KR20020063186A - Pharmaceutically active isoindoline derivatives - Google Patents

Abstract

Isoindolin-1-one and isoindolin-1,3-dione substituted with α- (3,4-disubstituted phenyl) alkyl groups in the 2-position and nitrogen-containing groups in the 4- and / or 5-position Are inhibitors of disease states mediated by TNFα and phosphodiesterases and are therefore useful as therapeutic agents for this disease. Typical embodiments are 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4,5-diaminoisoindolin-1,3-dione.

Description

Pharmaceutically active isoindoline derivatives

Tumor necrosis factor α, or TNFα, is a cytokine released mainly by mononuclear phagocytes in response to many immunostimulants. When administered to an animal or human, it produces an acute phase response similar to those seen during inflammation, fever, cardiovascular effects, bleeding, coagulation, and acute infections and shock conditions.

Thus, excessive or unregulated TNFα production is involved in many disease states. These include endotoxin and / or toxic shock syndrome (Tracey et al ., Nature 330, 662-664 (1987) and Hinshaw et al . , Circ.Shock 30, 279-292 (1990)); Adults with rheumatoid arthritis, Crohn's disease, IBD, cachexia (Dezube et al., Lancet , 335 (8690), 662 (1990)) and TNAα at concentrations above 12,00 0 pg / mL are detected in pulmonary domestic fluid of ARDS patients Sex Respiratory Distress Syndrome (Millar et al., Lancet 2 (8665), 712-714 (1989)). In addition, systemic infusion of recombinant TNFα resulted in changes typically seen in ARDS (Ferrai-Baliviera et al., Arch. Surg. 124 (12), 1400-1405 (1989)).

TNFα appears to be involved in bone resorption diseases, including arthritis. When activated, white blood cells will cause bone resorption. Activity data suggest that TNFα contributes to this (Bertolini et al ., Nature 319, 516-518 (1986) and Johnson et al., Endocr-inology 124 (3), 1424-1427 (1989)). TNFα is also known to stimulate bone resorption and inhibit bone formation in vitro and in vivo through stimulation of osteoblast formation and activation in combination with inhibition of osteoblast function. TNFα may be involved in many bone resorption disorders, including arthritis, but the link to the most inevitable disease is the association between TNFα production by tumors or host tissues and hypercalcemia-related malignancies ( Calci. Tissue). Int. (US) 46 (Suppl.), S3-10 (1990)). In graft versus host response, elevated serum TNFα levels have been associated with major complications after acute allogeneic bone marrow transplantation (Holler et al., Blood , 75 (4), 1011-1016 (1990)).

Brain malaria is a fatal superacute nervous system syndrome associated with high TNFα blood levels and is the most serious complication of malaria. Serum TNFα levels correlate directly with the severity of the disease and its prognosis in patients with acute malaria attack (Grau et al . , N. Engl. J. Med. 320 (24), 1586-1591 (1989)).

Unregulated angiogenesis is pathological and sustains the progression of many dysplastic and non-dysplastic diseases, including solid tumor growth and metastasis, arthritis, some kind of ocular, and psoriasis. See, eg, Moses et al., 1991, Biotech. 9: 630-634; Folkman et al., 1995, N. Engl. J. Med. 333: 1757-1763; Auerbach et al., 1985, J. Microvasc. Res. 29: 401 -411; Folkman, 1985, Advances in Cancer Research, eds . Klein and Waynehouse, New York Academic Press, pp. 175-203; Patz, 1982, Am. J. Opthalmol . 94: 715-743; Folkman et al., 1983, Science 221: 719-725; And Folkman and Klagsbrun, 1987, Science 235: 442-447. In addition, maintenance of the avascular state of the cornea, lens and trabecular meshwork is important for vision as well as cell physiology. For example, Waltman et al., 1978, Am. J. Ophthal. 85 : 704-710 and Gartner et al., 1978, Surv. Ophthal .22: 291-312 see.

Thus, angiogenesis is encountered in various disease states, tumor metastases, and abnormal growth by endothelial cells. Pathological conditions caused by uncontrolled angiogenesis are classified together as angiogenesis dependent or angiogenesis related diseases. Control of the angiogenesis process can lead to alleviation of these conditions.

The components of angiogenesis involved in vascular endothelial cell proliferation, migration and invasion have been found to be partially regulated by polypeptide growth factors. Endothelial cells exposed to medium containing a suitable growth factor may be induced to elicit some or all angiogenic responses. Polypeptides that have endothelial growth promoting activity in vitro include acidic and basic fibroblast growth factors, transforming growth factors α and β, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, interleukin-8, hepatocyte growth factor, ph. Roliperin, vascular endothelial growth factor, and placental growth factor. Folkman et al., 1995, N. Engl. J. Med. , 333: 1757-1763.

The effect of inhibition is dominant in the naturally occurring balance between endogenous stimulants and angiogenesis inhibitors. Rastinejad et al., 1989, Cell 56: 345-355. In examples where neovascularization occurs under normal physiological conditions, such as wound healing, organ regeneration, embryonic development, and female reproductive processes, angiogenesis is tightly regulated, spatially and temporally defined. These regulatory controls fail under conditions of pathological angiogenesis such as those characterized by solid tumor growth.

Macrophage-induced angiogenesis is known to be mediated by TNFα. Leibovich et al . ( Nature , 329, 630-632 (1987)) showed that TNFα induces capillary formation in vivo in the retroretinal and developing chick chorio meninges with very low doses, which indicates that TNFα induces inflammation, wound repair. , And candidates for inducing angiogenesis in tumor growth.

In addition, TNFα production is independently associated with cancerous conditions, especially induced tumors (Chi-ng et al . , Brit. J. Cancer , (1955) 72, 339-343, and Koch, Progress in Medicinal Chemistry, 22, 166-242 ( 1985)). Whether or not TNFα production is involved, angiogenesis is prominent in solid tumor formation and metastasis, and angiogenesis factors have been found to be involved in some solid tumors such as rhabdomyosarcoma, retinoblastoma, Ewing's sarcoma, neuroblastoma, and osteosarcoma. Tumors of which angiogenesis is important include solid tumors and benign tumors such as auditory neuroma, neurofibroma, trachoma and purulent granulomas. Regardless of its action on TNFα production, prevention of angiogenesis can stop the growth of these tumors and the resulting damage due to the presence of tumors in the animal. Angiogenesis is associated with tumors with blood, such as leukemia, and various acute or chronic myelodysplastic diseases. In such conditions, uncontrolled proliferation of leukocytes occurs, usually accompanied by anemia, damage to blood coagulation, and enlargement of lymph nodes, liver and spleen.

Angiogenesis is also implicated in tumor metastasis. Thus, angiogenesis is stimulated during vascularization of the tumor, allowing tumor cells to enter the bloodstream and circulate in the body. After tumor cells leave the primary site and settle in the secondary metastasis site, angiogenesis must occur before new tumors grow and expand.

All the various cell types of the body can be transformed into benign or malignant tumor cells. The most frequent tumor sites are the lungs, followed by the colon, breast, prostate, bladder, and pancreas, followed by the ovaries. Other prevalent cancer types include cancers of the central nervous system, melanoma, lymphoma, red leukemia, uterine cancer, and cancers of the head and neck, including leukemia, brain cancer.

TNFα also plays a role in the field of chronic pneumonia disease. The deposition of silica particles leads to silicosis, a progressive respiratory failure disease caused by fibrotic reactions. Antibodies against TNFα completely blocked silica-induced pulmonary fibrosis in mice (Pignet et al ., Nature , 344: 245-247 (1990)). High levels of TNFα production (in serum and isolated macrophages) have been demonstrated in animal models of silica and asbestos induced fibrosis (Bisonn-ette et al., Inflammation 13 (3), 329-339 (1989)). In addition, alveolar macrophages in patients with pulmonary sarcoidosis have been found to spontaneously release large amounts of TNFα compared to macrophages of normal donors (Baughman et al. , J. Lab. Clin. Med. 115 (1), 36-42 ( 199 0).

TNFα is also a major cause of tissue damage after blood flow loss and is involved in the inflammatory response following reperfusion called reperfusion injury (Vedder et al. PNAS 87, 2643-2646 (1990)). In addition, TNFα alters the properties of endothelial cells, such as downregulating expression of thrombomodulin, as well as causing increased tissue factor pro-coagulant activity and inhibition of anticoagulant protein C pathways. It has various precoagulant activities (Sherry et al., J. Cell Biol. 107, 1269-1277 (1988)). TNFα has pre-inflammatory activity, which, along with the initial production of TNFα (during the initiation phase of the inflammatory event), is a promising mediator of TNFα in tissue injury in some important disorders including but not limited to myocardial infarction, stroke and cyclic shock. Make it. Among them, TNFα-induced expression of adhesion molecules, such as intracellular adhesion molecules (ICAM) or endothelial leukocyte adhesion molecules (ELAM) to endothelial cells, may be particularly important (Munro et al . , Am. J. Path. 135 ( 1), 121-132 (1989).

TNFα blockade with monoclonal anti-TNFα antibodies is useful for rheumatoid arthritis (Elliot et al., Int J. Pharmac. 1995, 17 (2), 141-145) and Crohn's disease (von Dullemen et al., Gastroe-nterology , 1995, 109 ( 1), 129-135).

Moreover, it is now known that TNFα is a potent activator for retroviral replication-induced activation of HIV-1 (Duh et al . , Proc. Nat Acad. Sci. 8 6, 5974-5978 (1989); Poll et al . , Proc. Nat Acad.Sci . 87, 782-785 (1990); Monto et al. , Blood 79, 2670 (1990); Clouse et al. , J. Immunol. 142, 431-438 (1989); Poll et al. , AIDS Res. Hum.Retrovirus , 191-197 (1992). AIDS is the result of infection with T lymphocytes with human immunodeficiency virus (HI V). At least three types or strains of HIV have been identified, namely HIV-1, HIV-2 and HIV-3. As a result of HIV infection, T-cell mediated immunity is impaired, and infected individuals clearly exhibit severe opportunistic infections and / or exceptional neoplasms. Entry of HIV into T lymphocytes requires T lymphocyte activation. Other viruses, such as HIV-1, HIV-2, infect T lymphocytes after T cell activation, and such viral protein expression and / or replication is mediated or maintained by such T cell activation. Once activated T lymphocytes are infected with HIV, T lymphocytes must remain activated to permit HIV gene expression and / or HIV replication. Cytokines, specifically TNFα, are involved in T cell mediated HIV protein expression and / or viral replication activated by playing a role in maintaining T lymphocyte activation. Thus, disruption of cytokine activity by preventing or inhibiting cytokine production, particularly TNFα, in HIV-infected individuals helps to limit maintenance of T lymphocytes due to HIV infection.

In addition, monocytes, macrophages, and related cells such as kupffer and glial cells are involved in the maintenance of HIV infection. These cells, like T cells, are targets for viral replication, and the level of viral replication depends on the activation state of the cells (Rosenberg et al., The Immunopat-hogenesis of HIV Infection , Advances in Immunology, 57 (1989)). Cytokines, such as TNFα, are known to activate HIV replication in monocytes and / or macrophages (Poli et al . , Proc. Natl. Acad. Sci. , 87, 782-784 (1990)) and, accordingly, cytokine or activity Prevention or inhibition helps to limit HIV progression on T cells. Further studies have identified TNFα as a common factor in HIV activation in vitro and provide a clear mechanism of action by nuclear regulatory proteins found in the cytoplasm of cells (Osbom, et al., PNAS 86 2336-2340). This evidence suggests that a decrease in TNFα synthesis may have antiviral effects in HIV infection by reducing viral production by reducing transcription.

AIDS virus replication of HIV latent in T cells and macrophages can be induced by TNFα (Folks et al., PNAS 86, 2365-2368 (1989)). The molecular mechanism for viral inducing activity is implied by the ability of TNFα to activate gene regulatory protein (NFκB) found in the cytoplasm, which promotes HIV replication through binding to the cell's viral regulatory gene sequence (LTR). Osborn et al., PNAS 86, 2336-2340 (1989). TNFα of AID S related cachexia is implied by elevated serum TNFα and high levels of spontaneous TNFα production in the peripheral blood monocytes of patients (Wright et al. , J. Immunol. 141 (1), 99-104 (1988)). . TNFα is involved in a variety of roles in other viral infections such as cytomegalovirus (CMV), influenza virus, adenovirus, and viruses of the herpes family for similar reasons as well known.

Nuclear factor κB (NFκB) is a polymorphogenic transcriptional activator (Lenardo et al., Cell 1989, 58, 227-29). NFκB is involved as a transcriptional activator in various diseases and inflammatory conditions, but it is not limited to modulate cytokine levels, including TNFα, and are also thought to be active agents of HIV transcription (Dbaibo et al. , J. Biol. Chem. 1993, 17762-66; Duh et al . , Proc. Natl. Acad. Sci. 1989, 86, 5974-78; Bachelerie et al ., Nature 1991, 350, 709-12; Boswas et al., J Acquired Immune Defciency Syndrome 1993, 6, 778-786 uzuki et al. , Biochem. and Biophys.Res . Comm. 1993, 193, 277-83; Suzuki et al. , Biochem. and Biophys.Res . Comm. 1992, 189, 1709-15; Suzuki et al. , Biochem.Mol . Int 1993, 31 (4), 693-700;. Shakhov , etc., Proc Natl Acad Sci USA 1990, 171, 35-47;........ and so on and Staal, Proc Natl Acad Sci USA 1990 , 87, 9943-47). Thus, inhibition of NFκB binding can modulate the transcription of cytokine gene (s), and is useful for inhibiting many disease states through such coordination and other mechanisms. The compounds described herein can inhibit the action of NFκB in the nucleus and are, but are not limited to, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, other arthritis conditions, cancer, septic shock, sepsis, endotoxin shock, graft versus host It is useful for the treatment of a number of diseases including disease, wasting disease, Crohn's disease, inflammatory bowel disease, ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, leprosy ENL, HIV, AIDS, and opportunistic infection of AIDS. TNFα and NFκB levels are affected by mutual feedback loops. As noted above, the compounds of the present invention affect both the levels of TNFα and NFκB.

Many cellular functions are mediated by the levels of adenosine 3 ', 5'-cyclic monophosphate (cAMP). Such cellular function can contribute to inflammatory conditions and diseases, including asthma, inflammation, and other disease states (Lowe and Cheng, Drugs of the Future , 17 (9), 799-807, 1992). It is known that elevation of cAMP in inflammatory leukocytes inhibits the activation of inflammatory leukocytes followed by the release of inflammatory mediators, including TNFα and NFκB. In addition, increased cAMP levels result in relaxation of airway smooth muscle.

The primary cellular mechanism for inactivation of cAMP is the destruction of cAMP by the isoenzyme family, considered as ring nucleotide phosphodiesterases (PDEs) (Beavo and Reitsnyder, Trends in Pharm. , 11, 150-155, 1990). . There are seven known members of the PDE family. For example, it is recognized that inhibition of type IV PDE is particularly effective both in inflammatory mediator release inhibition and airway smooth muscle relaxation (Verghese, et al., Journal of Pharmacology and Experimental Therapeutics , 272 (3), 1313-1320, 1995). . Thus, compounds that specifically inhibit PDE IV will exhibit desirable inflammation inhibition and airway smooth muscle relaxation, while minimizing undesirable side effects such as cardiovascular or antiplatelet effects. Currently used PDE IV inhibitors lack selective action at acceptable therapeutic doses. The compounds of the invention are useful for the inhibition of phosphodiesterases, in particular PDE III and PDE IV, and for the treatment of disease states mediated by them.

Thus, decreasing TNFα levels, increasing cAMP levels, and inhibition of PDE IV constitute a valuable therapeutic strategy for the treatment of many inflammatory, infectious, immune or malignant diseases. These include septic shock, sepsis, endotoxin shock, hemodynamic shock and sepsis syndrome, ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, transplant rejection, cancer, autologous Immune diseases, opportunistic infections of AIDS, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, other arthritis conditions, Crohn's disease, ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, leprosy ENL, radiation damage, and high oxygen alveolar injury Including but not limited to.

This is a continuation of US Patent Application No. 09 / 590,344, filed June 8, 2000, which claims the benefit of US Provisional Patent Application No. 60/165, 168, filed November 12, 1999, of which The entire manual is included as a reference.

The present invention reduces the levels of tumor necrosis factor alpha (TNFα) and inhibits phosphodiesterase (PDE), in particular PDE 4 and PDE 3, and non-polypeptide isoindolin derivatives, and disease conditions mediated by It's about treatment. This compound inhibits angiogenesis and is useful for the treatment of cancer, inflammatory diseases, and autoimmune diseases. For example, compounds that selectively inhibit PDE 4 are useful for treating inflammation and for relaxing airway smooth muscle and have minimal undesirable side effects, such as cardiovascular or anti-platelet effects. The present invention also relates to methods of treatment and pharmaceutical compositions using such compounds.

The present invention relates to compounds of formula (1), wherein the carbon atoms marked with * are chiral centers.

[Formula 1]

In formula (1), R ¹ and R ² are each independently of each other alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, cycloalkoxy of 3 to 18 carbon atoms, cycloalkyl of 3 to 18 carbon atoms Or cycloalkyl is cycloalkylmethoxy having from 3 to 18 carbon atoms, one of X and X 'is = C = O or = S0 ₂ , and the other of X and X' is = C = O, = CH ₂ , = S0 ₂ or = CH ₂ C = O divalent selected from

n has a value of 1, 2, or 3;

R ³ is —SO ₂ —Y, —COZ, —CN, or hydroxyalkyl of 1 to 6 carbon atoms,

From here,

Y is alkyl, phenyl, or benzyl of 1 to 6 carbon atoms,

Z is -NR ^{6 "} R ^7" , alkyl of 1 to 6 carbon atoms, phenyl, or benzyl,

R ^{6 "} is hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, phenyl, benzyl, or alkanoyl of 2 to 5 carbon atoms, each of which is halo, amino, or 1 to 4 carbon atoms Unsubstituted or substituted with an alkylamino of the atom,

R ^{7 "} is hydrogen or alkyl of 1 to 4 carbon atoms,

R ⁴ and R ⁵ , when taken together, are —NH—CH ₂ —R ⁸ —, —NH—CO—R ⁸ — or —N═CH—R ⁸ —, where —R ⁸ — is —CH ₂ — , -O-, -NH-, -CH = CH-, -CH = N-, or -N = CH-.

Or, alternatively, when independent of one another, one of R ⁴ and R ⁵ is hydrogen and the other of R ⁴ and R ⁵ is imidazole, pyrrolyl, oxadiazolyl, triazolyl, or

, Where

z is 0 or 1,

When R ⁶ is independent of R ⁷ , hydrogen; Alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, alkanoyl of 2 to 5 carbon atoms, or cycloalkanoyl of 2 to 6 carbon atoms, these are halo, amino, monoalkylamino or dialkyl, respectively Unsubstituted or substituted with amino, wherein each alkyl group contains 1 to 4 carbon atoms; Phenyl; benzyl; Benzoyl; Alkoxycarbonyl of 2 to 5 carbon atoms; N-morpholinocarbonyl; Carbamoyl; Alkoxyalkylcarbonyl of 2 to 5 carbon atoms; N-substituted carbamoyl, wherein the substituents are alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, or alkanoyl of 2 to 5 carbon atoms, each of which is halo, amino, monoalkylamino Or unsubstituted or substituted with dialkylamino, wherein each alkyl group contains 1 to 4 carbon atoms; Phenyl; benzyl; Or methylsulfonyl;

R ⁷ is hydrogen, alkyl of 1 to 4 carbon atoms, or methylsulfonyl, or alkoxyalkylcarbonyl of 2 to 5 carbon atoms.

Preferably, (i) when R ³ is -SO ₂ -Y-COZ or -CN and (ii) when R ⁴ or R ⁵ is hydrogen, z is not zero.

R ⁶ and R ⁷ , when taken together, represent one or two carbon atoms substituted by —CH═CH—CH═CH—, —CH═CH—N═CH—, or amino, alkylamino, or dialkylamino; Alkylidene, wherein each alkyl group has 1 to 4 carbon atoms.

In addition, one of R ⁴ and R ⁵

Where R ⁶ , R ⁷ and z are each as just defined, and the other of R ⁴ and R ⁵ is

Wherein z 'is 0 or 1; R ^{6 'is} independently selected for R ⁶ but same meaning as R ^6; R ^{7 'is} only have the same meaning as that of R ⁷ is independently selected for R ^7.

Moreover, this invention relates to the acid addition salt of these isoindolin derivatives which are easy to carry out proton addition reaction. Such salts include, but are not limited to, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, alisilic acid, phthalic acid, emborn acid, enanthic acid And those derived from organic and inorganic acids such as and the like.

The compound is preferably administered as substantially chirally pure (S) -isomer or (R) -isomer, but may also be administered as a mixture of (S) -isomer and (R) -isomer.

Compounds can be prepared through many methods. Primarily, it is advantageous to use protecting groups which include, but are not limited to, functional groups which can be converted into the desired groups. For example, the reactions described herein can be carried out using intermediates in which either or both of R ⁴ and R ⁵ are nitro groups, which are then catalytically amines or diamines, where appropriate. Is reduced (hydrogenated). Similarly, one method may use intermediates in which either or both of R ⁴ and R ⁵ are cyano groups, and then the final compound is reduced to obtain the corresponding aminomethyl compound. Likewise, the carbonyl comprised by R ³ can be treated in the form of a secondary alcohol, which is then oxidized to a carbonyl compound using, for example, pyridinium chlorochromate.

Protecting groups, as used herein, refer to groups that are deliberately introduced at any stage of synthesis to protect groups that are generally not found in the final therapeutic compound but may be otherwise altered during chemical manipulation. Such protecting groups are either removed in a later synthesis step or converted to the desired groups, thus compounds with such protecting groups have primary importance as chemical intermediates (although some derivatives also exhibit biological activity). Therefore, the exact structure of the protecting group is not important. Numerous reactions to the formation and removal of such protecting groups are described, for example, “protecting groups in organic chemistry”, Plenum Press, London and New York, 1973; Greene, Th. W. "Protectors in Organic Synthesis", Willy, New York, 1981; "Peptides", Vol. I, Schroder and Lubke, Academic Press, London and New York, 1965; Many reference works are described, including "Methoden der organischen Chemie", Houben-Weyl, 4th edition, Vol. 15/1, Georg Thieme Verlag, Stuttgart 1974, the description of which is incorporated herein by reference.

Thus, amino groups may be selectively removed under moderate conditions, especially for acyl groups, especially for formyl, lower alkanoyl groups branched at the 1- or α position with respect to the carbonyl group, especially tertiary alkanoyls such as pivaloyl, or carbonyl groups It can be protected with an amide using a lower alkanoyl group substituted at the a position, for example trifluoroacetyl.

If the carboxyl group requires protection, it may be selected from esters which can be selectively removed under sufficiently moderate conditions that do not destroy the desired molecular structure, in particular methyl or ethyl, and especially branched at the 1- or α position, such as t-butyl. Lower alkyl esters of the same 1 to 12 carbon atoms; And (i) lower alkoxy, for example methoxymethyl, 1-methoxyethyl and ethoxymethyl, (ii) lower alkylthio, for example methylthiomethyl and 1-ethylthioethyl, (iii) 2 Halogen, such as 2,2-trichloroethyl, 2-bromoethyl and 2-iodoethoxycarbonyl, (iv) each unsubstituted, or lower alkyl such as tert-butyl, methoxy and One or two phenyl groups which may be mono-, di- or tri-substituted, such as lower alkoxy, hydroxy, halo such as chloro, for example benzyl, 4-nitrobenzyl, diphenylmethyl, di- ( 4-methoxyphenyl) methyl; Or (v) such lower alkyl esters substituted at the 1- or 2-position with aroyl, such as phenacyl. The carboxyl groups can also be protected in the form of organic silyl groups such as trimethylsilylethyl or tri lower alkylsilyl, for example as tri-methylsilyloxycarbonyl.

Although all are known, many of the compounds described herein begin with compounds wherein either or both of R ⁴ and R ⁵ are amino or protected amino groups. Next, the amino groups are further processed as described herein below. One method may also use starting materials in which R ⁴ and / or R ⁵ are amides, for example 4-acetamidophthalic acid or 2-chloroacetamide. The latter reaction product can then be allowed to react with sodium azide followed by triphenylphosphine, thereby obtaining 2-amino-N-substituted acetamide.

In one embodiment, the anhydride or lactone is allowed to react with α, 3,4-trisubstituted benzylamine.

Wherein at least one of X and X 'is = C = O. In addition, one method may use diacids, such as R ⁴ , R ⁵ disubstituted phthalic acid, and the water formed is removed. In addition, activated derivatives thereof can be used.

Compounds wherein X is = CH ₂ can be prepared from the same trisubstituted benzylamine and formyl or bromomethyl benzoate derivatives.

Similarly, R ⁴ , R ⁵ benzene orthodialdehyde may be allowed to react with the α, 3,4-trisubstituted benzylamine in the form of ammonium chloride salts.

In addition, the above reaction can be carried out using a compound in which R ⁴ and R ⁵ form a heterocycle. For example, using furano [3,4-h] quinoline-1,3-dione instead of phthalic anhydride, the corresponding 2-substituted pyrrolino [3,4-h] quinoline-1,3-dione Is obtained.

When R ⁴ and R ⁵ in Formula 1 are both amino, the compound may be further reacted. For example, dimethylformamide dimethyl acetal is used to obtain pyrrolino [3,4-e] benzimidazole in which R ⁴ and R ⁵ together form -N = CH-NH-. The corresponding hydropyrrolino [3,4-e] benzimidazoles can be obtained from diamines and triphosgens, and if diamines and glyoxal are used instead, the product is obtained from the corresponding 3-pyrrolino [3, 4-f] quinoxaline.

If only one of R ⁴ and R ⁵ in Formula 1 is an amine, the compound may be reacted with a suitable acid halide or anhydride to provide the corresponding amide. The same reaction can be carried out using chloroformate to obtain methoxycarboxyamide derivatives.

If the amide is formed from amine and chloroacetyl chloride, ie to produce chloroacetamide derivatives, it can then be treated with ammonia or primary or secondary amines to obtain the corresponding aminoacetamides. For example, treatment with dimethylamine yields the corresponding dimethylaminoacetamide. In addition, reducing formylation may be performed to a compound in which either or both of R ⁴ and R ⁵ are amino to form the corresponding N, N-dimethylamino compound.

In addition, compounds in which either or both of R ⁴ and R ⁵ are amino can be reacted with dimethylformamide dimethyl acetal to provide the corresponding 1-aza-2- (dimethylamino) vinyl compound.

