and there is an urgent need for more effective anticancer drugs. Dithiolopyrrolones are a group of compounds with ring 1,2

Dithiolo [4,3b] pyrrole-5 (4H) -one. Substitutes attached to the ring, particularly in position 2 and 6, lead to various subgroups of derivatives with different structural characteristics and bio-activities. Compounds that carry this basic structural feature have been known in the art. Natural dithiolopyrrolones have been shown to have activity against microorganisms as well as others

20 activities such as chemopreventives (Sharma et al., 1994) and anticancer (documents US6020360 and WO 99/12543, both of Webster et al.). Certain synthetic dithiolopyrrolones and their antimicrobial activities have been described (DS Bhate and YM Sambray, 1963. Hindustan, Antibiotic Bulletin 6 (1): 17-18; Katsuaki Hagio et al. Bull. Chem. Soc. 1974, 47, 1484 -1489; Broom, et al., WO 9505384 and Godfrey and Dell,

25 GB2170498). The present invention relates to certain new types of particular specific dithiolopyrrolones and dithiolopyrrolones that have been found to have particular use in the treatment of cancers. The invention relates to such particular types and compounds as new chemical compounds, and also to

30 pharmaceutical compositions containing them and methods for the treatment of the disease when used.

Furthermore, and more generally, it is found that such types of specific dithiolopyrrolones and dithiolopyrrolones are useful against proliferative diseases in general. Proliferative diseases are, but not limited to, 35 disorders in which unwanted proliferation of cells from one or more subsets of cells in a multicellular organism occurs, resulting in damage

(for example, malaise or a reduced life expectancy) on the multicellular organism. Proliferative diseases can appear in different types of animals and humans. Proliferative diseases include leukemia and proliferative disorders in the blood vessels, and fibrotic disorders such as

5 cancers, tumors, hyperplasia, fibrosis (especially pulmonary fibrosis, but also other types of fibrosis, such as renal fibrosis), angiogenesis, psoriasis, atherosclerosis and proliferation of smooth muscle cells in blood vessels, such as stenosis or restenosis after angioplasty.

In one aspect, the invention provides uses and compositions for the

Treatment of proliferative diseases, such as cancer and psoriasis, which comprise administering to an individual in need of such treatment, an effective amount of a compound of one of the structures shown below. In another aspect, the invention deals with pharmaceutical compositions containing compounds of the structures shown below, for the treatment of proliferative diseases and

15 especially cancer. In another aspect, the invention includes, as new chemical compounds, those compounds of the structures shown below. The structures of the compounds according to the invention are the following: Compounds of the following formula (formula I)

image 1

twenty

in which

Code

X Y Z

BLI-066

2,4-dimethoxy-phenyl H N-methyl-3-pyridinium chloride

BLI-081

2,4-dimethoxy-phenyl H 2-fury

BLI-090

2,4-dimethoxy-phenyl H 2,4-dimethoxy-phenyl

BLI-093

2,4-dimethoxy-phenyl H 4-trifluoromethylphenyl

WBL-004

2,4-dimethoxy-phenyl 2-thiophenylcarboxy 2-thiophenyl

WBL-007

2,4-dimethoxy-phenyl H 2-thiophenyl

R3

2,4-dimethoxy-phenyl H 3,5-difluorophenyl

R4

2,4-dimethoxy-phenyl H 2,3,4-trifluorophenyl

WBL-018

2,4-dimethoxy-phenyl H 4-fluoro-phenyl

0037

2,4-dimethoxy-phenyl H Thiophene-2-methyl

0038

2,4-dimethoxy-phenyl H 4-nitrophenyl

0040

2,4-dimethoxy-phenyl H 4-N, N-dimethylamino-phenyl

0041

2,4-dimethoxy-phenyl H 4-aminophenyl

0042

2,4-dimethoxy-phenyl H

0043

2,4-dimethoxy-phenyl H

0044

2,4-dimethoxy-phenyl H

0047

2,4-dimethoxy-phenyl H 3-trifluoromethylphenyl

0052

2,4-dimethoxy-phenyl H image 1

0054

4-iso-butylphenyl H 4-trifluoromethylphenyl

0055

4-iso-butylphenyl H 2-fury

0056

4-iso-butylphenyl H 2-thiophenyl

0057

4-iso-butylphenyl H 3-trifluoromethylphenyl

0058

2,4-dimethoxy-phenyl H 3,5-di-trifluoromethylphenyl

0059

4-iso-butylphenyl H 3,5-di-trifluoromethylphenyl

0062

2,4-dimethoxy-phenyl H image 1

0066

2,4-dimethoxy-phenyl H

0068

2,4-dimethoxy-phenyl H

0069

2,4-dimethoxy-phenyl H

WBI-4

4-isopropylphenyl H

WBI-5

4-isobutylphenyl H

WBI-6

Methyl H

0096

4-isopropanylphenyl H 3,5-dihydroxy-4-isopropanyl-phenyl

0102

2,4-dimethoxy-phenyl H 3,5-dihydroxy-4-isopropanyl-phenyl

0107

Benzyl H 3,5-dihydroxy-4-isopropanyl-phenyl

0110

Methyl H 3,5-dihydroxy-4-isopropanyl-phenyl

0113

Benzyl H 2-thiophenyl

0116

Benzyl H

0122

2,4-dimethoxy-phenyl methyl

0125

4-isopropanylphenyl H

0126

2,4-dimethoxy-phenyl H

0128

4-isopropanylphenyl H Pyridin-3-yl

0135

Benzyl H Pyridin-3-yl

0136

Benzyl H

0137

Benzyl H

2,4-dimethoxy-phenyl

H 2- (2-thiophenyl) -vinyl

2,4-dimethoxy-phenyl

H 1-methylimidazol-5-yl

4-methyl-phenyl

H 2-thiophenyl

2,4-dimethoxy-phenyl

Methyl 2-thiophenyl

2,4-dimethoxy-phenyl

benzyl 2-fury

2,4-dimethoxy-phenyl

H 1-methyl pyrrolyl

2,4-dimethoxy-phenyl

H 2-thiazolyl

2,4-dimethoxy-phenyl

H N-methyl-2-lindolyl

In this description, the above dithiolopyrrolones are referred to as "types of dithiolopyrrolones" according to the invention or by a similar wording, and the individual compounds described herein are referred to as "specific dithiolopyrrolones", "specific compounds", " particular compounds "or" compounds of the invention "or with similar wording.

The present invention also provides a process for the preparation of a compound of the formula shown below:

image 1

in which

Code

X Y Z

BLI-081

2,4-dimethoxy-phenyl H 2-fury

BLI-090

2,4-dimethoxy-phenyl H 2,4-dimethoxy-phenyl

BLI-093

2,4-dimethoxy-phenyl H 4-trifluoromethylphenyl

WBL-007

2,4-dimethoxy-phenyl H 2-thiophenyl

R3

2,4-dimethoxy-phenyl H 3,5-difluorophenyl

R4

2,4-dimethoxy-phenyl H 2,3,4-trifluorophenyl

WBL-018

2,4-dimethoxy-phenyl H 4-fluoro-phenyl

0037

2,4-dimethoxy-phenyl H Thiophene-2-methyl

0038

2,4-dimethoxy-phenyl H 4-nitrophenyl

0040

2,4-dimethoxy-phenyl H 4-N, N-dimethylamino-phenyl

0041

2,4-dimethoxy-phenyl H 4-aminophenyl

0042

2,4-dimethoxy-phenyl H

0043

2,4-dimethoxy-phenyl H

0044

2,4-dimethoxy-phenyl H

0047

2,4-dimethoxy-phenyl H 3-trifluoromethylphenyl

0052

2,4-dimethoxy-phenyl H image 1

0054

4-iso-butylphenyl H 4-trifluoromethylphenyl

0055

4-iso-butylphenyl H 2-fury

0056

4-iso-butylphenyl H 2-thiophenyl

0057

4-iso-butylphenyl H 3-trifluoromethylphenyl

0058

2,4-dimethoxy-phenyl H 3,5-di-trifluoromethylphenyl

0059

4-iso-butylphenyl H 3,5-di-trifluoromethylphenyl

0062

2,4-dimethoxy-phenyl H

0066

2,4-dimethoxy-phenyl H

0068

2,4-dimethoxy-phenyl H

0069

2,4-dimethoxy-phenyl H

0096

4-isopropanylphenyl H 3,5-dihydroxy-4-isopropanyl-phenyl

0102

2,4-dimethoxy-phenyl H 3,5-dihydroxy-4-isopropanyl-phenyl

0107

Benzyl H 3,5-dihydroxy-4-isopropanyl-phenyl

0110

methyl H 3,5-dihydroxy-4-isopropanyl-phenyl

0113

Benzyl H 2-thiophenyl

0116

Benzyl H

0122

2,4-dimethoxy-phenyl methyl

0125

4-isopropanylphenyl H

0126

2,4-dimethoxy-phenyl H

0128

4-isopropanylphenyl H Pyridin-3-yl

0135

Benzyl H Pyridin-3-yl

0136

Benzyl H

0137

Benzyl H

where the procedure follows the synthesis scheme of

image 1

In this invention, it is discovered that different substitutes have large and unpredictable effects on the global anticancer properties of different dithiolopyrrolones. It was found that the introduction of water soluble groups, such as carboxyl groups, polyhydroxyl groups (such as a sugar unit) drastically reduced the anticancer activity of the corresponding unsubstituted compounds. However, another group of recently designed compounds, together with the introduction of water soluble groups, not only have a water solubility

10 significantly improved but, surprisingly, provide enhanced anticancer activity of the corresponding unsubstituted compounds. This unexpected discovery is described in this invention, and allows the inventors to invent different types of dithiolopyrrolones. The types of dithiolopyrrolones and dithiolopyrrolones specific to the subject of

The invention is prepared by the methods described below together with the structure of each dithiolopyrrolone compound for which it is determined, and has been confirmed by its NMR spectroscopy (Nuclear Magnetic Resonance) and MS (Mass Spectroscopy), structural information. Experienced pharmacists may use the procedures described

20 here and others to manufacture these types of specific dithiolopyrrolones and dithiolopyrrolones from commercially available substances. In carrying out such operations, any suitable filtration, chromatography and other purification techniques can be employed by those skilled in the art. A more complete understanding of the invention can be obtained as a reference to the preferred embodiments of the invention, which are illustrated by the following specific examples and methods of the invention. It will be apparent to those skilled in the art that the examples will involve the use of materials and reagents that are commercially

5 available through chemical companies, so no details are given regarding them.

