RU2448101C2 - 5-substituted isoindoline compounds - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I):

or pharmaceutically acceptable salt thereof, or stereoisomer, in which: n equals 0 or 1; X denotes CH₂, C=O; R¹ denotes a) -(CH₂)_mR³ or -CO(CH₂)_mR³, where m equals 0, 1; and R³ denotes a 5-10-member aryl or heteroaryl, where the heteroaryl denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected oxygen, nitrogen or sulphur, optionally substituted with one or more halogens; b) -C=YR⁴, where Y denotes O; and R⁴ denotes: (C₁-C₁₀)alkyl; (C₁-C₁₀)alkoxy; (C₀-C₁₀)alkyl-(5-10-member heteroaryl), where "heteroaryl" denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected from oxygen, nitrogen or sulphur, said heteroaryl is optionally substituted with one or more substitutes selected from halogen, oxo or 2-(C₁-C₆)alkyl, where Z denotes S; (C₀-C₁₀)alkyl-(5-10-member aryl), said aryl is optionally substituted with one or more substitutes selected from halogen; (C₁-C₆)alkoxy, which itself is optionally substituted with one or more halogens; (C₁-C₆)alkyl, which itself is optionally substituted with one or more halogens; or -Z-(C₁-C₆)alkyl, where Z denotes S or SO₂, and where said (C₁-C₆)alkyl can be optionally substituted with one or more halogens; or (C₁-C₆)alkyl-CO-O-R¹², where R¹² denotes H or (C₁-C₆)alkyl; or c) -C=ZNHR⁶, where Z denotes O or S; and R⁶ denotes: (C₁-C₁₀)alkyl; (C₁-C₁₀)alkoxy; 5-10-member aryl or heteroaryl, where "heteroaryl" denotes a bicyclic aromatic ring containing 9 ring atoms, from which at least one or two atoms are oxygen atoms; optionally substituted with one or more substitutes selected from halogen; cyano; (C₁-C₆)alkoxy, which itself is optionally substituted with one or more halogens; (C₁-C₆)alkyl, which itself is optionally substituted with one or more halogens; and R² denotes H or (C₁-C₆)alkyl. Also described is a pharmaceutical composition for inhibiting TNFα, based on the compound of formula I.

EFFECT: novel compounds which can regulate production of certain cytokines, including TNF-α, are obtained and described.

27 cl, 81 ex, 1 tbl

Description

This application claims priority on the basis of provisional applications US 60/841365, filed August 30, 2006; 60/925513, filed April 20, 2007, and 60/937782, filed June 28, 2007, which in their entirety are incorporated into the description by reference.

1. Field of invention

This invention relates to 5-substituted isoindoline compounds. Also disclosed are pharmaceutical compositions containing the compounds, and methods for treating, preventing and controlling the course of various disorders.

2. Background of the invention

2.1 Pathobiology of cancer and other diseases

Cancer, in the first place, is characterized by an increase in the number of abnormal cells originating from a given normal tissue, invasion of these abnormal cells to neighboring tissues, or the transfer of malignant cells by the lymphatic or circulatory system to peripheral lymph nodes and to the removed sections (metastasis). Clinical data and molecular biological studies show that cancer is a multi-stage process and begins with minor preneoplastic changes, which, under certain conditions, progress to neoplasia. Neoplastic damage can develop by cloning and develop an increasing ability to invasion, growth, metastasis and heterogeneity, especially in conditions in which neoplastic cells slip out of control of the host immune system. Roitt, I., Brostoff, J. and Kale, D., Immunology, 17.1-17.12 ( 3 ^{rd ed., St. Louis, Mo.} , 1993).

There is a huge variety of cancers that are described in detail in the medical literature. Examples include cancer of the lung, rectum, anus, prostate, breast, brain, and intestines. The prevalence of cancer continues to increase with the general aging of the population, with the advent of new types of cancer and with an increase in the susceptibility of the population to cancer (for example, people infected with AIDS or excessively exposed to solar radiation). However, the options for treating cancer are limited. For example, in the case of various types of blood cancer (for example, multiple myeloma), only a few options are available, especially if conventional chemotherapy is unsuccessful and bone marrow transplantation is not an option. Therefore, there is an urgent need for new methods and compositions that can be used to treat patients suffering from cancer.

Many types of cancer are associated with the formation of new blood vessels, with a process known as angiogenesis. Several mechanisms involved in cancer-induced angiogenesis have been identified. The most direct of these mechanisms is the secretion by cancer cells of cytokines having angiogenetic properties. Examples of such cytokines are acidic and basic fibroblast growth factors (a, b-FGF), angiogenin, endothelial vessel growth factor (VEGF), and TNF-α. Alternatively, cancer cells can release angiogenetic peptides by producing proteases and subsequent destruction of the extracellular matrix when certain cytokines accumulate (e.g., b-FGF). Angiogenesis can also be induced indirectly through the recruitment of inflammatory cells (especially macrophages) and their subsequent release of angiogenetic cytokines (e.g., TNF-α, b-FGF).

Many other diseases and disorders are associated with or characterized by unwanted angiogenesis. For example, increased and uncontrolled angiogenesis is involved in the following series of diseases and medical conditions, not limited to: ocular neovascular diseases, choroidal neovascular diseases, neovascular diseases of the retina, rubeosis (neovascularization of the eye angle), viral diseases, genetic diseases, inflammatory diseases, allergic diseases and autoimmune diseases. Examples of such diseases and conditions include, but are not limited to, diabetic retinopathy, premature retinopathy, corneal transplant rejection, neovascular glaucoma, retrolental fibroplasia, arthritis, and proliferative vitreoretinopathy.

Accordingly, compounds that can regulate angiogenesis or inhibit the production of certain cytokines, including TNF-α, may be useful for the treatment and prevention of various diseases and conditions.

2.2 Cancer treatments

Current cancer treatments may include surgery, chemotherapy, hormone therapy, and / or radiation treatment to eradicate the patient’s neoplastic cells (see, e.g., Stockdale, 1998, Medicine , vol. 3, Rubenstein and Federman, eds., Chapter 12, Section IV ) More recently, cancer treatment may also include biological therapy and immunotherapy. All of these approaches have significant disadvantages for the patient. Surgery may be contraindicated for health reasons or may not be acceptable to the patient. In addition, surgery may not completely remove the neoplastic tissue. Radiation therapy is only effective if the neoplastic tissue exhibits a higher sensitivity to radiation than normal tissue. Radiation therapy can also often have serious side effects. Hormone therapy is rarely performed by a single agent. Although hormone therapy can be effective, it is often used to prevent or delay the re-emergence of cancer after most cancer cells have been removed by other treatments. Biological therapies and immunotherapy are few in number and can produce side effects such as a rash and swelling, flu-like symptoms, including fever, chills and fatigue, digestive problems or allergic reactions.

As for chemotherapy, there are a number of chemotherapeutic agents suitable for treating cancer. Most anticancer chemotherapeutic agents act by inhibiting DNA synthesis either directly or indirectly by inhibiting the biosynthesis of deoxyribonucleotide triphosphate precursors to prevent DNA replication and subsequent cell division (Gillman et al ., Goodman and Gillman's: The Pharmacological Basis of Therapeutics , Tenth E. (McGraw Hill , New York).

Despite the availability of various chemotherapeutic agents, chemotherapy has many disadvantages. Stockdale, Medicine , vol. 3, Rubenstein and Federman, eds., Chapter 12, Section 10, 1998. Almost all chemotherapeutic agents are toxic, and chemotherapy causes significant and often dangerous side effects, including severe nausea, bone marrow suppression, and immune suppression. In addition, even with the introduction of combinations of chemotherapeutic agents, many tumor cells are resistant or develop resistance to chemotherapeutic agents. Indeed, such cells that are resistant to specific chemotherapeutic agents used in accordance with the treatment protocol often prove to be resistant to other drugs, even if such agents act by a mechanism different from that used for drugs for this treatment. This phenomenon is called pleotropic or multidrug resistance. Due to drug resistance, many cancers are definitely or become resistant to the standard protocols for treatment with chemotherapeutic agents.

Other diseases or conditions associated with or characterized by unwanted angiogenesis are also difficult to treat. However, some compounds have been proposed, such as protamine, hepain and steroids, which are useful for treating certain specific diseases. Taylor et al ., Nature 297: 307 (1982); Folkman et al ., Science 221: 719 (1983); U.S. Patent Nos. 5001116 and 4994443.

There is still an urgent need for effective methods of treating, preventing and managing the course of cancer and other diseases and conditions, especially for conditions that are immune to standard methods of treatment, such as surgery, radiation therapy, chemotherapy and hormone therapy, while reducing or eliminating toxicity and / or side effects associated with conventional therapies.

3. Summary of invention

This invention, in particular, is directed to 5-substituted isoindole compounds and their pharmaceutically acceptable salts, solvates (eg hydrates), prodrugs and stereoisomers.

The invention also encompasses methods for treating and managing the course of various diseases and disorders. The methods include administering to the patient for such treatment or control of the course of the disease a therapeutically effective amount of a compound of this invention or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

The invention also encompasses methods of preventing various diseases and disorders, which include administering for the purpose of such prevention to a patient a prophylactically effective amount of a compound of this invention or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

The invention also encompasses pharmaceutical compositions, discrete dosage forms containing a unit dose, dosage regimens, and kits that include a compound of this invention or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

4. Detailed description of the invention

In one embodiment, the invention encompasses 5-substituted isoindole compounds and their pharmaceutically acceptable salts, solvates, stereoisomers and prodrugs.

In another embodiment, the invention encompasses methods for treating, managing and preventing various diseases and disorders that include administering to a patient for such treatment or prophylaxis a therapeutically or prophylactically effective amount of a compound of this invention or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof. Examples of diseases and disorders are described.

In particular embodiments, the compounds of this invention or their pharmaceutically acceptable salts, solvates, stereoisomers or prodrugs are used in combination with another drug (“second active agent”) or treatment. Second active agents include small molecules and large molecules (e.g., proteins and antibodies), examples of which are presented in the description, as well as stem cells. Methods or therapies that can be used in combination with the administration of the compounds of this invention include, but are not limited to, surgery, blood transfusion, immunotherapy, biological therapy, radiation therapy and other non-drug therapies currently used for treatment, prevention and management the course of various disorders disclosed in the description.

The invention also encompasses pharmaceutical compositions (eg, dosage forms containing a unit dose) that can be used in the methods disclosed herein. Specific pharmaceutical compositions include a compound of the invention or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and optionally a second active agent.

4.1. Connections

In one embodiment, the invention encompasses compounds of formula (I):

and their pharmaceutically acceptable salts, solvates, stereoisomers and prodrugs, in which:

n is 0 or 1;

X represents CH ₂ , C = O or C = S;

R ¹ represents:

a) - (CH ₂ ) _m R ³ or - СО (CH ₂ ) _m R ³ , where

m is 0, 1, 2 or 3; and

R ³ represents a 5-10 membered aryl or heteroaryl optionally substituted with one or more halogens;

b) -C = YR ⁴ , where

Y represents O or S; and

R ⁴ represents:

(C ₁ -C ₁₀ ) alkyl; (C ₁ -C ₁₀ ) alkoxy;

(C ₀ -C ₁₀ ) alkyl (5-10 membered heteroaryl or heterocycle), said heteroaryl or heterocycle is optionally substituted with one or more substituents from (C ₁ -C ₆ ) alkyl, halogen, oxo, (C ₁ -C ₆ ) alkoxy, or -Z- (C ₁ -C ₆ ) alkyl, wherein Z is S or SO ₂ and where said (C ₁ -C ₆ ) alkyl may be optionally substituted with one or more halogens;

(C ₀ -C ₁₀ ) alkyl- (5-10 membered aryl), said aryl is optionally substituted with one or more halogen substituents; (C ₁ -C ₆ ) alkoxy, which itself is optionally substituted with one or more halogens; (C ₁ -C ₆ ) alkyl, which itself is optionally substituted with one or more halogens; or -Z- (C ₁ -C ₆ ) alkyl, where Z is S or SO ₂ and wherein said (C ₁ -C ₆ ) alkyl may optionally be substituted with one or more halogens; or

(C ₁ -C ₆ ) alkyl-CO-O-R ¹² where R ¹² is H or (C ₁ -C ₆ ) alkyl; or

c) -C = ZNHR ⁶ , where

Z represents O or S; and

R ⁶ represents:

(C ₁ -C ₁₀ ) alkyl; (C ₁ -C ₁₀ ) alkoxy;

5-10 membered aryl or heteroaryl optionally substituted with one or more halogen substituents; cyano; (C ₁ -C ₆ ) alkylenedioxy; (C ₁ -C ₆ ) alkoxy, which itself is optionally substituted with one or more halogens; (C ₁ -C ₆ ) alkyl, which itself is optionally substituted with one or more halogens; (C ₁ -C ₆ ) alkylthio, which itself is optionally substituted with one or more halogens; and

R ² represents H or (C ₁ -C ₆ ) alkyl.

In one particular embodiment, the invention encompasses compounds of formula (II):

and their pharmaceutically acceptable salts, solvates, stereoisomers and prodrugs, in which:

n is 0 or 1;

X represents CH ₂ or C = O;

R ⁷ represents - (CH ₂ ) _m R ⁹ where m is 0, 1, 2 or 3; and R ⁹ represents a 5-10 membered aryl or heteroaryl optionally substituted with one or more halogens; and

R ⁸ represents H or (C ₁ -C ₆ ) alkyl.

In one embodiment, X represents C = O. In another embodiment, X is CH ₂ .

In one embodiment, n is 0. In another embodiment, n is 1.

In one embodiment, m is 0. In another embodiment, m is 1. In another embodiment, m is 2. In another embodiment, m is 3.

In one embodiment, R ⁹ is a 5-10 membered aryl. In some particular embodiments, R ⁹ is phenyl optionally substituted with one or more halogens.

In one embodiment, R ⁹ is a 5-10 membered heteroaryl. In some particular embodiments, R ⁹ is furyl or benzofuryl.

In one embodiment, R ⁸ is H. In another embodiment, R ⁸ is (C ₁ -C ₆ ) alkyl. In some particular embodiments, R ⁸ is methyl.

All combinations of the above embodiments are encompassed by this invention.

Examples including, but not limited to, the above compounds or their pharmaceutically acceptable salts, solvates (e.g. hydrates), prodrugs or stereoisomers are:

In another embodiment, the invention encompasses compounds of formula (III):

,

,

and their pharmaceutically acceptable salts, solvates, stereoisomers and prodrugs, in which:

X represents CH ₂ or C = O;

Y represents O or S;

R ¹⁰ represents:

(C ₁ -C ₁₀ ) alkyl; (C ₁ -C ₁₀ ) alkoxy;

(C ₀ -C ₁₀ ) alkyl (5-10 membered heteroaryl or heterocycle), said heteroaryl or heterocycle is optionally substituted with one or more substituents from (C ₁ -C ₆ ) alkyl, halogen, oxo, (C ₁ -C ₆ ) alkoxy, or -Z- (C ₁ -C ₆ ) alkyl, wherein Z is S or SO ₂ and where said (C ₁ -C ₆ ) alkyl may be optionally substituted with one or more halogens;

(C ₀ -C ₁₀ ) alkyl- (5-10 membered aryl), said aryl is optionally substituted with one or more halogen substituents; (C ₁ -C ₆ ) alkoxy, which itself is optionally substituted with one or more halogens; (C ₁ -C ₆ ) alkyl, which itself is optionally substituted with one or more halogens; or -Z- (C ₁ -C ₆ ) alkyl, where Z is S or SO ₂ and wherein said (C ₁ -C ₆ ) alkyl may optionally be substituted with one or more halogens; or

(C ₁ -C ₆ ) alkyl-CO-O-R ¹² where R ¹² is H or (C ₁ -C ₆ ) alkyl; and

R ¹¹ represents H or (C ₁ -C ₆ ) alkyl.

In one embodiment, X is CH ₂ . In another embodiment, X represents C = O.

In one embodiment, Y is O. In another embodiment, Y is S.

In one embodiment, R ¹⁰ is (C ₁ -C ₁₀ ) alkyl. In some particular embodiments, R ¹⁰ is (C ₅ -C ₁₀ ) alkyl. In some particular embodiments, R ¹⁰ is pentyl or hexyl.

In one embodiment, R ¹⁰ is (C ₁ -C ₁₀ ) alkoxy. In some particular embodiments, R ¹⁰ is (C ₅ -C ₁₀ ) alkoxy. In some particular embodiments, R ¹⁰ is pentyloxy or hexyloxy.

In one embodiment, R ¹⁰ is a 5-10 membered heteroaryl. In some particular embodiments, R ¹⁰ is thiophenyl or furyl.

In one embodiment, R ¹⁰ is a 5-10 membered aryl optionally substituted with one or more halogens. In some particular embodiments, R ¹⁰ is phenyl optionally substituted with one or more halogens.

In one embodiment, R ¹⁰ is a 5-10 membered aryl or heteroaryl, optionally substituted with (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkoxy, which are themselves optionally substituted with one or more halogens. In certain particular embodiments, R ¹⁰ is phenyl substituted with (C ₁ -C ₃ ) alkyl or (C ₁ -C ₆ ) alkoxy substituted with one or more halogens. In some particular embodiments, R ¹⁰ is phenyl substituted with methyl or methoxy substituted with 1, 2 or 3 halogens.

In one embodiment, R ¹⁰ is aryl or heteroaryl substituted with -S- (C ₁ -C ₆ ) alkyl, wherein said alkyl is optionally substituted with one or more halogens. In another embodiment, R ¹⁰ is aryl or heteroaryl substituted with —SO ₂ - (C ₁ -C ₆ ) alkyl, wherein said alkyl is optionally substituted with one or more halogens.

In one embodiment, R ¹⁰ is (C ₁ -C ₆ ) alkyl-CO-O-R ¹² , where R ¹² is (C ₁ -C ₆ ) alkyl. In one particular embodiment, R ¹⁰ is butyl-CO-O-tBu.

In one embodiment, R ¹⁰ is (C ₁ -C ₆ ) alkyl-CO — O — R ¹² , where R ¹² is H. In one particular embodiment, R ¹⁰ is butyl-COOH.

In one embodiment, R ¹¹ is H. In another embodiment, R ¹¹ is (C ₁ -C ₆ ) alkyl. In some particular embodiments, R ¹¹ is methyl.

All combinations of the above embodiments are encompassed by this invention.

Examples including, but not limited to, the above compounds or their pharmaceutically acceptable salts, solvates (e.g. hydrates), prodrugs or stereoisomers are:

In another embodiment, the invention encompasses compounds of formula (IV):

,

,

and their pharmaceutically acceptable salts, solvates, stereoisomers and prodrugs, in which:

X represents CH ₂ or C = O;

Y represents O or S;

R ¹³ represents:

(C ₁ -C ₁₀ ) alkyl; (C ₁ -C ₁₀ ) alkoxy;

5-10 membered aryl or heteroaryl optionally substituted with one or more substituents from halogen, cyano, (C ₁ -C ₆ ) alkylenedioxy; (C ₁ -C ₆ ) alkoxy, which itself is optionally substituted with one or more halogens; (C ₁ -C ₆ ) alkyl, which itself is optionally substituted with one or more halogens; (C ₁ -C ₆ ) alkylthio, which itself is optionally substituted with one or more halogens; and

R ¹⁴ represents H or (C ₁ -C ₆ ) alkyl.

In one embodiment, X is CH ₂ . In another embodiment, X represents C = O.

In one embodiment, Y is O. In another embodiment, Y is S.

In one embodiment, R ¹³ is (C ₁ -C ₁₀ ) alkyl. In some particular embodiments, R ¹³ is (C ₁ -C ₆ ) alkyl. In some particular embodiments, R ¹³ is propyl, butyl pentyl or hexyl.

In one embodiment, R ¹³ is (C ₁ -C ₁₀ ) alkoxy.

In one embodiment, R ¹³ is a 5-10 membered aryl or heteroaryl optionally substituted with cyano. In some particular embodiments, R ¹³ is phenyl optionally substituted with cyano.

In one embodiment, R ¹³ is a 5-10 membered aryl or heteroaryl optionally substituted with (C ₁ -C ₆ ) alkylenedioxy. In some particular embodiments, R ¹³ is phenyl optionally substituted with methylenedioxy.

In one embodiment, R ¹³ is a 5-10 membered aryl or heteroaryl optionally substituted with one or more halogens. In some particular embodiments, R ¹³ is phenyl optionally substituted with one or more halogens.

In one embodiment, R ¹³ is a 5-10 membered aryl or heteroaryl, optionally substituted with (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkoxy, which are themselves optionally substituted with one or more halogens. In some particular embodiments, R ¹³ is phenyl optionally substituted with methyl or methoxy, which are themselves optionally substituted with 1, 2 or 3 halogens.

In one embodiment, R ¹³ is a 5-10 membered aryl or heteroaryl, optionally substituted with (C ₁ -C ₆ ) alkylthio, which itself is optionally substituted with one or more halogens.

In one embodiment, R ¹⁴ is H. In another embodiment, R ¹⁴ is (C ₁ -C ₆ ) alkyl. In some particular embodiments, R ¹⁴ is methyl.

All combinations of the above embodiments are encompassed by this invention.

Examples including, but not limited to, the above compounds or their pharmaceutically acceptable salts, solvates (e.g. hydrates), prodrugs or stereoisomers are:

The term “pharmaceutically acceptable salt,” as used herein, unless otherwise indicated, refers to salts derived from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Suitable non-toxic acids include inorganic and organic acids such as, but not limited to, acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, furovaya, gluconic, glutamic, glucuric, hydrochloric, hydrochloric, hydrochloric, hydrochloric, hydrochloric , isethionic, dairy, maleic, apple, almond, methanesulfonic, muconic, nitric, pamova, pantothenic, phenylacetic, propionic, phosphoric, salicylic, stearin , Succinic, sulfanilic, sulfuric, tartaric, p-toluenesulfonic and the like. Suitable are hydrobromic, hydrochloric, phosphoric and sulfuric acids.

The term “solvate”, as used herein, unless otherwise indicated, means a compound of this invention or a salt thereof, which further comprises a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. If the solvent is water, then the solvate is a hydrate.

The term “prodrug,” as used herein, unless otherwise indicated, means a derivative of a compound that is capable of hydrolysing, oxidizing, or otherwise reacting under biological conditions ( in vitro or in vivo ) to form a compound. Examples of prodrugs include, but are not limited to, compounds that contain biologically hydrolyzable moieties, such as biologically hydrolyzable amide, biologically hydrolyzable ester, biologically hydrolyzable carbamate, biologically hydrolyzable carbonate, biologically hydrolyzable ureide and biologically hydrolyzable phosphate analogues. Other examples of prodrugs include compounds that contain —NO, —NO ₂ , —ONO, or —ONO ₂ fragments. Prodrugs can usually be obtained using well-known methods, such as described in Burger's Medicinal Chemistry and Drug Discovery , 172-178, 949-982 (Manfred E. Wolff ed., 5 ^th ed., 1995) and Design of Prodrugs (H Bundgaard ed., Elsevier, New York, 1985).

The terms “biologically hydrolyzable carbamate”, “biologically hydrolyzable carbonate”, “biologically hydrolyzable ureide” and “biologically hydrolyzable phosphate” as used herein, unless otherwise indicated, mean, respectively, carbamate, carbonate, ureide and phosphate compounds which: 1) do not affect the biological activity of the compound, but it can improve the in vivo advantageous properties of the compound, such as absorption, duration of action and time before the onset of action, or 2) are biologically inactive, but turn in vi vo is a biologically active compound. Examples of biologically hydrolyzable carbamates include, but are not limited to, lower alkyl amines, substituted ethylenediamines, amino acids, hydroxyalkamines, heterocyclic and heteroaromatic amines and polyetheramines.

The term “stereoisomer”, as used herein, unless otherwise indicated, encompasses all enantiomerically / stereoisomerically pure and enantiomerically / stereoisomerically enriched compounds of this invention.

The term “stereoisomerically pure”, as used herein, unless otherwise indicated, means a composition that contains one stereoisomer of a compound and is substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure composition of a compound having one chiral center should be free of the opposite enantiomer of the compound. A stereoisomerically pure composition of a compound having two chiral centers should be free of other diastereomers of the compound. Typically, a stereoisomerically pure compound contains more than 80% by weight of one stereoisomer of the compound and less than 20% by weight of other stereoisomers of the compound, more preferably more than 90% by weight of one stereoisomer of the compound and less than 10% by weight of other stereoisomers of the compound, even more preferably more than 95 % by weight of one stereoisomer of the compound and less than 5% by weight of other stereoisomers of the compound, and most preferably more than 97% by weight of one stereoisomer of the compound and less than 3% by weight of other stereoisomers of the compound.

The term “stereoisomerically enriched”, as used herein, unless otherwise indicated, means a composition that contains more than about 55% by weight of one stereoisomer of the compound, more than about 60% by weight of one stereoisomer of the compound, preferably more than about 70% by weight of one stereoisomer of the compound, more preferably more than about 80% by weight of one stereoisomer of the compound.

The term “enantiomerically pure”, as used herein, unless otherwise indicated, means a stereoisomerically pure composition of a compound having one chiral center. Similarly, the term “enantiomerically enriched” refers to a stereoisomerically enriched composition of a compound having one chiral center.

The term “alkyl,” as used herein, unless otherwise indicated, refers to a straight or branched chain saturated hydrocarbon having the number of carbon atoms indicated for it. Representative saturated normal chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl; whereas saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl and the like. The term “alkyl” also encompasses cycloalkyl.

The term “cycloalkyl” as used herein, unless otherwise indicated, refers to a type of alkyl containing from 3 to 15 carbon atoms without alternation or resonance of double bonds between carbon atoms. It can contain from 1 to 4 rings. Examples of unsubstituted cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl. Cycloalkyl may be substituted with one or more substituents as defined below.

The term “alkoxy,” as used herein, unless otherwise indicated, refers to —O— (alkyl), where alkyl is defined herein. Examples of alkoxy include, but are not limited to, —OCH ₃ , —OCH ₂ CH ₃ , —O (CH ₂ ) ₂ CH ₃ , —O (CH ₂ ) ₃ CH ₃ , —O (CH ₂ ) ₄ CH ₃ and —O (CH ₂ ) ₅ CH ₃ .

The term “aryl” as used herein, unless otherwise indicated, means a carbocyclic aromatic ring containing from 5 to 14 atoms in the ring. All atoms in the ring of a carbocyclic aromatic group are carbon atoms. Aryl ring structures include compounds having one or more ring structures, such as mono-, bi- or tricyclic compounds, as well as benzofused carbocyclic moieties, such as 5,6,7,8-tetrahydronaphthyl and the like. Representative aryl groups include phenyl, anthracenyl, fluorenyl, indenyl, azulenyl, phenanthrenyl and naphthyl.

The term “heteroaryl”, as used herein, unless otherwise indicated, means an aromatic ring containing from 5 to 14 atoms in the ring, among which at least one (eg, one, two or three) is a heteroatom (eg, nitrogen, oxygen or gray). Heteroaryl ring structures include compounds having one or more ring structures, such as mono-, bi- or tricyclic compounds, as well as fused heterocyclic fragments. Examples of heteroaryl include, but are not limited to, triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, thiazolyl, benzothiophenyl, benzoisoxazolyl, benzoisothiazolyl, quinolinyl, isoquinolyl, aziazolazole, aziazolazole, aziazolazole, aziazolazole isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzoquinazolinyl, quinoxalinyl, acridinyl, pyrimidyl, oxazolyl, benzo [1,3] dioxol dioxide.

The term “heterocycle” as used herein, unless otherwise indicated, means a monocyclic or polycyclic ring containing carbon and hydrogen atoms, optionally having 1 or 2-fold bonds, and ring atoms contain at least one heteroatom, in particular from 1 up to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. Heterocyclic ring structures include, but are not limited to, mono-, bi-, or tricyclic compounds. Special cases of heterocycles are monocyclic or bicyclic. Representative heterocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl pyrothyridinyl tetrahydrinyl. The heterocyclic ring may be unsubstituted or substituted.

The term “heterocycloalkyl” as used herein, unless otherwise indicated, refers to a cycloalkyl group in which at least one of the carbon atoms in the ring is replaced by a heteroatom (for example, O, S or N).

It should be noted that if there is a discrepancy between the depicted structure and the name given to such a structure, then the depicted structure is of greater importance. In addition, if the stereochemistry of the structure or part of the structure is not indicated, for example, by bold or dashed lines, then the structure or part of the structure is considered as encompassing all its stereoisomers.

4.2 Methods of treatment, prevention and management of the disease

The invention encompasses methods of treating, preventing and / or controlling the course of various diseases using a compound of the invention or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

Examples of diseases or disorders include, but are not limited to, cancer, angiogenesis-related disorders, pain, including complex regional pain syndrome (CRPS), macular degeneration (MD) and related syndromes, skin diseases, pulmonary diseases, asbestos-related disorders, parasitic diseases, immunodeficiency disorders, central nervous system disorders, central nervous system damage, atherosclerosis and related disorders, sleep disorders and related disorders, hemoglobinopathy and related disorders (e.g. anemia), p disorders associated with TNFα, and various other diseases and disorders.

The terms “treat” and “treatment”, as used herein, unless otherwise indicated, refer to eradicating or improving the course of a disease or disorder, or one or more symptoms associated with the disease or disorder. In certain embodiments, the terms refer to minimizing the spread or worsening of a disease or disorder resulting from the administration of one or more prophylactic or therapeutic agents to a patient having such a disease or disorder.

The terms “prevent,” “prevention,” and “prophylaxis,” as used herein, unless otherwise indicated, refer to preventing the onset, recurrence, or spread of a disease or disorder or one or more of its symptoms.

The terms “control the course” and “control the course”, as used herein, unless otherwise indicated, refer to preventing or slowing the progression, spread or worsening of a disease or disorder or one or more of its symptoms. Often, the beneficial effects of a prophylactic or therapeutic agent that are achieved in a patient do not cure the disease or disorder.

As used herein, the term “therapeutically effective amount” of a compound, unless otherwise indicated, defines an amount sufficient to provide a therapeutic effect in the treatment or management of a disease or disorder or to delay the onset or minimize one or more symptoms associated with the disease or disorder. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other types of therapy, that provides a therapeutic effect in the treatment or management of a disease or disorder. The term “therapeutically effective amount” may encompass an amount that improves general therapy, reduces or avoids the symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.

As used herein, the term “prophylactically effective amount” of a compound, unless otherwise indicated, defines an amount sufficient to prevent a disease or disorder or to prevent its reappearance. A prophylactically effective amount of a compound means an amount of a therapeutic agent alone or in combination with other agents that provides a prophylactic effect in preventing disease. The term "prophylactically effective amount" may encompass an amount that improves overall prophylaxis or increases the prophylactic efficacy of another prophylactic agent.

In one embodiment, the compounds described herein are used to treat, prevent, and / or control the course of cancer or precancerous conditions. As disclosed in the description, without limitation by any particular theory and unless otherwise indicated, it was found that some of the compounds described in the description exhibit antiproliferative effects on various cancer cells, which was found by methods both specified in the description and known from prior art. Examples of cancer cells include, but are not limited to, Namalwa, HN 5q (oral carcinoma), HT-1080 (fibrosarcoma), SK-MES-1 (5q, lungs), U87MG (glioblastoma, astrocytoma), T98G (p53 mutant, glioblastoma) , SH-SY5Y (neuroblastoma), SK-N-MC (neuroblastoma), PC-3 (prostate), MCF-7 (breast), T-47D (breast), SF-268 (CNS), HCT-116 (direct intestine), 786-O (kidneys), AN98 (kidneys), SN12C (kidneys), TK-10 (kidneys), CCRF-CEM (leukemia), HL-60 (leukemia), K0562 (leukemia), A549 (lungs) , Nor 92 (lungs), NCI-H1650 (lungs), NCI-H522 (lungs), GRANTA-519 (integument cell lymphoma), REC-1 (integument cell lymphoma), Malme-3M (melanoma), MDA-MB- 435 (melanoma), SK-MEL-28 (melanoma), M1 4 (melanoma), SK-MEL-2 (melanoma), U266B1 (multiple myeloma), KARPAS-1106P (non-Hodgkin lymphoma), KARPAS-422 (non-Hodgkin lymphoma), OCI-LY-19 (non-Hodgkin lymphoma), WSU-DLCL2 ( non-Hodgkin's lymphoma).

Examples of cancerous and precancerous conditions include, but are not limited to, those described in US Pat. Nos. 6,282,230 and 5,635,517 issued to Muller et al. In various patent publications of Zeldis in the USA, including publication 2004 / 0220144A1 published on November 4, 2004 (treatment of myelodysplastic syndrome ), 2004 / 0029832A1 published on February 12, 2004 (treatment of various types of cancer) and 2004/0087546, published on May 6, 2004 (treatment of myeloproliferative diseases). Examples also include disclosed in PCT / US04 / 14004, filed May 5, 2004. All of these sources are included in this description in their entirety by reference.

Particular examples of cancer include, but are not limited to, various types of skin cancer, such as melanoma, lymph node, breast, cervix, uterus, gastrointestinal tract, lungs, ovaries, prostate, rectum, anus, oral cavity, brain, head and neck, throat, testicles, kidneys, pancreas, bones, spleen, liver, bladder, larynx, nasal passages, and AIDS-related cancer. The compounds are particularly useful for the treatment of blood and bone marrow cancers, such as multiple myeloma and acute and chronic leukemias, for example, lymphoblastic, myelogenous, lymphocytic and myelocytic leukemias. The compounds of the invention can be used to treat, prevent and control the course of both primary and metastatic tumors.

Other particular cancers include, but are not limited to, advanced malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforme, glioblastoma, cerebral stem glioma, malignant brain tumors, malignant glioma, recurrent malignant glioma, astrocytoma, anaplastic oligodendroglioma, neuroendocrine cancer, rectal adenocarcinoma, Duke C and D colorectal cancer, inoperable colorectal carcinoma, Tastatic liver cell carcinoma, Kaposi’s sarcoma, acute carotypic myeloblastic leukemia, chronic lymphocytic leukemia (CLL), Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse mast cell lymphoma, undeveloped follicular lymphoma melanoma (localized melanoma, including, but not limited to, ocular melanoma), malignant mesothelioma, malignant pleural effuse mesotheliomatic syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecological sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histocytosis, leiomyosarcoma, progressive bone fibrodysplasia, prostate cancer that is not amenable to hormonal therapy, operated soft tissue sarcoma with high risk, non-surgical neurocysteine carcinoma sluggish myeloma, painless myeloma, cancer of the fallopian tubes, prostate cancer independent of androgens, non-metastatic stage IV prostate cancer dependent on androgen in prostate cancer refractory to chemotherapy, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma. In a particular embodiment, the cancer is immune or resistant to chemotherapy or radiation.

In one particular embodiment, the invention encompasses methods for treating, preventing, or controlling the course of various forms of leukemia, such as chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, and acute myeloblastic leukemia, including leukemias that are relapsed or resistant to as described in US patent publication No. 2006/0030594, published February 9, 2006, which is incorporated in its entirety by reference.

The term "leukemia" refers to malignant neoplasms in the hematopoietic tissues. Leukemia includes, but is not limited to, chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, and acute myeloblastic leukemia. Leukemia can have a relapse, be immune or resistant to conventional therapy. The term “relapse” refers to a situation in which a patient who has previously entered the stage of remission of leukemia after therapy has a return of leukemic cells in the bone marrow and a decrease in the level of normal blood cells. The term “refractory or resistant” refers to circumstances in which patients, even after intensive treatment, have residual leukemic cells in the bone marrow.

In another particular embodiment, the invention encompasses methods for treating, preventing and controlling the course of various lymphomas, including non-Hodgkin lymphoma (NHL). The term "lymphoma" refers to a heterogeneous group of neoplasms arising in the reticuloendothelial and lymphatic systems. "NHL" refers to the malignant monoclonal proliferation of lymphoid cells in parts of the immune system, including lymph nodes, bone marrow, spleen, liver and gastrointestinal tract. Examples of NHL include, but are not limited to, integumentary cell lymphoma, MCL, intermediate differentiated lymphocytic lymphoma, intermediate lymphocytic lymphoma, ILL, diffuse weakly differentiated lymphocytic lymphoma, PDL, centrocytic lymphoma, diffuse lymphocytic lymphoma with poorly split cells, DSCCL lymphoma, and follicoma lymphoma cells that can be observed under a microscope (nodular, diffuse, blastic and lymphoma of the integumentary zone).