Compounds in which one of R ⁴ and R ⁵ are heterocyclic groups can be prepared in many ways. Isoindolin 4- or 5-carboxylic acid is reacted with carbonyldiimidazole followed by acet hydrazide to give the corresponding 4- (5-methyl-1,3,4-oxadiazol-2-yl) isoin Doline or 5- (5-methyl-1,3,4-oxadiazol-2-yl) isoindoline or 5- (5-methyl-1,3,4-oxadiazol-2-yl) isoin Can provide a turn. Alternatively, monoamine and 2,5-dimethoxytetrahydrofuran are reacted to give 4- or 5-pyrrolylisoindolin. Similarly, 4-aminomethyl or 5-aminomethyl (prepared as described above) and dimethoxytetrahydrofuran are reacted to give the corresponding pyrrolylmethyl compound.

A first preferred subgroup is a compound of formula 1 wherein R ⁴ and R ⁵ together are —NH—CH ₂ —R ⁸ —, —NH—CO—R ⁸ — or —N═CH—R ⁸ —, wherein R ⁸ -is -CH _2- , -O-, -NH-, -CH = CH-, -CH = N-, or -N = CH-. It will be appreciated that non-symmetrical chains can each be arranged in either of two directions, each of which is also within the scope of the present invention.

A second preferred subgroup is a compound of formula 1, wherein one of R ⁴ and R ⁵ is hydrogen and the other of R ⁴ and R ⁵ is imidazolyl, oxadiazolyl, pyrrolyl, or triazolyl.

The third preferred subgroup is that one of R ⁴ and R ⁵

Is a compound of Formula 1,

Wherein z is 0 or 1; R ⁶ , when independent of R ⁷ , is hydrogen, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, carboncycloalkyl of 3 to 18 carbon atoms; Phenyl, benzyl, alkanoyl of 2 to 5 carbon atoms, haloalkanoyl of 2 to 5 carbon atoms, aminoalkanoyl of 2 to 5 carbon atoms, N-alkylaminoalkanoyl of 2 to 5 carbon atoms, benzoyl, 2 to 5 carbon atoms Alkoxycarbonyl, N-morpholinocarbonyl, carbamoyl, and N-substituted carbamoyl of 5 carbon atoms, wherein the substituents are alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, Cycloalkyl of 3 to 18 carbon atoms; Aminoalkanoyl of 2 to 5 carbon atoms, N-alkylaminoalkanoyl of 2 to 5 carbon atoms, phenyl, benzyl, or methylsulfonyl; R ⁷ is hydrogen or alkyl of 1 to 4 carbon atoms, or R ⁶ and R ⁷ together are —CH═CH—CH═CH—, —CH═CH—N═CH—, or amino, alkylamino or dialkyl Alkylidene of 1 or 2 carbon atoms substituted by amino, wherein each alkyl group has 1 to 4 carbon atoms.

Within the scope of this third preferred subgroup, the first more preferred subgroup is that R ⁶ is hydrogen, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms , Phenyl or benzyl. The second more preferred subgroup is R ⁶ is alkanoyl of 2 to 5 carbon atoms, haloalkanoyl of 2 to 5 carbon atoms, aminoalkanoyl of 2 to 5 carbon atoms, benzoyl, alkoxycar of 2 to 5 carbon atoms Carbonyl, N-morpholinocarbonyl, carbamoyl, and N-substituted carbamoyl, wherein the substituents are methyl, ethyl, or trifluoromethyl; R ⁷ is hydrogen.

The fourth preferred subgroup is that one of R ⁴ and R ⁵

ego,

The other one of R ⁴ and R ⁵

Is a compound of Formula 1,

Wherein z and z 'are independently 0 or 1; R ⁶ has the meaning given above, R ^{6 'has} the same meaning as R ^6, but is selected independently of R ^6; R ⁷ has the meaning given above, R ^{7 'are} independently selected in the same meaning, but R ⁷ and R ^7.

Within the scope of this fourth preferred subgroup, the first more preferred subgroups are those in which R ⁶ and R ^{6 '} are each independently of each other hydrogen, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, Or cycloalkyl, phenyl, or benzyl of 3 to 18 carbon atoms. The second more preferred subgroup is R ⁶ and R ^{6 '} are each independently of each other alkanoyl of 2 to 5 carbon atoms, haloalkanoyl of 2 to 5 carbon atoms, aminoalkanoyl of 2 to 5 carbon atoms, benzoyl, Alkoxycarbonyl, N-morpholinocarbonyl, carbamoyl, and N-substituted carbamoyl of 2 to 5 carbon atoms, wherein the substituents are methyl, ethyl, or trifluoromethyl; R ⁷ and R ^{7 '} are each a hydrogen compound.

A third more preferred subgroup is that one of R ⁶ and R ^{6 '} is alkanoyl of 2 to 5 carbon atoms, haloalkanoyl of 2 to 5 carbon atoms, aminoalkanoyl of 2 to 5 carbon atoms, benzoyl, 2 to Alkoxycarbonyl, N-morpholinocarbonyl, carbamoyl, and N-substituted carbamoyl of 5 carbon atoms, wherein the substituents are methyl, ethyl, or trifluoromethyl; The other of R ⁶ and R ^{6 ′} is hydrogen, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, phenyl, or benzyl; R ⁷ and R ^{7 '} are each a hydrogen compound.

Further preferred subgroups for all of the above are compounds wherein one of X and X 'is = C = O and the other is = C = O, = CH ₂ , or = S0 ₂ , and R ¹ and R ² are each Independently of one another, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propoxy, i-propoxy, cyclopentoxy, cyclohexoxy, cycloheptoxy, cyclopentyl, cyclohexyl, Cycloheptyl, or cyclopropylmethoxy.

The compound has a chiral center and can therefore exist as an optical isomer. Chirally pure (R)-and (S) -isomers, mixtures of these isomers (including but not limited to racemic mixtures), and diastereomers with two chiral centers are all within the scope of the present invention. have. The mixture can be used as it is or can be mechanically separated into their individual isomers, such as by chromatography using a chiral absorbent. Alternatively, the individual isomers may be prepared in chiral form or chiral acids, for example camphorsulfonic acid, camphoric acid, bromocamphoric acid, methoxyacetic acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone- Can be chemically separated from the mixture by forming a salt with 5-carboxylic acid and the like, then removing one or both of the dissociated bases and optionally repeating this process, thereby substantially freeing other materials, That is, a form having an optical purity of 95% or more can be obtained.

Inhibition of PDE III, PDE IV, TNFα and NFκB by these compounds can be conveniently assayed using methods known in the art, for example, enzyme immunoassay, radioimmunoassay, immunoelectrophoresis, affinity labeling, and the like. Of these, the following are typical:

PBMCs from normal donors are obtained by Ficoll-Hypaque density centrifugation. Cells are cultured in RPMI supplemented with 10% AB + serum, 2 mM L-glutamine, 100 U / mL penicillin and 100 mg / mL streptomycin.

The test compound is dissolved in dimethyl sulfoxide (Sigma Chemical) and further dilution is done at RPMI supplemented. The drug is present or absent in PBMC or the final dimethyl sulfoxide concentration is 0.25 wt%. Test compounds are analyzed with half-log dilutions starting at 50 mg / L. Test compounds are added to PBMCs (10 ⁶ cells / mL) in 96 well plates 1 hour prior to the addition of LPS.

The presence or absence of test compounds or PBMCs (10 ⁶ cells / mL) is stimulated by treatment with 1 mg / mL LPS from Salmonella minnesota R595 (List Biological Labs, Campbell, CA). The cells are then incubated at 37 ° C. for 18-20 hours. Supernatants are collected and immediately analyzed for TNFα levels or frozen at −70 ° C. until analyzed (no more than 4 days).

TNFα concentration of the supernatant is measured by the human TNFα ELISA kit (ENDOGEN, Boston, MD) according to the manufacturer's instructions.

Phosphodiesterases can be measured in conventional models. For example, using Hill and Mitchell's method, U937 cells of the human primitive monocyte cell line are grown to 1 × 10 ⁶ cells / mL and collected by centrifugation. Cell pellets of 1 × ^{10 9} cells were washed with phosphate buffered saline and then frozen at −70 ° C. for later purification, or cold homogenization buffer (20 mM Tris-HCl, pH 7.1, 3 mM 2-mercaptoethanol, 1 mM magnesium chloride, 0.1 mM ethylene glycol-bis (β-aminoethyl ether) -N, N, N ', N'-tetraacetic acid (EGTA), 1 μM phenylmethylsulfonyl fluoride (PMSF), and 1 μg / mL leupetin) Dissolves immediately in. The cells are homogenized 20 strokes in a Dounce homogenizer and the supernatant containing the cytosol fraction is obtained by centrifugation. The supernatant is then loaded onto a Sephacryl S-200 column equilibrated with homogenization buffer. Phosphodiesterase elutes in homogenization buffer at a rate of approximately 0.5 mL / min and fractions are analyzed for phosphodiesterase activity-/ + rolipram. Fractions containing phosphodiesterase activity (rollifram sensitivity) are pooled and separated for later use.

Phosphodiesterase assays are performed with 100 μl total volume containing various concentrations of test compound, 50 mM Tris-HCl, pH 7.5, 5 mM magnesium chloride and 1 μM cAMP (1% was 3H cAMP). The reaction is incubated at 30 ° C. for 30 minutes and terminated by boiling for 20 minutes. The amount of phosphodiesterase IV containing the extract used in these experiments is pre-measured so that the reaction is in the linear range and less than 15% of the total substrate is consumed. After completion of the reaction, the sample was cooled at 4 ° C. and then treated with 10 μl 10 mg / mL snake venom at 30 ° C. for 15 minutes. The unused substrate is then removed by adding 200 μl of quaternary ammonium ion exchange resin (AG1-X8, BioRad) for 15 minutes. The sample is then spun at 3000 rpm for 5 minutes and 50 μl of the aqueous phase is taken for counting. Each data point is performed in duplicate and the activity is expressed as a percentage of the control. The IC ₅₀ of the compound is then determined from the dose response curves of at least three independent experiments.

In order to inhibit the undesirable effects of TNFα, NFκB and phosphodiesterases, the compounds can be used under the supervision of a qualified expert. The compound may be administered to a mammal in need of treatment orally, rectally, or parenterally, alone or in combination with other therapeutic agents such as antibiotics, steroids, and the like. Oral dosage forms include tablets, capsules, dragees, and pharmaceutical forms compressed into similar shapes. Isotonic solutions containing 20-100 mg / mL may be used for parenteral administration, including administration of intramuscular, intradural, intravenous and intraarterial routes. Rectal administration can be through the use of suppositories formulated from conventional carriers such as cocoa butter.

The dosage regimen should be determined according to the particular indication, the age, body weight, and general physical condition of the patient, and the desired response, but in general the dosage will be from 1 to 1000 mg / day in single or multiple daily administrations as needed. In general, the initial therapeutic regimen may be mimicked by compounds of the invention that are known to be effective in interfering with TNFα activity in TNFα mediated disease states. Treated subjects are regularly subject to progression of problems related to cytokines such as T cell numbers and T4 / T8 ratios, and / or levels of reverse transcriptase or viral proteins, and / or cytokine mediated diseases such as cachexia or muscle degeneration. Will be checked. If no effect is observed after a normal treatment regimen, the amount of cytokine activity blocker administered next is increased, for example, by 50% per week.

In addition, the compounds of the present invention are also useful for the treatment or prevention of local diseases that are mediated or aggravated by excessive TNFα production, such as viral infections, such as those caused by herpes virus or viral conjunctivitis, psoriasis, other skin disorders and diseases, and the like. Can be used locally.

In addition, the compounds may be used in veterinary treatment of mammals other than humans, which require the prevention or inhibition of TNFα production. TNFα mediated diseases treated therapeutically or prophylactically in animals include disease states such as those noted above, in particular viral infections. Examples include feline immunodeficiency virus, equine infectious anemia virus, goat arthritis virus and maddy virus, and other lentiviruses.

Accordingly, the present invention provides a method for inhibiting PDE IV by administering to a mammal an effective amount of a substantially chirally pure (R)-or (S) -isomer or a mixture of these isomers of a compound of Formula 1, which is undesirable. How to reduce or inhibit levels of TNFα, how to reduce or inhibit undesirable levels of matrix metalloproteinases, how to treat undesirable angiogenesis, how to treat cancer, how to treat inflammatory diseases, autoimmunity How to treat disease, how to treat arthritis, how to treat rheumatoid arthritis, how to treat inflammatory bowel disease, how to treat Crohn's disease, how to treat ulcerative colitis, how to treat cachexia, how to treat graft versus host disease, how to treat asthma, adult respiration Methods of treating difficulty syndrome, and methods of treating acquired immunodeficiency syndrome. These methods may overlap, but they may also differ with respect to the method of administration, dose level, dosage regimen (such as single or multiple doses), and therapeutic agents administered simultaneously.

In addition, the invention provides that (i) substantially chirally pure (R)-or (S) -isomers or mixtures of these isomers of a pharmaceutically effective amount of a compound of Formula 1 when administered in a single or multiple dose regimen ( ii) a pharmaceutical composition in combination with a pharmaceutically acceptable carrier.

Pharmaceutical compositions may be represented by oral dosage forms, including tablets, capsules, dragees, and similarly compressed pharmaceutical forms containing 1 to 100 mg of drug per unit dosage. Mixtures containing 20 to 100 mg / mL can be formulated for parenteral administration, including administration of intramuscular, intradural, intravenous and intraarterial routes. Rectal administration can be through the use of suppositories formulated from conventional carriers such as cocoa butter.

The pharmaceutical composition may comprise one or more compounds of the present invention in association with at least one pharmaceutically acceptable carrier, diluent, or excipient. In the preparation of such compositions, the active ingredient is usually contained in such a carrier which may be mixed with the excipient or diluted with the excipient, or in the form of a capsule or sachet. When an excipient is used as a diluent, it may be a solid, semisolid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, flours, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile package flours. Examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations may additionally include lubricants such as talc, magnesium stearate and mineral oil, wetting agents, emulsifiers and suspending agents, preservatives such as methyl- and propylhydroxybenzoate, sweeteners or flavoring agents.

Preferably, the composition is formulated in unit dosage form, which refers to physically discrete units suitable for single administration, or in defined single doses administered as a single or multiple dosage regimen to a human subject or other mammal, each unit being suitable pharmaceutical It contains a predetermined amount of active substance calculated to produce the desired therapeutic effect in association with a pharmaceutical excipient. The compositions can be formulated such that the active ingredient is released immediately, continuously or delayed after administration to a patient by using procedures well known in the art.

The following examples further illustrate the nature of the invention, but do not limit the scope of the invention, which is defined only by the appended claims.

Example 1

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4,5-dinitroisoindolin-1,3-dione

3,4-dinitrophthalic acid (4.63 g, 18.1 mmol) and 2- (3-ethoxy-4-methoxyphenyl) -1- (methylsulfonyl) eth-2-ylamine (4.94) in toluene (70 mL) g, 18.1 g) was heated to reflux for 15 hours. Water was removed by Dean-Stark trap. Ethyl acetate (150 mL) was added to the reaction mixture. The organic layer was extracted with water, sodium hydrogencarbonate (saturated) and brine (100 mL each) and dried over magnesium sulfate. The solvent was removed in vacuo to give a solid. This solid was recrystallized from ethanol (300 mL) to give 2- [1- (3-ethoxy-4-methoxyphenyl) 2-methylsulfonylethyl] -4,5 as an orange solid (4.35 g, 49% yield). -Dinitroisoindolin-1,3-dione was obtained:

mp, 122.0-124.0 ° C .; ¹ H NMR (CDCl ₃ ) δ 1.47 (t, J = 6.9 Hz, 3H, CH ₃ ), 2.93 (s, 3H, CH ₃ ), 3.65 (dd, J = 3.9, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH ₃ ), 4.10 (q, J = 6.9 Hz, 2H, CH ₂ ), 4.56 (dd, J = 11.4, 14.1 Hz, 1H, CHH), 5.90 (dd, J = 3.9, 11.1 Hz , 1H, NCH), 6.84 (d, J = 8.0 Hz, 1H, Ar), 7.07-7.11 (m, 2H, Ar), 8.16 (d, J = 8.2 Hz, 1H, Ar), 8.60 (d, J = 7.9 Hz, 1 H, Ar); ¹³ C NMR (CDCl ₃ ) δ 14.66, 41.66, 49.57, 53.38, 55.98, 64.61, 111.61, 112.42, 120.64, 123.93, 126.18, 127.85, 131.93, 136.74, 138.10, 142.45, 148.77, 150.17, 161.57, 163.47, 163.47 Analytical theory of C ₂ 0H ₁₉ N ₃ O ₁₀ S + 0.1 ethyl acetate: C, 48.78; H, 3.97; N, 8.37. Found: C, 48.50; H, 3.77; N, 8.07. (HNMR showing sample contained in about 10% equivalent of ethyl acetate)

Example 2

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4,5-diaminoisoindolin-1,3-dione

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4,5-dinitroisoindolin-1,3-dione (4.35 g, in ethyl acetate (200 mL) 8.81 mmol) and Pd / C (800 mg) were shaken under hydrogen (50-60 psi) in a Parr bottle for 16 hours. The suspension was filtered through a pad of celite filter material. Celite filter material was washed with acetone (200 mL). The solvent was removed in vacuo to give a solid. This solid was stirred in ethyl acetate (10 mL) for 2 hours. The suspension was filtered to give 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4,5-diaminoisoindolin as yellow solid (2.79 g, 73% yield). -1,3-dione was obtained:

mp, 205-207 ° C; ¹ H NMR (DMSO-d6) δ 1.32 (t, J = 6.9 Hz, 3H, CH ₃ ), 2.99 (s, 3H, CH ₃ ), 3.73 (s, 3H, CH ₃ ), 3.95-4.07 (m, 3H, CHH), 4.37 (dd, J = 10.4, 14.0 Hz, 1H, CHH), 5.67 (dd, J = 3.9, 10.2 Hz, 1H, NCH), 5.90-6.00 (m, 4H, 2NH ₂ ), 6.64 (d, J = 7.7 Hz, 1H, Ar), 6.88-6.92 (m, 3H, Ar), 7.06 (s, 1H, Ar); ¹³ C NMR (CDCl ₃ ) 14.64, 40.94, 46.65, 53.53, 55.46, 63.79, 109.36, 111.74, 112.29, 114.42, 117.04,119.55, 130.68, 133.98, 134.06, 142.38, 147.74, 148.63, 167.16, 169.38 Analytical theory of C ₂₀ H ₂₃ N ₃ 0 ₆ S: C, 55.42; H, 5. 35; N, 9.69. Found: C, 55.71; H, 5. 30; N, 9.29. ^{MS: 434 (M + +1)} , 456 (M + + 23Na).

Example 3

7- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -3-pyrrolino [3,4-e] benzimidazole-6,8-dione

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4,5-diaminoisoindolin-1,3-dione (310 mg, 0.72 mmol in acetic acid (5 mL) Dimethylformamide dimethyl acetal (3 mL) was added to the solution. The solution was heated to reflux for 17 hours. The solvent was removed in vacuo to give an oil. This oil was stirred in sodium bicarbonate (50 mL, saturated) and ethyl acetate (100 mL). The organic layer was separated, washed with brine (50 mL) and dried over magnesium sulfate. The solvent was removed in vacuo to give an oil. The oil was separated by chromatography (silica gel, 7: 13: 0.5 methylene chloride: ethyl acetate: MeOH) to give 7- [1- (3-ethoxy-4-methoxy as a white solid (220 mg, yield 69%). Phenyl) -2-methylsulfonylethyl] -3-pyrrolino [3,4-e] benzimidazole-6,8-dione was obtained:

mp, 143-145 ° C .; ¹ H NMR (DMSO-d6) δ 1.32 (t, J = 6.9 Hz, 3H, CH ₃ ), 3.02 (s, 3H, CH ₃ ), 3.73 (s, 3H, CH ₃ ), 4.02 (q, J = 6.9 Hz, 2H, CH ₂ ), 4.15 (dd, J = 4.3, 14.3 Hz, 1H, CHH), 4.40 (dd, J = 10.5, 14.3 Hz, 1H, CHH), 5.81 (dd, J = 4.3, 10.4 Hz, 1H, NCH), 6.92-7.01 (m, 2H, Ar), 7.12 (s, 1H, Ar), 7.67 (d, J = 8.2 Hz, 1H, Ar), 8.02 (d, J = 8.0 Hz, 1H, Ar), 8.62 (s, 1H, CH), 13.49 (s, 1H, NH); ¹³ C NMR (DMSO-d6) δ 14.64, 41.02, 47.17, 53.24, 55.46, 63.81, 111.78, 112.33, 116.34, 119.67, 125.84, 129.98, 147.64, 147.85, 148.79, 166.63, 168.23; Analytical theory of C ₂₁ H ₂₁ N ₃ 0 ₆ S: C, 54.23; H, 5.07; N, 9.03. Found: C, 54.13; H, 4.65; N, 8.76; ^{MS: 444 (M + +1)} , 466 (M + + 23Na).

Example 4

7- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl) hydro-3-pyrrolino [3,4-e] benzimidazole-2,6,8-tri On

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4,5-diaminoisoindolin-1,3-dione (600 mg, 1.38 in methylene chloride (100 mL) mmol) was added to the triphosphene (0.43g, 1.4mmol) at room temperature, and allowed to stand for 30 minutes. To the mixture was added sodium hydrogen carbonate (50 mL, saturated) and ethyl acetate (80 mL). The organic layer was washed with brine (50 mL) and dried over magnesium sulfate. The solvent was removed in vacuo to give a solid. This solid was then recrystallized from ethanol to give 7- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] hydro-3- as a brown solid (390 mg, yield 62%). Pyrrolino [3,4-e] benzimidazole-2,6,8-trione was obtained:

mp, 242-244 ° C .; ¹ H NMR (DMSO-d6) δ 1.32 (t, J = 6.9 Hz, 3H, CH ₃ ), 3.01 (s, 3H, CH ₃ ), 3.73 (s, 3H, CH ₃ ), 4.01 (q, J = 6.9 Hz, 2H, CH ₂ ), 4.11 (dd, J = 4.3, 14.3 Hz, 1H, CHH), 4.37 (dd, J = 10.7, 14.3 Hz, 1H, CHH), 5.76 (dd, J = 4.1, 10.3 Hz, 1H, NCH), 6.91-6.92 (m, 2H, Ar), 7.08 (s, 1H, Ar), 7.23 (d, J = 7.7 Hz, 1H, Ar), 7.45 (d, J = 7.8 Hz, 1H, Ar), 11.47 (s, 1H, NH), 11.87 (s, 1H, N); 13C NMR (DMSO-d6) δ 14.64, 41.01, 47.07, 53.14, 55.46, 63.83, 110.41, 111.78, 112.00, 112.37, 116.72, 119.67, 122.79, 125.76, 129.96, 136.29, 147.81, 148.80, 155.86, 167.166. Analytical theory of C ₂₁ H ₂₁ N ₃ 0 ₇ S + 1.1H ₂ 0: C, 52.63; H, 4.88; N, 8.77; H ₂ 0, 4.13. Found: C, 52.48; H, 4.73; N, 8.53; H ₂ 0, 4.07.

Example 5

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -3-pyrrolino [3,4-h] quinoline-1,3-dione

2- (3-ethoxy-4-methoxyphenyl) -1- (methylsulfonyl) eth-2-ylamine (0.69 g, 2.5 mmol) in acetic acid (10 mL), furano [3,4-h] A mixture of quinoline-1,3-dione (0.50 g, 2.5 mmol) and sodium acetate (0.25 g, 3.1 mmol) was heated to reflux for 18 hours. The solvent was removed in vacuo to give an oil. The resulting oil was stirred in ether / hexane / water (30/5/30 mL) for 18 hours. The suspension was filtered to give a solid. This solid was stirred in hot methanol. The suspension was filtered to give 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -3-pyrrino as a grayish white solid (0.8 g, yield 70%). [3,4-h] quinoline-1,3-dione was obtained:

mp, 223-225 ° C .; ¹ H NMR (CDCl ₃ ); δ 1.47 (t, J = 6.8 Hz, 3H, CH ₃ ), 2.89 (s, 3H, CH ₃ ), 3.79-3.86 (m, 1H, CHH), 3.84 (s, 3H, CH ₃ ), 4.12 (q , J = 6.9 Hz, 2H, CH ₂ ), 4.63 (dd, J = 10.4, 14.3 Hz, 1H, CHH), 5.98 (dd, J = 4.5, 10.3 Hz, 1H, NCH), 6.82-6.85 (m, 1H, Ar), 7.19-7.22 (m, 2H, Ar), 7.57 (dd, J = 4.2, 8.4 Hz, 1H, Ar), 7.95 (t, J = 8.2 Hz, 1H, Ar), 8.17 (d, J = 8.3 Hz, 1H, Ar), 8.27 (dd, J = 1.4, 8.4 Hz, 1H, Ar), 9.24 (dd, J = 1.7, 4.2 Hz, 1H, Ar); ¹³ C NMR (CDCl ₃ ) δ 14.61, 41.36, 48.90, 54.73, 55.88, 64.47, 11.41, 112.57, 119.55, 120.55, 123.20, 126.89, 129.48, 132.19, 134.43, 135.69, 136.68, 142.79, 148.55, 149.59. 167.11, 167.62; Analytical theory of C ₂₃ H ₂₂ N ₂ 0 ₆ S: C, 60.78; H, 4.88; N, 6.16. Found: C, 60.57; H, 4.79; N, 5.95.

Example 6

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -3-pyrrolino [3,4-f] quinoxaline-1,3-dione

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4,5-diaminoisoindolin-1,3-dione (433 mg, in tetrahydrofuran (2 mL) 1.0 mmol) was added glyoxal (0.15 mL, 1.3 mmol). The solution was heated to reflux for 7 hours. Ether (10 mL) was added to the suspension. The suspension was filtered and washed with ether to give an orange solid. This solid was stirred in ethanol (20 mL) for 18 h. The suspension was filtered and washed with ethanol to give 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -3-pyrrino as an orange solid (200 mg, 44% yield). [3, 4-f] quinoxaline-1,3-dione was obtained:

mp, 122.0-124.0 ° C .; ¹ H NMR (DMSO-d6) δ 1.32 (t, J = 6.9 Hz, 3H, CH ₃ ), 3.03 (s, 3H, CH ₃ ), 3.73 (s, 3H, CH ₃ ), 4.03 (q, J = 6.9 Hz, 2H, CH ₂ ), 4.20 (dd, J = 4.5, 14.4 Hz, 1 H, CHH), 4.39 (dd, J = 10.5, 14.1 Hz, 1H, CHH), 5.87 (dd, J = 4.5, 10.2 Hz, 1H, NCH), 6.92-6.96 (m, 1H, Ar), 7.03-7.07 (m, 1H, Ar), 7.15 (d, J = 1.7 Hz, 1H, Ar), 8.23 (d, J = 8.4 Hz, 1H, Ar), 8.53 (d, J = 8.4 Hz, 1H, Ar), 9.14 (d, J = 1.7 Hz, 1H, Ar), 9.22 (d, J = 1.7 Hz, 1H, Ar); ¹³ C NMR (DMSO-d6) δ 14.63, 41.05, 47.49, 53.07, 55.47, 63.81, 111.73, 112.41, 119.80, 122.66, 126.93, 129.48, 134.08, 137.06, 137.25, 145.02, 147.87, 147.93, 148.87, 148.87 , 167.05; Analytical theory of C ₂₂ H ₂₁ N ₃ 0 ₆ S + 0.2H ₂ 0: C, 57.56; H, 4. 70; N, 9.15; H ₂ 0, 0.78. Found: C, 57.34; H, 4. 70; N, 9.15; H ₂ 0, 0.41.