The dithiolopyrrolones form salts, therefore, the compounds of the invention and the types of dithiolopyrrolones of the invention include the salts of the compounds described herein and the types of dithiolopyrrolones described herein. The term "sales" used

10 here indicates acidic and / or basic salts, formed with inorganic and / or organic acids and bases. Suitable acids include, for example, hydrochloric, sulfuric, nitric, benzenesulfonic, acetic, maleic, tartaric and the like, which are pharmaceutically acceptable. Although pharmaceutically acceptable salts are preferred, particularly when the compounds of the invention are used as medicaments, other salts

15 may be useful, for example, in the manufacture of these compounds, or where non-medicated uses are contemplated. The types of dithiolopyrrolones and the particular compounds described herein have a strong antiproliferative activity, in particular, strong activity against a wide range of human cancer cell lines and especially in the

20 treatment of malignant mammary cells. Importantly, they inhibit the growth of leukemia, lung, melanoma, colon, CNS, kidney, prostate, ovarian and breast cancer cell lines. They are also useful against other proliferative diseases, including proliferative blood vessel disorders, and fibrotic disorders such as cancers, tumors,

25 hyperplasias, fibrosis (especially pulmonary fibrosis, but also other types of fibrosis, such as renal fibrosis), angiogenesis, psoriasis, atherosclerosis and proliferation of smooth muscle cells in the blood vessels, such as stenosis or restenosis after angioplasty. The present invention provides compounds for use in the treatment

30 of a mammal affected by cancers or other pro-life diseases sensitive to particular compounds and types of dithiolopyrrolones, which comprises administering to the affected individual a therapeutically effective amount of one of the specific compounds or of a compound selected from the described types of dithiolopyrrolones, one of its salts or one of its pharmaceutical compositions. In

In particular, the compounds and salts thereof of the invention can be used to treat cancers of mammals and other proliferative diseases. The present invention also relates to pharmaceutical compositions containing an active ingredient of these compounds or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable compound or salt selected from a type of dithiolopyrrolone of the invention, as well as with the process for preparation of a

5 pharmaceutical composition of this type.

Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, powders, etc.) or liquid (solutions, suspensions or emulsions) in a composition suitable for oral, topical or parenteral administration. These formulations may contain the pure compound or be

10 in combination with a vehicle or some other pharmaceutically active compound. These compositions may need to be sterile when administered parenterally.

The administration of the described compounds of the invention and the described types of dithiolopyrrolones, and their pharmacologically active and physiologically compatible derivatives, is useful for treating animals or humans that have, for example, leukemia, melanoma, lung cancers, of colon, CNS, kidney, prostate, ovarian, breast and the like using protocols accepted by the National Cancer Institute (NCI). The dose administered will depend on the identity of the cancer or proliferative disease; the type of host involved including their age, health and weight; the type of concurrent treatment, if any; and the frequency of treatment and therapeutic proportion. Illustratively, the dosage levels of the active ingredients administered are intravenous, 0.1 to about 200 mg / kg; intramuscular, 1 to about 500 mg / kg; orally, 1 to about 1,000 mg / kg; intranasal instillation, 1 to about 1,000 mg / kg; and aerosol, 1 to about 1,000 mg / kg of host body weight. Expressed in terms of concentration, an active ingredient may be present in the compositions of the present invention for use located around the skin, intranasally, pharyngolargeal, in the bronchi, in the bronchioles, intravaginally, in a way rectal, or ocular in a concentration from about 0.01% to about 50% weight / weight of the composition; preferably about 1% to about 20% weight / weight of the composition; and for parenteral use in a composition of from about 0.05% to about 50% weight / vol of the composition and, preferably, from about 5% to about 20% weight / vol. The specific compounds and types of dithiolopyrrolones described, used as active ingredients to be used as anti-cancer agents and agents

antiproliferatives, can easily be prepared in a unit dose form of this type with the use of pharmaceutical materials which are available in the art and can be prepared by established procedures.

In alternative aspects of the invention, the compounds of the invention

5 can be used in treatments of cancers susceptible to such compounds, including both primary and metastatic solid tumors, including carcinomas of the breast, colon, rectum, lung, oropharynx, hypopharynx, esophagus, stomach, pancreas, liver, gallbladder and bile ducts, small intestine, urinary tract (including the kidney, the veille and the urothelium), female genital tract (including

10 the cervix, uterus and ovaries as well as choriocarcinoma and trophoblastic disease), male genital apparatus (including prostate tumor, seminal vesicles, testicles and reproductive cells), endocrine glands (including glands thyroid, adrenal and pituitary) and the skin, as well as hemangiomas, melanomas, sarcomas (including those that originate in the bones and

15 soft tissues as well as Kaposi's sarcoma) and tumors of the brain, nerves, eyes and meninges (including astrocytomas, gliomas, glioblastomas, retinoblastomas, neuromas, neuroblastomas, Schwannomas and meningiomas).

In some aspects of the invention, the types of dithiolopyrrolones and compounds of the invention are useful in the treatment of proliferative diseases that originate in hematopoietic malignant tumors such as leukemias (i.e., chloromas, plasmacytomas, and fungoid mycosis plaques and tumors). and cutaneous T-cell lymphoma leukemia) as well as in the treatment of lymphomas (both Hodgkin and non-Hodgkin lymphoma). In addition, the types of dithiolopyrrolone and compounds of the invention are useful in preventing metastasis of the described tumors.

25 above when used alone or in combination with radiotherapy and / or other chemotherapeutic agents. In some aspects of the invention, the types of dithiolopyrrolone and compounds of the invention are useful in the treatment of other proliferative diseases such as proliferative blood vessel disorders, and fibrotic disorders.

30 such as cancers, tumors, hyperplasia, fibrosis (especially pulmonary fibrosis, but also other types of fibrosis, such as renal fibrosis), angiogenesis, psoriasis, atherosclerosis and proliferation of smooth muscle cells in blood vessels, such as stenosis or restenosis after angioplasty and proliferative skin diseases, such as psoriasis.

35

EXAMPLE 1 The antiproliferative activity of a particular dithiolopyrrolone can be demonstrated by standard tests. These tests are normally used by

5 experts in the art and are accepted as indicative of antiproliferative activity in mammals. The antiproliferative activities of the compounds of the invention have been determined in human ovarian cancer cell cultures, using a standard antiproliferative test of the National Cancer Institute (NCI) of the United States [Monks, A. et al., J. Natl. Cancer Inst. 83 (11): 757-766, 1991].

The compounds in this example are species of Formula 1 that show superior antiproliferative activity against the ovcar-3 cell line of ovarian proliferative cancer (Table 1) compared to a dithiolopyrrolone, XN3, which was described in US documents. 6020360 and WO 99012543 with antiproliferative activities. The result showed that these new dithiolopyrrolones have a

15 anti-proliferative activity much stronger than XN3. The new compound had activity against 56 cancerous cell lines from a wide range of major cancers (Table 1a).

Table 1a. Anti-proliferative activity of new compounds compared to 20 XN3 against ovcar-3 ovarian cancer cells.

Compounds

IC50 ( image2 M)

BLI-093 (BLI093)

0.054

0037 (JS-02)

0.071

0038 (JS-03)

0.068

0058 (JS-38)

0.034

WBL-007 (WBI007)

0.028

WBL-018

0.070

R3 (WBL-R3)

0.078

R4 (WBL-R4)

0.046

XN3 (Reference Example)

0.22

Table 1a. Anti-proliferative activity of the new compound 0058 (JS-38) against 56 lines of cancer cells.

25

PROLIFERATIVE CELLS

IC50 ( image2 M)

Leukemia

CCRF-CEM

0.01 <

HL-60TB

0.019

K-562

0.019

MOLT-4

0.15

RPMI-8226

0.01 <

MR

0.02

Amicrocytic lung carcinomas

A549 / ATCC

0.42

EKVX

0.13

HOP-62

0.13

HOP-92

0.18

NCI-H226

0.27

NCI-H23

0.21

NCI-H322M

8.56

NCI-H460

0.26

NCI-H522

0.19

Colon cancer

COLO 205

0.15

HCC-2998

0.11

HCT-116

0.016

HCT-15

0.02

HT29

0.05

KM12

2.97

SW-620

0.034

CNS cancer

SF-268

0.14

SF-295

0.23

SF-539

0.18

SNB-19

0.23

U251

0.15

Melanoma

LOX IMVI

0.014

MALME-3M

0.19

M14

0.24

SK-MEL-2

0.18

SK-MEL-28

0.016

SK-MEL-5

0.12

UACC-257

0.15

UACC-62

0.19

Ovarian cancer

IGROV1

0.17

OVCAR-3

0.03

OVCAR-5

0.45

OVCAR-8

0.17

Kidney cancer

786-0

0.06

A498

0.19

ACHN

0.14

CAKI-1

0.44

RXF 393

0.04

SN12C

0.12

TK-10

1.37

UO-31

0.20

Prostate cancer

PC-3

0.04

DU-145

0.013

Breast cancer

MCF7

0.17

NCI / ADR-RES

1.04

MDA-MB-231 / ATCC

0.13

HS 578T

0.22

MDA-MB-435

0.22

BT-549

0.15

T-47D

0.013

EXAMPLE 2

The compounds shown in Table 2 were tested against the strain of H460 cancer cells as set forth in Example 1, the results showed that the anti-proliferative activity varied widely between derivatives with different modifications of the dithiolopyrrolone base structure.

Table 2. Anti-proliferative activity of compounds together with other dithiolopyrrolones against lines of H460 and LCC6 cancer cells.

Compound

IC50 (µM)

H460

0024 (Ex. Of Ref.)

0.26

0066

<0.01

0068

<0.01

0069

0.04

WBI-4

<0.01

WBI-5

<0.01

WBI-6

0.046

0136

0.092

BLI-031-2 (Ex. Of Ref.)

> 50

0044

> 1

JS-26 (Ex. Of Ref.)

> 1

EXAMPLE 3

The compounds of the present invention

be prepare according with he

10

following synthesis scheme (Scheme 1):

image 1

Intermediates prepared in accordance with the previous procedure of the synthesis scheme (Scheme 1) and used in the subsequent synthesis are listed in the following table.