Examples of diseases and disorders associated with or characterized by unwanted angiogenesis include, but are not limited to, inflammatory diseases, autoimmune diseases, viral diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases, choroidal neovascular diseases, retinal neovascular diseases and rubeosis (neovascularization of the angle of the eye). Particular examples of diseases and disorders associated with or characterized by unwanted angiogenesis include, but are not limited to, endometriosis, Crohn's disease, heart failure, advanced heart failure, kidney damage, endotoxemia, toxic shock syndrome, osteoarthritis, replication of retroviruses, exhaustion, meningitis, silica fibrosis, asbestos fibrosis, veterinary disorders, malignancy hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, macrocyte new anemia, immune anemia and 5q removal syndrome.

Examples of pain include, but are not limited to, those described in US Patent Publication 2005/0203142, published September 15, 2005, which is incorporated herein by reference. Particular examples of pain include, but are not limited to, malignant pain, neuropathic pain, mixed nociceptive and neuropathic pain, pain in the internal organs, migraine, headache, and postoperative pain.

Examples of nociceptive pain include, but are not limited to, pain associated with chemical or thermal burns, skin cuts, skin bruises, osteoarthritis, rheumatoid arthritis, tendonitis, and myofascial pain.

Examples of neuropathic pain include, but are not limited to, CRPS type 1, CRPS type 2, reflex sympathetic dystrophy (RSD), reflex neurovascular dystrophy, reflex dystrophy, sympathetically-maintained pain syndrome, causalgia, bone atrophy Zyudeka, algoneyrodistrofiyu, shoulder hand syndrome (shoulder hand ), post-traumatic dystrophy, trigeminal neuralgia, postherpetic neuralgia, cancer-related pain, phantom limb pain, fibromyalgia, chronic fatigue syndrome, pain in case of spinal injury, central post-stroke pain, radiculopathy, diabetic neuropathy, post-stroke pain, syphilitic neuropathy and other painful neuropathic conditions, in particular those induced by drugs such as vincristine and Velcad.

The terms “complex regional pain syndrome”, “CRPS” and “syndromes related to CRPS” as used herein, unless otherwise indicated, refer to a chronic pain disorder characterized by one or more of the following: pain, spontaneous or caused by something, including allodynia (a painful response to a stimulus that is usually not painful) and hyperalgesia (excessive response to a stimulus that is usually moderately painful); pain disproportionate to the event causing it (for example, years of severe pain after sprains in the ankle); regional pain, which is not limited to a single peripheral nerve congestion, and an independent disorder (for example, rash, changes in blood flow and hyperhidrosis) associated with trophic changes in the skin (anomalies in hair and nail growth and skin ulceration).

Examples of macular degeneration (MD) and related syndromes include, but are not limited to, those described in US Patent Publication No. 2004/0091455, published May 13, 2004, which is incorporated herein by reference. Particular examples include, but are not limited to, atrophic (dry) MD, exudative (wet) MD, age-related maculopathy (ARM), choroidal neovascularization (CNVM), retinal pigment epithelium detachment (PED), and retinal pigment epithelium atrophy (RPE).

Examples of skin diseases include, but are not limited to, those described in US Patent Publication No. 2005 / 0214328A1, published September 29, 2005, which is incorporated herein by reference. Particular examples include, but are not limited to, keratoses and related symptoms, diseases or skin disorders characterized by excessive growth of the epidermis, acne and wrinkles.

The term “keratosis,” as used herein, unless otherwise indicated, refers to any epidermal lesion marked by the presence of outlined overgrowth of the stratum corneum, including but not limited to actinic keratosis, seborrheic keratosis, keratoacanthoma, follicular keratosis (Deriere’s disease), reversed follicular , palmoplastic keratoderma (RRK, palmar and plantar keratosis), pilar keratosis, and stucco-like keratosis. The term "actinic keratosis" also refers to senile keratosis, senile wart, flat senile wart, solar keratosis, keratoderma or keratoma. The term "seborrheic keratosis" also refers to a seborrheic wart, senile wart or basal cell papilloma. Keratosis is characterized by one or more of the following symptoms: gross appearance, scaly erythematous nodules, plaques, spicules and nodular thickenings on affected surfaces (for example, face, hands, ears, neck, legs and chest), keratin formation is called skin keratinization, hyperkeratosis, telangiectasis, elastosis, pigmented bulges, acanthosis, parakeratosis, dyskeratosis, papillomatosis, hyperpigmentation of basal cells, cell atypia, mitotic figures, abnormal intercellular adhesion, p otnymi inflammatory infiltrates and small prevalence of squamous cell carcinomas.

Examples of skin diseases or disorders characterized by excessive growth of the epidermis include, but are not limited to, diseases or disorders marked by the presence of excess growth of the epidermis, including, but not limited to infections associated with the papillomavirus, arsenic keratosis, signs of Leser-Trel, warty diskerata (WD), bundled hair (TS), variable erythrokeratoderma (EKV), serum ichthyosis (harlequin ichthyosis), pillows on the joints of the fingers, cutaneous melanocanthoma, porokeratosis, psoriasis, squamous cell carcinoma, fused and reticular papillomatosis (CRP), acrochordones, skin keratinization, Cowden's disease (multiple hamartoma syndrome), black papular dermatosis (DPN), epidermal nevus syndrome (ENS), common ichthyosis, molluscum contagiosum, nodular pruritus and blackening acanthosis (AN).

Examples of pulmonary disorders include, but are not limited to, those described in US 2005/0239842A1 published October 27, 2005, which is incorporated herein by reference. Particular examples include pulmonary hypertension and related disorders. Examples of pulmonary hypertension and related disorders include, but are not limited to, primary pulmonary hypertension (PPH), secondary pulmonary hypertension (SPH), familial PPH, sporadic PPH, precapillary pulmonary hypertension, pulmonary arterial hypertension (RAS), pulmonary hypertension, idiopathic , thrombotic pulmonary arteriopathy (TPA), plexogenic pulmonary arteriopathy, functional classes of pulmonary hypertension I to IV or pulmonary hypertension associated with or secondary to dysfunction left ventricular cysts, mitral valve disease, constricting pericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, abnormal pulmonary venous drainage, pulmonary vein obstruction disease, collagen vascular disease, congenital heart disease, HIV virus infection, effects of drugs and toxins such as fenfoxins and toxins such as , congenital heart disease, pulmonary venous hypertension, chronic obstructive pulmonary disease, interstitial pulmonary disease, sleep disturbance, distention swelling with alveolar hypoventilation, chronic exposure of high altitude, pulmonary disease of the newborn, alveolar capillary dysplasia, sickle cell disease, other coagulation disorders, chronic thromboembolism, connective tissue disease, lupus, including systemic and cutaneous lupus erythematosus, schistosomiasis, and hematosomiasis.

Examples of asbestos-related disorders include, but are not limited to, those described in US Application No. 2005/0100529, filed May 12, 2005, which is incorporated herein by reference. Particular examples include, but are not limited to, asbestos mesothelioma, malignant pleural effusion, benign exudative effusion, pleural plaques, pleural calcification, diffuse pleural thickening, circular atelectasis, fibrotic masses, and lung cancer.

Examples of parasitic diseases include, but are not limited to, those described in US Application No. 11/271963, filed November 14, 2005, which is incorporated herein by reference. Parasitic diseases include diseases and disorders caused by human intracellular parasites, such as, but not limited to, P. falcifarium, P. ovale, P. vivax, P. malariae, L. donovari, L. infantum, L. aethiopica, L. major , L. tropica, L. mexicana, L. braziliensis, T. Gondii, B. microti, B. divergens, B. coli, C. parvum, C. cayetanensis, E. histolytica, I. belli, S. mansonii, S .haematobium, Trypanosoma ssp., Toxoplasma ssp. and O. volvulus . Other diseases and disorders caused by intracellular parasites of species other than humans, such as, but not limited to, Babesia bovis, Babesia canis, Banesia Gibsoni, Besnoitia darlingi, Cytauxzoon felis, Eimeria ssp., Hammondia ssp. and Theileria ssp . Specific examples include, but are not limited to, malaria, babesiosis, trypanosimiasis, leishmaniasis, toxoplasmosis, meningoencephalitis, keratitis, amoebiasis, giardiasis, cryptosporidiosis, isosporiasis, cyclosporiasis, microsporidiosis, trichiosis trichiosis, trichiosis, ankylosis, ankylosis, trichiosis, ankylosis, ankylosis, trichiosis, ankylosis, ankylosis, trichiosis, ankylosis, ankylosis, trichiosis, ankylosis, ankylosis, trichiosis, ankylosis, ankylosis, a lymphocytosis, an anesthesia , filariasis, schistosomiasis and dermatitis caused by animal schistosomes.

Examples of immunodeficiency disorders include, but are not limited to, those described in US Application No. 11/271963, filed November 30, 2005. Particular examples include, but are not limited to, adenosine deaminase deficiency, antibody deficiency with normal or elevated Ig, ataxia-tenlangiectasia, bare lymphocyte syndrome, common variable immunodeficiency, Ig deficiency with hyper-IgM, heavy chain Ig removal, IgA deficiency, thymoma immunodeficiency , reticular dysgenesis, Nezelov’s syndrome, selective IgG subclass deficiency, transient childhood hypogammaglobulinemia, Wiskott-Aldrich syndrome, X-linked agammaglobulinemia, X-linked severe combined immunodeficiency.

Examples of CNS disorders include, but are not limited to, those described in US publication No. 2005/0143344A1, published June 30, 2005, which is incorporated herein by reference. Particular examples include, but are not limited to, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, and other neuroimmune disorders such as Tourette’s syndrome, delirium or consciousness disorders that occur in a short period of time, or amnestic disorder, or partial memory damage that occurs in the absence of other damage to the central nervous system.

Examples of CNS lesions include, but are not limited to, those described in US Application No. 11/284403, filed November 18, 2005, which is incorporated herein by reference. Particular examples include, but are not limited to, CNS lesions / lesions and related syndromes, including, but not limited to, primary brain damage, secondary brain damage, traumatic brain damage, focal brain damage, diffuse axon damage, head damage, concussion, post-mortem syndrome concussion, contusion or rupture of the spine, subdural hematoma, epidermal hematoma, post-traumatic epilepsy, chronic vegetative state, full SCI, incomplete SCI, acute SCI, subacute SCI, chro SCI, central cord syndrome, Brown-Sequard syndrome, outer cord syndrome, cerebral cone syndrome, ponytail syndrome, neurogenic shock, spinal shock, alternating levels of consciousness, headache, motion sickness, vomiting, memory loss, dizziness, diplopia, blurred vision, emotional lability, sleep disturbances, irritability, inability to concentrate, nervousness, behavioral disturbances, cognitive deficits and seizures.

Other diseases or disorders include, but are not limited to, viral, genetic, allergic, and autoimmune diseases. Particular examples include, but are not limited to, HIV, hepatitis, adult respiratory distress syndrome, bone resorption diseases, chronic inflammatory pulmonary diseases, dermatitis, vesiculate fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock, septic syndrome, postischemic reperfusion injury , meningitis, psoriasis, fibrotic disease, cachexia, graft versus host disease, graft rejection, autoimmune disease, rheumatoid spondylitis, Crohn’s disease, I ulcerative colitis, inflammatory disease of the stomach, multiple sclerosis, systemic lupus erythrematosis, ENL with leprosy, radiation damage, cancer, asthma or hyperoxic alveolar damage.

Examples of atherosclerosis and related conditions include, but are not limited to, those described in US Publication No. 2002/0054899, published May 9, 2002, which is incorporated herein by reference. Particular examples include, but are not limited to, all forms of conditions including atherosclerosis, including restenosis after vascular intervention, such as angioplasty, stenting, atherectomy, and transplantation. The invention encompasses all forms of vascular interventions, including those performed for diseases of the cardiovascular and renal systems, such as, but not limited to, renal angioplasty, subcutaneous coronary intervention (PCI), subcutaneous transluminal coronary angioplasty (PTCA), subcutaneous transluminal angioplasty of the carotid artery ), coronary artery bypass grafting, stent implantation angioplasty, peripheral subcutaneous transluminal surgery on the iliac, femoral or popliteal arteries, and surgical BM Persistence using impregnated artificial grafts. The following table contains a list of the main systemic arteries that may need treatment, all of which are covered by the invention:

Artery Provides blood supply to the body Axillary Shoulder and armpit Humeral Upper arm Shoulder Head Head, neck and arm Abdominal It is divided into the left gastric, splenic and hepatic arteries Total sleepy Neck Total iliac Divided into the external and internal iliac arteries Coronary Heart Deep femoral Hip Finger Fingers Rear foot Leg Outdoor sleepy Neck and external areas of the head External iliac Femoral artery Femoral Hip Gastric Stomach Hepatic Liver, gall bladder, pancreas and duodenum Inferior mesenteric The descending part of the rectum, the anus and the wall of the renal pelvis Inner carotid Neck and internal areas of the head Internal iliac Anus, bladder, external genitalia, gluteus, uterus and vagina Left gastric Esophagus and stomach Middle sacral Sacrum Ovarian Ovaries Palm arc Palm Fibular Hind tibia Popliteal Knee Posterior tibial Hind tibia Pulmonary Lungs Beam Forearm Renal Kidney Splenic Stomach, pancreas and spleen Subclavian Shoulder Superior mesenteric Pancreas, small intestine, ascending and transverse colon Testicular Testicles Elbow Forearm

Examples of sleep disorders and related syndromes include, but are not limited to, those described in US Publication No. 2005 / 0222209A1, published October 6, 2005, which is incorporated herein by reference. Particular examples include, but are not limited to, snoring, sleep apnea, insomnia, narcolepsy, tired leg syndrome, nightmares, sleepwalking, eating food in sleep, and sleep disorders associated with chronic neurological or inflammatory conditions. Chronic neurological or inflammatory conditions include, but are not limited to, complex regional pain, chronic lower back pain, musculoskeletal pain, arthritis, radiculopathy, cancer-related pain, fibromyalgia, chronic fatigue syndrome, pain in the internal organs, pain in the bladder, chronic pancreatitis, neuropathies (diabetic, postherpetic, traumatic or inflammatory) and neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, lateral myotrophic sclerosis, multiple sclerosis, Huntington’s disease, bradykinesia, muscle stiffness, parkinsonian tremor, parkinsonian gait, stiffness of movement, depression, long-term memory impairment, Rubinstein-Teiba syndrome (RTS), dementia, body position instability, hypokinetic disorders, synuclein systemic atrophies, degeneration of the striatum and black body, olivopontocerebellar atrophy, Shay-Draeger syndrome, disease of motor neurons with parkinsonian features, dementia ia Levy, tau-pathological disorders, progressive supranuclear palsy, corticobasal degeneration, temporary anterior brain dementia, amyloid pathological disorders, moderate cognitive impairment, Alzheimer's disease with parkinsonism, Wilson's disease, Hallerforden-Spac disease, Hedeyax-Hag disease spinal cord SCA-3, parkinsonism with X-linked dystonia, prion disease, hyperkinetic disorders, chorea, ballism, dystonic tremors, amyotrophic lateral sclerosis (ALS), trauma to the central nervous system and myoclonus.

Examples of hemoglobinopathies and related disorders include, but are not limited to, those described in US publication No. 2005/0143420A1, published June 30, 2005, which is incorporated herein by reference. Particular examples include, but are not limited to, hemoglobinopathy, sickle cell anemia, and any other disorders associated with the differentiation of CD34 + cells.

Examples of disorders associated with TNFα include, but are not limited to, those described in WO 98/03502 and WO 98/54170, both of which are incorporated herein by reference in their entireties. Particular examples include, but are not limited to, endotoxemia or toxic shock syndrome, cachexia, adult respiratory distress syndrome, bone resorption diseases such as arthritis, hypercalcemia, graft versus host disease, cerebral malaria, inflammation, tumor growth, chronic pulmonary inflammatory diseases, reperfusion injury, myocardial infarction, stroke, circulatory shock, rheumatoid arthritis, Crohn's disease, HIV and AIDS infection, other disorders such as rheumatoid arthritis, rheumatoid sp ndilitis, osteoarthritis and other arthritic conditions, septic shock, sepsis, endotoxic shock, graft versus host disease, depletion, Crohn's disease, ulcerative colitis, multiple sclerosis, systemic lupus erythromatosis, ENL for leprosy, HIV, AIDS and associated infections with AIDS cAMP disorders such as septic shock, sepsis, endotoxic shock, hemodynamic shock and septic syndrome, postischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congenital rock heart, fibrotic disease, cachexia, graft rejection, oncogenic or cancerous conditions, asthma, autoimmune disease, radiation damage, and hyperoxic alveolar damage, viral infections such as those caused by the herpes viruses, viral conjunctivitis, or atopic dermatitis.

In other embodiments, the invention also encompasses various immunological uses of the compounds of this invention, in particular as adjuvants of vaccines, especially as adjuvants of anti-cancer vaccines, as disclosed in provisional application US No. 60/712823, filed September 1, 2005, which is included in the description throughout completeness by reference. This aspect of the invention also relates to uses of the compounds of the invention in combination with vaccines for the treatment or prevention of cancer or infectious diseases, and to various other uses of immunomodulatory compounds, such as reducing or desensitizing allergic reactions.

Doses of the compound of this invention or its pharmaceutically acceptable salt, solvate, stereoisomer or prodrug vary depending on factors such as: specific indications for the treatment, prophylaxis or control of the course of the disease, the age and condition of the patient, and the amount of the second active agent, if any. Typically, the compound of this invention or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, may be used in an amount of from about 0.1 mg to about 500 mg per day, and may be administered in a conventional manner (for example, the same amount administered each day during the period of treatment, prophylaxis or management of the disease), cyclically (for example, one week of administration, one week without administration) or in an amount that increases or decreases in the course of treatment, prevention or management of the disease tions.

In other embodiments, the dose may be from about 1 mg to about 300 mg, from about 0.1 mg to about 150 mg, from about 1 mg to about 200 mg, from about 10 mg to about 100 mg, from about 0.1 mg up to about 50 mg, from about 1 mg to about 50 mg, from about 10 mg to about 50 mg, from about 10 mg to about 25 mg, from about 20 mg to about 30 mg, or from about 1 mg to about 20 mg .

4.3 Second Active Agents

The compound of this invention or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, can be combined with other pharmacologically active compounds (“second active agents”) in the methods and compositions of the invention. It is contemplated that certain combinations may act synergistically in the treatment of certain types of diseases or disorders and the conditions and symptoms associated with such diseases or disorders. The compound of this invention or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof can also help reduce side effects associated with the second active agents, and vice versa.

One or more second active ingredients or agents may be used in the methods and compositions of the invention. The second active agents may be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic or organic molecules).

Examples of active agents with large molecules include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies. Particular examples of active agents are anti-CD40 monoclonal antibodies (such as, for example, SGN-40), histone deacetylase inhibitors (such as, for example, SAHA and LAQ 824), heart-shock protein-90 inhibitors (such as, for example, 17-AAG ), insulin-like growth factor-1 receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors (such as, for example, PTK787), insulin growth factor receptor inhibitors, lysophosphatidyl acid acyltransferase inhibitors, pk38 lysophosphatidyl acid kinase inhibitors, EGFR inhibitors (such as, for example, gefitinib and erlotinib HCL), anti-HER-2 antibodies (such as, for example, trastuzumab (Herceptin®) and pertuzumab (Omnitarg ™), anti-VEGFR antibodies (such as, for example, bevacizumab (Avastin ™), VEGFR inhibitors (such as, for example, flk-1 specific kinase inhibitors, SU5416 and ptk787 / zk222584), P13K inhibitors (such as, for example, wortmannin), C-Met inhibitors (such as, for example, PHA-665752) monoclonal antibodies (such as, for example, rituximab (Rituxan®), tositumomab (Bexxar®), edrecolomab (Panorex®) and G250) and anti-TNFα antibodies. Examples of small molecule active agents include, but are not limited to, small molecule anti-cancer agents and antibiotics (e.g., clarithromycin).

Particular second active compounds that can be combined with the compounds of this invention vary depending on the specific indications for the treatment, prophylaxis, or control of the course of the disease.

For example, for treating, preventing, or controlling the course of cancer, the second active agent includes, but is not limited to, semaxanib, cyclosporine, etanercept, doxycycline, bortezomib, acivicin, aclarubicin, acodazole hydrochloride, acronine, adocelesin, aldesleukin, altretamine, ambomycin, ambiticin, acetate , anastrozole, anthramycin, asparaginase, asperlin, azazitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisanthrene hydrochloride, bisanthide dimesilate, bleisomyne sulfate, sodium brechinus, brobrimine, , cactinomycin, calusterone, caratsemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carcelisin, cedefingol, celecoxib, chlorambucil, cirolemicin, cisplatin, cladribine, cisnatol azidecin dicin dacin dacin dicarabin dibasin, desaguanin mesylate, diaziquon, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin, edatrexate, eflornithine hydrochloride, elzamitrucin, enloplatin, enpromate, epipropidine, epirubicin hydrochloride, erbulosol, esorubicin hydrochloride, estramustine, estramustine sodium phosphate, ethanidazole, etoposide, etoposide phosphate, etoprin, fadrozin hydrochloride, fenretin phosphorfin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin phosphoridin, gemcitabine hydrochloride, hydroxyurea, idorubicin hydrochloride, ifosfamide, ilmofosin, iproplatin, irinotecan, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, lometrexo sodium, lomustine, losoxantrone hydrochloride, mazoprokol, maytansine, mechlorethamine hydrochloride, magestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, methotrexitene, methotermitinitromitin, metarometin mitrominitocin, metarometin mitrominitocin, mitomecinitromitocin, , mitoxantrone hydrochloride, mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran, paclitaxel, pegaspargase, peliomycin, pentamustine, peplomycin sulfate, perphosphamide, pipobromane, piposulfan, pi hydrochloride oxantrone, plicamycin, plomestan, sodium porphymer, porphyromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, riboprine, safingol, safingol hydrochloride, semustine, simtrazene, sparfrinosyrrhimpropin syrphosphinosyrrhimpropin syrfin synthromin, sulofenur, talisomycin, tecogalan sodium, taxotere, tegafur, teloxantrone hydrochloride, temoporfin, teniposide, teroxiron, testolactone, thiamiprine, thioguanine, thiotepa, thiazofurin, tirapazamine, toremifene citrate, trestolone acetate, tricyribine phosphate, trimethrexate, trimerexate glucuronate, triptorelin, tubulozole hydrochloride, uracil mustard gas, uredepa, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate, vindehydin sulfate, vindethine sulfate, vindethine sulfate, vindethine sulfate, vindethine sulfate, vindepartine sulfate, vindethine sulfate Vinrozidine sulfate, Vinzolidine sulfate, Vorozol, Zeniplatin, Zinostatin and Zorubicin hydrochloride.

Other second agents include, but are not limited to, 20-epi-1,25-dihydroxy-vitamin D3, 5-ethynyluracil, abiraterone, aclarubicin, acylfulven, adecenol, adocelesin, aldesleukin, ALL-TK antagonists, altretamine, ambamustine, amidexin, amide , aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, andrografide, angiogenesis inhibitors, antagonist D, antagonist G, antarelix, antidorsalizing morphogenetic protein-1, antiandrogen, antiestrogen, antineoplaston, antisyntolic oligidines and apoptosis, apoptosis regulators, apuric acid, ara-CDP-DL-PTBA, arginine deaminase, azulacrine, atamestan, atrimustine, axinastatin 1, axinastatin 2, axinastatin 3, azasetron, azatoxin, azathyrosine, bacastin anastasia, baccatin batin, III / ABL, benzochlorins, benzoylstavrosporin, beta-lactam derivatives, beta-aletin, betaclamycin B, betulinic acid inhibitor, bFGF inhibitor, bicalutamide, bisanthrene, bisaziridinyl spermine, bisnaphide, bistanten A, bicelisin, brefolcipotin, biripflotin calipotin, biripflotin caliphtin, biripflotin, caliphtin, biripflotin, caliphtin, birfolipitotin, biripolithin, birpolithin, calcin, birifolithin, birpolithin, calcin stin C, camptothecin derivatives, capecitabine, carboxamide-amino-triazole, carboxyamidotriazole, CaRest M3, CARN 700, cartilage-derived inhibitors, carcelesin, casein kinase inhibitors (ICOS), castanospermin, cecropin B, cetroreloxin, chlorine, chlorine, chlorine, chlorine cis-porphyrin, cladribine, clomiphene analogues, clotrimazole, collismicin A, collismicin B, combretastatin A4, combretastatin analog, conagenin, crambescidin 816, crisnatol, cryptophycin 8, cryptophycin derivatives A, curacin A, cyclopentaminophen, cyclopentamin SFAT cytarabine, cytolytic factor tsitostatin, dakliksimab, decitabine, dehydrodidemnin B, deslorelin, dexamethasone, deksifosfamid, dexrazoxane, deksverapamil, diazikon, didemnin B, didoks, dietilnorspermin, dihydro-5-azacytidine, digidrotaksol-9 dioksamitsin, difenilspiromustin, docetaxel, docosanol, dolasetron, doxyfluuridine, doxorubicin, droloxifene, dronabinol, duocarmycin SA, ebselen, ecomustine, edelfosin, edrecolomab, eflornithine, elemene, emitfur, epirubicin, episteride, an estrogen estrogen analogue, estrogen estrogen omena, ethanidazole, etoposide phosphate, exemestane, fadrozole, fazarabin, phenretinide, filgrastim, finasteride, flavopyridol, fleselastine, fluasterone, fludarabine, fluorodaunorunicin hydrochloride, forfenimex, formestane finalinitricin ginolithinolithinin telecinolin tecinolin ginolithinolithinin telecinolin ginolithinin telecinolin tecinolin ginitrinithin ginolithinolin , gemcitabine, glutathione inhibitors, hepsulfam, heregulin, hexamethylene bisacetamide, hypericin, ibandronic acid, idarubicin, idoxifene, idramanton, ilmofosin, ilomastat, imatinib (Gleevec®), imimodim, immunostimulatory peptides, an insulin-like growth factor 1 receptor inhibitor, interferon agonists, interferons, interleukins, iobenguang, iododoxorubicin, 4-ipomeanol, iroplact, irsogladine, isobengazole, isogomogalicondrin B, itacetron, jadeglamelamine lameglamine lameglamegal , lentinan sulfate, leptolstatin, letrozole, leukemia inhibition factor, alpha-leukocyte interferon, leuprolide + estrogen + progesterone, leuprorelin, levamisole, liarozole, linear polyamine analogue, lipophilic disaccharide peptide, l core compounds of platinum, lissoclinamide 7, lobaplatin, lombricin, lometrexol, lonidamine, losoxantrone, loxoribine, lurotekan, texafirin lutetium, lysophylline, lytic peptides, maytansine, mannostatin A, marimastat, masoprocaritol matrix, inhibitors, metalloporolitin, matricin inhibitors, mazoprotorolitin, , meteralin, methioninase, metoclopramide, MIF inhibitor, mifepristone, miltefosin, mirimostim, mitoguazone, mitolactol, mitomycin analogues, mitonafide, mitotoxin fibroblast growth factor-saporin, mitoxantrone, mofaroten , molgramostim, Erbitux, human chorionic gonadotropin, complex monophosphoryl lipid A + myobacteria cell wall, mopidamol, mustard gas as an anticancer agent, mikaperoxide B, myobacteria cell wall extract, myriaporon, N-acetyldyline, N-substituted benzamide oxides, n-substituted benzamides, nenfarfenamides + pentazocine, napavin, nafteprin, nartograstim, nedaplatin, nemorubicin, neridronic acid, nilutamide, nizamycin, nitric oxide modulators, nitroxide antioxidants, nitrulline, oblimersen (Genasense®), O6-benzylguanine, octreotide, okits non, oligonucleotides, onapristone, ondansetron, oratsin inductor oral cytokine ormaplatin, ozateron, oxaliplatin, oksaunomitsin, paclitaxel, paclitaxel analogues, paclitaxel derivatives, palauamin, palmitoilrizoksin, pamidronic acid, panaksitriol, panomifen, parabaktin, patselliptin, pegaspargazu, peldezin, pentosan sodium polysulfate, pentostatin, pentrozole, perflubron, perfosfamide, perilyl alcohol, phenazinomycin, phenylacetate, phosphatase inhibitors, picybanil, pilocarpine hydrochloride, pyrarubicin, pyritrexime, placenta A, placetin B, plasminogen activator inhibitor, platinum complex, platinum compounds, platinum-triamine complex, sodium porphymer, porphyromycin, prednisone, propyl bis-acridone, prostaglandin J2, proteasome inhibitors, protein A immunomodulator, protein kinase C inhibitor, microalgal, protein tyrosine phosphatase inhibitors, purine nucleoside phosphorylase inhibitors, purpurins, pyrazoloacridine, pyridixylated hemoglobin-polyoxyethylene conjugate, raf antagonists, altitrexed, ramosetron, ras-farnesylproteinrans inhibitors erases, ras inhibitors, ras-GAP inhibitor, demethylated retilliptin, rhenium ethidronate Re 186, rhizoxin, ribozymes, retinamide RII, rogitukin, romurtid, roquinimex, rubiginon B1, ruboxyl, safingol, sintopin, SarCNU sarcom, sarco 1 sarco , semustine, inhibitor 1 - senescene derivative, semantic oligonucleotides, signal transmission inhibitors, sisofiran, sobuzoxan, sodium borocaptate, sodium phenylacetate, solverol, somatomedin binding protein, sonermin, sparfosic acid, spicamycin D, spiromustine, splenopentin 1, sponghistam, sponistamine, spon in, stipiamid inhibitors of stromelysin, sulfinozin antagonist superactive vasoactive intestinal peptide suradistu, suramin, svainsonin, tallimustin, methiodide tamoxifen tauromustin, tazarotene, tekogalan sodium, tegafur, tellurapirily, telomerase inhibitors, temoporfin, teniposide, tetrahlordekaoksid, tetrazomin, taliblastin, thiocoralin, thrombopoietin, thrombopoietin mimetic, thymalfasin, thymopoietin receptor agonist, thymotrinan, thyroid stimulating hormone, etiopurpurin ethyltin, tirapazamine, titanocene bichloride, topsent n, toremifene, translation inhibitor, tretinoin, triacetyluridine, tricyribine, trimethrexate, triptorelin, tropisetron, tourosteride, tyrosine kinase inhibitors, tyrfostins, UBC inhibitors, ubenimex, growth inhibitory urogenital factor, sine, antagonist resins, variotapol receptor antagonists, receptor antagonists , Veraminum, Verdins, Verteporfin, Vinorelbine, Vinxaltinum, Vitaksin, Vorozol, Zanoteronum, Zeniplatin, Ziloscorb and Zinostatin Stimalamer.

Particular second active agents include, but are not limited to, 2-methoxyestradiol, telomestatin, substances that cause apoptosis in multiple myeloma cells (such as, for example, TRAIL), statins, semaxanib, cyclosporine, etanercept, doxycycline, bortezomib, oblimersen (Genasense®) , remicad, docetaxel, celecoxib, melphalan, dexamethasone (Decadron®), steroids, gemcitabine, cisplatin, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, Tykerb®, metatrecine, lapate taxol, taxotere, fluorouracil, watering can rin, irinotecan, xeloda, CPT-11, alpha interferon, pegylated alpha interferon (for example, PEG INTRON-A), capecitabine, cisplatin, thiotepu, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxolin, paclatin, paclatin, paclabin, paclatin, paclatin, paclatin, paclin 2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil®), ganciclovir, adriamycin, estramustine sodium phosphate, Emoid

Similarly, examples of private second agents corresponding to indications for the treatment, prophylaxis, or control of various diseases can be found in the following references, which are incorporated by reference in their entirety: US Pat. Nos. 6,282,230 and 5,635,517, US Applications Nos. 10/441649, 10 / 483213, 10/411656, 10/693794, 10/699154 and 10/981189 and provisional applications US No. 60/554923, 60/565172, 60/626975, 60/630599, 60/631870 and 60/533862.

Examples of second active agents that can be used to treat, prevent and / or manage pain include, but are not limited to, conventional therapeutic agents used to treat or prevent pain, such as antidepressants, anticonvulsants, antihypertensive agents, anxiolytics, calcium blockers canals, muscle relaxants, non-narcotic analgesics, opioid analgesics, anti-inflammatory drugs, cox-2 inhibitors, immunomodulating agents, agonists or antagonists of al pf-adrenergic receptor, immunosuppressants, corticosteroids, hyperbaric oxygen, ketamine, other anesthetics, NMDA antagonists and other therapeutic agents, which, for example, can be found in the Physician's Desk Reference 2003. Specific examples include, but are not limited to, salicylic acid acetate (Aspirin ®), celecoxib (Celebrex®), Enbrel®, ketamine, gabatentin (Neurontin®), phenytoin (Dilantin®), carbamazepine (Tegretol®), oxcarbazepine (Trileptal®), valproic acid (Depakene®), morphine sulfate, hydromine, prednisone, griseofulvin, pentonium, alendronate, difengi dramide, guanethidine, ketorolac (Acular®), tyrocalcitonin, dimethyl sulfoxide (DMSO), clonidine (Catapress®), bretilium, ketanserin, reserpine, droperidol, atropine, phentolamine, bupivacaine, lidocaine, acetaminriptyline®, (acetaminriptyline, n ®), imipramine (Tofranil®), doxepin (Sinequan®), clomipramine (Anafranil®), fluoxetine (Prozac®), sertraline (Zoloft®), nefazodone (Serzone®), venlafaxine (Effexor®), trazodone (Desyrel®) , bupropion (Wellbutrin®), mexiletine, nifedipine, propranolol, tramadol, lamotrigine, ziconotide, ketamine, dextromotorfan, benzodiazepines, baclofen, tizanidine and phenoxib nzamin.

Examples of second active agents that can be used for the treatment, prophylaxis, and / or management of MD and related syndromes include, but are not limited to, a steroid, light detector, integrin, antioxidant, interferon, xanthine derivative, growth hormone, neurotrophic factor, neovascularization regulator , anti-VEGF antibody, prostaglandin, antibiotic, phytoestrogen, anti-inflammatory compound or anti-angiogenetic compound, or a combination thereof. Specific examples include, but are not limited to, verteporfin, purlitin, an angiostatic steroid, rhuFab, interferon-2α, pentoxifylline, etiopurpurin tin, lutecium motexafine, 9-fluoro-11,21-dihydroxy-16,17-methylethylidenbis (hydroxy) pregna-1 , 4-diene-3,20-dion, latanoprost (see US patent No. 6225348), tetracycline and its derivatives, rifamycin and its derivatives, macrolides, metronidazole (see US patent No. 6218369 and 6015803), genistein, genistin, 6'-O-Mal genistin, 6'-O-ac genistin, daidzein, daidzin, 6'-O-Mal daidzin, 6'-O-Ac daidzin, glycitein, glycithin, 6'-O-Mal glycithin, biochanin A formononite in (US patent No. 6001368), triamcinolone acetamide, dexamethasone (US patent No. 5770589), thalidomide, glutathione (US patent No. 5632984), main fibroblast growth factor (bFGF), transforming growth factor b (TGF-b), neurotrophic growth factor derived from the brain (BDNF), plasminogen activator factor 2 (PAI-2), EYE101 (Eyetech Pharmaceuticals), LY333531 (Eli Lilly), Miravant and RETISERT implant (Bausch & Lomb). All of the above sources are included in the description in their entirety by reference.