Example 7

Cyclopropyl-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl)-]-1,3-dioxoisoindolin-4-yl} carboxyamide

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-aminoisoindolin-1,3-dione (570 mg, 1.4 mmol) with cyclopropane carbonyl chloride ( 2 mL) was heated to reflux for 15 minutes. Methanol (20 mL) and water (5 mL) were added to the mixture at room temperature, and left to stand for 30 minutes. The solvent was removed in vacuo to give an oil. The oil was stirred for 1 h in ether / hexane (15 mL each) to give a suspension. The suspension was filtered and washed with ether to give a yellow solid. This solid was then stirred in ethanol (10 mL) overnight. The suspension was filtered and washed with ethanol to give cyclopropyl-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] as a yellow solid (380 mg, yield 57.4%). -1,3-dioxoisoindolin-4-yl} carmoxiamide;

mp, 153-155 ° C .; ¹ H NMR (CDCl ₃ ) δ 0.92-0.99 (m, 2H, 2CHH), 1.11-1.17 (m, 2H, 2CHH), 1.48 (t, J = 6.9 Hz, 3H, CH ₃ ), 1.61-1.71 (m , 1H, CH), 2.88 (s, 3H, CH ₃ ), 3.75 (dd, J = 4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH ₃ ), 4.12 (q, J = 7.1 Hz , 2H, CH ₂ ), 4.57 (dd, J = 10.4, 14.3 Hz, 1H, CHH), 5.89 (dd, J = 4.4, 10.3 Hz, 1H, NCH), 6.84-6.88 (m, 1H, Ar), 7.11-7.15 (m, 2H, Ar), 7.48 (d, J = 7.2 Hz, 1H, Ar), 7.65 (t, J = 7.4 Hz, 1H, Ar), 8.76 (d, J = 8.5 Hz, 1H, Ar), 9.69 (s, 1 H, NH); ¹³ C NMR (CDCl ₃ ) δ 8.71, 14.62, 16.16, 41.58, 48.59, 54.60, 55.89, 64.50, 111.49, 112.44, 114.83, 117.91, 120.26, 124.99, 129.27, 130.99, 136.02, 137.77, 148.63, 149.76, 167.167. 169.52, 172.79; Analytical theory of C ₂₄ H ₂₆ N ₂ 0 ₇ S: C, 59.25; H, 5.39; N, 5.76. Found: C, 59.06; H, 5. 30; N, 5.69.

Example 8

2-chloro-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} acetamide

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-aminoisoindolin-1,3-dione (2.0 g, 4.8 mmol) with chloroacetyl chloride (2 mL , 25 mmol) was heated to reflux for 30 minutes. The solvent was removed in vacuo to give a solid. This solid was stirred in ether (40 mL) for 1 h to give a suspension. The suspension is filtered and washed with ether to give 2-chloro-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyl as a white solid (2.28 g, 96% yield). Ethyl] -1,3-oxoisoindolin-4-yl} acetamide was obtained:

mp, 166-168 ° C .; ₁ H NMR (CDCl ₃ ) δ 1.48 (t, J = 6.9 Hz, 3H, CH ₃ ), 2.88 (s, 3H, CH ₃ ), 3.75 (dd, J = 4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH ₃ ), 4.13 (q, J = 7.0 Hz, 2H, CH ₂ ), 4.24 (s, 2H, CH ₂ ), 4.57 (dd, J = 10.5, 14.3 Hz, 1H, CHH), 5.89 (dd, J = 4.5, 10.3 Hz, 1H, NCH), 6.84-6.88 (m, 1H, Ar), 7.11-7.15 (m, 2H, Ar), 7.57 (d, J = 7.2 Hz, 1H, Ar ), 7.70 (t, J = 7.6 Hz, 1H, Ar), 8.77 (d, J = 8.3 Hz, 1H, Ar), 10.53 (s, 1H, NH); ¹³ C NMR (CDCl ₃ ) δ 14.60, 41.52, 42.67, 48.72, 54.51, 55.88, 64.48, 111.46, 112.44, 116.37, 119.06, 120.38, 124.74, 129.17, 131.22, 136.04, 136.29, 148.58, 149.75, 165.25. 169.01; Analytical theory of C ₂₂ H ₂₃ N ₂ 0 ₇ ClS + 0.1H ₂ 0: C, 53.19; H, 4.71; N, 5.50; H ₂ 0, 0.36. Found: C, 52.89; H, 4.52; N, 5.50; H ₂ 0, 0.17.

Example 9

2-amino-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} acetamide

2-Chloro-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl in acetone (10 mL) } A mixture of acetamide (0.30 g, 0.61 mmol) and sodium azide (90 mg, 1.38 mmol) was heated to reflux for 8 hours. Triphenylphosphine (0.30 g, 1.1 mmol) and water (0.4 mL) were added to the solution. The solution was heated to reflux for at least 5 hours. The solvent was removed in vacuo to give an oil. This oil was stirred overnight in ether (10 mL) and water (10 mL) to give a suspension. The suspension is filtered and washed with ether to give 2-amino-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl as a yellow solid (250 mg, yield 86%). ] -1,3-dioxoisoindolin-4-yl} acetamide was obtained:

mp, 111-112 ° C .; ¹ H NMR (CDCl ₃ ) 1.48 (t, J = 6.9 Hz, 3H, CH ₃ ), 1.74 (brs, 2H, NH ₂ ), 2.86 (s, 3H, CH ₃ ), 3.57 (s, 2H, CH ₂ ), 3.77 (dd, J = 4.6, 14.5 Hz, 1H, CHH), 3.86 (s, 3H, CH ₃ ), 4.11 (q, J = 7.0 Hz, 2H, CH ₂ ), 4.56 (dd, J = 10.2 , 14.2 Hz, 1H, CHH), 5.89 (dd, J = 4.6, 10.2 Hz, 1H, NCH), 6.82-6.85 (m, 1H, Ar), 7.12-7.15 (m, 2H, Ar), 7.52 (d , J = 7.2 Hz, 1H, Ar), 7.67 (t, J = 7.5 Hz, 1H, Ar), 8.86 (d, J = 8.3 Hz, 1H, Ar), 11.21 (s, 1H, NH); ¹³ C NMR (CDCl ₃ ) 14.68, 41.51, 48.65, 54.69, 55.88,64.49, 111.45, 112.50, 115.81, 118.24, 120.37, 124.94, 129.38, 131.29, 135.90, 136.88, 148.55, 149.68, 167.64, 168.172.4 Analytical theory of C ₂₂ H ₂₅ N ₀ 0 ₇ S: C, 55.57; H, 5. 30; N, 8.84. Found: C, 55.46; H, 5. 33; N, 8.35.

Example 10

2-N, N-dimethylamino-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl Acetamide HCl

2-azido-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4- in ethanol (90 mL) A mixture of acetamide (0.80 g, 1.59 mmol), Pd / C (0.2 g) and formaldehyde (10 mL, 37% in water) was shaken under hydrogen (50-60 psi) in a Parr flask for 3 days. The suspension was filtered through a pad of celite and washed with acetone (50 mL). The solvent was removed in vacuo to give an oil. This oil was stirred in methanol (10 mL). The suspension was filtered and washed with methanol to give a white solid. Hydrochloric acid in ether (1.5 mL, 1N) was added to this solid in ethyl acetate (20 mL) to obtain a suspension. The suspension is filtered and washed with ether to give 2-N, N-dimethylamino-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2 as a yellow solid (300 mg, 35% yield). -Methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} acetamide hydrochloride was obtained:

mp, 105-107 ° C .; ¹ H NMR (DMSO-d6) δ 1.33 (t, J = 6.9 Hz, 3H, CH ₃ ), 2.87 (s, 6H, 2CH ₃ ), 3.03 (s, 3H, CH ₃ ), 3.74 (s, 3H, CH ₃ ), 4.02 (q, J = 7.0 Hz, 2H, CH ₂ ), 4.16 (dd, J = 4.2, 14.3 Hz, 1H, CHH) 4.25 (brs, 2H, CH ₂ ), 4.34 (dd, J = 10.8, 14.4 Hz, 1H, CHH), 5.79 (dd, J = 4.2, 10.4 Hz, 1H, NCH), 6.92-6.99 (m, 2H, Ar), 7.08 (s, 1H, Ar), 7.69 (d, J = 7.3 Hz, 1H, Ar), 7.88 (t, J = 7.7 Hz, 1H, Ar), 8.21-8.27 (m, 1H, Ar), 10.29 (s, 1H, HCl), 10.64 (s, 1H, NH); ¹³ C NMR (DMSO-d6) δ 14.65, 41.04, 43.36, 47.23, 52.86, 55.51, 58.09, 63.86, 111.79, 112.39, 119.22, 119.68, 127.78, 127.99, 129.42, 131.76, 134.25, 134.34, 135.95, 147.95. , 164.60, 166.79; Analytical theory of C ₂₄ H ₂₉ N ₃ 0 ₇ S + 1.1HCl + 0.3H ₂ O: C, 52.50; H, 5. 64; N, 7.65; Cl, 7.10. Found: C, 52.16; H, 5.75; N, 7.37; Cl, 7.20.

Example 11

N- [2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl-1,3-dioxoisoindolin-4-yl} -2,2,2-trifluoro Loacetamide

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-aminoisoindolin-1,3-dione (1.0 g, 2.4 mmol) with trifluoroacetic anhydride (3 mL) was heated to reflux for 30 min. The solvent was removed in vacuo to give an oil. This oil was stirred for 3 days in ether (5 mL) and hexane (40 mL). The suspension was filtered and washed with ether to give a yellow solid. This solid was then recrystallized from ethanol (10 mL) to yield N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyl as a yellow solid (280 mg, yield 23%). Ethyl] -1,3-dioxoisoindolin-4-yl-2,2,2-trifluoroacetamide was obtained:

mp, 130-132 ° C .; ¹ H NMR (CDCl ₃ ) δ 1.48 (t, J = 6.9 Hz, 3H, CH ₃ ), 2.92 (s, 3H, CH ₃ ), 3.70 (dd, J = 4.2, 14.3 Hz, 1H, CHH), 3.87 (s, 3H, CH ₃ ), 4.13 (q, J = 6.9 Hz, 2H, CH ₂ ), 4.59 (dd, J = 10.9, 14.3 Hz, 1H, CHH), 5.90 (dd, J = 4.2, 10.9 Hz , 1H, NCH), 6.86 (d, J = 8.3 Hz, 1H, Ar), 7.11-7.15 (m, 2H, Ar), 7.66 (d, J = 7.2 Hz, 1H, Ar), 7.77 (t, J = 7.5 Hz, 1H, Ar), 8.70 (d, J = 8.4 Hz, 1H, Ar), 10.39 (s, 1H, NH); ¹³ C NMR (CDCl ₃ ) δ 14.59, 41.57, 48.68, 54.10, 55.89, 64.50, 111.48, 112.38, 115.16 (q, J _CF = 286 Hz), 117.19, 120.28, 120.31, 125.01, 128.85, 131.26, 134.63, 136.35, 148.63, 149.85, 155.36 (q, J ² _CF = 38 Hz), 166.78, 169.14; Analytical theory of C ₂₂ H ₂₁ N ₂ O ₇ F ₃ S: C, 51.36; H, 4.11; N, 5.44. Found: C, 51.20; H, 4.07; N, 5.20.

Example 12

N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} methoxycarboxyamide

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-aminoisoindolin-1,3-dione (0.70 g, 1.7 mmol) and methyl chloroformate ( 25 mL) was heated to reflux for 30 minutes. Ethanol (5 mL) was added to this mixture. The suspension was filtered and washed with ethanol to give N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1 as a white solid (0.48 g, 60% yield). , 3-dioxoisoindolin-4-yl} methoxycarboxyamide was obtained:

mp, 178-180 ° C .; ¹ H NMR (CDCl ₃ ); δ 1.48 (t, J = 7.1 Hz, 3H, CH ₃ ), 2.86 (s, 3H, CH ₃ ), 3.76 (dd, J = 4.4, 14.4 Hz, 1H, CHH), 3.84 (s, 3H, CH ₃ ), 3.86 (s, 3H, CH ₃ ), 4.12 (q, J = 6.9 Hz, 2H, CH ₂ ), 4.55 (dd, J = 10.3, 14.4 Hz, 1H, CHH), 5.87 (dd, J = 4.5 , 10.3 Hz, 1H, NCH), 6.83-6.87 (m, 1H, Ar), 7.09-7.13 (m, 2H, Ar), 7.45 (d, J = 7.0 Hz, 1H, Ar), 7.66 (t, J = 8.3 Hz, 1H, Ar), 8.50 (d, J = 8.5 Hz, 1H, Ar), 8.93 (brs, 1H, NH); ¹³ C NMR (CDCl ₃ ) δ 14.61, 41.52, 48.62, 52.70, 54.58, 55.88, 64.46, 111.40, 112.39, 114.78, 117.42, 120.29, 123.43, 129.27, 131.22, 135.97, 137.74, 148.59, 149.69, 153.42, 153.42 169.23; Analytical theory of C ₂₂ H ₂₄ N ₂ 0 ₈ S: C, 55.45; H, 5.08; N, 5.88. Found: C, 55.32; H, 5.00; N, 5.73.

Example 13

4- [1-Aza-2- (dimethylamino) vinyl] -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] isoindoline-1,3-dione

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-aminoisoindolin-1,3-dione (1.5 g, 3.6 mmol) with dimethylformamide dimethyl acetal (4 mL) was heated to reflux for 30 min. The solvent was removed in vacuo to give an oil. This oil was stirred in ether (20 mL). The suspension is filtered and washed with ether, 4- [1-aza-2- (dimethylamino) vinyl] 2- [1- (3-ethoxy-4-methoxy as yellow solid (1.1 g, yield 65%) Phenyl) -2-methylsulfonylethyl] isoindoline-1,3-dione was obtained:

mp, 161-163 ° C .; ¹ H NMR (CDCl ₃ ) δ 1.46 (t, J = 6.9 Hz, 3H, CH ₃ ), 2.79 (s, 3H, CH ₃ ), 3.11-3.12 (2s, 6H, 2CH ₃ ), 3.82 (dd, J = 5.2, 14.5 Hz, 1H, CHH), 3.85 (s, 3H, CH ₃ ), 4.10 (q, J = 6.9 Hz, 2H, CH ₂ ), 4.49 (dd, J = 9.5, 14.6 Hz, 1H, CHH ), 5.86 (dd, J = 5.2, 9.4 Hz, 1H, NCH), 6.80-6.83 (m, 1H, Ar), 7.11-7.19 (m, 3H, Ar), 7.39-7.52 (m, 2H, Ar) , 7.72 (s, 1 H, CH); ¹³ C NMR (CDCl ₃ ) δ 14.68, 34.49, 40.41, 41.49, 48.78, 55.45, 55.93, 64.47, 111.41, 111.65, 116.99, 118.98, 120.54, 129.99, 130.58, 133.16, 134.49, 148.48, 149.50, 152.06, 156.156 168.06, 168.19; Analytical theory of C ₂₃ H ₂₇ N ₃ 0 ₆ S: C, 58.34; H, 5.75; N, 8.87. Found: C, 58.17; H, 5.71; N, 8.69.

Example 14

4- [1-Aza-2- (dimethylamino) prop-1-enyl] -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] isoindoline- 1,3-dione

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-aminoisoindolin-1,3-dione (1.5 g, 3.6 mmol) with dimethylacetamide dimethyl acetal (4 mL) was heated to reflux for 30 min. The solvent was removed in vacuo to give an oil. This oil was stirred overnight in ether / hexane / ethyl acetate (10/10/1 mL). The suspension was filtered to give an orange solid. The solid was separated by chromatography (silica gel, methanol in methylene chloride 1%) to yield 4- [1-aza-2- (dimethylamino) prop-1-enyl]-as a yellow solid (140 mg, yield 8%). 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] isoindoline-1,3-dione was obtained:

mp, 111-113 ° C .; ¹ H NMR (CDCl ₃ ) δ 1.46 (t, J = 6.9 Hz, 3H, CH ₃ ), 1.87 (s, 3H, CH ₃ ), 2.79 (s, 3H, CH ₃ ), 3.12 (s, 3H, CH ₃ ), 3.79 (dd, J = 4.9, 14.6 Hz, 1H, CHH), 3.87 (s, 3H, CH ₃ ), 4.10 (q, J = 6.9 Hz, 2H, CH ₂ ), 4.50 (dd, J = 9.8, 14.6 Hz, 1H, CHH), 5.84 (dd, J = 4.9, 9.7 Hz, 1H, NCH), 6.80-6.83 (m, 2H, Ar), 7.20 (d, J = 8.3 Hz, 1H, Ar) , 7.10-7.12 (m, 2H, Ar), 7.36 (d, J = 7.1 Hz, 1H, Ar), 7.49 (t, J = 7.6 Hz, 1H, Ar); ¹³ C NMR (CDCl ₃ ) δ 14.61, 15.59, 38.06, 41.36, 48.51, 55.25, 55.86, 64.41, 111.36, 112.56, 116.20, 118.78, 120.36, 129.98, 131.24, 132.67, 134.36, 148.41, 149.42, 150.80, 150.80 167.78, 168.27; Analytical theory of C ₂₄ H ₂₉ N ₃ 0 ₆ S: C, 59.12; H, 6.00; N, 8.62. Found: C, 58.84; H, 6.01; N, 8.36.

Example 15

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl-4- (5-methyl-1,3,4-oxadiazol-2-yl) isoindolin- 1,3-dione

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-carboxylic acid (1.5 g) in tetrahydrofuran (10 mL) , 3.4 mmol) and carbonyldiimidazole (600 mg, 3.7 mmol) were stirred at room temperature for 2 hours. Acetic hydrazide (411 mg, 5.54 mmol) was added to the mixture and left for 16 hours. The mixture was extracted with ethyl acetate (125 mL) and water (40 mL). The organic layer was washed with sodium hydrogen carbonate (50 mL, saturated) and dried over magnesium sulfate. The solvent was removed in vacuo to yield a yellow solid (0.8 g). This solid in acetonitrile (20 mL) and phosphoryl trichloride (2 mL) were heated to reflux for 15 hours. Water was added to the mixture, followed by addition of sodium hydrogencarbonate (60 mL, saturated) until the pH was about 8. The aqueous layer was extracted with ethyl acetate (150 mL). The organic layer was washed with sodium hydrogen carbonate (50 mL, saturated), brine (50 mL) and dried over magnesium sulfate. The solvent was removed in vacuo to yield a yellow solid. The solid was separated by chromatography (silica gel, 50:50 ethyl acetate / methylene chloride) to give 2- [1- (3-ethoxy-4-methoxyphenyl) -2 as a yellow solid (450 mg, yield 28%). -Methylsulfonylethyl] -4- (5-methyl-1,3,4-oxadiazol-2-yl) isoindoline-1,3-dione was obtained:

mp, 99-101 ° C .; ¹ H NMR (CDCl ₃ ) δ 1.48 (t, J = 6.9 Hz, 3H, CH ₃ ), 2.71 (s, 3H, CH ₃ ), 2.88 (s, 3H, CH ₃ ), 3.78 (dd, J = 4.6 , 14.5 Hz, 1H, CHH), 3.86 (s, 3H, CH ₃ ), 4.11 (q, J = 6.9 Hz, 2H, CH ₂ ), 4.57 (dd, J = 10.3, 14.3 Hz, 1H, CHH), 5.94 (dd, J = 4.6, 10.2 Hz, 1H, NCH), 6.83-6.86 (m, 1H, Ar), 7.12-7.16 (m, 2H, Ar), 7.86 (t, J = 7.8 Hz, 1H, Ar ), 8.04 (dd, J = 0.8, 7.2 Hz, 1H, Ar), 8.28 (dd, J = 1.0, 7.9 Hz, 1H, Ar); ¹³ C NMR (CDCl ₃ ) δ 11.14, 14.60, 41.49, 48.95, 54.51, 55.8, 64.48, 111.43, 112.49, 120.49, 121.49, 125.95, 128.43, 129.09, 133.11, 134.36, 135.26, 148.58, 149.74, 161.94, 164.99, 164.99 165.07, 166.69; Analytical theory of C ₂₃ H ₂₃ N ₃ 0 ₇ S + 0.6 ethyl acetate: C, 56.67; H, 5.20; N, 7.80. Found: C, 56.29; H, 4. 82; N, 7.97.

Example 16

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-pyrrolylisoindolin-1,3-dione

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-aminoisoindolin-1,3-dione (1.0 g, 2.4 mmol) in acetic acid (1 mL) A mixture of 2,5-dimethoxytetrahydrofuran (0.33 mL, 2.5 mmol) was heated to reflux for 2 hours. The solvent was removed in vacuo to yield a yellow solid. This solid was stirred in ethanol (25 mL) for 1 hour. The suspension was filtered and washed with ethanol to afford 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-pyrrolyl as a brown solid (1.12 g, 100% yield). Soindolin-1,3-dione was obtained:

mp, 95-97 ° C .; ¹ H NMR (CDCl ₃ ) δ 1.47 (t, J = 6.9 Hz, 3H, CH ₃ ), 2.87 (s, 3H, CH ₃ ), 3.73 (dd, J = 4.5, 14.4 Hz, 1H, CHH), 3.86 (s, 3H, CH ₃ ), 4.11 (q, J = 6.9 Hz, 2H, CH ₂ ), 4.60 (dd, J = 10.6, 14.4 Hz, 1H, CHH), 5.91 (dd, J = 4.4, 10.4 Hz , 1H, NCH), 6.39-6.41 (m, 2H, Ar), 6.84 (d, J = 8.0 Hz, 1H, Ar), 7.12-7.17 (m, 4H, Ar), 7.60-7.65 (m, 1H, Ar), 7.74-7.78 (m, 2H, Ar); ¹³ C NMR (CDCl ₃ ) δ 14.60, 41.44, 48.77, 54.32, 55.88, 64.48, 110.74, 111.41, 112.57, 120.52, 120.99, 122.00, 129.25, 130.09, 133.74, 135.36, 138.62, 148.52, 149.67, 165.77, 166.82 Analytical theory of C ₂₄ H ₂₄ N ₂ 0 ₆ S: C, 61.53; H, 5. 16; N, 5.98. Found: C, 61.34; H, 5. 17; N, 5.83.

Example 17

4- (aminomethyl) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -isoindolin-1,3-dione hydrochloride

4-cyano-2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] isoindoline-1,3-dione in 4N hydrochloric acid (1 mL) and methanol (40 mL) (0.5 g, 1.17 mmol) and 10% Pd / C (0.15 g) were hydrogenated overnight in a Parr shaker apparatus under 50 psi of hydrogen. Water (2 mL) was added to the resulting slurry to dissolve the product. The reaction mixture was then filtered through celite and the filtrate was concentrated in vacuo. The residue was slurried in ethyl acetate (10 mL) to afford 0.52 g of crude product. The product was slurried again in hot ethanol (15 mL) and 4- (aminomethyl) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] isoindolin-1 , 3-dione hydrochloride (0.44 g, yield 80%) was obtained:

mp, 237-239 ° C .; ¹ H NMR (DMSO-d6) δ 8.79 (s, 3H, Ar), 8.04-7.89 (m, 3H, Ar), 7.11-6.91 (m, 3H, Ar), 5.83-5.77 (dd, J = 4.2, 10.1 Hz, 1H, NCH), 4.49-4.47 (m, 2H, CH ₂ ), 4.41-4.31 (m, 1H, CHH), 4.21-4.13 (m, 1H, CHH), 4.04 (q, J = 6.8 Hz , 2H, CH ₂ ), 3.73 (s, 3H, CH ₃ ), 3.64 (s, 3H, CH ₃ ), 1.32 (t, J = 6.8 Hz, 3H, CH ₃ ); ¹³ C NMR (DMSO-d6) δ 167.48, 166.93, 148.95, 147.87, 135.39, 134.71, 132.82, 131.32, 129.50, 128.30, 123.34, 119.89, 112.55, 111.79, 63.87, 55.52, 53.07,47.46, 41.08, 36.08. ; Analytical theory of C ₂₁ H ₂₅ N ₂ O ₆ SCl: C, 53.79; H, 5. 37; N, 5.97; S, 6.84; Cl, 7.56. Found: C, 53.49, H, 5.47; N, 5.75; S, 6.61; Cl, 7.51.

Example 18

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4- (pyrrolylmethyl) isoindoline-1,3-dione

4- (aminomethyl) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] isoindoline-1,3-dione (0.34 g, in acetic acid (5 mL) 0.79 mmol) and a mixture of 2,5-dimethoxytetrahydrofuran (0.10 g, 0.79 mmol) were heated to reflux for 1 hour. The reaction mixture was then concentrated in vacuo and the residue was stirred in ethyl acetate (50 mL) and saturated sodium bicarbonate (25 mL). The organic layer was washed with water (25 mL) and brine (25 mL), and concentrated to dryness. The residue was purified by flash chromatography (methylene chloride: ethyl acetate, 95: 5) to give 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4- ( Pyrrolylmethyl) isoindolin-1,3-dione (0.23 g, yield 60%) was obtained:

mp, 80-82 ° C .; ¹ H NMR (CDCl ₃ ) δ 7.71 (d, J = 7.3 Hz, 1H, Ar), 7.57 (t, J = 7.7 Hz, 1H, Ar), 7.26 (m, 2H, Ar), 7.15 (d, J = 7.0 Hz, 2H, Ar), 6.96 (d, J = 7.8 Hz, 1H, Ar), 6.71 (d, J = 1.7 Hz, 1H, Ar), 6.22 (d, J = 1.8 Hz, 1H, Ar) , 5.94-5.88 (dd, J = 4.4 and 10.3 Hz, 1H, NCH), 5.57 (s, 2H, CH ₂ ), 4.63-4.53 (dd, J = 10.7, 14.4 Hz, 1H, CHH), 4.13 (q , J = 7.0 Hz, 2H, CH ₂ ), 3.85 (s, 3H, CH ₃ ), 3.80-3.72 (dd, J = 4.4, 14.4 Hz, 1H, CHH), 2.86 (s, 3H, CH ₃ ), 1.47 (t, J = 6.9 Hz, 3H, CH ₃ ); ¹³ C NMR (CDCl ₃ ) δ 168.08, 167.69, 149.72, 148.63, 138.71, 134.74, 132.65, 131.86, 129.44, 126.92, 122.69, 121.46, 120.47, 112.49, 111.44, 109.15, 64.51, 55.95, 54.65, 54.65 41.58, 14.69; Analytical theory of C ₂₅ H ₂₆ N ₂ 0 ₆ S: C, 62.23; H, 5. 43; N, 5.81; S, 6.64. Found: C, 62.25; H, 5.56; N, 5.63; S, 6.83.