Intermediate product

X Y Z

1 and 2

to 2,4-dimethoxy-phenyl

b

1-ethylpyrazol-5-yl

C

3,4,5-trimethoxy-phenyl

d

Benzyl

and

phenyl

F

4-methylphenyl

g

4-methoxyphenyl

h

4-isobutylphenyl

i

4-isopropanyl-phenyl

j

methyl

3

to 2,4-dimethoxy-phenyl H

b

1-ethylpyrazol-5-yl H

C

3,4,5-trimethoxy-phenyl H

d

benzyl H

and

phenyl H

F

4-methylphenyl H

g

4-methoxyphenyl H

h

4-isobutylphenyl H

i

4-isopropanylphenyl H

j

methyl H

k

H H

l

4-methoxyphenyl benzyl

m

4-hydroxyphenyl benzyl

n

2,4-dimethoxy-phenyl Methyl

4

to 2,4-dimethoxy-phenyl H acetyl

b

2,4-dimethoxy-phenyl H nicotinoyl

C

2,4-dimethoxy-phenyl H trifluoroacetyl

d

2,4-dimethoxy-phenyl Methyl methyl

and

2,4-dimethoxy-phenyl Methylsulfonyl methylsulfonyl

F

2,4-dimethoxy-phenyl 2-thiophenecarbonyl 2-thiophenecarbonyl

g

2,4-dimethoxy-phenyl H �-hydroxyacetyl

h

H H nicotinoyl

i

4-methoxyphenyl acetyl Acetyl

j

4-methoxyphenyl H trifluoroacetyl

k

4-methoxyphenyl trifluoroacetyl Benzyl

l

4-hydroxyphenyl trifluoroacetyl benzyl

m

3,4,5-trimethoxy-phenyl H acetyl

n

4-methylphenyl H acetyl

or

1-ethylpyrazol-5-yl H trifluoroacetyl

p

4-methoxyphenyl H acetyl

that

4-isobutylphenyl H trifluoroacetyl

r

4-isopropanylphenyl H trifluoroacetyl

s

Methyl H trifluoroacetyl

t

Benzyl H trifluoroacetyl

or

2-4-dimethoxy-phenyl methyl trifluoroacetyl

Detailed Synthesis:

Synthesis of compounds 1a-j. To a well stirred solution of 1,3-bis (t-butyl) -acetone (10 mmol), R1NH2 (10 mmol) and triethylamine Et3N (20 mmol) in dry THF (100 mL), a solution of TiCl4 (5, 5 mmol) in 15 ml of dry hexanes solution dropwise in 30 min at 0-5 ° C under N2. After the addition, the

Reaction mixture was refluxed for 2 hours. The imine compounds thus obtained were used in the next step without purification of compound 1. Synthesis of compounds 2a-j. At -10 ° C, oxalyl chloride (0.84 ml, 10 mmol) was added to the solution obtained in the previous step. At the same temperature and with

With stirring, Et3N (20 mmol) in 100 mmol of THF was added dropwise in 30 min. Then, the solution was stirred at room temperature for 10 hours. The precipitate was filtered and washed with ether (250 ml). The organic solution was washed three times with water and the solvent was evaporated to give a dark brown powder. It was recrystallized from ethyl acetate and hexanes to give a light yellow crystal of compound 2. All

10 compounds 2a-j can be prepared in the same way as described in these two stages. The total yield of these two stages for each of the compounds was approximately 60-70%.

Synthesis of compounds 3a-k. A 250 ml three-mouth flask with 50 g of ammonium acetate was heated in an oil bath under N2 to molten NH4 + OAc. Compound 2 (5 mmol) was added to the flask and the resulting solution was stirred for one hour. The reaction temperature was between 140 ° C and 165 ° C depending on the properties of compound 2. An hour later, heating was stopped and the reaction mixture was cooled to room temperature. The reaction mixture was dissolved in 100 ml of water and extracted three times with 100 ml of ether. The extracts are

20 combined, dried over Na2SO4 and evaporated under reduced pressure. The residue was chromatographed on a silica gel column to give compound 3. The yields for 3a-i were about 50-60%. Compound 3k was obtained as a byproduct in the preparations of compounds 3a-j and their yields depended on the reaction temperature and the duration of the reaction time.

Synthesis of compounds 3l and 3m. A 150 ml flask with 30 g of benzylamine acetate and 2 g (2 mmol) of Compound 2 was heated at 170 ° C under N2. The mixture was stirred at this temperature for about an hour. When cooled, 50 ml of water was added and extracted twice with 50 ml of ether. The organic solvent was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified

30 with silica gel. Two 3l and 3m compounds were obtained with yields of 25% and 15% respectively. Synthesis of 3n compounds. A 100 ml flask with 20 g of methylamine acetate and compound 2a (1 mmol) was heated at 170 ° C under N2. The mixture was stirred at this temperature for about an hour. When cooled, they were added

50 ml of water and extracted twice with 50 ml of ether. The organic solvent was dried

over Na2SO4 and evaporated under reduced pressure. The residue was purified with silica gel. 3n was obtained with a yield of 40%. Synthesis of 4th. To a well stirred solution of 200 mg (0.474 mmol) of 3a in 10 ml of acetic anhydride, 20 mg of concentrated H2SO4 was added. Half an hour

5 The solution was then transferred to a silica gel column and developed with 200 ml of CH2Cl2, then with 500 ml of 20% ether in CH2Cl2 to give 190 mg (0.41 mmol, 86%) of 4a.

Synthesis of 4b. A solution of 100 mg (0.24 mmol) of 3a, 200 mg (1.12 mmol) of nicotinoyl chloride hydrochloride and 250 mg (2.47 mmol) of triethylamine,

10 in 10 ml of THF, stirred for 24 hours at room temperature. Then 50 ml of ether was added and the solution was washed three times with water. After drying over Na2SO4, the solvent was evaporated and the residue was purified on a silica gel column to give 90 mg (0.171 mmol, 72%) of 4b. Synthesis of 4c. To a solution of 100 mg (0.24 mmol) of 3a in 5 ml of

Dichloromethane was added 300 mg of trifluoroacetic anhydride. The resulting solution was stirred for half an hour and then the solvent was evaporated under reduced pressure to give 122 mg (0.237 mmol, 100%) of 4c.

4d synthesis. In 5 ml of acetonitrile, 211 mg (0.5 mmol) of 3a and 1 ml of formalin were mixed with 100 mg of NaCNBH3. While stirring, 0.1 ml of glacial acetic acid was added dropwise over about 30 minutes. This reaction mixture was stirred for 4 hours and in the middle of the reaction another 0.1 ml of glacial acetic acid was added. It was diluted with 50 ml of ether and extracted with 1N NaOH, as well as with water. After drying, it was evaporated in vacuo and the residue was chromatographed on a silica gel column to obtain 150 mg (0.33 mmol) of 4d in a yield.

25 of 67%. Synthesis of 4e. To a solution of 100 mg (0.24 mmol) of 3a and 300 mg of methylsulfonyl chloride in 5 ml of dry THF, 300 mg of triethylamine was added dropwise at room temperature in one minute. This solution was stirred for half an hour and 50 ml of ether was added and the solution was washed three times with water.

After it was dried over Na2SO4, the solvent was evaporated and the residue was chromatographed on a silica gel column to give 110 mg (0.19 mmol, 80%) of 4e. Synthesis of 4f. A solution of 100 mg (0.24 mmol) of 3a, 200 mg (1.37 mmol) of 2-thiophenecarbonyl chloride and 200 mg (1.98 mmol) of trimethylamine in 10 ml of THF was refluxed for 10 hours. Then, 50 ml of ether and the

35 solution was washed three times with water. After drying over Na2SO4, the solvent was

evaporated and the residue was chromatographed on a silica gel column to give 120 mg (0.187 mmol, 79%) of 4f. 4g synthesis. A solution of 100 mg (0.24 mmol) of 3a, 118 mg (1.0 mmol) of acetoxyacetyl chloride and 120 mg (1.19 mmol) of triethylamine, in 10 ml of THF, is

5 stirred for 24 hours at room temperature. Then, 50 ml of ether was added and the solution was washed three times with water. The solvent was evaporated and the residue was dissolved in a solution of 1 ml of 0.1 N sodium hydroxide in 10 ml of ethanol. This solution was stirred for 1 hour. After the solvent was evaporated under reduced pressure, the residue was chromatographed on a silica gel column to give 105 mg (0.22

10 mmol, 91%) of 4g. Synthesis of 4h. A solution of 100 mg (0.35 mmol) of 3i, 250 mg (1.40 mmol) of nicotinoyl chloride hydrochloride and 350 mg (3.46 mmol) of triethylamine, in 10 ml of THF, was stirred for 24 hours at room temperature. Then, 50 ml of ether was added and the solution was washed three times with water. Then it was dried over Na2SO4,

The solvent was evaporated and the residue was chromatographed on a silica gel column to give 100 mg (0.256 mmol, 73%) of 4h. Synthesis of 4i. A solution of 100 mg (0.255 mmol) of 3g, 100 mg (1.28 mmol) of acetyl chloride and 260 mg (2.56 mmol) of triethylamine, in 10 ml of THF, was stirred at 50 ° C for 12 hours. Then, 50 ml of ether was added and the solution was

20 washed three times with water. After drying over Na2SO4, the solvent was evaporated and the residue was chromatographed on a silica gel column to give 110 mg (0.231 mmol, 90%) of 4i.

Synthesis of 4j. To a solution of 100 mg (0.255 mmol) of 3g in 5 ml of dichloromethane was added 300 mg of trifluoroacetic anhydride. The solution was stirred for half an hour and then the solvent was evaporated under reduced pressure to give

125 mg (0.255 mmol, 100%) of 4j.

4k synthesis. To a solution of 50 mg (0.104 mmol) of 3 l in 5 ml of dichloromethane 150 mg of trifluoroacetic anhydride was added. The solution was stirred for half an hour and then the solvent was evaporated under reduced pressure to give 60

30 mg (0.104 mmol, 100%) of 4k. Synthesis of 4l. To a solution of 50 mg (0.107 mmol) of 3m in 5 ml of dichloromethane was added 200 mg of trifluoroacetic anhydride. The solution was stirred for half an hour and then the solvent was evaporated under reduced pressure to give 60 mg (0.107 mmol, 100%) of 4L.

35 Synthesis of 4m. A solution of 100 mg (0.22 mmol) of 3c, 70 mg (0.9 mmol) of acetyl chloride and 100 mg (0.99 mmol) of triethylamine, in 10 ml of THF, was stirred at room temperature for 24 hours. Then, 50 ml of ether was added and the solution was washed three times with water. After drying over Na2SO4, the solvent was evaporated and the residue was chromatographed on a silica gel column to give 80 mg (0.162 mmol, 73%) of 4m.

5 Synthesis of 4n. A solution of 100 mg (0.266 mmol) of 3f, 70 mg (0.9 mmol) of acetyl chloride and 100 mg (0.99 mmol) of triethylamine, in 10 ml of THF, was stirred at room temperature for 24 hours . Then, 50 ml of ether was added and the solution was washed three times with water. After drying over Na2SO4, the solvent was evaporated and the residue was chromatographed on a silica gel column to give 90 mg.

10 (0.215 mmol, 81%) of 4n. Synthesis of 4th. To a solution of 80 mg (0.210 mmol) of 3b in 5 ml of dichloromethane was added 300 mg of trifluoroacetic anhydride. The solution was stirred for half an hour and then the solvent was evaporated under reduced pressure to give 100 mg (0.210 mmol, 100%) of 4 °.

15 Synthesis of 4p. A solution of 100 mg (0.255 mmol) of 3g, 50 mg (0.64 mmol) of acetyl chloride and 130 mg (1.28 mmol) of triethylamine, in 10 ml of THF, was stirred at 25 ° C for 24 hours. Then, 50 ml of ether was added and the solution was washed three times with water. After drying over Na2SO4, the solvent was evaporated and the residue was chromatographed on a silica gel column to give 90 mg (0.19 mmol, 70%) of

20 4p. Synthesis of 4q. To a solution of 100 mg (0.24 mmol) of 3h in 5 ml of dichloromethane was added 300 mg of trifluoroacetic anhydride. The solution was stirred for half an hour and then the solvent was evaporated under reduced pressure to give 120 mg (0.24 mmol, 100%) of 4q.