Examples of second active agents that can be used to treat, prevent, and / or control the progression of skin diseases include, but are not limited to, keratolytics, retinoids, α-hydroxy acids, antibiotics, collagen, botulinum toxin, interferon, steroids, and immunomodulating agents. Particular examples include, but are not limited to, 5-fluorouracil, mazoprokol, trichloroacetic acid, salicylic acid, lactic acid, ammonium lactate, urea, tretinoin, isotretinoin, antibiotics, collagen, botulinum toxin, interferon, interferon, corticosteroid, collagen, transretin, transretin, transretin such as human placenta collagen, animal placenta collagen, Dermalogen, AlloDerm, Fascia, Cymetra, Autologen, Zyderm, Zyplast, Resoplast and Isolagen.

Examples of second active agents that can be used to treat, prevent and / or control the course of pulmonary hypertension and related disorders include, but are not limited to, anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, vasodilators, prostacyclin analogs, endothelin antagonists, inhibitors phosphodiesterases (e.g. PDE V inhibitors), endopeptidase inhibitors, lipid lowering agents, thromboxane inhibitors and other known therapeutic agents that reduce yes Lenie in the pulmonary artery. Particular examples include, but are not limited to, warfarin (Coumadin®), a diuretic, cardiac glycoside, digoxin oxygen, diltiazem, nifedipine, a vasodilator such as prostacyclin (e.g. prostaglandin 12 (PG 12), epoprostenol (EPO, Floran®), treprostinil (Remodulin®), nitric oxide (NO), bosentan (Tracleer®), amlodipine, prostacyclin, tadalafil (Cialis®), simvastatin (Zocor®), omapatrilat (Vanlev®), irbesartan (Avapro®), pravastatin (Pravachol®) ), digoxin, L-arginine, iloprost, betaprost and sildenafil (Viagra®).

Examples of second active agents that can be used to treat, prevent and / or control the course of asbestos-related disorders include, but are not limited to, anthracycline, platinum, an alkylating agent, oblimersen (Genasense®), cisplatin, cyclophosphamide, temodar, carboplatin , procarbazine, gliadel, tamoxifen, topotecan, methotrexate, taxotere, irinotecan, capecitabine, cisplatin, thiotepu, fludarabine, liposomal daunorubicin, cytarabine, doxetaxol, paclitaxel, vinblastine, IL-2, GM-azelbinozine, vin-zarbinozin, , palmitronate, biaxin, busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil®), ganciclovir, adriamycin, bleomycin, hyaluronidase, mitomycin C, mepacrine, tetracycline and gemcitabine.

Examples of second active agents that can be used to treat, prevent and / or control the progress of parasitic diseases include, but are not limited to, chloroquine, quinine, quinidine, pyrimethamine, sulfadiazine, doxycycline, clindamycin, mefloquine, halofantrine, primaquine, hydroxychloroquine, proguanil , atovacon, azithromycin, suramin, pentamidine, melarsoprol, nifurtimox, benznidazole, amphotericin B, pentavalent antimony compounds (e.g. sodium stilboglucuronate), gamma interferon, itraconazole, a combination of dead promastigo Comrade and BCG, leucovorin, corticosteroids, sulfonamide, spiramycin, IgG (serology), trimethoprim and sulfomethoxazole.

Examples of second active agents that can be used to treat, prevent and / or control the course of immunodeficiency disorders include, but are not limited to, antibiotics (therapeutic or prophylactic), such as, but not limited to, ampicillin, clarithromycin, tetracycline, penicillin, cephalosporins , streptomycin, kanamycin and erythromycin, antiviral agents such as, but not limited to, amantadine, rimantadine, acyclovir and ribavirin, immunoglobulin, plasma, immunology enhancing drugs, such as, but not limited to restrictions, levamisole and isoprinosine, biological agents such as, but not limited to, gamma globulin, transfer factor, interleukins and interferons, hormones such as, but not limited to, thymic and other immunological agents, such as, but not limited to, stimulants B cells (e.g. BAFF / BlyS), cytokines (e.g. IL-2, IL-4 and IL-5), growth factors (e.g. TGF-α), antibodies (e.g. anti-CD40 or IgM), oligonucleotides containing unmethylated CpG motifs and vaccines (e.g., viral or tumor peptide vaccines).

Examples of second active agents that can be used to treat, prevent, and / or control the course of central nervous system disorders include, but are not limited to, a dopamine agonist or antagonist, such as, but not limited to, levodopa, L-DOPA, cocaine, α-methyl tyrosine, reserpine, tetrabenazine, benzotropin, pargyline, phenodolpam mesylate, cabergoline, pramipexole hydrochloride, ropinorol, amantadine hydrochloride, selegiline hydrochloride, carbidopa, pergolide mesylate, Sinemet CR and Symmetrel, but inhibitor, inhibitor, , f enelzine and isocarboxazide, a COMT inhibitor, such as, but not limited to, tolcapone and entacapone, a cholinesterase inhibitor, such as, but not limited to, physostigmine salicylate, physostigmine sulfate, physostigmine bromide, meostigmine bromide, neostigminononium methyl chloride sulfate, amoridonium chloride , pralidoxime chloride, obidoxime chloride, trimedoxim bromide, diacetyl monoxime, endrophonium, pyridostigmine and demecarium, an anti-inflammatory agent such as, but not limited to, naproxen sodium, diclofenac sodium, diclofenac potassium, celeck sib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone, refekoksib, methotrexate, leflunomide, sulfasalazine, gold salts, Rho-D immunoglobulin mikofenilat mofetil, cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid, sodium meclofenamate, tolmetin, ketorolac, diclofenac, flurbinprofen, oxaprosime, meloxicum, pyroxene, pyroxene roxicam, droxicam, pivoxicum, tenoxicam, phenylbutazone, oxyphenylbutazone, antipyrine, aminopyrine, apazone, cileiton, aurothioglucose, gold-sodium thiomalate, auranofin, methotrexate, colchicine, allopurinolinoronocarbonecidone, othermethylene glucose, benzene, benzene, benzene, benzene, benzene, and other such as, but not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondasetron, granisetron, hydroxyzine, acetyleucine monoethanolamine, alizapride, azasetron, benzinamide, bioethanautin , bromoprid, buklizin, kleboprid, cyclizine, dimenhydrinate, diphenidol, dolasetron, meklizin, metallal, metoprimazine, nabilon, oxypernidil, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, triethyl perazine, thiopropetrazine and their mixtures.

Examples of second active agents that can be used to treat, prevent and / or control the progression of central nervous system damage and related syndromes include, but are not limited to, immunomodulatory agents, immunosuppressants, antihypertensive agents, anticonvulsants, fibrinolytic agents, anti-plaque agents, antipsychotic agents, antidepressants, benzodiazepines, buspirone, amantadine and other known or generally accepted agents used in patients with central nervous system damage / affection and relatedness GOVERNMENTAL syndromes. Specific examples include, but are not limited to, steroids (e.g. glucocorticoids such as, but not limited to, methylprednisolone, dexamethasone and betamethasone), an anti-inflammatory agent, including, but not limited to, naproxen sodium, diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone, refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, Rho-D immunoglobulin, mycophenylate mofetil, cyclosporine, azathioprine, tacrolimus, doprolimus, tacrolimus, salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid, meclofenamate sodium, tolmetin, ketoricoxicroficromicroficroxicroxycicroficroficroficroficroficroficroficroficroficrofibromicroficroficromicroficroficromicroficrofibromicin phenylbutazone, oxyphenylbutazone, antipyrine, aminopyrine, apazone, cileiton, aurothioglucose, gold-sodium thiomalate, auranofin, methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone and benzbromarone, cAMP analogue, VK Available, but not limited to, db-cAMP, an agent comprising a methylphenidate drug that includes l-threo-methylphenidate, d-threo-methylphenidate, dl-threo-methylphenidate, l-erythro-methylphenidate, d-erythro-methylphenidate, dl erythro-methylphenidate and mixtures thereof, a diuretic agent, such as, but without limitation, mannitol, furosemide, glycerin and urea.

Examples of second active agents that can be used to treat, prevent and / or control sleep disorders and related syndromes include, but are not limited to, a tricyclic antidepressant agent, a selective serotonin reuptake inhibitor, an antiepileptic agent (gabapentin, pregabalin, carbamazepine, oxcarbazepine, levitiracetam, topiramate), a non-arrhythmic agent, a sodium channel blocking agent, a selective inhibitor of an inflammatory mediator, an opioid agent, a second immunomodulatory e compound, combination agent and other known or generally accepted agents used in sleep therapy. Specific examples include, but are not limited to, Neurontin, oxycontin, morphine, topiramate, amitriptyline, nortriptyline, carbamazepine, levodopa, L-DOPA, cocaine, α-methyl-tyrosine, reserpine, tetrabenazine, benzotropin, pargyline, mesylate phenodollo dolamide, mesylate phenodollo dolamide, pramipexole, ropinorol, amantadine hydrochloride, selegiline hydrochloride, carbidopa, pergolide mesylate, Sinemet CR, Symmetrel, iproniazide, clorgilin, phenelzine, isocarboxazide, tolcapone, entacapone, physostigmine hydrochloride, physostigmine hydrochloride, sulfate, sulfate neostigmine, ambenonium chloride, edrophonium chloride, tacrine, pralidoksimhlorid, obidoksimhlorid, trimedoksimbromid, diatsetilmonoksim, endrofony, pyridostigmine, demekary, naproxen sodium, diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone , refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, Rho-D immunoglobulin, mycophenylate mofetil, cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylic acid , Methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, diclofenac, flurbinprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoksikam, tenoxicam, phenylbutazone, oksifenilbutazon, antipyrine , aminopyrine, apazone, cileiton, aurothioglucose, gold-sodium thiomalate, auranofin, methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone, benzbromarone, betamethasone and other glucocorticoids, metoclopromide, domperido m, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetyleucine monoethanolamine, alizapride, azasetron, benquinamide, bietanautin, bromopride, buclizine, kleboprid, cyclizin, dimenlidene dimenidenfin dimenidenidene dimenidene dimenidene dimenidene dimene , pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, triethylperazine, thioproperazine, tropisetron and mixtures thereof.

Examples of second active agents that can be used to treat, prevent and / or control hemoglobinopathy and related disorders include, but are not limited to, interleukins such as IL-2 (including recombinant IL-II ("rIL2") and canarypox IL -2), IL-10, IL-12 and IL-18, interferons such as interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-1a and interferon gamma-1b, and G-CSF, hydroxyurea, butyrates or derivatives of butyrates, nitric oxide, HEMOXIN ™ (NIPRISAN ™, see US patent No. 5800819), channel antagonists Gardos, such as clotrimazole and derivatives of triarylmethane, Deferoxamine, protein C, and a blood transfusion or blood substitute such as Hemospan ™ or Hemospan PS ™ (Sangart).

Administration to a patient of a compound of this invention, a pharmaceutically acceptable salt, solvate, stereoisomer and prodrug thereof, and second active agents thereof can be carried out simultaneously or sequentially by the same or different routes of administration. The suitability of the particular route of administration used for the private active agent will depend on the active agent itself (for example, whether it can be administered orally without decomposition before it enters the bloodstream) and the disease to be treated. Preferred routes of administration of the second active agents or ingredients of the invention are known to one of ordinary skill in the art. See, for example, Physician's Desk Reference , 1755-1760 (56 ^th ed., 2002).

In one embodiment of the invention, the second active agent is administered intravenously or subcutaneously, once or twice a day, in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, from about 50 to about 200 mg The specific amount of the second active agent will depend on the particular agent used, the type of disease to be treated or controlled, the severity and stage of the disease, the amounts of the compounds of the invention and any additional active agents of choice administered simultaneously to the patient.

As discussed in any part of the description, the invention encompasses a method of reducing, eliminating and / or preventing side and undesirable effects associated with conventional treatment, including, but not limited to, surgery, chemotherapy, radiation therapy, hormone therapy, biological therapy and immunotherapy. The compounds of the invention and other active ingredients can be administered to a patient before, during, or after a side effect associated with conventional treatment is manifested.

4.4 Cyclic therapy

In some embodiments, the prophylactic or therapeutic agents of the invention are administered cyclically to a patient. Cyclic therapy involves the administration of the active agent for a period of time followed by a period of rest and repeating this sequential administration. Cyclic therapy can reduce the development of resistance to one or more types of therapy, avoid or reduce the side effects of one of the therapies, and / or improve the effectiveness of the treatment.

Further, in one particular embodiment of the invention, the compound of the invention is administered daily in a single dose or in divided doses in a cycle of four to six weeks with a rest period of about a week to two weeks. The invention further allows to increase the frequency, number and duration of dosing cycles. Thus, another particular embodiment of the invention encompasses the administration of a compound of the invention in a greater than usual number of cycles when administered separately. In yet another particular embodiment of the invention, the compound of the invention is administered in more cycles than usually causing dose-limiting toxicity in a patient to whom the second active ingredient has not been administered.

In one embodiment, the compound of the invention is administered daily and continuously for three or four weeks at a dosage of from about 0.1 mg to about 500 mg per day, followed by a break of one or two weeks. In other embodiments, the dosage may be from about 1 mg to about 300 mg, from about 0.1 mg to about 150 mg, from about 1 mg to about 200 mg, from about 10 mg to about 100 mg, from about 0.1 mg up to about 50 mg; from about 1 mg to about 50 mg; from about 10 mg to about 50 mg; from about 20 mg to about 30 mg; from about 1 mg to about 20 mg, followed by a break.

In one embodiment of the invention, the compound of the invention and the second active ingredient are orally administered with the administration of the compound of the invention 30-60 minutes before the second active ingredient in a cycle of four to six weeks. In another embodiment of the invention, a combination of a compound of the invention and a second active ingredient is administered by intravenous infusion over a period of about 90 minutes in each cycle.

Typically, the number of cycles during which a patient receives combination treatment will be from about one to about 24 cycles, more typically from about two to about 16 cycles, and even more typically from about four to about three cycles.

4.5 Pharmaceutical compositions and dosage forms

Pharmaceutical compositions can be used to produce discrete unit dosage forms. The pharmaceutical compositions and dosage forms of the invention comprise a compound of the invention or a pharmaceutically acceptable salt, solvate, stereoisomer and prodrug thereof. The pharmaceutical compositions and dosage forms of the invention may further comprise one or more excipients.

The pharmaceutical compositions and dosage forms of the invention may also contain one or more additional active ingredients. Examples of optional or additional active ingredients are given above in section 4.3.

Unit dosage forms according to the invention are suitable for oral, mucous (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., subcutaneous, intravenous, bolus-injection, intramuscular or intra-arterial), local (e.g., eye drops or other ophthalmic drugs), transdermal or transdermal administration to the patient. Examples of dosage forms include, but are not limited to, tablets, elongated tablets, capsules, such as soft elastic gelatin capsules, sachets, tablets, lozenges, dispersions, suppositories, powders, aerosols (e.g., nasal sprays or inhalers), gels, liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (eg, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs, liquid dosage forms suitable for couples parenteral administration, eye drops and other ophthalmic preparations suitable for topical administration, and sterile solids (e.g., crystalline or amorphous solids) from which liquid dosage forms suitable for parenteral administration to a patient can be reconstituted.

The composition, type and type of dosage forms of the invention will usually depend on their use. For example, dosage forms used to treat acute forms of diseases may contain larger amounts of one or more active ingredients than the dosage form used to treat a chronic form of the same disease. Similarly, parenteral dosage forms may contain smaller amounts of one or more active ingredients than the oral dosage form used to treat the same disease. This and other aspects in which the particular dosage forms encompassed by this invention are different from each other are clearly apparent to one skilled in the art. See., E.g., Remington's Pharmaceutical Sciences, 18 ^{th ed., Mack Publishing, Easton} PA ( 1990).

Typical pharmaceutical compositions and dosage forms include one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are described. The suitability of a particular excipient for inclusion in a pharmaceutical composition or dosage form depends on a set of factors well known in the art, including, but not limited to, the route by which the dosage form will be administered to the patient. For example, oral dosage forms, such as tablets, may contain excipients not suitable for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the particular active ingredients in dosage form. For example, the decomposition of certain active ingredients may be accelerated by certain excipients, such as lactose, or if they are exposed to water. Active ingredients that contain primary or secondary amines are especially susceptible to such accelerated decomposition. Therefore, this invention encompasses pharmaceutical compositions and dosage forms that contain little lactose or other mono- or disaccharides, if any. As used herein, the phrase “lactose free” means that the amount of lactose, if present, is insufficient to substantially increase the rate of crushing of the active ingredient.

Lactose-free compositions of the invention may include excipients that are well known in the art and are listed, for example, in US Pharmacopeia (USP) 25-NF20 (2002). In general, lactose-free compositions include active ingredients, a binder / filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Preferred lactose-free dosage forms include active ingredients, microcrystalline cellulose, pregelatinized starch and magnesium stearate.

The present invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising the active ingredients, since water may contribute to the breakdown of certain compounds. For example, the addition of water (for example, 5%) is widely acceptable in the pharmaceutical field as a means of simulating long-term storage in order to determine characteristics such as shelf life or drug stability over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice , 2 ^nd Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In fact, water and heating accelerate the decomposition of certain compounds. Thus, the effect of water on the drug can be of great importance, since moisture and / or humidity are often encountered during the production, processing, packaging, storage, transportation and use of drugs.

Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture ingredients under conditions of low moisture or low humidity. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient that contains a primary or secondary amine are preferably anhydrous if significant contact with moisture and / or humidity is expected during manufacture, packaging and / or storage.

Anhydrous pharmaceutical compositions should be prepared and stored in such a way as to maintain their anhydrous nature. Accordingly, the anhydrous compositions are preferably packaged using materials known as water proofing so that they can be included in suitable kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, containers containing a unit dose (e.g., ampoules), blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosage forms that contain one or more compounds, which reduces the degree of decomposition of the active ingredient. Such compounds, which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific types of active ingredients in dosage forms may vary depending on factors such as, but not limited to, the way in which they are to be administered to the patient. However, typical dosage forms of the invention comprise a compound of the invention in an amount of from about 0.10 to about 500 mg. Typical dosage forms of the invention comprise a compound of the invention in an amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg.

Typical dosage forms contain a second active ingredient in an amount of from 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, from about 50 to about 200 mg. Of course, the specific amount of the second active agent will depend on the particular agent used, the type of cancer being treated or controlled, the amounts (a) of the compound of the invention and any optional active agents administered in parallel to the patient.

4.5.1 Oral dosage forms

Pharmaceutical compositions of the invention suitable for oral administration may be presented in discrete dosage forms, such as, but not limited to, tablets (e.g., lozenges), elongated tablets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients and can be prepared by pharmaceutical methods well known to those skilled in the art. See, in general, Remington's Pharmaceutical Sciences , 18 ^th ed., Mack Publishing, Easton PA (1990).

Typical oral dosage forms according to the invention are prepared by combining the active ingredients in an initial mixture with at least one excipient in accordance with generally accepted pharmaceutical formulation techniques. Excipients can have a wide variety of forms depending on the form of the drug desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavors, preservatives and colorants. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules and elongated tablets) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents.

Because of their easy administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid excipients are used. If desired, tablets may be coated using standard aqueous or non-aqueous techniques. Such dosage forms can be obtained by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and thoroughly mixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then molding the product into the desired form if desired.

For example, tablets may be prepared by compression or molding. Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free flowing form, such as a powder or granules, optionally mixed with an excipient. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Examples of excipients that can be used in the dosage forms of the invention include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch and other starches, gelatin, natural and synthetic resins such as gum, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g. ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized collapse al, hydroxypropylmethylcellulose (e.g., №№ 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA) and mixtures thereof. A particular binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103 ™ and Starch 1500 LM.

Examples of excipients suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, mannitol, silicic acid, sorbitol, starch, pregelatinized starch and mixtures thereof. The binder or excipient in the pharmaceutical compositions of the invention is usually present in an amount of from about 50 to about 99 weight percent by weight of the pharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the invention to produce tablets that are destroyed by exposure to the aquatic environment. Tablets that contain too much disintegrant may break down during storage, while those containing too much may not break down at the desired speed under the desired conditions. Thus, in order to obtain solid oral dosage forms according to the invention, a sufficient amount of disintegrant should be used, which is not too large, not too small to cause damage by altering the release of the active ingredients. The amount of disintegrant used varies based on the type of preparation and can easily be determined by one of ordinary skill in the art. Typical pharmaceutical compositions include from about 0.5 to about 15 weight percent of the disintegrant, preferably from about 1 to about 5 weight percent of the disintegrant.

Disintegrants that can be used in the pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, potassium polacryline, sodium starch glycolate, potato starch tapioca, other starches, pregelatinized starch, clays, other alginines, other celluloses, resins and mixtures thereof.

Lubricants that can be used in the pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate , talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar and mixtures thereof. Additional lubricants include, for example, silica gel silica gel (AEROSIL200 manufactured by WR Grace Co. of Baltimore, MD), synthetic silica coagulated aerosol (marketed by Degussa Co. of Plano, TX), CAB-O-SIL (fumed silica, product sold by Cabot Co. of Boston, MA) and mixtures thereof. If at all used, lubricants are used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are administered.

Solid oral dosage forms according to the invention include a compound of the invention, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica and gelatin.

4.5.2 Controlled Release Dosage Forms

The active ingredients of the invention can be administered using controlled release agents or delivery devices that are well known to one of ordinary skill in the art. Examples include, but are not limited to, those described in US Pat. Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123 and 4,008,719, 5,674,533, 5,095,595, 5,591,767, 5,120,548, 5,073,543, 5,639,473, 535,456 and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled release of one or more active ingredients, using, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to obtain the desired release profile in various ratios. Suitable controlled release formulations known to those of ordinary skill in the art, including those disclosed herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gelatine capsules and elongated tablets which are adapted for controlled release.

All controlled release pharmaceutical products have the common goal of improving drug therapy compared to their uncontrolled release competitors. Ideally, the use of an optimally designed drug with controlled release in medical treatment is characterized by a minimum of drug substance used to treat or control the course of the condition in a minimum time. The benefits of controlled release formulations include improved drug activity, reduced frequency of administration, and increased patient compatibility. In addition, controlled release formulations can be used to affect the onset of action or other characteristics, such as the level of the drug in the blood, and thus can affect the occurrence of (for example, undesirable) side effects.

Most controlled release formulations are designed to initially release the amount of drug (active ingredient) that immediately produces the desired therapeutic effect, and to gradually and continuously release other amounts of the drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that compensates for the amount of drug metabolized and excreted from the body. The controlled release of the active ingredient can be stimulated by a variety of conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.

4.5.3 Parenteral dosage forms

Parenteral dosage forms can be administered to patients in various ways, including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular and intraarterial. Since their administration usually bypasses the patient’s natural defenses against foreign substances, the parenteral dosage forms are preferably sterile or sterilizable prior to administration to the patient. Examples of parenteral dosage forms include, but are not limited to, ready-made injectable solutions, dry products ready to be dissolved or suspended in a pharmaceutically acceptable carrier for injection, ready-made suspension for injection and emulsion.

Suitable carriers that can be used to prepare parenteral dosage forms according to the invention are well known to those skilled in the art. Examples include, but are not limited to, USP Pharmacopeia water for injection, aqueous vehicles such as, but not limited to, sodium chloride for injection, Ringer's solution for injection, dextrose for injection, dextrose and sodium chloride for injection, Ringer's solution with lactate for water miscible carriers, such as, but not limited to, ethyl alcohol, polyethylene glycol and polypropylene glycol, and non-aqueous vehicles, such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl alcohol at, isopropyl myristate and benzyl benzoate.

Compounds that increase the solubility of one or more of the active ingredients disclosed herein may also be formulated in parenteral dosage forms according to the invention. For example, cyclodextrin and its derivatives can be used to increase the solubility of the immunomodulatory compounds of the invention and its derivatives. See, for example, US Pat. No. 5,134,127, which is incorporated herein by reference.

4.5.4 Dosage forms for topical application and for mucous membranes

Dosage forms for topical application and for mucous membranes according to the invention include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops and other ophthalmic preparations or other forms known to a person skilled in the art. See., E.g., Remington's Pharmaceutical Sciences, 16 ^th and 18 ^{th ed., Mack Publishing, Easton} PA ( 1980 & 1990) and Introduction to Pharmaceutical Dosage Forms, 4 ^{th ed., Lea & Febiger,} Philadelphia ( 1985). Dosage forms suitable for treating mucous tissues in the oral cavity can be prepared as mouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materials that can be used to prepare dosage forms for topical application and for the mucous membranes covered by this invention are well known to the person skilled in the pharmaceutical art and depend on the particular tissue on which the pharmaceutical composition or the dosage form will be applied. Given this fact, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmiate, mineral oil and mixtures thereof to form solutions, emulsions or gels that are non-toxic and pharmaceutically acceptable. If desired, wetting agents or humectants can also be added to pharmaceutical compositions and dosage forms. Examples of such additional ingredients are well known in the art. See., E.g., Remington's Pharmaceutical Sciences, 16 ^th and 18 ^{th ed., Mack Publishing, Easton} PA ( 1980 & 1990).

The pH of the pharmaceutical composition or dosage form can also be adjusted to improve the delivery of one or more ingredients. Similarly, the polarity of the carrier solvent, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can be added to pharmaceutical compositions or dosage forms in order to favorably change the hydrophilicity and lipophilicity of one or more ingredients, so as to improve delivery. In this regard, stearates can serve as a lipid carrier for preparations, as an emulsifying agent or surfactant, and as an agent that improves delivery or enhances penetration. Various salts, hydrates or solvates of the active ingredients can be used to further control the properties of the resulting composition.

4.6 Sets

In one embodiment, the active ingredients of the invention are preferably not administered to the patient simultaneously or in the same route of administration. Therefore, the present invention encompasses kits which, when used by a medical practitioner, can simplify the administration to a patient of suitable amounts of active ingredients.

A kit according to the invention includes a dosage form of a compound of the invention. The kits covered by the invention may further include additional active ingredients such as oblimersen (Genasense ^® ), melphalan, G-CSF, GM-CSF, EPO, topotecan, dacarbazine, irinotecan, taxotere, IFN, COX-2 inhibitor, pentoxifylline, ciprofloxacin , dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, 13-cis-retinic acid or their pharmacologically active mutants or derivatives, or combinations thereof. Examples of additional active ingredients include, but are not limited to, those described herein (see, for example, section 4.3).

Kits according to the invention may further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, dropper tanks, patches, and inhalers.

The kits of the invention may further include cells or blood for transplantation, as well as pharmaceutically acceptable carriers that can be used to administer one or more active ingredients. For example, if the active ingredient is presented in solid form, which must be reconstituted for parenteral administration, the kit may contain a sealed container with a suitable carrier in which the active ingredient can be dissolved to form a particulate-free sterile solution suitable for parenteral administration. Examples of pharmaceutically acceptable carriers include, but are not limited to, USP Water for Injection, aqueous vehicles such as, but not limited to, sodium chloride for injection, Ringer's solution for injection, dextrose for injection, dextrose and sodium chloride for injection, Ringer's solution with injection lactate, water miscible carriers such as, but not limited to, ethyl alcohol, polyethylene glycol and polypropylene glycol, and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, green oil lyanyh nuts, sesame oil, ethyl oleate and benzyl benzoate.

5. Examples

Some embodiments of the invention are illustrated by the following non-limiting examples.

5.1 5 - {[(Benzofuran-2-ylmethyl) amino] methyl] -2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione

To a mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol) in CH ₂ Cl ₂ (20 ml) diisopropylethylamine (0.52 ml, 3.0 mmol), 2-benzofurancarboxaldehyde (0.36 ml, 3.0 mmol) and glacial acetic acid (0.17 ml, 3.0 mmol) are added. The reaction mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (1.27 g, 6.0 mmol) was added and the mixture was left overnight with stirring at room temperature. Water (20 ml) was added to quench the reaction, and the mixture was extracted with CH ₂ Cl ₂ (2 × 50 ml). The organic layer was washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml) and dried (MgSO ₄ ) and evaporated in vacuo. The residue was chromatographed using a gradient of ethyl acetate-hexanes, eluting with 0.38 g of the product at an ethyl acetate-hexanes ratio of 83:17 in 30% yield. T. pl. 133-135ºС, Waters Xterra RP18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% HCO ₂ (NH ₄ ), 5.11 min (98 , 22%); ¹ H NMR (DMSO-d ₆ ) δ 2.04-2.10 (m, 1H), 2.50-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3 , 20 (broad, 1H), 3.85 (s, 2H), 3.94 (s, 2H), 5.14 (dd, J = 12.6 Hz, 5.1 Hz, 1H), 6.73 (s, 1H), 7.17-7.27 (m, 2H), 7.48-7.58 (m, 2H), 7.84 (t, J = 7.8 Hz, 2H), 7, 93 (s, 1H); 11.12 (s, 1H);

¹³ C NMR (DMSO-d ₆ ) δ 22.0, 30.9, 45.0, 48.9, 51.5, 103.6, 110.8, 120.7, 122.6, 123.2, 123.6, 128.2, 129.6, 131.4, 134.1, 148.8, 154.1, 157.3, 167.1, 167.2, 169.8, 172.7.

Analysis: Calculated for C ₂₃ H ₁₉ N ₃ O ₅ : C, 66.18; H, 4.59; N, 10.07. Found: C, 66.02; H, 4.27; N, 9.94.

5.2 5-Benzylamino-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione

Stage 1: A mixture of dimethyl 4-nitrophthalate (15.0 g, 62.7 mmol) and 10% Pd-C (1.5 g) in ethyl acetate (100 ml) is left overnight for hydrogenation at 50 psi . The reaction mixture was filtered through celite, and the filter was washed further with ethyl acetate (50 ml). The solvent was evaporated and the residue was stirred in hexanes. The solid phase is filtered off, further washed with hexanes and dried, yielding 12.77 g of 4-amino-phthalic acid dimethyl ester as a pale orange solid in 97% yield. ¹ H NMR (DMSO-d ₆ ) δ 3.71 (s, 3H), 3.75 (s, 3H), 6.17 (s, 2H), 6.58-6.65 (m, 2H), 7.57 (d, J = 8.4 Hz, 1H).

Stage 2: A mixture of 4-amino-phthalic acid dimethyl ester (0.84 g, 4.0 mmol), benzaldehyde (0.81 ml, 8.0 mmol) and acetic acid (1.37 ml, 24.0 mmol) in CH ₂ Cl ₂ (40 ml) was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (2.54 g, 12.0 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with CH ₂ Cl ₂ (20 ml), washed with water (2 × 100 ml), saturated sodium bicarbonate solution (1 × 100 ml) and brine (1 × 100 ml) and dried (MgSO ₄ ), and evaporated in a vacuum. The resulting oil is chromatographed using an ethyl acetate-hexanes gradient, eluting the product with an ethyl acetate-hexanes ratio of 20:80, 1.1 g of 4-benzylamino-phthalic acid dimethyl ester in 93% yield. ¹ H NMR (DMSO-d ₆ ) δ 3.70 (s, 3H), 3.74 (s, 3H), 4.36 (d, J = 6.0 Hz, 2H), 6.57-6, 69 (m, 2H), 7.22-7.39 (m, 6H), 7.60 (d, J = 8.4 Hz, 1H).

Step 3: A mixture of 4-benzylamino-phthalic acid dimethyl ether (1.11 g, 3.71 mmol) and 3 N sodium hydroxide (50 ml) in ethanol (100 ml) is refluxed for one hour. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in water (100 ml), washed with CH ₂ Cl ₂ (2 × 100 ml) and acidified (HCl), the resulting mixture was extracted with ethyl acetate (2 × 100 ml). The combined organic extracts were washed with water (2 × 100 ml) and dried (MgSO ₄ ), and evaporated in vacuo. The resulting solid was stirred in ether for 2 hours. The solid is filtered off and dried, yielding 0.50 g of 4-benzylamino-phthalic acid in 74% yield. ¹ H NMR (DMSO-d ₆ ) δ 4.35 (d, J = 5.7 Hz, 2H), 6.59-6.62 (m, 2H), 7.10-7.34 (m, 6H ), 7.54-7.57 (m, 1H), 12.48 (broad, 2H).

Stage 4: A mixture of 4-benzylamino-phthalic acid (0.47 g, 1.7 mmol) and rac -α-aminoglutarimide hydrochloride (0.29 g, 1.7 mmol) in pyridine (10 ml) is left overnight at the boil with reflux condenser. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (150 ml) and dilute aqueous HCl (150 ml). The aqueous phase was extracted with ethyl acetate (100 ml). The combined organic phases were washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml), and the solvent was removed in vacuo. The residue was chromatographed using a methanol-CH ₂ Cl ₂ gradient, eluting the product with a methanol-CH ₂ Cl ₂ ratio of 2:98. The solid thus obtained was stirred for 30 minutes in ether and filtered, further washed with ether and dried, yielding 0.49 g of the product as a yellow solid in 78% yield. T. pl. 239-241 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 9.15 (95.32% ) ¹ H NMR (DMSO-d ₆ ) δ 1.94-2.01 (m, 1H), 2.43-2.59 (m, 2H), 2.81-2.93 (m, 1H), 4 46 (d, J = 6.0 Hz, 2H), 5.02 (dd, J = 12.9 Hz, J = 5.4 Hz, 1H), 6.89 (dd, J = 8.4 Hz , J = 1.8 Hz, 1H), 6.96 (d, J = 1.5 Hz, 1H), 7.23-7.33 (m, 1H), 7.35 (d, J = 4, 2 Hz, 4H), 7.56 (d, J = 8.4 Hz, 1H), 7.71 (t, J = 5.7 Hz, 1H), 11.06 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.2, 30.9, 45.9, 48.6, 105.7, 115.9, 116.5, 125.0, 127.0, 127.1, 128.5, 134.0, 138.6, 154.2, 167.1, 167.6, 170.1, 172.8. Analysis: Calculated for C ₂₀ H ₁₇ N ₃ O ₄ + 0.1H ₂ O: C, 65.78; H, 4.75; N, 11.51. Found: C, 65.49; H, 4.71; N: 11.45.

5.3 2- (2,6-dioxo-piperidin-3-yl) -5 - [(furan-2-yl-methyl) amino] -isoindol-1,3-dione

Stage 1: A mixture of 4-amino-phthalic acid dimethyl ester (0.84 g, 4.0 mmol), 2-furaldehyde (0.66 ml, 8.0 mmol) and acetic acid (1.37 ml, 24.0 mmol) in CH ₂ Cl ₂ (40 ml) was stirred for 10 minutes at room temperature. Sodium triacetoxyborohydride (2.54 g, 12.0 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with CH ₂ Cl ₂ (20 ml), washed with water (2 × 100 ml), saturated sodium bicarbonate solution (100 ml) and brine (100 ml) and dried (MgSO ₄ ) and evaporated in vacuo. The resulting oil is chromatographed using an ethyl acetate-hexanes gradient, eluting the product with an ethyl acetate-hexanes ratio of 40:60, 1.11 g of 4 - [(furan-2-ylmethyl) amino] -phthalic acid dimethyl ester in 96% yield. ¹ H NMR (DMSO-d ₆ ) δ 3.71 (s, 3H), 3.76 (s, 3H), 4.34 (d, J = 5.7 Hz, 2H), 6.27-6, 40 (m, 2H), 6.62-6.78 (m, 2H), 7.18 (t, J = 5.7 Hz, 1H), 7.59-7.64 (m, 2H).

Step 2: A mixture of 4 - [(furan-2-ylmethyl) amino] phthalic acid dimethyl ester (1.11 g, 3.84 mmol) and 3 N sodium hydroxide (50 ml) in ethanol (100 ml) is refluxed one hour. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was dissolved in water (100 ml), washed with CH ₂ Cl ₂ (2 × 100 ml) and acidified (HCl). The resulting mixture was extracted with ethyl acetate (2 × 100 ml), and the organic phase was washed with water (2 × 100 ml) and dried (MgSO ₄ ) and evaporated. The resulting solid was stirred in ether for 2 hours. The solid is filtered off and dried, yielding 0.44 g of 4 - [(furan-2-ylmethyl) amino] -phthalic acid in 44% yield. ¹ H NMR (DMSO-d ₆ ) δ 4.33 (d, J = 5.1 Hz, 2H), 6.31 (d, J = 3.0 Hz, 1H), 6.39 (dd, J = 3.0 Hz, 1.8 Hz, 1H), 6.65-6.71 (m, 2H), 7.00 (t, J = 5.7 Hz, 1H), 7.57-7.60 ( m, 2H); 12.51 (broad, 2H).