Example 19

3- (tert-Butyloxycarbonylamino) -3- (3-ethoxy-4-methoxyphenyl) propionic acid

A mixture of 3-amino-3- (ethoxy-4-methoxyphenyl) propionic acid (20 g, 83.5 mmol), 2N sodium hydroxide (50 mL), t-butanol (42 mL) and water (80 mL) was stirred at 10 ° C. . Di- (ter t-butyl) dicarbonate (20 g, 91.6 mmol) was added over 25 minutes. The resulting mixture was slurried at room temperature for 2 hours (2N sodium hydroxide was added to maintain pH 10). The mixture was washed with ether and the aqueous solution was acidified to pH 2 with 6N hydrochloric acid. The slurry was filtered and washed with water to give 3- (tert-butyloxycarbonylamino) -3- (3-ethoxy-4-methoxyphenyl) propionic acid as white solid (28.3 g, 100%):

¹ H NMR (CDCl ₃ / DMSO-d 6) δ 6.86-6.78 (m, 3H), 5.83 (d, J = 8.3 Hz, 1H), 4.98 (b, 1H), 4.09 (q, J = 7.0 Hz, 2H ), 3.83 (s, 3H), 2.77 (m, 2H), 1.46-1.41 (m, 12H); ¹³ C NMR (CDCl ₃ / DMSO-d 6) δ 173.22, 155.02, 148.15, 147.89, 134.31, 117.97, 111.22, 111.07, 79.12, 64.01, 55.09, 50.76, 40.78, 28.11, 14.55.

Example 20

3- (tert-butyloxycarbonylamino) -3- (3-ethoxy-4-methoxyphenyl) -N-methoxy-N-methylpropanamide

Carbonyldiimidazole (0.96 g, 5.9 mmol), 3- (tert-butoxycarbonylamino) -3- (3-ethoxy-4-methoxyphenyl) propionic acid (2.0 g, 5.9 mmol) and methylene chloride (25 mL) was stirred at rt for 1 h and then cooled to 5 ° C. A solution of N, O-dimethylhydroxyamine hydrochloride (0.86 g, 8.85 mmol) and 1-methylpiperidine (0.87 g, 8.85 mmol) in methylene chloride (10 mL) was slowly added. The mixture was stirred at rt for 1 h and then quenched with water (20 mL). The organic layer was separated and washed with 1N citric acid, water and brine. The organic layer was dried and concentrated in vacuo to give an oil. The oil was purified by chromatography (silica gel, methylene chloride: ethyl acetate 8: 2) to give 3- (tert-butyloxycarbonylamino) -3- (3-ethoxy as a white solid (1.76 g, 78%). 4-methoxyphenyl) -N-methoxy-N-methylpropanamide was obtained:

¹ H NMR (CDCl ₃ ) δ 6.86-6.78 (m, 3H), 6.07 (b, 1H), 5.01 (m, 1H), 4.10 (q, J = 6.9 Hz, 2H), 3.84 (s, 3H), 3.50 (s, 3H), 3.10 (s, 3H), 3.02 (m, 2H), 2.84-2.75 (dd, J = 5.3 and 15.2 Hz, 1H), 1.45 (t, J = 7.1 Hz, 3H), 1.41 (s, 9H); ¹³ C NMR (CDCl ₃ ) δ 171.81, 155.18, 148.39, 148.19, 134.82, 118.12, 111.41, 111.18, 79.27, 64.26, 61.19, 55.90, 51.25, 37.80, 31.87, 28.33, 14.73.

Example 21

(tert-butoxy) -N- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] carboxyamide

Methyl magnesium bromide (3M, 19.6 mL, 58.8 mmol) was added to 3- (tert-butyloxycarbonylamino) -3- (3-ethoxy-4-methoxyphenyl in tetrahydrofuran (80 mL) at 5-12 ° C. It was added slowly to a stirred solution of) -N-methoxy-N-methylpropanamide (9.0 g, 23.5 mmol). After the addition was complete, the mixture was stirred for 1.5 hours at room temperature. The mixture was then cooled to 5 ° C., quenched with saturated ammonium chloride (40 mL) and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with 1N citric acid, saturated sodium bicarbonate, H ₂ O, brine and concentrated to give an oil. The oil was purified by chromatography (silica gel, methylene chloride: ethyl acetate 9: 1) to obtain (tert-butoxy) -N- [1- (3-ethoxy-4 as white solid (6.4 g, 81%). -Methoxyphenyl) -3-oxobutyl] carboxyamide was obtained:

mp, 118-120 ° C .; ¹ H NMR (CDCl ₃ ) δ 6.83-6.80 (m, 3H), 5.30 (b, 1H), 5.01-4.99 (m, 1H), 4.10 (q, J = 6.9 Hz, 2H), 3.84 (s, 3H ), 2.99-2.85 (m, 2H), 2.09 (s, 3H), 1.48-1.41 (m, 12H); ¹³ C NMR (CDCl ₃ ) 206.98, 155.07, 148.61, 148.32, 118.15, 117.47, 111.36, 79.65, 64.34, 55.93, 50.99, 49.42, 30.58, 28.31, 14.25; Analytical theory of C ₁₈ H ₂₇ NO ₅ : C, 64.07; H, 8.07; N, 4.15. Found: C, 63.90; H, 8.13; N, 3.97.

Example 22

(tert-butoxy) -N- [1- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] carboxyamide

(Tert-butoxy) -N- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] carboxyamide (2.0 g, 5.92 mmol) in methanol (40 mL) and tetrahydrofuran (10 mL) ) And sodium borohydride (0.4 g, 12.0 mmol) were stirred at -10 to -20 <0> C for 4 hours. The mixture was quenched with water (10 mL) and then concentrated in vacuo to afford an oil. This oil was dissolved in ethyl acetate, washed with water, brine, dried and concentrated in vacuo to afford an oil. The oil was purified by chromatography (silica gel, methylene chloride: ethyl acetate 8: 2) to give (tert-butoxy) -N- [1- (3-ethoxy-4-methoxyphenyl) -3-hydroxy The diastereomers of butyl) carboxyamide were obtained:

A; 0.98 g (49%); ¹ H NMR (CDCl ₃ ) δ 6.83-6.81 (m, 3H), 4.99-4.96 (m, 1H), 4.85-4.83 (m, 1H), 4.11 (q, J = 6.9 Hz, 2H), 3.85 (s , 3H), 3.78 (m, 1H), 1.80-1.75 (m, 2H), 1.49-1.45 (m, 12H), 1.24 (d, J = 6.1 Hz, 3H).

B; 0.84 g (42%); ¹ H NMR (CDCl ₃ ) δ 6.82 (m, 3H), 5.06-5.03 (m, 1H), 4.68 (m, 1H), 4.11 (q, J = 7.0 Hz, 2H), 3.85 (s, 3H), 3.82-3.70 (m, 1H), 1.941.82 (m, 2H), 1.48-1.40 (m, 12H), 1.21 (d, J = 6.2 Hz, 3H).

Example 23

4-amino-4- (3-ethoxy-4-methoxyphenyl) butan-2-ol hydrochloride

(Tert-butoxy) -N- [1- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] carboxyamide (0.98 g, 2.89 mmol) and 4N hydrochloric acid in methylene chloride (10 mL) The mixture of dioxane (3 mL) was stirred at rt for 16 h. The resulting slurry was filtered and washed with ethyl acetate to give 4-amino-4- (3-ethoxy-4-methoxyphenyl) butan-2-ol hydrochloride as a white solid (0.68 g, 85%):

¹ H NMR (D ₂ 0) δ 7.12 (m, 3H), 4.47 (t, J = 7.0 Hz, 1H), 4.20 (q, J = 7.4 Hz, 2H), 3.90 (s, 3H), 3.83-3.76 (m, 1H), 2.21-2.15 (m, 2H), 1.43 (t, J = 6.9 Hz, 3H), 1.24 (d, J = 6.1 Hz, 3H); ¹³ C NMR (D ₂ O) δ 151.75, 150.48, 131.92, 123.09, 115.05, 114.54, 67.86, 66.98, 58.53, 55.35, 44.41, 24.49, 16.68.

Example 24

N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide

4-amino-4- (3-ethoxy-4-methoxyphenyl) butan-2-ol hydrochloride (0.5 g, 1.81 mmol), 3-acetamidophthal anhydride (0.37 g, in dimethylformamide (10 mL) 1.81 mmol) and triethylamine (0.18 g, 1.81 mmol) were heated to 80-90 ° C. for 7 hours. The mixture was concentrated in vacuo to give an oil. The oil was dissolved in ethyl acetate, washed with water, brine, filtered and concentrated to an oil. The oil was purified by chromatography (silica gel, methylene chloride / ethyl acetate 8: 2) to obtain N- {2- [1- (3-ethoxy-4-methoxy as white solid (0.5 g, 65%). Phenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide was obtained:

mp, 132-134 ° C .; ¹ H NMR (CDCl ₃ ) δ 9.54 (s, 1H), 8.73 (d, J = 8.4 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H) , 7.12-7.08 (m, 2H), 6.83 (d, J = 8.0 Hz, 1H), 5.46 (t, J = 7.8 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 3.80 (m, 1H), 2.59-2.42 (m, 2H), 2.25 (s, 3H), 1.65 (s, 1H), 1.45 (t, J = 7.0 Hz, 3H), 1.27 (d, J) = 6.3 Hz, 3H); ¹³ C NMR (CDCl ₃ ) δ 170.36, 169.20, 167.96, 149.04, 148.26, 137.29, 135.70, 131.50, 131.35, 124.60, 120.61, 117.85, 113.10, 111.25, 66.00, 64.39, 55.89, 52.43, 40.19, 24. 14.73; Analytical theory of C ₂₃ H ₂₆ N ₂ 0 ₆ : C, 64.78; H, 6. 15; N, 6.57. Found: C, 64.86; H, 6. 10; N, 6.46.

Example 25

N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide

N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide in methylene chloride (35 mL) 1.2 g, 2.81 mmol), pyridium chlorochromate (1.21 g, 5.63 mmol) and celite (0.6 g) were stirred at room temperature for 4 hours. The mixture was filtered through celite and the celite was washed with methylene chloride. The filtrate was washed with water, brine and concentrated to dryness. The residue was purified by chromatography (silica gel, methylene chloride: ethyl acetate 9: 1) to give N- {2- [1- (3-ethoxy-4-methoxyphenyl as white solid (0.9 g, 76%). ) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide was obtained:

mp, 128-129 ° C .; ¹ H NMR (CDCl ₃ ) δ 9.52 (s, 1H), 8.71 (d, J = 8.4Hz, 1H), 7.62 (t, J = 7.5Hz, 1H), 7.46 (d, J = 7.2Hz, 1H) , 7.06-7.03 (m, 2H), 6.82 (d, J = 8.9 Hz, 1H), 5.73-5.07 (dd, J = 5.2 and 10.0 Hz, 1H), 4.11 (q, J = 7.0 Hz, 2H), 4.04-3.93 (dd, J = 10.0 and 18.0 Hz, 1H), 3.83 (s, 3H), 3.28-3.19 (dd, J = 5.2 and 18.0 Hz, 1H), 2.26 (s, 3H), 2.18 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H); ¹³ C NMR (CDCl ₃ ) δ 205.18, 170.62, 169.17, 167.10, 149.21, 148.40, 137.38, 135.81, 131.34, 131.24, 124.69, 120.02, 117.91, 115.30, 112.57, 111.37, 64.44, 55.93, 49.96, 49.96, 49.96 24.93, 14.73; Analytical theory of C ₂₃ H ₂₄ N ₂ 0 ₆ : C, 65.08; H, 5. 70; N, 6.60. Found: C, 65.11; H, 5. 64; N, 6.50.

Example 26

N- {2- [1R- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide

R-4-amino-4- (3-ethoxy-4-methoxyphenyl) butan-2-ol (1.5 g, 5.44 mmol), 3-acetamidophthal anhydride (1.11 g, 5.44 mmol) and triethyl The mixture of amines (0.55 g, 5.44 mmol) was heated to 80-90 ° C. for 7 hours. The mixture was concentrated in vacuo to give an oil. This oil was dissolved in ethyl acetate, washed with water, brine and concentrated to dryness. The residue was purified by chromatography (silica gel, methylene chloride: ethyl acetate 8: 2) to give N- {2- [1R- (3-ethoxy-4-methoxyphenyl as white solid (1.87 g, 80%). ) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide was obtained:

¹ H NMR (CDCl ₃ ) δ 9.61 (s, 1H), 8.75 (d, J = 8.4Hz, 1H), 7.63 (t, J = 7.6Hz, 1H), 7.47 (d, J = 7.2Hz, 1H) , 7.06 (m, 2H), 6.83-6.80 (m, 1H), 5.58-5.51 (dd, J = 4.2 and 11.7 Hz, 1H), 4.11 (q, J = 7.0 Hz, 2H), 3.84 (s, 3H ), 3.80-3.73 (m, 1H), 2.92-2.80 (m, 1H), 2.25 (s, 3H), 2.12-2.01 (m, 1H), 1.45 (t, J = 7.0 Hz, 3H), 1.29 ( d, J = 6.1 Hz, 3H); ¹³ C NMR (CDCl ₃ ) δ 170.39, 169.21, 167.96, 149.01, 148.17, 137.36, 135.86, 131.61, 131.19, 124.75, 120.35, 117.95, 115.30, 112.90, 111.13, 64.88, 64.39, 55.88, 51.32, 39.93, 39.93 23.77, 14.74.

Example 27

N- {2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide

N- {2- [1R- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide in methylene chloride (40 mL) ( 1.8 g, 4.2 mmol), pyridinium chlorochromate (1.44 g, 6.62 mmol) and celite (0.7 g) were stirred at room temperature for 4 hours. The mixture was filtered through celite and the filtrate was washed with water, brine and concentrated to dryness. The crude product was purified by chromatography (silica gel, methylene chloride: ethyl acetate 9: 1) to obtain N- {2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] as a white solid. -1,3-dioxoisoindolin-4-yl} acetamide was obtained:

mp, 81-83 ° C .; ¹ H NMR (CDCl ₃ ) δ 9.52 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 7.62 (t, 7.6 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.06 -7.03 (m, 2H), 6.83 (d, J = 8.8 Hz, 1H), 5.73-5.67 (dd, J = 5.2 and 9.9 Hz, 1H), 4.12 (q, J = 7.0 Hz, 2H), 2.26 ( s, 3H), 2.18 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H); ¹³ C NMR (CDCl ₃ ) δ 205.17, 170.02, 169.14, 167.84, 149.14, 148.35, 137.34, 135.79, 131.29, 131.20, 124.65, 119.97, 117.88, 115.25, 112.48, 111.29, 64.39, 55.89, 49.89, 49.92 24.92, 14.70; Analyzes for C ₂₃ H ₂₄ N ₂ 0 ₆ : C, 65.08; H, 5. 70; N, 6.60. Found: C, 65.10; H, 5.68; N, 6.45.

Example 28

N- {2- [1S- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide

S-4-amino-4- (3-ethoxy-4-methoxyphenyl) butan-2-ol (1.5 g, 5.44 mmol) and 3-acetamidophthal anhydride (1.11 g) in dimethylformamide (20 mL) , 5.44 mmol) and triethylamine (0.55 g, 5.44 mmol) were heated to 80-90 ° C. for 7 hours. The mixture was concentrated in vacuo to give an oil. This oil was dissolved in ethyl acetate, washed with water, brine and concentrated to dryness. The crude product was purified by chromatography (silica gel, methylene chloride: ethyl acetate 8: 2) to give N- {2- [1S- (3-ethoxy-4-methoxyphenyl as white solid (1.81 g, 78%). ) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide was obtained:

¹ H NMR (CDCl ₃ ) δ 9.54-9.52 (d, 1H), 8.76-8.70 (m, 1H), 7.66-7.58 (m, 1H), 7.49-7.43 (m, 1H), 7.12-7.05 (m, 2H), 6.85-6.80 (m, 1H), 5.58-5.43 (m, 1H), 4.16-4.04 (q, 2H), 3.84 (s, 3H), 3.80-3.74 (m, 1H), 2.95-2.82 ( m, 1H), 2.57-2.44 (m, 1H), 2.26 (s, 3H), 1.47 (t, 3H), 1.25 (d, 3H).

Example 29

N- {2- [1S- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide

N- {2- [1S- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide in methylene chloride (50 mL) ( 1.79 g, 4.2 mmol), pyridinium chlorochromate (1.43 g, 6.63 mmol) and celite (0.7 g) were stirred at room temperature for 4 hours. The mixture was filtered through celite and the filtrate was washed with water, brine and concentrated to dryness. The crude product was purified by chromatography (silica gel, methylene chloride / ethyl acetate 9: 1) to give N- {2- [1S- (3-ethoxy-4methoxyphenyl) as a white solid (1.43 g, 79%). 3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide was obtained:

mp, 80-82 ° C .; ¹ H NMR (CDCl ₃ ) δ 9.52 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H) , 7.06-7.03 (m, 2H), 6.83 (d, J = 8.8 Hz, 1H), 5.73-5.67 (dd, J = 5.2 and 9.9 Hz, 1H), 4.11 (q, J = 7.0 Hz, 2H), 4.04-3.93 (dd, J = 10.0 and 18.1 Hz, 1H), 3.83 (s, 3H), 3.283.19 (dd, J = 5.3 and 18.1 Hz, 1H), 2.26 (s, 3H), 2.18 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H); ¹³ C NMR (CDCl ₃ ) δ 205.19, 170.04, 169.16, 167.86, 149.16, 148.36, 137.36, 135.80, 131.31, 131.22, 124.67, 119.99, 117.90, 115.27, 112.49, 111.30, 64.41, 55.90, 49.93, 44.93, 44.93 24.94, 14.72; Analyzes for C ₂₃ H ₂₄ N ₂ 0 ₆ : C, 65.08; H, 5. 70; N, 6.60. Found: C, 65.05; H, 5.77; N, 6.61.

Example 30

4-amino-2- [1- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl) isoindoline-1,3-dione

4-amino-4- (3-ethoxy-4-methoxyphenyl) butan-2-ol hydrochloride (1.0 g, 3.63 mmol) and 3-amino-N-ethoxycarbonylphthal in dimethylformamide (15 mL) A mixture of imide (0.85 g, 3.63 mmol) and triethylamine (2.37 g, 3.63 mmol) was heated to 80-90 ° C. for 16 hours. The mixture was concentrated in vacuo and the residue was stirred in methylene chloride (10 mL). The mixture was filtered, the filtrate was concentrated and purified by chromatography (silica gel, methylene chloride: ethyl acetate 8: 2) to give 4-amino-2- [1- (ethoxy) as a white solid (0.72 g, 52%). 4-methoxyphenyl) -3-hydroxybutyl] isoindolin-1,3-dione was obtained:

¹ H NMR (CDCl ₃ ) δ 7.41-7.35 (m, 1 H), 7.117.05 (m, 3H), 6.83-6.80 (m, 2H), 5.54-5.48 (dd, J = 4.1 and 11.8 Hz, 1H ), 5.22 (s, 2H), 4.10 (q, 2H), 3.85 (s, 3H), 3.77 (m, 1H), 2.88-2.77 (m, 1H), 2.07-1.00 (m, 1H), 1.67 ( s, 1H), 1.45 (t, 3H), 1.27 (d, 3H).

Example 31

4-amino-2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] isoindoline-1,3-dione

4-amino-2- [1- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] isoindoline-1,3-dione (0.7 g, 1.82 mmol) in methylene chloride (40 mL) , A mixture of pyridinium chlorochromate (0.79 g, 3.64 mmol) and celite (0.6 g) was stirred at room temperature for 4 hours. The mixture was filtered through celite and the filtrate was washed with water, brine and concentrated to dryness. The residue was purified by chromatography (silica gel, methylene chloride: ethyl acetate 95: 5) to give 4-amino-2- [1- (3-ethoxy-4-methoxy as white solid (0.49 g, 71%). Phenyl) -3-oxobutyl] isoindolin-1,3-dione was obtained:

¹ H NMR (CDCl ₃ ) δ 7.38-7.31 (t, J = 7.3 Hz, 1H), 7.08-7.05 (m, 3H), 6.81-6.77 (m, 2H), 5.74-5.67 (dd, J = 5.9 and 9.4 Hz, 1H), 5.20 (s, 2H), 4.11 (q, J = 7.0 Hz, 2H), 3.98-3.87 (dd, J = 9.5 and 17.8 Hz, 1H), 3.83 (s, 3H), 3.33- 3.23 (dd, J = 5.6 and 17.7 Hz, 1 H), 2.18- (s, 3H), 1.44 (t, J-6.9 Hz, 3H).

Example 32

2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -4-pyrrolylisoindolin-1,3-dione

4-amino-2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] isoindoline-1,3-dione (0.35 g, 0.92 mmol) in cold acetic acid (5 mL) A mixture of 2,5-dimethoxytetrahydrofuran (0.12 g, 0.92 mmol) was refluxed for 1 hour. The mixture was dissolved in ethyl acetate (50 mL), washed with saturated sodium bicarbonate, water, brine and concentrated to dryness. The residue was purified by chromatography (silica gel, methylene chloride: ethyl acetate 95: 5) to give 2- [1- (3-ethoxy-4-methoxyphenyl) -3- as a yellow solid (0.27 g, 69%). Oxobutyl] -4-pyrrolylisoindolin-1,3-dione was obtained:

mp, 93-95 ° C .; ¹ H NMR (CDCl ₃ ) δ 7.77-7.55 (m, 3H), 7.14-7.08 (m, 4H), 6.80 (d, J = 8.8 Hz, 1H), 6.39-6.37 (m, 2H), 5.77-5.71 (dd, J = 5.5 and 9.8 Hz, 1H), 4.10 (q, J = 7.0 Hz, 1H), 4.05-3.93 (dd, J = 9.8 and 18.0 Hz, 1H), 3.82 (s, 3H), 3.31- 3.22 (dd, J = 5.4 and 18.0 Hz, 1H), 2.16 (s, 3H), 1.44 (t, J = 7.0 Hz, 3H); ¹³ C NMR (CDCl ₃ ) 205.27, 167.27, 166.13, 149.09, 148.25, 138.39, 135.11, 133.99, 131.39, 129.92, 122.06, 121.28, 120.74, 120.29, 112.69, 111.28, 110.66, 64.38, 55.89, 50.16, 50.16. , 14.69; Analytical theory of C ₂₅ H ₂₄ N ₂ 0 ₅ : C, 69.43; H, 5.59; N, 6.48. Found: C, 69.49; H, 5.65; N, 6.33.

Example 33

2-chloro-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindol-4-yl} acetamide

4-amino-2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] isoindoline-1,3-dione (0.9 g, 2.34 mmol) in tetrahydrofuran (20 mL) And a mixture of chloroacetyl chloride (0.29 g, 2.57 mmol) were heated to reflux for 10 minutes. The mixture was concentrated in vacuo to give 2-chloro-N-2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} Acetamide (1.07 g, 100%) was obtained:

¹ H NMR (CDCl ₃ ) δ 10.56 (s, 1H), 8.71 (d, J = 8.4Hz, 1H), 7.66 (t, J = 7.6Hz, 1H), 7.53 (d, J = 7.3Hz, 1H) , 7.09-7.05 (m, 2H), 6.82 (d, J = 8.0 Hz, 1H), 5.75-5.69 (dd, J = 5.3 and 9.8 Hz, 1H), 4.22 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 4.04-3.93 (m, 1H), 3.83 (s, 3H), 3.31-3.21 (dd, J = 5.2 and 18.0 Hz, 1H), 2.18 (s, 3H), 1.45 (t, J = 7.0 Hz, 3H).

Example 34

2- (dimethylamino) -N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide hydrochloride

2-chloro-N-2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} in tetrahydrofuran (15 mL)} A mixture of acetamide (1.07 g, 2.34 mmol) and N, N-dimethylamine (2.0 M in methanol, 3.5 mL, 7.0 mmol) was stirred for 16 h at rt. The solvent was removed in vacuo to give an oil. This oil was purified by chromatography (silica gel, methylene chloride: ethyl acetate 7: 3) to give a white solid. To a solution of this solid in ethyl acetate (10 mL) was added hydrochloric acid (1N, 4 mL) in ether. The slurry was filtered and washed with ether to give 2- (dimethylamino) -N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxo as white solid (0.52 g, 44%). Butyl] -1,3-dioxoisoindolin-4-yl} acetamide hydrochloride was obtained:

mp, 100-102 ° C .; ¹ H NMR (DMSO-d6) δ 10.63 (s, 1H), 10.27 (s, 1H), 8.21 (d, J = 8.2 Hz, 1H), 7.84 (t, J = 7.7 Hz, 1H), 7.67 (d , J = 7.3 Hz, 1H), 6.98 (s, 1H), 6.89 (s, 2H), 5.63-5.57 (dd, J = 6.0 and 8.8 Hz, 1H), 4.19 (b, 2H), 3.99 (q, J = 6.9 Hz, 2H), 3.77-3.67 (m, 1H), 3.74 (s, 3H), 3.52-3.42 (dd, J = 6.1 and 18.1 Hz, 1H), 2.84 (s, 6H), 2.12 (s , 3H), 1.30 (t, J = 6.9 Hz, 3H); ¹³ C NMR (DMSO-d6) δ 205.81, 167.32, 167.14, 164.84, 148.49, 147.76, 135.85, 134.29, 131.74, 131.48, 127.70, 119.48, 119.27, 119.09, 112.19, 111.76, 63.76, 58.32, 55.48. , 43.47, 29.87, 14.69; Analytical theory of C ₂₅ H ₃₀ N ₃ 0 ₆ Cl: C, 59.58; H, 6.00; N, 8.34; Cl, 7.03. Found: C, 59.18; H, 6.03; N, 8.14; Cl, 6.68.