25 Synthesis of 4th. To a solution of 50 mg (0.124 mmol) of 3L in 5 ml of dichloromethane was added 200 mg of trifluoroacetic anhydride. The solution was stirred for half an hour and then the solvent was evaporated under reduced pressure to give 57 mg (0.124 mmol, 100%) of 4r. Synthesis of 4s. At a solution of 50 mg of 3 l in 5 ml of dichloromethane,

30 added 200 mg of trifluoroacetic anhydride. The solution was stirred for half an hour and then the solvent was evaporated under reduced pressure to give 66 mg of 4s. Yield: 100%

Synthesis of 4t. To a solution of 50 mg of 3d in 5 ml of dichloromethane 200 mg of trifluoroacetic anhydride were added. The solution was stirred for half an hour and then the solvent was evaporated under reduced pressure to give 65 mg of 4t.

Yield: 100%

Synthesis of 4u. To a solution of 50 mg of 3n in 5 ml of dichloromethane was added 200 mg of trifluoroacetic anhydride. The solution was stirred for half an hour and then the solvent was evaporated under reduced pressure to give 62 mg of 4u. Yield: 100%

Using these intermediates, the compounds of the Table were prepared

3. Table 3. New dithiolopyrrolone derivatives (* = Reference Example)

Code

X Y Z

BLI-017 *

4-methoxyphenyl H Methyl

BLI-020 *

4-methoxyphenyl Acetyl Methyl

BLI-023 *

4-methoxyphenyl H Trifluoromethyl

BLI-031-2 *

2,4-dimethoxy-phenyl H -CH2CH2COOH

BLI-038 *

4-methoxyphenyl H Methyl

BLI-044 *

4-methoxyphenyl Benzyl Trifluoromethyl

BLI-045 *

4-hydroxyphenyl Benzyl Trifluoromethyl

BLI-053 *

2,4-dimethoxy-phenyl H Methyl

BLI-063 *

3,4,5-trimethoxyphenyl H Methyl

BLI-065 *

2,4-dimethoxy-phenyl H 3-pyridyl

BLI-066

2,4-dimethoxy-phenyl H N-methyl-3-pyridinium chloride

BLI-075 *

2,4-dimethoxy-phenyl H Trilfuoromethyl

BLI-079 *

1-ethylpyrazol-5-yl H Trilfuoromethyl

BLI-081

2,4-dimethoxy-phenyl H 2-fury

BLI-090

2,4-dimethoxy-phenyl H 2,4-dimethoxy-phenyl

BLI-093

2,4-dimethoxy-phenyl H 4-trifluoromethylphenyl

WBL-004

2,4-dimethoxy-phenyl 2-thiophenylcarboxy 2-thiophenyl

WBL-007

2,4-dimethoxy-phenyl H 2-thiophenyl

R1 *

2,4-dimethoxy-phenyl H Hydroxymethyl

R2 *

2,4-dimethoxy-phenyl H hexyl

R3

2,4-dimethoxy-phenyl H 3,5-difluorophenyl

R4

2,4-dimethoxy-phenyl H 2,3,4-trifluorophenyl

WBL-018

2,4-dimethoxy-phenyl H 4-fluoro-phenyl

0037

2,4-dimethoxy-phenyl H Thiophene-2-methyl

0038

2,4-dimethoxy-phenyl H 4-nitrophenyl

0039 *

2,4-dihydroxyphenyl H methyl

0040

2,4-dimethoxy-phenyl H 4-N, N-dimethylamino-phenyl

0041

2,4-dimethoxy-phenyl H 4-aminophenyl

0042

2,4-dimethoxy-phenyl H

0043

2,4-dimethoxy-phenyl H

0044

2,4-dimethoxy-phenyl H

0047

2,4-dimethoxy-phenyl H 3-trifluoromethylphenyl

0052

2,4-dimethoxy-phenyl H image 1

JS-26 *

2,4-dimethoxy-phenyl H image 1

0054

4-iso-butylphenyl H 4-trifluoromethylphenyl

0055

4-iso-butylphenyl H 2-fury

0056

4-iso-butylphenyl H 2-thiophenyl

0057

4-iso-butylphenyl H 3-trifluoromethylphenyl

0058

2,4-dimethoxy-phenyl H 3,5-di-trifluoromethylphenyl

0059

4-iso-butylphenyl H 3,5-di-trifluoromethylphenyl

0062

2,4-dimethoxy-phenyl H

0066

2,4-dimethoxy-phenyl H

0068

2,4-dimethoxy-phenyl H

0069

2,4-dimethoxy-phenyl H

WBI-4

4-isopropylphenyl H

WBI-5

4-isobutylphenyl H

WBI-6

Methyl H image 1

0096

4-isopropanylphenyl H 3,5-dihydroxy-4-isopropanyl-phenyl

0102

2,4-dimethoxy-phenyl H 3,5-dihydroxy-4-isopropanyl-phenyl

0107

Benzyl H 3,5-dihydroxy-4-isopropanyl-phenyl

0110

Methyl H 3,5-dihydroxy-4-isopropanyl-phenyl

0113

Benzyl H 2-thiophenyl

0116

Benzyl H

0122

2,4-dimethoxy-phenyl methyl

0125

4-isopropanylphenyl H

0126

2,4-dimethoxy-phenyl H

0128

4-isopropanylphenyl H Pyridin-3-yl

0135

Benzyl H Pyridin-3-yl

0136

Benzyl H

0137

Benzyl H

CSL-25 *

Phenyl H Methyl

CSL-26 *

Benzyl H Phenyl

CSL-28 *

H H 3-pyridyl

2,4-dimethoxy-phenyl

H 2- (2-thiophenyl) -vinyl

2,4-dimethoxy-phenyl

H 1-methylimidazol-5-yl

4-methyl-phenyl

H 2-thiophenyl

*

H H 2-thiophenyl

*

H Methyl 2-thiophenyl

2,4-dimethoxy-phenyl

Methyl 2-thiophenyl

2,4-dimethoxy-phenyl

benzyl 2-fury

2,4-dimethoxy-phenyl

H 1-methyl pyrrolyl

*

Cyclohexyl H phenyl

*

benzyl H phenyl

*

H cyclohexyl phenyl

*

H 2-thiazolyl phenyl

2,4-dimethoxy-phenyl

H 2-thiazolyl

2,4-dimethoxy-phenyl

H propyl

2,4-dimethoxy-phenyl

H N-methyl-2-lindolyl

Synthesis of BLI-017. A solution of 90 mg (0.19 mmol) of 4p and 6.8 mg (0.19 mmol) of Hg (OAc) 2 in 10 ml of TFA was stirred at room temperature for one hour. Then, the TFA was evaporated under reduced pressure, the residue was dissolved in 100 ml

5 of CH3CN, SH2 was bubbled into the solution. An hour later, N2 was bubbled into the solution to remove traces of SH2, then 0.20 mmol of I2 in 10 ml of CH2Cl2 was added to the solution. Half an hour later, the solvent was evaporated under reduced pressure and the residue was chromatographed on a silica gel column to give 43 mg of BLI-017. Yield: 67%. 1H NMR (100 MHz, CDCl3) �2.2 (s, 3H), 3.9 (s, 3H),

10 6.7 (s, 1H), 7.0-7.4 (dd, 4H), 7.8 (s, 1H). Synthesis of BLI-020. BLI-020 was synthesized from 4l by the same method of synthesis as BLI-017. Yield: 60%. 1H NMR (100 MHz, CDCl3) �2.5 (s, 6H), 3.9 (s, 3H), 6.95 (s, 1H), 7.0-7.5 (dd, 4H), MS (IC): 363 (M + 1).

Synthesis of BLI-023. BLI-023 was synthesized from 4j by the same method of synthesis of BLI-017. Yield: 75%. 1H NMR (100 MHz, CDCl3) �3.9 (s, 3H), 6.82 (s, 1H), 7.0-7.4 (dd, 4H), 8.3 (s, 1H).

Synthesis of BLI-038. BLI-038 was synthesized from 4n by the same method of synthesis as BLI-017. Yield: 70%. 1H NMR (100 MHz, CDCl3) �2.1 (s, 3H), 2.4 (s, 3H), 6.7 (s, 1H), 7.3 (s, 4H), 8.0 (s , 1 HOUR).

20 Synthesis of BLI-044. BLI-044 was synthesized from 4k by the same method of synthesis as BLI-017. Yield: 72%. 1H NMR (100 MHz, CDCl3) �3.9 (s, 3H), 4.2-5.8 (dd, 2H), 6.9 (s, 1H), 7.0-7.4 (dd, 4H), 7.4 (s, 5H). MS (CI): 465 (M + 1).

Synthesis of BLI-045. BLI-045 was synthesized from 4l by the same method of synthesis as BLI-017. Yield: 65%. 1H NMR (100 MHz, CDCl3) �4.2-5.8 (dd, 25 2H), 6.6 (s, 1H), 7.1-7.5 (wide peak, 9H), 7.4 ( s, 5H).

Synthesis of BLI-053. BLI-053 was synthesized from 4 by the same method of synthesis of BLI-017. Yield: 77%. 1H NMR (100 MHz, CDCl3) �3.77 (s, 3H), 3.82 (s, 3H), 6.6 (s, 1H), 6.4-7.3 (multi, 3H), 8 , 0 (wide peak, 1H). MS: 350 (M).

Synthesis of BLI-063. BLI-063 was synthesized from 4m by the same method of synthesis of BLI-017. Yield: 55%. 1H NMR (100 MHz, CDCl3) �3.8 (s, 6H), 3.9 (s, 3H), 6.7 (s, 1H), 7.4 (s, 2H), 7.9 (peak wide, 1H). MS: 380 (M).

Synthesis of BLI-065. BLI-065 was synthesized from 4b by the same method of synthesis as BLI-017. Yield: 45%. 1H NMR (100 MHz, CD3OD) �3.8 (s, 3H), 3.9 (s, 3H), 6.7 (s, 1H), 6.6-9.2 (multi, 7H).

Synthesis of BLI-066. 10 mg (0.024 mmol) of BLI-065 was dissolved in 1 ml of

5 CH3I and the solution was left at room temperature for 10 hours. In the solution, red crystals formed which were filtered and 9 mg (0.016 mmol) of BLI-066 were obtained in 67% yield. 1H NMR (100 MHz, CD3OD) �3.7 (s, 3H), 3.8 (s, 3H), 4.4 (s, 3H), 6.9 (s, 1H), 6.5-9 , 4 (multi, 7H).

Synthesis of BLI-075. BLI-075 was synthesized from 4c by the same method of synthesis of BLI-017. Yield: 83%. 1H NMR (100 MHz, CDCl3) �3.8 (s, 3H), 3.9 (s, 3H), 6.6 (multi, 3H), 7.2 (d, 1H), 8.4 (s , 1 HOUR). MS: IC 405 (M + 1).

Synthesis of BLI-079. BLI-079 was synthesized from 4o by the same method of synthesis of BLI-017. Yield: 6.6%. 1H NMR (100 MHz, CDCl3) �1.5 (t, 3H), 4.0 (q, 2H), 6.3 (d, 1H), 6.9 (s, 1H), 7.7 (d , 1H), 8.4 (s, 1H). MS: IC 363 (M + 1).