Stage 3: A mixture of 4 - [(furan-2-ylmethyl) amino] -phthalic acid (0.43 g, 1.7 mmol) and rac -α-aminoglutarimide hydrochloride (0.27 g, 1.7 mmol) in pyridine (10 ml) is left overnight at the boil under reflux. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (150 ml) and dilute aqueous HCl (150 ml). The aqueous phase was extracted with ethyl acetate (100 ml). The combined organic phases were washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml), and the solvent was removed in vacuo. The residue was chromatographed using a methanol-CH ₂ Cl ₂ gradient, eluting the product with a methanol-CH ₂ Cl ₂ ratio of 4:96. The resulting solid was allowed to stand overnight with stirring in ether. The solid is filtered, washed additionally with ether and dried. Purify by preparative HPLC using isocratic elution with an acetonitrile-water mixture, eluting the product with an acetonitrile-water ratio of 45:55 to obtain 0.24 g of the product as a yellow solid in 41% yield. T. pl. 143-145 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.96 (96.16% ) ¹ H NMR (DMSO-d ₆ ) δ 1.96-2.03 (m, 1H), 2.44-2.60 (m, 2H), 2.82-2.94 (m, 1H), 4 44 (d, J = 5.7 Hz, 2H), 5.03 (dd, J = 12.6 Hz, J = 5.1 Hz, 1H), 6.35-6.42 (m, 2H) 6.94-7.07 (m, 2H); 7.53-7.61 (m, 3H); 11.06 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.2, 30.9, 39.3, 48.6, 105.7, 107.5, 110.4, 116.0, 116.8, 124.9, 134.0, 142.5, 151.8, 154.0, 167.1, 167.6, 170.1, 172.8. Analysis: Calculated for C ₁₈ H ₁₅ N ₃ O ₅ + 0.1H ₂ O: C, 60.88; H, 4.31; N, 11.83. Found: C, 60.58; H, 3.87; N: 11.59.

5.4 5- (3-Chloro-benzylamino) - (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione

Stage 1: Mixture of 4-amino-phthalic acid dimethyl ester (0.84 g, 4.0 mmol), 3-chloro-benzaldehyde (0.91 ml, 8.0 mmol) and acetic acid (1.37 ml, 24 , 0 mmol) in CH ₂ Cl ₂ (40 ml) was stirred for 10 minutes at room temperature. Sodium triacetoxyborohydride (2.54 g, 12.0 mmol) was added and the mixture was stirred overnight. The reaction mass was diluted with CH ₂ Cl ₂ (20 ml), washed with water (2 × 100 ml), saturated sodium bicarbonate solution (100 ml) and brine (100 ml) and dried (MgSO ₄ ) and evaporated. The resulting oil is chromatographed using an ethyl acetate-hexanes gradient, eluting the product with an ethyl acetate-hexanes ratio of 35:65, 1.10 g of 4- (3-chloro-benzylamino) -phthalic acid dimethyl ester in 82% yield. ¹ H NMR (DMSO-d ₆ ) δ 3.71 (s, 3H), 3.75 (s, 3H), 4.39 (d, J = 6.0 Hz, 2H), 6.66-6, 70 (m, 2H), 7.28-7.39 (m, 5H), 7.61 (d, J = 9.0 Hz, 1H).

Step 2: A mixture of 4- (3-chloro-benzylamino) -phthalic acid dimethyl ester (1.10 g, 3.30 mmol) and 3 N sodium hydroxide (50 ml) in ethanol (100 ml) is refluxed for one hour. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was dissolved in water (100 ml), washed with CH ₂ Cl ₂ (2 × 100 ml) and acidified (HCl). The resulting mixture was extracted with ethyl acetate (2 × 100 ml), and the organic phase was washed with water (2 × 100 ml), dried (MgSO ₄ ) and evaporated, yielding 1.00 g of 4- (3-chloro-benzylamino) -phthalic acid in yield 99% ¹ H NMR (DMSO-d ₆ ) δ 4.37 (d, J = 5.7 Hz, 2H), 6.59-6.62 (m, 2H), 7.18 (t, J = 6.0 Hz, 1H), 7.28-7.39 (m, 4H), 7.56-7.61 (m, 1H), 12.51 (broad, 2H).

Stage 3: A mixture of 4- (3-chloro-benzylamino) -phthalic acid (0.97 g, 3.2 mmol) and rac -α-aminoglutarimide hydrochloride (0.52 g, 3.2 mmol) in pyridine (20 ml ) left overnight at the boil under reflux. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (150 ml) and dilute aqueous HCl (150 ml). The aqueous phase was extracted with ethyl acetate (100 ml). The combined organic phases were washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml), and the solvent was removed in vacuo. The residue was chromatographed using a gradient of methanol-CH ₂ Cl ₂ eluting the product with a methanol-CH ₂ Cl ₂ ratio of 5:95. The resulting solid was allowed to stand overnight under stirring in methanol (5 ml). The solid is filtered, further washed with methanol and dried, yielding 0.96 g of the product as a yellow solid in 76% yield. T. pl. 250-252 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 6.46 (99.41% ) ¹ H NMR (DMSO-d ₆ ) δ 1.95-2.03 (m, 1H), 2.42-2.59 (m, 2H), 2.81-2.93 (m, 1H), 4 49 (d, J = 6.0 Hz, 2H), 5.02 (dd, J = 12.9 Hz, J = 5.4 Hz, 1H), 6.88-6.98 (m, 2H) 7.30-7.42 (m, 4H), 7.58 (d, J = 8.4 Hz, 1H), 7.72 (t, J = 6.0 Hz, 1H), 11.06 ( s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.1, 30.9, 45.2, 48.6, 105.7, 116.0, 116.8, 125.1, 125.7, 126.9, 127.0, 130.4, 133.2, 134.1, 141.5, 154.0, 167.0, 167.5, 170.1, 172.8. Analysis: Calculated for C ₂₀ H ₁₆ N ₃ O ₄ Cl + 0.15H ₂ O: C, 59.98; H, 4.10; N, 10.49. Found: C, 59.61; H, 3.84; N, 10.36.

5.5 5 - [(Benzofuran-2-ylmethyl) amino] -2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione

Stage 1: A mixture of 4-amino-phthalic acid dimethyl ester (0.84 g, 4.0 mmol), 2-benzofurancarboxaldehyde (0.83 ml, 8.0 mmol) and acetic acid (1.37 ml, 24.0 mmol) in CH ₂ Cl ₂ (40 ml) was stirred for 10 minutes at room temperature. Sodium triacetoxyborohydride (2.54 g, 12.0 mmol) was added and the mixture was stirred overnight. The reaction mass was diluted with CH ₂ Cl ₂ (20 ml), washed with water (2 × 100 ml), saturated sodium bicarbonate solution (100 ml) and brine (100 ml) and dried (MgSO ₄ ) and evaporated. The resulting oil is chromatographed using an ethyl acetate-hexanes gradient, eluting the product with an ethyl acetate-hexanes ratio of 25:75, 0.89 g of 4 - [(benzofuran-2-ylmethyl) amino] phthalic acid dimethyl ester in 65% yield. ¹ H NMR (DMSO-d ₆ ) δ 3.71 (s, 3H), 3.76 (s, 3H), 4.56 (d, J = 5.7 Hz, 2H), 6.76-6, 83 (m, 3H), 7.20-7.29 (m, 2H), 7.35 (t, J = 6.0 Hz, 1H), 7.51-7.65 (m, 3H).

Step 2: A mixture of 4 - [(benzofuran-2-ylmethyl) amino] phthalic acid dimethyl ester (0.89 g, 3.30 mmol) and 3 N sodium hydroxide (50 ml) in ethanol (100 ml) is refluxed refrigerator for one hour. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was dissolved in water (100 ml), washed with CH ₂ Cl ₂ (2 × 100 ml) and acidified (HCl). The resulting mixture was extracted with ethyl acetate (2 × 100 ml), and the combined organic layers were washed with water (2 × 100 ml), dried (MgSO ₄ ) and evaporated, yielding 0.80 g of 4 - [(benzofuran-2-ylmethyl) amino] -phthalic acid with a yield of 98%. ¹ H NMR (DMSO-d ₆ ) δ 4.54 (d, J = 4.5 Hz, 2H), 6.71-6.77 (m, 3H), 7.18-7.29 (m, 3H ), 7.51-7.61 (m, 3H), 12.52 (broad, 2H).

Stage 3: A mixture of 4 - [(benzofuran-2-ylmethyl) amino] phthalic acid (0.80 g, 2.6 mmol) and rac -α-aminoglutarimide hydrochloride (0.42 g, 2.6 mmol) in pyridine (20 ml) is left overnight at the boil under reflux. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (150 ml) and dilute aqueous HCl (150 ml). The aqueous phase was extracted with ethyl acetate (100 ml). The combined organic phases were washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml), and the solvent was removed in vacuo. The residue was chromatographed using a gradient of methanol-CH ₂ Cl ₂ eluting the product with a methanol-CH ₂ Cl ₂ ratio of 5:95. The appropriate fractions were collected and treated with charcoal to discolor (1.5 g), filtered through celite and evaporated to give 0.68 g of the product as a yellow solid in 66% yield. T. pl. 259-261 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 5.14 (99.16% ) ¹ H NMR (DMSO-d ₆ ) δ 1.95-2.01 (m, 1H), 2.43-2.60 (m, 2H), 2.81-2.93 (m, 1H), 4 66 (d, J = 6.0 Hz, 2H), 5.03 (dd, J = 12.9 Hz, J = 5.4 Hz, 1H), 6.81 (s, 1H), 7.01 (dd, J = 8.4 Hz, J = 2.1 Hz, 1H), 7.12 (d, J = 1.8 Hz, 1H), 7.18-7.29 (m, 2H), 7 52-7.61 (m, 3H); 7.72 (t, J = 5.7 Hz, 1H); 11.06 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.2, 30.9, 48.6, 104.0, 105.8, 110.9, 116.1, 117.1, 120.9, 122.8, 124.0, 125.0, 127.9, 134.0, 153.9, 154.2, 155.1, 167.1, 167.5, 170.1, 172.8. Analysis: Calculated for C ₂₂ H ₁₇ N ₃ O ₅ + 0.1H ₂ O: C, 65.21; H, 4.28; N, 10.37. Found: C, 65.07; H, 4.29; N, 10.32.

5.6 2- (4-Chloro-phenyl) -N- [2- (2,6-dioxo-piperidin-3-yl) -1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -acetamide

Mixture of 3- (5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidin-2,6-dione hydrochloride (0.40 g, 1.29 mmol), 4-chlorophenylacetyl chloride (0 , 19 ml, 1.29 mmol) and diisopropylethylamine (0.41 ml, 2.37 mmol) in acetonitrile (20 ml) was stirred at room temperature for 2 days. Additional 4-chlorophenylacetyl chloride (0.04 ml) was added and the reaction mixture was stirred for 2 hours. The solid phase is filtered off, washed additionally with acetonitrile and water, yielding 0.13 g of the product in 24% yield. T. pl. 264-266 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 3.23 (98.97% ) ¹ H NMR (DMSO-d ₆ ) δ 1.96-2.03 (m, 1H), 2.32-2.46 (m, 1H), 2.53-2.63 (m, 1H), 2 86-2.98 (m, 1H), 3.51 (s, 2H), 4.25-4.45 (m, 4H), 5.1 1 (dd, J = 13.2 Hz, J = 5.1 Hz, 1H), 7.29-7.42 (m, 6H), 7.67 (d, J = 7.8 Hz, 1H), 8.67 (t, J = 6.0 Hz, 1H), 10.99 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.5, 31.2, 41.5, 42.2, 47.1, 51.6, 122.0, 122.9, 127.0, 128.1, 130.4, 130.9, 131.1, 135.3, 142.3, 143.7, 167.9, 169.9, 171.0, 172.9. Analysis: Calculated for C ₂₂ H ₂₀ N ₃ O ₄ Cl + 0.2H ₂ O: C, 61.53; H, 4.79; N, 9.78. Found: C, 61.52; H, 4.44; N, 9.40.

5.7 N- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -4-trifluoromethoxybenzamide

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (1.0 g, 3.1 mmol), 4-trifluoromethoxybenzoyl chloride (0.70 g, 3.1 mmol) and triethylamine (0.63 g, 6.2 mmol) in DMF (20 ml) was stirred under nitrogen at room temperature for 1 hour. The mixture was partitioned between ethyl acetate (75 ml) and water (75 ml), and the aqueous phase was extracted with ethyl acetate (75 ml). The combined organic layers were washed with water (3 × 100 ml) and evaporated. The residue was chromatographed in ethyl acetate to give 1.1 g of the product in 75% yield. T. pl. 200-202 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.85 (97.90% ) ¹ H NMR (DMSO-d ₆ ) δ 2.02-2.10 (m, 1H), 2.46-2.63 (m, 2H), 2.83-2.95 (m, 1H), 4 66 (d, J = 6.0 Hz, 2H), 5.15 (dd, J = 12.9 Hz, J = 5.4 Hz, 1H), 7.48-7.51 (m, 2H) 7.81-7.91 (m, 3H), 8.02-8.05 (m, 2H), 9.34 (t, J = 6.0 Hz, 1H), 11.13 (s, 1H ); ¹³ C NMR (DMSO-d ₆ ) δ
22.0, 30.9, 42.7, 48.9, 119.9 (q, J = 255), 120.7, 122.0, 123.5, 129.6, 129.8, 131.6 , 133.0, 133.4, 147.3, 150.4, 165.2, 167.0, 167.1, 169.8, 172.7. Analysis: Calculated for C ₂₂ H ₁₆ F ₃ N ₃ O ₆ : C, 55.58; H, 3.39; N, 8.84. Found: C, 55.38; H, 3.18; N, 8.69.

5.8 N- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -4-methylbenzamide

Mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), 4- (trifluoromethyl) benzoyl chloride (0 , 45 ml, 3.0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (100 ml). The organic phase was washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml), dried (MgSO ₄ ) and evaporated in vacuo. The residue was chromatographed using a gradient of methanol-CH ₂ Cl ₂ eluting the product with a methanol-CH ₂ Cl ₂ ratio of 5:95. The resulting solid was allowed to stand overnight with stirring in ether, filtered and dried, yielding 0.66 g of the product in 48% yield. T. pl. 168-170 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 8.49 (95.33% ) ¹ H NMR (DMSO-d ₆ ) δ 2.02-2.09 (m, 1H), 2.46-2.63 (m, 2H), 2.84-2.96 (m, 1H), 4 68 (d, J = 6.0 Hz, 2H), 5.15 (dd, J = 12.6 Hz, J = 5.1 Hz, 1H), 7.71-8.12 (m, 7H) 9.46 (t, J = 6.0 Hz, 1H); 11.13 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 30.9, 42.7, 49.0, 122.0, 123.6, 123.9 (q, J = 270.8 Hz), 125, 4 (q, J = 3.75 Hz), 128.2, 129.9, 131.3 (q, J = 31.5 Hz), 131.6, 133.5, 137.7, 147.2, 165.3, 167.0, 167.1, 169.8, 172.7. Analysis: Calculated for C ₂₂ H ₁₆ N ₃ O ₅ F ₃ : C, 57.52; H, 3.51; N, 9.15. Found: C, 57.27; H, 3.35; N, 9.00.

5.9 [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] thiophene-2-carboxylic acid amide

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), 2-thiophenecarbonyl chloride (0.32 ml, 3.0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in CH ₂ Cl ₂ (20 ml) was stirred at room temperature for 2 days. The organic phase was washed with dilute aqueous HCl (2 × 50 ml) and water (2 × 50 ml), dried (MgSO ₄ ) and evaporated in vacuo. The residue was chromatographed using a methanol-CH ₂ Cl ₂ gradient, eluting the product with a methanol-CH ₂ Cl ₂ ratio of 3:97. The resulting solid was stirred in ethyl acetate for 1 hour, filtered, and 0.69 g of product was obtained in 58% yield. T. pl. 219-221 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 30/70 CH ₃ CN / 0.1% H ₃ PO ₄ , 5.84 (95.85% ) ¹ H NMR (DMSO-d ₆ ) δ 1.99-2.09 (m, 1H), 2.46-2.63 (m, 2H), 2.83-2.95 (m, 1H), 4 62 (d, J = 6.0 Hz, 2H), 5.15 (dd, J = 12.9 Hz, J = 5.4 Hz, 1H), 7.18 (dd, J = 5.1 Hz , J = 3.6 Hz, 1H), 7.79-7.84 (m, 4H), 7.91 (d, J = 7.8 Hz, 1H), 9.23 (t, J = 6, 0 Hz, 1H); 11.13 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 30.9, 42.4, 49.0, 121.9, 123.6, 128.0, 128.4, 129.8, 131.2, 131.6, 133.4, 139.3, 147.4, 161.4, 167.0, 167.1, 169.8, 172.7. Analysis: Calculated for C ₁₉ H ₁₅ N ₃ O ₅ S: C, 57.42; H, 3.80; N, 10.57. Found: C, 57.49; H, 3.42; N, 10.28.

5.10 [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] hexanoic acid amide

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), hexanoyl chloride (0.42 ml, 3, 0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in THF (20 ml) are left overnight with stirring at 40 ° C. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (150 ml), washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml), dried (MgSO ₄ ) and evaporated in vacuo. The residue is left overnight with stirring in ether (20 ml). The resulting solid was filtered and evaporated in vacuo to give 0.71 g of the product in 61% yield. T. pl. 178-180 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 30/70 CH ₃ CN / 0.1% H ₃ PO ₄ , 8.83 (98.70% ) ¹ H NMR (DMSO-d ₆ ) δ 0.86 (t, J = 6.6 Hz, 3H), 1.27-1.33 (m, 4H), 1.48-1.58 (m, 2H ), 2.02-2.09 (m, 1H), 2.16 (t, J = 7.5 Hz, 2H), 2.46-2.63 (m, 2H), 2.83-2, 96 (m, 1H), 4.43 (d, J = 6.0 Hz, 2H), 5.14 (dd, J = 12.9 Hz, J = 5.4 Hz, 1H), 7.72- 7.90 (m, 3H), 8.51 (t, J = 6.0 Hz, 1H), 11.13 (s, 1H); ¹³ C ¹ H NMR (DMSO-d ₆ ) δ 13.8, 21.8, 22.0, 24.9, 30.9, 30.9, 35.2, 41.8, 49.0, 121, 8, 123.5, 129.7, 131.6, 133.3, 147.8, 167.0, 167.1, 169.8, 172.5, 172.7. Analysis: Calculated for C ₂₀ H ₂₃ N ₃ O ₅ : C, 62.33; H, 6.02; N, 10.90. Found: C, 62.20; H, 5.99; N, 10.84.

5.11 [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] heptanoic acid amide

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), heptanoyl chloride (0.46 ml, 3, 0 mmol) and diisopropylethylamine (1.05 ml, 6.00 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The residue was dissolved in ethyl acetate (100 ml), washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml), dried (MgSO ₄ ) and evaporated in vacuo. The residue was purified by preparative HPLC using isocratic elution with a mixture of acetonitrile: water 45:65, yielding 0.60 g of product in 50% yield. T. pl. 141-143 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 3.99 (98.05% ) ¹ H NMR (DMSO-d ₆ ) δ 0.84 (t, J = 6.6 Hz, 3H), 1.24-1.30 (m, 6H), 1.48-1.54 (m, 2H ), 2.02-2.09 (m, 1H), 2.16 (t, J = 7.2 Hz, 3H), 2.51-2.63 (m, 2H), 2.83-2, 96 (m, 1H), 4.43 (d, J = 6.0 Hz, 2H), 5.14 (dd, J = 5.4, 12.9 Hz, 1H), 7.72-7.89 (m, 3H), 8.50 (t, J = 6.0 Hz, 1H), 11.12 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 13.9, 22.0, 25.2, 28.3, 30.9, 31.0, 35.3, 41.8, 49.0, 121.8, 123.4, 129.7, 131.6, 133.3, 147.8, 167.0, 167.1, 169.8, 172.5, 172.7. Analysis: Calculated for C ₂₁ H ₂₅ N ₃ O ₅ + 0.1H ₂ O: C, 62.86; H, 6.33; N, 10.47. Found: C, 62.54; H, 6.21; N, 10.38.

5.12 5 - {[2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -carbamoyl} -pentanoic tert-butyl ester acid

Step 1: To a solution of adipic acid monomethyl ester (4.8 g, 30 mmol) in DMF (30 ml) was added CDI (4.9 g, 30 mmol) and the resulting mixture was stirred under nitrogen at 40 ° C. for 1 hour. Tert-butanol (4.4 g, 60 mmol) and DBU (4.6 g, 30 mmol) are added and stirring is carried out at 40 ° C. for 70 hours. The mixture was poured into ether (100 ml) and the mixture was washed with 10% aq. HOAc (100 ml), 10% aq. To ₂ CO ₃ (100 ml) and water (3 × 100 ml), dried (MgSO ₄ ) and evaporated, yielding 5.1 g of hexanedicarboxylic acid tert-butyl methyl ester in 78% yield. ¹ H NMR (CDCl ₃ ) δ 1.44 (s, 9H), 1.59-1.67 (m, 4H), 2.21-2.26 (m, 2H), 3.67 (s, 3H )

Stage 2: Lithium hydroxide (0.53 g, 22 mmol) is added to a solution of tert-butyl methyl ether of hexanedicarboxylic acid (4.8 g, 22 mmol) in a mixture of methanol: water 3: 1 (80 ml) and the resulting mixture is stirred at room temperature for 16 hours. The mixture was evaporated in vacuo. The residue was partitioned between water (60 ml) and methylene chloride (75 ml), and the aqueous phase was washed with methylene chloride (3 × 75 ml) and evaporated to obtain 4.0 g of lithium salt of hexane dicarboxylic acid mono-tert-butyl ester. ¹ H NMR (D ₂ O) δ 1.45 (s, 9H), 1.54-1.58 (m, 4H), 2.15-2.20 (m, 2H), 2.25-2, 34 (m, 2H).

Stage 3: DBU (1.9 g, 12.3 mmol) is added to a stirred suspension of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (2, 5 g, 7.7 mmol) in acetonitrile (75 ml), which leads to the formation of a clear solution. The mixture was stirred at room temperature for 10 minutes, and then the lithium salt of hexane dicarboxylic acid mono-tert-butyl ester (1.9 g, 9.2 mmol) and HOBt (1.2 g, 9.2 mmol) were added, followed by EDC ( 2.2 g, 11.6 mmol). The mixture was stirred under N _{2 for} 1 hour and DMF (20 ml) was added. After stirring for an additional 16 hours, the mixture was evaporated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml), the aqueous phase was extracted with ethyl acetate (2 × 100 ml). The combined organic layers were washed with water (3 × 100 ml) and evaporated. The residue was chromatographed on silica, eluting with ethyl acetate to give 2.1 g of the product in 58% yield. T. pl. 108-110 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 35/65 CH ₃ CN / 0.1% H ₃ PO ₄ , 7.64 (96.65% ) ¹ H NMR (DMSO-d ₆ ) δ 1.38 (s, 9H), 1.45-1.55 (m, 4H), 2.02-2.08 (m, 1H), 2.15-2 21 (m, 4H), 2.46-2.63 (m, 2H), 2.83-2.95 (m, 1H), 4.43 (d, J = 5.8 Hz, 2H), 5.14 (dd, J = 12.9 Hz, J = 5.4 Hz, 1H), 7.72-7.76 (m, 2H), 7.87 (d, J = 7.5 Hz, 1H ), 8.51 (t, J = 5.8 Hz, 1H), 11.12 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 24.2, 24.6, 27.7, 30.9, 34.5, 34.9, 41.9, 49.0, 79.4, 121.9, 123.4, 129.7, 131.6, 133.3, 147.8, 167.0, 167.1, 169.8, 172.1, 172.2, 172.8. Analysis: Calculated for C ₂₄ H ₂₉ N ₃ O ₇ + 0.2H ₂ O: C, 60.67; H, 6.24; N, 8.84. Found: C, 60.60; H, 6.16; N, 8.65.

5.13 5 - {[2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] carbamoyl} -pentanoic acid

A solution of 5 - {[2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] carbamoyl} -pentanoic acid (0.85 g, 1.8 mmol) in formic acid (25 ml) was stirred at room temperature for 90 minutes. The mixture was evaporated in vacuo and the residue was triturated with ether / ethyl acetate and filtered to give 0.66 g in 88% yield. T. pl. 144-146 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 20/80 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.15 (95.81% ) ¹ H NMR (DMSO-d ₆ ) δ 1.44-1.59 (m, 4H), 2.02-2.09 (m, 1H), 2.16-2.24 (m, 4H), 2 , 46-2.63 (m, 2H), 2.83-2.95 (m, 1H), 4.43 (d, J = 6.0 Hz, 2H), 5.14 (dd, J = 12 , 9 Hz, J = 5.4 Hz, 1H), 7.72-7.77 (m, 2H), 7.87 (d, J = 7.8 Hz, 1H), 8.51 (t, J = 6.0 Hz, 1H), 11.12 (s, 1H), 12.00 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 24.1, 24.7, 30.9, 33.3, 34.9, 41.9, 48.9, 121.9, 123.5, 129.7, 131.6, 133.3, 147.8, 167.0, 167.1, 169.8, 172.2, 172.7, 174.3. Analysis: Calculated for C ₂₀ H ₂₁ N ₃ O ₇ + 0.2H ₂ O: C, 57.33; H, 5.13; N, 10.03. Found: C, 57.33; H, 4.89; N, 9.81.

5.14 [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -amide 6- (2-oxo-oxazolidin-3 -yl) -hexanoic acid

Stage 1: A mixture of 2-oxazolidinone (1.74 g, 20.0 mmol), ethyl 6-bromohexanoate (4.46 g, 20.0 mmol) and sodium hydride (0.80 g 60% dispersion, 20 mmol) in acetonitrile (10 ml) is heated to 160 ° C in a microwave reactor for 15 minutes. The mixture was cooled and the solvent was removed under reduced pressure. The crude product, 6- (2-oxo-oxazolidin-3-yl) -hexanoic acid ethyl ester, is used directly in the next step.

Stage 2: Lithium hydroxide (0.48 g, 20 mmol) is added to the crude product from stage 1 in a mixture of methanol-water (30 ml) and the resulting mixture was stirred at room temperature for 70 hours. The mixture was evaporated in vacuo. The residue was dissolved in water (75 ml), washed with methylene chloride (3 × 75 ml) and acidified (HCl). The resulting mixture was extracted with methylene chloride (6 × 50 ml), and the combined extracts were dried (MgSO ₄ ) and evaporated to give 2.0 g of 6- (2-oxo-oxazolidin-3-yl) -hexanoic acid in 49% overall yield in two stages. ¹ H NMR (CDCl ₃ ) δ 1.36-1.44 (m, 2H), 1.51-1.74 (m, 4H), 2.38 (t, J = 7.4 Hz, 2H), 3.28 (t, J = 7.2 Hz, 2H); 3.56 (t, J = 8.0 Hz, 2H); 4.33 (t, J = 8.0 Hz, 2H).

Stage 3 : DBU (1.2 g, 8.1 mmol) is added to a stirred suspension of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (1, 0 g, 3.1 mmol) in acetonitrile (35 ml), which leads to the formation of a clear solution. The mixture was stirred at room temperature for 10 minutes, and then 6- (2-oxo-oxazolidin-3-yl) -hexanoic acid (2.0 g, 10 mmol) and HOBt (0.5 g, 3.7 mmol) were added with subsequent addition of EDC (0.89 g, 4.7 mmol). After stirring for an additional 16 hours, the mixture was evaporated in vacuo. The residue was partitioned between ethyl acetate (50 ml) and water (100 ml), and the aqueous phase was extracted with ethyl acetate (3 × 50 ml). The combined organic layers were evaporated. The residue was chromatographed on silica using a methylene chloride-methanol gradient, eluting with 0.61 g of the product at a methylene chloride-methanol ratio of 93: 7 in 42% yield. T. pl. 178-180 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 25/75 CH ₃ CN / 0.1% H ₃ PO ₄ , 3.36 (98.33% ) ¹ H NMR (DMSO-d ₆ ) δ 1.26-1.28 (m, 2H), 1.43-1.61 (m, 4H), 2.04-2.08 (m, lH), 2 18 (t, J = 7.4 Hz, 2H), 2.46-2.63 (m, 2H), 2.83-2.96 (m, 1H), 3.12 (t, J = 7 , 1 Hz, 2H), 3.49 (t, J = 8.0 Hz, 2H), 4.42 (t, J = 8.0 Hz, 2H), 4.43 (d, J = 5.8 Hz, 2H), 5.15 (dd, J = 12.9 Hz, J = 5.4 Hz, 1H), 7.72-7.77 (m, 2H), 7.89 (d, J = 7 8 Hz, 1H), 8.51 (t, J = 5.8 Hz, 1H), 11.12 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 24.8, 25.7, 26.4, 30.9, 35.1, 41.9, 43.3, 43.8, 49.0, 61.5, 121.8, 123.5, 129.7, 131.6, 133.3, 147.8, 157.8, 167.0, 167.1, 169.8, 172.4, 172, 7. Analysis: Calculated for C ₂₃ H ₂₆ N ₄ O ₇ + 0.3H ₂ O: C, 58.05; H, 5.63; N, 11.77. Found: C, 58.05; H, 5.42; N, 11.62.

5.15 [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -carbamic acid hexyl ester

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (1.0 g, 3.1 mmol), hexyl chloroformate (0.51 g, 3, 1 mmol) and triethylamine (0.63 g, 6.2 mmol) in THF (35 ml) was stirred at 40 ° C. under a nitrogen atmosphere for 3 hours. The mixture was cooled and diluted with ethyl acetate (100 ml), washed with water (3 × 100 ml) and evaporated. The residue is chromatographed using a methylene chloride-methanol gradient, eluting the product with a methylene chloride-methanol ratio of 19: 1. This substance is further purified by preparative HPLC using isocratic elution with a mixture of acetonitrile-water 50-50, and get 0.40 g in the form of a white solid with a yield of 31%. T. Pl. 111-113 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 5.08 (99.11% ) ¹ H NMR (DMSO-d ₆ ) δ 1.11-1.57 (m, 11H), 2.02-2.07 (m, 1H), 2.46-2.63 (m, 2H), 2 , 84-2.96 (m, 1H), 3.97 (t, J = 8.3 Hz, 2H), 4.35 (d, J = 6.0 Hz, 2H), 5.15 (dd, J = 12.9 Hz, J = 5.4 Hz, 1H), 7.72-7.77 (m, 2H), 7.84-7.90 (m, 2H), 11.13 (s, 1H ); ¹³ C NMR (DMSO-d ₆ ) δ 13.8, 22.0, 25.0, 28.6, 30.8, 30.9, 43.5, 49.0, 64.0, 121.6, 123.5, 129.8, 131.6, 133.2, 147.9, 156.6, 167.0, 167.1, 169.8, 172.7. Analysis: Calculated for C ₂₁ H ₁₅ N ₃ O ₆ : C, 60.71; H, 6.07; N, 10.11. Found: C, 60.49; H, 6.13; N, 9.91.

5.16 4-Chloro-N- [2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-2,3-dihydro-1H-isoindol-5- ilmethyl] benzamide

Mixture of 5-aminomethyl-2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -isoindole-1,3-dione hydrochloride (0.4 g, 1.18 mmol), 4 -chlorobenzoyl chloride (0.15 ml, 1.18 mmol) and diisopropylethylamine (0.41 ml, 2.37 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, the residue was dissolved in ethyl acetate (100 ml), washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml), dried (MgSO ₄ ) and evaporated in vacuo to give 0.49 g of product in yield 94%. T. pl. 163-165 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 3.38 (98.94% ) ¹ H NMR (DMSO-d ₆ ) δ 1.89 (s, 3H), 2.02-2.08 (m, 1H), 2.53-2.60 (m, 2H), 2.63-2 71 (m, 1H), 4.62 (d, J = 6.0 Hz, 2H), 7.56-7.59 (m, 2H), 7.77-7.83 (m, 3H), 7.90-7.94 (m, 2H), 9.30 (t, J = 5.7 Hz, 1H), 11.02 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 21.0, 28.5, 29.1, 42.6, 58.7, 121.6, 123.2, 128.5, 129.2, 129.6, 131.4, 132.6, 133.4, 136.3, 147.2, 165.4, 167.7, 167.9, 172.1, 172.2. Analysis: Calculated for C ₂₂ H ₁₈ N ₃ O ₅ Cl: C, 60.08; H, 4.12; N, 9.55. Found: C, 59.70; H, 3.94; N, 9.43.

5.17 N- [2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -4 trifluoromethoxy benzamide

Mixture of 5-aminomethyl-2 - ((3S) -3-methyl-2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.4 g, 1.18 mmol), 4 - (trifluoromethoxy) benzoyl chloride (0.19 ml, 1.18 mmol) and diisopropylethylamine (0.41 ml, 2.37 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, the residue was dissolved in ethyl acetate (100 ml), washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml), dried (MgSO ₄ ) and evaporated in vacuo. The residue was stirred in ether (20 ml). The solid was filtered to obtain 0.42 g of product in 72% yield. T. pl. 161-163 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 5.58 (97.42% ) ¹ H NMR (DMSO-d ₆ ) δ 1.89 (s, 3H), 2.02-2.08 (m, 1H), 2.49-2.60 (m, 2H), 2.63-2 72 (m, 1H), 4.63 (d, J = 6.0 Hz, 2H), 7.48-7.51 (m, 2H), 7.78-7.84 (m, 3H), 8.00-8.05 (m, 2H), 9.34 (t, J = 5.7 Hz, 1H), 11.02 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 21.0, 28.5, 29.1, 42.6, 58.7, 119.9 (q, J = 255), 120.7, 121.6, 123 2, 125.0, 129.6, 131.4, 133.0, 133.4, 147.2, 150.4, 165.2, 167.7, 167.8, 172.1, 172.2 . Analysis: Calculated for C ₂₃ H ₁₈ N ₃ O ₆ F ₃ : C, 56.45; H, 3.71; N, 8.59. Found: C, 56.16; H, 3.39; N, 8.45.

5.18 [2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] hexanoic acid amide

Mixture of 5-aminomethyl-2 - ((3S) -3-methyl-2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.40 g, 1.2 mmol), hexanoyl chloride (0.17 ml, 1.2 mmol) and N, N-diisopropylethylamine (0.41 ml, 2.4 mmol) in anhydrous acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (100 ml), washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml), dried (MgSO ₄ ) and evaporated in vacuo. The resulting solid was allowed to stand overnight with stirring in ether, filtered and dried, yielding 0.36 g of the product in 77% yield. T. pl. 154-156 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.51 (97.79% ) ¹ H NMR (DMSO-d ₆ ) δ 0.85 (t, J = 6.9 Hz, 3H), 1.19-1.32 (m, 4H), 1.48-1.57 (m, 2H ), 1.89 (s, 3H), 2.02-2.08 (m, 1H), 2.15 (t, J = 7.5 Hz, 2H), 2.53-2.60 (m, 2H), 2.63-2.72 (m, 1H), 4.41 (d, J = 6.0 Hz, 2H), 7.68-7.81 (m, 3H), 8.49 (t J = 6.0 Hz, 1H); 11.02 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 13.8, 21.0, 21.8, 24.9, 28.6, 29.1, 30.9, 35.2, 41.8, 58.7, 121.4, 123.1, 129.5, 131.3, 133.2, 147.7, 167.7, 167.9, 172.1, 172.2, 172.4. Analysis: Calculated for C ₂₁ H ₂₅ N ₃ O ₅ : C, 63.15; H, 6.31; N, 10.52. Found: C, 63.06; H, 6.14; N, 10.48.