Example 35

4-amino-2- [1R- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] isoindoline-1,3-dione

4R-amino-4R- (3-ethoxy-4-methoxyphenyl) butan-2-ol hydrochloride (4.0 g, 14.5 mmol) in dimethylformamide (60 mL), 3-amino-N-ethoxycarbonylphthal A mixture of imide (3.57 g, 15.2 mmol) and triethylamine (1.47 g, 14.5 mmol) was heated to 80-90 ° C. for 16 hours. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with water, brine and concentrated to dryness. The crude product was purified by chromatography (silica gel, methylene chloride / ethyl acetate 8/2) to give 4-amino-2- [1R- (3-ethoxy-4-methoxyphenyl) -3-hydroxy as a yellow solid. Butyl] isoindolin-1,3-dione (2.3 g, 41%) was obtained.

Example 36

4-amino-2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] isoindoline-1,3-dione

4-amino-2- [1R- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] isoindoline-1,3-dione (2.2 g, 5.72 mmol) in methylene chloride (110 mL) , A mixture of pyridinium chlorochromate (2.5 g, 11.44 mmol) and celite (2 g) was stirred for 4 hours at room temperature. The mixture was filtered through celite and the filtrate was washed with water, brine and concentrated to dryness. The residue was purified by chromatography (silica gel, methylene chloride: ethyl acetate 95: 5) to give 4-amino-2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl as a yellow solid. ] Isoindolin-1,3-dione (1.23 g, 56%) was obtained:

¹ H NMR (CDCl ₃ ) δ 7.38-7.32 (m, 1H), 7.08-7.05 (m, 3H), 6.81-6.78 (m, 2H), 5.74-5.68 (dd, J = 5.8 and 9.3 Hz, 1H) , 5.20 (b, 2H), 4.11 (q, J = 6.9 Hz, 2H), 3.98-3.87 (dd, J = 9.5 and 17.8 Hz, 1H), 3.82 (s, 3H), 3.33-3.23 (dd, J = 5.6 and 17.8 Hz, 1 H), 2.17- (s, 3 H), 1.45 (t, J = 6.9 Hz, 3 H); ¹³ C NMR (CDCl ₃ ) δ 205.37, 169.98, 168.58, 148.89, 148.22, 145.19, 135.04, 132.48, 131.96, 120.94, 119.98, 112.62, 112.54, 112.20, 111.06, 64.31, 60.36, 55.88, 49.54, 45.18. 14.70.

Example 37

2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -4-pyrrolylisoindolin-1,3-dione

4-amino-2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] isoindoline-1,3-dione (0.34 g, 0.89 mmol) in cold acetic acid (5 mL) A mixture of 2,5-dimethoxytetrahydrofuran (0.12 g, 0.93 mmol) was refluxed for 1 hour. The mixture was dissolved in ethyl acetate (50 mL), washed with saturated sodium bicarbonate, water, brine and concentrated to dryness. The residue was purified by chromatography (silica gel, methylene chloride: ethyl acetate 95: 5) to give 2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -4- as a yellow solid. Pyrrolylisoindolin-1,3-dione (0.23 g, 60%) was obtained:

mp, 90-92 ° C .; ¹ H NMR (CDCl ₃ ) δ 7.73-7.56 (m, 3H), 7.157.08 (m, 4H), 6.81 (d, J = 8.8 Hz, 1H), 6.39-6.38 (m, 2H), 5.77-5.71 (dd, J = 5.4 and 9.8 Hz, 1H), 4.10 (q, J = 6.9 Hz, 2H), 4.05-3.94 (dd, J = 9.8 and 18.1 Hz, 1H), 3.82 (s, 3H), 3.31- 3.22 (dd, J = 5.4 and 18.1 Hz, 1H), 2.16 (s, 3H), 1.45 (t, J = 6.9 Hz, 3H); ¹³ C NMR (CDCl ₃ ) δ 205.28, 167.27, 166.13, 149.08, 148.24, 138.39, 135.11, 133.99,131.38, 129.03, 122.05, 121.28, 120.75, 120.28, 112.66, 111.26, 110.66, 64.37, 55.89, 50.89, 50. 30.14, 14.69; Analytical theory of C ₂₅ H ₂₄ N ₂ 0 ₅ : C, 69.43; H, 5.59; N, 6.48. Found: C, 69.49; H, 5.65; N, 6.33.

Example 38

2- (dimethylamino) -N- {2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide hydrochloride

4-amino-2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] isoindoline-1,3-dione (0.9 g, 2.34 mmol) in tetrahydrofuran (20 mL) And a mixture of chloroacetyl chloride (0.29 g, 2.58 mmol) were heated to reflux for 10 minutes, and 2-chloro-N-2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl ] -1,3-dioxoisoindolin-4-yl} acetamide was obtained, which was combined with N, N-dimethylamine (2.0 M in methanol, 3.5 mL) in tetrahydrofuran (15 mL) at room temperature for 16 hours. Stirred. The mixture was concentrated to an oil in vacuo. This oil was purified by chromatography (silica gel, methylene chloride: ethyl acetate 75:25) to give a white solid. To this solid in ethyl acetate (10 mL) was added 1N hydrochloric acid in ether (4 mL). The slurry was filtered and washed with ether to give 2- (dimethylamino) -N-2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] as a white solid (0.45 g,%). -1,3-dioxoisoindolin-4-yl} acetamide hydrochloride was obtained:

mp, 118-120 ° C .; ¹ H NMR (DMSO-d6) δ 10.60 (s, 1H), 10.29 (s, 1H), 8.16 (d, J = 8.2 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.67 (d , J = 7.2 Hz, 1H), 6.97 (s, 1H), 6.88 (s, 2H), 5.62-5.56 (dd, J = 5.9 and 8.8 Hz, 1H), 4.27 (s, 2H), 3.98 (q , J = 7.0 Hz, 2H), 3.77-3.66 (m, 1H), 3.70 (s, 3H), 3.51-3.41 (dd, J = 6.0 and 18.1 Hz, 1H), 2.88 (s, 6H), 2.11 ( s, 3H), 1.30 (t, J = 6.9 Hz, 3H); ¹³ C NMR (DMSO-d6) δ 205.81, 167.18, 167.12, 164.35, 148.49, 147.76, 135.83, 134.11, 131.78, 131.47, 128.05, 119.64, 119.42, 119.26, 112.17, 111.76, 63.76, 57.88, 55.48.55. , 43.27, 29.88, 14.70; Analytical theory of C ₂₅ H ₃₀ N ₃ 0 ₆ Cl + 0.27H ₂ 0: C, 59.01; H, 6.05; N, 8. 26; Cl, 6.97. Found: C, 59.06; H, 6.09; N, 8.14; Cl, 6.97.

Example 39

Tablets each containing 50 mg of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4,5-diaminoisoindolin-1,3-dione in the following manner It can be prepared by.

Composition (about 1000 tablets)

The solid component is first passed through a sieve of 0.6 mm mesh width. Next, half of the active ingredient, lactose, talc, magnesium stearate and starch are mixed. The other half of the starch is suspended in 40 mL of water and the suspension is added to a solution of polyethylene glycol in 100 mL of boiling water. The resulting paste is added to the fine powdered material and the mixture is granulated with water as needed. The granules are dried overnight at 35 ° C., passed through a 1.2 mm mesh sieve and compressed to form tablets of approximately 6 mm in diameter with both sides concave.

Example 40

100 mg of 7- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -3-pyrrolino [3,4-e] benzimidazole-6,8-dione, respectively Tablets containing can be prepared in the following manner.

Composition (about 1000 tablets)

The solid component is first passed through a sieve of 0.6 mm mesh width. Next, half of the active ingredient, lactose, magnesium stearate and starch are mixed. The other half of the starch is suspended in 40 mL of water and the suspension is added to 100 mL of boiling water. The resulting paste is added to the fine powdered material and the mixture is granulated with water as needed. The granules are dried overnight at 35 ° C., passed through a 1.2 mm mesh sieve and compressed to form tablets of approximately 6 mm in diameter with both sides concave.

Example 41

75 mg of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -3-pyrrolino [3,4-f] quinoxaline-1,3-dione each Tablets containing can be prepared in the following manner.

Composition (about 1000 tablets)

All solid components are first passed through a sieve of 0.25 mm mesh width. Mannitol and lactose are mixed, granulated with addition of gelatin solution, passed through a 2 mm mesh width sieve, dried at 50 ° C. and again passed through a 1.7 mm mesh sieve. Carefully mix 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3-phthalimidopropionamide, glycine and saccharin, add mannitol, lactose granules, stearic acid and talc, Mix thoroughly and compress to form tablets approximately 10 mm in diameter with both sides concave and grooved on the top.

Example 42

Tablets containing 10 mg of N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide each It can be produced in a manner.

Composition (about 1000 tablets)

The solid component is first passed through a sieve of 0.6 mm mesh width. Next, half of the active ingredient, lactose, talc, magnesium stearate and starch are mixed well. The other half of the starch is suspended in 65 mL of water and the suspension is added to a solution of polyethylene glycol in 260 mL of boiling water. The resulting paste is added to a fine powdered material, and the whole is mixed into granules with the addition of water as needed. The granules are dried overnight at 35 ° C., passed through a 1.2 mm mesh sieve, and compressed to form tablets approximately 10 mm in diameter with both sides concave and gold on the top.

Example 43

Dry gelatin containing 100 mg each of N-2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide Filled capsules can be prepared in the following manner.

Composition (about 1000 capsules)

Sodium lauryl sulfate 0.2 mm with N-2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide Sieve through a sieve of mesh width and mix the two components well for 10 minutes. Next, microcrystalline cellulose is added through a sieve of 0.9 mm mesh width and mixed for 10 minutes to mix well again. Finally, magnesium stearate is added through a 0.8 mm mesh sieve and mixed for another 3 minutes, and then the mixture is introduced into the size 0 (extended) dry gelatin filled capsules 140 mg each.

Example 44

0.2% injection or infusion solutions can be prepared, for example, in the following manner.

2- (dimethylamino) -N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide hydrochloride Is dissolved in 1000 mL of water and filtered through a microfilter. Add buffer and make up to 2500 mL whole with water. To prepare unit dosage forms, 1.0 or 2.5 mL of each was introduced into glass ampoules (containing 2.0 or 5.0 mg of imide, respectively).

Example 45

Cyclopentyl-N {-2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} carboxyamide

2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -4-aminoisoindolin-1,3-dione (0.85 g, 2.0 mmol) with cyclopentane chloride A mixture of carbonyl (0.8 mL, 6.6 mmol) was heated at 100 ° C. for 30 minutes. The mixture was cooled to room temperature. Methanol (10 mL) was added to the mixture. The mixture was stirred at 0 ° C. for 1 h. The resulting suspension was filtered to give a solid. This solid was stirred in ether (10 mL) for 1 h. The suspension is filtered and washed with ether to give cyclopentyl-N- {2- [1 (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl as a white solid (400 mg, 38% yield). ] -1,3-dioxoisoindolin-4-yl} carboxyamide was obtained:

mp, 134-136 ° C .; ¹ H NMR (CDCl ₃ ) δ 1.49 (t, J = 6.9 Hz, 3H, CH ₃ ), 1.57-2.06 (m, 8H, C ₅ H ₈ ), 2.76-2.83 (m, 1H, CH), 2.87 ( s, 3H, CH ₃ ), 3.75 (dd, J = 4.6, 14.4 Hz, 1H, CHH), 3.87 (s, 3H, CH ₃ ), 4.12 (q, J = 7.0 Hz, 2H, CH ₂ ), 4.56 (dd, J = 10.3, 14.4 Hz, 1H, CHH), 5.88 (dd, J = 4.5, 10.3 Hz, 1H, NCH), 6.84-6.87 (m, 1H, Ar), 7.10-7.14 (m, 2H , Ar), 7.48 (d, J = 7.2 Hz, 1H, Ar), 7.66 (t, J = 7.5 Hz, 1H, Ar), 8.79 (d, J = 8.4 Hz, 1H, Ar), 9.54 (s, 1H, NH); ¹³ C NMR (CDCl ₃ ) .14.61, 25.81, 30.19, 30.23, 41.57, 47.14, 48.6, 554.62, 55.88, 64.47, 111.42, 112.41, 115.08, 117.92, 120.29, 124.98, 129.28, 130.98, 136.02, 13758. 149.71, 167.53, 169.48, 175.45; Analytical theory of C ₂₆ H ₃₀ N ₂ 0 ₇ S + 0.1H ₂ 0: C, 60.47; H, 5.89; N, 5. 42; H20, 0.35. Found: C, 60.22; H, 5.67; N, 5.44; H20, 0.24.

Example 46

3- (dimethylamino) -N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1, 3-dioxoisoindolin-4-yl } Propanamide

2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -4-aminoisoindolin-1,3-dione (0.80 g, 1.9 mmol) with 2-chloride A mixture of bromopropionyl (0.8 mL, 7.9 mmol) was heated at 100 ° C. for 30 minutes. The mixture was cooled to room temperature. Methanol (10 mL) was added to the mixture. The solvent was removed in vacuo to give an oil. This oil was stirred in ether (10 mL) for 1 day. The resulting suspension was filtered and washed with ether to give 3-bromo-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2- as a yellow solid (0.84 g, 80% yield). (Methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} propanamide was obtained. A portion of the separated bromide (620 mg, 1.2 mmol) and dimethylamine (2 mL, 2 M in methanol, 4 mmol) were stirred at room temperature for 3 hours. The resulting suspension was filtered and washed with methanol to give a crude product of a yellow solid. This solid was purified by column chromatography to give 3- (dimethylamino) -N- {2- (1- (3-ethoxy-4-methoxyphenyl) -2- as a white solid (180 mg, yield 30%). (Methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} propanamide was obtained:

mp, 163-165 ° C .; ¹ H NMR (CDCl ₃ ) δ 1.47 (t, J = 6.9 Hz, 3H, CH ₃ ), 2.38 (s, 6H, CH ₃ ), 2.59 (t, J = 5.7 Hz, 2H, CH ₂ ), 2.70 ( t, J = 5.9 Hz, 2H, CH ₂ ), 2.82 (s, 3H, CH ₃ ), 3.78-3.85 (m, 1H, CHH), 3.86 (s, 3H, CH ₃ ), 4.10 (q, J = 7.0 Hz, 2H, CH ₂ ), 4.49 (dd, J = 9.8, 14.6 Hz, 1H, CHH), 5.86 (dd, J = 4.9, 9.7 Hz, 1H, NCH), 6.82-6.85 (m, 1H, Ar ), 7.10-7.13 (m, 2H, Ar), 7.48 (d, J = 7.2 Hz, 1H, Ar), 7.63 (t, J = 7.5 Hz, 1H, Ar), 8.82 (d, J = 8.4 Hz, 1H, Ar), 11.36 (s, 1H, NH); ¹³ C NMR (CDCl ₃ ) δ 14.62, 34.85, 41.49, 44.65, 48.74, 54.31, 55.01, 55.88, 64.44, 111.43, 112.52,115.99, 117.93, 120.39, 120.08, 129.52, 131.42, 135.59, 137.33, 148.55, 149. 168.00, 168.16, 171.86; Analytical theory of C ₂₅ H ₃₁ N ₃ 0 ₇ S: C, 58.01; H, 6.04; N, 8.12. Found: C, 57.75; H, 5.86; N, 7.91.

Example 47

2- (dimethylamino) -N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl } Propanamide, Hydrochloride

Step 1: 4-amino-2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] isoindolin-1,3-dione in methylene chloride (10 mL) 500 mg, 1.20 mmol) and 2-bromopropionyl bromide (0.140 mL, 1.34 mmol) were stirred overnight at room temperature. Further 0.1 mL of 2-bromopropionyl bromide (1 mol) was added and the mixture was stirred overnight. To the mixture was added brine (4 mL), sodium bicarbonate (saturated, 10 mL) and methylene chloride (15 mL). The organic layer was separated, washed with brine (10 mL) and dried over magnesium sulfate. The solvent was removed in vacuo to yield a yellow oil. This oil was stirred in ether (10 mL). The resulting suspension was filtered and the solid was washed with ether to give 2-bromo-N- {2- [1- (3-ethoxy-4-methoxyphenyl)-as a white solid (500 mg, yield 76%). 2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} propanamide was obtained:

¹ H NMR (CDCl ₃ ) δ 1.46 (t, J = 6.9 Hz, 3H, CH ₃ ), 1.97 (d, J = 6.9 Hz, 3H, CH ₃ ), 2.86 (s, 3H, CH ₃ ), 3.75 ( dd, J = 4.5, 14.4 Hz, 1H, CHH), 3.85 (s, 3H, CH ₃ ), 4.49-4.59 (m, 2H, CHH, CH), 4.09 (q, J = 6.9 Hz, 2H, CH ₂ ), 5.87 (dd, J = 4.4, 10.3 Hz, 1H, NCH), 6.82-6.85 (m, 1H, Ar), 7.09-7.13 (m, 2H, Ar), 7.53 (d, J = 7.3 Hz, 1H) Ar), 7.68 (t, J = 7.5 Hz, 1H, Ar), 8.73 (d, J = 8.4 Hz, 1H, Ar), 10.19 (s, 1H, NH); ¹³ C NMR (CDCl ₃ ) 14.61, 22.42, 41.54, 43.78, 48.67, 54.44, 55.87, 64.45, 111.39, 112.3, 116.10, 116.79, 120.35, 124.76, 129.14, 131.13, 136.02, 136.82, 148.55, 149.70, 167.42. , 169.11.

Step 2: 2-Bromo-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-di in acetonitrile (5 mL) To a suspension of oxoisoindolin-4-yl} propanamide (500 mg, 0.9 mmol) was added dimethylamine (1.5 mL, 2M, 3.0 mmol) in methanol at room temperature and the mixture was stirred for 2 days. The mixture was diluted with methylene chloride (50 mL) and sodium hydrogen carbonate (25 mL). The organic layer was separated, washed with brine (25 mL) and dried over magnesium sulfate. The solvent was removed in vacuo to give an oil. To an oil solution in ethyl acetate (20 mL) was added hydrochloric acid (1.5 mL, 1N hydrochloric acid, 1.5 mmol) in ether. The resulting suspension was filtered and washed with ethyl acetate (10 mL) to give 2- (dimethylamino) -N- {2- [1- (3-ethoxy-4-methoxy as white solid (290 mg, yield 58%). Phenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} propanamide, hydrochloride:

mp, 138-140 ° C .; ¹ H NMR (DMSO-d6) δ 1.32 (t, J = 6.9 Hz, 3H, CH ₃ ), 1.56 (brs, 3H, CH ₃ ), 2.83 (brs, 6H, CH ₃ ), 3.01 (s, 3H, CH ₃ ), 3.73 (s, 3H, CH ₃ ), 4.02 (q, J = 6.9 Hz, 2H, CH ₂ ), 4.15 (dd, J = 4.4, 14.2 Hz, 1H, CHH), 4.27 (s, 1H , CH), 4.34 (dd, J = 10.6, 14.3 Hz, 1H, CHH), 5.78 (dd, J = 4.3, 10.3 Hz, 1H, NCH), 6.91-6.99 (m, 2H, Ar), 7.72 (d , J = 7.1 Hz, 1H <Ar), 7.87 (d, J = 7.5 Hz, 1H, Ar), 8.14 (m, 1H, Ar), 10.4 (brs, 1H, HCl), 10.71 (s, 1H, NH ); ¹³ C NMR (DMSO-d6) δ 13.42, 14.67, 41.07, 41.47, 47.31, 52.98, 55.51, 52.74, 63.84, 111.75, 112.31, 119.70, 120.16, 128.92, 129.47, 131.80, 134.05, 135.87, 147.87, 148.91 , 166.86, 167.65, 168.53; Analytical theory of C ₂₅ H ₃₁ N ₃ O ₇ S + 1.1HCl + 0.6H ₂ 0: C, 52.82; H, 5. 90; N, 7.39, Cl, 6.86, H 20, 1.90. Found: C, 52.57; H, 5.77; N, 7.10; Cl, 6.90; H20, 1.47.

Example 48

N- {2-[(1R) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} -2 -(Dimethylamino) acetamide hydrochloride

N- {2-[(1R) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin in acetonitrile (15 mL) A mixture of -4-yl-2-chloroacetamide (0.70 g, 1.41 mmol) and dimethylamine (2.4 mL, 2N, 4.8 mmol) in tetrahydrofuran was stirred overnight at room temperature. The solvent was removed in vacuo to give an oil. This oil was stirred in ethanol (5 mL). The suspension was filtered and washed with ethanol to give a white solid. To this solid solution in ethyl acetate (5 mL) was added hydrochloric acid (1.5 mL, 1N) in ether. The resulting suspension was filtered and the solid was washed with ether to give N- {2-[(1R) -1- (3-ethoxy-4-methoxyphenyl) -2 as a yellow solid (480 mg, yield 63%). -(Methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl-2- (dimethylamino) acetamide hydrochloride was obtained:

mp, 192-194 ° C .; ¹ H NMR (DMSO-d6) δ 1.33 (t, J = 6.9 Hz, 3H, CH 3), 2.87 (s, 6H, 2CH ₃ ), 3.03 (s, 3H, CH ₃ ), 3.74 (s, 3H, CH ₃ ), 4.02 (q, J = 7.0 Hz, 2H, CH ₂ ), 4.16 (dd, J = 4.2, 14.3 Hz, 1H, CHH), 4.25 (brs, 2H, CH ₂ ), 4.34 (dd, J = 10.8, 14.4 Hz, 1H, CHH), 5.79 (dd, J = 4.2, 10.4 Hz, 1H, NCH), 6.92-6.99 (m, 2H, Ar), 7.08 (s, 1H, Ar), 7.69 (d, J = 7.3 Hz, 1H, Ar), 7.88 (t, J = 7.7 Hz, 1H, Ar), 8.21-8.27 (m, 1H, Ar), 10.29 (s, 1H, HCl), 10.64 (s, 1H, NH); ¹³ C NMR (DMSO-d6) δ 14.65, 41.04, 43.36, 47.23, 52.86, 55.51, 58.09, 63.86, 111.79, 112.39, 119.22, 119.68, 127.78, 127.99, 129.42, 131.76, 134.25, 134.34, 135.95, 147.95. , 164.60, 166.79; Analytical theory of C ₂₄ H ₂₉ N ₃ 0 ₇ S + 1HCl: C, 53.38; H, 5. 60; N, 7.78; Cl, 6.56. Found: C, 53.52; H, 5. 70; N, 7.61; Cl, 6.44.

Example 49

N- {2-[(1S)-(3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3 dioxoisoindolin-4-yl-2- (dimethylamino Acetamide hydrochloride

N- {2 [(1S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin- in acetonitrile (17 mL) A mixture of 4-yl-2-chloroacetamide (1.79 g, 3.61 mmol) and dimethylamine (6.1 mL, 2N, 12.2 mmol) in tetrahydrofuran was stirred overnight at room temperature. The solvent was removed in vacuo to give an oil. The oil was stirred in ethanol (10 mL). The resulting suspension was filtered and the solid was washed with ethanol to give a white solid. This solid was purified by column chromatography (silica gel, 1: 3 ethyl acetate: methylene chloride) to give a white solid (900 mg, yield 50%). To this solid in ethyl acetate (10 mL) was added hydrochloric acid (2.6 mL, 1N) in ether. After 5 minutes, ether (10 mL) was added to the solution to obtain a suspension. The suspension is filtered and the solid is washed with ether to give N- {2-[(1S) -1- (3-ethoxy-4-methoxyphenyl) -2- (as yellow solid (830 mg, yield 86%). Methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl-2- (dimethylamino) acetamide hydrochloride was obtained:

mp, 202-204 ° C; ¹ H NMR (DMSO-d6) δ 1.33 (t, J = 6.9 Hz, 3H, CH ₃ ), 2.87 (s, 6H, 2CH ₃ ), 3.03 (s, 3H, CH ₃ ), 3.74 (s, 3H, CH ₃ ), 4.02 (q, J = 7.0 Hz, 2H, CH ₂ ), 4.16 (dd, J = 4.2, 14.3 Hz, 1H, CHH), 4.25 (brs, 2H, CH ₂ ), 4.34 (dd, J = 10.8, 14.4 Hz, 1H, CHH), 5.79 (dd, J = 4.2, 10.4 Hz, 1H, NCH), 6.92-6.99 (m, 2H, Ar), 7.08 (s, 1H, Ar), 7.69 (d , J = 7.3 Hz, 1H, Ar), 7.88 (t, J = 7.7 Hz, 1H, Ar), 8.21-8.27 (m, 1H, Ar), 10.29 (s, 1H, HCI), 10.64 (s, 1H , NH); ¹³ C NMR (DMSO-d6) δ 14.65, 41.04, 43.36, 47.23, 52.86, 55.51, 58.09, 63.86, 111.79, 112.39, 119.22, 119.68, 127.78, 127.99, 129.42, 131.76, 134.25, 134.34, 135.95, 147.95. , 164.60, 166.79; Analytical theory of C ₂₄ H ₂₉ N ₃ 0 ₇ S + 1HCl + 0.6H ₂ 0: C, 52.33; H, 5.71; N, 7.63; C1, 6.44; H ₂ 0, 1.96. Found: C, 52.46; H, 5.63; N, 7.46; C1, 6.43; H ₂ 0,2.16.

Example 50

4-3-[(dimethylamino) methyl] pyrrolyl-2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl) isoindoline-1,3-dione Hydrochloride

1- {2- [1- (3-ethoxy-4-methoxyphenyl) -2 (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} pyrrole-3-carboaldehyde (0.840 g, 1.69 mmol), a mixture of diethylamine (2.6 mL, 2N, 5.2 mmol) in tetrahydrofuran, and molecular sieves in methylene chloride (10 mL) were stirred overnight at room temperature. The mixture was cooled to 0 ° C. To the mixture was added methanol (10 mL) and sodium borohydride (32 mg, 0.84 mmol). After 1.5 hours, the suspension was filtered through a magnesium sulfate pad. The magnesium sulfate pad was washed with methylene chloride (50 mL). The filtrate was washed with ammonium chloride (aq) (saturated, 50 mL) and sodium bicarbonate (saturated, 50 mL). The solvent was removed in vacuo to give an oil. The oil was diluted with ethyl acetate (50 mL) and hydrochloric acid (100 mL, 1N). The organic layer was separated and extracted with 1N hydrochloric acid (2x100 mL). The combined aqueous layers were washed with ethyl acetate (30 mL) and then extracted with methylene chloride (3x50 mL). The combined methylene chloride layer was concentrated to give a solid. This solid was slurried in isopropanol (15 mL). The suspension is filtered, the solid is washed with ether and dried to give 4- {3-[(dimethylamino) methyl] pyrrolyl) -2- [1- (3-) as a white solid (370 mg, yield 39%). Methoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dione hydrochloride was obtained:

mp, 158-160 ° C .; ¹ H NMR (CDCl ₃ ) δ 1.46 (t, J = 6.9 Hz, 3H, CH ₃ ), 2.78 (s, 3H, CH ₃ ), 2.80 (s, 3H, CH ₃ ), 2.89 (s, 3H, CH ₃ ), 3.69 (dd, J = 4.2, 14 Hz, 1H, CHH), 3.84 (s, 3H, CH ₃ ), 4.04-4.12 (m, 4H, CH ₂ , CH ₂ ), 4.59 (dd, J = 11 , 14Hz, 1H, CHH), 5.89 (dd, J = 4.2, 11Hz, 1H, NCH), 6.50-6.52 (m, 1H, Ar), 6.83 (d, J = 8Hz, 1H, Ar), 7.08-7.14 (m, 3H, Ar), 7.47 (brs, 1H, Ar), 7.63-7.67 (m, 1H, Ar), 7.75-7.83 (m, 2H, Ar), 12.46 (brs, 1H, CIH); ¹³ C NMR (CDCl ₃ ) δ 14.63, 41.37, 41.42, 41.58, 48.67, 53.86, 54.16, 55.87, 64.48, 111.39, 112.20, 112.45, 112.58, 120.42, 121.59, 121.95, 123.10, 124.95, 128.97, 130.24, 133.68, 135.72, 137.37, 148.53, 149.72, 165.51, 166.69; Analytical theory of C ₂₇ H ₃₁ N ₃ 0 ₆ S + 1HCl + 0.8H ₂ 0: C, 56.25; H, 5.87; N, 7. 29; Cl, 6.15; H ₂ 0, 2.50. Found: C, 56.51; H, 5.78; N, 7.08; Cl, 6.05; H ₂ 0, 2.63.