15 Synthesis of 0024. 0024 was synthesized from 4d by the same method of synthesis of BLI-017. Yield: 19%. 1H NMR (100 MHz, CDCl3) �2.6 (s, 6H), 3.8 (s, 3H), 3.9 (s, 3H), 6.4 (s, 1H), 6.5 (multi , 2H), 7.2 (d, 1H). MS: 337 (M + 1).

Synthesis of WBL-004. WBLI-004 was synthesized from 4f by the same method of synthesis as BLI-017. Yield: 43%. 1H NMR (100 MHz, CDCl3) �3.8 (s, 20 3H), 3.9 (s, 3H), 6.5 (s, 1H), 6.65 (multi, 4H), 7.2 ( multi, 2H), 7.7 (multi, 3H). MS: 529

(M + 1).

Synthesis of R1. R1 was synthesized from 4g by the same method of synthesis as BLI-017. Yield: 41%. 1H NMR (100 MHz, CDCl3) �3.8 (s, 3H), 3.9 (s, 3H), 4.3 (s, 2H), 6.5 (s, 1H), 6.65 (multi , 2H), 7.2 (d, 1H), 8.35 (s, 1H). MS: 367 (M + 1).

25 Synthesis of CSL-25. The CSL-25 was synthesized using the procedure of Scheme 1. CSL-25 has the following characteristics: 1H NMR (100 MHz, CDCl3)

,22.2 (s, 3H), 6.8 (s, 1H), 7.4-7.6 (multi, 5H), 7.8 (s, 1H). Synthesis of CSL-26. CSL-26 was synthesized using the procedure of Scheme 1. CSL-26 has the following characteristics: 1H NMR (100 MHz, CDCl3) 30 �5.1 (s, 2H), 6.5 (s, 1H), 7 , 2-8.0 (multi, 10H), 8.3 (s, 1H).

Synthesis of CSL-28. The CSL-28 was synthesized from 4h by the same synthesis method as BLI-017. Yield: 43%. 1H NMR (100 MHz, CDCl3) �6.8 (s, 1H), 7.9 (s, 3H), 8.1-9.2 (multi, 4H). MS: IC, 278 (M + 1).

Synthesis of 0050. 0050 was synthesized from 4q by the same method of synthesis as BLI-017. Yield: 80%. 1H NMR (100 MHz, CDCl3) �0.9 (t, 3H), 1.38 (d, 3H), 1.65 (multi, 2H), 2.7 (multi, 1H), 6.9 (s , 1H), 7.3 (s, 4H), 8.4 (s, 1H).

Synthesis of 0061. 0061 was synthesized from 4s by the same method of synthesis of BLI-017. Yield: 82%. 1H NMR (100 MHz, CDCl3) �2.8 (s, 3H), 6.6 (s, 1H), 8.4 (s, 1H).

Synthesis of 0092. 0092 was synthesized from 4r by the same method of synthesis of BLI-017. Yield: 77%. 1H NMR (100 MHz, CDCl3) �1.26 (d, 6H), 3.0 (multi, 1H), 6.7 (s, 1H), 7.35 (s, 4H), 8.6 (s , 1 HOUR).

10 Synthesis of 0103. 0103 was synthesized from 4t by the same method of synthesis as BLI-017. Yield: 85%. 1H NMR (100 MHz, CDCl3) 4.3 (s, 2H), 6.6 (s, 1H), 7.3 (s, 5H), 8.4 (s, 1H).

Synthesis of 0119. 0119 was synthesized from 4u by the same method of synthesis as BLI-017. Yield: 85%. 1H NMR (100 MHz, CDCl3) �2.7 (s, 3H), 3.8 (s, 15 3H), 3.85 (s, 3H), 6.55 (s, 1H), 6.6 ( multi, 2H), 7.2 (d, 1H), 8.4 (s, 1H).

EXAMPLE 4 The following compounds of Examples 1-3 are prepared according to the following synthesis scheme (Scheme 2):

twenty

image 1

Scheme 2

According to this scheme the following intermediate products are synthesized

Code

X Y

0021

2,4-dimethoxy-phenyl H

0051

4-isobutylphenyl H

0079

Methyl H

0093

4-isopropanyl-phenyl H

0104

Benzyl H

0120

2,4-dimethoxy-phenyl Methyl

Detailed Synthesis:

5 Synthesis of 0021. 1 g of BLI-075 was dissolved in a solution of 5 ml of hydrochloric acid in 150 ml of methanol. The solution was refluxed for 2 hours. After the solvent was evaporated in vacuo, 0.76 g of 0021 was collected as a dark green powder.

Synthesis of BLI-081. 50 mg (0.16 mmol) of 0021 was dissolved in 20 ml of

10 dry THF. While stirring vigorously, 43 mg (0.32 mmol) of 2-furoyl chloride was added first, then 50 mg of triethylamine was added dropwise over more than 2 minutes. The reaction was completed in half an hour and the product was purified by a silica gel column to give 51 mg (0.12 mmol, 80%) of BLI-081. 1H NMR (100 MHz, CDCl3) �3.8 (s, 3H), 3.9 (s, 3H), 6.5 (s, 1H), 6.6 (multi s,

15 3H), 7.2 (multi, 2H), 7.6 (d, 1H), 8.4 (s, 1H). MS: 403 (M + 1). Synthesis of BLI-090. BLI-090 was synthesized by reaction of 0021 with 2,4-dimethoxy-benzoyl chloride by the same method of synthesis of BLI-081. Yield: 89%. 1H NMR (100 MHz, CDCl3) �3.8 (s, 3H), 3.9 (s, 3H), 3.93 (s, 3H), 4.07 (s, 3H), 6.4 (s , 1H), 6.6 (multi, 4H), 7.2 (d, 1H), 8.2 (d, 1H), 10.2 (s, 1H). MS: 473 (M + 1).

20 Synthesis of BLI-093. BLI-093 was synthesized by reaction of 0021 with 4-trifluoromethyl-benzoyl chloride by the same method of synthesis of BLI-081. Yield: 90%. 1H NMR (100 MHz, CDCl3) �3.8 (s, 3H), 3.9 (s, 3H), 6.5 (s, 1H), 6.6 (multi, 2H), 7.25 (d , 1H), 7.8 (d, 2H), 8.1 (d, 2H), 8.4 (s, 1H). MS: 480 (M). Synthesis of WBL-007. WBL-007 was synthesized by reaction of 0021 with

2-thiophenecarbonyl chloride by the same method of synthesis of BLI-081. Yield: 88%. 1H NMR (100 MHz, CDCl3) �3.8 (s, 3H), 3.9 (s, 3H), 6.55 (s, 1H), 6.63 (multi, 2H), 7.2 (multi , 2H), 7.7 (multi, 2H). MS: 418 (M). Synthesis of R2 (Ex. Of Ref.). R2 was synthesized by reaction of 0021 with heptanoyl chloride by the same method of synthesis as BLI-081. Yield: 74%. NMR

1H (100 MHz, CDCl3) �0.9 (t, 3H), 1.4 (multi, 8H), 2.4 (t, 2H), 3.8 (s, 3H), 3.9 (s, 3H), 4.3 (s, 2H), 6.6 (s, 1H), 6.65 (multi, 2H), 7.2 (d, 1H), 8.4 (s, 1H). MS: 420 (M).

Synthesis of R3. R3 was synthesized by reaction of 0021 with 3,4difluorobenzoyl chloride by the same method of synthesis as BLI-081. Yield: 81%. 5 1H NMR (100 MHz, CDCl3) �3.8 (s, 3H), 3.9 (s, 3H), 6.5 (s, 1H), 6.6 (multi, 2H), 7.1 ( multi,

2H), 7.5 (multi, 2H), 8.4 (s, 1H). MS: 448 (M).

Synthesis of R4. R4 was synthesized by reaction of 0021 with 2,3,4trifluorobenzoyl chloride by the same method of synthesis as BLI-081. Yield: 84%. 1H NMR (100 MHz, CDCl3) �3.8 (s, 3H), 3.9 (s, 3H), 6.5 (s, 1H), 6.6 (multi, 2H), 7.2 (multi ,

10 2H), 7.9 (multi, 1H), 8.6 (s, 1H). MS: 466 (M). Synthesis of WBL-018. WBL-018 was synthesized by reaction of 0021 with 4-fluorobenzoyl chloride by the same method of synthesis as BLI-081. Yield: 85%. 1H NMR (100 MHz, CDCl3) �3.8 (s, 3H), 3.9 (s, 3H), 6.5 (s, 1H), 6.65 (multi, 2H), 7.1 (multi , 2H), 7.5 (multi, 2H), 8.4 (s, 1H). MS: 430 (M).

Synthesis of 0037. 0037 was synthesized by reaction of 0021 with thiophenyl acetyl chloride by the same method of synthesis of BLI-081. Yield: 81%. 1H NMR (100 MHz, CDCl3) �3.75 (s, 3H), 3.85 (s, 3H), 3.9 (s, 2H), 6.42 (s, 1H), 6.55 (multi , 2H), 7.1-7.3 (multi, 4H), 8.2 (s, 1H). Synthesis of 0038. 0038 was synthesized by reaction of 0021 with 4 chloride

20 nitrobenzoyl by the same method of synthesis of BLI-081. Yield: 81%. 1H NMR (100 MHz, CDCl3) �3.8 (s, 3H), 3.85 (s, 3H), 6.55 (multi, 3H), 7.1-7.3 (dd, 1H), 8 , 2 (dd, 4H), 8.9 (s, 1H). Synthesis of 0040. 100 mg (0.32 mmol) of 0021, 55 mg (0.32 mmol) of 4 (dimethylamino) benzoic acid and 75 mg (0.34 mmol) of DCC were dissolved in 20 ml of

25 dry CH2Cl2. This solution had been stirred for 2 hours. After the solvent was evaporated, the product was purified by a silica gel column to give 65 mg (60%) of 0040. 1H NMR (100 MHz, CDCl3) �3.1 (s, 6H), 3, 8 (s, 3H), 3.85 (s, 3H), 6.4 (s, 1H), 6.5 (multi, 2H), 6.8 (d, 2H), 7.25 (d, 1H ), 7.85 (d, 2H), 8.1 (s, 1H). Synthesis of 0041. 100 mg (0.32 mmol) of 0021, 80 mg (0.32 mmol) of acid 4

30 trifluoroacetamido-benzoic acid and 75 mg (0.34 mmol) of DCC were dissolved in 20 ml of dry CH2Cl2. This solution had been stirred for 2 hours. After the solvent evaporated, the residue was dissolved in 40 ml of methanol. To this solution, 2 ml of concentrated HCl was added and the resulting solution was refluxed for 1 hour. The product was extracted with ethyl acetate, washed with water and

35 dried over sodium sulfate. After the solvent evaporated the residue was chromatographed on a silica gel column to give 50 mg (40%) of 0041. 1 H NMR

(100 MHz, DMSO-d6) �3.7 (s, 3H), 3.8 (s, 3H), 5.9 (s, 2H), 6.6 (d, 2H), 6.7 (multi , 2H), 6.8 (s, 1H), 7.2 (d, 1H), 7.75 (d, 2H), 9.55 (s, 1H). Synthesis of 0042. 100 mg (0.32 mmol) of 0021, 100 mg (0.33 mmol) of 2,3: 4,6-di-O-isopropylidene-2-keto-L-gluconic acid monohydrate and 80 mg (0.35 mmol) of

5 DCC were dissolved in 20 ml of dry CH2Cl2. This solution had been stirred for 2 hours. After the solvent was evaporated, the residue was chromatographed on a silica gel column to give 110 mg (60%) of 0042. 1 H NMR (100 MHz, CDCl 3)

�1.4 (s, 3H), 1.42 (s, 3H), 1.6 (s, 6H), 3.75 (s, 3H), 3.85 (s, 3H), 4.1- 4.7 (multi, 5H), 6.4 (s, 1H), 6.5-6.6 (multi, 2H), 7.2 (d, 1H), 9.0 (s, 1H).