5.19 {2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl} -carbamino hexyl ester acid

Mixture of 5-aminomethyl-2 - ((3S) -3-methyl-2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.40 g, 1.18 mmol), hexyl chloroformate (0.19 g, 1.18 mmol) and diisopropylethylamine (0.41 ml, 2.37 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (100 ml), washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml), dried (MgSO ₄ ) and evaporated in vacuo to give 0.45 g of product with 88% yield. T. pl. 95-97 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 6.94 (97.26% ) ¹ H NMR (DMSO-d ₆ ) δ 0.78-0.86 (m, 3H), 1.09-1.26 (m, 6H), 1.52-1.54 (m, 2H), 1 89 (s, 3H), 1.99-2.08 (m, 1H), 2.54-2.59 (m, 2H), 2.64-2.72 (m, 1H), 3.96 (t, J = 6.6 Hz, 2H), 4.33 (d, J = 6.0 Hz, 2H), 7.70-7.87 (m, 4H), 11.02 (s, 1H) ; ¹³ C NMR (DMSO-d ₆ ) δ 13.8, 21.0, 22.0, 25.0, 28.6, 29.1, 30.9, 43.5, 58.7, 64.0, 121.3, 123.1, 129.6, 131.4, 133.1, 147.7, 156.6, 167.7, 167.8, 172.1, 172.2. Analysis: Calculated for C ₂₂ H ₂₇ N ₃ O ₆ : C, 61.53; H, 6.34; N, 9.78. Found: C, 61.73; H, 6.33; N, 9.58.

5.20 3,4-Dichloro-N- [2- (2,6-dioxo-piperidin-3-yl) -1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl] benzamide

Mixture of 3- (5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidin-2,6-dione hydrochloride (0.50 g, 1.6 mmol), 3,4-dichlorobenzoyl chloride (0.34 g, 1.6 mmol) and TEM (0.32 g, 3.2 mmol) in THF (25 ml) are heated to 40 ° C. with stirring under N ₂ atmosphere for 2.5 hours. The mixture was filtered, the filtered solid was loaded onto a silica gel column, which was washed using a methylene chloride-methanol gradient. The product is eluted with a methylene chloride-methanol ratio of 93: 7, 0.42 g, yield 58%. T. pl. 260-262 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 3.36 (99.65% ) ¹ H NMR (DMSO-d ₆ ) δ 1.96-2.03 (m, 1H), 2.31-2.43 (m, 1H), 2.56-2.62 (m, 1H), 2 85-2.97 (m, 1H), 4.30 (d, J = 17.4 Hz, 1H), 4.44 (d, J = 17.4 Hz, 1H), 4.59 (d, J = 6.0 Hz, 2H), 5.11 (dd, J = 13.4 Hz, J = 5.0 Hz, 1H), 7.45-7.55 (m, 2H), 7.70 ( d, J = 7.8, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.88 (dd, J = 8.4 Hz, J = 1.8 Hz, 1H), 8.14 (d, J = 2.1 Hz, 1H), 9.33 (t, J = 6.0 Hz, 1H), 10.98 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.5, 31.2, 42.9, 47.1, 51.6, 122.2, 123.0, 127.2, 127.6, 129.2, 130.4, 130.7, 131.3, 134.1, 134.4, 142.4, 143.4, 164.0, 167.9, 171.0, 172.8. Analysis: Calculated for C ₂₁ H ₁₇ Cl ₂ N ₃ O ₄ + 0.25H ₂ O: C, 55.95; H, 3.91; N, 9.32. Found: C, 55.98; H, 3.55; N, 9.32.

5.21 N- [2- (2,6-dioxo-piperidin-3-yl) -1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -4-trifluoromethoxy-benzamide

Mixture of 3- (5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidin-2,6-dione hydrochloride (0.40 g, 1.29 mmol), 4- (trifluoromethoxy) benzoyl chloride (0.20 ml, 1.29 mmol) and diisopropylethylamine (0.41 ml, 2.37 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The solid is filtered, further washed with acetonitrile (20 ml) and dried, yielding 0.41 g of the product in 68% yield. T. pl. 133-135 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 5.44 (99.98% ) ¹ H NMR (DMSO-d ₆ ) δ
1.98-2.01 (m, 1H), 2.27-2.45 (m, 1H), 2.57-2.62 (m, 1H), 2.85-2.97 (m, 1H) ), 4.30 (d, J = 17.1 Hz, 1H), 4.45 (d, J = 17.4 Hz, 1H), 4.60 (d, J = 5.7 Hz, 2H), 5.11 (dd, J = 13.5 Hz, J = 5.1 Hz, 1H), 7.46-7.55 (m, 4H), 7.70 (d, J = 7.8 Hz, 1H ), 8.04 (d, J = 8.7 Hz, 2H), 9.27 (t, J = 5.7 Hz, 1H), 10.98 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.5, 31.2, 42.8, 47.1, 51.6, 119.9 (q, J = 255.8 Hz), 120.7, 122, 1, 122.9, 127.1, 129.6, 130.4, 133.2, 142.4, 143.7, 150.3, 165.1, 167.9, 171.0, 172.8. Analysis: Calculated for C ₂₂ H ₁₈ N ₃ O ₅ F ₃ + 0.15H ₂ O: C, 56.94; H, 3.97; N, 9.05. Found: C, 56.54; H, 3.63; N, 8.95.

5.22 [2- (2,6-dioxo-piperidin-3-yl) -1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl] furan-2-carboxylic acid amide

Mixture of 3- (5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidin-2,6-dione hydrochloride (0.40 g, 1.29 mmol), 2-furoyl chloride (0 , 13 ml, 1.29 mmol) and diisopropylethylamine (0.41 ml, 2.37 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was filtered and the solid was washed further with acetonitrile (20 ml) and dried, yielding 0.33 g of the product in 71% yield. T. pl. 338-340 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 20/80 CH ₃ CN / 0.1% H ₃ PO ₄ , 5.65 (96.68% ) ¹ H NMR (DMSO-d ₆ ) δ 1.97-2.10 (m, 1H), 2.19-2.45 (m, 1H), 2.50-2.62 (m, 1H), 2 , 73-3.03 (m, 1H), 4.30 (d, J = 17.1 Hz, 1H), 4.44 (d, J = 17.4 Hz, 1H), 4.53 (d, J = 5.7 Hz, 2H), 5.10 (dd, J = 13.2 Hz, J = 5.1 Hz, 1H), 6.64-8.20 (m, 6H), 9.04 ( t, J = 6.0 Hz, 1H); 10.98 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.5, 31.2, 42.0, 47.1, 51.6, 111.9, 113.6, 122.1, 122.9, 127.1, 130.4, 142.4, 143.7, 145.1, 147.7, 157.8, 167.9, 171.0, 172.8. Analysis: Calculated for C ₁₉ H ₁₇ N ₃ O ₅ + 0.1H ₂ O: C, 61.82; H, 4.70; N, 11.38. Found: C, 61.45; H, 4.46; N, 11.37.

5.23 [2- (2,6-dioxo-piperidin-3-yl] -1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl] hexanoic acid amide

A mixture of 3- (5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidin-2,6-dione hydrochloride (0.40 g, 1.29 mmol), hexanoyl chloride (0.18 ml, 1.29 mmol) and diisopropylethylamine (0.41 ml, 2.37 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The solid is filtered and further washed with acetonitrile to give 0.26 g of the product in 55% yield. T. pl. 206-208 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 30/70 CH ₃ CN / 0.1% H ₃ PO ₄ , 5.30 (98.77% ) ¹ H NMR (DMSO-d ₆ ) δ 0.86 (t, J = 6.6 Hz, 3H), 1.25-1.29 (m, 4H), 1.48-1.58 (m, 2H ), 1.98-2.01 (m, 1H), 2.14 (t, J = 7.2 Hz, 2H), 2.33-2.42 (m, 1H), 2.57-2, 63 (m, 1H), 2.86-2.98 (m, 1H), 4.27-4.47 (m, 4H), 5.11 (dd, J = 13.2 Hz, J = 4, 8 Hz, 1H), 7.37-7.45 (m, 2H), 7.68 (d, J = 7.8 Hz, 1H), 8.40 (t, J = 5.4 Hz, 1H) 10.98 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 13.8, 21.8, 22.5, 24.9, 30.9, 31.2, 35.3, 42.0, 47.1, 51.6, 122.0, 122.9, 127.0, 130.3, 142.3, 144.1, 167.9, 171.0, 172.2, 172.8. Analysis: Calculated for C ₂₀ H ₂₅ N ₃ O ₄ + 0.1H ₂ O: C, 64.36; H, 6.81; N, 11.26. Found: C, 64.16; H, 6.80; N, 11.17.

5.24 [2- (3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] amide pyridin-2- carboxylic acid

Mixture of 5-aminomethyl-2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -isoindole-1,3-dione hydrochloride (0.85 g, 2.5 mmol), hydrochloride picolinoyl chloride (0.45 g, 2.5 mmol) and triethylamine (0.76 g, 7.5 mmol) in anhydrous acetonitrile (20 ml) was stirred at room temperature for 13 hours. The reaction mixture is filtered. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate (100 ml). The organic phase is washed with 4N aqueous HCl (150 ml) and neutralized with sodium bicarbonate. The solid precipitate was isolated by filtration, washed with water (200 ml) and dried, obtaining the product as a white solid (0.47 g, 46%). T. pl. 365-367 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 30/70 CH ₃ CN / 0.1% H ₃ PO ₄ , 6.59 (96.15% ) ¹ H NMR (DMSO-d ₆ ) δ 1.88 (s, 3H), 2.01-2.07 (m, 1H), 2.54-2.74 (m, 3H), 4.64 (d , J = 6.3 Hz, 2H), 7.61-7.65 (m, 1H), 7.79-7.83 (m, 3H), 7.98-8.06 (m, 2H), 8.68 (d, J = 4.8 Hz, 1H), 9.61 (t, J = 6.3 Hz, 1H), 11.01 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 21.0, 28.5, 29.1, 42.3, 58.7, 121.8, 122.0, 123.1, 126.7, 129.6, 131.3, 133.5, 137.8, 147.3, 148.5, 149.7, 164.2, 167.7, 167.9, 172.1, 172.2. Analysis: Calculated for C ₂₁ H ₁₈ N ₄ O ₅ + 0.3H ₂ O: C, 61.25; H, 4.55; N, 13.61. Found: C, 60.88; H, 4.22; N, 13.33.

5.25 N- [2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -4 trifluoromethylbenzamide

Mixture of 5-aminomethyl-2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -isoindole-1,3-dione hydrochloride (0.85 g, 2.5 mmol), 4 - (trifluoromethyl) benzoyl chloride (0.52 ml, 2.5 mmol) and triethylamine (0.51 g, 5.0 mmol) in anhydrous acetonitrile (20 ml) was stirred at room temperature for 13 hours. The reaction mixture is filtered. The filtrate was concentrated and the resulting yellow residue was chromatographed on silica gel using a methanol-methylene chloride gradient, eluting with a methanol-methylene chloride ratio of 3:97 to give the product as a white solid (0.94 g, 80% yield). T. pl. 188-190 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 3.82 (99.33% ) ¹ H NMR (DMSO-d ₆ ) δ 1.89 (s, 3H), 2.02-2.08 (m, 1H), 2.53-2.72 (m, 3H), 4.65 (d , J = 6.0 Hz, 2H), 7.79-8.11 (m, 7H), 9.46 (t, J = 6.0 Hz, 1H), 11.02 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 21.0, 28.6, 29.1, 42.7, 58.8, 121.7, 123.2, 123.9 (q, J = 271 Hz), 125.5 (q, J = 3.8 Hz), 128.2, 129.7, 131.3 (q, J = 31.5 Hz), 131.4, 133.5, 137.7, 147, 0, 165.3, 167.7, 167.9, 172.1, 172.2. Analysis: Calculated for C ₂₃ H ₁₈ N ₃ O ₅ F ₃ : C, 58.35; H, 3.83; N, 8.88. Found: C, 58.05; H, 3.64; N, 8.65.

5.26 N- [2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -isonicotinamide

Mixture of 5-aminomethyl-2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -isoindole-1,3-dione hydrochloride (0.85 g, 2.5 mmol), hydrochloride isonicotinoyl chloride (0.45 ml, 2.5 mmol) and triethylamine (0.76 g, 7.5 mmol) in anhydrous acetonitrile (20 ml) were stirred at room temperature for 2 hours. The reaction mixture was concentrated and the resulting yellow residue was chromatographed on silica gel using a methanol-methylene chloride gradient, eluting the product with a methanol-methylene chloride ratio of 5:95. The product is stirred in water (20 ml) for 15 hours. The resulting solid was filtered and further washed with water (20 ml). The solid was then stirred in methanol (20 ml) for two days, filtered and further washed with methanol (20 ml) to give the product as a white solid (0.23 g, 23% yield). T. pl. 186-188 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 25/75 CH ₃ CN / H ₂ O, 3.06 (97.62%). ¹ H NMR (DMSO-d ₆ ) δ 1.89 (s, 3H), 2.02-2.08 (m, 1H), 2.53-2.76 (m, 3H), 4.65 (d , J = 5.7 Hz, 2H), 7.79-7.84 (m, 5H), 8.76 (d, J = 6.0 Hz, 2H), 9.51 (t, J = 6, 0 Hz, 1H); 11.02 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 21.0, 28.5, 29.1, 42.6, 58.8, 121.2, 121.7, 123.2, 129.7, 131.4, 133.5, 140.9, 146.8, 150.3, 164.9, 167.7, 167.8, 172.1, 172.2. Analysis: Calculated for C ₂₁ H ₁₈ N ₄ O ₅ + 0.2H ₂ O: C, 61.52; H, 4.52; N, 13.66. Found: C, 61.28; H. 4.36; N, 13.55.

5.27 4-Fluoro-N- [2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-2,3-dihydro-1H-isoindol-5- ilmethyl] benzamide

Mixture of 5-aminomethyl-2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -isoindole-1,3-dione hydrochloride (0.85 g, 2.5 mmol), 4 -fluorobenzoyl chloride (0.40 ml, 2.5 mmol) and triethylamine (0.51 g, 5.0 mmol) in anhydrous acetonitrile (20 ml) was stirred at room temperature for 2 hours. The reaction mixture is filtered. The filtrate was concentrated in vacuo, and the residue was chromatographed on silica gel using a methanol-methylene chloride gradient, eluting the product with a methanol-methylene chloride ratio of 5:95. The combined fractions were concentrated and the resulting solid was stirred in ether for 2 hours. The suspension was filtered and the solid was washed further with ether to give the product as a white solid (0.41 g, 38% yield). T. pl. 231-233 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 3.90 (96.87% ) ¹ H NMR (DMSO-d ₆ ) δ 1.89 (s, 3H), 2.02-2.06 (m, 1H), 2.54-2.75 (m, 3H), 4.62 (d , J = 5.7 Hz, 2H), 7.30-7.36 (m, 2H), 7.77-7.83 (m, 3H), 7.95-7.99 (m, 2H), 9.24 (t, J = 6.0 Hz, 1H); 11.02 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 21.0, 28.5, 29.1, 42.6, 58.7, 115.3 (d, J = 21 Hz), 121.6, 123.2, 129.6, 129.9 (d, J = 8.3 Hz), 130.4 (d, J = 3.0 Hz), 131.4, 133.4, 147.3, 164.0 (d, J = 247 Hz), 165.3, 167.7, 167.9, 172.1, 172.2. Analysis: Calculated for C ₂₂ H ₁₈ N ₃ O ₅ F: C, 62.41; H, 4.29; N, 9.92. Found: C, 62.46; H, 4.12; N, 9.88.

5.28 N- [2- (3S) - (3-methyl-2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -6 trifluoromethyl nicotinamide

Mixture of 5-aminomethyl-2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -isoindole-1,3-dione hydrochloride (0.65 g, 1.9 mmol), 6 - (trifluoromethyl) nicotinoyl chloride (0.40 ml, 1.9 mmol) and triethylamine (0.39 g, 3.8 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (100 ml) and washed with 4N HCl (2 × 150 ml) and water (2 × 150 ml), dried (MgSO ₄ ) and evaporated in vacuo. The residue was chromatographed on silica gel (ethyl acetate) to give 0.58 g of the product in 65% yield as a white solid. T. pl. 358-360 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 5.10 (99.34% ) ¹ H NMR (DMSO-d ₆ ) δ 1.89 (s, 3H), 2.00-2.08 (m, 1H), 2.55-2.72 (m, 3H), 4.69 (d , J = 6.0 Hz, 2H), 7.83 (s, 3H), 8.08 (d, J = 8.1 Hz, 1H), 8.51 (dd, J = 8.1 Hz and 1 8 Hz, 1H), 9.21 (d, J = 1.2 Hz, 1H), 9.61 (t, J = 6.0 Hz, 1H), 11.02 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 21.0, 28.6, 29.1, 42.7, 58.8, 120.7 (q, J = 3.0 Hz), 121.4 (q, J = 273 Hz), 121.8, 123.2, 129.8, 131.4, 132.6, 133.5, 137.5, 146.6, 148.2 (q, J = 33.8 Hz ), 149.0, 163.9, 167.7, 167.8, 172.1, 172.2. Analysis: Calculated for C ₂₂ H ₁₇ N ₄ O ₅ F ₃ + 0.1H ₂ O: C, 55.49; H, 3.64; N, 11.77. Found: C, 55.11; H, 3.35; N, 11.64.

5.29 3,4-Dichloro-N- [2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-2,3-dihydro-1H-isoindole- 5-ylmethyl] benzamide

Mixture of 5-aminomethyl-2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -isoindole-1,3-dione hydrochloride (0.65 g, 1.9 mmol), 3 , 4-Dichlorobenzoyl chloride (0.40 ml, 1.9 mmol) and triethylamine (0.39 g, 3.8 mmol) in anhydrous acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate (100 ml) and washed with 4N HCl (2 × 150 ml), water (2 × 150 ml), dried (MgSO ₄ ) and evaporated in vacuo. The solid is left overnight with stirring in ether and then filtered. The solid is chromatographed on silica gel using an ethyl acetate-hexane gradient, eluting the product with an ethyl acetate-hexane ratio of 90:10. The combined fractions were concentrated in vacuo and the resulting solid was stirred in ether for 2 hours. The suspension was filtered and the solid was washed further with ether to give the product as a white solid (0.54 g, 60% yield). T. pl. 162-164 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.89 (98.63% ) ¹ H NMR (DMSO-d ₆ ) δ 1.89 (s, 3H), 1.99-2.08 (m, 1H), 2.55-2.75 (m, 3H), 4.63 (d , J = 6.0 Hz, 2H), 7.78-7.89 (m, 5H), 8.13 (d, J = 2.1 Hz, 1H), 9.39 (t, J = 6, 0 Hz, 1H); 11.01 (s, 1H);

¹³ C NMR (DMSO-d ₆ ) δ 21.0, 28.6, 29.1, 42.7, 58.8, 121.7, 123.2, 127.6, 129.2, 129.7, 130.8, 131.3, 131.4, 133.5, 134.2, 134.3, 146.9, 164.2, 167.7, 167.8, 172.1, 172.2. Analysis: Calculated for C ₂₂ H ₁₇ N ₃ O ₅ Cl ₂ : C, 55.71; H, 3.61; N, 8.86. Found: C, 55.34; H, 3.66; N, 8.67.

5.30 [2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -amide thiophene 2-carboxylic acid

Mixture of 5-aminomethyl-2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -isoindole-1,3-dione hydrochloride (0.85 g, 2.5 mmol), 2 -thiophenecarbonyl chloride (0.37 ml, 2.5 mmol) and triethylamine (0.51 g, 5.0 mmol) in anhydrous acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel using a methanol-methylene chloride gradient, eluting the product with a methanol-methylene chloride ratio of 5:95. The solvent was concentrated in vacuo and the resulting solid was dissolved in DMF (4 ml) and the mixture was heated to 95 ° C for 1 hour. Then water (5 ml) was added dropwise and the mixture was allowed to cool to room temperature and was stirred overnight. The resulting suspension was filtered and further washed with water, obtaining the product as a white solid (0.62 g, 60% yield). T. pl. 222-224 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 30/70 CH ₃ CN / 0.1% H ₃ PO ₄ , 6.67 (96.69% ) ¹ H NMR (DMSO-d ₆ ) δ 1.89 (s, 3H), 2.02-2.08 (m, 1H), 2.53-2.73 (m, 3H), 4.60 (d , J = 6.0 Hz, 2H), 7.16-7.19 (m, 1H), 7.76-7.84 (m, 5H), 9.22 (t, J = 6.0 Hz, 1H), 11.01 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 21.0, 28.5, 29.1, 42.4, 58.7, 121.6, 123.2, 128.0, 128.4, 129.6, 131.1, 131.4, 133.4, 139.3, 147.3, 161.3, 167.7, 167.9, 172.1, 172.2. Analysis: Calculated for C ₂₀ H ₁₇ N ₃ O ₅ S: C, 58.39; H, 4.16; N, 10.21. Found: C, 58.55; H, 3.98; N, 10.06.

5.31 2- (4-Chlorophenyl) -N- [2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-2,3-dihydro-1H- isoindol-5-ylmethyl] -acetamide

Mixture of 5-aminomethyl-2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -isoindole-1,3-dione hydrochloride (0.65 g, 1.9 mmol), 4 -chlorophenylacetyl chloride (0.36 ml, 1.9 mmol) and triethylamine (0.39 g, 3.8 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. Additional 4-chlorophenylacetyl chloride (0.36 ml, 1.9 mmol) and triethylamine (0.39 g, 3.8 mmol) were added to the reaction mixture, and stirring was continued for an additional 3 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate (100 ml) and washed with 4N HCl (2 × 150 ml) and water (2 × 150 ml), dried (MgSO ₄ ) and concentrated in vacuo. The residue was chromatographed on silica gel using a methanol-CH ₂ Cl ₂ gradient, eluting the product with a methanol-CH ₂ Cl ₂ ratio of 5:95, yielding 0.60 g of product as a white solid in 69% yield. T. pl. 156-158 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 6.09 (95.59% ) ¹ H NMR (DMSO-d ₆ ) δ 1.89 (s, 3H), 2.02-2.08 (m, 1H), 2.53-2.76 (m, 3H), 4.42 (d , J = 6.0 Hz, 2H), 7.28-7.44 (m, 4H), 7.68-7.80 (m, 3H), 8.73 (t, J = 6.0 Hz, 1H), 11.03 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 21.0, 28.6, 29.1, 41.4, 42.1, 58.8, 121.5, 123.1, 128.2, 129.6, 130.9, 131.2, 131.4, 133.3, 135.1, 147.3, 167.7, 167.8, 170.1, 172.1, 172.2. Analysis: Calculated for C ₂₂ H ₁₇ N ₄ O ₅ F ₃ + 0.10H ₂ O + 0.15EtOAc: C, 60.45; H, 4.60; N, 8.96. Found: C, 60.37; H, 4.21; N, 8.56.

5.32 [2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -amide isoquinoline- 3-carboxylic acid

3-Isoquinolinecarboxylic acid hydrate (0.33 g, 1.9 mmol) was dissolved in DMF (20 ml) and CDI (0.34 g, 2.1 mmol) was added. The mixture was stirred at 40 ° C. for 1 hour. Then 5-aminomethyl-2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -isoindole-1,3-dione hydrochloride (0.65 g, 1.9 mmol) and triethylamine (0.39 g, 3.8 mmol), and the reaction mixture was stirred at 40 ° C. for an additional 90 minutes. The mixture was cooled to room temperature and left overnight with stirring. Water (30 ml) was added and a solid precipitated. The precipitated solid was isolated by filtration, washed additionally with water and dried, yielding 0.66 g of the product in 76% yield. T. pl. 259-261 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 3.24 (97.97% ) ¹ H NMR (DMSO-d ₆ ) δ 1.88 (s, 3H), 2.01-2.07 (m, 1H), 2.53-2.74 (m, 3H), 4.71 (d , J = 6.3 Hz, 2H), 7.80-7.92 (m, 5H), 8.19-8.28 (m, 2H), 8.58 (s, 1H), 9.42 ( s, 1H), 9.75 (t, J = 6.3 Hz, 1H), 11.02 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 21.0, 28.5, 29.1, 42.4, 58.7, 120.0, 121.8, 123.1, 127.8, 128.0, 129.2, 129.3, 129.6, 131.4, 133.6, 135.3, 143.5, 147.5, 151.6, 164.5, 167.7, 167.9, 172, 1, 172.2. Analysis: Calculated for C ₂₂ H ₂₀ N ₄ O ₅ + 0.20H ₂ O: C, 65.27; H, 4.47; N, 12.18. Found: C, 64.98; H, 4.33; N, 12.18.

5.33 N - ((2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-isoindolin-5-yl) methyl) -4- (trifluoromethylthio) benzamide

TEA is added to a stirred mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (1.0 g, 3.1 mmol) and 4- (trifluoromethylthio) benzoyl chloride (0.75 g, 3.1 mmol) in acetonitrile (30 ml), the resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (100 ml) and ethyl acetate (100 ml). The organic phase is separated and concentrated in vacuo. The residue was chromatographed on silica gel using a hexanes-ethyl acetate gradient, eluting with 1.2 g of product at 60-70% ethyl acetate, in 76% yield as a white solid. T. pl. 171-173 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.72 (97.94% ) ¹ H NMR (DMSO-d ₆ ) δ 2.02-2.10 (m, 1H), 2.46-2.63 (m, 2H), 2.83-2.95 (m, 1H), 4 66 (d, J = 5.8 Hz, 2H), 5.15 (dd, J = 12.8 Hz, J = 5.3 Hz, 1H), 7.81-7.92 (m, 5H) 8.00-8.03 (m, 2H); 9.41 (t, J = 5.8 Hz, 1H); 11.13 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 30.9, 42.7, 49.0, 122.0, 123.6, 126.4, 128.7, 129.5 (q, J = 306 Hz), 129.9, 131.6, 133.5, 135.9, 136.5, 147.2, 165.5, 167.0, 167.1, 169.8, 172.7. Analysis: Calculated for C ₂₂ H ₁₆ N ₃ O ₅ F ₃ S: C, 53.77; H, 3.28; N, 8.55. Found: C, 53.55; H, 3.14; N, 8.37.

5.34 N - ((2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-isoindolin-5-yl) methyl) -4- (1,1,2,2-tetrafluoroethoxy) benzamide

A mixture of 4- (1,1,2,2-tetrafluoroethoxy) benzoic acid (0.73 g, 3.1 mmol) and CDI (0.55 g, 3.4 mmol) in DMF (20 ml) was stirred at 40 ° From 2 hours, then 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (1.0 g, 3.1 mmol) is added. After 2 hours, the mixture was cooled to room temperature, poured into ethyl acetate (100 ml), and then washed with NaHCO ₃ (3 × 75 ml) and then concentrated. The residue was chromatographed on silica gel (ethyl acetate) to give 0.79 g of the product as a white solid in 51% yield. T. pl. 148-150 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.72 (98.94% ) ¹ H NMR (DMSO-d ₆ ) δ 1.99-2.10 (m, 1H), 2.48-2.63 (m, 2H), 2.84-2.96 (m, 1H), 4 66 (d, J = 5.8 Hz, 2H), 5.15 (dd, J = 12.9 Hz, J = 5.4 Hz, 1H), 6.85 (t, J = 51.9, J = 3.1, 1H), 7.42 (d, J = 8.7 Hz, 2H), 7.81-7.92 (m, 3H), 8.00-8.04 (m, 2H) 9.32 (t, J = 5.8 Hz, 1H); 11.13 (s, 1H); ¹ H NMR (DMSO-d ₆ ) δ 22.0, 30.9, 42.7, 49.0, 107.7 (tt, J = 247, J = 40), 116.4 (tt, J = 269 , J = 27), 121.2, 122.0, 123.5, 129.5, 129.8, 131.6, 132.5, 133.4, 147.4, 150.3, 165.4, 167.0, 167.1, 169.8, 172.7. Analysis: Calculated for C ₂₃ H ₁₇ N ₃ O ₆ F ₄ : C, 54.44; H, 3.38; N, 8.28. Found: C, 54.24; H, 3.28; N, 8.15.

5.35 4-Bromo-N- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] benzamide

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (1.0 g, 3.1 mmol), 4-bromobenzoyl chloride (0.68 g, 3.1 mmol) and triethylamine (0.63 g, 6.2 mmol) in acetonitrile (20 ml) was stirred for 3 hours at room temperature. The reaction mixture was filtered and the filtrate was concentrated. The residue was chromatographed on silica gel (ethyl acetate) to give 1.2 g of the product as a white solid in 83% yield. T. pl. 166-168 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 6.07 (97.97% ) ¹ H NMR (DMSO-d ₆ ) δ 2.02-2.10 (m, 1H), 2.46-2.63 (m, 2H), 2.83-2.95 (m, 1H), 4 64 (d, J = 6.0 Hz, 2H), 5.15 (dd, J = 12.6 Hz, J = 5.1 Hz, 1H), 7.69-7.74 (m, 2H) 7.80-7.91 (m, 5H); 9.30 (t, J = 6.0 Hz, 1H); 11.12 (s, 1H); ¹³ H NMR (DMSO-d ₆ ) δ 22.0, 30.9, 42.7, 49.0, 122.0, 123.5, 125.2, 129.4, 129.8, 131.4, 131.6, 133.0, 133.5, 147.4, 165.5, 167.0, 167.1, 169.8, 172.7. Analysis: Calculated for C ₂₁ H ₁₆ N ₃ O ₅ Br: C, 53.63; H, 3.43; N, 8.94; Br, 16.99. Found: C, 53.61; H, 3.14; N, 8.84; Br, 16.80.

5.36 N- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -4-ethyl-benzamide

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (1.00 g, 3.1 mmol), 4-ethylbenzoyl chloride (0.52 g, 3.1 mmol) and triethylamine (0.63 g, 6.2 mmol) in acetonitrile (20 ml) was stirred for 3 hours at room temperature. The reaction suspension is filtered and the solid phase is further washed with acetonitrile. The solid is then stirred in water for 2 hours, filtered and dried, yielding 0.51 g of product. The filtrate from the reaction mixture was concentrated. The residue was chromatographed on silica gel (ethyl acetate). The combined fractions are concentrated and the resulting solid is left overnight with stirring in ether, filtered and dried, yielding 0.59 g of the product in 85% overall yield. The product is a white solid. T. pl. 191-193 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 6.56 (99.32% ) ¹ H NMR (DMSO-d ₆ ) δ 1.20 (t, J = 5.7 Hz, 3H), 2.02-2.10 (m, 1H), 2.47-2.70 (m, 2H ), 2.83-2.95 (m, 1H), 4.64 (d, J = 5.7 Hz, 2H), 5.16 (dd, J = 12.9 Hz, J = 5.1 Hz , 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.79-7.91 (m, 5H), 9.15 (t, J = 6.0 Hz, 1H), 11 12 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 15.3, 22.0, 28.0, 30.9, 42.5, 49.0, 121.9, 123.5, 127.3, 127.7, 129.8, 131.4, 131.6, 133.4, 147.5, 147.7, 166.3, 167.0, 167.1, 169.8, 172.7. Analysis: Calculated for C ₂₃ H ₂₁ N ₃ O ₅ : C, 65.86; H, 5.05; N, 10.02. Found: C, 65.73; H, 4.86; N, 9.91.

5.37 N- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -4-ethoxybenzamide

4-Ethoxybenzoic acid (0.51 g, 3.1 mmol) was dissolved in DMF (20 ml) and CDI (0.55 g, 3.4 mmol) was added. The mixture was stirred at 40 ° C. for 1 hour. Then 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (1.00 g, 3.1 mmol) and triethylamine (0.63 g, 6 , 2 mmol) and the reaction mixture is stirred at 40 ° C for an additional 90 minutes. Then the mixture was cooled to room temperature and left overnight with stirring. Water (30 ml) was then added and a solid precipitated. The solid was isolated by filtration, washed with additional water and the resulting solid was chromatographed on silica gel (ethyl acetate) to give 0.21 g of the product in 16% yield as a white solid. T. pl. 213-215 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 3.77 (99.35% ) ¹ H NMR (DMSO-d ₆ ) δ 1.34 (t, J = 6.9 Hz, 3H), 2.02-2.09 (m, 1H), 2.46-2.62 (m, 2H ), 2.83-2.95 (m, 1H), 4.06-4.13 (m, 2H), 4.62 (d, J = 6.0 Hz, 2H), 5.14 (dd, J = 12.9 Hz, J = 5.4 Hz, 1H), 6.98-7.03 (m, 2H), 7.79-7.91 (m, 5H), 9.07 (t, J = 5.7 Hz, 1H); 11.12 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 14.5, 22.0, 30.9, 42.5, 49.0, 63.3, 114.0, 121.9, 123.5, 125.9, 129.1, 129.7, 131.6, 133.4, 147.9, 161.0, 165.9, 167.0, 167.1, 169.8, 172.7. Analysis: Calculated for C ₂₃ H ₂₁ N ₃ O ₆ : C, 63.44; H, 4.86; N, 9.65. Found: C, 63.41; H, 4.76; N, 9.41.

5.38 N- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -4-methanesulfonylbenzamide

4- (Methylsulfonyl) benzoic acid (0.62 g, 3.1 mmol) was dissolved in DMF (20 ml) and CDI (0.55 g, 3.4 mmol) was added. The mixture was stirred at 40 ° C. for 1 hour. 5-Aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (1.0 g, 3.1 mmol) and triethylamine (0.63 g, 6, 2 mmol) and the reaction mixture was stirred at 40 ° C for an additional 90 minutes. The mixture was cooled to room temperature and left overnight with stirring. The reaction mixture was concentrated and the residue was chromatographed on silica gel (ethyl acetate) to give 0.83 g of the product in 57% yield as a white solid. T. pl. 241-243 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 30/70 CH ₃ CN / 0.1% H ₃ PO ₄ , 3.48 (98.80% ) ¹ H NMR (DMSO-d ₆ ) δ 2.03-2.08 (m, 1H), 2.49-2.63 (m, 2H), 2.83-2.91 (m, 1H), 3 27 (s, 3H), 4.68 (d, J = 6.0 Hz, 2H), 5.15 (dd, J = 12.6 Hz, J = 5.1 Hz, 1H), 7.82 -7.92 (m, 3H), 8.04-8.07 (m, 2H), 8.12-8.15 (m, 2H), 9.49 (t, J = 5.7 Hz, 1H ), 1.12 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 30.9, 42.8, 43.3, 49.0, 122.0, 123.6, 127.1, 128.3, 129.9, 131.6, 133.5, 138.3, 143.1, 147.1, 165.2, 167.0, 167.1, 169.8, 172.7. Analysis: Calculated for C ₂₂ H ₁₉ N ₃ O ₇ S: C, 56.28; H, 4.08; N, 8.95. Found: C, 56.13; H, 3.90; N, 8.74.

5.39 N- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -4-iodo-benzamide

4-Iodobenzoic acid (0.77 g, 3.1 mmol) was dissolved in DMF (20 ml) and CDI (0.55 g, 3.4 mmol) was added. The mixture was stirred at 40 ° C. for 1 hour. 5-Aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (1.0 g, 3.1 mmol) and triethylamine (0.63 g, 6, 2 mmol), and the reaction mixture was stirred at 40 ° C for an additional 90 minutes. The mixture was cooled to room temperature and left overnight with stirring. The reaction mixture was concentrated and the residue was chromatographed on silica gel (ethyl acetate) to give a solid that was left overnight with stirring in ether, filtered and dried, yielding 1.33 g of the product in 83% yield as a white solid. T. pl. 163-165 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 3.27 (97.68% ) ¹ H NMR (DMSO-d ₆ ) δ 2.03-2.09 (m, 1H), 2.46-2.63 (m, 2H), 2.83-2.95 (m, 1H), 4 63 (d, J = 6.0 Hz, 2H), 5.14 (dd, J = 12.9 Hz, J = 5.4 Hz, 1H), 7.67-7.91 (m, 7H) 9.29 (t, J = 5.7 Hz, 1H); 11.12 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 30.9, 42.6, 49.0, 99.1, 122.0, 123.5, 129.2, 129.8, 131.6, 133.3, 133.5, 137.3, 147.4, 165.8, 167.0, 167.1, 169.8, 172.7. Analysis: Calculated for C ₂₁ H ₁₆ N ₃ O ₅ I: C, 48.76; H, 3.12; N, 8.12. Found: C, 48.64; H, 2.77; N, 7.85.