Example 51

Cyclopropyl-N- {2-[(1S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-3-yl } Carboxyamide

2-[(1S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -4-aminoisoindolin-1,3-dione (1.3 g, 3.1 mmol) And a stirred mixture of cyclopropane carbonyl chloride (3 mL) was heated to reflux for 45 minutes. Methanol (10 mL) was added to the cooled mixture at 0 ° C, and the mixture was stirred for 30 minutes. The solvent was removed in vacuo to give an oil. The oil was stirred for 2 hours in ethanol (10 mL) to give a suspension. The suspension is filtered and the solid is washed with ethanol to give cyclopropyl-N- {2-[(1S)-(3-ethoxy-4-methoxyphenyl) -2 as a white solid (1.3 g, yield 86%). -(Methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} carboxyamide was obtained:

mp, 140-141 ° C .; ¹ H NMR (CDCl ₃ ) δ 0.92-0.99 (m, 2H, 2CHH), 1.11-1.17 (m, 2H, 2CHH), 1.48 (t, J = 6.9 Hz, 3H, CH ₃ ), 1.61-1.71 (m , 1H, CH), 2.88 (s, 3H, CH ₃ ), 3.75 (dd, J = 4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH ₃ ), 4.12 (q, J = 7.1 Hz , 2H, CH ₂ ), 4.57 (dd, J = 10.4, 14.3 Hz, 1H, CHH), 5.89 (dd, J = 4.4, 10.3 Hz, 1H, NCH), 6.84-6.88 (m, 1H, Ar), 7.11-7.15 (m, 2H, Ar), 7.48 (d, J = 7.2 Hz, 1H, Ar), 7.65 (t, J = 7.4 Hz, 1H, Ar), 8.76 (d, J = 8.5 Hz, 1H, Ar), 9.69 (s, 1 H, NH); _{^{13 C NMR (CDCl 3) δ}} 8.71, 14.62, 16.16, 41.58, 48.59, 54.60, 55.89, 64.50, 111.49, 112.44, 114.83, 117.91, 120.26, 124.99, 129.27, 130.99, 136.02, 137.77, 148.63, 149.76, 167.49, 169.52, 172.79; Analytical theory of C ₂₄ H ₂₆ N ₂ 0 ₇ S: C, 59.25; H, 5.39; N, 5.76. Found: C, 58.92; H, 5. 21; N, 5.56.

Example 52

2- [1- (3,4-dimethoxyphenyl) -2- (methylsulfonyl) ethyl] -4-pyrrolylisoindolin-1,3-dione

2- [1- (3,4-dimethoxyphenyl) -2- (methylsulfonyl) ethyl] -4-aminoisoindolin-1,3-dione (0.92 g, 2.3 mmol) in acetic acid (9 mL); A stirred mixture of 2,5-dimethoxy (0.30 mL, 2.3 mmol) in tetrahydrofuran was heated to reflux for 2 hours. The solvent was removed in vacuo to give an oil. This oil was purified by column chromatography (silica gel, 1: 4 ethyl acetate: methylene chloride) to give 2- [1- (3,4-dimethoxyphenyl) -2- as a yellow solid (0.64 g, yield 62%). (Methylsulfonyl) ethyl] -4-pyrrolylisoindolin-1,3-dione was obtained:

mp, 116-118 ° C .; ¹ H NMR (CDCl ₃ ) δ 2.87 (s, 3H, CH ₃ ), 3.71 (dd, J = 4, 14Hz, 1H, CHH), 3.85 (s, 3H, CH ₃ ), 3.88 (s, 3H, CH ₃ ), 4.61 (dd, J = 11, 14 Hz, 1H, CHH), 5.92 (dd, J = 4, 11 Hz, 1H, NCH), 6.39 (t, J = 2.0 Hz, 2H, Ar), 6.82 (d , J = 8 Hz, 1H, Ar), 7.09-7.10 (m, 1H, Ar), 7.15-7.17 (m, 3H, Ar), 7.59-7.64 (m, 1H, Ar), 7.73-7.77 (m, 2H , Ar); ¹³ C NMR (CDCl ₃ ) δ 41.44, 48.73, 54.26, 55.83, 55.89, 110.75, 111.12, 120.55, 120.99, 121.07, 128.99, 129.31, 130.11, 133.71, 135.37, 138.61, 149.16, 149.37, 165.77, 166.82 Analytical theory of C ₂₃ H ₂₂ N ₂ 0 ₆ S: C, 60.78; H, 4.88; N, 6.16. Found: C, 60.58; H, 5.01; N, 5.88.

Example 53

N- {2- [1- (3,4-dimethoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} -2- (dimethylamino) acetamide Hydrochloride

N- {2- [1- (3,4-dimethoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl-2- in acetonitrile (20 mL) A mixture of chloroacetamide (1.3 g, 2.7 mmol) and dimethylamine (4.5 mL, 2N, 9.0 mmol) in tetrahydrofuran was stirred overnight at room temperature. The solvent was removed in vacuo to give an oil. This oil was stirred in ethanol (5 mL). The resulting suspension was filtered and the solid was washed with ethanol to give a yellow solid. To a stirred solution of this solid in ethyl acetate (10 mL) was added hydrochloric acid (3.0 mL, 1N) in ether. After 5 minutes ether (10 mL) was added. The resulting suspension was filtered and washed with ether to give N- {2- [1- (3,4-dimethoxyphenyl) -2- (methylsulfonyl) ethyl]-as a yellow solid (1.07 g, 74% yield). 1,3-dioxoisoindolin-4-yl-2- (dimethylamino) acetamide hydrochloride was obtained:

mp, 178-180 ° C .; ¹ H NMR (DMSO-d6) δ 2.69 (brs, 6H, 2CH ₃ ), 3.02 (s, 3H, CH ₃ ), 3.73 (s, 3H, CH ₃ ), 3.77 (s, 3H, CH ₃ ), 3.88 (brs, 2H, CH ₂ ), 4.16 (dd, J = 4.2, 14.3 Hz, 1H, CHH), 4.34 (dd, J = 10.8, 14.4 Hz, 1H, CHH), 5.79 (dd, J = 4.2, 10.4 Hz, 1H, NCH), 6.92-6.97 (m, 2H, Ar), 7.10 (d, J = 1.4 Hz, 1H, Ar), 7.65 (d, J = 7.2 Hz, 1H, Ar), 7.85 (t, J = 7.7 Hz, 1H, Ar), 8.37-8.40 (m, 1H, Ar), 10.15 (s, 1H, HCl), 10.68 (s, 1H, NH); ¹³ C NMR (DMSO-d6) δ 41.06, 44.18, 47.31, 52.95, 55.55, 55.59, 59.85, 111.26, 111.65, 119.16, 119.69, 127.00, 129.49, 121.64, 134.99, 136.09, 148.71, 148.76, 166.92 Analytical theory of C ₂₃ H ₂₇ N ₃ 0 ₇ S + 1.25HCl + 0.4H ₂ 0: C, 50.94; H, 5.40; N, 7.75; Cl, 8.17; H ₂ 0, 1.33. Found: C, 51.30; H, 5.50; N, 7.37; Cl, 8.28; H ₂ 0, 1.68.

Example 54

Cyclopropyl-N- {2- [1- (3,4-dimethoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} carboxyamide

2- [1- (3,4-dimethoxyphenyl) -2- (methylsulfonyl) ethyl] -4-aminoisoindolin-1,3-dione (0.68 g, 1.7 mmol) with cyclopropane carbonyl chloride ( 1.3 mL) of the stirred mixture was heated to reflux for 25 minutes. Ethanol (10 mL) was added to the mixture at 0 ° C, and allowed to stand for 30 minutes. The solvent was removed in vacuo to give an oil. This oil was stirred for 30 min in ether (20 mL) to give a suspension. The suspension was filtered and the solid was washed with ether to give a white solid. The solid was purified by chromatography (silica gel, 10% ethyl acetate in methylene chloride) to yield cyclopropyl-N- {2- [1- (3,4-dimethoxyphenyl) as a white solid (330 mg, yield 42%). ) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} carboxyamide was obtained:

mp, 130-132 ° C .; ¹ H NMR (CDCl ₃ ) 0.92-0.98 (m, 2H, 2CHH), 1.09-1.14 (m, 2H, 2CHH), 1.61-1.64 (m, 1H, CH), 2.88 (s, 3H, CH ₃ ), 3.73 (dd, J = 4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH ₃ ), 3.90 (s, 3H, CH ₃ ), 4.58 (dd, J = 10.4, 14.3 Hz, 1H, CHH ), 5.90 (dd, J = 4.4, 10.3 Hz, 1H, NCH), 6.84 (d, J = 8 Hz, 1H, Ar), 7.09-7.14 (m, 2H, Ar), 7.47 (d, J = 7.2 Hz) , 1H, Ar), 7.65 (t, J = 7.6 Hz, 1H, Ar), 8.75 (d, J = 8.4 Hz, 1H, Ar), 9.68 (s, 1H, NH); ¹³ C NMR (CDCl ₃ ) δ 6.75, 16.13, 41.54, 48.43, 54.36,55.81, 55.94, 110.98, 111.11, 114.78, 117.88, 120.27, 124.93, 129.30, 130.94, 136.00, 137.68, 149.19, 149.35, 167.45, 167.45 172.79; Analytical theory of C ₂₃ H ₂₄ N ₂ 0 ₇ S: C, 58.46; H, 5. 12; N, 5.93. Found: C, 58.10; H, 5. 16; N, 5.78.

Example 55

Cyclopropyl-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -3-oxoisoindolin-4-yl} carboxyamide

7-amino-2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] isoindolin-1-one (1.0 g, 2.5 mmol) and cyclopropane carbox A stirred mixture of bonyl chloride (1 mL) was heated to reflux for 7 minutes. Methanol (3 mL) was added to the cooled mixture at 0 ° C., and the mixture was stirred for 30 minutes. Ethanol (5 mL) was added to the suspension. The suspension was filtered and washed with ethanol to give cyclopropyl-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2- (as a grayish white solid (1.0 g, yield 86%). Methylsulfonyl) ethyl] -3-oxoisoindolin-4-yl} carboxyamide was obtained:

mp, 115-117 ° C .; ¹ H NMR (CDCl ₃ ) δ 0.86-0.93 (m, 2H, 2CHH), 1.07-1.14 (m, 2H, 2CHH), 1.46 (t, J = 6.9 Hz, 3H, CH ₃ ), 1.63-1.73 (m , 1H, CH), 2.95 (s, 3H, CH ₃ ), 3.68 (dd, J = 4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH ₃ ), 4.07 (q, J = 7.1 Hz , 2H, CH ₂ ), 4.20 (d, J = 16.7 Hz, 1H, CHH), 4.21 (dd, J = 9.9, 14.3 Hz, 1H, CHH), 4.44 (d, J = 16.7 Hz, 1H, CHH) , 5.73 (dd, J = 4.3, 9.9 Hz, 1H, NCH), 6.84-7.02 (m, 4H, Ar), 7.44 (t, J = 7.8 Hz, 1H, Ar), 8.43 (d, J = 8.3 Hz , 1H, Ar), 10.46 (s, 1H, NH); ¹³ C NMR (CDCl ₃ ) δ 8.24, 14.61, 16.10, 41.43, 47.81, 51.55, 55.75, 55.88, 64.56, 111.46, 112.09, 116.69, 116.99, 117.76, 119.17, 129.27, 133.54, 138.06, 141.22, 149.84,149. 169.96, 172.59; Analytical theory of C ₂₄ H ₂₈ N ₂ 0 ₆ S + 0.9H ₂ 0: C, 58.98; H, 6. 15; N, 5.73; H ₂ O, 3.32. Found: C, 58.62; H, 5.99; N, 5.53; H ₂ 0, 3.15.

Example 56

2- (dimethylamino) -N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -3-oxoisoindolin-4-yl} acetamide Hydrochloride

7-amino-2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] isoindolin-1-one (1.0 g, 2 mmol) in acetonitrile (25 mL) ) And dimethylamine (3.6 mL, 2N, 7.2 mmol) in tetrahydrofuran were stirred overnight at room temperature. The solvent was removed in vacuo to give a solid. The solid was recrystallized from ethanol (10 mL) to give a white solid. To a stirred solution of this solid in ethyl acetate (10 mL) was added hydrochloric acid (2.5 mL, 1N) in ether. After 5 minutes ether (10 mL) was added to give a suspension. The suspension is filtered and the solid is washed with ether to give 2- (dimethylamino) -N- {2- [1- (3-ethoxy-4-methoxyphenyl)-as a yellow solid (780 mg, yield 74%). 2- (methylsulfonyl) ethyl] -3-oxoisoindolin-4-yl} acetamide hydrochloride was obtained:

mp, 145-147 ° C .; ¹ H NMR (DMSO-d6) δ 1.32 (t, J = 7Hz, 3H, CH ₃ ), 2.87 (brs, 6H, 2CH ₃ ), 3.03 (s, 3H, CH ₃ ), 3.73 (s, 3H, CH ₃ ), 3.92-4.05 (m, 3H, CHH, CH ₂ ), 4.17 (d, J = 17.9 Hz, 1H, CHH), 4.31-4.41 (m, 3H, CH ₂ , CHH), 4.68 (d, J = 17.9 Hz, 1H, CHH), 5.88 (dd, J = 3.5, 10.7 Hz, 1H, NCH), 6.91-6.98 (m, 2H, Ar), 7.02 (s, 1H, Ar), 7.31 (d, J) = 7.3 Hz, 1H, Ar), 7.59 (t, J = 7.9 Hz, 1H, Ar), 8.15 (d, J = 8.0 Hz, 1H, Ar), 10.17 (s, 1H, HCl), 10.53 (s, 1H, NH); ¹³ C NMR (DMSO-d6) δ 14.72, 40.99, 43.40, 46.20, 48.81, 53.69, 55.32, 58.11, 63.93, 111.98, 112.16, 118.19, 118.58, 119.16, 119.76, 130.01, 133.01, 135.29, 142.55, 148.07, 148.07 , 163.88, 167.45; Analytical theory of C ₂₄ H ₃₁ N ₃ 0 ₆ S + 1.1HCl + 1.5H ₂ 0: C, 51.78; H, 6. 35; N, 7.55; Cl, 7.00; H ₂ 0, 4.85. Found: C, 51.58; H, 6. 13; N, 7.39; Cl, 6.87; H ₂ 0, 3.34.

Example 57

Cyclopropyl-N- {2-[(1S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl) -3-oxoisoindolin-4-yl} carboxyamide

7-amino-2-[(1S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] isoindolin-1-one in tetrahydrofuran (10 mL) ( 1.7 g, 4.2 mmol) and cyclopropane carbonyl chloride (0.46 mL, 5.1 mmol) were heated to reflux for 15 minutes. Methanol (4 mL) was added to the mixture at room temperature, and the mixture was stirred for 10 minutes. The solvent was removed in vacuo to give an oil. This oil was recrystallized from ethanol (20 mL) to obtain cyclopropyl-N- {2-[(1S) -1- (3-ethoxy-4-methoxyphenyl)-as a white solid (1.4 g, 71% yield). 2- (methylsulfonyl) ethyl] -3-oxoisoindolin-4-yl} carboxyamide was obtained:

mp, 172-174 ° C .; ¹ H NMR (CDCl ₃ ) δ 0.86-0.93 (m, 2H, 2CHH), 1.07-1.14 (m, 2H, 2CHH), 1.46 (t, J = 6.9 Hz, 3H, CH ₃ ), 1.63-1.73 (m , 1H, CH), 2.95 (s, 3H, CH ₃ ), 3.68 (dd, J = 4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH ₃ ), 4.07 (q, J = 7.1 Hz , 2H, CH ₂ ), 4.20 (d, J = 16.7 Hz, 1H, CHH), 4.21 (dd, J = 9.9, 14.3 Hz, 1H, CHH), 4.44 (d, J = 16.7 Hz, 1H, CHH) , 5.73 (dd, J = 4.3, 9.9 Hz, 1H, NCH), 6.84-7.02 (m, 4H, Ar), 7.44 (t, J = 7.8 Hz, 1H, Ar), 8.43 (d, J = 8.3 Hz , 1H, Ar), 10.46 (s, 1H, NH); ¹³ C NMR (CDCl ₃ ) δ 8.24, 14.61, 16.10, 41.43, 47.81, 51.55, 55.75, 55.88, 64.56, 111.46, 112.09, 116.69, 116.99, 117.76, 119.17, 129.27, 133.54, 138.06, 141.22, 149.84,149. 169.96, 172.59; Analytical theory of C ₂₄ H ₂₈ N ₂ 0 ₆ S: C, 61.00; H, 5.97; N, 5.93. Found: C, 60.87; H, 6. 13; N, 6.12.

Example 58

Cyclopropyl-N- {2-[(1R) -1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyl) ethyl] -3-oxoisoindolin-4-yl} carboxyamide

7-amino-2-[(1R) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] isoindolin-1-one in tetrahydrofuran (10 mL) ( 0.9 g, 2.2 mmol) and cyclopropane carbonyl chloride (0.25 mL, 2.8 mmol) were heated to reflux for 15 minutes. The solvent was removed in vacuo to give a solid. This solid was recrystallized from ethanol (10 mL) to yield cyclopropyl-N- {2-[(1R) -1- (3-ethoxy-4-methoxy as a grayish white solid (0.61 g, 56% yield). Phenyl) -2- (methylsulfonyl) ethyl] -3-oxoisoindolin-4-yl} carboxyamide was obtained:

mp, 173-175 ° C .; ¹ H NMR (CDCl ₃ ) δ 0.86-0.93 (m, 2H, 2CHH), 1.07-1.14 (m, 2H, 2CHH), 1.46 (t, J = 6.9 Hz, 3H, CH ₃ ), 1.63-1.73 (m , 1H, CH), 2.95 (s, 3H, CH ₃ ), 3.68 (dd, J = 4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH ₃ ), 4.07 (q, J = 7.1 Hz , 2H, CH ₂ ), 4.20 (d, J = 16.7 Hz, 1H, CHH), 4.21 (dd, J = 9.9, 14.3 Hz, 1H, CHH), 4.44 (d, J = 16.7 Hz, 1H, CHH) , 5.73 (dd, J = 4.3, 9.9 Hz, 1H, NCH), 6.84-7.02 (m, 4H, Ar), 7.44 (t, J = 7.8 Hz, 1H, Ar), 8.43 (d, J = 8.3 Hz , 1H, Ar), 10.46 (s, 1H, NH); ¹³ C NMR (CDCl ₃ ) δ 8.24, 14.61, 16.10, 41.43, 47.81, 51.55, 55.75, 55.88, 64.56, 111.46, 112.09, 116.69, 116.99, 117.76, 119.17, 129.27, 133.54, 138.06, 141.22, 149.84,149. 169.96, 172.59; Analytical theory of C ₂₄ H ₂₈ N ₂ 0 ₆ S: C, 61.00; H, 5.97; N, 5.93.

Found: C, 60.73; H, 5.91; N, 5.69.

Example 59

(3R) -3- [7- (acetylamino) -1-oxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide

(3R) -3- (7-amino-1-oxoisoindolin-2-yl) -3- (3-ethoxy-4methoxyphenyl) -N, N-dimethylpropanamide in tetrahydrofuran (5 mL) (400 mg, 1 mmol) and a stirred mixture of acetyl chloride (0.1 mL, 1.4 mmol) were heated to reflux for 2 hours. To the mixture was added 50% sodium hydrogen carbonate (40 mL) and ethyl acetate (50 mL). The organic layer was washed with sodium hydrogen carbonate (saturated, 20 mL), brine (20 mL) and dried over magnesium sulfate. The solvent was removed in the air to give an oil. The oil was purified by column chromatography (silica gel, 1.5: 1 ethyl acetate: methylene chloride) to give (3R) -3- [7- (acetylamino) -1-oxoisophosphate as a white solid (0.25 g, yield 57%). Dolin-2-yl] -3- (3-ethoxy4-methoxyphenyl) -N, N-dimethylpropanamide was obtained:

mp, 88-90 ° C .; ¹ H NMR (CDCl ₃ ) to 1.43 (t, J = 6.9 Hz, 3H, CH ₃ ), 2.22 (s, 3H, CH ₃ ), 2.90 (s, 3H, CH ₃ ), 3.04 (dd, J = 5.5 , 16 Hz, 1H, CHH), 3.09 (s, 3H, CH ₃ ), 3.52 (dd, J = 9.5, 15 Hz, 1 H, CHH), 3.84 (s, 3H, CH ₃ ), 4.07 (q, J = 7.1 Hz, 2H, CH ₂ ), 4.26 (d, J = 17 Hz, 1H, CHH), 4.44 (d, J = 17 Hz, 1H, CHH), 5.58 (dd, J = 5.5, 9.4 Hz, 1H, NCH) , 6.81-6.84 (m, 1H, Ar), 6.92-7.01 (m, 3H, Ar), 7.41 (t, J = 7.8 Hz, 1H, Ar), 8.41 (d, J = 8.3 Hz, 1H, Ar) 10.37 (s, 1 H, NH); ¹³ C NMR (CDCl ₃ ) to 14.65, 24.84, 35.47, 36.16, 37.31, 48.71, 53.54, 55.85, 64.44, 111.35, 112.44, 116.83, 117.40, 117.97, 119.10, 131.72, 132.84, 137.65, 141.53, 148.46, 149.46 168.98, 169.41, 169.57; Analytical theory of C ₂₄ H ₂₉ N ₃ 0 ₅ + 0.7H ₂ 0: C, 63.76; H, 6.78; N, 9.29; H ₂ 0, 2.79. Found: C, 63.89; H, 6. 64; N, 9.14; H ₂ 0, 2.70.

Example 60

(3R) -3- [7-cyclopropylcarbonylamino) -1-oxoisoindolin-2-yl] -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide

(3R) -3- (7-amino-1-oxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropane in tetrahydrofuran (5 mL) A mixture of amide (450 mg, 1 mmol) and cyclopropane carbonyl chloride (0.13 mL, 1.4 mmol) was heated to reflux for 15 minutes. To the mixture was added 50% sodium hydrogen carbonate (40 mL) and ethyl acetate (50 mL). The organic layer was washed with sodium hydrogen carbonate (saturated, 20 mL) and brine (20 mL) and dried over magnesium sulfate. The solvent was removed in vacuo to give an oil. The oil was purified by column chromatography (silica gel, 1: 1 ethyl acetate: methylene chloride) to give (3R) -3- [7- (cyclopropylcarbonylamino) -1 as a white solid (0.35 g, 67% yield). -Oxoisoindolin-2-yl] -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide was obtained:

mp, 92-94 ° C .; ¹ H NMR (CDCl ₃ ) to 0.82-0.89 (m, 2H, CH ₂ ), 1.05-1.11 (m, 2H, CH ₂ ), 1.43 (t, J = 6.9 Hz, 3H, CH ₃ ), 1.64-1.70 (m, 1H, CH), 2.90 (s, 3H, CH ₃ ), 3.05 (dd, J = 5.5, 16 Hz, 1H, CHH), 3.10 (s, 3H, CH ₃ ), 3.52 (dd, J = 9.5 , 15 Hz, 1H, CHH), 3.84 (s, 3H, CH ₃ ), 4.07 (q, J = 7 Hz, 2H, CH ₂ ), 4.26 (d, J = 17 Hz, 1H, CHH), 4.44 (d, J = 17 Hz, 1H, CHH), 5.60 (dd, J = 5.7, 9.4 Hz, 1H, NCH), 6.82 (d, J = 8.7 Hz, 1H, Ar), 6.63-6.99 (m, 2H, Ar), 7.39 (t, J = 7.9 Hz, 1H, Ar), 8.39 (d, J = 8.2 Hz, 1H, Ar), 10.59 (s, 1H, NH); ¹³ C NMR (CDCl ₃ ) δ 8.04, 14.64, 16.03, 35.46, 36.19, 37.31, 48.72, 53.56, 55.85, 64.46, 111.41, 112.52, 116.56, 117.41, 117.82, 119.13, 131.79, 132.84, 137.84, 141.54, 148.48, 148.48 149.04, 169.50, 169.58, 172.51; Analytical theory of C ₂₆ H ₃₁ N ₃ 0 ₅ + 0.5H ₂ 0: C, 65.81; H, 6. 80; N, 8.85; H ₂ 0, 1.90. Found: C, 65.83; H, 6. 72; N, 8.72; H ₂ 0, 1.94.

Example 61

3- {4- [2- (dimethylamino) acetylamino] -1,3-dioxoisoindolin-2-yl-3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropane Amide hydrochloride

Step 1: 3- [4- (2-chloroacetylamino) -1,3-dioxoisoindolin-2-yl] -3- (3-ethoxy-4-methoxyphenyl in tetrahydrofuran (7 mL) A solution of propanoic acid (1.0 g, 2.2 mmol) and carbonyldiimidazole (367 mg, 2.26 mmol) was heated at room temperature for 1 hour. Dimethylamine (1.3 mL, 2 N, 2.6 mmol) in tetrahydrofuran was added to the mixture, and the mixture was stirred for 2 hours. Next, water (60 mL) and methylene chloride (50 mL) were added to the mixture. The aqueous layer was separated and extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine / hydrochloric acid 1N (1: 1, 50 mL) and dried over magnesium sulfate. The solvent was removed in vacuo to give 3- [4- (2-chloroacetylamino) -1,3-dioxoisoindolin-2-yl] -3- (3- as a yellow solid (1.1 g, yield 100%). Ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide was obtained, which was used for the next step without further purification.