Synthesis of 0043. A solution of 50 mg of 0042 in 20 ml of 1N HCl and THF mixture (1: 5) was stirred at room temperature for 3 hours. The product was extracted with ethyl acetate and washed with water. After the solvent was evaporated, the residue was chromatographed on a silica gel column to give 42 mg (85%) of 0043. 1H NMR (100 MHz, CDCl3) �1.4 (s, 3H), 1, 42 (s, 3H), 3.8 (s, 3H), 3.9 (s, 3H), 4.1

15 4.7 (multi, 5H), 6.5 (s, 1H), 6.5-6.6 (multi, 2H), 7.2 (d, 1H), 9.0 (s, 1H). Synthesis of 0044. A solution of 50 mg of 0042 in 20 ml of mixture of acetic acid and water (7: 3) was refluxed for 4 hours. The solvents were evaporated under reduced pressure. The residue was chromatographed on a silica gel column to give 36 mg (85%) of 0044. 1H NMR (100 MHz, CDCl3) �2.6-4.5 (width, 10H),

20 3.8 (s, 3H), 3.9 (s, 3H), 6.5-6.6 (multi, 3H), 7.2 (d, 1H), 9.0 (s, 1H). Synthesis of 0047. The synthesis of 0047 was achieved by reaction of 0021 with 3-trifluoromethylbenzoyl chloride by the same method of synthesis of BLI-081. Yield: 85%. 1H NMR (100 MHz, CDCl3) �3.8 (s, 3H), 3.85 (s, 3H), 6.55 (s, 1H), 6.6 (multi, 2H), 7.2 (d , 1H), 7.8 (s, 1H), 7.7-8.4 (multi, 4H).

25 Synthesis of 0051 (Ex. Of Ref.). The synthesis of 0051 was achieved from 0050 by the same method of synthesis of 0021. Yield: 90%. Synthesis of 0052. 100 mg of 0021 was dissolved in 40 ml of dry THF. While stirring vigorously, 100 mg of chloroacetyl chloride was added, then 50 mg of triethylamine was added dropwise over more than 2 minutes. The

30 reaction was completed in half an hour. The product was extracted with ethyl acetate and washed with water. After the solvent evaporated the residue was dissolved in 10 ml of acetonitrile. To this solution 0.5 ml of morpholine was added and the solution was stirred at 60 ° C for 4 hours. The product was extracted with ethyl acetate and washed with water. After the solvent evaporated the residue was chromatographed on a

35 silica gel column to give 65 mg of 0052. Yield: 50%. 1H NMR (100

MHz, CDCl3) �2.8 (multi, 4H), 3.8 (multi, 4H), 3.81 (s, 3H), 3.85 (s, 3H), 6.45 (s, 1H), 6.6 (multi, 2H), 7.25 (d, 1H), 9.45 (s, 1H).

Synthesis of 0054. Compound 0054 was synthesized by reaction of 0051 and 4-trifluoromethylbenzoyl chloride using the same synthesis method as for BLI5 081. Yield: 85%. 1H NMR (100 MHz, CDCl3) �0.9 (t, 3H), 1.3 (d, 3H), 1.65 (multi,

2H), 2.7 (multi, 1H), 6.9 (s, 1H), 7.3 (s, 4H), 7.8 (d, 2H), 8.1 (d, 2H), 8, 4 (s, 1H).

Synthesis of 0055. Compound 0055 was synthesized by reaction of 0051 and 2-furoyl chloride using the same synthesis method as for BLI-081. Yield: 90%. 1H NMR (100 MHz, CDCl3) �0.9 (t, 3H), 1.3 (d, 3H), 1.65 (multi, 2H),

10 2.7 (multi, 1H), 6.6 (dd, 1H), 6.9 (s, 1H), 7.3 (s, 4H), 7.4 (d, 1H), 7.6 ( d, 1H), 8.4 (s, 1H). Synthesis of 0056. Compound 0056 was synthesized by reaction of 0051 and 2-thiophenecarbonyl chloride using the same synthesis method as for BLI-081. Yield: 90%. 1H NMR (100 MHz, CDCl3) �0.9 (t, 3H), 1.3 (d, 3H), 1.65 (multi, 2H), 2.7 (multi, 1H), 6.85 (s , 1H), 7.2 (dd, 1H), 7.3 (s, 4H), 7.6 (d, 2H), 7.8 (d, 2H), 8.4 (s, 1H).

Synthesis of 0057. Compound 0057 was synthesized by reaction of 0051 and 3-trifluoromethylbenzoyl chloride using the same method of synthesis as for BLI

081. Yield: 88%. 1H NMR (100 MHz, CDCl3) �0.9 (t, 3H), 1.3 (d, 3H), 1.65 (multi, 2H), 2.7 (multi, 1H), 6.9 (s , 1H), 7.35 (s, 4H), 7.6-8.3 (multi, 4H), 8.4 (s, 1H). Synthesis of 0058. Compound 0058 was synthesized by reaction of 0021 and

20,5-di-trifluoromethylbenzoyl chloride using the same synthesis method as for BLI-081. Yield: 88%. 1H NMR (100 MHz, CDCl3) �3.8 (s, 3H), 3.85 (s, 3H), 6.55 (s, 1H), 6.6 (multi, 2H), 7.2 (d , 1H), 8.1 (s, 1H), 8.4 (s, 2H), 8.6 (s, 1H). Synthesis of 0059. Compound 0059 was synthesized by reaction of 0051 and 3,5-ditrifluoromethylbenzoyl chloride using the same method of synthesis of para

25 BLI-081. Yield: 80%. 1H NMR (100 MHz, CDCl3) �0.9 (t, 3H), 1.3 (d, 3H), 1.65 (multi, 2H), 2.7 (multi, 1H), 6.95 (s , 1H), 7.3 (s, 4H), 8.1 (s, 1H), 8.4 (s, 2H), 8.6 (s, 1H).

Synthesis of 0062. 100 mg of 0021 was dissolved in 40 ml of dry THF. While stirring vigorously, 100 mg of chloroacetyl chloride was added, then 100 mg of triethylamine was added dropwise over more than 2 minutes. The reaction was completed in half an hour. The product was extracted with ethyl acetate and washed with water. After the solvent evaporated the residue was dissolved in 10 ml of DMF. To this solution, 200 mg of piperazine was added and the solution was stirred at 60 ° C for 4 hours. The product was extracted with ethyl acetate and washed with

35 water After the solvent evaporated the residue was chromatographed on a silica gel column to give 70 mg of 0062. Yield: 53%. 1H NMR (100

MHz, CDCl3) �2.7 (multi, 4H), 3.1 (multi, 4H), 3.2 (s, 2H), 3.4 (s, 1H), 3.8 (s, 3H), 3.9 (s, 3H), 6.4 (s, 1H), 6.6 (multi, 2H), 7.2 (d, 1H), 9.2 (s, 1H). Synthesis of 0066. 100 mg of 0021 was dissolved in 40 ml of dry THF. While stirring vigorously, 120 mg of 4-chloromethyl chloride was added

5 benzoic, then 100 mg of triethylamine was added dropwise over more than 2 minutes. The reaction was completed in half an hour. The product was extracted with ethyl acetate and washed with water. After the solvent evaporated the residue was dissolved in 2 ml of morpholine. This solution was stirred at 60 ° C for 2 hours and water was added. The product was extracted with ethyl acetate and washed with water. After

After the solvent evaporated, the residue was chromatographed on a silica gel column to give 110 mg of 0066. Yield: 68%. 1H NMR (100 MHz, CDCl3)

�2.5 (multi, 4H), 3.8 (multi, 4H), 3.6 (s, 2H), 3.85 (s, 3H), 3.9 (s, 3H), 6.5 ( s, 1H), 6.6 (multi, 2H), 7.2 (d, 1H), 7.7 (dd, 4H), 8.3 (s, 1H). Synthesis of 0068. 100 mg of 0021 was dissolved in 40 ml of dry THF.

15 While stirring vigorously, 120 mg of 4-chloromethylbenzoic chloride was added, then 100 mg of triethylamine was added dropwise over more than 2 minutes. The reaction was completed in half an hour. The product was extracted with ethyl acetate and washed with water. After the solvent evaporated the residue was dissolved in 2 ml of N-methylpiperazine. This solution was stirred at 60 ° C for 2 hours and

20 water was added. The product was extracted with ethyl acetate and washed with water. After the solvent evaporated the residue was chromatographed on a silica gel column to give 120 mg of 0068. Yield: 70%. 1H NMR (100 MHz, CDCl3) �2.4 (s, 3H), 2.6 (s, 8H), 3.6 (s, 2H), 3.85 (s, 3H), 3.9 (s , 3H), 6.45 (s, 1H), 6.6 (multi, 2H), 7.2 (d, 1H), 7.7 (dd, 4H), 8.3 (s, 1H).

Synthesis of 0069. 100 mg of 0021 was dissolved in 40 ml of dry THF. While stirring vigorously, 120 mg of 4-chloromethylbenzoyl chloride was added, then 100 mg of triethylamine was added dropwise over more than 2 minutes. The reaction was completed in half an hour. The product was extracted with ethyl acetate and washed with water. After the solvent evaporated the residue was

30 dissolved in 10 ml of DMF. To this solution, 200 mg of piperazine was added and the solution was stirred at 60 ° C for 4 hours. The product was extracted with ethyl acetate and washed with water. After the solvent was evaporated the residue was chromatographed on a silica gel column to give 125 mg of 0069. Yield: 70%. 1H NMR (100 MHz, CDCl3) �2.6 (s, 4H), 3.1 (multi, 4H), 3.6 (s, 2H), 3.85 (s, 3H),

35 3.9 (s, 3H), 6.5 (s, 1H), 6.6 (multi, 2H), 7.25 (d, 1H), 7.7 (dd, 4H), 8.4 ( s, 1H).