5.40 N- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -4-methylsulfanylbenzamide

4- (Methylthio) benzoic acid (0.52 g, 3.1 mmol) was dissolved in DMF (20 ml) and CDI (0.55 g, 3.4 mmol) was added. The mixture was stirred at 40 ° C. for 1 hour. 5-Aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (1.0 g, 3.1 mmol) and triethylamine (0.63 g, 6, 2 mmol) and the reaction mixture was stirred at 40 ° C for an additional 90 minutes. The mixture was cooled to room temperature and left overnight with stirring. The reaction mixture was concentrated and the residue was chromatographed on silica gel (ethyl acetate) to obtain 0.75 g of the product in 56% yield as a white solid. T. pl. 187-189 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.61 (95.58% ) ¹ H NMR (DMSO-d ₆ ) δ 2.03-2.10 (m, 1H), 2.46-2.63 (m, 2H), 2.52 (s, 3H), 2.83-2 95 (m, 1H), 4.63 (d, J = 6.0 Hz, 2H), 5.14 (dd, J = 12.6 Hz, J = 5.1 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.80-7.91 (m, 5H), 9.18 (t, J = 6.0 Hz, 1H), 11.12 (s, 1H) ; ¹³ C NMR (DMSO-d ₆ ) δ 14.1, 22.0, 30.9, 42.6, 49.0, 121.9, 123.5, 124.9, 127.7, 129.8, 129.9, 131.6, 133.4, 142.8, 147.7, 165.9, 167.0, 167.1, 169.8, 172.7. Analysis: Calculated for C ₂₂ H ₁₉ N ₃ O ₅ S + 0.1H ₂ O: C, 60.15; H, 4.41; N, 9.57. Found: C, 59.98; H, 4.32; N, 9.61.

5.41 N- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -4-ethylsulfanylbenzamide

4- (Ethylthio) benzoic acid (0.56 g, 3.1 mmol) was dissolved in DMF (20 ml) and CDI (0.55 g, 3.4 mmol) was added. The mixture was stirred at 40 ° C. for 1 hour. 5-Aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (1.00 g, 3.1 mmol) and triethylamine (0.63 g, 6, 2 mmol) and the reaction mixture was stirred at 40 ° C for an additional 90 minutes. The mixture was cooled to room temperature and left overnight with stirring. The reaction mixture was concentrated and the residue was chromatographed on silica gel using an ethyl acetate-hexane gradient, eluting the product with an ethyl acetate-hexane ratio of 80:20 to give 1.1 g of the product in 81% yield as a white solid. T. pl. 175-177 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 6.93 (99.44% ) ¹ H NMR (DMSO-d ₆ ) δ 1.27 (t, J = 7.5 Hz, 3H), 2.02-2.09 (m, 1H), 2.47-2.63 (m, 2H ), 2.83-2.95 (m, 1H), 3.06 (q, J = 7.5 Hz, 2H), 4.63 (d, J = 5.7 Hz, 2H), 5.14 (dd, J = 12.9 Hz, J = 5.4 Hz, 1H), 7.37-7.39 (m, 2H), 7.80-7.91 (m, 5H), 9.18 ( t, J = 6.0 Hz, 1H); 11.12 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 13.9, 22.0, 25.2, 30.9, 42.6, 49.0, 121.9, 123.5, 126.3, 127.8, 129.8, 130.4, 131.6, 133.4, 141.2, 147.6, 165.9, 167.0, 167.1, 169.8, 172.7. Analysis: Calculated for C ₂₃ H ₂₁ N ₃ O ₅ S: C, 61.19; H, 4.69; N, 9.31. Found: C, 60.80; H, 4.34; N, 9.21.

5.42 N - ((2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-isoindolin-5-yl) methyl) -2- (4- (trifluoromethylthio) phenyl) acetamide

A mixture of 4- (trifluoromethylthio) phenylacetic acid (0.73 g, 3.1 mmol) and CDI (0.55 g, 3.4 mmol) in DMF (20 ml) was stirred at 40 ° C. for 2 hours, and then hydrochloride was added 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione (1.0 g, 3.1 mmol). After 2 hours, the mixture was cooled to room temperature, poured into ethyl acetate (100 ml) and washed with NaHCO ₃ (3 × 75 ml) and concentrated. The residue was chromatographed on silica gel (ethyl acetate) to give 1.2 g of the product in 77% yield as a white solid. T. pl. 140-142 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 3.87 (98.06% ) ¹ H NMR (DMSO-d ₆ ) δ 2.02-2.09 (m, 1H), 2.47-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3 62 (s, 2H), 4.46 (d, J = 5.8 Hz, 2H), 5.15 (dd, J = 12.9 Hz, J = 5.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.65-7.77 (m, 4H), 7.87 (d, J = 7.5 Hz, 1H), 8.82 (t, J = 5.8 Hz, 1H); 11.13 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 21.2, 30.1, 40.9, 41.3, 48.2, 119.9, 120.0, 121.1, 122.6, 128.8 ( q, J = 306 Hz), 129.0, 129.9, 130.8, 132.5, 135.3, 139.2, 146.5, 166.1, 166.2, 167.0, 171, 9. Analysis: Calculated for C ₂₃ H ₁₈ N ₃ O ₅ F ₃ S: C, 54.65; H, 3.59; N, 8.31. Found: C, 54.45; H, 3.73; N, 7.93.

5.43 Tert-butyl-N - ((2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-isoindolin-5-yl) methyl) benzamide

TEA is added to a mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (1.0 g, 3.1 mmol) and 4- (tert-butyl ) benzoyl chloride (0.61 g, 3.1 mmol) in acetonitrile (35 ml) and the resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (100 ml) and ethyl acetate (100 ml) and the organic phase was separated and concentrated. The residue was chromatographed on silica gel using a hexanes-ethyl acetate gradient, eluting with 1.1 g of the product with an ethyl acetate content of 80-90%, in 80% yield as a white solid. T. pl. 164-166 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.26 (99.57% ) ¹ H NMR (DMSO-d ₆ ) δ 1.30 (s, 9H), 2.01-2.09 (m, 1H), 2.46-2.63 (m, 2H), 2.84-2 96 (m, 1H), 4.65 (d, J = 6.0 Hz, 2H), 5.15 (dd, J = 12.9 Hz, J = 5.4 Hz, 1H), 7.49 -7.52 (m, 2H), 7.79-7.91 (m, 5H), 9.16 (t, J = 6.0 Hz, 1H), 11.13 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 30.9, 34.6, 42.5, 49.0, 121.9, 123.5, 125.1, 127.1, 129.7, 131.1, 131.6, 133.3, 147.8, 154.3, 166.3, 167.0, 167.1, 169.8, 172.7. Analysis: Calculated for C ₂₅ H ₂₅ N ₃ O ₅ +0 _, 25H ₂ O: C, 66.43; H, 5.69; N, 9.30. Found: C, 66.49; H, 5.62; N, 8.96.

5.44 5-Bromo-N - [[2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-isoindolin-5-yl] methyl] -picolinamide

A mixture of 5-bromopicolinic acid (0.40 g, 2.0 mmol) and CDI (0.36 g, 2.2 mmol) in DMF (20 ml) was stirred under nitrogen at 40 ° C. for 2 hours. Then 5-aminomethyl-2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -isoindole-1,3-dione hydrochloride (0.67 g, 2.0 mmol) and the mixture is stirred at this temperature for an additional 2 hours. The mixture was cooled to room temperature and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (100 ml) and washed with saturated aqueous sodium bicarbonate (2 × 100 ml). The organic phase is evaporated. The residue was chromatographed on silica gel using methylene chloride as the mobile phase. A pale red solid is obtained, the solid is triturated with 10 ml of acetonitrile for 16 hours. The solid phase is filtered and further washed with 7 ml of acetonitrile. The product was dried in vacuo to give 0.55 g (57% yield) as a white solid. T. pl. 260-262 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 45/55 CH ₃ CN / 0.1% H ₃ PO ₄ , 3.61 (96.62% ) ¹ H NMR (DMSO-d ₆ ) δ 1.88 (s, 3H), 2.00-2.08 (m, 1H), 2.49-2.62 (m, 2H), 2.65-2 73 (m, 1H), 4.62 (d, J = 6.3 Hz, 2H), 7.76-7.82 (m, 3H), 7.97 (dd, J = 8.4 Hz, J = 0.6 Hz, 1H), 8.26 (dd, J = 8.4 Hz, J = 2.3 Hz, 1H), 8.81 (dd, J = 2.3 Hz, J = 0, 6 Hz, 1H), 9.63 (t, J = 6.3 Hz, 1H), 11.00 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 21.0, 28.5, 29.1, 42.4, 58.7, 121.8, 123.1, 123.5, 123.9, 129.6, 131.3, 133.6, 140.5, 147.1, 148.5, 149.3, 163.5, 167.7, 167.8, 172.0, 172.1. Analysis: Calculated for C ₂₁ H ₁₇ BrN ₄ O ₅ : C, 51.97; H, 3.53; N, 11.55. Found: C, 52.05; H, 3.44; N, 11.39.

5.45 N - [[2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-isoindolin-5-yl] methyl] -4- (methylmulphonyl) benzamide

A mixture of 4- (methylsulfonyl) benzoic acid (0.40 g, 2.0 mmol) and CDI (0.36 g, 2.2 mmol) in DMF (20 ml) was stirred under nitrogen at 40 ° C for 2 hours. Then 5-aminomethyl-2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -isoindole-1,3-dione hydrochloride (0.67 g, 2.0 mmol) and stirring is continued at this temperature for an additional 2 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate (100 ml). The organic phase was washed with saturated aqueous sodium bicarbonate (2 × 100 ml) and evaporated. The residue was chromatographed on silica gel using a 99: 1 methylene chloride-methanol mixture as the mobile phase, yielding 0.30 g in 32% yield. The product was obtained as a white solid. T. pl. 165.5-167.5 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 30/70 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.08 (96.23% ) ¹ H NMR (DMSO-d ₆ ) δ 2.09 (s, 3H), 2.22-2.28 (m, 1H), 2.73-2.95 (m, 3H), 3.47 (s , 3H), 4.86 (d, J = 5.7 Hz, 2H), 7.98-8.04 (m, 3H), 8.25 (d, J = 8.7 Hz, 2H), 8 32 (d, J = 8.7 Hz, 2H); 9.58 (t, J = 5.7 Hz, 1H); 11.21 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 23.0, 30.6, 31.1, 44.8, 45.6, 60.8, 123.7, 125.2, 129.2, 130.3, 131.7, 133.4, 135.5, 140.4, 145.2, 149.0, 167.2, 169.7, 169.9, 174.1, 174.2. Analysis: Calculated for C ₂₃ H ₂₁ N ₃ O ₇ S + 0.3H ₂ O: C, 56.50; H, 4.45; N, 8.59. Found: C, 56.61; H, 4.42; N, 8.30.

5.46 4-Ethyl-N - [[2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-isoindolin-5-yl] methyl] benzamide

TEA (0.44 g, 4.4 mmol) was added to a mixture of 4-ethylbenzoyl chloride (0.34 g, 2.0 mmol) and 5-aminomethyl-2 - [(3S) -3-methyl-2,6- hydrochloride dioxo-piperidin-3-yl] -isoindol-1,3-dione (0.67 g, 2.0 mmol) in acetonitrile (20 ml). The mixture was stirred at room temperature for 2 hours and evaporated in vacuo. The residue was partitioned between water (100 ml) and ethyl acetate (100 ml) and the organic phase was evaporated. The residue was chromatographed on silica gel using ethyl acetate as the mobile phase to give 0.65 g in 76% yield. The product was obtained as a white solid. T. pl. 160-162 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 45/55 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.20 (97.47% ) ¹ H NMR (DMSO-d ₆ ) δ 1.19 (t, J = 7.7 Hz, 3H), 1.89 (s, 3H), 2.02-2.08 (m, 1H), 2, 54-2.62 (m, 2H), 2.65-2.78 (m, 3H), 4.61 (d, J = 6.0 Hz, 2H), 7.32 (d, J = 8, 1 Hz, 2H), 7.76-7.84 (m, 5H), 9.14 (t, J = 6.0 Hz, 1H), 11.01 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 15.4, 21.1, 28.1, 28.6, 29.2, 42.6, 58.8, 121.6, 123.2, 127.4, 127.8, 129.6, 131.4, 131.5, 133.4, 147.6, 147.7, 166.4, 167.8, 167.9, 172.2, 172.3. Analysis: Calculated for C ₂₄ H ₂₃ N ₃ O ₅ : C, 66.50; H, 5.35; N, 9.69. Found: C, 66.30; H, 5.26; N, 9.56.

5.47 N - [[2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-isoindolin-5-yl] methyl] -4- (trifluoromethylthio) - benzamide

TEA (0.44 g, 4.4 mmol) was added to a mixture of 4- (trifluoromethylthio) benzoyl chloride (0.48 g, 2.0 mmol) and 5-aminomethyl-2 - [(3S) -3-methyl-2 hydrochloride , 6-dioxo-piperidin-3-yl] -isoindole-1,3-dione (0.67 g, 2.0 mmol) in acetonitrile (15 ml). The mixture was stirred at room temperature for 2 hours and evaporated in vacuo. The residue was partitioned between water (75 ml) and ethyl acetate (75 ml) and the organic phase was washed with water (2 × 75 ml) and evaporated. The residue was chromatographed on silica gel using ethyl acetate as the mobile phase to give 0.62 g of the product in 62% yield. The product was obtained as a white solid. T. pl. 138-140 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.77 (96.89% ) ¹ H NMR (DMSO-d ₆ ) δ 1.89 (s, 3H), 2.02-2.08 (m, 1H), 2.54-2.60 (m, 2H), 2.63-2 75 (m, 1H), 4.64 (d, J = 6.0 Hz, 2H), 7.78-7.86 (m, 5H), 7.99-8.03 (m, 2H), 9.40 (t, J = 6.0 Hz, 1H); 11.01 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 21.0, 28.5, 29.0, 42.7, 58.8, 121.7, 123.2, 126.5, 128.7, 129.5 ( q, J = 306), 129.7, 131.4, 133.4, 135.9, 136.5, 147.0, 165.4, 167.7, 167.8, 172.1, 172.2 . Analysis: Calculated for C ₂₃ H ₁₈ F ₃ N ₃ O ₅ S: C, 54.65; H, 3.59; N, 8.31. Found: C, 54.56; H, 3.36; N, 8.24.

5.48 N - [[2- (2,6-dioxo-piperidin-3-yl) -1-oxo-isoindolin-5-yl] methyl] -4- (trifluoromethylthio) benzamide

TEA (0.65 g, 6.4 mmol) was added to a mixture of 4- (trifluoromethylthio) benzoyl chloride (0.77 g, 3.2 mmol) and 3- (5-aminomethyl-1-oxo-1,3-dihydro hydrochloride -isoindol-2-yl) -piperidin-2,6-dione (1.0 g, 3.2 mmol) in DMF (25 ml). The mixture was stirred at room temperature for 1 hour, and then diluted with water (40 ml) and stirred for 15 minutes. The precipitated solid is filtered and further washed with water (40 ml). The substance is stirred in 4% aqueous HCl (15 ml) and filtered, the solid is further washed with 4% aqueous HCl (15 ml) and water (15 ml). The solid was dried in vacuo to give 0.90 g of the product as a cream-colored solid in 59% yield. T. pl. 203-205 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 2.91 (96.41% ) ¹ H NMR (DMSO-d ₆ ) δ 1.96-2.03 (m, 1H), 2.31-2.45 (m, 1H), 2.54-2.63 (m, 1H), 2 85-2.98 (m, 1H), 4.31 (d, J = 17.4 Hz, 1H), 4.45 (d, J = 17.4 Hz, 1H), 4.61 (d, J = 5.9 Hz, 2H), 5.11 (dd, J = 13.2 Hz, J = 5.1 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7 56 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 8.02 (d, J = 8, 1 Hz, 1H), 9.35 (t, J = 5.9 Hz, 1H), 10.98 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.5, 31.2, 42.8, 47.1, 51.6, 122.1, 122.9, 126.3, 127.1, 128.7, 129.5 (q, J = 306), 130.4, 135.9, 136.8, 142.4, 143.6, 165.3, 167.9, 171.0, 172.8. Analysis: Calculated for C ₂₂ H ₁₈ F ₃ N ₃ O ₄ S + 0.4H ₂ O: C, 54.52; H, 3.91; N, 8.65. Found: C, 54.51; H, 3.61; N, 8.64.

5.49 4-Ethylsulfanyl-N - [[2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-2,3-dihydro-1H-isoindole-5 -yl] methyl] benzamide

A mixture of 4- (ethylthio) benzoic acid (0.36 g, 2.0 mmol) and CDI (0.34 g, 2.1 mmol) in DMF (20 ml) was stirred under N ₂ at 40 ° C. for 2 hours. Then 5-aminomethyl - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -isoindole-1,3-dione hydrochloride (0.67 g, 2.0 mmol) was added and stirring continued at 40 ° C in an atmosphere of N ₂ an additional 3 hours. The mixture was partitioned between ethyl acetate (75 ml) and saturated aqueous sodium bicarbonate (100 ml), the aqueous phase was extracted with ethyl acetate (75 ml). The combined organic phases are then washed with saturated aqueous sodium bicarbonate (3 × 100 ml), dried (MgSO ₄ ) and evaporated. The residue was chromatographed (silica gel) using an ethyl acetate / hexanes gradient to give 0.92 g of the product in 61% yield as a white solid. T. pl. 135-137 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.03 (99.73% ) ¹ H NMR (DMSO-d ₆ ) δ 1.27 (t, 3H, J = 7.3 Hz), 1.99 (s, 3H), 2.00-2.02 (m, 1H), 2, 49-2.65 (m, 3H), 3.06 (q, 2H, J = 7.25 Hz), 4.61 (d, 2H, J = 6.0 Hz), 7.38 (dd, 2H , J = 6.0 Hz, J = 3.0 Hz), 7.76-7.85 (m, 5H), 9.17 (t, 1H, J = 6.0 Hz), 11.01 (s , 1H); ¹³ C NMR (DMSO-d ₆ ) δ 13.9, 21.0, 25.2, 28.5, 29.1, 42.6, 58.7, 121.6, 123.2, 126.3, 127.8, 129.6, 130.4, 131.4, 133.4, 141.2, 147.5, 165.9, 167.7, 167.9, 172.1, 172.2. Analysis: Calculated for C ₂₄ H ₂₃ N ₃ O ₅ S + 0.3H ₂ O: C, 61.21; H, 5.05; N, 8.92. Found: C, 61.27; H, 5.13; N, 8.80.

5.50 4-Ethoxy-N - [[(2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-2,3-dihydro-1H-isoindole- 5-yl] methyl] benzamide

A mixture of 4- (ethoxy) benzoic acid (0.33 g, 2.0 mmol) and CDI (0.34 g, 2.1 mmol) in DMF (20 ml) was stirred at 40 ° C. under N ₂ atmosphere for 2 hours. Then 5-aminomethyl-2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -isoindole-1,3-dione hydrochloride (0.67 g, 2.0 mmol) and stirring is continued at 40 ° C. under N _{2 for} an additional 2 hours. The reaction mixture was partitioned between ethyl acetate (75 ml) and saturated aqueous sodium bicarbonate (100 ml). The aqueous phase was extracted with ethyl acetate (75 ml). The combined organic phases are then washed with saturated aqueous sodium bicarbonate (3 × 100 ml), dried (MgSO ₄ ) and evaporated. The residue was chromatographed (silica gel) using an ethyl acetate / hexanes gradient to give 0.27 g of the product in 31% yield as a white solid. Mp 163-165 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 5.73 (97.04% ) ¹ H NMR (DMSO-d ₆ ) δ 1.34 (t, 3H, J = 6.0 Hz), 2.01 (s, 3H), 2.03-2.06 (m, 1H), 2, 49-2.71 (m, 3H), 4.09 (q, 2H, J = 7.0 Hz), 4.60 (d, 2H, J = 6.0 Hz), 7.00 (d, 2H , J = 9.0), 7.75-7.87 (m, 5H), 9.06 (t, 1H, J = 6.0 Hz), 11.01 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 14.5, 21.0, 28.5, 29.1, 42.5, 58.7, 63.3, 114.0, 121.5, 123.1, 125.9, 129.1, 129.5, 131.4, 133.3, 147.7, 161.0, 165.9, 167.7, 167.9, 172.1, 172.2. Analysis: Calculated for C ₂₄ H ₂₃ N ₃ O ₆ + 0.75H ₂ O: C, 62.26; H, 5.33; N, 9.08. Found: C, 62.25; H, 5.13; N, 9.17.

5.51 N - ((2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-isoindolin-5-yl) methyl) -5- (ethylthio) picolinamide

Stage 1: A mixture of 2-chloro-5-nitropyridine (25.0 g, 158 mmol) and dimethyl malonate (21.9 g, 166 mmol) in DMF (150 ml) is cooled to 0 ° C, sodium hydride (6) is added in small portions. 50 g of a 60% dispersion in mineral oil, 162 mmol). The mixture was stirred at 0 ° C. for 1 hour, completing the addition. Then, in small portions, another equivalent of sodium hydride is added (6.50 g of a 60% dispersion in mineral oil, 162 mmol). The reaction was quenched by the addition of acetic acid (10 ml) and the mixture was evaporated to dryness. The residue was left overnight for trituration with diethyl ether (150 ml), filtered to give crude dimethyl 2- (5-nitropyridin-2-yl) malonate as an orange solid.

Step 2: The crude product from Step 1 is suspended in 250 ml of water in an ice bath and 10N NaOH (15 ml) is added. A hot solution of KMnO ₄ (33.3 g, 210 mmol) in water (140 ml) and 10N NaOH (8 ml) are added from a dropping funnel. Additional solid KMnO ₄ (110 g, 690 mmol) was added in portions along with 10 N NaOH. Finishing the addition, the mixture is heated to 95 ° C for 90 minutes. Celite is added to the mixture and filtered while still hot through a celite pad. The filter was washed with hot 2N NaOH (200 ml). The filtrate was cooled and the pH was adjusted to 3-4 with concentrated HCl. The solid precipitate was filtered off and dried, yielding 9.4 g of 5-nitropicolinic acid as a cream-colored solid with a yield of 35% in two stages. ¹ H NMR (DMSO-d ₆ ) δ 8.26 (dd, 1H, J = 8.7 Hz, J = 0.6 Hz), 8.74 (dd, 1H, J = 8.7 Hz, J = 2.7 Hz), 9.44 (dd, 1H, J = 2.7 Hz, J = 0.6 Hz), 13.92 (broad, 1H).

Step 3: A suspension of 5-nitropicolinic acid (6.0 g, 36 mmol) in methanol HCl (1.25 M) was refluxed and stirred for 16 hours. The mixture is cooled to ambient temperature. The product is filtered and further washed with methanol (20 ml) and dried in vacuo to give 1.6 g of methyl 5-nitropicolinate in 94% yield. ¹ H NMR (DMSO-d ₆ ) δ 3.95 (s, 3H), 8.29 (dd, 1H, J = 8.4 Hz, J = 0.6 Hz), 8.75 (dd, 1n, J = 8.4 Hz, J = 2.7 Hz), 9.46 (dd, 1H, J = 2.7 Hz, J = 0.6 Hz).

Step 4: Sodium ethanethiolate (1.6 g, 17.2 mmol) was added to a solution of methyl 5-nitropicolinate (2.8 g, 16 mmol) in DMF (30 ml) and the resulting mixture was stirred at room temperature. After 3 hours, acetic acid (1 ml) was added and the mixture was evaporated to dryness. The residue was suspended in methanol (50 ml) and treated with 3N NaOH. The resulting mixture was stirred at room temperature for 16 hours, and then evaporated. The residue was dissolved in water (100 ml), washed with ethyl acetate (2 × 100 ml) and acidified to pH 3-4 (conc. HCl), which precipitated the product. The precipitate was filtered, washed with water (100 ml) and dried in vacuo to give 2.3 g of 5- (ethylthio) picolinic acid in 79% yield. ¹ H NMR (DMSO-d ₆ ) δ 1.23 (t, 3H, J = 7.3 Hz), 3.14 (q, 2H, J = 7.3 Hz), 7.86 (dd, 1H, J = 8.4 Hz, J = 2.4 Hz), 7.95 (dd, 1H, J = 8.4 Hz, J = 0.9 Hz), 8.57 (dd, 1H, J = 2, 4 Hz, J = 0.9 Hz), 13.09 (broad, 1H).

Stage 5: CDI (0.44 g, 2.7 mmol) was added to a mixture of 5- (ethylthio) picolinic acid (0.48 g, 2.6 mmol) and DMF (20 ml) and the resulting mixture was stirred at 40 ° C. 2 hours. Then 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione methanesulfonate (1.00 g, 2.6 mmol) was added and stirring was continued at 40 ° C. in atmosphere N ₂ extra 3 hours. The mixture was partitioned between ethyl acetate (75 ml) and saturated aqueous sodium bicarbonate (100 ml), the aqueous phase was extracted with ethyl acetate (75 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (3 × 100 ml), dried (MgSO ₄ ) and evaporated. The residue was chromatographed (silica gel) using an ethyl acetate / hexanes gradient to give 0.65 g of the product in 60% yield as a white solid. T. pl. 198-200 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 7.53 (97.70% ) ¹ H NMR (DMSO-d ₆ ) δ 1.28 (t, 3H, J = 7.3 Hz), 2.02-2.08 (m, 1H), 2.45-2.62 (m, 2H ), 2.83-2.95 (m, 1H), 3.13 (q, 2H, J = 7.3 Hz), 4.65 (d, 2H, J = 6.3 Hz), 5.14 (dd, 1H, J = 12.9 Hz, J = 5.4 Hz), 7.83-7.95 (m, 5H), 8.54 (dd, 1H, J = 2.3 Hz, J = 0.8 Hz), 9.53 (t, 1H, J = 6.3 Hz), 11.12 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 13.8, 22.0, 25.2, 30.9, 42.3, 49.0, 122.1, 122.2, 123.5, 129.8, 131.5, 133.5, 135.4, 138.0, 146.3, 146.4, 147.5, 164.1, 167.0, 167.1, 169.8, 172.7. Analysis: Calculated for C ₂₂ H ₂₀ N ₄ O ₅ S: C, 58.40; H, 4.46; N, 12.38. Found: C, 58.27; H, 4.35; N, 12.30.

5.52 1- (2-Chloro-phenyl -) - 3- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl ]urea

Stage 1: A mixture of 4-bromophthalic anhydride (10.0 g, 44.1 mmol), rac -α-aminoglutarimide hydrochloride (7.25 g, 44.0 mmol) and sodium acetate (3.61 g, 44.0 mmol ) in acetic acid (150 ml) is left overnight at the boil under reflux. The reaction mixture was cooled to room temperature and the solvent was evaporated in vacuo. The residue was stirred in water (170 ml) for 3 hours and the resulting solid was filtered off, further washed with water (80 ml) and dried in vacuo to give 13.8 g of 5-bromo-2- (2,6-dioxo-piperidin-3- silt) -isoindole-1,3-5-dione with a yield of 93%. ¹ H NMR (DMSO-d ₆ ) δ 2.03-2.10 (m, 1H), 2.43-2.63 (m, 2H), 2.82-2.97 (m, 1H), 5 , 17 (dd, J = 12.8 Hz, J = 5.3 Hz, 1H), 7.85-7.88 (d, J = 7.9 Hz, 1H), 8.10 (dd, J = 7.9 Hz, J = 1.7 Hz, 1H), 8.16 (d, J = 1.7 Hz, 1H), 11.15 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 21.9, 30.9, 49.2, 125.3, 126.4, 128.5, 130.1, 133.2, 137.6, 165.9, 166.4, 169.7, 172.7. Analysis: Calculated for C ₁₃ H ₉ N ₂ O ₄ Br: C, 46.32; H, 2.69; N, 8.31. Found: C, 46.23; H, 2.47; N, 8.41.

Stage 2: DMF is degassed through a nitrogen bubbler for 1 hour and 5-bromo-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione (13.7 g, 40.6 mmol) is added. , zinc cyanide (2.86 g, 24.4 mmol), tris (dibenzylideneacetone) dipalladium (0.74 g, 0.80 mmol) and 1,1'-bis (diphenylphosphino) ferrocene (0.90 g, 1, 6 mmol). The reaction mixture is heated to 120 ° C for 3 hours, cooled to 60 ° C and filtered through celite. The filter was further washed with DMF (160 ml) and the filtrate was evaporated in vacuo. The residue was stirred in water (300 ml) for 2 days and filtered, further washed with water and dried in vacuo. The resulting solid was triturated with acetone (300 ml) for 1 hour and filtered, the solid was further washed with acetone (300 ml) and dried in vacuo. The resulting material was refluxed for 1 hour in methanol, cooled to room temperature, filtered, washed with methanol and dried, to obtain 11.1 g of 2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo -2,3-dihydro-1H-isoindole-5-carbonitrile in 96% yield. T. pl.> 60 ° C. ¹ H NMR (DMSO-d ₆ ) δ 2.03-2.12 (m, 1H), 2.43-2.64 (m, 2H), 2.83-2.97 (m, 1H), 5 22 (dd, J = 12.8 Hz, J = 5.2 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 8.38 (dd, J = 7.8 Hz J = 1.4 Hz, 1H), 8.49 (s, 1H), 11.17 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 21.8, 30.9, 49.3, 117.0, 117.4, 124.2, 127.3, 131.8, 134.5, 139.1, 165.6, 165.9, 169.5, 172.7. Analysis: Calculated for C ₁₄ H ₉ N ₃ O ₄ + 0.3H ₂ O: C, 58.26; H, 3.35; N, 14.56. Found: C, 58.01; H, 3.01; N, 14.37.

Step 3: Mixture of 2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindole-5-carbonitrile (1.00 g, 3.53 mmol) 4N HCl (4.5 ml), 10% Pd-C (0.1 g) and charcoal for decolorization (0.06 g) in DMF (30 ml) were left overnight for hydrogenation at 50 psi. inch. Water (5 ml) was added and the reaction mixture was filtered through celite. The filter was washed with methanol (10 ml). The filtrate was concentrated, the residue was coevaporated with ethanol (2 × 5 ml). The resulting solid was triturated with ethanol (5 ml) for 1 hour, filtered, further washed with ethanol (10 ml) and dried, yielding 0.97 g of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) hydrochloride -isoindole-1,3-dione in the form of a white solid with a yield of 85%. T. pl.> 260 ° C. ¹ H NMR (DMSO-d ₆ ) δ 2.05-2.12 (m, 1H), 2.45-2.63 (m, 2H), 2.83-2.98 (m, 1H), 4 24 (s, 2H), 5.18 (dd, J = 12.6 Hz, J = 5.4 Hz, 1H), 7.96-8.03 (m, 2H), 8.11 (s, 1H); 8.73 (broad, 3H); 11.15 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 30.9, 41.7, 49.1, 123.6, 123.9, 131.0, 131.5, 135.4, 141.5, 166.8, 166.9, 169.8, 172.7. Analysis: Calculated for C ₁₄ H ₁₄ N ₃ O ₄ Cl + 0.15H ₂ O: C, 51.51; H, 4.42; N, 12.87. Found: C, 51.16; H, 4.40; N, 12.59.

Stage 4: Mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), 2-chlorophenylisocyanate (0, 36 ml, 3.0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in THF (20 ml) are left overnight with stirring at 40 ° C. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (100 ml) and washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml). A solid precipitates during this washing. It is filtered off and washed additionally with water. The organic phase of the filtrate was dried (MgSO ₄ ) and the solvent was removed in vacuo. The combined solids were stirred in ether for 3 hours and filtered to give 1.2 g of product in 92% yield. T. pl. 238-240 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.34 (98.10% ) ¹ H NMR (DMSO-d ₆ ) δ 1.99-2.08 (m, 1H), 2.50-2.63 (m, 2H), 2.82-2.95 (m, 1H), 4 51 (d, J = 5.8 Hz, 2H), 5.15 (dd, J = 12.6 Hz, J = 5.3 Hz, 1H), 6.94-7.43 (m, 3H) 7.65 (t, J = 5.8 Hz, 1H); 7.79-8.14 (m, 4H); 8.24 (s, 1H); 11.13 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 30.9, 42.6, 49.0, 121.1, 121.6, 121.7, 122.8, 123.6, 127.5, 129.1, 129.8, 131.7, 133.3, 136.5, 148.2, 154.9, 167.0, 167.2, 169.8, 172.7. Analysis: Calculated for C ₂₁ H ₁₇ N ₄ O ₅ Cl + 0.1H ₂ O: C, 56.98; H, 3.92; N, 12.66. Found: C, 56.71; H, 4.05; N, 12.33.

5.53 1- (3-Chlorophenyl) -3- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] urea

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), 3-chlorophenylisocyanate (0.37 ml, 3.0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in THF (20 ml) were left overnight with stirring at 40 ° C. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (150 ml), washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml), dried (MgSO ₄ ) and evaporated. The resulting solid was stirred in ether for 3 hours and filtered, yielding 1.2 g of product in 92% yield. T. pl. 214-216 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.58 (98.39% ) ¹ H NMR (DMSO-d ₆ ) δ 1.99-2.07 (m, 1H), 2.50-2.62 (m, 2H), 2.82-2.95 (m, 1H), 4 47 (d, J = 5.5 Hz, 2H), 5.14 (dd, J = 12.5 Hz, J = 5.1 Hz, 1H), 6.93-6.98 (m, 2H) 7.22-7.28 (m, 2H); 7.66-7.91 (m, 4H); 8.96 (s, 1H); 11.12 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 30.9, 42.7, 49.0, 116.2, 117.2, 120.8, 121.7, 123.5, 129.7, 130.2, 131.6, 133.1, 133.2, 141.9, 148.5, 155.1, 167.0, 167.2, 169.8, 172.7. Analysis: Calculated for C ₂₁ H ₁₇ N ₄ O ₅ Cl + 0.1H ₂ O: C, 56.98; H, 3.92; N, 12.66. Found: C, 56.96; H, 3.70; N, 12.29.

5.54 1- (4-Chlorophenyl) -3- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] urea

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), 4-chlorophenyl isocyanate (0.38 ml, 3.0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in THF (20 ml) was stirred at 40 ° C. for 2 days. The reaction mixture was cooled to room temperature. The solid was filtered, washed with water (20 ml), washed with ethyl acetate (20 ml) and dried, yielding 0.64 g of the product in 48% yield. T. pl. 278-280 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.18 (98.85% ) ¹ H NMR (DMSO-d ₆ ) δ 2.03-2.07 (m, 1H), 2.46-2.62 (m, 2H), 2.82-2.96 (m, 1H), 4 47 (d, J = 5.8 Hz, 2H), 5.14 (dd, J = 12.5 Hz, J = 5.2 Hz, 1H), 6.91 (t, J = 5.8 Hz , 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.9 Hz, 2H), 7.77-7.91 (m, 3H), 8 89 (s, 1H); 11.13 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 30.9, 42.7, 49.0, 119.3, 121.7, 123.5, 124.7, 128.5, 129.7, 131.6, 133.2, 139.3, 148.6, 155.1, 167.0, 167.2, 169.8, 172.7. Analysis: Calculated for C ₂₁ H ₁₇ N ₄ O ₅ Cl + 0.3H ₂ O: C, 56.52; H, 3.98; N, 12.55. Found: C, 56.19; H, 3.78; N, 12.28.