Step 2: 3- [4- (2-chloroacetylamino) -1,3-dioxoisoindolin-2-yl] -3- (3-ethoxy-4-methoxyphenyl) in acetonitrile (15 mL) To a stirred solution of -N, N-dimethylpropanamide (1.1 g, 2.3 mmol) was added dimethylamine (3.3 mL, 2N, 6.6 mmol) in tetrahydrofuran at room temperature and left overnight. The solvent was removed in vacuo to give a solid. This solid was diluted with methylene chloride (50 mL) and sodium hydrogencarbonate (25 mL). The separated organic layer was dried over magnesium sulfate. The solvent was removed in vacuo to give a solid. The solid was purified by chromatography to give 3- {4- [2-dimethylamino) acetylamino] -1,3-dioxoisoindolin-2-yl-3- (as white solid (640 mg, yield 57%). 3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide was obtained. 3-4- [2- (dimethylamino) acetylamino] -1,3-dioxoisoindolin-2-yl-3- (3-ethoxy-4-methoxyphenyl) -N in ethyl acetate (4 mL) To a stirred solution of, N-dimethylpropanamide was added hydrochloric acid (2 mL, 1N, 2 mmol) in ether at room temperature. The resulting suspension was filtered and washed with ethyl acetate to afford 3- {4- [2- (dimethylamino) acetylamino] -1,3-dioxoisoindolin-2-yl} as a white solid (580 mg, yield 84%). 3- (3-Ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide hydrochloride was obtained:

mp, 92-94 ° C .; ¹ H NMR (DMSO-d6) δ 1.30 (t, J = 6.9 Hz, 3H, CH ₃ ), 2.75 (s, 3H, CH ₃ ), 2.87 (s, 6H, 2CH ₃ ), 2.98 (s, 3H, CH ₃ ), 3.21 (dd, J = 5.7, 16.6 Hz, 1H, CHH), 3.61 (dd, J = 9.3, 16.5 Hz, 1H, CHH), 3.72 (s, 3H, CH ₃ ), 3.98 (q, J = 6.9 Hz, 2H, CH ₂ ), 4.26 (s, 2H, CH ₂ ), 5.62 (dd, J = 5.6, 9.1 Hz, 1H, NCH), 6.90-6.91 (m, 2H, Ar), 7.01 ( s, 1H, Ar), 7.65 (d, J = 7.2 Hz, 1H, Ar), 7.85 (t, J = 7.7 Hz, 1H, Ar), 8.21 (d, J = 8.2 Hz, 1H, Ar), 10.25 (brs, 1 H, HCI), 10.56 (s, 1 H, NH); ¹³ C NMR (DMSO-d6) δ 14.72, 26.37, 34.41, 34.81, 36.59, 43.34, 50.43, 55.52, 58.02, 63.78, 11.79, 112.38, 119.52, 127.79, 131.88, 131.94, 134.19, 135.79, 147.76, 148.76 164.52, 167.25, 167.40, 169.16; Analytical theory of C ₂₆ H ₃₂ N ₄ 0 ₆ + HCl + 0.48H ₂ 0: C, 57.65; H, 6. 32; N, 10.34; Cl, 6.55; H ₂ O, 1.60. Found: C, 57.70; H, 6. 28; N, 10.28, Cl, 6.81; H ₂ O, 1.61.

Example 62

(3R) -3- [7- {2-chloroacetylamino) -1-oxoisoindolin-2-yl] -3-3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide

(3R) -3- [7- (2-chloroacetylamino) -1-oxoisoindolin-2-yl] -3- (3-ethoxy-4-methoxyphenyl)-in acetonitrile (15 mL) A mixture of N, N-dimethylpropanamide (0.79 g, 1.7 mmol) and dimethylamine (2.5 mL, 2N, 5.0 mmol) in tetrahydrofuran was stirred overnight at room temperature. The solvent was removed in vacuo to give an oil. This oil was dissolved in ethyl acetate (100 mL), washed with sodium bicarbonate (2x20 mL, saturated), brine (10 mL) and dried over magnesium sulfate. The solvent was removed in vacuo to give a solid. This solid was slurried in ether / hexane (10 mL each) overnight to give a suspension. The suspension is filtered and the solid is washed with hexane to give (3R) -3- [7- (2-chloroacetylamino) -1-oxoisoindolin-2-yl]-as a white solid (622 mg, yield 77%). 3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide was obtained:

mp, 116-118 ° C .; ¹ H NMR (CDCl ₃ ) δ 1.44 (t, J = 7 Hz, 3H, CH ₃ ), 2.43 (brs, 6H, 2CH ₃ ), 2.89 (s, 3H, CH ₃ ), 3.04 (dd, J = 6.1, 15.3 Hz, 1H, CHH), 3.12 (s, 3H, CH ₃ ), 3.13 (d, J = 16 Hz, 1H, CHH), 3.19 (d, J = 16 Hz, 1H, CHH), 3.44 (dd, J = 9.1, 15 Hz, 1H, CHH), 3.85 (s, 3H, CH ₃ ), 4.07 (q, J = 7 Hz, 2H, CH ₂ ), 4.17 (d, J = 17 Hz, 1H, CHH), 4.43 (d, J = 17 Hz, 1H, CHH), 5.67 (dd, J = 6.2, 9 Hz, 1H, NCH), 6.82 (d, J = 8.4 Hz, 1H, Ar), 6.91-7.02 (m, 3H, Ar), 7.43 (t, J = 7.9 Hz, 1H, Ar), 8.52 (d, J = 8.3 Hz, 1H, Ar), 11.38 (s, 1H, NH); ¹³ C NMR (CDCl ₃ ) δ 14.65, 35.41, 36.34, 37.41, 45.92, 48.27, 53.03, 55.85, 64.06, 64.38, 111.26, 112.66, 117.05, 117.76, 118.82, 119.10, 131.79, 132.59, 137.00, 141.76, 148.148. 148.94, 168.90, 169.66, 170.03; Analytical theory of C ₂₆ H ₃₄ N ₄ 0 ₅ : C, 64.71; H, 7. 10; N, 11.61. Found: C, 64.37; H, 6.96; N, 11.53.

Example 63

(3R) -3- {4- [2- (dimethylamino) acetylamino] -1,3-dioxoisoindolin-2-yl} -3- (3-ethoxy-4-methoxyphenyl) -N , N-dimethylpropanamide hydrochloride

(3R) -3- [4- (2-chloroacetylamino) -1,3-dioxoisoindolin-2-yl] -3- (3-ethoxy-4-methoxy in acetonitrile (150 mL) A mixture of phenyl) -N, N-dimethylpropanamide (8.10 g, 16.6 mmol) and dimethylamine (27 mL, 2N, 54 mmol) in tetrahydrofuran was stirred overnight at room temperature. The solvent was removed in vacuo to give an oil. The oil was dissolved in ethyl acetate (150 mL), washed with sodium bicarbonate (2x50 mL, saturated), brine (50 mL) and dried over magnesium sulfate. The solvent was removed in vacuo to give a solid. The solid was purified by column chromatography (silica gel, 1.5% methanol in methylene chloride) to give (3R) -3- {4- [2- (dimethylamino) acetylamino as a white solid (6.3 g, yield 76%). ] -1,3-dioxoisoindolin-2-yl} -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide was obtained. To this solid in ethyl acetate (40 mL) was added hydrochloric acid (20 mL, 1N) in ether. The suspension was filtered and washed with ether to give (3R) -3- {4- [2- (dimethylamino) acetylamino] -1,3-dioxoisoindolin-2 as a yellow solid (6.4 g, 72% yield). -Yl} -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide hydrochloride was obtained:

mp, 122-124 ° C .; ¹ H NMR (DMSO-d6) δ 1.33 (t, J = 7 Hz, 3H, CH ₃ ), 2.75 (s, 3H, CH ₃ ), 2.89 (s, 6H, 2CH ₃ ), 2.98 (s, 3H, CH ₃ ), 3.22 (dd, J = 5.4, 16.5 Hz, 1H, CHH), 3.60 (dd, J = 9.2, 16.5 Hz, 1H, CHH), 3.71 (s, 3H, CH ₃ ), 3.97 (q, J = 7 Hz, 2H, CH ₂ ), 4.30 (s, 2H, CH ₂ ), 5.62 (dd, J = 5.6, 8.7 Hz, 1H, NCH), 6.86-6.93 (m, 2H, Ar), 7.00 (s, 1H, Ar), 7.65 (t, J = 7.1 Hz, 1H, Ar), 7.84 (t, J = 7.5 Hz, 1H, Ar), 8.17 (d, J = 7.9 Hz, 1H, Ar), 10.49 (s , 1H, ClH), 10.64 (s, 1H, NH); ¹³ C NMR (DMSO-d6) δ 14.72, 34.41, 34.81, 36.59, 43.21, 50.43, 55.53, 57.77, 63.78, 111.79, 112.38, 119.32, 119.45, 119.58, 127.97, 131.90, 131.95, 134.12, 135.77, 147.147. , 164.28, 167.24, 167.33, 169.15; Analytical theory of C ₂₆ H ₃₂ N ₄ 0 ₆ + HCl + 1.1H ₂ 0: C, 56.49; H, 6. 42; N, 10.13; Cl, 6.41; H ₂ 0, 3.58. Found: C, 56.33; H, 6. 61; N, 9.95; H ₂ 0, 3.51.

Example 64

3- (1,3-dioxo-4-pyrrolylisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide

3- (1,3-dioxo-4-pyrrolylisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propanoic acid (1.29 g, in tetrahydrofuran (13 mL) 2.97 mmol) and carbonylimidazole (481 mg, 2.97 mmol) were stirred at room temperature for 2 hours. Diethylamine (1.7 mL, 2N, 3.4 mmol) in tetrahydrofuran was added to the mixture, and the mixture was further stirred for 2 hours. Water (70 mL) and methylene chloride (50 mL) were added to the mixture. The organic layer was separated, washed with brine (20 mL) and dried over magnesium sulfate. The solvent was removed in vacuo to give a brown solid. This solid was purified by column chromatography (silica gel, 1: 5 ethyl acetate: methylene chloride + 0.1% MeOH) to give 3- (1,3-dioxo-4-pyrrolyl as a yellow solid (750 mg, 55% yield). Isoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide was obtained:

mp, 105-107 ° C .; ¹ H NMR (CDCl ₃ ) δ 1.43 (t, J = 7 Hz, 3H, CH ₃ ), 2.88 (s, 3H, CH ₃ ), 3.00 (s, 3H, 2CH ₃ ), 3.04 (dd, J = 4.9, 16 Hz, 1H, CHH), 3.82 (s, 3H, CH ₃ ), 3.91 (dd, J = 10.2, 16.6 Hz, 1H, CHH), 4.09 (q, J = 7 Hz, 2H, CH ₂ ), 5.82 (dd , J = 4.9, 10.2 Hz, 1H, NCH), 6.35 (t, J = 2 Hz, 2H, Ar), 6.77-6.81 (m, 1H, Ar), 7.11-7.15 (m, 4H, Ar), 7.52- 7.56 (m, 1 H, Ar), 7.63-7.71 (m, 2H, Ar); ¹³ C NMR (CDCl ³ ) δ 14.65, 34.71, 35.34, 37.02, 51.52, 55.83, 64.32, 110.48, 111.22, 112.76, 120.24, 120.66, 121.35, 122.02, 129.75, 132.00, 134.06, 134.94, 138.23, 148.15, 148.15, 166.19, 167.34, 169.58; Analytical theory of C ₂₆ H ₂₇ N ₃ 0 ₅ + 0.15H ₂ 0: C, 67.30; H, 5.99; N, 8.85. Found: C, 67.16; H, 5.88; N, 8.92.

Example 65

2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -4- (imidazolylmethyl) isoindolin-1,3-dione

4- (aminomethyl) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyl) isoindolin-1 in dilute H ₃ PO ₄ (20 mL, pH = 2), A mixture of 3-dione (1.38 g, 3.20 mmol), glyoxal (40%, 0.46 g, 3.20 mmol) and formaldehyde (37%, 0.26 g, 3.20 mmol) was heated to 80-90 ° C. Ammonium chloride (0.17 g) was added to the mixture and the mixture was kept at 80-90 ° C. for 2 hours. The mixture was cooled to 15 ° C. and basified to pH 8 with K ₂ CO ₃ . The mixture was extracted with methylene chloride and the methylene chloride solution was washed with water (30 mL), brine (30 mL) and dried. The solvent was removed and the residue was purified by chromatography (silica gel, methylene chloride: methanol 97: 3) to give 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methyl as a white solid). Sulfonyl) ethyl] -4- (imidazolemethyl) isoindolin-1,3-dione (0.5 g, 32%) was obtained. To this solid solution in ethyl acetate (5 mL) was added hydrochloric acid (2 mL, 1N) in ether. The resulting suspension was filtered and washed with ether to give 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -4- (imidazolemethyl) iso as a white solid. Indolin-1,3-dione hydrochloride (0.26 g) was obtained:

mp 126-128 ° C; ¹ H NMR (DMSO-d6) δ 9.19 (s, 1H), 7.93-7.83 (m, 2H), 7.72 (s, 1H), 7.58 (d, J = 7.2Hz, 1H), 7.11 (d, J = 1.2 Hz, 1H), 7.016.92 (m, 2H), 5.89 (s, 2H), 5.83-5.77 (dd, J = 4.5, 10.1 Hz, 1H), 4.40-4.30 (dd, J = 10.4, 14.3 Hz , 1H), 4.21-4.14 (dd, J = 4.7, 14.4 Hz, 1H), 4.03 (q, J = 6.9 Hz, 2H), 3.73 (s, 3H), 3.00 (s, 3H), 1.32 (t, J = 6.9 Hz, 3H); ¹³ C NMR (DMSO-d6) δ 167.57, 166.97, 148.94, 147.86, 136.21, 135.41, 134.21, 133.46, 131.76, 129.37, 127.88, 123.59, 122.20, 120.56, 119.86, 112.43, 111.72, 63.82, 51.82 , 47.03, 41.12, 14.67; Analytical theory of C ₂₄ H ₂₆ N ₃ 0 ₆ SCl + 0.53H ₂ 0: C, 54.44; H, 5. 15; N, 7.93; S, 6.06; Cl, 6.69. Found: C, 54.58; H, 5.11; N, 7.66; S, 6.23; Cl, 6.71.

Example 66

N-({2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} methyl) acetamide

4- (aminomethyl) -2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] isoindoline-1,3-dione (0.92 g, 2.13 mmol) The stirred mixture of and acetic anhydride (10 mL) was heated to reflux for 40 minutes and then cooled to room temperature. Excess acetic anhydride was removed in vacuo. The residue was dissolved in ethyl acetate (50 mL), washed with 2N hydrochloric acid (20 mL), water (20 mL), brine (20 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (silica gel, methylene chloride: ethyl acetate 75:25) to give N-({2- [1- (3-ethoxy-4-methoxy) as a white solid. Phenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} methyl) acetamide (0.56 g, 55%) was obtained:

mp, 84-86 ° C .; ¹ H NMR (CDCl ₃ ) δ 7.74-7.62 (m, 3H), 7.13-7.09 (m, 2H), 6.85-6.82 (m, 1H), 6.74-6.69 (m, 1H), 5.92-5.86 (dd, J = 4.5, 10.1 Hz, 1H), 4.73 (d, J = 6.3 Hz, 2H), 4.59-4.49 (dd, J = 10.5, 14.2 Hz, 1H), 4.12 (q, J = 6.8 Hz, 2H), 3.84 (s, 3H), 3.81-3.74 (m, 1H), 2.84 (s, 3H), 1.96 (s, 3H), 1.46 (t, J = 6.9 Hz, 3H); ¹³ C NMR (CDCl ₃ ) δ 170.15, 168.58, 167.77, 149.64, 148.54, 138.05, 135.38, 134.39, 132.07, 129.32, 128.21, 122.73, 120.40, 112.41, 111.37, 64.45, 55.88, 54.61, 48.65, 41.55, 41. 23.08, 14.62; Analytical theory of C ₂₃ H ₂₆ N ₂ 0 ₇ S: C, 58.22; H, 5.52; N, 5.90; S, 6.76. Found: C, 57.87; H, 5.52; N, 5.65; S, 6.66.

Example 67

2-chloro-N-({2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} methyl Acetamide

Triethylamine (0.52g, 5.11mmol) to 4- (aminomethyl) -2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -isoindolin- To a suspended solution of 1,3-dione hydrochloride (1.0 g, 2.13 mmol) was added. The clear solution was cooled to 5 ° C. in an ice bath. Chloroacetyl chloride (0.30 g, 2.56 mmol) was added keeping the temperature between 5-9 ° C. The mixture was stirred at 5 ° C. for 30 minutes and then warmed to room temperature for 2 hours. The mixture was washed with water (2x30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (silica gel, methylene chloride: ethyl acetate 7: 3) to give 2-chloro-N-({2- [1- (3-ethoxy-4-meth Toxylphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} methyl) acetamide (1.0 g, 92%) was obtained:

¹ H NMR (CDCl ₃ ) δ 7.84-7.65 (m, 4H), 7.14-7.12 (m, 2H), 6.86 (d, J = 8.9 Hz, 1H), 5.94-5.88 (dd, J = 4.6, 10.3 Hz , 1H), 4.79 (d, J = 6.5 Hz, 2H), 4.61-4.51 (dd, J = 10.4, 14.4 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 4.02 (s, 2H) , 3.85 (s, 3H), 3.80-3.72 (dd, J = 4.6, 14.4 Hz, 1H), 2.86 (s, 3H), 1.47 (t, J = 7.0 Hz, 3H).

Example 68

2- (dimethylamino) -N-({2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4- Methyl) acetamide hydrochloride

Dimethylamine / methanol (2.0 M, 2.95 mL) was added 2-chloro-N-({2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) in tetrahydrofuran. To a stirred solution of ethyl] -1,3-dioxoisoindolin-4-yl} methyl) acetamide (1.0 g, 1.96 mmol) was added and the mixture was stirred at room temperature for 24 hours. Tetrahydrofuran was removed in vacuo and the residue was dissolved in methylene chloride (60 mL). The methylene chloride solution was washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent is removed in vacuo and the residue is purified by chromatography (silica gel, methylene chloride: methanol 97.5: 2.5) to give 2- (dimethylamino) -N-({2- [1- (3-ethoxy-4 -Methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} methyl) acetamide (0.6 g, 59%) was obtained. To a stirred solution of amine in ethyl acetate (10 mL) was added 1N hydrochloric acid in ether (4 mL). The resulting suspension was filtered and washed with ether to give 2- (dimethylamino) -N-({2- [1- (3-ethoxy4-methoxyphenyl) -2- (methylsulfonyl) as a white solid. Ethyl] -1,3-dioxoisoindolin-4-yl} methyl) acetamide hydrochloride (0.55 g) was obtained:

mp, 103-105 ° C .; ¹ H NMR (DMSO-d6) δ 10.06 (s, 1H), 9.37 (m, 1H), 7.83-7.73 (m, 3H), 7.10 (s, 1H), 6.97-6.92 (m, 2H), 5.82- 5.76 (dd, J = 4.1, 10.2 Hz, 1H), 4.81 (d, J = 5.6 Hz, 2H), 4.38-4.32 (dd, J = 10.3, 14.1 Hz, 1H), 4.19-4.12 (dd, J = 4.4, 14.4 Hz, 1H), 4.05-3.08 (m, 4H), 3.73 (s, 3H), 3.02 (s, 3H), 2.82 (s, 6H), 1.32 (t, J = 6.9 Hz, 3H); ¹³ C NMR (DMSO-d6) δ 167.60, 167.20, 164.79, 148.88, 147.85, 137.84, 134.69, 133.36, 131.51, 129.59, 127.09, 122.14, 119.79, 112.41, 111.76, 63.84, 57.17, 55.49.52. , 41.09, 37.82, 14.67; Analytical theory of C ₂₅ H ₃₂ N ₃ 0 ₇ SCl + 0.56H ₂ 0: C, 53.23; H, 5.92; N, 7.45, S, 5.68; Cl, 6.28. Found: C, 53.22; H, 5.87; N, 7.37; S, 5.64; Cl, 6.52.

Example 69

4- [bis (methylsulfonyl) amino] -2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] isoindoline-1,3-dione

Methylsulfonyl chloride (0.3 g, 2.62 mmol) was added to 4-amino-2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) -ethyl] in methylene chloride (60 mL). To a stirred suspension of isoindolin-1,3-dione (0.55 g, 1.31 mmol) and triethylamine (0.4 g, 3.93 mmol) was added and the resulting mixture was stirred for 24 hours. The mixture was then washed with saturated sodium bicarbonate (25 mL), 1N hydrochloric acid (25 mL), H ₂ O (25 mL), brine (25 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The residue was slurried in methanol: tetrahydrofuran (2: 1) and separated by filtration to yield 4- [bis (methylsulfonyl) amino] -2- [1- (3-ethoxy-4 as white solid). -Methoxyphenyl) -2- (methylsulfonyl) ethyl] isoindoline-1,3-dione (0.53 g, 70%) was obtained:

mp, 277-279 ° C .; ¹ H NMR (DMSO-d6) δ 8.05-7.95 (m, 3H), 7.11-6.92 (m, 3H), 5.78-5.74 (dd, J = 5.5, 9.1 Hz, 1H), 4.31-4.22 (m, 2H ), 3.99 (q, J = 6.9 Hz, 2H), 3.73 (s, 3H), 3.55 (s, 6H), 2.95 (s, 3H), 1.31 (t, J = 7.0 Hz, 3H); ¹³ C NMR (DMSO-d6) δ 166.11, 165.35, 148.96, 147.88, 138.63, 136.05, 132.60, 129.64, 129.31, 129.27, 125.26, 119.89, 112.33, 111.76, 63.73, 55.46, 53.38, 47.92, 43.50 , 14.61; Analytical theory of C ₂₂ H ₂₆ N ₂ 0 ₁₀ S ₃ : C, 45.95; H, 4.56; N, 4.87; S, 16.74. Found: C, 45.90; H, 4.40; N, 4.75; S, 16.55.

Example 70

2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -4-[(methylsulfonyl) amino] isoindoline-1,3-dione

4- [bis (methylsulfonyl) amino] -2- [1- (3-ethoxy-4methoxyphenyl) -2- (methylsulfonyl) ethyl] isoindolin-1 in CH ₃ CN (120 mL) A mixture of, 3-dione (0.8 g, 1.39 mmol) and 2N NaOH (1.59 mL, 3.1 8 mmol) was stirred for 8 hours at room temperature. The mixture was neutralized with 6N hydrochloric acid (0.6 mL) and then concentrated. The residue was dissolved in methylene chloride (90 mL), washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent is removed in vacuo, the resulting solid is slurried in ethanol (50 mL) and separated by filtration to give 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methyl as white solid). Sulfonyl) ethyl] -4-[(methylsulfonyl) amino] isoindolin-1,3-dione (0.6 g, 86%) was obtained:

mp, 191-193 ° C; ¹ H NMR (DMSO-d6) δ 9.31 (s, 1H), 7.85-7.74 (m, 2H), 7.61 (d, J = 6.6 Hz, 1H), 7.08 (s, 1H), 7.00-6.91 (m, 2H), 5.80-5.74 (m, 1H), 4.38-4.28 (dd, J = 10.5, 14.3 Hz, 1H), 4.19-4.11 (dd, J = 4.5, 14.3 Hz, 1H), 4.03 (q, J = 6.9 Hz, 2H), 3.73 (s, 3H), 3.27 (s, 3H), 3.00 (s, 3H0, 1.32 (t, J = 6.9 Hz, 3H); ¹³ C NMR (DMSO -d6) δ 167.43, 166.71 , 148.92, 147.87, 136.26, 135.73, 131.91, 129.40, 125.01, 119.79, 118.39, 117.59, 112.41, 111.76, 63.83, 55.48, 53.00, 47.35, 41.06, 40.63, 14.64; C ₂₁ H ₂₄ N ₂ 0 ₈ S ₃ + Analytical Theory of 0.05 Disulfonamide: C, 50.56; H, 4.86; N, 5.60; S, 13.12 Found: C, 50.25; H, 4.81; N, 5.60; S, 13.12.

Example 71

N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-hydroxyphenyl] -1,3-dioxoisoindolin-4-yl} acetamide

5-amino-5- (3-ethoxy-4-methoxyphenyl) pentan-3-ol hydrochloride (1.15 g, 3.97 mmol) and 3-acetamidophthal anhydride (0.82 g, 3.97 mmol in DMF (20 mL) ) And triethylamine (0.4 g, 3.97 mmol) were heated at 80-90 ° C. for 6 hours. The mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate (80 mL), washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent is removed in vacuo and the residue is purified by chromatography (silica gel, methylene chloride: ethyl acetate 8: 2) to give N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3 -Hydroxypentyl] -1,3-dioxoisoindolin-4-yl} acetamide (1.35 g, 77%) was obtained:

¹ H NMR (CDCl ₃ ) δ 9.52 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.48 (d, J = 7.3 Hz, 1H) , 7.09-7.07 (m, 2H), 6.83-6.80 (m, 1H), 5.61-5.55 (J = 3.9, 11.9 Hz, 1H), 4.11 (q, J = 6.9 Hz, 2H), 3.84 (s, 3H ), 3.47 (m, 1H), 2.97-2.86 (m, 1H), 2.25 (s, 3H), 2.06-1.95 (m, 1H), 1.78 (b, 1H), 1.62-1.52 (m, 2H), 1.45 (t, J = 7.0 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H); ¹³ C NMR (CDCl ₃ ) δ 170.39, 169.23, 168.11, 148.94, 148.14, 137.32, 135.83, 131.81, 131.19, 124.72, 120.30, 117.94, 115.31, 112.87, 111.09, 70.01, 64.36, 55.86, 51.29.37. 24.92, 14.73, 9.90.