Synthesis of 0079 (Ex. Of Ref.). Compound 0079 was synthesized from 0061 by the same method as in the synthesis of 0021. It is a dark green powder. Synthesis of 0080 (Ex. Of Ref.). 80 mg of 0079 were dissolved in 20 ml of dry THF. To this solution 150 mg of 3-nicotinoylcarbonyl chloride was added and

5 added 100 mg of triethylamine dropwise. The resulting solution was stirred at room temperature for half an hour. The product was extracted with ethyl acetate and washed with water. After the solvent evaporated the residue was chromatographed on a silica gel column to give 90 mg of 0080. Yield: 80%. 1H NMR (100 MHz, CD3OD) �2.8 (s, 3H), 6.7 (s, 1H), 7.6 (d, 1H), 8.4 (dd, 1H),

10 8.7 (s, 1 H), 8.9 (d, 1 H), 9.2 (s, 1 H). Synthesis of 0110. 80 mg of 0079 were dissolved in 20 ml of dry THF. To this solution was added 180 mg of 3,5-dimethoxy-4-isopropyl-benzoyl chloride and 100 mg of triethylamine was added dropwise with stirring. The resulting solution was stirred at room temperature for half an hour. The product was extracted with acetate

15 ethyl and washed with water. After the solvent was evaporated, the residue was dissolved in 5 ml of dichloromethane and 100 mg of BBr3 was added to this solution at -78 ° C. This solution was allowed to stir overnight at room temperature, then 100 ml of water was added and the product was extracted with ethyl acetate and dried over sodium sulfate. After the solvent evaporated, the

The residue was chromatographed on a silica gel column to give 50 mg of 0110. Yield: 40%. 1H NMR (100 MHz, CDCl3) �1.24 (d, 3H), 1.26 (d, 3H), 3.1 (multi, 1H), 2.75 (s, 3H), 6.6 (s , 1H), 6.95 (s, 2H), 8.3 (s, 1H). Synthesis of 0093 (Ex. Of Ref.). Compound 0093 was synthesized from 0092 by the same method of synthesis as 0021. It is a dark green powder.

Synthesis of 0096. 100 mg of 0093 was dissolved in 20 ml of dry THF. To this solution was added 180 mg of 3,5-dimethoxy-4-isopropyl-benzoyl chloride and 100 mg of triethylamine was added dropwise with stirring. The resulting solution was stirred at room temperature for half an hour. The product was extracted with ethyl acetate and washed with water. After the solvent evaporated, the residue was

30 dissolved in 5 ml of dichloromethane and 100 mg of BBr3 was added to this solution at -78 ° C. This solution was stirred overnight at room temperature, then 100 ml of water was added and the product was extracted with ethyl acetate and dried over sodium sulfate. After the solvent evaporated, the residue was chromatographed on a silica gel column to give 60 mg of 0096. Yield:

35 43%. 1H NMR (100 MHz, CDCl3) �1.24 (d, 6H), 1.26 (d, 6H), 3.05 (multi, 2H), 6.88 (s, 1H), 6.98 (s , 2H), 7.3 (s, 4H).

Synthesis of 0102. In 10 ml of dry dichloromethane, 100 mg of 0021, 80 mg of 3,5-diacetoxy-4-isopropyl-benzoic acid and 80 mg of DCC were added. This solution was stirred for 2 hours at room temperature. After purification by column chromatograph, the product was dissolved in 20 ml of methanol. This

5 solution, a solution of 50 mg of sodium carbonate in 2 ml of water was added and the resulting solution was stirred at 50 ° C for 4 hours. The product was extracted with ethyl acetate and washed with water and purified by column to give 30 mg of 0102. Yield: 16%. 1H NMR (100 MHz, CDCl3) �1.24 (d, 6H), 1.26 (d, 6H), 3.1 (multi, 1H), 3.75 (s, 3H), 3.85 (s , 3H), 6.6 (s, 1H), 6.62 (multi, 2H), 6.95 (s, 2H), 7.2 (d, 1H), 8.3 (s,

10 1H). Synthesis of 0104 (Ex. Of Ref.). Compound 0104 was synthesized from 0103 by the same method of synthesis of 0021. It is a dark green powder.

Synthesis of 0107. Compound 0107 was synthesized from 0104 by it 0096 synthesis method. Yield: 52%. 1H NMR (100 MHz, CDCl3) �1.25 (d, 15 3H), 1.27 (d, 3H), 3.05 (multi, 1H), 5.02 (s, 2H), 6.6 (s, 1H), 6.95 (s, 2H), 7 , 1 (s, 5H), 8.4 (s,

1 HOUR).

Synthesis of 0113. Compound 0113 was synthesized by reaction of 0104 and 2-thiophenecarbonyl chloride by the same method of synthesis of BLI-081. Yield: 90%. 1H NMR (100 MHz, CDCl3) ,05.05 (s, 2H), 6.85 (s, 1H), 7.2 (dd, 1H),

20 7.25 (s, 5H), 7.6 (d, 1H), 7.8 (d, 1H), 8.3 (s, 1H). Synthesis of 0116. Compound 0116 was synthesized from 0104 by the same synthesis method of 0066. Yield: 50%. 1H NMR (100 MHz, CDCl3) �2.5 (multi, 4H), 3.6 (s, 2H), 3.8 (multi, 4H), 4.9 (s, 2H), 6.5 (s , 1H), 7.12 (s, 5H), 7.6 (dd, 4H), 8.3 (s, 1H).

25 Synthesis of 0120 (Ex. Of Ref.). Compound 0120 was synthesized from 0119, in the form of a dark green powder by the same method as in 0021. Synthesis of 0122. Compound 0122 was synthesized from 0120 by the same synthesis method of 0066. Yield : 55% 1H NMR (100 MHz, CDCl3) �2.5 (multi, 4H), 2.9 (s, 3H), 3.6 (s, 2H), 3.8 (multi, 4H), 3.85 (s , 3H), 3.9 (s, 3H), 6.6 (s, 1H), 6.7 (multi,

30 2H), 7.2 (d, 1H), 7.7 (dd, 4H), 8.4.

Synthesis of 0125. 100 mg of 0093 was dissolved in 40 ml of dry THF. While stirring vigorously, 120 mg of 3-chloromethylbenzoic chloride was added, then 100 mg of triethylamine was added dropwise over more than 2 minutes. The reaction was completed in half an hour. The product was extracted with ethyl acetate and washed with water. After the solvent evaporated, the residue was dissolved in 2 ml of morpholine. This solution was stirred at 60 ° C for 2 hours and was

He added water. The product was extracted with ethyl acetate and washed with water. After the solvent was evaporated, the residue was chromatographed on a silica gel column to give 100 mg of 0125. Yield: 60%. 1H NMR (100 MHz, CDCl3)

�1.27 (d, 6H), 2.6 (multi, 4H), 3 (multi, 1H), 3.65 (s, 2H), 3.8 (multi, 4H), 6.85 (s, 1H), 7.4 (s, 5 4H), 7.4-8.0 (multi, 4H), 8.35 (s, 1H).

Synthesis of 0126. Compound 0126 was synthesized from 0121 by the same synthesis method of 0125. Yield: 60%. 1H NMR (100 MHz, CDCl3)

�2.55 (multi, 4H), 3.6 (s, 2H), 3.8 (multi, 4H), 3.85 (s, 3H), 3.9 (s, 3H), 6.45 ( s, 1H), 6.6 (multi, 2H), 7.25 (d, 1H), 7.4-8.0 (multi, 4H), 8.25 (s, 1H).

Synthesis of 0128. Compound 0128 was synthesized from 0093 by the same synthesis method of 0080. Yield: 80%. 1H NMR (100 MHz, CDCl3) �1.26 (d, 6H), 3.0 (multi, 1H), 7.02 (s, 1H), 7.35 (s, 4H), 7.8 (s , 1H), 8.7 (s, 1H), 9.0 (s, 1H), 9.2 (s, H), 9.4 (s, 1H).

Synthesis of 0135. Compound 0135 was synthesized from 0104 by the same method of synthesis of 0080. Yield: 82%. 1H NMR (100 MHz, CDCl3) �4.1 (s, 2H), 6.7 (s, 1H), 7.25 (s, 5H), 7.6 (d, 1H), 8.4 (dd , 1H), 8.7 (s, 1H), 8.9 (d, 1H), 9.2 (s, 1H).

Synthesis of 0136. 100 mg of 0104 was dissolved in 40 ml of dry THF. While stirring vigorously, 120 mg of 3-chloromethylbenzoic chloride was added, then 100 mg of triethylamine was added dropwise over more than 2

20 minutes. The reaction was completed in half an hour. The product was extracted with ethyl acetate and washed with water. After the solvent was evaporated, the residue was dissolved in 2 ml of N-methyl-piperazine. This solution was stirred at 60 ° C for 2 hours and water was added. The product was extracted with ethyl acetate and washed with water. After the solvent evaporated, the residue was chromatographed on a

25 column of silica gel to give 115 mg of 0136. Yield: 70%. 1H NMR (100 MHz, CD3OD) �4.1 (s, 2H), 6.7 (s, 1H), 7.25 (s, 5H), 7.6 (d, 1H), 8.4 (dd , 1H), 8.7 (s, 1H), 8.9 (d, 1H), 9.2 (s, 1H).

Synthesis of 0137. 100 mg of 0104 was dissolved in 40 ml of dry THF. While stirring vigorously, 120 mg of benzoic 3-chloromethyl30 chloride was added and then 100 mg of triethylamine was added dropwise over more than 2 minutes. The reaction was completed in half an hour. The product was extracted with ethyl acetate and washed with water. After evaporating the solvent, the residue was dissolved in 2 ml of morpholine. This solution was stirred at 60 ° C for 2 hours and water was added. The product was extracted with ethyl acetate and washed with water. After evaporating the

As a solvent, the residue was chromatographed on a silica gel column to give 130 mg of 0137. Yield: 75%. 1H NMR (100 MHz, CD3OD) �2.4 (s, 3H), 2.6 (s, 8H), 3.6 (s, 2H), 5.05 (s, 2H), 6.5 (s , 1H), 7.35 (s, 5H), 7.4-8.0 (multi, 4H), 8.2 (s, 1H).

EXAMPLE 5 (Therapeutic Formulations)

In one aspect, the invention provides various therapeutic uses for the types of dithiolopyrrolones and the specific compounds described. In various embodiments, the compounds of the invention can be used therapeutically in formulations or medicaments for the treatment of human proliferative diseases, such as proliferative blood vessel disorders, and disorders.

10 fibrotic such as cancers, tumors, hyperplasia, fibrosis, angiogenesis, psoriasis, atherosclerosis, and proliferation of smooth muscle cells in blood vessels, such as stenosis and restenosis after angioplasty, including cancers susceptible to compounds of the invention ( such as susceptible solid tumors). The invention provides the corresponding medical treatment methods, in the

A therapeutic dose of a compound of the invention is administered in a pharmacologically acceptable formulation. Accordingly, the invention also provides therapeutic compositions comprising compounds of the invention and a pharmacologically acceptable carrier or excipient. The therapeutic composition may be soluble in an aqueous solution at a physiologically pH.

20 acceptable. The invention provides pharmaceutical compositions (medicaments) containing (comprising) compounds of the invention. In one embodiment, such compositions include compounds of the invention in a therapeutically amount.

or prophylactically effective enough to alter, and preferably inhibit, pathological cell proliferation (proliferative disease), and a pharmaceutically acceptable carrier.