5.55 1- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -3- (2-methoxyphenyl) urea

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), 2-methoxyphenyl isocyanate (0.40 ml, 3.0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in THF (20 ml) were left overnight with stirring at 40 ° C. The reaction mixture was cooled to room temperature, the solvent was removed in vacuo. The residue was suspended in a biphasic mixture of ethyl acetate (150 ml) and dilute aqueous HCl (150 ml). The solid is filtered and washed with water (50 ml). The resulting solid was chromatographed using a gradient of methanol-CH ₂ Cl ₂ , the product was eluted with a methanol-CH ₂ Cl ₂ ratio of 5:95 to give the product (0.090 g, 7% yield). T. pl. 276-278 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 30/70 CH ₃ CN / 0.1% H ₃ PO ₄ , 8.93 (98.32% ) ¹ H NMR (DMSO-d ₆ ) δ 2.02-2.09 (m, 1H), 2.46-2.62 (m, 2H), 2.83-2.95 (m, 1H), 3 84 (s, 3H), 4.48 (d, J = 5.8 Hz, 2H), 5.15 (dd, J = 12.8 Hz, J = 5.3 Hz, 1H), 6.83 -6.99 (m, 3H), 7.51 (t, J = 6.0 Hz, 1H), 7.78-8.11 (m, 5H), 11.13 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 30.9, 42.5, 49.0, 55.6, 110.59, 118.11, 120.4, 121.3, 121.6, 123.5, 129.1, 129.7, 131.6, 133.2, 147.4, 148.6, 155.2, 167.0, 167.2, 169.8, 172.7. Analysis: Calculated for C ₂₂ H ₂₀ N ₄ O ₆ + 1.2H ₂ O: C, 57.69; H, 4.93; N, 12.23. Found: C, 57.63; H, 4.19; N, 11.84.

5.56 1- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -3- (4-methoxyphenyl) urea

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), 4-methoxyphenyl isocyanate (0.39 ml, 3.0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in THF (20 ml) was stirred at 40 ° C. for 2 days. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (150 ml) and washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml). The solvent was removed in vacuo and the resulting solid was chromatographed using a gradient of methanol-CH ₂ Cl ₂ , eluting with a methanol-CH ₂ Cl ₂ ratio of 5:95, 0.57 g of product was obtained in 44% yield. T. pl. 241-243 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 30/70 CH ₃ CN / 0.1% H ₃ PO ₄ , 5.69 (98.79% ) ¹ H NMR (DMSO-d ₆ ) δ 2.04-2.08 (m, 1H), 2.49-2.63 (m, 2H), 2.85-2.90 (m, 1H), 3 69 (s, 3H), 4.45 (d, J = 6.0 Hz, 2H), 5.15 (dd, J = 12.6 Hz, J = 5.1 Hz, 1H), 6.75 (t, J = 6.0 Hz, 1H), 6.80-6.84 (m, 2H), 7.29-7.32 (m, 2H), 7.77-7.91 (m, 3H ), 8.51 (s, 1H), 11.13 (s, 1H); ¹ H NMR (DMSO-d ₆ ) δ 22.0, 30.9, 42.6, 49.0, 55.1, 113.8, 119.6, 121.7, 123.5, 129.6, 131.6, 133.2, 133.3, 148.9, 154.1, 155.5, 167.0, 167.2, 169.8, 172.7. Analysis: Calculated for C ₂₂ H ₂₀ N ₄ O ₆ : C, 60.55; H, 4.62; N, 12.84. Found: C, 60.22; H, 4.35; N, 12.62.

5.57 1- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -3-m-tolyl-urea

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), m-tolyl isocyanate (0.38 ml, 3.0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The solid phase is filtered, washed additionally with acetonitrile (20 ml) and dried in vacuo to give 0.72 g of product in 57% yield. T. pl. 220-222 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 5.21 (95.95% ) ¹ H NMR (DMSO-d ₆ ) δ 2.02-2.10 (m, 1H), 2.24 (s, 3H), 2.48-2.63 (m, 2H), 2.83-2 95 (m, 1H), 4.47 (d, J = 6.0 Hz, 2H), 5.15 (dd, J = 12.6 Hz, J = 5.1 Hz, 1H), 6.72 (d, J = 7.2 Hz, 1H), 6.83 (t, J = 6.0 Hz, 1H), 7.07-7.25 (m, 3H), 7.78-7.82 ( m, 2H), 7.90 (d, J = 7.8 Hz, 1H), 8.64 (s, 1H), 11.12 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 21.2, 22.0, 30.9, 42.6, 49.0, 115.0, 118.4, 121.7, 122.0, 123.5, 128.5, 129.6, 131.6, 133.2, 137.7, 140.2, 148.8, 155.3, 167.0, 167.2, 169.8, 172.7. Analysis: Calculated for C ₂₂ H ₂₀ N ₄ O ₅ : C, 62.85; H, 4.79; N, 13.33. Found: C, 62.54; H, 4.60; N, 13.38.

5.58 1- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -3-p-tolyl-urea

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), p-tolyl isocyanate (0.38 ml, 3.0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in CH ₂ Cl ₂ (20 ml) were left overnight with stirring at room temperature. The solid phase is filtered, further washed with CH ₂ Cl ₂ (20 ml). The solid phase is left overnight with stirring in methanol, refluxed for 3 hours and filtered. The filtrate was concentrated and the residue was stirred in ethyl acetate and filtered. The solid phases are combined to give 0.70 g of product in 56% yield. T. pl. 238-240 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.66 (98.56% ) ¹ H NMR (DMSO-d ₆ ) δ 1.99-2.10 (m, 1H), 2.21 (s, 3H), 2.47-2.63 (m, 2H), 2.83-2 95 (m, 1H), 4.46 (d, J = 5.7 Hz, 2H), 5.15 (dd, J = 12.6 Hz, J = 5.1 Hz, 1H), 6.79 (t, J = 6.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.78-7 91 (m, 3H); 8.59 (s, 1H); 11.12 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 20.3, 22.0, 30.9, 42.6, 49.0, 117.94, 121.7, 123.5, 129.0, 129.6, 130.0, 131.6, 133.2, 137.7, 148.9, 155.3, 167.0, 167.2, 169.8, 172.7. Analysis: Calculated for C ₂₂ H ₂₀ N ₄ O ₅ + 0.1H ₂ O: C, 62.58; H, 4.82; N, 13.27. Found: C, 62.37; H, 4.55; N, 12.92.

5.59 1- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -3- (4-trifluoromethoxyphenyl) urea

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), 4- (trifluoromethoxy) phenylisocyanate (0, 45 ml, 3.0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in THF (20 ml) are left overnight with stirring at 40 ° C. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (150 ml) and washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml). The solvent was removed in vacuo and the residue was left overnight with stirring in ether (20 ml). The resulting solid phase was filtered to give the product (1.3 g, 89% yield). T. pl. 226-228 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 9.50 (98.37% ) ¹ H NMR (DMSO-d ₆ ) δ 2.02-2.09 (m, 1H), 2.47-2.63 (m, 2H), 2.83-2.95 (m, 1H), 4 48 (d, J = 6.0 Hz, 2H), 5.15 (dd, J = 12.6 Hz, J = 5.1 Hz, 1H), 6.93 (t, J = 6.0 Hz , 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.49-7.54 (m, 2H), 7.79-7.91 (m, 3H), 8.96 ( s, 1H); 11.13 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 30.9, 42.6, 49.0, 118.9, 120.16 (q, J = 254 Hz), 121.6, 121.7, 123.5, 129.7, 131.6, 133.2, 139.59, 142.1, 148.6, 155.2, 167.0, 167.2, 169.8, 172.7. Analysis: Calculated for C ₂₂ H ₁₇ N ₄ O ₆ F ₃ : C, 53.88; H, 3.49; N, 11.42. Found: C, 53.80; H, 3.15; N, 11.25.

5.60 1- (4-Cyanophenyl) -3- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -urea

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), 4-cyanophenyl isocyanate (0.43 g, 3.0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in CH ₂ Cl ₂ (20 ml) was stirred at room temperature for 2 days. The solid phase is filtered and further washed with CH ₂ Cl ₂ (20 ml). The solid phase is stirred in ethyl acetate for 3 hours and filtered. The residue was purified by preparative HPLC using an acetonitrile-water gradient, eluting the product with an acetonitrile-water ratio of 35:65, and 0.56 g of product was obtained in 43% yield. T. pl. 265-267 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 30/70 CH ₃ CN / 0.1% H ₃ PO ₄ , 8.97 (97.25% ) ¹ H NMR (DMSO-d ₆ ) δ 2.04-2.08 (m, 1H), 2.50-2.63 (m, 2H), 2.83-2.95 (m, 1H), 4 49 (d, J = 6.0 Hz, 2H), 5.15 (dd, J = 12.9 Hz, J = 5.4 Hz, 1H), 7.18 (t, J = 5.7 Hz , 1H), 7.58-7.69 (m, 4H), 7.79-7.91 (m, 3H), 9.38 (s, 1H), 11.12 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 30.9, 42.6, 49.0, 102.6, 117.6, 119.4, 121.7, 123.5, 129.7, 131.6, 133.1, 133.2, 144.8, 148.3, 154.8, 167.0, 167.2, 169.8, 172.7. Analysis: Calculated for C ₂₂ H ₁₇ N ₅ O ₅ + 0.4H ₂ O: C, 60.25; H, 4.09; N, 15.97. Found: C, 59.87; H, 3.70; N, 15.87.

5.61 1- (4-Tert-butyl-phenyl) -3- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5- ilmethyl] urea

Mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), 4- (tert-butyl) phenylisocyanate (0.52 g, 3.0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in THF (20 ml) are left overnight with stirring at 40 ° C. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (100 ml) and washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml), dried (MgSO ₄ ) and evaporated. The solid was allowed to stand overnight with stirring in ether and filtered to give 0.34 g of the product in 24% yield. T. pl. 207-209 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.87 (95.56% ) ¹ H NMR (DMSO-d ₆ ) δ 1.24 (s, 9H), 2.02-2.09 (m, 1H), 2.49-2.63 (m, 2H), 2.83-2 95 (m, 1 H), 4.47 (d, J = 5.7 Hz, 2H), 5.15 (dd, J = 12.6 Hz, J = 5.1 Hz, 1H), 6, 79 (t, J = 6.0 Hz, 1H), 7.22-7.33 (m, 4H), 7.78-7.91 (m, 3H), 8.96 (s, 1H), 11 12 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 30.9, 31.2, 33.8, 42.6, 49.0, 117.7, 121.6, 123.5, 125.2, 129.6, 131.6, 133.2, 137.6, 143.5, 148.9, 155.3, 167.0, 167.2, 169.8, 172.7. Analysis: Calculated for C ₂₅ H ₂₆ N ₄ O ₅ + 0.15H ₂ O: C, 64.55; H, 5.70; N, 12.04. Found: C, 64.17; H, 5.44; N, 11.90.

5.62 1- (3,4-Dichloro-phenyl) -3- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5- ilmethyl] urea

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), 3,4-dichlorophenylisocyanate (0.56 g, 3.0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in pyridine (20 ml) were left overnight with stirring at 40 ° C. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was suspended in a biphasic mixture of CH ₂ Cl ₂ (150 ml) and water (150 ml) and stirred for 2 hours. The solid is filtered, further washed with water (50 ml) and dried. The resulting solid was stirred in methanol (200 ml) at room temperature for 1 hour, filtered and dried. This substance is refluxed in methanol (2 × 200 ml) for 3 hours, filtered and dried. The resulting solid was chromatographed using a gradient of methanol-CH ₂ Cl ₂ (with 0.1% triethylamine), 0.23 g of product was eluted with a methanol-CH ₂ Cl ₂ ratio (with 0.1% triethylamine) 7:93 in 16 yield % T. pl. 290-292 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 10.50 (97.00% ) ¹ H NMR (DMSO-d ₆ ) δ 2.03-2.07 (m, 1H), 2.56-2.62 (m, 2H), 2.82-2.94 (m, 1H), 4 47 (d, J = 5.9 Hz, 2H), 5.15 (dd, J = 12.6 Hz, J = 5.4 Hz, 1H), 7.05 (t, J = 6.1 Hz , 1H), 7.29 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.77-7.91 (m, 4H); 9.11 (s, 1H); 11.13 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 30.9, 42.7, 49.0, 117.9, 118.9, 121.7, 122.4, 123.5, 129.7, 130.4, 130.9, 131.6, 133.3, 140.6, 148.4, 155.0, 167.0, 167.2, 169.8, 172.7. Analysis: Calculated for C ₂₁ H ₁₆ N ₄ O ₅ Cl ₂ + 0.25H ₂ O: C, 52.57; H, 3.47; N, 11.68. Found: C, 52.22; H, 3.25; N, 11.56.

5.63 1- (3,4-Dimethyl-phenyl) -3- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5- ilmethyl] urea

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), 3,4-dimethylphenylisocyanate (0.42 g, 3.0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in THF (20 ml) was stirred at 40 ° C. for 2 days. The reaction mixture was cooled to room temperature. The solid was filtered, washed with water (20 ml), washed with ethyl acetate (20 ml) and dried, yielding 1.0 g of the product in 78% yield. T. pl. 238-240 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 5.35 (98.53% ) ¹ H NMR (DMSO-d ₆ ) δ 2.03-2.07 (m, 1H), 2.12 (s, 3H), 2.15 (s, 3H), 2.46-2.62 (m , 2H), 2.82-2.96 (m, 1H), 4.45 (d, J = 5.9 Hz, 2H), 5.14 (dd, J = 12.6 Hz, J = 5, 3 Hz, 1H), 6.77 (t, J = 5.9 Hz, 1H), 6.96 (d, J = 7.0 Hz, 1H), 7.09-7.18 (m, 2H) 7.77-7.91 (m, 3H); 8.52 (s, 1H); 11.12 (s, 1 H); ¹³ C NMR (DMSO-d ₆ ) δ 18.6, 19.6, 22.0, 30.9, 42.6, 49.0, 115.5, 119.3, 121.7, 123.5, 128.8, 129.5, 129.6, 131.6, 133.2, 136.1, 137.9, 148.9, 155.3, 167.0, 167.2, 169.8, 172, 7. Analysis: Calculated for C ₂₃ H ₂₂ N ₄ O ₃ + 0.4H ₂ O: C, 62.55; H, 5.20; N, 12.69. Found: C, 62.22; H, 5.12; N, 12.39.

5.64 1- (3-Chloro-4-methyl-phenyl) -3- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindole- 5-ylmethyl] urea

Mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), 3-chloro-4-methylphenylisocyanate (0 , 41 ml, 3.0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in THF (20 ml) are left overnight with stirring at 40 ° C. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was stirred in a biphasic mixture of CH ₂ Cl ₂ (150 ml) and water (150 ml) and the organic solvent was removed in vacuo. The resulting solid was filtered and allowed to stand overnight with stirring in methanol (100 ml) at room temperature, filtered and dried to give the product as a white solid (1.2 g, 88% yield). T. pl. 243-245 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 8.42 (98.48% ) ¹ H NMR (DMSO-d ₆ ) δ 2.04-2.09 (m, 1H), 2.24 (s, 3H), 2.47-2.64 (m, 2H), 2.83-2 96 (m, 1H), 4.47 (d, J = 5.6 Hz, 2H), 5.16 (dd, J = 12.3 Hz, J = 4.9 Hz, 1H), 6.92 (t, J = 5.7 Hz, 1H), 7.13-7.21 (m, 2H), 7.66-7.92 (m, 4H), 8.86 (s, 1H), 11, 14 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 18.7, 22.0, 30.9, 42.7, 49.0, 116.5, 117.8, 121.7, 123.5, 127.5, 129.7, 131.0, 131.6, 133.0, 133.2, 139.5, 148.6, 155.1, 167.0, 167.2, 169.8, 172.7. Analysis: Calculated for C ₂₂ H ₁₉ N ₄ O ₅ Cl + 0.4H ₂ O: C, 57.19; H, 4.32; N, 12.12. Found: C, 56.80; H, 4.12; N, 11.75.

5.65 1- (4-Chloro-3-methyl-phenyl) -3- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindole- 5-ylmethyl] urea

Mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), 4-chloro-3- (trifluoromethyl) phenylisocyanate (0.66 ml, 3.0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in CH ₂ Cl ₂ (20 ml) was stirred at room temperature for 2 days. The solid is filtered and further washed with CH ₂ Cl ₂ (20 ml) and dried, yielding 1.0 g of the product in 68% yield. T. pl. 285-287 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 6.01 (95.01% ) ¹ H NMR (DMSO-d ₆ ) δ 2.02-2.09 (m, 1H), 2.46-2.63 (m, 2H), 2.84-2.94 (m, 1H), 4 49 (d, J = 6.0 Hz, 2H), 5.15 (dd, J = 12.6 Hz, J = 5.4 Hz, 1H), 7.09 (t, J = 6.0 Hz , 1H), 7.54-7.65 (m, 2H), 7.79-7.94 (m, 3H), 8.06 (d, J = 2.4 Hz, 1H), 9.29 ( s, 1H); 11.13 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 30.9, 42.7, 49.0, 116.3 (q, J = 6.0 Hz), 122.8 (q, J = 270 Hz ), 121.6, 121.7, 122.5, 123.5, 126.6 (q, J = 30 Hz), 129.7, 131.8, 131.6, 133.2, 139.9, 148.4, 155.0, 167.0, 167.2, 169.8, 172.7. Analysis: Calculated for C ₂₀ H ₁₆ N ₄ O ₅ ClF ₃ + 0.2H ₂ O: C, 51.03; H, 3.31; N, 10.82. Found: C, 50.68; H, 2.96; N, 10.55.

5.66 1-Benzo [1,3] dioxol-5-yl-3- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindole- 5-ylmethyl] urea

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), 3,4- (methylenedioxy) phenylisocyanate ( 0.49 g, 3.0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in methylene chloride (20 ml) were stirred at room temperature for 1 hour. The solid is filtered and further washed with methylene chloride (20 ml), dried in vacuo to give 0.86 g of the product in 64% yield. T. pl. 200-202 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 3.10 (96.75% ) ¹ H NMR (DMSO-d ₆ ) δ 2.02-2.09 (m, 1H), 2.48-2.63 (m, 2H), 2.83-2.94 (m, 1H), 4 45 (d, J = 6.0 Hz, 2H), 5.15 (dd, J = 12.6 Hz, J = 5.1 Hz, 1H), 5.93 (s, 2H), 6.70 -6.80 (m, 3H), 7.16 (d, J = 1.8 Hz, 1H), 7.77-7.91 (m, 3H), 8.62 (s, 1H), 11, 13 (8, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 30.9, 42.6, 49.0, 110.6, 100.6, 108.0, 110.5, 121.7, 123.5, 129.6, 131.6, 133.2, 134.7, 141.6, 147.1, 148.8, 155.4, 167.0, 167.2, 169.8, 172.7. Analysis: Calculated for C ₂₂ H ₁₈ N ₄ O ₇ + 0.1H ₂ O: C, 58.43; H, 4.06; N, 12.39. Found: C, 58.20; H, 3.78; N, 12.21.

5.67 1- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -3-naphthalene-urea

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (1.0 g, 3.1 mmol), 1-naphthyl isocyanate (0.52 g, 3.1 mmol) and triethylamine (0.63 g, 6.2 mmol) in THF (35 ml) are heated to 40 ° C. under a nitrogen atmosphere with stirring for 21 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate (100 ml) and dilute aqueous HCl (100 ml) and the organic phase was washed with water (2 × 100 ml), dried (MgSO ₄ ) and evaporated. The residue is chromatographed using a methylene chloride-methanol gradient, eluting the product with a methylene chloride-methanol ratio of 19: 1. This material is further purified by preparative HPLC using isocratic elution with an acetonitrile-water 40-60 mixture to give 0.3 g as a white solid (21%). T. pl. 229-231 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.76 (96.81% ) ¹ H NMR (DMSO-d ₆ ) δ 1.96-2.03 (m, 1H), 2.40-2.56 (m, 2H), 2.76-2.89 (m, 1H), 4 48 (d, J = 6.0 Hz, 2H), 5.09 (dd, J = 12.6 Hz, J = 5.4 Hz, 1H), 7.17 (t, J = 6.0 Hz , 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.44-7.54 (m, 3H), 7.76-7.89 (m, 5H), 8.04 ( d, J = 7.8 Hz, 1H), 8.68 (s, 1H), 11.06 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 30.9, 42.7, 49.0, 117.2, 121.5, 121.7, 122.5, 123.5, 125.5, 125.8, 125.9, 128.3, 129.7, 131.6, 133.2, 133.7, 134.8, 148.7, 155.8, 167.0, 167.2, 169, 8, 172.7. Analysis: Calculated for C ₂₅ H ₂₆ N ₄ O ₅ + 0.2H ₂ O: C, 65.27; H, 4.47; N, 12.18. Found: C, 65.32; H, 4.17; N, 12.14.

5.68 1-Butyl-3- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -urea

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl] -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), butyl isocyanate (0.33 ml, 3, 0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour, the reaction mixture was concentrated, the residue was dissolved in ethyl acetate (100 ml) and washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml), dried (MgSO ₄ ) and evaporated in vacuo The residue was purified by preparative HPLC using isocratic elution with a mixture of acetonitrile-water 35:65, obtaining 0.20 g of product in 17 yield %. T. pl. 171-173 C. HPLC, Waters Symmetry C-18, 3,9 × 150 mm, 5 micron, 1 mL / min, 240 nm, 35/65 CH ₃ CN / 0,1% H ₃ PO _4, 3.13 (97 37%). ¹ H NMR (DMSO-d ₆ ) δ 0.87 (t, J = 6.9 Hz, 3H), 1.21-1.41 (m, 4H), 2.02-2.10 (m, 1H), 2.46-2.63 (m, 2H), 2.83-2.91 (m, 1H), 2.94-3.04 (m, 2H), 4.36 (d , J = 6.0 Hz, 2H), 5.14 (dd, J = 12.6 Hz, J = 5.4 Hz, 1H), 6.07 (t, J = 5.7 Hz, 1H), 6.51 (t, J = 6.0 Hz, 1H), 7.71-7.88 (m, 3H), 11.12 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 13, 7, 19.5, 22.0, 30.9, 32.1, 39.0, 42.7, 49.0, 121.5, 123.4, 129.5, 131.5, 133.0, 149.5, 158.0, 167.0, 167.2, 169.8, 172.7. Analysis: Calculated for C ₁₉ H ₂₂ N ₄ O ₅ : C, 59.06; H, 5.74; N, 14.50. Found: C, 58.84; H, 5.73; N, 14.29.

5.69 1- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -3-pentyl-urea

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), pentylisocyanate (0.39 ml, 3, 0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in CH ₂ Cl ₂ (20 ml) were left overnight with stirring at room temperature. The solid is filtered, further washed with CH ₂ Cl ₂ (20 ml) and methanol (20 ml). The substance dries, giving 0.54 g of the product with a yield of 45%. T. pl. 176-178 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 3.15 (98.59% ) ¹ H NMR (DMSO-d ₆ ) δ 0.86 (t, J = 6.6 Hz, 3H), 1.18-1.42 (m, 6H), 2.02-2.10 (m, 1H ), 2.46-2.63 (m, 2H), 2.83-3.03 (m, 3H), 4.46 (d, J = 6.3 Hz, 2H), 5.15 (dd, J = 12.9 Hz, J = 5.4 Hz, 1H), 6.07 (t, J = 5.7 Hz, 1H), 6.51 (t, J = 6.0 Hz, 1H), 7 71-7.88 (m, 3H); 11.12 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 13.9, 21.9, 22.0, 28.6, 29.6, 30.9, 39.3, 42.7, 48.9, 121.5, 123.4, 129.5, 131.5, 133.1, 149.5, 158.0, 167.0, 167.2, 169.8, 172.7. Analysis: Calculated for C ₂₀ H ₂₄ N ₄ O ₅ : C, 59.99; H, 6.04; N, 13.99. Found: C, 59.65; H, 5.89; N, 13.86.

5.70 1- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -3-hexyl-urea

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), hexyl isocyanate (0.43 ml, 3, 0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in THF (20 ml) are left overnight with stirring at 40 ° C. The reaction mixture was cooled to room temperature. and the solvent is removed in vacuo. The residue was dissolved in ethyl acetate (150 ml), washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml), dried (MgSO ₄ ) and evaporated. The residue was purified by preparative HPLC using isocratic elution with a 55:45 mixture of acetonitrile-water, affording 0.67 g of product in 54% yield. T. pl. 162-164 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 3.41 (99.34% ) ¹ H NMR (DMSO-d ₆ ) δ 0.85 (t, J = 6.3 Hz, 3H), 1.24-1.36 (m, 8H), 2.03-2.07 (m, 1H ), 2.45-2.62 (m, 2H), 2.82-2.91 (m, 1H), 2.96-3.03 (m, 2H), 4.36 (d, J = 5 , 9 Hz, 2H), 5.14 (dd, J = 12.5 Hz, J = 5.3 Hz, 1H), 6.07 (t, J = 5.6 Hz, 1H), 6.52 ( t, J = 6.0 Hz, 1H), 7.71-7.76 (m, 2H), 7.87 (d, J = 7.7 Hz, 1H), 11.12 (s, 1 H) ; ¹³ C NMR (DMSO-d ₆ ) δ 13.9, 22.0, 22.1, 26.0, 29.9, 30.9, 31.0, 39.37, 42.8, 49.0, 121.6, 123.4, 129.5, 131.5, 133.1, 149.5, 158.0, 167.1, 167.2, 169.8, 172.7. Analysis: Calculated for C ₂₁ H ₂₆ N ₄ O ₅ + 0.15H ₂ O: C, 60.46; H, 6.35; N, 13.43. Found: C, 60.17; H, 6.23; N, 13.57.

5.71 1- (4-Chlorophenyl) -3- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] thiourea

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), 4-chlorophenylisothiocyanate (0.51 g, 3.0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in THF (20 ml) were left overnight with stirring at 40 ° C. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (100 ml), washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml), dried (MgSO ₄ ) and evaporated in vacuo. The resulting solid was allowed to stand overnight with stirring in ether and filtered. The solid was purified by preparative HPLC using isocratic elution with a 40:60 acetonitrile-water mixture. The solid thus obtained was stirred in ether and filtered, yielding 0.75 g of product in 55% yield. T. pl. 239-241 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 6.19 (95.49% ) ¹ H NMR (DMSO-d ₆ ) δ 2.03-2.10 (m, 1H), 2.46-2.63 (m, 2H), 2.84-2.96 (m, 1H), 4 91 (d, J = 5.4 Hz, 2H), 5.15 (dd, J = 12.9 Hz, J = 5.4 Hz, 1H), 7.37-7.40 (m, 2H) 7.45-7.48 (m, 2H), 7.80-7.84 (m, 2H), 7.89-7.91 (m, 1H), 8.46 (s, 1H), 9 89 (s, 1H); 11.13 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.0, 30.9, 46.8, 49.0, 121.9, 123.4, 125.1, 128.3, 128.5, 129.7, 131.4, 133.4, 138.0, 147.2, 167.0, 167.2, 169.8, 172.7, 181.2. Analysis: Calculated for C ₂₁ H ₁₇ N ₄ O ₄ SCl: C, 55.20; H, 3.75; N, 12.26. Found: C, 54.81; H, 3.51; N, 12.05.

5.72 1- [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -3-p-tolyl-thiourea

A mixture of 5-aminomethyl-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), p-tolylisothiocyanate (0.45 g, 3.0 mmol) and N, N-diisopropylethylamine (1.05 ml, 6.00 mmol) in THF (20 ml) are heated to 40 ° C and left overnight with stirring. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (100 ml), washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml). The solid is filtered. The organic layer of the biphasic filtrate was evaporated and the residue was combined with the solid that had been filtered. This solid was allowed to stand overnight with stirring in ether and filtered. The resulting solid was stirred in DMF (10 ml), filtered, further washed with DMF and water. The solid was stirred in ether and filtered, yielding 0.31 g of product in 24% yield. T. pl. 246-248 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 6.47 (96.05% ) ¹ H NMR (DMSO-d ₆ ) δ 2.02-2.10 (m, 1H), 2.38 (s, 3H), 2.46-2.63 (m, 2H), 2.83-2 96 (m, 1H), 4.89 (d, J = 5.7 Hz, 2H), 5.15 (dd, J = 12.9 Hz, J = 5.4 Hz, 1H), 7.12 -7.26 (m, 4H), 7.79-7.95 (m, 3H), 8.23 (t, 1H), 9.71 (s, 1H), 11.13 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 20.5, 22.0, 30.9, 46.9, 49.0, 121.9, 123.4, 124.1, 129.3, 129.6, 131.4, 133.4, 134.1, 136.0, 147.6, 167.0, 167.2, 169.8, 172.7, 181.1. Analysis: Calculated for C ₂₂ H ₂₀ N ₄ O ₄ S + 0.1H ₂ O: C, 60.29; H, 4.65; N5 12.78, Found: C, 60.10; H, 4.36; N, 12.67.

5.73 1- (4-Chlorophenyl) -3- [2- (3S) - (3-methyl-2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H- isoindol-5-ylmethyl] -urea

Stage 1: A mixture of 4-bromophthalic anhydride (7.53 g, 33.2 mmol), hydrobromide (3S) -3-amino-3-methyl-piperidine-2,6-dione (8.00 g, 44.1 mmol ) and sodium acetate (2.72 g, 33.2 mmol) in acetic acid (150 ml) are refluxed for 24 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated in vacuo. The residue was stirred in water (170 ml) for 3 hours and the resulting solid was filtered, further washed with water (80 ml) and dried, yielding 6.3 g of 5-bromo-2 - [(3S) -3-methyl-2,6- dioxo-piperidin-3-yl] -isoindol-1,3-dione in 54% yield. ¹ H NMR (DMSO-d ₆ ) δ 1.89 (s, 3H), 2.01-2.09 (m, 1H), 2.53-2.73 (m, 3H), 7.79 (dd , J = 5.7 Hz, J = 2.7 Hz, 1H), 8.06 (m, 2H), 11.04 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 21.0, 28.5, 29.0, 58.9, 124.9, 125.9, 128.3, 130.0, 133.0, 137.4, 166.6, 167.2, 172.0, 172.1.

Stage 2: DMF (160 ml) is degassed through a nitrogen bubbler for 1 hour and 5-bromo-2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -isoindole-1,3- is added dion (6.31 g, 18.0 mmol), zinc cyanide (1.26 g, 10.8 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.33 g, 0.40 mmol) and 1.1 'bis (diphenylphosphino) ferrocene (0.4 g, 0.7 mmol). The reaction mixture is heated to 120 ° C for 3 hours, cooled to 60 ° C and filtered through celite. The filter was further washed with DMF (100 ml) and the filtrate was evaporated in vacuo. The residue was stirred in water (200 ml) for 2 days and filtered, further washed with water (50 ml) and dried. The resulting solid was triturated with acetone (50 ml) and stirred for 1 hour, and filtered, and further washed with acetone (40 ml). Drying affords 4.7 g of 2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-2,3-dihydro-1H-isoindole-5-carbonitrile c 88% yield. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 30/70 CH ₃ CN / 0.1% H ₃ PO ₄ , 5.21 (98.40% ) ¹ H NMR (DMSO-d ₆ ) δ 1.89 (s, 3H), 2.02-2.10 (m, 1H), 2.51-2.73 (m, 3H), 8.03 (d , J = 7.8 Hz, 1H), 8.33 (dd, J = 7.8 Hz, J = 1.5 Hz, 1H), 8.40 (s, 1H), 11.06 (s, 1H ); ¹³ C NMR (DMSO-d ₆ ) δ 21.0, 28.5, 28.9, 59.1, 116.7, 117.4, 123.8, 126.9, 131.7, 134.4, 138.8, 166.3, 166.6, 171.8, 172.2.

Stage 3: Mixture of 2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-2,3-dihydro-1H-isoindole-5-carbonitrile (4, 70 g, 15.8 mmol), 4N HCl (21 ml), 10% Pd-C (1.88 g) in CH ₃ OH (200 ml) was hydrogenated at 50 psi for ₂ hours. Water (24 ml) was added and the reaction mixture was filtered through celite. The filter is further washed with methanol (50 ml). The filtrate was concentrated and dried, yielding 3.5 g of 5-aminomethyl-2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -isoindole-1,3-dione hydrochloride in 66% yield . HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 30/70 CH ₃ CN / 0.1% H ₃ PO ₄ , 1.00 (97.70% ) ¹ H NMR (DMSO-d ₆ ) δ 1.91 (s, 3H), 2.03-2.10 (m, 1H), 2.49-2.61 (m, 2H), 2.66-2 75 (m, 1H), 4.23 (s, 2H), 7.89-8.03 (m, 3H), 8.68 (broad, 3H), 11.04 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 20.9, 28.6, 29.0, 41.6, 58.9, 123.2, 123.5, 130.8, 131.4, 135.3, 141.2, 167.5, 167.6, 172.1, 172.2.

Stage 4: Mixture of 5-aminomethyl-2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -isoindole-1,3-dione hydrochloride (0.51 g, 1.5 mmol ), 4-chlorophenyl isocyanate (0.19 ml, 1.5 mmol) and N, N-diisopropylethylamine (0.52 ml, 3.0 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (100 ml), washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml), dried (MgSO ₄ ) and evaporated in vacuo. The residue was chromatographed using a methanol-CH ₂ Cl ₂ gradient, eluting the product with a methanol-CH ₂ Cl ₂ ratio of 4:96. The resulting solid was allowed to stand overnight with stirring in ether, filtered and dried, yielding 0.39 g of product with a yield of 57%. T. pl. 245-247 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 45/55 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.76 (99.33% ) ¹ H NMR (DMSO-d ₆ ) δ 1.89 (s, 3H), 1.99-2.08 (m, 1H), 2.54-2.60 (m, 2H), 2.63-2 72 (m, 1H), 4.45 (d, J = 6.0 Hz, 2H), 6.89 (t, J = 6.0 Hz, 1H), 7.25-7.29 (m, 2H), 7.42-7.46 (m, 2H), 7.75-7.83 (m, 3H), 8.87 (s, 1H), 11.02 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 21.0, 28.6, 29.1, 42.6, 58.7, 119.3, 121.3, 123.1, 124.7, 128.4, 129.5, 131.3, 133.2, 139.3, 148.4, 155.1, 167.8, 167.9, 172.1, 172.2. Analysis: Calculated for C ₂₂ H ₁₉ N ₄ O ₅ Cl: C, 58.09; H, 4.21; N, 12.32. Found: C, 57.70; H, 4.20; N, 11.99.

5.74 1- [2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -3 - (4-trifluoromethoxy-phenyl) -urea

Mixture of 5-aminomethyl-2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -isoindole-1,3-dione hydrochloride (0.40 g, 1.2 mmol), 4 - (trifluoromethoxy) phenylisocyanate (0.18 ml, 1.2 mmol) and N, N-diisopropylethylamine (0.41 ml, 2.4 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (100 ml). The organic phase was washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml), dried (MgSO ₄ ) and evaporated in vacuo. The resulting solid was allowed to stand overnight with stirring in ether, filtered and dried, yielding 0.54 g of the product in 90% yield. T. pl. 168-170 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 50/50 CH ₃ CN / 0.1% H ₃ PO ₄ , 6.04 (98.93% ) ¹ H NMR (DMSO-d ₆ ) δ 1.89 (s, 3H), 2.02-2.08 (m, 1H), 2.52-2.60 (m, 2H), 2.63-2 72 (m, 1H), 4.46 (d, J = 6.0 Hz, 2H), 6.91 (t, J = 6.0 Hz, 1H), 7.22 (d, J = 8, 1 Hz, 2H), 7.48-7.53 (m, 2H). 7.75-7.83 (m, 3H), 8.95 (s, 1H), 11.02 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 21.0, 28.6, 29.1, 42.6, 58.7, 118.9, 120.2 (q, J = 254 Hz), 121.3, 121.6, 123.1, 129.5, 131.4, 133.2, 139.6, 142.1, 148.4, 155.1, 167.8, 167.9, 172.1, 172, 2. Analysis: Calculated for C ₂₃ H ₁₉ N ₄ O ₆ F ₃ : C, 54.77; H, 3.80; N, 11.11. Found: C, 54.57; H, 3.44; N, 10.93.