Example 72

N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxopentyl] -1,3-dioxoisoindolin-4-yl} acetamide

N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-hydroxypentyl] -1,3-dioxoisoindolin-4-yl} acetamide in methylene chloride (35 mL) 1.35 g, 3.06 mmol), pyridinium chlorochromate (1.32 g, 6.12 mmol) and celite (0.6 g) were stirred for 5 hours. The mixture was filtered through celite and the filtrate was washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (silica gel, methylene chloride: ethyl acetate 9: 1) to give N- {2- [1- (3-ethoxy-4-methoxyphenyl as a white solid. ) -3-oxopentyl] -1,3-dioxoisoindolin-4-yl} acetamide (1.08 g, 81%) was obtained:

mp, 137-139 ° C .; 1 H NMR (CDCl ₃ ) δ 9.53 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 7.3 Hz, 1H), 7.07-7.04 (m, 2H), 6.83 (d, J = 8.8 Hz, 1H), 5.76-5.70 (dd, J = 5.2, 10.1 Hz, 1H), 4.12 (q, J = 6.9 Hz, 2H), 4.02 -3.90 (dd, J = 10.1, 17.9 Hz, 1H), 3.83 (s, 3H), 3.26-3.17 (dd, J = 5.2, 17.9 Hz, 1H), 2.49 (q, J = 7.3 Hz, 2H), 2.26 (s, 3H), 1.46 (t, J = 6.9 Hz, 3H), 1.02 (t, J = 7.3 Hz, 3H); ¹³ C NMR (CDCl ₃ ) δ 208.03, 170.02, 169.15, 167.86, 149.12, 148.33, 137.34, 135.76, 131.39, 131.22, 124.64, 120.00, 117.87, 115.29, 112.50, 111.27, 64.38, 55.89,49.94, 43. 24.92, 14.71, 7.52; Analytical theory of C ₂₄ H ₂₆ N ₂ 0 ₆ : C, 65.74; H, 5.98; N, 6.39. Found: C, 65.74; H, 6. 34; N, 6.38.

Example 73

2-[(1R) -1- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -4- (pyrrolylmethyl) isoindolin-1,3-dione

(4R) -amino-4- (3-ethoxy-4-methoxyphenyl) butan-2-ol hydrochloride (1.1 4 g, 4.14 mmol), 3- (pyrrolylmethyl) phthalic anhydride (0.94) in DMF (25 mL) g, 4.14 mmol) and triethylamine (0.4 2 g, 4.14 mmol) were heated to 80-90 ° C. for 17 hours. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (80 mL), washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent is removed in vacuo and the residue is purified by chromatography (silica gel, methylene chloride: ethyl acetate 9: 1) to give 2-[(1R) -1- (3-ethoxy-4-methoxyphenyl)- 3-hydroxybutyl] -4- (pyrrolylmethyl) isoindolin-1,3-dione (1.27 g, 68%) was obtained:

¹ H NMR (CDCl ₃ ) δ 7.68 (d, J = 7.3 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.12-7.08 (m, 2H), 6.95 (d, J = 7.9 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.73-6.72 (m, 2H), 6.23-6.21 (m, 2H), 5.61-5.55 (dd, 1H), 4.13 (q, J = 7.1 Hz , 2H), 3.84 (s, 3H), 3.78 (m, 1H), 2.94-2.83 (m, 1H), 2.16-2.08 (m, 1H), 1.76 (s, 1H), 1.46 (t, J = 6.9 Hz, 3H), 1.29 (d, J = 6.2 Hz, 3H); ¹³ C NMR (CDCl ₃ ) δ 168.86, 168.35, 148.94, 148.11, 138.35,134.51, 132.43, 132.01, 131.77, 127.04, 122.37, 121.44, 120.55, 113.00, 111.09, 109.11, 64.98, 64.35, 55.87, 51.43, 51.43 , 40.03, 23.68, 14.73.

Example 74

2-[(1R) -1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -4- (pyrrolylmethyl) isoindolin-1,3-dione

2-[(1R) -1- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -4- (pyrrolylmethyl) isoindolin-1,3- in methylene chloride (35 mL) A mixture of dione (1.26 g, 2.81 mmol), pyridinium chlorochromate (1.21 g, 5.62 mmol) and celite (0.6 g) was stirred at room temperature for 4 hours. The mixture was filtered through celite and the filtrate was washed with water (30 mL) and brine (30 mL). The filtrate was dried over magnesium sulfate. The solvent is removed in vacuo and the residue is purified by chromatography (silica gel, hexanes: ethyl acetate 6: 4) to give 2-[(1R) -1- (3-ethoxy-4-methoxyphenyl as a white solid. ) -3-oxobutyl] -4- (pyrrolylmethyl) isoindolin-1,3-dione (0.83 g, 66%) was obtained:

mp, 143-145 ° C .; ¹ H NMR (CDCl ₃ ) δ 7.66 (d, J = 7.3 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.10-7.06 (m, 2H), 6.93 (d, J = 7.7 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.73-6.71 (m, 2H), 6.22-6.21 (m, 2H), 5.78-5.72 (dd, J = 5.4, 9.8 Hz, 1H), 3.32 -3.23 (dd, J = 5.4, 18.0 Hz, 1H), 2.18 (s, 3H), 1.46 (t, J = 6.9 Hz, 3H); ¹³ C NMR (CDCl ₃ ) δ 205.31, 168.53, 167.83, 149.11, 148.33, 138.31, 134.43, 132.37, 132.04,131.55, 127.05, 122.34, 121.46, 120.14, 112.59, 111.29, 109.08, 64.39, 55.91, 50.91, 50. 44.88, 30.17, 14.72; Analytical theory of C ₂₆ H ₂₆ N ₂ 0 ₅ : C, 69.94; H, 5.87; N, 6.27. Found: C, 70.01; H, 6.01; N, 6.08.

Example 75

N- {2-1- (3-cyclopentyloxy-4-methoxyphenyl) -3-hydroxybutyl])-1,3-dioxoisoindolin-4-yl} acetamide

4-amino-4- (3-cyclopentyloxy-4-methoxyphenyl) butan-2-ol hydrochloride (1.20 g, 3.80 mmol) and 3-acetamidophthal anhydride (0.78 g, 3.80 in DMF (15 mL) mmol) and triethylamine (0.38 g, 3.80 mmol) were heated at 80-90 ° C. for 7 hours. The mixture was cooled to rt and poured into water (80 mL). The resulting mixture was extracted with EtOAC (3 × 30 mL). The combined ethyl acetate extracts were washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (silica gel, methylene chloride: EtOAC 8: 2) to give N- {2-1- (3-cyclopentyloxy-4-methoxyphenyl) as a white solid. 3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide (1.3 g, 73%) was obtained:

¹ H NMR (CDCl ₃ ) δ 9.53 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.48 (d, J = 7.3 Hz, 1H) , 7.08-7.03 (m, 2H), 6.82 (d, J = 8.2 Hz, 1H), 5.57-5.51 (dd, J = 4.2, 11.6 Hz, 1H), 4.78 (m, 1H), 3.81 (s, 3H ), 3.77-3.74 (m, 1H), 2.91-2.81 (m, 1H), 2.25 (s, 3H), 2.13-1.60 (m, 10H), 1.29 (d, J = 6.1 Hz, 3H); ¹³ C NMR (CDCl ₃ ) δ 170.38, 169.21, 168.06, 149.70, 147.50, 137.33, 135.84, 131.54, 131.20, 124.71, 120.28, 117.93, 115.31.115.07, 111.55, 80.45, 64.89, 55.97, 51.35, 39.73. 24.91, 24.04, 23.76, 21.02.

Example 76

N- {2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide

N- {2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide in methylene chloride (35 mL) (1.28 g, 2.74 mmol), pyridinium chlorochromate (1.18 g, 5.48 mmol) and celite (0.6 g) were stirred at room temperature for 5 hours. The mixture was filtered through celite and the filtrate was washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (silica gel, methylene chloride: ethyl acetate 9: 1) to give N- {2- [1- (3-cyclopentyloxy-4-methoxyphenyl as a white solid. ) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide (1.09 g, 85%) was obtained:

mp, 145-147 ° C .; ¹ H NMR (CDCl ₃ ) δ 9.53 (s, 1H), 8.70 (d, J = 8.4Hz, 1H), 7.62 (t, J = 7.6Hz, 1H), 7.46 (d, J = 7.3Hz, 1H) , 7.07-7.01 (m, 2H), 6.81 (d, J = 8.2 Hz, 1H), 5.73-5.67 (dd, J = 5.1, 9.8 Hz, 1H), 4.77 (m, 1H), 4.04-3.93 (dd , J = 10.0, 18.1 Hz, 1H), 3.80 (s, 3H), 3.28-3.19 (dd, J = 5.1, 18.0 Hz, 1H), 2.26 (s, 3H), 2.18 (s, 3H), 1.97- 1.61 (m, 8 H); ¹³ C NMR (CDCl ₃ ) δ 205.22, 170.03, 169.15, 167.82, 149.83, 147.70, 137.33, 135.77, 131.23, 124.63, 119.88, 117.87, 115.28, 114.57, 111.72, 80.46, 55.99, 49.94, 44.82, 32.82, 44.82. 24.92, 24.05; Analytical theory of C ₂₆ H ₂₈ N ₂ 0 ₆ : C, 67.23; H, 6.08; N, 6.03. Found: C, 66.96; H, 6.06; N, 5.89.

Example 77

2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxobutyl] -4-pyrrolylisoindolin-1,3-dione

2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxobutyl] -4-aminoisoindolin-1,3-dione (0.41 g, in 1,2-dichloroethane (10 mL) 0.97 mmol), 2,5-dimethoxytetrahydrofuran (0.14 g, 1.07 mmol) and acetic acid (2 mL) were refluxed for 1 hour. The mixture was diluted with methylene chloride (25 mL), washed with water (2x20 mL), brine (20 mL) and dried. The solvent was removed and the residue was purified by chromatography (silica gel, hexanes: ethyl acetate 6: 4) to give 2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxobutyl as a white solid. ] -4-pyrrolylisoindolin-1,3-dione (0.41 g, 91%) was obtained:

mp, 142-144 ° C .; ¹ H NMR (CDCl ₃ ) δ 7.72-7.56 (m, 3H), 7.14-7.04 (m, 4H), 6.79 (d, J = 8.2 Hz, 1H), 6.38 (m, 2H), 5.77-5.71 (dd , J = 5.4, 9.8 Hz, 1H), 4.77 (m, 1H), 4.05-3.94 (dd, J = 9.9, 18.9 Hz, 1H), 3.79 (s, 3H), 3.30-3.21 (dd, J = 5.4 , 18.0 Hz, 1H), 2.16 (s, 3H), 1.98-1.60 (m, 8H); ¹³ C NMR (CDCl ₃ ) δ 205.31, 167.21, 166.14, 149.75, 147.61, 138.35, 135.09, 133.98, 131.34, 129.91, 126.04, 121.31, 120.74, 120.20, 114.72, 111.68, 110.61, 80.38, 55.9772 32.74, 30.12, 24.03; Analytical theory of C ₂₈ H ₂₈ N ₂ 0 ₅ : C, 71.17; H, 5.97; N, 5.93. Found: C, 71.09; H, 6.09; N, 5.80.

Example 78

2- [1- (3,4-dimethoxyphenyl) -3-oxobutyl] -4- [bis (methylsulfonyl) amino] isoindoline-1,3-dione

2- [1- (3,4-dimethoxyphenyl) -3-oxobutyl] -4-aminoisoindolin-1,3-dione (1.02 g, 2.77 mmol) and triethylamine in methylene chloride (40 mL) ( 1.40 g, 13.85 mmol) was cooled to 5 ° C. Methanesulfonyl chloride (1.27 g, 11.08 mmol) was added at 5-8 ° C. and the resulting mixture was stirred at room temperature for 2 hours. The mixture was washed with saturated sodium bicarbonate (20 mL), 1N hydrochloric acid (20 mL), water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (silica gel, methylene chloride: ethyl acetate 9: 1) to give 2- [1- (3,4-dimethoxyphenyl) -3-oxobutyl as a white solid. ] -4- [bis (methylsulfonyl) amino] isoindolin-1,3-dione (1.18 g, 81%) was obtained:

mp, 194-196 ° C; ¹ H NMR (DMSO-d6) δ 8.02-7.93 (m, 3H), 6.99-6.90 (m, 3H), 5.85 (t, J = 6.7 Hz, 1H), 3.75-3.65 (m, 1H), 3.71 ( s, 6H), 3.56 (s, 6H), 3.53-3.46 (m, 1H), 2.11 (s, 3H); ¹³ C NMR (DMSO-d6) δ 205.79, 166.58, 165.78, 148.64, 148.32, 138.48, 135.86, 132.68, 131.50, 129.85, 129.15, 125.06, 119.35, 111.58, 110.91, 55.49, 55.39, 49.27, 44. , 29.92; Analytical theory of C ₂₂ H ₂₄ N ₂ O ₉ S ₂ : C, 50.37; H, 4.61; N, 5.34, S, 12.23. Found: C, 50.43, H, 4.77; N, 5.16; S, 12.22.

Claims (37)

(a) isoindolin of formula (I): and (b) acid addition salts of the isoindolin derivatives which are susceptible to proton addition reactions; Compound selected from the group consisting of. (Formula 1) Where R ¹ and R ² are each independently of each other alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, cycloalkoxy of 3 to 18 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, or cycloalkyl Cycloalkylmethoxy having 3 to 18 carbon atoms; One of X and X 'is = C = O or = S0 ₂ , and the other of X and X' is _divalent selected from = C = O, = CH ₂ , = S0 ₂ or = CH ₂ C = O; R ³ is —SO ₂ —Y, —COZ, —CN, or hydroxyalkyl of 1 to 6 carbon atoms, From here, Y is alkyl of 1 to 6 carbon atoms, phenyl, or benzyl; Z is -NR ^{6 "} R ^7" , alkyl of 1 to 6 carbon atoms, phenyl, or benzyl; R ^{6 "} is hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, phenyl, benzyl, or alkanoyl of 2 to 5 carbon atoms, each of which is halo, amino, or 1 to 4 carbon atoms Unsubstituted or substituted with an alkylamino of the atom; R ^{7 ″} is hydrogen or alkyl of 1 to 4 carbon atoms; n has a value of 1, 2, or 3; (i) when R ⁴ and R ⁵ are taken together, -NH-CH ₂ -R ^8- , -NH-CO-R ⁸ -or -N = CH-R ^8- , wherein -R ⁸ -is- CH _2- , -O-, -NH-, -CH = CH-, -CH = N-, or -N = CH-, or (ii) when independent of one another, (1) one of R ⁴ and R ⁵ is hydrogen and the other of R ⁴ and R ⁵ is imidazole, pyrrolyl, oxadizolyl, triazolyl, or Is, Wherein z is 0 or 1, provided that (i) R ³ is SO ₂ -Y-COZ or -CN, and (ii) z is not 0 when R ⁴ or R ⁵ is hydrogen; When R ⁶ is independent of R ⁷ , hydrogen; Alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, alkanoyl of 2 to 5 carbon atoms, or cycloalkanoyl of 2 to 6 carbon atoms, these are halo, amino, monoalkylamino or dialkyl, respectively Unsubstituted or substituted with amino, wherein each alkyl group contains 1 to 4 carbon atoms; Phenyl; benzyl; Benzoyl; Alkoxycarbonyl of 2 to 5 carbon atoms; Alkoxyalkylcarbonyl of 2 to 5 carbon atoms; N-morpholinocarbonyl; Carbamoyl; N-substituted carbamoyl, wherein the substituents are alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, or alkanoyl of 2 to 5 carbon atoms, each of which is halo, amino, monoalkylamino Or unsubstituted or substituted with dialkylamino, wherein each alkyl group contains 1 to 4 carbon atoms; Phenyl; benzyl; Or methylsulfonyl; R ⁷ is hydrogen, alkyl of 1 to 4 carbon atoms, methylsulfonyl; Or alkoxyalkylcarbonyl of 2 to 5 carbon atoms; R ⁶ and R ⁷ , when taken together, represent one or two carbon atoms substituted by —CH═CH—CH═CH—, —CH═CH—N═CH—, or amino, alkylamino, or dialkylamino; Alkylidene, wherein each alkyl group has 1 to 4 carbon atoms; or (2) one of R ⁴ and R ⁵ Is, Wherein R ⁶ , R ⁷ and z are each as defined above; The other one of R ⁴ and R ⁵ Is, Wherein z 'is 0 or 1; R ^{6 'is} independently selected for R ⁶ but same meaning as R ^6; R ^{7 'are} independently selected to only have the same meaning as R ⁷ R ^7; Carbon atoms marked with * are chiral centers. The compound of claim 1, wherein R ⁴ and R ⁵ together are —NH—CH ₂ —R ₈ , —NH—CO—R ⁸ — or —N═CH—R ⁸ —, wherein —R ⁸ — is —CH _2- , -O-, -NH-, -CH = CH-, -CH = N-, or -N = CH-. 3. A compound according to claim 2 wherein X and X 'are both = C = O. 3. A compound according to claim 2, wherein one of X and X 'is = C = O and the other of X and X' is = CH ₂ . 3. A compound according to claim 2, wherein one of X and X 'is = C = O and the other of X and X' is = SO ₂ . 3. A compound according to claim 2, wherein R ¹ and R ² are each independently of each other methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propoxy, i-propoxy, cyclopentoxy, cyclohex Cycloheptoxy, cyclopentyl, cyclohexyl, cycloheptyl, or cyclopropylmethoxy. 2. The compound of claim 1, wherein one of R ⁴ and R ⁵ is hydrogen and the other of R ⁴ and R ⁵ is imidazolyl, pyrrolyl, oxdiazolyl, or triazolyl. 8. A compound according to claim 7, wherein X and X 'are both = C = O. 8. A compound according to claim 7, wherein one of X and X 'is = C = O and the other of X and X' is = CH ₂ . 8. A compound according to claim 7, wherein one of X and X 'is = C = O and the other of X and X' is = SO ₂ . 8. A compound according to claim 7, wherein R ¹ and R ² are each independently of each other methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propoxy, i-propoxy, cyclopentoxy, cyclohexoxy Cycloheptoxy, cyclopentyl, cyclohexyl, cycloheptyl, or cyclopropylmethoxy. The compound of claim 1, wherein one of R ⁴ and R ⁵ is Is, Wherein z is 0 or 1, provided that (i) R ³ is SO ₂ -Y-COZ or -CN, and (ii) z is not 0 when R ⁴ or R ⁵ is hydrogen; When R ⁶ is independent of R ⁷ , hydrogen; Alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, or alkanoyl of 2 to 5 carbon atoms, which are unsubstituted or substituted with halo, amino, monoalkylamino or dialkylamino, respectively, wherein Each alkyl group contains 1 to 4 carbon atoms; Phenyl; benzyl; Benzoyl; Alkoxycarbonyl of 2 to 5 carbon atoms; N-morpholinocarbonyl; Carbamoyl; N-substituted carbamoyl, wherein the substituents are alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, or alkanoyl of 2 to 5 carbon atoms, each of which is halo, amino, monoalkylamino Or unsubstituted or substituted with dialkylamino, wherein each alkyl group contains 1 to 4 carbon atoms; Phenyl; benzyl; Or methylsulfonyl; R ⁷ is hydrogen, alkyl of 1 to 4 carbon atoms, or methylsulfonyl; or R ⁶ and R ⁷ , when taken together, represent one or two carbon atoms substituted by —CH═CH—CH═CH—, —CH═CH—N═CH—, or amino, alkylamino, or dialkylamino; Alkylidene, wherein each alkyl group has from 1 to 4 carbon atoms Compound characterized by the above-mentioned. 13. A compound according to claim 12, wherein both X and X 'are = C = O. 13. The compound of claim 12, wherein one of X and X 'is = C = O and the other of X and X' is = CH ₂ . 13. The compound of claim 12, wherein one of X and X 'is = C = O and the other of X and X' is = SO ₂ . 13. A compound according to claim 12, wherein R ¹ and R ² are each independently of each other methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propoxy, i-propoxy, cyclopentoxy, cyclohex Cycloheptoxy, cyclopentyl, cyclohexyl, cycloheptyl, or cyclopropylmethoxy. The method of claim 12, When R ⁶ is independent of R ⁷ , hydrogen; Alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, or alkanoyl of 2 to 5 carbon atoms, which are unsubstituted or substituted with halo, amino, monoalkylamino or dialkylamino, respectively, wherein Each alkyl group contains 1 to 4 carbon atoms; Phenyl; benzyl; Benzoyl; Alkoxycarbonyl of 2 to 5 carbon atoms; N-morpholinocarbonyl; Carbamoyl; N-substituted carbamoyl, wherein the substituents are alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, or alkanoyl of 2 to 5 carbon atoms, each of which is halo, amino, monoalkylamino Or unsubstituted or substituted with dialkylamino, wherein each alkyl group contains 1 to 4 carbon atoms; Phenyl; benzyl; Or methylsulfonyl; R ⁷ is hydrogen, alkyl of 1 to 4 carbon atoms, or methylsulfonyl The compound characterized by the above-mentioned. 18. The compound of claim 17, wherein R ⁶ is hydrogen, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms; Phenyl, benzyl, or methylsulfonyl. The method of claim 17, R ⁶ is alkanoyl of 2 to 5 carbon atoms unsubstituted or substituted with halo, amino, monoalkylamino or dialkylamino, wherein each alkyl group contains 1 to 4 carbon atoms; Benzoyl; Alkoxycarbonyl of 2 to 5 carbon atoms; N-morpholinocarbonyl; Carbamoyl; And N-substituted carbamoyl, wherein the substituents are methyl, ethyl, or trifluoromethyl; R ⁷ is hydrogen The compound characterized by the above-mentioned. 13. A 1 or 2 carbon atom as defined in claim 12, wherein R ⁶ and R ⁷ together are substituted by CH═CH—CH═CH—, —CH═CH—N═CH—, or amino, alkylamino or dialkylamino. Alkylidene, wherein each alkyl group has 1 to 4 carbon atoms. The compound of claim 1, wherein one of R ⁴ and R ⁵ is Is, Wherein z is 0 or 1, provided that (i) R ³ is SO ₂ -Y-COZ or -CN, and (ii) z is not 0 when R ⁴ or R ⁵ is hydrogen; When R ⁶ is independent of R ⁷ , hydrogen; Alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, or alkanoyl of 2 to 5 carbon atoms, which are unsubstituted or substituted with halo, amino, monoalkylamino or dialkylamino, respectively, wherein Each alkyl group contains 1 to 4 carbon atoms; Phenyl; benzyl; Benzoyl; Alkoxycarbonyl of 2 to 5 carbon atoms; N-morpholinocarbonyl; Carbamoyl; N-substituted carbamoyl, wherein the substituents are alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, or alkanoyl of 2 to 5 carbon atoms, each of which is halo, amino, monoalkylamino Or unsubstituted or substituted with dialkylamino, wherein each alkyl group contains 1 to 4 carbon atoms; Phenyl; benzyl; Or methylsulfonyl; R ⁷ is hydrogen, alkyl of 1 to 4 carbon atoms, or methylsulfonyl; or R ⁶ and R ⁷ , when taken together, represent one or two carbon atoms substituted by —CH═CH—CH═CH—, —CH═CH—N═CH—, or amino, alkylamino, or dialkylamino; Alkylidene, wherein each alkyl group has 1 to 4 carbon atoms; One of R ⁴ and R ⁵ Is, Wherein z 'is 0 or 1, provided that (i) R ³ is SO ₂ -Y-COZ or -CN and (ii) z is not 0 when R ⁴ or R ⁵ is hydrogen; R ^{6 'is} independently selected for R ⁶ but same meaning as R ^6; R ^{7 'is} only have the same meaning as R ⁷ R ⁷ is independently selected in Compound characterized by the above-mentioned. 22. The compound of claim 21, wherein X and X 'are both = C = O. 22. The compound of claim 21, wherein one of X and X 'is = C = O and the other of X and X' is = CH ₂ . 22. The compound of claim 21, wherein one of X and X 'is = C = O and the other of X and X' is = SO ₂ . 22. The compound of claim 21, wherein R ¹ and R ² are each independently of each other methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propoxy, i-propoxy, cyclopentoxy, cyclohexoxy Cycloheptoxy, cyclopentyl, cyclohexyl, cycloheptyl, or cyclopropylmethoxy. 22. The compound of claim 21, wherein R ⁶ and R ^{6 '} are each independently of each other hydrogen, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, phenyl, benzyl, or Methylsulfonyl, and R ⁷ and R ^{7 '} are each hydrogen. 22. The compound of claim 21, wherein R ⁶ and R ^{6 '} are each, independently of one another, alkanoyl of 2 to 5 carbon atoms, haloalkanoyl of 2 to 5 carbon atoms, aminoalkanoyl of 2 to 5 carbon atoms, 2 to 5 carbon atoms Alkylaminoalkanoyl, benzoyl, alkoxycarbonyl, N-morpholinocarbonyl, carbamoyl, and N-substituted carbamoyl of 2 to 5 carbon atoms, wherein the substituents are methyl, ethyl, or Trifluoromethyl; R ⁷ and R ^{7 '} are each hydrogen. 22. The process of claim 21 wherein one of R ⁶ and R ^{6 '} is alkanoyl of 2 to 5 carbon atoms, haloalkanoyl of 2 to 5 carbon atoms, aminoalkanoyl of 2 to 5 carbon atoms, benzoyl, 2 to 5 carbon atoms Alkoxycarbonyl, N-morpholinocarbonyl, carbamoyl, and N-substituted carbamoyl of the atom, wherein the substituents are methyl, ethyl, or trifluoromethyl; The other of R ⁶ and R ^{6 ′} is hydrogen, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, phenyl, benzyl, or methylsulfonyl; R ⁷ and R ^{7 '} are each hydrogen. A compound according to claim 1, which is a substantially chirally pure (S) -isomer or a substantially chirally pure (R) -isomer. A compound according to claim 1, which is a mixture of (S) -isomers and (R) -isomers. A method of inhibiting PDE IV in a mammal comprising administering to the mammal an effective amount of a substantially chirally pure (R)-or (S) -isomer of the compound according to claim 1 or a mixture of said isomers. Reducing undesirable levels of TNFα in a mammal, comprising administering to the mammal an effective amount of a substantially chirally pure (R)-or (S) -isomer of a compound according to claim 1 or a mixture of said isomers How to suppress. Undesired levels of matrix metalloprote in a mammal comprising administering to the mammal an effective amount of a substantially chirally pure (R)-or (S) -isomer of a compound according to claim 1 or a mixture of said isomers How to reduce or suppress an agent. Inflammatory disease, autoimmune disease, arthritis, in a mammal comprising administering to the mammal an effective amount of a substantially chirally pure (R)-or (S) -isomer of a compound according to claim 1 or a mixture of said isomers, A method for treating a disease selected from the group consisting of rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, cachexia, graft-versus-host disease, asthma, adult respiratory distress syndrome, and acquired immunodeficiency syndrome. A method of treating cancer in a mammal comprising administering to the mammal an effective amount of a substantially chirally pure (R)-or (S) -isomer of the compound according to claim 1 or a mixture of said isomers. A method for treating undesirable angiogenesis in a mammal comprising administering to the mammal an effective amount of a substantially chirally pure (R)-or (S) -isomer of the compound according to claim 1 or a mixture of said isomers. . (i) a substantially chiralally pure (R)-or (S) -isomer or mixture of said isomers of a compound according to claim 1 in a pharmaceutically effective amount when administered in a single or multiple dose regimen, and (ii ) A pharmaceutical composition comprising a pharmaceutically acceptable carrier.