The compounds of the invention can be used in combination with other compositions and methods for the treatment of diseases. For example, a tumor can be treated conventionally with photodynamic therapy, surgery,

Radiation or chemotherapy combined with one of the compounds of the invention, and then the compounds of the invention can then be administered to the patient to prolong the lethargy of micrometastases and stabilize and inhibit the growth of any remaining primary tumor.

A "therapeutically effective amount" refers to an amount effective, at doses 35 and for the time necessary, to achieve the desired therapeutic result, such as reduced growth or elimination of a proliferative disease in the case of cancers. A therapeutically effective amount of a compound of the invention may vary according to factors such as disease status, age, sex and weight of the individual, and the ability of the compound of the invention to obtain a desired response in the individual. The dose of the regimens can be adjusted to provide the optimal therapeutic response. For example, a single rapid intravenous injection may be administered, several divided doses may be administered over a period of time or the dose may be proportionally reduced or increased as indicated by the requirements of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in unit dose form to facilitate the

10 administration and dose uniformity. The unit dose form, used herein, refers to physically discrete units adapted as unit doses, each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect associated with the required pharmaceutical vehicle. The specification for

15 unit dose forms of the invention are imposed by and directly depend on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the intrinsic limitations in the technique of combining an active compound. of that type with sensitivity treatment in individuals. A therapeutically effective amount is also one in which any toxic effect or

The harmful effect of the compound of the invention is overcome by the therapeutically beneficial effect. A "prophylactically effective amount" refers to an amount that is effective, at doses and for the period of time necessary to achieve the desired prophylactic result, such as preventing or inhibiting the rate of metastasis of a tumor or

25 beginning of intimate hyperplasia. A prophylactically effective amount can be determined as described above for the therapeutically effective amount. Typically, since a prophylactic dose is used in subjects before or at an early stage of the disease, the prophylactically effective amount will be less than the therapeutically effective amount.

In particular embodiments, a preferred range for therapeutically and prophylactically effective amounts of compounds of the invention may be 0.1 nM-0.1 M, 0.1 nM-0.05 M, 0.05 nM-15 µM or 0.01 nM-10 µM. Alternatively, the total daily dose may range from about 0.001 to about 1,000 mg / kg of a patient's body mass. The values of the

35 doses may vary depending on the severity of the condition to be relieved. It should also be understood that for any particular subject, the specific dose regimens should be adjusted over time according to the individual need and professional opinion of the person administering or supervising the administration of the compositions, and that the intervals of the doses presented here are only exemplary and are not intended to limit the scope or practice of the methods of

5 the invention.

As used herein, "pharmaceutically acceptable carrier" or "diluent" or "excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption retardants, and the like that are physiologically compatible . In a

10 embodiment, the vehicle is suitable for parenteral administration. Alternatively, the vehicle may be suitable for intravenous, intraperitoneal, intramuscular, sublingual or oral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. He

Use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, the use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds may also be incorporated into the compositions.

The therapeutic compositions should typically be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other structure suitable for a large concentration of drug. The vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol,

Propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as

Mannitol, sorbitol, or sodium chloride, and the like, in the composition. Prolonged absorption of injectable compositions may be caused by the inclusion in the composition of an agent that delays absorption, for example, monostearate and gelatin salts. In addition, the compounds of the invention can be administered in a formulation that is released over time, for example in

A composition that includes a slow release polymer. The active compounds can be prepared with vehicles that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated distribution systems. Biocompatible and biodegradable polymers can be used, such as ethylene-vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and copolymers of

5 polylactic and polyglycol (PLG). Many methods for preparing such formulations are patented or are generally known to those skilled in the art.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients from those listed above, if necessary, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound in a sterile vehicle containing a basic dispersion medium and the other required ingredients of those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods

Preferred preparation are vacuum drying and freeze drying which produces an active ingredient powder plus any additional desired ingredient from a previously filtered sterile solution thereof.

According to an alternative aspect of the invention, a compound of the invention can be formulated with one or more additional compounds that enhance the solubility of the compound of the invention.

According to another aspect of the invention, the therapeutic compositions of the present invention, which comprise compounds of the invention, can be provided in containers that have labels that provide instructions for the use of compounds of the invention to treat proliferative diseases,

25 including cancer and psoriasis.

CONCLUSION Although several embodiments of the invention are described herein, many adaptations and modifications can be made within the scope

30 of the invention according to the normal general knowledge of those skilled in this art. Such modifications include the replacement of known equivalents of any aspect of the invention to achieve the same result in substantially the same way. The numerical intervals include the numbers that define the interval.

35

Claims (6)

1. A compound of the formula shown below: image 1 in which

Code

X Y Z

BLI-066

2,4-dimethoxy-phenyl H N-methyl-3-pyridinium chloride

BLI-081

2,4-dimethoxy-phenyl H 2-fury

BLI-090

2,4-dimethoxy-phenyl H 2,4-dimethoxy-phenyl

BLI-093

2,4-dimethoxy-phenyl H 4-trifluoromethylphenyl

WBL-007

2,4-dimethoxy-phenyl H 2-thiophenyl

R3

2,4-dimethoxy-phenyl H 3,5-difluorophenyl

R4

2,4-dimethoxy-phenyl H 2,3,4-trifluorophenyl

WBL-018

2,4-dimethoxy-phenyl H 4-fluoro-phenyl

0037

2,4-dimethoxy-phenyl H Thiophene-2-methyl

0038

2,4-dimethoxy-phenyl H 4-nitrophenyl

0040

2,4-dimethoxy-phenyl H 4-N, N-dimethylamino-phenyl

0041

2,4-dimethoxy-phenyl H 4-aminophenyl

0042

2,4-dimethoxy-phenyl H

0043

2,4-dimethoxy-phenyl H

0044

2,4-dimethoxy-phenyl H

0047

2,4-dimethoxy-phenyl H 3-trifluoromethylphenyl

0052

2,4-dimethoxy-phenyl H image 1

0054

4-iso-butylphenyl H 4-trifluoromethylphenyl

0055

4-iso-butylphenyl H 2-fury

0056

4-iso-butylphenyl H 2-thiophenyl

0057

4-iso-butylphenyl H 3-trifluoromethylphenyl

0058

2,4-dimethoxy-phenyl H 3,5-di-trifluoromethylphenyl

0059

4-iso-butylphenyl H 3,5-di-trifluoromethylphenyl

0062

2,4-dimethoxy-phenyl H

0066

2,4-dimethoxy-phenyl H

0068

2,4-dimethoxy-phenyl H

0069

2,4-dimethoxy-phenyl H

WBI-4

4-isopropylphenyl H

WBI-5

4-isobutylphenyl H

WBI-6

methyl H

0096

4-isopropanylphenyl H 3,5-dihydroxy-4-isopropanyl-phenyl

0102

2,4-dimethoxy-phenyl H 3,5-dihydroxy-4-isopropanyl-phenyl

0107

Benzyl H 3,5-dihydroxy-4-isopropanyl-phenyl

0110

methyl H 3,5-dihydroxy-4-isopropanyl-phenyl

0113

Benzyl H 2-thiophenyl

0116

Benzyl H

0122

2,4-dimethoxy-phenyl Methyl

0125

4-isopropanylphenyl H

0126

2,4-dimethoxy-phenyl H

0128

4-isopropanylphenyl H Pyridin-3-yl

0135

Benzyl H Pyridin-3-yl

0136

Benzyl H

0137

Benzyl H

2,4-dimethoxy-phenyl

H 2- (2-thiophenyl) -vinyl

2,4-dimethoxy-phenyl

H 1-methylimidazol-5-yl

4-methyl-phenyl

H 2-thiophenyl

2,4-dimethoxy-phenyl

Methyl 2-thiophenyl

2,4-dimethoxy-phenyl

benzyl 2-fury

2,4-dimethoxy-phenyl

H 1-methyl pyrrolyl

2,4-dimethoxy-phenyl

H 2-thiazolyl

2,4-dimethoxy-phenyl

H N-methyl-2-indolyl

2. The compound according to claim 1, wherein image2 , wherein Z1 is a group with at least two hydrophilic atoms selected from N or O. 5 3. The compound according to claim 2, wherein Z1 is piperazinyl, 4-methyl-piperazinyl or morpholinyl. 4. The compound according to claim 1 for use in the treatment or prophylaxis of proliferative diseases. 5. Use of the compound according to claim 1 in the manufacture of a medicament for the treatment or prophylaxis of proliferative diseases. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, associated with a pharmaceutical carrier or diluent. 7. A process for the preparation of a compound of the formula 20 shown below: image 1 in which where the processes follow the synthesis scheme

Code

X Y Z

BLI-081

2,4-dimethoxy-phenyl H 2-fury

BLI-090

2,4-dimethoxy-phenyl H 2,4-dimethoxy-phenyl

BLI-093

2,4-dimethoxy-phenyl H 4-trifluoromethylphenyl

WBL-007

2,4-dimethoxy-phenyl H 2-thiophenyl

R3

2,4-dimethoxy-phenyl H 3,5-difluorophenyl

R4

2,4-dimethoxy-phenyl H 2,3,4-trifluorophenyl

WBL-018

2,4-dimethoxy-phenyl H 4-fluoro-phenyl

0037

2,4-dimethoxy-phenyl H Thiophene-2-methyl

0038

2,4-dimethoxy-phenyl H 4-nitrophenyl

0040

2,4-dimethoxy-phenyl H 4-N, N-dimethylamino-phenyl

0041

2,4-dimethoxy-phenyl H 4-aminophenyl

0042

2,4-dimethoxy-phenyl H

0043

2,4-dimethoxy-phenyl H

0044

2,4-dimethoxy-phenyl H

0047

2,4-dimethoxy-phenyl H 3-trifluoromethylphenyl

0052

2,4-dimethoxy-phenyl H image 1

0054

4-iso-butylphenyl H 4-trifluoromethylphenyl

0055

4-iso-butylphenyl H 2-fury

0056

4-iso-butylphenyl H 2-thiophenyl

0057

4-iso-butylphenyl H 3-trifluoromethylphenyl

0058

2,4-dimethoxy-phenyl H 3,5-di-trifluoromethylphenyl

0059

4-iso-butylphenyl H 3,5-di-trifluoromethylphenyl

0062

2,4-dimethoxy-phenyl H

0066

2,4-dimethoxy-phenyl H

0068

2,4-dimethoxy-phenyl H

0069

2,4-dimethoxy-phenyl H

0096

4-isopropanylphenyl H 3,5-dihydroxy-4-isopropanyl-phenyl

0102

2,4-dimethoxy-phenyl H 3,5-dihydroxy-4-isopropanyl-phenyl

0107

Benzyl H 3,5-dihydroxy-4-isopropanyl-phenyl

0110

Methyl H 3,5-dihydroxy-4-isopropanyl-phenyl

0113

Benzyl H 2-thiophenyl

0116

Benzyl H

0122

2,4-dimethoxy-phenyl methyl

0125

4-isopropanylphenyl H

0126

2,4-dimethoxy-phenyl H

0128

4-isopropanylphenyl H Pyridin-3-yl

0135

Benzyl H Pyridin-3-yl

0136

Benzyl H

0137

Benzyl H

image 1