5.75 1-Hexyl-3- [2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -1,3-dioxo-2,3-dihydro-1H-isoindol-5- ilmethyl] urea

Mixture of 5-aminomethyl-2 - [(3S) -3-methyl-2,6-dioxo-piperidin-3-yl] -isoindole-1,3-dione hydrochloride (0.51 g, 1.5 mmol), hexyl isocyanate (0.22 ml, 1.5 mmol) and N, N-diisopropylethylamine (0.52 ml, 3.00 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (100 ml), washed with dilute aqueous HCl (2 × 150 ml) and water (2 × 150 ml), dried (MgSO ₄ ) and evaporated in vacuo. The resulting solid was allowed to stand overnight with stirring in ether, filtered and dried, yielding 0.5 g of the product in 78% yield. T. pl. 195-197 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 45/55 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.25 (98.51% ) ¹ H NMR (DMSO-d ₆ ) δ 0.85 (t, J = 6.6 Hz, 3H), 1.24-1.30 (m, 6H), 1.32-1.38 (m, 2H ), 1.89 (s, 3H), 2.02-2.08 (m, 1H), 2.53-2.60 (m, 2H), 2.63-2.76 (m, 1H), 2.99 (dd, J = 12.9 Hz, J = 6.6 Hz, 2H), 4.34 (d, J = 6.0 Hz, 2H), 6.06 (t, J = 5.7 Hz, 1H), 6.50 (t, J = 6.3 Hz, 1H), 7.68-7.80 (m, 3H), 11.02 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 13.9, 21.0, 22.0, 26.0, 28.6, 29.1, 29.9, 31.0, 39.3, 42.7, 58.7, 121.2, 123.0, 129.3, 131.3, 133.0, 149.4, 158.0, 167.8, 167.9, 172.1, 172.2. Analysis: Calculated for C ₂₂ H ₂₈ N ₄ O ₅ + 0.10H ₂ O: C, 61.41; H, 6.61; N, 13.02. Found: C, 61.16; H, 6.66; N, 12.70.

5.76 1- (3-Chloro-4-methyl-phenyl) -3- [2- (2,6-dioxo-piperidin-3-yl) -1,3-oxo-2,3-dihydro-1H-isoindole- 5-ylmethyl] urea

Stage 1: A mechanically stirred mixture of 4-bromo-2-methylbenzoic acid (100 g, 465 mmol), iodomethane (95 g, 670 mmol) and sodium bicarbonate (112 g, 1340 mmol) in DMF (325 ml) are left overnight at heating to 80 ° C. The reaction mixture was cooled to room temperature and partitioned between water (1500 ml) and hexanes: ethyl acetate 4: 1 (1500 ml). The organic layer was washed with water and dried (Na ₂ SO ₄ ). The solvent was removed in vacuo to give 110 g of 4-bromo-2-methylbenzoic acid methyl ester as an oil in 100% yield. ¹ H NMR (DMSO-d ₆ ) δ 2.51 (s, 3H), 3.84 (s, 3H), 7.40-7.78 (m, 3H).

Stage 2: A mechanically stirred mixture of 4-bromo-2-methylbenzoic acid methyl ester (115 g, 500 mmol), N-bromosuccinimide (90 g, 500 mmol) and AIBN (3.1 g) in acetonitrile (700 ml) are heated in 45 minutes at low boil and incubated at reflux for 21 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bisulfite and concentrated in vacuo. The residue was partitioned between water and a mixture of hexanes: ethyl acetate 1: 1. The organic phase is washed with water, brine and filtered through a pad of silica gel. The solvent was removed in vacuo to give an oil / solid mixture, which was dissolved in ether and filtered. The filtrate is chromatographed on silica gel using a gradient of hexanes: ethyl acetate, eluting with 4: 1 hexanes: ethyl acetate to give 102 g of 4-bromo-2-bromomethyl-benzoic acid methyl ester in 66% yield. ¹ H NMR (DMSO-d ₆ ) δ 3.87 (s, 3H), 4.99 (s, 2H), 7.67-7.97 (m, 3H).

Stage 3: Mechanically stirred mixture of 4-bromo-2-bromomethyl-benzoic acid methyl ester (121 g, 390 mmol) and 3-amino-piperidin-2,6-dione hydrochloride (64.2 g, 390 mmol) in DMF ( 400 ml) was treated dropwise with triethylamine (98.5 g, 980 mmol) for 75 minutes. Upon completion of the addition, the reaction mixture was left overnight with stirring at room temperature. The mixture was quenched successively with acetic acid (50 ml), water (2500 ml) and ethyl acetate: hexanes 1: 1 (600 ml). After stirring the mixture for 20 minutes, the solid was filtered, washed with water and left to air dry overnight. The solid was stirred in acetic acid (200 ml) and refluxed for 2 hours. The mixture was cooled to room temperature and filtered. The solid is washed additionally with acetic acid, hexanes and left to air dry overnight to give 25.3 g of 3- (5-bromo-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidin-2, 6-dione as a gray solid in 20% yield. ¹ H NMR (DMSO-d ₆ ) δ 1.97-2.04 (m, 1H), 2.32-2.46 (m, 1H), 2.56-2.63 (m, 1H), 2 85-2.97 (m, 1H), 4.34 (d, J = 17.7 Hz, 1H), 4.47 (d, J = 17.7 Hz, 1H), 5.11 (dd, J = 13.2 Hz, J = 5.1 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.72 (dd, J = 8.1 Hz, J = 1, 5 Hz, 1H), 7.89 (d, J = 0.9 Hz, 1H), 11.00 (s, 1H).

Stage 4: Mechanically stirred mixture of 3- (5-bromo-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidin-2,6-dione (25.2 g, 78 mmol), bis (diphenylphosphino ) ferrocene (2.0 g), tris (dibenzylideneacetone) dipalladium (2.0 g) and zinc cyanide (9.4 g, 80 mmol) in DMF (300 ml) are heated to 120 ° C and stirred at this temperature for 19 hours . The reaction mixture is cooled to 40 ° C. and an additional 9.4 g of zinc cyanide, 2 g of bis (diphenylphosphino) ferrocene and 2 g of tris (dibenzylideneacetone) dipalladium are added. The mixture was stirred at 120 ° C for 2 hours, cooled to room temperature and quenched with water (900 ml). The solid phase is filtered, additionally washed with water and left overnight for drying in air. The solid is stirred with hot acetic acid (200 ml) for 20 minutes. The solid is filtered, washed with additional acetic acid, ethyl acetate and hexanes and dried in air to obtain 30.8 g of crude 2- (2,6-dioxo-piperidin-3-yl) -1-oxo-2,3-dihydro-1H -isoindole-5-carbonitrile as a gray solid. ¹ H NMR (DMSO-d ₆ ) δ 1.99-2.06 (m, 1H), 2.35-2.45 (m, 1H), 2.57-2.63 (m, 1H), 2 86-2.98 (m, 1H), 4.42 (d, J = 17.7 Hz, 1H), 4.55 (d, J = 17.7 Hz, 1H), 5.15 (dd, J = 13.2 Hz, J = 5.1 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.99 (dd, J = 7.8 Hz, J = 0, 9 Hz, 1H), 8.16 (s, 1H), 11.03 (s, 1H).

Step 5: Mixture of 2- (2,6-dioxo-piperidin-3-yl) -1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (9.2 g, 34 mmol), 10% Pd -C (1.7 g) and concentrated HCl (5.3 g) in N-methylpyrrolidone (300 ml) were left overnight for hydrogenation at 58 psi. The crude reaction mixture was filtered through celite, and the catalyst was washed with water. The combined filtrates were concentrated in vacuo, and the product, 3- (5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl) piperidin-2,6-dione hydrochloride, was isolated by fractional crystallization of the residue from isopropanol- water (1.9 g, 18%). ¹ H NMR (DMSO-d ₆ ) δ 1.85-2.20 (m, 1H), 2.35-2.45 (m, 1H), 2.58-2.80 (m, 1H), 2 87-2.99 (m, 1H), 4.16 (s, 2H), 4.35 (d, J = 17.5 Hz, 1H), 4.49 (d, J = 17.5 Hz, 1H), 5.13 (dd, J = 13.2 Hz, J = 4.8 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.72 (s, 1H) 7.79 (d, J = 7.8 Hz, 1H), 8.43 (broad, 3H), 11.01 (s, 1H).

Step 6: Mixture of 3- (5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidin-2,6-dione hydrochloride (0.50 g, 1.6 mmol), 3- chloro-4-methylphenylisocyanate (0.27 g, 1.6 mmol) and TEA (0.32 g, 3.2 mmol) in THF (25 ml) are heated to 40 ° C. with stirring in an atmosphere of N ₂ . After 3 hours, an additional portion of 3-chloro-4-methylisocyanate (0.17 g, 1.1 mmol) was added and stirring was continued for 2 hours. The mixture was filtered and the filter washed with ethyl acetate. The solid is triturated with 10 ml of a 1: 1 acetone-DMF mixture and filtered. The filter was washed with acetone and the solid was dried in vacuo to give 430 mg of product in 60% yield. T. pl. 258-260 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 4.49 (98.75% ) ¹ H NMR (DMSO-d ₆ ) δ 1.90-1.96 (m, 1H), 2.16 (s, 3H), 2.25-2.39 (m, 1H), 2.50-2 55 (m, 1H), 2.78-2.91 (m, 1H), 4.24 (d, J = 18.0 Hz, 1H), 4.33-4.41 (m, 3H), 5.04 (dd, J = 13.5 Hz, J = 4.5 Hz, 1H), 6.73 (t, J = 6.0 Hz, 1H), 7.04-7.13 (m, 2H ), 7.36-7.44 (m, 2H), 7.59-7.44 (m, 2H), 8.69 (s, 1H), 10.92 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 18.7, 22.5, 31.2, 42.8, 47.1, 51.5, 116.4, 117.6, 121.9, 122.9, 126.9, 127.4, 130.3, 131.0, 133.0, 139.6, 142.4, 144.7, 155.1, 167.9, 171.0, 172.9. Analysis: Calculated for C ₂₂ H ₂₁ ClN ₄ O ₄ : C, 59.93; H, 4.80; N, 12.71. Found: C, 59.77; H, 4.61; N, 12.69.

5.77 1- (4-Chloro-phenyl) -3- [2- (2,6-dioxo-piperidin-3-yl) -1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -urea

Mixture of 3- (5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidin-2,6-dione hydrochloride (0.50 g, 1.6 mmol), 4-chlorophenyl isocyanate (0 , 25 g, 1.6 mmol) and TEM (0.32 g, 3.2 mmol) in THF (25 ml) are heated to 40 ° C with stirring in an atmosphere of N ₂ . After 3 hours, an additional portion of 4-chlorophenyl isocyanate (0.17 g, 1.1 mmol) was added and stirring was continued for 2 hours. The mixture was filtered and the filter washed with ethyl acetate. The solid was purified by preparative HPLC using isocratic elution with a 35:65 acetonitrile-water mixture to obtain 0.22 g of the product in 32% yield. T. pl. 270-272 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 40/60 CH ₃ CN / 0.1% H ₃ PO ₄ , 3.28 (95.95% ) ¹ H NMR (DMSO-d ₆ ) δ 1.96-2.03 (m, 1H), 2.35-2.41 (m, 1H), 2.57-2.62 (m, 1H), 2 85-2.96 (m, 1H), 4.31 (d, J = 15.0 Hz, 1H), 4.41-4.48 (m, 3H), 5.11 (dd, J = 13 5 Hz, J = 4.5 Hz, 1H), 6.81 (t, J = 6.0 Hz, 1H), 7.24-7.52 (m, 6H), 7.70 (d, J = 9.0 Hz, 1H), 8.81 (s, 1H), 10.99 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 22.5, 31.2, 42.8, 47.1, 51.5, 119.2, 121.9, 122.9, 124.6, 126.9, 128.4, 130.3, 139.4, 142.4, 144.7, 155.1, 167.9, 171.0, 172.9. Analysis: Calculated for C ₂₁ H ₁₉ ClN ₄ O ₄ + 0.2H ₂ O: C, 58.60; H, 4.54; N, 13.02. Found: C, 58.50; H, 4.15; N, 12.69.

5.78 1- [2- (2,6-dioxo-piperidin-3-yl) -1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -3-hexyl-urea

A mixture of 3- (5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidin-2,6-dione hydrochloride (0.50 g, 1.6 mmol), hexyl isocyanate (0.20 g, 1.6 mmol) and TEM (0.32 g, 3.2 mmol) in THF (25 ml) are heated to 40 ° C with stirring in an atmosphere of N ₂ . After 3 hours, an additional portion of hexyl isocyanate (0.20 g, 1.6 mmol) was added and stirring was continued for 20 hours. The mixture was filtered and the filter washed with ethyl acetate and dried in vacuo to give 0.60 g of product in 92% yield. T. pl. 234-236 ° C. HPLC, Waters Symmetry C-18, 3.9 × 150 mm, 5 μm, 1 ml / min, 240 nm, 35/65 CH ₃ CN / 0.1% H ₃ PO ₄ , 3.57 (96.04% ) ¹ H NMR (DMSO-d ₆ ) δ 0.86 (t, J = 7.5 Hz, 3H), 1.25-1.38 (m, 8H), 1.99-2.02 (m, 1H ), 2.37-2.41 (m, 1H), 2.56-2.62 (m, 1H), 2.87-3.03 (m, 3H), 4.26-4.32 (m , 3H), 4.43 (d, J = 18.0 Hz, 1H), 5.10 (dd, J = 13.5 Hz, J = 4.5 Hz, 1H), 5.96 (t, J = 6.0 Hz, 1H), 6.39 (t, J = 6.0 Hz, 1H), 7.38 (d, J = 7.5, 1H), 7.44 (s, 1H), 7 66 (d, J = 6.0 Hz, 1H); 10.98 (s, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 13.9, 22.1, 22.5, 26.0, 29.9, 31.0, 31.1, 39.3, 42.9, 47.0, 51.5, 121.7, 122.8, 126.8, 130.1, 142.3, 145.6, 158.0, 168.0, 171.0, 172.9. Analysis: Calculated for C ₂₁ H ₂₈ N ₄ O ₄ + 0.1H ₂ O: C, 62.70; H, 7.07; N, 13.93. Found: C, 62.66; H, 6.89; N, 13.87.

5.79 (3'S) -3- (3'-methoxyphenyl) -1-methyl-1- [2- (3-methyl-2 ', 6'-dioxo-piperidin-3'-yl) -1,3-dioxo 2,3-dihydro-1H-isoindol-4-ylmethyl] -urea

5.79.1 (3'S) -4-methylaminomethyl-2- (3'-methyl-2 ', 6'-dioxo-piperidin-3'-yl) -isoindole-1,3-dione hydrochloride

Stage 1: A solution of potassium hydroxide (1.3 g, 23.1 mmol) in water (5 ml) is added to a stirred solution of 3 - [(tert-butoxycarbonyl-methyl-amino) methyl] phthalic acid dimethyl ester (2.6 g, 7.7 mmol) in methanol (35 ml). The resulting solution was left overnight with stirring at room temperature. The mixture was concentrated and water (30 ml) was added. The resulting mixture was washed with ether (30 ml). The aqueous layer was acidified with 4N HCl to pH 2. The mixture was extracted with CH ₂ Cl ₂ (3 × 40 ml) and dried. The solvent was removed to give a mixture of 3 - [(tert-butoxycarbonyl-methyl-amino) methyl] phthalic acid and its monomethyl ester, which was used in the next step without further purification.

Stage 2: A mixture of 3 - [(tert-butoxycarbonyl-methyl-amino) -methyl] phthalic acid (2.5 g, 7.71 mmol) and (3S) -3-amino-3-methylpiperidin-2.6 hydrobromide monohydrate -dione (2.0 g, 8.48 mmol) in pyridine (40 ml) was left overnight at the boil under reflux. The mixture was cooled and concentrated. The residue was dissolved in EtOAc (100 ml) and water (50 ml). The solution in EtOAc was washed with water (50 ml), 1N citric acid (50 ml), water (50 ml), sat. NaHCO3 (50 ml), water (50 ml) and brine (50 ml) and dried (MgSO ₄ ). The solvent was removed and the residue was purified by chromatography (SiO ₂ , CH ₂ Cl ₂ : EtOAc 9: 1) to obtain tert-butyl ether (3'S) -methyl- [2- (3'-methyl-2 ', 6'-dioxo-piperidine -3'-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl] carbamic acid (0.99 g, 31%).

Stage 3: 2N HCl / ether (3 ml) is added to a stirred solution of (3'S) -methyl- [2- (3'-methyl-2 ', 6'-dioxo-piperidin-3'-yl) - tert-butyl ester 1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl] carbamic acid (0.99 g, 2.4 mmol) in methylene chloride (20 ml). The mixture was left overnight with stirring at room temperature. Ether (20 ml) was added and the mixture was filtered and dried to give (3'S) -4-methylaminomethyl-2- (3'-methyl-2 ', 6'-dioxo-piperidin-3'-yl) -isoindole-1 hydrochloride, 3-dione (0.73 g, 87%). ¹ H NMR (DMSO-d ₆ ) δ l1.04 (s, 1H), 9.56 (s, 2H), 8.05-7.88 (m, 3H), 4.56-4.45 (m , 2H), 2.73-2.53 (m, 6H), 2.10-2.04 (m, 1H), 2.02 (s, 3H); ¹³ C NMR (DMSO-d ₆ ) δ 172.15, 171.96, 168.08, 167.31, 136.48, 134.68, 131.26, 130.23, 129.05, 123.59, 58.84, 54.88, 45.73, 32.42, 29.09, 28.55, 21.04.

5.79.2 (3'S) -3- (3-Methoxyphenyl) -1-methyl-1- [2- (3'-methyl-2 ', 6'-dioxo-piperidin-3'-yl) -1.3- dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl] urea

To a stirred suspension of (3'S) -4- (methylaminomethyl-2- (3'-methyl-2 ', 6'-dioxo-piperidin-3'-yl) -isoindole-1,3-dione and triethylamine hydrochloride g, 3.0 mmol) in THF (30 ml) was added 3-methoxyphenyl isocyanate (0.4 g, 2.6 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was dissolved in methylene chloride (70 ml) washed with 1N HCl (30 ml), water (2 × 30 ml) and brine (30 ml) and dried (MgSO ₄ ). The solvent was removed and the residue was purified by chromatography (SiO ₂ , CH ₂ Cl ₂ : EtOAc 9: 1 ), get (3'S) -3- (3-methoxyphenyl) -1-methyl-1- [2- (3'-me il-2 ', 6'-dioxo-piperidin-3'-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl] -urea (0.7 g, 74%). Mp 166-168 ° C. ¹ H NMR (DMSO-d ₆ ) δ 11.03 (s, 1H), 8.46 (s, 1H), 7.83 (t, J = 7.5 Hz, 1H ), 7.75 (d, J = 6.6 Hz, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.19-7.07 (m, 3H), 6.55 -6.51 (m, 1H), 4.98 (s, 2H), 3.70 (s, 3H), 3.03 (s, 3H), 2.72-2.51 (m, 3H), 2.10-2.04 (m, 1H), 1.91 (s, 3H); ¹³ C NMR (DMSO-d ₆ ) δ 172.46, 172.44, 168.70, 167.99, 159, 59, 155.88, 141.87, 138.74, 135.11, 132.51, 131.98, 129.20, 127.57, 121.78, 112.38, 107.68, 105.78, 59.01, 55.15, 47.67, 35.39, 29.38, 28.86, 21.31. Analysis: Calculated for C ₂₄ H ₂₄ N ₄ O ₆ : C, 62.06; H, 5.21; N, 12.06. Found: C, 62.15; H, 5.32; N, 11.71.

5.80 Research

5.80.1 Study of TNFα inhibition in RMBC

Peripheral blood mononuclear cells (PMBC) from normal donors were obtained by density centrifugation Ficoll Hypaque (Pharmacia, Piscataway, NJ, USA). Cells were cultured in RPMI 1640 (Life Technologies, Grand Island, NY, USA) supplemented with 10% AB + human serum (Gemini Bio-products, Woodland, CA, USA), 2 mM L-glutamine, 100 u / ml penicillin and 100 μg / ml streptomycin (Life Technologies).

RMBC (2 × 10 ⁵ cells) were plated three times in flat-bottomed 96-well Costar cell culture plates (Corning, NY, USA). Cells stimulate LPS (from Salmonella abortus equi , Sigma Cat No. L-1887, St. Louis, MO, USA) at a final concentration of 1 ng / ml in the absence or presence of compounds. The compounds of the invention are dissolved in DMSO (Sigma), and subsequent dilutions are carried out in culture medium immediately before use. The final concentration of DMSO in all studies should be about 0.25%. Compounds are added to the cells 1 hour before LPS stimulation. Cells are then incubated for 18-20 hours at 37 ° C in 5% CO ₂ and then the supernatant is collected, diluted with culture medium and examined for TNFα levels by ELISA (Endogen, Boston, MA, USA). The IC _{50 is} calculated using non-linear regression, the sigmoidal dose-response function, limiting the top 100% and the bottom 0%, allowing variation of the slope (GraphPad Prism v3.02).

5.80.2 Production of IL-2 and MIP-3α by T cells

RMBC exempt from tightly bound monocytes by placing 1 × 10 ⁸ PMBC in 10 ml of complete medium (RPMI 1640 supplemented with 10% heat-inactivated bovine serum, 2 mM L-glutamine, 100 u / ml penicillin and 100 μg / ml streptomycin ) per 10 cm cup of tissue culture, in an incubator at 37 ° C, 5% CO ₂ for 30-60 minutes. The cup is washed with medium to remove all unbound PMVC. T cells were purified by negative selection using the following mixture of antibodies (Pharmingen) and Dynabead (Dynal) for every 1 × 10 ⁸ unbound PMBCs: 0.3 ml anti-mouse sheep IgG beads, 0.15 μl anti-CD16 beads, 0.15 μl anti-CD33, 0.15 μl anti-CD56, 0.23 μl anti-CD19, 0.23 μl anti-HLA class II beads and 56 μl anti-CD14 beads. The mixture of cells and beads / antibodies is mixed by inversion for 30-60 minutes at 4 ° C. The purified T cells are separated from the beads using a Dynal magnet. The usual yield is 50% T cells, 87-95% CD3 ⁺ by flow cytometry.

Flat-bottomed 96-well tissue culture plates were coated with anti-CD3 OKT3 antibody at 5 μg / ml in PBS, 100 μl per well, incubated at 37 ° C for 3-6 hours, and washed four times with 100 μl / well of complete medium immediately before the addition of T- cells. The compounds are diluted to 20 times the final concentration in a round bottom 96-well tissue culture plate. Final concentrations range from about 10 μM to about 0.00064 μM. A concentrate of 10 mM of the compounds of the invention is diluted 1:50 for a first 20x dilution to 200 μM in 2% DMSO and subsequently diluted 1: 5 in 2% DMSO. The compound is added at 10 μl per 200 μl of culture, which gives a final concentration of DMSO of 0.1%. The cultures are incubated at 37 ° C, 5% CO ₂ for 2-3 days, and the supernatants are analyzed for IL-2 and MIP-3α by ELISA (R&D Systems). The levels of IL-2 and MIP-3α are normalized to the amount produced in the presence of an amount of the compound of the invention and the EC _{50 is} calculated using non-linear regression, the sigmoidal dose-response function, limiting the top to 100% and the bottom to 0%, allowing variation in slope (GraphPad Prism v3.02).

5.80.3 Cell proliferation assay

Namalwa, MUTZ-5, and UT-7 cell lines were obtained from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (Braunschweig, Germany). The KG-1 cell line was obtained from the American Type Culture Collection (Manassas, VA, USA). Cell proliferation according to indications of ³ H-thymidine incorporation was measured in all cell lines as follows.

Cells were placed in 96-well plates at 6,000 cells per well in medium. Cells were pretreated with compounds at approximately 100, 10, 1, 0.1, 0.01, 0.001, 0.0001 and 0 μM at a final concentration of DMSO of approximately 0.25% in three batches of 72 hours at 37 ° C in a humidified incubator at 5% CO ₂ . One microcurie of ³ H-thymidine (Amersham) was then added to each well, and the cells were again incubated for 6 hours at 37 ° C in a humidified incubator at 5% CO ₂ . All cells were collected in UniFilter GF / C filter plates (Perkin Elmer) using a cell collector (Tomtec), and then the cells were left overnight to dry. Microscint 20 (Packard) (25 μl / well) was added and the plates were analyzed on TopCount NXT (Packard). Each well was counted for one minute. The percentage inhibition of cell proliferation was calculated by averaging all three series and normalizing to a DMSO control (0% inhibition). Each compound was tested on each cell line in three separate experiments. The final IC _{50 was} calculated using non-linear regression, the sigmoidal dose-response function, limiting the top 100% and the bottom 0%, allowing variation of the slope (GraphPad Prism v3.02).

5.80.4 Immunoprecipitation and immunoblotting

Namalwa cells were treated for 1 hour with DMSO or an amount of a compound of the invention, then 10 U / ml EPO was stimulated for 30 minutes (R&D Systems). Cell lysates were prepared and either immunoprecipitated by the Ep receptor Ab, or SDS-PAGE was immediately isolated. Immunoblots probed Akt, phospho-Akt (Ser473 or Thr308), phospho-Gab1 (Y627), Gab1, IRS3, actin, and IRF-1 Abs and were analyzed on the Storm 860 Imager using ImageQuant (Molecular Dynamics) software.

5.80.5 Cell cycle analysis

Cells were left overnight to treat with DMSO or an amount of a compound of the invention. Cell cycle propidium iodide staining was performed using CycleTEST PLUS (Becton Dickinson) according to the manufacturer's protocol. After staining, cells were analyzed on a FACSCalibur flow cytometer using ModiFit LT software (Becton Dickinson).

5.80.6 Apoptosis analysis

Cells were treated with DMSO or an amount of a compound of the invention at various points in time, then washed with annexin-B wash buffer (BD Biosciences). Cells were incubated for 10 minutes with annexin-B binding protein and propidium iodide (BD Biosciences). Samples were analyzed using flow cytometry.

5.80.7 Study with luciferase

Namalwa cells were transfected with 4 μg of AP-1-luciferase (Stratagene) per 1 × 10 ⁶ cells and 3 μl of lipofectamine reagent (Invitrogen) according to the manufacturer's instructions. Six hours after transfection, cells were treated with DMSO or an amount of a compound of the invention. Luciferase activity was investigated using luciferase lysis buffer and substrate (Promega) and measured using a luminometer (Turner Designs).

5.81 Antiproliferative activity

In one experiment, the antiproliferative effect of some of the compounds described herein is tested using Namalwa, HN 5q, HT-1080, SK-MES-1, and PC-3 cells, in accordance with a proliferation assay that is substantially similar to that described above at 5.80. 3. The tested compounds show IC ₅₀ values ranging from 0.5 to 200 μM for Namalwa cells, from 0.0001 to 10 μM for HN 5q cells, from 0.01 to 20 μM for HT-1080 cells, from 0.001 to 30 μM for SK-MES-1 cells and from 0.005 to 10 μM for PC-3 cells. These results show that the compounds described herein exhibit an antiproliferative effect on various cancer cells.

In another experiment, two human glioblastoma cell lines, T98G (glioblastoma multiforme, mutant p53) and U87MG (glioblastoma-astrocytoma type III, wild type p53), and two human neuroblastoma cell lines, SH-SY5Y (obtained from the bone marrow metastatic site; trisomy of chromosome 1q; enhanced by MYCN) and SK-N-MC (obtained from the metastatic site of the suporbital region; pseudodiploid with 46 modal chromosomes; causes tumor in nude mice) were obtained from ATCC. These cell lines were grown, lower level concentrates were frozen in liquid nitrogen. Compounds were dissolved in DMSO to give 10 mM concentrates. Cells were placed in 96-well plates at 5 × 10 ³ cells / 100 μl of medium per well. Cells were left overnight to achieve adhesion at 37 ° C in an incubator with 94% humidity and 5% CO ₂ . After overnight incubation, the cells were treated in three series of 100, 10, 0.1, 0.01, 0.001, 0.0001 and 0 μM promising compounds at a final DMSO concentration of 0.1% over a treatment period of 72 hours. Cell proliferation was determined by examining cell proliferation with ³ H-thymidine. IC _{50s are} computed from transformed data using non-linear regression, a sigmoidal dose-response function using GraphPad Prism v4.0.

The tested compounds show IC ₅₀ values ranging from 0.1 μM to about 1 mm for T98G cells, from 0.05 to about 150 μM for U87MG cells, from 0.0001 to 0.5 μM for SH-SY5Y cells, and from 0.0001 to about 0.1 μM for SK-N-MC cells. These results show that the compounds described herein exhibit antiproliferative activity against various cancer cells.

The embodiments of the invention described above are intended to be examples only, and one skilled in the art should know the many equivalents of specific compounds, materials and methods, or should be able to come to them by means of extremely routine experimentation. All such equivalents are considered to be included in the scope of the invention and are covered by the attached claims.

All patents, patent applications and publications referenced in this description are included in its entirety. The citation or definition of any link in this application is not an assumption that such a link is available as the prior art of this invention. The full scope of the invention is better understood with reference to the attached claims.

Claims (27)

1. The compound of formula (I)

or its pharmaceutically acceptable salt, or stereoisomer, in which:
n is 0 or 1;
X represents CH ₂ , C = O;
R ¹ represents:
a) - (CH ₂ ) _m R ³ or -CO (CH ₂ ) _m R ³ , where
m is 0, 1; and
R ³ represents a 5-10 membered aryl or heteroaryl, where heteroaryl means a mono- or bicyclic aromatic ring containing from 5 to 10 ring atoms, of which at least one or two atoms are a heteroatom selected from oxygen, nitrogen or sulfur, optionally substituted with one or more halogens; b) -C = YR ⁴ , where
Y represents O; and
R ⁴ represents:
(C ₁ -C ₁₀ ) alkyl; (C ₁ -C ₁₀ ) alkoxy;
(C ₀ -C ₁₀ ) alkyl- (5-10 membered heteroaryl), where heteroaryl means a mono- or bicyclic aromatic ring containing from 5 to 10 ring atoms, of which at least one or two atoms are heteroatoms selected from oxygen, nitrogen or sulfur, said heteroaryl is optionally substituted with one or more substituents from halogen, oxo or Z- (C ₁ -C ₆ ) alkyl, where Z is S;
(C ₀ -C ₁₀ ) alkyl- (5-10 membered aryl), said aryl is optionally substituted with one or more halogen substituents; (C ₁ -C ₆ ) alkoxy, which itself is optionally substituted with one or more halogens; (C ₁ -C ₆ ) alkyl, which itself is optionally substituted with one or more halogens; or -Z- (C ₁ -C ₆ ) alkyl, where Z is S or SO ₂ , and wherein said (C ₁ -C ₆ ) alkyl may optionally be substituted with one or more halogens; or
(C ₁ -C ₆ ) alkyl-CO-OR ¹² where R ¹² is H or (C ₁ -C ₆ ) alkyl; or
c) -C = ZNHR ⁶ , where
Z represents O or S; and
R ⁶ represents:
(C ₁ -C ₁₀ ) alkyl; (C ₁ -C ₁₀ ) alkoxy;
5-10 membered aryl or heteroaryl, where heteroaryl means a bicyclic aromatic ring containing 9 ring atoms, of which at least one or two atoms are oxygen; optionally substituted with one or more halogen substituents; cyano; (C ₁ -C ₆ ) alkoxy, which itself is optionally substituted with one or more halogens; (C ₁ -C ₆ ) alkyl, which itself is optionally substituted with one or more halogens; and
R ² represents H or (C ₁ -C ₆ ) alkyl. 2. The compound of formula (II)

or a pharmaceutically acceptable salt or stereoisomer thereof, in which: n is 0 or 1;
X represents CH ₂ or C = O;
R ⁷ represents - (CH ₂ ) _m R ⁹ where m is 0, 1; and R ⁹ represents a 5-10 membered aryl or heteroaryl, where heteroaryl means a mono- or bicyclic aromatic ring containing from 5 to 10 ring atoms, of which at least one or two atoms are a heteroatom selected from oxygen, nitrogen or sulfur; optionally substituted with one or more halogens; and
R ⁸ represents H or (C ₁ -C ₆ ) alkyl. 3. The compound according to claim 2, in which X represents C = O. 4. The compound according to claim 2, in which X represents CH ₂ . 5. The compound of claim 2, wherein R ⁹ is phenyl optionally substituted with one or more halogens. 6. The compound according to claim 2, in which R ⁹ represents furyl or benzofuryl. 7. The compound according to claim 2, in which the compound is

,

,

,

or

. 8. The compound of formula (III)

or its pharmaceutically acceptable salt, or stereoisomer, in which:
X represents CH ₂ or C = O;
Y represents O;
R ¹⁰ represents:
(C ₁ -C ₁₀ ) alkyl; (C ₁ -C ₁₀ ) alkoxy;
(C ₀ -C ₁₀ ) alkyl- (5-10 membered heteroaryl), said heteroaryl means a mono- or bicyclic aromatic ring containing from 5 to 10 ring atoms, of which at least one or two atoms are heteroatoms selected from oxygen, nitrogen or sulfur; said heteroaryl is optionally substituted with one or more substituents from halogen, oxo or —Z- (C ₁ -C ₆ ) alkyl, wherein Z is S;
(C ₀ -C ₁₀ ) alkyl- (5-10 membered aryl), said aryl is optionally substituted with one or more halogen substituents; (C ₁ -C ₆ ) alkoxy, which itself is optionally substituted with one or more halogens; (C ₁ -C ₆ ) alkyl, which itself is optionally substituted with one or more halogens; or -Z- (C ₁ -C ₆ ) alkyl, where Z is S or SO ₂ , and wherein said (C ₁ -C ₆ ) alkyl may optionally be substituted with one or more halogens; or
(C ₁ -C ₆ ) alkyl-CO-OR ¹² where R ¹² is H or (C ₁ -C ₆ ) alkyl; and
R ¹¹ represents H or (C ₁ -C ₆ ) alkyl. 9. The compound of claim 8, in which X represents C = O. 10. The compound of claim 8, in which X represents CH ₂ . 11. The compound of claim 8, in which R ¹⁰ represents pentyl or hexyl. 12. The compound of claim 8, in which R ¹⁰ represents pentyloxy or hexyloxy. 13. The compound of claim 8, in which R ¹⁰ represents thiophenyl or furyl. 14. The compound of claim 8, wherein R ¹⁰ is phenyl or methyl phenyl optionally substituted with one or more halogens. 15. The compound of claim 8, in which the compound is:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

. 16. The compound of formula (IV)

or its pharmaceutically acceptable salt or stereoisomer, in which:
X represents CH ₂ or C = O;
Y represents O or S;
R ¹³ represents (C ₁ -C ₁₀ ) alkyl;
5-10 membered aryl or heteroaryl, where heteroaryl means a bicyclic aromatic ring containing 9 ring atoms, of which at least one or two atoms are oxygen; optionally substituted with one or more halogen substituents; cyano; (C ₁ -C ₆ ) alkoxy, which itself is optionally substituted with one or more halogens; (C ₁ -C ₆ ) alkyl, which itself is optionally substituted with one or more halogens; and
R ¹⁴ represents H or (C ₁ -C ₆ ) alkyl. 17. The compound according to clause 16, in which X represents C = O. 18. The compound according to clause 16, in which X represents CH ₂ . 19. The compound according to clause 16, in which R ¹³ represents propyl, butyl, pentyl or hexyl. 20. The compound of claim 16, wherein R ¹³ is phenyl optionally substituted with one or more halogens. 21. The compound according to clause 16, in which the compound is:

,

,

,

,

,

,

,

,

,

,

or

. 22. The compound of claim 16, wherein the compound is:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

. 23. A pharmaceutical composition for inhibiting TNFα, comprising a compound according to claim 1. 24. The pharmaceutical composition according to item 23 in the form of a unit dosage form. 25. The pharmaceutical composition according to paragraph 24, suitable for oral or parenteral administration. 26. The pharmaceutical composition according A.25, suitable for oral administration. 27. The pharmaceutical composition according p, which is a tablet or capsule.